AROMATIC COMPOUND

TECHNICAL FIELD

The present invention relates to an aromatic compound.

BACKGROUND ART

Currently, it is said that the disease known as fibrosis includes 130 types or more of diseases, if rare diseases are also included therein. Representative examples of such fibrosis include lung fibrosis, hepatic fibrosis, and glomerulosclerosis.

In general, lung fibrosis refers to a group of diseases associated with loss of lung functions due to a lesion regarding the reconstruction of an alveolar region, which is caused by the phenomenon whereby the alveoloar structure is destroyed by an inflammatory reaction, and as a result, growth of fibroblasts and an excessive increase in extracellular matrix mainly composed of collagen take place, so that the lung becomes hardened.

Moreover, hepatic fibrosis refers to a pathologic condition associated with fibrosis of the liver, which is caused by the phenomenon whereby hepatic cells are necrotized by various types of hepatopathy such as chronic viral hepatitis or alcoholic hepatitis, and thereafter, extracellular matrix increases to replenish the necrotized portion, resulting in such fibrosis of the liver. This pathologic condition finally leads to hepatic cirrhosis, in which the entire hepatic fibers shrink and become hardened.

In order to suppress the aforementioned hepatic fibrosis, drugs such as Penicillamine or Lufironil have been used. Penicillamine has been known as a drug for treating Wilkinson's disease that is developed as a result of accumulation of copper in the liver due to abnormality of copper metabolism. Lufironil has been studied for its use as a proline hydroxylase inhibitor.

However, taking into consideration their side effects and effectiveness, the aforementioned drugs do not sufficiently function as drugs for preventing fibrosis of the liver. Thus, as a matter of fact, neither therapeutic agents nor methods for treating fibrosis, which are effective for fibrosis, including hepatic fibrosis as a representative example, have been established to date. A method of specifically inhibiting a process of developing fibrosis has become a focus of attention in the research field.

As stated above, it has been known that an excessive increase in extracellular matrix mainly composed of collagen takes place during a process of development of fibrosis in the lung tissues or hepatic tissues. Moreover, it has also been known that such an increase in extracellular matrix in hepatic cells takes place mainly in sinusoidal wall Disse's space, and that Ito cells that are mesenchymal cells in the liver are main sources for production of such extracellular matrix.

Accordingly, in order to suppress fibrosis occurring in the liver, the lung, or other organs, it is important to suppress an excessive increase in extracellular matrix (namely, collagen).

JP-A-2002-507601 and JP-A-2001-89450 disclose that a certain type of pyridine derivative has an effect, of suppressing the generation of collagen and thus is effective for fibrosis. JP-A-2001-89412 discloses that a certain type of benzene derivative has an effect of suppressing the production of collagen and thus is effective for fibrosis.

However, the effect of suppressing the generation of collagen of the compounds described in JP-A-2002-507601, JP-A-2001-89450, and JP-A-2001-89412 are insufficient, or these compounds have serious side effects. Accordingly, it has strongly been desired that a compound, which has a superior effect of suppressing the production of collagen, less side effects, and excellent safety, will be developed.

DISCLOSURE OF THE INVENTION

It is an object of the present invention to provide a novel compound, which has a superior effect of suppressing the generation of collagen, for example, a pharmaceutical composition being useful for preventing and treating fibrosis such as lung fibrosis, hepatic fibrosis, glomerulosclerosis and the like, with less side effects, and excellent safety.

As a result of intensive studies directed towards achieving the aforementioned object, the present inventors have found that an aromatic compound represented by the following general formula (1) and a salt thereof have a superior effect of suppressing the generation of collagen, less side effects, and excellent safety. The present invention has been completed based on these findings.

The present invention provides an aromatic compound represented by the general formula (1) or a salt thereof:

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[wherein X₁represents a nitrogen atom or a group —CH═,

R¹represents a group —Z—R⁶,

Z represents a group —N(R⁸)—B—, a group —B—N(R⁸) a group —B₀—O—, a group

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a group —CO—, a group —CH(OH)—, a group

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a group —N═CH—, a group

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a lower alkenylene group, a group —NHCO—B₁—, a group —NHCO—B₂—(W)u-, a group —B₀—O—B_19a—, a group

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a group

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a group

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a group —S—, a lower alkynylene group, a lower alkylene group, a group

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or a group —CO—NH—B₁₈a-,

wherein R⁸represents a hydrogen atom, a lower alkyl group that may have a lower alkoxy group as a′ substituent, a lower alkanoyl group, a phenyl lower alkyl group, or a lower alkylsulfonyl group,

B represents a group —CO— or a lower alkylene group,

B₀represents a lower alkylene group,

each of R^9aand R^9b, which are identical or different, represents a hydrogen atom or a lower alkyl group

R^10arepresents a hydrogen atom or a lower alkyl group,

B_22arepresents a lower alkylene group or a lower alkenylene group,

e represents 0 or 1,

B₁represents a lower alkenylene group that may have a phenyl group as a substituent,

B₂represents a lower alkylene group that may be substituted by a group selected from the group consisting of a lower alkoxy group and a phenyl group,

W represents an oxygen atom, a group —NH—, or a sulfur atom,

u represents 0 or 1,

B_18arepresents a lower alkylene group,

B_19arepresents a lower alkylene group,

B_20arepresents a lower alkylene group,

B_21arepresents a lower alkylene group,

R^8drepresents a hydrogen atom or a lower alkyl group,

k represents 2 or 3,

c represents 0 or 1,

d′ represents 0 or 1,

R^10brepresents a hydrogen atom or a lower alkyl group,

R⁶represents a 5- to 15-membered monocyclic, dicyclic, or tricyclic saturated or unsaturated heterocyclic group having 1 to 4 nitrogen atoms, oxygen atoms, or sulfur atoms (wherein, the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of an oxo group; an optionally halogenated lower alkoxy group; an optionally halogenated lower alkyl group; a halogen atom; a lower alkylsulfonyl group; a phenyl group that may be substituted, on the phenyl ring, by an optionally halogenated lower alkyl group; a lower alkylthio group; a pyrrolyl group; a benzoyl group; a lower alkanoyl group; a lower alkoxycarbonyl group; and an amino group that may have a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group as a substituent), an adamantyl group, a naphthyl group (wherein, the naphthalene ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkyl group, a halogen atom, and an amino group that may have a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group as a substituent), an alkyl group that may have a lower alkoxy group as a substituent, a cycloalkyl group that may be substituted, on the cycloalkyl ring, by a group selected from the group consisting of an amino-substituted lower alkyl group that may have a lower alkyl group on the amino group and a lower alkyl group that may have a halogen atom as a substituent, a lower alkenyl group that may have a halogen atom as a substituent, a lower alkanoyl group, a benzoyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkyl group that may have a halogen atom as a substituent and a halogen atom, a group

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a halogen atom-substituted lower alkyl group, or a cycloalkyl lower alkyl group,

R⁷represents a hydrogen atom, a phenyl group, a carboxy group, a hydroxyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a phenoxy group, a lower alkoxy group that may have a halogen atom as a substituent, a lower alkylenedioxy group, an amino group that may have, as a substituent, a group selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a benzoyl group, and a cycloalkyl group, a cyano group, a lower alkanoyl group that may have a halogen atom as a substituent, a lower alkylsulfonyl group, an aminosulfonyl group, a lower alkoxycarbonyl group, a lower alkanoyloxy group, a 5- or 6-membered saturated or unsaturated heterocyclic group having 1 to 4 nitrogen atoms, oxygen atoms, or sulfur atoms (wherein the heterocyclic ring may be substituted, by an oxo group), or a lower alkoxycarbonyl lower alkyl group,

m represents an integer between 1 and 5, wherein when m represents 2 to 5, two to five Ws may be identical or different,

R²represents a hydrogen atom, a halogen atom, or a lower alkyl group,

Y represents a group —O—, a group —N(R⁵)—, a group —CO—, a group —CH(OH)—, a lower alkylene group, a group —S(O)n-, or a group —C(═N—OH)—,

R⁵represents a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a benzoyl group, a phenyl lower alkyl group, or a cycloalkyl group,

n represents 0, 1, or 2,

A represents a group

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or a group

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p represents 1 or 2,

R³represents a hydrogen atom, a lower alkoxy group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxycarbonyl group, a carboxy group, a group —CONR¹¹R¹², or a cyano group,

wherein each of R¹¹and R¹², which are identical or different, represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, or a phenyl group, or R¹¹and R¹², together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring,

R⁴represents an imidazolyl lower alkyl group, a 1,2,4-triazolyl lower alkyl group, a 1,2,3-triazolyl lower alkyl group, a 1,2,5-triazolyl lower alkyl group, a pyrazolyl lower alkyl group, a pyrimidinyl lower alkyl group that may have an oxo group as a substituent on the pyrimidine ring, a 3,5-dioxoisoxazolidin-4-ylidene lower alkyl group, a 1,2,4-oxadiazolyl lower alkyl group that may have a lower alkyl group as a substituent on the 1,2,4-oxadiazole ring, a thiazolidinyl lower alkyl group that may have an oxo group as a substituent on the thiazolidine ring, a group

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a group

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or a group -(T)₁-N(R¹⁴)R¹⁵,

R¹³represents a hydrogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkanoyl group that may have a halogen atom as a substituent, a lower alkoxycarbonyl group, a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, an imidazolyl lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a carboxy lower alkyl group, a benzoyl group, a morpholino-substituted lower alkanoyl group, a piperazinyl carbonyl lower alkyl group that may be substituted, on the piperazine ring, by a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, a piperazinyl lower alkanoyl group that may be substituted, on the piperazine ring, by a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, a morpholinocarbonyl-substituted lower alkyl group, or an imidazolyl lower alkanoyl group,

R^13arepresents a hydrogen atom or a hydroxyl group,

T represents a lower alkylene group, a group —N(R¹⁷)—B₃—CO—, a group —B₉—N(R¹⁸)—CO—, a group —B₄—CO—, a group -Q-B₅—CO—, a group —B₆—N(R¹⁹)—B₇—CO—, a group —CO—B₈—, a group —CH(OH)—B₉—, a group —CO—B₁₀—CO—, a group —CH(OH)—B₁₁—CO— a group —CO—, a group —SO₂—, or a group —B_23a—CO—CO—,

wherein R¹⁷represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a cycloalkylcarbonyl group, a lower alkanoyl group that may have a halogen atom as a substituent, a lower alkenyl group, an amino-substituted lower alkanoyl group that may have a lower alkyl group as a substituent, or a lower alkylsulfonyl group,

B₃represents a lower alkylene group,

B₁₉represents a lower alkylene group,

R¹⁸represents a hydrogen atom or a lower alkyl group,

B₄represents a lower alkenylene group or a lower alkylene group that may have a hydroxyl group as a substituent,

Q represents an oxygen atom or a group —S(O)n- (wherein

n has the same meanings as described above),

B₅represents a lower alkylene group,

B₆represents a lower alkylene group,

R¹⁹represents a hydrogen atom or a lower alkanoyl group,

B₇represents a lower alkylene group,

B₈represents a lower alkylene group,

B₉represents a lower alkylene group,

B₁₀represents a lower alkylene group,

B₁₁represents a lower alkylene group,

B_23arepresents a lower alkylene group,

l represents 0 or 1,

R¹⁴represents a hydrogen atom or an alkyl group that may have a hydroxyl group as a substituent,

R¹⁵represents (2) a hydroxyl group-substituted alkyl group, (3) a cycloalkyl group that may have a group selected from the group consisting of a hydroxyl group and a lower alkyl group as a substituent, (4) a phenoxy lower alkyl group, (5) a phenyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkyl group; a lower alkoxy group that may have a halogen atom as a substituent; a halogen atom; an amino lower alkoxy group that may have a lower alkyl group as a substituent; a hydroxyl group-substituted lower alkyl group; a phenyl lower alkyl group; a lower alkynyl group; an amino group that may have a lower alkylsulfonyl group as a substituent; a lower alkylthio group; a cycloalkyl group; a phenylthio group; an adamantyl group; an anilino group that may have a halogen atom as a substituent on the phenyl ring; a lower alkoxycarbonyl group; a piperazinyl group that may have a lower alkyl group as a substituent on the piperazine ring; a pyrrolidinyl group that may have an oxo group as a substituent on the pyrrolidine ring; a lower alkanoylamino group; a cyano group; and a phenoxy group, (6) a phenoxy group, (7) a phenyl lower alkyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkoxy group that may have a halogen atom as a substituent, and a lower alkyl group, (8) a phenyl lower alkyl group that has a lower alkylenedioxy group as a substituent on the phenyl ring, (10) a lower alkoxycarbonyl-substituted lower alkyl group, (11) a carboxy-substituted lower alkyl group, (12) an amino group that may have a lower alkanoyl group as a substituent, (13) a 1,2,3,4-tetrahydroquinolyl group that may have 1 to 3 groups selected from the group consisting of an oxo group, a lower alkoxy group, and a lower alkylenedioxy group as a substituent(s) on the tetrahydroquinoline ring, (14) a cycloalkyl lower alkyl group, (15) a piperazinyl lower alkanoyl group that may be substituted, on the piperazine ring, by a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, (16) a pyridyl lower alkyl group, (17) an amino group-substituted lower alkyl group that may have a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group as a substituent, (18) a lower alkoxy lower alkyl group, (19) an imidazolyl group, (20) an imidazolyl lower alkyl group, (21) a 1,2,3,4-tetrahydroisoquinolylcarbonyl-substituted lower alkyl group, (22) a piperidinylcarbonyl group that may have a group selected from the group consisting of a lower alkoxycarbonyl group, a phenyl lower alkyl group, and a furyl lower alkyl group as a substituent on the piperidine ring, (23) a thiazolidinyl lower alkanoyl group that may have an oxo group as a substituent on the thiazolidine ring, (24) a piperidinyl group that may be substituted, on the piperidine ring, by a group selected from the group consisting of a lower alkoxycarbonyl group, a phenyl lower alkyl group, a lower alkyl group, a benzoyl group, and a furyl lower alkyl group, (25) a carbonyl lower alkyl group substituted by a group

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(26) a carbonyl lower alkyl group substituted by a group

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(27) a group —CO—B₂₀—N(R³⁶)R³⁷, (26a) a pyrrolidinyl lower alkyl group, (27a) a morpholino lower alkyl group, (28a) a phenyl lower alkenyl group, (29a) an anilinocarbonyl lower alkyl group that may have a lower alkyl group as a substituent on the phenyl ring, (30a) an indolyl group, (31a) a piperazinyl lower alkyl group that may have, as a substituent on the piperazine ring, a group selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, (32a) an amidino lower alkyl group that may have a lower alkyl group as a substituent, (33a) a fluorenyl group, (34a) a carbazolyl group that may have a lower alkyl group as a substituent on the carbazole ring, (35a) an amidino group that may have a lower alkyl group as a substituent, (36a) a piperazinyl-substituted oxalyl group that may have 1 to 3 groups selected from the group consisting of a phenyl lower alkyl group (that may have 1 to 3 groups selected from the group consisting of a lower alkylenedioxy group and a lower alkoxy group as a substituent(s) on the phenyl ring) and a pyridyl lower alkyl group as a substituent(s) on the piperazine ring, or (37a) a cyano-substituted lower alkyl group,

R³⁴represents an oxo group or a phenyl group,

d represents an integer between 0 and 3,

B₂₀represents a lower alkylene group,

R³⁵and R³⁷, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may be substituted by 1 to 3 phenyl lower alkyl groups that may have a lower alkylenedioxy group as a substituent on the phenyl ring,

R¹⁴and R¹⁵, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 10-membered saturated or unsaturated heterocyclic ring; or a group

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wherein the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of (28) a phenyl-substituted lower alkyl group, which has 1 to 2 phenyl groups and which may have a pyridyl group on the lower alkyl group, wherein the phenyl ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkanoyl group, an amino group that may have a lower alkanoyl group as a substituent, a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxy group that may have a halogen atom as a substituent, a phenyl lower alkoxy group, a hydroxyl group, and a lower alkylenedioxy group, (29) a carbamoyl group, (30) a pyridyl lower alkyl group that may have, as a substituent(s) on the pyridine ring, 1 to 3 groups selected from the group consisting of a hydroxyl group and a lower alkyl group that may have a hydroxyl group as a substituent, (31) a pyrrolyl lower alkyl group that may have 1 to 3 lower alkyl groups as a substituent(s) on the pyrrole ring, (32) a benzoxazolyl lower alkyl group, (33) a benzothiazolyl lower alkyl group, (34) a furyl lower alkyl group, (35) a benzoyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a cyano group, an amino group that may have a lower alkylsulfonyl group as a substituent, a halogen atom, a lower alkoxy group, a lower alkyl group that may have a halogen atom as a substituent, a thiazolidinyl lower alkyl group that may have an oxo group as a substituent on the thiazolidine ring, a thiazolidinylidene lower alkyl group that may have an oxo group as a substituent on the thiazolidine ring, and a lower alkylenedioxy group, (36) a pyrimidinyl group (37) a pyrazinyl group, (38) a pyridyl group, (39) a lower alkoxycarbonyl group, (40) a thiazolidinyl lower alkanoyl group that may be substituted, on the thiazolidine ring, by a group selected from the group consisting of an oxo group and a group

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(wherein each of R^aand R^brepresents a lower alkyl group), (41) a lower alkyl group that may have a group selected from the group consisting of a hydroxyl group and a halogen atom as a substituent, (42) a lower alkanoyl group that may have a halogen atom as a substituent, (43) a phenyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a carbamoyl group that may have a group selected from the group consisting of a lower alkoxy lower alkyl group and a lower alkyl group, a lower alkoxycarbonyl group, a carboxy group, a cyano group, a phenyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxy group that may have a halogen atom as a substituent, a benzoyl group that may have a halogen atom as a substituent on the phenyl ring, a phenyl lower alkyl group that may have a halogen atom as a substituent on the phenyl ring, and a hydroxyl group, (44) a phenyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, (45) a naphthyl lower alkyl group, (46) a phenoxy group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a cyano group, a lower alkyl group that may have a halogen atom as a substituent, and a lower alkoxy group that may have a halogen atom as a substituent, (47) a phenoxy lower alkyl group, (48) a phenyl lower alkoxy group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, and a lower alkoxy group that may have a halogen atom as a substituent, (49) a group —(B₁₂CO)t-N(R²⁰)R²¹, (50) a group —(CO)o-B₁₃—N(R²²)R²³, (51) a 1,2,3,4-tetrahydronaphthyl-substituted lower alkyl group that may be substituted, on the 1,2,3,4-tetrahydronaphthalene ring, by 1 to 5 lower alkyl groups as a substituent(s), (52) a cycloalkyl group that may have a hydroxyl group as a substituent, (53) a piperidinyl group that may be substituted, on the piperidine ring, by 1 to 3 lower alkyl groups as a substituent(s), (54) a quinolyl lower alkyl group, (55) a 1,2,3,4-tetrazolyl lower alkyl group that may have a group selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group as a substituent on the tetrazole ring, (56) a thiazolyl lower alkyl group that may have a phenyl group as a substituent on the thiazole ring, (57) a benzoyl lower alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkoxy group and a halogen atom as a substituent(s) on the phenyl ring, (58) a piperidinyl lower alkyl group that may have a lower alkyl group as a substituent on the piperidine ring, (59) an imidazolyl group that may have 1 to 3 phenyl groups as a substituent(s) on the imidazole ring, (60) a benzimidazolyl group that may have 1 to 3 lower alkyl groups as a substituent(s) on the benzimidazole ring, (61) a pyridyl lower alkoxy group, (62) a 1,2,3,4-tetrahydroquinolyl lower alkyl group that may have an oxo group as a substituent on the tetrahydroquinoline ring, (63) a 1,3,4-oxadiazolyl lower alkyl group that may have an oxo group as a substituent on the 1,3,4-oxadiazole ring, (64) a cycloalkyl lower alkyl group, (65) a tetrahydropyranyl group, (66) a thienyl lower alkyl group, (67) a pyrimidinylcarbonyl group that may have an oxo group as a substituent on the pyrimidine ring, (68) a hydroxyl group, (69) a carboxy group, (70) a lower alkoxy lower alkyl group, (71) a lower alkoxy lower alkoxy group, (72) a benzoyloxy group, (73) a lower, alkoxycarbonyl lower alkoxy group, (74) a carboxy lower alkoxy group, (75) a phenoxy lower alkanoyl group, (76) a 1,2,3,4-tetrahydroquinolylcarbonyl group that may have an oxo group as a substituent on the tetrahydroquinoline ring, (77) a phenylsulfonyl group, (78) an imidazolyl lower alkanoyl group, (79) an imidazolyl lower alkyl group, (80) a pyridylcarbonyl group, (81) an imidazolylcarbonyl group, (82) a lower alkoxycarbonyl lower alkyl group, (83) a carboxy lower alkyl group, (84) a group —(O—B₁₅)s-CO—N(R²⁶)R²⁷, (85) a group —N(R²⁸)—CO—B₁₆—N(R²⁹)R³⁰, (86) a group —N(R³¹)—B₁₇—CO—N(R³²)R³³, (87) a benzoxazolyl group, (88a) a benzothienyl group, (89a) an oxo group, and (90a) a 1,2,3,4-tetrahydroquinolyl group that may have an oxo group as a substituent on the tetrahydroquinoline ring,

B₁₂represents a lower alkylene group,

t represents 0 or 1,

each of R²⁰and R²¹, which are identical or different, represents a hydrogen atom; a cycloalkyl group; an amino group that may have a lower alkoxycarbonyl group as a substituent; a benzoyl group that may have 1 to 3 lower alkoxy groups as a substituent(s) on the phenyl ring; a lower alkyl group; a lower alkyl group having 1 to 2 phenyl groups that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxy group that may have a halogen atom as a substituent, and a lower alkylthio group; a phenyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkoxy group that may have a halogen atom as a substituent and a lower alkyl group that may have a halogen atom as a substituent; a lower alkoxycarbonyl group; a cycloalkyl lower alkyl group; a pyrrolidinyl lower alkyl group that may have 1 to 3 lower alkyl groups that may have a hydroxyl group as a substituent on the pyrrolidine ring; an amino-substituted lower alkyl group that may have a group selected from the group consisting of a phenyl group and a lower alkyl group as a substituent; a 1,2,3,4-tetrahydronaphthyl-substituted lower alkyl group that may have 1 to 5 lower alkyl groups as a substituent(s) on the 1,2,3,4-tetrahydronaphthalene ring; a naphthyl lower alkyl group; a pyridyl lower alkyl group; a quinolyl lower alkyl group; a 1,2,3,4-tetrazolyl lower alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group as a substituent(s) on the tetrazole ring; a 1,2,4-triazolyl lower alkyl group; a tetrahydrofuryl lower alkyl group that may have a hydroxyl group as a substituent on the lower alkyl group; a phenoxy lower alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group and a nitro group as a substituent(s) on the phenyl ring; a phenyl lower alkanoyl group; a lower alkanoyl group that may have a halogen atom as a substituent; an imidazolyl lower alkanoyl group; a lower alkoxycarbonyl lower alkyl group; a pyridyl group; or a carboxy lower alkyl group, or R²⁰and R²¹, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring, wherein the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkyl group, a phenyl group that may have 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkyl group that may have a halogen atom as a substituent(s) on the phenyl ring, and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring,

o represents 0 or 1,

B₁₃represents a lower alkylene group,

each of R²²and R²³, which are identical or different, represents a hydrogen atom, a lower alkyl group, a benzoyl group that may have 1 to 3 lower alkoxy groups as a substituent(s) on the phenyl ring, a phenoxy lower alkyl group that may have a lower alkyl group as a substituent on the phenyl ring, a phenyl lower alkyl group, or a phenyl group, or R²²and R²³, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring, wherein the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring,

B₁₅represents a lower alkylene group,

s represents 0 or 1,

each of R²⁶and R²⁷, which are identical or different, represents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, or an imidazolyl lower alkyl group, or R²⁶and R²⁷, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring, wherein the heterocyclic ring may be substituted by 1 to 3 phenyl lower alkyl groups that may have a lower alkylenedioxy group as a substituent on the phenyl ring, as a substituent(s),

R²⁸represents a hydrogen atom or a lower alkyl group,

B₁₆represents a lower alkylene group,

R²⁹and R³⁰, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic group, wherein the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkyl group, a phenyl group, and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring,

R³¹represents a hydrogen atom or a lower alkyl group,

B₁₇represents a lower alkylene group,

R³²and R³³, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic group, wherein the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkyl group, a phenyl group, and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring,

provided that the above described aromatic compound or a salt thereof satisfy the following requirements (i) to (v)

- (i) when X₁represents a group —CH═, then R³represents a hydrogen atom;
- (ii) when X₁represents a group —CH—, l represents 1, T represents —CO—, and R¹⁴represents a hydrogen atom or an alkyl group that may have a hydroxyl group as a substituent, then R¹⁵represents the group (24) described above;
- (iii) when X₁represents a group —CH═, l represents 1, and T represents —N(R¹⁷)—B₃—CO—, then R¹⁴and R¹⁵, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 10-membered saturated or unsaturated heterocyclic ring, wherein the heterocyclic ring is substituted by 1 to 3 groups of (28) described above;
- (iv) when X₁represents a nitrogen atom, and l represents 0, or when X₁represents a nitrogen atom, l represents 1, and T represents —CO— or —SO₂, then R¹⁵is not the group being any one of (5), (7), (19), and (20) described above; and
- (v) when R⁶represents a cycloalkyl group wherein the cycloalkyl ring may be substituted by a group selected from the group consisting of an amino-substituted lower alkyl group that may have a lower alkyl group and a lower alkyl group that may have a halogen atom as a substituent, then R¹⁴represents a group -(T)₁-N(R¹⁴)R¹⁵(wherein T and l have the same meanings as described above, and R¹⁴and R¹⁵, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 10-membered saturated heterocyclic ring; or R¹⁴and R¹⁵form a group

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The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds or salts thereof represented by the general formulas (1-1) to (1-7):

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[wherein, in said general formulas (1-1) to (1-7), R⁶, B, R⁸, R², R⁵, n, X₁, and A have the same meanings as described above, and Y₃represents a lower alkylene group].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds or salts thereof represented by the general formulas (1-8) to (1-14):

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[wherein, in said general formulas (1-8) to (1-14), R⁶, B, R⁸, R², R⁵, n, X₁, A and Y₃have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds or salts thereof represented by the general formulas (1-15) to (1-21):

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[wherein, in said general formulas (1-15) to (1-21), R⁶, B₀, R², R⁵, n, X₁, A and Y₃have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds or salts thereof represented by the general formulas (1-22) to (1-28):

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[wherein, in said general formulas (1-22) to (1-28), R⁶, R², R⁵, n, X₁, A and Y₃have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds or salts thereof represented by the general formulas (1-29) to (1-35):

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[wherein, in said general formulas (1-29) to (1-35), R⁶, R², R⁵, n, X₁, A and Y₃have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds or salts thereof represented by the general formulas (1-36) to (1-42):

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[wherein, in said general formulas (1-36) to (1-42), R⁶, R², R⁵, n, X₁, A and Y₃have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds or salts thereof represented by the general formulas (1-43) to (1-49):

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[wherein, in said general formulas (1-43) to (1-49), R⁶, R², R⁵, n, X₁, A, R^9a, R^9band Y₃have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds or salts thereof represented by the general formulas (1-50) to (1-56):

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[wherein, in said general formulas (1-50) to (1-56), R⁶R², R⁵, n, X₁, A and Y₃have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds or salts thereof represented by the general formulas (1-57) to (1-63):

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[wherein, in said general formulas (1-57) to (1-63), R⁶, R², R⁶, n, X₁, A, R^10a, B_22a, e and Y₃have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds represented by the general formulas (1-64) to (1-70) or salts thereof:

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[wherein, in said general formulas (1-64) to (1-70), R⁶, R², R⁵, n, X₁, A and Y₃have the same meanings as described above, and Z₁represents a lower alkenylene group].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds represented by the general formulas (1-71) to (1-77) or salts thereof:

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[wherein, in said general formulas (1-71) to (1-77), R⁶R², B₁, R⁵, n, X₁, A and Y₃have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds represented by the general formulas (1-78) to (1-84) or salts thereof:

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[wherein, in said general formulas (1-78) to (1-84), R⁶, W, u, B₂, R², R⁵, n, X₁, A and Y₃have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds represented by the general formulas (1-85) to (1-91) or salts thereof:

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[wherein, in said general formulas (1-85) to (1-91), R⁵, R⁶, B_19a, B₀, R², X₁, n, A and Y₃have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds represented by the general formulas (1-92) to (1-98) or salts thereof:

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[wherein, in said general formulas (1-92) to (1-98), R⁶, R⁶, B_20a, R², X₁, A, n, d′, k and Y₃have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds represented by the general formulas (1-99) to (1-105) or salts thereof:

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[wherein, in said general formulas (1-99) to (1-105), R⁶, R⁵, B_21a, R², X₁, A, n, c and Y₃have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds represented by the general formulas (1-106) to (1-112) or salts thereof:

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[wherein, in said general formulas (1-106) to (1-112), R⁵, n, R⁶, R^10b, X₁, R², A and Y₃have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds represented by the general formulas (1-113) to (1-119) or salts thereof:

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[wherein, in said general formulas (1-113) to (1-119), R⁶, R², X₁, R⁵, n, A and Y₃have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds represented by the general formulas (1-120) to (1-126) or salts thereof:

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[wherein, in said general formulas (1-120) to (1-126), R⁶, R², X₁, A, R⁵, n and Y₃have the same meanings as described above, and Z₂represents a lower alkynylene group].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds represented by the general formulas (1-127) to (1-133) or salts thereof:

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[wherein, in said general formulas (1-127) to (1-133), R⁶, B_18a, R², X₁, A, R⁵, n and Y₃have the same meanings as described above].

The above aromatic compound represented by the general formula (1) or a salt thereof includes the following aromatic compounds represented by the general formulas (1-134) to (1-140) or salts thereof:

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[wherein, in said general formulas (1-134) to (1-140), R⁶, R², X₁, A, R⁵, and n have the same meanings as described in Claim 1, Y₃has the same meanings as described in Claim 2, and Z₃represents a lower alkylene group or a group

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(R^8dis the same meanings as described above)].

The present invention provides the above-mentioned aromatic compound or salt thereof wherein Y is a group —O—.

The present invention provides the above-mentioned aromatic compound or salt thereof wherein Y is a group —N(R⁵)— (R⁵has the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein Y is a group —CO—, a group —CH(OH)—, a lower alkylene group, a group —S(O)n- (n has the same meanings as described above), or a group —C(═N—OH)—.

The present invention provides the above-mentioned aromatic compound or salt thereof wherein A is a group

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(R³, R⁴and p have the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein A is a group

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(R⁴has the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein R⁴is an imidazolyl lower alkyl group, a 1,2,4-triazolyl lower alkyl group, a 1,2,3-triazolyl lower alkyl group, a 1,2,5-triazolyl lower alkyl group, a pyrazolyl lower alkyl group, a pyrimidinyl lower alkyl group that may have an oxo group as a substituent on the pyrimidine ring, a 3,5-dioxoisoxazolidin-4-ylidene lower alkyl group, a 1,2,4-oxadiazolyl lower alkyl group that may have a lower alkyl group as a substituent on the 1,2,4-oxadiazole ring, a thiazolidinyl lower alkyl group that may have an oxo group as a substituent on the thiazolidine ring, a group

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or a group

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(R¹³and R^13ahave the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein R⁴is a group -(T)₁-N(R¹⁴)R¹⁵(T, R¹⁴and R¹⁵have the same meanings as described above), and l is 0.

The present invention provides the above-mentioned aromatic compound or salt thereof wherein R⁴is a group -(T)₁-N(R¹⁴)R¹⁵, l is 1, and T is a group —N(R¹⁷)—B₃—CO— (R¹⁴, R¹⁵, R¹⁷and B₃have the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein R⁴is a group -(T)₁-N(R¹⁴)R¹⁵, l is 1, and T is a group —B₁₉—N(R¹⁸)—CO— (R¹⁴, R¹⁵, B₁₉and R¹⁸have the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein R⁴is a group -(T)₁-N(R¹⁴)R¹⁵, l is 1, and T is a group —B₄—CO— (R¹⁴, R¹⁵, and B₄have the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein R⁴is a group -(T)₁-N(R¹⁴)R¹⁵, l is 1, and T is a group -Q-B₅—CO— (R¹⁴, R¹⁵, Q and B₅have the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein R⁴is a group -(T)₁-N(R¹⁴)R¹⁵, l is 1, and T is a group —B₆—N(R¹⁹)—B₇— (R¹⁴, R¹⁵, B₆, R¹⁹and B₇have the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein R⁴is a group -(T)₁-N(R¹⁴)R⁵, l is 1, and T is a group —CO—B₈— (R¹⁴, R¹⁵, and B₈have the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein R⁴is a group -(T)₁-N(R¹⁴)R¹⁵, l is 1, and T is a group —CH(OH)—B₉— (R¹⁴, R¹⁵, and B₉have the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein R⁴is a group -(T)₁-N(R¹⁴)R¹⁵, l is 1, and T is a group —CO—B₁₀—CO— (R¹⁴, R¹⁵, and B₁₀have the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein R⁴is a group -(T)₁-N(R¹⁴)R¹⁵, l is 1, and T is a group —CH(OH)—B₁₁—CO— (R¹⁴, R¹⁵, and B₁₁have the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein R⁴is a group -(T)₁-N(R¹⁴)R¹⁵, l is 1, and T is a group —CO— (R¹⁴and R¹⁵have the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein R⁴is a group -(T)₁-N(R¹⁴)R¹⁵, l is 1, and T is a group —SO₂— (R¹⁴and R¹⁵have the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein R⁴is a group -(T)₁-N(R¹⁴)R¹⁵, l is 1, and T is a group B_23a—CO—CO— (R¹⁴, R¹⁵and B_23ahave the same meanings as described above).

The present invention provides the above-mentioned aromatic compound or salt thereof wherein R⁴is a group -(T)₁-N(R¹⁴)R¹⁵, l is 1, and T is a lower alkylene group (R¹⁴and R¹⁵have the same meanings as described above).

In the above-mentioned aromatic compound represented by the general formula (1) or salt thereof, the aromatic compounds represented by the general formulas (1-1), (1-2), (1-8), (1-9), (1-15), (1-16), (1-29), (1-30), (1-64) and (1-65) or salts thereof are preferable.

Further, those compounds represented by the general formulas (1-1), (1-2), (1-8), (1-9), (1-15), (1-16), (1-29), (1-30), (1-43), (1-44), (1-57), (1-58), (1-64) and (1-65) or salts thereof, wherein Y is a group —O— or a group —N(R⁵)—, A is a group

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and R⁴is a group -(T)₁-N(R¹⁴)R¹⁵(R³, R⁴, R⁵, R¹⁴, R¹⁵, p and l have the same meanings as described above), are more preferable.

The present invention provides the aromatic compounds represented by the general formulas (1-1), (1-2), (1-8), (1-9), (1-15), (1-16), (1-29), (1-30), (1-43), (1-44), (1-57), (1-58), (1-64) and (1-65) or salts thereof, wherein

l is 1, and T is a group —N(R¹⁷)—B₃—CO— (R¹⁷and B₃have the same meanings as described above).

l is 1, and T is a group —B₄—CO— (B₄have the same meanings as described above).

l is 1, and T is a group —CO—.

l is 0.

The present invention particularly provides the aromatic compounds selected from the group consisting of:

N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-methoxyphenoxy)pyridin-3-yl]-3,4-dichlorobenzamide,
N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}phenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide,
N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-fluorophenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide,
N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-fluorophenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide,
N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methoxyphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide,
N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-methoxyphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide,
N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-methylphenoxy)pyridin-3-yl]-3,4-dichlorobenzamide,
N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide,
N-(6-{4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenoxy}pyridin-3-yl)-3,4-dichlorobenzenesulfonamide,
N-[6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperazin-1-yl}phenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide,
N-[6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide,
N-{6-[(4-{-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenyl)methylamino]pyridin-3-yl}-4-trifluoromethylbenzamide,
N-[6-(4-{4-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide,
N-[6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide,
N-[6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methylphenoxy)pyridin-3-yl]-3,4-dichlorobenzamide,
N-{6-[4-(4-benzylpiperazine-1-carbonyl)phenoxy]pyridin-3-yl}-4-trifluoromethylbenzamide,
N-{6-[4-(4-benzylpiperazine-1-carbonyl)phenoxy]pyridin-3-yl}-3,4-dichlorobenzamide,
N-[6-({4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenyl}methylamino)pyridin-3-yl]-4-trifluoromethylbenzamide,
N-(6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-fluorophenoxy)pyridin-3-yl]-3,4-dichlorobenzamide,
N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-fluorophenoxy)pyridin-3-yl]-3,4-dichlorobenzamide,
N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methoxyphenoxy)pyridin-3-yl]-3,4-dichlorobenzamide,
N-(6-(4-{[2-[(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}phenoxy)pyridin-3-yl]-3,4-dichlorobenzamide,
1-(6-{4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenoxy}pyridin-3-yl)-3-(3,4-dichlorophenyl)-1-ethylurea,
N-(6-{4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenoxy}pyridin-3-yl)-4-trifluoromethylbenzamide,
N-[6-(4-{[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide,
N-[6-(4-{4-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenoxy)pyridin-3-yl]-3,4-dichlorobenzamide,
N-(6-{4-[3-(4-piperonylpiperazine-1-carbonyl)piperidin-1-yl]phenoxy}pyridin-3-yl)-3,4-dichlorobenzamide,
N-[6-(4-{4-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide,
N-{6-[(4-{4-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenyl)methylamino]pyridin-3-yl}-4-trifluoromethylbenzamide,
N-(6-{4-[(2-{4-[4-(4-fluorobenzoyl)phenyl]-piperazin-1-yl}-2-oxoethyl)methylamino]-2-methoxyphenoxy}pyridin-3-yl)-4-trifluoromethylbenzamide,
2-(4-piperonylpiperazin-1-yl)-N-{3-methyl-4-[5-(4-trifluoromethylphenoxymethyl)pyridin-2-yloxy]phenyl}-2-oxoacetamide,
N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-2-fluoro-4-trifluoromethylbenzamide,
N-[6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methoxyphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, and
4-(3-{3-methyl-4-[5-(4-trifluoromethylbenzoylamino)pyridin-2-yloxy]phenyl}-2-oxohexahydropyrimidin-1-yl)benzoic acid ethyl ester, or salts thereof.

The present invention provides processes for preparing the aromatic compound represented by the general formula (1) or a salt thereof according to any one of the processes described in Reaction formulas-1 to 46, 48, 49, 52, 59, 104, 105, 108 to 132 and 135 mentioned below.

The present invention provides a pharmaceutical composition for the treatment of fibrosis, which comprises an aromatic compound represented by the general formula (1A) or a salt thereof:

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[wherein X₁represents a nitrogen atom or a group —CH═, R¹represents a group —Z—R⁶,

Z represents a group —N(R⁸)—B—, a group —B—N(R⁸)—, a group —B₀—O—, a group

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a group —CO—, a group —CH(OH)—, a group

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a group —N═CH—, a group

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a lower alkenylene group, a group —NHCO—B₁—, a group —NHCO—B₂—(W)u-, a group —B₀—O—B_19a—, a group

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a group

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a group

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a group —S—, a lower alkynylene group, a lower alkylene group, a group

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or a group —CO—NH—B₁₈a-,

wherein R⁸represents a hydrogen atom, a lower alkyl group that may have a lower alkoxy group as a substituent, a lower alkanoyl group, a phenyl lower alkyl group, or a lower alkylsulfonyl group,

B represents a group —CO— or a lower alkylene group,

B₀represents a lower alkylene group,

each of R^9aand R^9b, which are identical or different, represents a hydrogen atom or a lower alkyl group

R^10arepresents a hydrogen atom or a lower alkyl group,

B_22arepresents a lower alkylene group or a lower alkenylene group,

e represents 0 or 1,

B₁represents a lower alkenylene group that may have a phenyl group as a substituent,

B₂represents a lower alkylene group that may be substituted by a group selected from the group consisting of a lower alkoxy group and a phenyl group,

W represents an oxygen atom, a group —NH—, or a sulfur atom,

u represents 0 or 1,

B_18arepresents a lower alkylene group,

B_19arepresents a lower alkylene group,

B_20arepresents a lower alkylene group,

B_21arepresents a lower alkylene group,

R^8drepresents a hydrogen atom or a lower alkyl group,

k represents 2 or 3,

c represents 0 or 1,

d′ represents 0 or 1,

R^10brepresents a hydrogen atom or a lower alkyl group,

R⁶represents a 5- to 15-membered monocyclic, dicyclic, or tricyclic saturated or unsaturated heterocyclic group having 1 to 4 nitrogen atoms, oxygen atoms, or sulfur atoms (wherein, the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of an oxo group; an optionally halogenated lower alkoxy group; an optionally halogenated lower alkyl group; a halogen atom; a lower alkylsulfonyl group; a phenyl group that may be substituted, on the phenyl ring, by an optionally halogenated lower alkyl group; a lower alkylthio group; a pyrrolyl group; a benzoyl group; a lower alkanoyl group; a lower alkoxycarbonyl group; and an amino group that may have a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group as a substituent), an adamantyl group, a naphthyl group (wherein, the naphthalene ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkyl group, a halogen atom, and an amino group that may have a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group as a substituent), an alkyl group that may have a lower alkoxy group as a substituent, a cycloalkyl group that may be substituted, on the cycloalkyl ring, by a group selected from the group consisting of an amino-substituted lower alkyl group that may have a lower alkyl group on the amino group and a lower alkyl group that may have a halogen atom as a substituent, a lower alkenyl group that may have a halogen atom as a substituent, a lower alkanoyl group, a benzoyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkyl group that may have a halogen atom as a substituent and a halogen atom, a group

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a halogen atom-substituted lower alkyl group, or a cycloalkyl lower alkyl group,

R⁷represents a hydrogen atom, a phenyl group, a carboxy group, a hydroxyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a phenoxy group, a lower alkoxy group that may have a halogen atom as a substituent, a lower alkylenedioxy group, an amino group that may have, as a substituent, a group selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a benzoyl group, and a cycloalkyl group, a cyano group, a lower alkanoyl group that may have a halogen atom as a substituent, a lower alkylsulfonyl group, an aminosulfonyl group, a lower alkoxycarbonyl group, a lower alkanoyloxy group, a 5- or 6-membered saturated or unsaturated heterocyclic group having 1 to 4 nitrogen atoms, oxygen atoms, or sulfur atoms (wherein the heterocyclic ring may be substituted, by an oxo group), or a lower alkoxycarbonyl lower alkyl group,

m represents an integer between 1 and 5, wherein when m represents 2 to 5, two to five R^7smay be identical or different,

R²represents a hydrogen atom, a halogen atom, or a lower alkyl group,

Y represents a group —O—, a group —N(R⁵)—, a group —CO—, a group —CH(OH)—, a lower alkylene group, a group —S(O)n-, or a group —C(═N—OH)—,

R⁵represents a hydrogen atom, a lower alkyl group, a Lower alkanoyl group, a benzoyl group, a phenyl lower alkyl group, or a cycloalkyl group,

n represents 0, 1, or 2,

A represents a group

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or a group

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a group

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or a group -(T)₁-N(R¹⁴)R¹⁵,

R¹³represents a hydrogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkanoyl group that may have a halogen atom as a substituent, a lower alkoxycarbonyl group, a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, an imidazolyl lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a carboxy lower alkyl group, a benzoyl group, a morpholino-substituted lower alkanoyl group, a piperazinyl carbonyl lower alkyl group that may be substituted, on the piperazine ring, by a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, a piperazinyl lower alkanoyl group that may be substituted, on the piperazine ring, by a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, a morpholinocarbonyl-substituted lower alkyl group, or an imidazolyl lower alkanoyl group,

R^13arepresents a hydrogen atom or a hydroxyl group,

T represents a lower alkylene group, a group —N(R¹⁷)—B₃—CO—, a group —(B₁₉)_e—N(R¹⁸)—CO—, a group —B₄—CO—, a group -Q-B₅—CO—, a group —B₆—N(R¹⁹)—B₇—CO—, a group —CO—B₈—, a group —CH(OH)—B₉—, a group —CO—B₁₀—CO—, a group —CH(OH)—B₁₁—CO—, a group —CO—, a group —SO₂—, or a group —B₂₃, —CO—CO—,

wherein R¹⁷represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a cycloalkylcarbonyl group, a lower alkanoyl group that may have a halogen atom as a substituent, a lower alkenyl group, an amino-substituted lower alkanoyl group that may have a lower alkyl group as a substituent, or a lower alkylsulfonyl group,

B₃represents a lower alkylene group,

B₁₉represents a lower alkylene group,

e represents 0 or 1,

R¹⁸represents a hydrogen atom or a lower alkyl group,

B₄represents a lower alkenylene group or a lower alkylene group that may have a hydroxyl group as a substituent,

Q represents an oxygen atom or a group —S(O)n- (wherein n has the same meanings as described above),

B₅represents a lower alkylene group,

B₆represents a lower alkylene group,

R¹⁹represents a hydrogen atom or a lower alkanoyl group,

B₇represents a lower alkylene group,

B₈represents a lower alkylene group,

B₉represents a lower alkylene group,

B₁₀represents a lower alkylene group,

B₁₁represents a lower alkylene group,

B_23arepresents a lower alkylene group,

l represents 0 or 1,

each of R¹⁴and R¹⁵, which are identical or different represents (1) a hydrogen atom, (2) an alkyl group that may have a hydroxyl group as a substituent, (3) a cycloalkyl group that may have a group selected from the group consisting of a hydroxyl group and a lower alkyl group as a substituent, (4) a phenoxy lower alkyl group, (5) a phenyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkyl group; a lower alkoxy group that may have a halogen atom as a substituent; a halogen atom; an amino lower alkoxy group that may have a lower alkyl group as a substituent; a hydroxyl group-substituted lower alkyl group; a phenyl lower alkyl group; a lower alkynyl group; an amino group that may have a lower alkylsulfonyl group as substituent; a lower alkylthio group; a cycloalkyl group; a phenylthio group; an adamantyl group; an anilino group that may have a halogen atom as a substituent on the phenyl ring; a lower alkoxycarbonyl group; a piperazinyl group that may have a lower alkyl group as a substituent on the piperazine ring; a pyrrolidinyl group that may have an oxo group as a substituent on the pyrrolidine ring; a lower alkanoylamino group; a cyano group; and a phenoxy group, (6) a phenoxy group, (7) a phenyl lower alkyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkoxy group that may have a halogen atom as a substituent, and a lower alkyl group, (8) a phenyl lower alkyl group that has a lower alkylenedioxy group as a substituent on the phenyl ring, (9) a lower alkanoyl group, (10) a lower alkoxycarbonyl-substituted lower alkyl group, (11) a carboxy-substituted lower alkyl group, (12) an amino group that may have a lower alkanoyl group as a substituent, (13) a 1,2,3,4-tetrahydroquinolyl group that may have 1 to 3 groups selected from the group consisting of an oxo group, a lower alkoxy group, and a lower alkylenedioxy group as a substituent(s) on the tetrahydroquinoline ring, (14) a cycloalkyl lower alkyl group, (15) a piperazinyl lower alkanoyl group that may be substituted, on the piperazine ring, by a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, (16) a pyridyl lower alkyl group, (17) an amino group-substituted lower alkyl group that may have a group selected from the group consisting of a lower alkyl group and a lower alkanoyl group as a substituent, (18) a lower alkoxy lower alkyl group, (19) an imidazolyl group, (20) an imidazolyl lower alkyl group, (21) a 1,2,3,4-tetrahydroisoquinolylcarbonyl-substituted lower alkyl group, (22) a piperidinylcarbonyl group that may have a group selected from the group consisting of a lower alkoxycarbonyl group, a phenyl lower alkyl group, and a furyl lower alkyl group as a substituent on the piperidine ring, (23) a thiazolidinyl lower alkanoyl group that may have an oxo group as a substituent on the thiazolidine ring, (24) a piperidinyl group that may be substituted, on the piperidine ring, by a group selected from the group consisting of a lower alkoxycarbonyl group, a phenyl lower alkyl group, a lower alkyl group, a benzoyl group, and a furyl lower alkyl group, (25) a carbonyl lower alkyl group substituted by a group

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(26) a carbonyl lower alkyl group substituted by a group

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(27) a group —CO—B₂₀—N(R³⁶)R³⁷, (26a) a pyrrolidinyl lower alkyl group, (27a) a morpholino lower alkyl group, (28a) a phenyl lower alkenyl group, (29a) an anilinocarbonyl lower alkyl group that may have a lower alkyl group as a substituent on the phenyl ring, (30a) an indolyl group, (31a) a piperazinyl lower alkyl group that may have, as a substituent on the piperazine ring, a group selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, (32a) an amidino lower alkyl group that may have a lower alkyl group as a substituent, (33a) a fluorenyl group, (34a) a carbazolyl group that may have a lower alkyl group as a substituent on the carbazole ring, (35a) an amidino group that may have a lower alkyl group as a substituent, (36a) a piperazinyl-substituted oxalyl group that may have 1 to 3 groups selected from the group consisting of a phenyl lower alkyl group (that may have 1 to 3 groups selected from the group consisting of a lower alkylenedioxy group and a lower alkoxy group as a substituent(s) on the phenyl ring) and a pyridyl lower alkyl group as a substituent(s) on the piperazine ring, or (37a) a cyano-substituted lower alkyl group,

R³⁴represents an oxo group or a phenyl group,

d represents an integer between 0 and 3,

B₂₀represents a lower alkylene group,

R³⁶and R³⁷, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may be substituted by 1 to 3 phenyl lower alkyl groups that may have a lower alkylenedioxy group as a substituent on the phenyl ring,

R¹⁴and R¹⁵, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 10-membered saturated or unsaturated heterocyclic ring; or a group

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wherein the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of (28) a phenyl-substituted lower alkyl group, which has 1 to 2 phenyl groups and which may have a pyridyl group on the lower alkyl group, wherein the phenyl ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkanoyl group, an amino group that may have a lower alkanoyl group as a substituent, a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxy group that may have a halogen atom as a substituent, a phenyl lower alkoxy group, a hydroxyl group, and a lower alkylenedioxy group, (29) a carbamoyl group, (30) a pyridyl lower alkyl group that may have, as a substituent(s) on the pyridine ring, 1 to 3 groups selected from the group consisting of a hydroxyl group and a lower alkyl group that may have a hydroxyl group as a substituent, (31) a pyrrolyl lower alkyl group that may have 1 to 3 lower alkyl groups as a substituent(s) on the pyrrole ring, (32) a benzoxazolyl lower alkyl group, (33) a benzothiazolyl lower alkyl group, (34) a furyl lower alkyl group, (35) a benzoyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a cyano group, an amino group that may have a lower alkylsulfonyl group as a substituent, a halogen atom, a lower alkoxy group, a lower alkyl group that may have a halogen atom as a substituent, a thiazolidinyl lower alkyl group that may have an oxo group as a substituent on the thiazolidine ring, a thiazolidinylidene lower alkyl group that may have an oxo group as a substituent on the thiazolidine ring, and a lower alkylenedioxy group, (36) a pyrimidinyl group, (37) a pyrazinyl group, (38) a pyridyl group, (39) a lower alkoxycarbonyl group, (40) a thiazolidinyl lower alkanoyl group that may be substituted, on the thiazolidine ring, by a group selected from the group consisting of an oxo group and a group

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(wherein each of R^aand R^brepresents a lower alkyl group), (41) a lower alkyl group that may have a group selected from the group consisting of a hydroxyl group and a halogen atom as a substituent, (42) a lower alkanoyl group that may have a halogen atom as a substituent, (43) a phenyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a carbamoyl group that may have a group selected from the group consisting of a lower alkoxy lower alkyl group and a lower alkyl group, a lower alkoxycarbonyl group, a carboxy group, a cyano group, a phenyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxy group that may have a halogen atom as a substituent, a benzoyl group that may have a halogen atom as a substituent on the phenyl ring, a phenyl lower alkyl group that may have a halogen atom as a substituent on the phenyl ring, and a hydroxyl group, (44) a phenyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring, (45) a naphthyl lower alkyl group, (46) a phenoxy group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a cyano group, a lower alkyl group that may have a halogen atom as a substituent, and a lower alkoxy group that may have a halogen atom as a substituent, (47) a phenoxy lower alkyl group, (48) a phenyl lower alkoxy group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, and a lower alkoxy group that may have a halogen atom as a substituent, (49) a group —(B₁₂CO)t-N(R²⁰)R²¹, (50) a group —(CO)o-B₁₃—N(R²²)R²³, (51) a 1,2,3,4-tetrahydronaphthyl-substituted lower alkyl group that may be substituted, on the 1,2,3,4-tetrahydronaphthalene ring, by 1 to 5 lower alkyl groups as a substituent(s), (52) a cycloalkyl group that may have a hydroxyl group as a substituent, (53) a piperidinyl group that may be substituted, on the piperidine ring, by 1 to 3 lower alkyl groups as a substituent(s), (54) a quinolyl lower alkyl group, (55) a 1,2,3,4-tetrazolyl lower alkyl group that may have a group selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group as a substituent on the tetrazole ring, (56) a thiazolyl lower alkyl group that may have a phenyl group as a substituent on the thiazole ring, (57) a benzoyl lower alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkoxy group and a halogen atom as a substituent(s) on the phenyl ring, (58) a piperidinyl lower alkyl group that may have a lower alkyl group as a substituent on the piperidine ring, (59) an imidazolyl group that may have 1 to 3 phenyl groups as a substituent(s) on the imidazole ring, (60) a benzimidazolyl group that may have 1 to 3 lower alkyl groups as a substituent(s) on the benzimidazole ring, (61) a pyridyl lower alkoxy group, (62) a 1,2,3,4-tetrahydroquinolyl lower alkyl group that may have an oxo group as a substituent on the tetrahydroquinoline ring, (63) a 1,3,4-oxadiazolyl lower alkyl group that may have an oxo group as a substituent on the 1,3,4-oxadiazole ring, (64) a cycloalkyl lower alkyl group, (65) a tetrahydropyranyl group, (66) a thienyl lower alkyl group, (67) a pyrimidinylcarbonyl group that may have an oxo group as a substituent on the pyrimidine ring, (68) a hydroxyl group, (69) a carboxy group, (70) a lower alkoxy lower alkyl group, (71) a lower alkoxy lower alkoxy group, (72) a benzoyloxy group, (73) a lower alkoxycarbonyl lower alkoxy group, (74) a carboxy lower alkoxy group, (75) a phenoxy lower alkanoyl group, (76) a 1,2,3,4-tetrahydroquinolylcarbonyl group that may have an oxo group as a substituent on the tetrahydroquinoline ring, (77) a phenylsulfonyl group, (78) an imidazolyl lower alkanoyl group, (79) an imidazolyl lower alkyl group, (80) a pyridylcarbonyl group, (81) an imidazolylcarbonyl group, (82) a lower alkoxycarbonyl lower alkyl group, (83) a carboxy lower alkyl group, (84) a group —(O—B₁₅)s-CO—N(R²⁶)R²⁷, (85) a group —N(R²⁸)—CO—B₁₆—N(R²⁹)R³⁰, (86) a group —N(R³¹)—B₁₇—CO—N(R¹²)R³³, (87) a benzoxazolyl group, (88a) a benzothienyl group, (89a) an oxo group, and (90a) a 1,2,3,4-tetrahydroquinolyl group that may have an oxo group as a substituent on the tetrahydroquinoline ring,

B₁₂represents a lower alkylene group,

t represents 0 or 1,

each of R²⁰and R²¹, which are identical or different, represents a hydrogen atom; a cycloalkyl group; an amino group that may have a lower alkoxycarbonyl group as a substituent; a benzoyl group that may have 1 to 3 lower alkoxy groups as a substituent(s) on the phenyl ring; a lower alkyl group; a lower alkyl group having 1 to 2 phenyl groups that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group that may have a halogen atom as a substituent, a lower alkoxy group that may have a halogen atom as a substituent, and a lower alkylthio group; a phenyl group that may be substituted, on the phenyl ring, by 1 to 3 groups selected from the group consisting of a lower alkoxy group that may have a halogen atom as a substituent and a lower alkyl group that may have a halogen atom as a substituent; a lower alkoxycarbonyl group; a cycloalkyl lower alkyl group; a pyrrolidinyl lower alkyl group that may have 1 to 3 lower alkyl groups that may have a hydroxyl group as a substituent on the pyrrolidine ring; an amino-substituted lower alkyl group that may have a group selected from the group consisting of a phenyl group and a lower alkyl group as a substituent; a 1,2,3,4-tetrahydronaphthyl-substituted lower alkyl group that may have 1 to 5 lower alkyl groups as a substituent(s) on the 1,2,3,4-tetrahydronaphthalene ring; a naphthyl lower alkyl group; a pyridyl lower alkyl group; a quinolyl lower alkyl group; a 1,2,3,4-tetrazolyl lower alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group as a substituent(s) on the tetrazole ring; a 1,2,4-triazolyl lower alkyl group; a tetrahydrofuryl lower alkyl group that may have a hydroxyl group as a substituent on the lower alkyl group; a phenoxy lower alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group and a nitro group as a substituent(s) on the phenyl ring; a phenyl lower alkanoyl group; a lower alkanoyl group that may have a halogen atom as a substituent; an imidazolyl lower alkanoyl group; a lower alkoxycarbonyl lower alkyl group; a pyridyl group; or a carboxy lower alkyl group, or R²⁰and R²¹, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring, wherein the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkyl group, a phenyl group that may have 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkyl group that may have a halogen atom as a substituent(s) on the phenyl ring, and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring,

o represents 0 or 1,

B₁₃represents a lower alkylene group,

each of R²²and R²³, which are identical or different, represents a hydrogen atom, a lower alkyl group, a benzoyl group that may have 1 to 3 lower alkoxy groups as a substituent(s) on the phenyl ring, a phenoxy lower alkyl group that may have a lower alkyl group as a substituent on the phenyl ring, a phenyl lower alkyl group, or a phenyl group, or R²²and R²³, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring, wherein the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring,

B₁₅represents a lower alkylene group,

s represents 0 or 1,

each of R²⁶and R²⁷, which are identical or different, represents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, or an imidazolyl lower alkyl group, or R²⁶and R²⁷, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic ring, wherein the heterocyclic ring may be substituted by 1 to 3 phenyl lower alkyl groups that may have a lower alkylenedioxy group as a substituent on the phenyl ring, as a substituent(s),

R²⁸represents a hydrogen atom or a lower alkyl group,

B₁₆represents a lower alkylene group,

R²⁹and R³⁰, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic group, herein the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkyl group, a phenyl group, and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring,

R³¹represents a hydrogen atom or a lower alkyl group,

B₁₇represents a lower alkylene group,

R³²and R³³, together with the nitrogen atom to which they bind, may bind to each other, directly or via a nitrogen atom, oxygen atom, or sulfur atom to form a 5- to 7-membered saturated heterocyclic group, wherein the heterocyclic ring may be substituted by 1 to 3 groups selected from the group consisting of a lower alkyl group, a phenyl group, and a phenyl lower alkyl group that may have a lower alkylenedioxy group as a substituent on the phenyl ring].

Further, the present invention provides the pharmaceutical composition for the treatment of fibrosis, comprising the aromatic compound represented by the general formula (1) or a salt thereof mentioned above.

The present invention provides the above-mentioned pharmaceutical composition for the treatment of fibrosis, comprising the aromatic compound or a salt thereof mentioned above, wherein the aromatic compound is selected from the group consisting of

N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-methoxyphenoxy)pyridin-3-yl]-3,4-dichlorobenzamide,
N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}phenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide,
N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-fluorophenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide,
N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-fluorophenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide,
N-[6-(4-{∂2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-methoxyphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide,
N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-methoxyphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide,
N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-methylphenoxy)pyridin-3-yl]-3,4-dichlorobenzamide,
N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide,
N-(6-{4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenoxy}pyridin-3-yl)-3,4-dichlorobenzenesulfonamide,
N-[6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperazin-1-yl}phenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide,
N-[6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide,
N-{6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenyl)methylamino]pyridin-3-yl}-4-trifluoromethylbenzamide,
N-[6-(4-{4-[(2-(4-benzylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide,
N-[6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide,
N-[6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methylphenoxy)pyridin-3-yl]-3,4-dichlorobenzamide,
N-{6-[4-(4-benzylpiperazine-1-carbonyl)phenoxy]pyridin-3-yl}-4-trifluoromethylbenzamide,
N-{6-[4-(4-benzylpiperazine-1-carbonyl)phenoxy]pyridin-3-yl}-3,4-dichlorobenzamide,
N-[6-({4-[3-(4-piperonylpiperazin-1-yl]-3-oxopropyl]phenyl}methylamino)pyridin-3-yl]-4-trifluoromethylbenzamide,
N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-fluorophenoxy)pyridin-3-yl]-3,4-dichlorobenzamide,
N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-fluorophenoxy)pyridin-3-yl]-3,4-dichlorobenzamide,
N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methoxyphenoxy)pyridin-3-yl]-3,4-dichlorobenzamide,
N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}phenoxy)pyridin-3-yl]-3,4-dichlorobenzamide,
1-(6-{4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenoxy}pyridin-3-yl)-3-(3,4-dichlorophenyl)-1-ethylurea,
N-(6-{4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenoxy}pyridin-3-yl)-4-trifluoromethylbenzamide,
N-[6-(4-{[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide,
N-[6-(4-{4-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenoxy)pyridin-3-yl]-3,4-dichlorobenzamide,
N-(6-{4-[3-(4-piperonylpiperazine-1-carbonyl)piperidin-1-yl]phenoxy}pyridin-3-yl)-3,4-dichlorobenzamide,
N-[6-(4-{4-[(2-(4-benzylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide,
N-{6-[(4-{4-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenyl)methylamino]pyridin-3-yl}-4-trifluoromethylbenzamide,
N-(6-{4-[(2-{4-[4-(4-fluorobenzoyl)phenyl]-piperazin-1-yl}-2-oxoethyl)methylamino]-2-methoxyphenoxy}pyridin-3-yl)-4-trifluoromethylbenzamide,
2-(4-piperonylpiperazin-1-yl)-N-{3-methyl-4-[5-(4-trifluoromethylphenoxymethyl)pyridin-2-yloxy]phenyl}-2-oxoacetamide,
N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-2-fluoro-4-trifluoromethylbenzamide,
N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methoxyphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide, and
4-(3-{3-methyl-4-[5-(4-trifluoromethylbenzoylamino)pyridin-2-yloxy]phenyl}-2-oxohexahydropyrimidin-1-yl)benzoic acid ethyl ester, or salts thereof.

The present invention provides the above-mentioned pharmaceutical composition for the treatment of fibrosis, wherein the fibrosis is lung fibrosis. The present invention provides the above-mentioned pharmaceutical composition for the treatment of fibrosis, wherein the fibrosis is hepatic fibrosis. The present invention provides the above-mentioned pharmaceutical composition for the treatment of fibrosis, wherein the fibrosis is glomerulosclerosis.

Specific examples of each group represented by the general formula (1) are as follows.

Examples of the lower alkynylene group include linear or branched alkynylene groups having 2 to 6 carbon atoms which have 2 to 6 triple bonds such as ethynylene, 1-propynylene, 1-methyl-1-propynylene, 2-methyl-1-propynylene, 2-propynylene, 2-butynylene, 1-butynylene, 3-butynylene, 2-pentynylene, 1-pentynylene, 3-pentynylene, 4-pentynylene, 2-pentyn-4-ynylene, 2-hexynylene, 1-hexynylene, 5-hexynylene, 3-hexynylene, 4-hexynylene, 3,3-diethyl-1-propynylene, 2-ethyl-1-propynylene groups.

Examples of the amino group which may have a substituent selected from the group consisting of a lower alkyl group and a lower alkanoyl group include amino groups which may have 1 or 2 substituents selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms and a linear or branched alkanoyl group having 1 to 6 carbon atoms such as amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, N-methyl-N-ethylamino, N-ethyl-N-propylamino, N-methyl-N-butylamino, N-methyl-N-hexylamino, N-acetylamino, N-formylamino, N-propionylamino, N-butyrylamino, N-isobutyrylamino, N-pentanoylamino, N-tert-butylcarbonylamino, N-hexanoylamino, diacetylamino, N-acetyl-N-methylamino, N-acetyl-N-ethylamino groups.

Examples of the benzoyl group (which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group which may have a halogen atom as a substituent and a halogen atom) include benzoyl groups (which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents and a halogen atom) such as benzoyl, 3,4-difluorobenzoyl, 2-fluorobenzoyl, 3-bromobenzoyl, 4-iodobenzoyl, 4-methylbenzoyl, 2-methylbenzoyl, 3-methylbenzoyl, 2-ethylbenzoyl, 3-ethylbenzoyl, 4-ethylbenzoyl, 4-isopropylbenzoyl, 3-butylbenzoyl, 4-pentylbenzoyl, 4-hexylbenzoyl, 3,4-dimethylbenzoyl, 3,4-diethylbenzoyl, 2,4-dimethylbenzoyl, 2,5-dimethylbenzoyl, 2,6-dimethylbenzoyl, 3,4,5-trimethylbenzoyl, 2-trifluoromethylbenzoyl, 3-trifluoromethylbenzoyl, 4-trifluoromethylbenzoyl, 2-(bromomethyl)benzoyl, 3-(2-chloroethyl)benzoyl, 4-(2,3-dichloropropyl)benzoyl, 4-(4-fluorobutyl)benzoyl, 3-(5-chloropentyl)benzoyl, 4-(5-bromohexyl)benzoyl, 4-(5,6-dibromohexyl)benzoyl, 3,4-di(trifluoromethyl)benzoyl, 3,4-di(4,4,4-trichlorobutyl)benzoyl, 2,4-di(3-chloro-2-methylpropyl)benzoyl, 2,5-di(3-chloropropyl)benzoyl, 2,6-di(2,2,2-trifluoroethyl)benzoyl, 3,4,5-tri(trifluoromethyl)benzoyl, 4-(2,2,2-trichloroethyl)benzoyl, 2-methyl-4-trifluoromethylbenzoyl, 3-ethyl-4-trichloromethylbenzoyl, 2-chloro-4-trifluoromethylbenzoyl, 3-ethyl-4-fluorobenzoyl, 3-fluoro-4-trichloromethylbenzoyl, 2-methyl-3-trifluoromethyl-4-trifluoromethylbenzoyl, 3-fluorobenzoyl, 4-fluorobenzoyl, 2-bromobenzoyl, 4-bromobenzoyl, 2-iodobenzoyl, 3-iodobenzoyl, 2,3-dibromobenzoyl, 2,4-diiodobenzoyl, 2,5-difluorobenzoyl, 2,6-dichlorobenzoyl, 2,4,6-trichlorobenzoyl, 2,4-difluorobenzoyl, 3,5-difluorobenzoyl, 2,6-difluorobenzoyl, 2-chlorobenzoyl, 3-chlorobenzoyl, 4-chlorobenzoyl, 2,3-dichlorobenzoyl, 2,4-dichlorobenzoyl, 2,5-dichlorobenzoyl, 3,4-dichlorobenzoyl, 2,6-dichlorobenzoyl, 3,5-dichlorobenzoyl, 2,4,6-trifluorobenzoyl, 2,4-difluorobenzoyl groups.

Examples of the halogen substituted lower alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms which have 1 to 3 halogen atoms as substituents such as a trifluoromethyl group, trichloromethyl group, chloromethyl group, bromomethyl group, fluoromethyl group, iodomethyl group, difluoromethyl group, dibromomethyl group, dichloromethyl group, 2-chloroethyl group, 2,2,2-trifluoroethyl group, 2,2,2-trichloroethyl group, 3-chloropropyl group, 2,3-dichloropropyl group, 4,4,4-trichlorobutyl group, 4-fluorobutyl group, 5-chloropentyl group, 3-chloro-2-methylpropyl group, 5-bromohexyl group, and 5,6-dibromohexyl group.

Examples of the lower alkanoyl substituted amino group include linear or branched alkanoyl groups having 2 to 6 carbon atoms which have 1 to 3 halogen atoms as substituents such as a acetyl amino group, propionyl amino group, butyryl amino group, pentanoyl amino group, 2-methylpropionyl amino group and hexanoyl amino group.

Examples of the piperazinyl substituted oxalyl group which may have, on the piperazine ring, 1 to 3 substituents selected from the group consisting of a phenyl lower alkyl group (which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkylenedioxy group and a lower alkoxy group) and a pyridyl lower alkyl group include piperazinyl substituted oxalyl groups which may have, on the piperazine ring, 1 to 3 substituents selected from the group consisting of a phenylalkyl group of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms (and which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a linear or branched alkylenedioxy group having 1 to 4 carbon atoms and a linear or branched alkoxy group having 1 to 6 carbon atoms) and a pyridylalkyl group of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as 4-(3,4-methylenedioxybenzyl)-(1-, 2-, or 3-)piperazinyloxalyl, 4-(2-, 3-, or 4-pyridylmethyl)-(1-, 2-, or 3-)piperazinyloxalyl, 4-(3,4-dimethoxybenzyl)-(1-, 2-, or 3-)piperazinyloxalyl, 4-(2,3-methylenedioxybenzyl)-(1, 2-, or 3-)piperazinyloxalyl, 4-(3,4-ethylenedioxybenzyl)-(1-, 2-, or 3-)piperazinyloxalyl, 4-[2-(2-, 3-, or 4-pyridyl)ethyl]-(1-, 2-, or 3-)piperazinyloxalyl, 4-[3-(2-, 3-, or 4-pyridyl)propyl-(1-, 2-, or 3-)piperazinyloxalyl, 2,4-bis(2-, 3-, or 4-pyridylmethyl)-(1-, 2-, or 3-)piperazinyloxalyl, 2-(3,4-methylenedioxybenzyl)-4-(2-, 3-, or 4-pyridylmethyl)-(1-, 2-, or 3-)piperazinyloxalyl, 2,3,4-tri(2-, 3-, or 4-pyridylmethyl)-(1-, 2-, or 3-)piperazinyloxalyl groups.

Examples of the cyano substituted lower alkyl group include cyanoalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a cyanomethyl group, 2-cyanoethyl group, 1-cyanoethyl group, 3-cyanopropyl group, 4-cyanobutyl group, 5-cyanopentyl group, 6-cyanohexyl group, 1,1-dimethyl-2-cyanoethyl group, and 2-methyl-3-cyanopropyl group.

Examples of the carbamoyl group which may have a group selected from the group consisting of a lower alkoxy lower alkyl group and a lower alkyl group include carbamoyl groups which may have 1 or 2 groups selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms which has a linear or branched alkoxy group having 1 to 6 carbon atoms and a linear or branched alkyl group having 1 to 6 carbon atoms such as carbamoyl, N-(2-methoxyethyl)carbamoyl, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, tert-butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl, dibutylcarbamoyl, dipentylcarbamoyl, dihexylcarbamoyl, N-methyl-N-ethylcarbamoyl, N-ethyl-N-propylcarbamoyl, N-methyl-N-butylcarbamoyl, N-methyl-N-hexylcarbamoyl, N-(methoxymethyl)carbamoyl, N-(3-propoxypropyl)carbamoyl, N-(4-butoxybutyl)carbamoyl, N-(4-ethoxybutyl)carbamoyl, N-(5-pentyloxypentyl)carbamoyl, N-(5-methoxypentyl)carbamoyl, N-(6-hexyloxyhexyl)carbamoyl, di(2-methoxyethyl)carbamoyl, N-(2-methoxyethyl)-N-methylcarbamoyl, N-(2-methoxyethyl)-N-ethylcarbamoyl groups.

Examples of the phenyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a halogen atom and a lower alkyl group which may have a halogen atom include phenyl groups which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a halogen atom and a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms such as phenyl, 3,4-difluorophenyl, 2-fluorophenyl, 3-bromophenyl, 4-iodophenyl, 4-methylphenyl, 2-methylphenyl, 3-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-butylphenyl, 4-pentylphenyl, 4-hexylphenyl, 3,4-dimethylphenyl, 3,4-diethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4,5-trimethylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-(bromomethyl)phenyl, 3-(2-chloroethyl)phenyl, 4-(2,3-dichloropropyl)phenyl, 4-(4-fluorobutyl)phenyl, 3-(5-chloropentyl)phenyl, 4-(5-bromohexyl)phenyl, 4-(5,6-dibromohexyl)phenyl, 3,4-di(trifluoromethyl)phenyl, 3,4-di(4,4,4-trichlorobutyl)phenyl, 2,4-di(3-chloro-2-methylpropyl)phenyl, 2,5-di(3-chloropropyl)phenyl, 2,6-di(2,2,2-trifluoroethyl)phenyl, 3,4,5-tri(trifluoromethyl)phenyl, 4-(2,2,2-trichloroethyl)phenyl, 2-methyl-4-trifluoromethylphenyl, 3-ethyl-4-trichloromethylphenyl, 2-chloro-4-trifluoromethylphenyl, 3-ethyl-4-fluorophenyl, 3-fluoro-4-trichloromethylphenyl, 2-methyl-3-trifluoromethyl-4-trifluoromethylphenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 2,3-dibromophenyl, 2,4-diiodophenyl, 2,5-difluorophenyl, 2,6-dichlorophenyl, 2,4,6-trichlorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 2,6-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,6-dichlorophenyl, 3,5-dichlorophenyl, 2,4,6-trifluorophenyl, 2,4-difluorophenyl groups.

Examples of the lower alkenylene group include linear or branched alkenylene groups having 2 to 6 carbon atoms which have 1 to 3 double bonds such as vinylene, 1-propenylene, 1-methyl-1-propenylene, 2-methyl-1-propenylene, 2-propenylene, 2-butenylene, 1-butenylene, 3-butenylene, 3-pentenylene, 1-pentenylene, 2-pentenylene, 4-pentenylene, 1,3-butadienylene, 1,3-pentadienylene, 2-penten-4-ynylene, 2-hexenylene, 1-hexenylene, 5-hexenylene, 3-hexenylene, 4-hexenylene, 3,3-dimethyl-1-propenylene, 2-ethyl-1-propenylene, 1,3,5-hexatrienylene, 1,3-hexadienylene, and 1,4-hexadienylene.

Examples of the lower alkoxy group include linear or branched alkoxy groups having 1 to 6 carbon atoms such as a methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, tert-butoxyl group, pentyloxy group, and hexyloxy group.

Examples of the lower alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms such as a methyl group, ethyl group, propyl group, isopropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, butyl group, isobutyl group, tert-butyl group, isopentyl group, pentyl group, and hexyl group.

Examples of the lower alkyl group which may have a lower alkoxy group as a substituent include, in addition to the above described lower alkyl groups, linear or branched alkyl groups having 1 to 6 carbon atoms which may have a linear or branched alkoxy group having 1 to 6 carbon atoms as a substituent such as a methoxymethyl group, 1-ethoxyethyl group, 2-methoxyethyl group, 2-propoxyethyl group, 3-isopropoxypropyl group, 4-butoxybutyl group, 5-pentyloxypentyl group, 6-hexyloxyhexyl, 1,1-dimethyl-2-methoxyethyl group, 2 ethyl-3-ethoxypropyl, and 3-methoxypropyl group.

Examples of the lower alkanoyl group include alkanoyl groups having 1 to 6 carbon atoms such as a formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, pentanoyl group, tert-butylcarbonyl, and hexanoyl group.

Examples of the phenyl lower alkyl group include phenylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a benzyl group, 2-phenylethyl group, 1-phenylethyl group, 3-phenylpropyl group, 4-phenylbutyl group, 5-phenylpentyl group, 6-phenylhexyl group, 1,1-dimethyl-2-phenylethyl group, and 2-methyl-3-phenylpropyl group.

Examples of the phenyl lower alkyl group (which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkylenedioxy group and a lower alkoxy group), include, in addition to the above described phenyl lower alkyl groups, phenylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms (and which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a linear or branched alkylenedioxy group having 1 to 4 carbon atoms and a linear or branched alkoxy group having 1 to 6 carbon atoms) such as 3,4-methylenedioxybenzyl, 3,4-trimethylenedioxybenzyl, 2-(2,3-ethylenedioxyphenyl)ethyl, 1-(3,4-trimethylenedioxyphenyl)ethyl, 3-(2,3-tetramethylenedioxyphenyl)propyl, 4-(3,4-methylenedioxyphenyl)butyl, 5-(2,3-ethylenedioxyphenyl)pentyl, 6-(3,4-trimethylenedioxyphenyl)hexyl, 1,1-dimethyl-2-(2,3-methylenedioxyphenyl)ethyl, 2-methyl-3-(3,4-ethylenedioxyphenyl)propyl, 2-methoxybenzyl, 2-(2-methoxyphenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(4-methoxyphenyl)ethyl, 4-methoxybenzyl, 1-(2-ethoxyphenyl)ethyl, 3-(3-ethoxyphenyl)propyl, 4-(4-ethoxyphenyl)butyl, 5-(4-isopropoxyphenyl)pentyl, 6-(3-butoxyphenyl)hexyl, 1,1-dimethyl-2-(4-pentyloxyphenyl)ethyl, 2-methyl-3-(4-hexyloxyphenyl)propyl, 3,4-dimethoxybenzyl, 3,4-diethoxybenzyl, 2,4-dimethoxybenzyl, 2,5-dimethoxybenzyl, 2,6-dimethoxybenzyl, 3,4,5-trimethoxybenzyl groups.

Examples of the lower alkylene group include linear or branched alkylene groups having 1 to 6 carbon atoms such as a methylene group, ethylene group, trimethylene group, 2-methyltrimethylene group, 2,2-dimethylethylene group, 2,2-dimethyltrimethylene group, 1-methyltrimethylene group, methylmethylene group, ethylmethylene group, tetramethylene group, pentamethylene group, and hexamethylene group.

Examples of the lower alkenylene group which may have a phenyl group as a substituent include linear or branched alkenylene groups having 2 to 6 carbon atoms which have 1 to 3 double bonds and may have a phenyl group as a substituent such as vinylene, 1-propenylene, 1-methyl-1-propenylene, 2-methyl-1-propenylene, 2-propenylene, 2-butenylene, 1-butenylene, 3-butenylene, 2-pentenylene, 1-pentenylene, 3-pentenylene, 4-pentenylene, 1,3-butadienylene, 1,3-pentadienylene, 2-penten-4-ynylene, 2-hexenylene, 1-hexenylene, 5-hexenylene, 3-hexenylene, 4-hexenylene, 3,3-dimethyl-1-propenylene, 2-ethyl-1-propenylene, 1,3,5-hexatrienylene, 1,3-hexadienylene, 1,4-hexadienylene, 1-phenylvinylene, 3-phenyl-1-propenylene, 3-phenyl-1-methyl-1-propenylene, 3-phenyl-2-methyl-1-propenylene, 1-phenyl-2-propenylene, 1-phenyl-2-butenylene, 3-phenyl-1-butenylene, 1-phenyl-3-butenylene, 5-phenyl-2-pentenylene, 4-phenyl-1-pentenylene, 2-phenyl-3-pentenylene, 1-phenyl-4-pentenylene, 1-phenyl-1,3-butadienylene, 1-phenyl-1,3-pentadienylene, 1-phenyl-2-penten-4-ynylene, 1-phenyl-2-hexenylene, 3-phenyl-1-hexenylene, 4-phenyl-5-hexenylene, 6-phenyl-3-hexenylene, 5-phenyl-4-hexenylene, 1-phenyl-3,3-dimethyl-1-propenylene, 1-phenyl-2-ethyl-1-propenylene, 6-phenyl-1,3,5-hexatrienylene, 1-phenyl-1,3-hexadienylene, 2-phenyl-1,4-hexadienylene groups.

Examples of the lower alkylene group which may be substituted with a group selected from the group consisting of a lower alkoxy group and a phenyl group include, in addition to the above described lower alkylene groups, linear or branched alkylene groups having 1 to 6 carbon atoms which may be substituted with 1 or 2 groups selected from the group consisting of a linear or branched alkoxy group having 1 to 6 carbon atoms and a phenyl group such as methoxymethylene, 2-phenylethylene, 3-ethoxytriethylene, 1-propoxy-2-methyltrimethylene, 1-phenyl-2,2-dimethylethylene, 3-phenyl-2,2-dimethyltrimethylene, 2-butoxy-1-methyltrimethylene, phenylmethylmethylene, 2-pentyloxyethylmethylene, 4-phenyl-2-hexyloxytetramethylene, 3-phenylpentamethylene, 5-phenylhexamethylene, ethoxymethylene, 1-phenylethylene, 3-phenyltrimethylene, 2-phenyl-1-methoxyethylene groups.

Examples of the 5- to 15-membered monocyclic, bicyclic or tricyclic saturated or unsaturated heterocyclic group which has 1 to 4 nitrogen atoms, oxygen atoms or sulfur atoms include pyrrolidinyl, piperidinyl, piperazinyl, morpholino, pyridyl, 1,2,5,6-tetrahydropyridyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 1,2,5-triazolyl, thiazolidinyl, 1,2,3,4-tetrazolyl, thienyl, quinolyl, 1,4-dihydroquinolyl, benzothiazolyl, pyrazyl, pyrimidyl, pyridazyl, 2H-pyrrolyl, pyrrolyl, 1,3,4-oxadiazolyl, tetrahydropyranyl, tetrahydrofuryl, furazanyl, carbostyryl, 3,4-dihydrocarbostyryl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, indolyl, isoindolyl, indolinyl, benzoimidazolyl, benzoxazolyl, imidazolidinyl, isoquinolyl, quinazolidinyl, quinoxalinyl, cinnolinyl, phthalazinyl, carbazoyl, acridinyl, chromanyl, isoindolinyl, isochromanyl, pyrazolyl, imidazolyl, pyrazolidinyl, phenothiazinyl, benzofuryl, 2,3-dihydrobenzo[b]furyl, benzothienyl, phenoxatiynyl, phenoxadinyl, 4H-chromenyl, 1H-indazolyl, phenazinyl, xanthenyl, thianthrenyl, 2-imidazolinyl, 2-pyrrolinyl, furyl, oxazolyl, isoxazolyl, isoxazolidinyl, thiazolyl, isothiazolyl, pyranyl, 2-thiazolinyl, 2-pyrazolinyl, quinuclidinyl, 1,4-benzoxadinyl, 3,4,-dihydro-2H-1,4-benzoxadinyl, 3,4-dihydro-2H-1,4-benthiazinyl, 1,4-benzothiazinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,3-dithia-2,4-dihydronaphthalenyl, phenanthridinyl, 1,4-dithianaphthalenyl, dibenz[b,e]azepine, 6,11-dihydro-5H-dibenz[b,e]azepine groups.

Examples of the halogen atom include a fluorine atom, chlorine atom, bromine atom and iodine atom.

Examples of the lower alkoxy group which may have a halogen atom as a substituent include linear or branched alkoxy groups having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, trifluoromethoxy, trichloromethoxy, chloromethoxy, bromomethoxy, fluoromethoxy, iodomethoxy, difluoromethoxy, dibromomethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 3-chloropropoxy, 2,3-dichloropropoxy, 4,4,4-trichlorobutoxy, 4-fluorobutoxy, 5-chloropentyloxy, 3-chloro-2-methylpropoxy, 6-bromohexyloxy, 5,6-dichlorohexyloxy groups.

Examples of the lower alkyl group which may have a halogen atom as a substituent include, in addition to the above described lower alkyl groups, linear or branched alkyl groups having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents such as a trifluoromethyl group, trichloromethyl group, chloromethyl group, dichloromethyl group, bromomethyl group, fluoromethyl group, iodomethyl group, difluoromethyl group, dibromomethyl group, dichloromethyl group, 2-chloroethyl group, 2,2,2-trifluoroethyl group, 2,2,2-trichloroethyl group, 3-chloropropyl group, 2,3-dichloropropyl group, 4,4,4-trichlobutyl group, 4-fluorobutyl group, 5-chloropentyl group, 3-chloro-2-methylpropyl group, 5-bromohexyl group, and 5,6-dibromohexyl group.

Examples of the lower alkylsulfonyl group include linear or branched alkylsulfonyl groups having 1 to 6 carbon atoms such as a methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylsulfonyl group, butylsulfonyl group, tert-butylsulfonyl group, pentylsulfonyl group, and hexylsulfonyl group.

Examples of the phenyl group which may be substituted on the phenyl ring with a lower alkyl group which may have a halogen atom include phenyl groups which may be substituted with 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms such as phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-butylphenyl, 4-pentylphenyl, 4-hexylphenyl, 3,4-dimethylphenyl, 3,4-diethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4,5-trimethylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-(bromomethyl)phenyl, 3-(2-chloroethyl)phenyl, 4-(2,3-dichloropropyl)phenyl, 4-(4-fluorobutyl)phenyl, 3-(5-chloropentyl)phenyl, 4-(5-bromohexyl)phenyl, 4-(5,6-dibromohexyl)phenyl, 3,4-di(trifluoromethyl)phenyl, 3,4-di(4,4,4-trichlorobutyl)phenyl, 2,4-di(3-chloro-2-methylpropyl)phenyl, 2,5-di(3-chloropropyl)phenyl, 2,6-di(2,2,2-trifluoroethyl)phenyl, 3,4,5-tri(trifluoromethyl)phenyl, 4-(2,2,2-trichloroethyl)phenyl, 2-methyl-4-trifluoromethylphenyl, 3-ethyl-4-trichloromethyl groups.

Examples of the lower alkylthio group include linear or branched alkylthio groups having 1 to 6 carbon atoms such as a methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, tert-butylthio group, pentylthio group, and hexylthio group.

Examples of the naphthyl group which may be substituted on the naphthalene ring with 1 to 3 substituents selected from the group consisting of a lower alkyl group, a halogen atom, and an amino group which may have a substituent selected from the group consisting of a lower alkyl group and a lower alkanoyl group include naphthyl groups which may have, on the naphthalene ring, 1 to 3 substituents selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms, a halogen atom, and an amino group which may have 1 or 2 substituents selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms and a linear or branched alkanoyl group having 1 to 6 carbon atoms such as (1- or 2-)naphthyl, 1-methyl-(2-, 3-, 4-, 5-, 6-, 7-, or 8-)naphthyl, 2-ethyl-(1-, 3-, 4-, 5-, 6-, 7-, or 8-)naphthyl, 3-n-propyl-(1-, 2-, 4-, 5-, 6-, 7-, or 8-)naphthyl, 4-n-butyl-(1-, 2-, 3-, 5-, 6-, 7-, or 8-)naphthyl, 4-methyl-(1-, 2-, 3-, 5-, 6-, 7-, or 8-)naphthyl, 5-n-pentyl-(1-, 2-, 3-, 4-, 6-, 7-, or 8-)naphthyl, 6-n-hexyl-(1-, 2-, 3-, 4-, 5-, 7-, or 8-)naphthyl, 1,7-dimethyl-(2-, 3-, 4-, 5-, 6-, or 8-)naphthyl, 1,2,8-trimethyl-(3-, 4-, 5-, 6-, or 7-)naphthyl, 1-dimethylamino-(2-, 3-, 4-, 5-, 6-, 7-, or 8-)naphthyl, 2-dimethylamino-(1-, 3-, 4-, 5-, 6-, 7-, or 8-)naphthyl, 3-methylamino-(1-, 2-, 4-, 5-, 6-, 7-, or 8-)naphthyl, 5-amino-(1-, 2-, 3-, 4-, 6-, 7-, or 8-)naphthyl, 5-dimethylamino-(1-, 2-, 3-, 4-, 6-, 7-, or 8-)naphthyl, 4-(N-methyl-N-ethylamino)-(1-, 2-, 3-, 5-, 6-, 7-, or 8-)naphthyl, 1-methyl-2-dimethylamino-(3-, 4-, 5-, 6-, 7-, or 8-)naphthyl, 1-chloro-(2-, 3-, 4-, 5-, 6-, 7-, or 8-)naphthyl, 1-acetylamino-(2-, 3-, 4-, 5-, 6-, 7-, or 8-)naphthyl groups.

Examples of the alkyl group which may have a lower alkoxy group as a substituent include, in addition to the above described alkyl groups which may have a lower alkoxy group as a substituent, linear or branched alkyl groups having 1 to 8 carbon atoms which may have a linear or branched alkoxy group having 1 to 6 carbon atoms as a substituent such as a heptyl group, 1-ethylpentyl group, octyl group, 7-methoxyheptyl group, 1-ethoxyheptyl group, 2-propoxyl-1-ethylpentyl group, 3-isopropoxyoctyl group, 7-butoxyheptyl group, 8-pentyloxyoctyl group, and 5-hexyloxy-1-ethylpentyl group.

Examples of the amino substituted lower alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms substituted with an amino group which may have 1 or 2 linear or branched alkyl groups having 1 to 6 carbon atoms such as aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1,1-dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl, methylaminomethyl, 1-ethylaminoethyl, 2-propylaminoethyl, 3-isopropylaminopropyl, 4-butylaminobutyl, 5-pentylaminopentyl, 6-hexylaminohexyl, dimethylaminomethyl, 2-diethylaminoethyl, 2-diisopropylaminoethyl, (N-ethyl-N-propylamino)methyl, 2-(N-methyl-N-hexylamino)ethyl groups.

Examples of the cycloalkyl group include cycloalkyl groups having 3 to 16 carbon atoms such as a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group, cyclodecyl group, cycloundecyl group, cyclododecyl group, cyclotridecyl group, cycloteradecyl group, cyclopentadecyl group, and cyclohexadecyl group.

Examples of the cycloalkyl group which may be substituted with a group selected from the group consisting of an amino substituted lower alkyl group which may have a lower alkyl group and a lower alkyl group which may have a halogen as a substituent include cycloalkyl groups having 3 to 16 carbon atoms which may be substituted on the cycloalkyl ring with 1 to 3 groups selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms substituted with an amino group which may have 1 or 2 linear or branched alkyl groups having 1 to 6 carbon atoms and a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents such as 4-dimethylaminomethylcyclohexyl, 2-(aminomethyl)cyclopropyl, 3-(2-aminomethyl)cyclobutyl, 2-(1-aminoethyl)cyclopentyl, 3-(3-aminopropyl)cyclohexyl, 3-(4-aminobutyl)cycloheptyl, 4-(5-aminopentyl)cyclooctyl, 4-(6-aminohexyl)cyclohexyl, 2-(1,1-dimethyl-2-aminoethyl)cycloheptyl, 3-(2-methyl-3-aminopropyl)cyclopentyl, 3-(methylaminomethyl)cyclohexyl, 2-(1-ethylaminoethyl)cyclooctyl, 2-(2-propylaminoethyl)cyclohexyl, 3-(3-isopropylaminopropyl)cyclopentyl, 4-(4-butylaminobutyl)cycloheptyl, 2-(5-pentylaminopentyl)cyclohexyl, 2-(6-hexylaminohexyl)cyclopentyl, 3-(dimethylaminomethyl)cyclohexyl, 3-[(N-ethyl-N-propylamino)methyl]cycloheptyl, 4-[2-(N-methyl-N-hexylamino)ethyl]cyclooctyl, 4-dimethylaminomethylcyclononyl, 2-(aminomethyl)cyclodecyl, 3-(2-aminomethyl)cycloundecyl, 2-(1-aminoethyl)cyclododecyl, 3-(3-aminopropyl)cyclotridecyl, 3-(4-aminobutyl)cyclotetradecyl, 4-(5-aminopentyl)cyclopentadecyl, 4-(6-aminohexyl)cyclohexadecyl, 2-(1,1-dimethyl-2-aminoethyl)cyclononyl, 3-(2-methyl-3-aminopropyl)cyclodecyl, 3-(methylaminomethyl)cycloundecyl, 2-(1-ethylaminoethyl)cyclododecyl, 2-(2-propylaminoethyl)cyclotridecyl, 3-(3-isopropylaminopropyl)cyclotetradecyl, 4-(4-butylaminobutyl)cyclopentadecyl, 2-(5-pentylaminopentyl)cyclohexadecyl, 2-(6-hexylaminohexyl)cyclononyl, 3-(dimethylaminomethyl)cyclododecyl, 3-[(N-ethyl-N-propylamino)methyl]cyclodecyl, 4-[2-(N-methyl-N-hexylamino)ethyl]cyclohexadecyl, 2,2-dimethylcyclopropyl, 2-trifluoromethylcyclopropyl groups.

Examples of the lower alkenyl group include linear or branched alkenyl groups having 2 to 6 carbon atoms which have 1 to 3 double bonds such as a vinyl group, 1-propenyl group, 1-methyl-1-propenyl group, 2-methyl-1-propenyl group, 2-propenyl group, 2-butenyl group, 1-butenyl group, 3-butenyl group, 2-pentenyl group, 1-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1,3-butadienyl group, 1,3-pentadienyl group, 2-penten-4-ynyl group, 2-hexenyl group, 1-hexenyl group, 5-hexenyl group, 3-hexenyl group, 4-hexenyl group, 3,3-dimethyl-1-propenyl group, 2-ethyl-1-propenyl group, 1,3,5-hexatrienyl group, 1,3-hexadienyl group, and 1,4-hexadienyl group.

Examples of the lower alkenyl group which may have a halogen atom as a substituent include, in addition to the above described lower alkenyl groups, linear or branched alkenyl groups having 2 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents and 1 to 3 double bonds such as 3,3,3-trifluoro-1-propenyl, 2-bromovinyl, 3-chloro-1-propenyl, 3-iodo-1-methyl-1-propenyl, 3-fluoro-2-methyl-1-propenyl, 2-butenyl, 4,4,3-trichloro-1-butenyl, 4,4-difluoro-3-butenyl, 5-fluoro-2-pentenyl, 5,5,3-tribromo-1-pentenyl, 5-chloro-3-pentenyl, 5,5,5-trifluoro-4-pentenyl, 4-chloro-1,3-butadienyl, 5-fluoro-1,3-pentadienyl, 5-bromo-2-penten-4-ynyl, 6-fluoro-2-hexenyl, 6,6,5-trifluoro-1-hexenyl, 6-chloro-5-hexenyl, 5-bromo-3-hexenyl, 6-chloro-4-hexenyl, 3,3-dimethyl-2-chloro-1-propenyl, 3-fluoro-2-ethyl-1-propenyl, 6-chloro-1,3,5-hexatrienyl, 6-bromo-1,3-hexadienyl, 6-fluoro-1,4-hexadienyl groups.

Examples of the lower alkylenedioxy group include linear or branched alkylene groups having 1 to 4 carbon atoms such as a methylenedioxy group, ethylenedioxy group, trimethylenedioxy group, and tetramethylenedioxy group.

Examples of the amino group which may have a substituent selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a benzoyl group and a cycloalkyl group include amino groups which may have 1 or 2 substituents selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkanoyl group having 1 to 6 carbon atoms, a benzoyl group, and a cycloalkyl group having 3 to 16 carbon atoms such as amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, N-methyl-N-ethylamino, N-ethyl-N-propylamino, N-methyl-N-butylamino, N-methyl-N-hexylamino, N-methyl-N-acetylamino, N-acetylamino, N-formylamino, N-propionylamino, N-butyrylamino, N-isobutyrylamino, N-pentanoylamino, N-tert-butylcarbonylamino, N-hexanoylamino, N-ethyl-N-acetylamino, N-benzoylamino, N-ethyl-N-benzoylamino, N-methyl-N-benzoylamino, N-acetyl-N-benzoylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, cyclooctylamino, N-methyl-N-cyclohexylamino, N-methyl-N-cyclopentylamino, N-methyl-N-cycloheptylamino, N-cyclohexyl-N-acetylamino, N-cyclopentyl-N-benzoylamino, cyclononylamino, cyclodecylamino, cyclododecylamino, cyclotridecylamino, cyclotetradecylamino, cyclopentadecylamino, N-methyl-N-cyclohexadecylamino, N-methyl-N-cyclononylamino, N-methyl-N-cyclodecylamino, N-cycloundecyl-N-acetylamino, N-cyclohexadecyl-N-benzoylamino groups.

Examples of the lower alkanoyl group which may have a halogen atom as a substituent include, in addition to the above described lower alkanoyl groups, linear or branched alkanoyl groups having 2-6 carbon atoms which may have 1 to 3 halogen atoms as substituents such as a 2,2,2-trifluoroacetyl group, 2,2,2-trichloroacetyl group, 2-chloroacetyl group, 2-bromoacetyl group, 2-fluoroacetyl group, 2-iodoacetyl group, 2,2-difluoroacetyl group, 2,2-dibromoacetyl group, 3,3,3-trifluoropropionyl group, 3,3,3-trichloropropionyl group, 3-chloropropionyl group, 2,3-dichloropropionyl group, 4,4,4-trichlorobutyryl group, 4-fluorobutyryl group, 5-chloropentanoyl group, 3-chloro-2-methylpropionyl group, 6-bromohexanoyl group, and 5,6-dibromohexanoyl group.

Examples of the lower alkoxycarbonyl group include linear or branched alkoxycarbonyl groups having 1 to 6 carbon atoms such as a methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, and hexyloxycarbonyl group.

Examples of the lower alkanoyloxy group include linear or branched alkanoyloxy groups having 2 to 6 carbon atoms such as an acetyloxy group, propionyloxy group, butyryloxy group, isobutyryloxy group, pentanoyloxy group, tert-butylcarbonyloxy group, and hexanoyloxy group.

Examples of the 5- or 6-membered saturated or unsaturated heterocyclic group having 1 to 4 nitrogen atoms, oxygen atoms or sulfur atoms include pyrrolidinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino, pyridyl, 1,2,5,6-tetrahydropyridyl, thienyl, pyrazyl, pyrimidyl, pyridazyl, pyrrolyl, 2H-pyrrolyl, imidazolidinyl, pyrazolyl, imidazolyl, pyrazolidinyl, furazanyl, 2-imidazolinyl, imidazolidinyl, 2-pyrrolinyl, furyl, oxazolyl, isoxazolidinyl, isoxazolyl, thiazolyl, isothiazolyl, pyranyl, 2-pyrazolidinyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 1,2,5-triazolyl, thiazolidinyl, 2-thiazolinyl, 1,2,3,4-tetrazolyl, 1,3,4-oxadiazolyl, tetrahydropyranyl, tetrahydrofuryl groups.

Examples of the 5- to 7-membered saturated heterocyclic ring formed by binding R¹and R¹²each other, together with nitrogen atoms bound to them, through or not through a nitrogen atom, a sulfur atom or an oxygen atom, include a pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholino group, thiomorpholino group, and homopiperazinyl group.

Examples of the imidazolyl lower alkyl group include imidazolylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a (1, 2, 4 or 5-)imidazolylmethyl group, 2-[(1, 2, 4 or 5-)imidazolyl]ethyl group, 1-[(1, 2, 4 or 5-)imidazolyl]ethyl group, 3-[(1, 2, 4 or 5-)imidazolyl]propyl group, 4-[(1, 2, 4 or 5-)imidazolyl]butyl group, 5-[(1, 2, 4 or 5-)imidazolyl]pentyl group, 6-[(1, 2, 4 or 5-)imidazolyl]hexyl group, 1,1-dimethyl-[(1, 2, 4 or 5-)imidazolyl]ethyl group, and 2-methyl-3-[(1, 2, 4 or 5-)imidazolyl]propyl group.

Examples of the 1,2,4-triazolyl lower alkyl group include 1,2,4-triazolylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (1, 3, or 5-)1,2,4-triazolylmethyl, 2-[(1, 3, or 5-)1,2,4-triazolyl]ethyl, 1-[(1, 3, or 5-)1,2,4-triazolyl]ethyl, 3-[(1, 3, or 5-)1,2,4-triazolyl]propyl, 4-[(1, 3, or 5-)1,2,4-triazolyl]butyl, 5-[(1, 3, or 5-)1,2,4-triazolyl]pentyl, 6-[(1, 3, or 5-)1,2,4-triazolyl]hexyl, 1,1-dimethyl-2-[(1, 3, or 5-)1,2,4-triazolyl]ethyl, 2-methyl-3-[(1, 3, or 5-)1,2,4-triazolyl]propyl groups.

Examples of the 1,2,3-triazolyl lower alkyl group include 1,2,3-triazolylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (1, 4, or 5-)1,2,3-triazolylmethyl, 2-[(1, 4, or 5-)1,2,3-triazolyl]ethyl, 1-[(1, 4, or 5-)1,2,3-triazolyl]ethyl, 3-[(1, 4, or 5-)1,2,3-triazolyl]propyl, 4-[(1, 4, or 5-)1,2,3-triazolyl]butyl, 5-[(1, 4, or 5-)1,2,3-triazolyl]pentyl, 6-[(1, 4, or 5-)1,2,3-triazolyl]hexyl, 1,1-dimethyl-2-[(1, 4, or 5-)1,2,3-triazolyl]ethyl, 2-methyl-3-[(1, 4, or 5-)1,2,3-triazolyl]propyl groups.

Examples of the 1,2,5-triazolyl lower alkyl group include 1,2,5-triazolylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (1, 3, or 4-)1,2,5-triazolylmethyl, 2-[(1, 3, or 4-)1,2,5-triazolyl]ethyl, 1-[(1, 3, or 4-)1,2,5-triazolyl]ethyl, 3-[(1, 3, or 4-)1,2,5-triazolyl]propyl, 4-[(1, 3, or 4-)1,2,5-triazolyl]butyl, 5-[(1, 3, or 4-)1,2,5-triazolyl]pentyl, 6-[(1, 3, or 4-)1,2,5-triazolyl]hexyl, 1,1-dimethyl-2-[(1, 3, or 4-)1,2,5-triazolyl]ethyl, 2-methyl-3-[(1, 3, or 4-)1,2,5-triazolyl]propyl groups.

Examples of the pyrazolyl lower alkyl group include pyrazolylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a (1, 3, 4 or 5-)pyrazolylmethyl group, 2-[(1, 3, 4 or 5-)1,2,5-pyrazolyl]ethyl group, 1-[(1, 3, 4 or 5-)pyrazolyl]ethyl group, 3-[(1, 3, 4 or 5-)pyrazolyl]propyl group, 4-[(1, 3, 4 or 5-)pyrazolyl]butyl group, 5-[(1, 3, 4 or 5-)pyrazolyl]pentyl group, 6-[(1, 3, 4 or 5-)pyrazolyl]hexyl group, 1,1-dimethyl-2-[(1, 3, 4 or 5-)pyrazolyl]ethyl group, and 2-methyl-3-[(1, 3, 4 or 5-)pyrazolyl]propyl group.

Examples of the pyrimidinyl lower alkyl group include pyrimidinylalkyl groups which may have 1 to 3 oxo groups as substituents on the pyrimidine ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (2, 4, 5, or 6-)pyrimidinylmethyl, 2-[(2, 4, 5, or 6-)pyrimidinyl]ethyl, 1-[(2, 4, 5, or 6-)pyrimidinyl]ethyl, 3-[(2, 4, 5, or 6-)pyrimidinyl]propyl, 4-[(2, 4, 5, or 6-)pyrimidinyl]butyl, 5-[(2, 4, 5, or 6-)pyrimidinyl]pentyl, 6-[(2, 4, 5, or 6-)pyrimidinyl]hexyl, 1,1-dimethyl-2-[(2, 4, 5, or 6-)pyrimidinyl]ethyl, 2-methyl-3-[(2, 4, 5, or 6-)pyrimidinyl]propyl, [(1, 3, 4, or 5-)2,6-dioxopyrimidinyl]methyl, [(1, 3, 4, 5, or 6-)-2-oxopyrimidinyl]methyl, [(1, 2, 4, or 5-)6-oxopyrimidinyl]methyl, [(1, 2, 5, or 6-)4-oxopyrimidinyl]methyl, [(1, 3, 5, or 6-)2,4-dioxopyrimidinyl]methyl, 2-[(4 or 6-)2,5-dioxopyrimidinyl]ethyl, 1-[(1, 3, 4, or 5-)2,6-dioxopyrimidinyl]ethyl, 3-[(1,3,5-)2,4,6-trioxopyrimidinyl]propyl, 4-[(1, 3, 4, or 5-)2,6-dioxopyrimidinyl]butyl, 5-[(4 or 6-)2,5-dioxopyrimidinyl]pentyl, 6-[(1, 3, 5, or 6-)2,4-dioxopyrimidinyl]hexyl, 1,1-dimethyl-2-[(1, 3, 4, or 5-)2,6-dioxopyrimidinyl]ethyl, 2-methyl-3-[(1, 3, 4, or 5-)2,6-dioxopyrimidinyl]propyl groups.

Examples of the 3,5-dioxoisoxazolidin-4-ylidene lower alkyl group include 3,5-dioxoisoxazolidin-4-ylidenealkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a 3,5-dioxoisoxazolidin-4-ylidenemethyl group, 3,5-dioxoisoxazolidin-4-ylideneethyl group, 3,5-dioxoisoxazolidin-4-ylidenepropyl group, 3,5-dioxoisoxazolidin-4-ylideneisopropyl group, 3,5-dioxoisoxazolidin-4-ylidenebutyl group, 3,5-dioxoisoxazolidin-4-ylidenepentyl group, and 3,5-dioxoisoxazolidin-4-ylidenehexyl group.

Examples of the 1,2,4-oxadiazolyl lower alkyl group which may have a lower alkyl group as a substituent on the 1,2,4-oxadiazol ring include 1,2,4-oxadiazolylalkyl groups which may have a linear or branched alkyl group having 1 to 6 carbon atoms as a substituent on the 1,2,4-oxadiazol ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (3 or 5-)1,2,4-oxadiazolylmethyl, 2-[(3 or 5-)1,2,4-oxadiazolyl]ethyl, 1-[(3 or 5-)1,2,4-oxadiazolyl]ethyl, 3-[(3 or 5-)1,2,4-oxadiazolyl]propyl, 4-[(3 or 5-)1,2,4-oxadiazolyl]butyl, 5-[(3 or 5-)1,2,4-oxadiazolyl]pentyl, 6-[(3 or 5-)1,2,4-oxadiazolyl]hexyl, 1,1-dimethyl-2-[(3 or 5-)1,2,4-oxadiazolyl]ethyl, 2-methyl-3-[(3 or 5-)1,2,4-oxadiazolyl]propyl, 5-methyl-3-(1,2,4-oxadiazolyl]methyl, 3-ethyl-2-[(5-(1,2,4-oxadiazolyl)]ethyl, 1-[3-propyl-5-(1,2,4-oxadiazolyl)]ethyl, 3-[5-butyl-3-(1,2,4-oxadiazolyl)]propyl, 4-[3-pentyl-5-(1,2,4-oxadiazolyl)]butyl, 5-[5-hexyl-3-(1,2,4-oxadiazolyl)]pentyl, 6-[3-methyl-5-(1,2,4-oxadiazolyl)]hexyl, 1,1-dimethyl-2-[(5-isopropyl-3-(1,2,4-oxadiazolyl)]ethyl, 2-methyl-3-[3-isobutyl-5-(1,2,4-oxadiazolyl)]propyl groups.

Examples of the thiazolydinyl lower alkyl group which may have an oxo group as a substituent on the thiazolydine ring include thiazolydinylalkyl groups which may have 1 to 3 oxo groups as substituents on the thiazolydine ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (2, 3, 4, or 5-)thiazolidinylmethyl, 2-[(2, 3, 4, or 5-)thiazolidinyl]ethyl, 1-[(2, 3, 4, or 5-)thiazolidinyl]ethyl, 3-[(2, 3, 4, or 5-)thiazolidinyl]propyl, 4-[(2, 3, 4, or 5-)thiazolidinyl]butyl, 5-[(2, 3, 4, or 5-)thiazolidinyl]pentyl, 6-[(2, 3, 4, or 5-)thiazolidinyl]hexyl, 1,1-dimethyl-2-[(2, 3, 4, or 5-)thiazolidinyl]ethyl, 2-methyl-3-[(2, 3, 4, or 5-)thiazolidinyl]propyl, 2,4-dioxo-5-thiazolidinylmethyl, 2-[2-oxo-(3, 4, or 5-)thiazolidinyl]ethyl, 1-[(4-oxo-(2, 3, or 5-)thiazolidinyl]ethyl, 3-[5-oxo-(2, 3, or 4-)thiazolidinyl]propyl, 4-[2,5-dioxo-(3 or 4-)thiazolidinyl]butyl, 5-[2,4,5-trioxo-3-thiazolidinyl]pentyl, 6-[4,5-dioxo-(2 or 3-)thiazolidinyl]hexyl, 1,1-dimethyl-2-[2,4-dioxo-(3 or 5-)thiazolidinyl]ethyl, 2-methyl-3-[2,4-dioxo-(3 or 5-)thiazolidinyl]propyl, 3-[2,4-dioxo-(3 or 5-)thiazolidinyl]propyl groups.

Examples of the phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring include, in addition to the above described phenyl lower alkyl groups, phenylalkyl groups which may have a linear or branched alkylenedioxy group as a substituent on the phenyl ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as 3,4-methylenedioxybenzyl, 3,4-trimethylenedioxybenzyl, 2-(2,3-ethylenedioxyphenyl)ethyl, 1-(3,4-trimethylenedioxyphenyl)ethyl, 3-(2,3-tetramethylenedioxyphenyl)propyl, 4-(3,4-methylenedioxyphenyl)butyl, 5-(2,3-ethylenedioxyphenyl)pentyl, 6-(3,4-trimethylenedioxyphenyl)hexyl, 1,1-dimethyl-2-(2,3-methylenedioxyphenyl)ethyl, 2-methyl-3-(3,4-ethylenedioxyphenyl)propyl groups.

Examples of the lower alkoxycarbonyl lower alkyl group include alkoxycarbonylalkyl groups of which the alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms and the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a methoxycarbonylmethyl group, ethoxycarbonylmethyl group, 2-methoxycarbonylethyl group, 2-ethoxycarbonylmethyl group, 1-ethoxycarbonylethyl group, 3-methoxycarbonylpropyl group, 3-ethoxycarbonylpropyl group, 4-ethoxycarbonylbutyl group, 5-isopropoxycarbonylpentyl group, 6-propoxycarbonylhexyl group, 1,1-dimethyl-2-butoxycarbonylethyl group, 2-methyl-3-tert-butoxycarbonylpropyl-group, 2-pentyloxycarbonylethyl group, and hexyloxycarbonylmethyl group.

Examples of the carboxy lower alkyl group include carboxyalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a carboxymethyl group, 2-carboxyethyl group, 1-carboxyethyl group, 3-carboxypropyl group, 4-carboxybutyl group, 5-carboxypentyl group, 6-carboxyhexyl group, 1,1-dimethyl-2-carboxyethyl group, and 2-methyl-3-carboxypropyl group.

Examples of the morpholino substituted lower alkanoyl group include morpholino substituted alkanoyl groups of which the alkanoyl moiety is a linear or branched alkanoyl group having 2 to 6 carbon atoms such as a 2-[(2, 3 or 4-)morpholino]acetyl group, 3-[(2, 3 or 4-)morpholino]propionyl group, 2-[(2, 3 or 4-)morpholino]propionyl group, 4-[(2, 3 or 4-)morpholino]butyryl group, 5-[(2, 3 or 4-)morpholino]pentanoyl group, 6-[(2, 3 or 4-)morpholino]hexanoyl group, 2,2-dimethyl-2-[(2, 3 or 4-)morpholino]propionyl group, and 2-methyl-3-[(2, 3 or 4-)morpholino]propionyl group.

Examples of the piperazinylcarbonyl lower alkyl group which may be substituted on the piperazine ring with a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring include piperazinylcarbonylalkyl groups which may be substituted on the piperazine ring with 1 to 3 phenylalkyl groups which may have a linear or branched alkylenedioxy group having 1 to 4 carbon atoms and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, the piperazinylcarbonylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, such as [(1, 2, or 3-)piperazinyl]carbonylmethyl, 2-[(1, 2, or 3-)piperazinyl]carbonylethyl, 1-[(1, 2, or 3-)piperazinyl]carbonylethyl, 3-[(1, 2, or 3-)piperazinyl]carbonylpropyl, 4-[(1, 2, or 3-)piperazinyl]carbonylbutyl, 5-[(1, 2, or 3-)piperazinyl]carbonylpentyl, 6-[(1, 2, or 3-)piperazinyl]carbonylhexyl, 1,1-dimethyl-2-[(1, 2, or 3-)piperazinyl]carbonylethyl, 2-methyl-3-[(1, 2, or 3-)piperazinyl]carbonylpropyl, (4-benzyl-1-piperazinylcarbonyl)methyl, 2-[4-(2-phenylethyl)-1-piperazinylcarbonyl]ethyl, 1-[4-(3-phenylpropyl)-1-piperazinylcarbonyl]ethyl, 3-[4-(4-phenylbutyl)-1-piperazinylcarbonyl]propyl, 4-[4-(5-phenylpentyl)-1-piperazinylcarbonyl]butyl, 5-[4-(6-phenylpropyl)-1-piperazinylcarbonyl]pentyl, 6-(4-benzyl-1-piperazinylcarbonyl)hexyl, 1,1-dimethyl-2-(4-benzyl-1-piperazinylcarbonyl)ethyl, 2-methyl-3-(4-benzyl-1-piperazinylcarbonyl)propyl, [4-(3,4-methylenedioxybenzyl)-1-piperazinylcarbonyl]methyl, 2-{4-[2-(2,3-ethylenedioxyphenyl)ethyl]-1-piperazinylcarbonyl}ethyl, 1-{4-[3-(3,4-trimethylenedioxyphenyl)propyl]-1-piperazinylcarbonyl}ethyl, 3-{4-[4-(2,3-tetramethylenedioxyphenyl)butyl]-1-piperazinylcarbonyl}propyl, 4-{4-[5-(3,4-methylenedioxyphenyl)pentyl]-1-piperazinylcarbonyl}butyl, 5-{4-[3-(2,3-ethylenedioxyphenyl)propyl]-1-piperazinylcarbonyl}pentyl, 6-[4-(3,4-trimethylenedioxybenzyl)-1-piperazinylcarbonyl]hexyl, 1,1-dimethyl-2-[4-(2,3-tetramethylenedioxybenzyl)-1-piperazinylcarbonyl]ethyl, 2-methyl-3-[4-(3,4-methylenedioxybenzyl)-1-piperazinylcarbonyl]propyl, (3,4-dibenzyl-1-piperazinylcarbonyl)methyl, (3,4,5-tribenzyl-1-piperazinylcarbonyl)methyl, [2,4-di(3,4-methylenedioxybenzyl)-1-piperazinylcarbonyl])methyl, [2,4,6-tri(3,4-methylenedioxybenzyl)-1-piperazinylcarbonyl]methyl, [3-benzyl-4-(3,4-methylenedioxybenzyl)-1-piperazinylcarbonyl]methyl groups.

Examples of the piperazinyl lower alkanoyl group which may be substituted on the piperazine ring with a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring include piperazinylalkanoyl groups which may be substituted on the piperazine ring with 1 to 3 phenylalkyl groups which may have a linear or branched alkylenedioxy group having 1 to 4 carbon atoms as a substituent on the phenyl ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, the piperazinylalkanoyl groups of which the alkanoyl moiety is a linear or branched alkanoyl group having 2 to 6 carbon atoms, such as 2-[(1, 2, or 3-)piperazinyl]acetyl, 3-[(1, 2, or 3-)piperazinyl]propionyl, 2-[(1, 2, or 3-)piperazinyl]propionyl, 4-[(1, 2, or 3-)piperazinyl]butyryl, 5-[(1, 2, or 3-)piperazinyl]pentanoyl, 6-[(1, 2, or 3-)piperazinyl]hexanoyl, 2,2-dimethyl-3-[(1, 2, or 3-)piperazinyl]propionyl, 2-methyl-3-[(1, 2, or 3-)piperazinyl]propionyl, 2-(4-benzyl-1-piperazinyl]acetyl, 3-[4-(2-phenylethyl)-1-piperazinyl]propionyl, 2-[4-(3-phenylpropyl)-1-piperazinyl]propionyl, 4-[4-(4-phenylbutyl)-1-piperazinyl]butyryl, 5-[4-(5-phenylpentyl)-1-piperazinyl]pentanoyl, 6-[4-(6-phenylpropyl)-1-piperazinyl]hexanoyl, 6-(4-benzyl-1-piperazinyl)hexanoyl, 2,2-dimethyl-3-(4-benzyl-1-piperazinyl)propionyl, 2-methyl-3-(4-benzyl-1-piperazinyl)propionyl, 2-[(4-(3,4-methylenedioxybenzyl)-1-piperazinyl])acetyl, 3-{4-[2-(2,3-ethylenedioxyphenyl)ethyl]-1-piperazinyl}propionyl, 2-{4-[(3-(3,4-trimethylenedioxyphenyl)propyl]-1-piperazinyl}propionyl, 4-{4-[4-(2,3-tetramethylenedioxyphenyl)butyl]-1-piperazinyl}butyryl, 5-{4-[5-(3,4-methylenedioxyphenyl)pentyl]-1-piperazinyl}pentanoyl, 5-{4-[3-(2,3-ethylenedioxyphenyl)propyl]-1-piperazinyl}pentanoyl, 6-(4-(3,4-trimethylenedioxybenzyl)-1-piperazinyl])hexanoyl, 2,2-dimethyl-3-[(4-(2,3-tetramethylenedioxybenzyl)-1-piperazinyl]propionyl, 2-methyl-3-[4-(3,4-methylenedioxybenzyl)-1-piperazinyl]propionyl, 2-(3,4-dibenzyl-1-piperazinyl)acetyl, 2-(3,4,5-tribenzyl-1-piperazinyl)acetyl, 2-[2,4-di(3,4-methylenedioxybenzyl)-1-piperazinyl])acetyl, 2-[2,4,6-tri(3,4-methylenedioxybenzyl)-1-piperazinyl])acetyl, 2-[3-benzyl-4-(3,4-methylenedioxybenzyl)-1-piperazinyl])acetyl groups.

Examples of the morpholinocarbonyl substituted lower alkyl group include morpholinocarbonylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [(2, 3, or 4-)morpholino]carbonylmethyl, 2-[(2, 3, or 4-)morpholino]carbonylethyl, 1-[(2, 3, or 4-)morpholino]carbonylethyl, 3-[(2, 3, or 4-)morpholino]carbonylpropyl, 4-[(2, 3, or 4-)morpholino]carbonylbutyl, 5-[(2, 3, or 4-)morpholino]carbonylpentyl, 6-[(2, 3, or 4-)morpholino]carbonylhexyl, 1,1-dimethyl-2-[(2, 3, or 4-)morpholino]carbonylethyl, 2-methyl-3-[(2, 3, or 4-)morpholino]carbonylpropyl groups.

Examples of the imidazolyl lower alkanoyl group include imidazolylalkanoyl groups of which the alkanoyl moiety is a linear or branched alkanoyl group having 2 to 6 carbon atoms such as a 2-[(1, 2, 4 or 5-)imidazolyl]acetyl group, 3-[(1, 2, 4 or 5-)imidazolyl]propionyl group, 2-[(1, 2, 4 or 5-)imidazolyl]propionyl group, 4-[(1, 2, 4 or 5-)imidazolyl]butyryl group, 5-[(1, 2, 4 or 5-)imidazolyl]pentanoyl group, 6-[(1, 2, 4 or 5-)imidazolyl]hexanoyl group, 2,2-dimethyl-3-[(1, 2, 4 or 5-)imidazolyl]propionyl group, and 2-methyl-3-[(1,2,4 or 5-)imidazolyl]propionyl group.

Examples of the cycloalkylcarbonyl group include cycloalkylcarbonyl groups of which the cycloalkyl moiety is a cycloalkyl group having 3 to 16 carbon atoms such as a cyclopropylcarbonyl group, cyclobutylcarbonyl group, cyclopentylcarbonyl group, cyclohexylcarbonyl group, cycloheptylcarbonyl group, cyclooctylcarbonyl group, cyclononylcarbonyl group, cyclodecylcarbonyl group, cycloundecylcarbonyl group, cyclododecylcarbonyl group, cyclotridecylcarbonyl group, cyclotetradecylcarbonyl group, cyclopentadecylcarbonyl group, and cyclohexadecylcarbonyl group.

Examples of the amino substituted lower alkanoyl group which may have a lower alkyl group as a substituent include linear or branched alkanoyl groups having 2 to 6 carbon atoms substituted with an amino group which may have 1 or 2 linear or branched alkyl groups having 1 to 6 carbon atoms as substituents such as aminoacetyl, 2-aminopropionyl, 3-aminopropionyl, 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 2,2-dimethyl-3-aminopropionyl, 2-methyl-3-aminopropionyl, methylaminoacetyl, 2-ethylaminopropionyl, 3-propylaminopropionyl, 3-isopropylaminopropionyl, 4-butylaminobutyryl, 5-pentylaminopentanoyl, 6-hexylaminohexanoyl, dimethylaminoacetyl, 3-diisopropylaminopropionyl, (N-ethyl-N-propylamino)acetyl, 2-(N-methyl-N-hexylamino)acetyl groups.

Examples of the lower alkylene group which may have a hydroxyl group as a substituent include, in addition to the above described lower alkylene groups, linear or branched alkylene groups having 1 to 6 carbon atoms which may have 1 to 3 hydroxyl groups as substituents such as 1-hydroxymethylene, 2-hydroxyethylene, 1-hydroxyethylene, 2-hydroxytrimethylene, 3-hydroxytrimethylene, 1-hydroxytrimethylene, 3-hydroxy-2-methyltrimethylene, 1-hydroxy-2-methyltrimethylene, 3-hydroxy-2,2-dimethyltrimethylene, 1-hydroxy-2,2-dimethyltrimethylene, 3-hydroxy-1-methyltrimethylene, 2-hydroxy-1-methyltrimethylene, 1-hydroxymethylmethylene, hydroxymethylmethylene, 2-hydroxymethyltrimethylene, 2-hydroxymethyl-2-methyltrimethylene, (2-hydroxyethyl)methylene, (1-hydroxyethyl)methylene, 4-hydroxytetramethylene, 2-hydroxytetramethylene, 3-hydroxytetramethylene, 1-hydroxytetramethylene, 5-hydroxypentamethylene, 4-hydroxypentamethylene, 3-hydroxypentamethylene, 2-hydroxypentamethylene, 1-hydroxypentamethylene, 6-hydroxyhexamethylene, 5-hydroxyhexamethylene, 4-hydroxyhexamethylene, 3-hydroxyhexamethylene, 2-hydroxyhexamethylene, 1-hydroxyhexamethylene, 1,2-dihydroxytrimethylene, 2,2,4-trihydroxytetramethylene, 1,2,6-trihydroxyhexamethylene, 3,4,5-trihydroxypentamethylene groups.

Examples of the alkyl group which may have a hydroxyl group as a substituent include, in addition to the above described lower alkyl groups, linear or branched alkyl groups having 1 to 16 carbon atoms which have 1 to 3 hydroxyl groups as substituents such as a heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, 1-methylhexyl group, hexadecyl group, hydroxymethyl group, 2-hydroxyethyl group, 1-hydroxyethyl group, 3-hydroxypropyl group, 2,3-dihydroxypropyl group, 4-hydroxybutyl group, 1,1-dimethyl-2-hydroxyethyl group, 5,5,4-trihydroxypentyl group, 5-hydroxypentyl group, 6-hydroxyhexyl group, 1-hydroxyisopropyl group, and 2-methyl-3-hydroxypropyl group.

Examples of the hydroxyl group substituted alkyl group include linear or branched alkyl groups having 1 to 16 carbon atoms having 1 to 3 hydroxyl groups as substituents such as a hydroxymethyl group, 2-hydroxyethyl group, 1-hydroxyethyl group, 3-hydroxypropyl group, 2,3-dihydroxypropyl group, 4-hydroxybutyl group, 1,1-dimethyl-2-hydroxyethyl group, 5,5,4-trihydroxypentyl group, 5-hydroxypentyl group, 6-hydroxyhexyl group, 1-hydroxyisopropyl group, and 2-methyl-3-hydroxypropyl group.

Examples of the cycloalkyl group which may have a substituent selected from the group consisting of a hydroxyl group and a lower alkyl group include, in addition to the above described cycloalkyl groups, cycloalkyl groups having 3 to 16 carbon atoms which may have 1 to 3 substituents selected from the group consisting of a hydroxyl group and a linear or branched alkyl group having 1 to 6 carbon atoms such as 2-hydroxycyclopropyl, 3-hydroxycyclobutyl, 3-hydroxycyclopentyl, 2-hydroxycyclohexyl, 4-hydroxycyclohexyl, 3-hydroxycycloheptyl, 4-hydroxycyclooctyl, 5-hydroxycyclononyl, 3-hydroxycyclodecyl, 4-hydroxycycloundecyl, 5-hydroxycyclododecyl, 6-hydroxycyclotridecyl, 7-hydroxycyclotetradecyl, 6-hydroxycyclopentadecyl, 8-hydroxycyclohexadecyl, 2,4-dihydroxycyclohexyl, 2,4,6-trihydroxycyclohexyl, 1-methylcyclopentyl, 2-ethylcyclopropyl, 3-n-propylcyclobutyl, 2-n-butylcyclohexyl, 4-n-pentylcycloheptyl, 4-n-hexylcyclooctyl, 2,3-dimethylcyclohexyl, 2,3,4-trimethylcyclohexyl, 2-methyl-4-hydroxycyclohexyl groups.

Examples of the phenoxy lower alkyl group include phenoxyalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a phenoxymethyl group, 2-phenoxyethyl group, 1-phenoxyethyl group, 3-phenoxypropyl group, 4-phenoxybutyl group, 1,1-dimethyl-2-phenoxyethyl group, 5-phenoxypentyl group, 6-phenoxyhexyl group, 1-phenoxyisopropyl group, and 2-methyl-3-phenoxypropyl group.

Examples of the amino lower alkoxy group which may have a lower alkyl group as a substituent include linear or branched alkoxy groups having 1 to 6 carbon atoms substituted with an amino group which may have 1 or 2 linear or branched alkyl groups having 1 to 6 carbon atoms such as aminomethoxy, 2-aminoethoxy, 1-aminoethoxy, 3-aminopropoxy, 4-aminobutoxy, 5-aminopentyloxy, 6-aminohexyloxy, 1,1-dimethyl-2-aminoethoxy, 2-methyl-3-aminopropoxy, methylaminomethoxy, 1-ethylaminoethoxy, 2-propylaminoethoxy, 3-isopropylaminopropoxy, 4-butylaminobutoxy, 5-pentylaminopentyloxy, 6-hexylaminohexyloxy, dimethylaminomethoxy, 2-diethylaminoethoxy, 2-diisopropylaminoethoxy, (N-ethyl-N-propylamino)methoxy, 2-(N-methyl-N-hexylamino)ethoxy groups.

Examples of the hydroxyl group substituted lower alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms which have 1 to 3 hydroxyl groups as substituents such as a hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 3-hydroxypropyl group, 2,3-dihydroxypropyl group, 4-hydroxybutyl group, 1,1-dimethyl-2-hydroxyethyl group, 5,5,4-trihydroxypentyl group, 5-hydroxypentyl group, 6-hydroxyhexyl group, 1-hydroxyisopropyl group, and 2-methyl-3-hydroxypropyl group.

Examples of the amino group which may have a lower alkylsulfonyl as a substituent include amino groups which may have 1 or 2 linear or branched alkylsulfonyl groups having 1 to 6 carbon atoms as substituents such as amino, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino, tert-butylsulfonylamino, pentylsulfonylamino, hexylsulfonylamino, dimethylsulfonylamino, diethylsulfonylamino, dipropylsulfonylamino, dibutylsulfonylamino, dipentylsulfonylamino, dihexylsulfonylamino, N-methylsulfonyl-N-ethylsulfonylamino, N-ethylsulfonyl-N-propylsulfonylamino, N-methylsulfonyl-N-butylsulfonylamino, N-methylsulfonyl-N-hexylsulfonylamino groups.

Examples of the lower alkynyl group include linear or branched alkynyl groups having 2 to 6 carbon atoms include an ethynyl group, 2-propynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 2-pentynyl group, and 2-hexynyl group.

Examples of the aniline group which may have a halogen atom as a substituent on the phenyl ring include anilino groups which may have 1 to 3 halogen atoms as substituents on the phenyl ring such as aniline, 2-fluoroanilino, 3-fluoroanilino, 4-fluoroanilino, 2-bromoanilino, 3-bromoanilino, 4-bromoanilino, 2-iodoanilino, 3-iodoanilino, 4-iodoanilino, 2,3-dibromoanilino, 2,4-diiodoanilino, 2,5-difluoroanilino, 2,6-dichloroanilino, 2,4,6-trichloroanilino, 2,6-difluoroanilino, 3,5-difluoroanilino, 2,6-difluoroanilino, 2-chloroanilino, 3-chloroanilino, 4-chloroanilino, 2,3-dichloroanilino, 2,4-dichloroanilino, 2,5-dichloroanilino, 3,4-dichloroanilino, 2,6-dichloroanilino, 3,5-dichloroanilino, 2,4,6-trifluoroanilino, 2,4-difluoroanilino, 3,4-difluoroanilino groups.

Examples of the piperazinyl group which may have a lower alkyl group as a substituent on the piperazine ring include piperazinyl groups which may have 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms as substituents on the piperazine ring such as a (1-, 2- or 3-)piperazinyl group, 4-methyl-(1-, 2- or 3-)piperazinyl group, 2,3-dimethyl-(1 or 5-)piperazinyl group, and 2,3,4-trimethyl-(1-, 5- or 6-)piperazinyl group.

Examples of the pyrrolidinyl group which may have an oxo group as a substituent on the pyrrolidine ring include pyrrolidinyl groups which may have 1 or 2 oxo groups as substituents on the pyrrolidine ring such as a (1-, 2- or 3-)pyrrolidinyl group, 2-oxo-(1-, 3-, 4- or 5-)pyrrolidinyl group, 3-oxo-(1-, 2-, 4-5-)pyrrolidinyl group, 2,3-dioxo-(1-, 4- or 5-)pyrrolidinyl group, and 2,5-dioxo-(1-, 3-4-)pyrrolidinyl group.

Examples of the phenyl group which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a lower alkyl group; a lower alkoxy groups which may have a halogen atom as a substituent; a halogen atom; an amino lower alkoxy group which may have a lower alkyl group as a substituent; a hydroxyl group substituted lower alkyl group; a phenyl lower alkyl group; a lower alkynyl group; an amino group which may have a lower alkylsulfonyl group as a substituent; a lower alkylthio group; a cycloalkyl group; a phenylthio group; an adamantyl group; an anilino group which may have a halogen atom as a substituent on the phenyl ring; a lower alkoxycarbonyl group; a piperazinyl group which may have a lower alkyl group as a substituent on the piperazine ring; a pyrrolidinyl group which may have an oxo group as a substituent on the pyrrolidine ring; a lower alkanoylamino group; a cyano group; and a phenoxy group include phenyl groups which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms; a linear or branched alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms; a halogen atom; an aminoalkoxy group of which the alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms and which may have 1 or 2 linear or branched alkyl groups having 1 to 6 carbon atom as substituents; a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 hydroxyl groups as substituents; a phenylalkyl group of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms; a linear or branched alkynyl group having 2 to 6 carbon atoms; an amino group which may have 1 or 2 linear or branched alkylsulfonyl groups having 1 to 6 carbon atoms as substituents; a linear or branched alkylthio group having 1 to 6 carbon atoms; a cycloalkyl group having 3 to 16 carbon atoms; a phenylthio group; an adamantyl group; an anilino group which may have 1 to 3 halogen atoms as substituents on the phenyl ring; a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms; a piperazinyl group which may have 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms as substituents on the piperazine ring; a pyrrolidinyl group which may have 1 or 2 oxo groups as substituents on the pyrrolidine ring; an amino group which may have 1 or 2 linear or branched alkanoyl groups having 2 to 6 carbon atoms; a cyano group; and a phenoxy group such as phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-isopropylphenyl, 4-isopropylphenyl, 3-butylphenyl, 4-pentylphenyl, 4-hexylphenyl, 3,4-dimethylphenyl, 3,4-diethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4,5-trimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, 3-butoxyphenyl, 4-pentyloxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl, 3,4-diethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-(bromomethoxy)phenyl, 3-(2-chloroethoxy)phenyl, 4-(2,3-dichloropropoxy)phenyl, 4-(4-fluorobutoxy)phenyl, 3-(5-chloropentyloxy)phenyl, 4-(5-bromohexyloxy)phenyl, 4-(5,6-dibromohexyloxy)phenyl, 3,4-di(trifluoromethoxy)phenyl, 3,4-di(4,4,4-trichlorobutoxy)phenyl, 2,4-di(3-chloro-2-methoxypropyl)phenyl, 2,5-di(3-chloropropoxy)phenyl, 2,6-di(2,2,2-trifluoroethoxy)phenyl, 3,4,5-tri(trifluoromethoxy)phenyl, 4-(2,2,2-trichloroethoxy)phenyl, 2-methyl-4-trifluoromethoxyphenyl, 3-ethyl-4-trichloromethoxyphenyl, 2-methoxy-4-trifluoromethoxyphenyl, 3-ethoxy-4-trichloromethoxyphenyl, 2-methyl-3-trifluoromethoxy-4-trifluoromethoxyphenyl, 2-phenoxyphenyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 2,3-diphenoxyphenyl, 3,4-diphenoxyphenyl, 2,6-diphenoxyphenyl, 3,4,5-triphenoxyphenyl, 2-methyl-4-phenoxyphenyl, 3-ethyl-4-phenoxyphenyl, 2-methoxy-4-phenoxyphenyl, 3-ethoxy-4-phenoxyphenyl, 2-methyl-3-phenoxy-4-trifluoromethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,6-dichlorophenyl, 3,5-dichlorophenyl, 2,4,6-trichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,5-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,6-difluorophenyl, 2,4,6-trifluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2,3-dibromophenyl, 2,4-diiodophenyl, 4-methylthiophenyl, 4-cyclohexylphenyl, 4-chloro-2-anilinophenyl, 2-(4-chloroanilino)-5-ethoxycarbonylphenyl, 4-(2-(N,N-diethylamino)ethoxy]phenyl, 4-(4-methyl-1-piperazinyl)phenyl, 4-(2-oxo-1-pyrrolidinyl)phenyl, 4-methylsulfonylaminophenyl, 4-(2-hydroxyethyl)phenyl, 4-benzylphenyl, 4-ethinylphenyl, 4-phenylthiophenyl, 4-(1-adamantyl)phenyl, 5-acetylamino-2-chlorophenyl, 3-cyanophenyl, 2-cyanophenyl, 4-cyanophenyl, 2-propanoylaminophenyl, 3,4-dicyanophenyl, 3,4,5-tricyanophenyl groups.

Examples of the phenyl lower alkyl group which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkoxy group which may have a halogen atom as a substituent, and a lower alkyl group include, in addition to the above described phenyl lower alkyl groups, phenylalkyl groups which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a halogen atom, a linear or branched alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents, and a linear or branched alkyl group having 1 to 6 carbon atoms, and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, such as 4-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-(2-fluorophenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2-(4-chlorophenyl)ethyl, 3,4-dibromobenzyl, 3,4-diiodobenzyl, 2,4-difluorobenzyl, 2,5-dichlorobenzyl, 2,6-dichlorobenzyl, 3,4,5-trifluorobenzyl, 3-(4-chlorophenyl)propyl, 1-(2-bromophenyl)ethyl, 4-(3-fluorophenyl)butyl, 5-(4-iodophenyl)pentyl, 6-(4-chlorophenyl)hexyl, 1,1-dimethyl-2-(3-fluorophenyl)ethyl, 2-methyl-3-(4-chlorophenyl)propyl, 2-methylbenzyl, 2-(3-methylphenyl)ethyl, 3-(4-methylphenyl)propyl, 1-(2-ethylphenyl)ethyl, 4-(3-ethylphenyl)butyl, 5-(4-ethylphenyl)pentyl, 6-(4-isopropylphenyl)hexyl, 1,1-dimethyl-2-(3-butylphenyl)ethyl, 2-methyl-3-(4-pentylphenyl)propyl, 4-hexylbenzyl, 3,4-dimethylbenzyl, 3,4-diethylbenzyl, 2,4-dimethylbenzyl, 2,5-dimethylbenzyl, 2,6-dimethylbenzyl, 3,4,5-trimethylbenzyl, 2-methoxybenzyl, 2-(2-methoxyphenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(4-methoxyphenyl)ethyl, 4-methoxybenzyl, 1-(2-ethoxyphenyl)ethyl, 3-(3-ethoxyphenyl)propyl, 4-(4-ethoxyphenyl)butyl, 5-(4-isopropoxyphenyl)pentyl, 6-(3-butoxyphenyl)hexyl, 1,1-dimethyl-2-(4-pentyloxyphenyl)ethyl, 2-methyl-3-(4-hexyloxyphenyl)propyl, 3,4-dimethoxybenzyl, 3,4-diethoxybenzyl, 2,4-dimethoxybenzyl, 2,5-dimethoxybenzyl, 2,6-dimethoxybenzyl, 3,4,5-trimethoxybenzyl, 2-trifluoromethoxybenzyl, 3-trifluoromethoxybenzyl, 4-trifluoromethoxybenzyl, 2-[2-(bromomethoxy)phenyl]ethyl, 1-[3-(2-chloroethoxy)phenyl]ethyl, 3-[4-(2,3-dichloropropoxy)phenyl]propyl, 4-[4-(4-fluorobutoxy)phenyl]butyl, 5-[3-(5-chloropentyloxy)phenyl]pentyl, 6-[(4-(5-bromohexyloxy)phenyl]hexyl, 1,1-dimethyl-2-[4-(5,6-dibromohexyloxy)phenyl]ethyl, 3,4-di(trifluoromethoxy)benzyl, 3,4-di(4,4,4-trichlorobutoxy)benzyl, 2,4-di(3-chloro-2-methoxypropyl)benzyl, 2,5-di(3-chloropropoxy)benzyl, 2,6-di(2,2,2-trifluoroethoxy)benzyl, 3,4,5-tri(trifluoromethoxy)benzyl, 4-(2,2,2-trichloroethoxy)benzyl, 2-methyl-4-trifluoromethoxybenzyl, 3-ethyl-4-trichloromethoxybenzyl, 2-methoxy-4-trifluoromethoxybenzyl, 3-ethoxy-4-trichloromethoxybenzyl, 2-methyl-3-trifluoromethoxy-4-trifluoromethoxybenzyl, 2-chloro-3-methylbenzyl, 4-fluoro-2-trifluoromethoxybenzyl, 3-chloro-2-methyl-4-methoxybenzyl groups.

Examples of the phenyl lower alkyl group which has a lower alkylenedioxy group as a substituent on the phenyl ring include phenylalkyl groups which has a linear or branched alkylenedioxy group having 1 to 4 carbon atoms on the phenyl ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a 3,4-methylenedioxybenzyl group, 3,4-trimethylenedioxybenzyl group, 2-(2,3-ethylenedioxyphenyl)ethyl group, 1-(3,4-trimethylenedioxyphenyl)ethyl group, 3-(2,3-tetramethylenedioxyphenyl)propyl group, 4-(3,4-methylenedioxyphenyl)butyl group, 5-(2,3-ethylenedioxyphenyl)pentyl group, 6-(3,4-trimethylenedioxyphenyl)hexyl group, 1,1-dimethyl-2-(2,3-methylenedioxyphenyl)ethyl group, and 2-methyl-3-(3,4-ethylenedioxyphenyl)propyl group.

Examples of the amino group which may have a lower alkanoyl group as a substituent include which may have a linear or branched alkanoyl group having 1 to 6 carbon atoms as a substituent such as an amino group, N-acetylamino group, N-formylamino group, N-propionylamino group, N-butyrylamino group, N-isobutyrylamino group, N-pentanoylamino group, N-tert-butylcarbonylamino group, and N-hexanoylamino group.

Examples of the 1,2,3,4-tetrahydroquinolyl group which may have, on the tetrahydroquinoline ring, 1 to 3 substituents selected from the group consisting of an oxo group, a lower alkoxy group, and a lower alkylenedioxy group include 1,2,3,4-tetrahydroquinolyl groups which may have, on the tetrahydroquinoline ring, 1 to 3 substituents selected from the group consisting of an oxo group, a linear or branched alkoxy group having 1 to 6 carbon atoms, and a linear or branched alkylenedioxy group having 1 to 4 carbon atoms such as (1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl, 2-oxo-(1, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl, 2-oxo-6,7-methylenedioxy-(1, 3, 4, 5, or 8-)1,2,3,4-tetrahydroquinolyl, 4-oxo-(1, 2, 3, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl, 2,4-dioxo-(1, 3, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl, 2,4-dioxo-6,7-methylenedioxy-(1, 3, 5, or 8-)1,2,3,4-tetrahydroquinolyl, 5,6-ethylenedioxy-(1, 2, 3, 4, 7, or 8-)1,2,3,4-tetrahydroquinolyl, 7,8-trimethylenedioxy-(1, 2, 3, 4, 5, or 6-)1,2,3,4-tetrahydroquinolyl, 6,7-tetramethylenedioxy-(1, 2, 3, 4, 5, or 8-)1,2,3,4-tetrahydroquinolyl, 5-methoxy-2-oxo-(1, 3, 4, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl, 2-oxo-6,7-ethylenedioxy-(1, 3, 4, 5, or 8-)1,2,3,4-tetrahydroquinolyl groups.

Examples of the cycloalkyl lower alkyl group include cycloalkylalkyl groups having 3 to 16 carbon atoms of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a cyclopropylmethyl group, cyclohexylmethyl group, 2-cyclopropylethyl group, 1-cyclobutylethyl group, 3-cyclopentylpropyl group, 4-cyclohexylbutyl group, 5-cycloheptylpentyl group, 6-cyclooctylhexyl group, 1,1-dimethyl-2-cyclononylethyl group, 2-methyl-3-cyclodecylpropyl group, cycloundecylmethyl group, 2-cyclododecylethyl group, 1-cyclotridecylethyl group, 3-cyclotetradecylpropyl group, 4-cyclopentadecylbutyl group, and 5-cyclodecylpentyl group.

Examples of the pyridyl lower alkyl group include pyridylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a (2, 3 or 4-)pyridylmethyl group, 2-[(2, 3 or 4-)pyridyl]ethyl group, 1-[(2, 3 or 4-)pyridyl]ethyl group, 3-[(2, 3 or 4-)pyridyl]propyl group, 4-[(2, 3 or 4-)pyridyl]butyl group, 1,1-dimethyl-2-[(2, 3 or 4-)pyridyl]ethyl group, 5-[(2, 3 or 4-)pyridyl]pentyl group, 6-[(2, 3 or 4-)pyridyl]hexyl group, 1-[(2, 3 or 4-)pyridyl]isopropyl group, and 2-methyl-3-[(2, 3 or 4-)pyridyl]propyl group.

Examples of the amino group substituted lower alkyl group which may have a substituent selected from the group consisting of a lower alkyl group and a lower alkanoyl group include linear or branched alkyl groups having 1 to 6 carbon atoms which has an amino group which may have 1 or 2 substituents selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms and a linear or branched alkanoyl group having 1 to 6 carbon atoms such as aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1,1-dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl, methylaminomethyl, 1-ethylaminoethyl, 2-propylaminoethyl, 3-isopropylaminopropyl, 4-butylaminobutyl, 5-pentylaminopentyl, 6-hexylaminohexyl, dimethylaminomethyl, 2-diisopropylaminoethyl, (N-ethyl-N-propylamino)methyl, 2-(N,N-dimethylamino)ethyl, 2-(N-methyl-N-hexylamino)ethyl, formylaminomethyl, acetylaminomethyl, 1-propionylaminoethyl, 2-acetylaminoethyl, 3-butyrylaminopropyl, 4-pentanoylaminobutyl, 5-hexanoylaminopentyl, 6-acetylaminohexyl, N-methyl-N-acetylaminomethyl, 2-(N-ethyl-N-propanoylamino)ethyl, (N-ethyl-N-butyrylamino)methyl, 2-(N-methyl-N-hexanoylamino)ethyl, 3-(N,N-dimethylamino)propyl groups.

Examples of the lower alkoxy lower alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms which have a linear or branched alkoxy group having 1 to 6 carbon atoms as a substituent such as a methoxymethyl group, 1-ethoxyethyl group, 2-methoxyethyl group, 2-propoxyethyl group, 3-isopropoxypropyl group, 4-butoxybutyl group, 5-pentyloxypentyl group, 6-hexyloxyhexyl group, 1,1-dimethyl-2-methoxyethyl group, 2-methyl-3-ethoxypropyl group, and 3-methoxypropyl group.

Examples of the 1,2,3,4-tetrahydroisoquinolylcarbonyl substituted lower alkyl group include 1,2,3,4-tetrahydroisoquinolylcarbonyl-alkyl groups of which the alkyl moiety is a linear or branched alkyl group such as (1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroisoquinolylcarbonylmethyl, 2-[(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroisoquinolylcarbonyl]ethyl, 1-[((1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroisoquinolylcarbonyl]ethyl, 3-[(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroisoquinolylcarbonyl]propyl, 4-[(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroisoquinolylcarbonyl]butyl, 1,1-dimethyl-2-[(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroisoquinolylcarbonyl]ethyl, 5-[(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroisoquinolylcarbonyl]pentyl, 6-[(1, 2, 3, 4, 5, 6, 7, or 8-) 1,2,3,4-tetrahydroisoquinolylcarbonyl]hexyl, 1-[(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroisoquinolylcarbonyl]isopropyl, 2-methyl-3-[(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroisoquinolylcarbonyl]propyl groups.

Examples of the piperidinylcarbonyl group which may have, on the piperidine ring, a substituent selected from the group consisting of a lower alkoxycarbonyl group, a phenyl lower alkyl group, and a furyl lower alkyl group include piperidinylcarbonyl groups which may have, on the piperidine ring, 1 to 3 substituents selected from the group consisting of an alkoxycarbonyl group of which the alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms, a phenylalkyl group of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, and a furylalkyl group of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (1, 2, 3, or 4-)piperidinylcarbonyl, 1-benzyl-(2, 3, or 4-)piperidinylcarbonyl, 1-(2 or 3-)furylmethyl-(2, 3, or 4-)piperidinylcarbonyl, 1-(2-phenylethyl)-(2, 3, or 4-)piperidinylcarbonyl, 1-{2-[(1 or 2-)furyl]ethyl}-(2, 3, or 4-)piperidinylcarbonyl, 1-(1-phenylethyl)-(2, 3, or 4-)piperidinylcarbonyl, 1-{3-[(1 or 2-)furyl]propyl]}-(2, 3, or 4-)piperidinylcarbonyl, 1-(3-phenylpropyl)-(2, 3, or 4-)piperidinylcarbonyl, 1-{1-[(1 or 2-)furyl]ethyl]}-(2, 3, or 4-)piperidinylcarbonyl, 1-(4-phenylbutyl)-(2, 3, or 4-)piperidinylcarbonyl, 1-{4-[(1 or 2-)furyl]-butyl]}-(2, 3, or 4-)piperidinylcarbonyl, 1-(5-phenylpentyl)-(2, 3, or 4-)piperidinylcarbonyl, 1-{5-[(1 or 2-)furyl]pentyl]}-(2, 3, or 4-)piperidinylcarbonyl, 1-(6-phenylhexyl)-(2, 3, or 4-)piperidinylcarbonyl, 1-{(6-[(1 or 2-)furyl]hexyl]}-(2, 3, or 4-)piperidinylcarbonyl, 1,2-dibenzyl-(3, 4, 5, or 6-)piperidinylcarbonyl, 1,3-di(1 or 2-)furylmethyl-(2, 4, 5, or 6-)piperidinylcarbonyl, 1,3,5-tribenzyl-(2,4, or 6-)piperidinylcarbonyl, 1,2,6-tri(1 or 2-)furylmethyl-(3, 4, or 5-)piperidinylcarbonyl, 1-benzyl-3-(1 or 2-)furylmethyl-(2, 4, 5, or 6-)piperidinylcarbonyl, 1-{1-[(1 or 2-)furyl]ethyl]}-(2, 3, or 4-)piperidinylcarbonyl, 1-methoxycarbonyl-(2, 3, or 4-)piperidinylcarbonyl, 1-ethoxycarbonyl-(2,3, or 4-)piperidinylcarbonyl, 1-propoxycarbonyl-(2, 3, or 4-)piperidinylcarbonyl, 1-butoxycarbonyl-(2, 3, or 4-) piperidinylcarbonyl, 1-tert-butoxycarbonyl-(2, 3, or 4-)piperidinylcarbonyl, 1-pentyloxycarbonyl-(2, 3, or 4-)piperidinylcarbonyl, 1-hexyloxycarbonyl-(2, 3, or 4-)piperidinylcarbonyl, 1,2-dimethoxycarbonyl-(3, 4, 5, or 6-)piperidinylcarbonyl, 1,2,6-triethoxycarbonyl-(3, 4, or 5-)piperidinylcarbonyl, 1-(1 or 2-)furylmethyl-3-tert-butoxycarbonyl-(3, 4, 5, or 6-)piperidinylcarbonyl, 1-benzyl-2-methoxycarbonyl-(2, 4, 5, or 6-)piperidinylcarbonyl, 1-(1 or 2-)furylmethyl-2,4-dimethoxycarbonyl-(3, 5, or 6-)piperidinylcarbonyl groups.

Examples of the thiazolidinyl lower alkanoyl group which may have an oxo group as a substituent on the thiazolidine ring include thiazolidinylalkanoyl groups which may have 1 to 3 oxo groups as substituents on the thiazolidine ring and of which the alkanoyl moiety is a linear or branched alkanoyl group having 1 to 6 carbon atoms such as 2-[(2, 3, 4, or 5-)thiazolidinyl]acetyl, 3-[(2, 3, 4, or 5-)thiazolidinyl]propionyl, 2-[(2, 3, 4, or 5-)thiazolidinyl]propionyl, 4-[(2, 3, 4, or 5-)thiazolidinyl]butyryl, 5-[(2, 3, 4, or 5-)1,2,4-thiazolidinyl]pentanoyl, 6-[(2, 3, 4, or 5-)thiazolidinyl]hexanoyl, 2,2-dimethyl-3-[(2, 3, 4, or 5-)thiazolidinyl]propionyl, 2-methyl-3-[(2, 3, 4, or 5-)thiazolidinyl]propionyl, 2,4-dioxo-(3 or 5-)thiazolidinylacetyl, 3-[2-oxo-(3, 4, or 5-)thiazolidinyl]propionyl, 2-[4-oxo-(2, 3, or 5-)thiazolidinyl]propionyl, 4-[5-oxo-(2, 3, or 4-)thiazolidinyl]butyryl, 5-[2,5-dioxo-(3 or 4-)thiazolidinyl]pentanoyl, 6-[2,4,5-trioxo-3-thiazolidinyl]hexanoyl, 2-[4,5-dioxo-(2 or 3-)thiazolidinyl]acetyl, 2,2-dimethyl-3-[2,4-dioxo-(3 or 5-)thiazolidinyl]propionyl, 2-methyl-3-[2,4-dioxo-(3 or 5-)thiazolidinyl]propionyl groups.

Examples of the piperidinyl group which may be substituted on the piperidine ring with a group selected from the group consisting of a lower alkoxycarbonyl group, a phenyl lower alkyl group, a lower alkyl group, a benzoyl group and a furyl lower alkyl group include piperidinyl groups which may be substituted on the piperidine ring with 1 to 3 groups selected from the group consisting of an alkoxycarbonyl group of which the alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms, a phenylalkyl group of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkyl group having 1 to 6 carbon atoms, a benzoyl group, and a furylalkyl group of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (1, 2, 3, or 4-)piperidinyl, 1-benzyl-(2, 3, or 4-)piperidinyl, 1-(2 or 3-)furylmethyl-(2, 3, or 4-)piperidinyl, 1-(2-phenylethyl)-(2, 3, or 4-)piperidinyl, 1-{2-[(1 or 2-)furyl]ethyl}-(2, 3, or 4-)piperidinyl, 1-(1-phenylethyl)-(2, 3, or 4-)piperidinyl, 1-{3-[(1 or 2-)furyl]propyl]}-(2, 3, or 4-)piperidinyl, 1-(3-phenylpropyl)-(2, 3, or 4-)piperidinyl, 1-{1-[(1 or 2-)furyl]ethyl]}-(2, 3, or 4-)piperidinyl, 1-(4-phenylbutyl)-(2, 3, or 4-)piperidinyl, 1-{4-[(1 or 2-)furyl]butyl]}-(2, 3, or 4-)piperidinyl, 1-(5-phenylpentyl)-(2, 3, or 4-)piperidinyl, 1-{5-[(1 or 2-)furyl]pentyl]}-(2, 3, or 4-)piperidinyl, 1-(6-phenylhexyl)-(2, 3, or 4-)piperidinyl, 1-{6-[(1 or 2-)furyl]hexyl]}-(2, 3, or 4-)piperidinyl, 1,2-dibenzyl-(3, 4, 5, or 6-)piperidinyl, 1,3-di(1 or 2-)furylmethyl-(2, 4, 5, or 6-)piperidinyl, 1,3,5-tribenzyl-(2, 4, or 6-)piperidinyl, 1,2,6-tri(1 or 2-)furylmethyl-(3, 4, or 5-)piperidinyl, 1-benzyl-3-(1 or 2-)furylmethyl-(2, 4, 5, or 6-)piperidinyl, 1-{1-[(1 or 2-)furyl]ethyl]}-(2, 3, or 4-)piperidinyl, 1-benzoyl-(2, 3, or 4-)piperidinyl, 1,2-dibenzoyl-(3, 4, 5, or 6-)piperidinyl, 1,3,5-tribenzoyl-(2, 4, or 6-)piperidinyl, 1-methyl-(2, 3, or 4-)piperidinyl, ethyl-(2, 3, or 4-)piperidinyl, 1-propyl-(2, 3, or 4-)piperidinyl, 1-isopropyl-(2, 3, or 4-)piperidinyl, 1-butyl-(2, 3, or 4-)piperidinyl, 1-isobutyl-(2, 3, or 4-)piperidinyl, 1-tert-butyl-(2, 3, or 4-)piperidinyl, 1-pentyl-(2, 3, or 4-)piperidinyl, 1-hexyl-(2, 3, or 4-)piperidinyl, 1,2-dimethyl-(3, 4, 5, or 6-)piperidinyl, 1,2,6-trimethyl-(3, 4, or 5-)piperidinyl, 1-methyl-3-benzyl-(3, 4, 5, or 6-)piperidinyl, 1-benzoyl-2-methyl-(2, 4, 5, or 6-)piperidinyl, 1-(1 or 2-)furylmethyl-2,4-dimethyl-(3, 5, or 6-)piperidinyl, 1-methoxycarbonyl-(2, 3, or 4-)piperidinyl, 1-ethoxycarbonyl-(2, 3, or 4-)piperidinyl, 1-propoxycarbonyl-(2, 3, or 4-)piperidinyl, 1-butoxycarbonyl-(2, 3, or 4-)piperidinyl, 1-tert-butoxycarbonyl-(2, 3, or 4-)piperidinyl, 1-pentyloxycarbonyl-(2, 3, or 4-)piperidinyl, 1-hexyloxycarbonyl-(2, 3, or 4-)piperidinyl, 1,2-dimethoxycarbonyl-(3, 4, 5, or 6-)piperidinyl, 1,2,6-triethoxycarbonyl-(3, 4, or 5-)piperidinyl, 1-methyl-3-tert-butoxycarbonyl-(3, 4, 5, or 6-)piperidinyl, 1-benzoyl-2-methoxycarbonyl-(2, 4, 5, or 6-)piperidinyl, 1-(1 or 2-)furylmethyl-2,4-dimethoxycarbonyl-(3, 5, or 6-)piperidinyl, 1-benzyl-2,4-dimethoxycarbonyl-(3, 5, or 6-)piperidinyl groups.

Examples of the carbonyl lower alkyl group substituted with a group:

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(hereinafter called “A group”) include A group substituted carbonylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as an A group substituted carbonylmethyl group, 2-A group substituted carbonylethyl group, 1-A group substituted carbonylethyl group, 3-A group substituted carbonylpropyl group, 4-A group substituted carbonylbutyl group, 1,1-dimethyl-2-A group substituted carbonylethyl group, 5-A group substituted carbonylpentyl group, 6-A group substituted carbonylhexyl group, 1-A group substituted carbonylisopropyl group, and 2-methyl-3-A group substituted carbonylpropyl group.

Examples of the carbonyl lower alkyl group substituted with a group:

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wherein R³⁴is an oxo group or phenyl group, and d is an integer of 0 to 3 (hereinafter called “B group”), B group substituted carbonylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a B group substituted carbonylmethyl group, 2-B group substituted carbonylethyl group, 1-B group substituted carbonylethyl group, 3-B group substituted carbonylpropyl group, 4-B group substituted carbonylbutyl group, 1,1-dimethyl-2-B group substituted carbonylethyl group, 5-B group substituted carbonylpentyl group, 6-B group substituted carbonylhexyl group, 1-B group substituted carbonylisopropyl group, and 2-methyl-3-B group substituted carbonypropyl group.

Examples of the pyrrolidinyl lower alkyl group include pyrrolidinylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a (1-, 2-, or 3-)pyrrolydinylmethyl group, 2-[(1-, 2-, or 3-)pyrrolydinyl]ethyl group, 1-[(1-, 2-, or 3-)pyrrolydinyl]ethyl group, 3-[(1-, 2-, or 3-)pyrrolydinyl]propyl group, 4-[(1-, 2-, or 3-)pyrrolydinyl]butyl group, 5-[(1-, 2-, or 3-)pyrrolydinyl]pentyl group, 6-[(1-, 2-, or 3-)pyrrolydinyl]hexyl group, 1,1-dimethyl-2-[(1-, 2-, or 3-)pyrrolydinyl]ethyl group, and 2-methyl-3-[(1-, 2-, or 3-)pyrrolydinyl]propyl group.

Examples of the morpholino lower alkyl group include morpholinoalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a (2-, 3- or 4-)morpholinomethyl group, 2-[(2-, 3- or 4-)morpholino]ethyl group, 1-[(2-, 3- or 4-)morpholino]ethyl group, 3-[(2-, 3- or 4-)morpholino]propyl group, 4-[(2-, 3- or 4-)morpholino]butyl group, 5-[(2-, 3- or 4-)morpholino]pentyl group, 6-[(2-, 3- or 4-)morpholino]hexyl group, 1,1-dimethyl-2-[(2-, 3- or 4-)morpholino]ethyl group, and 2-methyl-3-[(2-, 3- or 4-)morpholino]propyl group.

Examples of the phenyl lower alkenyl group include phenylalkenyl groups of which the alkenyl moiety is a linear or branched alkenyl group having 2 to 6 carbon atoms and which have 1 to 3 double bonds such as a styryl group, 3-phenyl-2-propenyl group (trivial name; cinnamyl group), 4-phenyl-2-butenyl group, 4-phenyl-3-butenyl group, 5-phenyl-4-pentenyl group, 5-phenyl-3-pentenyl group, 6-phenyl-5-hexenyl group, 6-phenyl-4-hexenyl group, 6-phenyl-3-hexenyl group, 4-phenyl-1,3-butadienyl group, and 6-phenyl-1,3,5-hexatrienyl group.

Examples of the anilinocarbonyl lower alkyl group which may have a lower alkyl group as a substituent on the phenyl ring include anilinocarbonylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms and which may have 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms as substituents on the phenyl ring such as anilinocarbonylmethyl, 2-anilinocarbonylethyl, 1-anilinocarbonylethyl, 3-anilinocarbonylpropyl, 4-anilinocarbonylbutyl, 5-anilinocarbonylpentyl, 6-anilinocarbonylhexyl, 1,1-dimethyl-2-anilinocarbonylethyl, 2-methyl-3-anilinocarbonylpropyl, (4-methylanilinocarbonyl)methyl, 2-(3-methylanilinocarbonyl)ethyl, 3-(4-methylanilinocarbonyl)propyl, 1-(2-ethylanilinocarbonyl)ethyl, 4-(3-ethylanilinocarbonyl)butyl, 5-(4-ethylanilinocarbonyl)pentyl, 6-(4-isopropylanilinocarbonyl)hexyl, 1,1-dimethyl-2-(3-butylanilinocarbonyl)ethyl, 2-methyl-3-(4-pentylanilinocarbonyl)propyl, 4-hexylanilinocarbonylmethyl, 3,4-dimethylanilinocarbonylmethyl, 3,4-diethylanilinocarbonylmethyl, 2,4-dimethylanilinocarbonylmethyl, 2,5-dimethylanilinocarbonylmethyl, 2,6-dimethylanilinocarbonylmethyl, 3,4,5-trimethylanilinocarbonylmethyl groups.

Examples of the piperazinyl lower alkyl group which may have, on the piperazine ring, a substituent selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring include piperazinylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms and which may have, on the piperazine ring, 1 to 3 substituents selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms and a phenylalkyl group which may have a linear or branched alkylenedioxy group having 1 to 4 carbon atoms as a substituent on the phenyl ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [(1-, 2-, or 3-)piperazinyl]methyl, 2-[(1-, 2-, or 3-)piperazinyl]ethyl, 1-[(1-, 2-, or 3-)piperazinyl]ethyl, 3-[(1-, 2-, or 3-)piperazinyl]propyl, 4-[(1-, 2-, or 3-)piperazinyl]butyl, 5-[(1-, 2-, or 3-)piperazinyl]pentyl, 6-[(1-, 2-, or 3-)piperazinyl]hexyl, 1,1-dimethyl-2-[(1-, 2-, or 3-)piperazinyl]ethyl, 2-methyl-3-[(1-, 2-, or 3-)piperazinyl]propyl, [1-methyl-(2-, 3-, or 4-)piperazinyl]methyl, 2-[1-ethyl-(2-, 3-, or 4-)piperazinyl]ethyl, 1-[4-propyl-(1-, 2-, or 3-)piperazinyl]ethyl, 3-[3-isopropyl-(1-, 2-, 4-, 5-, or 6-)piperazinyl]propyl, 4-[2-butyl-(1-, 3,4-, 5-, or 6-)piperazinyl]butyl, 5-[1-isobutyl-(2-, 3-, or 4-)piperazinyl]pentyl, 3-[4-methyl-(1-, 2-, or 3-)piperazinyl]propyl, 6-(1-tert-butyl-(2-, 3-, or 4-)piperazinyl]hexyl, 1,1-dimethyl-2-[(4-pentyl-(1-, 2-, or 3-)piperazinyl]ethyl, [1,2-dimethyl-(3-, 4-, 5-, or 6-)piperazinyl]methyl, [1,2,6-trimethyl-(3-, 4-, or 5-)piperazinyl]methyl, 2-[(4-(3,4-methylenedioxybenzyl)-(1-, 2-, or 3-)piperazinyl]ethyl groups.

Examples of the amidino lower alkyl group which may have a lower alkyl group as a substituent include amidinoalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms and which may have 1 or 2 linear or branched alkyl groups having 1 to 6 carbon atoms such as an amidinomethyl group, 2-amidinoethyl group, 1-amidinoethyl group, 3-amidinopropyl group, 4-amidinobutyl group, 5-amidinopentyl group, 6-amidinohexyl group, 1,1-dimethyl-2-amidinoethyl group, 2-methyl-3-amidinopropyl group, N,N-dimethylamidinomethyl group, 2-(N,N-dimethylamidino)ethyl group, 1-(N-methylamidino)ethyl group, 3-(N-ethylamidino)propyl group, 4-(N-n-propylamidino)propyl group, 5-(N-n-pentylamidino)pentyl group, 6-(N-n-hexylamidino)hexyl group, and (N-methyl-N-ethylamidino)methyl group.

Examples of the carbazolyl group which may have a lower alkyl group as a substituent on the carbazole ring include carbazolyl groups which may have 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms as substituents on the carbazole ring such as (1-, 2-, 3-, or 4-)carbazolyl, 9-methyl-(1-, 2-, 3-, or 4-)carbazolyl, 9-ethyl-(1-, 2-, 3-, or 4-)carbazolyl, 1-ethyl-(2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-)carbazolyl, 2-n-propyl-(1-, 3-, 4-, 5-, 6-, 8-, or 9-)carbazolyl, 3-n-butyl-(1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-)carbazolyl, 4-n-pentyl-(1-, 2-, 3-, 5-, 6-, 7-, 8-, or 9-)carbazolyl, 5-n-hexyl-(1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-)carbazolyl, 6,9-dimethyl-(1-, 2-, 3-, 4-, 5-, 7-, or 8-)carbazolyl, 1,7,8-trityl-(2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-)carbazolyl groups.

Examples of the amidino group which may have a lower alkyl group as a substituent include amidino groups which may have 1 or 2 linear or branched alkyl groups having 1 to 6 carbon atoms as substituents such as an amidino group, N,N-dimethylamidino group, N-methylamidino group, N-ethylamidino group, N-n-propylamidino group, N-n-butylamidino group, N-n-pentylamidino group, N-n-hexylamidino group, N,N-diethylamidino group, and N-methyl-N-ethylamidino group.

Examples of the 5- to 7-membered saturated heterocyclic group formed by binding R³⁶and R³⁷each other, together with nitrogen atoms bound to them, through or not through a nitrogen atom, an oxygen atom or a sulfur atom, include a pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholino group, thiomorpholino group, and homopiperazinyl group.

Examples of the 5- to 10-membered saturated or unsaturated heterocyclic group formed by binding R¹⁴and R¹⁵each other, together with nitrogen atoms bound to them, through or not through a nitrogen atom, an oxygen atom or a sulfur atom, include 1,2,3,4,5,6-hexahydropyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino, homopiperazinyl, homopiperidinyl, thiazolidinyl, 1,2,5,6-tetrahydropyridyl, pyrrolyl, pyrazolyl, imidazolyl, 2-pyrrolinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, 1,2-dihydropyridyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2-dihydroisoquinolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, 3,4-dihydro-2H-1,4-benzoxadinyl, 3,4-dihydro-2H-1,4-benzothiazolidinyl, 1,4-benzothiazinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,2,3,1-tetrahydroquinolinyl, 1,2,3,4-tetrahydrophthalazinyl, 1,2,3,4-tetrahydroquinazolinyl, 1,2-dihydroquinoxalinyl, 3,4-dihydroquinoxalinyl, 1,4-dihydroquinoxalinyl, 1,2-dihydroquinolinyl, 1,2-dihydrophthalazinyl, 3,4-dihydrophthalazinyl, 1,2-dihydroquinazolinyl, 3,4-dihydroquinazolinyl, indazolyl, indazolinyl, 6-azabicyclo[3,2,1]octyl, aza-spiro[5,5]undecyl, thiazolidinyl groups.

Examples of the phenyl lower alkoxy group include phenylalkoxy groups of which the alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms such as a benzyloxy group, 2-phenylethoxy group, 1-phenylethoxy group, 3-phenylpropoxy group, 4-phenylbutoxy group, 5-phenylpentyloxy group, 6-phenylhexyloxy group, 1,1-dimethyl-2-phenylethoxy group, and 2-methyl-3-phenylpropoxy group.

Examples of the phenyl substituted lower alkyl group which has 1 or 2 phenyl groups which may be substituted on the phenyl ring with 1 to 3 substituents selected from the group consisting of a lower alkanoyl group, an amino group which may have a lower alkanoyl group as a substituent, a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group which may have a halogen atom as a substituent, a phenyl lower alkoxy group, a hydroxyl group, and a lower alkylenedioxy groups; and which may have a pyridyl group on the lower alkyl group include, in addition to the above described phenyl lower alkyl groups, phenyl substituted alkyl groups which have 1 or 2 phenyls which may be substituted on the phenyl ring with 1 to 3 substituents selected from the group consisting of a linear branched alkanoyl group having 1 to 6 carbon atoms, an amino group which may have 1 or 2 linear or branched alkanoyl groups having 1 to 6 carbon atoms as substituents, a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms, a cyano group, a nitro group, a phenyl group, a halogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents, a linear or branched alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents, a phenylalkoxy groups of which the alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms, a hydroxy group, and a linear or branched alkylenedioxy group having 1 to 4 carbon atoms; and which may have a pyridyl group on the alkyl group, of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, such as 1-phenyl-1-(2, 3, or 4-)pyridylmethyl, 1,1-diphenylmethyl, 1,1-di(4-fluorophenyl)methyl, 1-phenyl-1-(4-methoxyphenyl)methyl, 3,4-methylenedioxybenzyl, 3,4-ethylenedioxybenzyl, 3,4-trimethylenedioxybenzyl, 2,5-difluorobenzyl, 2,4-difluorobenzyl, 3,4-difluorobenzyl, 3,5-difluorobenzyl, 2,6-difluorobenzyl, 3-trifluoromethylbenzyl, 2-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 3,4-dimethylbenzyl, 2,3-dimethylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-cyanobenzyl, 2-cyanobenzyl, 3-cyanobenzyl, 4-methoxybenzyl, 2,3-dichlorobenzyl, 2,4-dichlorobenzyl, 2,5-dichlorobenzyl, 3,4-dichlorobenzyl, 2,6-dichlorobenzyl, 4-fluorobenzyl, 3-fluorobenzyl, 2-fluorobenzyl, 4-nitrobenzyl, 3-nitrobenzyl, 2-nitrobenzyl, 3-trifluoromethoxybenzyl, 4-trifluoromethoxybenzyl, 2-trifluoromethoxybenzyl, 4-methoxycarbonylbenzyl, 3-methoxycarbonylbenzyl, 4-tert-butylbenzyl, 4-ethylbenzyl, 4-isopropylbenzyl, 4-methoxy-3-chlorobenzyl, 2-(4-methoxyphenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2-(4-chlorophenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(4-methylphenyl)ethyl, 4-phenylbenzyl, 3,3-diphenylpropyl, 3-methyl-4-nitrobenzyl, 4-(4-methoxyphenyl)butyl, 2-(4-methylphenyl)ethyl, 4-tert-butoxycarbonylbenzyl, 3-chloro-6-methoxybenzyl, 4-acetylaminobenzyl, 4-nitro-3-methylbenzyl, 4-hydroxybenzyl, 3-hydroxybenzyl, 2-hydroxybenzyl, 4-tert-butyrylbenzyl, 4-benzyloxybenzyl, 4-pivaloylbenzyl, 2-(4-acetylphenyl)ethyl, 1-(3-propionylphenyl)ethyl, 3-(2-butyrylphenyl)propyl, 4-(4-pentanoylphenyl)butyl, 5-(3-hexanoylphenyl)pentyl, 6-(2,4-diacetylphenyl)hexyl, 1,1-dimethyl-2-(2,4,6-triacetylphenyl)ethyl, 2-methyl-3-(3,4-diacetylphenyl)propyl, 2-(4-aminophenyl)ethyl, 1-(3-propionylaminophenyl)ethyl, 3-(2-butyrylaminophenyl)propyl, 4-(4-pentanoylamino)phenylbutyl, 5-(hexanoylaminophenyl)pentyl, 6-(N-acetyl-N-propionylaminophenyl)hexyl, 1,1-dimethyl-2-(3,4-diaminophenyl)ethyl, 2-methyl-3-(3,4,5-triacetylaminophenyl)propyl, 2-(2-ethoxycarbonylphenyl)ethyl, 1-(3-propoxycarbonylphenyl)ethyl, 3-(4-pentyloxycarbonylphenyl)propyl, 4-(3-hexyloxycarbonylphenyl)butyl, 5-(3,4-dimethoxycarbonylphenyl)pentyl, 6-(3,4,5-triethoxycarbonylphenyl)hexyl, 1,1-dimethyl-2-(4-butoxycarbonylphenyl)ethyl, 2-methyl-3-(4-methoxycarbonylphenyl)propyl, 2-(2-cyanophenyl)ethyl, 1-(3-cyanophenyl)ethyl, 3-(4-cyanophenyl)propyl, 4-(2-cyanophenyl)butyl, 5-(3-cyanophenyl)pentyl, 6-(4-cyanophenyl)hexyl, 1,1-dimethyl-2-(2,4-dicyanophenyl)ethyl, 2-methyl-3-(2,4,6-tricyanophenyl)propyl, 2-(2-nitrophenyl)ethyl, nitrophenyl)ethyl, 3-(4-nitrophenyl)propyl, 4-(2-nitrophenyl)butyl, 5-(3-nitrophenyl)pentyl, 6-(4-nitrophenyl)hexyl, 1,1-dimethyl-2-(2,4-dinitrophenyl)ethyl, 2-methyl-3-(2,4,6-trinitrophenyl)propyl, 2-(2-phenylphenyl)ethyl, 1-(3-phenylphenyl)ethyl, 3-(4-phenylphenyl)propyl, 4-(2-phenylphenyl)butyl, 5-(3-phenylphenyl)pentyl, 6-(4-phenylphenyl)hexyl, 1,1-dimethyl-2-(2,4-diphenylphenyl)ethyl, 2-methyl-3-(2,4,6-triphenylphenyl)propyl, 2-(2-fluorophenyl)ethyl, 1-(3-bromophenyl)ethyl, 3-(4-iodophenyl)propyl, 4-(2-bromophenyl)butyl, 5-(3-chlorophenyl)pentyl, 6-(4-bromophenyl)hexyl, 1,1-dimethyl-2-(2,4-dichlorophenyl)ethyl, 2-methyl-3-(2,4,6-trifluorophenyl)propyl, 2-(2-ethylphenyl)ethyl, 1-(3-propylphenyl)ethyl, 3-(4-butylphenyl)propyl, 4-(2-pentylphenyl)butyl, 5-(3-hexylphenyl)pentyl, 6-(4-trifluoromethylphenyl)hexyl, 1,1-dimethyl-2-(2,4-dimethylphenyl)ethyl, 2-methyl-3-[2,4,6-tri(trifluoromethyl)phenyl]propyl, 2-(2-ethoxyphenyl)ethyl, 1-(3-propoxyphenyl)ethyl, 3-(4-butoxyphenyl)propyl, 4-(2-pentyloxyphenyl)butyl, 5-(3-hexyloxyphenyl)pentyl, 6-(4-trifluoromethoxyphenyl)hexyl, 1,1-dimethyl-2-(2,4-dimethoxyphenyl)ethyl, 2-methyl-3-(2,4,6-tri(trifluoromethoxy)phenyl]propyl, 2-(2-benzyloxyphenyl)ethyl, 1-[3-(2-phenylethoxy)phenyl]ethyl, 3-[4-(3-phenylpropoxy)phenyl]propyl, 4-[2-(4-phenylbutoxy)phenyl]butyl, 5-(3-(5-phenylpentyloxy)phenyl]pentyl, 6-[4-(6-phenylhexyloxy)phenyl]hexyl, 1,1-dimethyl-2-(2,4-dibenzyloxyphenyl)ethyl, 2-methyl-3-(2,4,6-tribenzyloxyphenyl)propyl, 2-(2-hydroxyphenyl)ethyl, 1-(3-hydroxyphenyl)ethyl, 3-(4-hydroxyphenyl)propyl, 4-(2-hydroxyphenyl)butyl, 5-(3-hydroxyphenyl)pentyl, 6-(4-hydroxyphenyl)hexyl, 1,1-dimethyl-2-(2,4-dihydroxyphenyl)ethyl, 2-methyl-3-(2,4,6-trihydroxyphenyl)propyl, 2-(3,4-methylenedioxyphenyl)ethyl, 1-(2,3-ethylenedioxyphenyl)ethyl, 3-(3,4-trimethylenedioxyphenyl)propyl, 4-(3,4-tetramethylenedioxyphenyl)butyl, 5-(3,4-methylenedioxyphenyl)pentyl, 6-(3,4-ethylenedioxyphenyl)hexyl, 1,1-dimethyl-2-(3,4-methylenedioxy)ethyl, 2-methyl-3-(3,4-methylenedioxyphenyl)propyl groups.

Examples of the pyridyl lower alkyl group which may have, on the pyridine ring, 1 to 3 substituents selected from the group consisting of a hydroxyl group and a lower alkyl group which may have a hydroxyl group as a substituent include, in addition to the above described pyridyl lower alkyl groups, pyridylalkyl groups which may have, on the pyridine ring, 1 to 3 substituents selected from the group consisting of a hydroxy group and a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 hydroxy groups as substituents, and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [2-methyl-(3, 4, 5, or 6-)pyridyl]methyl, [2-methyl-3-hydroxy-5-hydroxymethyl-(4 or 6-)pyridyl]methyl, 2-[3-ethyl-(2, 4, 5, or 6-)pyridyl]ethyl, 1-[4-propyl-(2, 3, 5, or 6-)pyridyl]ethyl, 3-[2-butyl-(3, 4, 5, or 6-)pyridyl]propyl, 4-[3-pentyl-(2, 4, 5, or 6-)pyridyl]butyl, 1,1-dimethyl-2-(4-hexyl-(2, 3, 5, or 6-)pyridyl]ethyl, 5-[2,3-dimethyl-(4, 5, or 6-)pyridyl]pentyl, 6-[2,4,6-trimethyl-(3 or 5-)pyridyl]hexyl, 1-[2-hydroxy-(2, 3, 5, or 6-)pyridyl]isopropyl, 2-methyl-3-[3-hydroxy-(2, 4, 5, or 6-)pyridyl]propyl, [2-hydroxy-(3, 4, 5, or 6-)pyridyl]methyl, 2-[3-hydroxy-(2, 4, 5, or 6-)pyridyl]ethyl, 1-[4-hydroxy-(2, 3, 5, 6-)pyridyl]ethyl, 3-[2-hydroxy-(3, 4, 5, or 6-)pyridyl]propyl, 4-[3-hydroxy-(2, 4, 5, or 6-)pyridyl]butyl, 1,1-dimethyl-2-[4-hydroxy-(2, 3, 5, or 6-)pyridyl]ethyl, 5-[2,3-dihydroxy-(4, 5, or 6-)pyridyl]pentyl, 6-[2,4,6-trihydroxy-(3 or 5-)pyridyl]hexyl, [2-hydroxymethyl-(3, 4, 5, or 6-)pyridyl]methyl, 2-[(3-(2-hydroxyethyl)-(2, 4, 5, or 6-)pyridyl]ethyl, 1-[4-(3-hydroxypropyl)-(2, 3, 5, or 6-)pyridyl]ethyl, 3-[2-(4-hydroxybutyl)-(3, 4, 5, or 6-)pyridyl]propyl, 4-[3-(5-hydroxypentyl)-(2, 4, 5, or 6-)pyridyl]butyl, 1,1-dimethyl-2-[4-(6-hydroxyhexyl)-(2, 3, 5, or 6-)pyridyl]ethyl, 5-[2,3-di(hydroxymethyl)-(4, 5, or 6-)pyridyl]pentyl, 6-[2,4,6-tri(hydroxymethyl)-(3 or 5-)pyridyl]hexyl, 1-[2-hydroxymethyl-(2, 3, 5, or 6-)pyridyl]isopropyl, 2-methyl-3-[(3-(2,3-dihydroxypropyl)-(2, 4, 5, or 6-)pyridyl]propyl, (2-methyl-3-(2,2,4-trihydroxybutyl)-(4, 5, or 6-)pyridyl]methyl, (2-methyl-5-hydroxymethyl-(3, 4, or 6-)pyridyl]methyl groups.

Examples of the pyrrolyl lower alkyl group which may have 1 to 3 lower alkyl groups as substituents on the pyrrole ring include pyrrolylalkyl groups which may have 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms on the pyrrole and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [(1, 2, or 3-)pyrrolyl]methyl, 2-[(1, 2, or 3-)pyrrolyl]ethyl, 1-[(1, 2, or 3-)pyrrolyl]ethyl, 3-[(1, 2, or 3-)pyrrolyl]propyl, 4-[(1, 2, or 3-)pyrrolyl]butyl, 5-[(1, 2, or 3-)pyrrolyl]pentyl, 6-[(1, 2, or 3-)pyrrolyl]hexyl, 1,1-dimethyl-2-[(1, 2, or 3-)pyrrolyl]ethyl, 2-methyl-3-[(1, 2, or 3-)pyrrolyl]propyl, [1-methyl-(2 or 3-)pyrrolyl]methyl, 2-[2-ethyl-(1, 3, 4, or 5-)pyrrolyl]ethyl, 1-[3-propyl-(1, 2, 4, or 5-)pyrrolyl]ethyl, 3-[1-butyl-(2, 3, or 4-)pyrrolyl]propyl, 4-[2-pentyl-(1, 3, 4, 5-)pyrrolyl]butyl, 5-[3-hexyl-(1, 2, 4, or 5-)pyrrolyl]pentyl, 6-[1,2-dimethyl-(3, 4, or 5-)pyrrolyl]hexyl, 1,1-dimethyl-2-[1,2,3-trimethyl-(4 or 5-)pyrrolyl]ethyl, 2-methyl-3-[1-ethyl-2-methyl-(3, 4, or 5-)pyrrolyl]propyl groups.

Examples of the benzoxazolyl lower alkyl group include benzoxazolylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [(2, 4, 5, 6, or 7-)benzoxazolyl]methyl, 2-[(2, 4, 5, 6, or 7-)benzoxazolyl]ethyl, 1-[(2, 4, 5, 6, or 7-)benzoxazolyl]ethyl, 3-[(2, 4, 5, 6, or 7-)benzoxazolyl]propyl, 4-[(2, 4, 5, 6, or 7-)benzoxazolyl]butyl, 5-[(2, 4, 5, 6, or 7-)benzoxazolyl]pentyl, 6-[(2, 4, 5, 6, or 7-)benzoxazolyl]hexyl, 1,1-dimethyl-2-[(2, 4, 5, 6, or 7-)benzoxazolyl]ethyl, 2-methyl-3-[(2, 4, 5, 6, or 7-)benzoxazolyl]propyl.

Examples of the benzothiazolyl lower alkyl group include benzothiazolylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [(2, 4, 5, 6, or 7-)benzothiazolyl]methyl, 2-[(2, 4, 5, 6, or 7-)benzothiazolyl]ethyl, 1-[(2, 4, 5, 6, or 7-)benzothiazolyl]ethyl, 3-[(2, 4, 5, 6, or 7-)benzothiazolyl]propyl, 4-[(2, 4, 5, 6, or 7-)benzothiazolyl]butyl, 5-[(2, 4, 5, 6, or 7-)benzothiazolyl]pentyl, 6-[(2, 4, 5, 6, or 7-)benzothiazolyl]hexyl, 1,1-dimethyl-2-[(2, 4, 5, 6, or 7-)benzothiazolyl]ethyl, 2-methyl-3-[(2, 4, 5, 6, or 7-)benzothiazolyl]propyl.

Examples of the furyl lower alkyl group include furylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a [(2 or 3-)furyl]methyl group, 2-[(2 or 3-)furyl]ethyl group, 1-[(2 or 3-)furyl]ethyl group, 3-[(2 or 3-)furyl]propyl group, 4-[(2 or 3-)furyl]butyl group, 5-[(2 or 3-)furyl]pentyl group, 6-[(2 or 3-)furyl]hexyl group, 1,1-dimethyl-2-[(2 or 3-)furyl]ethyl group, and 2-methyl-3-[(2 or 3-)furyl]propyl group.

Examples of the thiazolidinyl lower alkyl group which may have an oxo group as a substituent on the thiazolidine ring include thiazolidinylalkyl groups which may have 1 to 3 oxo groups as substituents on the thiazolidine ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (2, 3, 4, or 5-)thiazolidinylmethyl, 2-[(2, 3, 4, or 5-)thiazolidinyl]ethyl, 1-[(2, 3, 4, or 5-)thiazolidinyl]ethyl, 3-[(2, 3, 4, or 5-)thiazolidinyl]propyl, 4-[(2, 3, 4, or 5-)thiazolidinyl]butyl, 5-[(2, 3, 4, or 5-)thiazolidinyl]pentyl, 6-[(2, 3, 4, or 5-)thiazolidinyl]hexyl, 1,1-dimethyl-2-[(2, 3, 4, or 5-)thiazolidinyl]ethyl, 2-methyl-3-[(2, 3, 4, or 5-)thiazolidinyl]propyl, [2,4-dioxo-(3 or 5-)thiazolidinyl]methyl, 2-[2-oxo-(3, 4, or 5-)thiazolidinyl]ethyl, 1-[(4-oxo-(2, 3, or 5-)thiazolidinyl]ethyl, 3-[2-oxo-(3, 4, or 5-)thiazolidinyl]propyl, 4-[5-oxo-(2, 3, or 4-) thiazolidinyl]butyl, 5-[(2,5-dioxo-(3 or 4-)thiazolidinyl]pentyl, 6-[2,4,5-trioxo-3-thiazolidinyl]hexyl, 1-[(4,5-dioxo-(2 or 3-)thiazolidinyl]ethyl, 2-[4,5-dioxo-(2- or 3-)thiazolidinyl]ethyl, 1,1-dimethyl-2-[(2,4-dioxo-(3 or 5-)thiazolidinyl]ethyl, 2-methyl-3-[(2,4-dioxo-(3 or 5-)thiazolidinyl]propyl groups.

Examples of the thiazolidinylidene lower alkyl group which may have an oxo group as a substituent on the thiazolidine ring include thiazolidinylidenealkyl groups which may have 1 to 3 oxo groups as substituents on the thiazolidine ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (2, 4, or 5-)thiazolidinylidenemethyl, (2, 4, or 5-)thiazolidinylideneethyl, (2, 4, or 5-)thiazolidinylidenepropyl, (2, 4, or 5-)thiazolidinylideneisopropyl, (2, 4, or 5-)thiazolidinylidenebutyl, (2, 4, or 5-)thiazolidinylidenepentyl, (2, 4, or 5-)thiazolidinylidenehexyl, 4,5-dioxo-2-thiazolidinylidenemethyl, 2,5-dioxo-4-thiazolidinylidenemethyl, 2,4-dioxo-5-thiazolidinylidenemethyl, 4-oxo-(2 or 5-)thiazolidinylideneethyl, 5-oxo-(2 or 4-)thiazolidinylidenepropyl, 2-oxo-(4, or 5-)thiazolidinylidenebutyl groups.

Examples of the benzoyl group which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a cyano group, an amino group which may have a lower alkylsulfonyl group as a substituent, a halogen atom, a lower alkoxy group, a lower alkyl group which may have a halogen atom, a thiazolidinyl lower alkyl group which may have an oxo group as a substituent on the thiazolidine ring, a thiazolidinylidene lower alkyl group which may have an oxo group as a substituent on the thiazolidine ring, and a lower alkylenedioxy group include benzoyl groups which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a cyano group; an amino group which may have 1 or 2 linear or branched alkylsulfonyl groups having 1 to 6 carbon atoms as substituents; a halogen atom; a linear or branched alkoxy group having 1 to 6 carbon atoms; a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents; a thiazolidinylalkyl group which may have 1 to 3 oxo groups as substituents on the thiazolidine ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms; a thiazolidinylidenealkyl group which may have 1 to 3 oxo groups as substituents on the thiazolidine ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms; and a linear or branched alkylenedioxy group having 1 to 4 carbon atoms such as benzoyl, 4-cyanobenzoyl, 3,4-methylenedioxybenzoyl, 2-aminobenzoyl, 3-aminobenzoyl, 4-aminobenzoyl, 3,4-diaminobenzoyl, 2,4,6-triaminobenzoyl, 4-methoxybenzoyl, 4-trifluoromethylbenzoyl, 4-chlorobenzoyl, 3,4-difluorobenzoyl, 2-fluorobenzoyl, 3-bromobenzoyl, 4-iodobenzoyl, 3,4-dimethoxybenzoyl, 4-fluorobenzoyl, 3-cyanobenzoyl, 2-cyanbenzoyl, 2,3-dicyanobenzoyl, 3,4,5-tricyanobenzoyl, 4-methylbenzoyl, 4-(2,4-dioxothiazolidinylmethyl)benzoyl, 4-(2,4-dioxothiazolidinylidenemethyl)benzoyl, 2-methylbenzoyl, 3-methylbenzoyl, 2-ethylbenzoyl, 3-ethylbenzoyl, 4-ethylbenzoyl, 4-isopropylbenzoyl, 3-butylbenzoyl, 4-pentylbenzoyl, 4-hexylbenzoyl, 3,4-dimethylbenzoyl, 3,4-diethylbenzoyl, 2,4-dimethylbenzoyl, 2,5-dimethylbenzoyl, 2,6-dimethylbenzoyl, 3,4,5-trimethylbenzoyl, 2-methoxybenzoyl, 3-methoxybenzoyl, 2-ethoxybenzoyl, 3-ethoxybenzoyl, 4-ethoxybenzoyl, 4-isopropoxybenzoyl, 3-butoxybenzoyl, 4-pentyloxybenzoyl, 4-hexyloxybenzoyl, 3,4-diethoxybenzoyl, 2,4-dimethoxybenzoyl, 2,5-dimethoxybenzoyl, 2,6-dimethoxybenzoyl, 3,4,5-trimethoxybenzoyl, 2-trifluoromethylbenzoyl, 3-trifluoromethylbenzoyl, 4-trifluoromethylbenzoyl, 2-(bromomethyl)benzoyl, 3-(2-chloroethyl)benzoyl, 4-(2,3-dichloropropyl)benzoyl, 4-(4-fluorobutyl)benzoyl, 3-(5-chloropentyl)benzoyl, 4-(5-bromohexyl)benzoyl, 4-(5,6-dibromohexyl)benzoyl, 3,4-di(trifluoromethyl)benzoyl, 3,4-di(4,4,4-trichlorobutyl)benzoyl, 2,4-di(3-chloro-2-methylpropyl)benzoyl, 2,5-di(3-chloropropyl)benzoyl, 2,6-di(2,2,2-trifluoroethyl)benzoyl, 3,4,5-tri(trifluoromethyl)benzoyl, 4-(2,2,2-trichloroethyl)benzoyl, 2-methyl-4-trifluoromethylbenzoyl, 3-ethyl-4-trichloromethylbenzoyl, 2-methoxy-4-trifluoromethylbenzoyl, 3-ethyl-4-fluorobenzoyl, 3-ethoxy-4-trichloromethylbenzoyl, 2-methyl-3-trifluoromethyl-4-trifluoromethylbenzoyl, 3-fluorobenzoyl, 4-fluorobenzoyl, 2-bromobenzoyl, 4-bromobenzoyl, 2-iodobenzoyl, 3-iodobenzoyl, 2,3-dibromobenzoyl, 2,4-diiodobenzoyl, 2,5-difluorobenzoyl, 2,6-dichlorobenzoyl, 2,4,6-trichlorobenzoyl, 2,4-difluorobenzoyl, 3,4-difluorobenzoyl, 3,5-difluorobenzoyl, 2,6-difluorobenzoyl, 2-chlorobenzoyl, 3-chlorobenzoyl, 4-chlorobenzoyl, 2,3-dichlorobenzoyl, 2,4-dichlorobenzoyl, 2,5-dichlorobenzoyl, 3,4-dichlorobenzoyl, 2,6-dichlorobenzoyl, 3,5-dichlorobenzoyl, 2,4,6-trifluorobenzoyl, 2,4-difluorobenzoyl, 3,4-difluorobenzoyl, 3,4-methylenedioxybenzoyl, 3,4-trimethylenedioxybenzoyl, 2,3-ethylenedioxybenzoyl, 3,4-trimethylenedioxybenzoyl, 2,3-tetramethylenedioxybenzoyl, 2,3-methylenedioxybenzoyl, 3,4-ethylenedioxybenzoyl, 2-methanesulfonylaminobenzoyl groups.

Examples of the thiazolidinyl lower alkanoyl group which may be substituted on the thiazolidine ring with 1 to 3 groups selected from the group consisting of an oxo group and a group of the formula:

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wherein R^aand R^beach represent a lower alkyl group, include thiazolidinylalkanoyl groups which may be substituted on the thiazolidine ring with 1 to 3 substituents selected from the group consisting of an oxo group and a group of the formula:

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wherein R^aand R^beach represent a linear or branched alkyl group having 1 to 6 carbon atoms, and of which the alkanoyl moiety is a linear or branched alkanoyl group having 2 to 6 carbon atoms such as 2-[(2,3,4, or 5-)thiazolidinyl]acetyl, 3-[(2, 3, 4, or 5-)thiazolidinyl]propionyl, 2-[(2, 3, 4, or 5-)thiazolidinyl]propionyl, 4-[(2, 3, 4, or 5-)thiazolidinyl]butyryl, 5-[(2, 3, 4, or 5-)thiazolidinyl]pentanoyl, 6-[(2, 3, 4, or 5-)thiazolidinyl]hexanoyl, 2,2-dimethyl-3-[(2, 3, 4, or 5-)thiazolidinyl]propionyl, 2-methyl-3-[(2, 3, 4, or 5-)thiazolidinyl]propionyl, [2,4-dioxo-(3 or 5-)thiazolidinyl]acetyl, 3-[2-oxo-(3, 4, or 5-)thiazolidinyl]propionyl, 2-[4-oxo-(2, 3, or 5-)thiazolidinyl]propionyl, 4-[5-oxo-(2, 3, or 4-)thiazolidinyl]butyryl, 5-[2,5-dioxo-(3 or 4-)thiazolidinyl]pentanoyl, 6-[2,4,5-trioxo-3-thiazolidinyl]hexanoyl, 2-[4,5-dioxo-(2 or 3-)thiazolidinyl]acetyl, 2,2-dimethyl-3-[(2,4-dioxo-(3 or 5-)thiazolidinyl]propionyl, 2-methyl-3-[2,4-dioxo-(3 or 5-)thiazolidinyl]propionyl, 2-[4-oxo-2-isopropylidenehydrazono-(3 or 5-)thiazolidinyl]acetyl, 2-[2-oxo-5-isopropylidenehydrazono-(3 or 4-)thiazolidinyl]acetyl, 2-[(2,4-di(isopropylidenehydrazono)-(3 or 5-)thiazolidinyl]acetyl, 3-[2-methylidenehydrazono-(3, 4, or 5-)thiazolidinyl]propionyl, 2-[4-ethylidenehydrazono-(2, 3, or 5-)thiazolidinyl]-propionyl, 4-[(5-propylidenehydrazono-(2, 3, or 4-)thiazolidinyl]butyryl, 5-[(2,5-di(isopropyl-idenehydrazono)-(3 or 4-)thiazolidinyl]pentanoyl, 6-[2,4,5-tri(isopropylidenehydrazono)-3-thiazolidinyl]-hexanoyl, 2-[4,5-di(isopropylidenehydrazono)-(2 or 3-)thiazolidinyl]acetyl, 2,2-dimethyl-3-[4-butylidenehydrazono-(2, 3, or 5-)thiazolidinyl]-propionyl, 2-methyl-3-[5-pentylidene-(2, 3, or 4-)thiazolidinyl]propionyl, 2-(hexylidenehydrazono)-(3, 4, or 5-)thiazolidinylacetyl groups.

Examples of the lower alkyl group which may have a substituent selected from the group consisting of a hydroxyl group and a halogen atom include, in addition to the above described lower alkyl groups, linear or branched alkyl groups having 1 to 6 carbon atoms which may have 1 to 3 substituents selected from the group consisting of a hydroxy group and a halogen atom such as hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 5,5,4-trihydroxypentyl, 5-hydroxypentyl, 6-hydroxyhexyl, 1-hydroxyisopropyl, 2-methyl-3-hydroxypropyl, trifluoromethyl, trichloromethyl, chloromethyl, bromomethyl, fluoromethyl, iodomethyl, difluoromethyl, dibromomethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 3-chloropropyl, 2,3-dichloropropyl, 4,4,4-trichlorobutyl, 4-fluorobutyl, chloropentyl, 3-chloro-2-methylpropyl, 5-bromohexyl, 5,6-dibromohexyl, 2-hydroxy-3-fluoropropyl, 2,2-dichloro-3-hydroxybutyl groups.

Examples of the phenyl group which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a carbamoyl group which may have a group selected from the group consisting of a lower alkoxy lower alkyl group and a lower alkyl group, a lower alkoxycarbonyl group, a carboxy group, a cyano group, a phenyl group, a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group which may have a halogen atom as a substituent, a benzoyl group which may have a halogen atom as a substituent on the phenyl ring, a phenyl lower alkyl group which may have a halogen atom as a substituent on the phenyl ring, and a hydroxyl group include phenyl groups which may be substituted on the phenyl group with 1 to 3 groups selected from the group consisting of a carbamoyl group which may have 1 or 2 groups selected from the group consisting of an alkoxyalkyl group of the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms and a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms, a carboxy group, a cyano group, a phenyl group, a halogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents, a linear or branched alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents, a benzoyl group which may have 1 to 3 halogen atoms as substituents on the phenyl ring, a phenylalkyl group which may have 1 to 3 halogen atoms as substituents on the phenyl ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, and a hydroxyl group such as phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-butylphenyl, 4-pentylphenyl, 4-hexylphenyl, 3,4-dimethylphenyl, 3,4-diethylphenyl, 2,4-dimethylphenyl, 2,3-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4,5-trimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, 3-butoxyphenyl, 4-pentyloxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl, 3,4-diethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-(bromomethoxy)phenyl, 3-(2-chloroethoxy)phenyl, 4-(2,3-dichloropropoxy)phenyl, 4-(4-fluorobutoxy)phenyl, 3-(5-chloropentyloxy)phenyl, 4-(5-bromohexyloxy)phenyl, 4-(5,6-dibromohexyloxy)phenyl, 3,4-di(trifluoromethoxy)phenyl, 3,4-di(4,4,4-trichlorobutoxy)phenyl, 2,4-di(3-chloro-2-methoxypropyl)phenyl, 2,5-di(3-chloropropoxy)phenyl, 2,6-di(2,2,2-trifluoroethoxy)phenyl, 3,4,5-tri(trifluoromethoxy)phenyl, 4-(2,2,2-trichloroethoxy)phenyl, 2-methyl-4-trifluoromethoxyphenyl, 3-ethyl-4-trichloromethoxyphenyl, 2-methoxy-4-trifluoromethoxyphenyl, 3-ethoxy-4-trichloromethoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-(bromomethyl)phenyl, 3-(2-chloroethyl)phenyl, 4-(2,3-dichloropropyl)phenyl, 4-(4-fluorobutyl)phenyl, 3-(5-chloropentyl)phenyl, 4-(5-bromohexyl)phenyl, 4-(5,6-dibromohexyl)phenyl, 3,4-di(trifluoromethyl)phenyl, 3,4-di(4,4,4-trichlorobutyl)phenyl, 2,4-di(3-chloro-2-methylpropyl)phenyl, 2,5-di(3-chloropropyl)phenyl, 2,6-di(2,2,2-trifluoroethyl)phenyl, 3,4,5-tri(trifluoromethyl)phenyl, 4-(2,2,2-trichloroethyl)phenyl, 2-methyl-4-trifluoromethylphenyl, 3-ethyl-4-trichloromethylphenyl, 2-methoxycarbonylphenyl, 3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, 2-ethoxycarbonylphenyl, 3-ethoxycarbonylphenyl, 4-ethoxycarbonylphenyl, 4-isopropoxycarbonylphenyl, 3-butoxycarbonylphenyl, 4-tert-butoxycarbonylphenyl, 4-pentyloxycarbonylphenyl, 4-hexyloxycarbonylphenyl, 3,4-dimethoxycarbonylphenyl, 3,4-diethoxycarbonylphenyl, 2,4-dimethoxycarbonylphenyl, 2,5-diethoxycarbonylphenyl, 2,6-dimethoxycarbonylphenyl, 3,4,5-triethoxycarbonylphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3,4-dicyanophenyl, 3,5-dicyanophenyl, 2,4-dicyanophenyl, 2,5-dicyanophenyl, 2,6-dicyanophenyl, 3,4,5-tricyanophenyl, 2-phenylphenyl, 3-phenylphenyl, 4-phenylphenyl, 3,4-diphenylphenyl, 3,5-diphenylphenyl, 2,4-diphenylphenyl, 2,5-diphenylphenyl, 2,6-diphenylphenyl, 3,4,5-triphenylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,6-dichlorophenyl, 3,5-dichlorophenyl, 2,4,6-trichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,5-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3, 5-1© difluorophenyl, 2,6-difluorophenyl, 2,4,6-trifluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2,3-dibromophenyl, 2,4-diiodophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, 3,5-dihydroxyphenyl, 2,4-dihydroxyphenyl, 2,5-dihydroxyphenyl, 2,6-dihydroxyphenyl, 3,4,5-trihydroxyphenyl, 3-benzylphenyl, 2-(2-phenylethyl)phenyl, 4-(1-phenylethyl)phenyl, 2-(3-phenylpropyl)phenyl, 3-(4-phenylbutyl)phenyl, 4-(5-phenylpentyl)phenyl, 2-(6-phenylhexyl)phenyl, 4-(1,1-dimethyl-2-phenylethyl)phenyl, 3-(2-methyl-3-phenylpropyl)phenyl, 2-(4-fluorobenzyl)phenyl, 2-methyl-5-chlorophenyl, 2-methoxy-5-chlorophenyl, 4-(4-fluorobenzoyl)phenyl, 4-(4-fluorobenzyl)phenyl, 3-(2-chlorobenzyl)phenyl, 4-(3-chlorobenzyl)phenyl, 2-(4-chlorobenzyl)phenyl, 3-(2-(4-fluorophenyl)ethyl]phenyl, 4-[2-(4-chlorophenyl)ethyl]phenyl, 2-(3,4-dibromobenzyl)phenyl, 3-(3,4-diiodobenzyl)phenyl, 4-(2,4-difluorobenzyl)phenyl, 2-(2,5-dichlorobenzyl)phenyl, 3-(2,6-dichlorobenzyl)phenyl, 4-(3,4,5-trifluorobenzyl)phenyl, 2-[3-(4-chlorophenyl)propyl]phenyl, 3-[1-(2-bromophenyl)ethyl]phenyl, 4-[4-(3-fluorophenyl)butyl]phenyl, 2-[5-(4-iodophenyl)pentyl]phenyl, 3-[6-(4-chlorophenyl)hexyl]phenyl, 2-[1,1-dimethyl-2-(3-fluorophenyl)ethyl]phenyl, 4-[2-methyl-3-(4-chlorophenyl)propyl]phenyl, 2,4-dibenzylphenyl, 2,4,6-tribenzylphenyl, 2-chloro-4-cyanophenyl, 3-hydroxy-4-phenylphenyl, 3-ethoxycarbonyl-2-benzoylphenyl, 2-benzyl-4-methyl-6-methoxyphenyl, 4-[(2-methoxyethyl)carbamoyl]phenyl, 3-(N-ethyl-N-isopropylcarbamoyl)phenyl, 4-dimethylcarbamoylphenyl, 2-carboxyphenyl, 3-carboxyphenyl, 4-carboxyphenyl, groups.

Examples of the phenyl group which has a lower alkylenedioxy group as a substituent on the phenyl ring include phenyl groups which has a linear or branched alkylenedioxy group having 1 to 4 carbon atom as a substituent on the phenyl ring such as a 3,4-methylenedioxyphenyl group, 3,4-trimethylenedioxyphenyl group, 2,3-ethylenedioxyphenyl group, 2,3-tetramethylenedioxyphenyl group, 2,3-methylenedioxyphenyl group, 3,4-ethylenedioxyphenyl group, and 2,3-trimethylenedioxyphenyl group.

Examples of the naphthyl lower alkyl group include naphthylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a (1 or 2-)naphthylmethyl group, 2-[(1 or 2-)naphthyl]ethyl group, 1-[(1 or 2-)naphthyl]ethyl group, 3-[(1 or 2-)naphthyl]propyl group, 4-[(1 or 2-)naphthyl]butyl group, 5-[(1 or 2-)naphthyl]pentyl group, 6-[(1 or 2-)naphthyl]hexyl group, 1,1-dimethyl-2-[(1 or 2-)naphthyl]ethyl group, and 2-methyl-3-[(1 or 2-)naphthyl]propyl group.

Examples of the phenoxy group which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a cyano group, a lower alkyl group which may have a halogen atom as a substituent, and a lower alkoxy group which may have a halogen atom as a substituent include phenoxy groups which may be substituted on the phenyl group with 1 to 3 groups selected from the group consisting of a cyano group, a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents, and a linear or branched alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents such as phenoxy, 2-methylphenoxy, 3-methylphenyl, 4-methylphenoxy, 2-ethylphenoxy, 3-ethylphenoxy, 4-ethylphenoxy, 4-isopropylphenoxy, 3-butylphenoxy, 4-pentylphenoxy, 4-hexylphenoxy, 3,4-dimethylphenoxy, 3,4-diethylphenoxy, 2,4-dimethylphenoxy, 2,5-dimethylphenoxy, 2,6-dimethylphenoxy, 3,4,5-trimethylphenoxy, methoxyphenoxy, 3-methoxyphenoxy, 4-methoxyphenoxy, 2-ethoxyphenoxy, 3-ethoxyphenoxy, 4-ethoxyphenoxy, 4-isopropoxyphenoxy, 3-butoxyphenoxy, 4-pentyloxyphenoxy, 4-hexyloxyphenoxy, 3,4-dimethoxyphenoxy, 3,4-diethoxyphenoxy, 2,4-dimethoxyphenoxy, 2,5-dimethoxyphenoxy, 2,6-dimethoxyphenoxy, 3,4,5-trimethoxyphenoxy, 2-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, 2-(bromomethoxy)phenoxy, 3-(2-chloroethoxy)phenoxy, 4-(2,3-dichloropropoxy)phenoxy, 4-(4-fluorobutoxy)phenoxy, 3-(5-chloropentyloxy)phenoxy, 4-(5-bromohexyloxy)phenoxy, 4-(5,6-dibromohexyloxy)phenoxy, 3,4-di(trifluoromethoxy)phenoxy, 3,4-di(4,4,4-trichlorobutoxy)phenoxy, 2,4-di(3-chloro-2-methoxypropyl)phenoxy, 2,5-di(3-chloropropoxy)phenoxy, 2,6-di(2,2,2-trifluoroethoxy)phenoxy, 3,4,5-tri(trifluoromethoxy)phenoxy, 4-(2,2,2-trichloroethoxy)phenoxy, 2-methyl-4-trifluoromethoxyphenoxy, 3-ethyl-4-trichloromethoxyphenoxy, 2-methoxy-4-trifluoromethoxyphenoxy, 3-ethoxy-4-trichloromethoxyphenoxy, 2-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 4-trifluoromethylphenoxy, 2-(bromomethyl)phenoxy, 3-(2-chloroethyl)phenoxy, 4-(2,3-dichloropropyl)phenoxy, 4-(4-fluorobutyl)phenoxy, 3-(5-chloropentyl)phenoxy, 4-(5-bromohexyl)phenoxy, 4-(5,6-dibromohexyl)phenoxy, 3,4-di(trifluoromethyl)phenoxy, 3,4-di(4,4,4-trichlorobutyl)phenoxy, 2,4-di(3-chloro-2-methylpropyl)phenoxy, 2,5-di(3-chloropropyl)phenoxy, 2,6-di(2,2,2-trifluoroethyl)phenoxy, 3,4,5-tri(trifluoromethyl)phenoxy, 4-(2,2,2-trichloroethyl)phenoxy, 2-methyl-4-trifluoromethylphenoxy, 3-ethyl-4-trichloromethylphenoxy, 2-cyanophenoxy, 3-cyanophenoxy, 4-cyanophenoxy, 3,5-dicyanophenoxy, 3,4-dicyanophenoxy, 2,3-dicyanophenoxy, 2,4-dicyanophenoxy, 2,5-dicyanophenoxy, 2,6-dicyanophenoxy, 3,4,5-tricyanophenoxy, 2-cyano-4-methylphenoxy, 3-cyano-4-methoxyphenoxy, 3-cyano-5-trifluoromethylphenoxy, 4-cyano-3-trifluoromethoxyphenoxy groups.

Examples of the phenyl lower alkoxy group which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, and a lower alkyoxy group which may have a halogen atom as a substituent include, in addition to the above described phenyl lower alkoxy groups, phenylalkoxy groups which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a halogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents, and a linear or branched alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents, and of which the alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms such as 2,5-difluorobenzyloxy, 2,4-difluorobenzyloxy, 3,4-difluorobenzyloxy, 3,5-difluorobenzyloxy, 2,6-difluorobenzyloxy, 3-trifluoromethylbenzyloxy, 2-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy, 3,4-dimethoxybenzyloxy, 3,5-dimethoxybenzyloxy, 2-chlorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 2-methylbenzyloxy, 3-methylbenzyloxy, 4-methylbenzyloxy, 3,4-dimethylbenzyloxy, 2,3-dimethylbenzyloxy, 2-methoxybenzyloxy, 3-methoxybenzyloxy, 4-methoxybenzyloxy, 2,3-dichlorobenzyloxy, 2,4-dichlorobenzyloxy, 2,5-dichlorobenzyloxy, 3,4-dichlorobenzyloxy, 2,6-dichlorobenzyloxy, 4-fluorobenzyloxy, 3-fluorobenzyloxy, 2-fluorobenzyloxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 2-trifluoromethxybenzyloxy, 4-tert-butylbenzyloxy, 4-ethylbenzyloxy, 4-isopropylbenzyloxy, 4-methoxy-3-chlorobenzyloxy, 2-(4-methoxyphenyl)ethoxy, 2-(4-fluorophenyl)ethoxy, 2-(4-chlorophenyl)ethoxy, 2-(3-methoxyphenyl)ethoxy, 2-(4-methylphenyl)ethoxy, 3-methyl-4-chlorobenzyloxy, 4-(4-methoxyphenyl)butoxy, 2-(4-methylphenyl)ethoxy, 4-tert-butoxybenzyloxy, 3-chloro-6-methoxybenzyloxy, 4-methoxy-3-methylbenzyloxy, 2-(2-fluorophenyl)ethoxy, 1-(3-bromophenyl)ethoxy, 3-(4-iodophenyl)propoxy, 4-(2-bromophenyl)butoxy, 5-(3-chlorophenyl)pentyloxy, 6-(4-bromophenyl)hexyloxy, 1,1-dimethyl-2-(2,4-dichlorophenyl)ethoxy, 2-methyl-3-(2,4,6-trifluorophenyl)propoxy, 2-(2-ethylphenyl)ethoxy, 1-(3-propylphenyl)ethoxy, 3-(4-butylphenyl)propoxy, 4-(2-pentylphenyl)butoxy, 5-(3-hexylphenyl)pentyloxy, 6-(4-trifluoromethylphenyl)hexyloxy, 1,1-dimethyl-2-(2,4-dimethylphenyl)ethoxy, 2-methyl-3-[2,4,6-tri(trifluoromethyl)phenyl]propoxy, 2-(2-ethoxyphenyl)ethoxy, 1-(3-propoxyphenyl)ethoxy, 3-(4-butoxyphenyl)propoxy, 4-(2-pentyloxyphenyl)butoxy, 5-(3-hexyloxyphenyl)pentyloxy, 6-(4-trifluoromethoxyphenyl)hexyloxy, 1,1-dimethyl-2-(2,4-dimethoxyphenyl)ethoxy, 2-methyl-3-[2,4,6-tri(trifluoromethoxy)phenyl]propoxy groups.

Examples of the 1,2,3,4-tetrahydronaphthyl substituted lower alkyl group which may have 1 to 5 lower alkyl groups as substituents on the 1,2,3,4-tetrahydronaphthalene ring include 1,2,3,4-tetrahydronaphthyl substituted alkyl groups which may have 1 to 5 linear or branched alkyl groups having 1 to 6 carbon atoms as substituents on the 1,2,3,4-tetrahydronaphthalene ring, and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (1, 2, 5, or 6-)1,2,3,4-tetrahydronaphthylmethyl, 2-[(1, 2, 5, or 6-)1,2,3,4-tetrahydronaphthyl]ethyl, 1-[(1, 2, 5, or 6-)1,2,3,4-tetrahydronaphthyl]ethyl, 3-[(1, 2, 5, or 6-)1,3,4-tetrahydronaphthyl]propyl, 4-[(1, 2, 5, or 6-)1,2,3,4-tetrahydronaphthyl]butyl, 5-[(1, 2, 5, or 6-)1,2,3,4-tetrahydronaphthyl]pentyl, 6-[(1, 2, 5, or 6-)1,2,3,4-tetrahydronaphthyl]hexyl, 1,1-dimethyl-2-[(1,2,5,6-)1,2,3,4-tetrahydronaphthyl]ethyl, 2-methyl-3-[(1,2,5, or 6-)1,2,3,4-tetrahydronaphthyl]propyl, 1,1,4,4-tetramethyl(2, 3, 5, or 6-)1,2,3,4-tetrahydronaphthylmethyl, 1,1,4,4,5-pentamethyl(2, 3, 6, 7, or 8-)1,2,3,4-tetrahydronaphthylmethyl, 1,4,4-trimethyl(2, 3, 5, 6, 7, or 8-)1,2,3,4-tetrahydronaphthylmethyl, 5,6-dimethyl(2, 3, 7, or 8-)1,2,3,4-tetrahydronaphthylmethyl, 2-[1-methyl-(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydronaphthyl]ethyl, 1-[2-ethyl-(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydronaphthyl]ethyl, 3-[3-propyl-(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydronaphthyl]propyl, 4-[(4-butyl-1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydronaphthyl]butyl, 5-[5-pentyl-(1, 2, 3, 4, 6, 7, or 8-)1,2,3,4-tetrahydronaphthyl]pentyl, 6-[6-hexyl-(1, 2, 3, 4, 5, 7, or 8-)1,2,3,4-tetrahydronaphthyl]hexyl, 1,1-dimethyl-2-[1,7-dimethyl-(1, 2, 3, 4, 5, 6, or 8-)1,2,3,4-tetrahydronaphthyl]ethyl, 2-methyl-3-[1,1,4-trimethyl-(2, 3, 4, 5, 6, 7, or 8-) 1,2,3,4-tetrahydronaphthyl]propyl groups.

Examples of the piperidinyl group which may have 1 to 3 lower alkyl groups as substituents on the piperidine ring include piperidinyl group which may have 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms as substituents on the piperidine ring such as (1, 2, 3, or 4-)piperidinyl, 1-methyl-(2, 3, or 4-)piperidinyl, 1-ethyl-(2, 3, or 4-)piperidinyl, 1-propyl-(2, 3, or 4-)piperidinyl, 1-isopropyl-(2, 3, or 4-)piperidinyl, 1-butyl-(2, 3, or 4-)piperidinyl, 1-isobutyl-(2, 3, or 4-)piperidinyl, 1-tert-butyl-(2, 3, or 4-)piperidinyl, 1-pentyl-(2, 3, or 4-)piperidinyl, 1-hexyl-(2, 3, or 4-)piperidinyl, 1,2-dimethyl-(3, 4, 5, or 6-)piperidinyl, 1,2,6-trimethyl-(3, 4, or 5-)piperidinyl groups.

Examples of the quinolyl lower alkyl group include quinolylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a (2, 3, 4, 5, 6, 7 or 8-)quinolylmethyl group, 2-[(2, 3, 4, 5, 6, 7 or 8-)quinolyl]ethyl group, 1-[(2, 3, 4, 5, 6, 7 or 8-)quinolyl]ethyl group, 3-[(2, 3, 4, 5, 6, 7 or 8-)quinolyl]propyl group, 4-[(2, 3, 4, 5, 6, 7 or 8-)quinolyl]butyl group, 5-[(2, 3, 4, 5, 6, 7 or 8-)quinolyl]pentyl group, and 6-[(2, 3, 4, 5, 6, 7 or 8-)quinolyl]hexyl group.

Examples of the 1,2,3,4-tetrazolyl lower alkyl group which may have, on the tetrazole ring, a substituent selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group include 1,2,3,4-tetrazolylalkyl groups which may have, on the tetrazole ring, a substituent selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, the 1,2,3,4-tetrazolylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, such as [(1 or 5-)1,2,3,4-tetrazolyl]methyl, 2-[(1 or 5-)1,2,3,4-tetrazolyl]ethyl, 1-[(1 or 5-)1,2,3,4-tetrazolyl]ethyl, 3-[(1 or 5-)1,2,3,4-tetrazolyl]propyl, 4-[(1 or 5-)1,2,3,4-tetrazolyl]butyl, 5-[(1 or 5-)1,2,3,4,-tetrazolyl]pentyl, 6-[(1 or 5-)1,2,3,4-tetrazolyl]hexyl, 5-[1-methyl-5-(1,2,3,4-tetrazolyl)]pentyl, 6-[1-methyl-5-(1,2,3,4-tetrazolyl)]hexyl, 5-methyl-1-(1,2,3,4-tetrazolyl)methyl, 2-[5-ethyl-1-(1,2,3,4-tetrazolyl]hexyl, 1,1-dimethyl-2-[(1 or 5-)1,2,3,4-tetrazolyl)]ethyl, 2-methyl-3-[(1 or 5-)1,2,3,4-tetrazolyl]propyl, [1-methyl-5-(1,2,3,4-tetrazolyl)]methyl, [1-ethyl-5-(1,2,3,4-tetrazolyl)]methyl, 2-[1-propyl-5-(1,2,3,4-tetrazolyl)]ethyl, 1-[1-butyl-5-(1,2,3,4-tetrazolyl)]ethyl, 3-[1-pentyl-5-(1,2,3,4-tetrazolyl)]propyl, 3-[5-propyl-1-(1,2,3,4-tetrazolyl)]propyl, 4-[5-butyl-1-(1,2,3,4-tetrazolyl)]butyl, 5-[5-pentyl-1-(1,2,3,4-tetrazolyl)]pentyl, 6-[5-hexyl-1-(1,2,3,4-tetrazolyl)]hexyl, [1-ethyl-5-(1,2,3,4-tetrazolyl)]methyl, [1-benzyl-5-(1,2,3,4-tetrazolyl)]methyl, 1-[(2-phenylethyl)-5-(1,2,3,4-tetrazolyl)]methyl, 2-[1-(3-phenylpropyl)-5-(1,2,3,4-tetrazolyl)]ethyl, 1-[(1-(4-phenylbutyl)-5-(1,2,3,4-tetrazolyl)]ethyl, 3-[(1-(5-phenylpentyl)-5-(1,2,3,4-tetrazolyl)]propyl, 4-(1-(6-phenylhexyl)-5-(1,2,3,4-tetrazolyl)]butyl, 5-[1-(1,1-dimethyl-2-phenylethyl)-5-(1,2,3,4-tetrazolyl)]methyl, 6-[(1-(2-methyl-3-phenylpropyl)-5-(1,2,3,4-tetrazolyl)]hexyl, 5-benzyl-1-(1,2,3,4-tetrazolyl)methyl, 2-(5-(1-phenylethyl)-1-(1,2,3,4-tetrazolyl)]ethyl, 3-[5-(3-phenylpropyl)-1-(1,2,3,4-tetrazolyl)]propyl, 4-[(5-(4-phenylbutyl)-1-(1,2,3,4-tetrazolyl)]butyl, 5-[(5-(5-phenylpentyl)-1-(1,2,3,4-tetrazolyl)]pentyl, 6-[5-(6-phenylhexyl)-1-(1,2,3,4-tetrazolyl)]hexyl groups.

Examples of the thiazolyl lower alkyl group which may have a phenyl group as a substituent on the thiazole ring include thiazolylalkyl groups which may have 1 or 2 phenyl groups as substituents on the thiazole ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [(2, 4, or 5-)thiazolyl]methyl, 2-[(2, 4, or 5-)thiazolyl]ethyl, 1-[(2, 4, or 5-)thiazolyl]ethyl, 3-[(2, 4, or 5-)thiazolyl]propyl, 4-[(2, 4, or 5-)thiazolyl]butyl, 5-[(2, 4, or thiazolyl]pentyl, 6-[(2, 4, or 5-)thiazolyl]hexyl, 1,1-dimethyl-2-[(2, 4, or 5-)thiazolyl]ethyl, 2-methyl-3-[(2, 4, or 5-)thiazolyl]propyl, [2-phenyl-(4 or 5-)thiazolyl]-methyl, 2-[(4-phenyl-(2 or 5-)thiazolyl]ethyl, 1-[(5-phenyl-(2 or 4-)thiazolyl]ethyl, 3-[(2-phenyl-(2 or 5-)thiazolyl]propyl, 4-(2,4-diphenyl-5-thiazolyl)butyl, 5-(2,5-diphenyl-4-thiazolyl)pentyl, 6-(4,5-diphenyl-2-thiazolyl)hexyl, 1,1-dimethyl-2-[2-phenyl-(4 or 5-)thiazolyl]ethyl, 2-methyl-3-[4-phenyl-(2 or 5-)thiazolyl]propyl, [4-phenyl-(2 or 5-)thiazolyl]-methyl, [5-phenyl-(2 or 4-)thiazolyl]methyl, (2,4-diphenyl-5-thiazolyl)methyl, (2,5-diphenyl-4-thiazolyl)methyl, (4,5-diphenyl-2-thiazolyl)methyl groups.

Examples of the benzoyl lower alkyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkoxy group and a halogen atom include benzoylalkyl groups which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a linear or branched alkoxy group having 1 to 6 carbon atoms and a halogen atom such as benzoylmethyl, 2-benzoylethyl, 1-benzoylethyl, 3-benzoylpropyl, 4-benzoylbutyl, 5-benzoylpentyl, 6-benzoylhexyl, 1,1-dimethyl-2-benzoylethyl, 2-methyl-3-benzoylpropyl, 4-fluorobenzoylmethyl, 2-chlorobenzoylmethyl, 3-chlorobenzoylmethyl, 4-chlorobenzoylmethyl, 2-(4-fluorobenzoyl)ethyl, 2-(4-chlorobenzoyl)ethyl, 3,4-dibromobenzoylmethyl, 3,4-diiodobenzoylmethyl, 2,4-difluorobenzoylmethyl, 2,5-dichlorobenzoylmethyl, 2,6-dichlorobenzoylmethyl, 3,4,5-trifluorobenzoylmethyl, 3-(4-chlorobenzoyl)propyl, 1-(2-bromobenzoyl)ethyl, 4-(3-fluorobenzoyl)butyl, 5-(4-iodobenzoyl)pentyl, 6-(4-chlorobenzoyl)hexyl, 1,1-dimethyl-2-(3-fluorobenzoyl)ethyl, 2-methyl-3-(4-chlorobenzoyl)propyl, 2-methoxybenzoylmethyl, 2-(3-methoxybenzoyl)ethyl, 2-(4-methoxybenzoyl)ethyl, 4-methoxybenzoylmethyl, 1-(2-ethoxybenzoyl)ethyl, 3-(3-ethoxybenzoyl)propyl, 4-(4-ethoxybenzoyl)butyl, 5-(4-isopropoxybenzoyl)pentyl, 6-(3-butoxybenzoyl)hexyl, 1,1-dimethyl-2-(4-pentyloxybenzoyl)ethyl, 2-methyl-3-(4-hexyloxybenzoyl)propyl, 3,4-dimethoxybenzoylmethyl, 3,4-diethoxybenzoylmethyl, 2,4-dimethoxybenzoylmethyl, 2,5-dimethoxybenzoylmethyl, 2,6-dimethoxybenzoylmethyl, 3,4,5-trimethoxybenzoylmethyl, 2-chloro-4-methoxybenzoylmethyl, 3-fluoro-5-ethoxybenzoylmethyl groups.

Examples of the piperidinyl lower alkyl group which may have a lower alkyl group as a substituent on the piperidine ring include piperidinylalkyl groups which may have 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms on the piperidine ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [(1, 2, 3, or 4-)piperidinyl]methyl, 2-[(1, 2, 3, or 4-)piperidinyl]-ethyl, 1-[(1, 2, 3, or 4-)piperidinyl]ethyl, 3-[(1, 2, 3, or 4-)piperidinyl]propyl, 4-[(1, 2, 3, or 4-)piperidinyl]butyl, 5-[(1, 2, 3, or 4-)piperidinyl]pentyl, 6-[(1, 2, 3, or 4-)piperidinyl]hexyl, 1,1-dimethyl-2-[(1, 2, 3, or 4-)piperidinyl]ethyl, 2-methyl-3-[(1, 2, 3, or 4-)piperidinyl]propyl, [1-methyl-(2, 3, or 4-)piperidinyl]methyl, 2-[1-ethyl-(2, 3, or 4-)piperidinyl]ethyl, 1-[4-propyl-(1, 2, or 3-)piperidinyl]ethyl, 3-[3-isopropyl-(1, 2, 4, 5, 6-)piperidinyl]propyl, 4-[2-butyl-(1, 3, 4, 5, or 6-)piperidinyl]butyl, 5-[1-isobutyl-(2, 3, or 4-)piperidinyl]pentyl, 6-[1-tert-butyl-(2, 3, or 4-)piperidinyl]hexyl, 1,1-dimethyl-2-[4-pentyl-(1 ,2, or 3-)piperidinyl]ethyl, 2-methyl-3-[1-hexyl-(2, 3, or 4-)piperidinyl]propyl, [1,2-dimethyl-(3, 4, 5, or 6-)piperidinyl]methyl, [1,2,6-trimethyl-(3, 4, or 5-)piperidinyl]methyl groups.

Examples of the imidazolyl group which may have 1 to 3 phenyl groups as substituents on the imidazole ring include imidazolyl groups which may have 1 to 3 phenyl groups as substituents on the imidazole ring such as a (1, 2, 4 or 5-)imidazolyl group, 1-phenyl-(2, 4 or 5-)imidazolyl group, 2-phenyl-(1, 4 or 5-)imidazolyl group, 4-phenyl-(1, 2 or 5-)imidazolyl group, 5-phenyl-(1, 2 or 4-)imidazolyl group, 1,2-diphenyl-(4 or 5-)imidazolyl group, 2,4-diphenyl-(1 or 5-)imidazolyl group, 4,5-diphenyl-(1 or 2-)imidazolyl group, 2,5-diphenyl-(1 or 4-)imidazolyl group, and 2,4,5-triphenyl-1-imidazolyl group.

Examples of the benzimidazolyl group which may have 1 to 3 lower alkyl groups as substituents on the benzimidazole ring include benzimidazolyl group which may have 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms as substituents on the benzimidazole ring such as (1, 2, 4, 5, 6, or 7-)benzimidazolyl, 1-methyl-(2, 4, 5, 6, or 7-)benzimidazolyl, 2-ethyl-(1, 4, 5, 6, or 7-)benzimidazolyl, 4-propyl-(1, 2, 5, 6, or 7-)benzimidazolyl, 5-butyl-(1, 2, 4, 6, or 7-)benzimidazolyl, 6-pentyl-(1, 2, 4, 5, or 7-)benzimidazolyl, 7-hexyl-(1, 2, 4, 5, or 6-)benzimidazolyl, 1-ethyl-(2, 4, 5, 6, or 7-)benzimidazolyl]hexyl, 1-butyl-(2, 4, 5, 6, or 7-)benzimidazolyl, 1-isopropyl-(1, 2, 4, 5, 6, or 7-)benzimidazolyl, 1,2-dimethyl-(4, 5, 6, or 7-)benzimidazolyl, 1-methyl-4-ethyl-(2, 5, 6, or 7-)benzimidazolyl, 1-propyl-5-methyl-(2, 4, 6, or 7-)benzimidazolyl, 1,2,5-trimethyl-(2, 4, 5, 6, or 7-)benzimidazolyl groups.

Examples of the pyridyl lower alkoxy group include pyridylalkoxy group of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a (2, 3 or 4-)pyridylmethoxy group, 2-[(2, 3 or 4-)pyridyl]ethoxy group, 1-[(2, 3 or 4-)pyridyl]ethoxy group, 3-[(2, 3 or 4-)pyridyl]propoxy group, 4-[(2, 3 or 4-)pyridyl]butoxy group, 1-1-dimethyl-2-[(2, 3 or 4-)pyridyl]ethoxy group, 5-[(2, 3 or 4-)pyridyl]pentyloxy group, 6-[(2, 3 or 4-)pyridyl]hexyloxy group, 1-[(2, 3 or 4-)pyridyl]isopropoxy group, and 2-methyl-3-[(2, 3 or 4-)pyridyl]propoxy group.

Examples of the 1,2,3,4-tetrahydroquinolyl lower alkyl group which may have an oxo group as a substituent on the tetrahydroquinoline ring include 1,2,3,4-tetrahydroquinolylalkyl groups which may have 1 or 2 oxo groups as substituents on the tetrahydroquinoline ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolylmethyl, 2-[(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]ethyl, 1-[(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]ethyl, 3-[(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]propyl, 4-[(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]butyl, 5-[(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]pentyl, 6-[(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]hexyl, 1,1-dimethyl-2-[(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]ethyl, 2-methyl-3-[(1, 2, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]propyl, [2-oxo-(1, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]methyl, [4-oxo-(1, 2, 3, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]methyl, [2,4-dioxo-(1, 3, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]methyl, 2-[(2-oxo-(1, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]ethyl, 3-[4-oxo-(1, 2, 3, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]propyl, 4-[2,4-dioxo-(1, 3, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]butyl, 5-[(2-oxo-(1, 3, 4, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]pentyl, 6-[4-oxo-(1, 2, 3, 5, 6, 7, or 8-)1,2,3,4-tetrahydroquinolyl]hexyl groups.

Examples of the 1,3,4-oxadiazolyl lower alkyl group which may have an oxo group as a substituent on the oxadiazole ring include 1,3,4-oxadiazolylalkyl groups which may have an oxo group as a substituent on the oxadiazole ring and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as (2 or 5-)1,3,4-oxadiazolylmethyl, 2-[(2 or 5-)1,3,4-oxadiazolyl]ethyl, 1-[(2 or 5-)1,3,4-oxadiazolyl]ethyl, 3-[(2 or 5-)1,3,4-oxadiazolyl]propyl, 4-[(2 or 5-)1,3,4-oxadiazolyl]butyl, 5-[(2 or 5-)1,3,4-oxadiazolyl]pentyl, 6-[(2 or 5-)1,3,4-oxadiazolyl]hexyl, 1,1-dimethyl-2-[(2 or 5-)1,3,4-oxadiazolyl]ethyl, 2-methyl-3-[(2 or 5-)1,3,4-oxadiazolyl]propyl, 2-oxo-[(3 or 5-)1,3,4-oxadiazolyl]methyl, 5-oxo-[(2 or 3-)1,3,4-oxadiazolyl]methyl, 2-[2-oxo-(3 or 5-)(1,3,4-oxadiazolyl]ethyl, 1-[5-oxo-(2 or 3-)1,3,4-oxadiazolyl]ethyl, 3-[(2 or 5-)1,3,4-oxadiazolyl]propyl, 4-[(2-oxo(3 or 5-)1,3,4-oxadiazolyl]butyl, 5-[5-oxo(2 or 3-)1,3,4-oxadiazolyl]pentyl, 6-[2-oxo(3 or 5-)1,3,4-oxadiazolyl]hexyl, 1,1-dimethyl-2-[5-oxo(2 or 3-)1,3,4-oxadiazolyl]ethyl, 2-methyl-3-[(2-oxo(3 or 5-)1,3,4-oxadiazolyl]propyl groups.

Examples of the thienyl lower alkyl group include thienylalkyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as a (2 or 3-)thienylmethyl group, 2-[(2 or 3-)thienyl]ethyl group, 1-[(2 or 3-)thienyl]ethyl group, 3-[(2 or 3-)thienyl]propyl group, 4-[(2 or 3-)thienyl]butyl group, 5-[(2 or 3-)thienyl]pentyl group, 6-[(2 or 3-)thienyl]hexyl group, 1,1-dimethyl-2-[(2 or 3-)thienyl]ethyl group, and 2-methyl-3-[(2 or 3-)thienyl]propyl group.

Examples of the pyrimidinylcarbonyl group which may have an oxo group as a substituent on the pyrimidine ring include pyrimidinylcarbonyl groups which may have 1 to 3 oxo groups as substituents on the pyrimidine ring such as a (2, 3, 4 or 6-)pyrimidinylcarbonyl group, 2,6-dioxo-(1, 3, 4 or 5-)pyrimidinylcarbonyl group, 2-oxo-(1, 3, 4, 5 or 6-)pyrimidinylcarbdnyl group, 6-oxo-(1, 2, 3, 4 or 5-)pyrimidinylcarbonyl group, 4-oxo-(1, 2, 3, 4 or 6-)pyrimidylcarbonyl group, 2,4-dioxo-(1, 3, 4 or 6-)pyrimidinylcarbonyl group, and 2,4,6-trioxo-(1, 3 or 5-)pyrimidylcarbonyl group.

Examples of the lower alkoxy lower alkoxy group include linear or branched alkoxy groups having 1 to 6 carbon atoms which may have a linear or branched alkoxy group having 1 to 6 carbon atoms as a substituent such as a methoxymethoxy group, 1-ethoxyethoxy group, 2-methoxyethoxy group, 2-propoxyethoxy group, 3-isopropoxypropoxy group, 4-butoxybutoxy group, 5-pentyloxypentyloxy group, 6-hexyloxyhexyloxy group, 1,1-dimethyl-2-methoxyethoxy group, 2-methyl-3-ethoxypropoxy group, and 3-methoxypropoxy group.

Examples of the lower alkoxycarbonyl lower alkoxy group include alkoxycarbonylalkoxy groups of which both alkoxy moieties are linear or branched alkoxy groups having 1 to 6 carbon atoms such as methoxycarbonylmethoxy, ethoxycarbonylmethoxy, 2-methoxycarbonylethoxy, 2-ethoxycarbonylethoxy, 1-ethoxycarbonylethoxy, 3-methoxycarbonylpropoxy, 3-ethoxycarbonylpropoxy, 4-ethoxycarbonylbutoxy, 5-isopropoxycarbonylpentyloxy, 6-propoxycarbonylhexyloxy, 1,1-dimethyl-2-butoxycarbonylethoxy, 2-methyl-3-tert-butoxycarbonylpropoxy, 2-pentyloxycarbonylethoxy, hexyloxycarbonylmethoxy groups.

Examples of the carboxy lower alkoxy group include carboxyalkoxy groups of which the alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms such as a carboxymethoxy group, 2-carboxyethoxy group, 1-carboxyethoxy group, 3-carboxypropoxy group, 4-carboxybutoxy group, 5-carboxypentyloxy group, 6-carboxyhexyloxy group, 1,1-dimethyl-2-carboxyethoxy group, and 2-methyl-3-carboxypropoxy group.

Examples of the phenoxy lower alkanoyl group include phenoxyalkanoyl groups of which the alkanoyl moiety is a linear or branched alkanoyl group having 2 to 6 carbon atoms such as a 2-phenoxyacetyl group, 3-phenoxypropionyl group, 2-phenoxypropionyl group, 4-phenoxybutyryl group, 5-phenoxypentanoyl group, 6-phenoxyhexanoyl group, 2,2-dimethyl-2-phenoxypropionyl group, and 2-methyl-3-phenoxypropionyl group.

Examples of the 1,2,3,4-tetrahydroquinolylcarbonyl group which may have an oxo group as a substituent on the tetrahydroquinoline ring include 1,2,3,4-tetrahydroquinolylcarbonyl groups which may have 1 or 2 oxo groups as substituents on the tetrahydroquinoline ring such as a [(1, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl]carbonyl group, [2-oxo-(1, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl]carbonyl group, [4-oxo-(1, 2, 3, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl]carbonyl group, and [2,4-dioxo-(1, 3, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl]carbonyl group.

Examples of the 1,2,3,4-tetrahydroquinolyl group which may have an oxo group as a substituent on the tetrahydroquinoline ring include 1,2,3,4-tetrahydroquinolyl groups which may have 1 or 2 oxo groups as substituents on the tetrahydroquinoline ring such as a (1, 2, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl group, 2-oxo-(1, 3, 4, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl group, 4-oxo-(1, 2, 3, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl group, and 2,4-dioxo-(1, 3, 5, 6, 7 or 8-)1,2,3,4-tetrahydroquinolyl group.

Examples of the amino group which may have a lower alkoxycarbonyl group as a substituent include amino groups which may have a linear or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms such as an amino group, methoxycarbonylamino group, ethoxycarbonylamino group, propoxycarbonylamino group, isopropoxycarbonylamino group, butoxycarbonylamino group, tert-butoxycarbonylamino group, pentyloxycarbonylamino group, and hexyloxycarbonylamino group.

Examples of the benzoyl group which may have 1 to 3 lower alkoxy groups as substituents on the phenyl ring include benzoyl groups which may have 1 to 3 linear or branched alkoxy groups having 1 to 6 carbon atoms as substituents on the phenyl ring such as a benzoyl group, 2-methoxybenzoyl group, 3-methoxybenzoyl group, 4-methoxybenzoyl group, 2-ethoxybenzoyl group, 3-ethoxybenzoyl group, 4-ethoxybenzoyl group, 4-isopropoxybenzoyl group, 3-butoxybenzoyl group, 4-pentyloxybenzoyl group, 4-hexyloxybenzoyl group, 3,4-dimethoxybenzoyl group, 3,4-diethoxybenzoyl group, 2,4-dimethoxybenzoyl group, 2,5-dimethoxybenzoyl group, 2,6-dimethoxybenzoyl group, and 3,4,5-trimethoxybenzoyl group.

Examples of the lower alkyl group which have 1 or 2 phenyls which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group, and a lower alkylthio group include, in addition to the above described phenyl lower alkyl groups, linear or branched alkyl groups which have 1 to 6 carbon atoms which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms, a cyano group, a nitro group, a phenyl group, a halogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents, a linear or branched alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents, and a linear or branched alkylthio group having 1 to 6 carbon atoms such as 1,1-diphenylmethyl, 1,1-di(4-fluorophenyl)methyl, 1-phenyl-1-(4-methoxyphenyl)methyl, 3,3-diphenylpropyl, 2,5-difluorobenzyl, 2,4-difluorobenzyl, 3,4-difluo benzyl, 3,5-difluorobenzyl, 2,6-difluorobenzyl, 3-trifluoromethylbenzyl, 2-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 3,4-dimethylbenzyl, 2,3-dimethylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-cyanobenzyl, 2-cyanobenzyl, 3-cyanobenzyl, 4-methoxybenzyl, 2,3-dichlorobenzyl, 2,4-dichlorobenzyl, 2,5-dichlorobenzyl, 3,4-dichlorobenzyl, 2,6-dichlorobenzyl, 4-fluorobenzyl, 3-fluorobenzyl, 2-fluorobenzyl, 4-nitrobenzyl, 3-nitrobenzyl, 2-nitrobenzyl, 3-trifluoromethoxybenzyl, 4-trifluoromethoxybenzyl, 2-trifluoromethoxybenzyl, 4-methoxycarbonylbenzyl, 3-methoxycarbonylbenzyl, 4-tert-butylbenzyl, 4-ethylbenzyl, 4-isopropylbenzyl, 4-methoxy-3-chlorobenzyl, 2-(4-methoxyphenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2-(4-chlorophenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(4-methylphenyl)ethyl, 4-phenylbenzyl, 3,3-diphenylpropyl, 3-methyl-4-nitrobenzyl, 4-(4-methoxyphenyl)butyl, 2-(4-methylphenyl)ethyl, 4-tert-butoxycarbonylbenzyl, 3-chloro-6-methoxybenzyl, 4-nitro-3-methylbenzyl, 4-tert-butyrylbenzyl, 2-(2-ethoxycarbonylphenyl)ethyl, 1-(3-propoxycarbonylphenyl)ethyl, 3-(4-pentyloxycarbonylphenyl)propyl, 4-(3-hexyloxycarbonylphenyl)butyl, 5-(3,4-dimethoxycarbonylphenyl)pentyl, 6-(3,4,5-diethoxycarbonylphenyl)hexyl, 1,1-dimethyl-2-(4-butoxycarbonylphenyl)ethyl, 2-methyl-3-(4-methoxycarbonylphenyl)propyl, 2-(2-cyanophenyl)ethyl, 1-(3-cyanophenyl)ethyl, 3-(4-cyanophenyl)propyl, 4-(2-cyanophenyl)butyl, 5-(3-cyanophenyl)pentyl, 6-(4-cyanophenyl)hexyl, 1,1-dimethyl-2-(2,4-dicyanophenyl)ethyl, 2-methyl-3-(2,4,6-tricyanophenyl)propyl, 2-(2-nitrophenyl)ethyl, 1-(3-nitrophenyl)ethyl, 3-(4-nitrophenyl)propyl, 4-(2-nitrophenyl)butyl, 5-(3-nitrophenyl)pentyl, 6-(4-nitrophenyl)hexyl, 1,1-dimethyl-2-(2,4-dinitrophenyl)ethyl, 2-methyl-3-(2,4,6-trinitrophenyl)propyl, 2-(2-phenylphenyl)ethyl, 1-(3-phenylphenyl)ethyl, 3-(4-phenylphenyl)propyl, 4-(2-phenylphenyl)butyl, 5-(3-phenylphenyl)pentyl, 6-(4-phenylphenyl)hexyl, 1,1-dimethyl-2-(2,4-diphenylphenyl)ethyl, 2-methyl-3-(2,4,6-triphenylphenyl)propyl, 2-(2-fluorophenyl)ethyl, 1-(3-bromophenyl)ethyl, 3-(4-iodophenyl)propyl, 4-(2-bromophenyl)butyl, 5-(3-chlorophenyl)pentyl, 6-(4-bromophenyl)hexyl, 1,1-dimethyl-2-(2,4-dichlorophenyl)ethyl, 2-methyl-3-(2,4,6-trifluorophenyl)propyl, 2-(2-ethylphenyl)ethyl, 1-(3-propylphenyl)ethyl, 3-(4-butylphenyl)propyl, 4-(2-pentylphenyl)butyl, 5-(3-hexylphenyl)pentyl, 6-(4-trifluoromethylphenyl)hexyl, 1,1-dimethyl-2-(2,4-dimethylphenyl)ethyl, 2-methyl-3-(2,4,6-tri(trifluoromethyl)phenyl]propyl, 2-(2-ethoxyphenyl)ethyl, 1-(3-propoxyphenyl)ethyl, 3-(4-butoxyphenyl)propyl, 4-(2-pentyloxyphenyl)butyl, 5-(3-hexyloxyphenyl)pentyl, 6-(4-trifluoromethoxyphenyl)hexyl, 1,1-dimethyl-2-(2,4-dimethoxyphenyl)ethyl, 2-methyl-3-(2,4,6-tri(trifluoromethoxy)phenyl]propyl, 2-methylthiobenzyl, 3-methylthiobenzyl, 4-methylthiobenzyl, 3,4-dimethylthiobenzyl, 2,3-dimethylthiobenzyl, 2-(2-ethylthiophenyl)ethyl, 2-(4-methylthiophenyl)ethyl, 1-(3-propylthiophenyl)ethyl, 3-(4-butylthiophenyl)propyl, 4-(2-pentylthiophenyl)butyl, 5-(3-hexylthiophenyl)pentyl, 6-(4-methylthiophenyl)hexyl, 1,1-dimethyl-2-(2,4-dimethylthiophenyl)ethyl, 2-methyl-3-[2,4,6-trimethylthiophenyl]propyl, 2-methyl-4-cyanobenzyl, 3-ethoxy-4-ethoxycarbonylbenzyl, 4-phenyl-3-nitrobenzyl, 3-fluoro-4-methoxybenzyl, 4-trifluoromethyl-3-cyanobenzyl, 3-trifluoromethoxy-3-fluorobenzyl groups.

Examples of the phenyl group which may have, on the phenyl ring, 1 to 3 groups selected from the group consisting of a linear or branched alkoxy group having 1 to 6 carbon atoms which may have a halogen atom as a substituent and a linear or branched alkyl group having 1 to 6 carbon atoms which may have a halogen atom as a substituent include phenyl groups which may have, on the phenyl ring, 1 to 3 groups selected from the group consisting of a linear or branched alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents and a linear or branched alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms as substituents such as phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-butylphenyl, 4-pentylphenyl, 4-hexylphenyl, 3,4-dimethylphenyl, 3,4-diethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4,5-trimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxy]phenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, 3-butoxyphenyl, 4-pentyloxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl, 3,4-diethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-(bromomethoxy)phenyl, 3-(2-chloroethoxy)phenyl, 4-(2,3-dichloropropoxy)phenyl, 4-(4-fluorobutoxy)phenyl, 3-(5-chloropentyloxy)phenyl, 4-(5-bromohexyloxy)phenyl, 4-(5,6-dibromohexyloxy)phenyl, 3,4-di(trifluoromethoxy)phenyl, 3,4-di(4,4,4-trichlorobutoxy)phenyl, 2,4-di(3-chloro-2-methoxypropyl)phenyl, 2,5-di(3-chloropropoxy)phenyl, 2,6-di(2,2,2-trifluoroethoxy)phenyl, 3,4,5-tri(trifluoromethoxy)phenyl, 4-(2,2,2-trichloroethoxy)phenyl, 2-methyl-4-trifluoromethoxyphenyl, 3-ethyl-4-trichloromethoxyphenyl, 2-methoxy-4-trifluoromethoxyphenyl, 3-ethoxy-4-trichloromethoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-(bromomethyl)phenyl, 3-(2-chloroethyl)phenyl, 4-(2,3-dichloropropyl)phenyl, 4-(4-fluorobutyl)phenyl, 3-(5-chloropentyl)phenyl, 4-(5-bromohexyl)phenyl, 4-(5,6-dibromohexyl)phenyl, 3,4-di(trifluoromethyl)phenyl, 3,4-di(4,4,4-trichlorobutyl)phenyl, 2,4-di(3-chloro-2-methylpropyl)phenyl, 2,5-di(3-chloropropyl)phenyl, 2,6-di(2,2,2-trifluoroethyl)phenyl, 3,4,5-tri(trifluoromethyl)phenyl, 4-(2,2,2-trichloroethyl)phenyl, 2-methyl-4-trifluoromethylphenyl, 3-ethyl-4-trichloromethylphenyl groups.

Examples of the pyrrolidinyl lower alkyl group which may have, on the pyrrolidine ring, 1 to 3 lower alkyl groups which may have a hydroxyl group as a substituent include pyrrolidinylalkyl groups which may have, on the pyrrolidine ring, 1 to 3 linear or branched alkyl groups having 1 to 6 carbon atoms which may have 1 to 3 hydroxyl groups as substituents and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [(1, 2, or 3-)pyrrolidinyl]methyl, 2-[(1, 2, or 3-)pyrrolidinyl]-ethyl, 1-[(1, 2, or 3-)pyrrolidinyl]ethyl, 3-[(1, 2, or 3-)pyrrolidinyl]propyl, 4-[(1, 2, or 3-)pyrrolidinyl]-butyl, 5-[(1, 2, or 3-)pyrrolidinyl]pentyl, 6-[(1,2, or 3-)pyrrolidinyl]hexyl, 1,1-dimethyl-2-[(1, 2, or 3-)pyrrolidinyl]ethyl, 2-methyl-3-[(1, 2, or 3-)pyrrolidinyl]propyl, [1-methyl-(2 or 3-)pyrrolidinyl]methyl, 2-[2-ethyl-(1, 3, 4, or 5-)pyrrolidinyl]ethyl, 1-[3-propyl-(1, 2, 4, or 5-)pyrrolidinyl]ethyl, 3-[1-butyl-(2 or 3-)pyrrolidinyl]propyl, 4-[2-pentyl-(1, 3, 4, or 5-)pyrrolidinyl]butyl, 5-[3-hexyl-(1, 2, 4, or 5-)pyrrolidinyl]pentyl, 6-[1,2-dimethyl-(3, 4, or 5-)pyrrolidinyl]hexyl, 1,1-dimethyl-2-[1,2,3-trimethyl-(4 or 5-)pyrrolidinyl]ethyl, 2-methyl-3-[(1-ethyl-2-methyl-(3, 4, or 5-)pyrrolidinyl]propyl, [1-(2-hydroxyethyl)-(2 or 3-)pyrrolidinyl]methyl, [2-hydroxymethyl-(1, 3, 4, or 5-)pyrrolidinyl]methyl, 2-[(2-hydroxymethyl-(1, 3, 4, or 5-)pyrrolidinyl]ethyl, 1-[(3-(3-hydroxypropyl)-(1, 2, 4, or 5-)pyrrolidinyl]ethyl, 3-[(1-(4-hydroxybutyl)-(2 or 3-)pyrrolidinyl]propyl, 4-[(2-(5-hydroxypentyl)-(1, 3, 4, or 5-)pyrrolidinyl]butyl, 5-[(3-(6-hydroxyhexyl)-(1, 2, 4, or 5-)pyrrolidinyl]pentyl, 6-[1,2-dihydroxymethyl-(3, 4, or 5-)pyrrolidinyl]hexyl, 1,1-dimethyl-2-[(1,2,3-trihydroxymethyl-(4 or 5-)pyrrolidinyl]ethyl, 2-methyl-3-[2-(1,2-hydroxyethyl)-(1, 3, 4, or 5-)pyrrolidinyl]propyl, [2-(2,3,4-trihydroxybutyl)-(1, 3, 4, or 5-)pyrrolidinyl]methyl groups.

Examples of the amino substituted lower alkyl group which may have a substituent selected from the group consisting of a phenyl group and a lower alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms substituted with an amino group which may have 1 or 2 substituents selected from the group consisting of a phenyl group and a linear or branched alkyl group having 1 to 6 carbon atoms such as aminomethyl, 2-aminomethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1,1-dimethyl-2-aminoethyl, N,N-diethyl-2-aminoethyl, 2-methyl-3-aminopropyl, methylaminomethyl, 1-ethylaminoethyl, 2-propylaminoethyl, 3-isopropylaminopropyl, 4-butylaminobutyl, 5-pentylaminopentyl, 6-hexylaminohexyl, dimethylaminomethyl, 2-diisopropylaminoethyl, (N-ethyl-N-propylamino)methyl, 2-(N-methyl-N-hexylamino)ethyl, phenylaminomethyl, 1-phenylaminoethyl, 2-phenylaminoethyl, 3-phenylaminopropyl, 4-phenylaminobutyl, 5-phenylaminopentyl, 6-phenylaminohexyl, N-methyl-N-phenylaminomethyl, 2-(N-ethyl-N-phenylamino)ethyl, (N-ethyl-N-phenylamino)methyl, 2-(N-methyl-N-phenylamino)ethyl groups.

Examples of the tetrahydrofuryl lower alkyl group which may have a hydroxyl group as a substituent on the lower alkyl group include tetrahydrofurylalkyl groups which may have a hydroxyl group as a substituent on the lower alkyl group and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as [(2 or 3-)tetrahydrofuryl]methyl, 2-[(2 or 3-)tetrahydrofuryl]ethyl, 1-[(2 or 3-)tetrahydrofuryl]ethyl, 3-[(2 or 3-)tetrahydrotetrahydrofuryl]propyl, 4-[(2 or 3-)tetrahydrofuryl]butyl, 5-[(2 or 3-)tetrahydrofuryl]pentyl, 6-[(2 or 3-)tetrahydrofuryl]hexyl, 1,1-dimethyl-2-[(2 or 3-)tetrahydrofuryl]ethyl, 2-methyl-3-[(2 or 3-)tetrahydrofuryl]propyl, 1-hydroxy-1-[(2 or 3-)tetrahydrofuryl]methyl, 2-hydroxy-2-[(2 or 3-)tetrahydrofuryl]ethyl, 2-hydroxy-1-[(2 or 3-)tetrahydrofuryl]ethyl, 3-hydroxy-3-[(2 or 3-)tetrahydrotetrahydrofuryl]propyl, 4-hydroxy-4-[(2 or 3-)tetrahydrofuryl]butyl, 5-hydroxy-5-[(2 or 3-)tetrahydrofuryl]pentyl, 6-hydroxy-6-[(2 or 3-)tetrahydrofuryl]hexyl, 2-hydroxy-1,1-dimethyl-2-[(2 or 3-)tetrahydrofuryl]ethyl, 3-hydroxy-2-methyl-3-[(2 or 3-)tetrahydrofuryl]propyl groups.

Examples of the phenoxy lower alkyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group and a nitro group include, in addition to the above described phenoxy lower alkyl groups, phenoxyalkyl groups which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms and a nitro group and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as 2-methylphenoxymethyl, 3-methylphenoxymethyl, 4-methylphenoxymethyl, 3,4-dimethylphenoxymethyl, 2,3-dimethylphenoxymethyl, 3,4,5-trimethylphenoxymethyl, 2-(2-ethylphenoxy)ethyl, 2-(3-methylphenoxy)ethyl, 2-(4-methylphenoxy)ethyl, 1-(3-propylphenoxy)ethyl, 3-(4-butylphenoxy)propyl, 4-(2-pentylphenoxy)butyl, 5-(3-hexylphenoxy)pentyl, 6-(4-methylphenoxy)hexyl, 1,1-dimethyl-2-(2,4-dimethylphenoxy)ethyl, 2-methyl-3-(2,4,6-trimethylphenoxy)propyl, 2-(4-nitro-3-methylphenoxy)ethyl, 4-nitrophenoxymethyl, 3-nitrophenoxymethyl, 2-nitrophenoxymethyl, 2-(2-nitrophenoxy)ethyl, 2-(4-nitrophenoxy)ethyl, 1-(3-nitrophenoxy)ethyl, 3-(4-nitrophenoxy)propyl, 4-(2-nitrophenoxy)butyl, 5-(3-nitrophenoxy)pentyl, 6-(4-nitrophenoxy)hexyl, 1,1-dimethyl-2-(2,4-dinitrophenoxy)ethyl, 2-methyl-3-(2,4,6-trinitrophenoxy)propyl.

Examples of the phenyl lower alkanoyl group include phenylalkanoyl groups of which the alkanoyl moiety is a linear or branched alkanoyl group having 2 to 6 carbon atoms such as a 2-phenylacetyl group, 3-phenylpropionyl group, 2-phenylpropionyl group, 4-phenylbutyryl group, 5-phenylpentanoyl group, 6-phenylhexanoyl group, 2,2-dimethyl-3-phenylpropionyl group, and 2-methyl-3-phenypropionyl group.

Examples of the 5- to 7-membered saturated heterocyclic group formed by mutually binding R²⁰and R²¹, R²²and R²³, R²⁶and R²⁷, R²⁹and R³⁰or R³²and R³³together with the nitrogen atoms bound to them, through or not through a nitrogen atom, a oxygen atom or a sulfur atom, include a pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholino group, thiomorpholino group, and homopiperazinyl group.

Examples of the phenoxy lower alkyl group which may have a lower alkyl group as a substituent on the phenyl ring include, in addition to the above described phenoxy lower alkyl groups, phenoxyalkyl groups which may have, on the phenyl ring, 1 to 3 linear or branched alkyls having 1 to 6 carbon atoms as substituents and of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as 2-methylphenoxymethyl, 3-methylphenoxymethyl, 4-methylphenoxymethyl, 3,4-dimethylphenoxymethyl, 2,3-dimethylphenoxymethyl, 3,4,5-trimethylphenoxymethyl, 2-(2-ethylphenoxy)ethyl, 2-(4-methylphenoxy)ethyl, 1-(3-propylphenoxy)ethyl, 3-(4-butylphenoxy)propyl, 4-(2-pentylphenoxy)butyl, 5-(3-hexylphenoxy)pentyl, 6-(4-methylphenoxy)hexyl, 1,1-dimethyl-2-(2,4-dimethylphenoxy)ethyl, 2-methyl-3-(2,4,6-trimethylphenoxy)propyl groups.

Methods for producing the compound of the present invention will be described below.

The compound of the present invention of the general formula (1) which have various Ys is produced, for example, as shown by the following reaction formulas 1 to 4.

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In the formula, R¹, R², X₁and A are the same as described before, Y₁represents an —O— group, an —S— group or an —NH group, and X₂represents a halogen atom.

The reaction between the compound (2) and the compound (3) is generally carried out in an appropriate solvent or without a solvent, and in the presence or absence of a basic compound.

Examples of the inert solvent used include aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, lower alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol, fatty acids such as acetic acid, esters such as ethyl acetate and methyl acetate, ketones such as acetone and methyl ethyl ketone, acetonitrile, pyridine, dimethylsulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, and hexamethylphosphoric acid triamide, and a mixture thereof.

Examples of the basic compound include carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and cesium carbonate, metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide, sodium hydride, potassium hydride, potassium, sodium, sodium amide, metal alcoholates such as sodium methylate, sodium ethylate, and sodium n-butoxide, and organic bases such as pyridine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO), and a mixture thereof.

When the reaction is carried out in the presence of a basic compound, the basic compound is used in an amount typically equimolar to the compound (2), and preferably 1 to 10 times of the compound (2) on a molar basis.

The compound (3) is used in an amount typically at least equimolar to the compound (2), and preferably 1 to 10 times of the compound (2) on a molar basis.

The reaction is carried out typically at −30 to 200° C., and preferably at about −30 to 150° C., and is generally completed in about 5 minutes to 80 hours.

To this reaction system, an alkali metal halide such as sodium iodide or potassium iodide may be added, and a phase-transfer catalyst may be added.

Examples of the phase-transfer catalyst include quaternary ammonium salts substituted with a group selected from the group consisting of a linear or branched alkyl group having 1 to 18 carbon atoms, a phenyl lower alkyl group which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms and a phenyl group, such as tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium iodide, tetrabutylammonium hydroxide, tetrabutylammonium hydrogensulfite, tributylmethylammonium chloride, tributylbenzylammonium chloride, tetrapentylammonium chloride, tetrapentylammonium bromide, tetrahexylammonium chloride, benzyldimethyloctylammonium chloride, methyltrihexylammonium chloride, benzyldimethyloctadecanylammonium chloride, methyltridecanylammonium chloride, benzyltripropylammonium chloride, benzyltriethylammonium chloride, phenyltriethylammonium chloride, tetraethylammonium chloride, tetramethylammonium chloride; phosphonium salts substituted with a linear or branched having 1 to 18 carbon atoms such as tetrabutylphosphonium chloride; and pyridinium salts substituted with a linear or branched alkyl group having 1 to 18 carbon atoms such as 1-dodecanylpyridinium chloride. These phase-transfer catalysts are used singly or in a combination of two or more.

Typically the phase-transfer catalyst is used in an amount of 0.1 to 1 times of the compound (2), and preferably 0.1 to 0.5 times of the compound (2).

The compound (1a), wherein Y₁represents an —NH group, may also be produced by reacting the compound (2) with the compound (3) in the presence of an acid in place of a base. Examples of the acid used here include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid. These acids are used singly or as a mixture of two or more.

The compound (1), wherein Y represents an —N(R⁵)— group, and R⁵is R⁵other than a hydrogen atom, may be produced from the corresponding compound (1) wherein Y represents an —NH— group, as shown in the following reaction formula 2.

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wherein R¹, R², X₁, A and X₂are the same as described above, R^5arepresents a lower alkyl group, phenyl lower alkyl, group or cycloalkyl group, R^5brepresents a hydrogen atom, lower alkyl group, phenyl group or phenyl lower alkyl group, R^5crepresents a lower alkanoyl group or benzoyl group. R^Brepresents a hydrogen atom or lower alkyl group, and R^5band R^B, together with carbon atoms bound to these groups, may form a cycloalkyl ring by binding each other, provided that the alkyl moiety in the —CHR^BR^5bgroup of the compound (1d) has 1 to 6 carbon atoms.

The reaction of the compound (1b) with the compound (4) is carried out under the similar condition as that for the reaction of the compound (2) with the compound (3) as shown by the above described reaction formula 1.

The reaction of the compound (1b) with the compound (5) is carried out, for example, in the presence of a reducing agent without a solvent or with an appropriate solvent. Hereinafter, this method is called “method A”.

Examples of the solvent used here include water, lower alcohols such as, methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol, acetonitrile, fatty acids such as formic acid, and acetic acid, ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme, aromatic hydrocarbons such as benzene, toluene, and xylene, and halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, and a mixture thereof.

Examples of the reducing agent include fatty acids and alkali metal salts thereof such as formic acid, sodium formate, and sodium acetate, hydride reducing agents such as sodium borohydride, sodium cyanoborohydride, sodium triacetyloxyborohydride, and aluminum lithium hydride, or a mixture of these hydride reducing agents, and catalytic hydrogen reducing agents such as palladium black, palladium-carbon, platinum oxide, platinum black, and Raney nickel.

In using a fatty acid or an alkali metal salt thereof such as formic acid, sodium formate, or sodium acetate as a reducing agent, the appropriate reaction temperature is typically from room temperature to about 200° C., and preferably about 50 to about 150° C., and the reaction is completed generally in about 10 minutes to 10 hours. It is preferable to use a fatty acid or an alkali metal salt thereof in a large excess amount with respect to the compound (1b).

In using a hydride reducing agent, the appropriate reaction temperature is typically −80 to 100° C., and preferably −80 to 70° C., and the reaction is completed in general in 30 minutes to 60 hours. The hydride reducing agent is used in an amount typically 1 to 20 times of the compound (1b), and preferably 1 to 6 times of the compound (1b) on a molar basis. Especially in using aluminum lithium hydride as a hydride reducing agent, it is preferable to employ an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, or diglyme, or an aromatic hydrocarbon such as benzene, toluene, or xylene. To the reaction system, an amine such as trimethylamine, triethylamine, and N-ethyldiisopropylamine, or molecular sieves such as Molecular Sieves 3A (MS-3A) or Molecular Sieves 4A (MS-4A) may be added.

In using a catalytic hydrogen reducing agent, the reaction is preferably carried out in a hydrogen atmosphere typically at a normal pressure to about 20 atm, and preferably at a normal atmosphere to about 10 atm, or in the presence of a hydrogen donor such as formic acid, ammonium formate, cyclohexene, or hydrazine hydrate, at a temperature of typically −30 to 100° C., and preferably 0 to 60° C. The above described reaction is in general completed in about 1 to 12 hours. The catalytic hydrogen reducing agent is used typically in an amount of about 0.1% to 40% by weight, and about 1 to 20% by weight based on the compound (1b).

In the reaction of the compound (1b) with the compound (5), the compound (5) is typically used in an amount at least equimolar to the compound (1b), and preferably used in an equal amount to a large excess amount of compound (5) on a molar basis.

When the compound (5), wherein R^Band R^5bare mutually bound together with the carbon atoms which bind to these groups to form a cycloalkyl ring, is used as a starting material, and the hydride reducing agent is used to carry out the reaction, cycloalkyloxytrialkylsilane such as [(1-ethoxycyclopropyl)oxy]trimethylsilane may be used in place of the compound (5) as the starting material to produce the above described compound (5) in the reaction system.

The compound (1d) may be produced by reacting the compound (1b) with compound (5) under the reaction condition similar to the reaction condition of the compound (1f) with hydroxylamine of the later described reaction formula 3, and then reducing the resulting compound represented by the general formula:

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wherein R¹, R², X₁, R^Band R^5bare the same as described above.

A reaction condition similar to that of the method A may be applied to this reducing reaction.

The reaction of the compound (1b) with the compound (6) is carried out by a method for reacting the compound (1b) with carboxylic acid of the compound (6) in a typical reaction for producing an amide bond. Known reactions for producing an amide bond may be applied to this reaction for producing an amide bond. Specific methods thereof include: (a) a mixed acid anhydride method, specifically, a method of reacting an alkylhalocarboxylic acid with the carboxylic acid (6) to prepare a mixed acid anhydride, and then reacting the amine (1b) with the mixed acid anhydride; (b) an active ester method, specifically, a method of preparing, from the carboxylic acid (6), an active ester such as a phenyl ester, p-nitrophenyl ester, hydroxysuccinimide ester, or 1-hydroxybenzotriazole ester, or an active amide with benzoxazoline-2-thione, and then reacting the active ester or amide with the amine (1b); (c) a carbodiimide method, specifically, a method of condensation reaction of wherein the carboxylic acid (6) with the amine (1b) in the presence of an activator such as dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC), or carbonyldiimidazole; (d) other methods, for example, a method of preparing carboxylic anhydride from the carboxylic acid (6) by the action of a dehydrator such as acetic anhydride, and then reacting the carboxylic anhydride with the amine (1b), a method of reacting an ester of the carboxylic acid (6) with a lower alcohol with the amine (1b) at a high pressure and a high temperature, and a method of reacting an acid halide of the carboxylic acid (6), that is, carboxylic acid halide, with the amine (1b).

The mixed acid anhydride used in the mixed anhydride method (a) described above, may be obtained by a typical Schotten-Baumann reaction, and the compound of the present invention of the general formula (1e) can be produced by reacting the amine (2) with the mixed acid anhydride without isolation.

The Schotten-Baumann reaction described above is carried out in the presence of a basic compound.

The basic compounds used include compounds commonly used in Schotten-Baumann reaction, for example, organic bases such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-ethyldiisopropylamine, diethylaminopyridine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7, and 1,4-diazabicyclo[2.2.2]octane (DABCO), and inorganic bases such as carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate, metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide, potassium hydride, sodium hydride, potassium, sodium, sodium amide, and metal alcoholates such as sodium methylate and sodium ethylate. These basic compounds are used singly or in a combination of two or more. The reaction is carried out at typically about −20 to 100° C., and preferably about 0 to 50° C., and the reaction time is about 5 minutes to 10 hours, and preferably about 5 minutes to 2 hours.

The resulting mixed acid anhydride is reacted with the amine (1b) at typically about −20 to 150° C., preferably about 10 to 50° C., and the reaction time is about 5 minutes to 1.0 hours, and preferably about 5 minutes to 5 hours.

The mixed acid anhydride method is, in general, carried out in a solvent. Any of the solvent conventionally used for the mixed acid anhydride method may be used. Specific examples of the solvent include halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dimethoxyethane, esters such as methyl acetate, ethyl acetate, and isopropyl acetate, and aprotic polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric acid triamide, and a mixture thereof.

Examples of the alkylhalocarboxylic acid used in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chlorformate, ethyl bromoformate, and isobutyl chloroformate.

In the mixed acid anhydride method, it is typically preferable to use the carboxylic acid (6), alkylhalocarboxylic acid and the amine (1b) equimolar to each other. However, each of alkyl halocarboxylic acid and the carboxylic acid (6) may be used 1 to 1.5 times of the amine (1b) on a molar basis, respectively.

In the above described method (c) of condensation reaction in the presence of an activator, the reaction is carried out in an appropriate solvent in the presence or absence of a basic compound. Any of the solvents and basic compounds used in the reaction in the other methods (d) described above of reacting carboxylic acid halide with the amine may be used for this reaction. It is appropriate to use the activator in an amount typically at least equimolar to the compound (1b), and preferably 1 to 5 times of the compound (1b) on a molar basis. When WSC is used as an activator, the reaction may be carried out advantageously by adding 1-hydroxybenzotriazole and/or an acid such as hydrochloric acid. This reaction is carried out at typically about −20 to 180° C., and preferably about 0 to 150° C., and is completed typically in about 5 minutes to 90 hours.

In the other method (d) described above, wherein the amine (1b) is reacted with carboxylic acid halide, the reaction is carried out in an appropriate solvent in the presence of a basic compound. As such a basic compound, known basic compounds may be widely used, and, for example, any of compounds used for the Shotten-Baumann reaction described above may be used. Examples of the solvent include, in addition to the solvents used in the mixed acid anhydride method described above, alcohols such as methanol, ethanol, isopropanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve, acetonitrile, pyridine, acetone, and water. The ratio of the amine (1b) to the carboxylic acid halide in the reaction is not specified and may be appropriately selected in a wide range. Typically, the former may be used in an amount at least about equimolar to the latter, and preferably about 1 to 5 times of the latter on a molar basis. This reaction is carried out at typically about −20 to 180° C., and preferably about 0 to 150° C., and is completed typically in 5 minutes to 50 hours.

Further, the reaction for producing an amide bond shown in the above described reaction formula 2 may be carried out by reacting the carboxylic acid (6) and the amine (1b) in the presence of a condensation agent of a phosphorus compound such as triphenylphosphine, diphenylphosphinyl chloride, phenyl-N-phenylphosphoramide chloridate, diethyl chlorophosphate, diethyl cyanophosphate, diphenylphosphoric acid azide, or bis(2-oxo-3-oxazolidinyl)phosphinic chloride. The condensation agent described above is used singly or in a combination of two or more.

The above described reaction is carried out, in the presence of the solvent and the basic compound which are used in the method for reacting the carboxylic acid halide with the amine (1b) described above, at typically about −20 to 150° C., and preferably about 0 to 100° C., and is completed typically in 5 minutes to about 30 hours. The condensation agent and the carboxylic acid (6) may be used respectively in an amount at least about equimolar to the amine (1b), and preferably about 1 to 2 times of the amine (1b) on a molar basis.

The compound (1), wherein Y represents a —CH(OH)— or —C(═N—OH) group, is produced from the corresponding compound wherein Y represents a —CO— group, as shown in the reaction formula 3.

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wherein R¹, R², X₁and A are the same as described above.

The compound (1g) is produced by reducing the compound (1f).

In the reducing reaction described above, a reducing method employing a hydride reducing agent is favorably used. Examples of the reducing agent used include aluminum lithium hydride, sodium borohydride, borane, diborane, and lithium borohydride-trimethoxyborane. These reducing agents are used singly or in a mixture of two or more. The reducing agent may be used in an amount typically at least equimolar to the compound (1f), and preferably 1 to 15 times of the compound (1f) on a molar basis. This reducing reaction is typically carried out in an appropriate solvent, for example, water, a lower alcohol such as methanol, ethanol, or isopropanol, an ether such as tetrahydrofuran, diethyl ether, diisopropyl ether, or diglyme, or a halogenated hydrocarbon such as dichloromethane, chloroform, or carbon tetrachloride, or a mixture thereof, at about −60 to 150° C., preferably from about −30 to 100° C., in general for about 10 minutes to 40 hours. In the case where aluminum lithium hydride or borane is used as the reducing agent, it is preferable to use an anhydrous solvent of tetrahydrofuran, diethyl ether, diisopropyl ether, diglyme, or the like.

The compound (1h) is produced by reacting the compound (1f) and hydroxylamine in an appropriate inert solvent in the presence or absence of a basic compound.

Examples of the basic compound used in this reaction include inorganic basic compounds such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, and potassium carbonate, fatty acid alkali metal salts such as sodium acetate, organic bases such as piperidine, piperidinium acetate, triethylamine, trimethylamine, pyridine, dimethylaniline, N-ethyldiisopropylamine, dimethylaminopyridine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO). These basic compounds may be used singly or in a mixture of two or more.

Any of inert solvents which do not have adverse effects on the reaction may be used. Examples thereof include water, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, lower alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol, fatty acids such as acetic acid, esters such as ethyl acetate and methyl acetate, ketones such as acetone and methyl ethyl ketone, acetonitrile, pyridine, dimethyl sulfoxide, N,N-dimethylformamide, and hexamethyl phosphate triamide, and a mixture thereof.

Hydroxylamine is used in an amount typically at least equimolar to the compound (1f), and preferably 1 to 5 times of the compound (1f) on a molar basis. The reaction temperature is typically at room temperature to 200° C., and preferably about 50 to 150° C., and the reaction is in general completed in about 5 minutes to 30 hours.

The compound (1), wherein Y represents an —S(O)n group (n=1 or 2), is produced from the corresponding compound wherein Y represents an —S— group, as shown in the reaction formula 4.

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wherein R¹, R², X₁and A are the same as described above, A₁₆represents a -A group or a -A₁₀-T₂-COOR^59agroup, T₂represents an —N(R¹⁷)—B₃— group, a —B¹⁹—N(R¹⁸) group, a —B₄— group, a -Q-B₅— group, a —B₆—N— (R¹⁹)—B₇— group, a —CO—B₁₀— group, a —CH(OH)—B₁₁— group, a —B_23a—CO— group, or a direct bond, wherein R¹⁷, B₃, B₁₉, R¹⁸, B₄, B₅, B₆, R¹⁹, B₇, B₁₀and B₁₁are the same as described above, A¹⁰represents a group of the formula:

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wherein R³and p are the same as described above, provided that the a is bound to a —S group or a —S(O)j group, and the b is bound to -T₂,

R^59ais a hydrogen atom or a lower alkyl group, and j is 1 or 2.

The reaction for converting the compound (1zzzz) into the compound (1aaaaa) is carried out in an appropriate solvent and in the presence of an oxidizing agent.

Examples of the solvent include water, fatty acids such as formic acid, acetic acid, and trifluoroacetic acid, alcohols such as methanol and ethanol, and halogenated hydrocarbons such as chloroform and dichloromethane, and a mixture thereof.

The oxidizing agent is appropriately used in an amount typically at least equimolar to the compound (1zzzz), and preferably 1 to 2 times of the compound (1zzzz) on a molar basis. In the oxidizing reaction which converts a sulfur atom into a sulfonyl group (j=2), it is appropriate to use the oxidizing agent in an amount typically at least two times of the compound (1zzzz), and preferably 2 to 4 times of the compound (1zzzz) on a molar basis.

The above described reaction is carried out at typically −10 to 150° C., and preferably about −10 to 100° C. and is, in general, completed in about 1 to 100 hours.

The compound of the present invention, which has the general formula (1) with various As, is produced, for example, as shown in the following reaction formulas 5 to 36.

The compound (1), wherein A represents a group of the formula:

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wherein R⁴represents an imidazolyl lower alkyl group, a 1,2,4-triazolyl lower alkyl group, a 1,2,3-triazolyl lower alkyl group, a 1,2,5-triazolyl lower alkyl group, a pyrazolyl lower alkyl group, a pyrimidinyl lower alkyl group which may have an oxo group as a substituent on the pyrimidine ring, a 1,2,4-oxadiazolyl lower alkyl group which may have an lower alkyl group as a substituent on the 1,2,4-oxadiazole ring, a thiazolidinyl lower alkyl group which may have an oxo group as a substituent on the thiazolidine ring, or a -(T)₁-NR¹⁴R¹⁵group, wherein T is a lower alkylene group and l is 1, is produced by reacting the compound (7) with the compound (8) as shown in the reaction formula 5.

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wherein R¹, R²Y₁and X₁are the same as described above, A₁represents a group of the formula:

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wherein R³and p are the same as described above, R^37arepresents a —B₂₁—X₂group, B₂₁represents a lower alkylene group, and X₂is the same as described above, and A₂represents a group of the formula:

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wherein R³and p are the same as described above, R³⁰represents a —B₂₁—R^4agroup, B₂₁is the same as described above, R^4arepresents an imidazolyl group, a 1,2,4-triazolyl group, a 1,2,3-triazolyl group, a 1,2,5-triazolyl group, a pyrazolyl group, a pyrimidinyl group which has an oxo group as a substituent on the pyrimidine ring, a 1,2,4-oxadiazolyl group which may have as a lower alkyl group as a substituent on the 1,2,4-oxadiazole ring, a thiazolidinyl group which may have an oxo group as a substituent on the thiazolidine ring, or an —NR¹⁴R¹⁵group, and R¹⁴and R¹⁵are the same as described above.

The reaction of the compound (7) with the compound (8) is carried out under the reaction condition similar to that of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

The compound (1), wherein A represents a group of the formula:

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wherein R⁴is an imidazolyl lower alkyl group, a 1,2,4-triazolyl lower alkyl group, a 1,2,3-triazolyl lower alkyl group, a 1,2,5-triazolyl lower alkyl group, a pyrazolyl lower alkyl group, a pyrimidinyl lower alkyl group which has an oxo group as a substituent on the pyrimidine ring, a 1,2,4-oxadiazolyl lower alkyl group which has a lower alkyl group as a substituent on the 1,2,4-oxadiazole ring, a thiazolidinyl lower alkyl group which has an oxo group as a substituent on the thiazolidin ring, or a (T)₁-NR¹⁴R¹⁵group, wherein T is a lower alkylene group and l is 1, is also produced by reacting the compound (8) with the compound (9) as shown in the reaction formula 6.

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wherein R¹, R², X₁and Y₁and R^4aare the same as described above, A₃represents a group of the formula:

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wherein R³and p are the same as described above, R³⁹represents a (B₂)_fCOR^Agroup, B₂₁is the same as described above, R^Arepresents a hydrogen atom or a lower alkyl group, and f represents 0 or 1, and A₄represents a group of the formula:

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wherein R³and p are the same as described above, R⁴⁰represents a —(B₂₁)_fCHR^AR^4agroup, and B₂₁, R^A, f and R^4aare the same as described above, provided that the alkyl moiety of the —(B₂₁)_fCHR^AR^4agroup has not more than 6 carbon atoms.

The reaction of the compound (9) with the compound (8) is carried out under the same condition as in the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

The compound (1), wherein A represents a group of the formula:

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wherein R⁴represents a 3,5-dioxoisooxazolidinyl lower alkylidene group which may have an oxo group as a substituent on the 3,5-dioxoisooxazolidine ring, is produced by reacting the compound (11) with the compound (10) as shown in the reaction formula 7.

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wherein R¹, R², X₁and Y are the same as described above,

A⁵represents a group of the formula:

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wherein R²and p are the same as described above, R⁴¹represents a —B₂₂(CO₂R⁴³)(CO₂R⁴⁴) group, B₂₂represents a lower alkylidene group, and R⁴²and R⁴⁴represent a lower alkyl group, and

A⁶represents a group of the formula:

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wherein R³and p are the same as described above, and R⁴²represents

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wherein B₂₂is the same as described above.

The reaction of the compound (10) with the compound (11) is carried out under the same condition as that of the reaction which converts the compound (1f) into the compound (1h) of the reaction formula 3.

The compound (1), wherein A represents a group of the formula:

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wherein R⁴represents a group of the formula:

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is produced from the compound (13), as shown in the reaction formula 8.

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wherein R¹, R², X₁, Y and R¹³are the same as described above,

A₇represents of the formula:

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wherein R³and p are the same as described above, and

R⁴⁵represents a halogen atom,

A₈represents a group of the formula:

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wherein R³and p are the same as described above, and

R⁴⁶represents

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wherein R¹³is the same as described above,

A⁹represents a group of the formula:

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wherein R³and p are the same as described above, and

R⁴⁷represents a group of the formula:

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wherein R¹³is the same as described above, and

A^8arepresents a group of the formula:

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wherein R³and p are the same as described above, and

R^46′ represents a group

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wherein R¹³is the same as described above.

The reaction of the compound (13) with the compound (12) is carried out in an appropriate inert solvent in the presence of a basic compound.

Examples of the basic compound used here include such as sodium, potassium, magnesium, sodium hydride, sodium amide, metal alcoholates such as sodium methylate, sodium ethylate, and potassium tert-butoxide, and alkyl and aryl lithiums or lithium amides such as methyl lithium, n-butyl lithium, phenyl lithium, and lithium diisopropylamide. These basic compounds are used singly or in a mixture of two or more.

The basic compound is appropriately used in an amount typically at least equimolar to the compound (13), and preferably 1 to 5 times of the compound (13) on a molar basis.

Examples of the inert solvent used include aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme, aliphatic hydrocarbons such as n-hexane, heptane, and cyclohexane, halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride, dimethylsulfoxide, and N,N-dimethylformamide, and a mixture thereof.

The reaction is carried out at typically about −90 to 150° C., and preferably about −90 to 120° C., and is completed in general in about 10 minutes to 10 hours.

The compound (12) is appropriately used in an amount typically at least equimolar to the compound (13), and preferably 1 to 5 times of the compound (13) on a molar basis.

The reaction which converts the compound (11) into the compound (1m) is carried out in an appropriate inert solvent and in the presence of an acid.

Examples of the acid used here include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as sulfonic acids including p-toluenesulfonic acid. These acids are used singly or in a mixture of two or more.

It is appropriate to use the acid typically in an amount at least equimolar to the compound (11), and preferably in an equal amount to a large excess amount with respect to the compound (11) on a molar basis.

Any of the inert solvents used in the reaction of the compound (13) with the compound (12) may be used in this reaction.

This reaction is suitably carried out at typically room temperature to 200° C., preferably room temperature to about 150° C., and is completed in general in about 1 to 20 hours.

The reaction which converts the compound (11) into the compound (11′) is carried out in an appropriate solvent and in the presence of an acid and a catalyst.

Examples of the solvent used include water, lower alcohols such as methanol, ethanol, and isopropanol, ketones such as acetone and methyl ethyl ketone, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran, diisopropyl ether, diglyme, and 1,4-dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene, acetonitrile, dimethyl sulfoxide, N,N-dimethylacetamide, N,N-dimethylformamide, and N-methylpyrrolidone, and a mixture thereof.

Examples of the acid used here include inorganic acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as boron trifluoride diethyl etherate, formic acid, acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid.

Examples of the catalyst include alkylsilane compounds such as triethylsilane.

The acids and the catalysts described above are respectively used typically in an amount about 0.01 to 5 times of the compound (11), and preferably about 0.01 to 1 time of the compound (11) on a molar basis.

The above described reaction is carried out at about room temperature to 200° C., and preferably about room temperature to 150° C., and is completed in general in about 1 to 10 hours.

The reaction which converts the compound (11) into the compound (11′) may be carried out in an appropriate solvent and in the presence of a catalytic hydrogen reducing agent.

Examples of the solvent used include water, fatty acids such as acetic acid, alcohols such as methanol, ethanol, and isopropanol, aliphatic hydrocarbons such as n-hexane, alicyclic hydrocarbons such as cyclohexane, ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran, monoglyme, diglyme, and 1,4-dioxane, esters such as methyl acetate, ethyl acetate, and butyl acetate, and aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and a mixture thereof.

Examples of the catalytic hydrogen reducing agent include palladium, palladium-black, palladium-carbon, palladium hydroxide-carbon, rhodium-alumina, platinum, platinum oxide, copper chromite, Raney nickel, and palladium acetate.

The catalytic hydrogen reducing agent is used typically in an amount of 0.01 to 1 times of the compound (11) on a weight basis.

The above described reaction favorably proceeds at typically about −20 to 100° C., and preferably about 0 to 80° C., and is completed generally in about 0.5 to 20 hours, and the hydrogen pressure is typically at 1 to 10 atm.

It is preferable to add a mineral acid such as hydrochloric acid to this reaction system.

The compound (1), wherein A represents a group of the formula:

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wherein R⁴represents a group of the formula:

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wherein R¹³represents a group other than a hydrogen atom, is produced from the corresponding compound wherein R¹³is a hydrogen atom, as shown in the following reaction formula 9.

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wherein R¹, R², X₁, Y, A₁₀, R^A, R^13aand X₂are the same as described above, provided that the a and the b of A₁₀are bound to Y and the piperidinyl group, respectively, R^13brepresents a lower alkyl group which may have a halogen atom as a substituent, a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, an imidazolyl lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a carboxy lower alkyl group, a piperazinylcarbonyl lower alkyl group which may be substituted on the piperazine ring with a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, or a morpholinocarbonyl substituted lower alkyl group,

R^13crepresents a lower alkanoyl group which may have a halogen atom as a substituent, a lower alkoxy carbonyl group, a benzoyl group, a morpholino substituted alkanoyl group, a piperazinyl lower alkanoyl group which may be substituted on the piperazine ring with a phenyl lower alkyl group which may have a lower alkylenedioxy group on the phenyl ring; or an imidazolyl lower alkanoyl group, and

R^13drepresents a hydrogen atom, a lower alkyl group which may have a halogen atom as a substituent, a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, a phenyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, an imidazolyl group, an imidazolyl lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a carboxy lower alkyl group, a piperazinylcarbonyl lower alkyl group which may be substituted on the piperazine ring with a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, or a morpholinocarbonyl substituted lower alkyl group,

provided that the alkyl moiety of the side chain (—CHR^AR^13d) of the compound (1q) has not more than 6 carbon atoms.

The reaction of the compound (1n-1) with the compound (13′) is carried out under the condition similar to that of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (1n-1) with the compound (14) is carried out under the condition similar to that of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (1n-1) with the compound (15) is carried out under the condition to similar that of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

Also, the reaction of the compound (1n-2) with the compound (13′) is carried out under the condition similar to that of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2, the reaction of the compound (1n-2) with the compound (14) is carried out under the condition similar to that of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2, and the reaction of the compound (1n-2) with the compound (15) is carried out under the condition to similar that of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

In the reaction formula 9, the hydrolysis of the compounds (1o-1) and (1o-2), wherein R^13brepresents a lower alkoxycarbonyl lower alkyl group, may produce the corresponding compounds (1o-1) and (1o-2), wherein R^13brepresents a carboxy lower alkyl group.

In the reaction formula 9, the hydrolysis of compounds (1p-1) and (1p-2), wherein R^13crepresents a lower alkoxycarbonyl group, may produce the corresponding compounds (1p-1) and (1p-2), wherein R^13cis a hydrogen atom.

The hydrolysis reaction (hereinafter this hydrolysis reaction is called “hydrolysis B”) may be carried out in an appropriate solvent or without a solvent, in the presence of an acidic or basic compound.

Examples of the solvent used include water, lower alcohols such as methanol, ethanol, isopropanol, and tert-butanol, ketones such as acetone and methyl ethyl ketone, ethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme, and diglyme, fatty acids such as acetic acid and formic acid, esters such as methyl acetate and ethyl acetate, halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride, dimethylsulfoxide, N,N-dimethylformamide, and hexamethylphosphoric acid triamide, and a mixture thereof.

Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, organic acids such as formic acid, acetic acid, trifluoroacetic acid, sulfonic acids including p-toluenesulfonic acid, and Lewis acids such as boron tribromide and boron trichloride. These acids are used singly or in a mixture of two or more.

Examples of the basic compound include carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate, and metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and lithium hydroxide. These basic compounds are used singly or in a mixture of two or more.

The hydrolysis reaction is favorably carried out at typically about 0 to about 200° C., and preferably about 0 to 150° C., and is completed in general in about 10 minutes to 50 hours.

The compound (1), wherein A represents a group of the formula:

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wherein R⁴represents a group of the formula:

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wherein R¹³represents an imidazolyl lower alkyl group, is produced as shown in the following reaction formula 10.

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wherein R¹, R², X₁, Y, A₁₀, R^13a, B₂₁and X₂are the same as described above, provided that the a and b of A₁₀are bound to Y and the piperidinyl group, respectively.

The reaction of the compound (1r-1) with the compound (16) with and the reaction of the compound (1r-2) with the compound (16) are carried out under the condition similar to that of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

The compound (1), wherein A represents a group of the formula:

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wherein R⁴represents a group of the formula:

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wherein R¹³represents a morpholino substituted alkanoyl group, a piperazinyl lower alkanoyl group which may be substituted on the piperazine ring with a phenyl lower alkyl group which has a lower alkylenedioxy group as a substituent on the phenyl ring, or an imidazolyl lower alkanoyl group, may be produced from the corresponding compound, wherein R¹³represents a lower alkanoyl group which may have a halogen atom as a substituent, as shown in the following reaction formula 11.

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wherein R¹, R², X₁, Y, R^13a, B₂₁and X₂are the same as described above, and R^47′ is a morpholino group, a piperazinyl group which may be substituted on the piperazine ring with a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, or an imidazolyl group, provided that the a and b of A₁₀are bound to Y and the piperidinyl group, respectively.

The reaction of the compound (1t-1) with the compound (17) and the reaction of the compound (1t-2) with the compound (17) are carried out under the condition similar to that of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

The compound (1), wherein A represents a group of the formula:

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wherein R⁴represents a group of the formula:

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wherein R¹³represents a piperazinylcarbonyl lower alkyl group which is substituted on the piperazine ring with a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, or a morpholinocarbonyl substituted lower alkyl group, is produced from the corresponding compound, wherein R¹³is a carboxy group, as shown in the following reaction formula 12.

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wherein R¹, R², X₁, Y, A₁₀, R^13a, and B₂₁, are the same as described above, R⁴⁸is a piperazinyl group which may be substituted on the piperazine ring with a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, or a morpholino group, provided that the a and b of A₁₀are bound to Y and the piperidinyl group, respectively.

The reaction of the compound (1v-1) with the compound (18) and the reaction of the compound (1v-2) with the compound (18) are carried out under the condition similar to that of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The compound (1), wherein A represents a group of the formula:

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wherein R⁴represents -(T)₁-NR¹⁴R¹⁵, is produced as shown in the reaction formulas 13 and 14.

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In the formula, R¹, R², X₁, Y, A₁₀, X₂, l, R¹⁴and R¹⁵are the same as described above, T₁is a lower alkylene group, —COB₈—, —SO₂— or a —CH(OH)—B₉—, and B⁸and B⁹are the same as described above, provided that, in the compounds (35) and (1pp), the a and b of A₁₀are bound to Y and -(T₁)₁, respectively.

The reaction of the compound (35) with the compound (36) is carried out in the reaction condition similar to that of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

The compound (35), wherein l is 0, may also be produced by reacting the corresponding compound (35) with the compound (36) in an appropriate solvent in the presence of a basic compound and a catalyst.

Any of the solvents and basic compounds which are used in the reaction of the compound (2) with the compound (3) of the above described reaction formula 1 may be used here.

Examples of the catalyst to be used include various metal complexes as well as various combinations of a metal complex with ligand. Examples of the metal complex include, for instance, palladium acetate (II), tetrakis(triphenylphosphine)palladium (0), tris(dibenzylideneacetone)dipalladium (0) and the like. Examples of the ligand include, for instance, R-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (R-BINAP), S-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (S-BINAP), RAC-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (RAC-BINAP), t-butylphosphine, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and the like.

The catalyst is appropriately used in an amount typically at least equimolar to the compound (35), and preferably 1 to 5 times of the compound (35) on a molar basis.

This reaction is carried out at typically about 0 to 200° C., and preferably about 0 to 150° C., and is completed in general in about 1 to 60 hours. This reaction is called “reaction C” hereinafter.

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In the formula, R², X₁, Y, A₁₀, T₂, R¹⁴and R¹⁵are the same as described above, provided that, in the compounds (37) and (1qq), the a and b of A₁₀are bound to Y and T₂, respectively, and R⁹⁵represents R¹or a halogen atom.

The reaction of the compound (37) with the compound (36) is carried out in the reaction condition similar to that of the reaction of the compound (1b) with, the compound (6) in the above described reaction formula 2.

The compound (1), wherein A represents a group of the formula:

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wherein R⁴represents -(T)₁-NR¹⁴R¹⁵, and l represents 0, may also be produced by the method shown in the reaction formula 15.

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wherein R¹, R², X₁, Y, R^A, X₂, T, l, and A₁₀, are the same as described above, R¹⁹is the same group as R¹⁵defined in (15), (22), (23), (27) and (36a), R^49ais R¹⁵defined in (2) to (5), (7), (8), (10), (11), (13), (14), (16) to (21), (24), (25), (26), (26a), (27a), (28a), (29a), (30a), (31a), (32a), (33a), (34a), (35a), or (37a), a phenoxycarbonyl group and a lower alkylsulfonyl group,

R^49brepresents a hydrogen atom, an alkyl group which may have a hydroxyl group as a substituent, a phenoxy lower alkyl group, a phenyl lower alkyl group which may be substituted on the phenyl ring with 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkoxy group which may have a halogen atom as a substituent, and a lower alkyl group, a phenyl group which may be substituted on the phenyl ring with 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkoxy group which may have a halogen atom as a substituent, and a lower alkyl group, a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, a phenyl group which may have a lower alkylenedioxy group on the phenyl ring, a lower alkoxycarbonyl substituted lower alkyl group, a carboxy substituted lower alkyl group, a cycloalkyl lower alkyl group, a cycloalkyl group, a pyridyl lower alkyl group, a pyridyl group, an amino group substituted lower alkyl group which may have a substituent selected from the group consisting of a lower alkyl group and a lower alkanoyl group, a lower alkoxy lower alkyl group, an imidazolyl group, an imidazolyl lower alkyl group, a 1,2,3,4-tetrahydroisoquinolylcarbonyl substituted lower alkyl group, an A group-substituted carbonyl lower alkyl group, a pyrrolidinyl group, a pyrrolidinyl lower alkyl group, a morpholino group, a morpholino lower alkyl group, an anilinocarbonyl lower alkyl group which may have a lower alkyl group as a substituent on the phenyl ring, a piperazinyl group which may have, on the piperazine ring, a substituent selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, a piperazinyl lower alkyl group which may have, on the piperazine ring, a substituent selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, an amidino group which may have a lower alkyl group as a substituent, an amidino lower alkyl group which may have a lower alkyl group as a substituent, a B group substituted carbonyl lower alkyl group, or a cyano substituted lower alkyl group,

R^14arepresents a hydrogen atom or a lower alkyl group which may have a hydroxyl group as a substituent, and R³⁴, d, R³⁶, R³⁷and B₂₀are the same as described above, provided that, in the compounds (1rr), (1ss), (1ss′) and (1ss′), the a and b of A₁₀are bound to Y and N, respectively, and, in the compound (1ss′), the CHR^AR^49bmoiety of the side chain, (—Y-A₁₀N(R^14a)(CHR^AR^49b) has not more than 6 carbon atoms.

The reaction of the compound (1rr) with the compound (38a) is carried out under the condition to similar that of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (1rr) with the compound (38) is carried out under the condition similar to that of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (1rr) with the compound (38b) is carried out under the condition similar to that of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2 described above.

The compound (1), wherein A represents a group of the formula:

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wherein R⁴represents a -(T)₁-NR¹⁴R¹⁵group, l represents 1, and T represents a —CH(OH)—B₉— group, may also be produced by the method shown in the following reaction formula 16.

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wherein R¹, R², X₁, A₁₀, Y, B₈, B₉, R¹⁴, and R¹⁵are the same as described above, provided that, in the compounds (1tt) and (1uu), the a and b of A₁₀are bound to Y and B₈or B₉, respectively.

The reaction which converts the compound (1tt) into the compound (1uu) is carried out under the similar condition similar to that of the reaction which converts the compound (1f) into the compound (1g) of the above described reaction formula 3.

The compound (1), wherein A represents a group of the formula:

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wherein R⁴represents a -(T)₁-NR¹⁴R¹⁵group, l represents 1, and T represents a —CH(OH)—B₁₁—CO— group, may also be produced by the method shown in the following reaction formula 17.

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wherein R¹, R², X₁, A₁₀, Y, B₁₀, B₁₁, R¹⁴and R¹⁵are the same as described above, provided that, in the compounds (1vv) and (1ww), the a and b of A₁₀are bound to Y and a —COB₁₀or —CH(OH)B₁₁— group, respectively.

The reaction which converts the compound (1vv) into the compound (1ww) is carried out under the condition similar to that of the reaction which converts the compound (1f) into the compound (1g) of the above described reaction formula 3.

The compound (1), wherein A represents a group of the formula:

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wherein R⁴is a -(T)₁NR¹⁴R¹⁵group, and R¹⁴and R¹⁵are bound with each other to form a 5- to 10-membered saturated or unsaturated heterocyclic group which has various substituents thereon, may be produced as shown in the following reaction formulas 18 to 20, 22, 24 to 31, and 34 to 36.

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In the formula, R¹, R², R^B, X₁, Y, T, l, A₁₀and X₂are the same as described above, provided that the a and b of A₁₀are bound to Y and (T)l,

respectively;

R^41band R^15arepresent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic group has at least one secondary amine thereon;

R^14cand R^15brepresent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic group has at least one tertiary amine thereon substituted with R⁵⁰;

R^14dand R^15crepresent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic group has at least one tertiary amine thereon substituted with R⁵¹;

R^14eand R^15drepresent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic group has at least one tertiary amine thereon substituted with a R⁵²(R^B)CH— group;

R^14fand R^15erepresent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic group has at least one tertiary amine thereon substituted with a group of the formula:

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R⁵⁰is the same substituent of the heterocyclic ring, which is formed by R¹⁴and R¹⁵bound each other, as the above described (28), (30), (31), (32), (33), (34), (36), (37), (38), (41), (43), (44), (45), (47), (49) (provided that t is 1), (50) (provided that o is 0), (51), (52), (53), (54), (55), (56), (57), (58), (59), (60), (62), (63), (64), (65), (66), (70), (77), (79), (82), (83), (87), (88a), or (90a):

R⁵¹is the same substituent of the heterocyclic group, which is formed by R¹⁴and R¹⁵bound each other, as the above described (35), (39), (40), (42), (50) (provided that o is 1), (67), (75), (76), (77), (78), (80), (81) or (84) (provided that s is 0);

R⁵²is a hydrogen atom, a lower alkyl group which has 1 or 2 phenyls which may be substituted on the phenyl ring with 1 to 3 substituents selected from the group consisting of a lower alkanoyl group, an amino group which may have a lower alkanoyl group as a substituent, a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group which may have a halogen atom as a substituent, a phenyl lower alkoxy group, a hydroxyl group, and a lower alkylenedioxy group and which may have a pyridyl group on the lower alkyl group, a phenyl group which may be substituted on the phenyl ring with 1 to 3 substituents selected from the group consisting of a lower alkanoyl group, an amino group which have a lower alkanoyl group as a substituent, a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group which may have a halogen atom as a substituent, a phenyl lower alkoxy group, a hydroxy group, and a lower alkylenedioxy group, a pyridyl lower alkyl group which may be substituted on the pyridine ring with 1 to 3 substituents selected from the group consisting of a hydroxyl group and a lower alkyl group which may have a hydroxyl groups as a substituent, a pyridyl group which may be substituted on the pyridine ring with 1 to 3 substituents selected from the group consisting of a hydroxyl group and a lower alkyl group which may have a hydroxyl group as a substituent, a pyrrolyl lower alkyl group which may have 1 to 3 lower alkyl groups as substituents on the pyrrole ring, a pyrrolyl group which may have 1 to 3 lower alkyl groups as substituents on the pyrrole ring, a benzoxazolyl lower alkyl group, a benzoxazolyl group, a benzthiazolyl lower alkyl group, a benzothiazolyl group, a furyl lower alkyl group, a furyl group, a lower alkyl group which may have a substituent selected from the group consisting of a hydroxyl group and a halogen atom, a naphtyl lower alkyl group, a naphthyl group, a phenoxy lower alkyl group, a —B₁₂CO—NR²⁰R²¹group; a —B₁₃NR²²R²³group, a 1,2,3,4-tetrahydronaphthyl substituted lower alkyl group which may have 1 to 5 lower alkyl groups as substituents on the 1,2,3,4-tetrahydronaphthalene ring, a 1,2,3,4-tetrahydronaphthyl group which may have 1 to 5 lower alkyl groups as substituents on the 1,2,3,4-tetrahydronaphthalene ring, a quinolyl lower alkyl group, a quinolyl group, a 1,2,3,4-tetrazolyl lower alkyl group which may have, on the tetrazole ring, a substituent selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group, a 1,2,3,4-tetrazolyl group which may have, on the tetrazole ring, a substituent selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group, a thiazolyl lower alkyl group which may have a phenyl group as a substituent on the thiazole ring, a thiazolyl group wherein may have a phenyl group as a substituent on the thiazole ring, a benzoyl lower alkyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkoxy group and a halogen atom, a piperidinyl lower alkyl group which may have a lower alkoxy group as a substituent on the piperidine ring, a benzoyl lower alkyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkoxy group and a halogen atom, a piperidinyl group which may have a lower alkyl group on the piperidine ring, a 1,2,3,4-tetrahydroquinolyl lower alkyl group which may have an oxo group as a substituent on the tetrahydroquinoline ring, a 1,2,3,4-tetrahydroquinolyl group which may have an oxo group as a substituent on the tetrahydroquinoline ring, a 1,3,4-oxadiazolyl lower alkyl group which may have an oxo group as a substituent on the 1,3,4-oxadiazole ring, a 1,3,4-oxadiazolyl group which may have an oxo group as a substituent on the 1,3,4-oxadiazole ring, a cycloalkyl lower alkyl group, a cycloalkyl group, a thienyl lower alkyl group, a thienyl group, a lower alkoxy lower alkyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, an imidazolyl lower alkyl group, or an imidazolyl group; and

R^Band R⁵², together with carbon atoms to which they bind, may form a cycloalkyl group or a tetrahydro-4H-pyranyl group;

provided that the alkyl moiety of the R⁵²(R^B)CH— group in the compound (1aaa) has not more than six carbon atoms.

The reaction of the compound (35′) with the compound (39) is carried out under the condition similar to that of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (35′) with the compound (40) is carried out under the condition similar to that of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (35′) with the compound (41) is carried out under the condition similar to that of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

When the reaction is carried out using the compound (41) as a starting material, wherein R³and R⁵²together with carbon atoms bound to them form a cycloalkyl ring or a tetrahydro-4H-pyran ring using a hydride reducing agent, a cycloalkyloxytrialkylsilane such as [(1-ethoxycyclopropyl)oxy]trimethylsilane may be used as a starting material in place of the compound (41) to generate the above described compound (41) in the reaction system.

The reaction of the compound (35′) with the compound (42) is carried out under the condition to similar that of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

The compound (35′) may also be produced from the compound (1yy), (1zz) or (1aaa) under the reaction condition similar to that of the reaction which converts the compound (1iii′) into the compound (1hhh′) of the later described reaction formula 24.

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In the formula, R¹, R², X₁, Y, T, l, A₁₄₀and X₂are the same as described above, provided that the a and b of A₁₀are bound to Y and (T)l, respectively;

R^14gand R^15fare a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic group has at least one tertiary amine thereon substituted with a lower alkoxycarbonyl group; and

R^14hand R^15gare a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic group has at least one secondary amine thereon.

The reaction which converts the compound (1ccc) into the compound (1ddd) may be carried out under the reaction condition similar to that of the hydrolysis B described for the above described reaction formula 9.

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In the formula, R^74arepresents a nitro group or a —R¹group, and R¹, R², X₁, Y, T, l and A₁₀are the same as described above, provided that the a and b of A₁₀are bound to Y and (T)l, respectively;

R¹⁴ⁱand R^15hare a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic group has at least one lower alkoxycarbonyl lower alkoxy group, lower alkoxycarbonyl group, lower alkoxycarbonyl lower alkyl group, or —(B₁₂CO)t-N(R^20a)R^51′ group thereon;

R^14jand R¹⁵ⁱare a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic group has at least one carboxy lower alkoxy group, carboxy group, carboxy lower alkyl group, or —(B₁₂CO) t-N(R^20a)R^52′ group thereon;

B₁₂and t are the same as described above;

R^20arepresents a hydrogen atom, a cycloalkyl group, an amino group which have a lower alkoxycarbonyl group as a substituent, a benzoyl group which may have 1 to 3 alkoxy groups as substituents on the phenyl ring, a lower alkyl group, a lower alkyl group which has 1 or 2 phenyls which may be substituted on the phenyl ring with 1 to 3 substituents selected from the group consisting of an lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group which may have a halogen atom as a substituent, and a lower alkylthio group, a phenyl group which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a lower alkoxy group which may have a halogen atom as a substituent and a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxycarbonyl group, a cycl alkyl lower alkyl group, a pyrrolidinyl lower alkyl group which may have, on the pyrrolidine ring, 1 to 3 lower alkyl groups which may have a hydroxyl group as a substituent, an amino substituted lower alkyl group which may have a substituent selected from the group consisting of a phenyl group and a lower alkyl group, a 1,2,3,4-tetrahydronaphthyl substituted lower alkyl group which may have 1 to 5 lower alkyl groups as substituents on the 1,2,3,4-tetrahydronaphthalene ring, a naphthyl lower alkyl group, a pyridyl lower alkyl group, a quinolyl lower alkyl group, a 1,2,3,4-tetrazolyl lower alkyl group which may have, on the tetrazole ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group, a 1,2,4-triazolyl lower alkyl group, a tetrahydrofuryl lower alkyl group which may have a hydroxyl group as a substituent on the lower alkyl group, a phenoxy lower alkyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group and a nitro group, a phenyl lower alkanoyl group, a lower alkanoyl group which may have a halogen atom as a substituent, an imidazolyl lower alkanoyl group, a lower alkoxycarbonyl lower alkyl group, a pyridyl group, or a carboxy lower alkyl group;

R^51′ is a lower alkoxycarbonyl group or a lower alkoxycarbonyl lower alkyl group;

R^52′ is a hydrogen atom or a carboxy lower alkyl group; and

R⁵³is a lower alkyl group.

The reaction which converts the compound (1eee) into the compound (1fff) may be carried out under the reaction condition similar to that of the hydrolysis B as described in the above described reaction formula 9.

Any of the reaction conditions for typical esterification reaction may be used for the reaction of the compound (1fff) with the compound (43). For example, the above described reaction is carried out in the presence of a mineral acid such as hydrochloric acid or sulfuric acid, and a halogenation agent such as thionylchloride, phosphorus oxychloride, phosphorus pentachloride, or phosphorus trichloride. The compound (43) is used in large excess over the compound (1fff). The above described reaction favorably proceeds at typically about 0 to 150° C., preferably about 50 to 100° C., and is completed in general in about 1 to 10 hours. The esterification described above may be carried out using a condensation agent such as carbodiimide in the presence of a basic compound such as dimethylaminopyridine. A typical reaction condition for generating an amide bond, which is used in the reaction of the compound (1b) with the compound (6) in the reaction formula 2, may also be used.

The reaction of the compound (1fff) with compound (43) may also be carried out in the presence of the same basic compound and the solvent as those used in the reaction of the compound (2) with the compound (3) of the reaction formula 1. The reaction is carried out at typically about 0 to 100° C., and preferably about 0 to 70° C., and is completed in general in about 1 to 30 hours.

The compound (1eee) may also be produced using a halogenated lower alkyl such as methyl iodide in place of the compound (43) under the condition similar to that of the reaction of the compound (2) with the compound (3) of the reaction formula 1.

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In the formula, R¹, R², X₁, Y, A₁₀, R^13a, B₂₁and R⁵³are the same as described above, and R⁵⁴is a lower alkyl group, provided that the a and b of A₁₀are bound to Y and the piperidinyl group, respectively.

The reaction which converts the compound (1ggg-1) into the compound (1v-1) and the reaction which converts the compound (1ggg-2) into the compound (1v-2) may be carried out under the reaction condition similar to that of the hydrolysis B described for the above described reaction formula -9, respectively.

The reaction of the compound (1v-1) with the compound (43) and the reaction of the compound (1v-2) with the compound (43) is carried out under the reaction condition similar to that of the reaction of the compound (1fff) with the compound (43) of the above described reaction formula 20.

The compound (1ggg-1) may also be produced using a halogenated lower alkyl such as methyl iodide in place of the compound (43) under the condition similar to that of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

Similarly, the compound (1ggg-2) may also be produced using a halogenated lower alkyl such as methyl iodide in place of the compound (43) under the condition similar to that of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

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In the formula, R¹, R², X₁, Y, T, l and A₁₀are the same as described above, provided that the a and b of A₁₀are bound to Y and (T)l, respectively;

R^14kand R^15jare a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic group has at least one —B₂₁CONHNH₂group, wherein B²¹is the same as described above, thereon; and

R^14land R^15kare a 5- to 10-membered saturated or unsaturated heterocyclic ring the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic group has at least one group of the formula:

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thereon.

The reaction which converts the compound (1hhh) into compound (1iii) is carried out under the condition similar to that of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

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In the formula, R¹, R², X₁, Y, A₁₀, B₂₁and X₂are the same as described above, the a and b of A₁₀are bound to Y and (T)l, respectively, R⁵⁵is a lower alkanoyl group, and R^55ais a lower alkyl group.

The reaction of the compound (44) with the compound (45) is carried out under the condition to similar that of the reaction which converts the compound (1f) into the compound (1h) of the above described reaction formula 3.

The reaction of the compound (44a) with the compound (46) is carried out under the condition similar to that of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

The reaction which converts the compound (47) into the compound (1rrr) is carried out under the condition similar to that of the reaction which converts the compound (1f) into the compound (1h) of the above described reaction formula 3.

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In the formula, R¹, R², X₁, Y, T, l, A₁₀and X₂are the same as described above, provided that the a and b of A₁₀are bound to Y and (T)l, respectively;

R^14mand R^15lare a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic group has at least one hydroxyl group or hydroxyl group substituted lower alkyl group thereon;

R¹⁴ⁿand R^15mare a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic group has at least one —OR⁵⁶group thereon;

R⁵⁶represents a phenyl group which may be substituted on the phenyl ring with 1 to 3 substituents selected from the group consisting of a cyano group, a lower alkyl group which may have a halogen atom as a substituent, and a lower alkoxy group which may have a halogen atom as a substituent, a phenyl lower alkyl group which may be substituted on the phenyl ring with 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, and a lower alkoxy group which may have a halogen atom as a substituent, a pyridyl lower alkyl group, a lower alkyl group, a lower alkoxy lower alkyl group, a benzoyl group, a lower alkoxycarbonyl lower alkyl group, a carboxy lower alkyl group; or a —B₁₅—CO—NR²⁶R²⁷group, wherein B₁₅, R²⁶and R²⁷are the same as described above,

provided that, the R⁵⁶of the compound (48), which reacts with the above described heterocyclic group substituted with at least one hydroxyl group substituted lower alkyl group of the compound (1hhh′), is an unsubstituted phenyl group or a lower alkyl group.

The reaction of the compound (1hhh′) with the compound (48) is carried out under the condition similar to that of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

The reaction which converts the compound (1iii′) into the compound (1hhh′) may be carried out under the condition to similar that of the hydrolysis B described in the above described reaction formula 9.

The compound (1iii′) may be converted into the compound (1hhh′) by a reduction reaction. This reduction reaction is, for example, carried out in an appropriate solvent in the presence of a catalytic hydrogen reducing agent.

Examples of the solvent used include water, fatty acids such as acetic acid, alcohols such as methanol, ethanol, and isopropanol, aliphatic hydrocarbons such as hexane and cyclohexane, ethers such as dioxane, tetrahydrofuran, diethyl ether, monoglyme, and diglyme, esters such as ethyl acetate and methyl acetate, aprotic polar solvents such as N,N-dimethylformamide, and a mixture thereof.

Examples of the catalytic hydrogen reducing agent used include palladium, palladium black, palladium-carbon, platinum, platinum oxide, copper chromite, and Raney nickel. These reducing agents may be used singly or as a mixture of two or more.

The catalytic hydrogen reducing agent is favorably used generally in an amount of 0.02 to 1 time of the compound (1iii′) on a weight basis.

The reaction temperature is typically at about −20 to 100° C., and preferably at about 0 to about 80° C. The reaction is preferably carried out at a hydrogen pressure of typically 1-10 atm, and is completed in general in about 0.5 to 20 hours.

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In the formula R¹, R², X₁, Y, T, l, A₁₀, R^Aand X₂are the same as described above, provided that the a and b of A₁₀are bound to Y and (T)l, respectively;

R^14oand R¹⁵ⁿare a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹¹and R¹⁵, except that the heterocyclic group has at least one —(B₁₂CO) tNHR^20agroup thereon;

R^14pand R^15oare a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic group has at least one —(B₁₂CO) tN(R^20a)R^21bgroup thereon; and

R^14qand R^15pare a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic group has at least one —(B₁₂CO)tN(R^20a)R^21cgroup thereon;

R^14rand R^15qrepresent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵except that the heterocyclic ring has at least one —(B₁₂CO)tN(R^20a)(CHR^AR^21d) group thereon,

wherein B₁₂, t and R^20aare the same as described above;

R^21brepresents a lower alkyl group, a cycloalkyl group, a lower alkyl group which have 1 or 2 phenyls which may be substituted on the phenyl ring with 1 to 3 substituents selected from the group consisting of a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group which may have a halogen atom as a substituent and a lower alkylthio group, a phenyl group which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a lower alkoxy group which may have a halogen atom as a substituent and a lower alkyl group which may have a halogen atom as a substituent, a cycloalkyl lower alkyl group, a pyrrolidinyl lower alkyl group which may have, on the pyrrolidine ring, 1 to 3 lower alkyl groups which may have a hydroxyl group as a substituent, an amino substituted lower alkyl group which may have a substituent selected from the group consisting of a phenyl group and a lower alkyl group, a 1,2,3,4-tetrahydronaphthyl substituted lower alkyl group which may have 1 to 5 lower alkyl groups as substituents on the 1,2,3,4-tetrahydronaphthalene ring, a naphthyl lower alkyl group, a pyridyl lower alkyl group, a quinolyl lower alkyl group, a 1,2,3,4-tetrazolyl lower alkyl group which may have, on the tetrazole ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group, a 1,2,4-triazolyl lower alkyl group, a tetrahydrofuryl lower alkyl group which may have a hydroxyl group as a substituent on the lower alkyl group, a phenoxy lower alkyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group and a nitro group, a lower alkoxycarbonyl lower alkyl group, a pyridyl group, or a carboxy lower alkyl group;

R^21crepresents a benzoyl group which may have 1 to 3 lower alkoxy groups as substituents on the phenyl ring, a lower alkoxycarbonyl group, a phenyl lower alkanoyl group, a lower alkanoyl group which may have a halogen atom as a substituent or an imidazolyl lower alkanoyl group; and

R^21drepresents a hydrogen atom, a lower alkyl group, a lower alkyl group which have 1 or 2 phenyl groups which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group which may have a halogen atom as a substituent and a lower alkylthio group, a phenyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group which may be substituted with a halogen atom, a lower alkoxy group which may be substituted with a halogen atom and a lower alkylthio group, a cycloalkyl lower alkyl group, a cycloalkyl group, a pyrrolidinyl lower alkyl group which may have, on the pyrrolidine ring, 1 to 3 lower alkyl groups which may have a hydroxyl group as a substituent, a pyrrolidinyl group which may have, on the pyrrolidine ring, 1 to 3 lower alkyl groups which may have a hydroxyl group as a substituent, an amino substituted lower alkyl group which may have a group selected from the group consisting of a phenyl group and a lower alkyl group, a 1,2,3,4-tetrahydronaphthyl substituted lower alkyl group which may have 1 to 5 lower alkyl groups as substituents on the 1,2,3,4-tetrahydronaphthalene ring, a 1,2,3,4-tetrahydronaphthyl group which may have 1 to 5 lower alkyl groups as substituents on the 1,2,3,4-tetrahydronaphthalene ring, a naphthyl lower alkyl group, a naphthyl group, a pyridyl lower alkyl group, a pyridyl group, a quinolyl lower alkyl group, a quinolyl group, a 1,2,3,4-tetrazolyl lower alkyl group which may have, on the tetrazole ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group, a 1,2,3,4-tetrazolyl group which may have, on the tetrazole ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group, a 1,2,4-triazolyl lower alkyl group, a 1,2,4-triazolyl group, a tetrahydrofuryl lower alkyl group which may have a hydroxyl group as a substituent on the lower alkyl group, a tetrahydrofuryl group which may have a hydroxyl group as a substituent on the lower alkyl group, a phenoxy lower alkyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group and a nitro group, a lower alkoxycarbonyl lower alkyl group or a carboxy lower alkyl group;

provided that the alkyl moiety of CHR^AR^21din the side chain (—(B₂₁CO)tN(R^20a)(CHR^AR^21d)) has not more than 6 carbon atoms.

The reaction of the compound (1uuu) with the compound (49) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (1uuu) with the compound (51) is carried out under reaction conditions similar to those of the reaction of the compound (1b) and the compound (5) of the above described reaction formula 2.

The reaction of the compound (1uuu) with the compound (50) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

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In the formula, R¹, R², X₁, Y, T, l, and A₁₀are the same as described above, provided that the a and b of A₁₀are bound to Y and (T)l, respectively;

R^14sand R^15rrepresent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic ring has at least one —(CO)oB₁₃X₂group thereon;

R^14tand R^15srepresent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic ring has at least one —(CO)oB₁₃R⁸⁴group thereon; and

R⁸⁴is an —NR²²R²³group or an imidazolyl group;

wherein B₁₃, o, X₂, R²²and R²³are the same as described above.

The reaction of the compound (1yyy) with the compound (52) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

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In the formula, R¹, R², X₁, Y, T, l, and A₁₀are the same as described above, provided that the a and b of A₁₀are bound to Y and (T)l, respectively;

R^14s′ and R^15r′ represent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic ring has at least one —N(R²⁸)—CO—B₁₆X₂group thereon; and

R^14uand R^15trepresent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic ring has at least one —N(R²⁸)—CO—B₁₆NR²⁹R³⁰group thereon;

wherein R²⁸, B₁₆, X₂, R²⁹and R³⁰represent the same as described above.

The reaction of the compound (1aaaa) with the compound (53) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

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In the formula, R^74a, R², X₁, Y, T, l, and A₁₀are the same as described above, provided that the a and b of A₁₀are bound to Y and (T)l, respectively; R^14vand R^15urepresent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic ring has at least one —B₁₂COOH group thereon; and

R^14wand R^15vrepresent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic ring has at least one —B₁₂CONR²⁰R²¹group thereon;

wherein B₁₂, R²⁰and R²¹are the same as described above.

The reaction of the compound (1cccc) with the compound (54) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

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In the formula, R¹, R², X₁, Y, T, l, and A₁₀are the same as described above, provided that the a and b of A₁₀are bound to Y and (T)l, respectively; R^14xand R^15wrepresent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic ring has at least one —O—B₁₅COOH group thereon; and

R^14yand R^15xrepresent a 5- to 10-membered saturated or unsaturated heterocyclic group as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic ring has at least one —O—B₁₅CONR²⁶R²⁷group thereon; wherein B₁₅, R²⁶and R²⁷are the same as described above.

The reaction of the compound (1eeee) with the compound (55) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

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are the same as described above, provided that the a and b of A₁₀are bound to Y and (T)l, respectively;

R^14zand R^15yrepresent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic ring has at least one —N(R³¹)—B₁₇—COOH group thereon; and

R^14aaand R^15zrepresent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic ring has at least one —N(R³¹)—B₁₇CONR³²R³³group thereon;

wherein R³¹, B₁₇, and R³², R³³are the same as described above.

The reaction of the compound (1gggg) with the compound (56) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

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In the formula, R¹, R², X₁, Y, T, l, and A₁₀are the same as described above, provided that the a and b of A₁₀are bound to Y and (T)l, respectively; R^14bband R^15aarepresent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic ring has at least one —COOH group thereon; and

R^14ccand R^15bbrepresent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic ring has at least one —CONR²⁶R²⁷group thereon;

wherein R²⁶and R²⁷are the same as described above.

The reaction of the compound (1iiii) with the compound (57) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

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In the formula, R¹, R², X₁, Y, T, l, R^14aand A₁₀are the same as described above, provided that the a and b of A₁₀are bound to Y and (T)l, respectively;

h represents 0 or 1; and

R⁵⁷represents a lower alkoxycarbonyl group.

The reaction which converts the compound (1kkkk) into the compound (1llll) may be carried out under reaction conditions similar to those of the hydrolysis B described for the above described reaction formula 9.

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In the formula, R¹, R², X₁, R³, R⁴, Y, R^Hand R¹²are the same as described above, R⁵⁸represents a lower alkyl group, and g represents 0 or 1.

The reaction which converts the compound (1mmmm) into the compound (1nnnn) may be carried out under reaction conditions similar to those of the hydrolysis B described for the above described reaction formula 9.

The reaction of the compound (1nnnn) with the compound (58) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

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In the formula, R¹, R², X₁, Y, T, l, A₁₀and X₂are the same as described above, provided that the a and b of A₁₀are bound to Y and (T)l, respectively; R^14hhand R^15ggrepresent 5- to -10 membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic ring has at least one —(CO)o-B₁₃NH(R^22a) group thereon;

R¹⁴ⁱⁱand R^15hhrepresent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic ring has at least one —(CO)o-B N(R^22a)R^23agroup thereon;

R^14jjand R¹⁵ⁱⁱrepresent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic ring has at least one —(CO)o-B₁₃N(R^22a)R^23bgroup thereon;

R^14kkand R^15jjrepresent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic ring has at least one —(CO)o-B₁₃N(R^22a)(CHR^AR^23c) group thereon,

wherein R^A, B₁₃and o are the same as described above;

R^22ais a hydrogen atom, a lower alkyl group, a benzoyl group which may have 1 to 3 lower alkoxy groups as substituents on the phenyl ring, a phenoxy lower alkyl group which may have a lower alkyl group as a substituent on the phenyl ring, a phenyl lower alkyl group or a phenyl group;

R^23arepresents a lower alkyl group, a phenoxy lower alkyl group which may have a lower alkyl group as a substituent on the phenyl ring, a phenyl lower alkyl group or a phenyl group;

R^23brepresents a benzoyl group which may have 1 to 3 lower alkoxy groups as substituents on the phenyl ring; and

R^23crepresents a hydrogen atom, a lower alkyl group, a phenoxy lower alkyl group which may have a lower alkyl group as a substituent on the phenyl ring, a phenyl lower alkyl group or a phenyl group; provided that the alkyl moiety of the —CHR^AR^23cgroup in the side chain (—(CO)o-B₁₃—N(R^22a)(CHR^AR^23c)) of the compound (1ssss) has not more than 6 carbon atoms.

The reaction of the compound (1pppp) with the compound (59) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (1pppp) with the compound (61) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

The reaction of the compound (1pppp) with the compound (60) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

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In the formula, R¹, R², X₁, Y, T, l, A₁₀and X₂are the same as described above, provided that the a and b of A₁₀are bound to Y and (T)l, respectively; R^14lland R^15kkrepresent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic ring has at least one —(O—B₁₅)s-CONH(R^26a) group thereon;

R^14mmand R^15llrepresent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic ring has at least one —(O—B₁₅)s-CON(R^26a)(R^27a) group thereon;

R¹⁴ⁿⁿand R^15mmrepresent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic ring has at least one —(O—B₁₅)s-CON(R^26a)(CHR^AR^27b) group,

wherein B₁₅, s and R^Aare the same as described above; R^26arepresents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group or an imidazolyl lower alkyl group;

R^27arepresents a lower alkyl group, a phenyl lower alkyl group or an imidazolyl lower alkyl group; and

R^27brepresents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, a phenyl group, an imidazolyl group or an imidazolyl lower alkyl group;

provided that the alkyl moiety of the —CHR^AR^27bgroup in the side chain (—(O—B₁₅)s-CO(R^26a)(CHR^AR^27b)) of the compound (1vvvv) has not more than 6 carbon atoms.

The reaction of the compound (1tttt) with the compound (62) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (1tttt) with the compound (63) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

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In the formula, R¹, R², X₁, Y, T, l, A₁₀, R^14v, R^15u, R^14kand R^14jare the same as described above, provided that the a and b of A₁₀are bound to Y and (T)l, respectively;

R⁵⁹represents a lower alkyl group; and

R^14ooand R¹⁵ⁿⁿrepresent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic ring has at least one —B₂₁CONHNHCOOR⁵⁹group,

wherein B₂₁is the same as described above.

The reaction of the compound (1cccc′) with the compound (102) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction which converts the compound (1yyyy) into the compound (1hhh) may be carried out under reaction conditions similar to those of the hydrolysis B described for the above described reaction formula 9.

The compound of the present invention of the general formula (1) having various R¹s is produced, for example, as shown by the following reaction formulas 37 to 46.

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In the formula, R², X₁, Y, A₁₆, R⁶, R⁸, B₂₁, R^Aand X₂are the same as described above, provided that the B₂₁CHR^Amoiety of the (R⁶—B₂₁CHR^A—) group of the compound (1y) has not more than 6 carbon atoms.

The reaction of the compound (19) with the compound (20) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (19) with the compound (21) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

The reaction of the compound (19) with the compound (22) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

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In the formula, R², X₁, Y, A, R⁶, B, R^Aand X₂are the same as described above, R^8arepresents a lower alkyl group which may have a lower alkoxy group as a substituent, a lower alkylsulfonyl group or a phenyl lower alkyl group, R^8brepresents a hydrogen atom, a phenyl group, phenyl lower alkyl group or a lower alkyl group which may have a lower alkoxy group as a substituent, and R^8crepresents a lower alkanoyl group, provided that the alkyl moiety of the —CHR^AR^8bgroup of the compound (1cc) has not more than 6 carbon atoms.

The reaction of the compound (1aa) with the compound (23) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (1aa) with the compound (24) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

The reaction of the compound (1aa) with the compound (25) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

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In the formula, R², X₁, Y, A, B₂₁, f, R^Aand R⁶are the same as described above, provided that the (B₂₁)fCHR^Amoiety of the (—(B₂₁)fCHR^ANHR⁶) group of the compound (1ee) has not more than 6 carbon atoms.

The reaction of the compound (26) with the compound (27) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

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In the formula, R⁸⁶represents a —Y-A group or a halogen atom, and R², X₁, Y, A, and R⁶, are the same as described above.

The reaction of the compound (28) with the compound (27) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

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In the formula, R², X₁, Y, A, R⁶, R^8a, R^8b, R^8c, R^Aand X₂are the same as described above, provided that the alkyl moiety of the —CHR^AR^8bgroup of the compound (1hh) has not more than 6 carbon atoms.

The reaction of the compound (1ff′) with the compound (23) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (1ff′) with the compound (24) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

The reaction of the compound (1ff′) with the compound (25) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

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In the formula, R², X₁, Y, A, R⁶and X₂are the same as described above.

The reaction which converts the compound (30) into the compound (1jj) may be carried out under reaction conditions similar to those of the reaction which converts the compound (1f) into the compound (1h) of the above described reaction formula 3.

The reaction which converts the compound (1jj) into the compound (1kk) may be carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

The reaction of the compound (30) with the compound (32) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

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In the formula, R², X₁, Y, A, X₂and R⁶are the same as described above, B₂₃represents a lower alkylene group or a lower alkenylene group, and the B₂₃—HC═CH— moiety in the side chain (R⁶B₂₃—HC═CH—) in the compound (1mm) has 1 to 3 double bonds and has not more than 6 carbon atoms.

The reaction of the compound (33) with the compound (34) is carried out in an appropriate inert solvent and in the presence of a condensation agent.

Examples of the inert solvent used in the above described reaction include aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, lower alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol, fatty acids such as α-dimethylaminoacetic acid and acetic acid, esters such as ethyl acetate and methyl acetate, ketones such as acetone and methyl ethyl ketone, acetonitrile, 1-methyl-2-pyrrolidone, pyridine, dimethyl sulfoxide, dimethylformamide, and hexamethylphosphoric acid triamide, and a mixture thereof.

Examples of the condensation agent include palladium complexes such as bis(benzonitrile)dichloropalladium (II).

The condensation agent is appropriately used in an amount typically 0.01 to 1 times, and preferably 0.01 to 0.5 times of the compound (33) on a molar basis.

The above described reaction favorably proceeds typically at 0 to 200° C., and preferably at about room temperature to about 150° C. and is, in general, completed in about 10 minutes to 20 hours.

The above described reaction proceeds advantageously by adding a alkali metal salt of fatty acid such as sodium acetate to the reaction system.

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In the formula, R², X₁, Y, A and R⁶are the same as described above.

The reaction which converts the compound (1nn) into the compound (1oo) may be carried out under reaction conditions similar to those of the reaction which converts the compound (1f) into the compound (1g) of the above described reaction formula 3.

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In the formula, A₁₇represents a group of the formula:

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wherein R², R³, p, X₁, Y, A, Bo and R⁶are the same as described above.

The reaction of the compound (64) with the compound (65) is carried out in an appropriate solvent in the presence of a condensation agent.

Any of the solvents, which are used in the reaction of carboxylic acid halide with amine (1b) by the method (d) of the formula 2 for reacting the compound (1b) with the compound (6) (reaction which Produces an amide bond); may be used in this reaction.

Examples of the condensation agent used include a mixture of an azocarboxylate (such as diethyl azodicarboxylate) with a phosphorus compound (such as triphenylphosphine).

The condensation agent is appropriately used in an amount typically at least equimolar to the compound (64), and preferably 1 to 2 times of the compound (64) on a molar basis.

The compound (65) is appropriately used in an amount typically at least equimolar to the compound (64), and preferably 1 to 2 times of the compound (64) on a molar basis.

The above described reaction favorably proceeds typically at 0 to 200° C., preferably at around 0 to 150° C. and is, in general, completed in around 1 to 10 hours.

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In the formula, R², X₁, Y, A, and R⁶are the same as described above.

The reaction of the Compound (30) with the compound (66) is carried out in the presence or absence of a basic compound, and preferably in the absence of the basic compound in an appropriate solvent or without a solvent.

Any of the inert solvents and the basic compounds, which are used in the reaction of carboxylic acid halide with amine (1b) by the method (d) of the formula 2 for reacting the compound (1b) with the compound (6) (reaction which produces an amide bond), may be used in this reaction.

The compound (66) may be used in an amount typically at least about 1 to 5 times, and preferably about 1 to 3 times of the compound (30) on a molar basis.

The above described reaction is carried out typically at 0 to 200° C., and preferably at around room temperature to 150° C. and is, in general, completed in around 5 minutes to 50 hours.

A boron compound such as a boron trifluoride-diethyl ether complex may be added to the system of the above described reaction.

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In the formula, R², X₁, Y, T₂, A₁₀, R¹⁴, R¹⁵, B₂₁, R^A, X₂, R⁶and R⁵⁹are the same as described above, provided that the a and b of A₁₀are bound to Y and T₂, respectively.

The reaction which converts the compound (68) into the compound (71) may be carried out under reaction conditions similar to those of the hydrolysis B described for the above described reaction formula 9.

The reaction of the compound (71) with the compound (100) is carried out under reaction conditions similar to those of the reaction of the compound (1fff) with the compound (43) in formula 20 as described above.

The compound (68) may also be produced using a halogenated lower alkyl group such as methyl iodide in place of the compound (100) in a reaction similar to the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

The reaction which converts the compound (68) into the compound (69) may be carried out, for example, (1) by reducing the compound (68) with a catalytic hydride reducing agent in an appropriate solvent, or (2) by reducing the compound (68) with a reducing agent such as a mixture of a metal or a metal salt with an acid, or a mixture of a metal or a metal salt with an alkali metal hydroxide, a sulfide, an ammonium salt or the like, in an appropriate inert solvent.

Examples of the solvent in using the method (1) include water, acetic acid, alcohols such as methanol, ethanol, and isopropanol, hydrocarbons such as n-hexane and cyclohexane, ethers such as dioxane, tetrahydrofuran, diethyl ether, and diethylene glycol dimethyl ether, esters such as ethyl acetate and methyl acetate, and aprotic polar solvents such as N,N-dimethylformamide, and a mixture thereof. Examples of the catalytic hydride reducing agent used include palladium, palladium black, palladium-carbon, platinum-carbon, platinum, platinum oxide, copper chromite, and Raney nickel. These reducing agents may be used singly or in a mixture of two or more. In general, the reducing agent may be used in an amount 0.02 to 1 times of the compound (68) on a weight basis. The reaction temperature is typically about −20 to 150° C., and preferably about 0 to 100° C., and the hydrogen pressure is typically at 1 to 10 atm. In general, the above described reaction is completed in about 0.5 to 100 hours. An acid such as hydrochloric acid may be added to the above described reaction system.

The reducing agent which may be used in using the method (2) is a mixture of iron, zinc, tin or stannous chloride with a mineral acid such as hydrochloric acid or sulfuric acid; or a mixture of iron, ferrous sulfate, zinc or tin with an alkali metal hydroxide such as sodium hydroxide, a sulfate such as ammonium sulfate or an ammonium salt such as ammonium hydroxide or ammonium chloride. Examples of the inert solvent include water, acetic acid, alcohols such as methanol and ethanol, and ethers such as dioxane, and a mixture thereof. The reaction conditions may be chosen appropriately depending on the reducing agent used. For example, when stannous chloride or hydrochloric acid is used as the reducing agent, the reaction is appropriately carried out advantageously at about 0 to 150° C., and for around 0.5 to 10 hours. The above described reducing agent is used in an amount at least equal molar to the compound (68), and typically 1 to 5 times of the compound (68) on a molar basis.

The reaction of the compound (69) with the compound (20) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (69) with the compound (22) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (69) with the compound (21) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

The reaction which converts the compound (69) into the compound (37a), the reaction which converts the compound (70a) into the compound (37d), the reaction which converts the compound (70b) into the compound (37c) and the reaction which converts the compound (70c) into the compound (37b) may be carried out under reaction conditions similar to those of the hydrolysis B described for the above described reaction formula 9.

The reaction of the compound (71) with the compound (36) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (69) with the compound (32) is carried out under reaction conditions similar to those of the reaction of the compound (30) with the compound (32) in the reaction formula 42 as described above.

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In the formula, R², X₁, Y, A₁₀, B₃, R¹⁴, R¹⁵, R^A, R^74aand X₂are the same as described above;

R^crepresents a —CONR¹⁴R¹⁵group or —COOR^59bgroup, R^59brepresents a lower alkyl group or a phenyl lower alkyl group;

R^17arepresents a lower alkyl group, a cycloalkyl group, a lower alkyl sulfonyl group or a lower alkenyl group;

R^17brepresents a hydrogen atom or a lower alkyl group; and

R^17crepresents a cycloalkylcarbonyl group, a lower alkanoyl group which may have a halogen atom as a substituent or an amino substituted lower alkanoyl group which may have a lower alkyl group as a substituent; wherein the a of A₁₀is bound to the Y group and the b is bound to an —NHB₃—Rc group, —N(R^17a)B₃-Rc group, —N(CH(R^A)(R^17b))B₃-Rc group or —N(R^17c) B₃—Rc group.

The reaction of the compound (72a) with the compound (73) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (72a) with the compound (75) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (72a) with the compound (74) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

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In the formula, R², X₁, Y, A₁₀, B₃, R¹⁴and R¹⁵are the same as described above, R^17drepresents a lower alkanoyl group which is substituted with a halogen atom, R⁶⁰represents an amino group which may be substituted with a lower alkyl group, and R⁶¹represents an amino substituted lower alkanoyl group which may be substituted with a lower alkyl group, wherein the a A₁₀is bound to the Y group and the b is bound to an N(R^17d)B₃—CONR¹⁴R¹⁵group or —NR⁶¹B₃—CONR¹⁴R¹⁵group.

The reaction of the compound (72e) with the compound (76) is carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) in the reaction formula 1 as described above.

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In the formula, R², X₁, Y, R⁶, B₂₁, R^Aand X₂are the same as described above, and A₁₁represents a group of the formula:

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wherein R³and p are the same as described above, provided that the alkyl moiety in the side chain (—NHCH(R^A)(B₂₁R⁶) group) of the compound (78b) has not more than 6 carbon atoms.

The reaction which converts the compound (77a) into the compound (77b) may be carried out under reaction conditions similar to those of the reaction which converts the compound (68) into the compound (69) of the above described reaction formula 47.

The reaction of the compound (77b) with the compound (20) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (77b) with the compound (22) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (77b) with the compound (21) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

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In the formula, R¹, R², X₁, Y and A₁₁are the same as described above, and i represents an integer of 2 to 4.

In general, the reaction of the compound (77c) with the compound (79) is called Friedel-Crafts reaction and is carried out in an appropriate solvent in the presence of a Lewis acid.

Any of the Lewis acids typically used in the Friedel-Crafts reaction may be used here. Examples of these Lewis acids include aluminum chloride, zinc chloride, iron chloride, tin chloride, boron tribromide, and concentrated sulfuric acid. These Lewis acids are used singly or in a mixture of two or more. The Lewis acid is used typically in an amount 2 to 6 times of the compound (77c) on a molar basis.

Examples of the solvent used here include aromatic hydrocarbons such as carbon disulfide, nitrobenzene, and chlorobenzene, and halogenated hydrocarbons such as dichloromethane, dichloroethane, carbon tetrachloride, and tetrachloroethane, and a mixture thereof.

The compound (79) is typically used in an amount at least equimolar to the compound (77c), and preferably 1 to 5 times of the compound (77c) on a molar basis.

Typically the above described reaction proceeds favorably at 0 to 120° C., and preferably about 0 to 70° C., and is generally completed in about 0.5 to 24 hours.

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In the formula, R², X₁, Y, R⁶, X₂, B₂₁and R^Aare the same as described above. A₁₂represents a group of the formula:

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R³and p are the same as defined above, and

R⁶²represents a lower alkanoyl group or a hydroxyl group substituted lower alkyl group, provided that the alkyl moiety in the side chain (NHCH(R^A)(B₂₁R⁶) group) of the compound (81b) has not more than 6 carbon atoms.

The reaction which converts the compound (80a) into the compound (80b) is carried out under reaction conditions similar to those of the reaction which converts the compound (68) into the compound (69) of the above described reaction formula 47.

The reaction of the compound (80b) with the compound (20) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (80b) with the compound (22) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (80b) with the compound (21) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

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In the formula, R¹, R², X₁, and Y are the same as above,

A₁₃represents a group of the formula:

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wherein R³and p are the same as described above, and

R^63arepresents a lower alkanoyl group or a lower alkyl group, and

A₁₄represents a group of the formula:

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wherein R^63brepresents a lower alkanoyl group which is substituted with a halogen atom at the α-position or a lower alkyl group which is substituted with a halogen atom at the 2 position.

The reaction which converts the compound (80b′) into the compound (35a) is carried out in the presence of a halogenating agent in an appropriate solvent.

Examples of the halogenating agent include halogen atoms such as bromine and chlorine, iodine chloride, sulfuryl chloride, copper compounds such as cupric bromide, and N-halogenated succinic acid imides such as N-bromosuccinic acid imide and N-chlorosuccinic acid imide.

Examples of the solvent used include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, fatty acids such as acetic acid and propionic acid, and carbon disulfide.

The halogenated agent is appropriately used in an amount typically 1 to 10 times, and preferably 1 to 5 times of the compound (80b′) on a molar basis.

The above described reaction is carried out typically at 0° C. to the boiling point of the solvent, and preferably at about 0 to 100° C., and is completed typically in about 5 minutes to 30 hours.

When an N-halogenated succinic acid imide is used as a halogenated agent, a peroxide such as benzoyl peroxide may be added to the reaction system as a initiator for the radical reaction.

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In the formula, R², X₁, Y, A₁₀, T₂, R⁵⁹, R^8a, R^8b, R^8c, X₂and R^Aare the same as described above, and

R⁶⁴represents a phenyl lower alkoxycarbonyl group, provided that the alkyl moieties in the side chain (—N(CHR^AR^8b)(R⁶⁴) group) of the compound (84b) and the side chain (—NH(CHR^AR^8b) group) of the compound (84e) have not more than 6 carbon atoms, respectively, and the a and b of A₁₀are bound to the Y group and the T₂group, respectively.

The reaction of the compound (83) with the compound (23) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (69) with the compound (82), and the reaction of the compound (83) with the compound (25) are carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (83) with the compound (24) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

The reactions which respectively convert the compound (84a) into the compound (84d), the compound (84b) into the compound (84e), and the compound (84c) into the compound (84f) are carried out under reaction conditions similar to those of the reaction which converts the compound (1iii′) into the compound (1hhh′) by reduction as described for the above described reaction formula 24.

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In the formula, R², X₁, Y, A₁₀, B₂₁, R^74aand X₂are the same as described above, provided that the a and b of A₁₀are bound to the Y group and the B₂₁group, respectively.

The reaction which converts the compound (85) into the compound (7′) is carried out by reacting compound (85) to a halogenating agent in an appropriate solvent or without solvent.

Examples of the halogenating agent include mineral acids such as hydrochloric acid and hydrobromic acid, N,N-diethyl-1,2,2-trichlorovinyl azide, phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, sulfonyl halide compounds such as thionyl chloride, mesyl chloride, and tosyl chloride, and a mixture of carbon tetra bromide with triphenylphosphine. The sulfonyl halide compound is used together with a basic compound.

Any of the basic compounds used in the reaction of the compound (2) with the compound (3) of the reaction formula 1 may be used.

Examples of the solvent used include ethers such as dioxane, tetrahydrofuran, and diethyl ether, halogenated hydrocarbons such as chloroform, methylene chloride, and carbon tetrachloride, and dimethylformamide, and a mixture thereof.

When a sulfonyl halide compound is used together with a basic compound as a halogenating agent, the sulfonyl halide compound is appropriately used in an amount typically at least equimolar to the compound (85), and preferably 1 to 2 times of the compound (85) on a molar basis. The basic compound is used typically in a catalytic amount of the compound (85), and preferably in a catalytic amount to an amount equimolar to the compound (85). When another halogenating agent is used, such a halogenating agent is used at least equimolar to the compound (85), and typically used in a large excess amount.

The above described reaction proceeds favorably typically at room temperature to 200° C., and preferably at room temperature to 150° C., and in general is completed in about 1 to 80 hours.

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In the formula, R^74a, R², X₁, Y, A₁₀and B₂₁are the same as described above, and R⁶⁵represents a tri-lower alkyl silyl group, provided that the a and b of A₁₀are bound to the Y group and the B₂₁group, respectively.

Here, examples of the tri-lower alkyl silyl group include trialkylsilyl groups of which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms such as

a tert-butyldimethylsilyl group, trimethylsilyl group, and diethylmethylsilyl group.

The reaction which converts the compound (86) into the compound (85) may be carried out under reaction conditions similar to those of the hydrolysis B described for the above described reaction formula 9.

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In the formula, R^74a, R², X₁, Y, A₁₀, B₂₁, R⁶⁵and X₂are the same as described above, and R⁶⁶represents a hydrogen atom, a lower alkyl group or a lower alkoxycarbonyl group, provided that the a and b of A₁₀are bound to Y and B₂₁, respectively, and the alkyl moieties in the side chain (—Y-A₁₀-B₂₁CH₂OH) of the compound (85a) and the side chain (—Y-A₁₀-B₂₁CH₂OR⁶⁵) of the compound (86a) have not more than 6 carbon atoms.

The reaction which converts the compound (69a) into the compound (85a) is carried out under the similar reaction conditions as the reaction which converts the compound (1f) into the compound (1g) of the above described reaction formula 3.

The reaction of the compound (85a) with the compound (101) is carried out under reaction conditions similar to those of the reaction which converts the compound (2) into the compound (3) of the above described reaction formula 1.

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In the formula, R², X₁, Y, A₁₀, B₂₁, R⁶, R^A, f, R⁴³, R⁴⁴and X₂are the same as described above, and B_21′ represents a lower alkylene group, provided that the a and b of A₁₀are bound to Y and B_21′, respectively, and the (B_21′) f-CH═C moiety in the side chain (—Y-A₁₀-(B_21′)f-CH═C(COOR⁴³)(COOR⁴⁴)) of the compound (90c) and the alkyl moiety in the side chain (—NHCH(R^A) (B₂₁R⁶)) of the compound (90b) have not more than 6 carbon atoms, respectively.

The reaction of the compound (87) with the compound (88) is carried out under reaction conditions similar to those of the reaction of the compound (1f) and hydroxylamine of the above described reaction formula 3.

The reaction which converts the compound (89a) into the compound (89b) may be carried out under reaction conditions similar to those of the reaction which converts the compound (68) into the compound (69) of the above described reaction formula 47.

The reaction of the compound (89b) with the compound (20) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (89b) with the compound (22) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (89b) with the compound (21) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

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In the formula, R², X₁, Y, A₁₀, B_21′, R⁶⁵, R⁶, B₂₁, R^Aand X₂are the same as defined above, provided that the a and b of A₁₀are bound to the Y group and the B_21′ group, respectively, and the alkyl moiety in the side chain (—NHCH(R^A)(B₂₁R⁶)) of the compound (91b) has not more than 6 carbon atoms.

The reaction which converts the compound (86a′) into the compound (86b) may be carried out under reaction conditions similar to those of the reaction which converts the compound (68) into the compound (69) of the above described reaction formula 47.

The reaction of the compound (86b) with the compound (20) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (86b) with the compound (22) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (86b) with the compound (21) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

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In the formula, R², X₁, Y, A₁₀, B₂₁, B_21′, R⁶, R^Aand X₂are the same as described above, provided that the a and b of A₁₀are bound to the Y group and the B_21′ group, respectively, and the alkyl moiety in the side chain (—NHCH(R^A)(B₂₁R⁶)) of the compound (44c) has not more than 6 carbon atoms.

The reaction which converts the compound (92a) into the compound (92b) may be carried out under reaction conditions similar to those of the reaction which converts the compound (68) into the compound (69) of the above described reaction formula 47.

The reaction of the compound (92b) with the compound (20) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (92b) with the compound (22) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (92b) with the compound (21) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

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In the formula, R², X₁, and X₂are the same as described above, R⁶⁷represents an -A₁₀B₂₁CN group, -A₁₀-R^59dgroup, -A₁₀-T₂-COOR⁵⁹group or -A group, R^59drepresents a lower alkyl group, A₁₀, B₂₁, T₂and R^59aare the same as described above, and R⁶⁸represents a nitro group or a halogen atom.

The reaction of the compound (93) with the compound (94) is carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

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In the formula, R², R⁶⁷, and X₁are the same as described above.

The reaction which converts the compound (95a) into the compound (95b) may be carried out under reaction conditions similar to those of the reaction which converts the compound (68) into the compound (69) of the above described reaction formula 47.

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In the formula, R², X₁, Y, A₇, R⁶, B₂₁, R^Aand X₂are the same as described above, provided that the alkyl moiety in the side chain (—NHCH(R^A)(B₂₁R⁶)) of the compound (13b) has not more than 6 carbon atoms.

The reaction of the compound (96) with the compound (20) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (96) with the compound (22) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (96) with the compound (21) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

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In the formula, R², X₁, Y, B₂₁, f, i, R⁶, B₂₁, A₁₀, R^Aand X₂are the same as described above, and R^A′ represents a hydrogen atom or a lower alkyl group, provided that the alkyl moiety in the side chain (—NHCH(R^A)(B₂₁R⁶)) in compound (98b) has not more than 6 carbon atoms, and the a and b of A₁₀are bound to the Y group and the (B₂₁)f group, respectively.

The reaction which converts the compound (97a) into the compound (97b) is carried out under reaction conditions similar to those of the reaction which converts the compound (68) into the compound (69) of the above described reaction formula 47.

The reaction of the compound (97b) with the compound (20) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (97b) with the compound (22) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (97b) with the compound (21) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

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In the formula, R¹, R², X₁, Y, A₁₀, B₂₁, f, R^A′ and A₃are the same as described above, provided that the a and b of A₁₀are bound to the Y group and the (B₂₁)f group, respectively.

The reaction which converts the compound (98d) into the compound (9′) may be carried out under reaction conditions similar to those of the hydrolysis B described for the above described reaction formula 9.

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In the formula, R¹, R², X₁, Y, A₃, R⁵⁹, A₁₀, B₂₁and f are the same as described above, T₃represents a direct bond or B₇group, and B₇represents the same as described above, provided that The a and b of A₁₀are bound to the Y group and the (B₂₁)f group, respectively.

The reaction of the compound (9′) with the compound (99) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

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In the formula, R², X₁, Y, A₁₀, R^14a, R^49a, R⁴⁹, R^49b, T, l, R^Aand X₂are the same as described above, provided that the CHR^Amoiety in the side chain (—N(R^14a)(CHR^AR^49b)) of the compound (104c) has not more than 6, the a of A₁₀is bound to the Y group, and the b of A₁₀is bound to a —NR^14aH group, —NR^14aR^49agroup, —NR^14aR⁴⁹group, or —NR^14a(CHR^AR^49b) group.

The reaction of the compound (103) with the compound (38a) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (103) with the compound (38) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (103) with the compound (38b) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

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In the formula, R², X₁, Y and A are the same as described above.

The reaction which converts the compound (105) into the compound (19a) is carried out under reaction conditions similar to those of the reaction which converts the compound (68) into the compound (69) of the above described reaction formula 47. The compound (19a) may be used in the following reaction without isolation.

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In the formula, R², X₁, Y and A₁₀is the same as described above, R^69arepresents a thiazolidinyl group which may have an oxo group as a substituent on the thiazolidine ring, R⁶⁹represents a thiazolidinylidene lower alkyl group which may have an oxo group as a substituent on the thiazolidine ring, and R⁷⁰represents a thiazolidinyl lower alkyl group which may have an oxo group as a substituent on the thiazolidine ring, provided that the a of A₁₀are bound to the Y group and the b of A₁₀is bound to an —R⁶⁹group or —R⁷⁰group.

The reaction of the compound (106a) with the compound (160) is carried out under reaction conditions similar to those of the reaction of the compound (87) with the compound (88) of the above described reaction formula 58.

The reaction which converts the compound (106) into the compound (19b) may be carried out under reaction conditions similar to those of the reaction which converts the compound (68) into the compound (69) of the above described reaction formula 47.

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In the formula, R², X₁, X₂, A, Y₁, A₁₀, T₂, R⁵⁹and R^59aare the same as described above, X₃represents a halogen atom, R⁷¹represents an —R¹group (wherein R¹is the same as described above), a nitro group or a lower alkoxycarbonyl group, and R⁷²represents a lower alkyl group which may be substituted with a hydroxyl group, a nitro group, an amino group which may be substituted with a lower alkanoyl group, a carboxy lower alkyl group, a —(B₂₁)fC(═O)R^Agroup (wherein B₂₁, f and R^Aare the same as described above), a lower alkanoyl group, a lower alkoxy group or a hydrogen atom, provided that the a of A₁₀are bound to the Y₁group and the b of A₁₀is bound to a -T₂group or —R⁷²group.

The reaction of the compound (94a) with the compound (107), and the reaction of the compound (94a) with the compound (107a) are carried out in an appropriate solvent and in the presence of a catalyst.

Any of the solvents used in the reaction of the compound (2) with the compound (3) of the above described reaction formula 1 may be used in this reaction.

The above described catalyst is appropriately used in an amount typically equimolar to the compound (94a), and preferably 1 to 5 times of the compound (94a) on a molar basis.

The above described reaction is carried out typically at about 0 to 200° C., preferably at about 0 to 150° C., and, in general, is completed in around 30 minutes to 10 hours.

Addition of molecular sieves such as Molecular Sieves 3A (MS3A) or Molecular Sieves 4A (MS4A) or a phosphorus compound such as triphenylphosphine or tri(2-furyl)phosphine makes the reaction proceed advantageously.

The reaction of the compound (94a) with the compound (108), compound (3) or compound (110) is carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

The compound (109c), wherein R⁷¹represents a lower alkoxycarbonyl group, may be converted into the corresponding compound (109c), wherein R⁷¹represents a carboxy group, by hydrolyzing under reaction conditions similar to those of the hydrolysis B described for the above described reaction formula 9.

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In the formula, R¹, R², X₁, X₂, Y₁, A₁₀and T₂are the same as described above, and R^59crepresents a hydrogen atom, a lower alkyl or a phenyl lower alkyl group, provided that the a and b of A₁₀are bound to a —Y₁group and a -T₂group, respectively.

The reaction of the compound (2) with the compound (108′) is carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

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In the formula, R², X₁, R^5a, R^5b, R^A, R^5cand X₂are the same as described above, and R^73arepresents a -A₁₀-T₂-COOR⁵⁹group (wherein A₁₀, T₂and R⁵⁹are the same as described above) or an -A group (wherein A is the same as described above), provided that the a of A₁₀is bound to an —NH— group, NR^5a— group, —N(CHR^AR^5b) group or —NR^5c— group, and the b of A₁₀is bound to a -T₂group, and the alkyl moiety in the side chain (—N(R^73a)(CHR^AR^5b)) of the compound (68d) has not more than 6 carbon atoms.

The reaction of the compound (111) with the compound (4) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (111) with the compound (6) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (111) with the compound (5) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

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In the formula, R², X₁, Y, A₁₀, X₂, R¹⁷, B₃, R^74aand R^care the same as described above, provided that the a of A₁₀is bound to a —Y group and the b of A₁₀is bound to an —NHR¹⁷group or —NR¹⁷B₃R^cgroup.

The reaction of the compound (112) with the compound (113) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

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In the formula, R², X₁, Y, A₁₀, T₁, l, R¹⁴, and R¹⁵are the same as described above, provided that the a and b of A₁₀are bound to an —Y group and a -(T₁)l group, respectively.

The reaction of the compound (114) with the compound (36) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

The compound (109e), in which l is 0, may also be produced by reacting the corresponding compound (114) with the compound (36) in an appropriate solvent in the presence of a basic compound and a catalyst.

The above described reaction is carried out under reaction conditions similar to those of the reaction C described for the above described reaction formula 13.

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In the formula, R², X₁, Y, R⁸, B₂₁, R⁶, A₁₀, T₂, R⁵⁹, R^Aand X₂are the same as described above, provided that the CHR^AB₂₁moiety in the side chain (—N(R⁸)(CH(R^A) B₂₁R⁶)) of the compound (84i) has not more than 6 carbon atoms, and the a and b of A₁₀are bound to a —Y group and a -T₂group, respectively.

The reaction of the compound (84g) with the compound (20) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (84g) with the compound (22) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (84g) with the compound (21) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

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In the formula, R², X₁, Y, R^8a, R^8b, R^8c, B, R⁶, A₁₀, T₂, R⁵⁹, R^Aand X₂are the same as described above, provided that the CHR^Amoiety in the side chain (—NB(R⁶)(CH(R^A)^8b)) of the compound (116b) has not more than 6 carbon atoms, and the a and b of A₁₀are bound to a —Y group and a -T₂group, respectively.

The reaction of the compound (115) with the compound (23) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (115) with the compound (25) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (115) with the compound (24) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

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In the formula, R², X₁, Y, A₃, R¹⁴and R¹⁵are the same as described above, and A₁₅represents a group of the formula:

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wherein R⁷³represents a —(B₂₁) fCH(R^A)(NR¹⁴R¹⁹) group, and B₂₁, f and R^Aare the same as described above, provided that the (B₂₁)fCH(R^A) moiety has not more than 6 carbon atoms.

The reaction of the compound (117) with the compound (36) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

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In the formula, R², X₁, Y, A₁₀, T₂, R⁶, R^9aand R⁵⁹are the same as described above, provided that the a and b of A₁₀are bound to a —Y group and a -T₂group, respectively.

The reaction of the compound (69′) with the compound (66) is carried out under reaction conditions similar to those of the reaction of the compound (30) with the compound (66) of the above described reaction formula 46.

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In the formula, R², X₁, Y, A₁₀, T₂, R⁹⁵and R^59bare the same as described above, provided that the a and b of A₁₀are bound to a —Y group and a -T₂group, respectively.

The reaction which converts the compound (120a) into the compound (120b) may be carried out under reaction conditions similar to those of the hydrolysis B described for the above described reaction formula 9.

The reaction of the compound (120b) with the compound (100′) is carried out under reaction conditions similar to those of the reaction of the compound (1fff) with the compound (43) in the reaction formula 20 described above.

The compound (120a) may also be produced using a lower alkyl halide such as methyl iodide in place of the compound (100′) under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

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In the formula, R¹, R², X₁, Y, A₁₀, B₅, R^59aand j are the same as described above, provided that the a and b of A₁₀are bound to a —Y group and a —S group, respectively.

The reaction which converts the compound (120c) into the compound (120d) may be carried out under reaction conditions similar to those of the reaction which converts the compound (1zzzz) into the compound (1aaaaa) in formula 4 described above.

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In the formula, R², X₁, Y, A₁₀, T, l, R⁶, X₂, R^A, B₂₁and R^14aare the same as described above, and R^49crepresents a lower alkoxycarbonyl group, provided that the a and b of A₁₀are bound to a —Y group and a -(T)l group, respectively.

The reaction of the compound (103) with the compound (38c) is carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

The reaction which converts the compound (104d) into the compound (104e) is carried out under reaction conditions similar to those of the reaction which converts the compound (68) into the compound (69) of the above described reaction formula 47.

The reaction of the compound (104e) with the compound (20) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (104e) with the compound (22) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (104e) with the compound (21) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

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In the formula, R², X₁, Y, A₃, A₁₀, B₂₁, f, R^Aand i are the same as described above, provided that the a and b of A₁₀are bound to a —Y group and a —(B₂₁)f group, respectively, and (B₂₁)fC(R^A) in the side chain of the compound (123a) has not more than 6 carbon atoms in total.

The reaction of the compound (121) with the compound (122) may be carried out in an appropriate solvent in the presence of an acid.

Any of the solvents, which are used in the reaction of the compound (2) with the compound (3) of the above described reaction formula 1, may be used in this reaction.

Examples of the acid used include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as acetic acid, trifluoroacetic acid, and sulfonic acids including p-toluenesulfonic acid. These acids may be used singly or in a mixture of two or more. The acid is appropriately used in an amount typically at least 0.01 to 5 times, and preferably 0.01 to 2 times of the compound (121) on a molar basis. The compound (122) is appropriately used in an amount typically at least equimolar to the compound (121), and preferably 1 to 10 times of the compound (121) on a molar basis.

The above described reaction is carried out typically at 0 to 200° C., and preferably at around 0 to 150° C. and, in general, is completed in around 30 minutes to 10 hours.

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In the formula, R², X₁, Y and A₁₀are the same as described above, and R^72arepresents a lower alkoxy group, provided that the a of A₁₀is bound to a —Y group and the b of A₁₀is bound to a —R^72agroup or a hydroxyl group.

The reaction which converts the compound (109f) into the compound (124) may be carried out in an appropriate solvent in the presence of an acid.

In addition to water, any solvents which are used in the reaction of the compound (2) with the compound (3) of the above described reaction formula 1 may be used in this reaction.

Examples of the acid used include mineral acids such as hydrobromic acid, hydrochloric acid, and concentrated sulfuric acid, fatty acids such as formic acid and acetic acid, organic acids such as p-toluenesulfonic acid, Lewis acids such as aluminum chloride, zinc chloride, iron chloride, tin chloride, boron trifluoride, and boron tribromide, iodides such as sodium iodide and potassium iodide, a mixture of the above described Lewis acid with the above described iodide. The acid is appropriately used in an amount typically 0.1 to 5 times, and preferably 0.5 to 3 times of the compound (109f) on a molar basis.

The above described reaction is typically carried out at 0 to 150° C., and preferably at about 0 to 100° C., and, in general, is completed in about 0.5 to 15 hours.

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In the formula, R², X₁, Y, A₁₀, B₅, X₂, R¹⁴, and R¹⁵are the same as described above, and Q₁represents an oxygen atom or a sulfur atom, provided that the a and b of A₁₀are bound to a —X group and a -Q₁group, respectively.

The reaction of the compound (124a) with the compound (125) is carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

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In the formula, R², X₁, Y, R^14a, R^74a, T and l are the same as described above, and R^74brepresents a lower alkanoyl group or a lower alkoxycarbonyl group, provided that the a and b of A₁₀are bound to a —Y group and a -(T)l group, respectively.

The reaction which converts the compound (109g) into the compound (109h) may be carried out under reaction conditions similar to those of the hydrolysis B described for the above described reaction formula 9.

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In the formula, R², X₁, Y, A₁₀, T₂, X₂, R^59a, B₂₃and R⁶are the same as described above, provided that the a and b of A₁₀are bound to —Y group and -T₂group, respectively.

The reaction of the compound (126) with the compound (34) is carried out under reaction conditions similar to those of the reaction of the compound (33) with the compound (34) in formula 43 described above.

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In the formula, R², X₁, Y, R^74aand A₁₀are the same as described above, R^74crepresents an amino group or an —R¹group (wherein R¹is the same as described above), R⁷⁵represents a lower alkanoyl group, R⁷⁶represents a lower alkoxycarbonyl group, R⁷⁷and R⁷⁸are both lower alkoxy groups, and R⁷⁹represents a hydrogen atom or a lower alkyl group, provided that the a of A₁₀is bound to a —Y group, and the b of A₁₀is bound to a —R⁷⁵group, —C(R⁷⁹)═CHR⁷⁶group or —CH(R⁷⁹)CH₂R⁷⁶group, and the C(R⁷⁹)═CH moiety or the CH(R⁷⁹)CH₂moiety has not more than 6 carbon atoms.

The reaction of the compound (128) with the compound (129) is carried out in an appropriate solvent in the presence of a basic compound.

Any of the conventional solvents which do not affect the reaction may be used. Examples of such a solvent include ethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme, and diglyme, aromatic hydrocarbons such as benzene, toluene, and xylene, aliphatic hydrocarbons such as n-hexane, heptane, and cyclohexane, amines such as pyridine and N,N-dimethylaniline, aprotic polar solvents such as acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric acid triamide, and alcohols such as methanol, ethanol, and isopropanol, and a mixture thereof.

Examples of the basic compound include metal sodium, metal potassium, sodium hydride, sodium amide, metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide, carbonates such as sodium carbonate, potassium carbonate, and sodium bicarbonate, metal alcoholates such as sodium methylate, sodium ethylate, and potassium tert-butoxide, alkyl and aryl lithiums or lithium amides such as methyl lithium, n-butyryl lithium, phenyl lithium, and lithium diisopropylamide, and organic bases such as pyridine, piperidine, quinoline, trimethylamine, diisopropylethylamine, N,N-dimethylaniline. These basic compounds are used singly or in a mixture of two or more. The basic compound is appropriately used in an amount typically 0.1 to 10 times, and preferably 0.5 to 5 times of the compound (128) on a molar basis.

The compound (129) is appropriately used in an amount typically at least equimolar to the compound (128), and preferably 1 to 5 times of the compound (128) on a molar basis.

The above described reaction is carried out typically at −80 to 150° C., and preferably at about −80 to 120° C. and, in general, is completed in about 0.5 to 40 hours.

When an organic base is used as the basic compound, the reaction proceeds advantageously by adding a lithium salt such as lithium chloride to the reaction system.

The reaction which converts the compound (130) into the compound (131) may be carried out under reaction conditions similar to those of the reaction which converts the compound (68) into the compound (69) of the above described reaction formula 47.

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In the formula, R², X₁, Y, R⁶⁶and A₁₇are the same as described above.

The reaction which converts the compound (28′) into the compound (64a) is carried out under reaction conditions similar to those of the reaction which converts the compound (1f) into the compound (1g) of the above described reaction formula 3.

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In the formula, R², X₁, Y and A are the same as described above.

The reaction which converts the compound (64b) into the compound (26a) is carried out in an appropriate solvent in the presence of an oxidizing agent.

Examples of the solvent include water, fatty acids such as formic acid, acetic acid, trifluoroacetic acid, and propionic acid, esters such as ethyl acetate and methyl acetate, alcohols such as methanol, ethanol, and isopropanol, ethers such as dioxane, tetrahydrofuran, and diethyl ether, ketones such as acetone and methyl ethyl ketone, aromatic hydrocarbons such as benzene, toluene, chlorobenzene, and xylene, and halogenated hydrocarbons such as chloroform and dichloromethane, hexamethylphosphoric acid triamide, N,N-dimethylformamide, dimethyl sulfoxide, and pyridine, and a mixture thereof.

Examples of the oxidizing agent include peracids such as performic acid, peracetic acid, pertrifluoroacetic acid, perbenzoic acid, m-chloroperbenzoic acid, and o-carboxyperbenzoic acid, hydrogen peroxide, sodium metaperidodate, dichromic acid, dichromates such as sodium dichromate and potassium dichromate, manganese dioxide, permanganic acid, permanganates such as sodium permanganate and potassium permanganate, lead salts such as lead tetraacetate, silver oxide, and a Dess-Martin reagent (Dess-Martin periodinane). These oxidizing agents are used singly or in a mixture of two or more. The oxidizing agent is used in an amount typically at least equimolar to the compound (64b), and preferably 1 to 3 times of the compound (64b) on a molar basis.

The above described reaction is carried out typically at −10 to 100° C., and preferably at about 0 to 50° C., and is completed in about 30 minutes to 24 hours.

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In the formula, R², X₁, Y, A₁₀, B₁₉, R¹⁸, X₂, R¹⁴, R^74aand R¹⁵are the same as described above, provided that the a and b of A₁₀are bound to a —Y group and a —B₁₉group, respectively.

The reactions between compound (133) with the compound (134), and compound (135) with the compound (36) are carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

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In the formula, A₁₀, B₃, R^17a, R^17b, R^A, R¹⁷, Y₁, R^cand X₂are the same as described above, and R⁸⁰represents a —Y₁H group or a —OR⁸¹group, R⁸¹represents a protective group for the hydroxyl group, provided that the CHR^Amoiety in the side chain (—N(B₃R^c)(CHR^AR^17b)) of the compound (108c) has not more than 6 carbon atoms, the a of A₁₀is bound to a —R⁸⁰group, and the b is bound to an —NHB₃R^cgroup, —N(R^17a)B₃R^cgroup, —N(CHR^AR^17b)B₃R^cgroup or —N(R₁₇)B₃R^cgroup.

Here, examples of the protective group for the hydroxyl group include groups, which are previously mentioned, such as a phenyl lower alkyl group, a lower alkoxy lower alkyl group, tetrahydropyranyl group, tri lower alkysilyl group, a lower alkanoyl group, and a lower alkyl group.

The reaction of the compound (108a) with the compound (73) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (108a) with the compound (75′) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (108a) with the compound (74) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction, formula 2.

When the reaction is carried out using the compound (74) as a starting material, wherein R^Aand R^17bare bound with each other, together with carbon atoms bound to these groups, to form a cycloalkyl ring, and a hydride reducing agent, a cycloalkyloxytrialkylsilane such as [1-ethoxycyclopropyl]oxy]trimethylsilane may be used as a starting material in place of the compound (74) to produce the above described compound (74) in the reaction system.

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In the formula, R⁸⁰, A₁₀, R¹⁷, B₃, R^c, X₂, and R^59bare the same as described above, provided that the a of A₁₀is bound to a —R⁸⁰group and the b is bound to a —NHR¹⁷group, —N(R¹⁷)B₃R^cgroup or —N(R¹⁷)CH₂CH₂COOR⁵⁹group.

The reaction of the compound (108e) with the compound (113) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (108e) with the compound (137) is carried out in an appropriate solvent in the presence of an acid.

Any of the solvents used in the reaction of the compound (2) with the compound (3) of the above described reaction formula 1 may be used in this reaction.

Examples of the acid used include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, organic acids such as acetic acid, trifluoroacetic acid, and sulfonic acids including p-toluenesulfonic acid, and Lewis acids such as aluminum chloride, zinc chloride, iron chloride, tin chloride, boron tribromide, and a boron trifluoride/diethyl ether complex. These acids may be used singly or in a mixture of two or more. The acid is appropriately used in an amount typically at least 0.01 to 5 times, and preferably 0.1 to 2 times of the compound (108e) on a molar basis. The compound (137) is appropriately used in an amount typically at least equimolar to the compound (108e), and preferably 1 to 10 times of the compound (108e) on a molar basis.

The above described reaction is carried out typically at 0 to 200° C., and preferably at about 0 to 150° C., and, in general, is completed in about 30 minutes to 80 hours.

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In the formula, R⁸¹is the same as described above, R^73brepresents a -A₁₀-T₂-COOR^59aor -A group, and A₁₀, T₂, R^59Aand A are the same as described above, provided that the a of A₁₀is bound to an —OR⁸¹group or a hydroxyl group, and the b of A₁₀is bound to a -T₂group.

When R⁸¹of the material compound (138) represents a phenyl lower alkyl group, the reaction which converts the compound (138) into the compound (139) may be carried out under reaction conditions similar to those of the reduction reaction (1) (method using a catalytic hydrogen reducing agent) which is one reaction which converts the compound (68) into the compound (69) of the above described reaction formula 47.

When R⁸¹of the material compound (138) represents a tetrahydropyranyl group or tri-lower alkylsilyl group, the reaction which converts the compound (138) into the compound (139) may be carried out under reaction conditions similar to those of the hydrolysis reaction B described for above described reaction formula 9. The reaction which converts the compound (138) into the compound (139) is favorably carried out by hydrolysis using an acid. The acid is appropriately used in an amount typically 1 to 10 times, and preferably 1 to 2 times of the compound (138) on a molar basis.

When R⁸¹of the compound (138) represents a tri-lower alkylsilyl group, the compound (138) may be treated with a fluorine compound such as tetra-n-butyl ammonium fluoride, hydrogen fluoride or cesium fluoride.

When R⁸¹of the material compound (138) represents a lower alkoxy lower alkyl group or a lower alkyl group, the compound (138) may be treated in an appropriate solvent in the presence of an acid. Examples of the solvent include water, lower alcohols such as methanol, ethanol, and isopropanol, ethers such as dioxane, tetrahydrofuran, and diethyl ether, halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride, and polar solvents such as acetonitrile, and a mixture thereof. Examples of the acid used include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, fatty acids such as formic acid and acetic acid, sulfonic acids such as p-toluenesulfonic acid, Lewis acids such as boron trifluoride, aluminum chloride, and boron tribromide, iodides such as sodium iodide and potassium iodide, and a mixture of the above described iodide with the above described Lewis acid. The above described reaction is carried out at typically 0 to 200° C., and preferably at about room temperature to 150° C., and, in general, is completed in about 0.5 to 25 hours.

The above described hydrolysis may also be carried out using a basic compound under reaction conditions similar to those of the hydrolysis reaction B described for the above described reaction formula 9. Here, amines such as triethylamine may be used as the basic compound in addition to the basic compounds used in the hydrolysis reaction B.

When R⁸¹of the material compound (138) represents a lower alkanoyl group, the reaction which converts the compound (138) into the compound (139) may be carried out under reaction conditions similar to those of the hydrolysis reaction B described for the above described reaction formula 9.

When R^73aof the compound (138) represents a group of the formula:

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a dehydration reaction takes place under the above described hydrolysis conditions, and sometimes the compound (138), wherein the corresponding R^73arepresents a group of the formula:

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may be obtained.

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In the formula, R⁸⁰, A₁₀, T₂, R¹⁴and R¹⁵are the same as described above, provided that the a and b of A₁₀are bound to a —R⁸⁰group and a -T₂group, respectively.

The reaction of the compound (140) with the compound (36) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

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In the formula, Y₁, A₇, R¹³and A₉are the same as described above.

The reaction of the compound (141) with the compound (12) is carried out under reaction conditions similar to those of the reaction of the compound (13) with the compound (12) in formula 8 described above.

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In the formula, R⁸⁰, A₁₀, B₂₁and f are the same as described above, provided that the alkyl moiety in the side chain (—(B₂₁) f-CH₂NH₂) of the compound (144) has not more than 6 carbon atoms.

The reaction which converts the compound (143) into the compound (144) may be carried out under reaction conditions similar to those of the reaction using a hydride reducing agent which is one reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

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In the formula, R⁸⁰, A₁₀, B₁₉, X₂, R¹⁸, R¹⁴and R¹⁵are the same as described above, provided that the a of A₁₀is bound to a —R⁸⁰group and the b is bound to a —B₁₉group.

The reaction of the compound (145) with the compound (134) is carried out under reaction conditions similar to those of the reaction of the compound (133) with the compound (134) in the reaction formula 90 described above.

The reaction of the compound (146) with the compound (36) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

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In the formula, A₁₀, B₁₉, R¹⁴, R¹⁵, R⁸⁰and X₂are the same as described above, and R^18arepresents a lower alkyl group, provided that the a and b of A₁₀are bound to a —R⁸⁰group and a —B₁₉group, respectively.

The reaction of the compound (108j) with the compound (147) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

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In the formula, R², X₁, X₂, X₃and R⁶are the same as described above, R⁸²represents a lower alkyl group, and R⁸³represents a lower alkoxy group.

The reaction of the compound (148) with the compound (149) is carried out in an appropriate solvent in the presence of a catalyst.

Any of the solvents used in the reaction of the compound (2) with the compound (3) of the above described reaction formula 1 may be used in this reaction.

Examples of the catalyst include magnesium. The catalyst is appropriately used in an amount typically at least equimolar to the compound (148), and preferably 1 to 5 times of the compound (148) on a molar basis.

The above described reaction is carried out typically at 0 to 200° C., preferably at about 0 to 150° C., and, in general, is completed in about 30 minutes to 10 hours.

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In the formula, A₁₈represents a -A group or -A₁₀-T₂-COOR^59bgroup, and A, A₁₀, T₂, R^59band X₃are the same as described above.

The reaction which converts the compound (150) into the compound (107′) is carried out under reaction conditions similar to those of the reaction which converts the compound (85) into the compound (7′) of the above described reaction formula 55.

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In the formula, R², X₁, A₁₀, T₂and R⁶are the same as described above, provided that the a of A₁₀is bound to —CO group, —CH(OH) group or —CH₂, and the b is bound to a -T₂group.

The reaction which converts the compound (109a′) into the compound (151) may be carried out under reaction conditions similar to those of the reaction using a hydride reducing agent which is one reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

The reaction which converts the compound (151) into the compound (152) is carried out under reaction conditions similar to those of the reaction which converts the compound (08) into the compound (69) of the above described reaction formula 47.

The reaction of the compound (152) with the compound (22) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction which converts the compound (153) into the compound (154) may be carried out under reaction conditions similar to those of hydrolysis B reaction described for the above described reaction formula 9.

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In the formula, R¹, R², X₁, Y, A₁₀, B₆, B₇or R⁵⁹are the same as described above, and R^19arepresents a lower alkanoyl group, provided that the a and b of A₁₀are bound to a —Y group and a —B₆group, respectively.

The reaction of the compound (155) with the compound (156) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

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In the formula, R⁸⁰, A₁₀, X₂, R¹⁴and R¹⁵are the same as described above.

The reaction of the compound (158) with the compound (36) is carried out under similar reacting conditions as the reaction of the compound (114) with the compound (36) of the above described reaction formula 74 in which l is 0.

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In the formula, R¹, R², Y, A₁₀, R^14a, h, T, l, R⁸, X₁and X₂are the same as described above, R^85arepresents a benzoyl group, R^85brepresents a lower alkoxy carbonyl group, a phenyl lower alkyl group, a lower alkyl group or furyl lower alkyl group, and R^85crepresents a hydrogen atom, a lower alkyl group, a phenyl group, phenyl lower alkyl group, a furyl group or a furyl lower alkyl group, provided that the CH(R^B)R^85cgroup of the compound (1bbbbb) has not more than 6 carbon atoms.

The reaction of the compound (1yyyy′) with the compound (160′) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (1yyyy′) with the compound (161) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

The reaction of the compound (1yyyy′) with the compound (162) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described reaction formula 2.

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In the formula, R², B₀, Y, X₁, A₁₇, R⁸, X₂, X₃and R⁶are the same as described above, R⁸⁶represents a lower alkylsulfonyl group, and R⁸⁷represents a oxygen atom or a —N(R⁸)— group.

The reaction of the compound (165) with the compound (163) is carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

The reaction which converts the compound (165) into the compound (167) is carried out under reaction conditions similar to those of the reaction which converts the compound (85) into the compound (7′) of the above described formula 55.

The reaction of the compound (166) or the compound (167) with the compound (164) is carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) the above described reaction formula 1.

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In the formula, R⁸⁰and A₁₀are the same as described above, R^15′ represents the same group as (5) in R¹⁵described above.

The reaction of the compound (168) with the compound (170) is carried out under reaction conditions similar to those of the reaction of the compound (30) with the compound (66) of the above described reaction formula 46.

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In the formula, R⁸⁰, A₁₀, T, l, R^14bb, R^15aa, R^14cc, R^15bbb, R²⁶and R²⁷are the same as described above.

The reaction of the compound (171) with the compound (57) is carried out under reaction conditions similar to those of the reaction of the compound (1iiii) with the compound (57) of the above described reaction formula 31.

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In the formula, R¹, R², X₁, Y, A₁₀, R^15′ and X₂are the same as described above, and R⁸⁹represents a lower alkyl group.

The reaction of the compound (173) with the compound (170) is carried out under reaction conditions similar to those of the reaction of the compound (30) with the compound (66) of the above described reaction formula 46.

The reaction of the compound (1ddddd) with the compound (173) is carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

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In the formula, R¹, R², X₁, Y, X₂, B₃, R¹⁴and R¹⁵are the same as described above, and A₁₉represents a group of the formula:

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and A₂₀represents a group of the formula:

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wherein R³, p, B₃, R¹⁴and R¹⁵are the same as described above.

The reaction of the compound (174) with the compound (175) is carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

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In the formula, R¹, R², X₁and Y are the same as described above, A₂₁represents a group of the formula:

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and A₂₂represents a group of the formula:

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wherein R³, p, R¹⁷, B₃, R¹⁴and R¹⁵are the same as described above.

The reaction which converts the compound (1ggggg) into the compound (1hhhhh) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) the above described reaction formula 2 in which a hydrogen reducing agent is used.

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In the formula, R¹, R², X₁and Y are the same as described above,

A₂₃represents a group of the formula:

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and A₂₄represents a group of the formula:

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wherein R³and p are the same as described above.

The reaction which converts the compound (1iiiii) into the compound (1jjjjj) is carried out under reaction conditions similar to those of the reaction which converts the compound (68) into the compound (69) of the above described reaction formula 47.

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In the formula, R², X₁and Y are the same as described above,

A₂₅represents a group of the formula:

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and A₂₆represents a group of the formula:

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wherein B_4arepresents a lower alkenylene group, B_4brepresents a lower alkylene group, and R³, p, R¹⁴and R¹⁵are the same as described above.

The reaction which converts the compound (1kkkkk) into the compound (1lllll) is carried out under reaction conditions similar to those of the reaction which converts the compound (68) into the compound (69) in the (1) method of formula 47 described above.

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In the formula, R², X₁, Y, and R^59bare the same as described above,

A₂₈represents a group of the formula:

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and A₂₇represents a group of the formula:

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wherein R³, p and R^59bare the same as described above.

The reaction which converts the compound (1mmmmm) into the compound (1nnnnn) is carried out under reaction conditions similar to those of the hydrolysis B reaction described for the above described reaction formula 9.

The reaction of the compound (1nnnnn) with the compound (100′) is carried out under reaction conditions similar to those of the reaction of the compound (1fff) with the compound (43) of the above described reaction formula 20.

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In the formula, R², X₁, X₂and Y are the same as described above,

A₂₉represents a group of the formula:

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and A₃₀represents

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wherein R⁹⁰represents a lower alkyl group which may have a hydroxyl group as a substituent, and R³, p and R^59bare the same as described above.

The reaction of the compound (1ooooo) with the compound (176) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

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In the formula, R², X₁, X₂and Y are the same as described above,

A₃₁represents a group of the formula:

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and A₃₂represents

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wherein R³, p, R^59band R⁸⁹are the same as described above.

The reaction of the compound (1qqqqq) with the compound (173) is carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

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In the formula, R¹, R², X₁, Y, A₁₀, T, l, R⁹⁰and X₂are the same as described above.

R^15″ represents the group (2), (3), (4), (5), (6), (7), (8), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (20), (21), (22), (23), (24), (25), (26), (27), (26a), (27a), (28a), (29a), (30a), (31a), (32a), (33a), (34a), (35a), (36a), or (37a), which is defined for the above described R¹⁵described above.

The reaction of the compound (1sssss) with the compound (176) is carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

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In the formula, R¹, R², X₁, Y, A₁₀, T and l are the same as described above,

R^14AAand R^15BBrepresent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic ring has at least one —(B₁₂CO)t-N(R^20′)—CO—B₁₆X₂group thereon,

R^14CCand R^15DDrepresent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵, except that the heterocyclic ring has at least one —(B₁₂CO)t-N(R^20′)—CO—B₁₆R⁹¹group thereon, wherein B₁₂, t, B₁₆and X₂are the same as described above,

R⁹¹represents an imidazolyl group, and

R^20′ represents a hydrogen atom, a cycloalkyl group, an amino group which may have a lower alkoxycarbonyl group as a substituent, a benzoyl group which may have 1 to 3 lower alkoxy groups as substituents on the phenyl ring, a lower alkyl group, a lower alkyl group which have 1 or 2 phenyls which may be substituted on the phenyl ring with 1 to 3 substituents selected from the group consisting of a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group which may have a halogen atom as a substituent and a lower alkylthio group, a phenyl group which may be substituted on the phenyl ring with 1 to 3 groups selected from the group consisting of a lower alkoxy group which may have a halogen atom as a substituent and a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxycarbonyl group, a cycloalkyl lower alkyl group, a pyrrolidinyl lower alkyl group which may have, on the pyrrolidine ring, 1 to 3 lower alkyl groups which may have a hydroxyl group as a substituent, an amino substituted lower alkyl group which may have a substituent selected from the group consisting of a phenyl group and a lower alkyl group, a 1,2,3,4-tetrahydronaphthyl substituted lower alkyl group which may have 1 to 5 lower alkyl groups as substituents on the 1,2,3,4-tetrahydronaphthalene ring, a naphthyl lower alkyl group, a pyridyl lower alkyl group, a quinolyl lower alkyl group, a 1,2,3,4-tetrazolyl lower alkyl group which may have, on the tetrazole ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group, a 1,2,4-triazolyl lower alkyl group, a tetrahydrofuryl lower alkyl group which may have a hydroxyl group as a substituent on the lower alkyl group, a phenoxy lower alkyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkyl group and a nitro group, a phenyl lower alkanoyl group, a lower alkanoyl group which may have a halogen atom as a substituent, an imidazolyl lower alkanoyl group, a lower alkoxycarbonyl lower alkyl group, a pyridyl group or a carboxy lower alkyl group.

The reaction of the compound (1uuuuu) with the compound (177) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

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In the formula, X₁, X₂, R², Y, A and R⁶are the same as described above, and R⁹¹represents a hydrogen atom or a lower alkyl group.

The reaction of the compound (33) with the compound (178) may also be carried out in an appropriate solvent in the presence of a basic compound and a catalyst. Examples of the inert solvent used include water, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, 2-methoxyethanol, monoglyme, and diglyme, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, lower alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol, fatty acids such as acetic acid, esters such as ethyl acetate and methyl acetate, ketones such as acetone and methyl ethyl ketone, acetonitrile, pyridine, N-methylpyrrolidone, dimethyl sulfoxide, N,N-dimethylformamide, and hexamethylphosphoric acid triamide, and a mixture thereof.

Examples of the basic compound include carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and cesium carbonate, metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide, potassium phosphate, sodium phosphate, sodium hydride, potassium hydride, potassium, sodium, sodium amide, metal alcoholates such as sodium methylate, sodium ethylate, sodium n-butoxide, sodium tert-butoxide, and potassium tert-butoxide, alkylsilylamide alkali metal salts such as potassium bis(trimethylsilyl)amide, and organic bases such as pyridine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO), and a mixture thereof.

Examples of the catalyst may include palladium compounds such as palladium acetate, bis(tributyltin)/bis(dibenzylideneacetone)palladium, copper iodide/2,2′-bipyridyl, bis(dibenzylideneacetone)palladium, copper iodide/bis(triphenylphosphine)palladium dichloride, tris(dibenzylideneacetone)dipalladium, R-tris(dibenzylideneacetone)dipalladium, S-tris(dibenzylideneacetone)dipalladium, palladium (II) acetate, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), and tetrakis (triphenylphosphine)palladium, compounds such as R-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (R-BINAP), S-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (S-BINAP), RAC-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (RAC-BINAP), and 2,2-bis(diphenylimidazolidinyliden), xanthene compounds such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and borates such as tri-tert-butylphosphine tetrafluoroborate, and a mixture thereof.

The basic compound is appropriately used in an amount at least 0.5 times, and preferably 0.5 to 40 times of the compound (33) on a molar basis. The catalyst is appropriately used in a typical catalyst amount based on the compound (33).

The compound (178) is appropriately used in an amount at least in 0.5 times, and preferably 0.5 to 3 times of the compound (33) on a molar basis.

The above described reaction is carried out typically at room temperature to 200° C., preferably at room temperature to about 150° C., and is completed in about 0.5 to 20 hours.

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In the formula, B_o, X₁, R², Y, A₁₇, R⁶and X₂are the same as described above, R⁹²represents a R⁶—Z₄— group or R⁶— group and Z₄represents a lower alkylene group.

The reaction of the compound (64) with the compound (179) may be carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

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In the formula R², X₁, Y, A and R⁶are the same as described above.

The method for converting the compound (30) into the compound (1bbbbbb) is to obtain a compound (1bbbbbb) by subjecting the compound (30) to diazotization and by reacting the diazonium salt thus obtained with the compound (180).

The diazotization reaction 1. may be carried out in an appropriate solvent in the presence of an acid and a diazotizing agent. Examples of the solvent used in the above described reaction include water and acetonitrile. Examples of the acid used include hydrochloric acid, hydrobromic acid, sulfuric acid, tetrafluoroboric acid, and hexafluorophosophoric acid. Examples of the diazotizing agent include metal nitrites such as sodium nitrite and potassium nitrite, lower alkyl nitrites such as t-butyl nitrite and isoamyl nitrite. The acid is appropriately used in an amount typically about 1 to 10 times of the compound (30), and preferably about 1 to 5 times of the compound (30) on a molar basis. The diazotizing agent is appropriately used in an amount typically at least about equimolar to the compound (30), and preferably 1 to 3 times of the compound (30) on a molar basis. The above described reaction is typically carried out at about 0 to 70° C., and preferably at about 0° C. to room temperature, and is completed in about a few minutes to 5 hours. The reaction 2. of the diazonium salt obtained in the reaction 1. with the compound (180) may be carried out in the similar solvent as in the reaction 1 and in the presence of a basic compound. Any of the basic compounds used in the reaction of the compound (2) with the compound (3) of the above described reaction formula 1 may be used in this reaction. The basic compound is appropriately used in an amount at least equimolar to the compound (30), and preferably 1 to 5 times of the compound (30) on a molar basis. The compound (180) is appropriately used in an amount at least equimolar to the compound (30), and preferably 1 to 5 times of the compound (30) on a molar basis. The above described reaction is carried out typically at about 0 to 70° C., preferably at about 0° C. to room temperature, and is completed in about a few minutes to 5 hours.

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In the formula, X₁, R^8d, Y, A, R²and R⁶are the same as described above.

The reaction of the compound (30a) with the compound (181) may be carried out in an appropriate solvent in the presence of an acid and a catalyst. Examples of the inert solvent used include water, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, 2-methoxyethanol, monoglyme, and diglyme, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, lower alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol, fatty acids such as acetic acid, esters such as ethyl acetate and methyl acetate, ketones such as acetone and methyl ethyl ketone, acetonitrile, pyridine, dimethylsulfoxide, N,N-dimethylformamide, and hexamethylphosphoric acid triamide, and a mixture thereof.

Examples of the basic compound include carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and cesium carbonate, metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide, sodium hydride, potassium hydride, potassium, sodium, sodium amide, metal alcoholates such as sodium methylate, sodium ethylate, sodium n-butoxide, sodium tert-butoxide, and potassium tert-butoxide, organic bases such as pyridine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO), and a mixture thereof.

Examples of the catalyst include palladium compounds such as tetrakis(triphenylphosphine)palladium (0) and dichlorobis(triphenylphosphine)palladium (II), and copper compounds such as copper (II) acetate.

The basic compound is appropriately used in an amount at least equimolar to the compound (30a), and preferably 1 to 5 times of the compound (30a) on a molar basis. The catalyst is appropriately used in an amount 0.001 to 1 times, and preferably 0.01 to 0.5 times of the compound (30a) on a molar basis.

The compound (181) is appropriately used in an amount at least equimolar to the compound (30a), and preferably 1 to 5 times of the compound (30a) on a molar basis.

The above described reaction is carried out typically at −30 to 200° C., and preferably at 0 to 150° C. and is completed in 0.5 to about 30 hours. A molecular sieve such as Molecular Sieves 3A (MS-3A), Molecular Sieves 4A (MS-4A) or the like may be added to the reaction.

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In the formula, R⁶, Z₁, X₁, R², Y and A are the same as described above. Z₄represents a lower alkylene group.

The reaction which converts the compound (1dddddd) into the compound (1eeeeee) may be carried out in an appropriate solvent in the presence of a catalytic hydrogen reducing agent.

The above described catalytic hydrogen reducing agent is typically used in an amount 0.01 to 1 times of the compound (1dddddd) on a molar basis.

The above reaction favorably proceeds typically at about −20 to 150° C., and preferably at 0 to 100° C. and, in general, is completed in 0.5 to 20 hours. The hydrogen pressure may be applied typically at 1 to 10 atm.

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In the formula, R¹, R², Y, X₁, A₁₀, T and l are the same as described above; R^14IIand R^15JJrepresent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵except for having at least one phenyl group which has a lower alkoxycarbonyl group on the heterocyclic ring; R^14EEand R^15FFrepresent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵except for having at least one phenyl group which has a carboxy group on the heterocyclic ring; R^14GGand R^15HHrepresent a 5- to 10-membered saturated or unsaturated heterocyclic group the same as defined for the above described R¹⁴and R¹⁵except for having at least one phenyl group which has a carbamoyl group which may have a group selected from the group consisting of a lower alkoxy lower alkyl group and a lower alkyl group on the heterocyclic ring; and R⁹³and R⁹¹represent a hydrogen atom, a lower alkyl group or a lower alkoxy lower alkyl group.

The reaction which converts the compound (1hhhhhh) into the compound (1ffffff) may be carried out under reaction conditions similar to those of the hydrolysis B described for the above described reaction formula 9.

The reaction of the compound (1ffffff) with the compound (182) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

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In the formula, X₁, R², Y, A, X₂, k, X₃, R⁶, B_20aand d′ are the same as described above.

The reaction of the compound (30) with the compound (183) is carried out under reaction conditions similar to those of the reaction of the compound (30) with the compound (66) of the above described reaction formula 46.

The reaction which converts the compound (184) into the compound (1jjjjjj) may be carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

The reaction of the compound (1jjjjjj) with the compound (185) is carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

When d′ represents 0 in the compound (185), the reaction which converts the compound (1jjjjjj) into the compound (1kkkkkk) may also be carried out in an appropriate solvent in the presence of a halogenated copper such as copper iodide, an alkylglycine such as N,N-dimethylglycine, or an alkali metal phosphate such as potassium phosphate. Any of the solvents used in the reaction of the compound (2) with the compound (3) of the above described reaction formula 1 may be used here. Halogenated copper or alkylglycine is used in a typical catalyst amount. The alkali metal phosphate is appropriately used in an amount typically equimolar to the compound (1jjjjjj), and preferably 1 to 5 times of the compound (1jjjjjj) on a molar basis. The compound (185) is used in an amount typically 0.5 to 5 times, and preferably 0.5 to 3 times of the compound (1jjjjjj) on a molar basis. The above described reaction is carried out typically at about room temperature to 200° C., preferably at about room temperature to 150° C. and is completed in about 1 to 30 hours.

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In the formula, X₂, R², X₁, Y, A and R⁶are the same as described above.

The reaction of the compound (33) with the compound (186) is carried out under reaction conditions similar to those of the reaction of the compound (33) with the compound (178) of the above described reaction formula 118.

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In the formula, X₁, X₂, R², R⁶, Y, A, B_21aand c are the same as described above.

The reaction of the compound (33) with the compound (187) is carried out under reaction conditions similar to those of the reaction of the compound (33) with the compound (178) of the above described reaction formula 118.

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In the formula, R⁸, R², X₁, Y, A₁₆, X₂, R⁶and R^8bare the same as described above.

The reaction of the compound (188) with the compound (189) may be carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) by the method (d) of the formula 2 in which carboxylic acid halide is reacted with amine.

The reaction of the compound (190) with the compound (191) may be carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

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In the formula, R¹, R², X₁, Y and A₁₆are the same as described above. Xa represents a halogen atom.

The reaction which converts the compound (1oooooo) into the compound (1pppppp) may be carried out in an appropriate solvent in the presence of a catalytic hydrogenation reducing agent and a hydrogen donor such as formic acid, ammonium formate, cyclohexene, or hydrazine hydrate.

Any solvent and catalytic hydrogenation reducing agent, which are used in the reaction which converts the compound (1dddddd) into the compound (1eeeeee) of the above described reaction formula 122, may be used in the above described reaction.

The above described reaction is carried out under hydrogen atmosphere typically at about 1 atm to 20 atm, and preferably at about 1 atm to 10 atm, and at about −30 to 150° C., and preferably at about 0 to 100° C. In general, the reaction is completed in about 1 to 12 hours.

The catalytic hydrogenation reducing agent is typically used at 0.01 to 40 wt %, and preferably 0.01 to 20 wt % of the compound (1oooooo).

The hydrogen donor is typically used in an amount at least equimolar to the compound (1oooooo), and preferably 1 to 10 times of the compound (1oooooo) on a molar basis.

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In the formula, A₁₀, X₂, k, X₃, R⁸⁰and R⁸are the same as described above; R^94arepresents a group defined as a substituent (35), (40), (42) or (50), in which o is 1, or (67), (75) to (76), (78), (80) to (81) or (84), in which s is 0, in the case where the above described R¹⁴and R¹⁵form a heterocyclic ring; R^94brepresents a group defined as a substituent (28), (30) to (34), (36) to (39), (41), (43) to (45), (47) or (49), in which t is 1, (50), in which o is 0, (52) to (60), (62) to (66), (70), (77), (79), (82) to (83), (87), (88a) or (90a) in the case where the above described R¹⁴and R¹⁵form a heterocyclic ring; and R^94crepresents a group defined as a substituent (28), (30) to (34), (39), (41), (45), (47) or (49), in which t is 1, and (50), in which o is 0, (54) to (58), (62) to (64), (66), (70), (79) or (82) to (83) in the case where the above described R¹⁴and R¹⁵form a heterocyclic ring, a phenyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkanoyl group, an amino group which may have a lower alkanoyl group as a substituent, a lower alkoxycarbonyl group, a cyano group, a nitro group, a phenyl group, a halogen atom, a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group which may have a halogen atom as a substituent, a phenyl lower alkoxy group, a hydroxy group and a lower alkylenedioxy group, a pyridyl group which may have, on the pyridine ring, 1 to 3 substituents selected from the group consisting of a hydroxy group and a lower alkyl group which may have a hydroxyl group as a substituent, a pyrrolyl group which may have 1 to 3 lower alkyl groups as substituents, a benzoxazolyl group, a benzothiazolyl group, a furyl group, a lower alkyl group which may have a substituent selected from the group consisting of a hydroxy group and a halogen atom, a naphthyl group, a 1,2,3,4-tetrahydronaphthyl group which may have 1 to 5 lower alkyl groups as substituents on the 1,2,3,4-tetrahydronaphthalene ring, a quinolyl group, a 1,2,3,4-tetrazolyl group which may have, on the tetrazole ring, a substituent selected from the group consisting of a lower alkyl group and a phenyl lower alkyl group; a thiazolyl group which may have a phenyl group as a substituent on the thiazole ring; a benzoyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkoxy group and a halogen atom, a pipe idinyl group which may have a lower alkyl group as substituent on the piperidine ring, a 1,2,3,4-tetrahydroquinolyl group which may have an oxo group as a substituent on the tetrahydroquinoline ring, a 1,3,4-oxadiazolyl group which may have an oxo group as a substituent on the 1,3,4 oxadiazole ring, a cycloalkyl group, a thienyl group, or an imidazolyl group.

The reaction of the compound (192) with the compound (183) may be carried out under reaction conditions similar to those of the reaction of the compound (30) with the compound (183) of the above described reaction formula 124.

The reaction which converts the compound (193) into the compound (1qqqqqq) may be carried out under reaction conditions similar to those of the reaction which converts the compound (184) into the compound (1jjjjjj) of the above described reaction formula 124.

The reaction of the compound (1qqqqqq) with the compound (195) may be carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

When R^94bof the compound (195) represents (36) to (38), (43), (44), (53), (59) to (60), (87), (88a) or (90a), the reaction of the compound (1qqqqqq) with the compound (195) may also be carried out in an appropriate solvent in the presence of a copper halide such as copper iodide, an alkylglycine such as N,N-dimethylglycine, or an alkali metal phosphate such as potassium phosphate. In the above described reaction, any of the solvents used in the reaction of the compound (2) with the compound (3) of the above described reaction formula 1 may be used. The copper halide and alkylglycine are used in a normal catalyst amount. The alkali metal phosphate is appropriately used in an amount typically at least in equimolar to the compound (1qqqqqq), and preferably 1 to 5 times of the compound (1qqqqqq) on a molar basis. The compound (195) is appropriately used in an amount typically 0.5 to 5 times, and preferably 0.5 to 3 times of the compound (1qqqqqq) on a molar basis. The above described reaction is carried out typically at room temperature to 200° C., and preferably about room temperature to 150° C., and is completed in about 1 to 30 hours.

The reaction of the compound (1qqqqqq) with the compound (194) may be carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The reaction of the compound (1qqqqqq) with the compound (196) may be carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (5) of the above described formula 2.

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In the formula, X₁, Y, A, R², R⁶, B_22a, e and X₂are the same as described above, and R^10a′ represents a lower alkyl group.

The reaction of the compound (1uuuuuu) with the compound (197) may be carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described formula 2.

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In the formula, X₁, Y, A, R², R⁶and X₂are the same as described above. R^10b′ represents a lower alkyl group.

The reaction of the compound (1wwwwww) with the compound (197a) may be carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (4) of the above described reaction formula 2.

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In the formula, R¹, X₁, R², Y, A₁₀, X₂, R^14aand R^59bthe same as described above, and R⁹⁶represents a piperazinyl group which may have, on the piperazine ring, 1 to 3 substituents selected from the group consisting of a phenyl lower alkyl group (which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkylenedioxy group and a lower alkoxy group) and a pyridyl lower alkyl group.

The reaction of the compound (198) with the compound (199) may be carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

The reaction which converts the Compound (200) into the compound (201) may be carried out under reaction conditions similar to those of the hydrolysis B described for the above described reaction formula 9.

The reaction of the compound (201) with the compound (100′) is carried out under reaction conditions similar to those of the reaction of the compound (120b) with the compound (100′) of the above described reaction formula 79.

The reaction of the compound (201) with the compound (202) is carried out under reaction conditions similar to those of the reaction of the compound (1b) with the compound (6) of the above described reaction formula 2.

The compound (200) may also be produced by the method of the following reaction formula 133:

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wherein R^74a, R², X₁, Y, A₁₃, R^59band X₂are the same as described above, and R^14a′ represents a lower alkyl group which may have a hydroxy group as a substituent.

The reaction of the compound (200a) with the compound (203) may be carried out under reaction conditions similar to those of the reaction of the compound (2) with the compound (3) of the above described reaction formula 1.

The compound (3) may also be produced by the method of the following reaction formula 134:

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wherein R⁸⁰, A₁₀, B_23a, R¹⁴and R¹⁵are the same as described above.

The reaction which converts the compound (108l) into the compound (108m) may be carried out under reaction conditions similar to those of the reaction which converts the compound (1f) into the compound (1g) of the above described reaction formula 3.

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In the formula, R¹, R², X₁, Y, A₁₀, B_23a, R⁴and R¹⁵are the same as described above.

The reaction which converts the compound (1zzzzzz) into the compound (1AAAAAA) may be carried out under reaction conditions similar to those of the reaction which converts the compound (64b) into the compound (26a) of the above described reaction formula 89 described above.

Each of the target compounds obtained by the formulas shown above may be isolated and purified by separating the crude reaction product from the reaction mixture after cooling using an isolation procedure such as filtration, concentration, or extraction, and by purifying using a common purification procedure such as column chromatography or re-crystallization.

The compound of the present invention represented by the general formula (1) includes a stereoisomers and an optical isomer.

The compound of the present invention, which has a basic group, may easily form a salt with a common pharmacologically acceptable acid. Examples of such an acid include mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid, and organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, malonic acid, and lactic acid.

The compound of the present invention, which has an acidic group, may easily form a salt with a common pharmacologically acceptable basic compound. Examples of such a basic compounds include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate.

Next, medical formulations which contain the compound of the present invention as an active ingredient will be described.

The above described medical formulations, which are obtained by preparing the compound of the present invention formulated into a common pharmaceutical form, are prepared using a diluent or excipient commonly used such as a filler, expander, binder, moistener, disintegrator, surfactant, or lubricant.

Such medical formulations may be chosen from various forms according to the therapeutic objectives, and typical examples of such formulations include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (liquids, suspensions).

Carriers which are used for forming tablets may be chosen widely from the conventional ones, of which examples include excipients such as lactose, saccharose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, and crystalline cellulose, binders such as water, ethanol, propanol, simple syrup, a glucose solution, a starch solution, a gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, and polyvinylpyrrolidone, disintegrators such as dried starch, sodium arginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch, and lactose, anti-disintegrators such as saccharose, stearine, cacao butter, and hydrogenated oil, absorbefacients such as quartenary ammonium base, and sodium lauryl sulfate, wetting agents such as glycerol and starch, adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicate, and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol.

Further, tablets may be made into conventional coated tablets, for example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, or double or multi-layered tablets.

Carriers which are used for forming pills may be chosen widely from the conventional ones, of which examples include excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, and talc, binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol, and disintegrators such as laminaran and agar.

Carriers which are used for forming suppositories may be chosen widely from the conventional ones, of which examples include polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides.

The injection preparations in liquid, emulsion and suspension forms are preferably sterilized and isotonic with the blood. Diluents which are used for forming these liquid, emulsion and suspension preparations may be chosen widely from the conventional ones, of which examples include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid ester. In this case, the medical formulations may contain sodium chloride, glucose or glycerol enough to prepare isotonic solutions. Also, conventional solubilizers, buffers, analgestics, and the like, and, as necessary, coloring agents, preservatives, spices, flavors, sweets and the like, or other pharmaceuticals may be added.

Although the amount of the compound of the present invention included in the medical formulation is not limited and may be selected appropriately in a wide range, it is typically preferable that the medical formulation contains the compound of the present invention at 1 to 70 wt %.

The method for administration of the medical formulation of the present invention is not limited and the administration is carried out in accordance with the conditions such as forms of the medical formulation, patient's age, sex, severity of the disease and other conditions. For example, tablets, pills, liquids, suspensions, emulsions, granules and capsules are administered orally. The injection formulations are administered intravenously singly or by mixing with a conventional fluid replacement such as a glucose solution or amino acid solution, or, as necessary, administered singly and intramuscularly, intradermally, subcutaneously or intraperitoneally. The suppositories are administered into the rectum.

The dosage for the above mentioned medical formulation may be chosen appropriately according to the usage, patient's age, sex and severity of the disease and other conditions. Typically, 0.001 to 100 mg per kg body weight per day, preferably 0.001 to 50 mg per kg body weight per day, is administered once or in several times a day.

Since the above described dosage may vary in accordance with various conditions, it may be sufficient with a dosage smaller than in the above described range, or it may be necessary to administer a dosage larger than in the above described range.

The compound of the present invention has a superior effect on suppressing the production of collagen.

The compound of the present invention has lower side effects and is excellent in safety.

EXAMPLES

The present invention is explained in more detail by illustrating Reference Examples, Examples, Formulation Example and Pharmacological Test as follows.

Reference Example 1
Production of 1-(t-butoxycarbonyl)-4-(4-hydroxyphenyl)-1,2,5,6-tetrahydropyridine
Step 1
Production of 1-(t-butoxycarbonyl)-4-[(4-methoxymethoxy)phenyl]-4-hydroxypiperidine

A solution of 1-bromo-4-methoxymethoxybenzene (5.43 g, 25.0 mmol) in tetrahydrofuran (THF) (100 mL) Was stirred at −85° C., and a 2.46 M n-butyllithium hexane solution (10.2 mL, 25.0 mmol) was added dropwise to the stirred solution over 10 minutes. The resulting solution was stirred at the same temperature for 40 minutes. To the reaction solution was added dropwise for 10 minutes a solution of 1-(t-butoxycarbonyl)-4-piperidone (5.20 g, 26.0 mmol) in THF (30 mL). The temperature of the resulting solution was raised to −25° C. over 4 hours, and then the solution was stirred at that temperature for 2 hours. An aqueous solution of saturated ammonium chloride was then added to this solution. The reaction solution was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, after which the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:3, in ratio by volume; hereinafter the same), to thereby yield 7.63 g of the title compound.

Appearance: Colorless oil

¹H NMR (CDCl₃) δ 1.49 (9H, s), 1.73 (2H, d, J=12.0 Hz), 1.97 (2H, brs), 3.24 (2H, brs), 3.48 (3H, s), 4.00 (2H, brs), 5.17 (2H, s), 7.03 (2H, d, J=9.0 Hz), 7.39 (2H, d, J=9.0 Hz).

Step 2
Production of 1-(t-butoxycarbonyl)-4-(4-hydroxyphenyl)-1,2,5,6-tetrahydropyridine

To a solution of 1-(t-butoxycarbonyl)-4-[(4-methoxymethoxy)phenyl]-4-hydroxypiperidine (5.32 g, 15.8 mmol) in toluene (100 mL) was added p-toluenesulfonic acid monohydrate (0.56 g, 2.95 mmol), and the resulting solution was refluxed for 21 hours. The reaction solution was cooled to room temperature, and evaporated under reduced pressure. To this crude product were added ethanol (60 mL) and 2 M hydrochloric acid (40 mL, 80 mmol), and the resulting solution was stirred for 2 hours at 60° C. The reaction solution was again cooled to room temperature, and evaporated under reduced pressure. To the residue were added methanol (100 mL), triethylamine (9.0 mL, 64.6 mmol) and di-t-butyl dicarbonate (5.20 g, 23.8 mmol), and the resulting solution was stirred for 24 hours at room temperature. The solvent was evaporated under reduced pressure, after which to the residue was added 100 mL of ethyl acetate. Insoluble matter was removed by filtration, after which the filtrate was evaporated under reduced pressure. To the residue were added 1,4-dioxane (50 mL) and a 1 M aqueous solution of sodium hydroxide (50 mL, 50 mmol) and stirred for 14 hours at 60° C. To the resulting reaction solution was added at room temperature 2 M hydrochloric acid (25 mL, 50 mmol) to neutralize, and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated to thereby yield 4.10 g of the title compound.

Appearance: Brown amorphous

¹H NMR (CDCl₃) δ 1.49 (9H, s), 2.47 (2H, brs), 3.62 (2H, t, J=5.5 Hz), 4.05 (2H, brs), 5.91 (1H, brs), 6.81 (2H, d, J=9.0 Hz), 7.25 (2H, d, J=9.0 Hz).

Reference Example 2
Production of methyl 5-(4-benzylpiperazin-1-yl)-2-methoxymethoxybenzoate

To a solution of methyl 5-chloro-2-methoxymethoxybenzoate (1.45 g, 6.29 mmol) and 1-benzylpiperazine (1.66 g, 9.43 mmol) in toluene (50 mL) were added palladium acetate (28 mg, 0.126 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (157 mg, 0.252 mmol) and cesium carbonate (3.07 g, 9.43 mmol), and the resulting solution was refluxed for 3 hours. Water was added to the resulting solution, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2), to thereby yield 400 mg of the title compound.

Appearance: Yellow oil

¹H NMR (CDCl₃) δ 2.59-2.62 (4H, m), 3.12-3.16 (4H, m), 3.51 (3H, s), 3.57 (2H, s), 3.88 (3H, s), 5.16 (2H, s), 7.01 (1H, dd, J=9.1 Hz, 3.1 Hz), 7.10 (1H, d, J=9.1 Hz), 7.28-7.35 (6H, m).

The following compounds were produced in the same manner as in Reference Example 2.

TABLE 1

Reference

Example

No.
R₁₀₁
R₁₀₂
R₁₀₃

¹H NMR (CDCl₃) δ ppm

3
—CH₂OCH₃

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—H
1.27 (3H, t, J = 7.0 Hz), 1.43- 1.48 (2H, m), 1.83 (2H, brd, J = 13.0 Hz), 1.90 (1H, m), 2.28 (2H, d, J = 7.0 Hz), 2.66 (2H, dt, J = 2.5 Hz, 12.0 Hz), 3.47 (3H, s), 3.50 (2H, brd, J = 12.0 Hz), 4.15 (2H, q, J = 7.0 Hz), 5.10 (2H, s), 6.89 (2H, d, J = 9.0 Hz), 6.95 (2H, d, J = 9.0 Hz).

4
—CH₂OCH₃

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—H
1.27 (3H, t, J = 7.0 Hz), 1.57- 1.75 (2H, m), 1.82 (1H, m), 2.00 (1H, m), 2.68-2.75 (2H, m), 2.93 (1H, dd, J = 10.0 Hz, 12.0 Hz), 3.34 (1H, d, J = 12.0 Hz), 3.48 (3H, s), 3.56 (1H, brd, J = 10.0 Hz), 4.16 (2H, q, J = 7.0 Hz), 5.11 (2H, s), 6.91 (2H, d, J = 9.0 Hz), 6.96 (2H, d, J = 9.0 Hz).

5
—CH₃

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—H
1.27 (3H, t, J = 7.0 Hz), 1.9 (2H, dq, J = 3.0 Hz, 13.5 Hz), 2.02 (2H, dd, J = 13.5 Hz, 3.0 Hz), 2.38 (1H, m), 2.69 (2H, dt, J = 3.0 Hz, 12.0 Hz), 3.48 (2H, dt, J = 12.0 Hz, 3.0 Hz), 3.37 (3H, s), 4.16 (2H, q, J = 7.0 Hz), 6.83 (2H, d, J = 9.0 Hz), 6.91 (2H, d, J = 9.0 Hz).

6
—CH₂OCH₃

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—CH₃
1.27 (3H, t, J = 7.1 Hz), 1.82- 1.99 (4H, m), 2.22 (3H, s), 2.33- 2.42 (1H, m), 2.64-2.73 (2H, m), 3.50-3.52 (5H, m), 4.15 (2H, q, J = 7.1 Hz), 5.12 (2H, s), 6.70 (1H, dd, J = 8.9 Hz, 3.1 Hz), 6.78 (1H, d, J = 3.0 Hz), 6.95 (1H, d, J = 8.7 Hz).

7
—CH₂OCH₃

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—OCH₃
1.27 (3H, t, J = 7.1 Hz), 1.37- 1.47 (2H, m), 1.81-1.94 (3H, m), 2.29 (2H, d, J = 6.9 Hz), 2.64- 2.73 (2H, m), 3.51 (3H, s), 3.54 (2H, brs), 3.85 (3H, s), 4.15 (2H, q, J = 7.1 Hz), 5.13 (2H, s), 6.44 (1H, dd, J = 8.7 Hz, 2.6 Hz), 6.56 (1H, d, J = 2.6 Hz), 7.02 (1H, d, J = 8.7 Hz).

8
—CH₂OCH₃

embedded image

—CH₃
1.27 (3H, t, J = 7.1 Hz), 1.37- 1.49 (2H, m), 1.80-2.04 (3H, m), 2.22 (3H, s), 2.27 (2H, d, J = 6.9 Hz), 2.60-2.68 (2H, m), 3.48 (3H, s), 3.52 (2H, brs), 4.14 (2H, q, J = 7.1 Hz), 5.11 (2H, s), 6.69-6.79 (2H, m), 6.94 (1H, d, J = 8.7 Hz).

TABLE 2

Reference

Example

No.
R₁₀₄

¹H NMR (CDCl₃) δ ppm

9

embedded image

1.48 (9H, s), 1.76-1.89 (4H, m), 2.78 (3H, brs), 2.81 (2H, brt, J = 12.0 Hz), 3.71 (2H, brd, J = 12.0 Hz), 4.15 (1H, brs), 6.96 (2H, d, J = 9.0 Hz), 6.98 (4H, s), 8.17 (2H, d, J = 9.0 Hz).

10

embedded image

1.49 (9H, s), 3.13 (4H, t, J = 5.0 Hz), 3.60 (4H, t, J = 5.0 Hz), 6.96-7.00 (6H, m), 8.18 (2H, d, J = 9.0 Hz).

11

embedded image

1.79 (2H, m), 2.03 (2H, m), 2.96 (2H, m), 3.41 (3H, s), 3.51 (2H, m), 3.73 (1H, m), 4.74 (2H, s), 6.95-6.98 (6H, m), 8.17 (2H, d, J = 9.0 Hz).

12

embedded image

1.28 (3H, t, J = 7.0 Hz), 1.90 (2H, dq, J = 4.0 Hz, 13.0 Hz), 2.05 (2H, dd, J = 13.0 Hz, 4.0 Hz), 2.45 (1H, m), 2.82 (2H, dt, J = 2.5 Hz, 12.0 Hz), 3.62 (2H, brd, J = 12.5 Hz), 4.17 (2H, q, J = 7.0 Hz), 6.95-6.98 (6H, m), 8.17 (2H, d, J = 9.0 Hz).

13

embedded image

1.31 (3H, t, J = 7.0 Hz), 1.83 (2H, m), 2.05 (2H, m), 2.96 (1H, m), 3.07 (1H, m), 3.46 (1H, m), 3.53 (1H, m), 3.60 (1H, m), 4.16 (2H, s), 4.24 (2H, q, J = 7.0 Hz), 6.95-7.01 (6H, m), 8.17 (2H, d, J = 9.0 Hz).

Reference Example 14
Production of methyl 5-(4-benzylpiperazin-1-yl)-2-hydroxybenzoate

To a solution of 400 mg of methyl 5-(4-benzylpiperazin-1-yl)-2-methoxymethoxybenzoate (1.1 mmol) in 1,4-dioxane (20 mL) was added a solution of 4 N hydrogen chloride in 1,4-dioxane (4 mL, 16 mmol), and the resulting solution was stirred for 2 hours at 100° C. The resulting reaction solution was subjected to distillation under reduced pressure to obtain a residue. This residue was purified by silica gel column chromatography (dichloromethane:methanol 30:1), to thereby yield 353 mg of the title compound.

Appearance: Pale yellow powder

¹H NMR (CD₃OD) δ 3.29-3.40 (8H, m), 3.94 (3H, s), 4.39 (2H, s), 6.91 (1H, d, J=8.9 Hz), 7.28 (1H, dd, J=8.9 Hz, 3.0 Hz), 7.42 (1H, d, J=3.0 Hz), 7.49-7.60 (5H, m).

The following compounds were produced in the same manner as in Reference Example 14.

TABLE 3

Reference

Example

No.
R₁₀₅
R₁₀₆
Form

¹H NMR (solvent) δ ppm

15
—H

embedded image

free
(DMSO-d₆) 1.20 (3H, t, J = 7.0 Hz), 1.78 (2H, brs), 1.91 (2H, brs), 2.10 (1H, brs), 2.34 (2H, brs), 3.45 (2H, brs), 3.55 (2H, brs), 4.09 (2H, q, J = 7.0 Hz), 6.88 (2H, brs), 7.60 (2H, brs), 10.05 (1H, brs), 11.75 (1H, brs).

16
—H

embedded image

free
(DMSO-d₆) 1.20 (3H, t, J = 7.0 Hz), 1.64 (1H, brs), 1.93 (2H, brs), 2.08 (2H, brs), 3.30 (1H brs), 3.45 (2H, brs), 3.48 (2H, brs), 4.10 (2H, q, J = 7.0 Hz), 6.88 (2H, brs), 7.66 (2H, brs), 10.05 (1H, brs), 12.60 (1H, brs).

17
—CH₃

embedded image

hydro- chloride
(DMSO-d₆) 1.22 (3H, t, J = 7.1 Hz), 2.03-2.13 (4H, m), 2.14 (3H, s), 2.75 (1H, brs), 3.38-3.57 (4H, m), 4.12 (2H, q, J = 7.1 Hz), 6.89 (1H, d, J = 8.6 Hz), 7.46-7.53 (2H, m), 9.99 (1H, brs).

18
—OCH₃

embedded image

free
(CDCl₃) 1.27 (3H, t, J = 7.1 Hz), 1.98-2.18 (3H, m), 2.41-2.44 (4H, m), 3.30 (2H, t, J = 12.0 Hz), 3.66 (2H, d, J = 11.9 Hz), 3.95 (3H, s), 4.15 (2H, q, J = 7.1 Hz), 6.26 (1H, brs), 6.96-7.03 (2H, m), 7.85 (1H, s).

19
—CH₃

embedded image

hydro- chloride
(DMSO-d₆) 1.20 (3H, t, J = 7.1 Hz), 1.87 (4H, brs), 2.14 (4H, brs), 2.33 (2H, d, J = 6.4 Hz), 2.52 (2H, brs), 3.44 (2H, brs), 4.19 (2H, q, J = 7.1 Hz), 6.88 (1H, d, J = 8.6 Hz), 7.46-7.57 (2H, m), 9. 98 (1H, brs), 12.04 (1H, brs).

Reference Example 20
Production of ethyl N-(4-hydroxyphenyl)isonipecotate

To a solution of ethyl N-(4-methoxyphenyl)isonipecotate (2.63 g, 10 mmol) in dichloromethane (100 mL) was added a solution of 2 M boron tribromide in dichloromethane (20 mL, 40 mmol), and the resulting solution was stirred for 0.5 hours at room temperature. The resulting reaction solution was poured into ice water, then an aqueous solution of 1 M sodium hydroxide (110 mL) was added to the solution. After stirring, the resulting solution was separated. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to thereby yield 2.43 g of the title compound.

Appearance: Yellow oil

¹H NMR (CDCl₃) δ 1.27 (3H, t, J=7.0 Hz), 1.91 (2H, m), 2.02 (2H, brd, J=11.5 Hz), 2.38 (1H, m), 2.68 (2H, dt, J=2.0 Hz, 11.5 Hz), 3.46 (2H, dt, J=12.0 Hz, 3.0 Hz), 4.16 (2H, q, J=7.0 Hz), 4.45 (1H, brs), 6.75 (2H, d, J=9.0 Hz), 6.86 (2H, d, J=9.0 Hz).

The following compounds were produced in the same manner as in Reference Example 20.

Reference Example 21
4-(2-Fluoro-4-nitrophenoxy)phenol

¹H NMR (DMSO-d₆) δ 6.80-7.10 (5H, m), 8.04 (111, ddd, J=1.4 Hz, 2.7 Hz, 9.2 Hz), 8.29 (1H, dd, J=2.7 Hz, 10.9 Hz), 9.59 (1H, s).

Reference Example 22
1-Benzyl-3-(4-hydroxyphenyl)imidazolidin-2-one

¹H NMR (DMSO-d₆) δ 3.18-3.40 (2H, m), 3.61-3.80 (2H, m), 4.35 (2H, s), 6.71 (2H, d, J=8.8 Hz), 7.15-7.48 (7H, m), 9.10 (1H, s).

Reference Example 23
Production of 2-(4-hydroxyphenylamino)-1-(4-piperonylpiperazin-1-yl)ethanone

To a solution of N-(4-hydroxyphenyl)glycine (11.38 g, 68.1 mmol) in N,N-dimethylformamide (DMF) (150 mL) were added under ice cooling 1-piperonylpiperazine (15.0 g, 68.1 mmol), 1-hydroxybenzotriazole monohydrate (10.43 g, 68.1 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (15.66 g, 81.7 mmol), and the resulting solution was stirred for 30 minutes under ice cooling and for 4.5 hours at room temperature. The reaction solution was concentrated under reduced pressure. To the residue was added a saturated sodium bicarbonate solution (400 mL), and extracted with ethyl acetate (400 mL). The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated, to leave the resulting product solidified in a powdered form. Ethyl acetate was added, and the resulting product was filtered off and washed with ethyl acetate, to thereby yield 18.58 g of the title compound.

Appearance: Brown powder

¹H NMR (DMSO-d₆) δ 2.30 (2H, brs), 2.36 (2H, brs), 3.40 (2H, s), 3.47 (4H, t, J=14.5 Hz), 4.03 (2H, d, J=7.0 Hz), 4.90 (1H, brs), 5.99 (2H, s), 6.49 (2H, d, J=8.9 Hz), 6.54 (2H, d, J=8.9 Hz), 6.75 (1H, dd, J=8.0 Hz, 1.1 Hz), 6.85 (1H, d, J=8.0 Hz), 6.87 (1H, s), 8.42 (1H, s).

The following compounds were produced in the same manner as in Reference Example 23.

Reference Example 24
6-Chloro-N-(3,4-dichlorophenyl)nicotinamide

¹H NMR (CDCl₃) δ 7.64 (1H, d, J=8.9 Hz), 7.72 (1H, dd, J=8.7 Hz, 2.3 Hz), 7.73 (1H, dd, J=8.3 Hz, 0.7 Hz), 8.12 (1H, d, J=2.3 Hz), 8.35 (1H, dd, J=8.3 Hz, 2.5 Hz), 8.95 (1H, dd, J=2.5 Hz, 0.7 Hz), 10.71 (1H, brs).

Reference Example 25
4-(4-Piperonylpiperazine-1-carbonyl)-1-(4-hydroxyphenyl)pyrrolidin-2-one

¹H NMR (CDCl₃) δ 2.43-2.43 (4H, m), 2.73-2.95 (2H, m), 3.45 (2H, s), 3.49-3.54 (4H, m), 3.65-3.72 (1H, m), 3.78-3.87 (1H, m), 4.17-4.23 (1H, m), 5.96 (2H, s), 6.71-6.80 (4H, m), 6.84-6.85 (1H, m), 7.29 (2H, d, J=8.9 Hz).

TABLE 4

Reference

Example

No.
X_a1
X_a2
R₁₀₇
R₁₀₈
Form

¹H NMR (solvent) δ ppm

26
—NH—
—CH₂—
—H
benzyl
free
(CDCl₃) 2.46-2.48 (4H, m), 3.45 (2H, t, J =

5.0 Hz), 3.54 (2H, s), 3 68 (2H, t, J =

5.0 Hz), 3.82 (2H, s), 6.53 (2H, d, J = 8.7

Hz), 6.70 (2H, d, J = 8.7 Hz), 7.27-

7.34 (5H, m).

27
—CH₂—
—CH₂—
—H
benzyl
free
(CDCl₃) 2.30-2.33 (2H, m), 2.41-

2.45 (2H, m), 2.55-2.60 (2H, m), 2.85-

2.91 (2H, m), 3.36-3.40 (2H, m), 3.52 (2H,

s), 3.62-3.66 (2H, m), 5.10 (1H, brs),

6.74-6.77 (2H, m), 7.03 (2H, d, J = 8.6

Hz), 7.27-7.32 (5H, m).

28
—CH₂—
—CH₂—
—H
piperonyl
hydro-
(DMSO-d₆) 2.56-3.47 (10H, m), 4.01-

chloride
4.07 (1H, m), 4.18-1.48 (3H, m), 6.07 (2H,

s), 6.65-6.68 (2H, m), 7.00-7.03 (4H, m),

7.21 (1H, s), 9.18 (1H, brs), 11.04 (1H,

brs).

29
—O—
—CH₂—
—H
piperonyl
free
(CDCl₃) 2.31-2.50 (4H, m), 3.41 (2H, s),

3.52-3.72 (4H, m), 4.63 (2H, s), 5.94 (2H,

s), 6.25 (1H, brs), 6.70 (2H, d, J = 9.1

Hz), 6.69-6.77 (1H, m), 6.73 (1H, s),

6.77 (2H, d, J = 9.1 Hz), 6.83 (1H, d, J =

0.9 Hz).

30
—O—
—CH₂—
—H
benzyl
free
(CDCl₃) 2.40-2.52 (4H, m), 3.51 (2H, s),

3.53-3.73 (4H, m), 4.63 (2H, s), 5.89 (1H,

brs), 6.70 (2H, d, J = 9.2 Hz), 6.78 (2H,

d, J = 9.2 Hz), 7.22-7.43 (5H, m).

31
—CH(OH)—
none
—H
benzyl
free
(CDCl₃) 1.89-2.03 (1H, m), 2.21-

2.32 (1H, m), 2.32-2.57 (2H, m), 3.00-

3.18 (1H, m), 3.20-3.35 (1H, m), 3.40 (1H,

d, J = 13.1 Hz), 3.46 (1H, d, J = 13.1

Hz), 3.60-3.83 (2H, m), 5.13 (1H, s),

6.71 (2H, d, J = 8.6 Hz), 7.09 (2H, d, J =

8.6 Hz), 7.18-7.35 (5H, m).

32
none
none
—H
3-pyridyl
free
(DMSO-d₆) 3.18-3.35 (4H, m), 3.64 (4H,

brs), 6.82 (2H, d, J = 8.4 Hz), 7.21-

7.37 (4H, m), 8.02-8.03 (1H, m), 8.32

(1H, d, J = 2.4 Hz), 9.90 (1H, brs).

33
—CH₂—
—CO—
—H
—CO₂C(CH₃)₃
free
(CDCl₃) 1.44 (9H, s), 2.93-3.15 (4H, m),

3.32 (2H, t, J = 5.2 Hz), 3.50 (2H, t, J =

5.2 Hz), 3.97 (2H, s), 5.48 (1H, brs),

6.81 (2H, d, J = 8.6 Hz), 7.11 (2H, d, J =

8.6 Hz).

34
—NH—
—CH₂—
—CH₃
piperonyl
free
(CDCl₃) 2.20 (3H, s), 2.41-2.46 (4H, m),

3.44 (4H, brs), 3.67 (2H, t, J = 4.8 Hz),

3.81 (2H, s), 4.34 (1H, brs), 4.52 (1H,

brs), 5.95 (2H, s), 6.37 (1H, dd, J = 8.4

Hz, 2.6 Hz), 6.44 (1H, d, J = 2.8 Hz),

6.64 (1H, d, J = 8.4 Hz), 6.70-6.77 (2H,

m), 6.85 (1H, s).

Reference Example 35

Production of ethyl (4-hydroxy-3-methylphenylamino)acetate

Potassium carbonate (5.04 g, 36.5 mmol) was added at room temperature to a solution of 4-amino-o-cresol (3.00 g, 24.4 mmol) and ethyl bromoacetate (2.70 mL, 24.4 mmol) in DMF (30 mL). The resulting solution was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), to thereby yield 5.10 g of the title compound.

Appearance: Yellow solid

¹H NMR (CDCl₃) δ 1.28 (3H, t, J=7.1 Hz), 2.19 (3H, s), 3.84 (2H, s), 3.95 (1H, brs), 4.22 (2H, q, J=7.1 Hz), 4.59 (1H, brs), 6.36 (1H, dd, J=8.4 Hz, 2.9 Hz), 6.44 (1H, d, J=2.9 Hz), 6.63 (1H, d, J=8.4 Hz).

The following compounds were produced in the same manner as in Reference Example 35.

Reference Example 36
Ethyl (3-hydroxyphenylamino)acetate

¹H NMR (CDCl₃) δ 1.30 (3H, t, J=7.1 Hz), 3.88 (2H, s), 4.25 (2H, q, J=7.1 Hz), 4.29 (1H, brs), 4.85 (1H, s), 6.08-6.10 (1H, m), 6.18-6.24 (2H, m), 7.01-7.07 (1H, m).

Reference Example 37
Benzyl (4-hydroxy-3-methoxyphenylamino)acetate

¹H NMR (CDCl₃) δ 3.81 (3H, s), 3.92 (2H, brs), 4.01 (1H, brs), 5.09 (1H, brs), 5.20 (2H, s), 6.11 (1H, dd, J=8.4 Hz, 2.6 Hz), 6.23 (1H, d, J=2.6 Hz), 6.76 (1H, d, J=8.4 Hz), 7.31-7.38 (5H, m).

Reference Example 38
t-Butyl [3-(4-benzyloxy-3-methylphenyl)-2-oxotetrahydropyrimidin-1-yl]acetate

¹H NMR (CDCl₃) δ 1.47 (9H, s), 2.04-2.21 (2H, m), 2.25 (3H, s), 3.45 (2H, t, J=5.9 Hz), 3.67 (2H, t, J=5.9 Hz), 4.04 (2H, s), 5.06 (2H, s), 6.82 (1H, d, J=8.6 Hz), 7.01 (1H, dd, J=2.6 Hz, 8.6 Hz), 7.06-7.12 (1H, m), 7.26-7.48 (5H, m).

TABLE 5

Reference

Example

No.
R₁₀₉
R₁₁₀
R₁₁₁
R₁₁₂
R₁₁₃

¹H NMR (CDCl₃) δ ppm or MS

39
—CH₃
—CH₃
—H
—H
—H

¹H NMR 1.30 (3H, t, J = 7.1 Hz), 2.14 (3H,

s), 2.20 (3H, s), 3.87 (2H, s), 4.24 (2H, q, J =

7.1 Hz), 4.42 (1H, brs), 6.29 (1H, d, J = 8.6

Hz), 6.58 (1H, d, J = 8.6 Hz).

40
—F
—H
—F
—H
—H

¹H NMR 1.30 (3H, t, J = 7.1 Hz), 3.85 (2H,

s), 4.25 (2H, q, J = 7.1 Hz), 4.77 (1H, s),

6.37 (1H, dd, J = 7.9 Hz, 11.8 Hz), 6.73 (1H,

dd, J = 7.9 Hz, 11.6 Hz).

41
—CH₃
—H
—CH₃
—H
—H

¹H NMR 1.30 (3H, t, J = 7.1 Hz), 2.15 (3H,

s), 2.19 (3H, s), 3.84 (1H, brs), 3.89 (2H, s),

4.17 (1H, s), 4.25 (2H, q, J = 7.1 Hz),

6.28 (1H, s), 6.57 (1H, s).

42
—H
—CH₃
—CH₃
—H
—H
MS 223 (M⁺)

43
—OCH₃
—H
—H
—H
—H

¹H NMR 1.29 (3H, t, J = 7.1 Hz), 3.82 (3H,

s), 3.85 (2H, s), 4.23 (2H, q, J = 7.1 Hz),

5.26 (1H, brs), 6.11 (1H, dd, J = 8.4 Hz, 2.6

Hz), 6.25 (1H, d, J = 2.6 Hz), 6.76 (1H, d,

J = 8.4 Hz).

44
—F
—H
—H
—H
—H

¹H NMR 1.30 (3H, t, J = 7.1 Hz), 3.83 (2H,

s), 4.08(1H, brs), 4.24 (2H, q, J = 7.1 Hz),

4.62 (1H, d, J = 3.3 Hz), 6.30-6.41 (2H, m),

6.85 (1H, t, J = 8.9 Hz).

45
—H
—H
—H
—CH₃
—CH₃

¹H NMR 1.20 (3H, t, J = 7.1 Hz), 1.48 (6H,

s), 4.15 (2H, q, J = 7.1 Hz), 6.60-6.69 (4H,

m).

46
—CH₃
—H
—H
—CH₃
—H

¹H NMR 1.24 (3H, t, J = 7.3 Hz), 1.44 (3H,

d, J = 6.9 Hz), 2.18 (3H, s), 3.80 (1H, brs),

4.03 (1H, q, J = 6.9 Hz), 4.17 (2H, q, J = 7.3

Hz), 4.25 (1H, brs), 6.37 (1H, dd, J = 8.4 Hz,

3.0 Hz), 6.45 (1H, d, J = 2.8 Hz), 6.62 (1H,

d, J = 8.4 Hz).

47
—H
—H
—H
—CH₃
—H

¹H NMR 1.24 (3H, t, J = 7.1 Hz), 1.44 (3H,

d, J = 6.7 Hz), 3.88 (1H, brs), 4.04 (1H, q, J =

6.9 Hz), 4.17 (2H, q, J = 7.1 Hz), 4.59 (1H,

brs), 6.54 (2H, d, J = 8.9 Hz), 6.68 (2H, d,

J = 8.9 Hz).

48
—CF₃
—H
—H
—H
—H
MS 263 (M⁺)

TABLE 6

Reference

Example

No.
R₁₁₄
R₁₁₅
R₁₁₆
R₁₁₇
R₁₁₈

¹H NMR (solvent) δ ppm or MS

49

embedded image

—H
—H
—H
—H

¹H NMR (DMSO-d₆) 1.18 (3H, t, J = 7.1 Hz), 3.89 (2H, d, J = 6.2 Hz), 4.11 (2H, q, J = 7.1 Hz), 6.14 (1H, t, J = 6.2 Hz), 6.62 (2H, d, J = 8.8 Hz), 6.90 (1H, t, J = 9.0 Hz), 6.97 (2H, d, J = 8.8 Hz), 8.03 (1H, dd, J = 2.6 Hz, 9.0 Hz), 8.24 (1H, dd, J = 2.6 Hz. 10.9 Hz).

50

embedded image

—F
—H
—F
—CH₃

¹H NMR (CDCl₃) 1.29 (3H, t, J = 7.1 Hz), 3.07 (3H, s), 4.03 (2H, s), 4.22 (2H, q, J = 7.1 Hz), 6.22- 6.35 (2H, m), 7.15 (1H, d, J = 9.0 Hz), 8.49 (1H, dd, J = 2.8 Hz, 9.0 Hz), 9.01 (1H, d, J = 2.8 Hz).

51

embedded image

—F
—F
—H
—CH₃

¹H NMR (CDCl₃) 1.28 (3H, t, J = 7.1 Hz), 3.05 (3H, s), 4.06 (2H, s), 4.20 (2H, q, J = 7.1 Hz), 6.72 (1H, td, J = 2.2 Hz, 9.0 Hz), 6.90 (1H, td, J = 1.8 Hz, 9.4 Hz), 7.11 (1H, d, J = 9.0 Hz), 8.50 (1H, dd, J = 2.7 Hz, 9.0 Hz), 9.02 (1H, d, J = 2.7 Hz).

52

embedded image

—H
—H
—H
—SO₂CH₃

¹H NMR (CDCl₃) 1.31 (3H, t, J = 7.1 Hz), 3.17 (3H, s), 4.25 (2H, q, J = 7.1 Hz), 4.47 (2H, s), 7.09 (1H, d, J = 8.9 Hz), 7.20 (2H, d, J = 8.7 Hz), 7.60 (2H, d, J = 8.9 Hz), 8.51 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.03 (1H, d, J = 2.8 Hz).

53

embedded image

—CH₃
—H
—H
—SO₂CH₃

¹H NMR (CDCl₃) 1.31 (3H, t, J = 7.1 Hz), 2.16 (3H, s), 3.17 (3H, s), 4.25 (2H, q, J = 7.1 Hz), 4.46 (2H, s), 7.07 (1H, dd, J = 9.1 Hz, 0.7 Hz), 7.08 (1H, d, J = 7.3 Hz), 7.40 (1H, d, J = 2.6 Hz), 7.44 (1H, dd, J = 7.3 Hz, 2.6 Hz), 8.50 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.01 (1H, dd, J = 2.8 Hz. 0.7 Hz).

54
—H
—CF₃
—H
—H
—C₂H₅
MS 291 (M⁺)

TABLE 7

Refer-

ence

Exam-

ple

No.
R₁₁₉
R₁₂₀
R₁₂₁

¹H NMR (CDCl₃) δ ppm

55
4-CF₃Ph—
—H
—H
1.30 (3H, t, J = 7.1 Hz), 3.89

(2H, d, J = 4.6 Hz), 3.95

(2H, s), 4.20 (1H, brs), 4.25

(2H, q, J = 7.1 Hz), 6.62

(2H, d, J = 8.9 Hz), 6.77

(1H, d, J = 8.4 Hz), 6.97

(2H, d, J = 8.9 Hz), 7.27 (2H,

d, J = 7.9 Hz), 7.39 (1H,

dd, J = 8.4 Hz, 2.5 Hz),

7.54 (2H, d, J = 7.9 Hz),

8.03 (1H, d, J = 2.5 Hz).

56
4-CF₃PhO—
—H
—SO₂CH₃
1.30 (3H, t, J = 7.1 Hz), 3.15

(3H, s), 4.23 (2H, q, J = 7.1

Hz), 4.45 (2H, s), 5.06

(2H, s), 6.99-7.04 (3H, m),

7.16 (2H, d, J = 8.9 Hz),

7.54 (2H, d, J = 8.9 Hz),

7.56 (2H, d, J = 9.2 Hz),

7.79-7.83 (1H, m), 8.23

(1H, d, J = 2.0 Hz).

57
4-CF₃PhO—
—CH₃
—SO₂CH₃
1.30 (3H, t, J = 7.1 Hz), 2.19

(3H, s), 3.16 (3H, s), 4.24

(2H, q, J = 7.1 Hz), 4.44

(2H, s), 5.05 (2H, s), 6.96-

7.07 (4H, m), 7.36 (1H, dd,

J = 8.7 Hz, 2.6 Hz), 7.42

(1H, d, J = 2.3 Hz), 7.56

(2H, d, J = 8.9 Hz), 7.80

(1H, dd, J = 8.6 Hz, 2.3 Hz),

8.20 (1H, d, J = 2.3 Hz).

(Ph means a benzene ring having 1 to 4 free valences. Hereinafter Ph indicates

the same meaning.)

Reference Example 58
t-Butyl (3-cyano-4-hydroxyphenylamino)acetate

MS 248 (M⁺)

Reference Example 59
Production of 2-[4-(2-fluoro-4-nitrophenoxy)phenoxy]-1-(4-piperonylpiperazin-1-yl)ethanone

Potassium carbonate (0.350 g, 2.53 mmol) was added to a solution of 4-(2-fluoro-4-nitrophenoxy)phenol (0.420 g, 1.69 mmol) and 1-chloroacetyl-4-piperonylpiperazine (0.500 g, 1.70 mmol) in DMF (8 mL). The resulting reaction mixture was stirred for 40 minutes at 100° C. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated, to thereby yield 0.860 of the title compound.

Appearance: Brown oil

¹H NMR (CDCl₃) δ 2.50-2.60 (4H, m), 3.43 (2H, s), 3.50-3.70 (4H, m), 4.71 (2H, s), 5.95 (2H, s), 6.65-6.75 (2H, m), 6.80-7.05 (6H, m), 7.94 (1H, dd, J=2.3 Hz, 9.1 Hz), 8.06 (1H, dd, J=2.3 Hz, 10.4 Hz).

The following compound was produced in the same manner as in Reference Example 59.

Reference Example 60
2-(4-(2-fluoro-4-nitrophenoxy)phenylamino]-1-(4-piperonylpiperazin-1-yl)ethanone

¹H NMR (DMSO-d₆) δ 2.25-2.40 (4H, m), 3.43 (2H, s), 3.45-3.50 (4H, m), 3.90 (2H, d, J=5.1 Hz), 5.75 (1H, t, J=5.1 Hz), 5.99 (2H, s), 6.70-6.75 (3H, m), 6.80-7.00 (5H, m), 8.05 (1H, ddd, J=1.4 Hz, 2.7 Hz, 10.5 Hz), 8.27 (1H, dd, J=2.7 Hz, 11.0 Hz).

Reference Example 61
Production of methyl 3-(4-benzyloxyphenylamino)propionate

Under nitrogen, 4-benzyloxyaniline (13.0 g, 65 mmol) was dissolved by heating at 70° C., and a boron trifluoride-diethyl ether complex (0.82 mL, 6.5 mmol) was added dropwise at the same temperature to the dissolved solution. Methyl acrylate (5.85 mL, 65 mmol) was then slowly added dropwise to the resulting solution. This solution was stirred for 10 hours at 70° C. After cooling with ice, ethyl acetate was added to the reaction mixture and washed with aqueous 1 N sodium hydroxide and brine. The organic layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 17.5 g of the title compound.

Appearance: Brown powder

¹H NMR(CDCl₃) δ 2.60 (2H, t, J=6.4 Hz), 3.39 (2H, t, J=6.4 Hz), 3.69 (3H, s), 3.77 (1H, brs), 4.98 (2H, s), 6.58 (2H, d, J=8.9 Hz), 6.85 (2H, d, J=8.9 Hz), 7.30-7.44 (5H, m).

Reference Example 62
Production of ethyl 3-(4-Methoxyphenylamino)propionate

3-(4-hydroxyphenylamino)propionic acid (4.00 g, 20.5 mmol) was added to 48% hydrobromic acid (50 mL), and the resulting solution was stirred for 2.5 hours at 100° C. After concentration under reduced pressure, ethanol (10 mL) was added to the residue, and concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the residue, and extracted with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby yield 1.27 g of the title compound.

Appearance: Yellow oil

¹H NMR (CDCl₃) δ 1.27 (3H, t, J=7.2 Hz), 2.59 (2H, t, J=6.4 Hz), 3.38 (2H, t, J=6.4 Hz), 4.15 (2H, q, J=7.2 Hz), 6.55 (2H, d, J=8.8 Hz), 6.70 (2H, d, J=8.8 Hz).

Reference Example 63

Production of ethyl [(3-fluoro-4-hydroxyphenyl)methylamino]acetate

Ethyl (3-fluoro-4-hydroxyphenylamino)acetate (1.06 g, 5.1 mmol) was dissolved in methanol (150 mL) and the resulting solution was cooled with ice. To the resulting solution were added aqueous 37% formaldehyde (1.5 mL), sodium triacetoxyborohydride (1 g, 16 mmol) and acetic acid (0.9 mL, 15 mmol), and then stirred at room temperature under a nitrogen atmosphere for 14 hours. The solvent was evaporated under reduced pressure. Water was added to the residue, and the resulting solution was neutralized with a saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2), to the by yield 0.93 g of the title compound.

Appearance: Light brown oil

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7.1 Hz), 3.00 (3H, s), 3.98 (2H, s), 4.17 (2H, q, J=7.1 Hz), 4.68 (1H, brs), 6.31-6.52 (2H, m), 6.87 (1H, t, J=8.9 Hz).

The following compounds were produced in the same manner as in Reference Example 63.

Reference Example 64
Ethyl (methyl{4-[5-(4-trifluoromethylbenzyl)pyridin-2-yloxy]phenyl}amino)acetate

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7.1 Hz), 3.07 (3H, s), 3.95 (2H, s), 4.04 (2H, s), 4.18 (2H, q, J=7.1 Hz), 6.69 (2H, d, J=9.1 Hz), 6.75 (1H, d, J=8.5 Hz), 7.00 (2H, d, J=9.1 Hz), 7.27 (2H, d, J=8.1 Hz), 7.39 (1H, dd, J=8.5 Hz, 2.5 Hz), 7.54 (2H, d, J=8.1 Hz), 8.04 (1H, d, J=2.5 Hz).

Reference Example 65
Ethyl [(4-hydroxy-2-trifluoromethylphenyl)methylamino]-acetate

MS 277 (M⁺).

TABLE 8

Reference

Example

No.
R₁₂₂
R₁₂₃
R₁₂₄
R₁₂₅
M

¹H NMR (CDCl₃) δ ppm

66
—H
—H
—CH₃
—CH₃
1
3.00 (3H, s), 3.71 (3H, s), 4.01 (2H,

s), 4.55 (1H, brs), 6.62 (2H, d, J =

9.2 Hz), 6.75 (2H, d, J = 9.2 Hz).

67
Benzyl
—H
—CH₃
—CH₃
2
2.51-2.57 (2H, m), 2.86 (3H, s),

3.56-3.62 (2H, m), 3.66 (3H, s),

5.00 (2H, s), 6.72 (2H, d, J = 9.1

Hz), 6.91 (2H, d, J = 9.1 Hz), 7.30-

7.45 (5H, m).

68
—H
—F
—C₂H₅
—C₂H₅
1
1.18 (3H, t, J = 7.1 Hz), 1.26 (3H, t,

J = 7.1 Hz), 3.38 (2H, q, J = 7.1

Hz), 3.94 (2H, s), 4.19 (2H, q, J =

7.1 Hz), 4.61 (1H, brs), 6.30-6.35

(1H, m), 6.43 (1H, dd, J = 13.7 Hz,

3.0 Hz), 6.86 (1H, t, J = 8.9 Hz).

69
—H
—OCH₃
—C₂H₅
—C₂H₅
1
1.17 (3H, t, J = 7.1 Hz), 1.25 (3H, t,

J = 7.1 Hz), 3.39 (2H, q, J = 7.1

Hz), 3.85 (3H, s), 3.95 (2H, s),

4.18 (2H, q, J = 7.1 Hz), 5.30 (1H,

brs), 6.21 (1H, dd, J = 8.6 Hz, 2.8

Hz), 6.33 (1H, d, J = 2.8 Hz),

6.79 (1H, d, J = 8.7 Hz).

70

embedded image

—CH₃
—C₂H₅
—C₂H₅
1
1.23 (3H, t, J = 7.1 Hz), 1.28 (3H, t, J = 7.1 Hz), 2.08 (3H, s), 3.47 (2H, q, J = 7.1 Hz), 4.01 (2H, s), 4.22 (2H, q, J = 7.1 Hz), 6.40- 6.59 (2H, m), 6.81-7.00 (2H, m), 8.43 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.06 (1H, d, J = 2.8 Hz).

71

embedded image

—CH₃
—CH₃
—C₂H₅
1
1.27 (3H, t, J = 7.1 Hz), 2.10 (3H, s), 3.08 (3H, s), 4.06 (2H, s), 4.21 (2H, q, J = 7.1 Hz), 6.50- 6.62 (2H, m), 6.85-6.99 (2H, m), 8.43 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05 (1H, d, J = 2.8 Hz).

72

embedded image

—OCH₃
—CH₃
—C₂H₅
1
1.27 (3H, t, J = 7.1 Hz), 3.11 (3H, s), 3.74 (3H, s), 4.07 (2H, s), 4.21 (2H, q, J = 7.1 Hz), 6.27 (1H, dd, J = 8.7 Hz, 2.8 Hz), 6.34 (1H, d, J = 2.8 Hz), 6.95-7.01 (2H, m), 8.42 (1H, dd, J = 9.2 Hz, 3.0 Hz), 9.03 (1H, d, J = 2.8 Hz).

(M means the number of the methylene groups. Hereinafter M indicates the same meaning.)

TABLE 9

Reference

Example

No.
R₁₂₆
R₁₂₇

¹H NMR (CDCl₃) δ ppm

73
—H
—CH₃
2.41 (4H, brs), 2.88 (3H, s), 3.42 (2H, s), 3.50 (2H, brs),

3.60 (2H, brs), 3.94 (2H, s), 5.92 (2H, s), 6.55-6.69 (4H,

m), 6.72 (2H, s), 6.82 (1H, s), 7.47 (1H, brs).

74
—H
—C₂H₅
1.05 (3H, t, J = 7.1 Hz), 2.44 (4H, brs), 3.25 (2H, q, J =

7.1 Hz), 3.46 (2H, s), 3.60 (4H, brs), 3.91 (2H, s),

5.94 (2H, s), 6.63 (4H, s), 6.72-6.74 (2H, m), 6.82 (1H,

s), 7.43 (1H, brs).

75

embedded image

—CH₃
2.44 (4H, brs), 3.06 (3H, s), 3.44 (2H, s), 3.49 (2H, brs), 3.63 (2H, brs), 4.11 (2H, s), 5.94 (2H, s), 6.69-6.77 (4H, m), 6.85 (1H, s), 6.92-7.02 (3H, m), 8.41 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04 (1H, d, J = 3.0 Hz).

76

embedded image

—C₂H₅
1.20 (3H, t, J = 7.1 Hz), 2.42-2.46 (4H, m), 3.44-3.51 (6H, m), 3.64 (2H, q, J = 7.1 Hz), 4.06 (2H, s), 5.95 (2H, s), 6.67 (2H, d, J = 9.2 Hz), 6.74 (2H, brs), 6.85 (1H, brs), 6.94 (1H, d, J = 9.1 Hz), 6.99 (2H, d, J = 9.1 Hz), 8.42 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05 (1H, d, J = 2.8 Hz).

Reference Example 77
Production of 1-(4-piperonylpiperazin-1-yl]-2-[cyclopropyl(4-hydroxyphenyl)amino]ethanone

To a solution of 1-(4-piperonylpiperazin-1-yl)-2-(4-hydroxyphenylamino)ethanone (1.00 g, 2.7 mmol) in methanol (10 mL) were added acetic acid (1.55 mL, 27 mmol), molecular sieves 3A1/16 (1.00 g), [(1-ethoxycyclopropyl)oxy]trimethylsilane (0.653 mL, 3.2 mmol) and sodium cyanoborohydride (770 mg, 12 mmol). The resulting solution was stirred for 16 hours at 60° C. This reaction solution was filtered and concentrated, and to the residue were added ethyl acetate and water. The aqueous layer was adjusted to pH 10 using aqueous 6 N sodium hydroxide. This layer was stirred for some time, and once insoluble matter had dissolved, the ethyl acetate layer was removed, and washed with aqueous 2 N sodium hydroxide and a saturated sodium bicarbonate solution, then dried over anhydrous magnesium sulfate. The solvent was evaporated, to thereby yield 770 mg of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 0.54-0.59 (2H, m), 0.72-0.79 (2H, m), 2.39-2.45 (4H, m), 2.70-2.77 (1H, m), 3.44 (2H, s), 3.48-3.51 (2H, m), 3.57-3.60 (2H, m), 4.12 (2H, s), 5.95 (2H, s), 6.62-6.67 (2H, m), 6.74-6.85 (5H, m).

The following compound was produced in the same manner as in Reference Example 77.

Reference Example 78
Ethyl {cyclopropyl[3-methyl-4-(5-nitropyridin-2-yloxy)phenyl]amino}acetate

¹H NMR (CDCl₃) δ 0.66-0.72 (2H, m), 0.83-0.89 (2H, m), 1.26 (3H, t, J=7.3 Hz), 2.10 (3H, s), 2.71-2.79 (1H, m), 4.08-4.22 (4H, m), 6.77-6.82 (2H, m), 6.91-6.95 (2H, m), 8.40-8.45 (1H, m), 9.05 (1H, d, J=2.8 Hz).

Reference Example 79
Production of ethyl [(3-hydroxyphenyl)methylamino]-acetate

Potassium bicarbonate (1.42 mL, 14.19 mmol) was added to a solution of ethyl (3-hydroxyphenylamino)acetate (2.77 g, 14.19 mmol) in DMF (15 mL). To the resulting solution was further added methyl iodide (1.77 mL, 28.38 mmol), and then stirred at room temperature for 18 hours. To the resulting reaction solution was added brine (150 mL), and the obtained mixture was extracted with ethyl acetate (150 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, after which solvent was evaporated, to thereby yield 2.48 g of the title compound.

Appearance: Pale yellow oil

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7.1 Hz), 3.04 (3H, s), 4.03 (2H, s), 4.18 (2H, q, J=7.1 Hz), 5.17 (1H, brs), 6.17-6.27 (3H, m), 7.04-7.10 (1H, m).

The following compounds were produced in the same manner as in Reference Example 79.

TABLE 10

Reference

Example

No.
R₁₂₈
R₁₂₉
R₁₃₀
R₁₃₁

¹H NMR (CDCl₃) δ ppm or MS

80
—H
—H
—H

embedded image

¹H NMR 1.22 (3H, t, J = 7.1 Hz), 1.43 (3H, d, J = 7.1 Hz), 2.83 (3H, s), 4.16 (2H, q, J = 7.1 Hz), 4.33 (1H, q, J = 7.1 Hz), 4.84 (1H, brs), 6.75 (4H, s).

81
—CH₃
—H
—H

embedded image

¹H NMR 1.23 (3H, t, J = 7.3 Hz), 1.42 (3H, d, J = 7.1 Hz), 2.22 (3H, s), 2.82 (3H, s), 4.08-4.21 (2H, m), 4.30 (1H, s), 4.33 (1H, q, J = 7.1 Hz), 6.58 (1H, dd, J = 8.6 Hz, 3.0 Hz), 6.65 (1H, d, J = 2.8 Hz), 6.68 (1H, d, J = 8.6 Hz).

82
—OCH₃
—H
—H

embedded image

¹H NMR 1.17 (3H, t, J = 7.1 Hz), 3.39 (2H, q, J = 7.1 Hz), 3.75 (3H, s), 4.00 (2H, brs), 5.11 (1H, brs), 5.15 (2H, s), 6.21 (1H, dd, J = 8.6 Hz, 2.8 Hz), 6.27 (1H, d, J = 2.8 Hz), 6.77 (1H, d, J = 8.6 Hz), 7.27-7.37 (5H, m).

83
—F
—H
—F

embedded image

¹H NMR 1.24 (3H, t, J = 7.1 Hz), 2.92 (3H, s), 3.93 (2H, s), 4.15 (2H, q, J = 7.1 Hz), 4.96 (1H, d, J = 2.8 Hz), 6.70 (1H, d, J = 8.2 Hz, 12.9 Hz), 6.77 (1H, d, J = 8.1 Hz, 12.2 Hz).

84
—CH₃
—H
—CH₃

embedded image

¹H NMR 0.99 (3H, t, J = 7.1 Hz), 1.21 (3H, t, J = 7.1 Hz), 2.18 (3H, s), 2.24 (3H, s), 3.10 (2H, q, J = 7.1 Hz), 3.68 (2H, s), 4.11 (2H, q, J = 7.1 Hz), 4.47 (1H, s), 6.59 (1H, s), 6.94 (1H, s).

85
—H
—H
—H

embedded image

¹H NMR 1.26 (3H, t, J = 7.3 Hz), 1.33 (6H, s), 2.80 (3H, s), 4.18 (2H, q, J = 7.3 Hz), 5.15 (1H, brs), 6.71 (2H, d, J = 8.9 Hz), 7.00 (2H, d, J = 8.9 Hz).

86
—H
—CH₃
—CH₃

embedded image

MS 237 (M⁺)

87
—CH₃
—H
—CH₃

embedded image

¹H NMR 1.24 (3H, t, J = 7.1 Hz), 2.19 (3H, s), 2.24 (3H, s), 2.79 (3H, s), 3.64 (2H, s), 4.15 (2H, q, J = 7.1 Hz), 4.45 (1H, brs), 6.59 (1H, s), 6.89 (1H, s).

88
—CF₃
—H
—H

embedded image

MS 277 (M⁺)

89
—CN
—H
—H

embedded image

MS 262 (M⁺)

TABLE 11

Reference

Example

No.
R₁₃₂
R₁₃₃
R₁₃₄
R₁₃₅
R₁₃₆
M

¹H NMR (CDCl₃) δ ppm

90
—H
—H
—H
—C₂H₅
—C₂H₅
1
1.24 (3H, t, J = 7.1 Hz), 1.28 (3H, t, J =

7.0 Hz), 3.48 (2H, q, J = 7.1 Hz),

4.02 (2H, s), 4.21 (2H, q, J = 7.0 Hz),

6.67 (2H, d, J = 8.9 Hz), 6.95 (1H,

d, J = 9.1 Hz), 7.00 (2H, d, J = 8.9 Hz),

8.42 (1H, dd, J = 2.8 Hz, 9.1 Hz),

9.06 (1H, d, J = 2.8 Hz).

91
—H
—H
—H
—CH₃
—C₂H₅
1
1.27 (3H, t, J = 7.2 Hz), 3.10 (3H, s),

4.07 (2H, s), 4.20 (2H, q, J = 7.2 Hz),

6.71 (2H, d, J = 9.2 Hz), 6.95 (1H, d,

J = 9.1 Hz), 7.02 (2H, d, J = 9.2 Hz),

8.43 (1H, dd, J = 2.8 Hz, 9.1 Hz),

9.05 (1H, d, J = 2.8 Hz).

92
—F
—H
—H
allyl
—C₂H₅
1
1.29 (3H, t, J = 7.1 Hz), 4.02 (4H, brs),

4.23 (2H, q, J = 7.1 Hz), 5.21-5.30

(2H, m), 5.84-5.94 (1H, m), 6.40-6.52

(2H, m), 7.01-7.08 (2H, m), 8.47 (1H,

dd, J = 8.9 Hz, 2.8 Hz), 9.03 (1H,

d, J = 2.6 Hz).

93
—F
—H
—F
—C₂H₅
—C₂H₅
1
1.22 (3H, t, J = 7.1 Hz), 1.27 (3H, t, J =

7.1 Hz), 3.37 (2H, q, J = 7.1 Hz), 4.02

(2H, s), 4.20 (2H, q, J = 7.1 Hz), 6.77

(1H, dd, J = 8.1 Hz, 12.3 Hz), 6.92

(1H, dd, J = 7.3 Hz, 12.7 Hz), 7.09

(1H, d, J = 9.0 Hz), 8.49 (1H, dd, J =

2.8 Hz, 9.0 Hz), 9.02 (1H, d, J = 2.8

Hz).

94
—F
—F
—H
—CH₃
—C(CH₃)₃
0
1.45 (9H, s), 3.26 (3H, s), 6.90-7.11 (2H,

m), 7.16 (1H, d, J = 9.0 Hz), 8.53 (1H,

dd, J = 2.8 Hz, 9.0 Hz), 9.01 (1H, d,

J = 2.8 Hz).

TABLE 12

Reference

Example

No.
R₁₃₇
R₁₃₈
R₁₃₉
Xa₃
Xa₄

¹H NMR (CDCl₃) δ ppm

95

embedded image

—H
piperonyl
none
—CH₂—
2.44 (8H, brs), 2.96 (2H, s), 3.30 (3H, s), 3.38 (2H, s), 5.92 (2H, s), 6.72 (2H, brs), 6.82 (1H, s), 7.09 (1H, d, J = 9.1 Hz), 7.20 (2H, d, J = 8.9 Hz), 7.29 (2H, d, J = 8.9 Hz), 8.51 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04 (1H, d, J = 2.8 Hz).

96

embedded image

—H
benzyl
none
none
1.55-1.80 (3H, m), 1.81- 2.15 (3H, m), 2.23 (4H, t, J = 5.0 Hz), 3.16 (3H, s), 3.20 (4H, t, J = 5.0 Hz), 3.42 (2H, s), 3.55-3.69 (1H, m), 3.85-4.00 (1H, m), 5.36 (1H, t, J = 3.2 Hz), 6.99 (4H, s), 7.16-7.36 (5H, m).

97
—H
—CH₃
piperonyl
—CH₂—
none
2.18 (3H, s), 2.38-2.42 (4H,

m), 2.89 (3H, s), 3.41 (2H, s),

3.50 (2H, brs), 3.61 (2H, brs),

3.95 (2H, brs), 5.93 (2H, s),

6.44-6.57 (3H, m), 6.73-

6.76 (2H, m), 6.83 (1H, s).

TABLE 13

Reference

Example

No.
R₁₄₀

¹H NMR (CDCl₃) δ ppm

98
—NO₂
1.07 (3H, t, J = 7.1 Hz), 2.15 (3H, s),

3.38 (3H, s), 4.19 (2H, q, J = 7.1

Hz), 7.06-7.20 (4H, m), 8.51 (1H,

dd, J = 9.1 Hz, 2.8 Hz), 8.97 (1H,

d, J = 2.8 Hz).

99
4-CF₃PhOCH₂—
1.07 (3H, t, J = 7.1 Hz), 2.18 (3H, s),

3.36 (3H, s), 4.08 (2H, q, J = 7.1

Hz), 5.04 (2H, s), 6.97 (1H, d, J =

8.6 Hz), 7.01-7.13 (4H, m), 7.16

(1H, d, J = 2.3 Hz), 7.57 (2H, d,

J = 8.6 Hz), 7.80 (1H, dd, J = 8.6

Hz, 2.3 Hz), 8.17 (1H, d, J = 2.3 Hz).

Reference Example 100
Production of ethyl [acetyl(3-fluoro-4-hydroxyphenyl)amino]acetate

Ethyl (3-fluoro-4-hydroxyphenylamino)acetate (0.84 g, 4 mmol) was dissolved in N,N-dimethylacetamide (4 mL). To the resulting solution was added acetyl chloride (0.6 mL, 10 mmol), and the resulting solution was stirred at room temperature for 1 hour. Water (1 mL), methanol (10 mL) and saturated sodium carbonate (10 mL) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the solution. 10% hydrochloric acid was employed to turn the solution acidic, and then the solution was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:1), to thereby yield 0.84 g of the title compound.

Appearance: Colorless powder

¹H NMR (CDCl₃) δ 1.28 (3H, t, J=7.3 Hz), 1.94 (3H, s), 4.20 (2H, q, J=7.3 Hz), 4.32 (2H, s), 6.02 (1H, brs), 6.99-7.07 (2H, m), 7.13-7.18 (1H, m).

The following compounds were produced in the same manner as in Reference Example 100.

TABLE 14

Reference

Example

No.
R₁₄₁
R₁₄₂
M

¹H NMR (CDCl₃) δ ppm

101
—H
—CH₃
1
1.26 (3H, t, J = 7.1 Hz), 1.92 (3H, s),

2.24 (3H, s), 4.19 (2H, q, J = 7.1 Hz),

4.32 (2H, s), 5.38 (1H, brs), 6.78 (1H, d,

J = 8.4 Hz), 7.04 (1H, dd, J = 8.4 Hz,

2.5 Hz), 7.10 (1H, d, J = 2.5 Hz).

102
—H
—H
2
1.21 (3H, t, J = 7.2 Hz), 1.83 (3H, s),

2.56 (2H, t, J = 7.4 Hz), 3.97 (2H, t, J =

7.4 Hz), 4.06 (2H, q, J = 7.2 Hz),

6.05 (1H, brs), 6.87 (2H, d, J = 8.7 Hz),

7.03 (2H, d, J = 8.7 Hz).

103
benzyl
—H
1
1.26 (3H, t, J = 7.1 Hz), 1.91 (3H, s),

4.18 (2H, q, J = 7.1 Hz), 4.33 (2H, s),

5.07 (2H, s), 6.98 (2H, d, J = 8.9 Hz),

7.26 (2H, d, J = 8.9 Hz), 7.35-7.45

(5H, m).

104

embedded image

—H
1
1.24 (3H, t, J = 7.1 Hz), 1.89 (3H, s), 4.15 (2H, q, J = 7.1 Hz), 4.32 (2H, s), 6.95 (2H, d, J = 8.9 Hz), 7.12 (1H, t, J = 9.0 Hz), 7.27-7.32 (3H, m), 7.52- 7.60 (1H, m), 7.70-7.80 (2H, m), 7.99 (1H, s), 8.05 (1H, s).

TABLE 15

Reference

Example

No.
R₁₄₃

¹H NMR (CDCl₃) δ ppm

105
—C₂H₅
1.09 (3H, t, J = 7.4 Hz), 2.20 (2H, q,

J = 7.4 Hz), 2.40-2.45 (4H, m), 3.43

(4H, brs), 3.61 (2H, brs), 4.47 (2H,

s), 5.94 (2H, s), 6.70-6.76 (2H,

m), 6.84 (1H, s), 7.08 (1H, d,

J = 9.0 Hz), 7.19 (2H, d, J = 8.7

Hz), 7.52 (2H, d, J = 8.7 Hz),

8.51 (1H, dd, J = 2.8 Hz, 9.0 Hz),

9.04 (1H, d, J = 2.8 Hz).

106
—CH₂Cl
2.40-2.48 (4H, m), 3.43 (4H, s), 3.62

(2H, brs), 3.97 (2H, s), 4.49 (2H,

s), 5.95 (2H, s), 6.70-6.77 (2H, m),

6.84 (1H, s), 7.11 (1H, d, J = 9.0

Hz), 7.23 (2H, d, J = 8.7 Hz), 7.59

(2H, d, J = 8.7 Hz), 8.52 (1H, dd, J =

2.8 Hz, 9.0 Hz), 9.04 (1H, d, J = 2.8

Hz).

107
cyclopropyl
0.65-1.52 (5H, m), 2.43 (4H, brs),

3.43 (4H, brs), 3.61 (2H, brs),

4.50 (2H, brs), 5.95 (2H, s), 6.72-

6.75 (2H, m), 6.84 (1H, s), 7.08 (1H,

d, J = 9.1 Hz), 7.20 (1H, d, J = 8.8

Hz), 7.59 (2H, d, J = 8.8 Hz),

8.50 (1H, dd, J = 2.9 Hz, 9.1

Hz), 9.04 (1H, d, J = 2.9 Hz).

TABLE 16

Reference

Example

No.
R₁₄₄

¹H NMR (CDCl₃) δ ppm

108
—H
1.44 (3H, t, J = 7.1 Hz), 4.43 (2H, q, J = 7.1 Hz),

5.05 (2H, s), 6.93 (1H, d, J = 8.6 Hz), 7.02 (2H,

d, J = 8.6 Hz), 7.17 (2H, d, J = 8.9 Hz), 7.56 (2H,

d, J = 8.4 Hz), 7.69 (2H, d, J = 8.9 Hz), 7.79 (1H,

dd, J = 8.4 Hz, 2.5 Hz), 8.22 (1H, d, J = 2.5 Hz),

8.90 (1H, brs).

109
—CH₃
1.44 (3H, t, J = 7.1 Hz), 2.19 (3H, s), 4.43 (2H, q,

J = 7.1 Hz), 5.03 (2H, s), 6.94 (1H, d, J = 8.4 Hz),

7.02 (2H, d, J = 8.4 Hz), 7.07 (1H, d, J = 8.6

Hz), 7.51-7.58 (4H, m), 7.78 (1H, dd, J = 8.6 Hz,

2.5 Hz), 8.20 (1H, d, J = 2.5 Hz), 8.84 (1H, brs).

Reference Example 110
Production of (6-chloropyridin-3-yl) (4-trifluoromethylphenyl)methanone

Under an argon gas flow, half of a solution of 4-bromobenzotrifluoride (1.20 g, 5.33 mmol) in THF (6 mL) was added to magnesium (156 mg, 6.41 mmol). The resulting solution was stirred, and further 1,2-dibromoethane (3 drops) was added. Once the reaction began, the balance of the 4-bromobenzotrifluoride in THF solution was added dropwise, and once dropping had finished, the resulting solution was stirred for 30 minutes at 60° C. A solution of 6-chloro-N-methoxy-N-methylnicotinamide (990 mg, 5.36 mmol) in THF (3 mL) was charged into a separate reaction vessel, into which the above reaction solution was added dropwise under an argon gas flow and ice cooling. After dropping had finished, the resulting solution was stirred for 30 minutes at room temperature, and then heated to reflux for 1 hour. The reaction solution was cooled with ice, then aqueous ammonium chloride and water were added. The resulting solution was extracted with ethyl acetate, and washed with brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 610 mg of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 7.52 (1H, d, J=8.3 Hz), 7.80 (2H, d, J=8.0 Hz), 7.90 (2H, d, J=8.0 Hz), 8.11 (1H, dd, J=8.3 Hz, 2.0 Hz), 8.77 (1H, d, J=2.0 Hz).

Reference Example 111
Production of ethyl 3-[4-(4-nitrophenoxy)phenyl]-propionate

To a solution of ethyl 3-(4-hydroxyphenyl)propionate (6.00 g, 30.9 mmol) in DMF (60 mL) were added 4-fluoronitrobenzene (6.54 g, 46.3 mmol) and potassium carbonate (5.12 g, 37.1 mmol). The resulting reaction solution was stirred for 1 hour at 80° C. To the reaction solution was added water and extracted with ethyl acetate. The resulting ethyl acetate layer was washed with water and then with brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 9.64 g of the title compound.

Appearance: Pale yellow oil

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=7.1 Hz), 2.62 (2H, t, J=7.7 Hz), 2.96 (2H, t, J=7.7 Hz), 4.12 (2H, q, J=7.1 Hz), 6.93-7.06 (4H, m), 7.24 (2H, d, J=8.5 Hz), 8.17 (2H, d, J=9.2 Hz).

The following compounds were produced in the same manner as in Reference Example 111.

TABLE 17

Reference

Example

No.
R₁₄₅

¹H NMR (solvent) δ ppm

112
—Ac
(DMSO-d₆) 2.58 (3H, s), 7.26 (2H, d,

J = 8.8 Hz), 7.40 (1H, t, J = 8.4 Hz),

8.04 (2H, d, J = 8.8 Hz), 8.15 (1H, ddd,

J = 1.4 Hz, 2.6 Hz, 8.4 Hz), 8.39 (1H,

dd, J = 2.6 Hz, 10.7 Hz).

113
—CH₂COOCH₃
(DMSO-d₆) 3.63 (3H, s), 3.72 (2H, s),

7.11-7.17 (3H, m), 7.38 (2H, d, J = 8.4

Hz), 8.09 (1H, ddd, J = 1.4 Hz, 2.7 Hz,

9.1 Hz), 8.33 (1H, dd, J = 2.7 Hz, 10.2

Hz).

114
—(CH₂)₂COOC₂H₅
(CDCl₃) 1.22 (3H, t, J = 7.1 Hz), 2.62

(2H, t, J = 7.6 Hz), 2.96 (2H, t, J = 7.6

Hz), 4.12 (2H, q, J = 7.1 Hz), 6.92 (1H,

dd, J = 9.0 Hz, 8.0 Hz), 6.99 (2H, d,

J = 8.6 Hz), 7.24 (2H, d, J = 8.6 Hz),

7.90-8.00 (1H, m), 8.06 (1H, dd, J =

10.3 Hz, 2.7 Hz).

115
—NHAc
(DMSO-d₆) 2.05 (3H, s), 7.07 (1H,

t, J = 8.6 Hz), 7.16 (2H, d, J = 9.0 Hz),

7.67 (2H, d, J = 9.0 Hz), 8.06 (1H, ddd,

J = 1.4 Hz, 2.7 Hz, 8.6 Hz), 8.31

(1H, dd, 2.7 Hz, 10.9 Hz), 10.06

(1H, s).

116
—SCH₂COOC₂H₅
(CDCl₃) 1.24 (3H, t, J = 7.1 Hz), 3.62

(2H, s), 4.18 (2H, q, J = 7.1 Hz), 6.95-

7.05 (3H, m), 7.49 (2H, d, J = 8.8 Hz),

8.00 (1H, ddd, J = 1.5 Hz, 2.6 Hz, 9.1

Hz), 8.08 (1H, dd, J = 2.6 Hz, 10.2 Hz).

117
—OCH₃
(DMSO-d₆) 3.77 (3H, s), 6.90-7.10

(3H, m), 7.16 (2H, d, J = 9.1

Hz), 8.03 (1H, ddd, J = 1.4 Hz, 2.6

Hz, 9.2 Hz), 8.27 (1H, dd, J = 2.6

Hz, 10.9 Hz).

118
—H
(CDCl₃) 6.95 (1H, dd, J = 9.0 Hz, 8.0

Hz), 7.07 (2H, d, J = 7.9 Hz), 7.24 (2H,

t, J = 7.9 Hz), 7.42 (2H, t, J = 7.9 Hz),

7.91-8.02 (1H, m), 8.07 (1H, dd, J =

10.3 Hz, 2.7 Hz).

119
—(CH₂)₃COOC₂H₅
(CDCl₃) 1.25 (3H, t, J = 7.1 Hz), 1.88-

2.03 (2H, m), 2.32 (2H, t, J = 7.4 Hz),

2.66 (2H, t, J = 7.4 Hz), 4.12 (2H, q,

J = 7.1 Hz), 6.91 (1H, dd, J = 9.0 Hz,

8.0 Hz), 6.99 (2H, d, J = 8.5 Hz),

7.22 (2H, d, J = 8.5 Hz), 7.91-7.98

(1H, m), 8.06 (1H, dd, J = 10.3 Hz, 2.7

Hz)

120
—CHO
(DMSO-d₆) 7.33 (2H, d, J = 8.7 Hz), 7.47

(1H, t, J = 9.0 Hz), 8.00 (2H, d, J = 8.7

Hz), 8.16 (1H, ddd, J = 1.4 Hz, 2.7 Hz,

9.0 Hz), 8.40 (1H, dd, J = 2.7 Hz, 10.6

Hz), 9.99 (1H, s).

121
—COOC₂H₅
(DMSO-d₆) 1.32 (3H, t, J = 7.1 Hz), 4.31

(2H, q, J = 7.1 Hz), 7.26 (2H, d, J =

8.9 Hz), 7.41 (1H, t, J = 8.4 Hz), 8.03

(2H, d, J = 8.9 Hz), 8.14 (1H, ddd, J =

1.4 Hz, 2.6 Hz, 8.4 Hz), 8.39 (1H, dd,

J = 2.6 Hz, 10.6 Hz).

(Ac means an acetyl group. Hereinafter Ac indicates the same meaning.)

TABLE 18

Reference

Example

No.
R₁₄₆
R₁₄₇

¹H NMR (solvent) δ ppm

122
4-NO₂

embedded image

(DMSO-d₆) 1.33 (3H, t, J = 7.1 Hz), 4.32 (2H, q, J = 7.1 Hz), 7.24-7.31 (4H, m), 8.05 (2H, d, J = 8.9 Hz), 8.29 (2H, d, J = 9.3 Hz).

123
4-NO₂

embedded image

(CDCl₃) 3.10 (3H, s), 3.75 (3H, s), 4.10 (2H, s), 6.71 (2H, d, J = 9.2 Hz), 6.96 (2H, d, J = 9.2 Hz), 6.98 (2H, d, J = 9.2 Hz), 8.17 (2H, d, J = 9.2 Hz).

124
2-NO₂

embedded image

(CDCl₃) 1.22 (3H, t, J = 7.1 Hz), 2.60 (2H, t, J = 7.7 Hz), 2.93 (2H, t, J = 7.7 Hz), 4.11 (2H, q, J = 7.1 Hz), 6.92- 6.99 (3H, m), 7.13-7.23 (3H, m), 7.45 (1H, dt, J = 1.6 Hz, 8.2 Hz), 7.92 (1H, dd, J = 8.2 Hz, 1.6 Hz).

125
4-NO₂

embedded image

(CDCl₃) 1.50 (9H, s), 2.53 (2H, brs), 3.66 (2H, m), 4.10 (2H, brs), 6.05 (1H, brs), 7.02 (2H, d, J = 9.0 Hz), 7.06 (2H, d, J = 8.5 Hz), 7.43 (2H, d, J = 8.5 Hz), 8.21 (2H, d, J = 8.0 Hz).

126
4-NO₂

embedded image

(CDCl₃) 1.21 (3H, t, J = 7.1 Hz), 2.61 (2H, t, J = 7.7 Hz), 2.95 (2H, t, J = 7.7 Hz), 4.10 (2H, q, J = 7.1 Hz), 6.88- 6.94 (2H, m), 6.98 (2H, d, J = 9.2 Hz), 7.08 (1H, d, J = 7.6 Hz), 7.32 (1H, t, J = 7.6 Hz), 8.18 (2H, d, J = 9.2 Hz).

127
4-NO₂

embedded image

(CDCl₃) 2.58 (2H, t, J = 7.7 Hz), 2.87 (2H, t, J = 7.7 Hz), 3.62 (3H, s), 6.89-7.01 (3H, m), 7.13-7.37 (3H, m), 8.18 (2H, d, J = 9.2 Hz).

TABLE 19

Refer-

ence

Exam-

ple

No.
R₁₄₈
R₁₄₉
R₁₅₀

¹H NMR (CDCl₃) δ ppm

128
—H
—H
—C₂H₅
1.41 (3H, t, J = 7.3 Hz), 4.40

(2H, q, J = 7.3 Hz), 7.09 (1H,

d, J = 8.9 Hz), 7.22-7.26 (2H, m),

8.14-8.17 (2H, m), 8.52 (1H,

dd, J = 8.9 Hz, 3.0 Hz), 9.04 (1H,

d, J = 3.0 Hz).

129
—H
—H
—CH₃
3.94 (3H, s), 7.10 (1H, d, J = 8.9

Hz), 7.22-7.26 (2H, m), 8.13-8.16

(2H, m), 8.52 (1H, dd, J = 8.9

Hz, 2.7 Hz), 9.04 (1H, d, J = 2.7

Hz).

130
—F
—H
—CH₃
3.95 (3H, s), 7.18 (1H, d, J = 8.8

Hz), 7.29-7.35 (1H, m), 7.87-

7.96 (2H, m), 8.54 (1H, dd, J =

8.8 Hz, 2.6 Hz), 8.99 (1H,

d, J = 2.6 Hz).

131
—F
—H
—C₂H₅
1.41 (3H, t, J = 7.1 Hz), 4.41 (2H,

q, J = 7.1 Hz), 7.18 (1H, d, J = 9.1

Hz), 7.29-7.35 (1H, m), 7.88-7.96

(2H, m), 8.54 (1H, dd, J = 9.1 Hz,

2.8 Hz), 8.99 (1H, d, J = 2.8 Hz).

132
—CH₃
—H
—CH₃
2.21 (3H, s), 3.93 (3H, s), 7.08-

7.15 (2H, m), 7.97 (1H, dd, J = 8.4

Hz, 2.2 Hz), 8.02 (1H, d, J = 2.2

Hz), 8.52 (1H, dd, J = 8.9 Hz,

2.7 Hz), 9.01 (1H, d, J = 2.7 Hz).

133
—OCH₃
—H
—C₂H₅
1.41 (3H, t, J = 7.1 Hz), 3.80 (3H,

s), 4.40 (2H, q, J = 7.1 Hz), 7.09

(1H, d, J = 8.9 Hz), 7.21 (1H,

d, J = 8.2 Hz), 7.71-7.77 (2H,

m), 8.49 (1H, dd, J = 8.9 Hz, 2.8

Hz), 8.97 (1H, d, J = 2.8 H).

134
—H
—OCH₃
—CH₃
3.90 (3H, s), 3.91 (3H, s), 6.77-

6.81 (2H, m), 7.11 (1H, dd,

J = 9.1 Hz, 0.5 Hz), 7.91-7.95

(1H, m), 8.53 (1H, dd, J = 9.1 Hz,

2.7 Hz), 9.06 (1H, d, J = 2.7 Hz).

135
—H
—CH₃
—CH₃
2.64 (3H, s), 3.91 (3H, s), 7.02-

7.10 (3H, m), 8.03-8.06 (1H,

m), 8.52 (1H, dd, J = 8.9 Hz, 2.7

Hz), 9.05 (1H, dd, J = 2.7 Hz, 0.5

Hz).

136
—Cl
—H
—CH₃
3.95 (3H, s), 7.17-7.20 (1H, m),

7.31 (1H, d, J = 8.6 Hz), 8.03-

8.07 (1H, m), 8.20 (1H, d, J = 2.0

Hz), 8.55 (1H, dd, J = 9.1 Hz, 2.8

Hz), 8.98 (1H, dd, J = 2.8 Hz, 0.5

Hz).

137
—F
—F
—CH₃
3.97 (3H, s), 7.06-7.16 (1H, m),

7.21 (1H, dd, J = 0.3 Hz, 9.0 Hz),

7.77-7.88 (1H, m), 8.56 (1H, dd,

J = 2.8 Hz, 9.0 Hz), 8.99 (1H, dd,

J = 0.3 Hz, 2.8 Hz)

TABLE 20

Refer-

ence

Exam-

ple

No.
R₁₅₁
R₁₅₂
M

¹H NMR (CDCl₃) δ ppm

138
—H
—CH₃
2
2.64-2.70 (2H, m), 2.97-3.02 (2H, m),

3.69 (3H, s), 7.01-7.10 (3H, m), 7.26-

7.30 (2H, m), 8.47 (1H, dd, J = 8.9 Hz,

2.6 Hz), 9.04 (1H, d, J = 2.6 Hz).

139
—OCH₃
—C₂H₅
2
1.26 (3H, t, J = 7.1 Hz), 2.67 (2H, t,

J = 7.5 Hz), 2.99 (2H, t, J = 7.5 Hz),

3.74 (3H, s), 4.16 (2H, q, J = 7.1 Hz),

6.76-6.91 (2H, m), 7.02 (1H, d, J =

9.1 Hz), 7.06 (1H, d, J = 8.0 Hz), 8.45

(1H, dd, J = 9.1 Hz, 2.6 Hz), 9.01 (1H,

d, J = 2.6 Hz).

140
—H
—CH₃
1
3.67 (2H, s), 3.72 (3H, s), 7.04 (1H,

d, J = 8.9 Hz), 7.12 (2H, d, J = 8.6

Hz), 7.38 (2H, d, J = 8.6 Hz), 8.45-

8.50 (1H, m), 9.04 (1H, d, J = 3.0 Hz).

141
—H
—C₂H₅
2
1.23 (3H, t, J = 7.1 Hz), 2.63 (2H, t,

J = 7.8 Hz), 2.97 (2H, t, J = 7.8 Hz),

4.11 (2H, q, J = 7.1 Hz), 7.00 (1H,

d, J = 9.1 Hz), 7.06 (2H, d, J = 8.5

Hz), 7.26 (2H, d, J = 8.5 Hz), 8.45

(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.02

(1H, d, J = 2.8 Hz).

142
—OCH₃
—CH₃
2
2.66-2.71 (2H, m), 2.97-3.02 (2H,

m), 3.70 (3H, s), 3.74 (3H, s), 6.83-

6.88 (2H, m), 7.01-7.08 (2H, m),

8.45 (1H, dd, J = 9.1 Hz, 2.8 Hz),

9.01 (1H, d, J = 2.8 Hz).

143
—OC₂H₅
—C₂H₅
2
1.15 (3H, t, J = 7.0 Hz), 1.26 (3H,

t, J = 7.1 Hz), 2.53-2.72 (2H, m),

2.87-3.05 (2H, m), 3.98 (2H, q,

J = 7.0 Hz), 4.15 (2H, q, J = 7.1

Hz), 6.73-6.93 (2H, m), 7.02

(1H, d, J = 9.0 Hz), 7.07 (1H, d,

J = 8.0 Hz), 8.45 (1H, dd, J = 9.0

Hz, 2.8 Hz), 9.01 (1H, d, J = 2.8

Hz).

144
—F
—C₂H₅
2
1.26 (3H, t, J = 7.1 Hz), 2.57-2.71

(2H, m), 2.89-3.06 (2H, m), 4.15

(2H, q, J = 7.1 Hz), 6.98-7.21 (4H,

m), 8.50 (1H, dd, J = 9.0 Hz, 2.8 Hz),

9.01 (1H, d, J = 2.8 Hz).

145
—H
—C₂H₅
4
1.26 (3H, t, J = 7.3 Hz), 1.60-1.80

(4H, m), 2.30-2.40 (2H, m), 2.60-

2.75 (2H, m), 4.13 (2H, q, J = 7.3

Hz), 7.01 (1H, d, J = 9.0 Hz), 7.06

(2H, d, J = 8.6 Hz), 7.25 (2H, d, J =

8.6 Hz), 8.46 (1H, dd, J = 9.0 Hz, 3.0

Hz), 9.04 (1H, d, J = 3.0 Hz).

TABLE 21

Reference

Example

No.
R₁₅₃
R₁₅₄
M

¹H NMR (CDCl₃) δ ppm or MS

146
—CH₃
—H
1

¹H NMR 1.32 (3H, t, J = 7.1 Hz), 2.08

(3H, s), 3.90 (2H, d, J = 5.3 Hz), 4.15-

4.39 (3H, m), 6.39-6.59 (2H, m), 6.81-

7.01 (2H, m), 8.44 (1H, dd, J = 9.1 Hz,

2.8 Hz), 9.05 (1H, dd, J = 2.8 Hz, 0.4

Hz).

147
—CH₃
—Ac
1

¹H NMR 1.29 (3H, t, J = 7.1 Hz), 1.99

(3H, s), 2.17 (3H, s), 4.22 (2H, q, J =

7.1 Hz), 4.38 (2H, s), 7.05-7.12 (2H,

m), 7.22-7.28 (2H, m), 7.31 (1H, s),

8.50 (1H, d, J = 9.0 Hz), 9.01 (1H, s).

148
—H
—H
1

¹H NMR 1.32 (3H, t, J = 7.1 Hz), 3.91

(2H, d, J = 5.4 Hz), 4.27 (2H, q, J = 7.1

Hz), 4.37 (1H, t, J = 5.4 Hz), 6.66 (2H,

d, J = 8.9 Hz), 6.96 (1H, d, J = 9.1 Hz),

6.98 (2H, d, J = 8.9 Hz), 8.43 (1H, dd,

J = 2.8 Hz, 9.1 Hz), 9.05 (1H, d, J = 2.8

Hz).

149
—H
—Ac
2

¹H NMR 1.23 (3H, t, J = 7.1 Hz), 1.90

(3H, s), 2.62 (2H, t, J = 7.3 Hz), 4.03

(2H, t, J = 7.3 Hz), 4.08 (2H, q, J =

7.1 Hz), 7.10 (1H, d, J = 9.0 Hz), 7.21-

7.28 (4H, m), 8.52 (1H, dd, J = 2.8 Hz,

9.0 Hz), 9.04 (1H, d, J = 2.8 Hz).

150
—F
—C₂H₅
1

¹H NMR 1.21-1.32 (6H, m), 3.47 (2H,

q, J = 7.1 Hz), 4.01 (2H, s), 4.23 (2H,

q, J = 7.1 Hz), 6.38-6.49 (2H, m),

7.01-7.07 (2H, m), 8.46 (1H, dd, J =

9.1 Hz, 2.8 Hz), 9.03 (1H, d, J = 2.8

Hz).

151
—OCH₃
—C₂H₅
1

¹H NMR 1.25 (3H, t, J = 7.1 Hz), 1.28

(3H, t, J = 7.1 Hz), 3.50 (2H, q, J =

7.1 Hz), 3.72 (3H, s), 4.03 (2H, s),

4.22 (2H, q, J = 7.1 Hz), 6.23 (1H,

dd, J = 8.9 Hz, 2.8 Hz), 6.30 (1H, d,

J = 2.6 Hz), 6.95-6.99 (2H, m), 8.42

(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04

(1H, d, J = 2.8 Hz).

152
—F
—CH₃
1

¹H NMR 1.28 (3H, t, J = 7.1 Hz),

3.09 (3H, s), 4.06 (2H, s), 4.21 (2H,

q, J = 7.1 Hz), 6.42-6.54 (2H, m),

7.03-7.10 (2H, m), 8.47 (1H, dd, J =

9.1 Hz, 2.8 Hz), 9.03 (1H, d, J = 2.8

Hz).

153
—OCH₃
—H
1

¹H NMR 1.32 (3H, t, J = 7.1 Hz), 3.72

(3H, s), 3.92 (2H, d, J = 5.3 Hz), 4.27

(2H, q, J = 7.1 Hz), 4.41 (1H, brt),

6.19 (1H, dd, J = 8.4 Hz, 2.5 Hz), 6.29

(1H, d, J = 2.5 Hz), 6.96-7.00 (2H, m),

8.42 (1H, dd, J = 9.1 Hz, 2.8 Hz),

9.03 (1H, d, J = 2.8 Hz).

154
—F
—Ac
1

¹H NMR 1.30 (3H, t, J = 7.1 Hz), 2.02

(3H, s), 4.23 (2H, q, J = 7.1 Hz), 4.38

(2H, s), 7.16-7.33 (4H, m), 8.54

(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.01

(1H, dd, J = 2.8 Hz, 0.5 Hz).

155
—F
—H
1

¹H NMR 1.32 (3H, t, J = 7.1 Hz),

3.89 (2H, d, J = 5.3 Hz), 4.28 (2H,

q, J = 7.1 Hz), 4.35-4.55 (1H, m),

6.31-6.50 (2H, m), 6.91-7.11 (2H,

m), 8.47 (1H, dd, J = 9.1 Hz, 2.8 Hz),

9.02 (1H, dd, J = 2.8 Hz, 0.4 Hz).

156
—CF₃
—CH₃
1
MS 399 (M⁺)

157
—CF₃
—C₂H₅
1
MS 413 (M⁺)

TABLE 22

Reference

Example

No.
R₁₅₅
R₁₅₆
R₁₅₇
R₁₅₈
R₁₅₉
M

¹H NMR or MS

158
—H
—H
—H
—CH₃
—CH₃
1

¹H NMR (CDCl₃) δ 3.10 (3H, s), 3.74 (3H, s), 4.09 (2H, s), 6.72 (2H, d, J = 9.1 Hz), 6.96 (1H, d, J = 9.0 Hz), 7.03 (2H, d, J = 9.1 Hz), 8.43 (1H, dd, J = 9.0 Hz, 2.9 Hz), 9.06 (1H, d, J = 2.9 Hz).

159
—H
—H
—H
—Ac
—C₂H₅
1

¹H NMR (DMSO-d₆) δ 1.20 (3H, t, J = 7.1 Hz), 1.87 (3H, s), 4.12 (2H, q, J = 7.1 Hz), 4.37 (2H, s), 7.28- 7.35 (3H, m), 7.48 (2H, d, J = 8.7 Hz), 8.65 (1H, dd, J = 2.9 Hz, 9.1 Hz), 9.05 (1H, d, J = 2.9 Hz).

160
—H
—H
—H
—CH₃
—CH₃
2

¹H NMR (CDCl₃) δ 2.59-2.64 (2H, m), 2.96 (3H, s), 3.67-3.72 (5H, m), 6.76 (2H, d, J = 9.1 Hz), 6.97 (1H, d, J = 9.1 Hz), 7.05 (2H, d, J = 8.9 Hz), 8.43 (1H, dd, J = 9.1 Hz, 3.0 Hz), 9.06 (1H, d, J = 2.8 Hz).

161
—F
—H
—F
—H
—C₂H₅
1

¹H NMR (CDCl₃) δ 1.32 (3H, t, J = 7.1 Hz), 3.91 (2H, d, J = 5.5 Hz), 4.28 (2H, q, J = 7.1 Hz), 4.57- 4.71 (1H, m), 6.43 (1H, dd, J = 7.9 Hz, 11.6 Hz), 6.94 (1H, dd, J = 7.0 Hz, 11.0 Hz), 7.08 (1H, d, J = 9.0 Hz), 8.49 (1H, dd, J = 2.8 Hz, 9.0 Hz), 9.01 (1H, d, J = 2.8 Hz).

162
—F
—F
—H
—CH₃
—(CH₃)₃
0

¹H NMR (CDCl₃) δ 1.51 (9H, s), 3.30 (3H, s), 6.95-7.10 (2H, m), 7.21 (1H, d, J = 9.1 Hz), 8.54 (1H, dd, J = 2.8 Hz, 9.1 Hz), 9.00 (1H, d, J = 2.8 Hz).

163
—CH₃
—H
—CH₃
—C₂H₅
—C₂H₅
1

¹H NMR (CDCl₃) δ 1.08 (3H, t, J = 7.1 Hz), 1.24 (3H, t, J = 7.1 Hz), 2.07 (3H, s), 2.28 (3H, s), 3.21 (2H, q, J = 7.1 Hz), 3.78 (2H, s), 4.15 (2H, q, J = 7.1 Hz), 6.86 (1H, s), 6.95 (1H, d, J = 9.1 Hz), 7.07 (1H, s), 8.45 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.06 (1H, d, J = 2.8 Hz).

164
—COOCH₃
—H
—H
—C₂H₅
—(CH₃)₃
1
MS 431(M⁺)

165
—CH₃
—H
—CH₃
—CH₃
—C₂H₅
1

¹H NMR (CDCl₃) δ 1.27 (3H, t, J = 7.1 Hz), 2.08 (3H, s), 2.28 (3H, s), 2.89 (3H, s), 3.73 (2H, s), 4.19 (2H, q, J = 7.1 Hz), 6.85 (1H, s), 6.96 (1H, d, J = 9.1 Hz), 7.01 (1H, s), 8.45 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.06 (1H, d, J = 2.8 Hz).

166
—CN
—H
—H
—CH₃
—(CH₃)₃
1
MS 384(M⁺)

167
—H
—H
—CF₃
—C₂H₅
—C₂H₅
1
MS 413(M⁺)

TABLE 23

Reference

Example

No.
R₁₆₀
R₁₆₁

¹H NMR (CDCl₃) δppm

168
—H

embedded image

1.27 (3H, t, J = 7.0 Hz), 1.41-1.48 (2H, m), 1.85 (2H, brd, J = 13.0 Hz), 1.95 (1H, m), 2.29 (2H, d, J = 7.0 Hz), 2.76 (2H, dt, J = 2.5 Hz, 12.0 Hz), 3.65 (2H, brd, J = 12.0 Hz), 4.16 (2H, q, J = 7.0 Hz), 6.96- 6.99 (3H, m), 7.03 (2H, d, J = 9.0 Hz), 8.44 (1H, dd, J = 9.0 Hz, 3.0 Hz), 9.05 (1H, d, J = 3.0 Hz).

169
—H
morpholino
3.18-3.19 (4H, m), 3.86-3.89 (4H, m), 6.94-7.01 (3H, m), 7.05-7.11 (2H, m), 8.45 (1H, dd, J = 9.2 Hz, 3.0 Hz), 9.05 (1H, d, J = 3.0 Hz).

170
—H

embedded image

2.47-2.62 (4H, m), 2.96-3.14 (4H, m), 3.49 (2H, s), 7.11 (1H, d, J = 9.0 Hz), 7.19-7.37 (7H, m), 7.81 (2H, d, J = 8.7 Hz), 8.52 (1H, dd, J = 9.0 Hz, 2.0 Hz), 9.02 (1H. d, J = 2.0 Hz).

171
—H

embedded image

1.28 (3H, t, J = 7.0 Hz), 1.90 (2H, dq, J = 4.0 Hz, 11.5 Hz), 2.04 (2H, brd, J = 13.0 Hz), 2.43 (1H, m), 2.82 (2H, dt, J = 3.0 Hz, 12.0 Hz), 3.63 (2H, dt, J = 13.0 Hz, 3.0 Hz), 4.17 (2H, q, J = 7.0 Hz), 6.97- 6.99 (3H, m), 7.04 (2H, d, J = 9.0 Hz), 8.44 (1H, dd, J = 9.0 Hz, 3.0 Hz), 9.05 (1H, d, J = 3.0 Hz).

172
—H

embedded image

1.28 (3H, t, J = 7.0 Hz); 1.70 (2H, m), 1.84 (1H, m), 2.04 (1H, m), 2.69 (1H, m), 2.86 (1H, m), 3.08 (1H, dd, J = 12.0 Hz, 10.0 Hz), 3.46 (1H, brd, J = 12.0 Hz), 3.69 (1H, dd, J = 12.0 Hz, 4.0 Hz), 4,18 (2H, q, J = 7.0 Hz), 6.97-7.05 (5H, m), 8.45 (1H, dd, J = 9.0 Hz, 3.0 Hz), 9.06 (1H, d, J = 3.0 Hz).

173
—COOCH₃

embedded image

2.61-2.64 (4H, m), 3.24-3.28 (4H, m), 3.58 (2H, s). 3.68 (3H, s), 7.03-7.16 (3H, m), 7.26-7.36 (5H, m), 7.54 (1H, d, J = 2.8 Hz), 8.46 (1H, dd, J = 9.1 Hz, 2.8 Hz), 8.97 (1H, d, J = 2.8 Hz).

174
—H

embedded image

2.43 (4H, t, J = 5.1 Hz), 3.40 (4H, t, J = 5.1 Hz), 3.43 (2H, s), 4.46 (2H, t, J = 5.5 Hz), 4.79 (1H, t, J = 5.5 Hz), 5.95 (2H, s), 6.74 (2H, s), 6.85 (1H, s), 7.05 (1H, d, J = 9.1 Hz), 7.12 (2H, d, J = 8.4 Hz), 7.40 (2H, d, J = 8.4 Hz), 8.48 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.03 (1H, d, J = 2.8 Hz).

175
—CH₃
—NHCOCOOC₂H₅
1.33 (3H, t, J = 7.1 Hz), 2.07 (3H, s), 4.32 (2H, q, J = 7.1 Hz), 7.15 (1H, d, J = 8.7 Hz), 7.27 (1H, dd, J = 9.2 Hz, 0.5 Hz), 7.63 (1H, dd, J = 8.6 Hz, 2.5 Hz), 7.71 (1H, d, J = 2.5 Hz), 8.62 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.01 (1H, dd, J = 2.8 Hz, 0.5 Hz), 10.82 (1H, brs).

TABLE 24

Reference

Example

No.
R₁₆₂
R₁₆₃

¹H NMR (solvent) δppm

176
—H
—Ac
(CDCl₃) 2.60 (3H, s), 7.10-9.00 (7H, m).

177
—H
—CHO
(CDCl₃) 7.14 (1H, d, J = 9.0 Hz), 7.35 (2H, d, J = 8.7 Hz), 8.00 (2H, d, J = 8.7 Hz), 8.54 (1H, dd, J = 9.0 Hz, 1.8 Hz), 9.04 (1H, d, J = 1.8 Hz), 10.03 (1H, s).

178
—H
—C₂H₅
(CDCl₃) 1.28 (3H, t, J = 7.6 Hz), 2.70 (2H, q, J = 7.6 Hz), 7.01 (1H, dd, J = 9.1 Hz, 0.7 Hz), 7.07 (2H, d, J = 8.7 Hz), 7.28 (2H, d, J = 8.7 Hz), 8.46 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05 (1H, dd, J = 2.8 Hz, 0.7 Hz).

179
—CH₃
—CHO
(CDCl₃) 2.25 (3H, s), 7.14 (1H, d, J = 8.9 Hz), 7.24 (1H, d, J = 8.2 Hz), 7.81 (1H, dd, J = 8.2 Hz, 2.0 Hz), 7.85 (1H, s), 8.53 (1H, dd, J = 8.9 Hz, 2.6 Hz), 9.00 (1H, d, J = 2.6 Hz), 10.00 (1H, s).

180
—H

embedded image

(CDCl₃) 1.70-1.93 (4H, m), 2.45-2.56 (2H, m), 3.22-3.36 (2H, m), 4.62 (2H, s), 7.03 (1H, d, J = 9.2 Hz), 7.12 (2H d, J = 8.6 Hz), 7.35 (2H, d, J = 8.6 Hz), 8.47 (1H, dd, J = 9.2 Hz, 2.6 Hz), 9.04 (1H, d, J = 2.6 Hz).

181
—H

embedded image

(CDCl₃) 2.46-2.47 (4H, m), 2.77-2.99 (2H, m), 3.46 (2H, s), 3.51-3.57 (4H, m), 3.64- 3.73 (1H, m), 3.90-3.96 (1H, m), 4.30- 4.36 (1H, m), 5.96 (2H, s), 6.75-6.86 (3H, m), 7.04 (1H, d, J = 9.1 Hz), 7.17 (2H, d, J = 9.1 Hz), 7.70 (2H, d, J = 8.9 Hz), 8.48 (1H, dd, J = 2.8 Hz, 9.1 Hz), 9.03 (1H, d, J = 2.8 Hz).

182
—H

embedded image

(CDCl₃) 1.51 (9H, s), 3.80 (4H, m), 4.27 (2H, s), 7.07 (1H, d, J = 9.1 Hz), 7.21 (2H, dd, J = 6.8 Hz, 2.1 Hz), 7.38 (2H, dd, J = 6.8 Hz, 2.1 Hz), 8.49 (1H, dd, J = 9.1 Hz, 2.8 Hz). 9.04 (1H, d, J = 2.8 Hz).

183
—H

embedded image

(CDCl₃) 3.35-3.55 (4H, m), 3.96 (2H, s), 4.58 (2H, s), 5.96 (2H, s), 6.73-6.78 (2H, m), 6.81 (1H, s), 6.91 (2H, d, J = 9.1 Hz), 7.00 (1H, d, J = 9.1 Hz), 7.09 (2H, d, J = 9.1 Hz), 8.45 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04 (1H, d, J = 2.8 Hz).

184
—H
—NHCONHPh
(DMSO-d₆) 6.96 (1H, t, J = 6.5 Hz), 7.14 (2H, d, J = 8.8 Hz), 7.21 (1H, d, J = 9.1 Hz), 7.27 (2H, t, J = 8.3 Hz), 7.45 (2H, d, J = 8.3 Hz), 7.52 (2H, d, J = 8.8 Hz), 8.60 (1H, dd, J = 2.8 Hz, 9.1 Hz), 8.70 (1H, s), 8.77 (1H, s), 9.02 (1H, d, J = 2.8 Hz).

TABLE 25

Reference

Example

No.
R₁₆₄
R₁₆₅
R₁₆₆
M
mp (° C.) or ¹H NMR (solvent) δppm

185
—NO₂
—CH₃
piperonyl
2
mp 142.0-143.0

186
—NO₂
—H
benzyl
1

¹H NMR (DMSO-d₆) 3.36 (2H, t, J = 8.1 Hz), 3.84 (2H, t, J = 8.1 Hz), 4.40 (2H, s), 7.15- 7.25 (3H, m), 7.26-7.34 (3H, m), 7.35- 7.41 (2H, m), 7.61-7.71 (2H, m), 8.59 (1H, dd, J = 2.9 Hz, 9.1 Hz), 9.02 (1H, d, J = 9.1 Hz).

187
—NO₂
—CH₃
piperonyl
1

¹H NMR (DMSO-d₆) 2.05 (3H, s), 3.29- 3.41 (2H, m), 3.71-3.88 (2H, m), 4.29 (2H, s), 5.60 (2H, s), 6.74-6.81 (1H, m), 6.82-6.92 (2H, m), 7.09 (1H, d, J = 8.8 Hz), 7.21 (1H, d, J = 9.1 Hz), 7.49 (1H, d, J = 2.6 Hz, 8.8 Hz), 7.51-7.57 (1H, m), 8.60 (1H, d, J = 9.1 Hz), 9.00 (1H, d. J = 2.9 Hz).

188
—NO₂
—CH₃
3,4- (CH₃O)₂PhCH₂—
2

¹H NMR (CDCl₃) 2.00-2.15 (2H, m), 2.14 (3H, s), 3.31 (2H, t, J = 6.0 Hz), 3.73 (2H, d, J = 6.0 Hz), 3.88 (3H, s), 3.89 (3H, s), 4.57 (2H, s), 6.83 (1H, d, J = 8.1 Hz), 6.87 (1H, dd, J = 1.9 Hz, 8.1 Hz), 6.91 (1H, d, J = 1.9 Hz), 698-7.06 (2H, m), 7.20 (1H, dd, J = 2.4 Hz, 8.6 Hz), 7.29 (1H, d, J = 2.4 Hz), 8.46 (1H, dd, J = 2.8 Hz, 9.1 Hz), 9.04 (1H, d, J = 2.8 Hz).

189
—NO₂
—CH₃
—CH₂COOC(CH₃)₃
2

¹H NMR (CDCl₃) 1.48 (9H, s), 2.12 (3H, s), 2.12-2.24 (2H, m), 3.48 (2H, t, J = 5.9 Hz), 3.77 (2H, t, J = 5.9 Hz), 4.05 (2H, s), 6.92- 7.06 (2H, m), 7.17 (1H, dd, J = 2.6 Hz, 8.6 Hz), 8.45 (1H, dd, J = 2.9 Hz, 9.1 Hz), 9.04 (1H, d, J = 2.9 Hz).

190
—Br
—CH₃
piperonyl
2

¹H NMR (CDCl₃) 1.94-2.18 (2H, m), 2.15 (3H, s), 3.30 (2H, d, J = 6.0 Hz), 3.71 (2H, d, J = 6.0 Hz), 4.52 (2H, s), 5.95 (2H, s), 6.69-6.82 (3H, m), 6.88 (1H, s), 7.00 (1H, d, J = 8.6 Hz), 7.15 (1H, dd, J = 2.6 Hz, 8.6 Hz), 7.24 (1H, d, J = 2.6 Hz), 7.73 (1H, dd, J = 2.5 Hz, 8.6 Hz), 8.20 (1H, d, J = 2.5 Hz).

191
—Br
—CH₃
3,4- (CH₃O)₂PhCH₂—
2

¹H NMR (CDCl₃) 1.95-2.11 (2H, m), 2.14 (3H, s), 3.30 (2H, t, J = 5.9 Hz), 3.70 (2H, t, J = 5.9 Hz), 3.88 (3H, s), 3.88 (3H, s), 4.56 (2H, s), 6.74-6.92 (4H, s), 7.00 (1H, d, J = 8.5 Hz), 7.15 (1H, dd, J = 2.4 Hz, 8.5 Hz), 7.24 (1H, d, J = 2.4 Hz), 7.73 (1H, dd, J = 2.6 Hz, 8.8 Hz), 8.19 (1H, dd, J = 0.5 Hz, 2.6 Hz).

TABLE 26

Reference

Example

No.
R₁₆₇

¹H NMR (CDCl₃) δppm or MS

192

embedded image

¹H NMR 1.24 (3H, t, J = 7.1 Hz), 3.07 (3H, s), 4.05 (2H, s), 4.18 (2H, q, J = 7.1 Hz), 6.44-6.45 (1H, m), 6.49-6.53 (1H, m), 6.57-6.61 (1H, m), 6.97 (1H, d, J = 9.1 Hz), 7.25-7.31 (1H, m), 8.44 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.07 (1H, d, J = 2.8 Hz).

193

embedded image

¹H NMR 3.93 (3H, s), 7.08-7.11 (1H, m), 7.26-7.40 (1H, m), 7.51-7.57 (1H, m), 7.83-7.84 (1H, m), 7.96-8.00 (1H, m), 8.49-8.53 (1H, m), 9.02-9.03 (1H, m).

194

embedded image

MS 488(M⁺)

195

embedded image

¹H NMR 4.00 (3H, s), 7.14 (1H, d, J = 8.9 Hz), 7.37 (1H, dd, J = 8.9 Hz, 2.3 Hz), 7.67 (1H, d, J = 2.3 Hz), 7.87 (1H. d, J = 8.6 Hz), 8.04 (1H, d, J = 8.9 Hz), 8.11 (1H, dd, J = 8.6 Hz, 1.7 Hz), 8.51- 8.55 (1H, m), 8.64 (1H, brs), 9.05 (1H, d, J = 2.8 Hz).

196

embedded image

¹H NMR 4.03 (3H, s), 7.20 (1H, d, J = 9.1 Hz), 7.31 (1H, d, J = 8.1 Hz), 7.51- 7.57 (1H, m), 7.65-7.71 (1H, m), 7.94 (1H, d, J = 8.4 Hz), 8.29 (1H, d, J = 8.1 Hz), 8.55 (1H, dd, J = 9.1 Hz, 2.8 Hz), 8.99 (1H, d, J = 2.8 Hz), 9.05 (1H, d, J = 8.7 Hz).

197

embedded image

¹H NMR 1.47 (3H, t, J = 7.1 Hz), 4.49 (2H, t, J = 7.1 Hz), 7.11 (1H, d, J = 8.9 Hz), 7.42 (1H, dd, J = 9.4 Hz, 2.5 Hz), 7.52-7.58 (1H, m), 7.67 (1H, d, J = 2.5 Hz), 7.99 (1H, d, J = 8.2 Hz), 8.21 (1H, dd, J = 7.3 Hz, 1.2 Hz), 8.51 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04-9.08 (2H, m).

198

embedded image

¹H NMR (CDCl₃) 2.11 (3H, s), 2.19 (2H, t, J = 5.9 Hz), 2.34-2.50 (4H, m), 3.42 (2H, s), 3.40-3.47 (2H, m), 3.51(2H, t, J = 5.9 Hz), 3.56-3.76 (2H, m), 3.78 (2H, t, J = 5.7 Hz), 4.20 (2H, s), 5.94 (2H, s), 6.69-6.77 (2H, m), 6.84 (1H, d, J = 1.0 Hz), 6.96-7.02 (2H, m), 7.17 (1H, dd, J = 2.6 Hz, 8.5 Hz), 7.24- 7.28 (1H, m), 8.45 (1H, dd, J = 2.8 Hz, 9.1 Hz), 9.04 (1H, d, J = 2.8 Hz).

TABLE 27

Reference

Example

No.
R₁₆₈
R₁₆₉
M

¹H NMR (solvent) δppm

199
—H
benzyl
2
(CDCl₃) 2.36-2.45 (4H, m), 2.63-2.68 (2H, m), 2.99- 3.05 (2H, m), 3.41-3.45 (2H, m), 3.52 (2H, s), 3.64- 3.67 (2H, m), 7.01-7.11 (3H, m), 7.29-7.34 (7H, m), 8.47 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05 (1H, d, J = 2.8 Hz).

200
—H
piperonyl
2
(CDCl₃) 2.33-2.41 (4H, m), 2.62-2.67 (2H, m), 2.98- 3.04 (2H, m), 3.39-3.43 (4H, m), 3.62-3.65 (2H, m), 5.94 (2H, s), 6.73-6.77 (2H, m), 6.84 (1H, s), 7.00- 7.10 (3H, m), 7.26-7.31 (2H, m), 8.44-8.48 (1H, m), 9.03 (1H, dd, J = 3.0 Hz, 0.5 Hz).

201
—F
benzyl
0
(CDCl₃) 2.49 (4H, brs), 3.49-3.56 (4H, m), 3.79 (2H, brs), 7.15 (1H, d, J = 8.9 Hz), 7.24-7.38 (3H, m), 8.53 (1H, dd, J = 9.1 Hz, 2.8 Hz), 8.99 (1H, d, J = 2.8 Hz).

202
—H
benzyl
0
(DMSO-d₆) 2.41 (4H, brs), 3.33 (2H, brs), 3.52 (4H, brs), 7.24-7.27 (8H, m), 7.50 (2H, d, J = 7.9 Hz), 8.64 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04 (1H, d, J = 2.8 Hz).

203
—H
4-CH₃OPhCH₂—
0
(CDCl₃) 2.46 (4H, brs), 3.44-3.90 (4H, m), 3.49 (2H, s), 3.81 (3H. s), 6.85-6.89 (2H, m), 7.06 (1H, d. J = 8.9 Hz), 7.18-7.27 (4H, m), 7.48-7.53 (2H, m), 8.48- 8.52 (1H, m), 9.03 (1H, d, J = 2.8 Hz).

204
—H
piperonyl
0
(CDCl₃) 2.46 (4H, brs), 3.46 (2H, s), 3.52 (2H, brs), 3.77 (2H, brs), 5.95 (2H, s), 6.75 (2H, s), 6.86 (1H, s), 7.07 (1H, dd, J = 9.1 Hz, 0.5 Hz), 7.20 (2H, d, J = 8.6 Hz), 7.51 (2H, d, J = 8.6 Hz), 8.50 (1H, dd, J = 8.9 Hz, 2.8 Hz), 9.03 (1H, dd, J = 2.8 Hz, 0.5 Hz).

205
—H
3-pyridyl
0
(CDCl₃) 3.27 (4H, brs), 3.84 (4H, brs), 7.08-7.12 (1H, m), 7.21-7.27 (4H, m), 7.54-7.59 (2H, m), 8.16- 8.18 (1H, m), 8.34 (1H, brs), 8.52 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05 (1H, dd, J = 2.8 Hz, 0.5 Hz).

TABLE 28

Reference

Example

No.
Xa₅
R₁₇₀
M

¹H NMR (CDC1₃) δppm

206
—O—
piperonyl
1
2.43 (4H, brs), 3.42 (2H, s), 3.58 (2H, t, J = 5.0 Hz), 3.64 (2H, t, J = 5.0 Hz), 4.70 (2H, s), 5.95 (2H, s), 6.70-6.79 (2H, m), 6.84 (1H, d, J = 0.6 Hz), 7.01 (3H, d, J = 9.1 Hz), 7.09 (2H, d, J = 9.1 Hz), 8.46 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04 (1H, d, J = 2.8 Hz).

207
—CH(OH)—
benzyl
0
1.90-2.05 (1H, m), 2.21-2.68 (3H, m), 3.11- 3.25 (1H, m), 3.28-3.40 (1H, m), 3.45 (2H, s), 3.73 (2H, t, J = 5.1 Hz), 4.77 (1H, d, J = 6.3 Hz), 5.24 (1H, d, J = 6.3 Hz), 7.04 (1H, d, J = 8.9 Hz), 7.16 (2H, d, J = 8.7 Hz), 7.21-7.35 (5H, m), 7.38 (2H, d, J = 8.7 Hz), 8.48 (1H, dd, J = 8.9 Hz, 2.8 Hz), 9.03 (1H, d, J = 2.8 Hz).

208

embedded image

piperonyl
1
0.65-0.70 (2H, m), 0.81-0.88 (2H, m), 2.41- 2.48 (4H, m), 2.77-2.85 (1H, m), 3.45 (2H, s), 3.49-3.52 (2H, m), 3.60-3.63 (2H, m), 4.20 (2H, s), 5.95 (2H, s), 6.71-6.78 (2H, m), 6.86 (1H, brs), 6.90-7.02 (5H, m), 8.39-8.44 (1H, m), 9.06 (1H, d, J = 2.8 Hz).

209
—O—
benzyl
1
2.45 (4H, t, J = 4.5 Hz), 3.52 (2H, s), 3.59 (2H, t, J = 4.9 Hz), 3.65 (2H, t, J = 4.9 Hz), 4.70 (2H, s), 7.00 (2H, d, J = 9.2 Hz), 7.01 (1H, d, J = 9.0 Hz), 7.08 (2H, d, J = 9.2 Hz), 7.21-7.40 (5H, m), 8.46 (1H, dd, J = 9.0 Hz, 2.8 Hz), 9.04 (1H, d, J = 2.8 Hz).

210
—N(CH₃)—
benzyl
0
2.32 (4H, brs), 3.24 (3H, s), 3.28 (4H, brs), 3.48 (2H, brs), 7.04 (1H, d, J = 9.1 Hz), 7.11 (2H, d, J = 9.0 Hz), 7.15 (2H, d, J = 9.0 Hz), 7.22- 7.40 (5H, m), 8.48 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04 (1H, d, J = 2.8 Hz).

TABLE 29

Reference

Example

¹H NMR (CDCl₃)

No.
R₁₇₁
R₁₇₂
Xa₆
R₁₇₃
R₁₇₄
R₁₇₅
δppm or MS

211
—NO₂
—H
—N(CH₃)—
—CH₃
—H
—C₂H₅

¹H NMR 1.25 (3H, t, J = 7.1 Hz), 1.50 (3H, d, J = 7.1 Hz), 2.93 (3H, s), 4.18 (2H, q, J = 7.1 Hz), 4.48 (1H, q, J = 7.3 Hz), 6.82 (2H, d, J = 9.2 Hz), 6.97 (1H, d, J = 9.1 Hz), 7.03 (2H, d, J = 9.0 Hz), 8.43 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.06 (1H, d, J = 2.8 Hz).

212
—NO₂
—H
—N(CH₃)—
—CH₃
—CH₃
—C₂H₅

¹H NMR 1.24 (3H, t, J = 7.1 Hz), 1.46 (6H, s), 2.94 (3H, s), 4.18 (2H. q, J = 7.1 Hz), 6.97 (1H, dd, J = 9.1 Hz, 0.5 Hz), 7.00- 7.08 (4H, m), 8.45 (1H, dd, J = 9.1 Hz, 3.0 Hz). 9.05 (1H, dd, J = 2.8 Hz, 0.5 Hz).

213
—NO₂
—CH₃
—N(CH₃)—
—CH₃
—H
—C₂H₅

¹H NMR 1.26 (3H, t, J = 7.1 Hz), 1.49 (3H, d, J = 7.3 Hz), 2.10 (3H, s), 2.91 (3H, s), 4.13- 4.24 (2H, m), 4.48 (1H, q, J = 7.3 Hz), 6.64- 6.68 (2H, m), 6.91- 6.96 (2H, m), 8.43 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.06 (1H, dd, J = 2.8 Hz, 0.5 Hz),

214
—NO₂
—H
none
—CH₃
—CH₃
—CH₃
MS 316(M⁺)

215
—Br
—OCH₃
—CH₂—
—H
—H
—C₂H₅

¹H NMR 1.26 (3H, t, J = 7.1 Hz), 2.63-2.68 (2H, m), 2.94- 3.00 (2H, m), 3.75 (3H, s), 4.15 (2H, q, J = 7.1 Hz), 6.80-6.86 (3H, m), 7.03 (1H, d, J = 7.9 Hz), 7.73 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.16 (1H, dd, J = 2.6 Hz, 0.7 Hz).

216
3,4-Cl₂PhCH₂NHCO—
—H
—CH₂—
—H
—H
—C₂H₅
MS 472(M⁺)

217
4-CF₃PhCH₂NHCO—
—H
—CH₂—
—H
—H
—C₂H₅
MS 472(M⁺)

TABLE 30

Reference

Example

No.
R₁₇₆
R₁₇₇

¹H NMR (CDCl3) δppm or MS

218
4-CF₃PhCO—

embedded image

¹H NMR 1.26 (3H, t, J = 7.1 Hz), 2.64-2.69 (2H, m), 2.95-3.01 (2H, m), 3.76 (3H, s), 4.15 (2H, q, J = 7.1 Hz), 6.83-6.89 (2H, m), 7.03- 7.10 (2H, m), 7.73-7.76 (2H, m), 7.86-7.89 (2H, m), 8.21 (1H, dd, J = 8.6 Hz, 2.5 Hz), 8.55(1H, dd, J = 2.5 Hz, 0.7 Hz).

219
3,4-Cl₂PhNHCO—

embedded image

¹H NMR 1.20 (3H, t, J = 7.1 Hz), 3.44 (2H, q, J = 7.1 Hz), 3.56 (3H, s), 4.04 (2H, s), 5.17 (2H, s), 6.15- 6.18 (2H, m), 6.83 (1H, d, J = 8.7 Hz), 6.88 (1H, d, J = 8.9 Hz), 7.29-7.35 (6H, m), 7.44 (1H, dd, J = 8.7 Hz, 2.5 Hz), 7.82 (1H, d, J = 2.3 Hz), 3.10 (1H, dd, J = 8.7 Hz, 2.5 Hz), 8.59 (1H, d, J = 2.5 Hz), 8.72 (1H, brs).

220
3,4-Cl₂PhNHCO—

embedded image

MS 501(M⁺)

221
4-CF₃PhNHCO—

embedded image

MS 501(M⁺)

222
—COOC₂H₅
4-NO₂Ph—

¹H NMR 1.40 (3H, t, J = 7.1 Hz), 4.40 (2H, q, J = 7.1 Hz), 7.08 (1H, d, J = 8.6 Hz), 7.32 (2H, d, J = 9.0 Hz), 8.31 (2H, d, J = 9.0 Hz), 8.37 (1H, dd, J = 8.6 Hz, 2.3 Hz), 8.82 (1H, d, J = 2.3 Hz).

223
4-CF₃PhNHCO—
4-CHOPh—
MS 386(M⁺)

224
—COOC₂H₅

embedded image

¹H NMR 1.39 (3H, t, J = 7.1 Hz), 2.28 (3H, s), 4.39 (2H, q, J = 7.1 Hz), 7.07 (1H, dd, J = 8.6 Hz, 0.5 Hz), 7.21 (1H, d, J = 8.9 Hz), 8.13 (1H, dd, J = 8.9 Hz, 2.8 Hz), 8.20 (1H, d, J = 2.8 Hz), 8.36 (1H, dd, J = 8.6 Hz, 2.3 Hz), 8.78 (1H, dd, J = 2.8 Hz, 0.6 Hz).

(CHOPh means a formylphenyl group. Hereinafter CHOPh indicates the same meaning.)

TABLE 31

Reference

Example

mp (° C.) or ¹H NMR

No.
R₁₇₈
R₁₇₉
R₁₈₀
Form
(solvent) δppm

225
4-CF₃PhNHCO—
—CH₃
—NHCOCOOC₂H₅
free

¹H NMR (DMSO-d₆) 1.33 (3H, t, J = 7.1 Hz), 2.08 (3H, s), 4.33 (2H, q, J = 7.1 Hz), 7.12 (1H, d, J = 8.7 Hz), 7.17 (1H, d, J = 8.6 Hz), 7.63 (1H, dd, J = 8.7 Hz, 2.5 Hz), 7.72- 7.75 (3H, m), 7.98 (2H, d, J = 8.7 Hz), 8.37 (1H, dd, J = 8.6 Hz, 2.5 Hz), 8.69 (1H, d, J = 2.5 Hz), 10.62 (1H, brs), 10.81 (1H, brs).

226
3,4-Cl₂PhNHCO—
—CH₃

embedded image

hydro- bromide
mp 132.0-134.0

227
—NO₂
—CH₃

embedded image

free

¹H NMR (CDCl₃) 1.28 (3H, t, J = 7.1 Hz), 1.86-1.95 (2H, m), 2.02- 2.06 (2H, m), 2.10 (3H, s), 2.40-2.48 (1H, m), 2.76- 2.85 (2H, m), 3.61- 3.65 (2H, m), 4.17 (2H, q, J = 7.1 Hz), 6.79-6.97 (4H, m), 8.43 (1H, dd, J = 9.1 Hz, 3.0 Hz), 9.04 (1H, d, J = 2.8 Hz).

228
—NO₂
—OCH₃

embedded image

free

¹H NMR (CDCl₃) 1.28 (3H, t, J = 7.1 Hz), 1.41-1.50 (2H, m), 1.84- 2.04 (3H, m), 2.30 (2H, d, J = 6.9 Hz), 2.78 (2H, dd, J = 12.0 Hz, 9.7 Hz), 3.65 (2H, d, J = 12.4 Hz), 3.73 (3H, s), 4.16 (2H, q, J = 7.3 Hz), 6.53 (1H, dd, J = 8.7 Hz, 2.6 Hz), 6.59 (1H, d, J = 2.6 Hz), 6.96- 7.02 (2H, m), 8.42 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.03 (1H, d, J = 2.8 Hz).

229
—NO₂
—CH₃

embedded image

free

¹H NMR (CDCl₃) 1.27 (3H, t, J = 7.1 Hz), 1.37-1.49 (2H, m), 1.83- 2.03 (3H, m), 2.10 (3H, s), 2.29 (2H, d, J = 6.9 Hz), 2.74 (2H, dd, J = 12.2 Hz, 10.1 Hz), 3.64 (2H, d, J = 12.4 Hz), 4.15 (2H, q, J = 7.3 Hz), 6.77-6.83 (2H, m), 6.91-6.97 (2H, m), 8.42 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.02 (1H, d. J = 2.8 Hz).

TABLE 32

Reference

Example

¹H NMR (CDCl₃)

No.
R₁₈₁
R₁₈₂
R₁₈₃
R₁₈₄
R₁₈₅
δppm or MS

230
—Br
—CH₃
—H
—H

embedded image

¹H NMR 2.09 (3H, s), 2.41-2.45 (4H, m), 3.01 (3H, s), 3.43 (2H, s), 3.49 (2H, brs), 3.63 (2H, brs), 4.07 (2H, brs), 5.93 (2H, s), 6.51-6.56 (2H, m), 6.68-6.77 (3H, m), 6.85-6.91 (2H, m), 7.68 (1H, dd, J = 8.7 Hz, 2.5 Hz), 8.19 (1H, d, J = 2.5 Hz).

231
3,4-Cl₂PhNHCO—
—H
—CF₃
—H
—N(CH₃)CH₂COOC₂H₅
MS 541(M⁺)

232
4-CF₃PhNHCO—
—H
—CF₃
—H
—N(CH₃)CH₂COOC₂H₅
MS 541(M⁺)

233
3,4- Cl₂PhCH₂NHCO—
—H
—CF₃
—H
—N(CH₃)CH₂COOC₂H₅
MS 555(M⁺)

234
4-CF₃CH₂NHCO—
—H
—CF₃
—H
—N(CH₃)CH₂COOC₂H₅
MS 555(M⁺)

235
—Br
—F
—H
—F
—N(CH₃)CH₂COOC₂H₅

¹H NMR 1.26 (3H, t, J = 7.1 Hz), 2.99 (3H, s), 4.03 (2H, s), 4.18 (2H, q J = 7.1 Hz), 6.76 (1H, d, J = 8.2 Hz, 12.1 Hz), 6.84- 6.95 (2H, m), 7.77 (1H, dd, J = 2.6 Hz, 8.7 Hz), 8.17 (1H, d, J = 2.6 Hz).

TABLE 33

Reference

Example

No.
R₁₈₆
Xa₇
R₁₈₇
M

¹H NMR (solvent) δppm

236
—COOC₂H₅
—CH₂—
piperonyl
1
(DMSO-d₆) 1.31 (3H, t, J = 7.0 Hz), 2.28 (1H, brs), 2.60-2.66 (2H, m), 2.80- 2.86 (2H, m), 3.38 (2H, s), 3.40- 3.46 (4H, m), 4.31 (2H, q, J = 7.0 Hz), 5.98 (2H, s), 6.72-6.76 (1H, m), 6.84 (2H, d, J = 8.4 Hz), 7.06-7.11 (3H, m), 7.30 (2H, d, J = 8.4 Hz), 8.30 (1H, dd, J = 8.6 Hz, 2.4 Hz), 8.68 (1H, d, J = 2.4 Hz).

237
—COOC₂H₅
none
benzyl
0
(CDCl₃) 1.39 (3H, t, J = 7.3 Hz), 2.48 (4H, brs), 3.55-3.91 (6H, m), 4.38 (2H, q, J = 7.3 Hz), 6.97 (1H, d, J = 8.6 Hz), 7.17-7.19 (2H, m), 7.20- 7.34 (5H, m), 7.46-7.49 (2H, m), 8.31 (1H, dd, J = 8.6 Hz, 2.4 Hz), 8.82 (1H,d, J = 2.4 Hz).

238
—Br
—N(CH₃)—
piperonyl
1
(CDCl₃) 2.41-2.45 (4H, m), 3.03 (3H, s), 3.43 (2H, s), 3.47-3.51 (2H, m), 3.61- 3.65 (2H, m), 4.09 (2H, s), 5.95 (2H, s), 6.68-6.85 (6H, m), 6.96-7.02 (2H, m), 7.70 (1H, dd, J = 8.7 Hz, 2.5 Hz), 8.20 (1H, d, J = 2.5 Hz).

239
—Br
—CH₂—
piperonyl
1
(CDCl₃) 2.31-2.41 (4H, m), 2.59- 2.65 (2H, m), 2.95-3.00 (2H, m), 3.38- 3.42 (4H, m), 3.61-3.65 (2H, m), 5.95 (2H, s), 6.70-6.77 (2H, m), 6.81- 6.84 (2H, m), 7.01-7.06 (2H, m), 7.22- 7.27 (2H, m), 7.76 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.20-8.21 (1H, m).

240
—Br
none
benzyl
0
(CDCl₃) 2.47 (4H, brs), 3.49-3.55 (6H, m), 6.86 (1H, d, J = 8.6 Hz), 7.14 (2H, d, J = 8.6 Hz), 7.28-7.33 (5H, m), 7.45 (2H, d. J = 8.6 Hz), 7.80 (1H, dd, J = 8.6 Hz, 2.5 Hz), 8.22 (1H, d, J = 2.5 Hz).

241
—COOCH₃
—N(CH₃)—
piperonyl
1
(CDCl₃) 2.41-2.45 (4H, m), 3.04 (3H, s), 3.43 (2H, s), 3.47-3.49 (2H, m), 3.63 (2H, s), 3.91 (3H, s), 4.10 (2H, s), 5.95 (2H, s), 6.69-6.75 (4H, m), 6.84 (1H, dd, J = 8.7 Hz, 0.7 Hz), 6.85 (1H, brs), 7.02 (2H, d, J = 9.2 Hz), 8.21 (1H, dd, J = 8.7 Hz, 2.5 Hz), 8.82 (1H, dd, J = 2.5 Hz, 0.7 Hz).

242
—COOC₂H₅
none
piperonyl
0
(CDCl₃) 1.39 (3H, t, J = 7.1 Hz), 2.45 (4H, brs), 3.45 (2H, s), 3.54- 3.75 (4H, m), 4.38 (2H, q, J = 7.1 Hz), 5.95 (2H, s), 6.71-6.75 (2H, m), 6.86 (1H, s), 6.97 (1H, d, J = 8.6 Hz), 7.19 (2H, d, J = 8.6 Hz), 7.48 (2H, d, J = 8.7 Hz), 8.30 (1H, dd, J = 2.3 Hz, 8.6 Hz), 8.82 (1H, d, J = 2.3 Hz).

TABLE 34

Reference

Example

No.
Chemical Structure
MS (M⁺)

243

embedded image

413

244

embedded image

504

245

embedded image

413

246

embedded image

574

Reference Example 247
Production of 4-(5-nitropyridin-2-yloxy)phenylamine

To a solution of sodium hydroxide (730 mg, 18.25 mmol) in methanol was added 4-aminophenol (2.00 g, 18.32 mmol). After the resulting mixture was made to dissolve, methanol was evaporated under reduced pressure. To the residue was added DMF (20 mL), and then 2-chloro-5-nitropyridine (2.91 g, 18.35 mmol). The reaction solution was stirred for 1.5 hours at 70° C., and then concentrated under reduced pressure. Water was added to the residue, and the resulting solution was extracted with ethyl acetate. The ethyl acetate layer was washed with brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, after which solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1), to thereby yield 3.37 g of the title compound.

Appearance: Black-red powder

¹H NMR (DMSO-d₆) δ 5.10 (2H, s), 6.61 (2H, d, J=8.9 Hz), 6.85 (2H, d, J=8.9 Hz), 7.08 (1H, d, J=9.0 Hz), 8.55 (1H, dd, J=9.0 Hz, 3.0 Hz), 9.01 (1H, d, J=3.0 Hz).

The following compounds were produced in the same manner as in Reference Example 247.

TABLE 35

Reference

Example

No.
Chemical Structure

¹H NMR (solvent) δppm

248

embedded image

(DMSO-d₆) 4.03 (2H, s), 6.96 (1H, d, J = 8.4 Hz), 7.10 (2H, d, J = 8.9 Hz), 7.17 (2H, d, J = 8.9 Hz), 7.48 (2H, d, J = 8.1 Hz), 7.66 (2H, d, J = 8.1 Hz), 7.77 (1H, dd, J = 8.4 Hz, 2.5 Hz), 8.08 (1H, d, J = 2.5 Hz), 9.12 (2H, brs).

249

embedded image

(CDCl₃) 1.47 (9H, s), 2.94 (2H, d, J = 5.1 Hz), 3.10-3.80 (9H, m), 4.62 (1H, d, J = 5.1 Hz), 7.03 (1H, d, J = 9.1 Hz), 7.10 (2H, d, J = 8.5 Hz), 7.31 (2H, d, J = 8.5 Hz), 8.46 (1H, dd, J = 9.1 Hz, 2.8 Hz), 9.01 (1H, d, J = 2.8 Hz).

TABLE 36

Reference

Example

No
R₁₈₈

¹H NMR (solvent) δppm

250
—CH₂OH
(CDCl₃) 4.74 (2H, s), 7.04 (1H, d, J = 8.9 Hz). 7.13-7.18 (2H, m), 7.46 (2H, d, J = 8.3 Hz), 8.48 (1H, dd, J = 8.9 Hz, 2.6 Hz), 9.03 (1H, d, J = 2.6 Hz).

251
—(CH₂)₂OH
(CDCl₃) 2.91 (2H, t, J = 6.6 Hz), 3.91 (2H, t, J = 6.6 Hz), 7.03 (1H, d, J = 9.2 Hz), 7.09-7.13 (2H, m), 7.32 (2H, d, J = 8.6 Hz), 8.47 (1H, dd, J = 9.2 Hz, 3.0 Hz), 9.04 (1H, d, J = 3.0 Hz).

252
—(CH₂)₂COOH
(CDCl₃) 2.73 (2H, t, J = 7.9 Hz), 3.01 (2H, t, J = 7.9 Hz), 7.03 (1H, d, J = 8.9 Hz), 7.09 (2H, d, J = 8.6 Hz), 7.30 (2H, d, J = 8.6 Hz), 8.47 (1H, dd, J = 9.2 Hz, 3.0 Hz), 9.04 (1H, d, J = 2.6 Hz).

253
—(CH₂)₃COOH
(DMSO-d₆) 2.01 (2H, dq, J = 15.0 Hz, 7.2 Hz), 2.46 (2H, t, J = 7.2 Hz), 2.72 (2H, t, J = 7.2 Hz), 7.02 (1H, d, J = 8.6 Hz), 7.08 (2H, d, J = 8.6 Hz), 7.27 (2H, d, J = 8.6 Hz), 8.46 (1H, dd, J = 8.6 Hz, 3.0 Hz), 9.04 (1H, d, J = 3.0 Hz).

Reference Example 254
Production of ethyl 3-[4-(3-nitrophenoxy)phenyl]-propionate

Under argon, to a solution of 3-iodonitrobenzene (3.00 g, 12.0 mmol) in pyridine (15 mL) were added ethyl 3-(4-hydroxyphenyl)propionate (2.81 g, 14.5 mmol), copper oxide (3.3.5 g, 42.2 mmol), and potassium carbonate (4.16 g, 30.1 mmol), and the resulting solution was heated to reflux for 40 hours. The reaction solution was concentrated under reduced pressure. Water and ethyl acetate were added to the residue, and once insoluble matter had been filtered off, and the filtrate was extracted with ethyl acetate out. The ethyl acetate layer was washed with 1 M hydrochloric acid, water and a saturated sodium bicarbonate solution, and then washed with brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1→6:1), to thereby yield 1.12 g of the title compound.

Appearance: Pale yellow oil

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=7.1 Hz), 2.62 (2H, t, J=7.7 Hz), 2.95 (2H, t, J=7.7 Hz), 4.12 (2H, q, J=7.1 Hz), 6.96 (2H, d, J=8.6 Hz), 7.22 (2H, d, J=8.6 Hz), 7.29 (1H, dd, J=8.2 Hz, 2.3 Hz), 7.43 (1H, t, J=8.2 Hz), 7.74 (1H, s), 7.90 (1H, dd, J=8.2 Hz, 2.3 Hz).

Reference Example 255
Production of 1-(t-butoxycarbonyl) 4-[4-(4-nitrophenoxy)phenyl]piperazine

Potassium carbonate (15.7 g, 114 mmol) was added to a solution of 2-chloro-5-nitropyridine (4.50 g, 28.4 mmol) and 1-(4-hydroxyphenyl)piperazine dihydrochloride (7.13 g, 28.4 mmol) in DMF (80 mL). The resulting solution was stirred at room temperature for 8 hours. To this reaction solution was added di-t-butyl dicarbonate (6.81 g, 31.2 mmol), and stirred at room temperature for 2.5 days. To the reaction solution was charged with ethyl acetate, washed with water, and dried with anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3), to thereby yield 7.05 q of the title compound.

Appearance: Yellow needles

¹H NMR (CDCl₃) δ 1.49 (9H, s), 3.15 (4H, t, J=5.0 Hz), 3.59 (4H, t, J=5.0 Hz), 6.98 (2H, d, J=9.0 Hz), 7.00 (1H, d, J=9.0 Hz), 7.07 (2H, d, J=9.0 Hz), 8.45 (1H, dd, J=9.0 Hz, 2.5 Hz), 9.05 (1H, d, J=2.5 Hz).

Reference Example 256
Production of (ethyl{3-methoxy-4-[5-(4-trifluoromethylphenylcarbamoyl)pyridin-2-yloxy]phenyl}amino)acetate

Benzyl [ethyl (4-hydroxy-3-methoxyphenyl)amino]acetate (9.46 g, 30 mmol) and 6-chloro-N-(4-trifluoromethylphenyl)nicotinamide (9.02 g, 30 mmol) were dissolved in DMF (100 mL). To the resulting solution was added potassium carbonate (6.22 g, 45 mmol), and then stirred for 12 hours at 120° C. The reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate and extracted with water. The pH of the aqueous layer was adjusted from 3 to 4 with 1 M hydrochloric acid, after which the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and evaporated to thereby yield 4.2 g of the title compound.

Appearance: crown powder

¹H NMR (DMSO-d₆) δ 1.19 (3H, t, J=7.1 Hz), 3.40 (2H, q, J=7.1 Hz), 3.63 (3H, s), 4.01 (2H, s), 6.17 (1H, d, J=8.9 Hz), 6.22 (1H, brs), 6.25 (1H, d, J=2.5 Hz), 6.87-6.90 (2H, m), 7.53 (2H, d, J=8.6 Hz), 7.76 (2H, d, J=8.4 Hz), 8.18 (1H, dd, J=8.7 Hz, 2.3 Hz), 8.67 (1H, d, J=2.1 Hz), 8.88 (1H, brs).

Reference Example 257
Production of ethyl methyl [2,5-difluoro-4-(5-nitropyridin-2-yloxy)phenyl]aminoacetate

To a solution of ethyl (2,5-difluoro-4-hydroxyphenyl)aminoacetate (1.1 g, 4.8 mmol) in DMF (25 mL) were added sodium bicarbonate (0.44 g, 5.2 mmol) and methyl iodide (1.69 mL, 28.6 mmol), and the resulting reaction solution was stirred for 2 days at room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. Once the ethyl acetate layer had been washed with water, the ethyl acetate layer was dried with anhydrous magnesium sulfate, and evaporated. The residue was dissolved in DMF (30 mL), and to this resulting solution were added potassium carbonate (0.72 g, 5.2 mmol) and 2-chloro-5-nitropyridine (0.79 g, 5.0 mmol). The reaction solution was stirred for 2.5 days at room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was then evaporated, and the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=8:1), to thereby yield 1.41 g of the title compound.

Appearance: Yellow oil

¹H NMR (CDCl₃) δ 1.27 (3H, t, J=7.1 Hz), 3.01 (3H, s), 4.05 (2H, s), 4.19 (2H, q, J=7.1 Hz), 6.77 (1H, dd, J=8.2 Hz, 12.2 Hz), 6.92 (1H, dd, J=7.2 Hz, 12.8 Hz), 8.49 (1H, dd, J=2.8 Hz, 9.0 Hz), 9.02 (1H, d, J=2.8 Hz).

The following compounds were produced in the same manner as in Reference Example 257.

TABLE 37

Reference

Example

No.
R₁₈₉
R₁₉₀
R₁₉₁

¹H NMR (CDCl₃) δppm

258
—NO₂
—CH₃
—CH₃
1.27(3H, t, J = 7.1 Hz), 2.05(3H, s), 2.29(3H, s), 2.87(3H, s), 3.71(2H, s), 4.18(2H, q, J = 7.1 Hz), 6.87(1H, d, J = 8.7 Hz), 6.97(1H, dd, J = 9.1 Hz, 0.3 Hz), 7.08(1H, d, J = 8.7 Hz), 8.45(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04(1H, dd, J = 2.8 Hz, 0.3 Hz).

259
4-CF₃PhCO—
—H
—C₂H₅
1.23(3H, t, J = 7.1 Hz), 1.28(3H, t, J = 7.1 Hz), 2.12(3H, s), 3.46(2H, q, J = 7.1 Hz), 4.01 (2H, s), 4.21(2H, q, J = 7.1 Hz), 6.49-6.53(2H, m), 6.92- 6.96(2H, m), 7.73-7.77(2H, m), 7.86-7.89(2H, m), 8.17(1H, dd, J = 8.7 Hz, 2.5 Hz), 8.59(1H, dd, J = 2.5 Hz, 0.7 Hz).

Reference Example 260
Production of ethyl 4-(3-[3-methyl-4-(5-nitropyridin-2-yloxy)phenyl]-2-oxotetrahydropyrimidin-1-yl)benzoate

Under a nitrogen atmosphere, to a solution of ethyl 4-[3-(4-benzyloxy-3-methyl)phenyl-2-oxotetrahydropyrimidin-1-yl]benzoate (1.82 g, 3.1 mmol) in ethanol-DMF (70 mL-30 mL) was added 10% palladium-carbon (0.4 g), and the resulting solution was stirred under a hydrogen atmosphere for 4 hours at room temperature. The resulting solution was filtered through Celite, and ethanol was evaporated under reduced pressure so as to give a DMF (30 mL) solution. To this solution was added 2-chloro-5-nitropyridine (0.52 g, 3.3 mmol) and stirred under a nitrogen atmosphere for 14 hours at room temperature, and then for 3 hours at 40° C. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 1.8 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 1.39 (3H, t, J=7.1 Hz), 2.14 (3H, s), 2.21-2.40 (2H, m), 3.75-3.97 (4H, m), 4.36 (2H, q, J=7.1 Hz), 7.01 (1H, d, J=9.1 Hz), 7.06 (1H, d, J=8.6 Hz), 7.23 (1H, dd, J=2.6 Hz, 8.6 Hz), 7.32 (1H, d, J=2.6 Hz), 7.40-7.49 (2H, m), 7.97-8.07 (2H, m), 8.46 (1H, dd, J=2.8 Hz, 9.1 Hz), 9.04 (1H, d, J=2.8 Hz).

Reference Example 261
Production of 3-[4-(5-nitropyridin-2-ylsulfanyl)phenyl]propionic acid

To a solution of 2-chloro-5-nitropyridine (1.74 g, 11.0 mmol) and 4-mercaptohydrocinnamic acid (2.00 g, 11.0 mmol) in DMF (30 mL) was added potassium carbonate (4.55 g, 32.9 mmol), and the resulting solution was stirred for 1 hour at 80° C. To the reaction solution were added water and concentrated hydrochloric acid, and then cooled with ice. The precipitated solid matter was collected by filtration, to thereby yield 3.29 g of the title compound.

Appearance: Pale yellow powder

¹H NMR (DMSO-d₆) δ 2.60 (2H, t, J=7.5 Hz), 2.91 (2H, t, J=7.5 Hz), 7.07 (1H, d, J=9.0 Hz), 7.43 (2H, d, J=8.2 Hz), 7.57 (2H, d, J=8.2 Hz), 8.39 (1H, dd, J=2.8 Hz, 9.0 Hz), 9.17 (1H, d, J=2.8 Hz), 12.19 (1H, s).

Reference Example 262
Production of ethyl 3-[3-methoxy-4-(5-nitropyridin-2-ylamino)phenyl]propionate

To 2-chloro-5-nitropyridine (3.11 g, 20 mmol) were added ethyl 3-(4-amino-3-methoxyphenyl)propionate (4.38 g, 20 mmol) and acetic acid (10 mL), and the resulting solution was stirred for 13 hours at 100° C. To the reaction solution were added ethyl acetate and water. The ethyl acetate layer was separated, washed with brine, a saturated sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby yield 3.78 g of the title compound.

Appearance: Yellow powder

¹H NMR (CDCl₃) δ 1.26 (3H, t, J=7.1 Hz), 2.61-2.67 (2H, m), 2.93-2.99 (2H, m), 3.89 (3H, s), 4.15 (2H, q, J=7.1 Hz), 6.73 (1H, d, J=9.2 Hz), 6.81-6.87 (2H, m), 7.43 (1H, brs), 7.92 (1H, d, J=8.1 Hz), 8.23 (1H, dd, J=9.2 Hz, 2.8 Hz), 9.11 (1H, d, J=2.8 Hz).

The following compounds were produced in the same manner as in Reference Example 262.

TABLE 38

Reference

Example

No.
R₁₉₂

¹H NMR (solvent) δppm

263
—COOC₂H₅
(DMSO-d₆) 1.32(3H, t, J = 7.1 Hz), 4.29(2H, q, J = 7.1 Hz), 7.01(1H, d, J = 9.3 Hz), 7.89(2H, d, J = 8.9 Hz), 8.36(1H, dd, J = 2.9 Hz, 9.3 Hz), 9.09(1H, d, J = 2.9 Hz), 10.43(1H, s).

264
—(CH₂)₂COOC₂H₅
(CDCl₃) 1.25(3H, t, J = 7.1 Hz), 2.64(2H, t, J = 7.6 Hz), 2.97(2H, t, J = 7.6 Hz), 4.14(2H, q, J = 7.1 Hz), 6.73(1H, d, J = 9.3 Hz), 7.20-7.40(4H, m), 8.23(1H, dd, J = 2.7 Hz, 9.3 Hz), 9.07(1H, d, J = 2.7 Hz).

265

embedded image

(CDCl₃) 1.30(3H, t, J = 7.1 Hz), 2.77(4H, t, J = 5.0 Hz), 3.28(4H, t, J = 5.0 Hz), 3.28(2H, s), 4.22(2H, q, J = 7.1 Hz), 6.61(1H, d, J = 9.4 Hz), 6.95(2H, d, J = 9.0 Hz), 7.11(1H, brs), 7.22(2H, d, J = 9.0 Hz), 8.18(1H, dd, J = 9.4 Hz, 2.5 Hz), 9.05(1H, d, J = 2.5 Hz).

266

embedded image

(CDCl₃) 1.28(3H, t, J = 7.1 Hz), 1.32-1.60(2H, m), 1.75- 2.12(3H, m), 2.29(2H, d, J = 6.9 Hz), 2.77(2H, td, J = 12.4 Hz, 2.4 Hz), 3.68(2H, d, J = 12.4 Hz), 4.16(2H, q, J = 7.1 Hz), 6.60(1H, d, J = 9.2 Hz), 6.96(2H, d, J = 8.9 Hz), 7.16(1H, brs), 7.20(2H, d, J = 8.9 Hz), 8.18(1H, dd, J = 9.2 Hz, 2.6 Hz), 9.05(1H, d, J = 2.6 Hz).

Reference Example 267
Production of 4-[(5-nitro-2-pyridyl)oxy]benzaldehyde ethylene acetal

To a solution of 4-[(5-nitro-2-pyridyl)oxy]benzaldehyde (5.00 g, 20.5 mmol) in benzene (100 mL) were added ethylene glycol (2.28 mL, 41.0 mmol) and p-toluenesulfonic acid (0.50 g), and the resulting solution was heated to reflux for 3 hours while removing water with a Dean-Stark. The reaction solution was washed with a saturated sodium bicarbonate solution, and subsequently washed with brine. The benzene layer was dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 5.88 g of the title compound.

Appearance: Yellow powder

¹H NMR (CDCl₃) δ 4.00-4.19 (4H, m), 5.83 (1H, s), 7.00 (1H, d, J=9.0 Hz), 7.15 (2H, d, J=8.5 Hz), 7.55 (2H, d, J=8.5 Hz), 8.45 (1H, dd, J=9.0 Hz, 2.0 Hz), 9.01 (1H, d, J=2.0 Hz).

The following compound was produced in the same manner as in Reference Example 267.

Reference Example 268
4-(2-Fluoro-4-nitrophenoxybenzaldehyde ethylene acetal

¹H NMR (DMSO-d₆) δ 3.90-4.10 (4H, m), 5.76 (1H, s), 7.15-7.25 (3H, m), 7.54 (2H, d, J=8.7 Hz), 8.10 (1H, ddd, J=1.3 Hz, 2.7 Hz, 9.1 Hz), 8.35 (1H, dd, J=2.7 Hz, 10.8 Hz).

Reference Example 269
Production of t-butyl [4-(5-nitropyridin-2-yloxy)phenyl]carbamate

To a solution of 4-(5-nitropyridin-2-yloxy)phenylamine (2.97 g, 12.85 mmol) in THF was added di-t-butyl dicarbonate (5.60 g, 25.66 mmol), and the resulting solution was stirred under reflux for 4 hours. The reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, evaporated, and to the resulting product was added diethyl ether. The obtained white powder was filtered, and the resulting product was washed with diethyl ether, to thereby yield 3.04 g of the title compound.

Appearance: Yellow powder

¹H NMR (CDCl₃) δ 1.53 (9H, s), 6.53 (1H, brs), 7.00 (1H, d, J=9.2 Hz), 7.09 (2H, d, J=8.9 Hz), 7.45 (2H, d, J=8.9 Hz), 8.46 (1H, dd, J=9.2 Hz, 3.0 Hz), 9.03 (1H, d, J=3.0 Hz).

Reference Example 270
Production of 5-[3-methyl-4-(5-nitropyridin-2-yloxy)benzylidene]thiazolidine-2,4-dione

To a solution of 3-methyl-4-(5-nitropyridin-2-yloxy)benzaldehyde (600 mg, 2.32 mmol) in toluene (35 mL) were added 2,4-thiazolidinedione (270 mg, 2.31 mmol) and piperidine acetate (135 mg, 0.93 mmol). The resulting solution was attached to a Dean Stark, and stirred under reflux for 1.5 hours. After being left to cool for 17 hours at room temperature, the precipitated yellow powder was filtered, to thereby yield 600 mg of the title compound.

Appearance: Yellow powder

¹H NMR (DMSO-d₆) δ 2.15 (3H, s), 7.33 (1H, d, J=8.4 Hz), 7.35 (1H, d, J=9.1 Hz), 7.52 (1H, dd, J=8.4 Hz, 2.0 Hz), 7.59 (1H, d, J=2.0 Hz), 7.79 (1H, s), 8.65 (1H, dd, J=9.1 Hz, 3.0 Hz), 9.02 (1H, d, J=3.0 Hz), 12.63 (1H, brs).

The following compounds were produced in the same manner as in Reference Example 270.

TABLE 39

Reference

Example

No.
R₁₉₃

¹H NMR (solvent) δppm

271

embedded image

(DMSO-d₆) 7.35(1H, d, J = 9.0 Hz), 7.42(2H, d, J = 8.6 Hz), 7.71 (2H, d, J = 8.6 Hz), 7.84(1H, s), 8.65(1H, dd, J = 9.0 Hz, 2.9 Hz), 9.04(1H, d, J = 2.9 Hz), 12.64(1H, brs).

272
—CH═C(COOCH₃)₂
(CDCl₃) 3.87(6H, s), 7.09(1H, d, J = 9.0 Hz), 7.20(2H, d, J = 8.5 Hz), 7.53(2H, d, J = 8.5 Hz), 7.77(1H, s), 8.51(1H, dd, J = 9.0 Hz, 2.8 Hz), 9.04(1H, d, J = 2.8 Hz).

Reference Example 273
Production of N-[4-(2-fluoro-4-nitrophenoxy)phenyl]-N-[2-(4-piperonylpiperazin-1-yl)-2-oxyethyl]acetamide

To a solution of N-[4-(2-fluoro-4-nitrophenoxy)phenyl]acetamide (0.800 g, 2.76 mmol) in DMF (5 mL) was added 60% sodium hydride (0.118 g, 2.95 mmol). The resulting solution was stirred for 10 minutes at room temperature, after which a solution of 1-chloroacetyl-4-piperonylpiperazine (0.870 g, 2.96 mmol) in DMF (4 mL) was added to the reaction solution. The reaction solution was stirred for 2 hours at 60° C., and then for 1 hour at 100° C. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=5:1), to thereby yield 0.730 g of the title compound.

Appearance: Yellow oil

¹H NMR (DMSO-d₆) δ 1.82 (3H, s), 2.20-2.40 (4H, m), 3.30-3.50 (6H, m), 4.43 (2H, s), 5.98 (2H, s), 6.70-6.85 (3H, m), 7.20-7.30 (3H, m), 7.48 (2H, (f, J=8.8 Hz), 8.12 (1H, ddd, J=1.4 Hz, 2.7 Hz, 10.5 Hz), 8.36 (1H, dd, J=2.7 Hz, 10.7 Hz).

The following compound was produced in the same manner as in Reference Example 273.

Reference Example 274
3-(4-Benzyloxy-3-methylphenyl)-1-[2-oxo-2-(4-piperonylpiperazin-1-yl)ethyl]tetrahydropyrimidin-2-one

¹H NMR (DMSO-d₆) δ 1.92-2.08 (2H, m), 2.15 (3H, s), 2.22-2.40 (4H, m), 3.25-3.49 (8H, m), 3.56 (2H, d, J=5.6 Hz), 4.08 (2H, s), 5.09 (2H, s), 5.97 (2H, s), 6.74 (1H, dd J=1.3 Hz, 7.9 Hz), 6.84 (1H, d, J=7.9 Hz), 6.85 (1H, d, J=1.3 Hz), 6.91 (1H, d, J=8.7 Hz), 6.95 (1H, dd, J=2.5 Hz, 8.6 Hz), 7.01 (1H, d, J=2.5 Hz), 7.28-7.34 (1H, m), 7.36-7.41 (2H, m), 7.42-7.48 (2H, m).

Reference Example 275
Production of 2-dimethylamino-N-[4-(5-nitropyridin-2-yloxy)phenyl]-N-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]acetamide

To a solution of 2-chloro-N-(4-(5-nitropyridin-2-yloxy)phenyl]-N-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]acetamide (0.300 g, 0.528 mmol) in acetonitrile (3 mL) was added at room temperature dimethylamine (0.150 mL, 1.63 mmol), and the resulting solution was stirred for 2 hours at 50° C. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol 10:1), to thereby yield 0.270 g of the title compound.

Appearance: Yellow powder

¹H NMR (CDCl₃) δ 2.29 (6H, s), 2.40-2.45 (4H, m), 3.02 (2H, s), 3.40-3.46 (4H, m), 3.61 (2H, s), 4.48 (2H, s), 5.95 (2H, s), 6.70-6.77 (2H, m), 6.84 (1H, s), 7.09 (1H, d, J=9.0 Hz), 7.19 (2H, d, J=8.7 Hz), 7.51 (2H, d, J=8.7 Hz), 8.51 (1H, dd, J=2.8 Hz, 9.0 Hz), 9.04 (1H, d, J=2.8 Hz).

Reference Example 276
Production of methyl 2-[4-(5-nitropyridin-2-yloxy)phenyl]propionate

To a solution of methyl 2-[4-(5-nitropyridin-2-yloxy)phenyl]acetate (0.50 g, 1.7 mmol) in DMF (10 mL) were added 60% sodium hydride (0.153 g, 3.8 mmol) and methyl iodide (0.13 mL, 2.1 mmol), and the resulting reaction solution was stirred for 1 hour at 0° C. To the reaction solution was added saturated aqueous ammonium chloride, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated aqueous sodium chloride. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=8:1), to thereby yield 0.32 g of the title compound.

Appearance: Colorless oil

¹H NMR (CDCl₃) δ 1.54 (3H, d, J=7.4 Hz), 3.69 (3H, s), 3.78 (1H, q, J=7.2 Hz), 7.03 (1H, d, J=9.1 Hz), 7.09-7.15 (2H, m), 7.36-7.41 (2H, m), 8.48 (1H, dd, J=9.1, 2.8 Hz), 9.05 (1H, d, J=2.8 Hz).

Reference Example 277
Production of ethyl 3-{3-methoxy-4-[methyl (5-nitropyridin-2-yl)amino]phenyl}propionate

To a solution of ethyl 3-[3-methoxy-4-(5-nitropyridin-2-ylamino)phenyl]propionate (3.70 g, 11 mmol) in DMF (60 mL) were added under ice-cooling sodium hydride (60%, 490 mg, 12 mmol) and methyl iodide (0.77 mL, 1.2 mmol), and the resulting reaction solution was stirred for 2 hours gradually warming up to room temperature. The reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate, washed with water and brine, and then dried with anhydrous magnesium sulfate. The solvent was evaporated, to thereby yield 4.27 g of the title compound.

Appearance: Yellow oil substance

¹H NMR (CDCl₃) δ 1.27 (3H, t, J=7.1 Hz), 2.66-2.71 (2H, m), 2.98-3.04 (2H, m), 3.46 (3H, s), 3.78 (3H, s), 4.17 (2H, q, J=7.1 Hz), 6.12 (1H, brd, J=9.5 Hz), 6.87-6.90 (2H, m), 7.11-7.14 (1H, m), 7.97-8.02 (1H, m), 9.11 (1H, d, J=2.7 Hz).

The following compounds were produced in the same manner as in Reference Example 277.

TABLE 40

Reference

Example

No.
R₁₉₄
R₁₉₅

¹H NMR (solvent) δppm

278
—CH₃
—COOC₂H₅
(DMSO-d₆) 1.34(3H, t, J = 7.1 Hz), 3.56(3H, s), 4.34(2H, q, J = 7.1 Hz), 6.70(1H, d, J = 9.5 Hz), 7.55(2H, d, J = 8.6 Hz), 8.06(2H, d, J = 8.6 Hz), 8.21(1H, dd, J = 2.8 Hz, 9.5 Hz), 9.05(1H, d, J = 2.8 Hz).

279
—CH₃
—(CH₂)₂COOC₂H₅
(CDCl₃) 1.26(3H, t, J = 7.1 Hz), 2.67(2H, t, J = 7.6 Hz), 3.01(2H, t, J = 7.6 Hz), 3.55(3H, s), 4.15(2H, q, J = 7.1 Hz), 6.32(1H, d, J = 9.5 Hz), 7.17(2H, d, J = 8.3 Hz), 7.32(2H, d, J = 8.3 Hz), 8.01(1H, dd, J = 2.7 Hz, 9.5 Hz), 9.11(1H, d, J = 2.7 Hz).

280
benzyl
—(CH₂)₂COOC₂H₅
(CDCl₃) 1.24(3H, t, J = 7.2 Hz), 2.64(2H, t, J = 7.7 Hz), 2.97(2H, t, J = 7.7 Hz), 4.14(2H, q, J = 7.2 Hz), 5.27(2H, s), 6.26(1H, d, J = 9.5 Hz), 7.06(2H, d, J = 8.3 Hz), 7.20-7.30(7H, m), 8.02(1H, dd, J = 2.7 Hz, 9.5 Hz), 9.12(1H, d, J = 2.7 Hz).

281
—CH₃

embedded image

(CDCl₃) 1.30(3H, t, J = 7.1 Hz), 2.78(4H, t, J = 5.0 Hz), 3.30(2H, s), 3.31(4H, t, J = 5.0 Hz), 3.53(3H, s), 4.22(2H, q, J = 7.1 Hz), 6.30(1H, d, J = 9.5 Hz), 6.99(2H, d, J = 8.9 Hz), 7.12(2H, d, J = 8.9 Hz), 7.99 (1H, dd, J = 9.5 Hz, 2.8 Hz), 9.10(1H, d, J = 2.8 Hz).

282
—CH₃

embedded image

(CDCl₃) 1.28(3H, t, J = 7.1 Hz), 1.45(2H, qd, J = 12.2 Hz, 3.7 Hz), 1.80-2.17(3H, m), 2.30(2H, d, J = 6.9 Hz), 2.80(2H, td, J = 12.2 Hz, 2.3 Hz), 3.52(3H, s), 3.72(2H, d, J = 12.4 Hz), 4.16(2H, q, J = 7.1 Hz), 6.30(1H, d, J = 9.5 Hz), 6.98(2H, d, J = 8.9 Hz), 7.10(2H, d, J = 8.9 Hz), 7.98(1H, dd, J = 9.5 Hz, 2.8 Hz), 9.10(1H, d, J = 2.8 Hz).

TABLE 41

Reference

Example

No.
R₁₉₆

¹H NMR (CDCl₃) δppm

283
—(CH₂)₂CH₃
0.93(3H, t, J = 7.4 Hz), 1.60-1.70(2H, m), 2.35-2.43(4H, m), 2.66(2H, t, J = 8.1 Hz), 3.03(2H, t, J = 8.1 Hz), 3.42(2H, s), 3.43- 3.45(2H, m), 3.62-3.65(2H, m), 3.96(2H, t, J = 7.7 Hz), 5.95(2H, s), 6.16(1H, d, J = 9.5 Hz), 6.70-6.80(2H, m), 6.84(1H, d. J = 1.3 Hz), 7.14(2H, d, J = 8.3 Hz), 7.33(2H, d, J = 8.3 Hz), 7.96(1H, dd, J = 2.8 Hz, 9.5 Hz), 9.08(1H, d, J = 2.8 Hz).

284
cyclopentyl
1.30-1.40(2H, m), 1.55-1.65(4H, m), 1.95-2.00(2H, m), 2.35- 2.45(4H, m), 2.67(2H, t, J = 7.4 Hz), 3.04(2H, t, J = 7.4 Hz), 3.42(2H, s), 3.43-3.47(2H, m), 3.55-3.68(2H, m), 5.18-5.28(1H, m), 5.88(1H, d, J = 9.5 Hz), 5.95(2H, s), 6.70-6.78(2H, m), 6.84(1H, s), 7.04(2H, d, J = 8.2 Hz), 7.34(2H, d, J = 8.2 Hz), 7.92(1H, dd, J = 2.8 Hz, 9.5 Hz), 9.09(1H, d, J = 2.8 Hz).

TABLE 42

Reference

Example

No.
Chemical Structure

¹H NMR (solvent) δppm

285

embedded image

(CDCl₃) 1.91-2.06(2H, m), 2.27(3H, s), 3.31-3.44 (2H, m), 3.58(2H, t, J = 6.3 Hz), 4.69-4.85(1H, m), 5.07(2H, s), 6.04(1H, s), 6.84(1H, d, J = 10.1 Hz), 7.01(1H, dd, J = 8.5 Hz, 2.5 Hz), 7.04 (1H, d, J = 2.5 Hz), 7.30-7.36(1H, m), 7.37- 7.46(4H, m).

286

embedded image

(CDCl₃) 1.96-2.11(2H, m), 2.27(3H, s), 3.20-3.34 (2H, m). 3.56-3.68(2H, m), 4.50(2H, s), 5.07(2H, s), 5.94(2H, s), 6.72-6.80(2H, m), 6.84(1H, d, J = 8.6 Hz), 6.88(1H, d, J = 1.2 Hz), 7.04(1H, dd, J = 2.6 Hz, 8.6 Hz), 7.11(1H, d, J = 2.6 Hz), 7.28-7.34(1H, m), 7.35- 7.41(2H, m), 7.42-7.48(2H, m).

287

embedded image

(DMSO-d₆) 3.20-3.40(2H, m), 3.71(3H, s), 3.64-3.83(2H, m), 4.36(2H, s), 6.84-6.95(2H, m), 7.22- 7.41(5H, m), 7.42-7.53(2H, m).

288

embedded image

(DMSO-d₆) 2.18(3H, s), 3.35(2H, t, J = 8.7 Hz), 3.69-3.84(2H, m), 5.05(2H, s), 6.74(1H, s), 6.93(1H, d, J = 8.9 Hz), 7.23(1H, dd, J = 2.8 Hz, 8.9 Hz), 7.27-7.48(6H, m).

289

embedded image

(CDCl₃) 2.29(3H, s), 3.28-3.39(2H, m), 3.68-3.81 (2H, m), 4.36(2H, s), 5.06(2H, s), 5.95(2H, s), 6.77(2H, s), 6.78-6.91(2H, m), 7.20-7.35(2H, m), 7.36-7.51(5H, m).

290

embedded image

(CDCl₃) 1.93-2.12(2H, m), 2.27(3H, s), 3.28(2H, t. J = 5.9 Hz), 3.63(2H, t, J = 5.9 Hz), 3.88(6H, s), 4.55 (2H, s), 5.07(2H, s), 6.71-6.92(4H, m), 6.96-7.08 (1H, m), 7.11(1H, d, J = 2.1 Hz), 7.25-7.51(5H, m).

Reference Example 291
Production of N-[4-(5-nitropyridin-2-yloxy)phenyl]-2-(4-piperonylpiperazin-1-yl)acetamide

A solution of (4-piperonylpiperazin-1-yl)acetic acid (13.9 g, 50 mmol) was suspended in DMF (400 mL), and to the resulting suspension were added 1-hydroxybenzotriazole monohydrate (8.42 g, 55 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.5 g, 55 mmol) and 4-(5-nitropyridin-2-yloxy)phenylamine (11.6 g, 50 mmol) under ice cooling. The resulting solution was stirred for 6 hours at room temperature. The reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate, and washed with a saturated sodium bicarbonate solution and brine. The organic layer was left for standing overnight at room temperature, and the resulting precipitated crystals were collected by suction filtration, to thereby yield 12.8 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 2.53 (4H, brs), 2.64-2.65 (4H, m), 3.15 (2H, s), 3.46 (2H, s), 5.95 (2H, s), 6.76 (2H, brs), 6.86 (1H, s), 7.04 (1H, d, J=9.1 Hz), 7.14 (2H, d, J=8.7 Hz), 7.67 (2H, d, J=8.9 Hz), 8.47 (1H, dd, J=9.1 Hz, 2.8 Hz), 9.03 (1H, d, J=2.8 Hz), 9.24 (1H, brs).

Reference Example 292
Production of ethyl{methanesulfonyl[ethoxy-4-(5-nitropyridin-2-yloxy)phenyl]amino}acetate

A solution of ethyl [3-methoxy-4-(5-nitropyridin-2-yloxy)phenylamino]acetate (2.43 g, 7.00 mmol) was dissolved in THF (15 mL), dichloromethane (20 mL) and DMF (10 mL), and to the resulting solution were added triethylamine (1.95 mL, 13.99 mmol), dimethylaminopyridine (0.86 g, 7.00 mmol) and methanesulfonyl chloride (1.08 mL, 13.99 mmol) under ice cooling. The resulting solution was stirred for 14 hours at 30° C. Water was added to the reaction mixture, and extracted with dichloromethane. The dichloromethane layer was washed with water and brine. The dichloromethane layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2), to thereby yield 1.10 g of the title compound.

Appearance: Yellow oil

¹H NMR (CDCl₃) δ 1.32 (3H, t, J=7.3 Hz), 3.18 (3H, s), 3.75 (3H, s), 4.26 (2H, q, J=7.3 Hz), 4.49 (2H, s), 7.09 (1H, d, J=9.1 Hz), 7.15 (2H, d, J=1.2 Hz), 7.25 (1H, s), 8.48 (1H, dd, J=9.1 Hz, 2.8 Hz), 8.98 (1H, d, J=2.8 Hz).

The following compounds were produced in the same manner as in Reference Example 292.

TABLE 43

Reference

Example

No.
Chemical Structure

¹H NMR (solvent) δppm or MS

293

embedded image

¹H NMR (DMSO-d₆) 3.00(3H, s), 5.17(2H, s), 7.05(1H, d, J = 8.4 Hz), 7.12(2H, d, J = 8.9 Hz), 7.19-7.26(4H, m), 7.67(2H, d, J = 8.9 Hz), 7.95(1H, dd, J = 8.4 Hz, 2.5 Hz), 8.25(1H, d, J = 2.3 Hz), 9. 69(1H, brs).

294

embedded image

¹H NMR (CDCl₃) 2.18(3H, s), 3.04(3H, s), 5.04(2H, s), 6.56(1H, brs), 6.96(1H, d, J = 8.6 Hz), 7.01-7.09(4H, m), 7.15(1H, d, J = 2.6 Hz), 7.56(2H, d, J = 8.4 Hz), 7.79(1H, dd, J = 8.6 Hz, 2.5 Hz), 8.19(1H, d, J = 2.5 Hz).

295

embedded image

MS 364(M⁺)

Reference Example 296
Production of 3-[4-(5-nitropyridin-2-yloxy)phenyl]-n-propanol

To a solution of 3-[4-(5-nitropyridin-2-yloxy)phenyl]propionic acid (2.64 g, 9.2 mmol) in THF (50 mL) was added dropwise a 1 M borane-THF complex THF solution (38.4 mL, 38.4 mmol) under ice cooling. The reaction solution was stirred for 2 hours at room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate, and the ethyl acetate layer was washed with water and then brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, after which solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate 1:1), to thereby yield 1.17 g of the title compound.

Appearance: Green oil

¹H NMR (CDCl₃) δ 1.90-1.96 (2H, m), 2.73-2.79 (2H, m), 3.69-3.74 (2H, m), 7.00-7.09 (3H, m), 7.26-7.30 (2H, m), 8.44-8.49 (1H, m), 9.05 (1H, d, J=2.6 Hz).

Reference Example 297
Production of 2-{4-[3-(t-butyldimethylsilanyloxy)propyl]phenoxy}-5-nitropyridine

To a solution of 3-[4-(5-nitropyridin-2-yloxy)phenyl]-n-propanol (1.17 g, 4.3 mmol) in DMF (10 mL) were added imidazole (580 mg, 8.5 mmol) and t-butylchlorodimethylsilane (640 mg, 4.2 mmol), and the resulting solution was stirred for 13 hours at room temperature. Water was added to the reaction mixture, and extracted with diethyl ether, and the diethyl ether layer was washed with water and then brine. The diethyl ether layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 1.14 g of the title compound.

Appearance: Pale yellow powder

¹H NMR (CDCl₃) δ 0.07 (6H, s), 0.92 (9H, s), 1.84-1.89 (2H, m), 2.69-2.75 (2H, m), 3.66 (2H, t, J=6.3 Hz), 6.99-7.08 (3H, m), 7.27 (2H, d, J=7.6 Hz), 8.46 (111, dd, J=8.9 Hz, 3.0 Hz), 9.05 (111, d, J=3.0 Hz).

The following compound was produced in the same manner as in Reference Example 297.

Reference Example 298
2-{4-[2-(t-Butyldimethylsilanyloxy)ethyl]phenoxy}-5-nitropyridine

¹H NMR (CDCl₃) δ 0.00 (6H, s), 0.88 (9H, s), 2.86 (2H, t, J=6.9 Hz), 3.84 (2H, t, J=6.9 Hz), 7.00 (1H, d, J=9.2 Hz), 7.05-7.08 (2H, m), 7.26-7.31 (2H, m), 8.46 (1H, dd, J=9.2 Hz, 3.0 Hz), 9.05 (1H, d, J=3.0 Hz).

Reference Example 299
Production of ethyl 4-[4-(5-nitropyridin-2-yloxy)phenyl]butanoate

To a solution of 4-[4-(5-nitropyridin-2-yloxy)phenyl]butanoic acid (9.98 g, 33.01 mmol) in dichloromethane were added ethanol (5.59 mL, 99.01 mmol), 4-dimethylaminopyridine (400 mg, 3.27 mmol), triethylamine (13.81 mL, 99.08 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.6 g, 39.65 mmol) under ice cooling, and the resulting solution was stirred for 20 minutes under ice cooling and then for 1 hour at room temperature. The reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate, and the ethyl acetate layer was washed with 1 N hydrochloric acid, a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 6.77 g of the title compound.

Appearance: Colorless oil

¹H NMR (CDCl₃) δ 1.27 (3H, t, J=7.0 Hz), 1.99 (2H, dt, J=15.0 Hz, 7.5 Hz), 2.36 (2H, t, J=7.5 Hz), 2.70 (2H, t, J=7.5 Hz), 4.14 (2H, q, J=7.0 Hz), 7.01 (1H, d, J=9.0 Hz), 7.08 (2H, d, J=8.5 Hz), 7.26 (2H, d, J=8.5 Hz), 8.46 (1H, dd, J=9.0 Hz, 3.0 Hz), 9.04 (1H, d, J=3.0 Hz).

Reference Example 300
Production of methyl 3-[4-(5-nitropyridin-2-ylsulfanyl)phenyl]propionate

To a solution of 3-[4-(5-nitropyridin-2-ylsulfanyl)phenyl]propionic acid (86.0 g, 0.283 mmol) in DMF (1 mL) were added potassium carbonate (59.0 mg, 0.424 mmol) and methyl iodide (0.0260 mL, 0.424 mmol), and the resulting solution was stirred for 1 hour at room temperature. Water was added to the reaction mixture, and then cooled with ice. The precipitated solid matter was collected by filtration, to thereby yield 76.9 mg of the title compound.

Appearance: Light brown powder

¹H NMR (DMSO-d₆) δ 2.70 (2H, t, J=7.6 Hz), 2.94 (2H, t, J=7.6 Hz), 3.60 (3H, s), 7.07 (1H, d, J=8.9 Hz), 7.43 (2H, d, J=8.1 Hz), 7.57 (2H, d, J=8.1 Hz), 8.39 (1H, dd, J=2.7 Hz, 8.9 Hz), 9.17 (1H, d, J=2.7 Hz).

Reference Example 301
Production of ethyl (Z)-3-[4-(5-nitro-2-pyridyloxy)phenyl]-2-butenoate

To a suspension of 60% sodium hydride (1.28 g, 32.0 mmol) in THF (80 mL) was added dropwise a solution of triethyl phosphonoacetate (8.71 g, 38.8 mmol) in THF (40 mL) under ice cooling, and the resulting solution was stirred for 10 minutes at the same temperature. To the reaction solution was added 4-[(5-nitro-2-pyridyl)oxy]acetophenone (5.90 g, 22.8 mmol) and the resulting solution was stirred at the same temperature for 10 minutes, and then stirred at room temperature for 60 hours. To the reaction solution was added saturated ammonium chloride and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution, and then washed with brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 1.17 g of the title compound.

Appearance: Colorless needles

¹H NMR (CDCl₃) δ 1.13 (3H, t, J=7.1 Hz), 2.20 (3H, d, J=1.4 Hz), 4.02 (2H, q, J=7.1 Hz), 5.93 (1H, q, J=1.4 Hz), 7.02 (1H, d, J=9.0 Hz), 7.12 (2H, d, J=8.6 Hz), 7.29 (2H, d, J=8.6 Hz), 8.45 (1H, dd, J=9.0 Hz, 2.8 Hz), 9.03 (1H, d, J=2.8 Hz).

The following compounds were produced in the same manner as in Reference Example 301.

Reference Example 302
Ethyl (E)-3-{4-[4-(3,4-dichlorobenzoylamino)-2-fluorophenoxy]phenyl}acrylate

Melting point: 166-167° C.

TABLE 44

Reference

Example

No.
R₁₉₇
R₁₉₈

¹H NMR (CDCl₃) δppm or MS

303
—H
—H

¹H NMR 1.35(3H, t, J = 7.1 Hz), 4.28(2H, q, J = 7.1 Hz), 6.43(1H, d, J = 16.0 Hz), 7.09(1H, d, J = 8.9 Hz), 7.20(2H, d, J = 8.7 Hz), 7.62(2H, d, J = 8.7 Hz), 7.70(1H, d, J = 16.0 Hz), 8.50(1H, dd, J = 8.9 Hz, 2.5 Hz), 9.04(1H, d, J = 2.5 Hz).

304
—H
—CH₃

¹H NMR 1.31(3H, t, J = 7.1 Hz), 2.58(3H, d, J = 1.2 Hz), 4.21(2H, q, J = 7.1 Hz), 6.14(1H, q, J = 1.2 Hz), 7.05(1H, d, J = 9.0 Hz), 7.16(2H, d, J = 8.7 Hz), 7.55(2H, d, J = 8.7 Hz), 8.48(1H, dd, J = 9.0 Hz, 2.8 Hz), 9.03(1H, d, J = 2.8 Hz).

305
—CH₃
—H
MS 328(M⁺)

Reference Example 306
Production of ethyl 3-[4-(5-nitropyridine-2-carbonyl)phenyl]propionate

A solution of bis(tributyltin) (1.37 g, 2.36 mmol) in toluene (7 mL) was added under an argon atmosphere to 2-chloro-5-nitropyridine (0.325 g, 2.05 mmol), bis(dibenzylideneacetone)palladium (0) (18.1 mg, 0.0315 mmol), tri(2-furyl)phosphine (29.3 mg, 0.126 mmol) and molecular sieves 4A (1.90 g), and the resulting solution was heated to reflux for 1 hour. To the reaction solution was added bis(dibenzylideneacetone)palladium (0) (27.2 mg, 0.0472 mmol) and tri(2-furyl)phosphine (43.9 mg, 0.189 mmol), and subsequently added a solution of 4-[2-ethoxycarbonyl]ethyl]benzoyl chloride (0.379 g, 1.57 mmol) in toluene (5 mL). The resulting reaction solution was stirred for 4 hours at 80° C. To the reaction solution was added saturated aqueous potassium fluoride and stirred for 0.5 hours at room temperature. Insoluble matter was then filtered off. The filtrate was extracted with ethyl acetate, and the ethyl acetate layer was washed with brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane→n-hexane:ethyl acetate=4:1), to thereby yield 0.323 g of the title compound.

Appearance: Pale yellow powder

¹H NMR (CDCl₃) δ 1.22 (3H, t, J=7.1 Hz), 2.65 (2H, t, 7.7 Hz), 3.03 (2H, t, J=7.7 Hz), 4.12 (2H, q, J=7.1 Hz), 7.34 (2H, d, J=8.3 Hz), 8.00 (2H, d, J=8.3 Hz), 8.18 (1H, d, J=8.5 Hz), 8.65 (1H, dd, J=8.5 Hz, 2.6 Hz), 9.49 (1H, d, J=2.6 Hz).

Reference Example 307
Production of ethyl 3-[4-(4-aminophenoxy)phenyl]propionate

To a suspension of 5% palladium-carbon (0.50 g) in ethanol (50 mL) was added ethyl 3-[4-(4-nitrophenoxy)phenyl]propionate (5.00 g, 15.9 mmol), and the resulting solution was subjected to catalytic reduction at atmospheric pressure and at room temperature. Once the absorption of hydrogen had stopped, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure, to thereby yield 4.52 g of the title compound.

Appearance: Light brown oil

¹H NMR (CDCl₃) δ 1.22 (3H, t, J=7.1 Hz), 2.57 (2H, t, J=7.8 Hz), 2.88 (2H, t, J=7.8 Hz), 3.55 (2H, brs), 4.10 (2H, q, J=7.1 Hz), 6.64 (2H, d, J=8.8 Hz), 6.78-6.86 (4H, m), 7.08 (2H, d, J=8.6 Hz).

The following compounds were produced in the same manner as in Reference Example 307.

TABLE 45

Reference

Example

No.
R₁₉₉
R₂₀₀

¹H NMR (CDCl₃) δppm

308
4-NH₂Ph—
2-(CH₂)₂COOCH₃
2.66(2H, t, J = 7.8 Hz), 3.00(2H, t, J = 7.8 Hz), 3.54 (2H, brs), 3.63(3H, s), 6.65(2H, d, J = 8.8 Hz), 6.70 (1H, d, J = 8.1 Hz), 6.79(2H, d, J = 8.8 Hz), 6.94(1H, t, J = 8.1 Hz), 7.08(1H, t, J = 8.1 Hz), 7.19(1H, d, J = 8.1 Hz).

309
4-NH₂Ph—
3-(CH₂)₂COOC₂H₅
1.21(3H, t, J = 7.2 Hz), 2.56(2H, t, J = 7.9 Hz), 2.87 (2H, t, J = 7.9 Hz), 3.54(2H, brs), 4.10(2H, q, J = 7.2 Hz), 6.66(2H, d, J = 8.8 Hz), 6.70-6.76(2H, m), 6.79-6.87(3H, m), 7.16(1H, t, J = 7.8 Hz).

310
2-NH₂Ph—
4-(CH₂)₂COOC₂H₅
1.22(3H, t, J = 7.2 Hz), 2.56(2H, t, J = 7.8 Hz), 2.89 (2H, t, J = 7.8 Hz), 3.55(2H, brs), 4.11(2H, q, J = 7.2 Hz), 6.72(1H, t, J = 7.8 Hz), 6.79-6.92(4H, m), 6.93 (1H, t, J = 7.8 Hz), 7.12(2H, d, J = 8.5 Hz).

311
4-NH₂Ph—
4-COOC₂H₅
1.37(3H, t, J = 7.1 Hz), 4.36(2H, q, J = 7.1 Hz), 4.00-4.50(2H, m), 6.78(2H, d, J = 8.9 Hz), 6.89-6.95 (4H, m), 7.97(2H, d, J = 8.9 Hz).

312
3-NH₂Ph—
4-(CH₂)₂COOC₂H₅
1.22(3H, t, J = 7.2 Hz), 2.59(2H, t, J = 7.8 Hz), 2.91 (2H, t, J = 7.8 Hz), 3.65(2H, brs), 4.12(2H, q, J = 7.2 Hz), 6.29(1H, t, J = 2.2 Hz), 6.32-6.41(2H, m), 6.92 (2H, d, J = 8.6 Hz), 7.06(1H, t, J = 8.0 Hz), 7.13(2H, d, J = 8.6 Hz).

313

embedded image

3-COOCH₃
3.56(2H, brs), 3.89(3H, s), 6.80(1H, dd, J = 8.6 Hz, 0.7 Hz), 7.11(1H, dd, J = 8.6 Hz, 3.0 Hz), 7.25-7.29 (1H, m), 7.39-7.44(1H, m), 7.69-7.72(2H, m), 7.78-7.82(1H, m).

TABLE 46

Reference

Example

No.
R₂₀₁
Form

¹H NMR (solvent) δppm

314
—Ac
hydrochloride
(DMSO-d₆) 2.53(3H, s), 3.30-4.20(3H, m), 6 88(1H, d, J = 8.8 Hz), 6.99-7.05(3H, m), 7.22(1H, t, J = 8.8 Hz), 7.96(1H, d, J = 8.9 Hz).

315
—CH₂COOCH₃
free
(CDCl₃) 3.57(2H, s), 3.60-3.80(5H, m), 6.41(1H, ddd, J = 1.2 Hz, 2.6 Hz, 8.6 Hz), 6.50(1H, dd, J = 2.6 Hz, 12.0 Hz), 6.80- 6.95(3H, m), 7.18(2H, d, J = 8.4 Hz).

316
—(CH₂)₂COOC₂H₅
free
(CDCl₃) 1.21(3H, t, J = 7.1 Hz), 2.56(2H, t, J = 7.8 Hz), 2.87(2H, t, J = 7.8 Hz), 3.66(2H, brs), 4.10(2H, q, J = 7.1 Hz), 6.34-6.43(1H, m), 6.48(1H, dd, J = 12.0 Hz, 2.7 Hz), 6.77- 6.93(3H, m), 7.08(2H, d, J = 8.7 Hz).

317
—H
free
(CDCl₃) 3.66(2H, brs), 6.35-6.44(1H, m), 6.49(1H, dd, J = 12.0 Hz, 2.7 Hz), 6.83- 6.96(3H, m), 7.01(1H, dd, J = 9.0 Hz, 8.0 Hz), 7.26(2H, t, J = 8.0 Hz).

318
—(CH₂)₃COOC₂H₅
free
(CDCl₃) 1.23(3H, t, J = 7.1 Hz), 1.83- 1.97(2H, m), 2.28(2H, t, J = 7.5 Hz), 2.57(2H, t, J = 7.6 Hz), 3.66(2H, brs), 4.09(2H, q, J = 7.1 Hz), 6.34-6.43(1H, m), 6.48(1H, dd, J = 12.0 Hz, 2.7 Hz), 6.81(2H, d, J = 8.5 Hz), 6.88(1H, dd, J = 9.0 Hz, 8.0 Hz), 7.05(2H, d, J = 8.5 Hz).

319
—COOC₂H₅
free
(DMSO-d₆) 1.29(3H, t, J = 7.1 Hz), 4.27(2H, q, J = 7.1 Hz), 5.42(2H, brs), 6.41(1H, dt, J = 1.6 Hz, 8.6 Hz), 6.50(1H, dd, J = 2.5 Hz, 13.3 Hz), 6.90-7.00(3H, m), 7.91(2H, d, J = 9.7 Hz).

320
—NHCH₂COOC₂H₅
free
(CDCl₃) 1.29(3H, t, J = 7.1 Hz), 3.62(2H, s), 3.86(2H, s), 4.12(1H, s), 4.23(2H, q, J = 7.1 Hz), 6.35-6.39(1H, m), 6.48(1H, dd, J = 2.7 Hz, 12.1 Hz), 6.55(2H, d, J = 8.9 Hz), 6.80- 6.85(3H, m).

321

embedded image

free
(CDCl₃) 3.70(2H, brs), 3.95-4.15(4H, m), 5.76(1H, s), 6 38-6.42(1H, m), 6.49(1H, dd, J = 2.7 Hz, 14.7 Hz), 6.85-6.93(3H, m), 7.39(2H, d, J = 8.7 Hz).

TABLE 47

Reference

Example

No.
R₂₀₂
R₂₀₃
R₂₀₄

¹H NMR (CDCl₃) δppm

322
—H
—H
—C₂H₅
1.38(3H, t, J = 7.3 Hz), 4.35(2H, q, J = 7.3 Hz), 6.82(1H, d, J = 8.6 Hz), 7.04-7.14(3H, m), 7.75(1H, d, J = 3.0 Hz), 8.01-8.04(2H, m).

323
—H
—H
—CH₃
3.30 (2H, brs), 3.89(3H, s), 6.82(1H, d, J = 8.6 Hz), 7.04-7.13 (3H, m), 7.75(1H, d, J = 3.0 Hz), 8.02(2H, dd, J = 6.6 Hz, 2.0 Hz).

324
—F
—H
—CH₃
3.57(2H, brs), 3.91(3H, s), 6.87(1H, d, J = 8.6 Hz), 7.10-7.23(2H, m), 7.64(1H, d, J = 3.0 Hz), 7.80- 7.82(1H, m), 7.83-7.85(1H, m).

325
—F
—H
—C₂H₅
1.38(3H, t, J = 7.1 Hz), 4.37(2H, q, J = 7.1 Hz), 6.87(1H, d, J = 8.6 Hz), 7.12(1H, dd, J = 8.6 Hz, 3.0 Hz), 7.15-7.22(1H, m), 7.64(1H, d, J = 3.0 Hz), 7.81- 7.86(2H, m).

326
—CH₃
—H
—CH₃
2.29(3H, s), 3.56(2H, brs), 3.89(3H, s), 6.79(1H, d, J = 8.6 Hz), 6.92(1H, d, J = 8.6 Hz), 7.11(1H, dd, J = 8.6 Hz, 3.0 Hz), 7.71(1H, d, J = 3.0 Hz), 7.85(1H, dd, J = 8.6 Hz, 2.4 Hz), 7.94(1H, d, J = 2.4 Hz).

327
—OCH₃
—H
—C₂H₅
1.38(3H, t, J = 7.1 Hz), 3.55(2H, brs), 3.85(3H, s), 4.37(2H, q, J = 7.1 Hz), 6.79-6.83(1H, m), 7.02- 7.10(2H, m), 7.63-7.67(3H, m).

328
—H
—OCH₃
—CH₃
3.63(2H, brs), 3.86(6H, s), 6.54-6.58(1H, m), 6.68(1H, d, J = 2.2 Hz), 6.81-6.84(1H, m), 7.13(1H, dd, J = 8.6 Hz, 3.0 Hz), 7.77(1H, dd, J = 3.0 Hz, 0.5 Hz), 7.83(1H, d, J = 8.9 Hz).

329
—H
—CH₃
—CH₃
2.58(3H, s), 3.63(2H, brs), 3.86(3H, s), 6.80-6.88(3H, m), 7.13(1H, dd, J = 8.6 Hz, 3.0 Hz), 7.75(1H, d, J = 3.0 Hz), 7.92-7.96(1H, m).

330
—Cl
—H
—CH₃
3.62(2H, brs), 3.91(3H, s), 6.88(1H, d, J = 8.6 Hz), 7.08-7.15(2H, m), 7.68(1H, d, J = 3.0 Hz), 7.91(1H, dd, J = 8.6 Hz, 2.1 Hz), 8.13(1H. d, J = 2.1 Hz).

TABLE 48

Reference

Example

No.
R₂₀₅
R₂₀₆
M

¹H NMR (CDCl₃) δppm or MS

331
—H
—CH₃
2
MS 272(M⁺)

332
—OCH₃
—C₂H₅
2

¹H NMR 1.25(3H, t, J = 7.1 Hz), 2.63(2H, t, J = 7.5 Hz), 2.94(2H, t, J = 7.5 Hz), 3.43(2H, brs), 3.77(3H, s), 4.14(2H, q, J = 7.1 Hz), 6.71-6.86(3H, m), 6.98(1H, d, J = 8.0 Hz), 7.06(1H, dd, J = 8.6 Hz, 2.9 Hz), 7.60(1H, d, J = 2.9 Hz).

333
—H
—CH₃
1

¹H NMR 3.60(2H, s), 3.69(3H, s), 6.76(1H, d, J = 8.6 Hz), 6.99-7.10 (3H, m), 7.24-7.27(2H, m), 7.71(1H, d, J = 3.0 Hz).

334
—H
—C₂H₅
2

¹H NMR 1.21(3H, t, J = 7.1 Hz), 2.58(2H, t, J = 7.7 Hz), 2.90(2H, t, J = 7.7 Hz). 4.11(2H, q, J = 7.1 Hz), 6.72(1H, d, J = 8.6 Hz), 6.95(2H, d, J = 8.5 Hz), 7.05(1H, dd, J = 8.6 Hz, 3.0 Hz), 7.14(2H, d, J = 8.5 Hz), 7.68(1H, d, J = 3.0 Hz).

335
—OCH₃
—CH₃
2

¹H NMR 2.62-2.68(2H, m), 2.91-2.97(2H, m), 3.45(2H, brs), 3.69(3H, s), 3.77(3H, s), 6.74-6.79(2H, m), 6.82(1H, d, J = 1.8 Hz), 6.98(1H, d. J = 7.9 Hz), 7.04-7.26(1H, m), 7.64(1H, d, J = 3.0 Hz).

336
—OC₂H₅
—C₂H₅
2

¹H NMR 1.20(3H, t, J = 7.0 Hz), 1.25(3H, t, J = 7.1 Hz), 2.51-2.68 (2H, m), 2.81-3.01(2H, m), 3.19-3.63(2H, m), 3.98(2H, q, J = 7.0 Hz), 4.14(2H, q, J = 7.1 Hz), 6.69- 6.83(3H, m), 6.95-7.09(2H, m), 7.60-7.67(1H, m).

337
—F
—C₂H₅
2

¹H NMR 1.25(3H, t, J = 7.1 Hz), 2.52-2.71(2H, m), 2.86- 3.02(2H, m), 3.47(2H, brs), 4.14(2H, q, J = 7.1 Hz), 6.81(1H, d, J = 8.6 Hz), 6.93-7.04(2H, m), 7.05-7.13(2H, m), 7.63(1H, d, J = 2.9 Hz).

338
—H
—C₂H₅
4

¹H NMR 1.25(3H, t, J = 7.2 Hz), 1.55-1.80(4H, m), 2.32(2H, t, J = 7.0 Hz), 2.60(2H, t, J = 7.0 Hz), 3.49(2H, brs), 4.12(2H, q, J = 7.2 Hz), 6.74(1H, d, J = 8.5 Hz), 6.97(2H, d, J = 8.5 Hz), 7.06(1H, dd, J = 8.5 Hz, 3.0 Hz), 7.14(2H, d, J = 8.5 Hz), 7.71(1H, d, J = 3.0 Hz).

339
—H
—C₂H₅
3

¹H NMR 1.26(3H, t, J = 7.5 Hz), 1.94(2H, dt, J = 15.0 Hz, 7.5 Hz), 2.33(2H, t, J = 7.5 Hz), 2.63(2H, t, J = 7.5 Hz), 3.50(2H, brs), 4.13 (2H, q, J = 7.0 Hz), 6.75(1H, d, J = 8.5 Hz), 6.98(2H, d, J = 8.5 Hz), 7.07(1H, dd, J = 8.5 Hz, 3.0 Hz), 7.15(2H, d, J = 8.5 Hz), 7.72(1H, d, J = 3.0 Hz).

TABLE 49

Reference

Example

No.
Xa₈
M
Form

¹H NMR (solvent) δppm

340
—NH—
2
free
(CDCl₃) 1.24(3H, t, J = 7.1 Hz), 2.60(2H, t, J = 7.6 Hz), 2.90(2H, t, J = 7.6 Hz), 3.35(2H, brs), 4.13(2H, q, J = 7.1 Hz), 6.16(1H, brs), 6.77(1H, d, J = 8.6 Hz), 6.98(1H, dd, J = 2.9 Hz, 8.6 Hz), 7.00- 7.15(4H, m), 7.78(1H, d, J = 2.9 Hz).

341
—N(CH₃)—
0
hydrochloride
(DMSO-d₆) 1.30(3H, t, J = 7.1 Hz), 3.43(3H, s), 4.23 (2H, q, J = 7.1 Hz), 7.03(1H, d, J = 9.1 Hz), 7.30(2H, d, J = 8.6 Hz), 7.55(1H, d, J = 9.1 Hz), 7.93(2H, d, J = 8.6 Hz), 8.05(1H, s).

342
—N(CH₃)—
2
free
(CDCl₃) 1.24(3H, t, J = 7.2 Hz), 2.63(2H, t, J = 7.7 Hz), 2.95(2H, t, J = 7.7 Hz), 3.53(3H, s), 4.14(2H, q, J = 7.2 Hz), 6.52(1H, d, J = 9.5 Hz), 7.07(1H, dd, J = 2.7 Hz, 9.5 Hz), 7.10(2H, d, J = 8.3 Hz), 7.22(2H, d, J = 8.3 Hz), 7.83(1H, d, J = 2.7 Hz).

343
—N(CH₂Ph)—
2
dihydrochloride
(CDCl₃) 1.22(3H, t, J = 7.1 Hz), 2.57(2H, t, J = 7.7 Hz), 2.90(2H, t, J = 7.7 Hz), 4.11(2H, q, J = 7.1 Hz), 5.28 (2H, s), 6.65(1H, d, J = 8.8 Hz), 7.08(2H, d, J = 7.8 Hz), 7.15-7.24(7H, m), 8.27(1H, d, J = 8.8 Hz), 8.80(lH, s).

344
—CO—
2
free
(CDCl₃) 1.21(3H, t, J = 7.1 Hz), 2.63(2H, t, J = 7.7 Hz), 2.98(2H, t, J = 7.7 Hz), 4.10(2H, q, J = 7.1 Hz), 7.18 (2H, brs), 7.27(2H, d, J= 8.1 Hz), 7.32(1H, d, J = 8.3 Hz), 7.88-7.99(3H, m), 8.27(1H, s).

(—CO— means a group of

embedded image

Hereinafter —CO— indicates the same meaning.)

TABLE 50

Reference

Example

No.
R₂₀₇
R₂₀₈
R₂₀₉
M

¹H NMR (solvent) δppm

345
—H
—H
—C(CH₃)₃
0
(CDCl₃) 1.51(9H, s), 3.49(2H, brs), 6.41(1H, brs), 6.72(1H, d, J = 8.6 Hz), 7.00(2H, d, J = 8.9 Hz), 7.06(1H, dd, J = 8.6 Hz, 3.0 Hz), 7.32(2H, d, J = 8.9 Hz), 7.69(1H, d, J = 3.0 Hz).

346
—H
—Ac
—C₂H₅
1
(CDCl₃) 1.27(3H, t, J = 7.1 Hz), 1.94(3H, s), 3.60(2H, brs), 4.18(2H, q, J = 7.1 Hz), 4.35(2H, s), 6.82(1H, d, J = 8.6 Hz), 7.07(2H, d, J = 8.8 Hz), 7.12(1H, dd, J = 3.0 Hz, 8.6 Hz), 7.31(2H, d, J = 8.8 Hz), 7.73(1H, d, J = 3.0 Hz).

347
—H
—Ac
—C₂H₅
2
(CDCl₃) 1.23(3H, t, J = 7.1 Hz), 1.85(3H, s), 2.57(2H, t, J = 7.4 Hz), 3.60(2H, s), 3.98(2H, t, J = 7.4 Hz), 4.07(2H, q, J = 7.1 Hz), 6.82(1H, d, J = 8.6 Hz), 7.08(2H, d, J = 8.8 Hz), 7.10-7.15 (3H, m), 7.74(1H, d, J = 3.0 Hz).

348
—CH₃
—Ac
—C₂H₅
1
(CDCl₃) 1.28(3H, t, J = 7.1 Hz), 1.95(3H, s), 2.23(3H, s), 3.52(2H, s), 4.19(2H, q, J = 7.1 Hz), 4.34(2H, s), 6.73(1H, d, J = 8.6 Hz), 6.91(1H, d, J = 8.4 Hz), 7.05-7.15(2H, m), 7.20(1H, s), 7.66(1H, s).

349
—H
—CH₃
—CH₃
1
(CDCl₃) 3.05(3H, s), 3.45(2H, brs), 3.72(3H, s), 4.05(2H, s), 6.67(3H, d, J = 9.0 Hz), 6.98(2H, d, J = 2.0 Hz), 7.04(1H, dd, J = 8.6 Hz, 3.0 Hz), 7.69(1H, d, J = 2.0 Hz).

350
—H
—CH₃
—C₂H₅
1
(CDCl₃) 1.25(3H, t, J = 7.1 Hz), 3.05(3H, s), 3.45(2H, brs), 4.03(2H, s), 4.18(2H, q, J = 7.1 Hz), 6.65-6.69(3H, m), 6.96 (2H, d, J = 9.0 Hz), 7.04(1H, dd, J = 2.9 Hz, 8.6 Hz), 7.69(1H, d, J = 2.9 Hz).

351
—H
—C₂H₅
—C₂H₅
1
(CDCl₃) 1.20(3H, t, J = 7.2 Hz), 1.26(3H, t, J = 7.2 Hz), 3.40-3.46(4H, m), 3.99(2H, s), 4.19(2H, q, J = 7.2 Hz), 6.63 (2H, d, J = 9.1 Hz), 6.67(1H, d, J = 8.6 Hz), 6.95(2H, d, J = 9.1 Hz), 7.04(1H, dd, J = 3.2 Hz, 8.6 Hz), 7.69(1H, d, J = 3.2 Hz).

352
—CH₃
—CH₃
—C₂H₅
1
(CDCl₃) 1.26(3H, t, J = 7.1 Hz), 2.13(3H, s), 3.05(3H, s), 3.41(2H, brs), 4.02(2H, s), 4.19(2H, q, J = 7.1 Hz), 6.46-6.68 (3H, m), 6.89(1H, d, J = 8.6 Hz), 7.03(1H, dd, J = 8.6 Hz, 3.0 Hz), 7.67(1H, d, J = 3.0 Hz).

353
—OCH₃
—CH₃
—C₂H₅
1
(CDCl₃) 1.26(3H, t, J = 7.1 Hz), 3.07(3H, s), 3.42(2H, brs), 3.75(3H, s), 4.04(2H, s), 4.19(2H, q, J = 7.1 Hz), 6.24(1H, dd, J = 8.7 Hz, 2.8 Hz), 6.33(1H, d, J = 2.8 Hz), 6.67(1H, d, J = 8.6 Hz), 6.95(1H, d, J = 8.7 Hz), 7.02(1H, dd, J = 8.6 Hz, 3.0 Hz), 7.63(1H, d, J = 2.8 Hz).

354
—OCH₃
—C₂H₅
—C₂H₅
1
(DMSO-d₆) 1.13(3H, t, J = 7.1 Hz), 1.20(3H, t, J = 7.1 Hz), 3.41(2H, q, J = 7.1 Hz), 3.63(3H, s), 4.09-4.17(4H, m), 4.81 (2H, brs), 6.11(1H, dd, J = 8.7 Hz, 2.8 Hz), 6.26(1H, d, J = 2.8 Hz), 6.55(1H, d, J = 8.6 Hz), 6.79(1H, d, J = 8.7 Hz), 6.99(1H, dd, J = 8.7 Hz, 3.0 Hz), 7.40(1H, d, J = 2.3 Hz).

TABLE 51

Reference

Example

No.
R₂₁₀

¹H NMR (CDCl₃) δppm

355

embedded image

1.48(9H, s), 3.04(4H, t, J = 5.0 Hz), 3.54(2H, brs), 3.57(4H, t, J = 5.0 Hz), 6.65(2H, d, J = 9.0 Hz), 6.82(2H, d, J = 9.0 Hz), 6.88(4H, ABq, J = 9.0 Hz).

356

embedded image

1.78(2H, m), 2.03(2H, m), 2.86(2H, m), 3.39(3H, s), 3.42(2H, m), 3.52(2H, brs), 3.70(1H, m), 4.72(2H, s), 6.64(2H, d, J = 9.0 Hz), 6.82(2H, d, J = 9.0 Hz), 6.88(4H, ABq, J = 9.0 Hz).

357

embedded image

1.27(3H, t, J = 7.0 Hz), 1.88(2H, dq, J = 3.5 Hz, 12.5 Hz), 2.03(2H, dd, J = 12.5 Hz, 3.0 Hz), 2.40(1H, m), 2.72(2H, dt, J = 2.5 Hz, 12.0 Hz), 3.51-3.53(4H, m), 4.16(2H, q, J = 7.0 Hz), 6.65(2H, d, J = 8.5 Hz), 6.82(2H, d, J = 8.5 Hz), 6.88(4H, s).

358

embedded image

1.48(9H, s), 1.74(2H, brd, J = 11.5 Hz), 1.85(2H, m), 2.74(2H, m), 2.77(3H, s), 3.53(2H, brs), 3.60(2H, brd, J = 12.0 Hz), 4.12(1H, brs), 6.65(2H, d, J = 8.5 Hz), 6.82(2H, d, J = 8.5 Hz), 6.87(4H, s).

359

embedded image

1.30(3H, t, J = 7.0 Hz), 1.81(2H, m), 2.03(2H, m), 2.84(1H, m), 2.95(1H, m), 3.35(1H, m), 3.44(1H, m), 3.54(3H, m), 4.15(2H, s), 4.23(2H, q, J = 7.0 Hz), 6.65(2H, d, J = 9.0 Hz), 6.82(2H, d, J = 9.0 Hz), 6.88(4H, s).

360

embedded image

1.48(9H, s), 1.60(2H, m), 1.80(2H, m), 2.59(1H, m), 2.78(2H, brs), 3.57(2H, brs), 4.23(2H, brs), 4.12(1H, brs), 6.67(2H, d, J = 9.0 Hz), 6.86(2H, d, J = 9.0 Hz), 6.87(2H, d, J = 9.0 Hz), 7.09(2H, d, J = 9.0 Hz).

TABLE 52

Reference

Example

No.
R₂₁₁
R₂₁₂

¹H NMR (CDCl₃) δ ppm or MS

361
—H
—Ac

¹H NMR 2.50 (3H, s), 3.60 (2H, brs), 6.80-7.90 (7H,

m).

362
—H
—NHCONHPh

¹H NMR 3.55 (2H, s), 6.76 (1H, d, J = 8.6 Hz),

6.89 (1H, s), 6.95-7.02 (3H, m), 7.03-7.12 (2H, m),

7.21-7.36 (6H, m), 6.68 (1H, d, J = 2.9 Hz).

363
—H

embedded image

¹H NMR 1.70-1.90 (4H, m), 2.18 (2H, brs), 2.40- 2.50 (2H, m), 3.13-3.29 (2H, m), 4.56 (2H, s), 6.76 (1H, d, J = 8.6 Hz), 7.01 (2H, d, J = 8.6 Hz), 7.09 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.23 (2H, d, J = 8.6 Hz), 7.72 (1H, d, J = 3.0 Hz).

364
—H
—CH(CH₃)COOCH₃
MS 272 (M⁺)

365
—H
—C(CH₃)₂COOCH₃
MS 286 (M⁺)

366
—H

embedded image

¹H NMR 1.50 (9H, s), 3.55 (2H, brs), 3.72 (2H, m), 3.78 (2H, m), 4.25 (2H, s), 6.80 (1H, d, J = 8.6 Hz), 7.08 (2H, d, J = 8.9 Hz), 7.10 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.24 (2H, d, J = 8.9 Hz), 7.72 (1H, d, J = 3.0 Hz).

367
—H

embedded image

¹H NMR 1.48 (9H, s), 3.07 (4H, brs), 3.47 (2H, brs), 3.57 (4H, t, J = 5.0 Hz), 6.72 (1H, d, J = 8.5 Hz), 6.92 (2H, d, J = 9.0 Hz), 7.00 (2H, d, J = 9.0 Hz), 7.06 (1H, dd, J = 8.5 Hz, 3.0 Hz), 7.70 (1H, d, J = 3.0 Hz).

368
—H

embedded image

¹H NMR 1.27 (3H, t, J = 7.0 Hz), 1.44 (2H, dq, J = 4.0 Hz, 12.5 Hz), 1.83 (2H, brd, J = 13.0 Hz), 1.91 (1H, m), 2.28 (2H, d, J = 7.0 Hz), 2.70 (2H, dt, J = 2.5 Hz, 12.0 Hz), 3.46 (2H, brs), 3.57 (2H, brd, J = 12.0 Hz), 4.15 (2H, q, J = 7.0 Hz), 6.69 (1H, d, J = 8.5 Hz), 6.92 (2H, d, J = 9.0 Hz), 6.97 (2H, d, J = 9.0 Hz), 7.05 (2H, dd, J = 8.5 Hz, 3.0 Hz), 7.70 (1H, d, J = 3.0 Hz).

369
—CH₃

embedded image

¹H NMR 1.27 (3H, t, J = 7.1 Hz), 1.86-2.05 (4H, m), 2.14 (3H, s), 2.35-2.44 (1H, m), 2.69-2.79 (2H, m), 3.43 (2H, brs), 3.55-3.59 (2H, m), 4.16 (2H, q, J = 7.1 Hz), 6.62 (1H, d, J = 8.6 Hz), 6.74-6.82 (2H, m), 6.89 (1H, d, J = 8.6 Hz), 7.03 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.68 (1H, d, J = 3.0 Hz).

370
—OCH₃

embedded image

¹H NMR 1.27 (3H, t, J = 7.1 Hz), 1.38-1.50 (2H, m), 1.87-2.06 (3H, m), 2.29 (2H, d, J = 7.1 Hz), 2.69- 2.77 (2H, m), 3.42 (2H, brs), 3.58 (2H, d, J = 12.2 Hz), 3.75 (3H, s), 4.15 (2H, q, J = 7.1 Hz), 6.49 (1H, dd, J = 8.6 Hz, 2.6 Hz), 6.59 (1H, d, J = 2.6 Hz), 6.70 (1H, d, J = 8.6 Hz), 6.96 (1H, d, J = 8.6 Hz), 7.04 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.65 (1H, d, J = 3.0 Hz).

371
—CH₃

embedded image

¹H NMR 1.27 (3H, t, J = 7.1 Hz), 1.37-1.49 (2H, m), 1.80-2.04 (3H, m), 2.13 (3H, s), 2.28 (2H, d, J = 6.9 Hz), 2.69 (2H, dd, J = 12.0 Hz, 9.9 Hz), 3.41- 3.59 (4H, m), 4.15 (2H, q, J = 7.3 Hz), 6.60 (1H, d, J = 8.6 Hz), 6.73-6.81 (2H, m), 6.88 (1H, d, J = 8.6 Hz), 7.02 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.66 (1H, d, J = 2.8 Hz).

TABLE 53

Reference

Example

No.
R₂₁₃

¹H NMR (CDCl₃) δ ppm

372

embedded image

3.51 (2H, brs), 3.94-4.12 (4H, m), 5.78 (1H, s), 6.73 (1H, d, J = 8.6 Hz), 6.99-7.09 (3H, m), 7.43 (2H, d, J = 8.5 Hz), 7.70 (1H, d, J = 2.7 Hz).

373

embedded image

0.05 (6H, s), 0.91 (9H, s), 1.77-1.88 (2H, m), 2.62- 2.68 (2H, m), 3.62-3.66 (2H, m), 6.73 (1H, d, J = 8.9 Hz), 6.95-7.17 (5H, m), 7.72 (1H, d, J = 3.0 Hz).

374

embedded image

−0.07 (6H, s), 0.81 (9H, s), 2.73 (2H, t, J = 7.3 Hz), 3.72 (2H, t, J = 7.3 Hz), 6.66 (1H, dd, J = 8.6 Hz, 0.7 Hz), 6.88-6.92 (2H, m), 6.99 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.10 (2H, d, J = 8.6 Hz), 7.64 (1H, d, J = 3.0 Hz).

375
morpholino
3.09-3.13 (4H, m), 3.84-3.87 (4H, m), 6.71 (1H, d, J =

8.6 Hz), 6.90 (2H, d, J = 8.9 Hz), 7.02 (2H, d,

J = 9.2 Hz), 7.05 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.69

(1H, d, J =3.0 Hz)

376

embedded image

3.12 (1H, dd, J = 14.2 Hz, 9.8 Hz), 3.52 (1H, dd, J = 14.2 Hz, 3.8 Hz), 3.70 (2H, s), 4.51 (1H, dd, J = 9.8 Hz, 3.8 Hz), 6.78 (1H, d, J = 8.6 Hz), 7.02 (2H, d, J = 8.6 Hz), 7.09 (1H, dd, J = 8.6 Hz, 3.1 Hz), 7.20 (2H, d, J = 8.6 Hz), 7.71 (1H, d, J = 3.1 Hz), 7.98 (1H, brs).

377
—CH═C(COOCH₃)₂
3.84 (3H, s), 3.85 (3H, s), 6.82 (1H, d, J = 8.3 Hz),

7.03 (2H, d, J = 8.9 Hz), 7.02-7.10 (1H, m), 7.42 (2H,

d, J = 8.9 Hz), 7.70-7.76 (2H, m).

378

embedded image

1.27 (3H, t, J = 7.0 Hz), 1.88 (2H, m), 2.02 (2H, m), 2.40 (1H, m), 2.75 (2H, dt, J = 3.0 Hz, 12.0 Hz), 3.46 (2H, brs), 3.56 (2H, dt, J = 13.0 Hz, 3.0 Hz), 4.15 (2H, q, J = 7.0 Hz), 6.70 (1H, d, J = 8.5 Hz), 6.92 (2H, d, J = 9.0 Hz), 6.98 (2H, d, J = 9.0 Hz), 7.05 (1H, dd, J = 8.5 Hz, 3.0 Hz), 7.70 (1H, d, J = 3.0 Hz).

379

embedded image

1.28 (3H, t, J = 7.0 Hz), 1.66-1.72 (2H, m), 1.82 (1H, m), 2.01 (1H, m), 2.68 (1H, m), 2.78 (1H, m), 2.99 (1H, dd, J = 12.0 Hz, 10.0 Hz), 3.39 (1H, brd, J = 12.0 Hz), 3.47 (2H, brs), 3.62 (1H, dd, J = 12.0 Hz, 4.0 Hz), 4.17 (2H, q, J = 7.0 Hz), 6.70 (1H, d, J = 8.5 Hz), 6.94 (2H, d, J = 9.0 Hz), 6.93 (2H, d, J = 9.0 Hz), 7.06 (1H, dd, J = 8.5 Hz, 3.0 Hz), 7.70 (1H, d, J = 3.0 Hz).

380
—CH(CH₃)CH₂COOC₂H₅
1.18 (3H, t, J = 7.2 Hz), 1.27 (3H, d, J = 7.0 Hz), 2.43-

2.60 (2H, m), 3.19-3.29 (1H, m), 3.48 (2H, brs),

4.06 (2H, q, J = 7.2 Hz), 6.72 (1H, d, J = 8.7 Hz),

6.96 (2H, d, J = 8.6 Hz), 7.05 (1H, dd, J = 8.7 Hz,

3.0 Hz), 7.16 (2H, d, J = 8.6 Hz), 7.70 (1H, d,

J = 3.0 Hz).

TABLE 54

Reference

Example

No.
R₂₁₄

¹H NMR (CDCl₃) δ ppm or MS

381

embedded image

MS 460 (M⁺)

382

embedded image

¹H NMR 1.90-2.03 (1H, m), 2.20- 2.55 (3H, m), 3.11-3.25 (1H, m), 3.25- 3.38 (1H, m), 3.43 (2H, s), 3.57 (2H, s), 3.60-3.88 (2H, m), 4.70 (1H, d, J = 6.5 Hz), 5.18 (1H, d, J = 6.5 Hz), 6.76 (1H, d, J = 8.6 Hz), 7.02 (2H, d, J = 8.5 Hz), 7.08 (1H, dd, J = 8.5 Hz, 3.0 Hz), 7.20- 7.35 (7H, m), 7.73 (1H, dd, J = 3.1 Hz, 0.5 Hz).

383

embedded image

¹H NMR 2.25 (4H, t, J = 5.0 Hz), 3.19 (3H, s), 3.22 (4H, t, J = 5.0 Hz), 3.43 (2H, s), 3.56 (2H, brs), 6.77 (1H, d, J = 8.6 Hz), 7.00 (2H, d, J = 9.2 Hz), 7.05 (2H, d, J = 9.2 Hz), 7.09 (1H, dd, J = 8.6 Hz, 2.8 Hz), 7.17-7.35 (5H, m), 7.72 (1H, d, J = 2.8 Hz).

384

embedded image

¹H NMR 2.20 (3H, s), 3.07 (1H, dd, J = 14.2 Hz, 10.1 Hz), 3.50 (2H, brs), 3.52 (1H, dd, J = 14.2 Hz, 3.8 Hz), 4.51 (1H, dd, J = 10.1 Hz, 3.8 Hz), 6.73 (1H, d, J = 8.5 Hz), 6.90 (1H, d, J = 8.5 Hz), 7.03 (1H, dd, J = 8.5 Hz, 3.0 Hz), 7.08 (1H, dd, J = 8.5 Hz, 3.0 Hz), 7.10 (1H, d, J = 3.0 Hz), 7.67 (1H, d, J = 3.0 Hz), 8.10 (1H, brs).

385

embedded image

¹H NMR 3.62 (2H, brs), 3.97 (3H, s), 6.86 (1H, d, J = 8.6 Hz), 7.12 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.32 (1H, dd, J = 8.9 Hz, 2.5 Hz), 7.41 (1H, d, J = 2.1 Hz), 7.72-7.75 (2H, m), 7.92 (1H, d, J = 8.9 Hz), 8.02 (1H, dd, J = 8.6 Hz, 1.7 Hz), 8.56 (1H, s).

386

embedded image

¹H NMR 3.63 (2H, brs), 3.98 (3H, s), 6.90 (1H, d, J = 8.6 Hz), 6.94 (1H, d, J = 8.2 Hz), 7.15 (1H, dd, J = 8.7 Hz, 3.0 Hz), 7.54-7.57 (1H, m), 7.62-7.68 (1H, m), 7.77 (1H, d, J = 3.0 Hz), 8.18 (1H, d, J = 8.2 Hz), 8.32-8.35 (1H, m), 9.03 (1H, d, J = 8.7 Hz).

387

embedded image

¹H NMR 1.45 (3H, t, J = 7.1 Hz), 3.57 (2H, brs), 4.47 (2H, q, J = 7.1 Hz), 6.83 (1H, d, J = 8.6 Hz), 7.12 (1H, dd, J = 8.6 Hz, 3.1 Hz), 7.38 (1H, dd, J = 9.4 Hz, 2.6 Hz), 7.43-7.49 (2H, m), 7.75 (1H, d, J = 3.0 Hz), 7.89 (1H, d, J = 8.2 Hz), 8.10 (1H, dd, J = 7.3 Hz, 1.3 Hz), 8.93 (1H, d, J = 9.4 Hz).

TABLE 55

Reference

Example

No.
R₂₁₅
R₂₁₆
R₂₁₇
Xa₉
Xa₁₀

¹H NMR (CDCl₃) δ ppm or MS

388
—H
—CH₃
piperonyl
—CH₂—
—CH₂—
MS 474 (M⁺)

389
—H
—F
benzyl
none
none

¹H NMR 2.46 (4H, brs),

3.54 (6H, brs), 6.83 (1H, d, J =

8.7 Hz), 7.09 (1H, dd, J =

8.6 Hz, 3.0 Hz), 7.16-7.36 (8H,

m), 7.61 (1H, d, J = 3.0 Hz).

390
—H
—OCH₃
piperonyl
—CH₂—
—CH₂—

¹H NMR 2.31-2.41 (4H, m),

2.59-2.65 (2H, m), 2.92-

2.98 (2H, m), 3.41 (4H, brs),

3.62-3.65 (2H, m), 3.76 (3H, s),

5.95 (2H, s), 6.71-6.79 (4H, m),

6.83-6.85 (2H, m), 6.97 (1H, d,

J = 8.1 Hz), 7.06 (1H, dd, J =

8.7 Hz, 3.0 Hz), 7.63 (1H, d,

J = 2.8 Hz).

391
—H
—H
—COOC(CH₃)₃
—CH₂—
—CH(OH)—

¹H NMR 1.47 (9H, s), 2.81-

2.98 (2H, m), 3.01-3.20 (1H,

m), 3.29 (3H, brs), 3.39 (2H,

brs), 3.51 (2H, brs), 3.58-

3.78 (3H, m), 4.58 (1H, q, J =

7.0 Hz), 6.75 (1H, d, J = 8.8 Hz),

6.99 (2H, d, J = 8.6 Hz),

7.07 (1H, dd, J = 8.8 Hz, 3.0 Hz),

7.19 (2H, d, J = 8.6 Hz),

7.67 (1H, d, J = 3.0 Hz).

392
—CH₃
—H
piperonyl
—CH₂—
—CH₂—
MS 474 (M ⁺)

TABLE 56

Reference

Example

No.
R₂₁₈
R₂₁₉
R₂₂₀

¹H NMR (CDCl₃) δ ppm or MS

393
—H
—H
—H

¹H NMR 2.42-2.49 (4H, m), 3.42-3.48 (4H,

m), 3.66-3.72 (2H, m), 3.86 (2H, d, J =

4.3 Hz), 4.82 (1H, t, J = 4.3 Hz), 5.96 (2H, s),

6.62 (2H, d, J = 8.8 Hz), 6.68 (1H, d, J =

8.6 Hz), 6.73-6.78 (2H, m), 6.86 (1H, d, J =

1.0 Hz), 6.95 (1H, d, J = 8.8 Hz), 7.05 (1H, dd,

J = 3.0 Hz, 8.6 Hz), 7.69 (1H, d, J = 3.0 Hz)

394
—H
—H
—Ac

¹H NMR 1.94 (3H, s), 2.45-2.55 (4H, m),

3.45-3.70 (8H, m), 4.42 (2H, s), 5.95 (2H, s),

6.75-6.85 (3H, m), 6.92 (1H, s), 7.04 (2H, d,

J = 8.8 Hz), 7.12 (1H, dd, J = 3.0 Hz, 8.6 Hz),

7.36 (2H, d, J = 8.8 Hz), 7.72 (1H, d,

J = 3.0 Hz).

395
—H
—H
—COC₂H₅

¹H NMR 1.06 (3H, t, J = 7.5 Hz), 2.17 (2H,

q, J = 7.5 Hz), 2.40-2.45 (4H, m), 3.41 (4H,

s), 3.59 (2H, s), 4.42 (2H, s), 5.94 (2H, s),

6.70-6.75 (2H, m), 6.80-6.85 (2H, m),

7.04 (2H, d, J = 8.7 Hz), 7.11 (1H, dd, J =

3.1 Hz, 8.6 Hz), 7.36 (2H, d, J = 8.7 Hz),

7.72 (1H, d, J = 3.1 Hz).

396
—H
—H

embedded image

¹H NMR 0.60-1.55 (5H, m), 2.39 (4H, brs), 3.42 (4H, brs), 3.55 (2H, brs), 4.46 (2H, brs), 5.94 (2H, s), 6.69-6.75 (2H, m), 6.77- 6.85 (2H, m), 7.00-7.15 (2H, m), 7.40- 7.46 (2H, m), 7.72 (1H, s).

397
—H
—H
cyclopropyl

¹H NMR 0.60-0.66 (2H, m), 0.77-0.83 (2H,

m), 2.42-2.44 (4H, m), 2.77-2.79 (1H, m),

3.43-3.52 (6H, m), 3.59-3.62 (2H, m),

4.16 (2H, s), 5.95 (2H, s), 6.66 (1H, d, J =

8.6 Hz), 6.75 (2H, s), 6.86-6.97 (5H, m), 7.03

(1H, dd, J = 8.6 Hz, 2.8 Hz), 7.70 (1H, d,

J = 2.8 Hz).

398
—CH₃
—CH₃
—C₂H₅
MS 517 (M⁺)

399
—COOCH₃
—H
—C₂H₅
MS 547 (M⁺)

TABLE 57

Reference

Example

No.
Xa₁₁
M

¹H NMR (CDCl₃) δ ppm

400
—NH—
0
2.40-2.50 (4H, m), 3.40-3.55 (6H, m), 3.68 (2H, brs),

5.95 (2H, s), 6.27 (1H, s), 6.30-6.55 (2H, m), 6.65-6.95 (5H,

m), 7.20-7.30 (2H, m).

401
—NH—
1
2.40-2.50 (4H, m), 3.35-3.45 (4H, m), 3.55-3.70 (4H, m),

3.83 (2H, d, J = 4.4 Hz), 4.72 (1H, t, J = 4.4 Hz), 5.95 (2H,

s), 6.30-6.40 (1H, m), 6.45-6.60 (3H, m).

402
—N(Ac)—
1
1.91 (3H, s), 2.40-2.50 (4H, m), 3.45-3.75 (8H, m), 4.41 (2H,

s), 5.94 (2H, s), 6.40-6.52 (2H, m), 6.70-6.75 (2H, m), 6.80-

6.95 (4H, m), 7.28 (2H, d, J = 9.0 Hz).

403
—O—
1
2.41 (4H, brs), 3.42 (2H, s), 3.50-3.80 (6H, m), 4.63 (2H, s),

5.94 (2H, s), 6.40 (1H, ddd, J = 1.2 Hz, 2.6 Hz, 7.4 Hz),

6.50 (1H, dd, J = 2.6 Hz, 12.1 Hz), 6.65-6.75 (2H, m), 6.80-

6.95 (6H, m).

Reference Example 404
Production of methyl 3-[(4-hydroxyphenyl)methylamino]-propionate

Methyl 3-[(4-benzyloxyphenyl)methylamino]-propionate (27.3 g, 91.1 mmol) was dissolved in ethanol (300 mL), and the resulting solution was cooled with ice and 10% palladium-carbon (3.0 g) was added. The resulting solution was stirred for 4.5 hours at room temperature under a hydrogen atmosphere. The reaction solution was filtered through Celite to remove insoluble matter, and the filtrate was concentrated under reduced pressure to thereby yield 19.1 g of the title compound.

Appearance: Red oil

¹H NMR (CDCl₃) δ 2.51-2.56 (2H, m), 2.83 (3H, brs), 3.57 (2H, brs), 3.66 (3H, s), 4.99 (1H, brs), 6.71-6.74 (4H, m).

The following compounds were produced in the same manner as in Reference Example 404.

Reference Example 405
Ethyl [acetyl(4-hydroxyphenyl)amino]acetate

¹H NMR (CDCl₃) δ 1.26 (3H, t, J=7.1 Hz), 1.92 (3H, s), 4.19 (2H, q, J=7.1 Hz), 4.34 (2H, s), 6.16 (1H, s), 6.87 (2H, d, J=8.8 Hz), 7.21 (2H, d, J=8.8 Hz).

TABLE 58

Reference

Example

No.
Chemical Structure
mp (° C.) or ¹H NMR (CDCl₃) δ ppm

406

embedded image

mp 172.0-173.0

407

embedded image

¹H NMR 2.24 (3H, s), 3.25-3.39 (2H, m), 3.66-3.81 (2H, m), 4.36 (2H, s), 4.93 (1H, s), 5.95 (2H, s), 6.71 (1H, d, J = 8.6 Hz), 6.77 (2H, d, J = 0.6 Hz), 6.83 (1H, s), 7.15 (1H, dd, J = 2.8 Hz, 8.6 Hz), 7.32 (1H, d, J = 2.8 Hz).

408

embedded image

¹H NMR 1.94-2.12 (2H, m), 2.08 (3H, s), 3.29 (2H, t, J = 6.0 Hz), 3.58 (2H, t, J = 6.0 Hz), 3.89 (3H, s), 3.93 (3H, s), 4.57 (2H, s), 6.34 (1H, d, J = 8.4 Hz), 6.71 (1H, dd, J = 2.6 Hz, 8.4 Hz), 6.75-6.93 (3H, m), 6.96 (1H, d, J = 1.3 Hz), 7.61 (1H, s).

409

embedded image

¹H NMR 2.07 (3H, s), 2.09-2.18 (2H, m), 2.37-2.50 (4H, m), 3.41 (2H, s), 3.43-3.54 (4H, m), 3.54-3.68 (4H, m), 4.22 (2H, s), 5.94 (2H, s), 6.35 (1H, d, J = 8.4 Hz), 6.62- 6.77 (3H, m), 6.83 (1H, d, J = 1.1 Hz), 6.88 (1H, d, J = 2.4 Hz).

410

embedded image

¹H NMR 1.49 (9H, s), 2.07 (3H, s), 2.07-2.21 (2H, m), 3.45 (2H, t, J = 5.9 Hz), 3.61 (2H, t, J = 5.9 Hz), 4.07 (2H, s), 6.33 (1H, d, J = 8.4 Hz), 6.71 (1H, dd, J = 2.6 Hz, 8.4 Hz), 6.87 (1H, d, J = 2.6 Hz), 7.26 (1H, s).

Reference Example 411
Production of [4-(5-aminopyridin-2-yloxy)phenyl](4-piperonylpiperazin-1-yl)methanone

[4-(5-nitropyridin-2-yloxy)phenyl] (4-piperonylpiperazin-1-yl)methanone (0.36 g, 0.78 mmol) was dissolved in a mixed solvent consisting of ethanol (5 mL) and THF (5 mL). To the resulting solution was added 5% platinum-carbon (0.06 g), and stirred at room temperature under a hydrogen atmosphere. Two hours later, the 5% platinum-carbon was removed by filtration, and the solvent was evaporated under reduced pressure, to thereby yield 0.32 g of the title compound.

Appearance: Pale yellow amorphous powder

¹H NMR (CDCl₃) δ 2.43 (4H, brs), 3.44 (2H, s), 3.58 (6H, brs), 5.95 (2H, s), 6.74 (2H, s), 6.80 (1H, d, J=8.6 Hz), 6.85 (1H, s), 7.05 (2H, d, J=8.6 Hz), 7.10 (1H, dd, J=8.6 Hz, 3.0 Hz), 7.40 (2H, d, J=8.7 Hz), 7.74 (1H, d, J=2.6 Hz).

The following compounds were produced in the same manner as in Reference Example 411.

Reference Example 412
4-[5-(4-Trifluoromethylphenoxymethyl)pyridin-2-yloxy]phenylamine

¹H NMR (CDCl₃) δ 3.63 (2H, brs), 5.02 (2H, s), 6.70 (2H, d, J=8.9 Hz), 6.88 (1H, d, J=8.4 Hz), 6.94 (2H, d, J=8.9 Hz), 7.01 (2H, d, J=8.6 Hz), 7.55 (2H, d, J=8.4 Hz), 7.72 (1H, dd, J=8.4 Hz, 2.5 Hz), 8.22 (1H, d, J=2.3 z).

Reference Example 413
3-Methyl-4-[5-(4-trifluoromethylphenoxymethyl)pyridin-2-yloxy]phenylamine

¹H NMR (CDCl₃) δ 2.08 (3H, s), 3.58 (2H, brs), 5.02 (2H, s), 6.65 (1H, dd, J=8.2 Hz, 2.8 Hz), 6.60 (1H, d, J=2.8 Hz), 6.83-6.87 (2H, m), 7.02 (2H, d, J=8.9 Hz), 7.56 (2H, d, J=9.1 Hz), 7.72 (1H, dd, J=8.6 Hz, 2.5 Hz), 8.21 (1H, d, J=2.5 Hz).

Reference Example 414
2-{[4-(4-Aminophenoxy)phenyl]methylamino}-1-(4-piperonylppiperazin-1-yl)ethanone

¹H NMR (CDCl₃) δ 2.41 (4H, t, J=5.1 Hz), 2.99 (3H, s), 3.42 (2H, s), 3.48 (2H, t, J=4.8 Hz), 3.50 (2H, brs), 3.62 (2H, t, J=4.8 Hz), 4.04 (2H, s), 5.95 (2H, s), 6.61-6.68 (4H, m), 6.73-6.88 (7H, m).

Reference Example 415
2-{[3-(5-Aminopyridin-2-yloxy)phenyl]methylamino}-1-(4-piperonylpiperazin-1-yl)ethanone

¹H NMR (CDCl₃) δ 2.40 (4H, t, J=4.9 Hz), 3.00 (3H, s), 3.41 (2H, s), 3.44-3.46 (2H, m), 3.51 (2H, brs), 3.59-3.61 (2H, m), 4.06 (2H, s), 5.95 (2H, s), 6.35-6.45 (3H, m), 6.70-6.74 (3H, m), 6.85 (1H, s), 7.05 (1H, dd, J=8.6 Hz, 3.1 Hz), 7.12-7.18 (1H, m), 7.73 (1H, d, J=3.1 Hz).

TABLE 59

Reference

Example

No.
R₂₂₁
R₂₂₂
R₂₂₃
R₂₂₄
R₂₂₅

¹H NMR (CDCl₃) δ ppm or MS

416
—H
—H
—CH₃
—CH₃
—CH₃

¹H NMR 1.25 (3H, t, J = 7.1 Hz),

1.38 (6H, s), 2.86 (3H, s), 3.50 (2H,

brs), 4.17 (2H, q, J = 7.1 Hz),

6.73 (1H, dd, J = 8.6 Hz, 0.3 Hz),

6.93 (2H, d, J = 9.1 Hz), 7.02-

7.09 (3H, m), 7.73 (1H, d, J = 3.0 Hz).

417
—F
—H
—CH₃
—H
—H

¹H NMR 1.26 (3H, t, J = 7.1 Hz),

3.05 (3H, s), 3.44 (2H, brs), 4.02 (2H,

s), 4.19 (2H, q, J = 7.1 Hz), 6.38-

6.51 (2H, m), 6.75 (1H, d, J =

8.6 Hz), 7.01-7.13 (2H, m), 7.63 (1H,

d, J = 3.0 Hz).

418
—F
—H
—C₂H₅
—H
—H

¹H NMR 1.16-1.30 (6H, m), 3.43 (2H,

brs), 3.43 (2H, q, J = 7.1 Hz),

3.98 (2H, s), 4.21 (2H, q, J = 7.1 Hz),

6.33-6.47 (2H, m), 6.75 (1H, d, J =

8.6 Hz), 6.99-7.09 (2H, m), 7.64 (1H,

d, J = 3.0 Hz).

419
—F
—H
—(CH₂)₂CH₃
—H
—H

¹H NMR 0.95 (3H, t, J = 7.4 Hz),

1.27 (3H, t, J = 7.3 Hz), 1.59-

1.70 (2H, m), 3.31 (2H, t, J = 7.6 z),

3.45 (2H, brs), 3.99 (2H, s), 4.20 (2H,

q, J = 7.1 Hz), 6.32-6.45 (2H, m),

6.75 (1H, dd, J = 8.7 Hz, 0.7 Hz),

7.04 (1H, t, J = 9.1 Hz), 7.05 (1H, dd,

J = 7.4 Hz, 5.8 Hz), 7.64 (1H, dd,

J = 3.0 Hz, 0.7 Hz).

420
—F
—H
—Ac
—H
—H

¹H NMR 1.29 (3H, t, J = 7.1 Hz),

1.98 (3H, s), 3.55 (2H, brs), 4.21 (2H,

q, J = 7.1 Hz), 4.35 (2H, s), 6.87 (1H,

d, J = 8.7 Hz), 7.10-7.29 (4H, m),

7.63 (1H, d, J = 3.0 Hz).

421
—H
—CF3
—C₂H₅
—H
—H
MS 383 (M⁺)

TABLE 60

Reference

Example

No.
Xa₁₂
R₂₂₆

¹H NMR (CDCl₃) δ ppm

422
—O—
—CH₂CN
3.54 (2H, brs), 3.72 (2H, s), 6.79 (1H, d,

J = 8.5 Hz), 7.06 (2H, d, J = 8.9 Hz),

7.09 (1H, dd, J = 8.5 Hz, 3.0 Hz),

7.30 (2H, d, J = 8.9 Hz), 7.71 (1H, d,

J = 3.0 Hz).

423
—O—

embedded image

2.41 (4H, t, J = 5.1 Hz), 3.38 (4H, t, J = 5.1 Hz), 3.42 (2H, s), 3.54 (2H, brs), 4.37 (2H, d, J = 5.1 Hz), 4.72 (1H, t, J = 5.1 Hz), 5.94 (2H, s), 6.74 (2H, s), 6.77 (1H, d, J = 8.7 Hz), 6.85 (1H, s), 7.01 (2H, d, J = 8.5 Hz), 7.08 (1H, dd, J = 8.7 Hz, 3.0 Hz), 7.28 (2H, d, J = 8.5 Hz), 7.68 (1H, d, J = 2.8 Hz).

424
—O—

embedded image

2.45-2.47 (4H, m), 2.73-2.98 (2H, m), 3.45 (2H, s), 3.49-3.72 (7H, m), 3.85- 3.91 (1H, m), 4.24-4.30 (1H, m), 5.96 (2H, s), 6.74-6.78 (3H, m), 6.86 (1H, s), 7.05-7.11 (3H, m), 7.53- 7.58 (2H, m), 7.70 (1H, d, J = 3.0 Hz).

425
—O—

embedded image

1.35 (3H, d, J = 6.6 Hz), 2.37-2.52 (4H, m), 3.31 (1H, q, J = 6.6 Hz), 3.67- 3.72 (4H, m), 6.76 (1H, d, J = 8.6 Hz), 6.99 (2H, d, J = 8.3 Hz), 7.08 (1H, dd, J = 8.6 Hz, 2.3 Hz), 7.27 (2H, d, J = 8.4 Hz), 7.72 (1H, d, J = 3.0 Hz).

426
—N(CH₃)—

embedded image

1.30 (3H, t, J = 7.1 Hz), 2.76 (4H, t, J = 5.0 Hz), 3.24 (4H, t, J = 5.0 Hz), 3.28 (3H, s), 3.35 (4H, s), 4.21 (2H, q, J = 7.1 Hz), 6.42 (1H, dd, J = 8.8 Hz, 0.7 Hz), 6.83 (1H, dd, J = 8.8 Hz, 2.9 Hz), 6.92 (2H, d, J = 8.9 Hz), 7.10 (2H, d, J = 8.9 Hz), 7.79 (1H, dd, J = 2.9 Hz, 0.7 Hz).

427
—N(CH₃)—

embedded image

1.28 (3H, t, J = 7.1 Hz), 1.46 (2H, qd, J = 12.3 Hz, 3.6 Hz), 1.77-2.10 (3H, m), 2.29 (2H, d, J = 6.9 Hz), 2.73 (2H, td, J = 12.3 Hz, 2.4 Hz), 3.23 (2H, brs), 3.35 (3H, s), 3.63 (2H, d, J = 12.3 Hz), 4.15 (2H, q, J = 7.1 Hz), 6.41 (1H, d, J = 8.9 Hz), 6.82 (1H, dd, J = 8.9 Hz, 3.0 Hz), 6.92 (2H, d, J = 8.9 Hz), 7.09 (2H, d, J = 8.9 Hz), 7.79 (1H, d, J = 2.5 Hz).

428
—O—

embedded image

3.28-3.42 (2H, m), 3.43-3.59 (2H, m), 3.71-3.88 (2H, m), 4.47 (2H, s), 6.73 (1H, d, J = 8.6 Hz), 7.01-7.11 (3H, m), 7.25-7.39 (5H, m), 7.51-7.59 (2H, m), 7.70 (1H, d, J = 2.9 Hz).

TABLE 61

Reference

Example

No.
R₂₂₇
R₂₂₈

¹H NMR (CDCl₃) δ ppm or MS

429
—F

embedded image

MS 478 (M⁺)

430
—CH₃

embedded image

¹H NMR 1.96-2.11 (2H, m), 2.19 (3H, s), 3.29 (2H, t, J = 5.9 Hz), 3.46 (2H, s), 3.68 (2H, t, J = 5.9 Hz), 4.52 (2H, s), 5.95 (2H, s), 6.67 (1H, d, J = 8.6 Hz), 6.73-6.81 (2H, m), 6.88 (1H, s), 6.93 (1H, d, J = 8.6 Hz), 7.05 (1H, dd, J = 3.0 Hz, 8.6 Hz), 7.09 (1H, dd, J = 2.6 Hz, 8.6 Hz), 7.18-7.22 (1H, m), 7.00 (1H, d, J = 3.0 Hz).

431
—CH₃

embedded image

¹H NMR 1.99-2.11 (2H, m), 2.19 (3H, s), 3.29 (2H, t, J = 6.0 Hz), 3.47 (2H, s), 3.68 (2H, d, J = 6.0 Hz), 3.88 (3H, s), 3.88 (3H, s), 4.56 (2H, s), 6.68 (1H, d, J = 8.6 Hz), 6.82 (1H, d, J = 8.1 Hz), 6.86 (1H, dd, J = 1.8 Hz, 8.1 Hz), 6.91 (1H, d, J = 1.8 Hz), 6.93 (1H, d, J = 8.6 Hz), 7.05 (1H, dd, J = 3.0 Hz, 8.6 Hz), 7.09 (1H, dd, J = 2.6 Hz, 8.6 Hz), 7.19 (1H, d, J = 2.6 Hz), 7.69 (1H, d, J = 3.0 Hz).

432
—CH₃

embedded image

¹H NMR 2.10-2.21 (2H, m), 2.35-2.48 (4H, m), 3.42 (2H, s), 3.43-3.54 (6H, m), 3.57-3.66 (2H, m), 3.73 (2H, t, J = 5.7 Hz), 4.21 (2H, s), 5.95 (2H, s), 6.66 (1H, d, J = 8.6 Hz), 6.69-6.77 (2H, m), 6.84 (1H, d, J = 1.2 Hz), 6.92 (1H, d, J = 8.6 Hz), 7.02-7.09 (2H, m), 7.17 (1H, d, J = 2.4 Hz), 7.69 (1H, d, J = 2.8 Hz).

433
—CH₃

embedded image

¹H NMR 1.38 (3H, t, J = 7.1 Hz), 2.19 (3H, s), 2.19-2.33 (2H, m), 3.47 (2H, s), 3.73-3.93 (4H, m), 4.36 (2H, q, J = 7.1 Hz), 6.67 (1H, d, J = 8.6 Hz), 6.94 (1H, d, J = 8.6 Hz), 7.05 (1H, dd, J = 3.0 Hz, 8.6 Hz), 7.12 (1H, dd, J = 2.6 Hz, 8.6 Hz), 7.22 (1H, d, J = 2.6 Hz), 7.40- 7.48 (2H, m), 7.69 (1H, d, J = 3.0 Hz), 7.95-8.04 (2H, m).

434
—CH₃

embedded image

¹H NMR 1.47 (9H, s), 2.05-2.24 (5H, m), 3.34-3.54 (4H, m), 3.77 (2H, t, J = 5.8 Hz), 4.04 (2H, s), 6.65 (1H, d, J = 8.6 Hz), 6.90 (1H, d, J = 8.6 Hz), 6.99- 7.10 (2H, m), 7.17 (1H, d, J = 2.4 Hz), 7.68 (1H, d, J = 3.0 Hz).

TABLE 62

Reference

Example

No.
R₂₂₉
Xa₁₃
R₂₃₀
Xa₁₄

¹H NMR (CDCl₃) δ ppm

435
—H
—CO—
3-pyridyl
—CH₂—
3.23 (4H, brs), 3.62 (2H, brs),

3.81 (4H, brs), 6.83 (1H, d, J =

8.6 Hz), 7.09 (2H, d, J = 8.6 Hz),

7.12 (1H, dd, J = 8.6 Hz, 3.1 Hz),

7.20-7.21 (2H, m), 7.45 (2H, d, J =

8.7 Hz), 7.55 (1H, d, J = 3.0 Hz),

8.14-8.17 (1H, m), 8.31-8.33 (1H, m).

436
—H
none
piperonyl
—CO—
3.37 (4H, s), 3.48 (2H, brs), 3.90 (2H,

s), 4.57 (2H, s), 5.95 (2H, s), 6.72 (1H,

dd, J = 8.5 Hz, 0.7 Hz), 6.74-

6.78 (2H, m), 6.78-6.82 (1H, m),

6.86 (2H, d, J = 9.1 Hz), 7.02 (2H, d,

J = 9.1 Hz), 7.06 (1H, dd, J = 8.5 Hz,

2.9 Hz), 7.69 (1H, d, J = 2.9 Hz).

437
—COOCH₃
none
benzyl
—CH₂—
2.58-2.62 (4H, m), 3.14-3.18 (4H, m),

3.61 (2H, s), 3.65 (3H, s), 6.63 (1H, d,

J = 8.7 Hz), 6.95 (1H, d, J = 8.9 Hz),

7.12-7.18 (2H, m), 7.25-7.36 (5H, m),

7.41 (1H, d, J = 3.0 Hz), 7.51 (1H, d,

J = 2.8 Hz).

438
—H
—CH₂—
—COOC(CH₃)₃
—CH₂—
1.45 (9H, s), 2.36-2.40 (4H, m), 3.40-

3.44 (4H, m), 3.47 (2H, s), 3.56 (2H,

brs), 6.76 (1H, d, J = 8.6 Hz), 6.97-

7.02 (2H, m), 7.08 (1H, dd, J = 8.6 Hz,

3.0 Hz), 7.25-7.29 (2H, m), 7.71 (1H,

d, J = 3.0 Hz).

439
—H
—CO—
benzyl
—CH₂—
2.38 (4H, brs), 3.33 (2H, brs),

3.50 (4H, brs), 5.17 (2H, brs),

6.82 (1H, d, J = 8.6 Hz), 6.96 (2H, d,

J = 8.7 Hz), 7.10 (1H, dd, J = 8.6 Hz,

3.0 Hz), 7.27-7.33 (5H, m), 7.36 (2H,

d, J = 8.7 Hz), 7.57 (1H, d,

J = 3.0 Hz).

440
—H
—CO—
4-CH₃OPhCH₂—
—CH₂—
2.44 (4H, brs), 3.48 (2H, s), 3.59 (4H,

brs), 3.81 (3H, s), 6.80 (1H, dd, J =

8.6 Hz, 0.7 Hz), 6.85-6.89 (2H, m),

7.03-7.08 (2H, m), 7.11 (1H, dd, J =

8.6 Hz, 3.0 Hz), 7.21-7.26 (2H, m),

7.38-7.43 (2H, m), 7.73-7.75 (1H, m).

441
—H
—SO₂—
benzyl
—CH₂—
2.42-2.57 (4H, m), 2.91-3.10 (4H, m),

3.47 (2H, s), 3.63 (2H, brs), 6.83 (1H,

d, J = 8.6 Hz), 7.07-7.14 (3H, m),

7.18-7.31 (5H, m), 7.68 (2H, d, J =

8.8 Hz), 7.74 (1H, d, J = 2.0 Hz).

TABLE 63

Reference

Example

No.
R₂₃₁
R₂₃₂
R₂₃₃
R₂₃₄
R₂₃₅

¹H NMR (CDCl₃) δ ppm

442
—F
—H
—H
—H
—H
2.43-2.48 (4H, m), 3.44-3.47 (6H, m), 3.67-

3.68 (2H, m), 3.82 (2H, d, J = 4.1 Hz),

4.96 (1H, brs), 5.96 (2H, s), 6.36-6.43 (2H, m),

6.71-6.78 (3H, m), 6.86 (1H, brs), 6.97-

7.03 (1H, m), 7.06 (1H, dd, J = 8.7 Hz,

3.0 Hz), 7.63 (1H, d, J = 3.0 Hz).

443
—F
—H
—H
—H
—CH₃
2.43-2.45 (4H, m), 3.01 (3H, s), 3.44 (2H, s),

3.47 (2H, brs), 3.63 (2H, brs), 4.07 (2H, s),

5.95 (2H, s), 6.39-6.50 (2H, m), 6.72-6.76 (3H,

m), 6.85 (1H, s), 7.00-7.08 (2H, m), 7.63 (1H,

dd, J = 3.0 Hz, 0.5 Hz).

444
—F
—H
—H
—H
—C₂H₅
1.18 (3H, t, J = 7.1 Hz), 2.43 (4H, t, J =

5.0 Hz), 3.37-3.48 (8H, m), 3.63 (2H, brs),

4.01 (2H, s), 5.95 (2H, s), 6.35-6.46 (2H, m),

6.72-6.77 (3H, m), 6.85 (1H, s), 6.99 (1H, d,

J = 8.9 Hz), 7.05 (1H, dd, J = 8.7 Hz, 3.0 Hz),

7.63 (1H, d, J = 3.0 Hz).

445
—F
—H
—H
—F
—CH₃
2.33-2.49 (4H, m), 2.93 (3H, s), 3.38-3.68 (8H,

m), 4.00 (2H, s), 5.95 (2H, s), 6.71-6.77 (2H,

s), 6.78-6.82 (2H, m), 6.83-6.91 (2H, m),

7.08 (1H, dd, J = 2.9 Hz, 8.6 Hz), 7.62 (1H, d,

J = 2.9 Hz).

446
—F
—H
—H
—F
—C₂H₅
1.11 (3H, t, J = 7.1 Hz), 2.31-2.49 (4H, m),

3.29 (2H, q, J = 7.1 Hz), 3.41 (2H, s), 3.42-

3.69 (6H, m), 3.96 (2H, s), 6.70-6.78 (2H, m),

6.79-6.91 (4H, m), 7.08 (1H, dd, J = 2.9 Hz,

8.6 Hz), 7.62 (1H, d, J = 2.9 Hz).

447
—F
—H
—F
—H
—CH₃
2.36-2.52 (4H, m), 3.01 (3H, s), 3.34-3.54 (6H,

m), 3.55-3.71 (2H, m), 4.05 (2H, s), 5.95 (2H,

s), 6.18-6.29 (2H, m), 6.70-6.79 (2H, m),

6.82 (1H, d, J = 8.6 Hz), 6.85 (1H, d, J =

0.98 Hz), 7.07 (1H, dd, J = 2.9 Hz, 8.6 Hz),

7.59 (1H, d, J = 2.9 Hz).

448
—F
—F
—H
—H
—CH₃
2.29-2.55 (4H, m), 2.95 (3H, s), 3.30-3.75 (8H,

m), 4.01 (2H, s), 5.95 (2H, s), 6.60-6.95 (6H,

m), 7.09 (1H, dd, J = 3.0 Hz, 8.6 Hz),

7.62 (1H, d, J = 3.0 Hz).

449
—CH₃
—CH₃
—H
—H
—CH₃
2.11 (3H, s), 2.25 (3H, s), 2.36-2.42 (4H, m),

2.66 (3H, s), 3.41 (2H, s), 3.45 (2H, brs), 3.53-

3.56 (2H, m), 3.61-3.64 (2H, m), 3.73 (2H, s),

5.95 (2H, s), 6.67 (1H, d, J = 8.7 Hz), 6.70-

6.85 (4H, m), 6.95 (1H, d, J = 8.7 Hz), 7.03-

7.08 (1H, m), 7.67 (1H, d, J = 3.0 Hz).

450
—CH₃
—H
—H
—H

embedded image

0.62-0.66 (2H, m), 0.76-0.83 (2H, m), 2.12 (3H, s), 2.40-2.46 (4H, m), 2.73-2.81 (1H, m), 3.43 (2H, s), 3.48-3.63 (4H, m), 4.15 (2H, s), 5.94 (2H, s), 6.58 (1H, d, J = 8.7 Hz), 6.68- 6.77 (4H, m), 6.87 (2H, d, J = 8.6 Hz), 7.01 (1H, dd, J = 8.7 Hz, 3.0 Hz), 7.67 (1H, d, J = 3.0 Hz).

TABLE 64

Reference

Example

No.
R₂₃₆
R₂₃₇
R₂₃₈
Xa₁₅

¹H NMR (CDCl₃) δ ppm or MS

451
—CH₃
—H
—H
—CO—

¹H NMR 2.20 (3H, s), 2.48-2.54 (4H, m),

3.44 (4H, s), 3.67-3.75 (2H, m), 4.23-4.27 (2H,

m), 5.95 (2H, s), 6.63-6.78 (3H, m), 6.86 (1H,

brs), 6.95 (1H, d, J = 8.7 Hz), 7.07 (1H, dd,

J = 8.6 Hz, 3.0 Hz), 7.37 (1H, dd, J = 8.7 Hz,

2.6 Hz), 7.52 (1H, d, J = 2.5 Hz), 7.66 (1H, d,

J = 3.0 Hz), 9.13 (1H, brs).

452
—CH₃
—H
—CH₃
—CO—

¹H NMR 2.21-2.31 (7H, m), 3.28-3.40 (9H, m),

3.53 (2H, brs), 5.93 (2H, s), 6.66-6.80 (4H, m,)

6.91 (1H, d, J = 8.6 Hz), 7.03-7.12 (3H, m),

7.66 (1H, d, J = 3.0 Hz).

453
—H
—H
—SO₂CH₃
—CH₂—

¹H NMR 2.41 (4H, brs), 3.19 (3H, s), 3.34-

3.38 (2H, m), 3.42 (2H, s), 3.57-3.60 (4H, m),

4.51 (2H, s), 5.95 (2H, s), 6.70-6.77 (2H, m),

6.80 (1H, d, J = 8.6 Hz), 6.84 (1H, brs),

7.02 (2H, d, J = 8.7 Hz), 7.10 (1H, dd, J =

8.6 Hz, 3.0 Hz), 7.59 (2H, d, J = 8.7 Hz),

7.71 (1H, d, J = 3.0 Hz).

454
—CH₃
—H
—SO₂CH₃
—CH₂—

¹H NMR 2.21 (3H, s), 2.41 (4H, brs), 3.20 (3H,

s), 3.34-3.38 (2H, m), 3.42 (2H, s), 3.53 (2H,

brs), 3.59-3.61 (2H, m), 4.51 (2H, s), 5.94 (2H,

s), 6.70-6.77 (3H, m), 6.83 (1H, brs), 6.90 (1H,

d, J = 8.6 Hz), 7.09 (1H, dd, J = 8.6 Hz,

3.0 Hz), 7.36 (1H, dd, J = 8.6 Hz, 2.1 Hz),

7.42 (1H, d, J = 2.3 Hz), 7.66 (1H, d, J =

3.0 Hz).

455
—CF₃
—H
—C₂H₅
—CH₂—
MS 557 (M⁺)

456
—CF₃
—H
—CH₃
—CH₂—
MS 543 (M⁺)

457
—CN
—H
—CH₃
—CH₂—
MS 500 (M⁺)

458
—OCH₃
—H
—SO₂CH₃
—CH₂—

¹H NMR 2.48 (4H, brs), 3.26 (3H, s), 3.42-

3.66 (8H, m), 3.82 (3H, s), 4.58 (2H, s),

5.99 (2H, s), 6.77-6.79 (2H, m), 6.81-6.88 (2H,

m), 7.06-7.30 (4H, m), 7.67 (1H, d, J = 2.3 Hz).

459
—CH₃
—CH₃
—CH₃
—CH₂—
MS 503 (M⁺)

TABLE 65

Reference

Example

No.
R₂₃₉
R₂₄₀
R₂₄₁

¹H NMR (CDCl₃) δ ppm

460
—H
—CH₃
—H
2.40-2.44 (4H, m), 3.00 (3H, s), 3.49 (4H, brs), 3.63 (2H, brs),

4.05 (2H, s), 5.95 (2H, s), 6.67 (1H, d, J = 8.6 Hz), 6.69 (2H, d,

J = 9.1 Hz), 6.74 (2H, brs), 6.85 (1H, brs), 6.97 (2H, d, J = 9.1 Hz),

7.03 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.68 (1H, d, J = 3.0 Hz).

461
—H
—CH₃
—CH₃
1.28 (3H, d, J = 6.6 Hz), 2.14-2.21 (1H, m), 2.28-2.35 (2H, m),

2.47-2.49 (1H, m), 2.75 (3H, s), 3.24-3.54 (3H, m), 3.38 (2H,

s), 3.45 (2H, s), 3.78-3.84 (1H, m), 4.54 (1H, q, J = 6.8 Hz),

5.93 (2H, s), 6.68-6.75 (5H, m), 6.82 (1H, s), 6.99 (2H, d,

J = 9.1 Hz), 7.05 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.69 (1H, dd,

J = 3.1 Hz, 0.7 Hz).

462
—CH₃
—CH₃
—CH₃
1.28 (3H, d, J = 6.6 Hz), 2.15 (3H, s), 2.15-2.21 (1H, m), 2.33-

2.36 (2H, m), 2.49 (1H, brs), 2.74 (3H, s), 3.25-3.55 (3H, m),

3.39 (2H, s), 3.42 (2H, s), 3.80 (1H, brs), 4.55 (1H, q, J = 6.4 Hz),

5.93 (2H, s), 6.55-6.59 (2H, m), 6.64 (1H, dd, J = 8.6 Hz,

0.5 Hz), 6.69-6.75 (2H, m), 6.83 (1H, brs), 6.90 (1H, d, J = 8.7 Hz),

7.04 (1H, dd, J = 8.7 Hz, 3.0 Hz), 7.67 (1H, dd, J = 3.0 Hz, 0.7 Hz).

463
—OCH₃
—CH₃
—H
2.31-2.50 (4H, m), 3.02 (3H, s), 3.31-3.57 (6H, m), 3.58-

3.70 (2H, m), 3.76 (3H, s), 4.06 (2H, s), 5.95 (2H, s), 6.24 (1H,

dd, J = 8.7 Hz, 2.8 Hz), 6.37 (1H, d, J = 2.8 Hz), 6.68 (1H, d,

J = 8.6 Hz), 6.69-6.79 (2H, m), 6.85 (1H, s), 6.94 (1H, d,

J = 8.7 Hz), 7.02 (1H, dd, J = 8.6 Hz, 3.0 Hz), 7.65 (1H, d,

J = 3.0 Hz).

464
—OCH₃
—C₂H₅
—H
1.18 (3H, t, J = 7.0 Hz), 2.31-2.51 (4H, m), 3.28-3.70 (10H,

m), 3.74 (3H, s), 4.01 (2H, s), 5.95 (2H, s), 6.22 (1H, dd,

J = 8.7 Hz, 2.8 Hz), 6.35 (1H, d, J = 2.8 Hz), 6.68 (1H dd,

J = 8.7 Hz, 0.5 Hz), 6.69-6.79 (2H, m), 6.81-6.88 (1H, m),

6.93 (1H, d, J = 8.7 Hz), 7.03 (1H, dd, J = 8.7 Hz, 3.0 Hz),

7.65 (1H, dd, J = 3.0 Hz, 0.5 Hz).

465
—CH₃
—CH₃
—H
2.13 (3H, s), 2.42 (4H, t, J = 3.0 Hz), 2.99 (3H, s), 3.35-

3.57 (6H, m), 3.58-3.70 (2H, m), 4.05 (2H, s), 5.95 (2H, s),

6.53 (1H, dd, J = 8.8 Hz, 3.1 Hz), 6.57 (1H, d, J = 3.1 Hz),

6.60 (1H, d, J = 8.8 Hz), 6.71-6.78 (2H, m), 6.85 (1H, brs),

6.88 (1H, d, J = 8.7 Hz), 7.02 (1H, dd, J =8.7 Hz, 3.0 Hz),

7.67 (1H, d, J = 3.0 Hz).

466
—CH₃
—C₂H₅
—H
1.15 (3H, t, J = 7.0 Hz), 2.12 (3H, s), 2.42 (4H, t, J = 5.1 Hz),

3.27-3.70 (10H, m), 4.00 (2H, s), 5.95 (2H, s), 6.46-6.57 (2H,

m), 6.60 (1H, dd, J = 8.7 Hz, 0.5 Hz), 6.69-6.78 (2H, m), 6.82-

6.90 (2H, m), 7.02 (1H, dd, J = 8.7 Hz, 3.0 Hz), 7.68 (1H, dd,

J = 3.0 Hz, 0.5 Hz).

467
—CH₃
—Ac
—H
1.95 (3H, s), 2.23 (3H, s), 2.31-2.52 (4H, m), 3.29-3.70 (8H, m),

4.43 (2H, s), 5.94 (2H, s), 6.69-6.79 (3H, m), 6.84 (1H, s),

6.92 (1H, d, J = 8.5 Hz), 7.10 (1H, dd, J = 8.6 Hz, 3.0 Hz),

7.19 (1H, dd, J = 8.5 Hz, 2.5 Hz), 7.28 (1H, d, J = 2.2 Hz),

7.68 (1H, d, J = 2.5 Hz).

TABLE 66

Reference

Example

No.
R₂₄₂
R₂₄₃
Xa₁₆
M
E

¹H NMR (solvent) δ ppm

468
—OCH₃
—H
—CH₂—
1
1
(DMSO-d₆) 2.32-2.40 (4H, m), 3.32 (2H, brs),

3.50 (4H, brs), 3.61 (3H, s), 3.88 (2H, brs),

4.88 (2H, brs), 5.44 (1H, brs), 5.99 (2H, s),

6.15 (1H, dd, J = 8.6 Hz, 2.5 Hz), 6.44 (1H, d,

J = 2.3 Hz), 6.51 (1H, d, J = 8.6 Hz), 6.71-

6.88 (4H, m), 6.98 (1H, dd, J = 8.6 Hz,

2.8 Hz), 7.40 (1H, d, J = 2.6 Hz).

469
—OCH₃
—H
—CH₂—
1
2
(DMSO-d₆) 2.32 (2H, brs), 2.40 (2H, brs),

3.39 (2H, s), 3.49 (4H, brs), 3.61 (3H, s),

3.89 (2H, brd), 4.22 (4H, s), 4.82 (2H, brs),

5.44 (1H, brt), 6.15 (1H, dd, J = 8.6 Hz,

2.5 Hz), 6.44-6.52 (2H, m), 6.70-6.81 (4H, m),

6.98 (1H, dd, J = 8.7 Hz, 3.0 Hz), 7.39 (1H, d,

J = 2.8 Hz).

470
—H
—CH₃
—CH₂—
2
1
(CDCl₃) 2.35 (4H, tt, J = 5.0 Hz, 5.0 Hz),

2.52-2.58 (2H, m), 2.91 (3H, s), 3.36-3.39 (4H,

m), 3.59-3.62 (2H, m), 3.65-3.73 (4H, m),

5.93 (2H, s), 6.64-6.76 (5H, m), 6.83 (1H, d,

J = 1.0 Hz), 6.97 (2H, d, J = 9.1 Hz), 7.03 (1H,

dd, J = 8.6 Hz, 3.1 Hz), 7.66 (1H, dd,

J = 3.1 Hz, 0.5 Hz).

471
—CH₃
—CH₃
—CO—
1
1
(CDCl₃) 2.12 (3H, s), 2.88-3.10 (3H, m),

3.26 (2H, t, J = 5.3 Hz), 3.40 (2H, brs), 3.60-

3.90 (2H, m), 4.00-4.15 (2H, m), 4.20-

4.40 (2H, m), 4.52 (2H, s), 5.95 (2H, s),

6.53 (1H, dd, J = 8.5 Hz, 3.0 Hz), 6.60 (1H, s),

6.60 (1H, d, J = 8.5 Hz), 6.71 (1H, d,

J = 8.5 Hz), 6.74 (1H, s), 6.76 (1H, d,

J = 8.5 Hz), 6.88 (1H, d, J = 8.8 Hz), 7.02 (1H,

dd, J = 8.5 Hz, 2.8 Hz), 7.66 (1H, d, J = 2.8 Hz).

472
—OCH₃
—C₂H₅
—CO—
1
1
(CDCl₃) 1.17 (3H, t, J = 7.0 Hz), 3.20-

3.31 (2H, m), 3.40-3.60 (2H, m), 3.41 (2H, q,

J = 7.0 Hz), 3.61-3.82 (2H, m), 3.74 (3H, s),

4.02 (2H, s), 4.30 (2H, s), 4.50 (2H, s),

5.95 (2H, s), 6.24 (1H, dd, J = 8.7 Hz, 2.8 Hz),

6.40 (1H, s), 6.68 (1H, d, J = 8.6 Hz),

6.70 (1H, dd, J = 7.9 Hz, 1.5 Hz), 6.76 (1H, d,

J = 1.5 Hz), 6.76 (1H, d, J = 7.9 Hz),

6.93 (1H, d, J = 8.6 Hz), 7.03 (1H, dd,

J = 8.5 Hz, 2.8 Hz), 7.64 (1H, d, J = 2.8 Hz).

(E means the number of the methylene groups. Hereinafter E indicates the same meaning.)

TABLE 67

Reference

Example

No.
Xa₁₇
M
E
R₂₄₄
Form
mp (° C.) or ¹H NMR (CDCl₃) δppm

473
—CH₂—
1
0
benzyl
free

¹H NMR 2.33-2.43(4H, m), 2.57-2.63

(2H, m), 2.91-2.97(2H, m), 3.38-

3.42(4H, m), 3.50(2H, s), 3.62-

3.65(2H, m), 6.75(1H, dd, J = 8.6 Hz,

0.5 Hz), 6.95-7.00(2H, m), 7.07(1H,

dd, J = 8.6 Hz, 3.0 Hz), 7.15-7.20(2H,

m), 7.28-7.33(5H, m), 7.70(1H, dd, J =

3.0 Hz, 0.5 Hz).

474
—CH₂—
1
0
piperonyl
trihydro-
mp 179-180 dec

chloride

475
—O—
1
0
piperonyl
free

¹H NMR 2.41(4H, brs), 3.42(2H, s),

3.48(2H, brs), 3.50-3.70(4H, m),

4.65(2H, s), 5.95(2H, s), 6.72(1H, d, J =

8.6 Hz), 6.74(2H, brs), 6.85(1H,

brs), 6.91(2H, d, J = 9.2 Hz),

7.00(2H, d, J = 9.2 Hz), 7.06(1H, dd,

J = 8.6 Hz, 3.0 Hz), 7.69(1H, d, J =

3.0 Hz).

476
—O—
1
0
benzyl
free

¹H NMR 2.44(4H, t, J = 5.0 Hz),

3.51(4H, s), 3.58(2H, t, J = 5.0 Hz),

3.64(2H, t, J = 5.0 Hz), 4.65(2H, s),

6.72(1H, d, J = 8.5 Hz), 6.92(2H, d, J =

9.2 Hz), 7.00(2H, d, J = 9.2 Hz),

7.06(1H, dd, J = 8.5 Hz, 3.0 Hz),

7.22-7.35(5H, m), 7.69(1H, d, J = 3.0

Hz).

477
—NH—
0
1
piperonyl
free

¹H NMR 2.51(4H, brs), 2.62-2.63(4H,

m), 3.12(2H, s), 3.45(2H, s), 3.52(2H,

brs), 5.94(2H, s), 6.74(1H, dd, J = 8.7

Hz, 0.7 Hz), 6.75(2H, brs), 6.85(1H,

s), 7.03(2H, d, J = 8.9 Hz), 7.07(1H,

dd, J = 8.7 Hz, 3.0 Hz), 7.54(2H, d, J =

9.1 Hz), 7.69(1H, dd, J = 3.0 Hz,

0.7 Hz), 9.10(1H, brs).

478
—N(CH₃)—
0
1
piperonyl
free

¹H NMR 2.44(8H, brs), 2.93(2H, s),

3.24(3H, s), 3.38(2H, s), 3.62(2H,

brs), 5.92(2H, s), 6.72(2H, brs), 6.80-

6.84(2H, m), 7.06(2H, d, J = 9.1 Hz),

7.12(1H, dd, J = 8.6 Hz, 3.1 Hz),

7.15(2H, d, J = 8.9 Hz), 7.73(1H, d, J =

3.0 Hz).

TABLE 68

Reference

Example

No.
R₂₄₅
R₂₄₆
R₂₄₇

¹H NMR (CDCl₃) δppm

479
—CH₃
—H
—CH₃
1.12(3H, d, J = 6.3 Hz), 2.10-2.12(1H, m), 2.47(1H,

brs), 2.67-2.72(1H, m), 2.80-3.11(6H, m), 3.47-

3.60(3H, m), 3.84-4.10(4H, m), 5.94(2H, s), 6.64-

6.74(5H, m), 6.85(1H, brs), 6.94-6.98(2H, m), 7.00-

7.05(1H, m), 7.68(1H, d, J = 2.8 Hz).

480
—CH₃
—CH₃
—H
1.28-1.37(3H, m), 1.94-2.03(1H, m), 2.11-2.15(1H, m),

2.63-2.67(1H, m), 2.79-2.82(1H, m), 2.95-3.00(4H, m),

3.30-3.46(5H, m), 4.03-4.69(3H, m), 5.94(2H, s).

6.66(1H, d, J = 8.7 H), 6.68(2H, d, J = 9.1 H), 6.74(2H,

brs), 6.87(1H, brs), 6.96(2H, d, J = 9.1 Hz), 7.03(1H,

dd, J = 8.7 Hz, 3.0 Hz), 7.68(1H, d, J = 3.0 Hz).

481
—C₂H₅
—H
—CH₃
1.11-1.18(6H, m), 2.04-2.13(1H, m), 2.45-2.47(1H, m),

2.66-2.73(1H, m), 2.85-3.64(8H, m), 3.84-4.11(4H, m),

5.94(2H, s), 6.64-6.69(3H, m), 6.74(2H, brs), 6.85(1H,

brs), 6.93-6.96(2H, m), 7.03(1H, dd, J = 8.7 Hz, 3.0 Hz),

7.69(1H, d, J = 3.0 Hz).

482
—C₂H₅
—CH₃
—H
1.15(3H, t, J = 7.1 Hz), 1.26-1.70(3H, m), 1.94-

2.04(1H, m), 2.14-2.17(1H, m), 2.63-2.67(1H, m),

2.80(1H, brs), 3.01-3.59(8H, m), 3.73-4.71(3H, m),

5.95(2H, s), 6.63-6.70(3H, m), 6.74(2H, brs), 6.87(1H,

brs), 6.95(2H, d, J = 9.1 Hz), 7.03(1H, dd, J = 8.6 Hz,

3.0 Hz), 7.69(1H, dd, J = 3.0 Hz, 0.7 Hz).

TABLE 69

Reference

Example

No.
R₂₄₈

¹H NMR (CDCl₃) δppm

483
piperonyl
1.36-1.46(2H, m), 1.82-1.99(3H, m), 2.13(3H, s), 2.28(2H, d, J = 6.8

Hz), 2.41(4H, brs), 2.70(2H, t, J = 12.0 Hz), 3.41-3.76(10H, m),

5.94(2H, s), 6.59-6.89(7H, m), 7.03(1H, dd, J = 8.6 Hz, 3.0 Hz),

7.67-7.69(1H, m).

484
benzyl
1.33-1.42(2H, m), 1.82-1.98(3H, m), 2.04(3H, s), 2.28(2H, d, J = 6.8

Hz), 2.41-2.45(4H, m), 2.70(2H, t, J = 12.0 Hz), 3.51-3.78(10H, m),

6.60(1H, d, J = 8.6 Hz), 6.69-6.92(3H, m), 7.03(1H, dd, J = 8.6 Hz,

3.0 Hz), 7.28-7.33(5H, m), 7.67(1H, d, J = 2.5 Hz).

TABLE 70

Reference Example

No.
R₂₄₉
R₂₅₀
R₂₅₁
MS (M⁺)

485
—H
—H
—C₂H₅
557

486
—H
—CH₃
—CH₃
557

487
—CH₃
—H
—CH₃
557

Reference Example 488
Production of ethyl {4-(4-amino-2-fluorophenoxy)phenylsulfanyl}acetate

To a solution of ethyl [4-(2-fluoro-4-nitrophenoxy)phenylsulfanyl]acetate (4.93 g, 14.0 mmol) in ethanol (100 mL) was added tin chloride dihydrate (9.50 g, 42.1 mmol), and the resulting solution was stirred for 8 hours at 50° C. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with 1 M hydrochloric acid, a saturated sodium bicarbonate solution, and brine, dried over anhydrous sodium sulfate, and evaporated, to thereby yield 3.45 g of the title compound.

Appearance: Brown oil

¹H NMR (CDCl₃) δ 1.20 (3H, t, J=7.1 Hz), 3.53 (2H, s), 3.80-4.20 (4H, m), 6.37-6.45 (1H, m), 6.49 (1H, dd, J=2.6 Hz, 12.0 Hz), 6.80-7.00 (3H, m), 7.38 (2H, d, J=8.9 Hz).

The following compounds were produced in the same manner as in Reference Example 488.

Reference Example 489
2-{Allyl[4-(5-aminopyridin-2-yloxy)-3-fluorophenyl]amino}-1-(4-piperonylpiperazin-1-yl)ethanone

¹H NMR (CDCl₃) δ 2.44-2.46 (4H, m), 3.44 (4H, brs), 3.44 (2H, s), 3.83 (2H, brs), 3.98 (2H, d, J=4.8 Hz), 4.03 (2H, s), 5.16-5.30 (2H, m), 5.82-5.95 (1H, m), 5.95 (2H, s), 6.35-6.46 (2H, m), 6.71-6.74 (3H, m), 6.85-6.87 (1H, m), 6.96-7.07 (2H, m), 7.63-7.64 (1H, m).

Reference Example 490
(E)-3-[3-(5-Aminopyridin-2-yloxy)phenyl]-1-(4-piperonylpiperazin-1-yl)propenone

MS 458 (M⁺).

Reference Example 491
Production of methyl 3-[4-(5-aminopyridin-2-ylsulfanyl)phenyl]propionate

To a solution of methyl 3-[4-(5-nitropyridin-2-ylsulfanyl)phenyl]propionate (2.97 g, 9.33 mmol) in methanol (50 mL) were added sodium borohydride (0.590 g, 15.6 mmol) and 10% palladium-carbon (1.80 g), and the resulting solution was stirred for 24 hours at room temperature under a hydrogen atmosphere at atmospheric pressure. The reaction solution was filtered through Celite, and to the resulting filtrate was added concentrated hydrochloric acid (1.5 mL), and concentrated under reduced pressure. To the residue was added a saturated sodium bicarbonate solution, and extracted with ethyl acetate, and the ethyl acetate layer was washed with brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 2.49 g of the title compound.

Appearance: Yellow powder

¹H NMR (CDCl₃) δ 2.62 (2H, t, J=7.6 Hz), 2.93 (2H, t, J=7.6 Hz), 3.67 (3H, s), 6.87 (1H, dd, J=2.9 Hz, 8.4 Hz), 6.98 (1H, d, J=8.4 Hz), 7.15 (2H, d, J=8.2 Hz), 7.35 (2H, d, J=8.2 Hz), 8.01 (1H, d, J=2.9 Hz).

Reference Example 492
Production of ethyl 3-[4-(5-aminopyridin-2-yloxy)phenyl]acrylate

To a solution of ethyl 3-[4-(5-nitropyridin-2-yloxy)phenyl]acrylate (2.02 g, 6.43 mmol) in methanol (100 mL) were added zinc (6.3 g, 96.3 mmol) and ammonium chloride (710 mg, 13.27 mmol). The resulting reaction solution was stirred for 2.5 hours under reflux, then acetic acid (5 mL) was added, and stirred for 20 minutes under reflux. Insoluble matter was filtered off through Celite, after which the filtrate was concentrated under reduced pressure. To the residue was added 5% potassium hydrogensulfate (150 mL), the mixture was extracted with dichloromethane, and the dichloromethane layer was washed with a saturated sodium bicarbonate solution and brine. The dichloromethane layer was dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 1.78 g of the title compound.

Appearance: Yellow oil

¹H NMR (CDCl₃) δ 1.34 (3H, t, J=7.1 Hz), 3.58 (2H, brs), 4.26 (2H, q, J=7.1 Hz), 6.35 (1H, dd, J=16.0 Hz, 2.0 Hz), 6.81 (1H, d, J=8.6 Hz), 7.05 (2H, d, J=8.6 Hz), 7.10 (1H, dd, J=8.6 Hz, 3.0 Hz), 7.50 (2H, d, J=8.6 Hz), 7.66 (1H, dd, J=16.0 Hz, 3.0 Hz), 7.73 (1H, d, J=3.0 Hz).

Reference Example 493
Production of 3-(4-(5-amino-4-methylpyridin-2-yloxy)phenyl)-1-(4-piperonylpiperazin-1-yl)propan-1-one

3-(4-hydroxyphenyl)-1-(4-piperonylpiperazin-1-yl)propan-1-one (0.38 g, 1.0 mmol) was dissolved in DMF (6 mL). To the resulting solution was added 60% sodium hydride (0.05 g, 1.2 mmol) and 2-chloro-4-methyl-5-nitropyridine (0.196 g, 1.1 mmol), and the resulting reaction solution was stirred overnight at room temperature. To the reaction solution was added saturated aqueous ammonium chloride, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate), to thereby yield the intermediate product 3-(4-(4-methyl-5-nitropyridin-2-yloxy)phenyl)-1-(4-piperonylpiperazin-1-yl)propan-1-one. The 3-(4-(4-methyl-5-nitropyridin-2-yloxy)phenyl)-1-(4-piperonylpiperazin-1-yl)propan-1-one was dissolved in a mixed solvent consisting of ethanol (4 mL) and dioxane (1 mL). To this solution was added 10% palladium-carbon (0.034 g), and the resulting solution was subjected to catalytic reduction for 8 hours at atmospheric pressure and room temperature. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (dichloromethane:methanol=20:1), to thereby yield 0.22 g of the title compound.

Appearance: Slightly yellow oil

¹H NMR (CDCl₃) δ 2.18 (3H, s), 2.30-2.45 (4H, m), 2.56-2.63 (2H, m), 2.91-2.97 (2H, m), 3.30-3.50 (6H, m), 3.55-3.70 (2H, m), 5.95 (2H, s), 6.65-6.80 (3H, m), 6.84 (1H, s), 6.95-7.05 (2H, m), 7.15-7.20 (2H, m), 7.64 (1H, s).

Reference Example 494
Production of ethyl 3-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}propionate

A solution of 3,4-dichlorobenzoyl chloride (3.65 g, 17.4 mmol) was added dropwise under ice cooling to a solution of ethyl 3-[4-(4-aminophenoxy)phenyl]propionate (4.52 g, 15.9 mmol) and triethylamine (2.65 mL, 19.0 mmol) in THF (80 mL), and the resulting solution was stirred for 1 hour at the same temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and evaporated. The residue was recrystallized from water-containing ethanol to thereby yield 6.67 g of the title compound.

Appearance: Colorless needles

Melting point: 139-141° C.

The following compounds were produced in the same manner as in Reference Example 494.

Reference Example 495
Ethyl 3-[4-(5-phenoxycarbonylaminopyridin-2-yloxy)phenyl]propionate

MS 406 (M⁺).

TABLE 71

Refer-

ence

Ex-

ample

mp

No.
Xa₁₈
R₂₅₂
(° C.) or ¹H NMR (CDCl₃) δppm

496
p-
2-(CH₂)₂COOCH₃
mp 117-119

phenylene

497
p-
3-(CH₂)₂COOC₂H₅
mp 111-113

phenylene

498
o-
4-(CH₂)₂COOC₂H₅
mp 72-73

phenylene

499
m-
4-(CH₂)₂COOC₂H₅

¹H NMR 1.22(3H, t, J = 7.2 Hz),

phenylene

2.59(2H, t, J = 7.7 Hz), 2.91(2H, t,

J = 7.7 Hz), 4.10(2H, q, J = 7.2 Hz),

6.78(1H, dt, J = 8.1 Hz, 1.1 Hz),

6.93(2H, d, J = 8.5 Hz), 7.14(2H,

d, J = 8.5 Hz), 7.20-7.36(3H, m),

7.52(1H, d, J = 8.3 Hz), 7.64(1H,

dd, J = 8.3 Hz, 2.1 Hz), 7.81(1H,

brs), 7.91(1H, d, J = 2.1 Hz).

TABLE 72

Reference

Example

No.
R₂₅₃
R₂₅₄
mp (° C.) or ¹H NMR (solvent) δppm

500
—F
—H
mp 168-169

501
—H
—COOC₂H₅
mp 144-145

502
—F
—COOC₂H₅
mp 145-146

503
—F
—CH₂COOCH₃
mp 127-129

504
—F
—(CH₂)₂COOC₂H₅
mp 131-133

505
—F
—(CH₂)₃COOC₂H₅
mp 110-111

506
—F
—SCH₂COOC₂H₅

¹H NMR (CDCl₃) 1.23(3H, t, J = 7.1 Hz), 3.56(2H,

s), 4.15(2H, q, J = 7.1 Hz), 6.90(2H, d, J = 8.7 Hz),

7.08(1H, t, J = 8.7 Hz), 7.20-7.30(1H, m), 7.42(2H,

d, J = 8.7 Hz), 7.58(1H, d, J = 8.3 Hz), 7.65-

7.80(2H, m), 7.82(1H, s), 7.96(1H, d, J = 2.1 Hz).

507
—F
—NHCH₂COOC₂H₅

¹H NMR (DMSO-d₆) 1.19(3H, t, J = 7.1 Hz),

3.87(2H, d, J = 6.4 Hz), 4.11(2H, q, J = 7.1 Hz),

5.93(1H, t, J = 6.4 Hz), 6.56(2H, d, J = 9.0 Hz),

6.81(2H, d, J = 9.0 Hz), 6.98(1H, t, J = 9.2 Hz),

7.44-7.47(1H, m), 7.82-7.86(2H, m), 7.93(1H, dd,

J = 2.0 Hz, 8.4 Hz), 8.20(1H, d, J = 2.0 Hz),

10.50(1H, s).

508
—H
—Br

¹H NMR (DMSO-d₆) 6.96(2H, d, J = 9.0 Hz),

7.08(2H, d, J = 9.0 Hz), 7.55(2H, d, J = 8.5 Hz),

7.79(2H, d, J = 8.5 Hz), 7.83(1H, d, J = 8.5 Hz),

7.94(1H, dd, J = 8.5 Hz, 2.0 Hz), 8.21(1H, d, J =

2.0 Hz), 10.44(1H, brs).

509
—F
—Ac
mp 143

510
—F

embedded image

¹H NMR (CDCl₃) 4.00-4.15(4H, m), 5.78(1H, s), 6.96(2H, d, J = 8.7 Hz), 7.00-7.10(1H, m), 7.20- 7.30(1H, m), 7.43(2H, d, J = 8.7 Hz), 7.57(1H, d, J = 8.3 Hz), 7.82(1H, s), 7.95(1H, d, J = 2.1 Hz).

TABLE 73

Reference

Example

No.
R₂₅₅
R₂₅₆
R₂₅₇

¹H NMR (CDCl₃) δppm

511
—Cl
—Cl

embedded image

3.98(3H, s), 7.06(1H, d, J = 8.7 Hz), 7.33-7.37(1H, m), 7.56-7.59(2H, m), 7.70-7.73(1H, m), 7.80(1H, d, J = 8.5 Hz), 7.95-8.07(4H, m), 8.23-8.30(2H, m), 8.60(1H, s).

512
—CF₃
—H

embedded image

3.98(3H, s), 7.07-7.10(1H, m), 7.37(1H, dd, J = 8.9 Hz, 2.3 Hz), 7.58(1H, d, J = 2.3 Hz), 7.76- 7.82(3H, m), 7.93-8.08(5H, m), 8.27- 8.31(2H, m), 8.60(1H, s).

513
—Cl
—Cl

embedded image

1.46(3H, t, J = 7.1 Hz), 4.47(2H, q, J = 7.1 Hz), 7.04(1H, d, J = 8.7 Hz), 7.41(1H, dd, J = 9.4 Hz, 2.5 Hz), 7.47-7.60(3H, m), 7.70(1H, dd, J = 8.4 Hz, 2.1 Hz), 7.82(1H, brs), 7.94(1H, d, J = 8.6 Hz), 7.98(1H, d, J = 2.1 Hz), 8.14(1H, dd, J = 7.3 Hz, 1.2 Hz), 8.20-8.27(2H, m), 8.92(1H, d, J = 9.4 Hz).

514
—CF₃
—H

embedded image

1.46(3H, t, J = 7.1 Hz), 4.47(2H, q, J = 7.1 Hz), 7.04(1H, d, J = 8.7 Hz), 7.40(1H, dd, J = 9.4 Hz, 2.5 Hz), 7.47-7.53(1H, m), 7.59(1H, d, J = 2.5 Hz), 7.75(2H, d, J = 8.2 Hz), 7.92- 8.00(4H, m), 8.14(1H, dd, J = 7.3 Hz, 1.2 Hz), 8.23-8.29(2H, m), 8.97(1H, d, J = 9.4 Hz).

515
—Cl
—Cl

embedded image

4.00(3H, s), 7.09(1H, d, J = 9.6 Hz), 7.16(1H, d, J = 8.1 Hz), 7.50- 7.57(2H, m), 7.62-7.72(2H, m), 7.98(2H, d, J = 2.1 Hz), 8.15- 8.29(4H, m), 9.01(1H, d, J = 8.7 Hz).

TABLE 74

Reference

Example

No.
R₂₅₈

¹H NMR (CDCl₃) δppm

516
—COOCH₃
3.91(3H, s), 7.03(1H, d, J = 8.9 Hz), 7.15-7.18(2H, m),

7.58(1H, d, J = 8.3 Hz), 7.69-7.73(1H, m), 7.89(1H, brs),

7.99(1H, d, J = 2.0 Hz), 8.06-8.09(2H, m), 8.23-8.30(2H,

m).

517
—COOC₂H₅
1.39(3H, t, J = 7.3 Hz), 4.37(2H, q, J = 7.3 Hz), 7.02(1H,

d, J = 8.6 Hz), 7.15-7.18(2H, m), 7.57(1H, d, J = 8.6 Hz),

7.70-7.73(1H, m), 7.97-7.99(2H, m), 8.06-8.09(2H, m),

8.23-8.30(2H, m)

518
—CH₂COOCH₃
3.63(2H, s), 3.71(3H, s), 6.94(1H, d, J = 8.9 Hz), 7.07(2H,

d, J = 8.2 Hz), 7.30(2H, d, J = 8.6 Hz), 7.55(1H, d, J = 8.6

Hz), 7.70(1H, dd, J = 8.2 Hz, 2.0 Hz), 7.97-8.08(2H, m),

8.17(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.24(1H, d, J = 2.6 Hz).

519
—(CH₂)₂COOCH₃
2.62-2.67(2H, m), 2.93-2.98(2H, m), 3.68(3H, s), 6.93

(1H, d, J = 8.9 Hz), 7.03-7.06(2H, m), 7.20-7.23(2H, m),

7.56(1H, d, J = 8.3 Hz), 7.68-7.72(1H, m), 7.96-7.98(2H,

m), 8.17(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.24(1H, d, J = 2.6

Hz).

520
—(CH₂)₃COOC₂H₅
1.26(3H, t, J = 7.0 Hz), 1.96(2H, dt, J = 15.0 Hz, 7.5 Hz),

2.34(2H, t, J = 7.5 Hz), 2.66(2H, t, J = 7.5 Hz), 4.13(2H,

q, J = 7.0 Hz), 6.93(1H, d, J = 8.8 Hz), 7.04(2H, d, J = 8.6

Hz), 7.20(2H, d, J = 8.6 Hz), 7.56(1H, d, J = 8.3 Hz),

7.70(1H, dd, J = 8.3 Hz, 2.0 Hz) ,7.89(1H, s), 7.98(1H, d,

J = 2.0 Hz), 8.16(1H, dd, J = 8.8 Hz, 2.6 Hz), 8.24(1H, d,

J = 2.6 Hz).

521
—(CH₂)₄COOC₂H₅
1.26(3H, t, J = 7.2 Hz), 1.60-1.75(4H, m), 2.33(2H, t, J =

7.0 Hz), 2.64(2H, t, J = 7.0 Hz), 4.13(2H, q, J = 7.2 Hz),

6.94(1H, d, J = 8.9 Hz), 7.04(2H, d, J = 8.5 Hz), 7.20(2H,

d, J = 8.5 Hz), 7.58(1H, d, J = 8.3 Hz), 7.70(1H, dd, J =

8.3 Hz, 2.3 Hz), 7.78(1H, brs), 7.98(1H, d, J = 2.3 Hz),

8.16(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.24(1H, d, J = 2.6 Hz).

522
—CH₂CN
3.76(2H, s), 7.00(1H, d, J = 8.8 Hz), 7.16(2H, d, J = 8.7

Hz), 7.37(2H, d, J = 8.7 Hz), 7.58(1H, d, J = 8.4 Hz),

7.70(1H, dd, J = 8.4 Hz, 2.1 Hz), 7.81(1H, s), 7.98(1H, d),

J = 2.1 Hz), 8.20(1H, dd, J = 8.8 Hz, 2.3 Hz), 8.25(1H, d,

J = 2.3 Hz).

523
—NHCOOC(CH₃)₃
1.52(9H, s), 6.49(1H, brs), 6.90(1H, d, J = 8.6 Hz),

7.05(2H, d, J = 8.9 Hz), 7.37(2H, d, J = 8.9 Hz), 7.56(1H,

d, J = 8.6 Hz), 7.69(1H, dd, J = 8.6 Hz, 2.3 Hz), 7.92(1H,

brs), 7.97(1H, d, J = 2.3 Hz), 8.14(1H, dd, J = 8.6 Hz, 2.6

Hz), 8.22(1H, d, J = 2.6 Hz).

524
—CH═C(COOCH₃)₂
3.85(3H, s), 3.86(3H, s), 7.02(1H, d, J = 8.8 Hz), 7.13(2H,

d, J = 8.5 Hz), 7.46(2H, d, J = 8.5 Hz), 7.59(1H, d, J = 8.2

Hz), 7.70(1H, dd, J = 8.2 Hz, 2.0 Hz), 7.74(1H, s),

7.88(1H, brs), 7.97(1H, d, J = 2.0 Hz), 8.22(1H, dd, J =

8.8 Hz, 2.5 Hz), 8.24(1H, d, J = 2.5 Hz).

TABLE 75

Reference

Example

No.
R₂₅₉
R₂₆₀
R₂₆₁

¹H NMR (solvent) δppm

525
—OCH₃
—H
—COOC₂H₅
(CDCl₃) 1.40(3H, t, J = 7.1 Hz), 3.81(3H, s),

4.39(2H, q, J = 7.1 Hz), 6.99-7.02(1H, m),

7.16(1H, d, J = 8.1 Hz), 7.56(1H, d, J = 8.4

Hz), 7.67-7.72(3H, m), 7.97-8.01(2H, m),

8.17-8.22(2H, m).

526
—CH₃
—H
—COOCH₃
(CDCl₃) 2.24(3H, s), 3.91(3H, s), 6.97-

7.01(1H, m), 7.07(1H, d, J = 8.4 Hz),

7.57(1H, d, J = 8.4 Hz), 7.69-7.73(1H, m),

7.91(1H, dd, J = 8.4 Hz, 2.4 Hz), 7.97-

7.99(3H, m), 8.21-8.26(2H, m).

527
—Cl
—H
—COOCH₃
(CDCl₃) 3.93(3H, s), 7.08(1H, d, J = 8.7 Hz),

7.26(1H, d, J = 1.7 Hz), 7.56(1H, d, J = 8.2

Hz), 7.69-7.73(1H, m), 7.95-7.99(2H, m),

8.10(1H, brs), 8.15(1H, d, J = 2.0 Hz) ,8.22-

8.24(1H, m), 8.27(1H, d, J = 2.8 Hz).

528
—F
—H
—COOCH₃
(CDCl₃) 3.92(3H, s), 7.07(1H, dd, J = 7.8 Hz,

1.8 Hz), 7.25-7.31(1H, m), 7.56(1H, d, J = 8.4

Hz), 7.71(1H, dd, J = 8.2 Hz, 2.1 Hz), 7.82-

7.89(2H, m), 7.97(1H, d, J = 2.1 Hz),

8.08(1H, brs), 8.21-8.25(2H, m).

529
—H
—OCH₃
—COOCH₃
(CDCl₃) 3.83(3H, s), 3.87(3H, s), 6.70(1H, dd,

J = 8.6 Hz, 2.2 Hz), 6.74(1H, d, J = 2.2 Hz),

7.01(1H, d, J = 8.6 Hz), 7.56(1H, d, J = 8.1

Hz), 7.75(1H, dd, J = 8.6 Hz, 2.2 Hz),

7.87(1H, d, J = 8.6 Hz), 8.01(1H, d, J = 2.2

Hz), 8.25-8.33(3H, m).

530
—H
—CH₃
—COOCH₃
(CDCl₃) 2.63(3H, s), 3.91(3H, s), 6.98-

7.05(3H, m), 7.60(1H, d, J = 8.4 Hz),

7.75(1H, dd, J = 8.4 Hz, 2.2 Hz), 7.97-

8.03(3H, m), 8.23-8.28(1H, m), 8.30-8.32(1H,

m).

531
—H
—COOCH₃
—H
(DMSO-d₆) 3.85(3H, s), 7.17(1H, d, J = 8.9

Hz), 7.43-7.47(1H, m), 7.56-7.62(2H, m),

7.78-7.86(2H, m), 7.93-7.97(1H, m), 8.22-

8.27(2H, m), 8.50(1H, d, J = 2.3 Hz),

10.60(1H, s).

TABLE 76

Reference

Example

No.
R₂₆₂
R₂₆₃
R₂₆₄

¹H NMR (CDCl₃) δppm

532
—OCH₃
—H
—COOC₂H₅
1.40(3H, t, J = 7.1 Hz), 3.82(3H, s),

4.39(2H, q, J = 7.1 Hz), 7.00-7.03(1H,

m), 7.17(1H, d, J = 8.1 Hz), 7.68-

7.76(4H, m), 8.01(2H, d, J = 8.1 Hz),

8.16(1H, brs), 8.22-8.25(2H, m).

533
—OCH₃
—H
—(CH₂)₂COOCH₃
2.63-2.69(2H, m), 2.93-2.99(2H, m),

3.69(3H, s), 3.74(3H, s), 6.78-6.84(2H,

m), 6.93(1H, d, J = 8.7 Hz), 7.03(1H, d,

J = 8.1 Hz), 7.73(2H, d, J = 8.1 Hz),

7.96-7.99(3H, m), 8.14-8.20(2H, m).

534
—CH₃
—H
—COOCH₃
2.25(3H, s), 3.91(3H, s), 6.99-7.03(1H,

m), 7.07(1H, d, J = 8.4 Hz), 7.75-

7.78(2H, m), 7.88-7.92(1H, m), 7.98-

8.01(4H, m), 8.26-8.29(2H, m).

535
—Cl
—H
—COOCH₃
3.93(3H, s), 7.09(1H, d, J = 8.7 Hz),

7.24-7.27(1H, m), 7.76(2H, d, J = 8.7

Hz), 7.96-8.03(4H, m), 8.16(1H, d, J =

2.1 Hz), 8.24(1H, d, J = 2.6 Hz),

8.29(1H, dd, J = 8.7 Hz, 2.6 Hz).

536
—F
—H
—COOCH₃
3.92(3H, s), 7.08(1H, d, J = 8.7 Hz),

7.26-7.32(1H, m), 7.75(2H, d, J = 8.4

Hz), 7.83-7.90(2H, m), 7.98(3H, d, J =

8.2 Hz), 8.22-8.28(2H, m).

537
—H
—OCH₃
—COOCH₃
3.87(3H, s), 3.88(3H, s), 6.71(1H, dd, J =

8.6 Hz, 2.2 Hz), 6.77(1H, d, J = 2.2

Hz), 7.04(1H, d, J = 8.9 Hz), 7.77(2H, d,

J = 8.1 Hz), 7.88(1H, d, J = 8.6 Hz), 8.02

(2H, d, J = 8.1 Hz), 8.17(1H, brs), 8.29-

8.35(2H, m).

538
—H
—CH₃
—COOCH₃
2.63(3H, s), 3.91(3H, s), 6.98-7.06(3H,

m), 7.79(2H, d, J = 8.1 Hz), 8.00-

8.04(4H, m), 8.27-8.34(2H, m).

539
—H
—COOCH₃
—H
3.91(3H, s), 6.99-7.04(1H, m), 7.32-

7.37(1H, m), 7.45-7.50(1H, m), 7.74-

7.80(3H, m), 7.86-7.90(1H, m), 7.96-

8.01(3H, m), 8.22-8.27(2H, m).

TABLE 77

Reference

Example

No.
R₂₆₅
R₂₆₆
R₂₆₇
R₂₆₈

¹H NMR (CDCl₃) δppm or mp (□)

540
—CF₃
—H
—H

embedded image

¹H NMR 1.17(3H, t, J = 7.1 Hz), 1.26(3H, d, J = 7.0 Hz), 2.44-2.61(2H, m), 3.19- 3.29(1H, m), 4.05(2H, q, J = 7.1 Hz), 6.88(1H, d, J = 8.8 Hz), 7.01(2H, d, J = 8.5 Hz), 7.19(2H, d, J = 8.5 Hz), 7.68(2H, d, J = 8.3 Hz), 7.94(2H, d, J = 8.3 Hz), 8.15(1H, dd, J = 8.8 Hz, 2.7 Hz), 8.23(1H, d, J = 2.7 Hz), 8.29(1H, brs).

541
—Cl
—Cl
—H

embedded image

¹H NMR 1.17(3H, t, J = 7.1 Hz), 1.26(3H, d, J = 7.0 Hz), 2.43-2.60(2H, m), 3.18- 3.28(1H, m), 4.05(2H, q, J = 7.1 Hz), 6.85(1H, d, J = 8.9 Hz), 6.99(2H, d, J = 8.4 Hz), 7.18(2H, d, J = 8.4 Hz), 7.48(1H, d, J = 8.3 Hz), 7.66(1H, dd, J = 8.3 Hz, 2.0 Hz), 7.92(1H, d, J = 2.0 Hz), 8.10(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.20(1H, d, J = 2.7 Hz), 8.39(1H, brs)

542
—CF₃
—H
—H

embedded image

¹H NMR 1.35(3H, t, J = 7.1 Hz), 4.27(2H, q, J = 7.1 Hz), 6.39(1H, dd, J = 16.0 Hz, 2.6 Hz), 7.03(1H, d, J = 8.9 Hz), 7.16(2H, d, J = 8.8 Hz), 7.56(2H, d, J = 8.8 Hz), 7.68(1H, dd, J = 16.0 Hz, 3.2 Hz), 7.77(2H, d, J = 8.1 Hz), 7.93(1H, brs), 8.01(2H, d, J = 8.1 Hz), 8.26(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.29(1H, d, J = 2.6 Hz).

543
—CF₃
—H
—H
—CH₂COOCH₃

¹H NMR 3.62(2H, s), 3.70(3H, s),

6.94(1H, d, J = 8.7 Hz), 7.05-7.09(2H, m),

7.26-7.32(2H, m), 7.72(2H, d, J = 8.6 Hz),

7.97(2H, d, J = 8.2 Hz), 8.17-8.26(3H, m).

544
—CF₃
—H
—H
—(CH₂)₂COOC₂H₅

¹H NMR 1.25(3H, t, J = 7.1 Hz), 2.62(2H,

t, J = 7.7 Hz), 2.95(2H, t, J = 7.7 Hz),

4.13(2H, q, J = 7.1 Hz), 6.94(1H, d, J =

8.8 Hz), 7.04(2H, d, J = 8.6 Hz), 7.22(2H,

d, J = 8.6 Hz), 7.75(2H, d, J = 8.3 Hz),

7.98(2H, d, J = 8.3 Hz), 8.03(1H, brs),

8.19(1H, dd, J = 8.8 Hz, 2.6 Hz), 8.26(1H,

d, J = 2.6 Hz).

545
—Cl
—Cl
—H

embedded image

¹H NMR 0.01(6H, s), 0.89(9H, s), 2.83(2H, t, J = 6.9 Hz), 3.82(2H, t, J = 6.9 Hz), 6.92(1H, d, J = 8.9 Hz), 7.05(2H, dd, J = 6.3 Hz, 2.0 Hz), 7.24(2H, d, J = 8.6 Hz), 7.58(1H, d, J = 8.3 Hz), 7.71(1H, dd, J = 8.3 Hz, 2.0 Hz), 7.80(1H, brs), 7.98(1H, d, J = 2.0 Hz), 8.15-8.19(1H, m), 8.25(1H, d, J = 2.6 Hz).

546
—Cl
—Cl
—H

embedded image

¹H NMR 0.07(6H, s), 0.91(9H, s), 1.82- 1.87(2H, m), 2.65-2.71(2H, m), 3.63- 3.68(2H, m), 6.92(1H, d, J = 8.9 Hz), 7.02-7.05(2H, m), 7.21(2H, d, J = 8.6 Hz), 7.57(1H, d, J = 8.3 Hz), 7.68-7.72(1H, m), 7.86(1H, brs), 7.97(1H, d, J = 2.0 Hz), 8.14-8.18(1H, m), 8.24(1H, d, J = 2.3 Hz).

547
—H
—F
—CF₃
—COOC₂H₅
mp 133-134

TABLE 78

Reference

Example

No.
R₂₆₉
R₂₇₀
Xa₁₉
R₂₇₁
M
mp (° C.) or ¹H NMR (solvent) δppm

548
—Cl
—Cl
—S—
—CH₃
2
mp 141-142

549
—Cl
—Cl
—NH—
—C₂H₅
2
mp 170-171

550
—Cl
—Cl
—N(CH₃)—
—C₂H₅
2

¹H NMR (DMSO-d₆) 1.17(3H, t, J = 7.1

Hz), 2.63(2H, t, J = 7.7 Hz), 2.85(2H, t,

J = 7.7 Hz), 3.36(3H, s), 4.07(2H, d, J =

7.1 Hz), 6.56(1H, d, J = 9.5 Hz),

7.18(2H, d, J = 8.3 Hz), 7.27(2H, d, J =

8.3 Hz), 7.75-7.95(3H, m), 8.20(1H, s),

8.47(1H, s), 10.26(1H, s).

551
—CF₃
—H
—N(CH₃)—
—C₂H₅
0
mp 135-136

552
—CF₃
—H
—N(CH₃)—
—C₂H₅
2

¹H NMR (CDCl₃) 1.26(3H, t, J = 7.2

Hz), 2.65(2H, t, J = 8.0 Hz), 2.97(2H, t,

J = 8.0 Hz), 3.45(3H, s), 4.16(2H, q, J =

7.2 Hz), 6.57(1H, d, J = 9.1 Hz),

7.18(2H, d, J = 8.3 Hz), 7.24(2H, d, J =

8.3 Hz), 7.35-7.45(1H, m), 7.65-

7.78(3H, m), 7.98(2H, d, J = 8.1 Hz),

8.28(1H, d, J = 2.5 Hz).

553
—Cl
—Cl
—N(CH₂Ph)—
—C₂H₅
2

¹H NMR (CDCl₃) 1.23(3H, t, J = 7.2

Hz), 2.61(2H, t, J = 7.6 Hz), 2.92(2H, t,

J = 7.6 Hz), 4.12(2H, q, J = 7.2 Hz),

5.20(2H, s), 6.54(1H, d, J = 9.1 Hz),

7.10-7.30(8H, m), 7.53(1H, d, J = 8.4

Hz), 7.60-7.75(3H, m), 7.94(1H, d, J =

1.3 Hz), 8.22(1H, d, J = 2.3 Hz).

554
—Cl
—H
—O—
—CH₃
0

¹H NMR (CDCl₃) 3.91(3H, s), 7.04(1H,

d, J = 9.9 Hz), 7.17(2H, d, J = 8.6 Hz),

7.49(2H, d, J = 8.6 Hz), 7.79(1H, brs),

7.83(2H, d, J = 8.6 Hz), 8.08(2H, d, J =

8.6 Hz), 8.27-8.29(2H, m).

555
—CF₃
—H
—O—
—C₂H₅
0

¹H NMR (CDCl₃) 1.39(3H, t, J = 7.3

Hz), 4.37(2H, q, J = 7.3 Hz), 7.04(1H,

dd, J = 8.3 Hz, 1.3 Hz), 7.15-7.19(2H,

m), 7.78(2H, d, J = 8.3 Hz), 7.91(1H,

brs), 8.00(2H, d, J = 6.9 Hz), 8.07-

8.10(2H, m), 8.27-8.31(2H, m).

556
—H
—OCF₃
—O—
—CH₃
0

¹H NMR (CDCl₃) 3.91(3H, s), 7.02(1H,

d, J = 8.7 Hz), 7.16(2H, d, J = 8.7 Hz),

7.42(1H, d, J = 8.2 Hz), 7.53(1H, t, J =

8.1 Hz), 7.76-7.81(2H, m), 8.05-

8.08(3H, m), 8.25-8.31(2H, m).

557
—H
—CF₃
—O—
—C₂H₅
0

¹H NMR (CDCl₃) 1.39(3H, t, J = 7.2

Hz), 4.37(2H, q, J = 7.2 Hz), 7.40(1H,

d, J = 8.7 Hz), 7.09-7.20(2H, m),

7.66(1H, t, J = 7.8 Hz), 7.76-7.90(1H,

m), 8.00(1H, brs), 8.00-8.10(3H, m),

8.10-8.18(1H, m), 8.20-8.35(2H, m).

TABLE 79

Reference

Example

No.
R₂₇₂
R₂₇₃
M
mp (° C.) or ¹H NMR (CDCl₃) δppm

558
—H
—Ac
1
mp 178-179

559
—H
—Ac
2

¹H NMR 1.22(3H, t, J = 7.2 Hz), 1.86(3H, s), 2.58(2H, t, J =

7.3 Hz), 3.99(2H, t, J = 7.3 Hz), 4.07(2H, q, J = 7.2 Hz), 7.02(1H, d,

J = 8.9 Hz), 7.15-7.20(4H, m), 7.58(1H, d, J = 8.4 Hz), 7.75(1H, dd,

J = 2.1 Hz, 8.4 Hz), 8.02(1H, d, J = 2.1 Hz), 8.24(1H, dd, J = 2.7 Hz,

8.9 Hz), 8.28(1H, s), 8.32(1H, d, J = 2.7 Hz).

560
—H
—CH₃
1

¹H NMR 1.26(3H, t, J = 7.1 Hz), 8.06(3H, s), 4.04(2H, s), 4.18(2H,

q, J = 7.1 Hz), 6.68(2H, d, J = 9.1 Hz), 6.85(1H, d, J = 8.9 Hz),

7.00(2H, d, J = 9.1 Hz), 7.55(1H, d, J = 8.4 Hz), 7.70(1H, dd, J =

1.9 Hz, 8.4 Hz), 7.94(1H, s), 7.97(1H, d, J = 1.9 Hz), 8.10(1H, dd, J =

2.6 Hz, 8.9 Hz), 8.21(1H, d, J = 2.6 Hz).

561
—H
—C₂H₅
1

¹H NMR 1.22(3H, t, J = 7.1 Hz), 1.27(3H, t, J = 7.1 Hz), 3.46(2H,

q, J = 7.1 Hz), 4.01(2H, s), 4.20(2H, q, J = 7.1 Hz), 6.64(2H, d, J =

9.1 Hz), 6.86(1H, d, J = 8.9 Hz), 6.98(2H, d, J = 9.1 Hz), 7.56(1H,

d, J = 8.4 Hz), 7.70(1H, dd, J = 1.9 Hz, 8.4 Hz), 7.82(1H, s),

7.97(1H, d, J = 1.9 Hz), 8.11(1H, dd, J = 2.6 Hz, 8.9 Hz), 8.22(1H,

d, J = 2.6 Hz).

562
—OCH₃
—CH₃
1

¹H NMR 1.25(3H, t, J = 7.1 Hz), 3.03(3H, s), 3.65(3H, s), 4.01(2H,

s), 4.17(2H, q, J = 7.1 Hz), 6.16(1H, d, J = 8.7 Hz), 6.21(1H, s),

6.76(1H, d, J = 8.9 Hz), 6.88(1H, d, J = 8.6 Hz), 7.43(1H, d, J =

8.4 Hz), 7.67(1H, d, J = 8.4 Hz), 7.94(1H, d, J = 1.8 Hz), 8.02(1H, d,

J = 8.9 Hz), 8.13(1H, d, J = 2.3 Hz), 8.88(1H, s).

563
—OCH₃
—C₂H₅
1

¹H NMR 1.21(3H, t, J = 7.1 Hz), 1.27(3H, t, J = 7.1 Hz), 3.44(2H,

q, J = 7.1 Hz), 3.68(3H, s), 3.98(2H, s), 4.20(2H, q, J = 7.1 Hz),

6.17(1H, dd, J = 8.9 Hz, 3.0 Hz), 6.24(1H, d, J = 2.8 Hz), 6.81(1H,

d, J = 8.9 Hz), 6.91(1H, d, J = 8.7 Hz), 7.48(1H, d, J = 8.4 Hz),

7.68(1H, dd, J = 8.4 Hz, 2.2 Hz), 7.96(1H, d, J = 2.0 Hz), 8.04(1H,

dd, J = 8.9 Hz, 2.8 Hz), 8.15(1H, d, J = 2.3 Hz), 8.34(1H, s).

564
—CH₃
—Ac
1

¹H NMR 1.26(3H, t, J = 7.1 Hz), 1.96(3H, s), 2.22(3H, s), 4.20(2H,

q, J = 7.1 Hz), 4.37(2H, s), 6.99(1H, d, J = 8.9 Hz), 7.07(1H, d, J =

8.4 Hz), 7.19(1H, dd, J = 2.4 Hz, 8.4 Hz), 7.59(1H, d, J = 8.4 Hz),

7.72(1H, d, J = 8.4 Hz), 7.90-8.12(2H, m), 8.21(1H, dd, J = 2.0 Hz,

8.4 Hz), 8.27(1H, s).

565
—CH₃
—CH₃
1

¹H NMR 1.26(3H, t, J = 7.1 Hz), 2.12(3H, s), 3.06(3H, s), 4.04(2H,

s), 4.20(2H, q, J = 7.1 Hz), 6.49-6.61(1H, m), 6.83(1H, d, J =

8.9 Hz), 6.93(1H, d, J = 8.5 Hz), 7.57(1H, d, J = 8.5 Hz), 7.70(1H,

dd, J = 8.5 Hz, 2.1 Hz), 7.73(1H, s), 7.97(1H, d, J = 2.1 Hz),

8.12(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.21(1H, d, J = 2.8 Hz).

566
—F
—Ac
1

¹H NMR 1.29(3H, t, J = 7.1 Hz), 2.00(3H, s), 4.21(2H, q, J =

7.1 Hz), 4.37(2H, s), 7.09(1H, dd, J = 7.9 Hz, 1.8 Hz), 7.18-7.32(3H,

m), 7.59(1H, d, J = 8.4 Hz), 7.72(1H, dd, J = 8.3 Hz, 2.1 Hz),

7.83(1H, brs), 7.99(1H, d, J = 2.0 Hz), 8.20-8.24(2H, m).

567
—F
—CH₃
1

¹H NMR 1.27(3H, t, J = 7.1 Hz), 3.06(3H, s), 4.04(2H, s), 4.20(2H,

q, J = 7.1 Hz), 6.40-6.52(2H, m), 6.96(1H, d, J = 9.2 Hz), 7.07(1H,

t, J = 9.1 Hz), 7.57(1H, d, J = 8.2 Hz), 7.70(1H, dd, J = 8.2 Hz,

2.0 Hz), 7.82(1H, brs), 7.97(1H, d, J = 2.1 Hz), 8.13-8.19(2H, m).

568
—F
—C₂H₅
1

¹H NMR 1.23(3H, t, J = 7.1 Hz), 1.28(3H, t, J = 7.1 Hz), 3.45(2H,

q, J = 7.1 Hz), 4.00(2H, s), 4.22(2H, q, J = 7.1 Hz), 6.37-6.48(2H,

m), 6.97(1H, d, J = 8.7 Hz), 7.05(1H, t, J = 9.1 Hz), 7.57(1H, d, J =

8.4 Hz), 7.70(1H, dd, J = 8.4 Hz, 2.2 Hz), 7.79(1H, brs), 7.98(1H, d,

J = 2.0 Hz), 8.13-8.20(2H, m).

TABLE 80

Reference

Example

No.
R₂₇₄
R₂₇₅
M
E
mp (° C.) or ¹H NMR (CDCl₃) δppm

569
—H
—Ac
1
2
mp 163-164

570
—H
—Ac
2
2

¹H NMR 1.22(3H, t, J = 7.2 Hz), 1.87(3H, s), 2.59(2H, t, J =

7.3 Hz), 4.00(2H, t, J = 7.3 Hz), 4.08(2H, q, J = 7.2 Hz),

7.03(1H, d, J = 8.8 Hz), 7.19(4H, s), 7.78(2H, d, J = 8.3

Hz), 7.95(1H, brs), 8.01(2H, d, J = 8.3 Hz), 8.27(1H, d, J =

8.8 Hz), 8.31(1H, s).

571
—H
—CH₃
1
1

¹H NMR 3.06(3H, s), 3.73(3H, s), 4.07(2H, s), 6.68(2H, d,

J = 9.1 Hz), 6.86(1H, d, J = 8.9 Hz), 7.00(2H, d, J = 9.1

Hz), 7.74(2H, d, J = 8.0 Hz), 7.98(2H, d, J = 8.0 Hz),

8.07(1H, s), 8.15(1H, dd, J = 8.9 Hz, 2.5 Hz), 8.24(1H, d,

J = 2.5 Hz).

572
—H
—C₂H₅
1
2

¹H NMR 1.18(3H, t, J = 7.1 Hz), 1.25(3H, t, J = 7.1 Hz),

3.41(2H, q, J = 7.1 Hz), 3.98(2H, s), 4.17(2H, q, J = 7.1

Hz), 6.59(2H, d, J = 9.1 Hz), 6.79(1H, d, J = 8.7 Hz),

6.92(2H, d, J = 9.1 Hz), 7.64(2H, d, J = 8.4 Hz), 7.94(2H,

d, J = 8.1 Hz), 8.07(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.22(1H,

d, J = 2.8 Hz), 8.75(1H, s).

573
—OCH₃
—CH₃
1
2

¹H NMR 1.24(3H, t, J = 7.1 Hz), 3.03(3H, s), 3.65(3H, s),

4.01(2H, s), 4.17(2H, q, J = 7.1 Hz), 6.17(1H, dd, J = 8.7

Hz, 2.6 Hz), 6.24(1H, d, J = 2.5 Hz), 6.77(1H, d, J = 8.9

Hz), 6.89(1H, d, J = 8.7 Hz), 7.63(2H, d, J = 8.3 Hz),

7.96(2H, d, J = 8.1 Hz), 8.06(1H, d, J = 8.7 Hz), 8.16(1H,

d, J = 2.5 Hz), 8.91(1H, s).

574
—OCH₃
—C₂H₅
1
2

¹H NMR 1.19(3H, t, J = 7.1 Hz), 1.26(3H, t, J = 7.1 Hz),

3.42(2H, q, J = 7.1 Hz), 3.64(3H, s), 3.97(2H, s), 4.18(2H,

q, J = 7.1 Hz), 6.14(1H, dd, J = 8.7 Hz, 2.8 Hz), 6.21(1H,

d, J = 2.8 Hz), 6.76(1H, d, J = 8.9 Hz), 6.87(1H, d, J = 8.7

Hz), 7.62(2H, d, J = 8.4 Hz), 7.96(2H, d, J = 8.3 Hz),

8.05(1H, dd, J = 8.9 Hz, 2.5 Hz), 8.18(1H, d, J = 2.6 Hz),

9.01(1H, s).

575
—CH₃
—Ac
1
2

¹H NMR 1.25(3H, t, J = 7.0 Hz), 1.93(3H, s), 2.21(3H, s),

4.18(2H, q, J = 7.0 Hz), 4.35(2H, s), 6.98(1H, d, J = 8.7

Hz), 7.06(1H, d, J = 8.5 Hz), 7.18(1H, d, J = 8.5 Hz),

7.23-7.28(1H, m), 7.75(2H, d, J = 7.8 Hz), 8.02(2H, d, J =

7.8 Hz), 8.22-8.33(2H, m).

576
—CH₃
—CH₃
1
2

¹H NMR 1.26(3H, t, J = 7.1 Hz), 2.11(3H, s), 3.05(3H, s),

4.04(2H, s), 4.19(2H, q, J = 7.1 Hz), 6.46-6.60(2H, m),

6.80(1H, d, J = 8.9 Hz), 6.91(1H, d, J = 8.5 Hz), 7.74(2H,

d, J = 8.4 Hz), 7.98(2H, d, J = 8.2 Hz), 8.07(1H, s), 8.15

(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.23(1H, d, J = 2.7 Hz).

577
—F
—Ac
1
2

¹H NMR 1.28(3H, t, J = 7.1 Hz), 1.98(3H, s), 4.20(2H, q,

J = 7.1 Hz), 4.36(2H, s), 7.09(1H, dd, J = 6.4 Hz, 3.5 Hz),

7.13-7.32(3H, m), 7.77(2H, d, J = 8.3 Hz), 8.01(2H, d, J =

8.1 Hz), 8.12(1H, s), 8.23-8.28(2H, m).

578
—F
—CH₃
1
2

¹H NMR 1.27(3H, t, J = 7.1 Hz), 3.07(3H, s), 4.04(2H, s),

4.20(2H, q, J = 7.1 Hz), 6.41-6.53(2H, m), 6.98(1H, d, J =

9.7 Hz), 7.07(1H, t, J = 9.1 Hz), 7.76(2H, d, J = 8.6 Hz),

7.84(1H, s), 7.99(2H, d, J = 8.1 Hz), 8.19-8.21(2H, m).

579
—F
—C₂H₅
1
2

¹H NMR 1.20-1.31(6H, m), 3.45(2H, q, J = 7.3 Hz),

4.00(2H, s), 4.22(2H, q, J = 7.1 Hz), 6.37-6.49(2H, m),

6.97-7.09(2H, m), 7.76-7.79(3H, m), 7.99(2H, d, J = 7.9

Hz), 8.19-8.21(2H, m).

Reference Example 580
Production of ethyl 3-{4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]-3-methoxyphenyl}propionate

Under ice cooling, to a solution of ethyl 3-(4-(5-aminopyridin-2-yloxy)-3-methoxyphenyl)propionate (1.43 g, 4.5 mmol) in dichloromethane (30 mL) was added pyridine (0.44 mL, 5.4 mmol), and then 3,4-dichlorobenzoyl chloride (0.99 g, 4.7 mmol). The resulting solution was stirred for 1 hour under ice cooling, and then for 10 hours at room temperature. To the resulting reaction solution was added 10% hydrochloric acid, and extracted with dichloromethane. The dichloromethane layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated. To the residue was added diethyl ether, and stirred. The precipitates were collected by filtration. After washing with water and diethyl ether, the precipitates were air dried at 60° C., to thereby yield 0.52 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 1.26 (3H, t, J=7.1 Hz), 2.56-2.79 (2H, m), 2.91-3.09 (2H, m), 3.75 (3H, s), 4.15 (2H, q, J=7.1 Hz), 6.75 (3H, m), 7.10 (1H, d, J=8.0 Hz), 7.56 (1H, d, J=8.2 Hz), 7.99 (1H, d, J=8.1 Hz), 8.17 (1H, s), 8.69 (1H, d, J=9.2 Hz), 8.79 (1H, s), 9.52 (1H, brs).

The following compounds were produced in the same manner as in Reference Example 580.

TABLE 81

Reference

Example

No.
R₂₇₆
R₂₇₇
Xa₂₀

¹H NMR (CDCl₃) δppm

581
3,4-Cl₂Ph—
—H
—CO—
1.23(3H, t, J = 7.2 Hz), 2.64(2H, t, J = 7.6 Hz),

3.01(2H, t, J = 7.6 Hz), 4.12(2H, q, J = 7.2 Hz),

7.30(2H, d, J = 8.2 Hz), 7.57(1H, d, J = 8.3

Hz), 7.73(1H, dd, J = 8.3 Hz, 2.2 Hz), 7.95-8.04

(3H, m), 8.09(1H, d, J = 8.6 Hz), 8.16(1H, brs),

8.41(1H, dd, J = 8.6 Hz, 2.6 Hz), 8.80(1H, d, J =

2.6 Hz).

582
4-CF₃Ph—
—OC₂H₅
—O—
1.22(3H, t, J = 6.9 Hz), 1.26(3H, t, J = 7.2 Hz),

2.51-2.73(2H, m), 2.87-3.06(2H, m), 4.02(2H,

q, J = 6.9 Hz), 4.15(2H, q, J = 7.2 Hz), 6.71-

6.96(3H, m), 7.17(1H, d, J = 7.9 Hz), 7.75(2H,

d, J = 7.6 Hz), 8.43(2H, d, J = 7.6 Hz), 9.15-

9.32(1H, m), 9.42(1H, s), 11.14(1H, brs).

583
3,4-Cl₂Ph—
—F
—O—
1.26(3H, t, J = 7.1 Hz), 2.53-2.70(2H, m), 2.85-

3.03(2H, m), 4.15(2H, q, J = 7.1 Hz), 6.97-

7.09(3H, m), 7.10-7.19(1H, m), 7.58(1H, d, J =

8.3 Hz), 7.70(1H, dd, J = 8.3 Hz, 2.1 Hz), 7.72

(1H, brs), 7.97(1H, d, J = 2.1 Hz), 8.15-

8.23(2H, m).

584
PhCH₂O—
—H
—O—
1.25(3H, t, J = 7.1 Hz), 2.53-2.71(2H, m), 2.84-

3.04(2H, m), 4.14(2H, q, J = 7.1 Hz), 6.51-

6.64(1H, m), 6.88(1H, d, J = 8.8 Hz), 6.98-

7.06(2H, m), 7.17-7.24(2H, m), 7.30-7.43(5H,

m), 7.87-8.02(1H, m), 8.05(1H, d, J = 2.5 Hz).

585
4-CF₃Ph—
—F
—O—
1.26(3H, t, J = 7.1 Hz), 2.56-2.71(2H, m), 2.89-

3.02(2H, m), 4.15(2H, q, J = 7.1 Hz), 6.97-

7.08(3H, m), 7.10-7.19(1H, m), 7.77(2H, d, J =

8.2 Hz), 7.82(1H, brs), 7.99(2H, d, J = 8.2 Hz),

8.17-8.26(2H, m).

TABLE 82

Reference

Example

No.
R₂₇₈
R₂₇₉
R₂₈₀
R₂₈₁
R₂₈₂

¹H NMR (CDCl₃) δppm

586
4-CF₃PhCO—
—F
—(CH₂)₂CH₃
—H
—H
0.96 (3H, t, J = 7.3 Hz), 1.28 (3H, t, J = 7.1 Hz), 1.63- 1.74 (2H, m), 3.32 (2H, t, J = 7.6 Hz), 4.01 (2H, s), 4.21 (2H, q, J = 7.1 Hz), 6.35-6.47 (2H, m), 6.97 (1H, d, J = 7.8 Hz), 7.01 (1H, t, J = 8.9 Hz), 7.77 (2H, d, J = 8.2 Hz), 7.81 (1H, s), 7.99 (2H, d, J = 8.2 Hz), 8.19-8.22 (2H, m).

587
4-CF₃PhCO—
—H
—CH₃
—CH₃
—CH₃
1.25 (3H, t, J = 7.1 Hz), 1.42 (6H, s), 2.91 (3H, s), 4.18 (2H, q, J = 7.1 Hz), 6.92 (1H, d, J = 8.7 Hz), 7.00 (2H, d, J = 9.2 Hz), 7.07 (2H, d, J = 9.1 Hz), 7.77 (2H, d, J = 8.2 Hz), 7.81 (1H, s), 8.00 (2H, d, J = 8.1 Hz), 8.20 (1H, dd, J = 8.7 Hz, 2.8 Hz), 8.28 (1H, d, J = 2.5 Hz).

588
3,4-Cl₂PhSO₂—
—F
—CH₃
—H
—H
1.29 (3H, t, J = 7.1 Hz), 3.05 (3H, s), 4.03 (2H, s), 4.22 (2H, q, J = 7.1 Hz), 6.38-6.49 (2H, m), 6.82 (1H, brs), 6.88 (1H, d, J = 8.7 Hz), 7.02 (1H, t, J = 8.8 Hz), 7.48 (1H, dd, J = 8.4, 1.6 Hz), 7.52 (1H, d, J = 8.4 Hz), 7.57 (1H, dd, J = 8.7 Hz, 2.6 Hz), 7.70 (1H, d, J = 2.6 Hz), 7.82 (1H, d, J = 1.8 Hz).

Reference Example 589
Production of ethyl 4-[5-(3,4-dimethylbenzoylamino)pyridin-2-yloxy]benzoate

To a solution of ethyl 4-(5-aminopyridin-2-yloxy)benzoate (14.15 g, 54.8 mmol) in DMF (100 mL) were added 3,4-dimethylbenzoic acid (8.23 g, 54.8 mmol), 1-hydroxybenzotriazole monohydrate (8.4 g, 54.8 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (12.6 g, 65.7 mmol) under ice cooling, and then stirred for 30 minutes under ice cooling and for 17 hours at room temperature. The reaction solution was concentrated under reduced pressure. To the residue was added water (200 mL), and extracted with ethyl acetate (250 mL). The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby yield 16.15 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 1.39 (3H, t, J=7.1 Hz), 2.33 (6H, s), 4.37 (2H, q, J=7.1 Hz), 6.99 (1H, d, J=9.7 Hz), 7.15 (2H, d, J=8.7 Hz), 7.24 (1H, d, J=7.7 Hz), 7.59 (1H, dd, J=7.7 Hz, 2.0 Hz), 7.65 (1H, d, J=2.0 Hz), 7.90 (1H, brs), 8.07 (2H, d, J=8.7 Hz), 8.25-8.35 (2H, m).

The following compounds were produced in the same manner as in Reference Example 589.

TABLE 83

Refer-

ence

Exam-

ple No.
R₂₈₃
R₂₈₄
R₂₈₅

¹H NMR (CDCl₃) δppm

590
—Cl
—Cl
—Ac
2.58 (3H, s), 7.19 (1H, d, J = 8.7 Hz), 7.22 (2H, d, J = 8.7 Hz), 6.06 (2H, s), 7.84 (1H, d, J = 8.4 Hz), 7.97 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.01 (1H, d, J = 8.7 Hz), 8.24 (1H, d, J = 2.1 Hz), 8.28 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.56 (1H, d, J = 2.6 Hz), 10.64 (1H, brs).

591
—CN
—H
—COOCH₃
3.92 (3H, s), 7.05 (1H, d, J = 8.9 Hz), 7.18 (2H, d, J = 8.6 Hz), 7.81 (2H, d, J = 8.6 Hz), 7.90 (1H, brs), 8.00 (2H, d, J = 8.6 Hz), 8.08 (2H, d, J = 8.6 Hz), 8.27 (1H, dd, J = 8.6 Hz, 2.6 Hz), 8.30 (1H, d, J = 2.3 Hz).

Reference Example 592
Production of ethyl 3-{4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]-3-ethoxyphenyl}propionate

To a solution of ethyl 3-[3-ethoxy-4-(5-nitropyridin-2-yloxy)phenyl]propionate (0.82 g, 2.3 mmol) in ethanol (40 mL) was added 10% palladium-carbon (0.15 g) under a nitrogen atmosphere, and the resulting solution was stirred under a hydrogen atmosphere at atmospheric pressure for 1 hour at room temperature. The palladium-carbon was removed by filtration, and the filtrate was concentrated. The obtained filtrate (0.58 g) was dissolved in dichloromethane (30 mL), and to the resulting solution were added pyridine (0.17 mL, 2.1 mmol) and 3,4-dichlorobenzoyl chloride (0.39 g, 1.84 mmol) under ice cooling. The resulting solution was stirred under ice cooling for 1 hour, and then stirred for 12 hours at room temperature. The reaction solution was made acidic by adding 10% hydrochloric acid, and extracted with dichloromethane. The dichloromethane layer was washed with a saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 0.94 g of the title compound.

Appearance: Yellow amorphous powder

¹H NMR (CDCl₃) δ 1.18 (3H, t, J=7.0 Hz), 1.26 (3H, t, J=7.1 Hz), 2.53-2.71 (2H, m), 2.86-3.01 (2H, m), 3.98 (2H, q, J=7.0 Hz), 4.15 (2H, q, J=7.1 Hz), 6.78-6.88 (2H, m), 6.95 (1H, d, J=8.8 Hz), 7.06 (1H, d, J=7.9 Hz), 7.58 (1H, d, J=8.3 Hz), 7.65-7.77 (2H, m), 7.98 (1H, d, J=2.1 Hz), 8.14 (1H, dd, J=8.8 Hz, 2.7 Hz), 8.19 (1H, d, J=2.3 Hz).

The following compound was produced in the same manner as in Reference Example 592.

Reference Example 593
N-{6-[(4-(3-hydroxypropyl)phenoxy]pyridin-3-yl}-4-trifluoromethylbenzamide

¹H NMR (CDCl₃) δ 1.86-1.97 (2H, m), 2.70-2.73 (2H, m), 3.68-3.73 (2H, m), 6.95 (1H, d, J=8.7 Hz), 7.03-7.08 (2H, m), 7.23 (2H, d, J=8.4 Hz), 7.77 (2H, d, J=8.2 Hz), 7.84 (1H, brs), 7.99 (2H, d, J=8.2 Hz), 8.20-8.23 (1H, m), 8.26 (1H, d, J=2.6 Hz).

Reference Example 594
Production of methyl 2-(4-{5-[3-(3,4-dichlorophenyl)ureido]pyridin-2-yloxy}phenyl]acetate

To a solution of methyl 2-[4-(5-aminopyridin-2-yloxy)phenyl]acetate (0.44 g, 1.7 mmol) in dichloromethane (7 mL) was added 3,4-dichlorophenylisocyanate (0.353 g, 1.9 mmol), and the resulting reaction solution was stirred for 1 hour at room temperature. To the reaction solution was added diisopropyl ether. Insoluble matter was removed by filtration, to thereby yield 0.60 g of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 3.63 (3H, s), 3.69 (2H, s), 6.99-7.05 (3H, m), 7.26-7.30 (2H, m), 7.35 (1H, dd, J=8.8, 2.4 Hz), 7.52 (1H, d, J=8.8 Hz), 7.86 (1H, d, J=2.4 Hz), 7.98 (1H, dd, J=8.8, 2.8 Hz), 8.18 (1H, d, J=2.7 Hz), 8.91 (1H, s), 9.10 (1H, s).

The following compounds were produced in the same manner as in Reference Example 594.

TABLE 84

Reference

Example

No.
R₂₈₆
MS (M⁺)

595
—H
459

596
—CH₃
473

TABLE 85

Reference

Example No.
R₂₈₇

¹H NMR (CDCl₃) δppm or MS

597
4-CF₃Ph—

¹H NMR 1.18 (3H, t, J = 7.1 Hz), 1.25 (3H, t, J = 7.1 Hz), 2.62- 2.68 (2H, m), 2.96-3.01 (2H, m), 3.76 (2H, q, J = 7.1 Hz), 4.14 (2H, q, J = 7.1 Hz), 6.17 (1H, brs), 7.05 (1H, dd, J = 8.7 Hz, 0.7 Hz), 7.11 (2H, d, J = 8.6 Hz), 7.28 (2H, d, J = 8.6 Hz), 7.40 (2H, d, J = 8.7 Hz), 7.49 (2H, d, J = 8.6 Hz), 7.63 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.14 (1H, dd, J = 2.6 Hz, 0.7 Hz).

598
3,4-Cl₂Ph—
MS 501 (M⁺)

TABLE 86

Reference

Example

No.
R₂₈₈
M

¹H NMR (CDCl₃) δppm

599
—H
3
1.90-2.11 (2H, m), 2.28-2.50 (4H, m), 2.51-2.72 (2H, m), 2.82- 3.07 (2H, m), 3.28-3.51 (4H, m), 3.52-3.78 (4H, m), 5.25-5.40 (1H, m), 5.96 (2H, s), 6.69-6.81 (2H, m), 6.82-6.94 (2H, m), 6.95- 7.08 (2H, m), 7.09-7.26 (3H, m), 7.88-8.07 (2H, m).

600
—H
2
2.20-2.46 (4H, m), 2.52-2.70 (2H, m), 2.82-3.02 (2H, m), 3.28- 3.50 (4H, m), 3.51-3.72 (6H, m), 5.52-5.71 (1H, m), 5.95 (1H, s), 6.68-6.78 (2H, m), 6.80-6.89 (2H, m), 6.91 (2H, d, J = 8.4 Hz), 7.17 (2H, d, J = 8.4 Hz), 7.36 (1H, s), 7.89-8.01 (2H, m).

601
—OCH₃
3
1.85-2.08 (2H, m), 2.27-2.46 (4H, m), 2.55-2.71 (2H, m), 2.88- 3.03 (2H, m) 3.30-3.46 (6H, m), 3.56 (2H, t, J = 6.3 Hz), 3.63 (2H, t, J = 4.9 Hz), 3.71 (3H, s), 5.20-5.36 (1H, m), 5.95 (2H, s), 6.68- 6.89 (6H, m), 7.00 (1H, d, J = 8.0 Hz), 7.15 (1H, s), 7.87 (1H, d, J = 2.4 Hz), 7.92 (1H, dd, J = 2.8 Hz, 8.8 Hz).

602
—OCH₃
2
2.25-2.49 (4H, m), 2.58-2.72 (2H, m), 2.87-3.05 (2H, m), 3.30- 3.71 (10H, m), 3.71 (3H, s), 5.40-5.52 (1H, m), 5.95 (2H, s), 6.66- 6.91 (6H, m), 7.00 (1H, d, J = 8.0 Hz), 7.07 (1H, s), 7.85-7.99 (2H, m).

TABLE 87

Reference

Example

No.
Chemical Structure

¹H NMR (solvent) δppm

603

embedded image

(DMSO-d₆) 3.38(2H, t, J = 6.1 Hz), 3.63(2H, t, J = 6.1 Hz), 3.68(3H, s), 6.27(1H, t, J = 6.1 Hz), 6.76-6.84(2H, m), 7.22- 7.31(2H, m), 8.41(1H, s).

604

embedded image

(CDCl₃) 2.00-2.20(5H, m), 3.27- 3.47 (4H, m), 3.48-3.60(2H, m), 3.61-3.78 (2H, m), 3.88(3H, s), 3.89(3H, s), 4.59 (2H, s), 5.94- 6.12(1H, m), 6.66(1H, d, J = 8.8 Hz), 6.83(1H, d, J = 8.6 Hz), 6.80- 6.92(3H, m), 7.04(1H, dd, J = 2.6 Hz, 8.6 Hz), 7.19(1H, d, J = 2.6 Hz), 7.50(1H, d, J = 2.8 Hz, 8.8 Hz), 7.73(1H. s), 7.95(1H, d, J = 2.8 Hz).

605

embedded image

(CDCl₃) 1.76-1.93(2H, m), 2.00- 2.20 (5H, m), 3.11-3.28(2H, m), 3.29-3.41 (2H, m), 3.42-3.57(2H, m), 3.60-3.78 (2H, m), 3.87(3H, s), 3.88(3H, s), 4.57 (2H, s), 5.70- 5.88(1H, m), 6.67(1H, d, J = 8.8 Hz), 6.83(1H, d, J = 8.6 Hz), 6.86(3H, m), 7.04(1H, dd, J = 2.6 Hz, 8.6 Hz), 7.17(1H, d, J = 2.6 Hz), 7.56(1H, dd, J = 2.8 Hz, 8.8 Hz), 7.68(1H, s), 7.93(1H, d, J = 2.8 Hz).

Reference Example 606
Production of methyl 3-(4-{5-[3-(4-trifluoromethylphenyl)ureido]pyridin-2-yloxy}phenyl)propionate

Methyl 3-[4-(5-nitropyridin-2-yloxy)phenyl]propionate (1.00 g, 3.3 mmol) was dissolved in a mixed solvent consisting of THF (1 mL) and ethanol (120 mL). To the resulting solution was added 10% palladium-carbon (100 mg), and stirred for 23 hours at room temperature under a hydrogen atmosphere. The reaction solution was filtered and the filtrate was concentrated. To the residue were added THF (20 mL), triethylamine (0.917 mL, 6.6 mmol) and phenyl 4-trifluoromethylisocyanate (0.61 mL, 4.3 mmol), and the resulting solution was stirred for 20 hours at room temperature. The reaction solution was evaporated under reduced pressure. The residue was washed with ethyl acetate, to thereby yield 850 mg of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 2.62-2.68 (2H, m), 2.83-2.68 (2H, m), 3.60 (3H, s), 6.97-7.02 (3H, m), 7.24 (2H, d, J=8.4 Hz), 7.65-7.69 (4H, m), 7.99 (1H, dd, J=8.9 Hz, 2.8 Hz), 8.19 (1H, d, J=2.8 Hz), 8.88 (1H, s), 9.20 (1H, s).

Reference Example 607
Production of methyl 3-fluoro-4-{5-[(4-rifluoromethylbenzylidene)amino]pyridin-2-yloxy}benzoate

Methyl 4-(5-aminopyridin-2-yloxy)-3-fluorobenzoate (2.0 g, 7.63 mmol) was dissolved in methanol (50 mL). To the resulting solution was added 4-trifluoromethylbenzaldehyde (1.04 mL, 7.63 mmol), and refluxed for 6 hours. The reaction solution was cooled to room temperature, and the resulting precipitated crystals were collected by suction filtration. The collected crystals were washed with methanol, to thereby yield 2.81 g of the title compound.

Appearance: Pale grey powder

¹H NMR (DMSO-d₆) δ 3.89 (3H, s), 7.32 (1H, d, J=8.7 Hz), 7.48-7.54 (1H, m), 7.85-7.92 (4H, m), 8.01 (1H, dd, J=8.7 Hz, 2.6 Hz), 8.13-8.16 (3H, m), 8.86 (1H, s).

The following compounds were produced in the same manner as in Reference Example 607.

TABLE 88

Reference

Example

No.
R₂₈₉
R₂₉₀
R₂₉₁
R₂₉₂

¹H NMR (solvent) δppm

608
—CF₃
—H
—H
—CH₃
(DMSO-d₆) 3.86(3H, s), 7.24-7.30(3H, m),

7.92(2H, d, J = 8.1 Hz), 7.98-8.05(3H, m),

8.16(2H, d, J = 8.1 Hz), 8.24(1H, d, J = 2.1

Hz), 8.88(1H, s).

609
—CF₃
—H
—H
—C₂H₅
(DMSO-d₆) 1.33(3H, t, J = 7.1 Hz), 4.32(2H,

q, J = 7.1 Hz), 7.24-7.30(3H, m), 7.92(2H, d, J =

8.3 Hz), 8.00(1H, dd, J = 8.7 Hz, 2.6 Hz),

8.02(2H, d, J = 8.7 Hz), 8.16(2H, d, J = 7.9

Hz) 8.24(1H, d, J = 2.6 Hz), 8.88(1H, s).

610
—Cl
—Cl
—F
—CH₃
(DMSO-d₆) 3.89(3H, s), 7.21(1H, d, J = 8.6

Hz), 7.48-7.54 (1H, m), 7.80-7.94(4H, m),

7.97(1H, dd, J = 8.7 Hz, 2.8 Hz), 8.12-

8.15(2H, m), 8.75(1H, s).

611
—Cl
—Cl
—F
—C₂H₅
(CDCl₃) 1.40(3H, t, J = 7.1 Hz), 4.39(2H, q, J =

7.1 Hz), 7.09(1H, d, J = 8.6 Hz), 7.26-

7.35(1H, m), 7.55-7.57(1H, m), 7.66-7.73(2H,

m), 7.86-7.92(2H, m), 8.02-8.03(2H, m),

8.40(1H, s).

Reference Example 612
Production of ethyl 4-{5-[1-(4-trifluoromethylphenyl)ethylideneamino]pyridin-2-yloxy}benzoate

Ethyl 4-(5-aminopyridin-2-yloxy)benzoate (16.0 g, 62 mmol) was dissolved in toluene (300 mL). To the resulting solution were added 4-trifluoromethylacetophenone (11.7 g, 62 mmol) and (±)-camphor-10-sulfonic acid (1.08 g, 4.65 mmol), and refluxed overnight. The reaction solution was concentrated under reduced pressure, to thereby yield 26.5 g of the title compound.

Appearance: Dark green oil

¹H NMR (CDCl₃) δ 1.35-1.41 (3H, m), 2.34 (3H, s), 4.36 (2H, d, J=7.1 Hz), 7.01-7.31 (4H, m), 7.70-7.77 (3H, m), 8.01-8.11 (4H, m).

Reference Example 613
Production of methyl 4-[5-(4-trifluoromethylbenzylamino)pyridin-2-yloxy]benzoate

Methyl 4-{5-[(4-trifluoromethylbenzylidene)amino]pyridin-2-yloxy}benzoate (2.64 g, 6.59 mmol) was suspended in methanol (25 mL), and to the resulting suspension was slowly added sodium borohydride (1.25 g, 33.0 mmol). The resulting solution was stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate, and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was washed with diethyl ether, to thereby yield 2.65 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 3.89 (3H, s), 4.16 (1H, brs), 4.42 (2H, s), 6.84 (1H, d, J=8.7 Hz), 7.01 (1H, dd, J=8.6 Hz, 3.0 Hz), 7.05 (2H, d, J=8.4 Hz), 7.49 (2H, d, J=8.4 Hz), 7.62 (2H, d, J=8.3 Hz), 7.67 (1H, d, J=3.1 Hz), 8.01 (2H, d, J=8.6 Hz).

The following compounds were produced in the same manner as in Reference Example 613.

TABLE 89

Reference

Example

No.
R₂₉₃
R₂₉₄
R₂₉₅
R₂₉₆
R₂₉₇

¹H NMR (CDCl₃) δppm

614
—CF₃
—H
—H
—H
—C₂H₅
1.37(3H, t, J = 7.1 Hz), 4.19(1H, brs),

4.35(2H, q, J = 7.1 Hz), 4,41(2H, brs),

6.83(1H, d, J = 8.7 Hz), 7.01(1H, dd, J =

8.6 Hz, 3.0 Hz), 7.04(2H, d, J = 8.6

Hz), 7.48(2H, d, J = 8.1 Hz), 7.61(2H,

d, J = 8.3 Hz), 7.66(1H, d, J = 3.0 Hz),

8.02(2H, d, J = 8.7 Hz).

615
—CF₃
—H
—CH₃
—H
—C₂H₅
1.37(3H, t, J = 7.1 Hz), 1.56(3H, d, J =

6.8 Hz), 4.06(1H, brs), 4.34(2H, q, J =

7.1 Hz), 4.49(1H, q, J = 6.6 Hz),

6.75(1H, d, J = 8.7 Hz), 6.87(1H, dd, J =

8.7 Hz, 3.0 Hz), 7.01(2H, d, J = 8.6

Hz), 7.47(2H, d, J = 8.1 Hz), 7.53(1H,

d, J = 3.0 Hz), 7.60(2H, d, J = 8.3 Hz),

8.00(2H, d, J = 8.7 Hz).

616
—CF₃
—H
—H
—F
—CH₃
3.90(3H, s), 4.40(2H, brs), 6.89(1H, d, J =

8.1 Hz), 7.03(1H, dd, J = 8.7 Hz, 3.0

Hz), 7.15-7.21(1H, m), 7.47(2H, d, J =

8.1 Hz), 7.55(1H, d, J = 3.0 Hz),

7.61(2H, d, J = 8.1 Hz), 7.80-7.84(2H,

m).

617
—Cl
—Cl
—H
—F
—CH₃
3.91(3H, s), 4.29(2H, brs), 6.88(1H, d, J =

8.7 Hz), 7.02(1H, dd, J = 8.7 Hz, 3.0

Hz), 7.15-7.21(2H, m), 7.41(1H, d, J =

8.3 Hz), 7.46(1H, d, J = 2.0 Hz),

7.53(1H, d, J = 3.0 Hz), 7.81-7.84(2H,

m).

Reference Example 618
Production of ethyl 3-{4-[5-(3,4-dichlorobenzylamino)pyridin-2-yloxy]phenyl}propionate

A solution of 3,4-dichlorobenzaldehyde (1.28 g, 7.3 mmol) was added to a solution of ethyl 3-[4-(5-aminopyridin-2-yloxy)phenyl]propionate (2.1 g, 7.3 mmol) in ethanol (20 mL), and the resulting solution was stirred for 2 hours at 40° C. To the resulting reaction solution was added sodium borohydride (0.55 g, 15.7 mmol) under ice cooling, and stirred at the same temperature for 1 hour. To the solution was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 2.71 g of the title compound.

Appearance: Colorless oil

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7.1 Hz), 2.50-2.68 (2H, m), 2.81-3.01 (2H, m), 3.71-4.20 (3H, m), 4.28 (2H, s), 6.76 (1H, d, J=8.7 Hz), 6.88-7.02 (3H, m), 7.06-7.23 (3H, m), 7.41 (1H, d, J=8.2 Hz), 7.46 (1H, d, J=2.0 Hz), 7.60 (1H, d, J=3.0 Hz).

The following compounds were produced in the same manner as in Reference Example 618.

TABLE 90

Reference

Example

No.
R₂₉₈
R₂₉₉
R₃₀₀
Xa₂₁

¹H NMR (CDCl₃) δppm

619
—CF₃
—H
—H
—CH₂—
1.24(3H, t, J = 7.3Hz), 2.60(2H, t, J = 8.1 Hz),

2.92(2H, t, J = 8.1 Hz), 4.13(2H, q, J = 7.3 Hz),

4.39(2H, s), 6.76(1H, d, J = 8.7 Hz), 6.97(2H, d, J =

8.4 Hz), 6.98(1H, dd, J = 8.6 Hz, 3.1 Hz), 7.17(2H,

d, J = 8.4 Hz), 7.47(2H, d, J = 8.1 Hz), 7.60(2H, d, J =

7.9 Hz), 7.61(1H, d, J = 3.1 Hz).

620
—Cl
—Cl
—OCH₃
—CH₂—
1.25(3H, t, J = 7.1 Hz), 2.65-2.74(2H, m), 2.94(2H,

t, J = 8.2 Hz), 3.76(3H, s), 3.93(1H, brs), 4.14(2H,

q, J = 7.1 Hz), 4.22-4.34(2H, m), 6.70-6.85(3H, m),

6.85-7.02(2H, m), 7.10-7.25(1H, m), 7.39 (1H, d, J =

8.2 Hz), 7.44(1H, d, J = 2.0 Hz), 7.53(1H, d, J =

2.7 Hz).

621
—CF₃
—H
—OCH₃
—CH₂—
1.25(3H, t, J = 7.1 Hz), 2.52-2.68(2H, m), 2.81-

3.01(2H, m), 3.76 (3H, s), 3.93(1H, brs), 4.14(2H,

q, J = 7.1 Hz), 4.30-4.40(2H, m), 6.72-6.84(3H, m),

6.96(1H, d, J = 8.0 Hz), 6.98(1H, dd, J = 8.0 Hz,

3.0 Hz), 7.40(2H, d, J = 8.0 Hz), 7.55(1H, d, J =

3.0 Hz), 7.59 (2H, d. J = 8.0 Hz).

622
—Cl
—Cl
—OC₂H₅
—CH₂—
1.18(3H, t, J = 7.0 Hz), 1.25(3H, t, J = 7.1 Hz),

2.52-2.69(2H, m), 2.82-3.00(2H, m), 3.81-4.02(3H,

m), 4.14(2H, q, J = 7.1 Hz), 4.27 (2H, d, J =

4.7 Hz), 6.72-6.82(3H, m), 6.93-7.02(2H, m), 7.18

(1H, dd, J = 8.2 Hz, 2.0 Hz), 7.39(1H, d, J = 8.4 Hz),

7.45(1H, d, J = 2.0 Hz), 7.52(1H, d, J = 3.0 Hz).

623
—CF₃
—H
—OC₂H₅
—CH₂—
1.18(3H, t, J = 7.0 Hz), 1.25(3H, t, J = 7.1 Hz),

2.51-2.72(2H, m), 2.83-3.01(2H, m), 3.87-4.06(3H,

m), 4.16(2H, q, J = 7.1 Hz), 4.30-4.42(2H, m), 6.72-

6.83(3H, m), 6.94-7.02(2H, m), 7.46(2H, d, J =

8.1 Hz), 7.54(1H, d, J = 3.0 Hz), 7.59(2H, d, J =

8.1 Hz).

624
—Cl
—Cl
—F
—CH₂—
1.12-1.35(3H, m), 2.50-2.74(2H, m), 2.93(2H, t, J =

7.7 Hz), 3.95 (1H, brs), 4.05-4.20(2H, m), 4.27

(2H, s), 6.82(1H, d, J = 8.4 Hz), 6.90-7.15(4H, m),

7.18(1H, dd, J = 8.4 Hz. 2.0 Hz), 7.35-7.60(3H, m).

625
—CF₃
—H
—F
—CH₂—
1.13-1.35(3H, m), 2.65-2.70(2H, m), 2.93(2H, t, J =

7.7 Hz), 4.01 (1H, brs), 4.05-4.23(2H, m),

4.37(2H, s), 6.82(1H, d, J = 8.8 Hz). 6.90-7.15(4H,

m), 7.37-7.55(3H, m), 7.55-7.70(2H, m).

626
—Cl
—Cl
—H
—N(Ac)—
1.27(3H, t, J = 7.1 Hz), 1.94(3H, s), 4.10(1H, brs),

4.19(2H, q, J = 7.1 Hz), 4.31(2H, s), 4.34(2H, s),

6.84(1H, d, J = 8.5 Hz), 7.00(1H, dd, J = 8.5 Hz,

3.0 Hz), 7.06(2H, d, J = 8.7 Hz), 7.20(1H, dd, J =

8.2 Hz, 2.2 Hz), 7.31(2H, d. J = 8.7 Hz), 7.42(1H, d,

J = 8.2 Hz), 7.47(1H, d, J = 2.2 Hz), 7.62(1H, d, J =

3.0 Hz).

627
—CF₃
—H
—H
—N(Ac)—
1.27(3H, t, d = 7.1 Hz), 1.93(3H, s), 4.15(1H, brs),

4.18(2H, q, J = 7.1 Hz), 4.34(2H, s), 4.35-4.50(2H,

m), 6.83(1H, d, J = 8.6 Hz), 7.01(1H, dd, J =

8.6 Hz, 3.0 Hz), 7.06(2H, d, J = 8.9 Hz), 7.31(2H, d,

J = 8.9 Hz), 7.48(2H, d, J = 8.1 Hz), 7.62(2H, d, J =

8.1 Hz), 7.64(1H, d, J = 3.6 Hz).

Reference Example 628
Production of ethyl 3-(4-{5-[benzyloxycarbonyl(2-methoxyethyl)amino]pyridin-2-yloxy}phenyl)propionate

Under a nitrogen atmosphere, to a solution of ethyl 3-[4-(5-benzyloxycarbonylaminopyridin-2-yloxy)phenyl]propionate (1.7 g, 4.0 mmol) in DMF (50 mL) was added 60% sodium hydride (0.19 g, 4.9 mmol) under ice cooling, and the resulting solution was stirred for 35 minutes at the same temperature. 2-Bromoethylmethyl ether (0.4 mL, 4.2 mmol) was added dropwise to the solution. The reaction solution was stirred for 2 hours under ice cooling, and then stirred for 2 days at room temperature. To the reaction solution was added water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 1.6 g of the title compound.

Appearance: Pale yellow oil

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7.1 Hz), 2.57-2.70 (2H, m), 2.89-3.02 (2H, m), 3.52 (2H, t, J=5.4 Hz), 3.79 (2H, t, J=5.4 Hz), 4.14 (2H, q, J=7.1 Hz), 5.14 (2H, brs), 6.87 (1H, d, J=8.7 Hz), 6.89-7.10 (2H, m), 7.11-7.41 (7H, m), 7.47-7.69 (1H, m), 8.10 (1H, brs).

The following compounds were produced in the same manner as in Reference Example 628.

Reference Example 629
Ethyl [(4-{5-[(3,4-dichlorophenyl)methylamino]pyridin-2-yloxy}-2-trifluoromethylphenyl)ethylamino]acetate

MS 541 (M⁺).

TABLE 91

Reference

Example

No.
R₃₀₁
R₃₀₂

¹H NMR (CDCl₃) δppm or MS

630
4-CF₃PhCH₂—
—(CH2)₂OCH₃

¹H NMR 1.24(3H, t, J = 7.1 Hz), 2.54-

2.67(2H, m), 2.76-2.98(2H, m), 4.13(2H, q, J =

7.1 Hz), 4.61(2H, s), 6.76(1H, d, J = 8.9 Hz),

6.93-7.01(2H, m), 7.07(1H, dd, J = 8.9 Hz, 3.3

Hz), 7.12-7.20 (2H, m), 7.33(2H, d, J = 8.0

Hz), 7.56(2H, d, J = 8.0 Hz), 7.65 (1H, d, J =

2.9 Hz).

631
4-CF₃PhCH₂—
—C₂H₅

¹H NMR 1.09-1.32(6H, m), 2.53-2.66(2H, m),

2.84-2.98(2H, m), 3.45 (2H, q, J = 7.1 Hz),

4.13(2H, q, J = 7.1 Hz), 4.49(2H, s), 6.77 (1H,

d, J = 8.5 Hz), 6.93-7.01(2H, m), 7.02-

7.09(1H, m), 7.12-7.20(2H, m), 7.11-7.39(2H,

m), 7.53-7.61(2H, m), 7.66 (1H, d, J = 3.0 Hz).

632
PhCH₂OCO—
—C₂H₅

¹H NMR 1.15(3H, t, J = 7.1 Hz), 1.25(3H, t, J =

7.1 Hz), 2.54-2.71(2H, m), 2.83-3.04(2H, m),

3.69(2H, q, J = 7.1 Hz), 4.14(2H, q, J = 7.1

Hz), 5.14(2H, brs), 6.88(1H, d, J =8.7 Hz),

7.02-7.11(2H, m), 7.18-7.40(7H, m), 7.44-

7.59(1H, m), 7.98-8.08(1H, m).

633
4-CF₃PhCH₂—
—SO₂CH₃
MS 522(M⁺)

634
3,4-Cl₂PhCH₂—
—SO₂CH₃
MS 522(M⁺)

635
3,4-Cl₂Ph—
—CH₃
MS 444(M⁺)

Reference Example 636
Production of ethyl 3-{4-[5-(2-methoxyethylamino)pyridin-2-yloxy]phenyl}propionate

To a solution of ethyl 3-(4-{5-[benzyloxycarbonyl(2-methoxyethyl)amino]pyridin-2-yloxy}phenyl]propionate (1.82 g, 3.8 mmol) in ethanol-ethyl acetate (10 mL-10 mL) was added under a nitrogen atmosphere 10% palladium-carbon (0.2 g), and the resulting solution was stirred for 3 hours under a hydrogen atmosphere at atmospheric pressure. The palladium-carbon was filtered off through Celite, and the filtrate was evaporated to yield 1.23 g of the title compound.

Appearance: Blue oil

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7.1 Hz), 2.55-2.68 (2H, m), 2.87-2.98 (2H, m), 3.20-3.31 (2H, m), 3.56-3.66 (2H, m), 4.13 (2H, q, J=7.1 Hz), 6.77 (1H, d, J=8.7 Hz), 6.93-7.01 (2H, m), 7.03 (1H, dd, J=8.7 Hz, 3.0 Hz), 7.13-7.22 (2H, m), 7.66 (1H, d, J=3.0 Hz).

The following compound was produced in the same manner as in Reference Example 636.

Reference Example 637
Ethyl 3-[4-(5-ethylaminopyridin-2-yloxy)phenyl]-propionate

¹H NMR (CDCl₃) δ 1.29-1.32 (6H, m), 2.55-2.67 (2H, m), 2.87-2.99 (2H, m), 3.14 (2H, q, J=7.1 Hz), 4.13 (2H, q, J=7.1 Hz), 6.77 (18, d, J=8.7 Hz), 6.89-7.02 (3H, m), 7.09-7.25 (3H, m), 7.63 (1H, d, J=3.0 Hz).

Reference Example 638
Production of ethyl 3-(3-methoxy-4-{5-[methyl-(4-trifluoromethylbenzyl)amino]pyridin-2-yloxy}phenyl]-propionate

To a solution of ethyl 3-{3-methoxy-4-[5-(4-trifluoromethylbenzylamino]pyridin-2-yloxy)phenyl}-propionate (0.8 g, 1.7 mmol) in methanol (15 mL) were added a 37% aqueous formaldehyde solution (0.38 mL, 5.1 mmol) and acetic acid (0.1 mL, 1.7 mmol). The reaction solution was stirred for 30 minutes at room temperature. After that, sodium cyanoborohydride (0.24 g, 3.4 mmol) was added to the reaction solution under ice cooling, and the mixture was stirred under ice cooling for 40 minutes. To the reaction solution was added water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 0.62 g of the title compound.

Appearance: Pale yellow oil

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7.1 Hz), 2.52-2.70 (2H, m), 2.87-3.02 (5H, m), 3.77 (3H, s), 4.14 (2H, q, J=7.1 Hz), 4.40-4.50 (2H, m), 6.74-6.86 ((3H, m), 6.97 (1H, d, J=8.0 Hz), 7.11 (1H, dd, J=8.9 Hz, 3.2 Hz), 7.34 (2H, d, J=8.1 Hz), 7.57 (2H, d, J=8.1 Hz), 7.65 (1H, d, 3.2 Hz).

The following compounds were produced in the same manner as in Reference Example 638.

TABLE 92

Reference

Example

No.
R₃₀₃
R₃₀₄
R₃₀₅

¹H NMR (CDCl₃) δppm

639
—H
—CH₃
—CH₃
3.07(3H, s), 3.89(3H, s), 4.56(2H, s), 6.87(1H, d, J =

8.9 Hz), 7.06(2H, d, J = 8.6 Hz), 7.13(1H, dd, J = 8.9

Hz, 3.3 Hz), 7.35(2H, d, J = 8.1 Hz), 7.60(2H, d, J =

8.3 Hz), 7.75(1H, d, J = 3.1 Hz), 8.02(2H, d, J = 8.6

Hz).

640
—H
—C₂H₅
—C₂H₅
1.24(3H, t, J = 7.1 Hz), 1.37(3H, t, J = 7.1 Hz),

3.49(2H, q, J = 7.1 Hz), 4.35(2H, q, J = 7.1 Hz),

4.53(2H, s), 6.84(1H, d, J = 8.9 Hz), 7.05(2H, d, J =

8.6 Hz), 7.06(1H, dd, J = 8.9 Hz, 3.1 Hz), 7.36(2H, d,

J = 8.4 Hz), 7.58(2H, d, J = 8.3 Hz), 7.69(1H, d, J =

3.1 Hz), 8.02(2H, d, J = 8.6 Hz).

641
—CH₃
—CH₃
—C₂H₅
1.38(3H, t, J = 7.1 Hz), 1.59(3H, d, J = 6.9 Hz),

2.74(3H, s), 4.36(2H, q, J = 7.1 Hz), 4.49(1H, q, J =

6.9 Hz), 6.89(1H, d, J = 8.9 Hz), 7.08 (2H, d, J = 8.9

Hz), 7.24(1H, dd, J = 8.9 Hz, 3.1 Hz), 7.43(2H, d, J =

8.6 Hz), 7.61(2H, d, J = 8.3 Hz), 7.84(1H, d, J = 3.1

Hz), 8.03(2H, d, J = 8.9 Hz).

TABLE 93

Reference

Example

No.
R₃₀₆
R₃₀₇
Xa₂₂

¹H NMR (CDCl₃) δppm

642
—CH₃
—H
—CH₂—
1.24(3H, t, J = 7.1 Hz), 2.60(2H, t, J = 7.8 Hz),

2.92(2H, t, J = 7.8 Hz), 3.02(3H, s), 4.12(2H, q, J =

7.1 Hz), 4.51(2H, s), 6.79(1H, d, J = 8.9 Hz),

6.97(2H, d, J = 8.4 Hz), 7.10(1H, dd, J = 8.9 Hz, 3.3

Hz), 7.17(2H, d, J = 8.3 Hz), 7.34(2H, d, J = 8.1 Hz),

7.58(2H, d, J = 8.3 Hz), 7.69(1H, d, J = 3.1 Hz).

643
—CH₃
—H
—N(Ac)—
1.27(3H, t, J = 7.1 Hz), 1.94(3H, s), 3.06(3H, s),

4.18(2H, q, J = 7.1 Hz), 4.34(2H, s), 4.55(2H, s),

6.87(1H, d, J = 8.9 Hz), 7.07(2H, d, J = 8.7 Hz),

7.13(1H, dd, J = 8.9 Hz, 3.1 Hz), 7.31(2H, d, J = 8.7

Hz), 7.35(2H, d, J = 8.0 Hz), 7.59(2H, d, J = 8.0 Hz),

7.72(1H, d, J = 3.1 Hz).

644
—CH₃
—F
—CH₂—
1.25(3H, t, J = 7.1 Hz), 2.55-2.70(2H, m), 2.93(2H, t,

J = 7.9 Hz), 3.00(3H, s), 4.13(2H, q, J = 7.1 Hz),

4.49(2H, s), 6.86(1H, d, J = 8.9 Hz), 6.90-7.16(4H,

m), 7.33(2H, d, J = 8.1 Hz), 7.57(2H, d, J = 8.1 Hz),

7.62(1H, d, J = 3.2 Hz).

645
—CH₃
—OC₂H₅
—CH₂—
1.19(3H, t, J = 7.0 Hz), 1.25(3H, t, J = 7.1 Hz), 2.50-

2.69(2H, m), 2.81-2.99(2H, m), 2.98(3H, s), 3.98(2H,

q, J = 7.0 Hz), 4.14(2H, q, J = 7.1 Hz), 4.48(2H, s),

6.68-6.88(3H, m), 7.00(1H, d, J = 8.0 Hz), 7.11(1H,

dd, J = 8.0 Hz, 3.0 Hz), 7.33(2H, d, J = 8.0 Hz),

7.56(2H, d, J = 8.0 Hz), 7.64(1H, d, J = 3.0 Hz).

646
—C₂H₅
—F
—CH₂—
1.19(3H, t, J = 7.1 Hz), 1.10-1.35(3H, m), 2.50-

2.70(2H, m), 2.93 (2H, t, J = 8.0 Hz), 3.43(2H, q, J =

7.1 Hz), 4.02-4.22(2H, m), 4.47 (2H, s), 6.83(1H, d, J =

9.0 Hz), 6.88-7.15(4H, m), 7.34(2H, d, J = 8.0 Hz),

7.41-7.70(3H, m).

647
—C₂H₅
—OCH₃
—CH₂—
1.18(3H, t, J = 7.0 Hz), 1.25(3H, t, J = 7.1 Hz), 2.57-

2.68(2H, m), 2.88-2.99(2H, m), 3.42(2H, q, J = 7.0

Hz), 3.77(3H, s), 4.14(2H, q, J = 7.1 Hz), 4.42-

4.50(2H, m), 6.72-6.86((3H, m), 6.97(1H, d, J = 8.0

Hz), 7.05(1H, dd, J = 9.0 Hz, 3.2 Hz), 7.30-7.38(2H,

m), 7.51-7.59 (2H, m), 7.60(1H, d, J = 3.2 Hz).

648
—C₂H₅
—OC₂H₅
—CH₂—
1.17(3H, t, J = 7.0 Hz), 1.18(3H, t, J = 7.0 Hz),

1.25(3H, t, J = 7.1 Hz), 2.55-2.69(2H, m), 2.84-

2.98(2H, m), 3.42(2H, q, J = 7.1 Hz), 3.97(2H, q, J =

7.0 Hz), 4.13(2H, q, J = 7.0 Hz), 4.46(2H, s), 6.71-

6.82(3H, m), 6.99(1H, d, J = 8.0 Hz), 7.05(1H, dd, J =

8.9 Hz, 3.1 Hz), 7.34(2H, d, J = 8.0 Hz), 7.55(2H,

d, J = 8.0 Hz), 7.59(1H, d, J = 3.1 Hz).

TABLE 94

Reference

Example

No.
R₃₀₈
R₃₀₉
Xa₂₃

¹H NMR (CDCl₃) δppm

649
—CH₃
—H
—N(Ac)—
1.27(3H, t, J = 7.1 Hz), 1.94(3H, s), 3.03(3H, s),

4.19(2H, q, J = 7.1 Hz), 4.34(2H, s), 4.43(2H, s),

6.87(1H, d, J = 9.0 Hz), 7.03-7.11(1H, m),

7.07(2H, d, J = 8.7 Hz), 7.13(1H, dd, J = 9.0 Hz,

3.1 Hz), 7.27-7.35(1H, m), 7.31(2H, d, J = 8.7 Hz),

7.40(1H, d, J = 8.2 Hz), 7.71(1H, d, J = 3.1 Hz).

650
—CH₃
—F
—CH₂—
1.15-1.30(3H, m), 2.53-2.70(2H, m), 2.93(2H, t, J =

7.9 Hz), 2.97(3H, s), 4.02-4.20(2H, m), 4.37(2H,

s), 6.86(1H, d, J = 8.9 Hz), 6.91-7.18(5H, m),

7.32(1H, d, J = 2.0 Hz), 7.38(1H, d, J = 8.2 Hz),

7.61(1H, d, J = 2.9 Hz).

651
—CH₃
—OCH₃
—CH₂—
1.25(3H, t, J = 7.1 Hz), 2.55-2.75(2H, m), 2.85-

3.05(2H, m), 2.95(3H, s), 3.77(3H, s), 4.14(2H, q,

J = 7.1 Hz), 4.36(2H, s), 6.71-6.88(3H, m),

6.98(1H, d, J = 8.1 Hz), 7.00-7.15(2H, m),

7.32(1H, d, J = 2.0 Hz), 7.38(1H, d, J = 8.1 Hz),

7.64(1H, d, J = 3.1 Hz).

652
—CH₃
—OC₂H₅
—CH₂—
1.19(3H, t, J = 7.0 Hz), 1.25(3H, t, J = 7.1 Hz),

2.55-2.72(2H, m), 2.84-3.01(5H, m), 3.98(2H, q, J =

7.0 Hz), 4.14(2H, q, J = 7.1 Hz), 4.29-4.40(2H,

m), 6.74-6.83(3H, m), 7.00(1H, d, J = 8.0 Hz),

7.06(1H, dd, J = 8.2 Hz, 2.0 Hz), 7.10(1H, dd, J =

9.0 Hz, 3.2 Hz), 7.31(1H, d, J = 2.0 Hz), 7.37(1H,

d, J = 8.2 Hz), 7.63(1H, d, J = 3.2 Hz).

653
—C₂H₅
—F
—CH₂—
1.17(3H, t, J = 7.1 Hz), 1.20-1.30(3H, m), 2.50-

2.72(2H, m), 2.93(2H, t, J = 7.8 Hz), 3.40(2H, q, J =

7.1 Hz), 4.00-4.22(2H, m), 4.36(2H, s), 6.83(1H,

d, J = 8.9 Hz), 6.85-7.15(5H, m), 728-7.32(1H, m),

7.37(1H, d, J = 8.2 Hz), 7.56(1H, d, J = 3.2 Hz).

654
—C₂H₅
—OCH₃
—CH₂—
1.16(3H, t, J = 7.1 Hz), 1.21-1.35(3H, m), 2.50-

2.75(2H, m), 2.82-3.05(2H, m), 3.39(2H, q, J = 7.1

Hz), 3.77(3H, s), 4.05-4.25 (2H, m), 4.35(2H, s),

6.68-6.88(3H, m), 6.90-7.00(1H, m), 7.00-7.11(2H,

m), 7.31(1H, d, J = 2.0 Hz), 7.37(1H, d, J = 8.2

Hz), 7.59(1H, d, J = 3.0 Hz).

655
—C₂H₅
—OC₂H₅
—CH₂—
1.11-1.22(6H, m), 1.25(3H, t, J = 7.1 Hz), 2.56-

2.67(2H, m), 2.86-2.97(2H, m), 3.39(2H, q, J = 7.1

Hz), 3.97(2H, q, J = 7.0 Hz), 4.14(2H, q, J = 7.1

Hz), 4.34(2H, s), 6.73-6.82(3H, m), 6.99 (1H, d, J =

8.0 Hz), 7.02-7.10(2H, m), 7.32(1H, d, J = 1.9

Hz), 7.36(1H, d, J = 8.2 Hz), 7.58(1H, d, J = 3.1

Hz).

Reference Example 656
Production of ethyl 3-(4-(5-(3,4-dichlorophenylamino)pyridin-2-yloxy)phenyl)propionate

Triethylamine (1.2 mL, 8.4 mmol) was added to a suspension of ethyl 3-(4-(5-aminopyridin-2-yloxy)phenyl)propionate (1.2 g, 4.2 mmol), 3,4-dichlorophenylboronic acid (1.6 g, 8.4 mmol), anhydrous copper acetate (0.762 g, 4.2 mmol) and molecular sieves 4A (5 g) in dichloromethane (24 mL), and the resulting reaction solution was stirred overnight at room temperature. After the resulting solution was filtered through Celite, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 1.5 g of the title compound.

Appearance: Slightly brown solid

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7.1 Hz), 2.60-2.66 (2H, m), 2.93-2.99 (2H, m), 4.14 (2H, q, J=7.1 Hz), 5.52 (1H, brs), 6.71 (1H, dd, J=8.7 Hz, 2.7 Hz), 6.90 (1H, d, J=8.7 Hz), 6.97 (1H, d, J=2.7 Hz), 7.04-7.08 (2H, m), 7.21-7.26 (3H, m), 7.49 (1H, dd, 8.7 Hz, 2.9 Hz), 8.01 (1H, d, J=2.8 Hz).

The following compound was produced in the same manner as in Reference Example 656.

Reference Example 657
Ethyl ({4-[5-(3,4-dichlorophenylamino)pyridin-2-yloxy]-2-trifluoromethylphenyl}ethylamino)acetate

MS 527 (M⁺).

Reference Example 658
Production of ethyl 4-[3-(4-benzyloxy-3-methyl)phenyl-2-oxotetrahydropyrimidin-1-yl]benzoate

Under a nitrogen atmosphere, to a solution of 1-(4-benzyloxy-3-methyl)phenyltetrahydropyrimidin-2-one (0.5 g, 1.7 mmol) in dioxane (5 mL) were added copper (I) iodide (16 mg, 0.08 mmol) and N,N-dimethylglycine hydrochloride (47 mg, 0.34 mmol). The resulting solution was stirred for 5 minutes, and then ethyl 4-iodobenzoate (0.39 g, 1.4 mmol) and potassium (III) phosphate (1.04 g, 4.9 mmol) were added to the reaction mixture. The resulting solution was stirred for 20 hours at 100° C., after which the resulting solution was sprinkled with silica gel. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=3:1→dichloromethane:methanol=40:1), to thereby yield 0.43 g of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 1.30 (3H, t, J=7.1 Hz), 2.08-2.22 (5H, m), 3.66 (2H, t, J=5.9 Hz), 3.81 (2H, t, J=5.9 Hz), 4.28 (2H, q, J=7.1 Hz), 5.10 (2H, s), 6.86-7.14 (3H, m), 7.26-7.51 (7H, m), 7.82-7.92 (2H, m).

Reference Example 659
Production of ethyl (E)-3-(3-methoxy-4-{5-[2-(4-trifluoromethylphenyl)vinyl]pyridin-2-yloxy}phenyl)propionate

To ethyl 3-[4-(5-bromopyridin-2-yloxy)-3-methoxyphenyl]propionate (610 mg, 1.6 mmol) were added 4-trifluoromethylstyrene (0.332 mL, 2.2 mmol), dichlorobis(benzonitrile)palladium (II) (33 mg, 0.082 mmol), N,N-dimethylglycine hydrochloride (17 mg, 0.16 mmol), sodium acetate (263 mg, 3.2 mmol) and N-methylpyrrolidone (5 mL) under an argon atmosphere. The resulting solution was stirred under an argon atmosphere for 17 hours at 130° C. To the reaction solution was added ethyl acetate and filtered. The filtrate was washed with water, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), to thereby yield 500 mg of the title compound.

Appearance: Pale yellow oil

¹H NMR (CDCl₃) δ 1.27 (3H, t, J=7.1 Hz), 2.64-2.69 (2H, m), 2.95-3.01 (2H, m), 3.76 (3H, s), 4.05 (2H, q, J=7.1 Hz), 6.71-6.88 (2H, m), 6.95 (1H, d, J=8.6 Hz), 6.98-7.08 (2H, m), 7.11 (1H, d, J=16.5 Hz), 7.56-7.63 (4H, m), 7.87-7.91 (1H, m), 8.23 (1H, d, J=2.3 Hz).

The following compound was produced in the same manner as in Reference Example 659.

Reference Example 660
Ethyl 3-(4-{5-[(E)-2-(3,4-dichlorophenyl)vinyl]pyridin-2-yloxy}-3-methoxyphenyl)propionate

¹H NMR (CDCl₃) δ 1.26 (3H, t, J=7.1 Hz), 2.63-2.69 (2H, m), 2.94-3.00 (2H, m), 3.76 (3H, s), 4.15 (2H, q, J=7.1 Hz), 6.81-6.90 (3H, m), 6.93 (1H, d, J=8.6 Hz), 6.99 (1H, d, J=15.3 Hz), 7.06 (1H, d, J=9.1 Hz), 7.27-7.31 (1H, m), 7.40 (1H, d, J=8.2 Hz), 7.55 (1H, d, J=2.0 Hz), 7.82-7.86 (1H, m), 8.19 (1H, d, J=2.5 Hz).

Reference Example 661
Production of ethyl {4-[4-(3,4-dichlorobenzoylamino)-2-fluorophenoxy]benzenesulfonyl}acetate

To a solution of ethyl {4-[(4-(3,4-dichlorobenzoylamino)-2-fluorophenoxy]phenylsulfanyl}-acetate (1.20 g, 2.43 mmol) in dichloromethane (20 mL) was added m-chloroperbenzoic acid (1.45 g, 6.06 mmol) at 0° C. The resulting solution was stirred for 2 hours at room temperature. To the reaction solution was added methanol and stirred for some time. To the resulting solution was then added water, and extracted with dichloromethane. The dichloromethane layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and evaporated. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1), to thereby yield 1.28 g of the title compound.

Appearance: Yellow amorphous powder

¹H NMR (CDCl₃) δ 1.22 (3H, t, J=7.1 Hz), 4.11 (2H, s), 4.16 (2H, q, J=7.1 Hz), 7.06 (2H, d, J=8.9 Hz), 7.19 (1H, t, J=8.7 Hz), 7.30 (1H, d, J=8.7 Hz), 7.59 (1H, d, J=8.3 Hz), 7.71 (1H, dd, J=2.0 Hz, 8.3 Hz), 7.75-7.85 (1H, m), 7.86-7.95 (3H, m), 7.98 (1H, d, J=2.0 Hz).

Reference Example 662
Production of methyl 3-{4-[5-(3,4-dichlorobenzoylamino)pyridine-2-sulfinyl]phenyl}propionate

To a solution of methyl 3-{4-[5-(3,4-dichlorobenzoylamino)pyridin-2-ylsulfanyl]phenyl}propionate (1.00 g, 2.17 mmol) in dichloromethane (20 mL) was added m-chloroperbenzoic acid (0.620 g, 2.60 mmol) at 0° C. The resulting solution was stirred for 1 hour at 0° C. To the reaction solution was added methanol and stirred for some time. To the resulting solution was then added water, and extracted with dichloromethane. The dichloromethane layer was washed with water, a saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and evaporated. The obtained residue was recrystallized from ethanol 3 times, to thereby yield 0.790 g of the title compound.

Appearance: White powder

Melting point: 164-166° C.

Reference Example 663
Production of methyl 3-{4-[5-(3,4-dichlor benzoylamino)pyridine-2-sulfonyl]phenyl}propionate

To a solution of methyl 3-{4-[5-(3,4-dichlorobenzoylamino)pyridin-2-ylsulfanyl]phenyl}-propionate (1.00 g, 2.17 mmol) in dichloromethane (20 mL) was added m-chloroperbenzoic acid (1.29 g, 5.42 mmol) at 0° C. The resulting solution was stirred for 1.5 hours at 0° C. To the reaction solution was added methanol and stirred for some time. To the resulting solution was then added water, and extracted with dichloromethane. The dichloromethane layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated. The obtained residue was recrystallized from ethanol, to thereby yield 0.890 g of the title compound.

Appearance: White powder

Melting point: 165-166° C.

Reference Example 664
Production of ethyl {4-[4-(3,4-dichlorobenzoylamino)-2-fluorophenoxy]benzenesulphenyl}acetate

To a solution of ethyl {4-[4-(3,4-dichlorobenzoylamino)-2-fluorophenoxy]phenylsulfanyl}acetate (0.800 g, 1.61 mmol) in methanol (20 mL) was added a 31% hydrogen peroxide solution (2.08 mL, 18.5 mmol). The resulting solution was refluxed for 16 hours. The reaction solution was cooled with ice, and the resulting precipitated solid was collected by filtration, to thereby yield 0.631 g of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 1.13 (3H, t, J=7.1 Hz), 3.90-4.10 (4H, m), 7.14 (2H, d, J=8.8 Hz), 7.34 (1H, t, J=9.0 Hz), 7.55-7.65 (1H, m), 7.72 (2H, d, J=8.8 Hz), 7.64 (1H, d, J=8.4 Hz), 7.90-8.00 (2H, m), 8.22 (1H, d, J=2.0 Hz), 10.63 (1H, s).

Reference Example 665
Production of ethyl 3-(4-{5-[(4-(trifluoromethyl)phenylcarbamoyl]pyridin-2-yloxy}phenyl)butyrate

To a suspension of 60% sodium hydride (0.133 g, 3.3 mmol) in THF (6 mL) was added dropwise triethylphosphono acetate (0.53 mL, 2.7 mmol) under ice cooling, and the resulting solution was stirred for 1 hour at room temperature. To the reaction solution was added a solution of 6-(4-acetylphenoxy)-N-[4-(trifluoromethyl)phenyl]nicotinamide (0.53 g, 1.3 mmol) in THF (6 mL), and the resulting solution was stirred for 10 hours at 60° C. To the reaction solution was added saturated aqueous ammonium chloride, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 0.57 g of the intermediate product ethyl 3-(4-{5-[4-(trifluoromethyl)phenylcarbamoyl]pyridin-2-yloxy}phenyl)-2-butenoate. 10% palladium-carbon (0.057 g) was suspended in a mixed solvent consisting of ethanol (8 mL) and dioxane (2 mL), and to this suspension was added ethyl 3-(4-{5-[4-(trifluoromethyl)phenylcarbamoyl]pyridin-2-yloxy}phenyl)-2-butenoate (0.57 g, 1.2 mmol). The resulting product was subjected to catalytic reduction at atmospheric pressure and room temperature. Once the absorption of hydrogen had stopped, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure, to thereby yield 0.56 g of the title compound.

Appearance: White solid

¹H NMR (CDCl₃) δ 1.21 (3H, t, J=7.1 Hz), 1.33 (3H, d, J=7.0 Hz), 2.51-2.67 (2H, m), 3.28-3.37 (1H, m), 4.10 (2H, J=7.1 Hz), 7.00 (1H, d, J=8.6 Hz), 7.07-7.12 (2H, m), 7.26-7.31 (2H, m), 7.60-7.65 (2H, m), 7.73-7.77 (2H, m), 7.81 (1H, brs), 8.21 (1H, dd, J=8.6, 2.6 Hz), 8.68 (1H, d, J=2.3 Hz).

The following compound was produced in the same manner as in Reference Example 665.

Reference Example 666
Ethyl 2-methyl-3-{4-[5-(4-trifluoromethylphenylcarbamoyl)pyridin-2-yloxy]phenyl}propionate

MS 472 (M⁺)

Reference Example 667
Production of 3,4-dichloro-N-{6-[4-(N-hydroxycarbamimidoylmethyl)phenoxy]pyridin-3-yl}benzamide

To a solution of 3,4-dichloro-N-[6-(4-cyanomethylphenoxy)pyridin-]-yl]benzamide (700 mg, 1.76 mmol) in ethanol (30 mL) were added water (2 mL), hydroxylamine (420 mg, 12.71 mmol) and potassium carbonate (1.76 g, 12.73 mmol). Under argon, the resulting solution was stirred under reflux for 4 hours. The resulting reaction solution was concentrated under reduced pressure. To the residue was added water, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=10:1), to thereby yield 510 mg of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 3.27 (2H, s), 5.41 (2H, brs), 7.03 (2H, d, J=8.4 Hz), 7.05 (1H, d, J=8.8 Hz), 7.31 (2H, d, J=8.4 Hz), 7.84 (1H, d, J=8.4 Hz), 7.94 (1H, dd, J=8.4 Hz, 2.0 Hz), 8.18 (1H, dd, J=8.8 Hz, 2.6 Hz), 8.22 (1H, d, J=2.0 Hz), 8.46 (1H, d, J=2.6 Hz), 8.88 (1H, s), 10.53 (1H, s).

Reference Example 668
Production of 3,4-dichloro-N-{6-[4-(N-acetoxycarbamimidoylmethyl)phenoxy]pyridin-3-yl}benzamide

To a solution of 3,4-dichloro-N-{6-[4-(N-hydroxycarbamimidoylmethyl)phenoxy]pyridin-3-yl}benzamide (510 mg, 1.18 mmol) in dioxane (8 mL) was added potassium carbonate (163 mg, 1.18 mmol). While stirring under ice cooling, to the resulting solution was added dropwise acetyl chloride (0.084 mL, 1.18 mmol), and the resulting solution was stirred for 15 minutes at room temperature. To the reaction solution was added THF (10 mL), and then water, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, evaporated. The residue was washed with ethyl acetate to yield 340 mg of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 2.05 (3H, s), 3.35 (2H, s), 6.43 (2H, brs), 7.06 (1H, d, J=9.0 Hz), 7.06 (2H, d, J=8.6 Hz), 7.36 (2H, d, J=8.6 Hz), 7.84 (1H, d, J=8.3 Hz), 7.94 (1H, dd, J=8.3 Hz, 2.0 Hz), 8.18 (1H, dd, J=9.0 Hz, 2.5 Hz), 8.22 (1H, d, J=2.0 Hz), 8.47 (1H, d, J=2.5 Hz), 10.54 (1H, s).

Reference Example 669
Production of 4-{4-[4-(3,4-dichlorobenzoylamino)-2-fluorophenoxy]phenyl}-4-oxobutyric acid

To a suspension consisting of 3,4-dichloro-3′-fluoro-4′-phenoxybenzanilide (5.05 g, 13.4 mmol) and succinic anhydride (1.48 g, 14.8 mmol) in 1,2-dichloroethane (25 mL) was added aluminum chloride (6.26 g, 47.0 mmol) under ice cooling, and the resulting mixture was stirred at the same temperature for 5 minutes, and then at room temperature for 1.5 hours. The resulting reaction solution was poured into ice water, and the resulting solid was collected by filtration. To the solid was added 50% aqueous acetone (200 mL), and the resulting solution was refluxed for 0.5 hours, then cooled. The obtained solid was collected by filtration, to thereby yield 6.30 g of the title compound.

Appearance: White powder

Melting point: 205-208° C.

Reference Example 670
Production of ethyl 3-{4-[hydroxy(5-nitro-2-pyridyl)methyl]phenyl}propionate

To a solution of ethyl 3-[4-(5-nitropyridine-2-carbonyl)phenyl]propionate (1.52 g, 4.63 mmol) in dichloromethane (15 mL) and ethanol (15 mL) was added sodium borohydride (0.175 g, 4.63 mmol) under ice cooling, and the resulting solution was stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was dissolved in water and ethyl acetate. To the solution was added acetic acid and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), to thereby yield 0.264 g of the title compound.

Appearance: Brown powder

¹H NMR (CDCl₃) δ 1.19 (3H, t, J=7.2 Hz), 2.56 (2H, t, J=7.8 Hz), 2.91 (2H, t, J=7.8 Hz), 4.09 (2H, q, J=7.2 Hz), 4.35 (1H, brs), 5.84 (1H, s), 7.17 (2H, d, J=8.1 Hz), 7.26 (2H, d, J=8.1 Hz), 7.46 (1H, d, J=8.7 Hz), 8.40 (1H, dd, J=8.7 Hz, 2.5 Hz), 9.36 (1H, d, J=2.5 Hz).

The following compound was produced in the same manner as in Reference Example 670.

Reference Example 671
t-Butyl 4-[(2-hydroxy-3-(4-hydroxyphenyl)propionyl]-piperazine-1-carboxylate

¹H NMR (CDCl₃) δ 1.47 (9H, s), 1.62 (1H, brs), 2.85 (2H, d, J=6.0 Hz), 3.00-3.80 (8H, m), 4.56 (1H, t, J=6.0 Hz), 5.35 (1H, brs), 6.74 (2H, d, J=8.4 Hz), 7.06 (2H, d, J=8.4 Hz).

Reference Example 672
Production of ethyl 3-(4-{5-[(bis(3,4-dichlorobenzoyl)amino]-2-pyridylmethyl}phenyl)propionate

To a suspension of 10% palladium-carbon (27 mg) in ethanol (5 mL) were added a solution of ethyl 3-{4-[hydroxy(5-nitro-2-pyridyl)methyl]phenyl}propionate (0.264 g, 0.799 mmol) and 0.5 M hydrogen chloride in ethanol (2 mL), and the resulting solution was subjected to catalytic reduction at atmospheric pressure at 50° C. Once the absorption of hydrogen had stopped, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was suspended in THF (5 mL), and triethylamine (0.267 mL, 2.40 mmol) was added. To the solution was added dropwise a solution of 3,4-dichlorobenzoyl chloride (0.255 g, 0.879 mmol) in THF (1 mL) under ice cooling, and stirred for 1 hour at the same temperature. To the resulting solution was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 0.177 g of the title compound.

Appearance: Pale yellow oil

¹H NMR (CDCl₃) δ 1.20 (3H, t, J=7.2 Hz), 2.56 (2H, t, J=7.8 Hz), 2.89 (2H, t, J=7.8 Hz), 4.09 (2H, q, J=7.2 Hz), 6.99 (1H, s), 7.17 (2H, d, J=8.2 Hz), 7.35 (2H, d, J=8.2 Hz), 7.42 (1H, d, J=8.6 Hz), 7.43-7.56 (2H, m), 7.63 (1H, dd, J=8.6 Hz, 2.1 Hz), 7.85-7.94 (2H, m), 8.15 (1H, d, J=2.0 Hz), 8.20-8.32 (2H, m), 8.57 (1H, d, J=2.5 Hz).

Reference Example 673
Production of ethyl 3-(4-(5-(N-(4-(trifluoromethyl)phenyl)sulfamoyl)pyridin-2-yloxy)phenyl)propionate

To a solution of ethyl 3-(4-(3-bromo-5-(N-(4-(trifluoromethyl)phenyl)sulfamoyl)pyridin-2-yloxy)phenyl)propionate (0.41 g, 0.7 mmol) in ethanol (10 mL) were added 10% palladium-carbon (0.041 g) and ammonium formate (0.226 g, 3.6 mmol), and the resulting solution was heated to reflux for 2 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was then purified by silica gel chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 0.28 g of the title compound.

Appearance: White solid

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7.1 Hz), 2.60-2.66 (2H, m), 2.93-2.99 (2H, m), 4.14 (2H, q, J=7.1 Hz), 6.95 (1H, d, J=8.8 Hz), 7.01-7.05 (2H, m), 7.20-7.26 (3H, m), 7.50-7.54 (3H, m), 8.03 (1H, dd, J=8.8 Hz, 2.6 Hz), 8.59 (1H, d, J=2.6 Hz).

Reference Example 674
Production of 1-(4-methoxyphenyl)imidazolin-2-one

To a suspension of 1-(2-chloroethyl)-3-(4-methoxyphenyl)urea (7.0 g, 30.6 mmol) in t-butanol (120 mL) was added potassium t-butoxide (6.4 g, 57.0 mmol) under a nitrogen atmosphere. The resulting solution was stirred for 10 minutes, and then potassium butoxide (3.0 g, 26.7 mmol) was added. This solution was stirred for 10 minutes, and then potassium t-butoxide (4.3 g, 38.3 mmol) was added. The resulting solution was stirred for 16 hours at room temperature. The pH was adjusted to between 2 and 3 with 10% hydrochloric acid, and the solvent was evaporated under reduced pressure. To the residue were added water (100 mL) and ethyl acetate (100 mL), and stirred for 1 hour at room temperature. Resulting precipitates were filtered, washed with diethyl ether, and then dried under reduced pressure, to thereby yield 5.1 g of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 3.29-3.44 (2H, m), 3.70 (3H, s), 3.71-3.88 (2H, m), 6.77 (1H, s), 6.81-6.95 (2H, m), 7.35-7.50 (2H, m).

The following compounds were produced in the same manner as in Reference Example 674.

Reference Example 675
1-(4-Benzyloxy-3-methylphenyl)tetrahydropyrimidin-2-one

¹H NMR (DMSO-d₆) δ 1.81-1.96 (2H, m), 2.16 (3H, s), 3.11-3.25 (2H, m), 3.51 (2H, t, J=5.6 Hz), 5.09 (2H, s), 6.42 (1H, s), 6.91 (1H, d, J=8.7 Hz), 6.98 (1H, dd, J=2.6 Hz, 8.7 Hz), 7.04 (111, d, J=2.6 Hz), 7.28-7.34 (1H, m), 7.36-7.41 (2H, m), 7.42-7.48 (2H, m).

TABLE 95

Reference

Example

No.
R₃₁₀
M
mp (° C.) or ¹H NMR (CDCl₃) δppm

676
—H
1
mp 162.0-163.0

677
—H
2
mp 179.0-180.0

678
—OCH₃
1

¹H NMR 2.29-2.45(4H, m), 2.59-2.69(2H, m), 2.91-3.04(2H, m),

3.34-3.47(4H, m), 3.53-3.69(4H, m), 3.75(3H, s), 3.85-3.96(2H,

m), 4.58(1H, s), 5.95(2H, s), 6.69-6.78(2H, m), 6.79-6.89(3H,

m), 6.91(1H, d, J = 9.0 Hz), 7.02(1H, d, J = 8.0 Hz), 7.99(1H, d,

J = 2.9 Hz), 8.25(1H, dd, J = 2.9 Hz, 9.0 Hz).

679
—OCH₃
2
mp 140.0-141.5

TABLE 96

Reference

Example

No.
M

¹H NMR (CDCl₃) δppm

680
1
1.98-2.14(2H, m), 2.18(3H, s), 3.30(2H, d, J = 6.0 Hz), 3.51-3.66(2H, m), 3.67-

3.78(2H, m), 3.80-4.05(8H, m), 4.57(2H, s), 4.79(1H, s), 6.78-6.94(4H, m),

6.99(1H, d, J = 8.6 Hz), 7.13(1H, dd, J = 2.6 Hz, 8.6 Hz), 7.22(1H, d, J = 2.6 Hz),

8.05(1H, d, J = 2.9 Hz), 8.22(1H, dd, J = 2.9 Hz, 9.0 Hz).

681
2
1.91-2.15(4H, m), 2.18(3H, s), 3.18-3.36(2H, m), 3.37-3.51(2H, m), 3.58-3.78(2H,

m), 3.88(3H, s), 3.88(3H, s), 4.56(2H, s), 4.89(1H, s), 6.76-6.94(4H, m), 7.00(1H,

d, J = 8.7 Hz), 7.13(1H, dd, J = 2.6 Hz, 8.7 Hz), 7.23(1H, d, J = 2.6 Hz),

7.67(1H, dd, J = 2.8 Hz, 8.8 Hz), 8.08(1H, d, J = 2.8 Hz).

Reference Example 682
Production of 3-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}propionic acid

To a solution of ethyl 3-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}propionate (6.00 g, 13.1 mmol) in THF (60 mL) and ethanol (30 mL) were added 5 M aqueous sodium hydroxide (3.14 mL, 15.7 mmol) and water (30 mL) and the resulting solution was refluxed for 1 hour. The reaction solution was cooled with ice. To the reaction solution were added 5 M hydrochloric acid (4.0 mL, 20.0 mmol) and water (100 mL). The obtained solid was collected by filtration, and recrystallized from water-containing acetone, to thereby yield 5.60 g of the title compound.

Appearance: White powder

Melting point: 188-190° C.

The following compounds were produced in the same manner as in Reference Example 682.

TABLE 97

Reference

Example

No.
R₃₁₁

¹H NMR (solvent) δppm or MS

683

embedded image

¹H NMR (CDCl₃) 1.51(3H, d, J= 7.1 Hz), 2.12(3H, s), 2.91 (3H, s), 4.49(1H, q, J = 7.1 Hz), 6.71- 6.75(2H, m), 6.95-7.00 (2H, m), 8.45(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04(1H, dd, J = 2.8 Hz, 0.5 Hz).

684

embedded image

MS 300(M⁺)

685

embedded image

¹H NMR (DMSO-d₆) 7.39(1H, td, J = 2.0 Hz, 8.9 Hz), 7.50 (1H, d, J = 9.0 Hz), 7.78(1H, td, J = 2.1 Hz, 8.9 Hz), 8.70(1H, dd, J = 2.8 Hz, 9.0 Hz), 9.04(1H, d, J = 2.8 Hz), 11.35-11.91 (1H, m).

686

embedded image

¹H NMR (CDCl₃) 2.72-2.77(2H, m), 2.98-3.03(2H, m), 3.74(3H, s), 6.85-6.89(2H, m), 7.03(1H, d, J = 9.1 Hz), 7.06-7.09(1H, m), 8.45(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.01.(1H, d, J = 2.8 Hz).

687

embedded image

¹H NMR (DMSO-d₆) 2.52(2H, t, J = 7.6 Hz), 2.80(2H, t, J = 7.6 Hz), 6.86(1H, d, J = 9.4 Hz), 7.21(2H, d, J = 8.5 Hz), 7.58 (2H, d, J = 8.5 Hz), 8.26(1H, dd, J = 2.9 Hz, 9.4 Hz), 9.01(1H, d, J = 2.9 Hz), 10.06(1H, s).

688

embedded image

¹H NMR (DMSO-d₆) 2.96(3H, s), 4.09(2H, s), 6.44- 6.49 (2H, m), 6.56(1H, dd, J = 8.3 Hz, 2.4 Hz), 7.15(1H, d, J = 9.1 Hz), 7.20-7.26(1H, m), 8.59(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05 (1H, d, J = 2.8 Hz).

689

embedded image

¹H NMR (CDCl₃) 1.53(3H, d, J = 7.1 Hz), 2.93(3H, s), 4.51 (1H, q, J = 7.1 Hz), 6.87(2H, d, J = 9.2 Hz), 6.98(1H, d, J = 9.1 Hz), 7.05(2H, d, J = 9.1 Hz), 8.44(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05(1H, d, J = 2.6 Hz).

690

embedded image

¹H NMR (CDCl₃) 2.63-2.69(2H, m), 2.97(3H, s), 3.68(2H, t, J = 7.1 Hz), 6.81(2H, d, J = 9.1 Hz), 6.98(1H, d, J = 9.1 Hz), 7.05(2H, d, J = 9.2 Hz), 8.44(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.06 (1H, d, J = 2.8 Hz).

691

embedded image

¹H NMR (DMSO-d₆) 3.55(3H, s), 6.67(1H, d, J = 9.5 Hz), 7.52(2H, d, J = 8.5 Hz), 8.04(2H, d, J = 8.5 Hz), 8.21(1H, dd, J = 2.8 Hz, 9.5 Hz), 9.05(1H, d, J = 2.8 Hz), 13.10(1H, brs).

692

embedded image

¹H NMR (DMSO-d₆) 1.28-1.32(2H, m), 1.75- 1.79(3H, m), 2.01(3H, s), 2.19(2H, d, J = 6.8 Hz), 2.65(2H, t, J = 12.0 Hz), 3.65(2H, d, J = 12.4 Hz), 6.80-6.96(3H, m), 7.15(1H, d, J = 9.2 Hz), 8.58(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.01(1H, d, J = 2.8 Hz), 10.71(1H, brs).

693

embedded image

MS 306(M⁺)

TABLE 98

Reference

Example

No.
R₃₁₂
R₃₁₃
R₃₁₄
R₃₁₅
R₃₁₆

¹H NMR (solvent) δppm

694
—F
—H
—H
—H
—CH₃
(CDCl₃) 3.09(3H, s), 4.12(2H, s), 6.45-

6.57(2H, m), 7.05-7.12(2H, m), 8.47(1H, dd,

J = 9.1 Hz, 2.8 Hz), 9.02(1H, dd, J = 2.8 Hz,

0.7 Hz).

695
—F
—H
—H
—H
—C₂H₅
(CDCl₃) 1.25(3H, t, J = 7.1 Hz), 3.47(2H, q,

J = 7.1 Hz), 4.06(2H, s), 6.42-6.53(2H, m),

7.04-7.10(2H, m), 8.47 (1H, dd, J = 9.1 Hz,

2.8 Hz), 9.02(1H, dd, J = 2.8 Hz, 0.5 Hz).

696
—F
—H
—H
—H
allyl
(CDCl₃) 4.03(2H, d, J = 5.0 Hz), 4.09(2H,

s), 5.25-5.32 (2H, m), 5.82-5.96(1H, m),

6.44-6.56(2H, m), 7.04-7.10 (2H, m),

8.47(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.02(1H,

d, J = 2.6 Hz).

697
—F
—H
—H
—F
—CH₃
(DMSO-d₆) 2.94(3H, s), 4.04(3H, s),

6.92(1H, dd, J = 8.5 Hz, 12.9 Hz), 7.30(1H,

dd, J = 7.5 Hz, 13.7 Hz), 7.35 (1H, d, J =

9.1 Hz), 8.63(1H, dd, J = 2.8 Hz, 9.1 Hz),

9.04(1H, d, J = 2.8 Hz), 12.41-12.82(1H,

m).

698
—F
—H
—H
—F
—C₂H₅
(DMSO-d₆) 1.10(3H, t, J = 7.0 Hz), 3.12-

3.48(2H, m), 4.01(2H, s), 6.90(1H, dd, J =

8.4 Hz, 13.1 Hz), 7.29(1H, dd, J = 7.6 Hz,

13.7 Hz), 7.35(1H, d, J = 9.0 Hz), 8.63 (1H,

dd, J = 2.8 Hz, 9.0 Hz), 9.04(1H, d, J = 2.8

Hz), 12.41-12.70(1H, m).

699
—F
—H
—F
—H
—CH₃
(DMSO-d₆) 2.96(3H, s), 4.26(2H, s), 6.41-

6.61(2H, m), 7.43(1H, d, J = 9.1 Hz),

8.65(1H, dd, J = 2.8 Hz, 9.1 Hz), 9.05(1H,

d, J = 2.8 Hz), 12.56-12.90(1H, m).

700
—CH₃
—CH₃
—H
—H
—CH₃
(CDCl₃) 2.07(3H, s), 2.32(3H, s), 2.85(3H,

s), 3.76(2H, s), 6.91(1H, d, J = 8.7 Hz),

7.00(1H, dd, J = 9.1 Hz, 0.6 Hz), 7.09(1H,

d, J = 8.7 Hz), 8.46(1H, dd, J = 9.1 Hz, 2.8

Hz), 9.04(1H, dd, J = 2.8 Hz, 0.6 Hz).

701
—CH₃
—H
—H
—CH₃
—C₂H₅
(DMSO-d₆) 0.98(3H, t, J =7.1 Hz),

1.98(3H, s), 2.20 (3H, s), 3.09(2H, q, J = 7.1

Hz), 3.70(2H, s), 6.91(1H, s), 7.06(1H, s),

7.18(1H, d, J = 9.1 Hz), 8.59(1H, dd, J = 9.1

Hz, 2.9 Hz), 9.03(1H, d, J = 2.9 Hz),

12.30(1H, brs).

702
—H
—H
—H
—H
—SO₂CH₃
(DMSO-d₆) 3.17(3H, s), 4.43(2H, s),

7.29(2H, d, J = 8.7 Hz), 7.31(1H, d, J = 9.1

Hz), 7.55(2H, d, J = 8.9 Hz), 8.64(1H, dd, J =

9.1 Hz, 2.8 Hz), 9.05(1H, d, J = 2.8 Hz).

703
—CH₃
—H
—H
—H
—SO₂CH₃
(DMSO-d₆) 2.09(3H, s), 3.11(3H, s),

4.42(2H, s), 7.20(1H, d, J = 8.6 Hz),

7.31(1H, d, J = 9.1 Hz), 7.37(1H, dd, J = 8.6

Hz, 2.5 Hz), 7.44(1H, d, J = 2.3 Hz),

8.64(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.03(1H,

d, J = 2.8 Hz), 12.88(1H, brs).

TABLE 99

Reference

Example

No.
R₃₁₇
R₃₁₈
R₃₁₉
R₃₂₀
R₃₂₁
R₃₂₂

¹H NMR (solvent) δppm or MS

704
—NO₂
—H
—CH₃
—H
—CH₃
—CH₃
MS 331(M⁺)

705
—NO₂
—H
—CF₃
—H
—H
—CH₃
MS 371(M⁺)

706
—NO₂
—H
—CF₃
—H
—H
—C₂H₅
MS 385(M⁺)

707
—NO₂
—CH₃
—H
—CF₃
—H
—CH₃
MS 385(M⁺)

708
—NO₂
—H
—F
—F
—H
—CH₃

¹H NMR (DMSO-d₆)

2.98(3H, s), 4.05 (2H, s),

6.64-6.88(1H, m), 6.96-7.20

(1H, m), 7.38(1H, d, J = 9.1

Hz), 8.64 (1H, dd, J = 2.7 Hz,

9.1 Hz), 9.04(1H, d, J = 2.7

Hz), 12.24-12.95(1H, m).

709
—NO₂
—H
—OCH₃
—H
—H
—SO₂CH₃

¹H NMR (DMSO-d₆)

3.16(3H, s), 3.70 (3H, s),

4.45(2H, s), 7.10-7.30(4H,

m), 8.61(1H, dd, J = 9.1 Hz,

2.8 Hz), 9.02 (1H, d, J = 2.8

Hz), 12.97(1H, brs).

710
—Br
—H
—F
—H
—F
—CH₃

¹H NMR (DMSO-d₆)

2.92(3H, s), 4.01 (2H, s),

6.80-6.93(1H, m), 7.11(1H, d,

J = 8.8 Hz), 7.14-7.26(1H,

m), 8.06 (1H, dd, J = 2.6 Hz,

8.8 Hz), 8.25(1H, d, J = 2.6

Hz), 12.18-12.89(1H, m).

711
4-CF₃PhCH₂—
—H
—H
—H
—H
—CH₃

¹H NMR (CDCl₃) 3.04(3H, s),

3.93(2H, s), 4.04(2H, s),

6.69(2H, d, J = 9.1 Hz),

6.70(1H, d, J = 8.5 Hz),

6.97(2H, d, J = 9.1 Hz),

7.25(2H, d, J = 8.6 Hz),

7.39(1H, dd, J = 8.5 Hz, 2.5

Hz), 7.52(2H, d, J = 8.6 Hz),

8.09(1H, d, J = 2.5 Hz),

11.26(1H, brs).

712
4-CF₃PhOCH₂—
—H
—H
—H
—H
—SO₂CH₃

¹H NMR (DMSO-d6)

3.11(3H, s), 4.40(2H, s),

5.18(2H, s), 7.12(1H, d, J =

8.9 Hz), 7.15-7.23(4H, m),

7.49(2H, d, J = 8.9 Hz),

7.67(2H, d, J = 8.6 Hz),

7.98(1H, dd, J = 8.4 Hz, 2.5

Hz), 8.28 (1H, d, J = 2.0 Hz),

12.41(1H, brs).

713
4-CF₃PhOCH₂—
—H
—CH₃
—H
—H
—SO₂CH₃

¹H NMR (DMSO-d6)

2.06(3H, s), 3.18 (3H, s),

3.89(2H, s), 5.15(2H, s), 7.02

(1H, d, J = 8.4 Hz), 7.07(1H,

d, J = 8.6 Hz), 7.21(2H, d, J =

8.4 Hz), 7.44(1H, dd, J = 8.6

Hz, 2.6 Hz), 7.49(1H, d, J =

2.3 Hz), 7.67(2H, d, J = 8.9

Hz), 7.95 (1H, dd, J = 8.4 Hz,

2.5 Hz), 8.24(1H, d, J = 2.5

Hz).

TABLE 100

Reference

Example

No.
R₃₂₃
R₃₂₄

¹H NMR (solvent) δppm

714
—H
—H
(DMSO-d₆) 3.35(1H, brs), 3.84(2H, s), 6.63(2H, d, J = 8.9 Hz),

6.96(2H, d, J = 8.9 Hz), 7.14(1H, d, J = 9.1 Hz), 8.59(1H, dd, J =

2.9 Hz, 9.1 Hz), 9.05(1H, d, J = 2.9 Hz).

715
—H
—CH₃
(CDCl₃) 3.09(3H, s), 4.11(2H, s), 6.74(2H, d, J = 9.1 Hz),

6.97(1H, dd, J = 9.1 Hz, 0.5 Hz), 7.04(2H, d, J = 9.1 Hz),

8.43(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.04(1H, dd, J = 2.8 Hz, 0.5

Hz).

716
—H
—C₂H₅
(CDCl₃) 1.24(3H, t, J = 7.1 Hz), 3.48(2H, q, J = 7.1 Hz),

4.07(2H, s), 6.73(2H, d, J = 9.2 Hz), 6.98(1H, d, J = 9.1 Hz),

7.04(2H, d, J = 9.2 Hz), 8.44(1H, dd, J = 9.1 Hz, 2.8 Hz),

9.05(1H, d, J = 2.8 Hz).

717
—OCH₃
—H
(DMSO-d₆) 3.62(3H, s), 3.83(2H, s), 6.13(1H, dd, J = 8.6 Hz,

2.5 Hz), 6.41(1H, d, J = 2.5 Hz), 6.90(1H, d, J = 8.6 Hz),

7.09(1H, d, J = 8.6 Hz), 8.54(1H, dd, J = 9.1 Hz, 3.0 Hz),

9.00(1H, d, J = 3.0 Hz).

718
—OCH₃
—CH₃
(DMSO-d₆) 3.00(3H, s), 3.65(3H, s), 4.12(2H, s), 6.21(1H, dd,

J = 8.8 Hz, 2.8 Hz), 6.39(1H, d, J = 2.8 Hz), 6.96(1H, d, J =

8.8 Hz), 7.11(1H, d, J = 9.1 Hz), 8.54(1H, dd, J = 9.1 Hz, 2.8

Hz), 9.00(1H, d, J = 2.8 Hz), 12.57(1H, s).

719
—OCH₃
—C₂H₅
(DMSO-d₆) 1.13(3H, t, J = 7.0 Hz), 3.42(2H, q, J = 7.0 Hz),

3.64(3H, s), 4.05(2H, s), 6.14(1H, dd, J = 8.8 Hz, 2.8 Hz),

6.31(1H, d, J = 2.8 Hz), 6.95(1H, d, J = 8.8 Hz), 7.12(1H, d, J =

9.1 Hz), 8.53(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.00(1H, d, J = 2.8

Hz), 12.59(1H, brs).

720
—CH₃
—Ac
(DMSO-d₆) 1.86(3H, s), 2.08(3H, s), 4.26(2H, s), 7.05-7.50(4H,

m), 8.63 (1H, dd, J = 9.1 Hz, 2.9 Hz), 9.02(1H, dd, J = 2.9 Hz,

0.4 Hz), 12.72(1H, brs).

721
—CH₃
—H
(CDCl₃) 2.09(3H, s), 3.98(2H, s), 5.26(1H, brs), 6.50-6.55(2H,

m), 6.92(1H, d, J = 8.4 Hz), 6.98(1H, d, J = 8.1 Hz), 8.45(1H,

dd, J = 8.1 Hz, 2.8 Hz), 9.04(1H, d, J = 2.8 Hz).

722
—CH₃
—CH₃
(DMSO-d₆) 1.99(3H, s), 2.97(3H, s), 4.09(2H, s), 6.52(1H, dd,

J = 8.8 Hz, 3.0 Hz), 6.59(1H, d, J = 3.0 Hz), 6.92(1H, d, J =

8.8 Hz), 7.13(1H, dd, J = 9.1 Hz, 0.3 Hz), 8.57(1H, dd, J = 9.1

Hz, 2.9 Hz), 9.01(1H, d, J = 2.9 Hz), 12.54(1H, brs).

723
—CH₃
—C₂H₅
(DMSO-d₆) 1.11(3H, t, J = 7.0 Hz), 1.98(3H, s), 3.89(2H, q, J =

7.0 Hz), 4.02(2H, s), 6.44(1H, dd, J = 8.8 Hz, 2.9 Hz), 6.51(1H,

d, J = 2.9 Hz), 6.90(1H, d, J = 8.8 Hz), 7.13(1H, d, J = 9.1 Hz),

8.56(1H, dd, J = 9.1 Hz, 2.9 Hz), 9.01(1H, d, J = 2.9 Hz),

12.53(1H, brs).

724
—CH₃

embedded image

(DMSO-d₆) 0.54-0.59(2H, m), 0.80-0.87(2H, m), 2.02(3H, s), 2.64-2.71 (1H, m), 4.11(2H, s), 6.77-6.81(1H, m), 6.85(1H, d, J = 2.8 Hz), 6.96(1H, d, J = 8.7 Hz), 7.17(1H, dd, J = 9.2 Hz, 0.5 Hz), 8.59(1H, dd, J = 9.1 Hz, 3.0 Hz), 9.04(1H, dd, J = 3.0 Hz, 0.5 Hz), 12.56(1H, brs).

725
—F
—H
(DMSO-d₆) 3.82(2H, s), 6.43(1H, dd, J = 8.7 Hz, 2.8 Hz),

6.53(1H, dd, J = 13.4 Hz, 2.6 Hz), 7.07(1H, t, J = 8.9 Hz),

7.28(1H, dd, J = 9.1 Hz, 0.5 Hz), 8.61(1H, dd, J = 9.1 Hz, 2.8

Hz), 9.03(1H, dd, J = 2.8 Hz, 0.5 Hz).

TABLE 101

Reference

Example

No.
R₃₂₅
R₃₂₆
mp (° C.) or ¹H NMR (solvent) δppm

726
4-NO₂Ph—
4-N(CH₃)CH₂COOH

¹H NMR (CDCl₃) 3.10(3H, s),

4.13(2H, s), 6.74(2H, d, J = 9.2

Hz), 6.95(2H, d, J = 9.2 Hz),

7.00(2H, d, J = 9.2 Hz), 8.17(2H,

d, J = 9.2 Hz).

727

embedded image

2-(CH₂)₂COOH
mp 157-159

728

embedded image

3-(CH₂)₂COOH
mp 192-194

729

embedded image

4-(CH₂)₂COOH

¹H NMR (CDCl₃) 2.67(2H, t, J = 7.7 Hz), 2.94(2H, t, J = 7.7 Hz), 6.78 (1H, dd, J = 8.2 Hz, 1.2 Hz), 6.97(2H, d, J = 8.6 Hz), 7.02- 7.19(2H, m), 7.20(2H, d, J = 8.6 Hz), 7.48(1H, d, J = 8.3 Hz), 7.56(1H, dd, J = 8.3 Hz, 2.1 Hz), 7.84(1H, d, J = 2.1 Hz), 8.38(1H, brs), 8.49(1H, dd, J = 8.3 Hz, 2.1 Hz), 10.46(1H, brs).

730

embedded image

4-(CH₂)₂COOH

¹H NMR (CDCl₃) 2.67(2H, t, J = 7.6 Hz), 2.93(2H, t, J = 7.6 Hz), 6.78 (1H, dt, J = 8.1 Hz, 1.2 Hz), 6.95(2H, d, J = 8.5 Hz), 7.16(2H, d, J = 8.5Hz), 7.22-7.34(3H, m), 7.53(1H, d, J = 8.3 Hz), 7.64(1H, dd, J = 8.3 Hz, 2.1 Hz), 7.73(1H, brs), 7.90(1H, d, J = 2.1 Hz), 10.23(1H, brs).

731

embedded image

4-(CH₂)₂COOH

¹H NMR (DMSO-d₆) 1.05(3H, t, J = 7.1 Hz), 2.56(2H, t, J = 7.6 Hz), 2.84(2H, t, J = 7.6 Hz), 3.64 (2H, q, J = 7.1 Hz), 7.05-7.10(3H, m), 7.28(2H, d, J = 8.6 Hz), 7.45(2H, brs), 7.76-7.80(2H, m), 8.08 (1H, dd, J = 2.8 Hz, 0.5 Hz), 8.27(1H, brs), 12.10(1H, brs).

732

embedded image

4-(CH₂)₂COOH

¹H NMR (DMSO-d₆) 1.06(3H, t, J = 7.1 Hz), 2.53-2.59(2H, m), 2.81-2.87(2H, m), 3.67(2H, q, J = 7.1 Hz), 7.05-7.10(3H, m), 7.29(2H, d, J = 8.7 Hz), 7.56(2H, d, J = 8.7 Hz), 7.66(2H, d, J = 8.7 Hz), 7.78(1H, dd, J = 8.6 Hz, 2.8 Hz), 8.09(1H, d, J = 2.8 Hz), 8.41(1H, brs), 12.14(1H, brs).

TABLE 102

Reference

Example

No.
R₃₂₇
Xa₂₄
M
Form
mp (° C.) of ¹H NMR (DMSO-d₆) δppm

733
—H
none
0
free
mp 252-255

734
—F
none
0
free
mp 257-259

735
—F
none
1
free
mp 204-206

736
—F
none
2
free
mp 173-174

737
—F
none
3
free
mp 175-177

738
—F
—S—
1
Na

¹H NMR 3.86(2H, s), 6.86(2H, d, J = 8.7 Hz),

salt
7.15(1H, t, J = 9.0 Hz), 7.25(2H, d, J = 8.7 Hz),

7.55(1H, d, J = 9.0 Hz), 7.80(1H, d, J = 8.4 Hz),

7.91(1H, dd, J = 2.4 Hz, 13.3 Hz), 7.98(1H, dd,

J = 2.0 Hz, 8.4 Hz), 8.25(1H, d, J = 2.0 Hz).

739
—F
—SO—
1
free

¹H NMR 3.79(1H, d, J = 14.3 Hz), 3.97(1H, d, J =

14.3 Hz), 7.12(2H, d, J = 8.8 Hz), 7.33(1H, t,

J = 9.1 Hz), 7.55-7.65(1H, m), 7.71(2H, d, J =

8.8 Hz), 7.84(1H, d, J = 8.4 Hz), 7.90-7.95(2H,

m), 8.20(1H, d, J = 2.0 Hz), 10.63(1H, s),

13.20(1H, brs).

740
—F
—SO₂—
1
free
mp 214-216

741
—F
—N(Ac)—
1
free

¹H NMR 1.80(3H, s), 4.22(2H, s), 7.00(1H, d, J =

8.9 Hz), 7.25-7.30(1H, m), 7.38(2H, d, J = 8.9

Hz), 7.50-7.60(1H, m), 7.84(1H, d, J = 8.4 Hz),

7.90-7.96(2H, m), 8.21(1H, d, J = 2.0 Hz),

10.61(1H, s), 12.68(1H, s).

742
—F

embedded image

0
free
mp 241-243

(—SO— means a group of

embedded image

and —SO₂— means a group of

embedded image

Hereinafter —SO— and —SO₂— indicate the same meanings.)

TABLE 103

Reference

Example

No.
R₃₂₈
R₃₂₉
Xa₂₅
M
mp (° C.) or ¹H NMR (DMSO-d₆) δppm

743
—Cl
—Cl
—CO—
2

¹H NMR 2.60(2H, t, J = 7.6 Hz), 2.91 (2H, t,

J = 7.6 Hz), 7.39(2H, d, J = 8.2 Hz), 7.82-

8.20(4H, m), 8.07(1H, d, J = 8.6 Hz),

8.25(1H, dd, J = 7.5 Hz, 2.1 Hz), 8.45(1H,

dd, J = 8.6 Hz, 2.5 Hz), 9.03(1H, d, J = 2.5

Hz), 10.91(1H, s), 12.16(1H, brs).

744
—Cl
—Cl
—S—
2
mp 201-202

745
—Cl
—Cl
—SO—
2
mp 202-205

746
—Cl
—Cl
—SO₂—
2
mp 172-173

747
—Cl
—Cl
—NH—
2

¹H NMR 2.76(2H, t, J = 7.6 Hz), 3.20-3.40

(2H, m), 6.86(1H, d, J = 8.8 Hz), 7.12(2H, d,

J = 8.3 Hz), 7.52(2H, d, J = 8.3 Hz),

7.83(1H, d, J = 8.4 Hz), 7.90-7.96(2H, m),

8.21(1H, d, J = 1.3 Hz), 8.45(1H, d, J = 2.4

Hz), 9.03(1H, brs), 10.37(1H, s), 12.11(1H,

brs).

748
—Cl
—Cl
—N(CH₃)—
2
mp 158-160

749
—CF₃
—H
—N(CH₃)—
0
mp 240-243

750
—CF₃
—H
—N(CH₃)—
2

¹H NMR 2.57(2H, t, J = 7.5 Hz), 2.84(2H, t,

J = 7.5 Hz), 3.38(3H, s), 6.61(1H, d, J = 9.1

Hz), 7.22(2H, d, J = 8.3 Hz), 7.29(2H, d, J =

8.3 Hz), 7.80-7.85(1H, m), 7.91(2H, d, J =

8.3 Hz), 8.15(2H, d, J = 8.3 Hz), 8.51(1H, d,

J = 2.5 Hz), 10.42(1H, s), 12.10(1H, brs).

751
—Cl
—Cl
—N(CH₂Ph)—
2

¹H NMR 2.53(2H, t, J = 7.9 Hz), 2.80(2H, t,

J = 7.9 Hz), 5.21(2H, s), 6.63(1H, d, J = 9.1

Hz), 7.15-7.30 (9H, m), 7.75-7.95(3H, m),

8.19(1H, d, J = 2.1 Hz), 8.45(1H, d, J = 2.5

Hz), 10.34(1H, s), 12.10(1H, brs).

TABLE 104

Reference

Example

No.
R₃₃₀
R₃₃₁
R₃₃₂
M
mp (° C.) or ¹H NMR (DMSO-d₆) δppm

752
—H
—CN
—H
0

¹H NMR 7.18-7.21(3H, m), 7.98(2H, d, J = 8.2 Hz),

8.05(2H, d, J = 8.9 Hz), 8.13(2H, d, J = 8.2 Hz),

8.28(1H, dd, J = 8.6 Hz, 2.6 Hz), 8.57(1H, d, J = 2.6

Hz), 10.70(1H, s), 12.87(1H, brs).

753
—Cl
—Cl
—H
0

¹H NMR 7.17-7.22(3H, m), 7.85(1H, d, J = 8.2 Hz),

7.94-8.01(3H, m), 8.23-8.29(2H, m), 8.55(1H, d, J = 2.6

Hz), 10.01(1H, s), 12.87 (1H, brs).

754
—H
—Cl
—H
0

¹H NMR 7.16-7.21(3H, m), 7.63(2H, d, J = 8.6 Hz),

7.97-8.02(4H, m), 8.28(1H, dd, J = 8.6 Hz, 2.6 Hz),

8.57(1H, d, J = 2.6 Hz), 10.53(1H, s), 12.86(1H, brs).

755
—H
—CF₃
—H
0

¹H NMR 7.18-7.22(3H, m), 7.93-8.00(4H, m), 8.18(2H,

d, J = 8.4 Hz), 8.30(1H, dd, J = 8.9 Hz, 2.7 Hz),

8.58(1H, d, J = 2.7 Hz), 10.69(1H, s), 12.91(1H, brs).

756
—CH₃
—CH₃
—H
0

¹H NMR 2.30(3H, s), 2.31(3H, s)(, 7.16(1H, d, J = 8.9

Hz), 7.18(2H, d, J = 8.7 Hz), 7.31(1H, d, J = 7.6 Hz),

7.72(1H, d, J = 7.6 Hz), 7.77 (1H, s), 7.98(2H, d, J = 8.7

Hz), 8.28(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.58(1H, d, J =

2.7 Hz), 10.35(1H, s), 12.88(1H, brs).

757
—CF₃
—H
—F
0
mp 238-239

758
—OCF₃
—H
—H
0

¹H NMR 7.18-7.22(3H, m), 7.61-7.81(2H, m), 7.89-

8.06(4H, m), 8.28(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.57(1H,

d, J = 2.3 Hz), 10.62(1H, s), 12.95(1H, brs).

759
—CF₃
—H
—H
0

¹H NMR 7.11-7.22(3H, m), 7.70-7.85(1H, m), 7.90-

8.05(3H, m), 8.2-8.35(3H, m), 8.6(1H, d, J = 2.4 Hz),

10.70(1H, s), 12.90(1H, brs).

760
—H
—CF₃
—H
1

¹H NMR 3.59(2H, s), 7.04-7.10(3H, m), 7.27-7.33(2H,

m), 7.94(2H, d, J = 8.4 Hz), 8.17(2H, d, J = 8.1 Hz),

8.21-8.25(1H, m), 8.51(1H, d, J = 2.6 Hz), 10.64(1H, s),

12.43(1H, brs).

761
—Cl
—Cl
—H
1

¹H NMR 3.59(2H, s), 7.04-7.09(3H, m), 7.27-7.32(2H,

m), 7.83(1H, d, J = 8.4 Hz), 7.95(1H, dd, J = 8.4 Hz, 2.1

Hz), 8.18-8.23(2H, m), 8.48(1H, d, J = 2.6 Hz),

10.55(1H, s), 12.37(1H, brs).

762
—Cl
—Cl
—H
2

¹H NMR 2.51-2.58(2H, m), 2.81-2.86(2H, m), 7.01-

7.06(3H, m), 7.26(2H, d, J = 8.6 Hz), 7.84(1H, d, J =

8.4 Hz), 7.93-7.97(1H, m), 8.16-8.23(2H, m), 8.47(1H,

d, J = 2.7 Hz), 10.54(1H, s), 12.13(1H, brs).

763
—H
—CF₃
—H
2

¹H NMR 2.56(2H, t, J = 7.5 Hz), 2.84(2H, t, J = 7.5

Hz), 7.03(2H, d, J = 8.6 Hz), 7.05(1H, d, J = 8.8 Hz),

7.27(2H, d, J = 8.6 Hz), 7.93(2H, d, J = 8.2 Hz),

8.17(2H, d, J = 8.2 Hz), 8.21(1H, dd, J = 8.8 Hz, 2.6

Hz), 8.50(1H, d, J = 2.6 Hz), 10.63(1H, s), 12.16(1H, s).

TABLE 105

Reference

Example

No.
R₃₃₃
R₃₃₄
M

¹H NMR (DMSO-d₆) δppm

764
—OCH₃
—H
0
3.76(3H, s), 7.09(1H, d, J = 8.9 Hz), 7.23(1H, d, J = 8.1

Hz), 7.59-7.63 (2H, m), 7.84(1H, d, J = 8.4 Hz), 7.93-

7.96(1H, m), 8.16-8.22(2H, m), 8.39(1H, d, J = 2.7 Hz),

10.53(1H, s), 13.00(1H, brs).

765
—H
—OCH₃
0
3.80(3H, s), 6.69(1H, dd, J = 8.4 Hz, 2.2 Hz), 6.90(1H, d, J =

2.2 Hz), 7.17(1H, d, J = 8.9 Hz), 7.73(1H, d, J = 8.4 Hz),

7.85(1H, d, J = 8.4 Hz), 7.97(1H, dd, J = 8.4 Hz, 2.2 Hz),

8.23-8.28(2H, m), 8.56(1H, d, J = 2.4 Hz), 10.62(1H, s),

12.56(1H, brs.)

766
—CH₃
—H
0
2.18(3H, s), 7.09-7.16(2H, m), 7.79-7.97(4H, m), 8.21-

8.26(2H, m), 8.47(1H, d, J = 2.2 Hz), 10.57(1H, s),

12.86(1H, brs).

767
—H
—CH₃
0
2.53(3H, s), 6.97-7.04(2H, m), 7.16(1H, d, J = 8.7 Hz),

7.77-7.98(3H, m), 8.23-8.27(2H, m), 8.54(1H, d, J = 2.6

Hz), 10.62(1H, s), 12.79(1H, brs).

768
—F
—H
0
7.24(1H, d, J = 8.9 Hz), 7.39-7.45(1H, m), 7.70-8.05(4H,

m), 8.23-8.28 (2H, m), 8.46(1H, d, J = 2.6 Hz), 10.64(1H,

s), 13.55(1H, brs).

769
—Cl
—H
0
7.25(1H, d, J = 8.9 Hz), 7.39(1H, d, J = 8.6 Hz), 7.84(1H,

d, J = 8.4 Hz), 7.93-7.97(2H, m), 8.06(1H, d, J = 2.0 Hz),

8.22(1H, d, J = 2.0 Hz), 8.25-8.29(1H, m), 8.47(1H, d, J =

2.6 Hz), 10.61(1H, s), 13.31(1H, brs).

770
—OCH₃
—H
2
2.5-2.65(2H, m), 2.71-2.92(2H, m), 3.67(3H, s), 6.81(1H,

dd, J = 8.1 Hz, 1.9 Hz), 6.95(1H, d, J = 8.9 Hz), 6.99-

7.05(2H, m), 7.82(1H, d, J = 8.4 Hz), 7.93(1H, dd, J = 8.4

Hz, 2.0 Hz), 8.10(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.20(1H, d, J =

2.0 Hz), 8.35(1H, m), 10.47(1H, s), 12.15(1H, brs).

771
—OC₂H₅
—H
2
1.06(3H, t, J = 7.0 Hz), 2.51-2.62(2H, m), 2.74-2.88(2H,

m), 3.94(2H, q, J = 7.0 Hz), 6.80(1H, dd, J = 8.1 Hz, 1.8

Hz), 6.92-7.04(3H, m), 7.82(1H, d, J = 8.4 Hz), 7.93(1H,

dd, J = 8.4 Hz, 2.0 Hz), 8.11(1H, dd, J = 8.9 Hz, 2.7 Hz),

8.20(1H, d, J = 2.0 Hz), 8.36(1H, d, J = 2.7 Hz), 10.47(1H,

s), 12.14(1H, brs)

772
—F
—H
2
2.50-2.67(2H, m), 2.75-2.93(2H, m), 7.03-7.29(4H, m),

7.82(1H, d, J = 8.4 Hz), 7.93(1H, dd, J = 8.4 Hz, 2.0 Hz),

8.12-8.24(2H, m), 8.39(1H, d, J = 2.5 Hz), 10.53(1H, s),

12.18(1H, brs).

TABLE 106

Reference

Example

No.
R₃₃₅
R₃₃₆
M

¹H NMR (DMSO-d₆) δppm

773
—OCH₃
—H
0
3.76(3H, s), 7.10(1H, d, J = 8.9 Hz), 7.23(1H, d, J = 8.1

Hz), 7.59-7.64 (2H, m), 7.93(2H, d, J = 8.1 Hz), 8.15-

8.23(3H, m), 8.42(1H, d, J = 2.2 Hz), 10.60(1H, s),

13.00(1H, brs).

774
—H
—OCH₃
0
3.80(3H, s), 6.69(1H, dd, J = 8.6 Hz, 2.2 Hz), 6.90(1H, d,

J = 2.2 Hz), 7.17(1H, d, J = 8.6 Hz), 7.73(1H, d, J = 8.4

Hz), 7.95(2H, d, J = 8.4 Hz), 8.18(2H, d, J = 8.4 Hz),

8.29(1H, dd, J = 8.6 Hz, 2.7 Hz), 8.58(1H, d, J = 2.7 Hz),

10.69(1H, s), 12.51(1H, brs).

775
—CH₃
—H
0
1.99(3H, s), 7.09-7.17(2H, m), 7.79-7.83(1H, m), 7.91-

7.95(3H, m), 8.12-8.18(2H, m), 8.27(1H, dd, J = 8.9 Hz,

2.7 Hz), 8.49(1H, d, J = 2.7 Hz), 10.64(1H, s), 12.87(1H,

brs).

776
—H
—CH₃
0
2.54(3H, s), 6.98-7.05(2H, m), 7.17(1H, d, J = 8.7 Hz),

7.87-7.97(3H, m), 8.13-8.19(2H, m), 8.26-8.30(1H, m),

8.57(1H, d, J = 2.8 Hz), 10.70(1H, s), 12.81(1H, brs).

777
—F
—H
0
7.26(1H, d, J = 8.9 Hz), 7.40-7.46(1H, m), 7.82-7.85(2H,

m), 7.94(2H, d, J = 8.2 Hz), 8.17(2H, d, J = 8.2 Hz),

8.30(1H, dd, J = 8.9 Hz, 2.1 Hz), 8.49(1H, d, J = 2.1 Hz),

10.70(1H, s), 13.39(1H, brs).

778
—Cl
—H
0
7.14(1H, d, J = 8.9 Hz), 7.19(1H, d, J = 8.2 Hz), 7.82-

7.86(1H, m), 7.92(2H, d, J = 8.4 Hz), 7.96(1H, d, J = 1.8

Hz), 8.20(2H, d, J = 8.2 Hz), 8.29(1H, dd, J = 8.9 Hz, 2.6

Hz), 8.47(1H, d, J = 2.6 Hz), 10.86(1H, s).

779
—OCH₃
—H
2
2.57-2.63(2H, m), 2.83-2.89(2H, m), 3.69(3H, s), 6.84(1H,

dd, J = 8.1 Hz, 1.8 Hz), 6.97(1H, d, J = 8.9 Hz), 7.01-

7.04(2H, m), 7.92(2H, d, J = 8.4 Hz), 8.14-8.18(3H, m),

8.40(1H, d, J = 2.5 Hz), 10.58(1H, s).

780
—OC₂H₅
—H
2
1.06(3H, t, mJ = 7.0 Hz), 2.47-2.67(2H, m), 2.72-2.91(2H,

m), 3.94(2H, q, J = 7.0 Hz), 6.80(1H, dd, J = 8.0 Hz, 1.8

Hz), 6.94-7.05(3H, m), 7.91(2H, d, J = 8.3 Hz), 8.09-

8.19(3H, m), 8.38(1H, d, J = 2.6 Hz), 10.55(1H, s),

12.14(1H, brs).

781
—F
—H
2
2.49-2.63(2H, m), 2.71-2.93(2H, m), 7.09(1H, dd, J = 8.3

Hz, 1.5 Hz), 7.14(1H, d, J = 8.9 Hz), 7.17-7.28(2H, m),

7.92(2H, d, J = 8.2 Hz), 8.15(2H, d, J = 8.2 Hz), 8.21(1H,

dd, J = 8.9 Hz, 2.7 Hz), 8.38-8.44(1H, m), 10.60(1H, s),

12.17(1H, brs).

TABLE 107

Reference

Example

No.
R₃₃₇
R₃₃₈
R₃₃₉

¹H NMR (DMSO-d₆) δppm

782
—Cl
—Cl

embedded image

7.20(1H, d, J = 8.7 Hz), 7.40(1H, dd, J = 8.7 Hz, 2.3 Hz), 7.60-7.67(1H, m), 7.82- 8.03(4H, m), 8.15(1H, d, J = 8.9 Hz), 8.26- 8.32(2H, m), 8.56-8.60(2H, m), 10.78(1H, s).

783
—CF₃
—H

embedded image

7.18(1H, d, J = 8.7 Hz), 7.36(1H, dd, J = 8.7 Hz, 2.3 Hz), 7.63(1H, d, J = 2.0 Hz), 7.84-8.11(5H, m), 8.23(2H, d, J = 8.1 Hz), 8.34(1H, dd, J = 8.9 Hz, 2.5 Hz), 8.54- 8.60(2H, m), 10.98(1H, s).

784
—Cl
—Cl

embedded image

7.19(1H, d, J = 8.7 Hz), 7.47(1H, dd, J = 9.4 Hz, 2.5 Hz), 7.57-7.63(1H, m), 7.73(1H, d, J = 2.5 Hz), 7.85(1H, d, J = 8.4 Hz), 7.96(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.10-8.14(2H, m), 8.23-8.28(2H, m), 8.52(1H, d, J = 2.5 Hz), 8.92(1H, d, J = 9.4 Hz), 10.60(1H, s), 13.20(1H, brs).

785
—CF₃
—H

embedded image

7.20(1H, d, J = 8.7 Hz), 7.48(1H, dd, J = 9.4 Hz, 2.6 Hz), 7.57-7.63(1H, m), 7.73(1H, d, J = 2.5 Hz), 7.94(2H, d, J = 8.2 Hz), 8.11-8.19(4H, m), 8.29(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.55(1H, d, J = 2.5 Hz), 8.93(1H, d, J = 9.4 Hz), 10.68(1H, s), 13.21(1H, brs).

786
—Cl
—Cl

embedded image

7.24(1H, d, J = 8.1 Hz), 7.32(1H, d, J = 8.7 Hz), 7.58-7.64(1H, m), 7.69-7.77(1H, m), 7.85(1H, d, J = 8.4 Hz), 7.97(1H, dd, J = 8.4 Hz, 2.1 Hz), 8.06-8.12 (1H, m), 8.20- 8.23(2H, m), 8.30(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.48(1H, d, J = 2.6 Hz), 9.02(1H, d, J = 8.7 Hz), 10.63(1H, s), 13.11(1H, brs).

787
—Cl
—Cl

embedded image

7.17(1H, d, ,J = 8.9 Hz), 7.38-7.43(1H, m), 7.53-7.59(2H, m), 7.76-7.86(2H, m), 7.93- 7.97(1H, m), 8.22-8.27(2H, m), 8.51(1H, d, J = 2.0 Hz), 10.60(1H, s), 13.15(1H, brs).

TABLE 108

Reference

Example

No.
R₃₄₀
R₃₄₁

¹H NMR (solvent) δppm

788
—H
—Ac
(DMSO-d₆) 1.85(3H, s), 4.26(2H, s), 7.13(1H, d, J = 8.8 Hz),

7.19(2H, d, J = 8.7 Hz), 7.42(2H, d, J = 8.7 Hz), 7.85(1H, d, J =

8.4 Hz), 7.95(1H, dd, J = 1.9 Hz, 8.4 Hz), 8.20-8.24(2H, m),

8.51(1H, d, J = 2.5 Hz), 12.77(1H, brs).

789
—H
—CH₃
(DMSO-d₆) 2.98(3H, s), 4.01(2H, s), 6.65(1H, d, J = 9.1 Hz),

6.90-6.95(3H, m), 7.82(1H, d, J = 8.4 Hz), 7.94(1H, dd, J = 2.1

Hz, 8.4 Hz), 8.13(1H, dd, J = 2.7 Hz, 8.9 Hz), 8.22(1H, d, J = 2.1

Hz), 8.43(1H, d, J = 2.7 Hz), 10.54(1H, s).

790
—H
—C₂H₅
(DMSO-d₆) 1.11(3H, t, J = 7.1 Hz), 3.39(2H, q, J = 7.1 Hz),

4.01(2H, s), 6.58(2H, d, J = 9.1 Hz), 6.90-6.95(3H, m), 7.81(1H,

d, J = 8.4 Hz), 7.92(1H, dd, J = 2.0 Hz, 8.4 Hz), 8.11(1H, dd, J =

2.7 Hz, 8.9 Hz), 8.19(1H, d, J = 2.0 Hz), 8.41(1H, d, J = 2.7 Hz),

10.48(1H, s), 12.53(1H, brs).

791
—OCH₃
—CH₃
(DMSO-d₆) 3.01(3H, s), 3.67(3H, s), 4.12(2H, s), 6.20(1H, dd, J =

8.7 Hz, 2.8 Hz), 6.39(1H, d, J = 2.8 Hz), 6.85-6.94(2H, m),

7.83(1H, d, J = 8.4 Hz), 7.94(1H, dd, J = 8.4 Hz, 2.1 Hz),

8.08(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.21(1H, d, J = 2.0 Hz),

8.36(1H, d, J = 2.5 Hz), 10.47(1H, s), 12.58(1H, brs).

792
—OCH₃
—C₂H₅
(DMSO-d₆) 1.15(3H, t, J = 7.1 Hz), 3.43(2H, q, J = 7.1 Hz),

3.65(3H, s), 4.06(2H, s), 6.13(1H, dd, J = 8.7 Hz, 2.6 Hz),

6.30(1H, d, J = 2.6 Hz), 6.87-6.91(2H, m), 7.83(1H, d, J = 8.4

Hz), 7.94(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.08(1H, dd, J = 8.9 Hz,

2.6 Hz), 8.21(1H, d, J = 2.0 Hz), 8.36(1H, d, J = 2.6 Hz),

10.48(1H, s), 12.58(1H, brs).

793
—CH₃
—Ac
(DMSO-d₆) 1.84(3H, s), 2.11(3H, s), 4.23(2H, s), 7.05-7.10(2H,

m), 7.20-7.25 (1H, m), 7.32(1H, d, J = 2.2 Hz), 7.75-7.85(1H, m),

7.92(1H, dd, J = 2.2 Hz, 8.4 Hz), 8.10-8.20(2H, m), 8.43(1H, d, J =

2.6 Hz), 10.53(1H, s), 12.66(1H, brs).

794
—CH₃
—CH₃
(DMSO-d₆) 2.01(3H, s), 2.97(3H, s), 4.07(2H, s), 6.49(1H, dd, J =

8.8 Hz, 3.0 Hz), 6.57(1H, d, J = 3.0 Hz), 6.85(1H, d, J = 8.8

Hz), 6.90(1H, d, J = 8.9 Hz), 7.82(1H, d, J = 8.4 Hz), 7.93(1H,

dd, J = 8.4 Hz, 2.0 Hz), 8.11(1H, dd, J = 8.9 Hz, 2.7 Hz),

8.20(1H, d, J = 2.0 Hz), 8.39(1H, d, J = 2.7 Hz), 10.47(1H, s),

12.51(1H, brs).

795
—F
—Ac
(CDCl₃+ DMSO-d₆) 1.99(3H, s), 4.35(2H, s), 7.03(1H, d, J = 8.9

Hz), 7.21-7.31 (3H, m), 7.57(1H, d, J = 8.4 Hz), 7.90(1H, dd, J =

8.4 Hz, 2.1 Hz), 8.19(1H, d, J = 2.0 Hz), 8.32(1H, dd, J = 8.9 Hz,

2.6 Hz), 8.46(1H, d, J = 2.5 Hz), 10.12(1H, s).

796
—F
—CH₃
(CDCl₃+ DMSO-d₆) 3.04(3H, s), 3.98(2H, s), 6.40-6.49(2H, m),

6.90(1H, d, J = 8.9 Hz), 7.02(1H, t, J = 8.7 Hz), 7.52(1H, d, J =

8.4 Hz), 7.85(1H, dd, J = 8.4 Hz, 2.1 Hz), 8.14(1H, d, J = 2.0

Hz), 8.23(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.34(1H, d, J = 2.5 Hz),

9.77(1H, s).

797
—F
—C₂H₅
(CDCl₃) 1.26(3H, t, J = 7.1 Hz, 3.44(2H, q, J = 7.1 Hz),

4.03(2H, s), 6.39-6.52 (2H, m), 6.96(1H, d, J = 9.7 Hz), 7.06(1H,

t, J = 8.9 Hz), 7.55(1H, d, J = 8.4 Hz), 7.69(1H, dd, J = 8.6 Hz,

2.1 Hz), 7.96-7.97(2H, m), 8.15-8.18(2H, m).

TABLE 109

Reference

Example

No.
R₃₄₂
R₃₄₃

¹H NMR (solvent) δppm

798
—H
—Ac
(DMSO-d₆) 1.85(3H, s), 4.26(2H, s), 7.13(1H, d, J = 8.8 Hz),

7.18(2H, d, J = 8.7 Hz), 7.42(2H, d, J = 8.7 Hz), 7.94(2H, d,

J = 8.2 Hz), 8.16(2H, d, J = 8.2 Hz), 8.25(1H, dd, J = 2.5

Hz, 8.8 Hz), 8.54(1H, d, J = 2.5 Hz), 10.66(1H, s),

12.70(1H, brs).

799
—H
—CH₃
(DMSO-d₆) 2.99(3H, s), 4.09(2H, s), 6.67(2H, d, J = 9.0 Hz),

6.96(3H, d, J = 9.0 Hz), 7.93(2H, d, J = 8.2 Hz), 8.16(2H, d,

J = 8.2 Hz), 8.12-8.20(1H, m), 8.46(1H, d, J = 2.3 Hz),

10.59(1H, s), 12.58(1H, brs).

800
—H
—C₂H₅
(DMSO-d₆) 1.13(3H, t, J = 7.1 Hz), 3.38(2H, q, J = 7.1 Hz),

4.00(2H, s), 6.65(1H, d, J = 8.9 Hz), 6.73(1H, d, J = 8.9 Hz),

6.92-6.97(3H, m), 7.93(2H, d, J = 8.1 Hz), 8.15-8.18(3H,

m), 8.46(1H, s), 10.59(1H, s).

801
—OCH₃
—CH₃
(DMSO-d₆) 3.01(3H, s), 3.67(3H, s), 4.12(2H, s), 6.20(1H,

dd, J = 8.7 Hz, 2.6 Hz), 6.39(1H, d, J = 2.5 Hz), 6.83-

6.95(2H, m), 7.93(2H, d, J = 8.3 Hz), 8.09-8.17(3H, m),

8.38(1H, d, J = 2.6 Hz), 10.56(1H, s), 12.58(1H, brs).

802
—OCH₃
—C₂H₅
(DMSO-d₆) 1.15(3H, t, J = 7.1 Hz), 3.43(2H, q, J = 7.1 Hz),

3.66(3H, s), 4.06(2H, s), 6.14(1H, dd, J = 8.7 Hz, 2.6 Hz),

6.31(1H, d, J = 2.8 Hz), 6.88-6.92(2H, m), 7.93(2H, d, J =

8.4 Hz), 8.09-8.17(3H, m), 8.39(1H, d, J = 2.5 Hz),

10.55(1H, s), 12.58(1H, brs).

803
—CH₃
—Ac
(DMSO-d₆) 1.84(3H, s), 2.11(3H, s), 4.23(2H, s), 7.05-

7.10(2H, m), 7.23 (1H, dd, J = 2.4 Hz, 8.5 Hz), 7.33(1H,

d, J = 2.4 Hz), 7.86(1H, d, J = 8.3 Hz), 7.91(2H, d, J =

8.3 Hz), 8.14(2H, d, J = 8.3 Hz), 8.20(1H, dd, J = 2.7 Hz,

8.9 Hz), 8.45(1H, d, J = 2.7 Hz), 10.61(1H, s), 12.67

(1H, brs).

804
—CH₃
—CH₃
(DMSO-d₆) 2.01(3H, s), 2.97(3H, s), 4.06(2H, s), 6.49(1H,

dd, J = 8.8 Hz, 3.1 Hz), 6.57(1H, d, J = 2.9 Hz), 6.85(1H, d,

J = 8.8 Hz), 6.91(1H, d, J = 8.9 Hz), 7.91(2H, d, J = 8.3 Hz),

8.04-8.23(3H, m), 8.41(1H, d, J = 2.6 Hz), 10.56(1H, s),

12.11-12.98(1H, m).

805
—F
—Ac
(CDCl₃) 1.96(3H, s), 4.32(2H, s), 7.09-7.31(4H, m), 7.75(2H,

d, J = 8.4 Hz), 8.02(2H, d, J = 8.3 Hz), 8.20(1H, d, J = 2.6

Hz), 8.40(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.44(1H, s).

806
—F
—CH₃
(CDCl₃+ DMSO-d₆) 3.08(3H, s), 4.02(2H, s), 6.47-6.52(2H,

m), 6.92(1H, d, J = 8.7 Hz), 7.06(1H, t, J = 9.0 Hz),

7.73(2H, d, J = 8.4 Hz), 8.11(2H, d, J = 8.4 Hz), 8.26(1H,

dd, J = 8.7 Hz, 2.5 Hz), 8.39(1H, d, J = 2.5 Hz), 9.76(1H,

s).

807
—F
—C₂H₅
(CDCl₃+ DMSO-d₆) 1.23(3H, t, J = 7.1 Hz), 3.45(2H, q, J =

7.1 Hz), 3.97 (2H, s), 6.39-6.48(2H, m), 6.91(1H, d, J = 8.7

Hz), 7.04(1H, t, J = 9.1 Hz), 7.73(2H, d, J = 7.9 Hz),

8.12(2H, d, J = 7.9 Hz), 8.25(1H, d, J = 9.1 Hz), 8.42(1H, d,

J = 2.5 Hz), 9.92(1H, s).

808
—F
—(CH₂)₂CH₃
(CDCl₃+ DMSO-d₆) 0.96(3H, t, J = 7.2 Hz), 1.61-1.72(2H,

m), 3.33(2H, t, J = 7.6 Hz), 3.99(2H, s), 6.37-6.48(2H, m),

6.93(1H, d, J = 8.8 Hz), 7.04 (1H, t, J = 9.1 Hz), 7.73(2H, d,

J = 8.1 Hz), 8.09(2H, d, J = 8.1 Hz), 8.26 (1H, dd, J = 8.9

Hz, 2.6 Hz), 8.36(1H, d, J = 2.5 Hz), 9.45(1H, s).

TABLE 110

Reference

Example

No.
R₃₄₄
R₃₄₅
R₃₄₆

¹H NMR (solvent) δppm

809
—Cl
—Cl
—N(Ac)(CH₂)₂COOH
(DMSO-d₆) 1.71(3H, s), 2.39(2H, t, J =

7.5 Hz), 3.78(2H, t, J = 7.5 Hz), 7.08(1H,

d, J = 8.8 Hz), 7.14(2H, d, J = 8.6 Hz),

7.31(2H, d, J = 8.6 Hz), 7.80(1H, d, J =

8.4 Hz), 7.91 (1H, dd, J = 2.1 Hz, 8.4 Hz),

8.15-8.21(2H, m), 8.49(1H, d, J = 2.5 Hz),

10.55(1H, s), 12.20(1H, brs).

810
—CF₃
—H
—N(Ac)(CH₂)₂COOH
(DMSO-d₆) 1.71(3H, s), 2.40(2H, t, J =

7.3 Hz), 3.78(2H, t, J = 7.3 Hz), 7.09(1H,

d, J = 8.7 Hz), 7.14(2H, d, J = 8.1 Hz),

7.31(2H, d, J = 8.1 Hz), 7.90(2H, d, J =

8.1 Hz), 8.12 (2H, d, J = 8.1 Hz), 8.21(1H,

d, J = 8.7 Hz), 8.52(1H, s), 10.63(1H, s),

12.25(1H, brs).

811
—Cl
—Cl
—CH(CH₃)CH₂COOH
(CDCl₃− CD₃OD) 1.26(3H, d, J = 7.0 Hz),

2.42-2.61(2H, m), 3.17-3.28(1H, m),

6.84(1H, d, J = 8.9 Hz), 6.98(2H, d, J =

8.5 Hz), 7.20(2H, d, J = 8.5 Hz), 7.50(1H,

d, J = 8.4 Hz), 7.73(1H, dd, J = 8.5 Hz,

2.1 Hz), 8.01(1H, d, J = 2.1 Hz), 8.14(1H,

d, J = 2.7 Hz), 8.26(1H, dd, J = 8.9 Hz,

2.7 Hz).

812
—CF₃
—H
—CH(CH₃)CH₂COOH
(CDCl₃− CD₃OD) 1.28(3H, d, J = 7.0 Hz),

2.44-2.61(2H, m), 3.18-3.29(1H, m),

6.88(1H, d, J = 8.9 Hz), 7.00(2H, d, J =

8.5 Hz), 7.20(2H, d, J = 8.5 Hz), 7.70(2H,

d, J = 8.2 Hz), 7.99(2H, d, J = 8.2 Hz),

8.17(1H, d, J = 2.6 Hz), 8.28(1H, dd, J =

8.9 Hz, 2.6 Hz).

813
—CF₃
—H
—CH═CHCOOH
(DMSO-d₆) 6.49(1H, d, J = 16.0 Hz),

(trans)
7.15(3H, d, J = 8.8 Hz), 7.61(1H, d, J =

16.0 Hz), 7.74(2H, d, J = 8.8 Hz),

7.94(2H, d, J = 8.3 Hz), 8.17(2H, d, J =

8.3 Hz), 8.26(1H, dd, J = 8.8 Hz, 2.7 Hz),

8.55(1H, d, J = 2.7 Hz), 10.67(1H, s),

12.36(1H, s).

814
—CF₃
—H

embedded image

(CDCl₃) 1.34(6H, s), 2.79(3H, s), 6.98(1H, d, J = 8.9 Hz), 7.10(2H, d, J = 8.9 Hz), 7.21(2H, d, J = 9.1 Hz), 7.76(2H, d, J = 8.2 Hz), 8.01(2H, d, J = 8.1 Hz), 8.10(1H, brs), 8.24(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.31(1H, d, J = 2.3 Hz).

TABLE 111

Reference

Example

No.
R₃₄₇
R₃₄₈
R₃₄₉
R₃₅₀
M

¹H NMR (solvent) δppm

815
—Cl
—Cl
—H
—F
0
(DMSO-d₆) 4.29(2H, d, J = 5.6 Hz), 6.46(1H, t, J =

5.9 Hz), 6.94(1H, d, J = 8.7 Hz), 7.15(1H, dd, J =

8.7 Hz, 3.0 Hz), 7.20 (1H, d, J = 8.3 Hz),

7.36(1H, dd, J = 8.3 Hz, 1.8 Hz), 7.47(1H, d, J =

2.8 Hz), 7.59(1H, d, J = 8.3 Hz), 7.63(1H, d, J =

2.0 Hz), 7.72-7.77(2H, m).

816
—CF₃
—H
—H
—F
0
(DMSO-d₆) 4.37(2H, d, J = 5.3 Hz), 6.47(1H,

brs), 6.89(1H, d, J = 8.7 Hz), 7.06-7.12(1H, m),

7.13(1H, dd, J = 8.7 Hz, 3.0 Hz), 7.45((1H, d, J =

3.0 Hz), 7.58(2H, d, J = 8.1 Hz), 7.65-7.69(2H,

m), 7.70(2H, d, J = 8.1 Hz).

817
—CF₃
—H
—CH₃
—H
0
(DMSO-d₆) 3.03(3H, s), 4.66(2H, s), 6.82(2H, d,

J = 8.7 Hz), 6.87(1H, d, J = 8.9 Hz), 7.29(1H, dd,

J = 8.9 Hz, 3.3 Hz), 7.45 (21H, d, J = 8.1 Hz),

7.68-7.72(3H, m), 7.82(2H, d, J = 8.7 Hz).

818
—CF₃
—H
—C₂H₅
—H
0
(DMSO-d₆) 1.13(3H, t, J = 7.1 Hz), 3.49(2H, q, J =

7.1 Hz), 4.61(2H, s), 6.81(2H, d, J = 8.6 Hz),

6.84(1H, d, J = 8.9 Hz), 7.22(1H, dd, J = 8.9 Hz,

3.3 Hz), 7.47(2H, d, J = 8.1 Hz), 7.62(1H, d, J =

3.3 Hz), 7.70(2H, d, J = 8.3 Hz), 7.80(2H, d, J =

8.7 Hz).

819
—Cl
—Cl
—CH₃
—OCH₃
2
(CDCl₃) 2.66(2H, t, J = 7.7 Hz), 2.93(2H, t, J =

7.7 Hz), 2.95 (3H, s), 3.75(3H, s), 4.35(2H, s),

6.68-6.88(3H, m), 6.90-7.00 (1H, m), 7.00-

7.17(2H, m), 7.31(1H, d, J = 2.0 Hz), 7.37(1H, d,

J = 8.2 Hz), 7.65(1H, d, J = 3.0 Hz), 8.21(1H,

brs).

820
—CF₃
—H
—CH₃
—OCH₃
2
(DMSO-d₆) 2.41-2.62(2H, m), 2.69-2.85(2H, m),

2.96(3H, s), 3.64(3H, s), 4.58(2H, s), 6.70-

6.79(2H, m), 6.88(1H, d, J = 8.0 Hz), 6.95(1H, d,

J = 1.8 Hz), 7.25(1H, dd, J = 9.2 Hz, 3.2 Hz),

7.42(2H, d, J = 8.0 Hz), 7.52(1H, d, J = 3.2 Hz),

7.67(2H, d, J = 8.0 Hz), 11.64-12.51(1H, m).

821
—Cl
—Cl
—CH₃
—OC₂H₅
2
(DMSO-d₆) 1.03(3H, t, J = 7.0 Hz), 2.523(2H, t, J =

7.6 Hz), 2.78(2H, t, J = 7.6 Hz), 3.89(2H, q, J =

7.0 Hz), 4.49(2H, s), 6.70-6.80(2H, m),

6.88(1H, d, J = 8.0 Hz), 6.92(1H, d, J = 1.9 Hz),

7.19(1H, dd, J = 8.3 Hz, 2.0 Hz), 7.26(1H, dd, J =

9.0 Hz, 3.2 Hz), 7.45(1H, d, J = 2.0 Hz),

7.52(1H, d, J = 3.2 Hz), 7.56(1H, d, J = 8.3 Hz),

11.81-12.30(1H, m).

822
—Cl
—Cl
—CH₃
—F
2
(DMSO-d₆) 2.55(2J, t, J = 7.6 Hz), 2.80(2H, t, J =

7.6 Hz), 2.96(3H, s), 4.50(2H, s),6.92(1H, d, J =

8.9 Hz), 7.00-7.22 (4H, m), 7.22-7.38(1H, m),

7.38-7.40(1H, m), 7.40-7.55(2H, m), 12.10(1H,

brs).

823
—Cl
—Cl
—C₂H₅
—F
2
(CDCl₃) 1.17(3H, t, J = 7.0 Hz), 2.66(2H, t, J =

7.7 Hz), 2.93 (2H, t, J = 7.7 Hz), 3.40(2H, q, J =

7.0 Hz), 4.36(2H, s), 6.72-6.86(1H, m), 6.90-

7.15(5H, m), 727-7.35(1H, m), 7.36 (1H, d, J =

8.2 Hz), 7.59(1H, d, J = 3.2 Hz).

TABLE 112

Reference

Example

No.
R₃₅₁
R₃₅₂
R₃₅₃
R₃₅₄

¹H NMR (solvent) δppm

824
—CF₃
—H
—CH₃
—H
(DMSO-d₆) 2.50-2.54(2H, m), 2.79(2H, t, J = 7.6 Hz),

3.02(3H, s), 4.64(2H, s), 6.86(1H, d, J = 8.9 Hz),

6.89(2H, d, J = 8.4 Hz), 7.19 (2H, d, J = 8.7 Hz),

7.29(1H, dd, J = 8.9 Hz, 3.3 Hz), 7.44(2H, d, J = 7.9

Hz), 7.69(2H, d, J = 7.9 Hz), 7.64(1H, d, J = 3.1 Hz).

825
—CF₃
—H
—CH₃
—OC₂H₅
(DMSO-d₆) 1.03(3H, t, J = 7.0 Hz), 2.47-2.59(2H, m),

2.71-2.83 (2H, m), 2.97(3H, s), 3.89(2H, q, J = 7.0

Hz), 4.59(2H, s), 6.69-6.79 (2H, m), 6.88(1H, d, J =

8.0 Hz), 6.91(1H, d, J = 1.9 Hz), 7.26(1H, dd, J = 9.0

Hz, 3.1 Hz), 7.41(2H, d, J = 8.0 Hz), 7.52(1H, d, J =

3.1 Hz), 7.66(2H, d, J = 8.0 Hz), 11.85-12.31(1H, m).

826
—CF₃
—H
—CH₃
—F
(CDCl₃) 2.67(2H, t, J = 7.7 Hz), 2.94(2H, t, J = 7.7

Hz), 3.00(3H, s), 4.49(2H, s), 6.86(1H, d, J = 8.9 Hz),

6.90-7.16(4H, m), 7.33(2H, d, J = 8.1 Hz), 7.57(2H,

d, J = 8.1 Hz), 7.64(1H, d, J = 3.1 Hz).

827
—CF₃
—H
—C₂H₅
—H
(DMSO-d₆) 1.11(3H, t, J = 7.0 Hz), 2.42-2.57(2H, m),

2.71-2.82 (2H, m), 3.47(2H, q, J = 7.0 Hz), 4.58(2H,

s), 6.82(1H, d, J = 8.9 Hz), 6.84-6.91(2H, m), 7.13-

7.21(2H, m), 7.20(1H, dd, J = 8.9 Hz, 3.1 Hz),

7.45(2H, d, J = 8.1 Hz), 7.57(1H, d, J = 3.1 Hz),

7.68(2H, d, J = 8.1 Hz), 12.06(1H, brs).

828
—Cl
—Cl
C₂H₅
OCH₃
(CDCl₃) 1.16(3H, t, J = 7.1 Hz), 2.55-2.78(2H, m),

2.94(2H, t, J = 7.7 Hz), 3.39(2H, q, J = 7.1 Hz),

3.77(3H, s), 4.35(2H, s), 6.70-6.88(3H, m), 6.92-

7.13(3H, m), 7.32(1H, d, J = 2.0 Hz), 7.36(1H, d, J =

8.2 Hz), 7.59(1H, d, J = 3.1 Hz).

829
—CF₃
—H
—C₂H₅
—OCH₃
(DMSO-d₆) 1.09(3H, t, J = 7.0 Hz), 2.48-2.61(2H, m),

2.72-2.86 92H, m), 3.40(2H, q, J = 7.0 Hz), 3.64(3H,

s), 4.54(2H, s), 6.73(1H, d, J = 9.0 Hz), 6.74(1H, dd,

J = 8.0 Hz), 1.9 Hz), 6.87(1H, d, J = 8.0 Hz), 6.95(1H,

d, J = 1.9 Hz), 7.18(2H, dd, J = 9.0 Hz, 3.2 Hz), 7.39-

7.49(3H, m), 7.62-7.71(2H, m), 11.90-12.31(1H, m).

830
—Cl
—Cl
—C₂H₅
—OC₂H₅
(DMSO-d₆) 0.95-1.11(6H, m), 2.41-2.57(2H, m),

2.77(2H, t, J = 7.7 Hz), 3.29-3.47(2H, m), 3.88(2H, q,

J = 7.0 Hz), 4.44(2H, s),6.73(1H, dd, J = 8.0 Hz, 1.9

Hz), 6.74(1H, d, J = 9.0 Hz), 6.88(1H, d, J = 8.0 Hz),

6.91(1H, d, J = 1.9 Hz), 7.15-7.24(2H, m), 7.41-7.48

(2H, m), 7.55(1H, d, J = 8/.2 Hz), 11.60-12.50(1H, m).

831
—CF₃
—H
—C₂H₅
—OC₂H₅
(DMSO-d₆) 1.02(3H, t, J = 7.0 Hz), 1.08(3H, t, J =

7.0 Hz), 2.46-2.59(2H, m), 2.71-2.83(2H, m),

3.43(2H, q, J = 7.0 Hz), 3.89 (2H, q, J = 7.0 Hz),

6.69-6.78(2H, m), 6.87(1H, d, J = 8.0 Hz), 6.91 (1H,

d, J = 1.8 Hz), 7.19(1H, dd, J = 9.0 Hz, 3.2 Hz), 7.39-

7.49(3H, m), 7.61-7.69(2H, m), 11.92-12.22(1H, m).

832
—CF₃
—H
—C₂H₅
—F
(CDCl₃) 1.19(3H, t, J = 7.1 Hz), 2.67(2H, t, J = 7.7

Hz), 2.93(2H, t, J = 7.7 Hz), 3.43(2H, q, J = 7.1 Hz),, q, J H

4.48(2H, s), 6.83(1H, d, J = 9.0 Hz), 6.90-7.20(4H,

m), 7.34(2H, d, J = 8.2 Hz), 7.50-7.65(3H, m)

TABLE 113

Reference

Example

No.
R₃₅₅
R₃₅₆
R₃₅₇
R₃₅₈
R₃₅₉
Form

¹H NMR (solvent) δppm

833
—CF₃
—H
—CH₃
—H
—COOH
free
(DMSO-d₆) 1.45(3H, t, J =

6.8 Hz), 4.61(1H, dt, J =

6.8 Hz, 6.8 Hz), 6.53 (1H,

d, J = 6.8 Hz), 6.85(1H, d,

J = 8.6 Hz), 6.97(2H, d, J =

8.7 Hz), 7.04(1H, dd, J =

8.7 Hz, 3.0 Hz), 7.51(1H, d,

J = 3.0 Hz), 7.62(2H, d, J =

8.3 Hz), 7.70 (2H, d, J =

8.3 Hz), 7.89(2H, d, J = 8.9

Hz), 12.79(1H, brs).

834
—CF₃
—H
—CH₃
—CH₃
—COOH
free
(DMSO-d₆) 1.54(3H, d, J =

6.8 Hz), 2.73(3H, s),

5.23(1H, q, J = 6.8 Hz),

7.00(1H, d, J = 8.9 Hz),

7.05(2H, d, J = 8.7 Hz),

7.46(1H, dd, J = 9.1 Hz,

3.3 Hz), 7.54(2H, d, J = 8.1

Hz), 7.72(2H, d, J = 8.4

Hz), 7.84(1H, d, J = 3.3

Hz), 7.93(2H, d, J = 8.6

Hz)

835
—CF₃
—H
—H
—CH₃

embedded image

dihydro- chloride
(DMSO-d₆) 1.81(3H, s), 3.05(3H, s), 4.22(2H, s), 4.67(2H, s), 6.95(1H, d, J = 8.7 Hz), 7.04(2H, d, J = 8.6 Hz), 7.28-7.40 (1H, m), 7.35(2H, d, J = 8.6 Hz), 7.45(2H, d, J = 8.1 Hz), 7.62-7.80 (1H, m), 7.70(2H, d, J = 8.1 Hz).

836
—Cl
—Cl
—H
—CH₃

embedded image

dihydro- chloride
(CDCl₃) 1.81(3H, s), 3.02(3H, s), 4.23 (2H, s), 4.57(2H, s), 6.95(1H, d, J = 8.8 Hz), 7.04(2H, d, J = 8.7 Hz), 7.22(1H, dd, J = 8.2 Hz, 2.0 Hz), 7.32-7.40(1H, m), 7.35(2H, d, J = 8.7 Hz), 7.51(1H, d, J = 2.0 Hz), 7.59(1H, d, J = 8.2 Hz), 7.71(1H, d, J = 3.0 Hz).

837
—CF₃
—H
—H
—(CH₂)₂OCH₃
—(CH₂)₂COOH
free
(DMSO-d₆) 2.43-2.57(2H,

m), 2.71-2.82(2H, m),

3.25(3H, s), 3.48-3.58(2H,

m), 3.59-3.68(2H, m), 4.66

(2H, s), 6.80(1H, d, J = 8.9

Hz), 6.83-6.90(2H, m),

7.11-7.25(3H, m), 7.44(2H,

d, J = 8.0 Hz), 7.56(1H, d,

J = 3.1 Hz), 7.67(2H, d, J =

8.0 Hz), 12.09 (1H, brs).

TABLE 114

Reference

Example

No.
R₃₆₀
R₃₆₁
R₃₆₂
Xa₂₆
Xa₂₇

¹H NMR (solvent) δppm or MS

838
—Cl
—Cl
—OCH₃
—CH═CH—
—CH₂—

¹H NMR (DMSO-d₆) 2.57-

(trans)

2.63(2H, m), 2.83-2.88(2H, m),

3.68(3H, s), 6.84(1H, dd, J =

8.1 Hz, 1.7 Hz), 6.98-7.05(3H,

m), 7.20 (1H, d, J = 16.5 Hz),

7.36(1H, d, J = 16.5 Hz), 7.54-

7.65(2H, m), 7.87(1H, d, J = 1.8

Hz), 8.07-8.11(1H, m), 8.22(1H,

d, J = 2.1 Hz), 12.20(1H, brs).

839
—CF₃
—H
—OCH₃
—CH═CH—
—CH₂—

¹H NMR (DMSO-d₆) 2.58-

(trans)

2.63(2H, m), 2.83-2.89(2H, m),

3.68(3H, s), 6.82-6.86 (1H, m),

6.99-7.06(3H, m), 7.31(1H, d, J =

16.5 Hz), 7.41(1H, d, J = 16.5

Hz), 7.71-7.81(4H, m), 8.15(1H,

dd, J = 8.7 Hz, 2.5 Hz),

8.27(1H, d, J = 2.1 Hz),

12.18(1H, brs).

840
—CF₃
—H
—OCH₃
—CO—
—CH₂—

¹H NMR (DMSO-d₆) 2.57-

2.63(2H, m), 2.83-2.89(2H, m),

3.70(3H, s), 6.86(1H, dd, J =

8.1 Hz, 2.0 Hz), 7.06-7.15(3H,

m), 7.90-7.97(4H, m), 8.18-

8.22(1H, m), 8.50 (1H, dd, J =

2.5 Hz, 0.7 Hz), 12.19(1H, brs).

841
—CF₃
—H
—CH₃
—CO—
—N(C₂H₅)—

¹H NMR (CDCl₃) 1.23(3H, t, J =

7.1 Hz), 2.12(3H, s), 3.467(2H,

q, J = 7.1 Hz), 4.04(2H, s),

5.77 (1H, brs), 6.55-6.59(2H, m),

6.97(2H, d, J = 8.7 Hz), 7.73-

7.89(4H, m), 8.17-8.21(1H, m),

8.58(1H, d, J = 2.3 Hz).

842
—Cl
—Cl
—H
—NHCONH—
none
MS 431(M⁺)

TABLE 115

Reference

Example

No.
R₃₆₃
R₃₆₄
Form

¹H NMR (solvent) δppm

843
—H

embedded image

hydro- chloride
(DMSO-d₆) 2.94(3H, s), 3.10-3.59(7H, m), 4.02- 4.39(5H, m), 6.07(2H, s), 6.68(2H, d, J = 9.1 Hz), 6.74-7.06(5H, m), 7.25(1H, brs), 8.23(1H, dd, J = 8.7 Hz, 2.3 Hz), 8.65(1H, d, J = 2.3 Hz), 11.23(1H, brs).

844
—H
—NO₂
free
(CDCl₃) 7.13(1H, d, J = 8.5

Hz), 7.35(2H, d, J = 9.1 Hz),

8.33(2H, d, J = 9.1 Hz),

8.41(1H, dd, J = 8.5 Hz, 2.5

Hz), 8.89(1H, d, J = 2.5 Hz).

845
—H

embedded image

free
(DMSO-d₆) 2.47(H, brs), 3.31-3.53(6H, m), 7.16(1H, d, J = 8.6 Hz), 7.23-7.34(7H, m), 7.45-7.48(2H, m), 8.31(1H, dd, J = 8.6 Hz, 2.4 Hz), 8.68(1H, d, J = 2.4 Hz), 13.20(1H, brs).

846
—H

embedded image

free
(DMSO-d₆) 3.36-3.55(8H, m), 3.58(2H, s), 6.00 (2H, s), 6.78-6.92(3H, m), 7.17(1H, d, J = 8.6 Hz), 7.26(2H, d, J = 8.6 Hz), 7.48(2H, d, J = 8.4 Hz), 8.31(1H, dd, J = 2.3 Hz, 8.6 Hz), 8.68(1H, d, J = 2.2 Hz).

847
—H

embedded image

free
(DMSO-d₆) 2.50(4H, brs), 2.63-2.68(2H, m), 2.81- 2.86(2H, m), 3.48-3.61(6H, m), 6.01(2H, s), 6.81- 6.90(2H, m), 6.96(1H, s), 7.06-7.10(3H, m), 7.30(2H, d, J = 8.6 Hz), 8.25-8.38(1H, m), 8.66(1H, d, J = 2.7 Hz), 12.58(1H, brs).

848
—CH₃
—NO₂
free
(DMSO-d₆) 2.22(3H, s),

7.28(1H, dd, J = 8.6 Hz, 0.7

Hz), 7.40(1H, d, J = 8.9 Hz),

8.14(1H, dd, J = 8.9 Hz, 2.8

Hz), 8.28(1H, d, J = 2.6 Hz),

8.36(1H, dd, J = 8.6 Hz, 2.3

Hz), 8.65(1H, dd, J = 2.3

Hz, 0.7 Hz).

TABLE 116

Reference

Example

No.
R₃₆₅
R₃₆₆
R₃₆₇

¹H NMR (solvent) δppm

849
—NO₂
—CH₃
—H
(DMSO-d₆) 2.06(3H, s), 7.14(1H, d, J =

8.6 Hz), 7.26(1H, d, J = 9.1 Hz), 7.64(1H,

dd, J = 8.7 Hz, 2.5 Hz), 7.74(1H, d, J =

2.5 Hz), 8.62(1H, dd, J = 9.1 Hz, 3.0 Hz),

9.02(1H, d, J = 2.8 Hz), 10.75(1H, brs).

850
—NO₂
—CH₃
—CH₃
(DMSO-d₆) 2.09(3H, s), 3.26(3H, s), 7.20-

7.36(4H, m), 8.64(1H, dd, J = 9.1 Hz, 2.8

Hz), 9.03(1H, d, J = 2.6 Hz).

851
4-CF₃PhNHCO—
—CH₃
—H
(DMSO-d₆) 2.08(3H, s), 7.11(1H, d, J =

8.7 Hz), 7.16(1H, d, J = 8.7 Hz), 7.64(1H,

dd, J = 8.7 Hz, 2.5 Hz), 7.72-7.75(3H, m),

7.98(2H, d, J = 8.6 Hz), 8.37(1H, dd, J =

8.7 Hz, 2.5 Hz), 8.69(1H, d, J = 2.5 Hz),

10.62(1H, brs), 10.74(1H, brs).

852
4-CF₃PhOCH₂—
—H
—H
(DMSO-d₆) 5.17(2H, s), 7.06(1H, d, J =

8.4 Hz), 7.13(2H, d, J = 8.9 Hz), 7.21(2H,

d, J = 8.6 Hz), 7.67(2H, d, J = 8.4 Hz),

7.79(2H, d, J = 9.1 Hz), 7.95(1H, dd, J =

8.4 Hz, 2.5 Hz), 8.25(1H, d, J = 2.0 Hz),

10.78(1H, brs).

853
4-CF₃PhOCH₂—
—CH₃
—H
(CDCl₃) 2.18(3H, s), 5.05(2H, s), 7.01-

7.08(5H, m), 7.51-7.58(4H, m), 7.83-

7.87(1H, m), 8.20(1H, d, J = 2.1 Hz),

9.02(1H, brs).

854
4-CF₃PhOCH₂—
—CH₃
—CH₃
(DMSO-d₆) 2.09(3H, s), 3.25(3H, s),

5.17(2H, s), 7.10(1H, d, J = 8.4 Hz),

7.11(1H, d, J = 8.4 Hz), 7.17-7.23(3H, m),

7.32(1H, d, J = 2.3 Hz), 7.67(2H, d, J =

8.7 Hz), 7.98(1H, dd, J = 8.4 Hz, 2.3 Hz),

8.24(1H, d, J = 2.3 Hz).

TABLE 117

Reference

Example

No.
R₃₆₈
R₃₆₉
R₃₇₀

¹H NMR (solvent) δppm

855
3,4-Cl₂PhSO₂NH—
—F
—CH₃
(DMSO-d₆) 2.96(3H, s), 4.11(2H, s),

6.43(1H, dd, J = 8.9 Hz, 2.1 Hz),

6.58(1H, dd, J = 14.4 Hz, 3.0 Hz), 6.97-

7.02(2H, m), 7.53(1H, dd, J = 8.9 Hz, 2.8

Hz), 7.63(1H, dd, J = 8.4 Hz, 2.1 Hz),

7.77(1H, d, J = 2.5 Hz), 7.86(1H, d, J =

8.6 Hz), 7.88(1H, d, J = 2.1 Hz),

10.40(1H, s), 12.61(1H, brs).

856
3,4-Cl₂PhNHCO—
—OCH₃
—C₂H₅
(CDCl₃) 1.26(3H, t, J = 7.1 Hz), 3.45(2H,

q, J = 7.1 Hz), 3.69(3H, s), 4.08(2H, s),

6.24(1H, dd, J = 8.7 Hz, 2.8 Hz),

6.31(1H, d, J = 2.6 Hz), 6.95(1H, d, J =

8.7 Hz), 7.00(1H, d, J = 8.7 Hz), 7.29-

7.50(1H, m), 7.55(1H, dd, J = 8.9 Hz, 2.5

Hz), 7.88(1H, d, J = 2.5 Hz), 8.24(1H, dd,

J = 8.7 Hz, 2.5 Hz), 8.56(1H, brs),

8.73(1H, d, J = 2.0 Hz).

Reference Example 857
Production of 3-{4-[5-(3,4-dichlorobenzylmethylamino)pyridin-2-yloxy]phenyl}propionic acid

To a solution of ethyl 3-{4-[5-(3,4-dichlorobenzylamino)pyridin-2-yloxy]phenyl}propionate (1.63 g, 3.7 mmol) in ethanol (30 mL) were added 37% aqueous formaldehyde (2.0 mL, 22 mmol) and acetic acid (0.21 mL, 3.7 mmol), and the resulting solution was stirred at room temperature for 1 hour. To this solution was then added sodium cyanoborohydride (0.46 g, 7.3 mmol) at 0° C., and the resulting solution was stirred at the same temperature for 1 hour. To this solution was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 1.55 g of ethyl 3-{4-[5-(3,4-dichlorobenzylmethylamino)pyridin-2-yloxy]phenyl}propionate. This product was dissolved in ethanol (40 mL), and to the resulting solution was added 10% aqueous sodium hydroxide (2.7 mL, 6.7 mmol) and stirred at room temperature for 2 hours. The resulting solution was then acidified by adding 10% hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 1.44 g of the title compound.

Appearance: Colorless oil

¹H NMR (DMSO-d₆) δ 2.38-2.60 (2H, m), 2.78 (2H, t, J=7.6 Hz), 4.52 (2H, s), 6.81-6.92 (3H, m), 7.12-7.23 (3H, m), 7.28 (1H, dd, J=8.9 Hz, 3.3 Hz), 7.48 (1H, d, J=1.9 Hz), 7.57 (1H, d, J=8.2 Hz), 7.63 (1H, d, J=3.3 Hz), 11.70-12.40 (1H, m).

The following compound was produced in the same manner as in Reference Example 857.

Reference Example 858
3-(4-{5-[(3,4-Dichlorobenzyl)ethylamino]pyridin-2-yloxy}phenyl) propionic acid

¹H NMR (DMSO-d₆) δ 1.09 (3H, t, J=6.9 Hz), 2.37-2.59 (2H, m), 2.64-2.83 (2H, m), 3.45 (2H, q, J=6.9 Hz), 4.48 (2H, s), 6.82 (1H, d, J=8.9 Hz), 6.85-6.92 (2H, m), 7.12-7.25 (4H, m), 7.48 (1H, d, J=1.8 Hz), 7.54-7.61 (2H, m), 11.77-12.38 (1H, m).

Reference Example 859
Production of N-[2-(4-formylphenoxy)-5-pyridyl]-3,4-dichlorobenzamide

To a solution of 4-[(5-amino-2-pyridyl)oxy]benzaldehyde ethylene acetal (5.27 g, 20.4 mmol) and triethylamine (3.41 mL, 24.5 mmol) in THF (80 mL) was added dropwise a solution of 3,4-dichlorobenzoyl chloride (4.49 g, 21.4 mmol) in THF (30 mL) under ice cooling. The resulting solution was stirred for 2 hours at the same temperature. The reaction solution was concentrated under reduced pressure, to the residue, 80% acetic acid (55 mL) was added, and the mixture was heated at 80° C. with stirring for 1 hour. The reaction solution was concentrated under reduced pressure and to the residue was added water, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The obtained solid was recrystallized from isopropanol, to thereby yield 5.63 g of the title compound.

Appearance: Pale yellow powder

¹H NMR (CDCl₃) δ 7.05 (1H, d, J=8.7 Hz), 7.24 (2H, d, J=8.7 Hz), 7.57 (1H, d, J=8.4 Hz), 7.70 (1H, dd, J=8.4 Hz, 2.1 Hz), 7.82-7.93 (3H, m), 7.97 (1H, d, J=2.1 Hz), 8.25 (1H, dd, J=8.7 Hz, 2.7 Hz), 8.29 (1H, d, J=2.7 Hz), 9.96 (1H, s).

Reference Example 860
Production of ethyl {4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]benzylamino}acetate

A solution of N-[2-(4-formylphenoxy)-5-pyridyl]-3,4-dichlorobenzamide (1.00 g, 2.58 mmol), glycine ethyl ester hydrochloride (0.400 g, 2.84 mmol) and sodium acetate (0.230 g, 2.84 mmol) in methanol (20 mL) was stirred for 30 minutes at 60° C. The reaction solution was cooled with ice, and then sodium cyanoborohydride (0.180 g, 2.84 mmol) was added. The resulting solution was stirred at the same temperature for 1 hour. To the reaction solution was added 5 M hydrochloric acid (2 mL) and concentrated under reduced pressure. To the residue was added a saturated sodium bicarbonate solution, and extracted with dichloromethane. The dichloromethane layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:2), to thereby yield 0.752 g of the title compound.

Appearance: Yellow oil

¹H NMR (CDCl₃) δ 1.27 (3H, t, J=7.1 Hz), 3.43 (2H, s), 3.81 (2H, s), 4.20 (2H, q, J=7.1 Hz), 6.95 (1H, d, J=8.8 Hz), 7.09 (2H, d, J=8.5 Hz), 7.36 (2H, d, J=8.5 Hz), 7.57 (1H, d, J=8.3 Hz), 7.71 (1H, dd, J=2.1 Hz, 8.3 Hz), 7.84 (1H, s), 7.98 (1H, d, J=2.1 Hz), 8.18 (1H, dd, J=2.7 Hz, 8.8 Hz), 8.24 (1H, d, J=2.7 Hz).

Reference Example 861
Production of (acetyl{4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]benzyl}amino)acetic acid

To a solution of ethyl {4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]benzylamino}acetate (0.811 g, 1.59 mmol) in dichloromethane (5 mL) were added triethylamine (0.332 mL, 2.39 mmol) and acetyl chloride (0.136 mL, 1.91 mmol) at room temperature. The resulting solution was stirred for 1 hour at the same temperature. To the reaction solution was added water, and extracted with dichloromethane. The dichloromethane layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated, to thereby yield 0.785 g of residue. This residue was dissolved in ethanol (5 mL). To the resulting solution was added 5 M aqueous sodium hydroxide (0.350 mL, 1.75 mmol) at room temperature and stirred at the same temperature for 14 hours. To the resulting reaction solution were added 5 N hydrochloric acid (0.400 mL) and water, and extracted with dichloromethane. The dichloromethane layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated, to thereby yield 0.776 g of the title compound.

Appearance: White amorphous powder

¹H NMR (DMSO-d₆at 375 K) δ 2.10 (3H, s), 4.02 (2H, s), 4.60 (2H, s), 7.03 (1H, d, J=8.8 Hz), 7.11 (2H, d, J=8.2 Hz), 7.32 (2H, d, J=8.2 Hz), 7.78 (1H, d, J=8.4 Hz), 7.97 (1H, dd, J=2.1 Hz, 8.4 Hz), 8.10-8.30 (2H, m), 8.53 (1H, d, J=2.6 Hz), 10.23 (1H, s).

Reference Example 862
Production of 1-(4-piperonylpiperazin-1-yl)-2-{methyl-[3-methyl-4-(5-nitropyridin-2-yloxy)phenyl]amino}-ethanone

To a solution of {methyl[3-methyl-4-(5-nitropyridin-2-yloxy)phenyl]amino}acetic acid (0.93 g, 2.9 mmol) in DMF (40 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.67 g, 3.5 mmol), 1-hydroxybenzotriazole monohydrate (0.54 g, 3.5 mmol), and 1-piperonylpiperazine (0.68 g, 3.08 mmol). The reaction mixture was stirred for 15 hours at room temperature under a nitrogen atmosphere. To the resulting solution was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→dichloromethane:methanol=100:1), to thereby yield 1.2 g of the title compound.

Appearance: Yellow powder

Melting point: 142-143° C.

The following compounds were produced in the same manner as in Reference Example 862.

TABLE 118

Reference

Example

No.
R₃₇₁
R₃₇₂
Xa₂₈
Xa₂₉

¹H NMR (CDCl₃) δppm

863
—CH₃
—CH₃
—CH₂—
—CO—
2.09(3H, s), 3.04(3H, s), 3.22-

3.39(2H, m), 3.60-3.90(2H, m),

4.11(2H, s), 4.19-4.40(2H, m),

4.53(2H, s), 5.95(2H, s), 6.51-

6.62(2H, m), 6.68-6.80(3H, m),

6.92(1H, d, J = 8.6 Hz), 6.94(1H, d,

J = 9.0 Hz), 8.42(1H, dd, J = 9.0 Hz,

2.6 Hz), 9.04(1H, d, J = 2.6 Hz).

864
—OCH₃
—C₂H₅
—CH₂—
—CO—
1.21(3H, t, J = 6.7 Hz), 3.20-

3.33(2H, m), 3.46(2H, q, J = 6.7 Hz),

3.71(3H, s), 3.65-3.85(2H, m), 4.07

(2H, s), 4.29(2H, s), 4.52(2H, s),

5.96(2H, s), 6.23(1H, dd, J = 8.7 Hz,

2.6 Hz), 6.39(1H, d, J = 2.6 Hz),

6.65-6.85(3H, m), 6.97(2H, d, J = 8.7

Hz), 8.41(1H, dd, J = 9.0 Hz, 2.8

Hz), 9.02(1H, d, J = 2.8 Hz).

865
—H
—CH₃
—CH₂—
—CH(CH₃)—
1.12-1.16(3H, m), 2.08-2.16(1H, m),

2.46-2.53(1H, m), 2.71-2.73(1H, m),

2.85-3.48(6H, m), 3.54-3.59(1H, m),

3.84-4.19(4H, m), 5.94(2H, s), 6.68-

6.74(4H, m), 6.85(1H, brs),

6.94(1H, d, J = 9.1 Hz), 7.01(2H, d,

J = 8.9 Hz), 8.41(1H, dd, J = 9.1 Hz,

2.8 Hz), 9.05(1H, d, J = 2.8 Hz).

866
—H
—C₂H₅
—CH₂—
—CH(CH₃)—
1.13-1.28(6H, m), 2.08-2.16(1H, m),

2.47-2.50(1H, m), 2.71-2.75(1H, m),

2.86-3.35(3H, m), 3.41-3.49(2H, m),

3.58-3.62(1H, m), 3.85-4.16(4H, m),

5.94(2H, s), 6.67(2H, d, J = 9.1 Hz),

6.74(2H, brs), 6.85(1H, brs),

6.94(1H, d, J = 9.1 Hz), 6.99(2H, d,

J = 9.1 Hz), 8.41(1H, dd, J = 9.1 Hz,

3.0 Hz), 9.05(1H, d, J = 2.5 Hz).

867
—H
—CH₃
—CH(CH₃)—
—CH₂—
1.29-1.40(8H, m), 1.96-2.06(1H, m),

2.17(1H, brs), 2.65-2.70(1H, m),

2.81-2.86(1H, m), 2.96-3.06(4H, m),

3.32-3.49(3H, m), 3.97-4.71(3H, m),

5.95(2H, s), 6.70(2H, d, J = 9.2 Hz),

6.74-6.75(2H, m), 6.87(1H, brs),

6.94(1H, dd, J = 9.1 Hz, 0.5 Hz),

7.01(2H, d, J = 9.2 Hz), 8.41(1H, dd,

J = 9.1 Hz, 2.8 Hz), 9.05(1H, dd, J =

2.8 Hz, 0.5 Hz)

868
—H
—C₂H₅
—CH(CH₃)—
—CH₂—
1.20(3H, t, J = 7.1 Hz), 1.26-

1.40(3H, m), 1.98-2.05(1H, m), 2.16-

2.17(1H, m), 2.65-2.69(1H, m), 2.81-

2.85(1H, m), 3.02-3.56(6H, m), 4.03-

4.71(3H, m), 5.94(2H, s), 6.66(2H,

d, J = 9.2 H), 6.74-6.75(2H, m),

6.87(1H, brs), 6.94(1H, dd, J = 9.1

Hz, 0.7 Hz), 6.99(2H, d, J = 9.1 Hz),

8.41(1H, dd, J = 9.1 Hz, 2.8 Hz),

8.05(1H, dd, J = 2.8 Hz, 0.7 Hz).

TABLE 119

Reference

Example

No.
R₃₇₃
R₃₇₄
R₃₇₅

¹H NMR (solvent) δppm or MS

869
—COOCH₃
—H
—C₂H₅
MS 577(M⁺)

870
—OCH₃
—H
—H

¹H NMR (DMSO-d₆) 2.32-2.40(4H, m), 3.42(2H, s),

3.50(4H, brs), 3.63(3H, s), 3.92(2H, d, J = 4.6 Hz),

5.65(1H, t, J = 4.8 Hz), 5.99(2H, s), 6.22(1H, dd, J =

8.6 Hz, 2.5 Hz), 6.51(1H, d, J = 2.5 Hz), 6.76(1H,

dd, J = 7.9 Hz, 1.5 Hz), 6.84-6.91(3H, m), 7.07(1H,

dd, J = 9.1 Hz, 0.5 Hz), 8.54(1H, dd, J = 9.1 Hz,

2.8 Hz), 9.00(1H, dd, J = 2.8 Hz, 0.5 Hz).

871
—OCH₃
—H
—CH₃

¹H NMR (CDCl₃) 2.35-2.52(4H, m), 3.07(3H, s),

3.44(2H, s), 3.41-3.55(2H, m), 3.56-3.70(2H, m),

3.73(3H, s), 5.95(2H, s), 6.24(1H, dd, J = 8.8 Hz,

2.8 Hz), 6.35(1H, d, J = 2.8 Hz), 6.64-6.79(2H, m),

6.85(1H, s), 6.89-7.04(2H, m), 8.41(1H, dd, J = 9.1

Hz, 2.8 Hz), 9.03(1H, d, J = 2.8 Hz).

872
—OCH₃
—H
—C₂H₅

¹H NMR (CDCl₃) 1.22(3H, t, J = 7.0 Hz), 2.33-

2.52(4H, m), 3.49-3.58(6H, m), 3.59-3.69(2H, m),

3.72(3H, s), 4.06(2H, s), 5.95(2H, s), 6.22(1H, dd, J =

8.8 Hz, 2.7 Hz), 6.33(1H, d, J = 2.7 Hz), 6.69-

6.79(2H, m), 6.85(1H, s), 6.95(1H, d, J = 9.1 Hz),

6.96(1H, d, J = 8.8 Hz), 8.41(1H, dd, J = 9.1 Hz,

2.8 Hz), 9.04(1H, d, J = 2.8 Hz).

873
—CH₃
—H
—H

¹H NMR (CDCl₃) 2.08(3H, s), 2.43-2.48(4H, m),

3.45-3.48(4H, m), 3.67-3.71(2H, m), 3.86(2H, d, J =

4.1 Hz), 4.93(1H, t, J = 4.1 Hz), 5.96(2H, s), 6.47-

6.52(2H, m), 6.71-6.78(2H, m), 6.86-6.96(3H, m),

8.44(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.05(1H, d, J =

2.8 Hz).

874
—CH₃
—H
—Ac

¹H NMR (CDCl₃) 1.98(3H, s), 2.16(3H, s), 2.32-

2.51(4H, m), 3.35-3.48(4H, m), 3.53-3.69(2H, m),

4.46(2H, s), 5.95(2H, s), 6.65-6.79(2H, m),

6.85(1H, s), 7.08(2H, d, J = 8.7 Hz), 7.27-7.34(1H,

m), 7.35-7.42(1H, m), 8.51(1H, dd, J = 9.0 Hz, 2.8

Hz), 9.02(1H, dd, J = 2.8 Hz, 0.3 Hz).

875
—CH₃
—H
—C₂H₅

¹H NMR (CDCl₃) 1.20(3H, t, J = 7.1 Hz), 2.08(3H,

s), 2.37-2.55(4H, m), 3.37-3.72(8H, m), 4.05(2H, s),

5.95(2H, s), 6.42-6.58(2H, m), 6.63-6.79(2H, m),

6.81-6.99(3H, m), 8.42(1H, dd, J = 9.1 Hz, 2.8 Hz),

9.05(1H, d, J = 2.8 Hz).

876
—CH₃
—H

embedded image

¹H NMR (CDCl₃) 0.64-0.69(2H, m), 0.80-0.87(2H, m), 2.09(3H, s), 2.41-2.49(4H, m), 2.76-2.84(1H, m), 3.44(2H, s), 3.49-3.52(2H, m), 3.60-3.64(2H, m), 4.18(2H, s), 5.95(2H, s), 6.71-6.93(7H, m), 8.39-8.44(1H, m), 9.05-9.06(1H, m).

877
—CH₃
—CH₃
—CH₃

¹H NMR (CDCl₃) 2.05(3H, s), 2.28(3H, s), 2.37-

2.43(4H, m), 2.72(3H, s), 3.42(2H, s), 3.52-

3.56(2H, m), 3.62-3.65(2H, m), 3.77(2H, s),

5.95(2H, s), 6.71-6.77(2H, m), 6.85-6.90(2H, m),

6.97-7.06(2H, m), 8.45(1H, dd, J = 9.1 Hz, 3.0 Hz),

9.04(1H, dd, J = 3.0 Hz, 0.5 Hz).

TABLE 120

Reference

Example

No.
R₃₇₆
R₃₇₇
R₃₇₈
R₃₇₉

¹H NMR (solvent) δppm or MS

878
—CH₃
—H
—CH₃
—C₂H₅
MS 547(M⁺)

879
—F
—H
—H
—H

¹H NMR (CDCl₃) 2.44-2.49(4H, m), 3.43-3.45(2H,

m), 3.45(2H, s), 3.68-3.71(2H, m), 3.84(2H, d, J =

4.1 Hz), 5.12(1H, brs), 5.96(2H, s), 6.40-6.45(2H,

m), 6.71-6.80(2H, m), 6.85(H, brs), 7.02(1H, t, J =

8.5 Hz), 7.05(1H, dd, J = 9.1 Hz, 0.5 Hz), 8.46(1H,

dd, J = 9.1 Hz, 2.8 Hz), 9.02(1H, dd, J = 2.8 Hz, 0.7

Hz).

880
—F
—H
—H
—CH₃

¹H NMR (CDCl₃) 2.44(4H, brs), 3.06(3H, s),

3.45(2H, s), 3.45-3.47(2H, m), 3.62-3.64(2H, m),

4.11(2H, s), 5.95(2H, s), 6.40-6.51(2H, m), 6.71-

6.78(2H, m), 6.85(1H, brs), 7.04(1H, d, J = 9.1 Hz),

7.05(1H, t, J = 8.9 Hz), 8.46(1H, dd, J = 9.1 Hz, 2.8

Hz), 9.02(1H, d, J = 2.3 Hz)

881
—F
—H
—H
—C₂H₅

¹H NMR (CDCl₃) 1.22(3H, t, J = 7.2 Hz), 2.45(4H,

brs), 3.40-3.49(4H, m), 3.45(2H, s), 3.65(2H, brs),

4.05(2H, s), 5.95(2H, s), 6.37-6.46(2H, m), 6.74-

6.75(2H, m), 6.86(1H, brs), 6.99-7.06(2H, m),

8.45(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.03(1H, d, J = 2.5

Hz).

882
—F
—H
—H
allyl

¹H NMR (CDCl₃) 2.46(4H, brs), 3.45(2H, s),

3.48(2H, brs), 3.65(2H, brs), 4.00(2H, d, J = 5.0 Hz),

4.07(2H, s), 5.19-5.29(2H, m), 5.82-5.94(1H, m),

5.95(2H, s), 6.37-6.47(2H, m), 6.71-6.78(2H, m),

6.86-6.87(1H, m), 6.98-7.05(2H, m), 8.45(1H, dd, J =

9.1 Hz, 2.8 Hz), 9.02(1H, dd, J = 2.8 Hz, 0.5 Hz)

883
—F
—H
—F
—CH₃

¹H NMR (CDCl₃) 2.33-2.49(4H, m), 2.99(3H, s),

3.43(2H, s), 3.37-3.50(2H, m), 3.51-3.68(2H, m),

4.10(2H, s), 5.95(2H, s), 6.69-6.78(2H, m), 6.81(1H,

dd, J = 8.2 Hz, 12.1 Hz), 6.85(1H, d, J = 0.96 Hz),

6.90(1H, dd, J = 7.1 Hz, 12.8 Hz), 7.09(1H, d, J =

9.1 Hz), 8.49(1H, dd, J = 2.8 Hz, 9.0 Hz), 9.01(1H,

d, J = 2.8 Hz).

884
—F
—H
—F
—C₂H₅

¹H NMR (CDCl₃) 1.17(3H, t, J = 7.1 Hz), 2.30-

2.52(4H, m), 3.35(2H, q, J = 7.1 Hz), 3.37-3.70(6H,

m), 4.04(2H, s), 5.95(2H, s), 6.68-6.78(2H, m),

6.82(1H, dd, J = 8.0 Hz, 12.1 Hz), 6.83-6.88(1H, m),

6.91(1H, dd, J = 7.2 Hz, 12.5 Hz), 7.09(1H, d, J =

9.0 Hz), 8.49(1H, dd, J = 2.8 Hz, 9.0 Hz), 9.02(1H,

d, J = 2.8 Hz).

885
—F
—F
—H
—CH₃

¹H NMR (DMSO-d₆) 2.20-2.45(4H, m), 2.91(3H, s),

3.34-3.53(6H, m), 4.31(2H, s), 5.98(2H, s), 6.47(2H,

d, J = 11.8 Hz), 6.70-6.79(1H, m), 6.80-6.91(2H, m),

7.42(1H, d, J = 9.1 Hz), 8.64(1H, dd, J = 2.8 Hz, 9.1

Hz), 9.05(1H, d, J = 2.8 Hz).

886
—CH₃
—H
—CH₃
—CH₃
MS 533(M⁺)

887
—CF₃
—H
—H
—C₂H₅
MS 587(M⁺)

888
—CF₃
—H
—H
—CH₃
MS 573(M⁺)

889
—H
—F
—F
—CH₃

¹H NMR (CDCl₃) 2.30-2.52(4H, m), 3.01(3H, s),

3.43(2H, s), 3.38-3.71(4H, m), 4.10(2H, s), 5.95(2H,

s), 6.65-6.81(3H, m), 6.82-6.96(2H, m), 7.10(1H, d, J =

9.1 Hz) ,8.49(1H, dd, J = 2.8 Hz, 9.1 Hz), 9.01(1H,

d, J = 2.8 Hz).

TABLE 121

Reference

Example

No.
R₃₈₀
R₃₈₁
Xa₃₀
R₃₈₂
mp (° C.) or ¹H NMR (CDCl₃) δppm

890
—CH₃
—CH₃
—CH₂—
benzyl

¹H NMR 2.12(3H, s), 2.40-2.55(4H, m),

3.04(3H, s), 3.45-3.55(2H, m), 3.54(2H,

s), 3.60-3.70(2H, m), 4.10(2H, s), 6.50-

6.61(2H, m), 6.91(1H, d, J = 8.5 Hz),

6.92(1H, d, J = 9.1 Hz), 7.22-7.40(5H,

m), 8.42(1H, dd, J = 9.1 Hz, 2.8 Hz),

9.05(1H, d, J = 2.8 Hz).

891
—CH₃
—C₂H₅
—CH₂—
benzyl
mp 134-136

892
—H
—CH₃
—CH₂CH₂—
piperonyl

¹H NMR 2.34-2.41(4H, m), 2.56-2.61

(2H, m), 2.97(3H, s), 3.39-3.42(4H, m),

3.60-3.64(2H, m), 3.71-3.76(2H, m),

5.94(2H, s), 6.72-6.76(5H, m), 6.83(1H,

brs), 6.97(1H, d, J = 9.1 Hz), 7.02(1H, d,

J = 9.1 Hz), 8.43(1H, dd, J = 9.1 Hz, 2.8

Hz), 9.04(1H, d, J = 2.8 Hz).

893
—CH₃
—CH₃
—CH(CH₃)—
piperonyl

¹H NMR 1.31(3H, d, J = 6.6 Hz), 2.11

(3H, s), 2.17-2.49(4H, m), 2.78(3H, s),

3.31-3.56(3H, m), 3.39(2H, s), 3.77(1H,

brs), 4.57(1H, q, J = 6.6 Hz), 5.94(2H, s),

6.60-6.63(2H, m), 6.68-6.75(2H, m),

6.83(1H, brs), 6.93-6.98(2H, m), 8.44(1H,

dd, J = 9.1 Hz, 2.8 Hz), 9.05(1H, d, J =

2.8 Hz).

894
—H
—CH₃
—CH(CH₃)—
piperonyl

¹H NMR 1.32(3H, d, J = 6.6 Hz), 2.19-

2.50(4H, m), 2.80(3H, s), 3.30-3.56(3H,

m), 3.32(2H, s), 3.78(1H, brs), 4.58(1H,

q, J = 6.6 Hz) ,5.93(2H, s), 6.68-6.82(3H,

m), 6.77(2H, d, J = 9.1 Hz), 6.98(1H, dd,

J = 8.6 Hz, 0.5 Hz), 7.04(2H, d, J = 9.2

Hz), 8.44(1H, dd, J = 9.1 Hz, 2.8 Hz),

9.05(1H, dd, J = 2.8 Hz, 0.5 Hz).

895
—CH₃
—H
—CO—
piperonyl

¹H NMR 2.15(3H, s), 2.49-2.55(4H, m),

3.45(2H, s), 3.71-3.75(2H, m), 4.25-

4.28(2H, m), 5.96(2H, s), 6.75(2H, brs),

6.86(1H, brs), 7.04(1H, d, J = 9.1 Hz),

7.06(1H, d, J = 8.6 Hz), 7.49(1H, dd, J =

8.7 Hz, 2.6 Hz), 7.61(1H, d, J = 2.5 Hz),

8.48(1H, dd, J = 9.1 Hz, 2.8 Hz),

9.02(1H, d, J = 2.8 Hz), 9.23(1H, brs).

896
—CH₃
—CH₃
—CO—
piperonyl

¹H NMR 2.15(3H, s), 2.25-2.33(4H, m),

3.33-3.42(9H, m), 5.93(2H, s), 6.66-

6.79(3H, m), 7.04-7.21(4H, m), 8.51(1H,

dd, J = 9.1 Hz, 2.8 Hz), 8.99(1H, dd, J =

2.8 Hz, 0.5 Hz).

TABLE 122

Reference

Example

No.
R₃₈₃

¹H NMR (CDCl₃) δppm or MS

897

embedded image

MS 502(M⁺)

898

embedded image

¹H NMR 2.44(4H, brs), 3.07(3H, s), 3.44(2H, s), 3.47-3.51(2H, m), 3.62-3.66(2H, m), 4.12(2H, s), 5.95(2H, s), 6.67-6.75(4H, m), 6.86(1H, s), 6.93-6.99(4H, m), 8.16(2H, d, J = 9.2 Hz).

899

embedded image

¹H NMR 2.42(4H, t, J = 4.9 Hz), 3.04(3H, s), 3.42(2H, s), 3.44(2H, t, J = 4.9 Hz), 3.62(2H, t, J = 4.9 Hz), 4.11(2H, s), 5.95(2H, s), 6.42- 6.44(1H, m), 6.50-6.51(1H, m), 6.54-6.58(1H, m), 6.70-6.77(2H, m), 6.84(1H, m), 6.96(1H, d, J = 9.1 Hz), 7.24-7.30(1H, m), 8.43(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.08(1H, d, J = 2.8 Hz).

900

embedded image

¹H NMR 2.44(4H, brs), 3.44(2H, s), 3.55(2H, brs), 3.73(2H, brs), 5.95(2H, s), 6.74(2H, s), 6.85(1H, s), 6.86(1H, d, J = 8.6 Hz), 7.14(2H, d, J = 8.6 Hz), 7.46(2H, d, J = 8.6 Hz), 7.79(1H, dd, J = 8.7 Hz, 2.5 Hz), 8.22(1H, d, J = 2.5 Hz).

901

embedded image

MS 508(M⁺)

902

embedded image

MS 587(M⁺)

903

embedded image

¹H NMR 2.31-2.50(4H, m), 2.96(3H, s), 3.42(2H, s), 3.40-3.52(2H, m), 3.53-3.67(2H, m), 4.05(2H, s), 5.95(2H, s), 6.65-6.95(6H, m), 7.77(1H, dd, J = 2.5 Hz, 8.7 Hz), 8.16(1H, dd, J = 0.5 Hz, 2.5 Hz).

TABLE 123

Reference

Example

No.
R₃₈₄

¹H NMR (CDCl₃) δppm

904
—H
2.29-2.34(4H, m), 3.15(3H, s), 3.34-3.43(6H, m), 4.63(2H, s), 5.98(2H,

s), 6.72-6.76(1H, m), 6.83-6.86(2H, m), 7.27(2H, d, J = 8.9 Hz),

7.31(1H, d, J = 9.3 Hz), 7.54(2H, d, J = 8.9 Hz), 8.64(1H, dd, J = 9.2

Hz, 2.8 Hz), 9.05(1H, d, J = 2.8 Hz).

905
—CH₃
2.15(3H, s), 2.42-2.43(4H, m), 3.22(3H, s), 3.39-3.41(2H, m), 3.43(2H,

s), 3.61-3.63(2H, m), 4.56(2H, s), 5.94(2H, s), 6.70-6.77(2H, m),

6.84(1H, brs), 7.06(1H, d, J = 8.2 Hz), 7.07(1H, d, J = 9.1 Hz), 7.48-

7.52(2H, m), 8.49(1H, dd, J = 9.1 Hz, 2.8 Hz), 9.01(2H, d, J = 2.8 Hz).

906
—OCH₃
2.42-2.46(4H, m), 3.24(3H, s), 3.40(2H, brs), 3.43(2H, s), 3.63(2H,

brs), 3.74(3H, s), 4.58(2H, s), 5.94(2H, s), 6.70-6.77(2H, m), 6.84

(1H, s), 7.06-7.14(2H, m), 7.23-7.28(1H, m), 7.32(1H, d, J = 2.3 Hz),

8.47(1H, dd, J = 9.1 Hz, 2.8 Hz), 8.98(1H, d, J = 2.8 Hz).

TABLE 124

Reference

Example

No.
R₃₈₅

¹H NMR (CDCl₃) δppm

907
piperonyl
1.33-1.46(2H, m), 1.86-2.00(3H, m), 2.10(3H, s), 2.29(2H, d, J = 6.8

Hz), 2.39-2.43(4H, m), 2.75(2H, t, J = 12.2 Hz), 3.40-3.48(4H, m),

3.62-3.66(4H, m), 5.94(2H, s), 6.73-6.85(5H, m), 6.91-6.96(2H, m),

8.43(1H, dd, J = 9.1 Hz, 3.0 Hz), 9.04(1H, d, J = 2.8 Hz).

908
benzyl
1.35-1.46(2H, m), 1.86-2.00(3H, m), 2.10(3H, s), 2.29(2H, d, J = 6.8

Hz), 2.41-2.45(4H, m), 2.75(2H, t, J = 12.2 Hz), 3.47-3.53(4H, m),

3.61-3.65(4H, m), 6.79-6.96(4H, m), 7.24-7.33(5H, m), 8.43(1H, dd, J =

9.1 Hz, 2.8 Hz), 9.05(1H, d, J = 2.8 Hz).

Reference Example 909
Production of (4-benzylpiperazin-1-yl){4-[methyl(5-nitropyridin-2-yl)amino]phenyl}ethanone

To a solution of 4-[methyl-(5-nitropyridin-2-yl)amino]benzoic acid (0.800 g, 2.93 mmol) and 1-benzylpiperazine (0.542 g, 3.08 mmol) in DMF (15 mL) were added triethylamine (1.02 mL, 7.32 mmol) and diethyl cyanophosphonate (0.593 mL, 3.52 mmol), and the resulting solution was stirred for 3 hours. To the resulting reaction solution was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate), to thereby yield 1.25 g of the title compound.

Appearance: Yellow amorphous powder

¹H NMR (CDCl₃) δ 2.25-2.65 (4H, m), 3.49 (2H, brs), 3.56 (2H, s), 3.57 (3H, s), 3.81 (2H, brs), 6.43 (1H, d, J=9.5 Hz), 7.25-7.35 (7H, m), 7.53 (2H, d, J=8.4 Hz), 8.06 (1H, dd, J=2.8 Hz, 9.5 Hz), 9.12 (1H, d, J=2.8 Hz).

The following compounds were produced in the same manner as in Reference Example 909.

TABLE 125

Reference

Example

No.
Xa₃₁
R₃₈₆
Xa₃₂
M

¹H NMR (DMSO-d₆) δppm

910
—NH—
—H
—CH₂—
1
2.20-2.30(4H, m), 2.59(2H, t, J = 7.3 Hz),

2.78(2H, t, J = 7.3 Hz), 3.35(2H, s), 3.36-

3.45(4H, m), 5.98(2H, s), 6.72(1H, dd, J = 1.3

Hz, 7.9 Hz), 6.80-6.90(3H, m), 7.21(2H, d, J =

8.4 Hz), 7.57(2H, d, J = 8.4 Hz), 8.26(1H, dd, J =

2.9 Hz, 9.3 Hz), 9.01(1H, d, J = 2.9 Hz),

10.06(1H, s).

911
—O—
—H
—NH—
1
2.32(2H, brs), 2.39(2H, brs), 3.41(2H, s),

3.50(4H, brs), 3.91(2H, d, J = 5.2 Hz), 5.68(1H,

t, J = 5.2 Hz), 5.99(2H, s), 6.70(2H, d, J = 8.9

Hz), 6.74-6.77(1H, m), 6.83-6.88(2H, m),

6.94(2H, d, J = 8.9 Hz), 7.11(1H, d, J = 9.1 Hz),

8.56(1H, dd, J = 2.9 Hz, 9.1 Hz), 9.02(1H, d, J =

2.9 Hz).

912
—O—
—OCH₃
—NH—
2
2.48(2H, brs0, 2.49(2H, brs), 3.89(2H, s),

3.50(4H, brs), 3.63(3H, s), 3.92(2H, d, J = 4.8

Hz), 4.22(4H, s), 5.65(1H, brt), 6.22(1H, dd, J =

8.6 Hz, 2.5 Hz), 6.51(1H, d, J = 2.5 Hz), 6.73-

6.81(3H, m), 6.89(1H, d, J = 8.6 Hz), 7.07(1H,

d, J = 9.1 Hz), 8.54(1H, dd, J = 9.1 Hz, 2.8 Hz),

9.00(1H, d, J = 2.8 Hz).

Reference Example 913
Production of N-[4-(5-nitropyridin-2-yloxy)phenyl]-N-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]acetamide

To a solution of ethyl (acetyl [4-(5-nitropyridin-2-yloxy)phenyl]amino]acetate (2.30 g, 6.40 mmol) in ethanol (50 mL) was added 5 M aqueous sodium hydroxide (1.92 mL, 9.60 mmol), and the resulting solution was stirred at room temperature for 30 minutes. To this reaction solution were added 5 M hydrochloric acid (2 mL) and water, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, evaporated, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1), to thereby yield 1.68 g of an oil. To a solution of this oil in DMF (10 mL) were added 1-piperonylpiperazine (1.29 g, 5.86 mmol), triethylamine (1.85 mL, 13.3 mmol) and diethyl cyanophosphonate (1.07 mL, 6.36 mmol), and the resulting solution was stirred for 1 hour at room temperature. To this reaction solution was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1), to thereby yield 2.21 g of the title compound.

Appearance: Yellow amorphous powder

¹H NMR (CDCl₃) δ 1.98 (3H, s), 2.40-2.50 (4H, m), 3.40-3.45 (4H, m), 3.62 (2H, brs), 4.48 (2H, s), 5.94 (2H, s), 6.70-6.76 (2H, m), 6.85 (1H, s), 7.09 (1H, d, J=9.1 Hz), 7.20 (2H, d, J=8.7 Hz), 7.51 (2H, d, J=8.7 Hz), 8.51 (1H, dd, J=2.8 Hz, 9.1 Hz), 9.04 (1H, d, J=2.8 Hz).

The following compounds were produced in the same manner as in Reference Example 913.

TABLE 126

Reference

Example

No.
R₃₈₇
R₃₈₈
MS (M⁺)

914
—CH₃
—CH₃
587

915
—H
—C₂H₅
587

Reference Example 916
Production of 3-[3-methoxy-4-(5-nitropyridin-2-yloxy)phenyl]-1-(4-piperonylpiperazin-1-yl)propan-1-one

3-[3-methoxy-4-(5-nitropyridin-2-yloxy)phenyl]propionic acid (3.18 g, 10 mmol) was dissolved in dichloromethane (30 mL). To the resulting solution were added thionyl chloride (0.88 mL, 12 mmol) and DMF (1 drop), and refluxed for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (20 mL). To the resulting solution were added triethylamine (1.67 mL, 12 mmol) and a solution of 1-piperonylpiperazine (2.20 g, 10 mmol) in dichloromethane (30 mL) under ice cooling, and the resulting solution was stirred for 1 hour at 0° C. The resulting reaction solution was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was recrystallized from ethyl acetate, to thereby yield 4.95 g of the title compound.

Appearance: Pale yellow powder

¹H NMR (CDCl₃) δ 2.33-2.42 (4H, m), 2.63-2.69 (2H, m), 2.97-3.03 (2H, m), 3.42 (4H, brs), 3.62-3.66 (2H, m), 3.74 (3H, s), 5.95 (2H, s), 6.73-6.75 (2H, m), 6.85-6.90 (3H, m), 7.04 (1H, d, J=9.1 Hz), 7.06 (1H, d, J=7.9 Hz), 8.45 (1H, dd, J=9.1 Hz, 2.8 Hz), 9.01 (1H, d, J=2.8 Hz).

The following compound was produced in the same manner as in Reference Example 916.

Reference Example 917
6-Chloro-N-(4-trifluoromethylphenyl)nicotinamide

¹H NMR (DMSO-d₆) δ7.74 (1H, d, J=8.4 Hz), 7.76 (2H, d, J=8.7 Hz), 8.00 (2H, d, J=8.7 Hz), 8.38 (1H, dd, J=8.7 Hz, 2.5 Hz), 8.97 (1H, d, J=2.5 Hz), 10.80 (1H, brs).

Reference Example 918
Production of 3-{3-methoxy-4-[methyl(5-nitropyridin-2-yl)amino]phenyl}-1-(4-piperonylpiperazin-1-yl)propan-1-one

To a solution of ethyl 3-{3-methoxy-4-[methyl-(5-nitropyridin-2-yl)amino]phenyl}propionate (3.85 g, 11 mmol) in ethanol (80 mL) was added 2 N aqueous sodium hydroxide (6.4 mL, 13 mmol), and the resulting solution was stirred at room temperature for 2.5 hours. To the resulting reaction solution was added 6 N hydrochloric acid (2.2 mL, 13 mmol), and the solvent was removed under reduced pressure. To the residue were added THF (80 mL) and N,N′-carbonyldiimidazole (2.08 g, 13 mmol), and the resulting solution was stirred at room temperature for 3 hours. To the resulting reaction solution were added 1-piperonylpiperazine (2.60 g, 12 mmol) and DMF (40 mL), and stirred at room temperature for 21 hours. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate), to thereby yield 4.59 g of the title compound.

Appearance: Yellow powder

¹H NMR (CDCl₃) δ 2.36-2.43 (4H, m), 2.64-2.70 (2H, m), 2.99-3.05 (2H, m), 3.42-3.46 (7H, m), 3.63-3.67 (2H, m), 3.77 (3H, s), 5.95 (2H, s), 6.12 (1H, brd, J=9.1 Hz), 6.70-6.77 (2H, m), 6.85-6.90 (3H, m), 7.12 (1H, d, J=8.1 Hz), 7.97-8.01 (1H, m), 9.11 (1H, d, J=2.6 Hz).

Reference Example 919
Production of 5-{methyl[2-oxo-2-(4-piperonylpiperazin-1-yl)ethyl]amino}-2-(5-nitropyridin-2-yloxy)benzonitrile

To a solution of t-butyl 2-((3-cyano-4-(5-nitropyridin-2-yloxy)phenyl)(methyl)amino)acetate (1.2 g, 3.1 mmol) in dichloromethane (12 mL) was added trifluoroacetic acid (12 mL), and the resulting reaction solution was stirred at room temperature for 5 hours. The solvent was evaporated, and water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated, to thereby yield crude 2-((3-cyano-4-(5-nitropyridin-2-yloxy)phenyl)(methyl)amino)acetic acid. To a solution of this compound in DMF (24 mL) were added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (659 mg, 3.4 mmol), 1-hydroxybenzotriazole monohydrate (526 mg, 3.4 mmol) and 1-piperonylpiperazine (757 mg, 3.4 mmol), and the resulting reaction solution was stirred for 8 hours at room temperature. Water was added to the reaction solution and extracted with ethyl acetate. The ethyl acetate layer was then washed with, in order, saturated aqueous sodium bicarbonate solution, water and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel chromatography (ethyl acetate), to thereby yield 412 g of the title compound.

Appearance: Yellow amorphous powder

¹H NMR (CDCl₃) δ 2.40-2.55 (4H, m), 3.09 (3H, s), 3.45-3.50 (4H, m), 3.55-3.70 (2H, m), 4.14 (2H, s), 5.95 (2H, s), 6.70-6.80 (2H, m), 6.80-6.95 (3H, m), 7.10-7.20 (2H, m), 8.50 (1H, dd, J=9.1 Hz, 2.8 Hz), 8.99 (1H, d, J=2.8 Hz).

Reference Example 920
Production of 2-{(2,3-difluoro-4-t-butoxycarbonylamino)phenoxy}-5-nitropyridine

To a solution of {2,3-difluoro-4-(5-nitropyridin-2-yloxy)}benzoic acid (1.22 g, 4.1 mmol) in t-butanol (50 mL) were added diphenylphosphorylazide (0.98 mL, 4.5 mmol) and triethylamine (0.63 mL, 4.5 mmol), and the resulting solution was refluxed for 4 hours under a nitrogen atmosphere. After cooling, water was added to the reaction solution and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1), to thereby yield 1.2 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 1.54 (9H, s), 6.59-6.78 (1H, m), 6.90-7.04 (1H, m), 7.13 (1H, d, J=9.0 Hz), 7.84-8.02 (1H, m), 8.51 (1H, dd, J=2.8 Hz, 9.0 Hz), 8.99 (1H, d, J=2.8 Hz).

Reference Example 921
Production of 3,4-dichloro-N-[3-fluoro-4-(4-formylphenoxy)phenyl]benzamide

3,4-Dichloro-N-[4-(4-[1,3]dioxsolane-2-ylphenoxy)-3-fluorophenyl]benzamide (17.4 g, 38.9 mmol) was added to 80% acetic acid, and the resulting solution was stirred for 1.5 hours at 80° C. The reaction solution was concentrated under reduced pressure, wherein the obtained residue was recrystallized from 80% ethanol to thereby yield 12.8 g of the title compound.

Appearance: Pale yellow powder

¹H NMR (DMSO-d₆) δ 7.13 (2H, d, J=8.6 Hz), 3.40 (1H, t, J=9.0 Hz), 7.63 (1H, d, J=9.0 Hz), 7.85 (1H, d, J=8.4 Hz), 7.90-8.00 (4H, m), 8.22 (1H, d, J=1.9 Hz), 9.93 (1H, s), 10.67 (1H, s).

Reference Example 922
Production of N-(6-(4-aminophenoxy)pyridin-3-yl]-3,4-dichlorobenzamide dihydrochloride

t-Butyl {4-(5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]phenyl}carbamate (4.31 g, 9.09 mmol) was dissolved in a mixed solution of chloroform-methanol-ethyl acetate. The resulting solution was concentrated to a volume of about 20 mL. To the residue solution was added a solution of 4 N hydrogen chloride in ethyl acetate (70 mL), and left to cool for 2 hours at room temperature. The precipitated white powder was filtered, and washed with ethyl acetate, to thereby yield 4.04 g of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 5.20 (2H, brs), 7.14 (1H, d, J=8.5 Hz), 7.25 (2H, d, J=8.9 Hz), 7.42 (2H, d, J=8.9 Hz), 7.84 (1H, d, J=8.5 Hz), 7.97 (1H, dd, J=8.5 Hz, 2.0 Hz), 8.24 (1H, dd, S=8.5 Hz, 2.6 Hz), 8.25 (1H, d, J=2.0 Hz), 8.51 (1H, d, J=2.6 Hz), 10.65 (1H, s).

The following compounds were produced in the same manner as in Reference Example 922.

TABLE 127

Reference

Example

¹H NMR (CDCl₃) δppm or

No.
R₃₈₉
R₃₉₀
R₃₉₁
R₃₉₂
R₃₉₃
MS

923
—F
—H
—F
—H
—CH₃

¹H NMR 2.83(3H, d, J = 5.2

Hz), 3.90-4.05(1H, m), 6.18-

6.27(2H, m), 7.15(1H, d, J =

9.0 Hz), 8.49(1H, dd, J = 2.8

Hz, 9.0 Hz), 9.02(1H, d, J =

2.8 Hz).

924
—F
—F
—H
—H
—CH₃

¹H NMR 2.92(3H, d, J = 3.8

Hz), 3.90-4.16(1H, m),

6.46(1H, td, J = 2.2 Hz, 8.8

Hz), 6.89(1H, td, J = 2.4 Hz,

7.8 Hz), 7.08(1H, d, J = 9.0

Hz), 8.49(1H, dd, J = 2.8 Hz,

9.0 Hz), 9.02(1H, d, J = 2.8

Hz).

925
—COOCH₃
—H
—H
—CH₂COOH
—C₂H₅
MS 375(M⁺)

Reference Example 926
Production of 4-(tetrahydropyran-2-yloxy)benzylamine

To a solution of lithium aluminum hydride (2.66 g, 70 mmol) in THF (200 mL) was added dropwise under ice cooling a solution of 4-(tetrahydropyran-2-yloxy)benzonitrile in THF (70 mL). The resulting solution was then refluxed for 1 hour. The resulting reaction solution was again cooled with ice, and then to the solution was added dropwise, in order, water (2.66 mL), 1 N aqueous sodium hydroxide (2.66 mL) and water (7.98 mL). Insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, after which the residue was purified by silica gel column chromatography (chloroform:methanol=7:1), to thereby yield 11.41 g of the title compound.

Appearance: Colorless oil

¹H NMR (CDCl₃) δ 1.56 (2H, s), 1.45-1.78 (3H, m), 1.78-2.12 (3H, m), 3.53-3.66 (1H, m), 3.80 (2H, s), 3.84-3.99 (1H, m), 5.41 (1H, t, J=3.2 Hz), 7.02 (2H, d, 8.7 Hz), 7.22 (2H, d, J=8.7 Hz).

Reference Example 927
Production of 4-(2-fluoro-4-nitrophenoxy)phenylamine hydrochloride

N-[4-(2-fluoro-4-nitrophenoxy)phenyl]-acetamide (1.00 g, 3.45 mmol) was added to 6 M hydrochloric acid (10 mL), and the resulting solution was refluxed for 2 hours. The resulting reaction solution was concentrated under reduced pressure, to thereby yield 0.910 g of the title compound.

Appearance: Pale yellow powder

¹H NMR (DMSO-d₆) δ 3.40-4.00 (2H, m), 7.18 (1H, t, J=8.7 Hz), 7.24 (2H, d, J=8.9 Hz), 7.32 (2H, d, J=8.9 Hz), 8.10 (1H, ddd, J=1.4 Hz, 2.6 Hz, 8.9 Hz), 8.35 (1H, dd, J=2.6 Hz, 10.8 Hz).

Reference Example 928
Production of {4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]phenyl}carbamate phenyl ester

To a suspension of N-[6-(4-aminophenoxy)pyridin-3-yl]-3,4-dichlorobenzamide dihydrochloride (700 mg, 1.57 mmol) in THF (20 mL) was added triethylamine (1.1 mL, 7.89 mmol). To the resulting solution was then added dropwise phenyl chlorocarbonate (0.39 mL, 3.14 mmol) under ice cooling. The resulting reaction solution was stirred for 1 hour at room temperature. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated, whereupon the residue solidified into a powder. The powder was filtered, and washed with diethyl ether, to thereby yield 470 mg of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 7.04 (1H, d, J=8.9 Hz), 7.11 (2H, d, J=8.9 Hz), 7.19-7.31 (3H, m), 7.38-7.49 (2H, m), 7.53 (2H, d, J=8.0 Hz), 7.84 (1H, d, J=8.4 Hz), 7.95 (1H, dd, J=8.4 Hz, 2.0 Hz), 8.18 (1H, dd, J=8.9 Hz, 2.2 Hz), 8.22 (1H, d, J=2.0 Hz), 8.47 (1H, d, J=2.2 Hz), 10.26 (1H, s), 10.54 (1H, s).

The following compounds were produced in the same manner as in Reference Example 928.

TABLE 128

Reference

Example

No.
R₃₉₄
M

¹H NMR (solvent) δppm

929

embedded image

0
(DMSO-d₆) 7.08(1H, t, J = 8.7 Hz), 7.15-7.30(5H, m), 7.35-7.50(2H, m), 7.60(2H, d, J = 8.9 Hz), 8.07(1H, dd, J = 1.1 Hz, 9.0 Hz), 8.31(1H, dd, J = 2.6 Hz, 10.9 Hz), 10.36(1H, s).

930

embedded image

0
(CDCl₃) 1.50-1.80(3H, m), 1.80-2.15(3H, m), 3.55- 3.67(1H, m), 3.85-4.00(1H, m), 5.37(1H, t, J = 3.3 Hz), 6.83(1H, brs), 7.03(2H, d, J = 9.1 Hz), 7.14-7.30(3H, m), 7.30-7.47(4H, m).

931

embedded image

1
(CDCl₃) 1.50-1.79(3H, m), 1.79-2.15(3H, m), 3.55- 3.60(1H, m), 3.82-4.00(1H, m), 3.39(2H, d, J = 6.0 Hz), 5.26(1H, brs), 5.42(1H, t, J = 3.1 Hz), 7.05(2H, d, J = 8.7 Hz), 7.27(2H, d, J = 8.7 Hz), 7.10-7.40(5H, m).

Reference Example 932
Production of 4-piperonylpiperazine-1-carboxylic acid [4-(2-fluoro-4-nitrophenoxy)phenyl]amide

To a solution of [4-(2-fluoro-4-nitrophenoxy)phenyl]carbamate phenyl ester (0.700 g, 1.90 mmol) in DMF (15 mL) was added 1-piperonylpiperazine (0.460 g, 2.09 mmol), and the resulting solution was stirred for 2 hours at room temperature. water was added to the resulting reaction solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, and evaporated, to thereby yield 0.939 g of the title compound.

Appearance: Yellow oil

¹H NMR (DMSO-d₆) δ 2.30-2.40 (4H, m), 3.35-3.50 (6H, m), 6.00 (2H, s), 6.70-6.90 (2H, m), 7.00-7.15 (2H, m), 7.55 (2H, d, J=9.1 Hz), 8.05-8.10 (1H, m), 8.30 (1H, dd, J=2.8 Hz, 10.9 Hz), 9.31 (1H, s).

The following compounds were produced in the same manner as in Reference Example 932.

Reference Example 933
Ethyl 3-(4-{5-[(3-(3,4-dichlorophenyl)-3-ethylureido]-pyridin-2-yloxy}phenyl)propionate

MS 501 (M⁺).

TABLE 129

Reference

Example

No.
R₃₉₅
M

¹H NMR (CDCl₃) δppm

934
benzyl
0
1.50-1.87(3H, m), 1.87-2.15(3H, m), 2.48(4H, t, J = 5.1 Hz),

3.48(4H, t, J = 5.1 Hz), 3.54(2H, s), 3.50-3.65(1H, m), 3.85-

4.00(1H, m), 5.34(1H, t, J = 3.2 Hz), 6.21(1H, brs), 6.98(2H,

d, J = 8.9 Hz), 7.22(2H, d, J = 8.9 Hz), 7.25-7.38(5H, m).

935
piperonyl
1
1.48-1.77(3H, m), 1.77-2.11(3H, m), 2.40(4H, t, J = 5.0 Hz),

3.36(4H, t, J = 5.0 Hz), 3.41(2H, s), 3.50-3.67(1H, m), 3.81-

3.96(1H, m), 4.34(2H, d, J = 5.1 Hz), 4.61(1H, t, J = 5.1 Hz),

5.40(1H, t, J = 3.2 Hz), 5.94(2H, s), 6.74(2H, s), 6.84(1H, s),

7.00(2H, d, J = 8.6 Hz), 7.22(2H, d, J = 8.6 Hz).

Reference Example 936
Production of 4-piperonylpiperazine-1-carboxylic acid 4-hydroxybenzylamide

To a solution of 4-piperonylpiperazine-1-carboxylic acid 4-(tetrahydropyran-2-yloxy)benzylamide (1.1 g, 2.43 mmol) in methanol (50 mL) was added p-toluenesulfonic acid monohydrate (1.0 g, 5.26 mmol), and the resulting solution was stirred for 1 hour at room temperature. The resulting reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 330 mg of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 2.41 (4H, t, J=5.0 Hz), 3.37 (4H, t, J=5.0 Hz), 3.42 (2H, s), 4.32 (2H, d, J=5.2 Hz), 4.68 (1H, t, J=5.2 Hz), 5.94 (2H, s), 6.15 (1H, brs), 6.70-6.80 (2H, m), 6.75 (2H, d, J=8.6 Hz), 6.84 (1H, s), 7.13 (2H, d, J=8.6 Hz).

The following compound was produced in the same manner as in Reference Example 936.

Reference Example 937
4-Benzylpiperazine-1-carboxylic acid (4-hydroxyphenyl)methylamide hydrochloride

¹H NMR (DMSO-d₆) δ 2.69-2.91 (2H, m), 3.03 (3H, s), 2.92-3.23 (4H, m), 3.68 (2H, d, J=13. Hz), 4.26 (2H, s), 6.75 (2H, d, J=8.7 Hz), 6.98 (2H, d, J=8.7 Hz), 7.45 (3H, brs), 7.54 (2H, brs), 9.52 (1H, s).

Reference Example 938
Production of 3,4-dichloro-N-{6-[(4-(3-hydroxypropyl)phenoxy]pyridin-3-yl}benzamide

To 2-{4-[3-(t-butyldimethylsilanyloxy)propyl]phenoxy}-5-nitropyridine (950 mg, 1.8 mmol) were added acetic acid (10 mL) and water (5 mL), and the resulting solution was stirred for 1 hour at room temperature. The resulting reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was recrystallized from ethyl acetate, to thereby yield 520 mg of the title compound.

Appearance: White prism

¹H NMR (DMSO-d₆) δ 1.70-1.78 (2H, m), 2.59-2.65 (2H, m), 3.32-3.47 (2H, m), 4.46-4.49 (1H, m), 7.00-7.05 (3H, m), 7.23 (2H, d, J=8.2 Hz), 7.84 (1H, d, J=8.2 Hz), 7.95 (1H, dd, J=8.3 Hz, 2.0 Hz), 8.16-8.22 (2H, m), 8.48 (1H, d, J=2.6 Hz), 10.54 (1H, s).

The following compound was produced in the same manner as in Reference Example 938.

Reference Example 939
3,4-Dichloro-N-{6-[4-(2-hydroxyethyl)phenoxy]pyridin-3-yl}benzamide

¹H NMR (DMSO-d₆) δ 2.73 (2H, t, J=6.9 Hz), 3.59-3.66 (2H, m), 4.65 (1H, t, J=5.3 Hz), 7.00-7.06 (3H, m), 7.25 (2H, d, J=8.3 Hz), 7.84 (1H, d, J=8.3 Hz), 7.95 (1H, dd, J=8.3 Hz, 2.0 Hz), 8.16-8.23 (2H, m), 8.47 (1H, d, J=2.6 Hz), 10.54 (1H, s).

Reference Example 940
Production of 3,4-dichloro-N-{6-[4-(5-hydroxypentyl)phenoxy]pyridin-3-yl}benzamide

To a solution of ethyl 5-{4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]phenyl}pentanoate (8.79 g, 18.0 mmol) in THF (140 mL) was added sodium borohydride (3.14 g, 144 mmol), and the resulting solution was refluxed for 3 hours under a nitrogen atmosphere. The resulting reaction solution was cooled with ice, and treated with 1 N hydrochloric acid. The resulting solution was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:2), to thereby yield 7.07 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 1.25-1.75 (7H, m), 2.62 (2H, t, J=7.6 Hz), 3.65 (2H, t, J=6.6 Hz), 6.92 (1H, d, J=8.5 Hz), 7.02 (2H, d, J=8.5 Hz), 7.19 (2H, d, J=8.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.69 (1H, dd, J=8.5 Hz, 2.0 Hz), 7.93 (1H, s), 7.97 (1H, d, J=2.0 Hz), 8.15 (1H, dd, J=8.5 Hz, 2.5 Hz), 8.22 (1H, d, J=2.5 Hz).

The following compounds were produced in the same manner as in Reference Example 940.

TABLE 130

Reference

Example

No.
M
mp (° C.)

941
1
162-163

942
2
104-105

943
3
111-113

944
4
102-104

TABLE 131

Reference

Example

No.
R₃₉₆
R₃₉₇
M

¹H NMR (DMSO-d₆) δppm

945
—Cl
—Cl
1
4.49(2H, d, J = 5.6 Hz), 5.17(1H, brs), 7.03-7.08(3H, m),

7.35(2H, d, J = 8.6 Hz), 7.84(1H, d, J = 8.6 Hz), 7.93-

7.97(1H, m), 8.17-8.22(2H, m), 8.47(1H, d, J = 2.6 Hz),

10.53(1H, s).

946
—CF₃
—H
1
4.50(2H, d, J = 5.7 Hz), 5.18(1H, t, J = 5.7 Hz), 7.04-

7.09(3H, m), 7.35(2H, d, J = 8.4 Hz), 7.93(2H, d, J = 8.4

Hz), 8.15-8.24(3H, m), 8.50(1H, d, J = 2.7 Hz), 10.61(1H,

s).

947
—Cl
—Cl
4
1.35-1.70(4H, m), 2.59(2H, t, J = 7.5 Hz), 3.42(2H, q, J =

6.0 Hz), 4.37(1H, t, J = 5.5 Hz), 7.02(2H, d, J = 8.2 Hz),

7.04(1H, d, J = 8.6 Hz), 7.22(2H, d, J = 8.2 Hz), 7.84(1H,

d, J = 8.2 Hz), 7.94(1H, dd, J = 8.2 Hz, 2.0 Hz), 8.18(1H,

dd, J = 8.9 Hz, 2.6 Hz), 8.22(1H, d, J = 2.0 Hz), 8.47(1H,

d, J = 2.6 Hz), 10.53(1H, s).

Reference Example 948
Production of 4-cyano-N-[6-(4-hydroxymethylphenoxy)pyridin-3-yl]benzamide

A suspension of 4-(5-(4-cyanobenzoylamino)pyridin-2-yloxy]benzoic acid (1.80 g, 5.01 mmol) in THF (20 mL) was cooled with ice-common salt, and to the solution was added triethylamine (0.77 mL, 5.51 mmol), and then ethyl chlorformate (0.53 mL, 5.51 mmol). The resulting solution was stirred at room temperature. Thirty minutes later, the reaction solution was filtered and insoluble matter was removed. The resulting filtrate was poured while stirring under ice cooling into an aqueous solution of sodium borohydride (0.95 g, 25.05 mmol) in 80% methanol (40 mL). After stirring for 30 minutes at room temperature, water (200 mL) was added to the reaction solution. The obtained mixture was extracted with ethyl acetate (200 mL). The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was recrystallized from a mixed solution of ethyl acetate-n-hexane, to thereby yield 1.26 g of the title compound.

Appearance: Slightly yellow powder

¹H NMR (DMSO-d₆) δ 4.50 (2H, d, J=5.3 Hz), 5.19 (1H, t, J=5.6 Hz), 7.04-7.09 (3H, m), 7.35 (2H, d, J=8.6 Hz), 8.04 (2H, d, J=8.9 Hz), 8.12 (2H, d, J=8.6 Hz), 8.21 (1H, dd, J=8.9 Hz, 2.6 Hz), 8.49 (1H, d, J=2.3 Hz), 11.63 (1H, s).

The following compounds were produced in the same manner as in Reference Example 948.

Reference Example 949
4-Chloro-N-[6-(4-hydroxymethylphenoxy)pyridin-3-yl]benzamide

¹H NMR (DMSO-d₆) δ 4.50 (2H, d, J=5.3 Hz), 5.18 (1H, t, J=5.6 Hz), 7.03-7.08 (3H, m), 7.35 (2H, d, J=8.6 Hz), 7.63 (2H, d, J=8.6 Hz), 8.00 (2H, d, J=8.6 Hz), 8.20 (1H, dd, J=8.9 Hz, 2.6 Hz), 8.48 (1H, d, J=2.3 Hz), 10.46 (1H, s).

TABLE 132

Reference

Example

No.
R₃₉₈
R₃₉₉

¹H NMR (CDCl₃) δ ppm

950
—H
—NO₂
4.71 (2H, s), 7.05 (1H, d, J = 8.4 Hz),

7.25 (2H, d, J = 8.9 Hz), 7.83 (1H,

dd, J = 8.3 Hz, 2.3 Hz), 8.19 (1H, d,

J = 2.5 Hz), 8.27 (2H, d, J = 8.9 Hz).

951
—CH₃
—NO₂
2.30 (4H, brs), 4.67 (2H, s), 7.02 (1H,

d, J = 8.41 Hz), 7.12 (1H, d, J = 8.90

Hz), 7.80 (1H, dd, J = 8.41 Hz, 2.47

Hz), 8.05-8.17 (3H, m).

952
—H

embedded image

2.45 (4H, brs), 3.45 (2H, s), 3.57 (2H, brs), 3.69 (2H, brs), 4.67 (2H, s), 5.95 (2H, s), 6.74-6.77 (2H, m), 6.85 (1H, s), 6.94 (1H, d, J = 8.4 Hz), 7.14 (2H, d, J = 8.4 Hz), 7.44 (2H, d, J = 8.4 Hz), 7.76 (1H, dd, J = 2.5 Hz, 8.4 Hz), 8.16 (1H, d, J = 2.5 Hz).

953
—H

embedded image

1.96 (1H, brs), 2.40-2.44 (4H, m), 3.02 (3H, s), 3.43 (2H, brs), 3.47-3.49 (2H, m), 3.62 (2H, brs), 4.07 (2H, s), 4.62 (2H, s), 5.94 (2H, s), 6.68-6.77 (4H, m), 6.81 (1H, d, J = 8.6 Hz), 6.85 (1H, brs), 6.99 (2H, d, J = 9.2 Hz), 7.66 (1H, dd, J = 8.4 Hz, 2.5 Hz), 8.13 (1H, d, J = 2.5 Hz).

954
—H

embedded image

1.75-2.01 (1H, m), 2.22-2.50 (4H, m), 2.51-2.70 (2H, m), 2.88-3.07 (2H, m), 3.30-3.51 (4H, m), 3.52-3.78 (2H, m), 4.67 (2H, s), 5.96 (2H, s), 6.69-6.81 (2H, m), 6.83-6.88 (1H, m), 6.91 (1H, d, J = 8.4 Hz), 7.01-7.11 (2H, m), 7.19-7.29 (2H, m), 7.74 (1H, dd, J = 2.5 Hz, 8.4 Hz), 8.16 (1H, dd, J = 0.5 Hz, 2.5 Hz).

Reference Example 955
Production of 2-[4-(1-bromoethyl)phenoxy]-5-nitropyridine

2-(4-ethylphenoxy)-5-nitropyridine (7.33 g, 30 mmol) was dissolved in carbon tetrachloride (100 mL), and to the resulting solution were added N-bromosuccimide (5.34 g, 30 mmol) and benzoyl peroxide (0.73 g, 3 mmol). This solution was refluxed overnight under a nitrogen atmosphere. The reaction solution was allowed to cool, after which insoluble matter was removed by filtration. The resulting filtrate was washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 1.34 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 2.08 (3H, d, J=6.9 Hz), 526 (1H, q, J=6.9 Hz), 7.05 (1H, d, J=9.1 Hz), 7.15 (2H, d, J=8.6 Hz), 7.53 (2H, d, J=8.7 Hz), 8.49 (1H, dd, J=9.1 Hz, 2.8 Hz), 9.04 (1H, d, J=2.8 Hz).

Reference Example 956
Production of N-[6-(4-chloromethylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide

To a solution of N-(6-(4-hydroxymethylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide (3.06 g, 7.9 mmol) in dichloromethane (90 mL) was added thionyl chloride (1.7 mL, 23.3 mmol), and the resulting solution was stirred for 4 hours at room temperature. To the residue was added a saturated sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was washed with diethyl ether, to thereby yield 2.95 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 4.61 (2H, s), 7.00 (1H, d, J=8.9 Hz), 7.11-7.14 (2H, m), 7.41-7.44 (2H, m), 7.77 (2H, d, J=8.4 Hz), 7.89 (1H, brs), 8.00 (2H, d, J=8.4 Hz), 8.22-8.28 (2H, m).

The following compounds were produced in the same manner as in Reference Example 956.

Reference Example 957
3,4-Dichloro-N-[4-(4-chloromethylphenoxy)-3-fluorophenyl]benzamide

¹H NMR (CDCl₃) δ 4.58 (2H, s), 6.95 (2H, d, J=8.6 Hz), 7.10 (1H, t, J=8.6 Hz), 7.20-7.30 (1H, m), 7.30-7.40 (3H, m), 7.59 (1H, d, J=8.3 Hz), 7.65-7.78 (2H, m), 7.96 (1H, d, J=2.1 Hz).

TABLE 133

Reference

Example

No.
R₄₀₀
R₄₀₁

¹H NMR (CDCl₃) δ ppm

958
—NO₂
—CH₂Cl
4.63 (2H, s), 7.06 (1H, d, J = 8.9

Hz), 7.16 (2H, dd, J = 6.6 Hz, 2.0

Hz), 7.47 (2H, d, J = 8.3 Hz),

8.47-8.51 (1H, m), 9.04 (1H, d,

J = 2.6 Hz)

959
3,4-Cl₂PhCONH—
—CH₂Cl
4.59 (2H, s), 6.95 (1H, d, J = 8.9

Hz), 7.10 (2H, d, J = 8.6 Hz), 7.40

(2H, d, J = 8.6 Hz), 7.54 (1H, d,

J = 8.2 Hz), 7.71-7.75 (1H, m),

7.99 (1H, d, J = 2.3 Hz), 8.18-8.22

(2H, m), 8.30 (1H, d, J = 2.6 Hz).

960
4-CNPhCONH—
—CH₂Cl
4.60 (2H, s), 6.99 (1H, d, J = 8.9

Hz), 7.12 (2H, d, J = 8.6 Hz), 7.42

(2H, d, J = 8.6 Hz), 7.79 (2H, d,

J = 8.3 Hz), 7.97-8.00 (3H, m),

8.21 (1H, dd, J = 8.9 Hz, 2.6 Hz),

8.27 (1H, d, J = 2.6 Hz).

961
4-ClPhCONH—
—CH₂Cl
4.61 (2H, s), 6.99 (1H, d, J = 9.6

Hz), 7.12 (2H, d, J = 8.3 Hz), 7.42

(2H, d, J = 8.3 Hz), 7.48 (2H, d,

J = 8.3 Hz), 7.75 (1H, brs), 7.85

(2H, d, J = 8.3 Hz), 8.20-8.25 (2H,

m).

962
—CH₂Cl

embedded image

2.41-2.45 (4H, m), 3.03 (3H, s), 3.43 (2H, brs), 3.49 (2H, brs), 3.63 (2H, brs), 4.08 (2H, s), 4.54 (2H, s), 5.94 (2H, s), 6.70 (2H, d, J = 9.2 Hz), 6.73-6.77 (2H, m), 6.82 (1H, d, J = 8.6 Hz), 6.85 (1H, brs), 7.00 (2H, d, J = 9.2 Hz), 7.67 (1H, dd, J = 8.6 Hz, 2.5 Hz), 8.15 (1H, d, J = 2.5 Hz).

(CNPh means a cyanophenyl group. Hereinafter CNPh indicates the same meaning.)

Reference Example 963
Production of 3,4-dichloro-N-{6-[4-(5-chloropentyl)phenoxy]pyridin-3-yl}benzamide hydrochloride

To 3,4-dichloro-N-{6-[4-(5-hydroxypentyl)phenoxy]pyridin-3-yl}benzamide (6.83 g, 15.34 mmol) was added thionyl chloride (35 mL). The resulting solution was stirred for 20 minutes at room temperature, followed by stirring for 1 hour at 50° C. Excess thionyl chloride was evaporated, after which to the resulting residue was added ethyl acetate (100 mL). The obtained white powder was filtered, and washed with ethyl acetate, to thereby yield 6.98 g of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 1.33-1.50 (2H, m), 1.50-1.68 (2H, m), 1.68-1.85 (2H, m), 2.59 (2H, t, J=7.6 Hz), 3.64 (2H, t, J=6.6 Hz), 7.02 (2H, d, J=8.5 Hz), 7.03 (1H, d, J=9.0 Hz), 7.23 (2H, d, J=8.5 Hz), 7.83 (1H, d, J=8.5 Hz), 7.97 (1H, dd, J=8.5 Hz, 2.0 Hz), 8.20 (1H, dd, J=9.0 Hz, 2.5 Hz), 8.25 (1H, d, J=2.0 Hz), 8.50 (1H, d, J=2.5 Hz), 10.63 (1H, s).

The following compounds were produced in the same manner as in Reference Example 963.

TABLE 134

Refer-

ence

Exam-

¹H NMR

ple

(solvent)

No.
R₄₀₂
R₄₀₃
M
Form
δ ppm

964
—Cl
—Cl
2
free
(CDCl₃) 3.04-3.10 (2H, m),

3.69-3.75 (2H, m), 6.95

(1H, d, J = 8.6 Hz),

7.06-7.09 (2H, m), 7.24

(2H, d, J = 8.2 Hz), 7.56

(1H, d, J = 8.2 Hz), 7.69

(1H, dd, J = 8.2 Hz, 2.0

Hz), 7.93 (1H, brs), 7.97

(1H, d, J = 2.0 Hz),

8.15-8.19 (1H, m), 8.24

(1H, d, J = 2.6 Hz).

965
—Cl
—Cl
3
free
(CDCl₃) 2.04-2.12 (2H, m),

2.76-2.81 (2H, m),

3.53-3.58 (2H, m), 6.94

(1H, d, J = 8.9 Hz),

7.04-7.07 (2H, m),

7.20-7.26 (2H, m), 7.56

(1H, d, J = 8.1 Hz), 7.70

(1H, dd, J = 8.4 Hz, 2.2

Hz), 7.90 (1H, brs), 7.97

(1H, d, J = 2.2 Hz),

8.14-8.18 (1H, m), 8.24

(1H, d, J = 2.7 Hz).

966
—CF₃
—H
3
free
(CDCl₃) 2.04-2.14 (2H, m),

2.75-2.81 (2H, m),

3.53-3.57 (2H, m), 6.93

(1H, d, J = 8.7 Hz),

7.03-7.07 (2H, m),

7.20-7.23 (2H, m), 7.73

(2H, d, J = 8.2 Hz), 7.97

(2H, d, J = 8.2 Hz), 8.09

(1H, brs), 8.16-8.21 (1H,

m), 8.25 (1H, d, J = 2.6

Hz).

967
—Cl
—Cl
4
hydro-
(DMSO-d₆) 1.60-1.85 (4H,

chloride
m), 2.62 (2H, t, J = 6.3 Hz),

3.68 (2H, t, J = 6.3 Hz),

7.03 (2H, d, J = 8.5 Hz),

7.04 (1H, d, J = 9.0 Hz),

7.24 (2H, d, J = 8.5 Hz),

7.83 (1H, d, J = 8.6 Hz),

7.97 (1H, dd, J = 8.6 Hz,

2.0 Hz), 8.20 (1H, dd,

J = 9.0 Hz, 2.7 Hz), 8.25

(1H, d, J = 2.2 Hz), 8.50

(1H, d, J = 2.7 Hz), 10.64

(1H, s).

Reference Example 968
Production of N-{6-[4-(2-bromoacetyl)phenoxy]pyridin-3-yl}-3,4-dichlorobenzamide

N-[6-(4-acetylphenoxy)pyridin-3-yl}-3,4-dichlorobenzamide (4.0 g, 10 mmol) was dissolved in chloroform (200 mL). To the resulting solution was added copper bromide (5.76 g, 25 mmol), and refluxed overnight. The resulting reaction solution was filtered, and the filtrate was washed with saturated sodium thiosulfate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. To the filtered product from the earlier step was added ethyl acetate, and washed with saturated sodium thiosulfate water and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residues were combined for purification by silica gel column chromatography (n-hexane:ethyl acetate 3:1), to thereby yield 1.86 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 4.43 (2H, s), 7.06 (1H, d, J=8.7 Hz), 7.21 (2H, d, J=8.9 Hz), 7.57 (1H, d, J=8.4 Hz), 7.72 (1H, dd, J=8.4 Hz, 2.0 Hz), 7.99 (1H, d, J=2.0 Hz), 8.03 (2H, d, J=8.9 Hz), 8.09 (1H, brs), 8.27 (1H, dd, J=8.7 Hz, 2.8 Hz), 8.32 (1H, d, J=2.2 Hz).

The following compound was produced in the same manner as in Reference Example 968.

Reference Example 969
N-{4-[4-(2-Bromoacetyl)phenoxy]-3-fluorophenyl}-3,4-dichlorobenzamide

¹H NMR (DMSO-D₆) δ 4.88 (2H, s), 7.06 (2H, d, J=8.9 Hz), 7.30-7.50 (1H, m), 7.60-7.70 (1H, m), 7.80-8.20 (5H, m), 8.22 (1H, d, J=2.0 Hz), 10.67 (1H, brs).

Reference Example 970
Production of 4′-[4-(3-bromopropyl)phenoxy]-3,4-dichloro-3′-fluorobenzanilide

To a suspension of 3,4-dichloro-3′-fluoro-4′-[4-(3-hydroxypropyl)phenoxy]benzanilide (2.32 g, 5.34 mmol) in dichloromethane (46 mL) were added carbon tetrabromide (2.13 g, 6.41 mmol) and triphenylphosphine (1.54 g, 5.88 mmol), and the resulting solution was stirred for 12 hours at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate 5:1), to thereby yield 2.41 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 2.08-2.11 (2H, m), 2.73 (2H, t, J=7.3 Hz), 3.38 (2H, t, J=6.5 Hz), 6.88 (2H, d, J=8.5 Hz), 7.02 (1H, dd, J=9.0 Hz, 8.0 Hz), 7.13 (2H, d, J=8.5 Hz), 7.17-7.28 (1H, m), 7.54 (1H, d, J=8.3 Hz), 7.60-7.74 (2H, m), 7.85 (1H, brs), 7.93 (1H, d, J=2.0 Hz).

The following compounds were produced in the same manner as in Reference Example 97

TABLE 135

Reference

Example

No.
M

¹H NMR (CDCl₃) δ ppm

971
2
3.13 (2H, t, J = 7.5 Hz), 3.55 (2H, t, J = 7.5 Hz), 6.91

(2H, d, J = 6.6 Hz), 7.08 (1H, t, J = 8.7 Hz), 7.15 (2H,

d, J = 6.6 Hz), 7.18-7.25 (1H, m), 7.56 (1H, d, J = 8.3

Hz), 7.65-7.75 (2H, m), 7.90-8.00 (2H, m).

972
4
1.67-1.79 (2H, m), 1.81-1.94 (2H, m), 2.60 (2H, t,

J = 7.5 Hz), 3.40 (2H, t, J = 6.6 Hz), 6.88 (2H, d,

J = 8.6 Hz), 7.02 (1H, dd, J = 9.0 Hz, 8.0 Hz), 7.11

(2H, d, J = 8.6 Hz), 7.14-7.21 (1H, m), 7.55 (1H, d,

J = 8.3 Hz), 7.60-7.73 (2H, m), 7.78 (1H, brs), 7.93

(1H, d, J = 1.9 Hz).

Reference Example 973
Production of t-butyl 4-[4-(5-nitropyridin-2-yloxy)benzyl]piperazine-1-carboxylate

To a solution of 2-(4-chloromethylphenoxy)-5-nitropyridine (12.32 g, 47 mmol) in DMF (120 mL) were added triethylamine (19.4 mL, 140 mmol) and t-butyl piperazine-1-carboxylate (11.27 g, 61 mmol), and the resulting solution was stirred for 3 hours at 50° C. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1), to thereby yield 11.26 g of the title compound.

Appearance: Yellow powder

¹H NMR (CDCl₃) δ 1.46 (9H, s), 2.40-2.44 (4H, m), 3.43-3.46 (4H, m), 3.54 (2H, s), 7.04 (1H, d, J=8.9 Hz), 7.09-7.14 (2H, m), 7.38-7.44 (2H, m), 8.48 (1H, dd, J=8.9 Hz, 2.8 Hz), 9.05 (1H, d, J=2.8 Hz).

The following compound was produced in the same manner as in Reference Example 973.

Reference Example 974
4-{1-[4-(5-Nitropyridin-2-yloxy)phenyl]ethyl}morpholine

¹H NMR (CDCl₃) δ 1.38 (3H, d, J=6.8 Hz), 2.36-2.54 (4H, m), 3.37 (1H, q, J=6.8 Hz), 3.69-3.72 (4H, m), 7.02 (1H, dd, J=9.1 Hz, 0.5 Hz), 7.11 (2H, d, J=8.6 Hz), 7.40 (2H, d, J=8.5 Hz), 8.47 (1H, dd, J=9.1 Hz, 2.8 Hz), 9.06 (1H, dd, J=2.8 Hz, 0.5 Hz).

Reference Example 975
Production of methanesulfonic acid 6-(4-nitrophenoxy)pyridin-3-ylmethyl ester

[6-(4-nitrophenoxy)pyridin-3-yl]methanol (6.1 g, 24.8 mmol) was dissolved in dichloromethane (150 mL), and to the resulting solution was added, triethylamine (4.15 mL, 29.8 mmol) under ice cooling. To the resulting solution was added dropwise methanesulfonic acid chloride (2.11 mL, 27.3 mmol), and then stirred under a nitrogen atmosphere for 30 minutes at 0° C. The reaction solution was washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. To the residue was added a mixed solvent (50 mL) of n-hexane:ethyl acetate=1:1. The precipitated crystals were removed by suction filtration, to thereby yield 7.9 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 3.04 (3H, s), 5.23 (2H, s), 7.09 (1H, d, J=8.4 Hz), 7.29 (2H, d, J=9.1 Hz), 7.88 (1H, dd, J=8.4 Hz, 2.5 Hz), 8.23 (1H, d, J=2.3 Hz), 8.28 (2H, d, J=9.1 Hz).

The following compounds were produced in the same manner as in Reference Example 975.

TABLE 136

Reference

Example

No.
R₄₀₄
R₄₀₅

¹H NMR (CDCl₃) δ ppm

976
—CH₃
—NO₂
2.29 (3H, s), 3.03 (3H, s), 5.22 (2H, s), 7.08

(1H, dd, J = 8.4 Hz, 0.5 Hz), 7.18 (1H, d,

J = 8.9 Hz), 7.86 (1H, dd, J = 8.4 Hz, 2.5

Hz), 8.11 (1H, dd, J = 8.9 Hz, 2.8 Hz), 8.17

(1H, dd, J = 2.5 Hz, 0.5 Hz), 8.19 (1H, d,

J = 2.8 Hz).

977
—H

embedded image

2.65 (4H, brs), 3.01 (3H, s), 3.65-3.75 (6H, m), 5.22 (2H, s), 5.97 (2H, s), 6.79 (2H, s), 6.92 (1H, s), 7.00 (1H, d, J = 8.4 Hz), 7.18 (2H, d, J = 8.6 Hz), 7.47 (2H, d, J = 8.7 Hz), 7.81 (1H, dd, J = 2.5 Hz, 8.4 Hz), 8.20 (1H, d, J = 2.0 Hz).

Reference Example 978
Production of 2-(4-nitrophenoxy)-5-(4-trifluoromethylphenoxymethyl)pyridine

Methanesulfonic acid 6-(4-nitrophenoxy)pyridin-3-ylmethyl ester (4.86 g, 15 mmol) was dissolved in DMF (250 mL), and to the resulting solution were added 4-hydroxybenzotrifluoride (2.92 g, 18 mmol) and potassium carbonate (3.11 g, 22.5 mmol). The resulting solution was stirred under a nitrogen atmosphere for 1 hour at 50° C. The reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate, and washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=80:1), to thereby yield 5.8 g of the title compound.

Appearance: Pale yellow powder

¹H NMR (CDCl₃) δ 5.09 (2H, s), 7.02-7.10 (3H, m), 7.26-7.31 (2H, m), 7.56-7.59 (2H, m), 7.88 (1H, dd, J=8.4 Hz, 2.5 Hz), 8.25-8.31 (3H, m).

The following compound was produced in the same manner as in Reference Example 978.

Reference Example 979
2-(2-Methyl-4-nitrophenoxy)-5-(4-trifluoromethyl-phenoxymethyl)pyridine

¹H NMR (CDCl₃) δ 2.31 (3H, s), 5.07 (2H, s), 7.03 (2H, d, J=8.6 Hz), 7.08 (1H, d, J=8.4 Hz), 1.17 (1H, d, J=8.9 Hz), 7.57 (2H, d, J=8.4 Hz), 7.87 (1H, dd, J=8.4 Hz, 2.5 Hz), 8.10 (1H, dd, J=8.9 Hz, 2.8 Hz), 8.18 (1H, d, J=2.6 Hz), 8.21 (1H, d, J=2.5 Hz).

Example 1
Production of N-{6-[4-(4-benzylpiperazine-1-carbonyl)phenoxy]pyridin-3-yl}-4-trifluoromethylbenzamide

To a solution of 4-[5-(4-trifluoromethylbenzoylamino)pyridin-2-yloxy]benzoic acid (1.19 g, 2.3 mmol) in DMF (30 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (530 mg, 2.8 mmol), 1-hydroxybenzotriazole monohydrate (370 mg, 2.7 mmol) and benzylpiperazine (0.475 mL, 2.7 mmol) under ice cooling. The resulting solution was stirred for 1 day gradually warming up to room temperature. To the residue was added a saturated sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (methanol:chloroform=1:19), to thereby yield 800 mg of the title compound.

Appearance: White needles

¹H NMR (CDCl₃) δ 2.46 (4H, brs), 3.55 (2H, s), 3.72 (4H, brs), 6.96 (1H, d, J=8.9 Hz), 7.10-7.13 (2H, m), 7.28-7.40 (7H, m), 7.74 (2H, d, J=8.3 Hz), 8.02 (2H, d, J=8.3 Hz), 8.16-8.21 (1H, m), 8.32 (1H, d, J=2.6 Hz), 8.53 (1H, brs).

The following compounds were produced in the same manner as in Example 1.

TABLE 137

Example

No.
R₅₀₁
R₅₀₂
Form
mp (° C.)

2
—H
—CH₃
hydrochloride
175-176

3
—H
benzyl
hydrochloride
187-189

4
—H
piperonyl
free
182-183

5
—H
—COOC(CH₃)₃
free
217-220

6
—H
—Ac
free
152-154

7
—H
—(CH₂)₂OH
hydrochloride
153-155

8
—F
benzyl
free
172-173

9
—F
piperonyl
free
170-171

TABLE 138

Example

No.
R₅₀₃
R₅₀₄
Form
mp (° C.)

10
—H
morpholino
free
189-192

11
—F
morpholino
free
203-204

12
—F

embedded image

free
210-211

13
—F

embedded image

hydrochloride
233-235

14
—F

embedded image

hydrochloride
247-249

15
—H

embedded image

free
174-175

16
—H

embedded image

hydrochloride
213-216

TABLE 139

Example

No.
R₅₀₅
R₅₀₆

¹H NMR (DMSO-d₆) δ ppm

17
—CH₃
—NHAc
1.92 (3H, s), 2.17 (3H, s), 7.13 (1H,

d, J = 8.2 Hz), 7.14 (1H, d, J = 8.9

Hz), 7.74 (1H, dd, J = 8.2 Hz, 2.2

Hz), 7.84 (1H, d, J = 8.2 Hz), 7.84

(1H, d, J = 2.2 Hz), 7.95 (1H, dd,

J = 8.2 Hz, 2.2 Hz), 8.22 (1H, d,

J = 2.2 Hz), 8.23 (1H, dd, J = 8.9 Hz,

2.6 Hz), 8.46 (1H, d, J = 2.6 Hz),

9.89 (1H, s), 10.24 (1H, s), 10.57

(1H, s).

18
—H
cyclopropyl
0.51-0.60 (2H, m), 0.66-0.74 (2H,

m), 2.80-2.89 (1H, m), 7.10-7.20

(3H, m), 7.81-7.89 (3H, m), 7.95

(1H, dd, J = 8.4 Hz, 2.1 Hz),

8.19-8.28 (2H, m), 8.42 (1H, brd),

8.52 (1H, d, J = 2.7 Hz), 10.59 (1H,

s).

19
—H
cyclohexyl
1.06-1.19 (1H, m), 1.21-1.36 (4H,

m), 1.55-1.65 (1H, m), 1.69-1.78

(2H, m), 1.78-1.87 (2H, m),

3.69-3.80 (1H, m), 7.10-7.20 (3H,

m), 7.85 (1H, d, J = 8.4 Hz),

7.86-7.92 (2H, m), 7.95 (1H, dd,

J = 8.4 Hz, 2.1 Hz), 8.17 (1H, brd),

8.20-8.29 (2H, m), 8.52 (1H, d,

J = 2.7 Hz), 10.58 (1H, s).

20
—H
cyclopentyl
1.46-1.60 (4H, m), 1.63-1.76 (2H,

m), 1.82-1.94 (2H, m), 4.17-4.28

(1H, m), 7.10-7.20 (3H, m), 7.85

(1H, d, J = 8.4 Hz), 7.87-7.92 (2H,

m), 7.95 (1H, dd, J = 8.4 Hz, 2.1 Hz),

8.19-8.28 (3H, m), 8.52 (1H, d,

J = 2.6 Hz), 10.58 (1H, s).

21
—H
cycloheptyl
1.36-1.71 (10H, m), 1.80-1.90 (2H,

m), 3.88-4.00 (1H, m), 7.10-7.20

(3H, m), 7.85 (1H, d, J = 8.4 Hz),

7.86-7.92 (2H, m), 7.95 (1H, dd,

J = 8.4 Hz, 2.1 Hz), 8.17-8.28 (3H,

m), 8.51 (1H, d, J = 2.6 Hz), 10.58

(1H, s).

22
—H
cyclododecanyl
1.20-1.57 (20H, m), 1.61-1.73 (2H,

m), 4.08-4.21 (1H, m), 7.10-7.21

(3H, m), 7.85 (1H, d, J = 8.4 Hz),

7.88-7.92 (2H, m), 7.95 (1H, dd,

J = 8.4 Hz, 2.1 Hz), 8.09 (1H, brd),

8.20-8.29 (2H, m), 8.51 (1H, d,

J = 2.7 Hz), 10.58 (1H, s).

23
—H
cyclooctyl
1.44-1.65 (8H, m), 1.65-1.80 (6H,

m), 3.98-4.09 (1H, m), 7.10-7.20

(3H, m), 7.85 (1H, d, J = 8.4 Hz),

7.88-7.92 (2H, m), 7.95 (1H, dd,

J = 8.4 Hz, 2.1 Hz), 8.17-8.27 (3H,

m), 8.51 (1H, d, J = 2.7 Hz), 10.58

(1H, s).

24
—H
cyclopropyl-
0.19-0.26 (2H, m), 0.38-0.47 (2H,

methyl
m), 0.99-1.09 (1H, m), 3.12-3.19

(2H, m), 7.12-7.21 (3H, m), 7.85

(1H, d, J = 8.4 Hz), 7.89-7.94 (2H,

m), 7.95 (1H, dd, J =8.4 Hz, 2.1 Hz),

8.21-8.29 (2H, m), 8.53 (1H, d,

J = 2.8 Hz), 8.54 (1H, brt), 10.60

(1H, s).

25
—H
—(CH₂)₂NHAc
1.81 (3H, s), 3.15-3.24 (2H, m),

3.24-3.33 (2H, m), 7.10-7.20 (3H,

m), 7.80-8.00 (5H, m), 8.20-8.26

(2H, m), 8.48 (1H, brt), 8.52 (1H, d,

J = 2.6 Hz), 10.59 (1H, s).

TABLE 140

Example

No.
R₅₀₇
Form

¹H NMR (solvent) δ ppm or MS

26
morpholino
hydro-

¹H NMR (DMSO-d₆) 3.50-3.65 (8H, m), 7.13-7.19

chloride
(3H, m), 7.47 (2H, d, J = 8.6 Hz), 7.84 (1H, d, J = 8.2

Hz), 7.97 (1H, dd, J = 8.3 Hz, 2.0 Hz), 8.23-8.27 (2H,

m), 8.54 (1H, d, J = 2.6 Hz), 10.63 (1H, s).

27

embedded image

free

¹H NMR (CDCl₃) 1.81-1.95 (2H, m), 2.59-2.77 (4H, m), 3.51-3.57 (4H, m), 3.75 (2H, brs), 5.94 (2H, s), 6.71-6.75 (2H, m), 6.83-6.93 (2H, m), 7.05-7.10 (2H, m), 7.32-7.37 (2H, m), 7.54 (1H, d, J = 8.2 Hz), 7.79 (1H, dd, J = 8.3 Hz, 2.0 Hz), 8.06-8.10 (2H, m), 8.30 (1H, s), 8.96 (1H, s).

28

embedded image

free
MS 574 (M⁺)

29

embedded image

free
MS 611 (M⁺)

30
—NH(CH₂)₂OCH₃
free

¹H NMR (DMSO-d₆) 3.32 (3H, s), 3.39-3.48 (4H, m),

7.15-7.20 (3H, m), 7.85 (1H, d, J = 8.3 Hz),

7.86-7.92 (2H, m), 7.95 (1H, dd, J = 8.4 Hz, 2.1 Hz),

8.20-8.26 (2H, m), 8.50 (1H, brt), 8.52 (1H, d, J = 2.5

Hz), 10.59 (1H, s).

31

embedded image

free
MS 601 (M⁺ − 1)

32

embedded image

free

¹H NMR (DMSO-d₆) 0.86-0.99 (2H, m), 1.10-1.27 (3H, m), 1.50-1.65 (2H, m), 1.65-1.78 (4H, m), 3.06-3.15 (2H, m), 7.11-7.22 (3H, m), 7.85 (1H, d, J = 8.4 Hz), 7.88-7.92 (2H, m), 7.95 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.20-8.28 (2H, m), 8.40 (1H, brt), 8.52 (1H, d, J = 2.7 Hz), 10.58 (1H, s).

33
—NH(CH₂)₂OPh
free

¹H NMR (DMSO-d₆) 3.63 (2H, t, J = 5.8 Hz), 4.12

(2H, t, J = 5.9 Hz), 6.90-7.01 (3H, m), 7.13-7.24 (3H,

m), 7.26-7.35 (2H, m), 7.85 (1H, d, J = 8.4 Hz),

7.90-8.00 (3H, m), 8.20-8.30 (2H, m), 8.52 (1H, d,

J = 2.6 Hz), 8.69 (1H, brt), 10.59 (1H, s).

34

embedded image

free
MS 574 (M⁺)

35

embedded image

free

¹H NMR (CDCl₃) 1.80-1.96 (2H, m), 2.61-2.79 (4H, m), 3.45-3.57 (2H, m), 3.62-3.67 (2H, m), 3.75-3.77 (2H, m), 6.94 (1H, d, J = 8.6 Hz), 7.08-7.13 (2H, m), 7.24-7.41 (7H, m), 7.56 (1H, d, J = 8.6 Hz), 7.76 (1H, dd, J = 8.6 Hz, 2.0 Hz), 8.04 (1H, d, J = 2.0 Hz), 8.07-8.14 (1H, m), 8.29 (1H, d, J = 2.0 Hz), 8.39 (1H, s).

TABLE 141

Example

No.
R₅₀₈
Property

36

embedded image

mp 221-224° C.

37

embedded image

mp 228-230° C.

38

embedded image

mp 193-194° C.

39
—N(CH₃)COOC(CH₃)₃

¹H NMR (CDCl₃) δ 1.47 (9H, s), 1.45-1.81 (4H, m),

2.73 (3H, s), 2.90 (2H, brs), 4.10 (2H, brs), 4.75 (1H,

brs), 6.95 (1H, d, J = 8.7 Hz), 7.11 (2H, d, J = 8.7 Hz),

7.39 (2H, d, J = 8.7 Hz), 7.55 (1H, d, J = 8.2 Hz), 7.77

(1H, dd, J = 8.2 Hz, 2.0 Hz), 8.05 (1H, d, J = 2.0 Hz),

8.14 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.30 (1H, d, J = 2.6

Hz), 8.77 (1H, s).

40
—OPh
MS 560 (M⁺ − 1)

41
4-CF₃PhO—
MS 629 (M⁺)

42
4-CF₃OPhO—
MS 644 (M⁺)

43
4-CNPhO—
MS 586 (M⁺)

44
—C₂H₅
MS 496 (M⁺ − 1)

45
—COOC₂H₅

¹H NMR (CDCl₃) δ 1.27 (3H, t, J = 7.0 Hz), 1.73 (2H,

brs), 1.95 (2H, brs), 2.58 (1H, m), 3.08 (2H, brs), 3.86

(1H, brs), 4.16 (2H, q, J = 7.0 Hz), 4.50 (1H, brs), 6.97

(1H, d, J = 9.0 Hz), 7.12 (2H, d, J = 8.5 Hz), 7.40 (2H,

d, J = 8.5 Hz), 7.57 (1H, d, J = 8.5 Hz), 7.75 (1H, dd,

J = 8.5 Hz, 2.0 Hz), 8.03 (1H, d, J = 2.0 Hz), 8.16 (1H,

dd, J = 9.0 Hz, 3.0 Hz), 8.30 (1H, d, J = 3.0 Hz), 8.34

(1H, brs).

46
—(CH₂)₂N(CH₃)Ph
MS 602 (M⁺)

47
2-FPhCH₂O—
MS 592 (M⁺ − 1)

48
PhCH₂O—
MS 574 (M⁺ − 1)

49
cyclohexyl
MS 550 (M⁺ − 1)

50
4-ClPh—
MS 580 (M⁺ + 1)

51
—Ph
MS 544 (M⁺ − 1)

52
—CHPh₂
MS 635 (M⁺)

53
2-NH₂PhCO—
MS 587 (M⁺ − 1)

54
4-CH₃OPhCONH—
MS 617 (M⁺ − 1)

55
—NHCOPh
MS 587 (M⁺ − 1)

56
4-CF₃PhCH₂O—
mp 186-187° C.

57
4-ClPhCH₂O—
mp 176-177° C.

TABLE 142

Example

No.
R₅₀₉
MS

58

embedded image

580 (M⁺ − 1)

59

embedded image

610 (M⁺ − 1)

60

embedded image

580 (M⁺ − 1)

61

embedded image

598 (M⁺ − 1)

62

embedded image

592 (M⁺ − 1)

63
Ph(CH₂)₂N(CH₃)—
600

(M⁺ − 2)

64
Ph₂CH(CH₂)₂N(CH₃)—
691

(M⁺ − 1)

65
4-CH₃SPh(CH₂)₂N(CH₃)—
648

(M⁺)

66

embedded image

678 (M⁺ + H)

67

embedded image

613 (M⁺ + H)

68
4-CH₃OPh(CH₂)₄N(CH₃)—
660

(M⁺)

69
4-CH₃Ph(CH₂)₂N(CH₃)—
617

(M⁺ + H)

70
PhO(CH₂)₂N(CH₃)—
618

(M⁺)

71
PhN(CH₃)(CH₂)₂N(CH₃)—
631

(M⁺)

72

embedded image

608 (M⁺)

73
—O(CH₂)₂Ph
588

(M⁺ − 1)

74

embedded image

575 (M⁺ − 1)

75

embedded image

576 (M⁺)

76
4-ClPhCH₂—
594

(M⁺ + 1)

77
4-CF₃PhNH—
644

(M⁺)

TABLE 143

Example

No.
R₅₁₀
MS

78
4-CH3PhO(CH₂)₂N(CH₃)—
633 (M⁺ + H)

79
Ph(CH₂)₃N(CH₃)—
616 (M⁺)

80
2-phenylmorpholino
630 (M⁺)

81
4-CH₃PhCH₂—
572 (M⁺ − 1)

82
morpholino
554 (M⁺)

83
4-CH₃OPhCH₂O—
606 (M⁺ + H)

84
3-ClPhCH₂O—
608 (M⁺ − 1)

85
2-ClPhCH₂O—
608 (M⁺ − 1)

86
3,4-Cl₂PhCH₂O—
644 (M⁺ + 1)

87
3-CH₃OPhCH₂O—
604 (M⁺ − 1)

88
3,5-(CH₃O)₂PhCH₂O—
634 (M⁺ − 1)

89
4-CH₃PhCH₂O—
588 (M⁺ − 1)

90
3-CH₃PhCH₂O—
588 (M⁺ − 1)

91
2-CH₃PhCH₂O—
588 (M⁺ − 1)

92
3,4-(CH₃)₂PhCH₂O—
602 (M⁺ − 1)

93
4-FPhCH₂O—
592 (M⁺ − 1)

94
3-FPhCH₂O—
592 (M⁺ − 1)

95
3,5-F₂PhCH₂O—
610 (M⁺ − 1)

96
2-CF₃PhCH₂O—
642 (M⁺ − 1)

97
4-CF₃OPhCH₂O—
658 (M⁺ − 1)

98
3-CF₃OPhCH₂O—
658 (M⁺ − 1)

99
2-CF₃OPhCH₂O—
658 (M⁺ − 1)

100

embedded image

638 (M⁺ − 1)

TABLE 144

Example

No.
R₅₁₁
mp (° C.) or ¹H NMR (CDCl₃) δ ppm

101

embedded image

mp 218-220

102

embedded image

mp 227-231

103

embedded image

¹H NMR 1.09-1.30 (1H, m), 1.60-1.87 (4H, m), 2.55-2.95 (4H, m), 3.80 (1H, brs), 4.59 (1H, brs), 6.92 (1H, d, J = 8.7 Hz), 7.05-7.35 (9H, m), 7.71 (2H, d, J = 8.6 Hz), 8.04 (2H, d, J = 8.1 Hz), 8.14 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.34 (1H, d, J = 2.6 Hz), 8.99 (1H, s).

104

embedded image

¹H NMR 1.27 (3H, t, J = 7.0 Hz), 1.74 (2H, brs), 1.95 (2H, brs), 2.58 (1H, m), 3.08 (2H, brs), 3.92 (1H, brs), 4.17 (2H, q, J = 7.0 Hz), 4.51 (1H, brs), 7.01 (1H, d, J = 9.0 Hz), 7.16 (2H, d, J = 8.5 Hz), 7.44 (2H, d, J = 8.5 Hz), 7.78 (2H, d, J = 8.0 Hz), 7.88 (1H, brs), 8.01 (2H, d, J = 8.0 Hz), 8.24 (1H, dd, J = 9.0 Hz, 3.0 Hz), 8.32 (1H, d, J = 3.0 Hz)

105

embedded image

¹H NMR 1.46 (9H, s), 1.50-1.90 (4H, m), 2.35-3.00 (2H, m), 2.89 (3H, s), 4.10-4.70 (3H, m), 6.99 (1H, d, J = 8.7 Hz), 7.14 (2H, d, J = 8.3 Hz), 7.40 (2H, d, J = 8.3 Hz), 7.76 (2H, d, J = 8.1 Hz), 8.03 (2H, d, J = 8.1 Hz), 8.22 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.33 (1H, d, J = 2.6 Hz), 8.34 (1H, brs).

TABLE 145

Example

¹H NMR (CDCl₃) δ ppm

No.
R₅₁₂
or MS

106
4-CH₃OPhCH(Ph)—
MS 665 (M⁺ − 1)

107
4-CH₃OPhCOCH₂—

¹H NMR 2.63 (4H, brs),

3.65 (4H, brs), 3.82 (2H,

s), 3.88 (3H, s), 6.92-6.98

(3H, m), 7.12 (2H, d,

J = 8.7 Hz), 7.41 (2H, d,

J = 8.7 Hz), 7.56 (1H, d,

J = 8.2 Hz), 7.75 (1H, dd,

J = 8.2 Hz, 2.1 Hz), 7.97

(2H, d, J = 8.9 Hz), 8.03

(1H, d, J = 2.0 Hz), 8.16

(1H, dd, J = 8.9 Hz, 2.8

Hz), 8.30 (1H, d, J = 2.8

Hz), 8.39 (1H, s).

108
4-ClPhCOCH₂—

¹H NMR 2.63 (4H, brs),

3.66 (4H, brs), 3.83 (2H,

s), 6.97 (1H, d, J = 8.7

Hz), 7.13 (2H, d, J = 8.6

Hz), 7.39-7.47 (4H, m),

7.56 (1H, d, J = 8.4 Hz),

7.74 (1H, dd, J = 8.2 Hz,

2.1 Hz), 7.94 (2H, d,

J = 8.6 Hz), 8.02 (1H, d,

J = 2.0 Hz), 8.16 (1H, dd,

J = 8.7 Hz, 2.8 Hz), 8.30

(1H, d, J = 2.8 Hz), 8.37

(1H s).

109
3-pyridyl

¹H NMR 3.20 (4H, brs),

3.78 (4H, brs), 6.93 (1H,

d, J = 8.7 Hz), 7.11 (2H,

d, J = 8.6 Hz), 7.19-7.21

(2H, m), 7.39 (2H, d,

J = 8.6 Hz), 7.46 (1H, d,

J = 8.4 Hz), 7.76 (1H, dd,

J = 8.4 Hz, 2.0 Hz), 8.03

(1H, d, J = 2.0 Hz),

8.11-8.25 (3H, m), 8.36

(1H, d, J = 2.5 Hz), 9.81

(1H, s).

110
—CH₂CONHPh
MS 603 (M⁺)

111
2-pyridyl
MS 547 (M⁺)

112
4-pyridyl
MS 547 (M⁺)

113

embedded image

MS 548 (M⁺)

114

embedded image

MS 548 (M⁺)

115
—(CH₂)₄Ph
MS 603 (M⁺ + H)

116
—CH(C₂H₅)₂
MS 540 (M⁺)

117
—CH(CH₃)₂
MS 511 (M⁺ − 1)

118
—(CH₂)₂N(CH₃)₂
MS 540 (M⁺ − 1)

TABLE 146

Example

No.
R₅₁₃
R₅₁₄
R₅₁₅
R₅₁₆
MS (M⁺)

119
—F
—H
—H
—H
564

120
—Cl
—H
—H
—H
582

121
—CF₃
—H
—H
—H
614

122
—OCH₃
—H
—H
—H
576

123
—CH₃
—H
—H
—H
560

124
—H
—CF₃
—H
—H
614

125
—H
—Cl
—H
—H
582

126
—H
—OCH₃
—H
—H
576

127
—H
—CH₃
—H
—H
560

128
—H
—H
—CN
—H
571

129
—H
—H
—OCF₃
—H
630

130
—H
—H
—CO₂C(CH₃)₃
—H
646

131
—H
—H
—F
—H
564

132
—H
—H
—Cl
—H
580

133
—H
—H
—OCH₃
—H
576

134
—H
—H
—CH₃
—H
560

135
—H
—H
—CF₃
—H
614

136
—H
—H
—Ph
—H
622

137
—Cl
—Cl
—H
—H
616

138
—CH₃
—CH₃
—H
—H
574

139
—H
—CH₃
—CH₃
—H
574

140
—F
—H
—F
—H
582

141
—OCH₃
—H
—H
—Cl
612

TABLE 147

Example

No.
R₅₁₇
R₅₁₈
R₅₁₉
mp (° C.) or ¹H NMR (CDCl₃) δppm

142
—H
—H
—H

¹H NMR 3.20(4H, brs), 3.79(4H, brs), 6.89-6.96(3H, m), 7.00(1H, d, J = 8.9 Hz),

7.14-7.19(2H, m), 7.27-7.33(2H, m), 7.43-7.48(2H, m), 7.76(2H, d, J = 8.1 Hz),

8.02(2H, d, J = 8.1 Hz), 8.23(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.31-8.34(2H, m).

143
—F
—H
—H
mp 193-194

144
—Cl
—H
—H

¹H NMR 3.07(4H, brs), 3.82(4H, brs), 7.00-7.06(3H, m), 7.18(2H, d, J = 8.4 Hz),

7.22-7.26(1H, m), 7.38-7.41(1H, m), 7.48(2H, d, J = 8.6 Hz), 7.77(2H, d, J = 8.1 Hz),

8.04(2H, d, J = 8.1 Hz), 8.24(1H, dd, J = 8.9 Hz, 2.4 Hz), 8.30(1H, brs), 8.35(1H, d,

J = 2.4 Hz).

145
—H
—Cl
—H

¹H NMR 3.19(4H, brs), 3.76(4H, brs), 6.77-6.81(1H, m), 6.86-6.88 (2H, m), 6.99(1H,

d, J = 8.9 Hz), 7.13-7.22(3H, m), 7.40-7.45(2H, m), 7.73(2H, d, J = 8.4 Hz), 8.02(2H,

d, J = 8.4 Hz), 8.21(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.34(1H, d, J = 2.7 Hz), 8.56(1H, s).

146
—H
—CH₃
—H

¹H NMR 2.31(3H, s), 3.15(4H, brs), 3.74(4H, brs), 6.71-6.73(3H, m), 6.97(1H, d, J =

8.9 Hz), 7.11-7.18(3H, m), 7.42(2H, d, J = 8.1 Hz), 7.72(2H, d, J = 8.1 Hz), 8.01(2H,

d, J = 8.1 Hz), 8.18-8.21(1H, m), 8.34(1H, brs), 8.54(1H, brs).

147
—H
—OCH₃
—H

¹H NMR 3.07(4H, brs), 3.73(4H, brs), 3.88(3H, s), 6.88-7.08(5H, m), 7.13-7.17(2H,

m), 7.42-7.47(2H, m), 7.75(2H, d, J = 8.4 Hz), 8.03 (2H, d, J = 7.8 Hz), 8.21(1H, dd,

J = 8.9 Hz, 2.4 Hz), 8.34(1H, d, J = 2.4 Hz), 8.45(1H, brs).

148
—H
—CF₃
—H
mp 147-177

149
—H
—H
—OH
mp 241-242

150
—H
—H
—OCH₃

¹H NMR 3.06(4H, brs), 3.63-3.91(7H, m), 6.83-6.93(4H, m), 6.99(1H, d, J = 8.6 Hz),

7.15(2H, d, J = 8.4 Hz), 7.44(2H, d, J = 8.4 Hz), 7.75 (2H, d, J = 8.4 Hz), 8.02(2H,

d, J = 8.1 Hz), 8.22(1H, dd, J = 8.9 Hz, 2.4 Hz), 8.33(1H, d, J = 2.4 Hz), 8.40(1H, brs).

151
—H
—H
—CN

¹H NMR 3.23(4H, brs), 3.79(4H, brs), 7.01(1H, d, J = 8.9 Hz), 7.12-7.19(5H, m), 7.33-

7.39(1H, m), 7.43-7.48(2H, m), 7.74(2H, d, J = 8.4 Hz), 8.02(2H, d, J = 8.4 Hz),

8.23(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.35(1H, d, J = 2.7 Hz), 8.47(1H, s).

TABLE 148

Example

No.
R₅₂₀
R₅₂₁

¹H NMR (solvent) δppm or MS

152
—H
piperonyl

¹H NMR (CDCl₃) 2.38-2.45(4H, m), 3.45(2H, s), 3.49-3.74 (4H, m), 5.95(2H, s),

6.74(2H, s), 6.85(1H, s), 6.97(1H, d, J = 8.6 Hz), 7.10(2H, d, J = 8.9 Hz), 7.41(2H,

d, J = 8.9 Hz), 7.58(1H, d, J = 8.3 Hz), 7.74(1H, dd, J = 8.3 Hz, 2.0 Hz), 8.02 (1H,

d, J = 2.3 Hz), 8.13-8.20(2H, m), 8.29(1H, d, J = 2.6 Hz).

153
—H
—COOC(CH₃)₃

¹H NMR (DMSO-d₆) 1.41(9H, s), 3.39-3.50(8H, m), 7.13-7.19(3H, m), 7.45-

7.48(2H, m), 7.84(1H, d, J = 8.4 Hz), 7.95(1H, dd, J = 8.4 Hz, 2.1 Hz), 8.21-

8.26(2H, m), 8.52(1H, d, J = 2.3 Hz), 10.58(1H, s).

154
—H
2-naphthylmethyl
MS 611(M⁺ + 1)

155
—H

embedded image

MS 671(M⁺ + 1)

156
—H
1-naphthylmethyl
MS 611 (M⁺ + H)

157
—CH₃
3,4-(CH₃O)₂PhCH₂—
MS 633(M⁺ + 1)

158
—H

embedded image

MS 631(M⁺⁻1)

159
—H
—CH(CH₃)Ph
MS 573(M⁺⁻1)

160
—H

embedded image

MS 637(M⁺)

161
—H
(4-FPh)₂CH—
MS 671(M⁺⁻1)

162
—H
—(CH₂)₃CH₃
MS 526(M⁺)

163
—H
—(CH₂)₃Ph
MS 588(M⁺)

164
—H
cyclopentyl
MS 538(M⁺)

165
—H
cycloheptyl
MS 565(M⁺⁻1)

TABLE 149

Example

No.
R₅₂₂
MS

166

embedded image

567(M⁺)

167

embedded image

581(M⁺)

168

embedded image

583(M⁺)

169

embedded image

567(M⁺)

170
4-pyridylmethyl
561(M⁺)

171
2-pyridylmethyl
562(M⁺ + H)

172

embedded image

643(M⁺ + H)

173

embedded image

580(M⁺)

174

embedded image

643(M⁺)

TABLE 150

Example

No.
R₅₂₃
R₅₂₄
mp (° C.) or ¹H NMR (solvent) δppm

175
—H
3-pyridyl

¹H NMR (CDCl₃) 3.21(4H, brs), 3.78(4H, brs), 6.98(1H, d, J = 8.7 Hz),

7.13-7.21(4H, m), 7.41-7.44(2H, m), 7.70(2H, d, J = 8.1 Hz), 8.02(2H, d,

J = 8.1 Hz), 8.12-8.14(1H, m), 8.20-8.27 (2H, m), 8.35(1H, d, J = 2.6 Hz),

8.99(1H, s).

176
—H
2-pyridyl
mp 222-224

177
—F
3-pyridyl

¹H NMR (CDCl₃) 3.21(4H, brs), 3.79(4H, brs), 7.05(1H, d, J = 8.4 Hz),

7.20-7.30(5H, m), 7.71(2H, d, J = 8.2 Hz), 8.00(2H, d, J = 8.2 Hz),

8.14(1H, brs), 8.21-8.25(3H, m), 8.78(1H, s).

178
—H

embedded image

mp 205-206

179
—H

embedded image

¹H NMR (DMSO-d₆) 2.38(4H, brs), 2.43(2H, t, J = 7.5 Hz), 2.86(2H, t, J = 7.5 Hz), 3.41(2H, s), 3.45(4H, brs), 6.80(1H, d, J = 7.9 Hz), 7.06(1H, d, J = 7.9 Hz), 7.10(1H, s), 7.15(1H, d, J = 8.8 Hz), 7.17(2H, d, J = 8.4 Hz), 7.44(2H, d, J = 8.4 Hz), 7.94(2H, d, J = 8.0 Hz), 8.17(2H, d, J = 8.0 Hz), 8.26(1H, dd, J = 8.8 Hz, 2.6 Hz), 8.54(1H, d, J = 2.6 Hz), 10.06( 1H, s), 10.68(1H, s).

180
—H

embedded image

¹H NMR (CDCl₃) 1.71-2.05(4H, m), 2.58(4H, brs), 3.16(2H, s), 3.36- 3.53(4H, m), 3.55(2H, brs), 3.74(2H, brs), 7.00(1H, d, J = 8.9 Hz), 7.14(2H, d, J = 8.6 Hz), 7.42(2H, d, J = 8.6 Hz), 7.76(2H, d, J = 8.1 Hz), 8.04(2H, d, J = 8.1 Hz), 8.26(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.34(1H, d, J = 2.6 Hz), 8.50(1H, s).

181
—H
—COOC(CH₃)₃

¹H NMR (CDCl₃) 1.48(9H, s), 3.45(4H, brs), 3.58(4H, brs), 6.99(1H, d,

J = 8.7 Hz), 7.15(2H, d, J = 8.7 Hz), 7.41(2H, d, J = 8.7 Hz), 7.74(2H, d,

J = 8.2 Hz), 8.02(2H, d, J = 8.2 Hz), 8.21(1H, dd, J = 8.7 Hz, 2.6 Hz),

8.33(1H, d, J = 2.6 Hz), 8.43 (1H, brs).

182
—H
—CH₂COOC₂H₅

¹H NMR (CDCl₃) 1.28(3H, t, J = 7.1 Hz), 2.61(4H, brs), 3.26 (2H, s),

3.57(2H, brs), 3.78(2H, brs), 4.19(2H, q, J = 7.1 Hz), 6.97(1H, d, J = 8.7

Hz), 7.12(2H, d, J = 8.7 Hz), 7.40(2H, d, J = 8.7 Hz), 7.74(2H, d, J = 8.1

Hz), 8.03(2H, d, J = 8.1 Hz), 8.19(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.33(1H, d,

J = 2.6 Hz), 8.61 (1H, brs).

183
—H
—CH₂CONHNHCOOC(CH₃)₃

¹H NMR (CDCl₃) 1.46(9H, s), 2.60(4H, brs), 3.17(2H, s), 3.67 (4H, brs),

6.48(1H, brs), 7.00(1H, d, J = 8.7 Hz), 7.14(2H, d, J = 8.5 Hz), 7.41(2H, d,

J = 8.5 Hz), 7.75(2H, d, J = 8.1 Hz), 8.02(2H, d, J = 8.1 Hz), 8.24(1H, dd,

J = 8.7 Hz, 2.6 Hz), 8.33 (1H, d, J = 2.6 Hz), 8.53(2H, s).

TABLE 151

Example

mp (° C.) or ¹H NMR

No.
R₅₂₅
R₅₂₆
R₅₂₇
R₅₂₈
R₅₂₉
Form
(solvent) δppm

184
—Cl
—Cl
—H
—F
3-pyridyl
free

¹H NMR (CDCl₃) 3.21(4H, brs), 3.79 (4H, brs), 7.02(1H,

d, J = 8.7 Hz), 7.18-7.28(5H, m), 7.49(1H, d, J = 8.2 Hz),

7.74(1H, dd, J = 8.2 Hz, 1.7 Hz), 8.00(1H, d, J = 1.7 Hz),

8.13(1H, brs), 8.17-8.21(1H, m), 8.26(2H, d, J = 2.3 Hz),

9.33(1H, brs).

185
—H
—Cl
—H
—H
4-CNPhCH₂—
free
mp 199-201

186
—OCF₃
—H
—H
—H
3-pyridylmethyl
free

¹H NMR (CDCl₃) 2.43-2.55(4H, m), 3.43-3.71(6H, m),

6.90(1H, d, J = 8.7 Hz), 7.05-7.08(2H, m), 7.25-7.46(5H,

m), 7.66-7.69(1H, m), 7.82-7.88(2H, m), 8.15(1H, dd, J =

8.9 Hz, 2.8 Hz), 8.36(1H, d, J = 2.5 Hz), 8.48(1H, dd, J =

4.8 Hz, 1.7 Hz), 8.51(1H, d, J = 1.7 Hz), 9.84(1H, s).

187
—CF₃
—H
—H
—H
4-CNPhCH₂—
free
mp 193-197

188
—F
—H
—CF₃
—H
4-CNPhCH₂—
oxalate
mp 136-139

189
—CH₃
—CH₃
—H
—H
—COOC(CH₃)₃
free

¹H NMR (CDCl₃) 1.48(9H, s), 2.34 (6H, s), 3.46(4H, brs),

3.60(4H, brs), 6.99(1H, d, J = 8.7 Hz), 7.14-7.17 (2H, m),

7.23-7.26(1H, m), 7.42-7.47 (2H, m), 7.61(1H, dd, J = 7.8

Hz, 2.0 Hz), 7.67(1H, d, J = 2.0 Hz), 7.93(1H, brs), 8.25-

8.31(2H, m).

TABLE 152

Example

No.
R₅₃₀
R₅₃₁
R₅₃₂
R₅₃₃
R₅₃₄
MS

190
—Cl
—H
—H
—H
—H
594(M⁺)

191
—OCH₃
—H
—H
—H
—H
590(M⁺)

192
—CH₃
—H
—H
—H
—H
574(M⁺)

193
—F
—H
—H
—H
—H
578(M⁺)

194
—NO₂
—H
—H
—H
—H
603(M⁺⁻2)

195
—CF₃
—H
—H
—H
—H
628(M⁺)

196
—OCF₃
—H
—H
—H
—H
645(M⁺ + 1)

197
—H
—Cl
—H
—H
—H
595(M⁺ + 1)

198
—H
—F
—H
—H
—H
579(M⁺ + 1)

199
—H
—NO₂
—H
—H
—H
605(M⁺)

200
—H
—CF3
—H
—H
—H
628(M⁺)

201
—H
—OCF₃
—H
—H
—H
644(M⁺)

202
—H
—COOCH₃
—H
—H
—H
618(M⁺)

203
—H
—H
—Cl
—H
—H
594(M⁺)

204
—H
—H
—F
—H
—H
578(M⁺)

205
—H
—H
—NO₂
—H
—H
605(M⁺)

206
—H
—H
—COOCH₃
—H
—H
618(M⁺)

207
—H
—H
—Ph
—H
—H
636(M⁺)

208
—H
—H
—C₂H₅
—H
—H
588(M⁺)

209
—Cl
—Cl
—H
—H
—H
630(M⁺)

210
—Cl
—H
—Cl
—H
—H
630(M⁺)

211
—H
—F
—H
—F
—H
596(M⁺)

212
—H
—OCH₃
—H
—OCH₃
—H
622(M⁺ + 2)

213
—F
—H
—F
—H
—H
596(M⁺)

214
—H
—Cl
—Cl
—H
—H
630(M⁺)

215
—F
—H
—H
—H
—F
596(M⁺)

216
—Cl
—H
—H
—H
—Cl
630(M⁺)

217
—F
—H
—H
—F
—H
596(M⁺)

218
—Cl
—H
—H
—Cl
—H
629(M⁺ + 1)

219
—H
—Cl
—OCH₃
—H
—H
624(M⁺)

TABLE 153

Example No.
R₅₃₅
R₅₃₆
R₅₃₇
R₅₃₈
mp (° C.) or ¹H NMR (CDCl₃) δppm

220
—Cl
—Cl
—H
—H
mp 164-166

221
—Cl
—Cl
—F
—H

¹H NMR 2.46(4H, brs), 3.39-3.82(6H, m), 7.00(1H,

d, J = 8.9 Hz), 7.13-7.33(8H, m), 7.52(1H, d, J =

8.4 Hz), 7.72(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.00(1H,

d, J = 2.0 Hz), 8.15(1H, dd, J = 8.9 Hz, 2.6 Hz),

8.23(1H, d, J = 2.6 Hz), 8.61(1H, brs).

222
—CF₃
—H
—F
—H

¹H NMR 2.44(4H, brs), 3.42-3.78(6H, m), 6.97(1H,

d, J = 8.7 Hz), 7.09-7.36(8H, m), 7.66(2H, d, J =

8.1 Hz), 7.96(2H, d, J = 8.1 Hz), 8.16(1H, dd, J =

8.7 Hz, 2.5 Hz), 8.26(1H, d, J = 2.5 Hz), 9.04(1H,

brs).

223
—Cl
—Cl
—Cl
—H

¹H NMR 2.47(4H, brs), 3.42-3.83(6H, m), 7.00(1H,

d, J = 8.9 Hz), 7.17(1H, d, J = 8.2 Hz), 7.25-

7.33(6H, m), 7.46(1H, d, J = 1.8 Hz), 7.53(1H, d,

J = 8.4 Hz), 7.74(1H, dd, J = 8.4 Hz, 2.1 Hz),

8.01(1H, d, J = 2.1 Hz), 8.17(1H, dd, J = 8.9 Hz,

2.6 Hz), 8.25(1H, d, J = 2.6 Hz), 8.64(1H, brs).

224
—CF₃
—H
—Cl
—H

¹H NMR 2.47(4H, brs), 3.42-3.82(6H, m), 7.02(1H,

d, J = 8.9 Hz), 7.19(1H, d, J = 8.4 Hz), 7.27-

7.33(6H, m), 7.47(1H, d, J = 1.8 Hz), 7.73(2H, d,

J = 8.4 Hz), 8.00(2H, d, J = 7.9 Hz), 8.20-8.26(2H,

m), 8.46(1H, brs).

225
—Cl
—Cl
—CH₃
—H

¹H NMR 2.15(3H, s), 2.45(4H, brs), 3.46-3.75(6H,

m), 6.85 (1H, d, J = 8.9 Hz), 6.95(1H, d, J = 8.4

Hz), 7.13-7.33(7H, m), 7.50(1H, d, J = 8.6 Hz),

7.75(1H, dd, J = 8.4 Hz, 2.2 Hz), 8.03 (1H, d, J =

2.2 Hz), 8.08(1H, dd, J = 8.9 Hz, 3.0 Hz), 8.27(1H,

d, J = 3.0 Hz), 9.06(1H, s).

226
—CF₃
—H
—CH₃
—H

¹H NMR 2.17(3H, s), 2.44(4H, brs), 3.40-3.82(6H,

m), 6.88 (1H, d, J = 8.9 Hz), 6.98(1H, d, J = 8.1

Hz), 7.14-7.18(1H, m), 7.23-7.33(6H, m), 7.70(2H,

d, J = 8.4 Hz), 8.01(2H, d, J = 8.1 Hz), 8.15(1H,

dd, J = 8.9 Hz, 2.7 Hz), 8.30(1H, d, J = 2.7 Hz),

8.90(1H, brs).

227
—Cl
—Cl
—OCH₃
—H
mp 197-199

228
—CF₃
—H
—OCH₃
—H
mp 152-154

229
—Cl
—Cl
—H
—CH₃
mp 182-183

230
—CF₃
—H
—H
—CH₃
mp 188-190

231
—Cl
—Cl
—H
—OCH₃
mp 196-198

232
—CF₃
—H
—H
—OCH₃

¹H NMR 2.32-2.50(4H, m), 3.30(2H, brs), 3.53(2H,

s), 3.70-3.81(5H, m), 6.61-6.65(2H, m), 6.91(1H,

d, J = 8.9 Hz), 7.11-7.15(1H, m), 7.26-7.36(5H, m),

7.72(2H, d, J = 8.4 Hz), 8.05-8.13(3H, m),

8.36(1H, d, J = 2.4 Hz). 9.07(1H, s).

TABLE 154

Example No.
R₅₃₉
R₅₄₀
R₅₄₁
R₅₄₂
Form
mp (° C.) or ¹H NMR (solvent) δppm

233
—CF₃
—H
—H
—H
hydrochloride

¹H NMR (DMSO-d₆) 2.90-3.70(6H, m), 3.80-4.60(2H, m),

4.24(2H, brs), 6.07(2H, s), 6.98(1H, d, J = 8.0 Hz), 7.05(1H,

dd, J = 8.0 Hz, 1.5 Hz), 7.16(1H, d, J = 8.7 Hz), 7.20(2H, d,

J = 8.6 Hz), 7.27(1H, s), 7.52(2H, d, J = 8.6 Hz), 7.93(2H, d,

J = 8.3 Hz), 8.21(2H, d, J = 8.3 Hz), 8.30(1H, dd, J = 8.7 Hz,

2.6 Hz), 8.60(1H, d, J = 2.6 Hz), 10.80(1H, s).

234
—Cl
—Cl
—F
—H
free

¹H NMR (CDCl₃) 2.42(4H, brs), 3.37-3.79(6H, m), 5.94(2H,

s), 6.70-6.77(2H, m), 6.84(1H, brs), 6.96(1H, d, J = 8.7 Hz),

7.10-7.22(3H, m), 7.47(1H, d, J = 8.2 Hz), 7.72(1H, dd, J =

8.2 Hz, 2.0 Hz), 7.99(1H, d, J = 2.0 Hz), 8.12(1H, dd, J = 8.9

Hz, 2.6 Hz), 8.25(1H, d, J = 2.6 Hz), 9.14(1H, brs).

235
—CF₃
—H
—F
—H
free

¹H NMR (CDCl₃) 2.41(4H, brs), 3.37-3.79(6H, m), 5.94(2H,

s), 6.69-6.76(2H, m), 6.84(1H, s), 6.99(1H, d, J = 8.9 Hz),

7.10-7.26(3H, m), 7.67(2H, d, J = 8.1 Hz), 7.97(2H, d, J = 8.1

Hz), 8.17(1H, dd, J = 8.9 Hz, 2.5 Hz), 8.26(1H, d, J = 2.5 Hz),

8.89(1H, brs).

236
—Cl
—Cl
—Cl
—H
free

¹H NMR (CDCl₃) 2.45(4H, brs), 3.38-3.81(6H, m), 5.95(2H,

s), 6.71-6.78(2H, m), 6.85(1H, s), 7.01(1H, d, J = 8.7 Hz),

7.17-7.30(2H, m), 7.45-7.47(1H, m), 7.54(1H, d, J = 8.4 Hz),

7.70-7.74(1H, m), 8.00(1H, d, J = 1.8 Hz), 8.17(1H, dd, J =

8.9 Hz, 2.6 Hz), 8.24(1H, d, J = 2.6 Hz), 8.48(1H, s).

237
—CF₃
—H
—CH₃
—H
free

¹H NMR (CDCl₃) 2.45(4H, brs), 3.40-3.81(6H, m), 5.95(2H,

s), 6.71-6.77(2H, m), 6.85(1H, s), 7.03(1H, d, J = 8.6 Hz),

7.20(1H, d, J = 8.2 Hz), 7.28-7.31(1H, m), 7.48(1H, d, J = 2.0

Hz), 7.74(2H, d, J = 8.4 Hz), 8.00(2H, d, J = 8.2 Hz), 8.21-

8.26(2H, m), 8.34(1H, brs).

238
—CF₃
—H
—CH₃
—H
free

¹H NMR (CDCl₃) 2.16(3H, s), 2.42(4H, brs), 3.44-3.70(6H, m),

5.94(2H, s), 6.70-6.77(2H, m), 6.85-6.89(2H, m), 6.97(1H, d,

J = 8.4 Hz), 7.14-7.23(2H, m), 7.69(2H, d, J = 8.1 Hz), 8.01(2H,

d, J = 8.1 Hz), 8.13-8.17(1H, m), 8.30(1H, d, J = 2.7 Hz),

8.97(1H, brs).

239
—Cl
—Cl
—OCH₃
—H
free
mp 194-196

240
—CF₃
—H
—OCH₃
—H
free
mp 134-136

241
—CF₃
—H
—H
—CH₃
free
mp 199-201

242
—CF₃
—H
—H
—OCH
free
mp 192-193

TABLE 155

Example No.
R₅₄₃
R₅₄₄
R₅₄₅

¹H NMR (CDCl₃) δppm

243
—Cl
—Cl
benzyl
2.39-2.62(4H, m), 3.42-3.91(6H, m), 6.94(1H, d, J = 8.9 Hz), 7.28-7.33(6H, m), 7.41(1H, dd,

J = 8.4 Hz, 1.6 Hz), 7.50-7.53 (2H, m), 7.72-7.75(2H, m), 7.81-7.84(2H, m), 8.02(1H, d, J =

2.1 Hz), 8.14(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.28(1H, d, J = 2.7 Hz), 8.66(1H, s).

244
—Cl
—Cl
piperonyl
2.41-2.74(4H, m), 3.42-3.91(6H, m), 5.94(2H, s), 6.73(2H, brs), 6.84(1H, brs), 6.97(1H, d,

J = 8.9 Hz), 7.29-7.33(1H, m), 7.42 (1H, d, J = 8.2 Hz), 7.52-7.57(2H, m), 7.71-7.85(4H, m),

8.02 (1H, d, J = 2.0 Hz), 8.18(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.28(1H, d, J = 2.8 Hz), 8.48(1H, brs).

245
—Cl
—Cl
3-pyridyl
3.25(4H, brs), 3.82(4H, brs), 7.01(1H, d, J = 8.7 Hz), 7.21-7.22 (2H, m), 7.35(1H, dd, J = 8.9

Hz, 2.3 Hz), 7.47-7.50(1H, m), 7.52-7.56(2H, m), 7.74(1H, dd, J = 8.2 Hz, 2.0 Hz), 7.80(1H,

d, J = 8.6 Hz), 7.86-7.91(2H, m), 8.01(1H, d, J = 2.0 Hz), 8.13-8.15(1H, m), 8.18-8.22(1H, m),

8.29-8.31(2H, m), 8.42 (1H, brs).

246
—CF₃
—H
benzyl
2.35-2.58(4H, m), 3.37-3.87(6H, m), 6.96(1H, d, J = 8.9 Hz), 7.28-7.34(6H, m), 7.41(1H, dd,

J = 8.4 Hz, 1.5 Hz), 7.52(1H, d, J = 2.0 Hz), 7.64-7.76(3H, m), 7.83(2H, d, J = 9.1 Hz),

8.00(2H, d, J = 8.2 Hz), 8.19(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.30(1H, d, J = 2.6 Hz), 8.68(1H,

brs).

247
—CF₃
—H
piperonyl
2.30-2.58(4H, m), 3.35-3.87(6H, m), 5.94(2H, s), 6.70-6.77 (2H, m), 6.85(1H, brs), 6.95(1H,

d, J = 8.7 Hz), 7.31(1H, dd, J = 8.9 Hz, 2.1 Hz), 7.39(1H, d, J = 8.4 Hz), 7.51(1H, brs), 7.66-

7.83(5H, m), 7.99(2H, d, J = 8.1 Hz), 8.17(1H, dd, J = 8.7 Hz, 2.3 Hz), 8.30(1H, brs), 8.89(1H,

brs).

248
—CF₃
—H
3-pyridyl
3.22(4H, brs), 3.79(4H, brs), 6.99(1H, d, J = 8.7 Hz), 7.17-7.23 (2H, m), 7.33(1H, dd, J = 8.9

Hz, 2.3 Hz), 7.45(1H, dd, J = 8.4 Hz, 1.5 Hz), 7.54(1H, d, J = 2.3 Hz), 7.66(2H, d, J = 8.4 Hz),

7.76-7.86(3H, m), 7.99(2H, d, J = 8.1 Hz), 8.13(1H, brs), 8.21-8.25(1H, m), 8.28(1H, brs),

8.33(1H, d, J = 2.5 Hz), 9.13(1H, s).

TABLE 156

Example

No.
R₅₄₆
R₅₄₇
R₅₄₈

¹H NMR (CDCl₃) δppm

249
—Cl
—Cl
benzyl
2.27-2.34(2H, m), 2.58-2.61(2H, m), 3.20-

3.29(2H, m), 3.53 (2H, s), 3.90-3.99(2H, m),

6.91(1H, d, J = 8.7 Hz), 7.29-7.32 (7H, m), 7.39-

7.45(1H, m), 7.53-7.56(2H, m), 7.71-7.81(3H,

m), 8.00-8.04(2H, m), 8.25(1H, d, J = 2.6 Hz),

8.47(1H, s).

250
—Cl
—Cl
piperonyl
2.25-2.31(2H, m), 2.55-2.59(2H, m), 3.22(2H,

brs), 3.44(2H, s), 3.86-4.01(2H, m), 5.94(2H, s),

6.69- 6.76(2H, m), 6.84-6.91 (2H, m), 7.25-

7.29(2H, m), 7.38-7.44(1H, m), 7.52-7.55(2H,

m), 7.71-7.80(3H, m), 7.97-8.03(2H, m),

8.24(1H, d, J = 2.8 Hz), 8.60(1H, s).

251
—CF₃
—H
benzyl
2.27-2.34(2H, m), 2.57-2.61(2H, m), 3.23-

3.25(2H, m), 3.53 (2H, s), 3.89-3.98(2H, m),

6.96(1H, d, J = 8.7 Hz), 7.27-7.31 (7H, m), 7.40-

7.45(1H, m), 7.55(1H, d, J = 2.3 Hz), 7.72-7.83

(4H, m), 8.00(2H, d, J = 8.1 Hz), 8.12(1H, dd, J =

8.9 Hz, 2.8 Hz), 8.30(1H, d, J = 2.6 Hz),

8.40(1H, brs).

252
—CF₃
—H
piperonyl
2.25-2.31(2H, m), 2.55-2.58(2H, m), 3.23(2H,

m), 3.43(2H, s), 3.85-4.00(2H, m), 5.94(2H, s),

6.70-6.76(2H, m), 6.84(1H, s), 6.96(1H, d, J =

8.9 Hz), 7.28-7.31(2H, m), 7.40-7.46(1H, m),

7.55(1H, d, J = 2.5 Hz), 7.72-7.83(4H, m).

8.00(2H, d, J = 7.9 Hz), 8.12(1H, dd, J = 8.9

Hz, 2.6 Hz), 8.30(1H, d, J = 2.6 Hz), 8.44(1H,

brs).

TABLE 157

Example

No.
R₅₄₉
R₅₅₀
R₅₅₁
R₅₅₂
R₅₅₃
Form

¹H NMR (solvent) δppm

253
—CF₃
—H
—CH₃
—H
3-pyridyl
free
(CDCl₃) 3.06(3H, s), 3.22(4H, brs), 3.81(4H, brs),

4.55(2H, s), 6.87(1H, d, J = 8.9 Hz), 7.09 (2H, d,

J = 8.7 Hz), 7.14(1H, dd, J = 8.9 Hz, 3.3 Hz), 7.19-

7.21(2H, m), 7.35(2H, d, J = 7.9 Hz), 7.44(2H, d,

J = 8.7 Hz), 7.60(2H, d, J = 8.1Hz), 7.74(1H, d, J =

3.0 Hz), 8.14-8.17(1H, m), 8.31-8.33(1H, m).

254
—CF₃
—H
—H
—F
benzyl
free
(CDCl₃) 2.46(4H, brs), 3.54(6H, brs), 4.11(1H,

brs), 4.38(2H, brs), 6.85(1H, d, J = 8.7 Hz), 7.01(1H,

dd, J = 8.7 Hz, 3.1 Hz), 7.16-7.25(3H, m), 7.28-

7.33(5H, m), 7.46(2H, d, J = 8.1 Hz), 7.52(1H, d,

J = 2.6 Hz), 7.60(2H, d, J = 8.1Hz).

255
—CF₃
—H
—CH₃
—H
piperonyl
hydrochloride
(DMSO-d₆) 2.49-2.52(2H, m), 3.06(5H, brs), 3.35(4H,

brs), 4.22(2H, brs), 4.68(2H, brs), 6.07(2H, s), 6.94-

7.05(5H, m), 7.23(1H, brs), 7.32(1H, dd, J = 8.9 Hz,

3.3 Hz), 7.43-7.46(4H, m), 7.69-7.72(3H, m), 11.23(1H,

brs).

256
—Cl
—Cl
—H
—F
benzyl
free
(CDCl₃) 2.47(4H, brs), 3.49-3.68(6H, m), 4.29 (2H, s),

6.86(1H, d, J = 8.7 Hz), 7.01(1H, dd, J = 8.7 Hz, 3.0 Hz),

7.17-7.22(4H, m), 7.32(5H, brs), 7.41(1H, d, J = 8.3

Hz), 7.45(1H, d, J = 1.8 Hz), 7.51(1H, d, J = 3.0 Hz).

257
—CF₃
—H
—CH₃
—H
4-CH₃OPhCH₂—
hydrochloride
(DMSO-d₆) 2.49-2.52(2H, m), 3.06(5H, brs), 3.32-

3.38(4H, m), 3.78(3H, s), 4.27(2H, d, J = 4.1 Hz),

4.68(2H, brs), 6.96(1H, d, J = 8.9 Hz), 7.00-7.05(4H,

m), 7.32(1H, dd, J = 8.9 Hz, 3.3 Hz), 7.43-7.49(6H, m),

7.68-7.72(3H, m), 10.72(1H, brs).

258
—CF₃
—H
—CH₃
—H
4-pyridylmethyl
hydrochloride
(DMSO-d₆) 2.49-2.52(2H, m), 3.05-3.44(9H, m),

4.26(2H, brs), 4.68(2H, brs), 6.96(1H, d, J = 8.9 Hz),

7.03(2H, d, J = 8.7 Hz), 7.32(1H, dd, J = 8.9 Hz, 3.3

Hz), 7.42-7.47(4H, m), 7.68-7.72(5H, m), 8.71(2H,

dd, J = 4.6 Hz, 1.5 Hz).

TABLE 158

Example

No.
R₅₅₄
R₅₅₅
R₅₅₆
Form

¹H NMR (solvent) δppm

259
—CH₃
—H
benzyl
hydrochloride
(DMSO-d₆) 1.44(3H, d, J = 6.8 Hz), 2.44-2.52(2H, m), 3.08-3.15(2H, m),

3.30-3.38(4H, m), 4.33(2H, brs), 4.55-4.62(1H, m), 6.51(1H, d, J = 6.3 Hz),

6.82(1H, d, J = 8.7 Hz). 6.97(2H, d, J = 8.7 Hz), 7.04(1H, dd, J = 8.7 Hz,

3.0 Hz), 7.41(2H, d, J = 8.6 Hz), 7.45-7.47(4H, m), 7.57(2H, brs), 7.61(2H,

d, J = 8.3 Hz), 7.69(2H, d, J = 8.4 Hz), 10.99(1H, brs).

260
—CH₃
—CH₃
benzyl
free
(CDCl₃) 1.58(3H, d, J = 6.9 Hz), 2.46(4H, brs), 2.72(3H, s), 3.46-3.53(6H,

m), 4.97(1H, q, J = 6.9 Hz), 6.86(1H, d, J = 8.9 Hz), 7.07(2H, d, J = 8.6

Hz), 7.23(1H, dd, J = 8.9 Hz, 3.3 Hz), 7.27-7.36(5H, m), 7.40(2H, d, J =

8.6 Hz), 7.43(2H, d, J = 7.3 Hz), 7.60(2H, d, J = 8.3 Hz), 7.82(1H, d, J =

3.3 Hz).

261
—CH₃
—CH₃
piperonyl
free
(CDCl₃) 1.58(3H, d, J = 6.9 Hz), 2.43(4H, brs), 2.72(3H, s), 3.44(2H, s),

3.48-3.68(4H, m), 4.97(1H, q, J = 6.9Hz), 5.95(2H, s), 6.74(2H, brs),

6.85(1 H, brs), 6.87(1H, d, J = 9.1 Hz), 7.07(2H, d, J = 8.7 Hz), 7.23(1H,

dd, J = 8.9 Hz, 3.3 Hz), 7.40(2H, d, J = 8.6 Hz), 7.43(2H, d, J = 7.9 Hz),

7.60(2H, d, J = 8.3 Hz), 7.82(1H, d, J = 3.1 Hz).

262
—CH₃
—H
piperonyl
hydrochloride
(DMSO-d₆) 1.44(3H, d, J = 6.8 Hz), 2.49-2.52(2H, m), 3.01-3.06(2H, m),

3.29-3.45(4H, m), 4.23(2H, brs), 4.58-4.62(1H, m), 6.07(2H, s), 6.51(1H,

d, J = 6.6 Hz), 6.82(1H, d, J = 8.7 Hz), 6.96-6.99(4H, m), 7.04(1H, dd, J =

8.7 Hz, 3.0 Hz), 7.20(1H, brs), 7.41(2H, d, J = 8.6 Hz), 7.46(1H, d, J = 3.0

Hz), 7.61(2H, d, J = 8.3 Hz), 7.69(2H, d, J = 8.4 Hz). 10.99(1H, brs).

263
—H
—C₂H₅
benzyl
hydrochloride
(DMSO-d₆) 1.14(3H, d, J = 6.9 Hz), 2.50-2.51(2H, m), 3.11(2H, brs),

3.35(4H, brs), 3.51(2H, q, J = 6.9 Hz), 4.33 (2H, brs), 4.63(2H, brs),

6.94(1H, d, J = 8.9 Hz), 7.03(2H, d, J = 8.6 Hz), 7.25(1H, dd, J = 8.9

Hz, 3.3 Hz), 7.42-7.48(7H, m), 7.57(2H, brs), 7.62(1H, d, J = 3.1 Hz),

7.70(2H, d, J = 8.1 Hz), 11.03(1H, brs).

264
—H
—C₂H₅
piperonyl
hydrochloride
(DMSO-d₆) 1.14(3H, d, J = 6.9 Hz), 2.50-2.51(2H, m), 3.06(2H, brs),

3.36(4H, brs), 3.52(2H, q, J = 6.9 Hz), 4.22 (2H, brs), 4.64(2H, brs),

6.07(2H, s), 6.94(1H, d, J = 8.9 Hz), 6.99(2H, brs), 7.03(2H, d, J = 8.6

Hz), 7.23(1H, brs), 7.25(1H, dd, J = 8.9 Hz, 3.3 Hz), 7.42-7.49(4H, m),

7.62 (1H, d, J = 3.1 Hz), 7.71(2H, d, J = 8.1 Hz), 11.29(1H, brs).

TABLE 159

Example No.
R₅₅₇
R₅₅₈

¹H NMR (solvent) δppm

265
3,4-Cl₂PhCONH—

embedded image

(CDCl₃) 2.39-2.49(4H, m), 3.39-3.79 (6H, m), 6.87(1H, d, J = 8.9 Hz), 7.06- 7.15(3H, m), 7.27-7.37(6H, m), 7.51(1H, d, J = 8.4 Hz), 7.74-7.78(1H, m), 8.01- 8.05(2H, m), 8.28(1H, d, J = 2.6 Hz), 9.10(1H, brs).

266
3,4-Cl₂PhCONH—

embedded image

(CDCl₃) 2.37-2.48(4H, m), 3.43-3.75 (6H, m), 5.94(2H, s), 6.70-6.77(2H, m), 6.84(1H, brs), 6.92(1H, d, J = 8.9 Hz), 7.09-7.17(3H, m), 7.34-7.40(1H, m), 7.55(1H, d, J = 8.4 Hz), 7.73-7.77(1H, m), 8.04(1H, d, J = 2.1 Hz), 8.09(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.28(1H, d, J = 2.8 Hz), 8.63(1H, brs).

267
4-CF₃PhCH₂N(CH₃)—

embedded image

(DMSO-d₆) 3.03-3.13(5H, m), 4.69- 4.75(3H, m), 6.88-6.98(3H, m), 7.06(2H, d, J = 8.6 Hz), 7.16- 7.23(2H, m), 7.33(1H, dd, J = 9.1 Hz, 3.1 Hz), 7.46(2H, d, J = 8.3 Hz), 7.69-7.73(3H, m), 7.91(2H, d, J = 8.7 Hz), 8.61(1H, d, J = 8.1 Hz), 10.35(1H, brs).

268
4-CF₃PhCH₂N(CH₃)—

embedded image

(DMSO-d₆) 2.89-3.06(2H, m), 3.06(3H, s), 4.61-4.72(3H, m), 5.96(2H, s), 6.50 (1H, s), 6.84(1H, s), 6.97(1H, d, J = 8.9 Hz), 7.06(2H, d, J = 8.7 Hz), 7.33(1H, dd, J = 8.9 Hz, 3.3 Hz), 7.46(2H, d, J = 8.1 Hz), 7.69-7.73(3H, m), 7.89(2H, d, J = 8.7 Hz), 8.56(1H, d, J = 8.3 Hz), 10.15 (1H, brs).

269
3,4-Cl₂PhCONH—

embedded image

(CDCl₃) 2.28-2.30(2H, m), 2.58-2.60 (2H, m), 3.25-3.29(2H, m), 3.44(2H, s), 3.92-3.98(2H, m), 5.94(2H, s), 6.73(2H, s), 6.84(1H, s), 6.96(1H, d, J = 8.7 Hz), 7.14(1H, d, J = 7.8 Hz). 7.37(1H d, J = 7.8 Hz), 7.50-7.59(3H, m), 7.73(1H, dd, J = 8.2 Hz, 2.1 Hz), 7.83(1H, dd, J = 7.6 Hz, 3.0 Hz), 8.03(1H, d, J = 2.1 Hz). 8.06- 8.13(2H, m), 8.17(1H, s), 8.24(1H, d, J = 3.0 Hz).

TABLE 160

Example

mp (° C.) or ¹H NMR

No.
R₅₅₉
R₅₆₀
Xb₁
Xb₂
R₅₆₁
Form
(DMSO-d₆) δppm

270
—Cl
—Cl
—O—

embedded image

piperonyl
free

¹H NMR (at 375 K) 2.00(3H, brs), 2.30-2.38 (4H, m), 3.34-3.43(6H, m), 4.12(2H, s), 4.51 (2H, brs), 5.91(2H, s), 6.73(1H, d, J = 7.9 Hz), 6.77(1H, d, J = 7.9 Hz), 6.81(1H, s), 6.98(1H, d, J = 8.8 Hz), 7.05(2H, d, J = 8.2 Hz), 7.26(2H, d, J = 8.2 Hz), 7.73(1H, d, J = 8.4 Hz), 7.91(1H, dd, J = 2.1 Hz, 8.4 Hz), 8.12-8.18(3H, m), 8.48 (1H, d, J = 2.6 Hz), 10.17(1H, s).

271
—Cl
—Cl
—O—

embedded image

benzyl
free

¹H NMR (at 375 K) 2.00(3H, brs), 2.33-2.40 (4H, m), 3.38-3.42(4H, m), 3.49-3.53(2H, m), 4.13(2H, s), 4.51(2H, brs), 6.98(1H, d, J = 8.8 Hz), 7.02-7.10(2H, m), 7.16-7.30(7H, m), 7.73 (1H, d, J = 8.4 Hz), 7.91(1H, dd, J = 8.4 Hz, 2.1 Hz), 8.11-8.17(2H, m), 8.48(1H, d, J = 2.5 Hz), 10.17(1H, s).

272
—CF₃
—H
—O—
—CH═CH—
benzyl
free

¹H NMR 2.39(4H, brs), 3.52(2H, s), 3.58(2H,

(trans)

brs), 3.71(2H, brs), 7.13(1H, d, J = 8.9 Hz),

7.14(2H, d, J = 8.7 Hz), 7.24(1H, d, J = 15.3Hz),

7.18-7.41(5H, m), 7.50(1H, d, J = 15.3 Hz),

7.76(2H, d, J = 8.7 Hz), 7.94(2H, d, J = 8.3 Hz),

8.17(2H, d, J = 8.3 Hz), 8.25(1H, dd, J = 8.9Hz,

2.7 Hz), 8.54(1H, d, J = 2.7 Hz), 10.66(1H, s).

273
—CF₃
—H
—O—
—CH═CH—
piperonyl
free

¹H NMR 2.37(4H, brs), 3.42(2H, s), 3.58(2H,

(trans)

brs), 3.70(2H, brs), 5.99(2H, s), 6.76(1H, dd,

J = 8.0 Hz, 2.4 Hz), 6.85(1H, d, J = 8.0 Hz),

6.88 (1H, d, J = 1.5 Hz), 7.13(1H, d, J = 8.9 Hz),

7.14(2H, d, J = 8.7 Hz), 7.20(1H, d, J = 15.4 Hz),

7.50(1H, d, J = 15.4 Hz), 7.76(2H, d, J = 8.7 Hz),

7.94(2H, d, J = 8.2 Hz), 8.17(2H, d, J = 8.2 Hz),

8.25(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.54(1H, d,

J = 2.6 Hz), 10.65(1H, s).

274
—CF₃
—H
—N(CH₃)—
none
piperonyl
dihydro-

¹H NMR 2.98-3.12(2H, m), 3.12-3.36(2H, m),

chloride
3.50(3H, s), 3.71-4.68(6H, m), 6.06(2H, s), 6.93-

7.06(3H, m), 7.26(1H, s), 7.42(2H, d, J = 8.3 Hz),

7.53(2H, d, J = 8.3 Hz), 7.92(2H, d, J = 8.3 Hz),

8.12(1H, d, J = 9.2 Hz), 8.20(2H, d, J = 8.3 Hz),

8.67(1H, s), 10.79(1H, s), 11.47(1H, brs).

275
—CF₃
—H
—N(CH₃)—
none
benzyl
free
mp 213-214

TABLE 161

Example

mp (° C.) or ¹H NMR (CDCl₃)

No.
R₅₆₂
R₅₆₃
R₅₆₄
δppm

276
—Cl
—Cl

embedded image

¹H NMR 1.62-1.80(2H, m), 1.82-1.87(2H, m), 2.71(1H, dt, J = 3 Hz, 11.0 Hz), 2.84 (1H, brs), 2.94(1H, t, J = 11.0 Hz), 3.55-3.70(10H, m), 6.89(1H, d, J = 9.0 Hz), 6.93(2H, dd, J = 7.0 Hz, 2.0 Hz), 7.02 (2H, dd, J = 7.0 Hz, 2.0 Hz), 7.56(1H, d, J = 8.0 Hz), 7.71(1H, dd, J = 9.0 Hz, 2.0 Hz), 7.99(1H, d, J = 2.0 Hz), 8.10(1H, s), 8.15 (1H, dd, J = 9.0 Hz, 2.5 Hz), 8.25(1H, d, J = 2.5 Hz).

277
—Cl
—Cl

embedded image

¹H NMR 2.38-2.42(4H, m), 2.62-2.67(4H, m), 3.14-3.17(4H, m), 3.22(2H, s), 3.42 (2H, s), 3.61-3.63(4H, m), 5.95(2H, s), 6.70-6.75(2H, m), 7.03(2H, d, J = 8.0 Hz), 7.55(1H, d, J = 8.0 Hz), 7.70(1H, brs), 7.73(2H, d, J = 8.0 Hz), 8.01(1H, s), 8.15 (1H, brd, J = 9.0 Hz). 8.27(1H, d, J = 2.5 Hz).

278
—Cl
—Cl

embedded image

¹H NMR 2.40-2.45(4H, m), 2.60-2.64(4H, m), 3.13(4H, brs), 3.20(2H, brs). 3.48(2H, brs), 3.62(4H, brs), 6.85-6.91(3H, m), 7.01 (2H, d, J = 8.0 Hz), 7.26-7.32(5H, m), 7.52 (1H, d, J = 8.5 Hz), 7.70(1H, brs), 7.74(1H, dd, J = 8.5 Hz, 2.0 Hz), 8.03(1H, d, J = 2.0 Hz). 8.15(1H, brd, J = 9.0, Hz), 8.29(1H, d, J = 2.5 Hz).

279
—H
—CF₃

embedded image

mp 180-183

280
—H
—CF₃

embedded image

mp 197-199

281
—H
—CF₃

embedded image

mp 133-135

TABLE 162

Example

No.
R₅₆₅
Form
mp (° C.)

282

embedded image

free
108-110

283

embedded image

free
136-138

284

embedded image

free
133-136

285

embedded image

free
147-151

286

embedded image

dihydrochloride
180-183

287

embedded image

free
111-113

288

embedded image

free
111-113

289

embedded image

free
246-249

290

embedded image

free
148-151

291

embedded image

free
120-121

TABLE 163

Example

No.
R₅₆₆
Form
mp (° C.)

292

embedded image

free
83-86

293

embedded image

free
130-133

294

embedded image

free
145-146

295

embedded image

trihydro- chloride
180-185

296

embedded image

free
184-186

297

embedded image

free
173-176

298

embedded image

free
181-183

299

embedded image

free
166-170

TABLE 164

Example

No.
R₅₆₇
mp (° C.)

300

embedded image

102-104

301

embedded image

106-109

302

embedded image

261-264

303

embedded image

173-175

304

embedded image

164-166

305

embedded image

158-160

306

embedded image

174-176

307

embedded image

206-207

308

embedded image

165-166

309

embedded image

164-167

310

embedded image

188-190

311

embedded image

130-132

TABLE 165

Example

No.
R₅₆₈
R₅₆₉
mp (° C.) or ¹H NMR (CDCl₃) δ ppm

312
—H

embedded image

mp 166-167

313
—H

embedded image

mp 157-158

314
—H

embedded image

mp 218-219

315

embedded image

benzyl

¹H NMR 0.25-0.31 (2H, m), 0.61- 0.69 (2H, m), 2.67-2.73 (1H, m), 2.86 (4H, brs), 3.18 (4H, brs), 3.83 (2H, s), 6.80-6.92 (3H, m), 7.16-7.62 (8H, m), 8.11 (2H, d, J = 8.1 Hz), 8.39 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.45 (1H, d, J = 2.5 Hz), 10.23 (1H, s), 10.93 (1H, brs).

316
—CONHPh
benzyl

¹H NMR 3.07 (4H, brs), 3.26 (4H, brs), 3.98 (2H, s), 6.83-7.59 (14H, m), 7.65 (2H, d, J = 8.3 Hz), 8.06 (2H, d, J = 8.1 Hz), 8.37 (1H, d, J = 2.6 Hz), 8.49 (1H, dd, J = 8.9 Hz, 2.6 Hz), 9.30 (1H, s), 9.71 (1H, brs).

317

embedded image

benzyl

¹H NMR 1.87 (4H, brs), 2.72 (4H, brs), 3.19 (4H, brs), 3.40 (4H, brs), 3.69 (2H, s), 6.58 (1H, d, J = 8.7 Hz), 6.80 (1H, s), 6.92 (1H, d, J = 9.2 Hz), 7.02 (1H, d, J = 8.9 Hz), 7.26-7.34 (5H, m), 7.57 (2H, d, J = 7.9 Hz), 7.90 (1H, d, J = 7.1 Hz), 8.05 (2H, d, J = 8.1 Hz), 8.40 (1H, s), 9.73 (1H, s).

TABLE 166

Example

No.
Xb₃
Xb₄
Xb₅
R₅₇₀
mp (° C.) or ¹H NMR (CDCl₃) δ ppm

318
—O—

embedded image

benzyl
mp 162-163

319
—O—

embedded image

piperonyl
mp 136-137

320
—O—

embedded image

—O—
none
mp 176-177

321
—N(CH₃)—

embedded image

benzyl

¹H NMR 2.43 (4H, brs), 2.67 (4H, t, J = 4.8 Hz), 3.22 (4H, t, J = 4.8 Hz), 3.24 (2H, s), 3.42 (3H, s), 3.52 (2H, s), 3.63 (4H, brs), 6.46 (1H, d, J = 9.1 Hz), 6.95 (2H, d, J = 8.9 Hz), 7.15 (2H, d, J = 8.9 Hz), 7.20-7.40 (5H, m), 7.65-7.80 (2H, m), 7.74 (2H, d, J = 8.2 Hz), 7.98 (2H, d, J = 8.2 Hz), 8.26 (1H, d, J = 2.5 Hz).

322
—N(CH₃)—

embedded image

piperonyl

¹H NMR 2.41 (4H, brs), 2.67 (4H, t, J = 4.8 Hz), 3.22 (4H, t, J = 6.1 Hz), 3.24 (2H, s), 3.42 (5H, s), 3.62 (4H, t, J = 4.5 Hz), 5.94 (2H, s), 6.46 (1H, d, J = 9.1 Hz), 6.74 (2H, s), 6.85 (1H, s), 6.95 (2H, d, J = 8.9 Hz), 7.15 (2H, d, J = 8.9 Hz), 7.65-7.75 (1H, m), 7.74 (2H, d, J = 8.1 Hz), 7.83 (1H, brs), 7.99 (2H, d, J = 8.1 Hz), 8.26 (1H, d, J = 2.5 Hz).

323
—N(CH₃)—

embedded image

benzyl

¹H NMR 1.31-1.52 (2H, m), 1.88 (2H, d, J = 12.3 Hz), 1.88-2.15 (1H, m), 2.29 (2H, d, J = 6.7 Hz), 2.44 (4H, t, J = 5.1 Hz), 2.76 (2H, t, J = 11.2 Hz), 3.42 (3H, s), 3.49 (2H, t, J = 4.9 Hz), 3.53 (2H, s), 3.59-3.78 (4H, m), 6.47 (1H, d, J = 9.1 Hz), 6.96 (2H, d, J = 8.9 Hz), 7.13 (2H, d, J = 8.9 Hz), 7.20-7.41 (5H, m), 7.61- 7.78 (2H, m), 7.75 (2H, d, J = 8.1 Hz), 7.98 (2H, d, J = 8.1 Hz), 8.25 (1H, d, J = 2.3 Hz).

324
—N(CH₃)—

embedded image

piperonyl

¹H NMR 1.30-1.51 (2H, m), 1.88 (2H, d, J = 2.9 Hz), 1.98-2.11 (1H, m), 2.29 (2H, d, J = 6.7 Hz), 2.41 (4H, m), 2.76 (2H, t, J = 11.2 Hz), 3.42 (3H, s), 3.43 (2H, s), 3.49 (2H, t, J = 4.8 Hz), 3.55-3.78 (4H, m), 5.95 (2H, s), 6.47 (1H, d, J = 9.0 Hz), 6.74 (2H, s), 6.86 (1H, s), 6.96 (2H, d, J = 8.9 Hz), 7.13 (2H, d, J = 8.9 Hz), 7.70 (1H, brs), 7.71 (1H, dd, J = 9.0 Hz, 2.7 Hz), 7.75 (2H, d, J = 8.2 Hz), 7.99 (2H, d, J = 8.2 Hz), 8.26 (1H, d, J = 2.7 Hz).

TABLE 167

Example

No.
Xb₆
M
R₅₇₁
Form
δ mp (°C) or ¹H NMR

325
—N(Ac)—
1

embedded image

hydro- chloride
mp 214-216

326
—N(Ac)—
1

embedded image

free

¹H NMR (DMSO-d₆) δ 1.77 (3H, s), 2.25-2.34 (4H, m), 3.30-3.50 (6H, m), 4.40 (2H, s), 6.97 (2H, d, J = 8.8 Hz), 7.22-7.35 (6H, m), 7.36 (2H, d, J = 8.8 Hz), 7.53- 7.59 (1H, m), 7.84 (1H, d, J = 8.3 Hz), 7.89-7.95 (2H, m), 8.20 (1H, d, J = 2.2 Hz), 10.61 (1H, s).

327
none
1

embedded image

free
mp 178-179

328
none
1
morpholino
free
mp 196-198

329
none
3

embedded image

free
mp 197-198

330
none
3
morpholino
free
mp 144-146

331
none
3

embedded image

hydro- chloride
mp 194-196

332
none
1

embedded image

hydro- chloride
mp 205-206

333
—S—
1

embedded image

free

¹H NMR (CDCl₃) δ 2.35- 2.45 (4H, m), 3.42 (2H, s), 3.42-3.48 (2H, m), 3.58 (2H, brs), 3.65 (2H, s), 5.94 (2H, s), 6.72-6.75 (2H, m), 6.84 (1H, d, J = 1.1 Hz), 6.89 (2H, d, J = 8.8 Hz), 7.00-7.10 (1H, m), 7.19-7.25 (1H, m), 7.42 (2H, d, J = 8.8 Hz), 7.58 (2H, d, J = 8.3 Hz), 7.65-7.76 (2H, m), 7.98 (1H, s), 7.99 (1H, s).

334
—SO—
1

embedded image

free
mp 133-135

335
—SO₂—
1

embedded image

free
mp 125-128

336
—CH═CH— (trans)
0

embedded image

free
mp 169-171

TABLE 168

Example No.
R₅₇₂
R₅₇₃

¹H NMR (solvent) δ ppm

337
4-CF₃Ph—
benzyl
(CDCl₃) 2.30-2.34 (2H, m), 2.39 2.43 (2H, m),

3.46-3.49 (4H, m), 3.62-3.66 (2H, m), 3.69 (2H,

s), 6.94 (1H, d, J = 8.7 Hz), 7.03-7.08 (2H, m),

7.19-7.35 (7H, m), 7.75 (2H, d, J = 8.2 Hz),

8.00 (2H, d, J = 8.2 Hz), 8.21 (1H, dd, J = 8.7

Hz, 2.8 Hz), 8.26 (1H, s), 8.29 (1H, d, J = 2.8

Hz).

338
4-CF₃Ph—
piperonyl
(CDCl₃) 2.28-2.32 (2H, m), 2.36-2.39 (2H, m),

3.39 (2H, s), 3.45-3.49 (2H, m), 3.60-3.64 (2H,

m), 3.68 (2H, s), 5.94 (2H, s), 6.69-6.76 (2H, m),

6.83 (1H, brs), 6.92 (1H, d, J = 8.7 Hz), 7.01-

7.06 (2H, m), 7.17-7.22 (2H, m), 7.72 (2H, d, J =

8.4 Hz), 8.00 (2H, d, J = 8.1 Hz), 8.17-8.21 (1H,

m), 8.29 (1H, d, J = 2.6 Hz), 8.49 (1H, brs).

339
3,4-Cl₂Ph—
benzyl
(CDCl₃) 2.31-2.34 (2H, m), 2.38-2.42 (2H, m),

3.46-3.50 (4H, m), 3.62-3.65 (2H, m), 3.69 (2H,

s), 6.90 (1H, d, J = 8.9 Hz), 7.00-7.05 (2H, m),

7.17-7.23 (2H, m), 7.28-7.35 (5H, m), 7.54 (1H, d,

J = 8.2 Hz). 7.73 (1H, dd, J = 8.4 Hz, 2.1 Hz),

7.99 (1H, d, J = 2.1 Hz), 8.12-8.17 (1H, m),

8.28 (1H, d, J = 2.8 Hz), 8.44 (1H, brs).

340
3,4-Cl₂Ph—
3-pyridyl
(CDCl₃) 3.02-3.06 (2H, m), 3.13-3.17 (2H, m),

3.63-3.67 (2H, m), 3.76-3.82 (4H, m), 6.91 (1H, d,

J = 8.9 Hz), 7.02-7.07 (2H, m), 7.17-7.24 (4H,

m), 7.52 (1H, d, J = 8.4 Hz), 7.73-7.76 (1H, m),

8.01 (1H, d, J = 2.0 Hz), 8.11-8.13 (1H, m),

8.18 (1H, dd, J = 8.9 Hz, 2.8 Hz), 8.23-8.25 (2H,

m), 8.95 (1H, brs).

341
3,4-Cl₂Ph—
piperonyl
(CDCl₃) 2.28-2.39 (4H, m), 3.39 (2H, s), 3.46-

3.49 (2H, m), 3.60-3.64 (2H, m), 3.69 (2H, s),

5.94 (2H, s), 6.69-6.76 (2H, m), 6.82-6.83 (1H,

m), 6.89 (1H, d, J = 8.9 Hz), 6.99-7.04 (2H, m),

7.15-7.21 (2H, m), 7.53 (1H, d, J = 8.4 Hz). 7.71-

7.75 (1H, m), 7.99 (1H, d, J = 2.1 Hz), 8.14 (1H,

dd, J = 8.9 Hz, 2.6 Hz), 8.28 (1H, d, J = 2.6 Hz),

8.56 (1H, s).

342
3,4-Cl₂PhNH—
piperonyl
(DMSO-d₆) 2.20-2.35 (4H, m), 3.38 (2H, s), 3.40-

3.55 (4H, m), 3.69 (2H, s), 5.98 (2H, s), 6.70-

6.76 (1H, m), 6.76-6.86 (2H, m), 6.97-7.00 (3H,

m), 7.02-7.24 (2H, m), 7.35 (1H, dd, J = 8.8 Hz,

2.5 Hz), 7.52 (1H, d, J = 8.8 Hz), 7.86 (1H, d, J =

2.5 Hz), 7.98 (1H, dd, J = 5.8 Hz, 2.8 Hz),

8.19 (1H, d, J = 2.6 Hz), 8.89 (1H, s), 9.08 (1H,

s).

TABLE 169

Example No.
R₅₇₄

¹H NMR (DMSO-d₆) δ ppm or MS

343
—H

¹H NMR 2.33 (2H, t, J = 7.7 Hz), 2.77 (2H, t, J = 7.7 Hz),

6.75 (1H, brs), 6.87 (2H, d, J = 8.6 Hz), 7.15-7.23 (3H, m),

7.28 (1H, brs), 7.54 (1H, d, J = 8.7 Hz), 7.85 (1H, d, J = 8.4

Hz), 7.89 (1H, dd, J = 13.2 Hz, 2.4 Hz), 7.94 (1H, dd, J = 8.4

Hz, 2.0 Hz), 8.21 (1H, d, J = 20 Hz), 10.57 (1H, s).

344
—CH₃
MS 460 (M⁺)

345
—C₂H₅

¹H NMR 0.97 (3H, t, J = 7.2 Hz), 2.32 (2H, t, J = 7.8 Hz),

2.77 (2H, t, J = 7.8 Hz), 3.00-3.08 (2H, m), 6.87 (2H, d, J = 8.6

Hz), 7.14-7.21 (3H, m), 7.54 (1H, d, J = 9.8 Hz) 7.78 (1H, brt),

7.85 (1H, d, J = 8.4 Hz), 7.89 (1H, dd, J = 13.2 Hz, 2.3 Hz),

7.94 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.21(1H, d, J = 2.1 Hz),

10.57 (1H, s).

346
—CH(CH₃)₂

¹H NMR 1.00 (6H, d, J = 6.6 Hz), 2.30 (2H, t, J = 7.7 Hz),

2.77 (2H, t, J = 7.7 Hz), 3.75-3.86 (1H, m), 6.87 (2H, d, J = 8.6

Hz), 7.13-7.20 (3H, m), 7.54 (1H, d, J = 8.9 Hz), 7.65 (1H,

brd), 7.85 (1H, d, J = 8.4 Hz), 7.89 (1H, dd, J = 13.1 Hz, 2.5

Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.22 (1H, d, J = 2.1

Hz), 10.58 (1H, s).

347
—CH₂CH(CH₃)₂

¹H NMR 0.78 (6H, d, J = 6.7 Hz), 1.56-1.68 (1H, m), 2.36 (2H,

t, J = 7.6 Hz), 2.78 (2H, t, J = 7.6 Hz), 2.81-2.82 (2H, m),

6.87 (2H, d, J = 8.6 Hz), 7.10-7.22 (3H, m), 7.51 (1H, d, J =

8.9 Hz), 7.77 (1H, brt), 7.85 (1H, d, J = 8.4 Hz), 7.89 (1H,

dd, J = 13.2 Hz, 2.4 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.1 Hz),

8.21 (1H, d, J = 2.1 Hz), 10.57 (1H, s).

348
—(CH₂)₃CH₃

¹H NMR 0.84 (3H, t, J = 7.3 Hz), 1.15-1.27 (2H, m), 1.27-

1.38 (2H, m), 2.33 (2H, t, J = 7.7 Hz), 2.77 (2H, t, J = 7.7 Hz),

2.97-3.05 (2H, m), 6.87 (2H, d, J = 8.6 Hz), 7.11-7.21 (3H, m),

7.50-7.58 (1H, m), 7.74 (1H, brt), 7.85 (1H, d, J = 8.4 Hz), 7.89

(1H, dd, J = 13.2 Hz, 2.4 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.1

Hz), 8.21 (1H, d, J = 2.1 Hz), 10.57 (1H, s).

349
cyclopropyl

¹H NMR 0.26-0.37 (2H, m), 0.51-0.63 (2H, m), 2.29 (2H, t, J =

7.7 Hz), 2.53-2.61 (1H, m), 2.76 (2H, t, J = 7.7 Hz), 6.87 (2H,

d, J = 8.6 Hz), 7.10-7.23 (3H, m), 7.54 (1H, d, J = 8.6 Hz),

7.80-8.00 (4H, m), 8.21 (1H, d, J = 2.1 Hz), 10.57 (1H, s).

350
cyclopentyl

¹H NMR 1.21-1.34 (2H, m), 1.41-1.51 (2H, m), 1.51-1.63 (2H,

m), 1.68-1.80 (2H, m), 2.31 (2H, t, J = 7.7 Hz), 2.76 (2H, t, J =

7.7 Hz), 3.90-3.99 (1H, m), 6.87 (2H, d, J = 8.6 Hz), 7.14-

7.21 (3H, m), 7.50-7.57 (1H, m), 7.72 (1H, brd), 7.85 (1H, d, J =

8.4 Hz), 7.89 (1H, dd, J = 13.2 Hz, 2.4 Hz), 7.91 (1H, dd, J =

8.4 Hz, 2.1 Hz), 8.22 (1H, d, J = 2.1 Hz), 10.58 (1H, s).

351
cyclohexyl

¹H NMR 1.00-1.15 (3H, m), 1.15-1.28 (2H, m), 1.48-1.58 (1H,

m), 1.58-1.70 (4H, m), 2.31 (2H, t, J = 7.6 Hz), 2.77 (2H, t, J =

7.6 Hz), 3.44-3.53 (1H, m), 6.87 (2H, d, J = 8.6 Hz), 7.11-

7.23 (3H, m), 7.50-7.57 (1H, m), 7.62 (1H, brd), 7.85 (1H, d, J =

8.4 Hz), 7.89 (1H, dd, J = 13.2 Hz, 2.4 Hz), 7.04 (1H, dd, J =

8.4 Hz, 2.1 Hz), 8.21 (1H, d, J = 2.1 Hz), 10.57 (1H, s).

TABLE 170

Example No.
R₅₇₅

¹H NMR (DMSO-d₆) δ ppm

352
cycloheptyl
1.28-1.40 (4H, m), 1.40-1.61 (6H, m), 1.63-1.77 (2H, m),

2.31 (2H, t, J = 7.6 Hz), 2.76 (2H, t, J = 7.6 Hz), 3.64-

3.74 (1H, m), 6.87 (2H, d, J = 8.6 Hz), 7.11-7.23 (3H, m),

7.54 (1H, d, J = 9.1 Hz), 7.67 (1H, brd), 7.85 (1H, d, J = 8.4

Hz), 7.89 (1H, dd, J = 13.2 Hz, 2.4 Hz), 7.94 (1H, dd, J =

8.4 Hz, 2.1 Hz), 8.21 (1H, d, J = 2.1 Hz), 10.57 (1H, s).

353
cyclooctyl
1.30-1.65 (14H, m), 2.31 (2H, t, J = 7.6 Hz), 2.76 (2H, t,

J = 7.6 Hz), 3.69-3.80 (1H, m), 6.87 (2H, d, J = 8.6 Hz),

7 10-7.22 (3H, m), 7.54 (1H, d, J = 8.9 Hz), 7.65 (1H, brd),

7.85 (1H, d, J = 8.4 Hz), 7.89 (1H, dd, J = 13.2 Hz, 2.3

Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.21 (1H, d, J = 2.0

Hz), 10.57 (1H, s).

354
cyclododecanyl
1.10-1.41 (20H, m), 1.41-1.54 (2H, m), 2.32 (2H, t, J = 7.5

Hz), 2.77 (2H, t, J = 7.5 Hz), 3.79-3.88 (1H, m), 6.86 (2H,

d, J = 8.6 Hz), 7.10-7.21 (3H, m), 7.48-7.57 (2H, m),

7.85 (1H, d, J = 8.4 Hz), 7.89 (1H, dd, J = 13.1 Hz, 2.5

Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.21 (1H, d, J = 2.1

Hz), 10.58 (1H, s).

355
cyclopropylmethyl
0.06-0.16 (2H, m), 0.28-0.42 (2H, m), 0.78-0.90(1H, m),

2.35 (2H, t, J = 7.7 Hz), 2.78 (2H, t, J = 7.7 Hz), 2.84-

2.97 (2H, m), 6.87 (2H, d, J = 8.5 Hz), 7.12-7.27 (3H, m),

7.54 (1H, d, J = 8.8 Hz), 7.85 (1H, d, J = 8.4 Hz), 7.87 (1H,

brt), 7.89 (1H, dd, J = 13.2 Hz, 2.3 Hz), 7.94 (1H, dd, J =

8.4 Hz, 2.0 Hz), 8.21 (1H, d, J = 2.0 Hz), 10.57 (1H, s).

356
cyclohexylmethyl
0.71-0.86 (2H, m), 1.03-1.20 (3H, m), 1.22-1.34 (1H, m)

1.50-1.69 (5H, m), 2.35 (2H, t, J = 7.6 Hz), 2.78 (2H, t, J =

7.6 Hz), 2.80-2.90 (2H, m), 6.86 (2H, d, J = 8.6 Hz) 7.12-

7.23 (3H, m), 7.54 (1H, d, J = 8.9 Hz), 7.73 (1H, brt),

7.85 (1H, d, J = 8.4 Hz), 7.89 (1H, dd, J = 13.2 Hz, 2.4

Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.21 (1H, d, J = 2.1

Hz), 10.57 (1H, s).

357
piperonyl
2.41 (2H, t, J = 7.6 Hz), 2.81 (2H, t, J = 7.6 Hz), 4.15 (2H,

d, J = 5.9 Hz), 5.96 (2H, s), 6.63(1H, d, J = 8.0 Hz),

6.74 (1H, d, J = 1.4 Hz), 6.80 (1H, d, J = 8.0 Hz), 6.87 (2H,

d, J = 8.8 Hz), 7.14-7.23 (3H, m), 7.54 (1H, d, J = 9.8 Hz),

7.85 (1H, d, J = 8.4 Hz), 7.89(1H, dd, J = 13.2 Hz, 2.4

Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.22 (1H, d, J = 2.1

Hz), 8.25 (1H, brt), 8.40-8.46 (2H, m), 10.58 (1H, s).

358
—CH(CH₃)Ph
1.30 (3H, d, J = 7.0 Hz), 2.40 (2H, t, J = 7.5 Hz), 2.78 (2H,

t, J = 7.5 Hz), 3.86-3.96 (1H, m), 6.82-6.99 (2H, m), 7.12-

7.24 (6H, m), 7.24-7.31 (2H, m), 7.55 (1H, dd, J = 8.9 Hz,

1.2 Hz), 7.85 (1H, d, J = 8.4 Hz), 7.90 (1H, dd, J = 13.2

Hz, 2.5 Hz), 7.94(1H, dd, J = 8.4 Hz, 2.1 Hz), 8.22 (1H, d,

J = 2.1 Hz), 8.24 (1H, brd), 10.59 (1H, s).

TABLE 171

Example

No.
R₅₇₆

¹H NMR (DMSO-d₆) δ ppm or MS

359
2-pyridylmethyl
MS 537 (M⁺)

360
3-pyridylmethyl

¹H NMR 2.44 (2H, t, J = 7.6 Hz), 2.82 (2H, t, J = 7.6

Hz), 4.27 (2H, d, J = 5.9 Hz), 6.86 (2H, dd, J = 6.7 Hz,

1.9 Hz), 7.14-7.22 (3H, m), 7.25-7.32 (1H, m), 7.46-

7.58 (2H, m), 7.85 (1H, d, J = 8.4 Hz), 7.90 (1H, dd,

J = 13.2 Hz, 2.5 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.1

Hz), 8.22 (1H, d, J = 2.1 Hz), 8.38 (1H, brt), 8.40-

8.46 (2H, m), 10.58 (1H, s).

361
4-pyridylmethyl
MS 537 (M⁺)

362
—(CH₂)₂NHAc

¹H NMR 1.78 (3H, s), 2.34 (2H, t, J = 7.8 Hz),

2.78 (2H, t, J = 7.8 Hz), 2.96-3.10 (4H, m), 6.83-

6.91 (2H, m), 7.14-7.23 (3H, m), 7.54 (1H, dd, J = 8.9

Hz, 1.3 Hz), 7.80-7.98 (5H, m), 8.21(1H, d, J = 2.1

Hz), 10.58 (1H, s).

363
—CH(CH₃)(CH₂)₄CH₃

¹H NMR 0.84 (3H, t, J = 7.0 Hz), 0.96 (3H, d, J = 6.6

Hz), 1.08-1.34 (8H, m), 2.32 (2H, t, J = 7.2 Hz),

2.77 (2H, t, J = 7.2 Hz), 3.65-3.76 (1H, m), 6.82-

6.89 (2H, m), 7.12-7.21 (3H, m), 7.50-7.60 (2H, m),

7.85 (1H, d, J = 8.4 Hz), 7.89 (1H, dd, J = 13.2 Hz, 2.5

Hz), 7.94 (1H, dd, J = 8.3 Hz, 2.1 Hz), 8.21 (1H, d, J =

2.1 Hz), 10.58 (1H, s).

364
—(CH₂)₂OCH₃

¹H NMR 2.35 (2H, t, J = 7.7 Hz), 2.77 (2H, t, J = 7.7

Hz), 3.13-3.22 (2H, m), 3.22 (3H, s), 3.29 (2H, t, J =

5.8 Hz), 6.82-6.92 (2H, m), 7.13-7.23 (3H, m),

7.54 (1H, d, J = 8.9 Hz) 7.85 (1H, d, J = 8.4 Hz), 7.85-

7.92 (2H, m), 7.94 (1H, dd, J = 8.4 Hz, 2.0 Hz),

8.21 (1H. d. J = 2.0 Hz), 10.57 (1H, s).

365

embedded image

MS 554 (M⁺)

366

embedded image

MS 619 (M⁺)

TABLE 172

Ex-

am-

ple

No.
R₅₇₇
R₅₇₈
mp (° C.) or MS

367
—H
morpholino
mp 160-162

368
—F
morpholino
mp 150-151

369
—F

embedded image

MS 657 (M⁺ + H)

370
—F

embedded image

MS 646 (M⁺ − 1)

371
—F
4-CH₃OPh(CH₂)₂N(C₂H₅)—
MS 608 (M⁺)

372
—F
4-CH₃OPhCH₂N(C₂H₅)—
MS 594 (M⁺)

373
—F
3,4-(CH₃O)₂PhCH₂N(CH₂CH₂CH₃)—
MS 638 (M⁺)

TABLE 173

Example

No.
R₅₇₉

¹H NMR (DMSO-d₆) δ ppm

374
Ph—
2.39-2.49 (2H, m), 2.78-2.88 (2H, m), 4.18-4.30 (2H, m),

6.87 (2H, d, J = 8.6 Hz), 7.02-7.33 (8H, m), 7.55 (1H, d, J = 8.9

Hz), 7.85 (1H, d, J = 8.4 Hz), 7.90 (1H, dd, J = 13.2 Hz, 2.4

Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.22 (1H, d, J = 2.0 Hz),

8.32 (1H, brt), 10.58 (1H, s).

375
4-FPh—
2.43 (2H, t, J = 7.6 Hz), 2.82 (2H, t, J = 7.6 Hz), 4.22 (2H, d, J =

5.9 Hz) 6.87 (2H, d, J = 8.6 Hz), 7.04-7.12 (2H, m), 7.12-

7.24 (5H, m) 7.55 (1H, d, J = 9.0 Hz), 7.85 (1H, d, J = 8.4 Hz),

7.90 (1H, dd, J =13.2 Hz, 2.4 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.1

Hz), 8.22 (1H, d, J = 2.1 Hz), 8.32 (1H, brt), 10.58 (1H, s).

376
3,4-(CH₃O)₂Ph—
2.42 (2H, t, J = 7.6 Hz), 2.82 (2H, t, J = 7.6 Hz), 3.70 (3H, s),

3.71 (3H, s), 4.18 (2H, d, J = 5.8 Hz), 6.67 (1H, d, J = 8.4 Hz),

6.77-6.90 (4H, m), 7.15-7.23 (3H, m), 7.55 (1H, d, J = 9.0 Hz),

7.85 (1H, d, J = 8.4 Hz), 7.89 (1H, dd, J = 13.2 Hz, 2.4 Hz),

7.94 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.21 (1H, d, J = 2.0 Hz),

8.25 (1H, brt), 11.58 (1H, s).

377
2-ClPH—
2.48 (2H, t, J = 7.5 Hz), 2.83 (2H, t, J = 7.5 Hz), 4.30 (2H, d, J =

5.9 Hz), 6.88 (2H, d, J = 8.6 Hz), 7.08-7.15 (1H, m), 7.15-

7.32 (5H, m), 7.38-7.46 (1H, m), 7.51-7.59 (1H, m), 7.85 (1H, d,

J = 8.4 Hz), 7.90 (1H, dd, J = 13.2 Hz, 2.4 Hz), 7.94 (1H, dd, J =

8.4 Hz, 2.1 Hz), 8.22 (1H, d, J = 2.0 Hz), 8.34 (1H, brt), 10.58

(1H, s).

378
3-ClPH—
2.45 (2H, t, J = 7.5 Hz), 2.83 (2H, t, J = 7.5 Hz), 4.25 (2H, d, J =

6.0 Hz), 6.87 (2H, d, J = 8.6 Hz), 7.07-7.12 (1H, m), 7.12-

7.21 (3H, m), 7.21-7.25 (1H, m), 7.25-7.33 (2H, m), 7.55 (1H, d,

J = 9.0 Hz), 7.85 (1H, d, J = 8.4 Hz), 7.90 (1H, dd, J = 13.2 Hz,

2.4 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.22 (1H, d, J = 2.1

Hz), 8.37 (1H, brt), 10.58 (1H, s).

379
4-ClPh—
2.44 (2H, t, J = 7.5 Hz), 2.82 (2H, t, J = 7.5 Hz), 4.22 (2H, d, J =

6.0 Hz), 6.87 (2H, d, J = 8.6 Hz), 7.14 (2H, d, J = 8.4 Hz),

7.16-7.22 (3H, m), 7.29-7.34 (2H, m), 7.55 (1H, d, J = 8.1 Hz),

7.85 (1H, d, J = 8.4 Hz), 7.90 (1H, dd, J = 13.2 Hz, 2.5 Hz),

7.94 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.21 (1H, d, J = 2.1 Hz),

8.34 (1H, brt), 10.58 (1H, s).

380
2-CH₃Ph—
2.21 (3H, s), 2.44 (2H, t, J = 7.5 Hz), 2.82 (2H, t, J = 7.5 Hz),

4.21 (2H, d, J = 5.7 Hz), 6.87 (2H, d, J = 8.6 Hz), 7.00-7.07 (1H,

m), 7.07-7.23 (6H, m), 7.55 (1H, d, J = 9.0 Hz), 7.85 (1H, d, J =

8.4 Hz), 7.90 (1H, dd, J = 13.2 Hz, 2.4 Hz), 7.94 (1H, dd, J =

8.4 Hz, 2.1 Hz), 8.16 (1H, brt), 8.22 (1H, d, J = 2.1 Hz),

10.58 (1H, s).

381
4-CH₃OPh—
2.41 (2H, t, J = 7.6 Hz), 2.81 (2H, t, J = 7.6 Hz), 3.71 (3H, s),

4.17 (2H, d, J = 5.8 Hz), 6.80-6.91 (4H, m), 7.07 (2H, d, J = 8.5

Hz), 7.13-7.25 (3H, m), 7.55 (1H, d, J = 8.5 Hz), 7.85 (1H, d, J =

8.4 Hz), 7.90 (1H, dd, J = 13.2 Hz, 2.4 Hz), 7.94 (1H, dd, J =

8.4 Hz, 2.1 Hz), 8.21 (1H, d, J = 2.1 Hz), 8.24 (1H, brt),

10.58 (1H, s).

TABLE 174

Example

No.
R₅₈₀

¹H NMR (DMSO-d₆) δ ppm

382
Ph—
2.33 (2H, t, J = 7.7 Hz), 2.66 (2H, t, J = 7.3 Hz), 2.77 (2H,

t, J = 7.7 Hz), 3.20-3.29 (2H, m), 6.87 (2H, d, J = 8.6 Hz),

7.12-7.22 (6H, m), 7.23-7.30 (2H, m), 7.54 (1H, dd, J =

8.9 Hz, 1.1 Hz), 7.85 (1H, d, J = 8.4 Hz), 7.85-7.91 (2H,

m), 7.94 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.21 (1H, d, J = 2.1

Hz), 10.57 (1H, s).

383
4-FPh—
2.33 (2H, t, J = 7.7 Hz), 2.65 (2H, t, J = 7.2 Hz), 2.76 (2H,

t, J = 7.7 Hz), 3.30-3.37 (2H, m), 6.87 (2H, d, J = 8.5 Hz),

7.04-7.11 (2H, m), 7.13-7.22 (5H, m), 7.54 (1H, d, J = 9.1

Hz), 7.85 (1H, d, J = 8.4 Hz), 7.80-7.92 (2H, m), 7.94 (1H,

dd, J = 8.4 Hz, 2.0 Hz), 8.21 (1H, d, J = 2.0 Hz),

10.58 (1H, s).

384
4-ClPh—
2.32 (2H, t, J = 7.6 Hz), 2.66 (2H, t, J = 7.1 Hz), 2.76 (2H,

t, J = 7.6 Hz), 3.18-3.27 (2H, m), 6.87 (2H, d, J = 8.5 Hz),

7.10-7.22 (5H, m), 7.31 (2H, d, J = 8.3 Hz), 7.54 (1H, d, J =

8.9 Hz), 7.84 (1H, d, J = 8.4 Hz), 7.85-7.92 (2H, m),

7.94 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.21 (1H, d, J = 2.0

Hz), 10.57 (1H, s).

385
3-CH₃OPh—
2.33 (2H, t, J = 7.7 Hz), 2.64 (2H, t, J = 7.3 Hz), 2.78 (2H,

t, J = 7.7 Hz), 3.18-3.27 (2H, m), 3.72 (3H, s), 6.70-

6.78 (3H, m), 6.87 (2H, d, J = 8.6 Hz), 7.12-7.23 (4H, m),

7.54 (1H, dd, J = 8.9 Hz, 1.2 Hz), 7.85 (1H, d, J = 8.4

Hz), 7.85-7.92 (2H, m), 7.94 (1H, dd, J = 8.4 Hz, 2.1 Hz),

8.21 (1H, d, J = 2.0 Hz), 10.57 (1H, s).

386
4-CH₃OPh—
2.33 (2H, t, J = 7.6 Hz), 2.59 (2H, t, J = 7.2 Hz), 2.77 (2H,

t, J = 7.6 Hz), 3.16-3.24 (2H, m), 3.71 (3H, s), 6.83 (2H, d,

J = 8.5 Hz), 6.87 (2H, d, J = 8.5 Hz), 7.07 (2H, d, J = 8.4

Hz), 7.13-7.23 (3H, m), 7.54 (1H, d, J = 8.5 Hz), 7.80-

7.98 (4H, m), 8.21 (1H. d, J = 1.8 Hz), 10.57 (1H, s).

387
PhO—
2.38 (2H, t, J = 7.7 Hz), 2.79 (2H, t, J = 7.7 Hz), 3.38-

3.43 (2H, m), 3.94 (2H, t, J = 5.7 Hz), 6.79-6.85 (2H, m),

6.89-6.96 (3H, m), 7.12-7.20 (3H, m), 7.23-7.31 (2H, m),

7.50-7.57 (1H, m), 7.85 (1H, d, J = 8.4 Hz), 7.89 (1H, dd,

J = 13.2 Hz, 2.4 Hz), 8.10 (1h, brt), 8.22 (1H, d, J = 2.1

Hz), 10.58 (1H, s).

388
PhCH₂—
1.60-1.70 (2H, m), 2.36 (2H, t, J = 7.4 Hz), 2.49-2.55 (2H,

m), 2.79 (2H, t, J = 7.4 Hz), 3.00-3.08 (2H, m), 6.83-

6.90 (2H, m), 7.10-7.21 (6H, m), 7.21-7.29 (2H, m),

7.53 (1H, d, J = 8.9 Hz), 7.89-7.92 (3H, m), 8.21 (1H, d,

J = 2.1 Hz). 10.57 (1H, s).

TABLE 175

Example

No.
R₅₈₁
MS

389
—CHPh₂
681 (M⁺ + 1)

390
—NHCOPh
633 (M⁺)

391
—O(CH₂)₂Ph
634 (M⁺)

392
—(CH₂)₂N(CH₃)Ph
647 (M⁺)

393

embedded image

675 (M⁺)

394
morpholino
599 (M⁺)

395

embedded image

626 (M⁺)

396
cyclohexyl
596 (M⁺)

397

embedded image

656 (M⁺)

398

embedded image

626 (M⁺)

399
4-CH₃OPhCONH—
664 (M⁺ + 1)

400

embedded image

644 (M⁺)

401

embedded image

620 (M⁺ − 1)

402

embedded image

623 (M⁺ + 2)

TABLE 176

Example

No.
R₅₈₂
R₅₈₃
Property

403
—H
4-CF₃OPhNH—
mp 91-95° C.

404
—F
4-CF₃OPhNH—
mp 145-147° C.

405
—H
4-CF₃PhO—
mp 118-121° C.

406
—H
4-CF₃OPhO—
mp 126-127° C.

407
—F
4-CF₃PhO—
mp 129-134° C.

408
—H
4-CNPhO—
mp 148-149° C.

409
—F
4-CNPhO—
mp 147-150° C.

410
—F
4-CF₃OPhO—

¹H NMR (CDCl₃) δ 1.69-1.85 (4H, m), 2.62 (2H,

t, J = 7.5 Hz), 2.90 (2H, t, J = 7.5 Hz), 3.36 (1H,

m), 3.57-3.67 (3H, m), 4.47 (1H, m), 6.85-

6.90 (4H, m), 7.00 (1H, t, J = 8.5 Hz), 7.10 (2H,

d, J = 8.5 Hz), 7.13 (2H, d, J = 8.5 Hz),

7.30 (1H, brd, J = 8.5 Hz), 7.52 (1H, d, J = 8.5

Hz), 7.69-7.75 (2H, m), 7.98 (1H, d, J = 2.0 Hz),

8.80 (1H, s).

411
—F
PhO—
MS 606 (M⁺)

412
—F
4-ClPhCH₂—
MS 638 (M⁺)

413
—F
4-CH₃PhCH₂—
MS 618 (M⁺)

414
—F
4-ClPh—
MS 626 (M⁺)

415
—F
Ph—
MS 590 (M⁺)

416
—F
2-NH₂PhCO—
MS 633 (M⁺)

TABLE 177

Example

No.
R₅₈₄
R₅₈₅
Form
mp (° C.) or MS

417
—F
—H
free
MS 543 (M⁺)

418
—F
—(CH₂)₂OPh
free
MS 664 (M⁺ + H)

419
—F
—(CH₂)₂Ph
free
MS 648 (M⁺ + H)

420
—F
—(CH₂)₂N(C₂H₅)₂
free
MS 643 (M⁺ + H)

421
—H
—(CH₂)₂Ph
fumarate
mp 148-151

422
—F
—(CH₂)₃Ph
free
MS 661 (M⁺)

423
—F
—(CH₂)₂CHPh₂
free
MS 737 (M⁺)

424
—F

embedded image

free
MS 638 (M⁺)

425
—F
4-CH₃SPh(CH₂)₂—
free
MS 692 (M⁺ − 1)

426
—F
4-CH₃PhO(CH₂)₂—
free
MS 678 (M⁺ + H)

427
—F

embedded image

free
MS 723 (M⁺ + H)

428
—F
4-CH₃OPh(CH₂)₄—
free
MS 705 (M⁺)

429
—F

embedded image

free
MS 658 (M⁺ + H)

430
—F
4-CH₃Ph(CH₂)₂—
free
MS 661 (M⁺)

431
—F
—(CH₂)₂N(CH₃)Ph
free
MS 676 (M⁺)

432
—F

embedded image

free
MS 653 (M⁺)

TABLE 178

Example

No.
R₅₈₆
R₅₈₇
R₅₈₈
R₅₈₉
R₅₉₀
mp (° C.) or MS

433
—H
—H
—H
—CF₃
—H
mp 124-126

434
—F
—H
—H
—CF₃
—H
mp 132-134

435
—F
—H
—H
—Cl
—H
MS 654 (M⁺)

436
—F
—F
—H
—H
—H
MS 638 (M⁺)

437
—F
—H
—H
—H
—H
MS 620 (M⁺)

438
—F
—H
—H
—OCH₃
—H
MS 651 (M⁺ + H)

439
—F
—H
—Cl
—H
—H
MS 656 (M⁺)

440
—F
—Cl
—H
—H
—H
MS 654 (M)

441
—F
—H
—Cl
—Cl
—H
MS 690 (M⁺)

442
—F
—H
—OCH₃
—H
—H
MS 650 (M⁺)

443
—F
—H
—OCH₃
—H
—OCH₃
MS 680 (M⁺)

444
—F
—H
—H
—CH₃
—H
MS 635 (M⁺ + H)

445
—F
—H
—CH₃
—H
—H
MS 636 (M⁺ + 2)

446
—F
—CH₃
—H
—H
—H
MS 635 (M⁺ + H)

447
—F
—H
—CH₃
—CH₃
—H
MS 648 (M⁺)

448
—F
—H
—H
—F
—H
MS 638 (M⁺)

449
—F
—H
—F
—H
—H
MS 638 (M⁺)

450
—F
—H
—F
—H
—F
MS 656 (M⁺)

451
—F
—CF₃
—H
—H
—H
MS 656 (M⁺)

452
—F
—H
—H
—OCF₃
—H
MS 705 (M⁺ + H)

453
—F
—H
—OCF₃
—H
—H
MS 704 (M⁺)

454
—F
—OCF₃
—H
—H
—H
MS 704 (M⁺)

455
—F
—H
—Cl
—OCH₃
—H
MS 685 (M⁺ + H)

TABLE 179

Example

No.
R₅₉₁
R₅₉₂
Property

456
—H
—CH₂CONHPh

¹H NMR (CDCl₃) δ 2.45 (2H, brt, J = 5.0 Hz),

2.55 (2H, brt, J = 5.0 Hz), 2.63 (2H, t, J =

7.5 Hz), 2.96 (2H, t, J = 7.5 Hz), 3.11 (2H, s),

3.47 (2H, brs), 3.70 (2H, brs), 6.93 (2H, d, J =

8.5 Hz), 6.98 (2H, d, J = 8.5 Hz), 7.13 (1H, t, J =

8.5 Hz), 7.15 (2H, d, J = 8.5 Hz), 7.34 (2H, t, J =

8.5 Hz), 7.52-7.59 (5H, m), 7.73 (1H, dd, J =

8.5 Hz, 2.0 Hz), 7.99 (1H, d, J = 2.0 Hz), 8.28 (1H, s),

8.92 (1H, s).

457
—F
—CH₂CONHPh

¹H NMR (CDCl₃) δ 2.39 (2H, brs), 2.51 (2H, brs),

2.61 (2H, t, J = 7.5 Hz), 2.93 (2H, t, J = 7.5 Hz),

3.08 (2H, s), 3.43 (2H, brs), 3.67 (2H, brs),

6.88 (2H, d, J = 8.5 Hz), 7.03 (1H, t, J = 8.5 Hz),

7.11-7.15 (3H, m), 7.30-7.35 (3H, m), 7.51-

7.54 (3H, m), 7.70 (1H, dd, J = 9.0 Hz, 2.0 Hz),

7.74 (1H, dd, J = 8.5 Hz, 2.0 Hz), 8.00 (1H, d, J =

2.0 Hz), 8.74 (1H, s), 8.93 (1H, s).

458
—F
—(CH₂)₃Ph
MS 633 (M⁺)

459
—F
—(CH₂)₄Ph
MS 647 (M⁺)

460
—F
—CH(C₂H₅)₂
MS 586 (M⁺ + 1)

461
—F
—CH(CH₃)₂
MS 556 (M⁺ − 1)

462
—F
—(CH₂)₃CH₃
MS 571 (M⁺)

463
—F
—(CH₂)₂N(CH₃)₂
MS 585 (M⁺ −1)

464
—F
—COOC(CH₃)₃
mp 155-157° C.

465
—F
—CH₂COPh
MS 633 (M⁺)

466
—H
3-pyridyl
mp 153-155° C.

467
—F
3-pyridyl
mp 183-185° C.

468
—F
2-pyridyl
MS 591 (M⁺ − 1)

469
—F
4-pyridyl
MS 592 (M⁺)

470
—F

embedded image

MS 593 (M⁺)

471
—F

embedded image

MS 593 (M⁺)

TABLE 180

Exam-

ple

No.
R₅₉₃
R₅₉₄
MS

472
—CH₃
benzyl
619 (M⁺)

473
2-pyridylmethyl
—H
606 (M⁺)

474
3-pyridylmethyl
—H
606 (M⁺)

475
4-pyridylmethyl
—H
605

(M⁺ − 1)

476
cyclopentyl
—H
583 (M⁺)

477
cycloheptyl
—H
611 (M⁺)

478

embedded image

—H
612 (M⁺)

479

embedded image

—H
627 (M⁺ + H)

480

embedded image

—H
628 (M⁺)

481

embedded image

—H
612 (M⁺)

482
2-quinolylmethyl
—H
657

(M⁺ + H)

483

embedded image

—H
686 (M⁺ − H)

484

embedded image

—H
625 (M⁺)

485

embedded image

—H
688 (M⁺)

TABLE 181

Example

No.
R₅₉₅
R₅₉₆
R₅₉₇
Form
mp (° C.) or MS

486
—H
—H
—COOC(CH₃)₃
free
mp 188-189

487
—H
—H
—CH₃
free
mp 189-191

488
—H
—H
benzyl
fumarate
mp 190-192

489
—F
—H
—(CH₂)₂Ph
hydrochloride
mp 191-200

490
—F
—H
piperonyl
hydrochloride
mp 226-228

491
—F
—H

embedded image

free
MS 714 (M⁺ − 1)

492
—F
—H
1-naphthylmethyl
free
MS 655 (M⁺)

493
—F
—CH₃
3,4-(CH₃O)₂PhCH₂—
free
MS 679 (M⁺)

494
—F
—H

embedded image

free
MS 678 (M⁺ + 1)

495
—F
—H
—CH(CH₃)Ph
free
MS 619 (M⁺)

496
—F
—H

embedded image

free
MS 682 (M⁺)

497
—F
—H
(4-FPh)₂CH—
free
MS 717 (M⁺)

498
—F
—H
4-CH₃OPhCH(Ph)—
free
MS 711 (M⁺)

TABLE 182

Example

No.
R₅₉₈
R₅₉₉
R₆₀₀
R₆₀₁
R₆₀₂
Form
mp (° C.) or MS

499
—F
—H
—H
—OCF₃
—H
hydrochloride
mp 118-121

500
—F
—H
—H
—CN
—H
free
mp 190-192

501
—H
—H
—H
—OCF₃
—H
hydrochloride
mp 148-149

502
—H
—H
—H
—CN
—H
free
mp 186-188

503
—F
—CF₃
—H
—H
—H
free
MS 659 (M⁺)

504
—F
—H
—CF₃
—H
—H
free
MS 659 (M⁺)

505
—F
—H
—H
—COOC(CH₃)₃
—H
free
MS 691 (M⁺)

506
—F
—H
—H
—F
—H
free
MS 609 (M⁺)

507
—F
—OCH₃
—H
—H
—H
free
MS 621 (M⁺)

508
—F
—Cl
—H
—H
—H
free
MS 625 (M⁺)

509
—F
—H
—H
—Cl
—H
free
MS 627 (M⁺)

510
—F
—H
—Cl
—H
—H
free
MS 625 (M⁺)

511
—F
—Cl
—Cl
—H
—H
free
MS 661 (M⁺)

512
—F
—H
—H
—OCH₃
—H
free
MS 621 (M⁺)

513
—F
—H
—OCH₃
—H
—H
free
MS 621 (M⁺)

514
—F
—H
—H
—CH₃
—H
free
MS 605 (M⁺)

515
—F
—H
—CH₃
—H
—H
free
MS 605 (M⁺)

516
—F
—CH₃
—H
—H
—H
free
MS 605 (M⁺)

517
—F
—CH₃
—CH₃
—H
—H
free
MS 619 (M⁺)

518
—F
—H
—CH₃
—CH₃
—H
free
MS 619 (M⁺)

519
—F
—H
—H
—CF₃
—H
free
MS 659 (M⁺)

520
—F
—H
—H
—Ph
—H
free
MS 667 (M⁺)

521
—F
—F
—H
—H
—H
free
MS 609 (M⁺)

522
—F
—F
—H
—F
—H
free
MS 627 (M⁺)

523
—F
—OCH₃
—H
—H
—Cl
free
MS 657 (M⁺)

TABLE 183

Example

No.
R₆₀₃
R₆₀₄
R₆₀₅
R₆₀₆
R₆₀₇
Form
mp (° C.) or MS

524
—H
—H
—H
—H
—H
fumarate
mp 168-170

525
—H
—H
—Cl
—H
—H
free
MS 638 (M⁺ − 1)

526
—H
—Cl
—H
—H
—H
free
MS 639 (M⁺)

527
—Cl
—H
—H
—H
—H
free
MS 641 (M⁺ + 2)

528
—Cl
—Cl
—H
—H
—H
free
MS 675 (M⁺ + 2)

529
—Cl
—H
—Cl
—H
—H
free
MS 673 (M⁺)

530
—Cl
—H
—H
—Cl
—H
free
MS 673 (M⁺)

531
—H
—Cl
—Cl
—H
—H
free
MS 676 (M⁺ + 3)

532
—H
—OCH₃
—H
—H
—H
free
MS 635 (M⁺)

533
—OCH₃
—H
—H
—H
—H
free
MS 635 (M⁺)

534
—H
—OCH₃
—H
—OCH₃
—H
free
MS 665 (M⁺)

535
—H
—CH₃
—H
—H
—H
free
MS 619 (M⁺)

536
—CH₃
—H
—H
—H
—H
free
MS 619 (M⁺)

537
—H
—CH₃
—CH₃
—H
—H
free
MS 633 (M⁺)

538
—H
—H
—F
—H
—H
free
MS 623 (M⁺)

539
—H
—F
—H
—H
—H
free
MS 623 (M⁺)

540
—F
—H
—H
—H
—H
free
MS 623 (M⁺)

541
—F
—H
—F
—H
—H
free
MS 641 (M⁺)

542
—F
—H
—H
—H
—F
free
MS 641 (M⁺)

543
—H
—H
—NO₂
—H
—H
free
MS 650 (M⁺)

544
—H
—NO₂
—H
—H
—H
free
MS 650 (M⁺)

545
—NO₂
—H
—H
—H
—H
free
MS 650 (M⁺)

546
—H
—CF₃
—H
—H
—H
free
MS 673 (M⁺)

547
—H
—H
—CN
—H
—H
free
MS 630 (M⁺)

548
—H
—OCF₃
—H
—H
—H
free
MS 689 (M⁺)

549
—H
—H
—COOCH₃
—H
—H
free
MS 664 (M⁺ + 1)

550
—H
—H
—C(CH₃)₃
—H
—H
free
MS 661 (M⁺)

551
—H
—H
—OCH₂Ph
—H
—H
free
MS 710 (M⁺ − 1)

552
—H
—H
—Ph
—H
—H
free
MS 681 (M⁺)

553
—Cl
—H
—H
—H
—Cl
free
MS 675 (M⁺ + 2)

554
—F
—H
—H
—F
—H
free
MS 641 (M⁺)

555
—H
—F
—H
—F
—H
free
MS 641 (M⁺)

556
—H
—H
—CF₃
—H
—H
free
MS 674 (M⁺ + 1)

557
—H
—H
—OCF₃
—H
—H
free
MS 689 (M⁺)

558
—OCF₃
—H
—H
—H
—H
free
MS 689 (M⁺)

559
—H
—COOCH₃
—H
—H
—H
free
MS 663 (M⁺)

560
—H
—H
—C₂H₅
—H
—H
free
MS 633 (M⁺)

561
—H
—H
—CH(CH₃)₂
—H
—H
free
MS 647 (M⁺)

562
—H
—Cl
—OCH₃
—H
—H
free
MS 669 (M⁺)

TABLE 184

Example

mp (° C.) or

No.
R₆₀₈
R₆₀₉
R₆₁₀
Form

¹H NMR (solvent) δ ppm

563
—H
—CH₃
piperonyl
free
mp 147-149

564
—H
—H
piperonyl
free
mp 138-140

565
—H
—CH₃
benzyl
free
mp 150-152

566
—H
—H
benzyl
free

¹H NMR (CDCl₃) 2.34-2.42 (4H,

m), 2.58-2.64 (2H, m), 2.91-

2.96 (2H, m), 3.40-3.43 (2H, m),

3.51 (2H, s), 3.60-3.64 (2H, m),

6.93 (1H, d, J = 8.9 Hz), 7.01-

7.04 (2H, m), 7.20 (2H, d, J =

8.6 Hz), 7.27-7.33 (5H, m), 7.56

(1H, d, J = 8.3 Hz), 7.71-7.75 (1H,

m), 8.00 (1H, d, J = 2.0 Hz),

8.16-8.27 (3H, m).

567
—OCH₃
—H
piperonyl
free
mp 142.0-144.5

568
—F
—H
piperonyl
free
mp 156.5-157.5

569
—H
—H
—COOC(CH₃)₃
free

¹H NMR (CDCl₃) 1.46 (9H, s),

2.62-2.67 (2H, m), 2.96-3.01 (2H,

m), 3.33-3.39 (6H, m), 3.57-

3.60 (2H, m), 6.94-6.97 (1H, m),

7.05 (2H, d, J = 8.4 Hz), 7.23 (2H,

d, J = 8.4 Hz), 7.57 (1H, d, J =

8.1 Hz), 7.71-7.75 (1H, m), 8.00

(1H, d, J = 2.2 Hz), 8.13 (1H,

brs), 8.21-8.24 (2H, m).

570
—OC₂H₅
—H
piperonyl
oxalate

¹H NMR (DMSO-d₆) 1.06 (3H, t,

J = 6.9 Hz), 2.39-2.86 (8H, m),

3.40-3.60 (4H, m), 3.65 (2H, s),

3.70-5.20 (4H, m), 6.00 (2H, s),

6.76-6.84 (2H, m), 6.85-7.02 (5H,

m), 7.82 (1H, d, J = 8.4 Hz),

7.92 (1H, m), 8.03 (1H, m),

8.20 (1H, d, J = 2.0 Hz), 8.35 (1H,

d, J = 2.5 Hz), 10.47 (1H, s).

TABLE 185

Example

mp (° C.) or

No.
R₆₁₁
R₆₁₂
R₆₁₃
Form

¹H NMR (CDCl₃) δ ppm

571
—H
—CH₃
piperonyl
hydro-
mp 218-220

chloride

572
—H
—CH₃
benzyl
free
mp 142-144

573
—OCH₃
—H
benzyl
free

¹H NMR 2.34-2.40 (4H, m), 2.58-

2.63 (2H, m), 2.89-2.94 (2H, m),

3.39-3.42 (2H, m), 3.50 (2H, s),

3.58-3.61 (2H, m), 3.70 (3H, s),

6.75-6.80 (2H, m), 6.91 (1H, d, J =

8.7 Hz), 7.00 (1H, d, J = 7.9 Hz),

7.24-7.35 (5H, m), 7.69 (2H, d, J =

8.1 Hz), 7.98 (2H, d, J = 8.1 Hz),

8.14-8.18 (1H, m), 8.23 (1H, d, J =

2.3 Hz), 8.59 (1H, s).

574
—OCH₃
—H
piperonyl
free

¹H NMR 2.31-2.37 (4H, m), 2.57-

2.63 (2H, m), 2.88-2.94 (2H, m),

3.37-3.41 (4H, m), 3.57-3.60 (2H,

m), 3.70 (3H, s), 5.93 (2H, s), 6.69-

6.80 (4H, m), 6.84 (1H, brs),

6.90 (1H, d, J = 8.9 Hz), 7.00 (1H,

d, J = 7.9 Hz), 7.69 (2H, d, J =

8.1 Hz), 7.98 (2H, d, J = 8.1 Hz),

8.14-8.19 (1H, m), 8.24 (1H, d, J =

2.5 Hz), 8.67 (1H, s).

575
—F
—H
piperonyl
free
mp 170.5-171.0

576
—H
—H
—COOC(CH₃)₃
free

¹H NMR 1.46 (9H, s), 2.66 (2H, t,

J = 6.5 Hz), 2.97 (2H, t, J = 6.5 Hz),

3.25-3.48 (6H, m), 3.51-3.65 (2H,

m), 6.95 (1H, d, J = 9.7 Hz),

7.04 (2H, d, J = 8.4 Hz), 7.22 (2H,

d, J = 8.4 Hz), 7.75 (2H, d, J =

8.2 Hz), 8.01 (2H, d, J = 8.2 Hz),

8.18-8.33 (3H, m).

577
—OC₂H₅
—H
piperonyl
hydro-
mp 147.5-149.0

chloride

TABLE 186

Example

mp (° C.)

No.
R₆₁₄
R₆₁₅
R₆₁₆
Xb₇
Form
or ¹H NMR

578
—Cl
—Cl
morpholino
—O—
free

¹H NMR (CDCl₃) δ

2.60-2.66 (2H, m), 2.96-

3.02 (2H, m), 3.37-

3.41 (2H, m), 3.55-

3.64 (6H, m), 6.96 (1H,

d, J = 8.4 Hz), 7.06 (2H,

d, J = 8.6 Hz), 7.23-

7.26 (2H, m), 7.58 (1H,

d, J = 8.4 Hz), 7.70-

7.74 (1H, m), 7.86 (1H,

brs), 7.99 (1H, d, J =

1.9 Hz), 8.19-8.25 (2H, m).

579
—Cl
—Cl

embedded image

—NH—
free
mp 141-142

580
—Cl
—Cl

embedded image

—S—
free
mp 169-170

581
—Cl
—Cl

embedded image

—SO₂—
free
mp 154-156

582
—CF₃
—H

embedded image

—N(CH₃)—
free
mp 175-176

583
—Cl
—Cl

embedded image

—N(CH₂Ph)—
free
mp 171-173

584
—Cl
—Cl

embedded image

—N(CH₂Ph)—
free
mp 144-146

585
—Cl
—Cl

embedded image

—CO—
free
mp 129-132

586
—Cl
—Cl

embedded image

—O—
free
mp 208-210

587
—Cl
—Cl
—NH(CH₂)₂OPh
—O—
free
mp 129-132

588
—Cl
—Cl

embedded image

—SO—
oxalate
mp 128-130

TABLE 187

Example

No.
R₆₁₇
R₆₁₈
Xb₈
R₆₁₉

¹H NMR (CDCl₃) δ ppm

589
—Cl
—Cl
—CH═CH—
piperonyl
2.33-2.42 (4H, m), 2.62-2.68 (2H, m),

(trans)

2.96-3.01 (2H, m), 3.40-3.44 (4H, m),

3.62-3.66 (2H, m), 3.76 (3H, s), 5.95 (2H,

s), 6.71-6.77 (2H, m), 6.82-7.07 (7H, m),

7.28-7.32 (1H, m), 7.38-7.46 (1H, m),

7.57 (1H, d, J = 2.0 Hz), 7.83-7.87 (1H,

m), 8.19 (1H, d, J = 2.3 Hz).

590
—CF₃
—H
—CH═CH—
piperonyl
2.33-2.42 (4H, m), 2.62-2.68 (2H, m),

(trans)

2.96-3.02 (2H, m), 3.40-3.43 (4H, m),

3.63-3.66 (2H, m), 3.76 (3H, s), 5.94 (2H,

s), 6.71-6.79 (2H, m), 6.82-6.89 (3H, m),

6.95 (1H, d, J = 8.7 Hz), 7.00 (1H, d, J =

16.5 Hz), 7.05-7.14 (2H, m), 7.55-7.62

(4H, m), 7.86-7.90 (1H, m), 8.22 (1H, d,

J = 2.3 Hz).

591
—CF₃
—H
—CO—
benzyl
2.38-2.43 (4H, m), 2.63-2.68 (2H, m),

2.97-3.02 (2H, m), 3.43 (2H, brs),

3.51 (2H, s), 3.65 (2H, brs), 3.76 (3H, s),

6.84-6.89 (2H, m), 7.04-7.09 (2H, m),

7.27-7.31 (5H, m), 7.73-7.88 (4H, m),

8.19-8.22 (1H, m), 8.55 (1H, brs).

592
—CF₃
—H
—CO—
piperonyl
2.35-2.39 (4H, m), 2.62-2.68 (2H, m),

2.96-3.02 (2H, m), 3.41-3.44 (4H, m),

3.62-3.65 (2H, m), 3.76 (3H, s), 5.95 (2H,

s), 6.74-6.89 (5H, m), 7.04-7.09 (2H, m),

7.73-7.88 (4H, m), 8.19-8.22 (1H, m),

8.55 (1H, brs).

593
—CF₃
—H
—CO—
3-pyridyl
2.69-2.75 (2H, m), 3.01-3.06 (2H, m),

3.14-3.20 (4H, m), 3.59-3.62 (2H, m),

3.77 (3H, s), 3.80-3.84 (2H, m), 6.86-6.92

(2H, m), 7.04-7.11 (2H, m), 7.18-7.20 (2H,

m), 7.75 (2H, d, J = 8.4 Hz), 7.87 (2H, d,

J = 8.1 Hz), 8.15 (1H, t, J = 3.0 Hz), 8.20

(1H, dd, J = 8.7 Hz, 2.3 Hz), 8.30 (1H, t,

J = 1.8 Hz), 8.53 (1H, d, J = 2.3 Hz).

TABLE 188

Example

No.
R₆₂₀
R₆₂₁
M

¹H NMR (solvent ) δ ppm

594
3,4-Cl₂PhNHCON(C₂H₅)—
4-pyridyl-methyl
2
(CDCl₃) 1.16 (3H, t, J = 7.1 Hz), 2.35-

2.45 (4H, m), 2.62-2.67 (2H, m), 2.97-

3.03 (2H, m), 3.42-3.46 (2H, m),

3.51 (2H, s), 3.64-3.68 (2H, m),

3.73 (2H, q, J = 7.1 Hz), 6.07 (1H, d,

J = 5.0 Hz), 7.04 (1H, d, J = 8.7 Hz),

7.09-7.14 (3H, m), 7.25-7.30 (5H, m),

7.52 (1H, d, J = 2.6 Hz), 7.61 (1H, dd,

J = 8.7 Hz, 2.6 Hz), 8.11 (1H, d, J =

2.6 Hz), 8.54 (2H, d, J = 5.9 Hz).

595
4-CF₃PhNHCON(C₂H₅)—
piperonyl
2
(CDCl₃) 1.18 (3H, t, J = 7.1 Hz), 2.32-

2.41 (4H, m), 2.61-2.67 (2H, m), 2.97-

3.03 (2H, m), 3.39-3.43 (4H, m), 3.61-

3.65 (2H, m), 3.75 (2H, q, J = 7.1 Hz),

5.94 (2H, s), 6.15 (1H, brs), 6.72-

6.76 (2H, m), 6.83 (1H, d, J = 0.7 Hz),

7.05 (1H, dd, J = 8.7 Hz, 0.5 Hz),

7.11 (2H, d, J = 8.6 Hz), 7.29 (2H, d,

J = 8.6 Hz), 7.40 (2H, d, J = 8.6 Hz),

7.49 (2H, d, J = 8.7 Hz), 7.63 (1H, dd,

J = 8.7 Hz, 2.8 Hz), 8. 14 (1H, dd, J =

2.8 Hz, 0.5 Hz).

596
4-CF₃PhNHCON(C₂H₅)—
4-pyridyl-methyl
2
(CDCl₃) 1.18 (3H, t, J = 7.1 Hz), 2.35-

2.45 (4H, m), 2.62-2.68 (2H, m), 2.98-

3.03 (2H, m), 3.42-3.46 (2H, m),

3.51 (2H, s), 3.66 (2H, t, J = 5.0 Hz),

3.75 (2H, q, J = 7.1 Hz), 6.18 (1H, brs),

7.05 (1H, dd, J = 8.7 Hz, 0.5 Hz),

7.11 (2H, d, J = 8.4 Hz), 7.25-7.31 (4H,

m), 7.40 (2H, d, J = 8.7 Hz), 7.49 (2H,

d, J = 8.7 Hz), 7.63 (1H, dd, J =

8.7 Hz, 2.8 Hz), 8.13 (1H, dd, J = 2.6 Hz,

0.5 Hz), 8.53-8.55 (2H, m).

597
4-CF₃PhNHCON(C₂H₅)—
2-pyridyl
2
(CDCl₃) 1.17 (3H, t, J = 7.1 Hz), 2.68-

2.74 (2H, m), 3.02-3.07 (2H, m), 3.46-

3.53 (6H, m), 3.70-3.78 (4H, m),

6.12 (1H, brs), 6.62-6.67 (2H, m),

7.04 (1H, d, J = 8.7 Hz), 7.12 (2H, d, J =

8.6 Hz), 7.31 (2H, d, J = 8.6 Hz),

7.40 (2H, d, J = 8.7 Hz). 7.45-7.52 (3H,

m), 7.60 (1H, dd, J = 8.7 Hz, 2.6 Hz),

8.07 (1H, d, J = 2.5 Hz), 8.16-8.19 (1H,

m).

TABLE 189

Example

No.
R₆₂₂
R₆₂₃
R₆₂₄
R₆₂₅
mp (° C.) or ¹H NMR (CDCl₃) δ ppm

598
—Cl
—Cl
—H

embedded image

mp 169-171

599
—Cl
—Cl
—H

embedded image

mp 158-160

600
—Cl
—Cl
—H

embedded image

mp 183-186

601
—CF₃
—H
—F

embedded image

¹H NMR 3.00 (3H, s), 3.20- 3.36 (2H, m), 3.57-3.80 (2H, m), 4.07 (2H, s), 4.14-4.34 (2H, m), 4.51 (2H, s), 5.94 (2H, s), 6.32- 6.50 (2H, m), 6.65-6.80 (3H, m), 6.92 (1H, d, J = 9.4 Hz), 7.02 (1H, t, J = 8.8 Hz), 7.71 (2H, d, J = 8.1 Hz), 7.98 (2H, d, J = 8.1 Hz), 8.10-8.20 (1H, m), 8.18 (1H, s), 8.30 (1H, s).

602
—CF₃
—H
—H

embedded image

¹H NMR 1.45 (6H, s), 2.14 (2H, brs), 2.33 (2H, brs), 2.87 (3H, s), 3.32 (2H, s), 3.63 (2H, brs), 3.92 (2H, brs), 5.93 (2H, s), 6.68- 6.75 (2H, m), 6.82 (1H, d, J = 1.0 Hz), 6.92 (2H, d, J = 9.2 Hz), 6.93 (1H, d, J = 9.1 Hz), 7.00 (2H, d, J = 9.2 Hz), 7.77 (2H, d, J = 8.1 Hz), 7.81 (1H, s), 8.00 (2H, d, J = 8.1 Hz), 8.19 (1H, dd, J = 8.7 Hz, 2.8 Hz), 8.26 (1H, d, J = 2.1 Hz).

603
—CF₃
—H
—OCH₃

embedded image

¹H NMR 1.33-1.45 (2H, m), 1.82-1.96 (3H, m), 2.28 (2H, d, J = 6.8 Hz), 2.39-2.41 (4H, m), 2.72 (2H, t, J = 10.1 Hz), 3.43 (2H, s), 3.48 (2H, brs), 3.57- 3.62 (4H, m), 3.72 (3H, s), 5.95 (2H, s), 6.48 (1H, dd, J = 8.7 Hz, 2.5 Hz), 6.56 (1H, d, J = 2.5 Hz), 6.71-6.77 (2H, m), 6.86 (2H, d, J = 8.6 Hz), 6.97 (1H, d, J = 8.6 Hz), 7.70 (2H, d, J = 8.4 Hz), 8.00 (2H, d, J = 8.1 Hz), 8.13 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.22 (1H, d, J = 2.5 Hz), 8.40 (1H, s).

TABLE 190

Example

mp (° C.) or

No.
R₆₂₆
R₆₂₇
R₆₂₈
R₆₂₉

¹H NMR (DMSO-d₆) δ ppm

604
—CF₃
—H
—CH₃
—OC₂H₅

¹H NMR 1.03 (3H, t, J = 6.9 Hz), 2.52-2.68 (6H, m),

2.69-2.82 (2H, m), 3.39-3.61 (4H, m), 3.72 (2H, s),

3.89 (2H, q, J = 6.9 Hz), 4.00-5.90 (4H, m), 6.01 (2H,

s), 6.74 (1H, dd, J = 8.0 Hz, 1.8 Hz), 6.76 (1H, d, J =

8.9 Hz), 6.82 (1H, dd, J = 8.0 Hz, 1.3 Hz), 6.84-

6.97 (4H, m), 7.26 (1H, dd, J = 9.0 Hz, 3.1 Hz),

7.41 (2H, d, J = 8.0 Hz), 7.50 (1H, d, J = 3.1 Hz),

7.65 (2H, d, J = 8.0 Hz).

605
—CF₃
—H
—C₂H₅
—OC₂H₅

¹H NMR 1.02 (3H, t, J = 6.9 Hz), 1.08 (3H, t, J =

6.9 Hz), 2.53-2.84 (8H, m), 3.43 (2H, q, J = 6.9 Hz),

3.46-3.62 (4H, m), 3.72 (2H, s), 3.88 (2H, q, J =

6.9 Hz), 4.30-5.90 (4H, m), 6.01 (2H, s), 6.69-

6.78 (2H, m), 6.82 (1H, dd, J = 8.0 Hz, 1.4 Hz), 6.83-

6.97 (4H, m), 7.19 (1H, dd, J = 9.0 Hz, 3.1 Hz), 7.37-

7.48 (3H, m), 7.65 (2H, d, J = 8.1 Hz).

606
—Cl
—Cl
—CH₃
—H

¹H NMR 2.48-2.67 (6H, m), 2.68-2.82 (2H, m),

2.98 (3H, s), 3.37-3.62 (4H, m), 3.70 (2H, s), 4.50-

5.90 (4H, m), 6.01 (2H, s), 6.78-6.95 (6H, m), 7.13-

7.23 (3H, m), 7.28 (1H, dd, J = 9.0 Hz, 3.3 Hz),

7.48 (1H, d, J = 2.0 Hz), 7.57 (1H, d, J = 8.3 Hz),

7.61 (1H, d, J = 3.1 Hz).

607
—Cl
—Cl
—C₂H₅
—H

¹H NMR 1.09 (3H, t, J = 6.9 Hz), 2.48-2.66 (6H, m),

2.69-2.82 (2H, m), 3.35-3.59 (6H, m), 3.67 (2H, s),

4.00-5.90 (4H, m), 6.00 (2H, s), 6.76-6.94 (6H, m),

7.13-7.25 (4H, m), 7.47 (1H, d, J = 1.9 Hz), 7.52-

7.61 (2H, m).

608
—CF₃
—H
—CH₃
—F

¹H NMR 2.50-2.72 (6H, m), 2.72-2.88 (2H, m),

2.98 (3H, s), 3.32-3.61 (4H, m), 3.70 (2H, brs),

4.67 (2H, s), 6.00 (2H, s), 6.80 (1H, dd, J = 7.9 Hz,

1.4 Hz), 6.85-6.95 (3H, m), 6.98-7.11 (2H, m),

7.11-7.22 (1H, m), 7.29 (1H, dd, J = 9.0 Hz, 3.1 Hz),

7.41 (2H, d, J = 8.0 Hz), 7.50 (1H, d, J = 3.1 Hz),

7.66 (2H, d, J = 8.0 Hz).

609
—Cl
—Cl
—C₂H₅
—F

¹H NMR 1.00-1.20 (3H, m), 2.46-2.72 (6H, m),

2.72-2.89 (2H, m), 3.29-3.61 (6H, m), 3.71 (2H, brs),

4.46 (2H, s), 6.01 (2H, s), 6.81 (1H, dd, J = 8.0 Hz,

1.4 Hz), 6.85-6.95 (3H, m), 6.98-7.11 (2H, m), 7.13-

7.28 (3H, m), 7.45 (1H, d, J = 3.1 Hz), 7.46 (1H, d,

J = 1.9 Hz), 7.56 (1H, d, J = 8.3 Hz).

610
—Cl
—Cl
—CH₃
—OC₂H₅

¹H NMR 1.02 (3H, t, J = 6.9 Hz), 2.42-2.81 (8H, m),

2.94 (3H, s), 3.00-4.30 (10H, m), 4.49 (2H, s),

6.00 (2H, s), 6.71-6.83 (3H, m), 6.84-6.95 (4H, m),

7.18 (1H, dd, J = 8.3 Hz, 2.0 Hz), 7.26 (1H, dd, J =

9.0 Hz, 3.2 Hz), 7.44 (1H, d, J = 2.0 Hz), 7.50 (1H,

d, J = 3.0 Hz), 7.55 (1H, d, J = 8.3 Hz).

611
—Cl
—Cl
—C₂H₅
—OC₂H₅

¹H NMR 1.01 (3H, t, J = 7.0 Hz), 1.06 (3H, t, J =

7.0 Hz), 2.40-2.83 (8H, m), 2.90-4.50 (14H, m),

6.00 (2H, s), 6.70-6.82 (3H, m), 6.84-6.95 (4H, m),

7.15-7.24 (2H, m), 7.39-7.48 (2H, m), 7.55 (1H,

d, J = 8.3 Hz).

612
—Cl
—Cl
—C₂H₅
—OCH₃
mp 91.0-96.5 dec

613
—CF₃
—H
—C₂H₅
—F
mp 104-107

TABLE 191

Example

No.
R₆₃₀
R₆₃₁
Form

¹H NMR (solvent) δ ppm

614
—H
piperonyl
free
(CDCl₃) 2.30-2.34 (2H, m), 2.36-2.40 (2H,

m), 2.56-2.62 (2H, m), 2.91-2.96 (2H, m),

3.01 (3H, s), 3.37-3.40 (4H, m), 3.60-

3.64 (2H, m), 4.50 (2H, s), 5.94 (2H, s), 6.72-

6.73 (2H, m), 6.80 (1H, d, J = 8.9 Hz),

6.84 (1H, brs), 6.98 (2H, d, J = 8.6 Hz),

7.11 (1H, dd, J = 8.9 Hz, 3.3 Hz), 7.18 (2H,

d, J = 8.4 Hz), 7.34 (2H, d, J = 7.9 Hz),

7.58 (2H, d, J = 8.3 Hz), 7.70 (1H, d, J =

3.3 Hz).

615
—H
3-pyridyl
free
(CDCl₃) 2.63-2.69 (2H, m), 2.95-3.01 (5H,

m), 3.08-3.18 (4H, m), 3.54-3.58 (2H, m),

3.78-3.81 (2H, m), 4.50 (2H, s), 6.79 (1H, d,

J = 8.9 Hz), 6.99 (2H, d, J = 8.6 Hz),

7.10 (1H, dd, J = 8.9 Hz, 3.1 Hz), 7.17-

7.22 (4H, m), 7.34 (2H, d, J = 8.1 Hz),

7.58 (2H, d, J = 7.9 Hz), 7.67 (1H, d, J =

2.8 Hz), 8.12-8.14 (1H, m), 8.29-8.30

(1H, m).

616
—H
4-pyridylmethyl
free
(CDCl₃) 2.33 (2H, t, J = 5.0 Hz), 2.41 (2H, t,

J = 5.1 Hz), 2.57-2.63 (2H, m), 2.92-

2.97 (2H, m), 3.02 (3H, s), 3.41 (2H, t, J =

5.0 Hz), 3.50 (2H, s), 3.65 (2H, t, J =

5.1 Hz), 4.51 (2H, s), 6.80 (1H, d, J = 8.9 Hz),

6.98 (2H, d, J = 8.4 Hz), 7.11 (1H, dd, J =

8.9 Hz, 3.1 Hz), 7.18 (2H, d, J = 8.4 Hz),

7.27 (2H, d, J = 5.6 Hz), 7.34 (2H, d, J =

8.3 Hz), 7.58 (2H, d, J = 8.3 Hz), 7.69 (1H,

d, J = 3.1 Hz), 8.55 (2H, d, J = 5.8 Hz).

617
—H
benzyl
hydrochloride
(DMSO-d₆) 2.64-2.69 (2H, m), 2.75-

2.81 (2H, m), 2.92-3.02 (5H, m), 3.23-

3.32 (2H, m), 3.41-3.51 (2H, m), 4.02-

4.08 (1H, m), 4.31 (2H, brs), 4.43-4.48 (1H,

m), 4.64 (2H, brs), 6.86 (1H, d, J = 9.1 Hz),

6.90 (2H, d, J = 8.6 Hz), 7.20 (2H, d, J =

8.4 Hz), 7.29 (1H, dd, J = 9.1 Hz, 3.1 Hz),

7.42-7.47 (5H, m), 7.56-7.57 (2H, m), 7.62

(1H, d, J = 3.1 Hz), 7.69 (2H, d, J = 8.1 Hz),

11.08 (1H, brs).

618
—OCH₃
piperonyl
hydrochloride
(DMSO-d₆) 2.59-3.09 (6H, m), 2.97 (3H, s),

3.16-3.61 (4H, m), 3.65 (3H, s), 3.97-

4.13 (1H, m), 4.14-4.28 (2H, m), 4.38-

4.51 (1H, m), 4.58 (2H, s), 6.06 (2H, s), 6.72-

6.80 (2H, m), 6.89 (1H, d, J = 8.0 Hz), 6.93-

7.03 (3H, m), 7.18 (1H, s), 7.26 (1H, dd, J =

9.0 Hz, 3.2 Hz), 7.42 (2H, d, J = 8.0 Hz),

7.49 (1H, d, J = 3.1 Hz), 7.67 (2H, d, J =

8.0 Hz), 10.81 (1H, brs).

TABLE 192

Example

No.
R₆₃₂
R₆₃₃
R₆₃₄
R₆₃₅
Form

¹H NMR (DMSO-d₆) δppm

619
—CF₃
—H
—C₂H₅
—H
TsOH
1.11(3H, t, J = 6.9 Hz), 2.28(3H, s),

salt
2.54-3.02(7H, m), 3.17-3.48(3H, m),

3.47(2H, q, J = 6.9 Hz), 3.97-4.12(1H,

m), 4.15-4.31(2H, m), 4.38-4.52 (1H,

m), 4.58(2H, s), 6.07(2H, s), 6.78-

7.26(11H, m), 7.39-7.49(4H, m),

7.53(1H, d, J = 3.1 Hz), 7.68(2H, d, J =

8.2 Hz), 9.45-9.69(1H, m).

620
—CF₃
—H
—(CH₂)₂OCH₃
—H
TsOH
2.27(3H, s), 2.52-3.03(7H, m),

salt
3.24(3H, s), 3.17-3.70(10H, m), 3,95-

4.13(1H, m), 4.15-4.32 (2H, m), 4.36-

4.54(1H, m), 4.66(2H, s), 6.07(2H, s),

6.80(1H, d, J = 8.9 Hz), 6.83-7.07(5H,

m), 7.10 (2H, d, J = 7.8 Hz), 7.13-

7.26(3H, m), 7.37-7.49 (4H, m),

7.52(1H, d, J = 3.1 Hz), 7.67(2H, d, J =

8.1 Hz), 9.46-9.69(1H, m).

621
—Cl
—Cl
—CH₃
—OCH₃
hydro-
2.60-3.15(7H, m), 2.94(3H, s), 3.15-

chloride
3.38(2H, m), 3.38-3.60(1H, m),

3.65(3H, s), 4.07(1H, d, J = 15.7 Hz),

4.20(2H, brs), 4.38-4.60(1H, m), 4.48

(2H, s), 6.06(2H, s), 6.73-6.81(2H, m),

6.90(1H, d, J = 8.0 Hz), 6.93-7.05(3H,

m), 7.16-7.24(2H, m), 7.29(1H, dd, J =

8.9 Hz, 3.2 Hz), 7.47(1H, d, J = 1.9

Hz), 7.50(1H, d, J = 3.1 Hz), 7.56(1H,

d, J = 8.2 Hz), 11.10(1H, brs).

622
—Cl
—Cl
—CH₃
—F
hydro-
2.58-3.17(7H, m), 2.96(3H, s), 3.18-

chloride
3.38(2H, m), 3.38-3.70(1H, m), 4.00-

4.18(1H, m), 4.20(2H, brs), 4.33-

4.60(1H, m), 4.50(2H, s), 6.06(2H, s),

6.92(1H,d, J = 9.0 Hz), 6.95-7.14(4H,

m), 7.16-7.25(3H, m), 7.31(1H, dd, J =

9.0 Hz, 3.1 Hz), 7.47(1H, d, J = 1.9

Hz), 7.51(1H, d, J = 3.1 Hz), 7.56(1H,

d, J = 8.2 Hz), 11.10(1H, brs).

623
—CF₃
—H
—C₂H₅
—OCH₃
hydro-
1.09(3H, t, J = 6.9 Hz), 2.58-3.11(8H,

chloride
m), 3.15-3.58(4H, m), 3.64(3H, s),

3.94-4.12(1H, m), 4.14-4.28(2H, m),

4.36-4.50(1H, m), 4.54(2H, s), 6.69-

6.79(2H, m), 6.88(1H, d, J = 8.0 Hz),

6.92-7.02(3H, m), 7.12-7.24(2H, m),

7.37-7.49 (3H, m), 7.67(2H, d, J = 8.1

Hz), 10.77(1H, brs).

(TsOH means a p-toluenesulfonic acid. Hereinafter TsOH indicates the same meaning.)

TABLE 193

Example

No.
R₆₃₆
R₆₃₇
R₆₃₈
R₆₃₉
R₆₄₀
R₆₄₁
Form
mp (° C.) or ¹H NMR

624
Y_a2
—H
—H
Y_a1
—H
—H
hydrochloride

¹H NMR (DMSO-d₆) δ 2.56-

2.72(2H, m), 2.73-2.94(3H,

m), 2.96-3.10(1H, m), 3.12-

3.52(4H, m), 3.91-4.07(1H,

m), 4.10-4.26(2H, m), 4.33-

4.48(1H, m), 6.05(2H, s),

6.82(1H, d, J = 8.2 Hz),

6.89-7.02(4H, m), 7.09(1H,

t, J = 76 Hz), 7.14-7.25(2H,

m), 7.35(1H, d, J = 7.6 Hz),

7.74(2H, d, J = 9.0 Hz),

7.81(1H, d, J = 8.4 Hz),

7.94(1H, dd, J = 8.4 Hz, 2.1

Hz), 8.22(1H, d, J = 2.1 Hz),

10.45 (1H, s), 11.15(1H,

brs).

625
Y_a2
—H
—H
—H
Y_a1
—H
oxalate
mp 134-143

626
—H
—H
Y_a2
—H
—H
Y_a1
fumarate
mp 123-126

627
—H
Y_a2
—H
—H
—H
Y_a1
hydrochloride
mp 141-153

embedded image

TABLE 194

Example

No.
R₆₄₂
MS (M⁺ + H)

628

embedded image

540

629

embedded image

574

630
morpholino
528

631

embedded image

574

632

embedded image

673

633

embedded image

513

634

embedded image

543

635

embedded image

632

636

embedded image

555

637

embedded image

689

638

embedded image

655

639

embedded image

626

TABLE 195

Example No.
R₆₄₃
R₆₄₄
MS (M⁺ + H)

640
—CH₃
cyclohexyl
554

641
—H
cyclohexyl
540

642
—C₂H₅
—Ph
562

643
—CH₃
4-CH₃Ph—
562

644
—H
cycloheptyl
554

645
—H
cyclooctyl
569

646
—H
benzyl
548

647
—H
2-ClPhCH₂—
584

648
—H
3-ClPhCH₂—
584

649
—H
4-ClPhCH₂—
584

650
—CH₃
Ph(CH₂)₂—
577

651
—CH₃
3,4-(CH₃O)₂PhCH₂—
623

652
—CH₃
benzyl
562

653
—C₂H₅
benzyl
576

654
—H
PhOCH₂CH(CH₃)—
593

655
—C₂H₅
cyclohexyl
569

656
—H
—C₂H₅
486

657
—H
—(CH₂)₂CH₃
500

658
—H
—(CH₂)₂OCH₃
516

659
—C₂H₅
cyclohexylmethyl
583

660
—H
4-CH₃OPhCH₂—
578

661
—H
4-CH₃OPh(CH₂)₂—
593

662
—H
4-CF₃OPhCH₂—
632

663
—H
4-CF₃OPh—
618

664
—H
4-ClPh(CH₂)₂—
598

665
—H
piperonyl
592

666
—H
—(CH₂)₂OPh
579

667
—H
cyclopentyl
527

668
—H
cyclohexylmethyl
554

669
—H
4-hydroxycyclohexan-1-yl
556

670
—H
4-FPhCH₂—
566

671
—H
—CH(CH₃)Ph
562

672
—H
—(CH₂)₃Ph
576

673
—H
—Ph
534

674
—H
4-CH₃OPh—
564

675
—H
—(CH₂)₂Ph
562

676
—H
3-PhOPh—
627

677
—H
4-PhOPh—
627

678
—H
2-CH₃OPh(CH₂)₂—
593

679
—H
2-FPh(CH₂)₂—
580

TABLE 196

Ex-

MS

ample

(M⁺ +

No.
R₆₄₅
R₆₄₆
H)

680
—H

embedded image

632

681
—H
—CH(CH₃)₂
501

682
—CH₃

embedded image

578

683
—(CH₂)₂OH
—(CH₂)₂OH
547

684
—CH₃
—(CH₂)₂N(CH₃)₂
544

685
—H
—(CH₂)₃CH₃
515

686
—H
cyclopropyl
499

687
—H
2-pyridylmethyl
550

688
—H
3-pyridylmethyl
550

689
—H
—CH₂CH(CH₃)₂
515

690
—H
cyclopropylmethyl
513

691
—H

embedded image

567

692
—H

embedded image

570

693
—H

embedded image

572

TABLE 197

Example

No.
R₆₄₇
R₆₄₈

¹H NMR or MS

694
—H
4-CF₃OPhO—
MS 702(M⁺ + H)

695
—H
benzyl
MS 617(M⁺ + H)

696
—OH
4-ClPh—
MS 654(M⁺ + H)

697
—H
—H
MS 526(M⁺ + H)

698
—H
—Ph
MS 602(M⁺ + H)

699
—H
piperonyl

¹H NMR (CDCl₃) δ

1.11-1.16(5H, m),

1.65-1.71(3H, m),

2.48(2H, d, J = 6.4

Hz), 2.54-2.58(1H,

m), 2.95-3.04(1H,

m), 3.35(2H, q, J =

7.1 Hz), 3.84-3.89

(1H, m), 4.01(2H,

s), 4.52-4.57(1H,

m), 5.93(2H, s),

6.56-6.63(4H, m),

6.73(1H, d, J = 7.8

Hz), 6.79(1H, d, J =

8.7 Hz), 6.92(2H, d,

J = 9.1 Hz), 7.52

(1H, d, J = 8.4 Hz),

7.72(1H, dd, J =

8.4 Hz, 2.0 Hz),

7.99(1H, d, J = 2.0

Hz), 8.04(1H, dd,

J = 8.9 Hz, 2.8 Hz),

8.26(1H, d, J =

2.5 Hz), 8.56(1H,

brs).

700
—H

embedded image

MS 610(M⁺ + H)

701
—H
4-CH₃OPhCONH—
MS 676(M⁺ + H)

702
—H
—N(CH₃)CH₂Ph
MS 646(M⁺ + H)

703
—H
4-
MS 690(M⁺ + H)

CH₃PhO(CH₂)₂N(CH₃)—

704
—OH
—Ph
MS 619(M⁺ + H)

705
—H
4-CNPhO—
MS 644(M⁺ + H)

706
—H
2-ClPhCH₂—
MS 653(M⁺ + H)

707
—CH₂(CH₂)₃CH₂—
MS 595(M⁺ + H)

TABLE 198

Example

No.
R₆₄₉
R₆₅₀
R₆₅₁
R₆₅₂
R₆₅₃
M

¹H NMR (solvent) δppm

708
—Cl
—Cl
—CH₃
—CONH₂
—H
1
(DMSO-d₆) 1.79-2.02(4H, m), 2.96(3H,

s), 3.37-3.67(3H, m), 4.19(2H, s), 6.61-

6.70(2H, m), 6.89-6.95(3H, m),

7.83(1H, d, J = 8.4 Hz), 7.94(1H, dd, J =

8.4 Hz, 2.0 Hz), 8.13(1H, dd, J = 8.9

Hz, 2.6 Hz), 8.22(1H, d, J = 2.0 Hz),

8.43(1H, d, J = 2.6 Hz), 10.51(1H, s).

709
—Cl
—Cl
—CH₃
—H
benzyl
2
(CDCl₃) 1.18-1.26(2H, m), 1.57(3H,

brs), 1.58-1.74(2H, m), 2.49-2.58(2H,

m), 3.83(1H, d, J = 13.5 Hz), 4.08 (2H,

s), 4.56(1H, d, J = 13.5 Hz), 6.40(1H, d,

J = 8.9 Hz), 6.67(2H, d, J = 9.1 Hz),

6.98(2H, d, J = 9.1 Hz), 7.12-7.32 (5H,

m), 7.56(1H, d, J = 8.4 Hz), 7.71(1H,

dd, J = 8.4 Hz, 2.1 Hz), 7.98(1H, d, J =

2.1 Hz), 8.03-8.10(2H, m), 8.24(1H, d, J =

2.6 Hz).

710
—CF₃
—H
—C₂H₅
—H
piperonyl
2
(CDCl₃) 1.12.1.17(5H, m), 1.64-

1.71(3H, m), 2.48(2H, d, J = 6.6 Hz),

2.53-2.58(1H, m), 2.94-3.03(1H, m),

3.37(2H, q, J = 7.1 Hz), 3.84-3.89(1H,

m), 4.01(2H, s), 4.53.4.58(1H, m),

5.93(2H, s), 6.56-6.63(4H, m), 6.73 (1H,

d, J = 7.8 Hz), 6.82(1H, d, J = 8.9 Hz),

6.95(2H, d, J = 9.1 Hz), 7.72 (2H, d, J =

8.3 Hz), 7.99 (2H, d, J = 8.1 Hz),

8.10(1H, dd, J = 8.9 Hz, 2.8 Hz),

8.27(1H, d, J = 2.6 Hz), 8.37(1H, brs).

711
—Cl
—Cl
—CH₃
—H
piperonyl
2
(CDCl₃) 1.03.1.17(2H, m), 1.64-1.74

(3H, m), 2.46-2.57(3H, m), 2.97-3.04

(4H, m), 3.80-3.85(1H, m), 4.07(2H, s),

4.51-4.55(1H, m), 5.92(2H, s), 6.56-

6.63(4H, m), 6.73(1H, d, J = 7.8 Hz),

6.79(1H, d, J = 8.9 Hz), 6.94(2H, d, J =

8.9 Hz), 7.52(1H, d, J = 8.4 Hz), 7.71

(1H, dd, J = 8.4 Hz, 2.1 Hz), 7.98(1H,

d, J = 2.1 Hz), 8.04(1H, d, J = 8.9 Hz),

8.25(1H, d, J = 2.3 Hz), 8.49(1H, brs).

712
—CF₃
—H
—CH₃
—H
piperonyl
2
(CDCl₃) 1.09-1.17(2H, m), 1.67-

1.70(3H, m), 2.47-2.52(3H, m), 2.94-

3.03(4H, m), 3.80-3.85(1H, m),

4.06(2H, s), 4.50-4.55(1H, m), 5.92(2H,

s), 6.55-6.65(4H, m). 6.73(1H, d, J = 7.9

Hz), 6.81(1H, d, J = 8.9 Hz), 6.95(2H,

d, J = 8.9 Hz), 7.70(2H, d, J = 8.1 Hz),

7.99 (2H, d, J = 8.1 Hz), 8.09(1H, dd, J =

8.9 Hz, 2.1 Hz), 8.26(1H, d, J = 2.6

Hz), 8.48(1H, brs).

TABLE 199

Example

No.
R₆₅₄
R₆₅₅
R₆₅₆

¹H NMR (solvent) δppm

713
—OCH₃
—CH₃

embedded image

(CDCl₃) 2.38-2.43(4H, m), 2.95(3H, s), 3.40(2H, s), 3.47-3.58(4H, m), 3.63(3H, s), 4.05(2H, s), 4.24(4H, s), 6.12(1H, dd, J = 8.7 Hz, 2.6 Hz), 6.21(1H, d, J = 2.6 Hz), 6.74-6.87(5H, m), 7.44(1H, d, J = 8.4 Hz), 7.69(1H, dd, J = 8.4 Hz, 2.0 Hz), 7.96(1H, d, J = 2.0 Hz), 8.02 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.19(1H, d, J = 2.6 Hz), 9.00(1H, s).

714
—F
—CH₃
3-furylmethyl
(DMSO-d₆) 2.32(2H, brs), 2.41(2H, brs),

2.93(3H, s), 3.37(2H, s), 3.44(4H, brs),

4.29(2H, s), 6.40-6.44(2H, m), 6.56(1H,

dd, J = 14.5 Hz, 2.8 Hz), 7.01-7.08(2H,

m), 7.58(1H, s), 7.62(1H, s), 7.84(1H, d, J =

8.4 Hz), 7.94 (1H, dd, J = 8.4 Hz, 2.0

Hz), 8.16(1H, dd, J = 8.9 Hz, 2.8 Hz),

8.22(1H, d, J = 2.0 Hz), 8.39(1H, d, J =

2.6 Hz), 10.53(1H, s).

715
—F
—CH₃

embedded image

(DMSO-d₆) 2.30(2H, brs), 2.39(2H, brs), 2.93(3H, s), 3.38(2H, s), 3.44(4H, brs), 4.22(4H, s), 4.28(2H, s), 6.41(1H, dd, J = 8.6 Hz, 2.2 Hz), 6.56(1H, dd, J = 14.4 Hz, 2.8 Hz), 6.76-6.81(3H, m), 7.01-7.08(2H, m), 7.84 (1H, d, J = 8.4 Hz), 7.94(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.16(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.22(1H, d, J = 2.0 Hz), 8.39(1H, d, J = 2.5 Hz), 10.53(1H, s).

716
—H
—CH₃
3-furylmethyl
(CDCl₃) 2.42(4H, brs), 2.97(3H, s),

3.40(2H, s), 3.50(2H, brs), 3.61(2H, brs),

4.07(2H, s), 6.38(1H, d, J = 1.5 Hz),

6.63(2H, d, J = 9 1 Hz), 6.80(1H, d, J =

8.9 Hz), 6.95 (2H, d, J = 9.1 Hz), 7.34(1H,

s), 7.40(1H, t, J = 1.5 Hz) 7.52(1H, d, J =

8.4 Hz), 7.70(1H, dd, J = 8.4 Hz, 2.0 Hz),

7.97(1H, d, J = 2.0 Hz), 8.04(1H, dd, J =

8.9 Hz, 2.6 Hz), 8.24(1H, d, J = 2.6 Hz),

8.42(1H, s).

717
—OCH₃
—CH₃
3-furylmethyl
(CDCl₃) 2.40-2.44(4H, m), 2.96(3H, s),

3.39(2H, s), 3.49-3.63(4H, m), 3.63(3H, s),

4.06(2H, s), 6.12(1H, dd, J = 8.7 Hz, 2.6

Hz), 6.22(1H, d, J = 2.5 Hz), 6.38(1H, s)

6.76(1H, d, J = 8.7 Hz), 6.86(1H, d, J =

8.7 Hz), 7.33-7.47(3H, m), 7.69(1H, dd, J =

8.4 Hz, 2.0 Hz), 7.96-8.04(2H, m),

8.20(1H, d. J = 2.3 Hz), 8.92(1H, s).

TABLE 200

Example

No.
R₆₅₇
R₆₅₈
R₆₅₉
Property

718
—CH₃
—CH₃
3-furylmethyl
mp 116.5-118.0° C.

719
—H
—C₂H₅

embedded image

MS 606(M⁺ + H)

720
—H
—C₂H₅

embedded image

MS 645(M⁺ + H)

721
—H
—C₂H₅

embedded image

¹H NMR (CDCl₃) δ 1.16(3H, t, J = 7.1 Hz), 3.04(4H, brs), 3.40(2H, q, J = 7.1 Hz), 3.66- 3.76(4H, m), 4.07(2H, s), 5.91 (2H, s), 6.36(1H, dd, J = 8.4 Hz, 2.5 Hz), 6.55(1H, d, J = 2.3 Hz), 6.66(2H, d, J = 9.1 Hz), 6.73(1H, d, J = 8.4 Hz), 6.83(1H, d, J = 8.9 Hz), 6.96(2H, d, J = 8.9 Hz), 7.54(1H, d, J = 8.4 Hz), 7.71(1H, dd, J = 8.4 Hz, 2.1 Hz), 7.98(1H, d, J = 2.1 Hz), 8.07(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.22(1H, brs), 8.24(1H, d, J = 2.5 Hz).

722
—H
—CH₃

embedded image

¹H NMR (CDCl₃) δ 3.00-3.03(7H, m), 3.64(2H, brs), 3.75 (2H, brs), 4.12(2H, s), 5.91(2H, s), 6.36(1H, dd, J = 8.4 Hz, 2.5 Hz), 6.55(1H, d, J = 2.3 Hz), 6.68(2H, d, J = 9.1 Hz), 6.73 (1H, d, J = 8.4 Hz), 6.83(1H, d, J = 8.9 Hz), 6.98(2H, d, J = 9.1 Hz), 7.54(1H, d, J = 8.4 Hz), 7.71(1H, dd, J = 8.4 Hz, 2.1 Hz), 7.98(1H, d, J = 2.1 Hz), 8.07(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.22(1H, brs), 8.23(1H, d, J = 3.0 Hz).

723
—H
—C₂H₅

embedded image

¹H NMR (DMSO-d₆) δ 1.11(3H, t, J = 7.1 Hz), 2.31(2H, brs), 2.38(2H, brs), 3.22- 3.58(8H, m), 4.16(2H, s), 4.21(4H, s), 6.56(2H, d, J = 9.0 Hz), 6.71-6.85(3H, m), 6.90(2H, d, J = 9.0 Hz), 6.93(1H, d, J = 8.9 Hz), 7.83(1H, d, J = 8.4 Hz), 7.95 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.12(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.22(1H, d, J = 2.0 Hz), 8.43(1H, d, J = 2.6 Hz), 10.51(1H, s).

724
—H
—C₂H₅

embedded image

¹H NMR (CDCl₃) δ 1.13(3H, t, J = 7.0 Hz), 2.10-2.25(2H, m), 2.42(4H, brs), 3.34(2H, q, J = 7.0 Hz), 3.42(2H, s), 3.50 (2H, brs), 3.61(2H, brs), 4.01(2H, s), 4.11-4.31(4H, m), 6.59 (2H, d, J = 9.2 Hz), 6.79(1H, d, J = 8.9 Hz), 6.82-6.98(5H, m), 7.51(1H, d, J = 8.4 Hz), 7.70(1H, dd, J = 8.4 Hz, 2.0 Hz), 7.98 (1H, d, J = 2.8 Hz), 8.03(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.24(1H, d, J = 2.8 Hz), 8.54(1H, s).

TABLE 201

Example

No.
R₆₆₀
R₆₆₁
R₆₆₂
mp (° C.) or ¹H NMR (solvent) δppm

725
—CH₃
—Ac
piperonyl
mp 216-217

726
—CH₃
—Ac
benzyl

¹H NMR (DMSO-d₆) 1.82(3H, s), 2.09(3H,

s), 2.28-2.36 (4H, m), 3.35-3.50(6H, m),

4.44(2H, s), 7.05-7.10(2H, m), 7.20-7.32(7H,

m), 7.82(1H, d, J = 8.5 Hz), 7.92(1H, dd, J =

1.9 Hz, 8.5 Hz), 8.15-8.20(2H, m), 8.42(1H,

d, J = 2.5 Hz), 10.53(1H, s).

727
—H
—C₂H₅
3-pyridyl

¹H NMR (DMSO-d₆) 1.13(3H, t, J = 7.1 Hz),

3.21(2H, brs), 3.29(2H, brs), 3.37(2H, q, J =

7.1 Hz), 3.51-3.78 (4H, m), 4.26(2H, s),

6.60(2H, d, J = 9.0 Hz), 6.92(2H, d, J = 9.0

Hz), 6.94(1H, d, J = 8.9 Hz), 7.23(1H, dd, J =

8.5 Hz, 4.6 Hz), 7.36(1H, dd, J = 8.5 Hz,

1.6 Hz), 7.83(1H, d, J = 8.5 Hz), 7.94(1H,

dd, J = 8.5 Hz, 2.0 Hz), 8.03(1H, d, J = 4.6

Hz), 8.12(1H, dd, J = 8.9 Hz, 2.8 Hz),

8.22(1H, d, J = 2.0 Hz), 8.34(1H, d, J = 2.8

Hz), 8.43(1H, d J = 2.8 Hz), 10.51(1H, s).

728
—F
—C₂H₅
piperonyl
mp 149-151

729
—F
—CH₃
piperonyl
mp 199-201

730
—F
—Ac
piperonyl
mp 233-235

731
—OCH₃
—CH₃
piperonyl

¹H NMR (CDCl₃) 2.41-2.43(4H, m),

3.02(3H, s), 3.42(2H, s), 3.49-3.62(4H, m),

3.72(3H, s), 4.08(2H, s), 5.95(2H, s),

6.21(1H, dd, J = 8.7 Hz. 2.6 Hz), 6.32(1H, d,

J = 2.8 Hz), 6.73-6.77(2H, m), 6.84(2H, t, J =

4.5 Hz), 6.95(1H, d, J = 8.7 Hz), 7.54(1H,

d, J = 8.4 Hz), 7.70(1H, dd, J = 8.2 Hz, 2.0

Hz), 7.97(2H, d, J = 2.0 Hz), 8.05-8.09(1H,

m), 8.19(1H, d, J = 2.5 Hz).

732
—H
—CH₃
3-pyridylmetyl

¹H NMR CDCl₃) 2.40-2.42(4H, m),

2.93(3H, s), 3.44(2H, s), 3.48-3.58(4H, m),

4.06(2H, s), 6.58(2H, d, J = 9.1 Hz),

6.74(1H, d, J = 8.9 Hz), 6.90(2H, d, J = 9.1

Hz), 7.25-7.30(1H, m), 7.43(1H, d, J = 8.4

Hz), 7.66-7.73(2H, m), 7.97(1H, d, J = 2.0

Hz), 8.03(1H, dd, J = 8.9 Hz, 2.6 Hz),

8.25(1H, d, J = 2.5 Hz), 8.47-8.51(2H, m),

9.59(1H s).

733
—H
—CH₃

embedded image

¹H NMR (DMSO-d₆) 2.96(3H, s), 3.07- 3.15(4H, m), 3.59 (4H, brs), 3.83(2H, s), 4.31(2H, s), 6.66(2H, d, J = 9.1 Hz), 6.88- 6.95(5H, m), 7.05-7.13(4H, m), 7.20- 7.24(2H, m), 7.83(1H, d, J = 8.4 Hz), 7.95(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.12(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.22(1H, d, J = 2.0 Hz), 8.43(1H, d, J = 2.5 Hz), 10.50(1H, s).

TABLE 202

Example

No.
R₆₆₃
R₆₆₄
MS or ¹H NMR

734
—H
—CHPh₂
MS 694(M⁺ + H)

735
—H
3-CH₃OPh—
MS 634(M⁺ + H)

736
—H
4-CH₃OPh—
MS 634(M⁺ + H)

737
—H
3,4-(CH₃)₂Ph—
MS 632(M⁺ + H)

738
—H
2,3-Cl₂Ph—
MS 673(M⁺ + H)

739
—H
2,4-F₂Ph—
MS 640(M⁺ + H)

740
—H
2-CH₃OPh—
MS 634(M⁺ + H)

741
—H
3-CF₃Ph—
MS 671(M⁺ + H)

742
—H
2-ClPh—
MS 639(M⁺ + H)

743
—H
4-CF₃Ph—
MS 671(M⁺ + H)

744
—H
—Ph
MS 604(M⁺ + H)

745
—H
2-pyridylmethyl
MS 619(M⁺ + H)

746
—H
2-pyridyl
MS 605(M⁺ + H)

747
—H
—(CH₂)₃Ph
MS 646(M⁺ + H)

748
—H
—(CH₂)₄Ph
MS 660(M⁺ + H)

749
—H
—(CH₂)₂N(CH₃)₂
MS 599(M⁺ + H)

750
—H
cyclopentyl
MS 596(M⁺ + H)

751
—H

embedded image

MS 625(M⁺ + H)

752
—H

embedded image

MS 641(M⁺ + H)

753
—H
—CH(CH₃)Ph
MS 634(M⁺ + H)

754
—H
—(CH₂)₂Ph
MS 632(M⁺ + H)

755
—H
—CH₂CONHPh
MS 661(M⁺ + H)

756
—H
—(CH₂)₃N(CH₃)₂
MS 613(M⁺ + H)

757
—H

embedded image

MS 639(M⁺ + H)

758
—H
—CH₃
MS 542(M⁺ + H)

759
—OCH₃
—H

¹H NMR (CDCl₃) 1.26(3H, t, J = 6.9 Hz),

2.70(1H, brs), 2.82-2.87(4H, m), 3.33(2H,

q, J = 6.9 Hz), 3.49-3.57(4H, m), 3.62(3H,

s), 4.00(2H, s), 6.09(1H, d, J = 8.7 Hz),

6.20(1H, s), 6.73(1H, d, J = 8.7 Hz),

6.83(1H, d, J = 8.6 Hz), 7.42(1H, d, J = 8.3

Hz), 7.70(1H, d, J = 7.4 Hz), 7.97-8.03(2H,

m), 8.23(1H, s), 9.26(1H, brs).

TABLE 203

Example

No.
R₆₆₅
R₆₆₆
Form

¹H NMR (DMSO-d₆) δppm

760
—Ac
piperonyl
hydro-
1.84(3H, s), 2.83-3.14(2H, m), 3.23-3.32(2H,

chloride
m), 4.02(1H, d, J = 13.6 Hz), 4.18-4.27(2H,

m), 4.40(1H, d, J = 13.6 Hz), 4.50-4.60 (2H,

m), 6.07(2H, s), 6.96-7.03(2H, m), 7.10-

7 25(4H, m), 7.43 (2H, d, J = 8.8 Hz),

7.85(1H, d, J = 8.4 Hz), 7.98(1H, dd, J = 2.0

Hz, 8.4 Hz), 8.24(1H, dd, J = 2.6 Hz, 8.9 Hz),

8.26(1H, d, J = 2.0 Hz), 8.54(1H, d, J = 2.6

Hz), 10.69(1H, s), 11.07(1H, brs).

761
—Ac
benzyl
hydro-
1.84(3H, s), 2.90-3.17(2H, m), 3.23-3.35(2H,

chloride
m), 4.03(1H, d, J = 14.4 Hz), 4.28-4.43(3H,

m), 4.50-4.62(2H, m), 7.13(1H, d, J = 8.8 Hz),

7.17(2H, d, J = 8.8 Hz), 7.40-7.50(5H, m),

7.58-7.62 (2H, m), 7.85(1H, d, J = 8.4 Hz),

8.00(1H, dd, J = 2.0 Hz, 8.4 Hz), 8.20-

8.29(2H, m), 8.54(1H, d, J = 2.6 Hz),

10.70(1H, s), 11.21 (1H, brs).

762
—C₂H₅
3-furylmethyl
trihydro-
1.11(3H, t, J = 7.1 Hz), 2.75-3.30(3H, m),

chloride
3.30-3.50(2H, m), 3.40(2H, q, J = 7.1 Hz),

3.51-3.72(1H, m), 3.95-4.15(1H, m), 4.22(2H,

s), 4.30-4.62(3H, m), 6.80-6.85(1H, m),

6.89(2H, d, J = 8.9 Hz), 7.00(1H, d, J = 8.9

Hz), 7.01(2H, d, J = 8.9 Hz), 7.70-7.80(1H,

m), 7.84(1H, d, J = 8.5 Hz), 7.88(1H, s),

7.99(1H, dd, J = 8.5 Hz, 2.0 Hz), 8.19(1H, dd,

J = 8.9 Hz, 2.7 Hz), 8.27 (1H, d, J = 2.0 Hz),

8.50(1H, d, J = 2.7 Hz), 10.69(1H, s).

763
—C₂H₅
4-pyridylmethyl
tetrahydro-
1.11(3H, t, J = 7.0 Hz), 3.00-3.66(6H, m),

chloride
3.41(2H, q, J = 7.0 Hz), 3.90(2H, brs),

4.42(2H, brs), 4.63(2H, brs), 6.82(2H, d, J =

8.8 Hz), 6.98(3H, d, J = 8.8 Hz), 7.84(1H, d, J =

8.4 Hz), 7.98(1H, dd, J = 8.4 Hz, 2.0 Hz),

8.17(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.22-

8.39(3H, m), 8.49(1H, d, J = 2.5 Hz), 8.99(2H,

d, J = 6.2 Hz), 10.67(1H, s).

764
—CH₃

embedded image

dihydro- chloride
2.94(3H, s), 2 80-3.22(3H, m), 3.22-3.70(3H, m), 3.95-4.60(6H, m), 6.68(2H, d, J = 9.1 Hz), 6.92(2H, d, J = 9.1 Hz), 6.95(1H, d, J = 8.9 Hz), 7.79(1H, dd, J = 8.4 Hz, 1.6 Hz), 7.84(1H, d, J = 8.4 Hz), 7.96(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.14(1H, dd, J = 8.9 Hz, 2.3 Hz), 8.20(1H, d, J = 8.4 Hz), 8.24(1H, d, J = 2.0 Hz), 8.40(1H, d, J = 1.6 Hz), 8.44(1H, d, J = 2.3 Hz), 9.51(1H, s), 10.57(1H, s).

TABLE 204

Example

No.
R₆₆₇
R₆₆₈
R₆₆₉
R₆₇₀
R₆₇₁
mp (° C.) or ¹H NMR (solvent) δppm

765
—Cl
—Cl
—H
—CH₃
piperonyl
mp 198-200

766
—Cl
—Cl
—H
—C₂H₅
benzyl

¹H NMR (DMSO-d₆) 1.12(3H, t, J =

7.1 Hz), 2.98(4H, brs), 3.34(2H, q, J =

7.1 Hz), 3.20-3.50(2H, m),

3.67(2H, brs), 4.10(2H, brs),

4.23(2H, s), 6.11(2H, s), 6.59(2H, d,

J = 9.2 Hz), 6.91(2H, d, J = 9.2 Hz),

6.94(1H, d, J = 8.9 Hz), 7.45(5H, s),

7.84(1H, d, J = 8.4 Hz), 7.94(1H,

dd, J = 8.4 Hz, 2.6 Hz), 8.12 (1H,

dd, J = 8.9 Hz, 2.6 Hz), 8.22(1H, d,

J = 2.0 Hz), 8.43(1H, d, J = 2.6 Hz),

10.51(1H, s).

767
—Cl
—Cl
—H
—CH₃

embedded image

¹H NMR (DMSO-d₆) 2.94(3H, s), 3.05(4H, brs), 3.40(2H, brs), 3.63(2H, brs), 4.04(2H, brs), 4.26(4H, s), 4.31(2H, brs), 6.09(2H, s), 6.65(2H, d, J = 9.1 Hz), 6.82- 7.06(6H, m), 7.84(1H, d, J = 8.4 Hz), 7.94(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.12(1H, dd, J = 8.8 Hz, 2.5 Hz), 8.22(1H, d, J = 2.0 Hz), 8.43(1H, d, J = 2.5 Hz), 10.51(1H, s).

768
—Cl
—Cl
—OCH₃
—C₂H₅
piperonyl
mp 172-177

769
—CF₃
—H
—H
—C₂H₅
benzyl

¹H NMR (CDCl₃+ CD₃OD) 1.13(3H,

t, J = 6.9 Hz), 3.08(4H, brs),

3.36(2H, q, J = 6.9 Hz), 3.85(4H,

brs), 4.09(2H, s), 4.18(2H, s), 6.31

(2H, 5), 6.73(2H, d, J = 8.9 Hz),

6.87(1H, d, J = 9.2 Hz), 6.98(2H, d,

J = 8.9 Hz), 7.40-7.44 (5H, m),

7.73(2H, d, J = 8.4 Hz), 8.07(2H, d,

J = 8.3 Hz), 8.27(2H, d, J = 7.4 Hz),

9.63(1H, s).

770
—CF₃
—H
—H
—CH₃

embedded image

¹H NMR (DMSO-d₆) 2.94(3H, s), 2.95(4H, brs), 3.33(4H, brs), 4.03(2H, brs), 4.26(4H, s), 4.31(2H, brs), 6.09(2H, s), 6.65(2H, d, J = 9.2 Hz), 6.85-7.03(6H, m), 7.93(2H, d, J = 8.2 Hz), 8.14(1H, dd, J = 8.9 Hz, 2.5 Hz), 8.16(2H, d, J = 8.2 Hz), 8.45(1H, d, J = 2.5 Hz), 10.59(1H, s).

TABLE 205

Example

No.
R₆₇₂
R₆₇₃
R₆₇₄
mp (° C.) or ¹H NMR (solvent) δppm

771
—H
—Ac
benzyl
mp 161-162

772
—CH₃
—Ac
piperonyl

¹H NMR (DMSO-d₆) 1.82(3H, s), 2.10(3H, s),

2.23-2.36(4H, m), 3.33-3.45(6H, m), 4.44(2H,

s), 5.96(2H, s), 6.72(1H, d, J = 8.0 Hz),

6.82(1H, d, J = 8.0 Hz), 6.84(1H, s), 7.02-

7.10(2H, m), 7.23(1H, d, J = 8.6 Hz), 7.33(1H,

s), 7.91(2H, d, J = 8.4 Hz), 8.14(2H, d, J = 8.4

Hz), 8.20(1H, d, J = 8.6 Hz), 8.45 (1H, s),

10.60(1H, s).

773
—CH₃
—Ac
benzyl

¹H NMR (DMSO-d₆) 1.82(3H, s), 2.10(3H, s),

2.30-2.37(4H, m), 3.35-3.45(4H, m), 3.47(2H,

s), 4.44(2H, s), 7.03-7.10 (2H, m), 7.20-

7.35(7H, m), 7.91(2H, d, J = 8.4 Hz), 8.14(2H,

d, J = 8.4 Hz), 8.21(1H, dd, J = 2.5 Hz, 8.9

Hz), 8.45(1H, d, J = 2.5 Hz), 10.60(1H, s).

774
—H
—C₂H₅
piperonyl
mp 178-180

775
—F
—C₂H₅
piperonyl
mp 170-172

776
—F
—CH₃
piperonyl
mp 220-221

777
—OCH₃
—CH₃
piperonyl

¹H NMR (CDCl₃) 2.38-2.42(4H, m), 2.96(3H,

s), 3,41(2H, s), 3,47-3.58(4H, m), 3.64(3H, s),

4.05(2H, s), 5.94(2H, s), 6.13 (1H, dd, J = 8.9

Hz, 2.8 Hz), 6.24(1H, d, J = 2.8 Hz), 6.70-

6.89(5H, m), 7.64(2H, d, J = 8.3 Hz), 7.96(2H,

d, J = 8.1 Hz), 8.06(1H, dd, J = 8.9 Hz, 2.6

Hz), 8.20(1H, d, J = 2.6 Hz), 8.93(1H, s).

778
—OCH₃
—CH₃

embedded image

¹H NMR (CDCl₃) 2.38-2.42(4H, m), 2.96(3H, s), 3.40(2H, s), 3.47-3.57(4H, m), 3.98(3H, s), 4.05(2H, s), 4.24(4H, s), 6.13 (1H, dd, J = 8.9 Hz, 2.8 Hz), 6.23(1H, d, J = 2.6 Hz), 6.73- 6.88(5H, m), 7.63(2H, d, J = 8.3 Hz), 7.97(2H, d, J = 8.1 Hz), 8.07(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.20(1H, d, J = 2.5 Hz), 9.11(1H, s).

779
—F
—CH₃

embedded image

¹H NMR (DMSO-d₆) 2.30(2H, brs), 2.39(2H, brs), 2.93(3H, s), 3.38(2H, s), 3.44(4H, brs), 4.22(4H, s), 4.28(2H, s), 6.40-6.43(1H, m), 6.56(1H, dd, J = 14.2 Hz, 2.6 Hz), 6.73- 6.81(3H, m), 7.02-7.08(2H, m), 7.93(2H, d, J = 8.6 Hz), 8.14-8.21(3H, m), 8.49(1H, d, J = 2.6 Hz), 10.61(1H, s).

780
—F
—CH₃
3-furylmethyl

¹H NMR (DMSO-d₆) 2.32(2H, s), 2.41(2H, s),

2.93(3H, s), 3.37(2H, s), 3.44(4H, brs),

4.29(2H, s), 6.40-6.44(2H, m), 6.55(1H, dd, J =

14.5 Hz, 2.8 Hz), 7.02-7.08(2H, m), 7.58-

7.62(2H, m), 7.93(2H, d, J = 8.4 Hz), 8.14-

8.21(3H, m), 8.41(1H, d, J = 2.6 Hz),

10.61(1H, s).

TABLE 206

Example

No.
R₆₇₅
R₆₇₆
R₆₇₇
mp (° C.) or ¹H NMR (solvent) δppm

781
—OCH₃
—C₂H₅

embedded image

¹H NMR (CDCl₃) 1.16(3H, t, J = 6.9 Hz), 2.38- 2.43(4H, m), 3.33-3.62(8H, m), 3.66(3H, s), 4.02(2H, s), 4.26(4H, s), 6.14 (1H, dd, J = 8.7 Hz, 2.6 Hz), 6.25(1H, d, J = 2.6 Hz), 6.75- 6.90(5H, m), 7.66(2H, d, J = 8.3 Hz), 8.01(2H, d, J = 8.3 Hz), 8.09(1H, dd, J = 9.1 Hz, 2.8 Hz), 8.26(1H, d, J = 2.6 Hz), 9.19(1H, s).

782
—F
—Ac
piperonyl

¹H NMR (DMSO-d₆) 1.88(3H, s), 2.33(4H, brs),

3.40(2H, s), 3.40(4H, brs), 4.50(2H, s),

5.99(2H, s), 6.73-6.76(1H, m), 6.83-6.86(2H,

m), 7.21(1H, d, J = 8.9 Hz), 7.32-7.49(3H, m),

7.94(2H, d, J = 8.3 Hz), 8.16(2H, d, J = 8.1

Hz), 8.25(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.46(1H,

d, J = 2.6 Hz), 10.66(1H, s).

783
—H
—CH₃
3-furylmethyl

¹H NMR (CDCl₃) 2.44(4H, brs), 2.99(3H, s),

3.40(2H, s), 3.50 (2H, t, J = 4.9 Hz), 3.62(2H,

t, J = 4.9 Hz), 4.07(2H, s), 6.38 (1H, d, J = 1.0

Hz), 6.67(2H, d, J = 9.1 Hz), 6.84(1H, d, J =

8.8 Hz), 6.98(2H, d, J = 9.1 Hz), 7.34(1H, s),

7.40(1H, t, J = 1.6 Hz), 7.73(2H, d, J = 8.2 Hz),

7.99(2H, d, J = 8.2 Hz), 8.11 (1H, dd, J = 8.8

Hz, 2.6 Hz), 8.24(1H, s), 8.25(1H, d, J = 2.6

Hz).

784
—OCH₃
—C₂H₅
3-furylmethyl
mp 174-176

785
—OCH₃
—CH₃
3-furylmethyl
mp 160-164

786
—CH₃
—CH₃
—COOC(CH₃)₃

¹H NMR (CDCl₃) 1.47(9H, s), 2.12(3H, s),

3.01(3H, s), 3.30-3.71(8H, m), 4.09(2H, s),

6.44-6.66(2H m), 6.83(1H d, J = 8.9 Hz),

6.93(1H, d, J = 8.4 Hz), 7.75(2H, d, J = 8.1

Hz), 7.94(1H, s), 7.99(2H, d, J = 8.1 Hz),

8.15(1H, d, J = 9.2 Hz), 8.22(1H, s).

787
—H
—C₂H₅

embedded image

¹H NMR (CDCl₃) 1.18(3H, t, J = 7.1 Hz), 3.03(4H, brs), 3.43 (2H, q, J = 7.1 Hz), 3.67- 3.77(4H, m), 4.08(2H, s), 5.91(2H, s), 6.36(1H, dd, J = 8.4 Hz, 2.3 Hz), 6.55(1H, d, J = 2.5 Hz), 6.68-6.75(3H, m), 6.87(1H, d, J = 8.7 Hz), 7.00(2H, d, J = 8.9 Hz), 7.75(2H, d, J = 8.4 Hz), 7.98(1H, brs), 7.99(2H, d. J = 8.3 Hz), 8.13(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.25(1H, d, J = 2.6 Hz)

TABLE 207

Example

No.
R₆₇₈
R₆₇₉
R₆₈₀
Form
mp (° C.) or ¹H NMR (solvent) δppm

788
—F
—(CH₂)₂CH₃
piperonyl
free

¹H NMR (CDCl₃) 0.94(3H, t, J = 7.3

Hz), 1.58-1.69(2H, m), 2.45(4H,

brs), 3.29(2H, t, J = 7.6 Hz),

3.45(2H, s), 3.49(2H, brs), 3.64(2H,

brs), 4.05(2H, s), 5.95(2H, s), 6.34-

6.44(2H, m), 6.75(2H, s), 6.86(1H,

s), 6.96(1H, d, J = 8.9 Hz), 7.03(1H,

t, J = 9.1 Hz), 7.76(2H, d, J = 8.2

Hz), 7.86(1H, brs), 8.00(2H, d, J =

8.1 Hz), 8.16-8.22(2H, m).

789
—H
—CH₃

embedded image

free

¹H NMR (CDCl₃) 3.02(7H, brs), 3.64(2H, brs), 3.75(2H, brs), 4.12(2H, s), 5.91(2H, s), 6.36(1H, dd, J = 8.4 Hz, 2.5 Hz), 6.55(1H, d, J = 2.5 Hz), 6.70(2H, d, J = 9.1 Hz), 6.73(1H, d, J = 8.3 Hz), 6.85(1H, d, J = 8.9 Hz), 6.99(2H, d, J = 9.2 Hz), 7.73(2H, d, J = 8.3 Hz), 7.98(2H, d, J = 8.3 Hz), 8.12(1H, dd, J = 9.1 Hz, 2.8 Hz), 8.15(1H, brs), 8.24(1H, d, J = 2.5 Hz).

790
—OCH₃
—CH₃
4-(4-FPhCO)Ph—
free

¹H NMR (CDCl₃) 3.03(3H, s),

3.39(4H, brs), 3.70(3H, s), 3.71-

3.79(4H, m), 4.14(2H, s), 6.23 (1H,

dd, J = 8.9 Hz, 2.8 Hz), 6.36(1H, d,

J = 2.6 Hz), 6.81-6.96(4H, m), 7.09-

7.17(2H, m), 7.68 (2H, d, J = 8.4

Hz), 7.72-7.78(4H, m), 7.99(2H, d, J =

8.3 Hz), 8.09(1H, dd, J = 8.9 Hz,

2.8 Hz), 8.21(1H, d, J = 2.6 Hz),

8.53(1H, s).

791
—OCH₃
—C₂H₅
4-(4-FPhCO)Ph—
free

¹H NMR (CDCl₃) 1.17(3H, t, J = 6.9

Hz), 3.37-3.42(6H, m), 3.67(3H, s),

3.71-3.76(4H, m), 4.08(2H, s),

6.19(1H, dd, J = 8.9 Hz, 2.8 Hz),

6.33(1H, d, J = 2.6 Hz), 6.77-

6.92(4H, m), 7.09-7.15(2H, m),

7.64(2H, d, J = 8.3 Hz), 7.71-

7.77(4H, m), 7.98(2H, d, J = 8.1

Hz), 8.07 (1H, dd, J = 8.9 Hz, 2.6

Hz), 8.23(1H, d, J = 2.6 Hz),

8.83(1H, s).

792
—CH₃
—CH₃
3-furylmethyl
hydrochloride
mp 158.5-161.0

TABLE 208

Example

No.
R₆₈₁
R₆₈₂
R₆₈₃

¹H NMR (DMSO-d₆) δppm

793
—Cl
—Cl
piperonyl
1.74(3H, s), 2.19-2.34(4H, m), 2.54(2H, t, J = 7.7

Hz), 3.32-3.46(6H, m), 3.76(2H, t, J = 7.7 Hz),

5.96(2H, s), 6.72(1H, d, J = 7.9 Hz), 6.77-6.85(2H,

m), 7.11(1H, d, J = 8.8 Hz), 7.17(2H, d, J = 8.6 Hz),

7.31(2H, d, J = 8.6 Hz), 7.83(1H, d, J = 8.4 Hz),

7.93(1H, dd, J = 8.4 Hz, 2.1 Hz), 8.17-8.25(2H, m),

8.51(1H, d, J = 2.4 Hz), 10.57(1H, s).

794
—Cl
—Cl
benzyl
1.74(3H, s), 2.25-2.37(4H, m), 2.54(2H, t, J = 7.7

Hz), 3.36-3.42(4H, m), 3.46(2H, s), 3.76(2H, t, J =

7.7 Hz), 7.11(1H, d, J = 8.8 Hz), 7.16 (2H, d, J = 8.6

Hz), 7.20-7.31(5H, m), 7.34(2H, d, J = 8.6 Hz),

7.83(1H, d, J = 8.4 Hz), 7.93(1H, dd, J = 8.4 Hz, 2.1

Hz), 8.19-8.25(2H, m), 8.51 (1H, d, J = 2.5 Hz),

10.57(1H, s).

795
—CF₃
—H
piperonyl
1.74(3H, s), 2.20-2.35(4H, m), 2.54(2H, t, J = 7.7

Hz), 3.34-3.42(6H, m), 3.76(2H, t, J = 7.7 Hz),

5.96(2H, s), 6.72(1H, d, J = 7.8 Hz), 6.78-6.86(2H,

m), 7.12(1H, d, J = 8.8 Hz), 7.17(2H, d, J = 8.5 Hz),

7.35 (2H, d, J = 8.5 Hz), 7.92(2H, d, J = 8.2 Hz),

8.15(2H, d, J = 8.2 Hz), 8.24(1H, dd, J = 8.8 Hz, 2.5

Hz), 8.54(1H, d, J = 2.5 Hz), 10.65(1H, s).

796
—CF₃
—H
benzyl
1.74(3H, s), 2.18-2.36(4H, m), 2.54(2H, t, J = 7.7

Hz), 3.35-3.45(4H, m), 3.46(2H, s), 3.76(2H, t, J =

7.7 Hz), 7.12(1H, d, J = 8.8 Hz), 7.17 (2H, d, J = 8.6

Hz), 7.20-7.33(5H, m), 7.34(2H, d, J = 8.6 Hz),

7.92(2H, d, J = 8.3 Hz), 8.15(2H, d, J = 8.3 Hz),

8.24(1H, dd, J = 8.8 Hz, 2.5 Hz), 8.54(1H, d, J = 2.5

Hz), 10.65(1H, s).

TABLE 209

Example

No.
R₆₈₄
R₆₈₅
R₆₈₆

¹H NMR (DMSO-d₆) δppm

797
—Cl
—Cl
benzyl
1.80(3H, s), 3.02(3H, s), 2.70-3.40(5H, m), 3.41-

3.68(1H, m), 3.88-4.10 (1H, m), 4.32(2H, brs), 4.25-

4.50(1H, m), 4.50(2H, d, J = 3.8 Hz), 4.57 (2H, s),

6.94(1H, d, J = 8.9 Hz), 7.02(2H, d, J = 8.7 Hz),

7.22(1H, dd, J = 8.2 Hz, 2.0 Hz), 7.34(1H, dd, J = 8.9

Hz, 3.2 Hz), 7.36(2H, d, J = 8.7 Hz), 7.42-7.49(3H,

m), 7.50(1H, d, J = 2.0 Hz), 7.55-7.64(1H, m), 7.62

(2H, d, J = 8.2 Hz), 7.66(1H, d, J = 6.1 Hz).

798
—Cl
—Cl
piperonyl
1.81(3H, s), 2.75-3.40(5H, m), 3.02(3H, s), 3.43-

3.67(1H, m), 3.90-4.10 (1H, m), 4.22(2H, brs), 4.30-

4.50(1H, m), 4.50(2H, d, J = 4.6 Hz), 4.57 (2H, s),

6.07(2H, s), 6.94(2H, d, J = 8.8 Hz), 6.97-7.07(1H,

m), 7.02(2H, d, J = 8.9 Hz), 7.22(1H, dd, J = 8.3 Hz,

1.8 Hz), 7.24(1H, s), 7.34(1H, dd, J = 8.8 Hz, 3.0 Hz),

7.36(2H, d, J = 8.9 Hz), 7.50(1H, d, J = 1.8 Hz),

7.60(1H, d, J = 8.3 Hz), 7.67(1H, d, J = 3.0 Hz).

799
—CF₃
—H
benzyl
1.80(3H, s), 3.05(3H, s), 2.70-3.40(5H, m), 3.41-

3.68(1H, m), 3.90-4.08 (1H, m), 4.22-4.45(1H, m),

4.32(2H, brs), 4.50(2H, d, J = 3.5 Hz), 4.67 (2H, s),

6.94(1H, d, J = 8.9 Hz), 7.02(2H, d, J = 8.8 Hz),

7.34(1H, dd, J = 8.9 Hz, 3.3 Hz), 7.36(2H, d, J = 8.8

Hz), 7.39-7.50(5H, m), 7.54-7.64 (2H, m), 7.67(1H, d,

J = 3.3 Hz). 7.70(2H, d, J = 8.1 Hz).

800
—CF₃
—H
piperonyl
1.80(3H, s), 2.70-3.40(5H, m), 3.05(3H, s), 3.43-

3.65(1H, m), 3.90-4.09 (1H, m), 4.22(2H, s), 4.29-

4.48(1H, m), 4.50(2H, d, J = 4.8 Hz), 4.67(2H, s),

6.07(2H, s), 6.94(1H, d, J = 8.9 Hz), 7.00(2H, d, J =

7.0 Hz), 7.02(2H, d, J = 8.8 Hz), 7.24(1H, d, J = 1.1

Hz), 7.35(1H, dd, J = 8.9 Hz, 2.3 Hz), 7.36(2H, d, J =

8.8 Hz), 7.45(2H, d, J = 8.1 Hz), 7.67(1H, d, J = 3.3

Hz), 7.70(2H, d, J = 8.1 Hz).

TABLE 210

Example

No.
R₆₈₇
R₆₈₈
R₆₈₉

¹H NMR (CDCl₃) δppm

801
4-CF₃PhCO—
—CH₃
—C₂H₅
1.19(3H, t, J = 7.1 Hz), 2.11(3H, s), 2.42-

2.45(4H, m), 3.39-3.53(6H, m), 3.63-

3.66(2H, m), 4.04(2H, s), 5.95(2H, s),

6.50-6.54(2H, m), 6.71-6.77(2H, m),

6.85(1H, s), 6.90-6.95(2H, m), 7.75(2H, d,

J = 8.2 Hz), 7.87(2H, d, J = 8.1 Hz),

8.17(1H, dd, J = 8.7 Hz, 2.5 Hz),

8.59(1H, d, J = 2.0 Hz).

802
3,4-Cl₂PhNHCO—
—OCH₃
—C₂H₅
1.19(3H, t, J = 7.1 Hz), 2.42(4H, brs),

3.42(2H, q, J = 7.1 Hz), 3.43(2H, s),

3.51(2H, s), 3.62(2H, brs), 3.68(3H, s),

4.04(2H, s), 5.95(2H, s), 6.17(1H, dd, J =

8.7 Hz, 2.6 Hz), 6.28(1H, d, J = 2.6 Hz),

6.73-6.74(2H, m), 6.85(1H, brs), 6.88(1H,

d, J = 8.6 Hz), 6.90(1H, d, J = 8.7 Hz),

7.37(1H, d, J = 8.7 Hz), 7.47(1H, dd, J =

8.7 Hz, 2.5 Hz), 7.86(1H, d, J = 2.5 Hz),

8.11(1H, dd, J = 8.6 Hz, 2.5 Hz),

8.31(1H, brs), 8.58(1H, d, J = 2.3 Hz).

803
4-CF₃PhNHCO—
—OCH₃
—C₂H₅
1.19(3H, t, J = 7.1 Hz), 2.42(4H, brs),

3.38-3.47(4H, m), 3.51(2H, brs), 3.62(2H,

brs), 3.68(3H, s), 4.05(2H, s), 5.94 (2H,

s), 6.17(1H, dd, J = 8.7 Hz, 2.8 Hz),

6.29(1H, d, J = 2.8 Hz), 6.73-6.74(2H, m),

6.84(1H, brs), 6.89(1H, d, J = 8.7 Hz),

6.91(1H, d, J = 8.7 Hz), 7.58(2H, d, J =

8.7 Hz), 7.76(2H, d, J = 8.7 Hz), 8.13(1H,

dd, J = 8.7 Hz, 2.5 Hz), 8.44(1H, brs),

8.64(1H, d, J = 2.5 Hz).

804
3,4-Cl₂PhNHCONH—
—CONHCH₃
—C₂H₅
1.07(3H, t, J = 7.0 Hz), 2.30-2.45(4H, m),

2.85(3H, d, J = 4.9 Hz), 3.33(2H, q, J =

7.0 Hz), 3.38(2H, s), 3.38-3.50(2H, m),

3.50-3.65(2H, m), 4.01(2H, s), 5.95(2H,

s), 6.55-6.65 (1H, m), 6.69-6.84(5H, m),

7.14(1H, d, J = 3.1 Hz), 7.25-7.35(2H, m),

7.35-7.45(1H, m), 7.65(1H, d, J = 1.5 Hz),

7.72(1H, d, J = 2.6 Hz), 7.84(1H, dd, J =

8.9 Hz, 2.7 Hz), 8.02(1H, s), 8.61(1H, s).

805
4-CF₃PhCH₂—
—H
—CH₃
2.42(4H, t, J = 5.1 Hz), 3.02(3H, s),

3.43(2H, s), 3.48(2H, brs), 3.63(2H, brs),

3.95(2H, s), 4.06(2H, s), 5.94(2H, s),

6.70(2H, d, J = 9.0 Hz), 6.73(2H, s),

6.74(1H, d, J = 10.0 Hz), 6.84(1H, s),

7.00(2H, d, J = 9.0 Hz), 7.27(2H, d, J =

8.1 Hz), 7.38(1H, dd, J = 8.4 Hz, 2.5 Hz),

7.54(2H, d, J = 8.1 Hz), 8.03(1H, d, J =

2.5 Hz).

TABLE 211

Example

No.
R₆₉₀
R₆₉₁
R₆₉₂
R₆₉₃

¹H NMR (solvent) δppm

806
4-CF₃PhNHCO—
—CH₃
—H
piperonyl
(CDCl₃) 2.17(3H, s), 2.49-2.54(4H,

m), 3.45(2H, s), 3.71-3.75(2H, m),

4.26(2H, brs), 5.96(2H, s), 6.75(2H,

brs), 6.86(1H, brs), 7.02(1H, d, J =

8.7 Hz), 7.06(1H, d, J = 8.7 Hz),

7.47(1H, dd, J = 8.7 Hz, 2.5 Hz),

7.58(1H, d, J = 2.3 Hz), 7.63(2H, d,

J = 8.4 Hz), 7.75(2H, d, J = 8.3 Hz),

7.84(1H, brs), 8.22(1H, dd, J = 8.7

Hz, 2.6 Hz), 8.64(1H, d, J = 2.5 Hz),

9.20(1H, brs).

807
4-CF₃PhOCH₂—
—H
—H
piperonyl
(CDCl₃) 2.51-2.54(4H, m), 3.45(2H,

s), 3.71-3.75(2H, m), 4.27-4.29(2H,

m), 5.05(2H, s), 5.95(2H, s),

6.85(2H, brs), 6.86(1H, brs),

6.96(1H, d, J = 8.4 Hz), 7.02(2H, d,

J = 8.6 Hz), 7.14(2H, d, J = 8.9 Hz),

7.56(2H, d, J = 8.6 Hz), 7.64(2H, d,

J = 8.9 Hz), 7.78(1H, dd, J = 8.4 Hz,

2.3 Hz), 8.22(1H, d, J = 2.3 Hz),

9.21(1H, brs).

808
4-CF₃PhOCH₂—
—H
—H
4-pyridylmethyl
(CDCl₃) 2.52-2.58(4H, m), 3.55(2H,

s), 3.74-3.77(2H, m), 4.29-4.32(2H,

m), 5.04(2H, s), 6.96(1H, d, J = 8.4

Hz), 7.02(2H, d, J = 8.4 Hz),

7.15(2H, d, J = 8.9 Hz), 7.26-

7.30(2H, m), 7.56(2H, d, J = 8.6

Hz), 7.64(2H, d, J = 9.1 Hz),

7.78(1H, dd, J = 8.6 Hz, 2.5 Hz),

8.22(1H, d, J = 2.0 Hz), 8.56-

8.58(2H, m), 9.24(1H, brs).

809
4-CF₃PhOCH₂—
—CH₃
—CH₃
piperonyl
a mixture of the rotational isomers

(DMSO-d₆) 2.07-2.43 (7H, m), 3.24-

3.57(11H, m), 5.17(2H, brs), 5.95-

5.99(2H, m), 6.66-6.89(3H, m), 7.07-

7.12(2H, m), 7.16-7.37(4H, m),

7.66(2H, d, J = 8.4 Hz), 7.85-

8.00(1H, m), 8.22(1H, d, J = 2.0

Hz).

810
4-CF₃PhOCH₂—
—CH₃
—CH₃
3,4-(CH₃O)₂PhCH₂—
a mixture of the rotational isomers

(DMSO-d₆) 2.07-2.43(7H, m), 3.26-

3.75(15H, m), 5.17(2H, brs), 6.70-

6.91(3H, m), 7.07-7.12(2H, m), 7.16-

7.37(4H, m), 7.66(2H, d, J = 8.9

Hz), 7.95-8.00(1H, m), 8.22(1H, d, J =

2.0 Hz).

TABLE 212

Example

No.
R₆₉₄

¹H NMR (CDCl₃) δppm

811
piperonyl
2.18(3H, s), 2.49-2.54(4H, m), 3.45(2H, s), 3.70-3.74(2H,

m), 4.23-4.27(2H, m), 5.03(2H, s), 5.95(2H, s), 6.71-

6.78(2H, m), 6.86(1H, brs), 6.92(1H, d, J = 8.6 Hz), 7.00-

7.06(3H, m), 7.44(1H, dd, J = 8.7 Hz, 2.6 Hz), 7.54-

7.58(3H, m), 7.77(1H, dd, J = 8.6 Hz, 2.5 Hz), 8.20(1H, d,

J = 2.3 Hz), 9.20(1H, brs).

812
3,4-(CH3O)₂PhCH₂—
2.18(3H, s), 2.50-2.55(4H, m), 3.48(2H, s), 3.71-3.75(2H,

m), 3.88(3H, s), 3.90(3H, s), 4.24-4.28(2H, m), 5.03(2H, s),

6.79-6.86(2H, m), 6.88(1H, brs), 6.93(1H, d, J = 8.4 Hz),

7.00-7.06(3H, m), 7.44(1H, dd, J = 8.6 Hz, 2.6 Hz), 7.54-

7.58(3H, m), 7.77(1H, dd, J = 8.4 Hz, 2.5 Hz), 8.20(1H, d,

J = 2.5 Hz), 9.19(1H, brs).

813
4-pyridylmethyl
2.18(3H, s), 2.52-2.58(4H, m), 3.55(2H, s), 3.73-3.77(2H,

m), 4.27-4.31(2H, m), 5.03(2H, s), 6.93(1H, d, J = 8.4 Hz),

7.00-7.06(3H, m), 7.28(2H, d, J = 5.9 Hz), 7.44(1H, dd, J =

8.7 Hz, 2.6 Hz), 7.54-7.57(3H, m), 7.77(1H, dd, J = 8.4 Hz,

2.3 Hz), 8.19(1H, d, J = 2.1 Hz), 8.56(2H, d, J = 5.9 Hz),

9.23(1H, brs).

TABLE 213

Example

No.
R₆₉₅
R₆₉₆

¹H NMR (CDCl₃) δppm

814
—H
piperonyl
2.42(4H, brs), 3.21(3H, s), 3.37(2H, brs), 3.42(2H,

s), 3.62(2H, brs), 4.54(2H, s), 5.06(2H, s), 5.94(2H,

s), 6.70-6.77(2H, m), 6.83(1H, brs), 6.98-7.04(3H,

m), 7.14(2H, d, J = 8.7 Hz), 7.56(2H, d, J = 8.7

Hz), 7.62(2H, d, J = 8.9 Hz), 7.81(1H, dd, J = 8.4

Hz, 2.3 Hz), 8.23(1H, d, J = 2.1 Hz).

815
—H
4-pyridylmethyl
2.48(4H, brs), 3.21(3H, s), 3.41(2H, brs), 3.53(2H,

s), 3.65(2H, brs), 4.55(2H, s), 5.06(2H, s), 7.01(1H,

d, J = 8.2 Hz), 7.03(2H, d, J = 8.4 Hz), 7.14(2H, d,

J = 8.9 Hz), 7.26-7.28(2H, m), 7.57(2H, d, J = 8.7

Hz), 7.62(2H, d, J = 8.7 Hz), 7.81(1H, dd, J = 8.4

Hz, 2.3 Hz), 8.23(1H, d, J = 2.1 Hz), 8.56(2H, d, J =

5.6 Hz).

816
—CH₃
piperonyl
2.18(3H, s), 2.41-2.44(4H, m), 3.22(3H, s), 3.36-

3.39(2H, m), 3.43(2H, s), 3.60-3.64(2H, m),

4.54(2H, s), 5.05(2H, s), 5.94(2H, s), 6.73-6.74(2H,

m), 6.84(1H, brs), 6.97(1H, d, J = 8.4 Hz),

7.02(1H, d, J = 8.6 Hz), 7.04(2H, d, J = 8.6 Hz),

7.45(1H, dd, J = 8.6 Hz, 2.6 Hz), 7.49(1H, d, J =

2.5 Hz), 7.56(2H, d, J = 8.4 Hz), 7.80(1H, dd, J =

8.6 Hz, 2.5 Hz). 8.20(1H, d, J = 2.0 Hz).

817
—CH₃
3,4-(CH₃O)₂PhCH₂—
2.18(3H, s), 2.44(4H, brs), 3.22(3H, s), 3.38-

3.40(2H, m), 3.46(2H, s), 3.63-3.65(2H, m),

3.87(3H, s), 3.89(3H, s), 4.55(2H, s), 5.04(2H, s),

6.81(2H, brs), 6.87(1H, brs), 6.98(1H, d, J = 8.6

Hz), 7.02(1H, d, J = 8.4 Hz), 7.04(2H, d, J = 8.4

Hz), 7.45(1H, dd, J = 8.6 Hz, 2.6 Hz), 7.49(1H, d, J =

2.6 Hz), 7.56(2H, d, J = 8.4 Hz), 7.80(1H, dd, J =

8.4 Hz, 2.5 Hz), 8.20(1H, d, J = 2.3 Hz).

TABLE 214

Example

No.
R₆₉₇
R₆₉₈
mp (° C.)

818
4-CF₃PhCO—

embedded image

207.0-209.0

819
4-CF₃PhCO—

embedded image

237.0-238.0

820
3,4-Cl₂PhSO₂—

embedded image

115.0-116.0

821
3,4-Cl₂PhNHCO—
—CH₂CONHPh
147.0-148.0

822
3,4-Cl₂PhNHCO—

embedded image

207.0-208.0

TABLE 215

Example

No.
R₆₉₉

¹H NMR or MS

823

embedded image

¹H NMR (DMSO-d₆) δ 1.40-1.80(2H, m), 1.80-2.10 (2H, m), 2.93(3H, s), 3.15-3.50(2H, m), 3.60-3.90(2H, m), 4.31(2H, s), 4.60-4.70(1H, m), 6.35-6.45(1H, m), 6.54 (1H, dd, J = 14.4 Hz, 2.6 Hz), 6.96-7.11(4H, m), 7.27-7.31(2H, m), 7.52(1H, dd, J = 8.7 Hz, 2.7 Hz), 7.63 (1H, dd, J = 8.5 Hz, 2.1 Hz), 7.76(1H, d, J = 2.7 Hz), 7.84-7.88(2H, m), 10.39(1H, brs).

824

embedded image

MS 682(M⁺ + H)

825

embedded image

MS 618(M⁺ + H)

826
—N[CH₂CH(CH₃)₂]₂
MS 611(M⁺ + H)

827

embedded image

MS 571(M⁺ + H)

828

embedded image

MS 635(M⁺ + H)

829
—N[(CH₂)₃N(CH₃)₂]₂
MS 669(M⁺ + H)

830

embedded image

MS 645(M⁺ + H)

831

embedded image

MS 712(M⁺ + H)

832

embedded image

MS 665(M⁺ + H)

833

embedded image

MS 595(M⁺ + H)

834

embedded image

MS 764(M⁺ + H)

TABLE 216

Example

No.
R₇₀₀
MS (M⁺ + H)

835

embedded image

635

836

embedded image

714

837

embedded image

581

838
4-CF₃OPhCH₂NH—
673

839

embedded image

553

840
—NH(CH₂)₅OH
585

841
—NHCH(CH₃)COOCH₃
585

842
3,5-F₂PhCH₂N(C₂H₅)—
653

843
4-CH₃PhNHCOCH₂N(CH₃)—
660

844
3,4-(CH₃O)₂PhCH₂N(C₂H₅)—
677

845
4-CH₃PhCH₂N(C₂H₅)—
631

846

embedded image

614

847

embedded image

686

848
3,4-Cl₂Ph—
714

849

embedded image

695

850

embedded image

734

851
—N(CH₂Ph)CH₂CH₂CN
642

852
—N(C₂H₅)CH(CH₃)₂
569

853
—NHC(CH₃)₂CH₂Ph
631

854
3-CNPhNH—
600

855
3,5-F₂PhNH—
611

TABLE 217

Example

No.
R₇₀₁
MS (M⁺ + H)

856

embedded image

700

857

embedded image

652

858

embedded image

583

859

embedded image

662

860

embedded image

665

861

embedded image

659

862

embedded image

673

863

embedded image

702

864

embedded image

674

865

embedded image

674

866

embedded image

666

TABLE 218

Example

No.
R₇₀₂
MS (M⁺ + H)

867

embedded image

698

868

embedded image

639

869

embedded image

639

870

embedded image

673

871

embedded image

610

872

embedded image

596

873

embedded image

555

874

embedded image

569

875

embedded image

663

876

embedded image

692

TABLE 219

Example

MS

No.
R₇₀₃
R₇₀₄
R₇₀₅
R₇₀₆
(M⁺ + H)

877
—H
—H
—OCF₃
—H
659

878
—H
—H
—CH₃
—H
589

879
—OCH₃
—OCH₃
—H
—H
635

880
—H
—H
—SCH₃
—H
621

881
—CH(CH₃)₂
—H
—H
—H
617

882
—H
—H
cyclohexyl
—H
657

883
—NHPh
—H
—Cl
—H
702

884
4-ClPhNH—
—H
—H
—COOC₂H₅
774

885
—H
—H
—O(CH₂)₂N(C₂H₅)₂
—H
690

886
—H
—H

embedded image

—H
673

887
—H
—H

embedded image

—H
658

888
—H
—H
—NHSO₂CH₃
—H
668

889
—H
—H
—(CH₂)₂OH
—H
619

890
—H
—H
—(CH₂)₄CH₃
—H
645

891
—H
—H
benzyl
—H
665

892
—H
—H
—SPh
—H
683

893
—H
—H

embedded image

—H
709

TABLE 220

Example

No.
R₇₀₇
R₇₀₈
R₇₀₉

¹H NMR (CDCl₃) δppm

894
4-CF₃Ph—
—CH₃
piperonyl
1.34-1.42(2H, m), 1.80-1.98(3H, m), 2.03(3H,

s), 2.29(2H, d, J = 6.6 Hz), 2.41(4H, brs),

2.65(2H, t, J = 12.0 Hz), 3.43(2H, s), 3.49-

3.65(6H, m), 5.94(2H, s), 6.69-6.87(8H, m),

7.56(1H, dd, J = 8.9 Hz, 2.8 Hz), 7.68(2H, d, J =

8.6 Hz), 7.76-7.85(3H, m).

895
3,4-Cl₂Ph—
—CH₃
piperonyl
1.34-1.39(2H, m), 1.79-1.98(3H, m), 2.04(3H,

s), 2.29(2H, d, J = 6.6 Hz), 2.41(4H, brs),

2.64(2H, t, J = 11.9 Hz), 3.43(2H, s), 3.49-

3.65(6H, m), 5.94(2H, s), 6.70-6.88(7H, m),

7.45-7.50(3H, m), 7.55(1H, dd, J = 8.9 Hz. 2.8

Hz), 7.78-7.82(2H, m).

896
4-CF₃Ph—
—CH₃
benzyl
1.34-1.43(2H, m), 1.80-2.01(3H, m), 2.03(3H,

s), 2.29(2H, d, J = 6.6 Hz), 2.43(4H, brs),

2.65(2H, t, J = 12.0 Hz), 3.49-3.65(8H, m),

6.70-6.76(3H, m), 6.86(1H, d, J = 8.7 Hz),

7.26-7.32 (6H, m), 7.55(1H, dd, J = 8.7 Hz, 2.6

Hz), 7.68(2H, d, J = 8.6 Hz), 7.76(1H, d, J =

2.8 Hz), 7.84(2H, d, J = 8.4 Hz).

897
3,4-Cl₂Ph—
—CH₃
benzyl
1.27-1.39(2H, m), 1.79-2.01(3H, m), 2.04(3H,

s), 2.29(2H, d, J = 6.8 Hz), 2.43(4H, brs),

2.64(2H, t, J = 11.9 Hz), 3.53-3.66(8H, m),

6.69-6.76(3H, m), 6.86(1H, d, J = 8.7 Hz),

7.29-7.32 (6H, m), 7.44-7.50(2H, m), 7.55(1H,

dd, J = 8.7 Hz, 2.6 Hz), 7.79-7.82(2H, m).

898
4-CF₃Ph—
—H
3,4-Cl₂Ph—
1.34-1.46(2H, m), 1.83-2.02(3H, m), 2.34(2H,

d, J = 6.8 Hz), 2.67(2H, t, J = 12.0 Hz), 3.15-

3.17(4H, m), 3.55-3.65(4H, m), 3.78-3.80(2H,

m), 6.72-6.97(7H, m), 7.26-7.31(2H, m), 7.56

(1H, dd, J = 8.9 Hz, 2.8 Hz), 7.70(2H, d, J =

8.24 Hz), 7.78-7.86(3H, m).

899
4-CF₃Ph—
—H
4-CF₃Ph—
1.35-1.47(2H, m), 1.83-2.02(3H, m), 2.36(2H,

d, J = 6.8 Hz), 2.67(2H, t, J = 12.0 Hz), 3.28-

3.30(4H, m), 3.57(2H, d, J = 12.2 Hz),

3.68(2H, brs), 3.82(2H, brs), 6.76(1H, d, J =

8.7 Hz), 6.87-6.96(7H, m), 7.50(2H, d, J = 8.6

Hz), 7.56(1H, dd, J = 8.9 Hz, 2.8 Hz), 7.69(2H,

d, J = 8.4 Hz), 7.80-7.86(3H, m).

900
3,4-Cl₂Ph—
—H
4-CF₃Ph—
1.34-1.47(2H, m), 1.83-2.02(3H, m), 2.35(2H,

d, J = 6.8 Hz), 2.68(2H, t, J = 12.0 Hz), 3.29-

3.31(4H, m), 3.58(2H, d, J = 12.2 Hz),

3.68(2H, brs), 3.83(2H, brs), 6.79(1H, d, J =

8.7 Hz), 6.88-6.98(7H, m), 7.50-7.59(5H, m),

7.79(1H, d, J = 2.8 Hz), 7.83-7.84(1H, m).

TABLE 221

Example

No.
R₇₁₀
R₇₁₁
R₇₁₂

¹H NMR (CDCl₃) δppm

901
3,4-Cl₂Ph—
—H
3,4-Cl₂Ph—
1.34-1.46(2H, m), 1.82-2.02(3H, m), 2.35(2H, d,

J = 6.6 Hz), 2.66(2H, t, J = 12.0 Hz), 3.16-

3.17(4H, m), 3.57(2H, d, J = 12.2 Hz), 3.65(2H,

brs), 3.80(2H, brs), 6.72-6.78(2H, m), 6.87-

6.97(6H, m), 7.29(1H, d, J = 8.9 Hz), 7.49(2H,

s), 7.57(1H, dd, J = 8.7 Hz, 2.6 Hz), 7.81-

7.84(2H, m).

902
4-CF₃Ph—
—CH₃
3,4-Cl₂Ph—
1.34-1.46(2H, m), 1.82-2.01(3H, m), 2.03(3H,

s), 2.35(2H, d, J = 6.8 Hz), 2.67(2H, t, J = 12.0

Hz), 3.15-3.17(4H, m), 3.58(2H, d, J = 12.2 Hz),

3.65(2H, brs), 3.79(2H, brs), 6.70-6.76 (4H, m),

6.86(1H, d, J = 8.6 Hz), 6.96(1H, d, J = 2.8 Hz),

7.29(1H, d, J = 8.7 Hz), 7.53-7.57(1H, m),

7.68(2H, d, J = 8.2 Hz), 7.77(1H, d, J = 2.5 Hz),

7.84(2H, d, J = 8.2 Hz), 8.05(1H, s).

903
4-CF₃Ph—
—H
piperonyl
1.27-1.41(2H, m), 1.83-2.05(3H, m), 2.29(2H, d,

J = 6.8 Hz), 2.40-2.44(4H, m), 2.66-2.75(2H,

m), 3.44-3.56(4H, m), 3.65-3.74(4H, m),

5.95(2H, s), 6.75-6.99(8H, m), 7.57(1H, dd, J =

8.9 Hz, 2.8 Hz), 7.71-7.74(4H, m), 7.85(2H, d, J =

8.2 Hz).

904
3,4-Cl₂Ph—
—H
benzyl
1.31-1.40(2H, m), 1.80-2.05(3H, m), 2.29(2H, d,

J = 6.8 Hz), 2.62-2.71(2H, m), 3.53-3.58(6H,

m), 3.66(2H, brs), 6.79(1H, d, J = 8.7 Hz), 6.88-

6.98(4H, m), 7.31(5H, brs), 7.50(2H, s), 7.56

(1H, dd, J = 8.9 Hz, 2.8 Hz), 7.77-7.84(3H, m).

905
4-CF₃Ph—
—H
benzyl
1.30-1.43(2H, m), 1.80-2.04(3H, m), 2.28(2H, d,

J = 6.8 Hz), 2.42-2.46(4H, m), 2.62-2.70(2H,

m), 3.47-3.58(6H, m), 3.66(2H, brs), 6.78(1H, d,

J =8.7 Hz), 6.87-6.97(4H, m), 7.26-7.32 (6H,

m), 7.56(1H, dd, J = 8.9 Hz, 2.8 Hz), 7.68-

7.77(3H, m), 7.83-7.86(2H, m).

906
3,4-Cl₂Ph—
—H
piperonyl
1.33-1.39(2H, m), 1.79-2.00(3H, m), 2.30(2H, d,

J = 6.8 Hz), 2.42-2.44(4H, m), 2.65(2H, t, J =

10.4 Hz), 3.43(2H, s), 3.49-3.57(4H, m),

3.65(2H, brs), 5.94(2H, s), 6.74-6.77(3H, m),

6.84-6.97(5H, m), 7.49-7.59(3H, m), 7.81-

7.85(3H, m).

907
4-CF₃Ph—
—OCH₃
piperonyl
1.33-1.44(2H, m), 1.82-1.95(3H, m), 2.29(2H, d,

J = 6.8 Hz), 2.41(4H, brs), 2.70(2H, t, J = 12.2

Hz), 3.43-3.64(8H, m), 3.67(3H, s), 5.94(2H, s),

6.46(1H, dd, J = 8.7 Hz, 2.6 Hz), 6.54(1H, d, J =

2.5 Hz), 6.70-6.78(4H, m), 6.85(1H, s),

6.92(1H, d, J = 8.6 Hz), 7.55(1H, dd, J = 8.7

Hz, 2.6 Hz), 7.67(2H, d, J = 8.4 Hz), 7.74(1H, d,

J = 2.6 Hz), 7.84(2H, d, J = 8.2 Hz).

TABLE 222

Example

No.
R₇₁₃
R₇₁₄
R₇₁₅

¹H NMR (CDCl₃) δppm

908
3,4-Cl₂Ph—
—H
benzyl
1.76-1.99(4H, m), 2.45-2.73(7H, m), 3.53(4H,

brs), 3.66(4H, brs), 6.75(1H, d, J = 8.7 Hz),

6.87-6.97(4H, m), 7.29-7.59(9H, m), 7.83(2H,

d, J = 2.0 Hz).

909
4-CF₃Ph—
—H
benzyl
1.77-1.99(4H, m), 2.45(4H, brs), 2.53-2.76(3H,

m), 3.54(4H, brs), 3.65-3.69(4H, m), 6.81(1H,

d, J = 8.7 Hz), 6.90-6.99(4H, m), 7.28-7.34(6H,

m), 7.57(1H, dd, J = 8.9 Hz, 2.8 Hz), 7.71-

7.75(3H, m), 7.85(2H, d, J = 8.2 Hz).

910
4-CF₃Ph—
—CH₃
piperonyl
1.75-1.96(4H, m), 2.04(3H, s), 2.44(4H, brs),

2.53-2.73(3H, m), 3.43(2H, s), 3.53(2H, brs),

3.63(4H, brs), 5.94(2H, s), 6.70-6.89(8H, m),

7.56(1H, dd, J = 8.9 Hz, 2.8 Hz), 7.67(2H, d, J =

8.6 Hz), 7.78(1H, d, J = 2.6 Hz), 7.84(2H, d,

J = 8.2 Hz).

911
4-CF₃Ph—
—CH₃
benzyl
1.75-2.02(4H, m), 2.03(3H, s), 2.45(4H, brs),

2.55-2.72(3H, m), 3.53(4H, brs), 3.66(4H, brs),

6.72-6.77(3H, m), 6.87(1H, d, J = 8.6 Hz),

7.25-7.31(6H, m), 7.56(1H, dd, J = 8.7 Hz, 2.6

Hz), 7.66(2H, d, J = 8.2 Hz), 7.78-7.86(3H, m).

912
3,4-Cl₂Ph—
—CH₃
piperonyl
1.76-1.98(4H, m), 2.04(3H, s), 2.44(4H, brs),

2.54-2.72(3H, m), 3.43(2H, s), 3.54(2H, brs),

3.63-3.67(4H, m), 5.94(2H, s), 6.70-6.89(8H,

m), 7.44-7.59(3H, m), 7.80(2H, d, J = 2.0 Hz).

913
3,4-Cl₂Ph—
—CH₃
benzyl
1.77-1.97(4H, m), 2.07(3H, s), 2.45(4H, brs),

2.53-2.75(3H, m), 3.54(4H, brs), 3.66(4H, brs),

6.75-6.81(3H, m), 6.90(1H, d, J = 8.6 Hz),

7.26-7.33(6H, m), 7.51-7.58(3H, m), 7.72(1H,

d, J = 2.6 Hz), 7.79(1H, s).

914
3,4-Cl₂Ph—
—H
piperonyl
1.76-1.99(4H, m), 2.44(4H, brs), 2.54-2.74(3H,

m), 3.43(2H, s), 3.54(2H, brs), 3.63-3.67(4H,

m), 5.94(2H, s), 6.74-6.98(8H, m), 7.45-

7.59(3H, m) 7.81-7.84(3H, m).

915
4-CF₃Ph—
—H
piperonyl
1.76-1.80(2H, m), 1.91-1.95(2H, m), 2.43(4H,

brs), 2.59-2.73(3H, m), 3.43(2H, s), 3.54(2H,

brs), 3.62(4H, brs), 5.94(2H, s), 6.72-6.75(3H,

m), 6.84-6.96(5H, m), 7.57(1H, dd, J = 8.7 Hz,

2.8 Hz), 7.66(2H, d, J = 8.4 Hz), 7.82-7.87(4H,

m).

TABLE 223

Example

No.
R₇₁₆
R₇₁₇
M

¹H NMR (CDCl₃) δppm

916
—H
piperonyl
1
1.31-1.45(2H, m), 1.82-2.02(3H, m), 2.33(2H, d, J =

6.8 Hz), 2.43(4H, brs), 2.69(2H, t, J = 12.0 Hz),

3.43(2H, s), 3.51-3.67(6H, m), 5,93(2H, s), 6.73-

6.99(8H, m), 7.28(2H, d, J = 8.6 Hz), 7.50(2H, d, J =

8.6 Hz), 8.28(1H, d, J = 2.1 Hz), 8.43(1H, d, J = 2.1

Hz).

917
—H
benzyl
1
1.34-1.44(2H, m), 1.82-2.00(3H, m), 2.32(2H, d, J =

6.8 Hz), 2.43-2.47(4H, m), 2.69(2H, t, J = 12.0 Hz),

3.51-3.67(8H, m), 6.88(2H, d, J = 9.2 Hz), 6.98(2H,

d, J = 9.2 Hz), 7.25-7.32(8H, m), 7.50(2H, d, J = 8.6

Hz), 8.28(1H, d, J = 2.3 Hz), 8.43(1H, d, J = 2.1 Hz).

918
—CH₃
piperonyl
1
1.31-1.45(2H, m), 1.82-2.00(3H, m), 2.02(3H, s),

2.33(2H, d, J = 6.8 Hz), 2.43(4H, brs), 2.68(2H, t, J =

11.9 Hz), 3.41-3.67(8H, m), 5.92(2H, s), 6.73-

6.92(7H, m), 7.25-7.30(2H, m), 7.50(2H, d, J = 8.6

Hz), 8.30(1H, d, J = 2.3 Hz), 8.41(1H, d, J = 2.3 Hz).

919
—CH₃
benzyl
1
1.37-1.40(2H, m), 1.83-2.01(3H, m), 2.03(3H, s),

2.31(2H, d, J = 6.9 Hz), 2.43-2.47(4H, m), 2.70(2H, t,

J = 12.0 Hz), 3.51-3.67(8H, m), 6.74-6.80(2H, m),

6.91(1H, d, J = 8.6 Hz), 7.24-7.33(8H, m), 7.52(2H,

d, J = 8.4 Hz), 8.29(1H, d, J = 2.1 Hz), 8.42(1H, d,

J = 2.3 Hz).

920
—H
piperonyl
0
1.79-2.03(4H, m), 2.45(4H, brs), 2.57-2.76(3H, m),

3.44(2H, s), 3.55(2H, brs), 3.66(4H, brs), 5.94(2H, s),

6.72-6.78(2H, m), 6.85-7.00(6H, m), 7.28(2H, d, J =

8.6 Hz), 7.50(2H, d, J = 8.6 Hz), 8.28(1H, d, J = 2.1

Hz), 8.42(1H, d, J = 2.1 Hz).

TABLE 224

Example

No.
R₇₁₈
R₇₁₉

¹H NMR (CDCl₃) δppm

921
3,4-Cl₂Ph—
piperonyl
1.37-1.44(2H, m), 1.81-2.02(3H, m), 2.30(2H, d, J = 6.8

Hz), 2.42(4H, brs), 2.69(2H, t, J = 11.9 Hz), 3.43(2H, s),

3.43-3.65(6H, m), 3.68(3H, s), 5.94(2H, s), 6.46(1H, dd,

J = 8.7 Hz, 2.5 Hz), 6.54(1H, d, J = 2.3 Hz), 6.73-

6.76(3H, m), 6.85(1H, s), 6.93(1H, d, J = 8.6 Hz), 7.44-

7.57(3H, m), 7.79-7.83(3H, m).

922
4-CF₃Ph—
benzyl
1.37-1.44(2H, m), 1.81-2.02(3H, m), 2.29(2H, d, J = 6.8

Hz), 2.42-2.46(4H, m), 2.69(2H, t, J = 12.0 Hz), 3.48-

3.63(8H, m), 3.67(3H, s), 6.46(1H, dd, J = 8.7 Hz, 2.6

Hz), 6.54(1H, d, J = 2.6 Hz), 6.75(1H, d, J = 8.9 Hz),

6.92(1H, d, J = 8.7 Hz), 7.26-7.36(6H, m), 7.54(1H, dd,

J = 8.7 Hz, 2.8 Hz), 7.67(2H, d, J = 8.6 Hz), 7.75(1H, d,

J = 2.8 Hz), 7.83(2H, d, J = 8.1 Hz).

923
3,4-Cl₂Ph—
benzyl
1.37-1.44(2H, m), 1.81-2.02(3H, m), 2.30(2H, d, J = 6.8

Hz), 2.42-2.46(4H, m), 2.69(2H, t, J = 11.9 Hz), 3.50-

3.66(8H, m), 3.67(3H, s), 6.45(1H, dd, J = 8.7 Hz, 2.5

Hz), 6.54(1H, d, J = 2.5 Hz), 6.74(1H, d, J = 8.7 Hz),

6.93(1H, d, J = 8.6 Hz), 7.26-7.32(5H, m), 7.43-7.56(3H,

m), 7.79-7.83(3H, m).

TABLE 225

Example

No.
R₇₂₀

¹H NMR (CDCl₃) δppm

924
benzyl
1.63-1.77(2H, m), 1.81-1.98(2H, m), 2.44(4H, brs), 2.53-2.72 (3H, m),

3.53(4H, brs), 3.65-3.69(4H, m), 6.90-7.04(5H, m), 7.26-7.33(5H, m),

7.74(2H, d, J = 8.2 Hz), 7.99(2H, d, J = 8.2 Hz), 8.14-8.19(2H, m),

8.27(1H, d, J = 2.6 Hz).

925
piperonyl
1.64-1.77(2H, m), 1.89-1.97(2H, m), 2.39-2.41 (4H, m), 2.56-2.75(3H,

m), 3.43(2H, s), 3.52-3.69(6H, m), 5.94(2H, s), 6.70-6.77(2H, m), 6.85-

7.04(6H, m), 7.74(2H, d, J = 8.2 Hz), 7.99(2H, d, J = 8.2 Hz), 8.14-

8.18(2H, m), 8.27(1H, d, J = 2.5 Hz).

The following compounds were made in the same manner as in Reference Example 918.

TABLE 226

Example

No.
R₇₂₁
Xb₉
R₇₂₂
M

¹H NMR (CDCl₃) δppm

926
4-CF₃Ph—
—CH₂—
benzyl
1
2.38-2.44(4H, m), 2.63-2.68(2H, m), 2.89-

2.95(2H, m), 3.45-3.49(2H, m), 3.52(2H,

s), 3.64-3.68(2H, m), 6.85(1H, d, J = 8.9

Hz), 6.93-6.98(2H, m), 7.08-7.13 (2H, m),

7.28-7.36(5H, m), 7.44-7.51(4H, m), 7.96

(1H, d, J = 2.5 Hz), 8.00-8.04(1H, m),

8.14(1H, s), 8.18(1H, s).

927
3,4-Cl₂Ph—
—CH(CH₃)—
piperonyl
0
1.47(3H, d, J = 6.8 Hz), 2.00-2.15(1H, m),

2.25-2.50 (3H, m), 3.36(2H, s), 3.36-

3.80(4H, m), 3.98(1H, q, J = 6.8 Hz),

5.93(2H, s), 6.65-6.75(2H, m), 6.79(1H, d,

J = 1.2Hz), 6.89(1H, d, J = 8.8 Hz), 7.02-

7.06(2H, m), 7.16-7.33(4H, m), 7.57(1H, d,

J = 2.4 Hz), 7.91 (1H, d, J = 2.7 Hz),

8.00(1H, brs), 8.05-8.10(2H, m).

928
3,4-Cl₂Ph—
—C(CH₃)₂—
piperonyl
0
1.55(6H, s), 1.80-2.15(2H, m), 2.20-

2.55(2H, m), 2.95-3.20(2H, m), 3.31(2H,

s), 3.50-3.90(2H, m), 5.91(2H, s), 6.60-6.72

(2H, m), 6.76(1H, d, J = 1.3 Hz), 6.90(1H, d,

J = 8.9 Hz), 7.07-7.33(6H, m), 7.58 (1H, d,

J = 2.4 Hz), 7.88(1H, d, J = 2.7 Hz), 8.09-

8.11(2H, m), 8.17(1H, dd, J = 8.9 Hz, 2.8 Hz).

TABLE 227

Example

No.
R₇₂₃

¹H NMR (CDCl₃) δppm

929
benzyl
2.33-2.55 (4H, m), 3.36-3.79(6H, m), 6.89(1H, d, J = 8.7 Hz), 7.07-

7.15(3H, m), 7.24-7.38(6H, m), 7.67-7.70(2H, m), 8.00(2H, d, J = 7.9

Hz), 8.09-8.13(1H, m), 8.32(1H, d, J = 2.3 Hz), 9.05(1H, brs).

930
piperonyl
2.36-2.44(4H, m), 3.37-3.76(6H, m), 5.93(2H, s), 6.69-6.75(2H, m),

6.83(1H, brs), 6.86(1H, d, J = 8.7 Hz), 7.04-7.06(2H, m), 7.10-

7.14(1H, m), 7.27-7.36(1H, m), 7.65(2H, d, J = 8.4 Hz), 7.99(2H, d, J =

8.1 Hz), 8.07-8.12(1H, m), 8.34(1H, d, J = 2.6 Hz), 9.41(1H, s).

TABLE 228

Example

No.
R₇₂₄

¹H NMR (CDCl₃) δppm

931
4-CF₃PhCH₂N(SO₂CH₃)—
2.31-2.41(4H, m), 2.58-2.64(2H, m), 2.94-2.97 (2H, m),

2.99(3H, s), 3.38-3.41(4H, m), 3.60-3.65(2H, m),

4.85(2H, s), 5.94(2H, s), 6.65-6.75(2H, m), 6.83-

6.87(2H, m), 6.95-7.05(2H, m), 7.20-7.30(2H, m), 7.38-

7.41(2H, m), 7.52(1H, dd, J = 8.8 Hz, 2.8 Hz), 7.54-

7.57(2H, m), 8.04(1H, d, J = 2.3 Hz).

2.25-2.45(4H, m), 2.59-2.65(2H, m), 2.94-3.05 (5H, m),

932
3,4-Cl₂PhCH₂N(SO₂CH₃)—
3.30-3.45(4H, m), 3.55-3.70(2H, m), 4.74(2H, s),

5.95(2H, s), 6.65-6.80(2H, m), 6.84-6.89(2H, m), 7.02-

7.15(3H, m), 7.23-7.30(3H, m), 7.30-7.40(2H, m),

8.03(1H, d, J = 2.7 Hz).

933
3,4-Cl₂PhCH₂NHCO—
2.25-2.45(4H, m), 2.59-2.65(2H, m), 2.94-3.00(2H, m),

3.37-3.41(4H, m), 3.59-3.65(2H, m), 4.58(2H, d, J = 5.9

Hz), 5.94(2H, s), 6.50-6.65(1H, m), 6.65-6.80(2H, m),

6.84(1H, s), 6.94 (1H, d, J = 8.6 Hz), 7.03-7.06(2H, m),

7.17(1H, dd, J = 8.2 Hz, 2.0 Hz), 7.22-7.26(2H, m),

7.38-7.42(2H, m), 8.14(1H, dd, J = 8.6 Hz, 2.5 Hz),

8.57(1H, d, J = 2.3 Hz).

934
3,4-Cl₂PhNHCON(C₂H₅)—
1.17(3H, t, J = 7.1 Hz , 2.32-2.42 (4H, m), 2.61-

2.67(2H, m), 2.97-3.03(2H, m), 3.39-3.43(4H, m), 3.61-

3.65(2H, m), 3.74(2H, q, J = 7.1 Hz), 5.94(2H, s),

6.00(1H, brs), 6.70-6.85(3H, m), 7.05(1H, d, J = 8.7

Hz), 7.09-7.13(3H, m), 7.26-7.31(3H, m), 7.52(1H, d, J =

2.5 Hz), 7.61(1H, dd, J = 8.7 Hz, 2.8 Hz), 8.12(1H, d,

J = 2.4 Hz).

935
3,4-Cl₂PhN(CH₃)—
2.25-2.45(4H, m), 2.59-2.65(2H, m), 2.95-3.00(2H, m),

3.25(3H, s), 3.38-3.42(4H, m), 3.61-3.65(2H, m),

5.94(2H, s), 6.55-6.65(1H, m), 6.65-6.80(2H, m), 6.80-

6.85(2H, m), 6.89-6.93(1H, m), 7.06-7.10(2H, m), 7.20-

7.27(3H, m), 7.45-7.50(1H, m), 8.01(1H, d, J = 2.4 Hz).

936
3,4-Cl₂PhNH—
2.31-2.41(4H, m), 2.59-2.65(2H, m), 2.94-3.00(2H, m),

3.37-3.41(4H, m), 3.61-3.65(2H, m), 5.61(1H, brs),

5.94(2H, s), 6.69-6.80(3H, m), 6.84(1H, s), 6.90(1H, d ,

J = 8.7 Hz), 6.96(1H, d, J = 2.7 Hz), 7.04-7.07(2H, m),

7.21-7.25(3H, m), 7.49(1H, dd, J = 8.7 Hz, 2.9 Hz),

8.00(1H, d, J = 2.8 Hz).

937
4-CF₃PhCH₂NHCO—
2.31-2.40(4H, m), 2.59-2.65(2H, m), 2.95-3.01(2H, m),

3.38-3.41(4H, m), 3.60-3.64(2H,m), 4.70(2H, d, J = 5.8

Hz), 5.94(2H, s), 6.35-6.50(1H, m), 6.70-6.77(2H, m),

6.84(1H, s), 6.95 (1H, d, J = 8.6 Hz), 7.03-7.07(2H, m),

7.23-7.26(2H, m), 7.44-7.47(2H, m), 7.59-7.62(2H, m),

8.14(1H, dd, J = 8.6 Hz, 2.5 Hz), 8.57(1H, d, J = 2.4 Hz).

938
3,4-Cl₂PhN(C₂H₅)CONH—
1.17 (3H, t, J = 7.1 Hz), 2.30-2.40(4H, m), 2.57-

2.63(2H, m), 2.92-2.98(2H, m), 3.37-3.40(4H, m), 3.60-

3.64(2H, m), 3.77(2H, q, J = 7.1 Hz), 5.94(2H, s), 6.65-

6.80(2H, m), 6.81-6.85(2H, m), 6.98-7.00(2H, m), 7.17-

7.21(3H, m), 7.45(1H, d, J = 2.4 Hz), 7.57(1H, d, J =

8.5 Hz), 7.85-7.91(2H, m).

TABLE 229

Example

No.
R₇₂₅
R₇₂₆

¹H NMR (CDCl₃) δppm

939
3,4-Cl₂PhNHCO—
—CH₃
2.30-2.50(4H, m), 2.78(3H, s), 3.42(2H, s), 3.50-

3.65(4H, m), 3.82(2H, s), 5.95(2H, s), 6.65-

6.75(2H, m), 6.85(1H, s), 7.05(1H, d, J = 8.6

Hz), 7.26-7.30(1H, m), 7.39-7.43(2H, m), 7.49-

7.53(2H, m), 7.88(1H, d, J = 2.4 Hz), 8.24(1H,

dd, J = 8.6 Hz, 2.5 Hz), 8.31(1H, brs), 8.66(1H,

d, J = 2.4 Hz).

940
4-CF₃PhNHCO—
—CH₃
2.30-2.45(4H, m), 2.78(3H, s), 3.41(2H, s), 3.55-

3.59(4H, m), 3.82(2H, s), 5.94(2H, s), 6.65-

6.80(2H, m), 6.85(1H, s), 7.05(1H, d, J = 8.6

Hz), 7.26-7.30(1H, m), 7.41(1H, d, J = 2.8 Hz),

7.51(1H, d, J = 8.8 Hz), 7.59-7.63(2H, m), 7.77-

7.80(2H, m), 8.26(1H, dd, J = 8.6 Hz, 2.5 Hz),

8.54(1H, brs), 8.66(1 H, d, J = 2.2 Hz).

941
3,4-Cl₂PhCH₂NHCO—
—CH₃
2.30-2.45(4H, m), 2.80(3H, s), 3.42(2H, s), 3.50-

3.65(4H, m), 3.81(2H, s), 4.59(2H, d, J = 5.9

Hz), 5.95(2H, s), 6.50-6.60(1H, m), 6.65-

6.80(2H, m), 6.85(1H, s), 7.01(1H, d, J = 8.6

Hz), 7.18(1H, dd, J = 8.2 Hz, 2.0 Hz), 7.30(1H,

dd, J = 8.8 Hz, 2.7 Hz), 7.39-7.43(3H, m),

7.54(1H, d, J = 8.8 Hz), 8.18(1H, dd, J = 8.6 Hz,

2.5 Hz), 8.56(1H, d, J = 2.4 Hz).

942
4-CF₃PhCH₂NHCO—
—CH₃
2.30-2.45(4H, m), 2.80(3H, s), 3.42(2H, s), 3.50-

3.65(4H, m), 3.81(2H, s), 4.70(2H, d, J = 5.9

Hz), 5.94(2H, s), 6.50-6.65(1H, m), 6.70-

6.80(2H, m), 6.85(1H, s), 7.00(1H, d, J =8.6

Hz), 7.29(1H, dd, J = 8.8 Hz, 2.7 Hz), 7.39-

7.62(6H, m), 8.18(1H, dd, J = 8.6 Hz, 2.5 Hz),

8.57(1H, d, J = 2.4 Hz).

943
3,4-Cl₂PhN(CH₃)—
—C₂H₅
1.02(3H, t, J = 7.1 Hz), 2.35-2.40(4H, m),

3.22(2H, q, J = 7.1 Hz), 3.27(3H, s), 3.40(2H, s),

3.45-3.60(4H, m), 3.85(2H, s), 5.94(2H, s),

6.64(1H, dd, J = 8.9 Hz, 2.9 Hz), 6.65-6.75(2H,

m), 6.84(1H, s), 6.90(1H, d, J = 2.8 Hz),

6.96(1H, d, J = 8.7 Hz), 7.22-7.26(1H, m), 7.26-

7.35(1H, m), 7.42(1H, d, J = 2.8 Hz), 7.50(1H,

dd, J = 8.7 Hz, 2.9 Hz), 7.66(1H, d, J = 8.8 Hz),

8.00(1H, d, J = 2.6 Hz).

Example

No.
R₇₂₇
R₇₂₈
R₇₂₉
R₇₃₀
R₇₃₁
Xb₁₀

¹H NMR (CDCl₃) δppm

944
—Cl
—Cl
—CH₃
—CH₃
—H
—N(CH₃)—
2.30(6H, s), 2.32-2.45(4H, m),

2.83(3H, s), 3.30-3.45(4H, m), 3.55-

3.70(2H, m), 3.83(2H, s), 5.94(2H, s),

6.69-6.76(4H, m), 6.83(1H, s),

6.96(1H, d, J = 8.6 Hz), 7.40(1H, d, J =

8.7 Hz), 7.50(1H, dd, J = 8.8 Hz,

2.5 Hz), 7.87(1H, d, J = 2.4 Hz),

8.19(1H, dd, J = 8.6 Hz, 2.5 Hz),

8.31(1H, brs), 8.68(1H, d, J = 2.2

Hz).

945
—CF₃
—H
—CH₃
—CH₃
—H
—N(CH₃)—
2.30-2.45(10H, m), 2.86(3H, s), 3.30-

3.45(4H, m), 3.55-3.70(2H, m),

3.84(2H, s), 5.94(2H, s), 6.65-

6.78(4H, m), 6.84(1H, s), 6.99(1H, d,

J = 8.6 Hz), 7.60-7.65(2H, m), 7.70-

7.78(2H, m), 8.07(1H, brs), 8.21(1H,

dd, J = 8.6 Hz, 2.6 Hz), 8.70(1H, d, J =

2.5 Hz).

946
—CF₃
—H
—H
—H
—H
—CH(CH₃)—
1.30-1.36(3H, m), 2.10-2.40(4H, m),

2.47-2.67(2H, m), 3.25-3.45(5H, m),

3.50-3.65(2H, m), 5.93(2H, s), 6.65-

6.75(2H, m), 6.83(1H, d, J = 0.9 Hz),

7.01(1H, dd, J = 8.6 Hz, 0.6 Hz),

7.06-7.15(2H, m), 7.25-7.30 (2H, m),

7.60-7.64(2H, m), 7.74-7.78(2H, m),

8.14(1H, brs), 8.22(1H, dd, J = 8.6

Hz, 2.6 Hz), 8.67-8.68(1H, m).

947
—CF₃
—H
—H
—H
—CH₃
—CH₂—
1.14-1.17(3H, m), 1.95-2.10(1H, m),

2.15-2.45(3H, m), 2.55-2.70(1H, m),

2.85-3.05(2H, m), 3.15-3.45(4H, m),

3.45-3.70(2H, m), 5.92-5.94(2H, m),

6.65-6.85(3H, m), 6.95-7.06(3H, m),

7.10-7.30(2H, m), 7.59-7.63(2H, m),

7.75-7.79(2H, m), 8.24(1H, dd, J =

8.6 Hz, 2.6 Hz), 8.40(1H, brs),

8.71(1H, d, J = 2.4 Hz).

TABLE 231

Example

No.
R₇₃₂

¹H NMR (DMSO-d₆) δppm

948
—Br
2.20-2.35(4H, m), 2.59-2.65(2H, m), 2.79-2.85(2H, m), 3.20-3.60(6H,

m), 5.99(2H, s), 6.73-6.77(1H, m), 6.83-6.86(2H, m), 7.07-7.10(2H, m),

7.27-7.34(4H, m), 7.62-7.65(2H, m), 8.44-8.48(2H, m), 10.90(1H, brs).

949
—H
2.20-2.35(4H, m), 2.59-2.65(2H, m), 2.78-2.84(2H, m), 3.38-3.44(6H,

m), 5.98(2H, s), 6.72-6.76(1H, m), 6.82-6.86(2H, m), 7.04-7.08(2H, m),

7.17(1H, d, J = 8.8 Hz), 7.26-7.33(4H, m), 7.61-7.65(2H, m), 8.17(1H,

dd, J = 8.7 Hz, 2.6 Hz), 8.55(1H, d, J = 2.6 Hz), 10.98(1H, brs).

Example 950
Production of 3,4-dichloro-N-{6-[4-(4-phenethylpiperazine-1-carbonyl)phenoxy]pyridin-3-yl}benzamide

To a solution of ethyl 4-(5-aminopyridin-2-yloxy)benzoate (690 mg, 2.7 mmol) in THF (10 mL) were added triethylamine (0.73 mL, 5.3 mmol) and 3,4-dichlorobenzoyl chloride (570 mg, 2.7 mmol) under ice cooling, and the resulting solution was stirred for 1 hour under ice cooling. This reaction solution was concentrated under reduced pressure, and to the residue was added ethyl acetate. The resulting solution was washed with water, 1 N hydrochloric acid and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was washed, when hot, with n-hexane:dichloromethane=1:2. The product was dissolved in THF (20 mL). To the residue was added 1 N aqueous sodium hydroxide (2.9 mL, 2.9 mmol), and this solution was stirred for 5 hours at 100° C. THF was evaporated, and the aqueous layer was made to have a pH of 3 with 1 N hydrochloric acid. Precipitated matter was collected by filtration, and dried. The resulting product was dissolved in DMF (10 mL), and 1-phenethylpiperazine (200 mg, 1.1 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (240 mg, 1.3 mmol) and 1-hydroxybenzotriazole monohydrate (170 mg, 1.3 mmol) were added to the solution. The resulting solution was stirred for 1 day at room temperature. This reaction solution was concentrated under reduced pressure, and to the residue was added chloroform. The resulting solution was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (methanol:chloroform=1:99), to thereby yield 310 mg of the title compound.

Appearance: White Powder

¹H NMR (CDCl₃) δ 2.54 (4H, brs), 2.62-2.68 (2H, m), 2.79-2.85 (2H, m), 3.60-3.73 (4H, m), 6.95 (1H, d, J=8.9 Hz), 7.09-7.23 (5H, m), 7.27-7.33 (2H, m), 7.37-7.41 (2H, m), 7.55 (1H, d, J=8.3 Hz), 7.74-7.78 (1H, m), 8.04 (1H, d, J=2.0 Hz), 8.11-8.15 (1H, m), 8.31 (1H, d, J=2.6 Hz), 8.57 (1H, brs).

The following compounds were produced in the same manner as in Example 950.

TABLE 232

Example

No.
R₇₃₃
R₇₃₄
R₇₃₅
R₇₃₆
R₇₃₇
MS (M⁺ + H)

951
—CH₃
—F
—H
—H
4-CNPhCH₂—
550

952
—H
—F
—F
—H
4-CNPhCH₂—
554

953
—H
—Cl
—H
—Cl
4-CNPhCH₂—
586

954
—H
—OCF₃
—H
—H
4-CNPhCH₂—
602

955
—CH₃
—F
—H
—H
2-pyridylmethyl
526

956
—H
—CH₃
—CH₃
—H
2-pyridylmethyl
522

957
—H
—F
—F
—H
2-pyridylmethyl
530

958
—H
—Cl
—H
—Cl
2-pyridylmethyl
530

959
—H
—CF₃
—H
—H
2-pyridylmethyl
562

960
—H
—H
—Cl
—H
2-pyridylmethyl
528

961
—H
—CF₃
—H
—F
2-pyridylmethyl
580

962
—H
—OCF₃
—H
—H
2-pyridylmethyl
578

963
—CH₃
—F
—H
—H
3-pyridylmethyl
526

964
—H
—CH₃
—CH₃
—H
3-pyridylmethyl
522

965
—H
—F
—F
—H
3-pyridylmethyl
530

966
—H
—Cl
—H
—Cl
3-pyridylmethyl
562

967
—H
—CF₃
—H
—H
4-pyridylmethyl
562

968
—H
—H
—Cl
—H
3-pyridylmethyl
528

969
—H
—CF₃
—H
—F
3-pyridylmethyl
580

970
—CH₃
—F
—H
—H
4-pyridylmethyl
526

971
—H
—CH₃
—CH₃
—H
4-pyridylmethyl
522

972
—H
—F
—F
—H
4-pyridylmethyl
530

973
—H
—Cl
—H
—Cl
4-pyridylmethyl
562

974
—H
—CF₃
—H
—H
4-pyridylmethyl
562

975
—H
—H
—Cl
—H
4-pyridylmethyl
528

976
—H
—CF₃
—H
—F
4-pyridylmethyl
580

977
—H
—OCF₃
—H
—H
4-pyridylmethyl
578

978
—CH₃
—F
—H
—H
piperonyl
569

979
—H
—CH₃
—CH₃
—H
piperonyl
565

980
—H
—F
—F
—H
piperonyl
573

981
—H
—Cl
—H
—Cl
piperonyl
605

982
—H
—CF₃
—H
—H
piperonyl
605

983
—H
—CF₃
—H
—F
piperonyl
623

Example

No.
R₇₃₈
8₇₃₉
8₇₄₀
R₇₄₁
R₇₄₂
MS (M⁺ + H)

984
—H
—OCF₃
—H
—H
piperonyl
621

985
—H
—CH₃
—CH₃
—H
benzyl
521

986
—H
—F
—F
—H
benzyl
529

987
—CH₃
—F
—H
—H
4-AcNHPhCH₂—
582

988
—H
—CH₃
—CH₃
—H
4-AcNHPhCH₂—
578

989
—H
—F
—F
—H
4-AcNHPhCH₂—
586

990
—H
—Cl
—H
—Cl
4-AcNHPhCH₂—
618

991
—H
—CF₃
—H
—H
4-AcNHPhCH₂—
618

992
—H
—H
—Cl
—H
4-AcNHPhCH₂—
584

993
—H
—CF₃
—H
—F
4-AcNHPhCH₂—
636

994
—H
—OCF₃
—H
—H
4-AcNHPhCH₂—
634

995
—CH₃
—F
—H
—H
2,3-(CH₃)₂PhCH₂—
553

996
—H
—CH₃
—CH₃
—H
2,3-(CH₃)2PhCH₂—
549

997
—H
—F
—F
—H
2,3-(CH₃)₂PhCH₂—
557

998
—H
—Cl
—H
—Cl
2,3-(CH₃)₂PhCH₂—
589

999
—H
—CF₃
—H
—H
2,3-(CH₃)₂PhCH₂—
589

1000
—H
—H
—Cl
—H
2,3-(CH₃)₂PhCH₂—
555

1001
—H
—CF₃
—H
—H
2,3-(CH₃)₂PhCH₂—
607

1002
—H
—OCF₃
—H
—H
2,3-(CH₃)₂PhCH₂—
605

1003
—CH₃
—F
—H
—H
3-furylmethyl
515

1004
—H
—CH₃
—CH₃
—H
3-furylmethyl
511

1005
—H
—F
—F
—H
3-furylmethyl
519

1006
—H
—Cl
—H
—Cl
3-furylmethyl
551

1007
—H
—CF₃
—H
—H
3-furylmethyl
551

1008
—H
—H
—Cl
—H
3-furylmethyl
517

1009
—H
—Cl
—Cl
—H
3-furylmethyl
551

1010
—H
—CF₃
—H
—F
3-furylmethyl
569

1011
—H
—OCF₃
—H
—H
3-furylmethyl
567

1012
—CH₃
—F
—H
—H
3-pyridyl
512

1013
—H
—CH₃
—CH₃
—H
3-pyridyl
508

1014
—H
—F
—F
—H
3-pyridyl
516

1015
—H
—Cl
—H
—Cl
3-pyridyl
548

1016
—H
—CF₃
—H
—H
3-pyridyl
548

1017
—H
—CF₃
—H
—F
3-pyridyl
566

1018
—H
—OCF₃
—H
—H
3-pyridyl
564

TABLE 234

Example

No.
R₇₄₃
R₇₄₄
R₇₄₅
R₇₄₆
MS (M⁺ + H)

1019
—CH₃
—F
—H
—H
519

1020
—H
—CH₃
—CH₃
—H
515

1021
—H
—F
—F
—H
523

1022
—H
—Cl
—H
—Cl
555

1023
—H
—CF₃
—H
—H
555

1024
—H
—H
—Cl
—H
521

1025
—H
—Cl
—Cl
—H
555

1026
—H
—CF₃
—H
—F
573

1027
—H
—OCF₃
—H
—H
571

TABLE 235

Example

No.
R₇₄₇
MS (M⁺ + H)

1028
4-CNPhCH₂—
544

1029
2-pyridylmethyl
520

1030
3-pyridylmethyl
520

1031
4-pyridylmethyl
520

1032
4-AcNHPhCH₂—
576

1033
2,3-(CH₃)₂PhCH₂—
547

1034
3-furylmethyl
509

1035

embedded image

513

Example 1036
Production of 2-{3-methyl-4-[5-(4-trifluoromethylbenzoyl)pyridin-2-yloxy]phenylamino}-1-(4-piperonylpiperazin-1-yl)ethanone

To a solution of 2-chloro-5-(4-trifluoromethylbenzoyl)pyridine (1.00 g, 3.5 mmol) in DMF (30 mL) were added N-(4-hydroxy-3-methylphenyl)glycine ethyl ester (0.81 g, 3.9 mmol), cesium carbonate (1.71 g, 5.2 mmol) and copper (I) iodide (200 mg, 1.05 mmol), and the resulting solution was stirred for 3.5 hours at 60° C. under an argon atmosphere. The resulting reaction solution was filtered and concentrated. To the residue was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), to thereby yield 1.20 g of a yellow oil. The yellow oil was dissolved in THF (23 mL), and to the solution was added 1 M aqueous sodium hydroxide (3.9 mL, 3.9 mmol). The resulting solution was stirred for 3 hours at room temperature. This reaction solution was cooled with ice, and made to have a pH of 1 with 6 M hydrochloric acid. The resulting solution was extracted with ethyl acetate, and the ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, to thereby yield 1.04 g of a yellow oil. This yellow oil was dissolved in DMF (20 mL), and to the resulting solution were added 1-piperonylpiperazine (530 mg, 2.4 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (560 mg, 2.9 mmol) and 1-hydroxybenzotriazole monohydrate (390 mg, 2.6 mmol), and the resulting solution was stirred for 15 hours at room temperature. The reaction solution was concentrated under reduced pressure, and to the residue was added water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:2→ethyl acetate), to thereby yield 280 mg of a yellow oil. To this oil was added diethyl ether and left to stand. Precipitated matter was collected by filtration, to thereby yield 220 mg of the title compound.

Appearance: Yellow powder

¹H NMR (CDCl₃) δ 2.11 (3H, s), 2.43-2.48 (4H, m), 3.45-3.48 (4H, m), 3.67-3.71 (2H, m), 3.86 (2H, d, J=4.1 Hz), 4.90 (1H, t, J=4.1 Hz), 5.96 (2H, s), 6.49-6.53 (2H, m), 6.71-6.78 (2H, m), 6.86-6.97 (3H, m), 7.75 (2H, d, J=8.1 Hz), 7.87 (2H, d, J=8.1 Hz), 8.18 (1H, dd, J=8.7 Hz, 2.5 Hz), 8.58 (1H, d, J=2.1 Hz).

The following compound was produced in the same manner as in Example 1036.

Example 1037
6-(4-{[2-(4-Piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2,5-difluorophenoxy)-N-(4-trifluoromethylphenyl)nicotinamide hydrobromide

Melting point: 224.5-226.0° C.

Example 1038
Production of N-(6-{2-methyl-4-[methyl-(2-oxo-2-piperazin-1-ylethyl)amino]phenoxy}pyridin-3-yl)-3,4-dichlorobenzamide

To a solution of methyl{4-[5-(3,4-dichlorobenzoylamino)-pyridin-2-yloxy]-3-methylphenyl}aminoacetic acid (1.59 g, 3.5 mmol) in DMF (60 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.79 g, 4.1 ml), 1-hydroxybenzotriazole monohydrate (0.63 g, 4.1 mmol), and 1-t-butyloxycarbonylpiperazine (0.68 g, 3.6 mmol). The resulting solution was stirred for 15 hours at room temperature under a nitrogen atmosphere. Water was added to the solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and then the ethyl acetate layer was dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→3:2), to thereby yield an amide product. This amide product was dissolved in THF (20 mL). To the solution was then added 10% hydrochloric acid (10 mL), and the resulting solution was stirred for 14 hours at room temperature. To this reaction solution was added a saturated sodium bicarbonate solution to make the solution neutral, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=50:1→20:1), to thereby yield 0.38 g of the title compound.

Appearance: Colorless amorphous powder

¹H NMR (CDCl₃) δ 2.10 (3H, s), 2.75-2.94 (4H, m), 2.99 (3H, s), 3.40-3.70 (4H, m), 4.08 (2H, s), 6.46-6.59 (2H, m), 6.79 (1H, d, J=8.9 Hz), 6.89 (1H, d, J=8.6 Hz), 7.55 (1H, d, J=8.4 Hz), 7.71 (1H, dd, J=8.4 Hz, 2.1 Hz), 7.98 (1H, d, J=2.1 Hz), 8.03-8.14 (2H, m), 8.23 (1H, d, J=2.6 Hz).

Example 1039
Production of N-(6-{4-[3-(4-piperonylpiperazin-1-yl oxopropyl]phenoxy}pyridin-3-yl)-4-trifluoromethylbenzamide

To a solution of 3-[4-(5-aminopyridin-2-yloxy)phenyl]-1-(4-piperonylpiperazin-1-yl)propan-1-one trihydrochloride (200 mg, 0.35 mmol) in THF (4 mL) were added triethylamine (0.243 mL, 1.8 mmol) and 4-trifluoromethylbenzoyl chloride (0.055 mL, 0.37 mmol), and the resulting solution was stirred for 1 hour at room temperature. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate, evaporated, and the residue was recrystallized from diethyl ether, to thereby yield 170 mg of the title compound.

Appearance: White powder

Melting point: 140-141° C.

¹H NMR (CDCl₃) δ 2.32-2.40 (4H, m), 2.59-2.65 (2H, m), 2.93-2.99 (2H, m), 3.41 (4H, brs), 3.60-3.64 (2H, m), 5.94 (2H, s), 6.71-6.77 (2H, m), 6.85 (1H, s), 6.96 (1H, d, J=8.9 Hz), 7.05 (2H, d, J=8.4 Hz), 7.22 (2H, d, J=8.4 Hz), 7.76 (2H, d, J=8.4 Hz), 8.01 (2H, d, J=8.4 Hz), 8.11-8.14 (1H, m), 8.23 (1H, dd, J=8.9 Hz, 2.7 Hz), 8.28 (1H, d, J=2.7 Hz).

A crude titled product (77.4 g) obtained using the same procedures was recrystallized from ethyl acetate (400 mL), to thereby yield 49.66 g of the title compound.

Appearance: White powder; Melting point: 142-144° C.

The following compounds were produced in the same manner as in Example 1039.

TABLE 236

Example

No.
Xb₁₁
Xb₁₂
R₇₄₈
mp (°C) or ¹H NMR

1040

embedded image

—COOC(CH₃)₃
mp 197-199

1041

embedded image

—OCH₂OCH₃
mp 152-154

1042

embedded image

—COOC₂H₅
mp 189-190

1043

embedded image

—N(CH₃)COOC(CH₃)₃
mp 146-147

1044

embedded image

—COOC(CH₃)₃
mp 192-193

1045

embedded image

—OCH₂COOC₂H₅

¹H NMR (CDCl₃) δ 1.30(3H, t, J = 7.0 Hz), 1.75-1.81(2H, m), 2.03(2H, brs), 2.85-2.90(2H, m), 3.45-3.49(2H, m), 3.56(1H, m), 4.15(2H, s), 4.23(2H, q, J = 7.0 Hz), 6.90-6.95(6H, m), 7.50-7.53(3H, m), 7.69(1H, dd, J = 8.5 Hz, 2.0 Hz), 7.95(1H, d, J = 2.0 Hz), 8.04(1H, brs).

TABLE 237

Example

No.
R₇₄₉
R₇₅₀
R₇₅₁
Xb₁₃
M
Form
mp (° C.) or ¹H NMR

1046
—Cl
—Cl
—F
—N(Ac)—
1
free

¹H NMR (DMSO-d₆) δ 1.78(3H,

s), 2.22-2.38 (4H, m), 3.30-

3.50(6H, m), 4.41(2H, s),

5.98(2H, s), 6.74(1H, d, J = 8.1

Hz), 6.80-6.86(2H, m), 6.98(2H,

d, J = 8.8 Hz), 7.29(1H, t, J =

9.2 Hz), 7.38(2H, d, J = 8.8 Hz),

7.58(1H, d, J = 9.2 Hz),

7.84(1H, d, J = 8.4 Hz), 7.90-

7.96(2H, m), 8.21 (1H, d, J = 1.8

Hz), 10.61(1H, s).

1047
—Cl
—Cl
—F
—NH—
0
free
mp 224-228

1048
—Cl
—Cl
—F
—NH—
1
dihydrochloride
mp 174-1278

1049
—CF₃
—H
—H
—N(CH₃)—
1
free

¹H NMR (CDCl₃) δ 2.45(4H,

brs), 3.03(3H, s), 3.46(2H, s),

3.52(2H, brs), 3.64(2H, brs),

4.08 (2H, s), 5.95(2H, s),

6.67(2H, d, J = 9.1 Hz), 6.74-

6.78(2H, m), 6.87(1H, s), 6.92-

6.97(4H, m), 7.52(2H, d, J = 8.9

Hz), 7.74-7.81(3H, m), 7.98(2H,

d, J = 8.2 Hz).

1050
—Cl
—Cl
—H
—N(CH₃)—
1
free

¹H NMR (CDCl₃) δ 2.49(4H,

brs), 3.02(3H, s), 3.50(2H, s),

3.55(2H, brs), 3.66(2H, brs),

4.08 (2H, s), 5.96(2H, s),

6.67(2H, d, J = 9.1 Hz), 6.74-

6.78(2H, m), 6.88-6.96(5H, m),

7.50(2H, d, J = 8.9 Hz),

7.56(1H, d, J = 8.4 Hz),

7.70(1H, dd, J = 8.4 Hz, 2.1 Hz),

7.83(1H, s), 7.97(1H, d, J = 2.1

Hz).

1051
—Cl
—Cl
—F
—O—
1
hydrochloride

¹H NMR (DMSO-d₆) δ 2.83-

2.95(1H, m), 2.97-3.12(2H, m),

3.23-3.56(3H, m), 3.95-4.06 (1H,

m), 4.18-4.29(2H, m), 4.33-

4.44(1H, m), 4.75-4.92(2H, m),

6.07(2H, s), 6.90-6.96(4H, m),

6.97-7.04(2H, m), 7.11(1H, t, J =

9.1 Hz), 7.15-7.22(1H, m),

7.52(1H, d, J = 9.1 Hz), 7.84

(1H, d, J = 8.4 Hz), 7.88(1H, d,

J = 13.3 Hz), 7.94(1H, dd, J =

8.4 Hz, 1.9 Hz), 8.23(1H, d, J =

1.9 Hz), 10.60(1H, s), 11.10(1H,

brs).

TABLE 238

Example

No.
R₇₅₂
R₇₅₃
mp (° C.) or ¹H NMR (CDCl₃) δppm

1052
4-ClPh—
benzyl
mp 187-190

1053
3-ClPh—
benzyl

¹H NMR 2.38(4H, brs), 3.34-3.71(6H, m), 6.86(1H,

d, J = 8.8 Hz), 7.00-7.05(2H, m), 7.19-7.36(8H, m),

7.43-7.47(1H, m), 7.69-7.73(1H, m), 7.83(1H, t, J =

1.8 Hz), 8.08(1H, dd, J = 8.8 Hz, 2.8 Hz), 8.24(1H,

d, J = 2.6 Hz), 8.51(1H, brs).

1054
4-CH₃Ph—
4-CH₃OPhCH₂—

¹H NMR 2.32-2.50(7H, m), 3.44-3.79(9H, m), 6.84-

6.92(3H, m), 7.06-7.11(2H, m), 7.20-7.23(4H, m),

7.34-7.39(2H, m), 7.79(2H, d, J = 8.3 Hz), 8.16-

8.21(1H, m), 8.35(1H, d, J = 2.8 Hz), 8.76(1H, brs).

1055
2-naphthyl
4-CH₃OPhCH₂—

¹H NMR 2.41(4H, brs), 3.46-3.80(6H, m), 3.81(3H,

s), 6.83-6.90(2H, m), 6.95(1H, d, J = 8.7 Hz),

7.10(2H, d, J = 8.7 Hz), 7.22(2H, d, J = 8.6 Hz),

7.38(2H, d, J = 8.7 Hz), 7.52-7.63 (2H, m), 7.88-

7.97(4H, m), 8.27(1H, dd, J = 8.7 Hz, 2.8 Hz),

8.41-8.43(2H, m), 8.80(1H, brs).

1056
4-ClPh—
4-CH₃OPhCH₂—

¹H NMR 2.43(4H, brs), 3.48-3.77(6H, m), 3.80(3H,

s), 6.83-6.89(2H, m), 6.96(1H, d, J = 8.9 Hz), 7.10-

7.15(2H, m), 7.22(2H, d, J = 8.6 Hz), 7.38-7.48(4H,

m), 7.82-7.87(2H, m), 8.17-8.21(2H, m), 8.30(1H,

d, J = 2.6 Hz).

1057
3-ClPh—
4-CH₃OPhCH₂—

¹H NMR 2.41(4H, brs), 3.46-3.76(6H, m), 3.79(3H,

s), 6.83-6.89(3H, m), 7.05(2H, d, J = 8.4 Hz),

7.21 (2H, d, J = 8.6 Hz), 7.31-7.48(4H, m), 7.77(1H,

d, J = 7.8 Hz), 7.90(1H, s), 8.08-8.12(1H, m),

8.35(1H, d, J = 2.5 Hz), 9.26(1H, brs).

1058
4-CF₃OPh—
benzyl
mp 152-153

1059
2,4-Cl₂Ph—
benzyl
mp 196-197

1060
2,3-F₂Ph—
benzyl
mp 172-175

1061
4-ClPh—
piperonyl

¹H NMR 2.45(4H, brs), 3.45(2H, s), 3.45-3.75(4H,

m), 5.95(2H, s), 6.74-6.77(2H, m), 6.86(1H, s),

6.99(1H, d, J = 8.9 Hz), 7.14 (2H, d, J = 8.7 Hz),

7.42-7.51(4H, m), 7.84(2H, d, J = 8.7 Hz), 7.91(1H,

brs), 8.22(1H, dd, J = 8.7 Hz, 2.8 Hz), 8.29(1H, d,

J = 2.1 Hz)

1062
4-ClPh—
3-pyridyl

¹H NMR 3.24(4H, brs), 3.49-3.82(4H, m), 7.02(1H,

d, J = 8.7 Hz), 7.16-7.24(4H, m), 7.48(2H, d, J =

8.9 Hz), 7.49(2H, d, J = 8.7 Hz), 7.85(2H, d, J = 8.7

Hz), 8.04(1H, brs), 8.15-8.17(1H, m), 8.24(1H, dd,

J = 8.7 Hz, 2.8 Hz), 8.31-8.32(2H, m).

TABLE 239

Example

No.
R₇₅₄
R₇₅₅
Xb₁₄
Form
Property

1063
3-CF₃OPh—
benzyl
—CO—
maleate
mp 155-157° C.

1064
3,5-Cl₂Ph—
benzyl
—CO—
dihydrochloride

¹H NMR (DMSO-d₆) δ 3.15-

3.54(8H, m), 4.36(2H, s),

7.15-7.22(3H, m), 7.47-

7.60(7H, m), 7.90-7.91(1H,

m), 8.00(1H, s), 8.01(1H, s),

8.22-8.27(1H, m), 8.54(1H,

d, J = 2.2 Hz), 10.69(1H, s).

1065
PhCH═CH-(trans)
benzyl
—CO—
free
MS 518(M⁺)

1066
PhCH═CH-(trans)
piperonyl
—CO—
free

¹H NMR (CDCl₃) δ 2.45(4H,

brs), 3.44 (2H, s), 3.52(2H,

brs), 3.76(2H, brs), 5.95

(2H, s), 6.60(1H, d, J = 15.5

Hz), 6.74-6.77(2H, m),

6.85(1H, s), 6.95(1H, d, J =

8.7 Hz), 7.12(2H, d, J = 8.6

Hz), 7.38-7.45(5H, m), 7.53-

7.56(2H, m), 7.74 (1H, brs),

7.77(1H, d, J = 15.5 Hz),

8.21 (1H, d, J = 8.4 Hz),

8.25(1H, d, J = 2.5Hz).

1067
PhCH═CH-(trans)
3-pyridyl
—CO—
free

¹H NMR (CDCl₃) δ 3.20(4H,

brs), 3.79 (4H, brs),

6.67(1H, d, J = 15.7 Hz),

6.92 (1H, d, J = 8.7 Hz),

7.10-7.21(4H, m), 7.33-

7.46(7H, m), 7.73(1H, d, J =

15.7 Hz), 8.11-8.31(4H, m),

9.30(1H, s).

1068
3,4-Cl₂Ph—
benzyl
—SO₂—
hydrochloride
mp 253-256° C.

1069
4-CF₃Ph—
benzyl
—SO₂—
hydrochloride
mp 249-251° C.

TABLE 240

Example

No.
R₇₅₆
R₇₅₇
Xb₁₅
M

¹H NMR (solvent) δppm

1070
3,4-Cl₂Ph—
benzyl
—CH(OH)—
0
(CDCl₃) 1.95-2.15(1H, m), 2.15-2.40(3H,

m), 3.42 (2H, s), 3.49(4H, brs), 5.42(1H, d,

J = 6.6 Hz), 5.61 (1H, d, J = 6.6 Hz),

7.08(1H, d, J = 8.9 Hz), 7.09(2H, d, J = 8.6

Hz), 7.15-7.43(5H, m), 7.38(2H, d, J = 8.6

Hz), 7.85(1H, d, J = 8.4 Hz), 7.95(1H, dd, J =

8.4 Hz, 2.0 Hz), 8.20(1H, dd, J = 8.9 Hz,

2.7 Hz), 8.23(1H, d, J = 2.3 Hz), 8.50(1H,

d, J = 2.7 Hz), 10.57(1H, s).

1071
4-CF₃Ph—
benzyl
—CH(OH)—
0
(CDCl₃) 1.90-2.05(1H, m), 2.22-2.57(3H,

m), 3.10-3.40(2H, m), 3.44(2H, s), 3.58-

3.85(2H, m), 4.75(1H, d, J = 6.4 Hz),

5.21(1H, d, J = 6.4 Hz), 6.96 (1H, d, J = 8.9

Hz), 7.12(2H, d, J = 8.6 Hz), 7.20-7.38 (5H,

m), 7.32(2H, d, J = 8.6 Hz), 7.78(2H, d, J =

8.1 Hz), 7.92(1H, brs), 8.00(2H, d, J = 8.1

Hz), 8.22(1H, dd, J = 8.9 Hz, 2.5 Hz),

8.29(1H, d, J = 2.5 Hz).

1072
4-CF₃Ph—
piperonyl
—O—
1
(DMSO-d₆) 2.32(2H, brs), 2.40(2H, brs),

3.41(2H, s), 3.46(4H, brs), 4.81(2H, s),

5.99(2H, s), 6.73-6.88(3H, m), 6.94(2H, d, J =

9.2 Hz), 7.02(1H, d, J = 8.7 Hz), 7.05(2H,

d, J = 9.2 Hz), 7.93(2H, d, J = 8.4 Hz), 8.16

(2H, d, J = 8.4 Hz), 8.19(1H, dd, J = 8.7

Hz, 2.7 Hz), 8.47(1H, d, J = 2.7 Hz),

10.60(1H, s).

1073
4-CF₃Ph—
benzyl
—O—
1
(CDCl₃) 2.35-2.53(4H, m), 3.51(2H, s),

3.56(2H, t, J = 5.0 Hz), 3.62(2H, t, J = 5.0

Hz), 4.64(2H, s), 6.90 (1H, d, J = 8.8 Hz),

6.92(2H, d, J = 9.0 Hz), 7.04(2H, d, J = 9.0

Hz), 7.21-7.41(5H, m), 7.73(2H, d, J = 8.1

Hz), 8.00(2H, d, J = 8.1 Hz), 8.18(1H, dd, J =

8.8 Hz, 2.6 Hz), 8.27(1H, d, J = 2.6 Hz),

8.32(1H, brs).

1074
3-ClPh—
piperonyl
none
2
(CDCl₃) 2.31-2.38(4H, m), 2.58-2.64(2H,

m), 2.90-2.96(2H, m), 3.37-3.40(4H, m),

3.59-3.62(2H, m), 5.94(2H, s), 6.70-

6.77(2H, m), 6.84(1H, s), 6.92 (1H, d, J =

8.9 Hz), 7.03(2H, d, J = 8.4 Hz), 7.20(2H,

d, J = 8.4 Hz), 7.38-7.44(1H, m), 7.50-

7.54(1H, m), 7.77(1H, d, J = 7.8 Hz), 7.87-

7.88(1H, m), 8.21(1H, dd, J = 8.9 Hz, 2.7

Hz), 8.28(1H, d, J = 2.7 Hz), 8.36 (1H, s).

TABLE 241

Example

No.
R₇₅₈
mp (° C.) or ¹H NMR

1075
3-ClPh—

¹H NMR (CDCl₃) δ 2.33-2.38(4H, m), 2.55-2.61(2H, m), 2.86-

2.91(2H, m), 3.37-3.41(2H, m), 3.49(2H, s), 3.56-3.60(2H, m),

6.87(1H, d, J = 8.9 Hz), 6.97-7.01(2H, m), 7.14(2H, d, J = 8.6 Hz),

7.25-7.37(6H, m), 7.45-7.48(1H, m), 7.75-7.79(1H, m), 7.87(1H, t, J =

1.8 Hz), 8.18(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.32 (1H, d, J = 2.8 Hz),

9.06(1H, brs).

1076
4-ClPh—
mp 136-139

1077
2-ClPh—

¹H NMR (CDCl₃) δ 2.32-2.41(4H, m), 2.56-2.61(2H, m), 2.90-

2.96(2H, m), 3.37-3.41(2H, m), 3.50(2H, s), 3.58-3.61(2H, m),

6.92(1H, d, J = 8.7 Hz), 7.03 (2H, d, J = 8.4 Hz), 7.19-7.43(10H, m),

7.69-7.72(1H, m), 8.21-8.27(3H, m).

1078
Ph—

¹H NMR (CDCl₃) δ 2.36(4H, brs), 2.56-2.61(2H, m), 2.89-2.95(2H,

m), 3.36-3.41(2H, m), 3.49(2H, s), 3.58-3.62(2H, m), 6.99(1H, d, J =

8.7 Hz), 7.01 (2H, d, J = 8.1 Hz), 7.18(2H, d, J = 8.1 Hz), 7.26-

7.55(8H, m), 7.87(2H, d, J = 6.6 Hz), 8.20(1H, d, J = 8.7 Hz),

8.28(1H, brs), 8.50(1H, brs).

1079
4-CNPh—

¹H NMR (CDCl₃) δ 2.33-2.41(4H, m), 2.56-2.62(2H, m), 2.87-

2.92(2H, m), 3.38-3.42(2H, m), 3.50(2H, s), 3.56-3.60(2H, m),

6.91(1H, d, J = 8.9 Hz). 6.98-7.01(2H, m), 7.14-7.19(2H, m), 7.25-

7.35(5H, m), 7.71-7.75(2H, m), 7.99-8.02(2H, m), 8.17-8.29(2H, m),

8.75-8.97(1H, m).

1080
3-CH₃OPh—

¹H NMR (CDCl₃) δ 2.33-2.41(4H, m), 2.56-2.62(2H, m), 2.90-

2.95(2H, m), 3.38-3.42(2H, m), 3.51(2H, s), 3.60-3.63(2H, m),

3.83(3H, s), 6.90(1H, d, J = 8.7 Hz), 7.00-7.09(3H, m), 7.18(2H, d, J =

8.6 Hz), 7.26-7.44(8H, m), 8.19-8.23(1H, m), 8.29(1H, d, J = 2.8

Hz), 8.48(1H, brs).

1081
4-CH₃Ph—

¹H NMR (CDCl₃) δ 2.33-2.40(7H, m), 2.56-2.62(2H, m), 2.90

2.95(2H, m), 3.38-3.41(2H, m), 3.49(2H, s), 3.59-3.62(2H, m),

6.89(1H, d. J = 8.7 Hz), 7.01 (2H, d, J = 8.6 Hz), 7.16-7.32(9H, m),

7.78(2H, d, J = 8.2 Hz), 8.18-8.22(1H, m), 8.27(1H, d, J = 2.6 Hz),

8.33-8.44(1H, m).

1082
2-CH₃Ph—

¹H NMR (CDCl₃) δ 2.32-2.40(4H, m), 2.48(3H, s), 2.55-2.60(2H, m),

2.89-2.95 (2H, m), 3.37-3.40(2H, m), 3.50(2H, s), 3.57-3.60(2H, m),

6.89-6.92(1H, m), 7.00-7.05(2H, m), 7.18-7.47(10H, m), 7.45(1H, d,

J = 2.2 Hz), 8.04(1H, brs), 8.23-8.25(2H, m).

1083
4-CH₃OPh—

¹H NMR (CDCl₃) δ 2.31-2.38(4H, m), 2.54-2.60(2H, m), 2.87-

2.93(2H, m), 3.37-3.40(2H, m), 3.48(2H, s), 3.58-3.61(2H, m),

3.82(3H, s), 6.84-6.90(3H, m), 6.99(2H, d, J = 8.4 Hz), 7.15(2H, d, J =

8.6 Hz), 7.25-7.32(5H, m), 7.85(2H, d, J = 8.9 Hz), 8.17(1H, dd, J =

8.9 Hz, 2.7 Hz), 8.28(1H, d, J = 2.7 Hz). 8.73(1H, brs).

1084
2-CH₃OPh—

¹H NMR (CDCl₃) δ 2.33-2.42(4H, m), 2.58-2.64(2H, m), 2.93-

2.99(2H, m), 3.38-3.42(2H, m), 3.49(2H, s), 3.61-3.65(2H, m),

4.02(3H, s), 6.89-6.92(1H, m), 7.01-7.32(11H, m), 7.47-7.53(1H, m),

8.23-8.29(3H, m), 9.76(1H, s).

1085
2-naphthyl
mp 156-159

1086
4-CF₃Ph—

¹H NMR (DMSO-d₆) δ 2.30-2.32(4H, m), 2.59-2.65(2H, m), 2.79-

2.84(2H, m), 3.44-3.47(6H, m), 7.02(2H, d, J = 8.6 Hz), 7.05(1H, d,

J = 9.1 Hz), 7.25-7.35(7H, m), 7.93(2H, d, J = 8.3 Hz), 8.16(2H, d, J =

8.3 Hz), 8.21(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.49(1H, d, J = 2.6 Hz).

10.62(1H, brs).

TABLE 242

Example

No.
R₇₅₉
R₇₆₀
Form
mp (° C.) or ¹H NMR

1087
4-CF₃OPh—
benzyl
maleate
mp 144-146

1088
3-CF₃OPh—
benzyl
maleate
mp 125-128

1089
4-CF₃OPh—
piperonyl
free
mp 187-190

1090
2-CF₃OPh—
piperonyl
free

¹H NMR (CDCl₃) δ 2.31-2.39(4H, m), 2.57-

2.63(2H, m), 2.91-2.97(2H, m), 3.37-

3.40(4H, m), 3.58-3.62(2H, m), 5.93(2H, s),

6.70-6.76(2H, m), 6.84(1H, s), 6.93(1H, d, J =

8.9 Hz), 7.03-7.07(2H, m), 7.19-7.23(2H,

m), 7.32-7.36(1H, m), 7.40-7.46(1H, m),

7.53-7.59(1H, m), 7.99-8.03(1H, m),

8.20(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.27 (1H, d,

J = 2.7 Hz), 8.55(1H, brs).

1091
3-CF₃OPh—
piperonyl
free

¹H NMR (CDCl₃) δ 2.30-2.36(4H, m), 2.55-

2.61(2H, m), 2.86-2.92(2H, m), 3.37-

3.40(4H, m), 3.56-3.60(2H, m), 5.93(2H, s),

6.69-6.76(2H, m), 6.83(1H, s), 6.88-6.92 (1H,

m), 6.98-7.02(2H, m), 7.14-7.18(2H, m),

7.36-7.40 (1H, m), 7.44-7.52(1H, m), 7.78-

7.85(2H, m), 8.19(1H, dd, J = 8.9 Hz, 2.7

Hz), 8.29-8.31(1H, m), 8.78-8.92(1H, m).

1092
3,5-Cl₂Ph—
piperonyl
dihydrochloride

¹H NMR (DMSO-d₆) δ 2.69-3.33(10H, m),

3.99-4.11 (1H, m), 4.23(2H, s), 4.44-4.49(1H,

m), 6.07(2H, s), 6.97-7.07(5H, m), 7.20-

7.30(3H, m), 7.89-8.00(1H, m), 8.00(2H, d, J =

1.8 Hz), 8.19(1H, dd, J = 8.9 Hz, 2.6 Hz),

8.48(1H, d, J = 2.3 Hz), 10.64(1H, s).

1093
PhCH═CH-(trans)
piperonyl
free

¹H NMR (CDCl₃) δ 2.05-3.38(9H, m), 3.69-

4.71(5H, m), 5.96(2H, s), 6.72-6.79(2H, m),

6.95-7.05(4H, m), 7.13-7.23(3H, m), 7.35-

7.37(3H, m), 7.51-7.54(2H, m), 7.70-

7.76(1H, m), 8.41(1H, d, J = 2.3 Hz),

8.50(1H, d, J = 8.7 Hz), 8.95(1H, brs).

1094
2-naphthyl
piperonyl
free

¹H NMR (CDCl₃) δ 2.28-2.34(4H, m), 2.55-

2.61(2H, m), 2.89-2.95(2H, m), 3.38(4H,

brs), 3.58(2H, brs), 5.92 (2H, s), 6.69-

6.76(2H, m), 6.83(1H, s), 6.92(1H, d, J = 8.6

Hz), 7.02(2H, d, J = 8.4 Hz), 7.18(2H, d, J =

8.4 Hz), 7.51-7.61(2H, m), 7.86-7.94(4H, m),

8.27(1H, dd, J = 8.6 Hz, 2.7 Hz), 8.33-

8.38(2H, m), 8.55(1H, brs).

1095
4-ClPh—
piperonyl
free

¹H NMR (CDCl₃) δ 2.31-2.41(4H, m), 2.59-

2.65(2H, m), 2.94-3.00(2H, m), 3.38-

3.41(4H, m), 3.63(2H, brs), 5.94(2H, s), 6.71-

6.77(2H, m), 6.85(1H, s), 6.95(1H, d, J = 8.9

Hz), 7.05(2H, d, J = 8.4 Hz), 7.23(2H, d, J =

8.4 Hz), 7.48(2H, d, J = 8.6 Hz), 7.82-

7.89(3H, m), 8.19-8.25 (2H, m).

TABLE 243

Example

No.
R₇₆₁
R₇₆₂
R₇₆₃
R₇₆₄
R₇₆₅

¹H NMR (CDCl₃) δppm

1096
4-CF₃Ph—
—H
—H
—OH
—COOC(CH₃)₃
1.44(9H, s), 2.82-3.00(2H, m),

3.00-3.80 (9H, m), 4.60(1H, t, J =

6.5 Hz), 6.97(1H, d, J = 8.8 Hz),

7.06(2H, d, J = 8.6 Hz), 7.24 (2H,

d, J = 8.6 Hz), 7.75(2H, d, J = 8.1

Hz), 8.00(2H, d, J = 8.1 Hz),

8.07(1H, brs), 8.18 (1H, d, J = 2.6

Hz), 8.27(1H, dd, J = 8.8 Hz, 2.6

Hz).

1097
4-CF₃Ph—
—H
—CH₃
—H
piperonyl
2.32(3H, s), 2.32-2.40(4H, m),

2.59-2.64 (2H, m), 2.93-2.98(2H,

m), 3.30-3.45(4H, m), 3.55-

3.70(2H, m), 5.94(2H, s), 6.65-

6.75(2H, m), 6.82-6.84(2H, m),

7.03-7.07(2H, m), 7.20-7.24(2H,

m), 7.72(1H, brs), 7.75-7.79(2H,

m), 8.00-8.04(2H, m), 8.30(1H, s).

1098
4-CF₃Ph—
—CH₃
—H
—H
piperonyl
2.31-2.40(4H, m), 2.47(3H, s),

2.59-2.65(2H, m), 2.94-3.00(2H,

m), 3.38-3.41(4H, m), 3.60-

3.65(2H, m), 5.94(2H, s), 6.68-

6.77(3H, m), 6.84(1H, s), 7.04-

7.08(2H, m), 7.20-7.24(2H, m),

7.63(1H, brs), 7.77-7.80(2H, m),

7.99-8.11(3H, m).

1099
3,4-Cl₂Ph—
—CH₃
—H
—H
piperonyl
2.25-2.40(4H, m), 2.45(3H, s),

2.58-2.64(2H, m), 2.92-2.98(2H,

m), 3.38-3.41(4H, m), 3.60-

3.64(2H, m), 5.94(2H, s), 6.66-

6.76(3H, m), 6.84(1H, s), 7.03-

7.07(2H, m), 7.18-7.22(2H, m),

7.59(1H, d, J = 8.3 Hz), 7.67(1H,

brs), 7.72(1H, dd, J = 8.4 Hz, 2.0

Hz), 7.98-8.02(2H, m).

1100
3,4-Cl₂Ph—
—H
—CH₃
—H
piperonyl
2.31(3H, s), 2.31-2.40(4H, m),

2.58-2.64(2H, m), 2.92-2.98(2H,

m), 3.37-3.41(4H, m), 3.60-

3.64(2H, m), 5.94(2H, s), 6.65-

6.75(2H, m), 6.80-6.84(2H, m),

7.03-7.06(2H, m), 7.20-7.24(2H,

m), 7.58(1H, d, J = 8.3 Hz),

7.64(1H, brs), 7.73(1H, dd, J =

8.3 Hz, 1.8 Hz), 8.01(1H, d, J =

1.9 Hz), 8.26(1H, s).

TABLE 244

Example

No.
R₇₆₆
R₇₆₇
R₇₆₈
R₇₆₉
mp (° C.) or ¹H NMR (solvent) δppm

1101
4-CF₃Ph—
—H
—H
—Ac
mp 189-191

1102
3,4-Cl₂Ph—
—H
—H
—COC₂H₅
mp 204-206

1103
3,4-Cl₂Ph—
—H
—H
—H
mp 188-189

1104
3,4-Cl₂Ph—
—H
—H

embedded image

¹H NMR (DMSO-d₆) 0.60-0.70(2H, m), 0.75- 0.80 (2H, m), 1.42(1H, m), 2.25-2.35(4H, m), 3.35-3.45(6H, m), 4.49(2H, s), 5.98(2H, s), 6.74(1H, d, J = 7.9 Hz), 6.84(1H, d, J = 7.9 Hz), 6.86(1H, s), 7.12(1H, d, J = 8.8 Hz), 7.18(2H, d, J = 8.6 Hz), 7.47(2H, d, J = 8.6 Hz), 7.84(1H, d, J = 8.4 Hz), 7.95(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.20-8.23(2H, m), 8.51(1H, d, J = 2.5 Hz), 10.58(1H, s).

1105
4-CF₃Ph—
—H
—H
—CH₃
H NMR (DMSO-d₆) 2.31-2.39(4H, m),

2.94(3H, s), 3.31(2H, s), 3.42(4H, brs),

4.24(2H, s), 5.99(2H, s), 6.64 (2H, d, J = 9.1

Hz), 6.76(1H, dd, J = 7.9 Hz, 1.2 Hz), 6.84-

6.96(5H, m), 7.93(2H, d, J = 8.3 Hz),

8.13(1H, s), 8.16(2H, d, J = 8.6 Hz), 8.45(1H,

d, J = 2.5 Hz), 10.58(1H, s).

1106
3,4-Cl₂Ph—
—H
—H

embedded image

¹H NMR (CDCl₃) 0.57-0.62(2H, m), 0.75- 0.82(2H, m), 2.37-2.49(4H, m), 2.70-2.74(1H, m), 3.45(2H, s), 3.49-3.59(4H, m), 4.17(2H, s), 5.95(2H, s), 6.74-6.94 (8H, m), 7.49(1H, d, J = 8.2 Hz), 7.67-7.71(1H, m), 7.95 (1H, d, J = 2.1 Hz), 8.00(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.24 (1H, d, J = 2.6 Hz), 8.59(1H, brs).

1107
4-CF₃Ph—
—H
—H

embedded image

¹H NMR (CDCl₃) 0.57-0.62(2H, m), 0.74- 0.81(2H, m), 2.35-2.47(4H, m), 2.66-2.74(1H, m), 3.44(2H, s), 3.47-3.57(4H, m), 4.16(2H, s), 5.94(2H, s), 6.70-6.94 (8H, m), 7.66(2H, d, J = 8.2 Hz), 7.95(2H, d, J = 8.0 Hz), 8.04(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.25(1H, d, J = 2.6 Hz), 8.80(1H, s).

1108
4-CF₃Ph—
—CH₃
—CH₃
—CH₃

¹H NMR (CDCl₃) 2.09(3H, s), 2.26(3H, s),

2.39(4H, brs), 2.67(3H, s), 3.41(2H, s), 3.53-

3.63(4H, m), 3.74(2H, s), 5.94(2H, s), 6.71-

6.77(2H, m), 6.85-6.90(3H, m), 6.98 (1H, d, J =

8.7 Hz), 7.75(2H, d, J = 8.2 Hz), 7.98-8.01

(3H, m), 8.18(1H, dd, J = 8.9 Hz, 2.8 Hz),

8.25(1H, d, J = 2.3 Hz).

1109
3,4-Cl₂Ph—
—CH₃
—CH₃
—CH₃

¹H NMR (CDCl₃) 2.09(3H, s), 2.25(3H, s),

2.37-2.40 (4H, m), 2.66(3H, s), 3.41(2H, s),

3.53-3.63(4H, m), 3.73 (2H, s), 5.94(2H, s),

6.70-6.77(2H, m), 6.84-6.89(3H, m), 6.96(1H,

d, J = 8.7 Hz), 7.56(1H, d, J = 8.2 Hz), 7.70-

7.74(1H, m), 7.99(1H, d, J = 2.0 Hz), 8.10-

8.16(2H, m), 8.24(1H, d, J = 2.8 Hz).

TABLE 245

Example

No.
R₇₇₀
R₇₇₁
R₇₇₂
Form
mp (° C.) or ¹H NMR (solvent) δppm

1110
4-CF₃Ph—
—OCH₃
—C₂H₅
free
mp 142.6-146.5

1111
4-CF₃Ph—
—CH₃
—C₂H₅
hydrochloride
mp 173-175 dec

1112
3,4-Cl₂Ph—
—CH₃
—C₂H₅
hydrochloride
mp 168.5-171.0

1113
2,3-Cl₂Ph—
—CH₃
—CH₃
free

¹H NMR (CDCl₃) 2.12(3H, s), 2.41-2.45(4H,

m), 3.01(3H, s), 3.43(2H, s), 3.50(2H, brs),

3.63(2H, brs), 4.07(2H, s), 5.95(2H, s), 6.52-

6.58(2H, m), 6.71-6.77 (2H, m), 6.81-

6.93(3H, m), 7.32(1H, t, J = 7.8 Hz), 7.56-

7.61(2H, m), 7.68(1H, brs), 8.16(1H, dd, J =

8.7 Hz, 2.8 Hz), 8.20(1H, d, J = 2.2 Hz).

1114
3,4-Cl₂Ph—
—OCH₃
—H
free

¹H NMR (DMSO-d₆) 2.32-2.40(4H, m),

3.42(2H, s), 3.51(4H, brs), 3.63(3H, s),

3.91(2H, d, J = 4.8 Hz), 5.54 (1H, t, J = 4.8

Hz), 5.99(2H, s), 6.21(1H, dd, J = 8.6 Hz, 2.5

Hz), 6.50(1H, d, J = 2.5 Hz), 6.76(1H, dd, J =

7.9 Hz, 1.5 Hz), 6.82-6.88(4H, m),

7.82(1H, d, J = 8.4 Hz), 7.94(1H, dd, J = 8.4

Hz, 2.0 Hz), 8.07(1H, dd, J = 8.9 Hz, 2.6

Hz), 8.21(1H, d, J = 2.2 Hz), 8.37(1H, d, J =

2.5 Hz), 10.44(1H, s).

1115
4-CF₃Ph—
—OCH₃
—H
free

¹H NMR (CDCl₃) 2.32-2.40(4H, m), 3.42(2H,

s), 3.50(4H, brs), 3.63(3H, s), 3.91(2H, d, J =

4.6 Hz), 5.55 (1H, brt), 5.99(2H, s), 6.20(1H,

dd, J = 8.6 Hz, 2.5 Hz), 6.49(1H, d, J = 2.3

Hz), 6.74-6.88(5H, m), 7.92(2H, d, J = 8.4

Hz), 8.07-8.17(3H, m), 8.38(1H, d, J = 2.3

Hz), 10.53(1H, s).

1116
4-CF₃Ph—
—CH₃

embedded image

free

¹H NMR (CDCl₃) 0.59-0.64(2H, m), 0.76- 0.82(2H, m), 2.08(3H, s), 2.37-2.47(4H, m), 2.69-2.77(1H, m), 3.44 (2H, s), 3.48-3.59(4H, m), 4.16(2H, s), 5.94(2H, s), 6.67-6.77(5H, m), 6.86(2H, d, J = 8.6 Hz), 7.70(2H, d, J = 8.2 Hz), 7.97(2H, d, J = 8.1 Hz), 8.08(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.23(1H, d, J = 2.8 Hz), 8.39(1H, brs).

1117
3,4-Cl₂Ph—
—CH₃

embedded image

free

¹H NMR (CDCl₃) 0.59-0.65(2H, m), 0.76- 0.83(2H, m), 2.08(3H, s), 2.38-2.48(4H, m), 2.71-2.78(1H, m), 3.44(2H, s), 3.49-3.59 (4H, m), 4.17(2H, s), 5.95(2H, s), 6.67-6.77 (5H, m), 6.85-6.88(2H, m), 7.53(1H, d, J = 8.2 Hz), 7.68-7.72(1H, m), 7.96(1H, d, J = 2.0 Hz), 8.02-8.07(1H, m), 8.22-8.26(2H, m).

1118

embedded image

—CH₃
—CH₃
free

¹H NMR (CDCl₃) 0.83-0.85(2H, m), 1.07- 1.08(2H, m), 1.46-1.63(1H, m), 2.10(3H, s), 2.41-2.44(4H, m), 3.00(3H, s), 3.43(2H, s), 3.47-3.49(2H, m), 3.63(2H, brs), 4.06(2H, s), 5.94(2H, s), 6.51-6.55(2H, m), 6.70-6.77(3H, m), 6.85(1H, brs), 6.89(1H, d, J = 8.4 Hz), 7.44-7.64(1H, m), 8.01-8.04(1H, m), 8.08(1H, d, J = 2.3 Hz).

TABLE 246

Example

No.
R₇₇₃
R₇₇₄
R₇₇₅
Form

¹H NMR (solvent) δppm

1119

embedded image

—CH₃
—CH₃
hydrochloride
(DMSO-d₆) 2.01(3H, s), 2.80-3.18(3H, m), 2.93 (3H, s), 3.35(2H, s), 3.38- 3.62(1H, m), 3.95-4.50 (4H, m), 4.27(2H, s), 6.08(2H, s), 6.49(1H, dd, J = 8.7 Hz, 2.7 Hz), 6.58(1H, d, J = 2.7 Hz), 6.83(1H, d, J = 8.7 Hz), 6.92(1H, d, J = 8.9 Hz), 7.02(2H, s), 7.21(1H, s), 7.74(1H, d, J = 8.4 Hz), 7.90(1H, d, J = 8.4 Hz), 7.88-7.95(1H, m), 8.11(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.36(1H, d, J = 2.7 Hz), 10.71(1H, s).

1120

embedded image

—CH₃
—CH₃
free
(CDCl₃) 2.11(3H, s), 2.42(4H, brs), 3.00(3H, s), 3.43(2H, s), 3.47-3.49(2H, m), 3.63(2H, brs), 4.07(2H, s), 5.95(2H, s), 6.01(2H, s), 6.37(1H, d, J = 15.2 Hz), 6.52-6.56(2H, m), 6.74-6.85(5H, m), 6.91(1H, d, J = 8.6 Hz), 7.00- 7.02(2H, m), 7.49(1H, brs), 7.65(1H, d, J = 15.3 Hz), 8.16-8.17(2H, m).

1121

embedded image

—CH₃
—CH₃
free
(CDCl₃) 2.09(3H, s), 2.42-2.43(4H, m), 3.00(3H, s), 3.43(2H, s), 3.47-3.50(2H, m), 3.63(2H, brs), 4.08(2H, s), 5.95(2H, s), 6.49-6.61(3H, m), 6.70-6.91(6H, m), 7.01-7.03(2H, m), 7.63(1H, d, J = 15.3 Hz), 7.93(1H, brs), 8.16-8.19(2H, m).

1122

embedded image

—CH₃
—CH₃
free
(CDCl₃) 2.17(3H, s), 2.43(4H, brs), 2.82(3H, s), 3.01(3H, s), 3.44(2H, s), 3.50(2H, brs), 3.63(2H, brs), 4.08(2H, s), 5.95(2H, s), 6.53-6.57(2H, m), 6.74(2H, brs), 6.81(1H, d, J = 8.9 Hz), 6.85(1H, s), 6.92(1H, d, J = 8.6 Hz), 7.52(1H, brs), 7.73 (2H, d, J = 8.3 Hz), 8.04-8.09(3H, m), 8.18(1H, d, J = 2.8 Hz).

1123
4-CF₃Ph—
—F
allyl
free
(CDCl₃) 2.45(4H, brs), 3.45(2H, s),

3.45(2H, brs), 3.64(2H, brs), 3.99(2H,

d, J = 5.1 Hz), 4.05 (2H, s), 5.18-

5.28(2H, m), 5.83-5.93(1H, m),

5.95(2H, s), 6.36-6.47(2H, m), 6.75(2H,

s), 6.86-6.87(1H, m), 6.96(1H, d, J =

9.1 Hz), 7.03 (1H, t, J = 8.9 Hz), 7.75-

7.78(3H, m), 7.99(2H, d, J = 8.1 Hz),

8.15-8.22(2H, m).

1124

embedded image

—CH₃
—CH₃
free
(CDCl₃) 0.83-0.87(1H, m), 1.19- 1.22(7H, m), 1.37-1.42(1H, m), 2.10(3H, s), 2.41-2.44(4H, m), 3.00(3H, s), 3.43(2H, s), 3.48(2H, brs), 3.63(2H, brs), 4.06(2H, s), 5.94(2H, s), 6.51- 6.56(2H, m), 6.70-6.77(3H, m), 6.85- 6.91(2H, m), 7.40(1H, brs), 8.05- 8.06(2H, m).

TABLE 247

Example

No.
R₇₇₆
R₇₇₇
R₇₇₈
R₇₇₉
M
mp (° C.) or ¹H NMR

1125
4-CF₃Ph—
—F
—F
—CH₃
1
mp 160.0-161.5

1126
3,4-Cl₂Ph—
—F
—F
—CH₃
1
mp 207-209

1127
4-CF₃Ph—
—F
—F
—C₂H₅
1

¹H NMR (DMSO-d₆) δ 1.07(3H, t, J = 7.0

Hz), 2.20-2.41(4H, m), 3.20-3.30(2H, m),

3.39(2H, s), 3.39-3.52(4H, m), 4.11(2H, s),

5.97(2H, s), 6.71-6.76(1H, m), 6.78-

6.88(3H, m), 7.09-7.19 (2H, m), 7.92(2H,

d, J = 8.4 Hz), 8.15(2H, d, J = 8.4 Hz),

8.20(1H, dd, J = 2.7 Hz, 9.0 Hz), 8.42 (1H,

d, J = 2.7 Hz).

1128
3,4-Cl₂Ph—
—CH₃
—CH₃
—C₂H₅
1

¹H NMR (DMSO-d₆) δ 0.95(3H, t, J = 7.0

Hz), 2.01(3H, s), 2.19(3H, s), 2.20-

2.40(4H, m), 3.00 (2H, q, J = 7.0 Hz),

3.30-3.55(6H, m), 3.79(2H, s), 5.98(2H, s),

6.74(1H, dd, J = 7.9 Hz, 1.4 Hz), 6.82-6.86

(3H, m), 6.97(1H, d, J = 8.9 Hz), 7.05

(1H, s), 7.84(1H, d, J = 8.4 Hz), 7.94(1H,

dd, J = 8.4 Hz, 2.0 Hz), 8.15(1H, dd, J =

8.9 Hz, 2.7 Hz), 8.21(1H, d, J = 2.0 Hz),

8.42(1H, d, J = 2.6 Hz), 10.51(1H, brs).

1129
4-CF₃Ph—
—CH₃
—CH₃
—C₂H₅
1

¹H NMR (DMSO-d₆) δ 0.95(3H, t, J = 7.0

Hz), 2.02(3H, s), 2.19(3H, s), 2.20-

2.40(4H, m), 3.00 (2H, q, J = 7.0 Hz),

3.30-3.60(6H, m), 3.79(2H, s), 5.98(2H, s),

6.74(1H, d, J = 7.9 Hz), 6.82-6.85(3H, m),

6.98(1H, d, J = 8.6 Hz), 7.05(1H, s), 7.91-

7.95(2H, m), 8.14-8.20(3H, m), 8.44(1H,

d, J = 1.8 Hz), 10.59(1H, brs).

1130
4-CF₃Ph—
—OCH₃
—H
—H
2

¹H NMR (CDCl₃) δ2.44(4H, brs), 3.43(4H,

brs), 3.49(2H, s), 3.66(3H, s), 3.83(2H,

brs), 4.25(4H, s), 4.67(1H, brs), 6.10(1H,

dd, J = 8.6 Hz, 2.5 Hz), 6.23(1H, d, J = 2.5

Hz), 6.75-6.96(5H, m), 7.67(2H, d, J = 8.3

Hz), 7.96(2H, d, J = 8.1 Hz), 8.10(1H, dd,

J = 8.9 Hz, 2.6 Hz), 8.20-8.24(1H, m),

8.56(1H, s).

TABLE 248

Example

No.
R₇₈₀
R₇₈₁
R₇₈₂
R₇₈₃
mp (° C.) or ¹H NMR (solvent) δppm

1131

embedded image

—CH₃
—H
—H

¹H NMR (CDCl₃) 2.13(3H, s), 2.43(4H, t, J = 4.8 Hz), 3.02 (3H, s), 3.44(2H, s), 3.50(2H, brs), 3.64(2H, brs), 4.08(2H, s), 5.94(2H, s), 6.53-6.58(2H, m), 6.74(2H, brs), 6.83(1H, d, J = 8.9 Hz), 6.85(1H, s), 6.93(1H, d, J = 8.4 Hz), 7.42(1H, dd, J = 8.9 Hz, 2.0 Hz), 7.50(1H, d, J = 8.9 Hz), 7.53(1H, s), 7.69(1H, d, J = 1.8 Hz), 8.19(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.26(1H, brs), 8.31(1H, d, J = 2.6 Hz).

1132
3,4-Cl₂Ph—
—F
—F
—H
mp 204.5-204.5

1133
4-CF₃Ph—
—F
—F
—H
mp 230.0-231.5

1134
4-ClPh—
—CH₃
—H
—H

¹H NMR (CDCl₃) 2.08(3H, s), 2.42(4H,

brs), 2.97(3H, s), 3.43(2H, s), 3.49(2H,

brs), 3.60(2H, brs), 4.05(2H, s), 5.94 (2H,

s), 6.48-6.52(2H, m), 6.74-6.89(5H, m),

7.41(2H, d, J = 8.6 Hz), 7.80(2H, d, J = 8.4

Hz), 8.08(1H, dd, J = 8.9 Hz, 2.8 Hz),

8.21(1H, d, J = 2.6 Hz), 8.29(1H, s).

1135

embedded image

—CH₃
—H
—H

¹H NMR (CDCl₃) 2.11(3H, s), 2.43- 2.44(4H, m), 3.00(3H, s), 3.43(2H, s), 3.47- 3.49(2H, m), 3.63(2H, brs), 4.07(2H, s), 5.95(2H, s), 6.51-6.57(2H, m), 6.69- 6.93(6H, m), 7.19(1H, dd, J = 8.7 Hz, 7.5 Hz), 7.35-7.33(2H, m), 7.55(1H, brs), 7.86(1H, d, J = 15.8 Hz), 8.17-8.20(2H, m).

1136

embedded image

—CH₃
—H
—H

¹H NMR (CDCl₃) 2.10(3H, s), 2.43(4H, brs), 3.00(3H, s), 3.43(2H, s), 3.50(2H, brs), 3.64(2H, brs), 4.07(2H, s), 5.95 (2H, s), 6.50-6.56(2H, m), 6.67-6.92(6H, m), 7.07-7.19(2H, m), 7.31-7.36(1H, m), 7.47- 7.52(1H, m), 7.73(1H, brs), 7.80 (1H, d, J = 15.7 Hz), 8.14-8.20(2H, m).

1137

embedded image

—CH₃
—H
—H

¹H NMR (CDCl₃) 2.11(3H, s), 2.41- 2.44(4H, m), 3.00(3H, s), 3.43(2H, s), 3.47- 3.49(2H, m), 3.63(2H, brs), 4.06(2H, s), 5.94(2H, s), 6.09(1H, d, J = 14.7 Hz), 6.51- 6.56(2H, m), 6.70-6.96(7H, m), 7.30- 7.55(7H, m), 8.14(1H, d, J = 2.5 Hz), 8.14(1H, brs).

1138
4-CF₃Ph—
—F
—H
—F
mp 169.0-170.0

1139
3,4-Cl₂Ph—
—F
—H
—F
mp 138.0-139.0

text missing or illegible when filed

TABLE 249

Example

No.
R₇₈₄
R₇₈₅
R₇₈₆

¹H NMR (solvent) δppm

1140
3,4-Cl₂Ph—
—CH₃
—CH₃
(DMSO-d₆) 2.00(3H, s), 2.93(3H, s), 3.23(1H, brs),

3.36(1H, brs), 3.63(1H, brs), 3.72(1H, brs),

4.07(1H, s), 4.27(1H, s), 4.29(2H, s), 4.47(2H, s),

5.99(2H, s), 6.43-6.63(2H, m), 6.77(1H, dd, J =

8.0 Hz, 1.5 Hz), 6.77-6.88(2H, m), 6.82(1H, d, J =

8.8 Hz), 6.90(1H, d, J = 8.6 Hz), 7.83(1H, d, J =

8.4 Hz), 7.94(1H, dd, J = 8.4 Hz, 2.0 Hz),

8.12(1H, dd, J = 8.8 Hz, 2.6 Hz), 8.21(1H, d, J =

2.0 Hz), 8.40(1H, d, J = 2.6 Hz), 10.18(1H, s).

1141
4-CF₃Ph—
—CH₃
—CH₃
(CDCl₃) 2.10(3H, s), 2.90-3.06(3H, m), 3.20-

3.34(2H, m), 3.62-3.84(2H, m), 4.08(2H, s), 4.20-

4.33(2H, m), 4.52(2H, s), 5.95(2H, s), 6.53(1H, dd,

J = 8.6 Hz. 3.0 Hz), 6.58(1H, d, J = 3.0 Hz), 6.67-

6.79(3H, m), 6.82(1H, d, J = 8.9 Hz), 6.91(1H, d,

J = 8.1 Hz), 7.74(2H, d, J = 8.2 Hz), 7.99(2H, d, J =

8.2 Hz), 8.10(1H, s), 8.15(1H, dd, J = 9.2 Hz,

2.3 Hz), 8.22(1H, d, J = 2.3 Hz).

1142
3,4-Cl₂Ph—
—OCH₃
—C₂H₅
(CDCl₃) 1.17(3H, t, J = 6.4 Hz), 3.17-3.30(2H, m),

3.32-3.52(2H, m), 3.70(3H, s), 3.62-3.86(2H, m),

4.03(2H, s), 4.29(2H, s), 4.50 (2H, s), 5.95(2H, s),

6.22(1H, d, J = 8.9 Hz), 6.37(1H, s), 6.70(1H, d, J =

8.2 Hz), 6.75(1H, s), 6.76(1H, d, J = 8.9 Hz),

6.86(1H, d, J = 8.9 Hz), 6.94(1H, d, J = 8.7 Hz),

7.54(1H, d, J = 8.4 Hz), 7.70 (1H, dd, J = 8.4 Hz,

2.0 Hz), 7.98(1H, d, J = 2.0 Hz), 8.08(1H, s),

8.08(1H, dd, J = 8.9 Hz, 2.3 Hz), 8.20(1H, d, J =

2.3 Hz).

1143
4-CF₃Ph—
—OCH₃
—C₂H₅
(CDCl₃) 1.18(3H, t, J = 6.7 Hz), 3.16-3.33(2H, m),

3.33-3.50(2H, m), 3.72(2H, s), 3.62-3.85(3H, m),

4.04(2H, s), 4.29(2H, s), 4.50 (2H, s), 5.95(2H, s),

6.23(1H, dd, J = 8.7 Hz, 2.8 Hz), 6.38(1H, s),

6.71(1H, d, J = 8.1 Hz), 6.76(1H, s), 6.76(1H, d, J =

8.7 Hz), 6.88 (1H, d, J = 8.7 Hz), 6.95(1H, d, J =

8.7 Hz), 7.74(2H, d, J = 8.0 Hz), 7.99(2H, d, J =

8.0 Hz), 8.03(1H, s), 8.13(1H, dd, J = 8.7 Hz, 2.4

Hz), 8.21(1H, d, J = 2.4 Hz).

TABLE 250

Example

No.
R₇₈₇
R₇₈₈
Xb₁₆
Xb₁₇
Form

¹H NMR (solvent) δppm

1144
4-CF₃Ph—
—H
—N(CH₃)—
—CH(CH₃)—
free
(CDCl₃) 1.30(3H, d, J = 6.3 Hz),

2.16-2.48 (4H, m), 2.77(3H, s),

3.26-3.56(3H, m), 3.39 (2H, s),

3.78(1H, brs), 4.56(1H, q, J = 6.6

Hz), 5.92(2H, s), 6.68-6.77(4H,

m), 6.82(1H, s), 6.91(1H, d, J =

8.9 Hz), 7.04(2H, d, J = 9.1 Hz),

7.76(2H, d, J = 8.2 Hz), 7.90(1H,

brs), 7.99(2H, d, J = 8.1 Hz),

8.17(1H, dd, J = 8.9 Hz, 2.8 Hz),

8.25(1H, d, J = 2.6 Hz).

1145
4-CF₃Ph—
—CH₃
—N(CH₃)—
—CH(CH₃)—
free
(CDCl₃) 1.29(3H, d, J = 6.6 Hz),

2.14(3H, s), 2.14-2.22(1H, m),

2.29-2.35(2H, m), 2.48(1H, brs),

2.76(3H, s), 3.26-3.56(3H, m),

3.39(2H, s), 3.78(1H, brs),

4.57(1H, q, J = 6.6 Hz), 5.93 (2H,

s), 6.58-6.62(2H, m), 6.63-6.75

(2H, m), 6.83(1H, brs), 6.86 (1H,

d, J = 8.9 Hz), 6.95 (1H, d, J =

9.2 Hz), 7.76(2H, d, J = 8.3 Hz),

7.90(1H, brs), 7.99(2H, d, J = 8.3

Hz), 8.16 (1H, dd, J = 8.9 Hz, 2.8

Hz), 8.23(1H, d, J = 2.5 Hz).

1146
3,4-Cl₂Ph—
—H
—CH₂—
—NH—
hydrochloride
(DMSO-d₆) 2.78-3.10(2H, m),

3.10-3.35(4H, m), 4.00-4.19(2H,

m), 4.18-4.32(4H, m), 6.07 (2H,

s), 6.95-7.10(3H, m), 7.06(2H, d,

J = 8.6 Hz), 7.23(1H, s), 7.30(2H,

d, J = 8.6 Hz), 7.39 (1H, t, J =

5.5 Hz), 7.84(1H, d, J = 8.4 Hz),

7.97(1H, dd, J = 8.4 Hz, 2.0 Hz),

8.19(1H, dd, J = 8.7 Hz, 2.6 Hz),

8.25(1H, d, J = 2.0 Hz), 8.48(1H,

d, J = 2.6 Hz), 10.62(1H, s).

1147
4-CF₃Ph—
—H
—CH₂—
—NH—
hydrochloride
(DMSO-d₆) 2.80-3.05(2H, m),

3.11-3.38(4H, m), 4.00-4.35(4H,

m), 4.24(2H, s), 6.07(2H, s),

6.98(1H, d, J = 8.7 Hz), 6.92-

7.10(2H, m), 7.06(2H, d, J = 8.6

Hz), 7.24(1H, d, J = 1.3 Hz),

7.30(2H, d, J = 8.6 Hz), 7.35-

7.45(1H, m), 7.93(2H, d, J = 8.3

Hz), 8.19(2H, d, J = 8.3 Hz),

8.22(1H, dd, J = 8.7 Hz, 2.5 Hz),

8.51 (1H, d, J = 2.5 Hz),

10.70(1H, s).

TABLE 251

Example

No.
R₇₈₉
R₇₉₀
R₇₉₁

¹H NMR (solvent) δppm

1148
4-CF₃Ph—
—CH₃
—H
(CDCl₃) 2.17(3H, s), 2.50-2.55(4H, m), 3.46(2H, s),

3.71-3.74 (2H, m), 4.26(2H, brs), 5.95(2H, s), 6.74-

6.75(2H, m), 6.86(1H, brs), 6.91-6.95(1H, m),

7.04(1H, d, J = 8.7 Hz), 7.43(1H, dd, J = 8.7 Hz, 2.5

Hz), 7.56(1H, d, J = 2.3 Hz), 7.76(2H, d, J = 8.4 Hz),

7.94(1H, brs), 7.99(2H, d, J = 8.1 Hz), 8.20-8.23(2H,

m), 9.17 (1H, brs).

1149
3,4-Cl₂Ph—
—CH₃
—H
(CDCl₃) 2.18(3H, s), 2.50-2.56(4H, m), 3.47(2H, s),

3.72-3.75 (2H, m), 4.25-4.29(2H, m), 5.96(2H, s),

6.75(2H, brs), 6.86(1H, brs), 6.93(1H, d, J = 8.7 Hz),

7.04(1H, d, J = 8.7 Hz), 7.44(1H, dd, J = 8.7 Hz, 2.6

Hz), 7.56-7.57(1H, m), 7.58(1H, d, J = 8.3 Hz), 7.70

(1H, brs), 7.71(1H, dd, J = 8.3 Hz, 2.1 Hz), 7.98(1H,

d, J = 2.1 Hz), 8.15-8.21(2H, m), 9.16(1H, brs).

1150
3,4-Cl₂Ph—
—CH₃
—CH₃
(DMSO-d₆) 2.10-2.49(7H, m), 3.26-3.57(9H, m), 5.96-

5.99(2H, m), 6.69-6.89(3H, m), 7.05-7.11(2H, m),

7.16-7.28(1H, m), 7.30-7.37(1H, m), 7.84(1H, d, J =

8.4 Hz), 7.94(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.18-

8.22(2H, m), 8.42-8.47(1H, m), 10.54(1H, brs).

1151
4-CF₃Ph—
—CH₃
—CH₃
(DMSO-d₆) 2.10-2.46(7H, m), 3.26-3.57(9H, m), 5.96-

6.00(2H, m), 6.69-6.89(3H, m), 7.06-7.12(2H, m,

7.17-7.29(1H, m), 7.31-7.37(1H, m), 7.94(1H, d, J =

8.6 Hz), 8.16(2H, d, J = 8.6 Hz), 8.21-8.25(2H, m),

8.45-8.49(1H, m), 10.61(1H, brs).

1152
4-CF₃Ph—
—H
—SO₂CH₃
(CDCl₃) 2.45(4H, brs), 3.19(3H, s), 3.39(2H, brs),

3.46(2H, s), 3.62(2H, brs), 4.52(2H, s), 5.94(2H, s),

6.74(2H, brs), 6.84(1H, brs), 7.00(1H, d, J = 8.7 Hz),

7.10(2H, d, J = 8.7 Hz), 7.57(2H, d, J = 8.7 Hz),

7.75(2H, d, J = 8.1 Hz), 8.00(2H, d, J = 8.1 Hz), 8.15-

8.24(2H, m), 8.31(1H, brs).

1153
3,4-Cl₂Ph—
—CH₃
—SO₂CH₃
(CDCl₃) 2.16(3H, s), 2.46(4H, brs), 3.20(3H, s),

3.40(2H, brs), 3.47(2H, s), 3.63(2H, brs), 4.52(2H, s),

5.94(2H, s), 6.70-6.77 (2H, m), 6.83(1H, brs),

6.95(1H, d, J = 9.1 Hz), 6.99(1H, d, J = 8.7 Hz), 7.38-

7.57(3H, m), 7.71(1H, dd, J = 8.4 Hz, 2.0 Hz),

7.97(1H, d, J = 2.0 Hz), 8.11(1H, brs), 8.17(1H, dd, J =

8.9 Hz, 2.6 Hz), 8.25(1H, d, J = 2.6 Hz).

1154
4-CF₃Ph—
—CH₃
—SO₂CH₃
(CDCl₃) 2.18(3H, s), 2.42-2.46(4H, m), 3.21(3H, s),

3.39-3.40 (2H, m), 3.44(2H, s), 3.62(2H, brs),

4.53(2H, s), 5.94(2H, s), 6.70-6.77(2H, m), 6.84(1H,

brs), 6.96-7.03(2H, m), 7.41-7.46 (2H, m), 7.76(2H, d,

J = 8.2 Hz), 7.98-8.01(3H, m), 8.21(1H, dd, J = 8.7

Hz, 2.8 Hz), 8.26(1H, d, J = 2.3 Hz).

1155
3,4-Cl₂Ph—
—H
—SO₂CH₃
(CDCl₃) 2.41-2.45(4H, m), 3.19(3H, s), 3.38(2H, brs),

3.44(2H, s), 3.61(2H, brs), 4.52(2H, s), 5.94(2H, s),

6.72-6.74(2H, m), 6.83(1H, brs), 6.98(1H, d, J = 8.7

Hz), 7.09(2H, d, J = 8.7 Hz), 7.55(1H, d, J = 8.4 Hz),

7.56(2H, d, J = 8.7 Hz), 7.72(1H, dd, J = 8.4 Hz, 2.1

Hz), 7.98(1H, d, J = 2.1 Hz), 8.18(1H, dd, J = 8.7 Hz,

2.8 Hz), 8.27(1H, brs), 8.30(1H, d, J = 2.1 Hz).

TABLE 252

Example

No.
R₇₉₂
R₇₉₃
R₇₉₄

¹H NMR (CDCl₃) δppm

1156
4-CF₃Ph—
—H
—CH₃
1.21(3H, t, J = 6.8 Hz), 2.05-2.14(1H, m), 2.44-

2.51(1H, m), 2.70-2.74(1H, m), 2.83-3.32(6H, m),

3.55-3.59(1H, m), 3.84-4.08(4H, m), 5.94(2H, s),

6.66(2H, d, J = 8.9 Hz), 6.74(2H, brs), 6.81-6.85

(2H, m), 6.97(2H, d, J = 8.4 Hz), 7.72(2H, d, J =

8.3 Hz), 7.98(2H, d, J = 8.3 Hz), 8.11(1H, d, J =

9.1 Hz), 8.25(1H, d, J = 2.5 Hz), 8.31(1H, brs).

1157
4-CF₃Ph—
—CH₃
—H
1.26-1.39(3H, m), 1.99-2.04(1H, m), 2.13-

2.17(1H, m), 2.64-2.67(1H, m), 2.79-2.83(1H,

m), 2.98(4H, brs), 3.31-3.53(3H, m), 3,97-

4.66(3H, m), 5.95(2H, s), 6.64(2H, d, J = 9.1. Hz),

6.74(2H, brs), 6.82(1H, d, J = 8.9 Hz), 6.87(1H,

brs), 6.96(2H, d, J = 9.1 Hz), 7.71(2H, d, J = 7.9

Hz), 7.98(2H, d, J = 8.3 Hz), 8.10(1H, dd, J = 8.9

Hz, 2.5 Hz), 8.25(1H, d, J = 2.5 Hz), 8.40(1H,

brs).

1158
3,4-Cl₂Ph—
—H
—CH₃
1.21(3H, t, J = 6.8 Hz), 2.07-2.14(1H, m), 2.43-

2.52(1H, m), 2.70(1H, brs), 2.83-3.32(6H, m),

3.55-3.60(1H, m), 3.83-4.08(4H, m), 5.94(2H, s),

6.64(2H, d, J = 9.1 Hz), 6.74(2H, brs), 6.81(1H,

d, J = 8.9 Hz), 6.85(1H, brs), 6.96(2H, d, J = 8.7

Hz), 7.53(1H, d, J = 8.4 Hz), 7.71(1H, dd, J = 8.3

Hz, 2.1 Hz), 7.98(1H, d, J = 2.0 Hz), 8.05(1H, dd,

J = 8.9 Hz, 2.6 Hz), 8.24(1H, d, J = 2.5 Hz),

8.31(1H, brs).

1159
3,4-Cl₂Ph—
—CH₃
—H
1.26-1.39(3H, m), 1.99-2.17(2H, m), 2.64-

2.68(1H, m), 2.79-2.84 (1H, m), 2.99(4H, brs),

3.31-3.54(3H, m), 4.01-4.68(3H, m), 5.95(2H, s),

6.64(2H, d, 4 = 9.1 Hz), 6.74(2H, brs), 6.81(1H,

d, J = 8.9 Hz), 6.87(1H, brs), 6.96(2H, d, J = 8.9

Hz), 7.53(1H, d, J = 8.4 Hz), 7.71(1H, dd, J = 8.4

Hz, 2.0 Hz), 7.98(1H, d, J = 2.0 Hz), 8.06(1H, dd,

J = 8.9 Hz, 2.5 Hz), 8.24(1H, d, J = 2.3 Hz),

8.26(1H, brs).

TABLE 253

Example

No.
R₇₉₅
R₇₉₆
R₇₉₇

¹H NMR (CDCl₃) δppm

1160
3,4-Cl₂Ph—
—H
—CH₃
1.16-1.19(6H, m), 2.04-2.14(1H, m), 2.43-2.52(1H,

m), 2.66-2.74(1H, m), 2.83-3.36(5H, m), 3.59-

3.63(1H, m), 3.84-4.08(4H, m), 5.94(2H, s),

6.59(2H, d, J = 8.9 Hz), 6.74(2H, brs), 6.79(1H, d,

J = 8.9 Hz), 6.85(1H, brs), 6.92(2H, d, J = 8.9 Hz),

7.50(1H, d, J = 8.4 Hz), 7.71(1H, dd, J = 8.4 Hz,

2.1 Hz), 7.98(1H, d, J = 2.0 Hz), 8.03(1H, dd, J =

8.9 Hz, 2.6 Hz), 8.25(1H, d, J = 2.3 Hz), 8.64(1H,

brs).

1161
4-CF₃Ph—
—H
—CH₃
1.09-1.15(6H, m), 2.04-2.13(1H, m), 2.43-2.51(1H,

m), 2.66-2.74(1H, m), 2.83-3.38(5H, m), 3.58-

3.63(1H, m), 3.84-4.08(4H, m), 5.94(2H, s),

6.61(2H, d, J = 8.9 Hz), 6.74(2H, brs), 6.81(1H, d,

J = 8.9 Hz), 6.85(1H, brs), 6.94(2H, d, J = 8.3 Hz),

7.71(2H, d, J = 7.8 Hz), 7.99(2H, d, J = 8.1 Hz),

8.10(1H, d, J = 9.1 Hz), 8.26(1H, d, J = 2.5 Hz),

8.50(1H, brs).

1162
3,4-Cl₂Ph—
—CH₃
—H
1.15(3H, t, J = 7.1 Hz), 1.26-1.43(3H, m), 2.00(1H,

brs), 2.13(1H, brs), 2.64-2.68(1H, m), 2.79-

2.83(1H, m), 3.02-4.68(9H, m), 5.95(2H, s),

6.61(2H, d, J = 9.1 Hz), 6.74(2H, brs), 6.81(1H, d,

J = 8.7 Hz), 6.87(1H, brs), 6.94(2H, d, J = 8.9 Hz),

7.53(1H, d, J = 8.4 Hz), 7.71(1H, dd, J = 8.4 Hz,

2.1 Hz), 7.99(1H, d, J = 2.0 Hz), 8.06(1H, d, J =

8.9 Hz), 8.25(1H, d, J = 2.6 Hz), 8.32(1H, brs).

1163
4-CF₃Ph—
—CH₃
—H
1.15(3H, t, J = 6.9 Hz), 1.26-1.39(3H, m), 1.99(1H,

brs), 2.13(1H, brs), 2.63-2.67(1H, m), 2.79-

2.83(1H, m), 3.00-4.67(9H, m), 5.95(2H, s),

6.61(2H, d, J = 8.4 Hz), 6.74(2H, brs), 6.82(1H, d,

J = 8.7 Hz), 6.87(1H, brs), 6.95(2H, d, J = 8.9 Hz),

7.71(2H, d, J = 7.9 Hz), 7.99(2H, d, J = 8.1 Hz),

8.10(1H, d, J = 8.3 Hz), 8.27(1H, d, J = 2.5 Hz),

8.38(1H, brs).

TABLE 254

Example

No.
R₇₉₈
R₇₉₉

¹H NMR (CDCl₃) δppm

1164
4-CF₃Ph—
—H
2.52(4H, brs), 2.64(4H, brs), 3.12(2H, s), 3.45(2H, brs),

5.94(2H, s), 6.75 (2H, brs), 6.86(1H, brs), 6.95(1H, d, J =

8.7 Hz), 7.11(2H, d, J = 8.9 Hz), 7.60(2H, d, J = 8.9 Hz),

7.76(2H, d, J = 8.3 Hz), 7.98(1H, brs), 8.00(2H, d, J = 8.3

Hz), 8.21(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.26(1H, d, J = 2.5

Hz), 9.16(1H, brs).

1165
3,4-Cl₂Ph—
—H
2.52(4H, brs), 2.62-2.64(4H, m), 3.12(2H, s), 3.45(2H,

brs), 5.95(2H, s), 6.75(2H, brs), 6.86(1H, brs), 6.94(1H, d,

J = 8.7 Hz), 7.10(2H, d, J = 8.9 Hz), 7.57(1H, d, J = 8.4

Hz), 7.59(2H, d, J = 8.9 Hz), 7.72(1H, dd, J = 8.4 Hz, 2.1

Hz), 7.99(2H, brs), 8.17(1H, dd, J = 8.9 Hz, 2.8 Hz),

8.25(1H, d, J = 2.8 Hz), 9.17(1H, brs).

1166
3,4-Cl₂Ph—
—CH₃
2.44(8H, brs), 2.95(2H, s), 3.26(3H, s), 3.39(2H, s),

5.92(2H, s), 6.71(2H, brs), 6.81(1H, brs), 7.02(1H, d, J =

8.7 Hz), 7.14-7.22(4H, m), 7.58(1H, d, J = 8.4 Hz),

7.77(1H, dd, J = 8.4 Hz, 2.1 Hz), 8.05(1H, d, J = 2.1 Hz),

8.27(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.32(1H, d, J = 2.0 Hz),

8.33(1H, brs).

1167
4-CF₃Ph—
—CH₃
2.50(8H, brs), 2.95(2H, s), 3.24(3H, s), 3.47(2H, s),

5.92(2H, s), 6.72(2H, brs), 6,81(1H, brs), 7.02(1H, d, J =

8.7 Hz), 7.13-7.21(4H, m), 7.74(2H, d, J = 8.4 Hz),

8.05(2H, d, J = 8.1 Hz), 8.30(1H, dd, 3 = 8.9 Hz, 2.5 Hz),

8.35(1H, d, J = 2.3 Hz), 8.61(1H, brs).

TABLE 255

Example

No.
R₈₀₀
R₈₀₁
M
Form

¹H NMR (solvent) δppm

1168
3,4-Cl₂Ph—
piperonyl
2
hydrochloride
(DMSO-d₆) 2.60-2.61(2H, m), 2.75-

3.08(6H, m), 3.22-3.60(5H, m),

4.03(1H, d, J = 13.9 Hz), 4.20(2H,

d, J = 4.3 Hz), 4.46(1H, d, J = 13.9

Hz), 6.06(2H, s), 6.73(2H, d, J = 8.9

Hz), 6.93-6.99(5H, m), 7.20(1H,

brs), 7.83(1H, d, J = 8.4 Hz),

7.96(1H, dd, J = 8.4 Hz, 2.1 Hz),

8.14(1H, dd, J = 8.9 Hz, 2.6 Hz),

8.23(1H, d, J = 2.0 Hz), 8.45(1H, d,

J = 2.6 Hz), 10.57(1H, brs),

11.00(1H, brs).

1169
4-CF₃Ph—
piperonyl
2
hydrochloride
(DMSO-d₆) 2.60-2.62(2H, m), 2.88-

3.08(6H, m), 3.23-3.60(5H, m),

4.01-4.06(1H, m), 4.20-4.21(2H,

m), 4.43-4.49(1H, m), 6.07(2H, s),

6.73(2H, d, J = 8.6 Hz), 6.94-

6.99(5H, m), 7.20(1H, brs),

7.93(2H, d, J = 8.2 Hz), 8.14-

8.19(3H, m), 8.47(1H, d, J = 2.5

Hz), 10.64(1H, brs), 11.00(1H, brs).

1170
4-CF₃Ph—
benzyl
0
free
(CDCl₃) 2.25(4H, t, J = 4.9 Hz),

3.19(3H, s), 3.23(4H, t, J = 4.9 Hz),

3.43(2H, s), 6.95(1H, d, J = 8.7 Hz),

7.08(4H, s), 7.20-7.32(5H, m),

7.75(2H, d, J = 8.0 Hz), 8.02(2H, d,

J = 8.0 Hz), 8.24(1H, dd, J = 8.7

Hz, 2.5 Hz), 8.31(1H, d, J = 2.5

Hz), 8.34(1H, s).

1171
3,4-Cl₂Ph—
benzyl
0
hydrochloride
(DMSO-d₆) 2.70-3.00(2H, m),

3.14(3H, s), 2.95-3.30(4H, m),

3.72(2H, d, J = 13.7 Hz), 4.29(2H,

s), 7.08(1H, d, J = 8.7 Hz), 7.11(2H,

d, J = 8.9 Hz), 7.23(2H, d, J = 8.9

Hz), 7.39-7.48(3H, m), 7,51-

7.60(2H, m), 7.84(1H, d, J = 8.5

Hz), 7.97(1H, dd, J = 8.5 Hz, 2.0

Hz), 8.22(1H, dd, J = 8.7 Hz, 2.6

Hz), 8.25(1H, d, J = 2.0 Hz),

8.53(1H, d, J = 2.6 Hz), 10.67(1H,

s).

TABLE 256

Example

No.
R₈₀₂
R₈₀₃
R₈₀₄

¹H NMR (CDCl₃) δppm

1172
3,4-Cl₂Ph—
—H
—CH₃
2.34(3H, s), 2.34-2.50(4H, m), 2.78(3H, s),

3.42(2H, s), 3.50-3.70(4H, m), 3.80(2H, s),

5.95(2H, s), 6.70-6.80(2H, m), 6.85-6.89(2H, m),

7.26-7.35(1H, m), 7.40(1H, d, J = 2.8 Hz), 7.51

(1H, d, J = 8.9 Hz), 7,57-7.61(2H, m), 7.74(1H,

dd, J = 8.3 Hz, 2.0 Hz), 8.01(1H, d, J = 2.0 Hz),

8.29(1H, s).

1173
4-CF₃Ph—
—H
—CH₃
2.36(3H, s), 2.36-2.50(4H, m), 2.79(3H, s),

3.42(2H, s), 3.50-3.65(4H, m), 3.80(2H, s),

5.94(2H, s), 6.70-6.75(2H, m), 6.85-6.90(2H, m),

7.30(1H, dd, J = 8.8 Hz, 2.7 Hz), 7.40(1H, d, J =

2.8 Hz), 7.51(1H, d, J = 8.8 Hz), 7.68(1H, brs),

7.76-7.80(2H, m), 8.01-8.04(2H, m), 8.34(1H, s).

1174
3,4-Cl₂Ph—
—CH₃
—H
2.30-2.44(4H, m), 2.44(3H, s), 2.79(3H, s),

3.42(2H, s), 3.50-3.65(4H, m), 3.80(2H, s),

5.95(2H, s), 6.65-6.81(3H, m), 6.85(1H, s),

7.29(1H, dd, J = 8.8 Hz, 2.8 Hz), 7.41(1H, d, J =

2.7 Hz), 7.49(1H, d, J = 8.8 Hz), 7.59(1H, d, J =

8.3 Hz), 7.67(1H, brs), 7.72(1H, dd, J = 8.3 Hz,

2.1 Hz), 8.00(1H, d, J = 2.0 Hz), 8.09(1H, d, J =

8.7 Hz).

1175
4-CF₃Ph—
—CH₃
—H
2.35-2.45(4H, m), 2.45(3H, s), 2.79(3H, s),

3.42(2H, s), 3.50-3.65(4H, m), 3.80(2H, s),

5.95(2H, s), 6.65-6.82(2H, m), 6.85(1H, s),

7.30(1H, dd, J = 8.8 Hz, 2.8 Hz), 7.41(1H, d, J =

2.8 Hz), 7.50(1H, d, J = 8.8 Hz), 7.72(1H, brs),

7.77-7.80(2H, m), 8.00-8.03(2H, m), 8.15(1H, d, J =

8.6 Hz).

TABLE 257

Example

No.
R₈₀₅
R₈₀₆
R₈₀₇
R₈₀₈
Form

¹H NMR (DMSO-d₆) δppm

1176
3,4-Cl₂Ph—
—H
—H

embedded image

free
3.14(1H, dd, J = 14.0 Hz, 9.4 Hz), 3.40(1H, dd, J = 14.0 Hz, 4.5 Hz), 4.93(1H, dd, J = 9.4 Hz, 4.5 Hz), 7.07(1H, d, J = 8.9 Hz), 7.07(2H, d, J = 8.4 Hz), 7.29(2H, d, J = 8.4 Hz), 7.84(1H, d, J = 8.4 Hz), 7.95(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.20(1H, dd, J = 8.9 Hz, 2.5 Hz), 8.22(1H, d, J = 2.0 Hz), 8.48(1H, d, J = 2.5 Hz), 10.56(1H, s), 12.06(1H, s).

1177
4-CF₃OPh—
—CH₃
—H

embedded image

hydro- chloride
2.09(3H, s), 3.09(1H, dd, J = 14.3 Hz, 9.6 Hz), 3.40(1H, dd, J = 14.3 Hz, 4.3 Hz), 4.93(1H, dd, J = 9.6 Hz, 4.3 Hz), 6.99(1H, d, J = 8.1 Hz), 7.02(1H, d, J = 8.9 Hz), 7.12(1H, d, J = 8.1 Hz), 7.20 (1H, s), 7.55(2H, d, J = 8.8 Hz), 8.10(2H, d, J = 8.8 Hz), 8.20(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.44(1H, d, J = 2.6 Hz), 10.54(1H, s), 12.10(1H, s).

1178
3,4-Cl₂Ph—
—H
—CH₃
morpholino
hydro-
1.70(3H, d, J = 6.9 Hz), 2.94-3.01

chloride
(2H, m), 3.63-4.02(6H, m), 4.50

(1H, t, J = 6.6 Hz), 7.13(1H, d, J =

9.1 Hz), 7.23(2H, d, J = 8.7 Hz),

7.64 (2H, d, J = 8.7 Hz), 7.85(1H,

d, J = 8.4 Hz), 7.96(1H, dd, J =

8.4 Hz, 2.2 Hz), 8.23(1H, dd, J =

8.9 Hz, 2.6 Hz), 8.24(1H, d, J =

2.1 Hz), 8.54(1H, d, J = 2.1 Hz),

10.63(1H, brs), 10.89(1H, brs).

1179
4-CF₃Ph—
—H
—CH₃
morpholino
hydro-
1.72(3H, d, J = 6.6 Hz), 2.92(2H,

chloride
brs), 3.35(2H, brs), 3.69-3.99(4H,

m), 4.49(1H, brs), 7.14(1H, d, J =

8.7 Hz), 7.22(2H, d, J = 8.3 Hz),

7.69(2H , d, J = 8.3 Hz), 7.94(2H,

d, J = 8.3 Hz), 8.20(2H, d, J = 8.1

Hz), 8.28(1H, d, J = 8.9 Hz),

8.58(1H, brs), 10.77(1H, brs),

11.47(1H, brs).

1180
Ph—
—H
—CH₃
morpholino
hydro-
1.70(3H, d, J = 6.8 Hz), 2.94(2H,

chloride
brs), 3.38-3.43(2H, m), 3.62-

4.02(4H, m), 4.50(1H, t, J = 6.6

Hz), 7.12(1H, d, J = 8.7 Hz),

7.22(2H, d, J = 8.6 Hz), 7.52-

7.65(5H, m), 7.96-8.00(2H, m),

8.26(1H, dd, J = 8.7 Hz, 2.8 Hz),

8.56(1H, d, J = 2.8 Hz), 10.47(1H,

brs), 10.91(1H, brs).

TABLE 258

Example

No.
Chemical stracture
mp (° C.)

1181

embedded image

203.0-204.0

1182

embedded image

186.0-187.0

1183

embedded image

165.0-166.0

1184

embedded image

122.0-124.0

1185

embedded image

155.0-157.0

1186

embedded image

182.0-183.5

1187

embedded image

117.0-118.0

1188

embedded image

160.0-161.0

TABLE 259

Example

No.
R₈₀₉
R₈₁₀
R₈₁₁
Xb₁₈

¹H NMR (CDCl₃) δppm

1189
4-CF₃Ph—
—COOCH₃
benzyl
—O—
2.62(4H, brs), 3.23(4H, brs),

3.58(2H, s), 3.67(3H, s), 6.95(1H,

d, J = 9.7 Hz), 7.06-7.14(2H, m),

7.26-7.36(5H, m), 7.49 (1.11, d, J =

2.3 Hz), 7.74(2H, d, J = 8.3

Hz), 7.87(1H, s), 7.98(2H, d, J =

8.1 Hz), 8.16-8.18(2H, m).

1190
3,4-Cl₂Ph—
—H
—COOC(CH₃)₃
—O—
1.49(9H, s), 3.11(4H, t, J = 4.8

Hz), 3.58(4H, t, J = 4.8 Hz),

6.92(1H, d, J = 9.0 Hz), 6.96(2H,

d, J = 8.5 Hz), 7.06(2H, d, J = 8.5

Hz), 7.58(1H, d, J = 8.5 Hz), 7.70

(1H, dd, J = 8.5 Hz, 2.0 Hz),

7.74(1H, brs), 7.98(1H, d, J = 2.0

Hz), 8.15(1H, brd, J = 9.0 Hz),

8.24(1H, d, J = 2.5 Hz).

1191
4-CF₃Ph—
—H
—COOC(CH₃)₃
—O—
1.49(9H, s), 3.11(4H, t, J = 5.0

Hz), 3.58(4H, t, J = 5.0 Hz),

6.93(1H, d, J = 9.0 Hz), 6.96(2H,

d, J = 9.0 Hz), 7.06(2H, d, J = 9.0

(2H, brs), 7.99(2H, d, J = 8.0

Hz), 8.19(1H, dd, J = 9.0 Hz,

2.5 Hz), 8.25(1H, d, J = 2.5 Hz).

1192
4-CF₃Ph—
—H
—CH₂COOC₂H₅
—N(CH₃)—
1.30(3H, t, J = 7.1 Hz), 2.77(4H,

t, J = 5.0 Hz), 3.28(4H, t, J = 5.0

Hz), 3.29(2H, s), 3.42(3H, s),

4.22(2H, q, J = 7.1 Hz), 6.47(1H,

d, J = 9.2 Hz), 6.96(2H, d, J = 9.0

Hz), 7.15(2H, d, J = 9.0 Hz),

7.69(1H, brs), 7.70 (1H, d, J =

2.5 Hz), 7.74(2H, d, J = 8.1 Hz),

7.98(2H, d, J = 8.1 Hz), 8.26

(1H, d, J = 2.5 Hz).

TABLE 260

Example

No.
R₈₁₂
R₈₁₃
Xb₁₉
Xb₂₀

¹H NMR (solvent) δppm

1193
3,4-Cl₂Ph—
—COOC(CH₃)₃
—CO—
—CH₂—
(CDCl₃) 1.51(9H, s), 3.75(2H, m),

3.79(2H, m), 4.26(2H, s), 6.98(1H, d,

J = 8.8 Hz), 7.14(2H, dd, J = 6.9 Hz,

2.1 Hz), 7.28(2H, dd, J = 6.9 Hz, 2.1

Hz), 7.58(1H, d, J = 8.3 Hz), 7.72(1H,

dd, J = 8.3 Hz, 2.1 Hz), 7.99(1H, d,

J = 2.1 Hz), 8.13(1H, dd, J = 8.8 Hz,

2.7 Hz), 8.29(1H, d, J = 2.7 Hz).

1194
3,4-Cl₂Ph—
piperonyl
—CH₂—
—CO—
(DMSO-d₆) 3.22-3,50(4H, m),

3.84(2H, s), 4.50(2H, s), 6.00(2H, s),

6.77(1H, dd, J = 8.0 Hz, 1.4 Hz),

6.84(1H, d, J = 1.4 Hz), 6.87(1H, d, J =

8.0 Hz), 6.98(2H, d, J = 8.6 Hz),

6.97-7.06(3H, m), 7.84(1H, d, J = 8.4

Hz), 7.94(1H, dd, J = 8.4 Hz, 2.0 Hz),

8.15(1H, dd, J = 8.9 Hz, 2.8 Hz),

8.22(1H, d, J = 2.0 Hz), 8.44(1H, d, J =

2.3 Hz), 10.51(1H, s).

1195
4-CF₃Ph—
piperonyl
—CH₂—
—CO—
(DMSO-d₆) 3.27-3.40(2H, m), 3.40-

3.50(2H, m), 3.85(2H, s), 4.50(2H, s),

6.00(2H, s), 6.77(1H, dd, J = 7.9 Hz,

1.5 Hz), 6.84(1H, d, J = 1.5 Hz),

6.88(1H, d, J = 7.9 Hz), 6.95-7.07(5H,

m), 7.93(2H, d, J = 8.1 Hz), 8.16(2H,

d, J = 8.1 Hz), 8.17(1H, dd, J = 8.8

Hz, 2.5 Hz), 8.46(1H, d, J = 2.5 Hz),

10.60(1H, s).

TABLE 261

Example

No.
R₈₁₄
R₈₁₅
Xb₂₁

¹H NMR (CDCl₃) δppm

1196
3,4-Cl₂Ph—
—COOC₂H₅
—O—
1.28(3H, t, J = 7.0 Hz), 1.88-1.93(2H, m),

2.03(2H, brd, J = 10.0 Hz), 2.42(1H, m),

2.78(1H, t, J = 10.5 Hz), 3.59(2H, dt, J =

12.5 Hz, 3.5 Hz), 4.16(2H, q, J = 7.0 Hz),

6.90(1H, d, J = 9.0 Hz), 6.95(2H, d, J = 9.0

Hz), 7.03(2H, d, J = 9.0 Hz), 7.58(1H, d, J =

8.5 Hz), 7.70(1H, brs), 7.71(1H, dd, J = 8.5

Hz, 2.0 Hz), 7.98(1H, d, J = 2.0 Hz),

8.14(1H, dd, J = 9.0 Hz, 2.5 Hz), 8.24(1H, d,

J = 2.5 Hz).

1197
3,4-Cl₂Ph—
—CH₂COOC₂H₅
—O—
1.27(3H, t, J = 7.0 Hz), 1.40-1.46(2H, m),

1.82(2H, brd, J = 13.0 Hz), 1.90(1H, m),

2.27(2H, d, J = 7.0 Hz), 2.69(2H, brt, J =

13.0 Hz), 3.57(2H, brd, J = 12.0 Hz), 4.15

(2H, q, J = 7,0 Hz), 6.83(1H, d, J = 9.0 Hz),

6.90(2H, d, J = 9.0 Hz), 6.97(2H, d, J = 9.0

Hz), 7.49(1H, d, J = 8.5 Hz), 7.68(1H, dd, J =

8.5 Hz, 2.0 Hz), 7.95(1H, d, J = 2.0 Hz),

8.10(1H, dd, J = 9.0 Hz, 2.5 Hz), 8.21(1H, d,

J = 2.5 Hz), 8.48(1H, brs).

1198
4-CF₃Ph—
—CH₂COOC₂H₅
—O—
1.28(3H, t, J = 7.1 Hz), 1.46(2H, qd, J = 12.2

Hz, 3.4 Hz), 1.86(2H, d, J = 13.5 Hz), 1.85-

2.10(1H, m), 2.30(2H, d, J = 7.1 Hz),

2.76(2H, td, J = 12.2 Hz, 2.2 Hz), 3.42(3H,

s), 3.68(2H, d, J = 12.2 Hz), 4.16(2H, q, J

7.1 Hz), 6.46(1H, d, J = 9.0 Hz), 6.96(2H, d,

J = 8.9 Hz), 7.13(2H, d, J = 8.9 Hz), 7.72(1H,

dd, J = 9.0 Hz, 2.5 Hz), 7.73(1H, d, J = 2.5

Hz), 7.74(2H, d, J = 8.2 Hz), 7.98(2H, d, J =

8.2 Hz), 8.26(1H, d, J = 2.5 Hz).

1199
4-CF₃Ph—
—CH₂OOC₂H₅
—O—
1.28(3H, t, J = 7.0 Hz), 1.44(2H, dq, J = 3.5

Hz, 12.0 Hz), 1.84(2H, brd, J = 13.0 Hz),

1.93(1H, m), 2.29(2H, d, J = 7.0 Hz),

2.73(2H, dt, J = 2.5 Hz, 12.0 Hz), 3.61(2H,

brd, J = 12.0 Hz), 4.15(2H, q, J = 7.0 Hz),

6.91(1H, d, J = 9.0 Hz), 6.96(2H, d, J = 9.0

Hz), 7.04(2H, d, J = 9.0 Hz), 7.74(1H, brs),

7.77(2H, d, J = 8.5 Hz), 7.99(2H, d, J = 8.5

Hz), 8.18(1H, dd, J = 9.0 Hz, 2.5 Hz),

8.25(1H, d, J = 2.5 Hz).

1200
4-CF₃Ph—
—COOC₂H₅
—O—
1.26(3H, t, J = 7.1 Hz),1.17-1.98(4H, m),

2.35-2.43(1H, m), 2.68-2.76(2H, m), 3.51-

3.55(2H, m), 4.14(2H, q, J = 7.1 Hz),

6.78(1H, d, J = 8.9 Hz), 6.85-6.95(4H, m),

7.61(2H, d, J = 8.2 Hz), 7.93(2H, d, J = 8.1

Hz), 8.09(1H, dd, J = 8.9 Hz, 2.6 Hz),

8.25(1H, d, J = 2.6 Hz), 9.00(1H, s).

TABLE 262

Example

No.
R₈₁₆
R₈₁₇
R₈₁₈

¹H NMR (CDCl₃) δppm

1201
4-CF₃Ph—
—CH₃

embedded image

1.31-1.43(2H, m), 1.80-1.98(3H, m), 2.10(3H, s), 2.26(2H, d, J = 6.8 Hz), 2.38-2.44(4H, m), 2.66(2H, t, J = 12.2 Hz), 3.46-3.63(8H, m), 6.72-6.81(3H, m), 6.90(1H, d, J = 8.6 Hz), 7.26- 7.33(5H, m), 7.70(2H, d, J = 8.2 Hz), 8.00(2H, d, J = 8.1 Hz), 8.15(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.25(1H, d, J = 2.5 Hz), 8.60(1H, s).

1202
4- CF₃Ph—
—CH₃

embedded image

1.31-1.43(2H, m), 1.79-1.98(3H, m), 2.11(3H, s), 2.26(2H, d, J = 6.8 Hz), 2.36-2.39(4H, m), 2.66(2H, t, J = 12.0 Hz), 3.42(2H, s), 3.45-3.61(6H, m), 6.70-6.92(7H, m), 7.70(2H, d, J = 8.2 Hz), 7.99(2H, d, J = 8.1 Hz), 8.15(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.25(1H, d, J = 2.5 Hz), 8.55(1H, s).

1203
3,4- Cl₂Ph—
—CH₃

embedded image

1.29-1.41(2H, m), 1.77-1.98(3H, m), 2.09(3H, s), 2.26(2H, d, J = 6.8 Hz), 2.34-2.40(4H, m), 2.62(2H, t, J = 12.0 Hz), 3.41(2H, s), 3.46-3.60(6H, m), 6.70-6.90(7H, m), 7.49(1H, d, J = 8.4 Hz), 7.73(1H, dd, J = 8.2 Hz, 2.0 Hz), 7.99(1H, d, J = 2.0 Hz), 8.12(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.25(1H, d, J =2.6 Hz), 8.99(1H, s).

1204
3,4- Cl₂Ph—
—CH₃

embedded image

1.29-1.41(2H, m), 1.77-1.98(3H, m), 2.09(3H, s), 2.26(2H, d, J = 6.8 Hz), 2.37-2.44(4H, m), 2.63(2H, t, J = 11.9 Hz), 3.48-3.63(8H, m), 6.70-6.78(2H, m), 6.88(1H, d, J = 8.6 Hz), 7.26- 7.33(6H, m), 7.48(1H, d, J = 8.4 Hz), 7.72(1H, dd, J = 8.4 Hz, 2.1 Hz), 7.99(1H, d, J = 2.1 Hz), 8.12(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.26(1H, d, J = 2.6 Hz), 9.03(1H, s).

1205
4-
—OCH₃
—OC₂H₅
1.27(3H, t, J = 7.1 Hz), 1.39-1.42(2H,

CF₃Ph—

m), 1.80-1.85(3H, m), 2.28(2H, d, J =

6.9 Hz), 2.70(3H, t, J = 10.1 Hz),

3.56(2H, d, J = 12.2 Hz), 3.66(3H, s),

4.14(2H, q, J = 7.3 Hz), 6.43(1H, dd, J =

8.7 Hz, 2.5 Hz), 6.51(1H, d, J = 2.5

Hz), 6.78(1H, d, J = 8.9 Hz), 6.90(1H,

d, J = 8.7 Hz), 7.63(2H, d, J = 8.6 Hz),

7.96(2H, d, J = 8.2 Hz), 8.08(1H, dd, J =

8.9 Hz, 2.6 Hz), 8.18(1H, d, J = 2.6

Hz), 8.95(1H, s).

TABLE 263

Example

No.
R₈₁₉
R₈₂₀
mp (° C.) or ¹H NMR (solvent) δppm

1206
3,4-
morpholino

¹H NMR (DMSO-d₆) 3.07-3.10(4H, m), 3.73-

Cl₂Ph—

3.77(4H, m), 6.96-7.04(5H, m), 7.83(1H, d, J =

8.2 Hz), 7.94(1H, dd, J = 8.2 Hz, 2.0 Hz),

8.15(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.22(1H, d, J =

2.0 Hz), 8.45(1H, d, J = 2.6 Hz), 10.51(1H,

brs).

1207
3,4- Cl₂Ph—

embedded image

¹H NMR (CDCl₃) 1.72-1.90(4H, m), 2.40- 2.53(2H, m), 3.20-3.32(2H, m), 458(2N, s), 6.95(1H, d, J = 8.9 Hz), 7.08(2H, d, J = 8.6 Hz), 7.27(2H, d, J = 8.6 Hz), 7.58(1H, d, J = 8.6 Hz), 7.73(1H, dd, J = 8.6 Hz, 2.0 Hz), 8.01(1H, d, J = 2.0 Hz), 8.11(1H, s), 8.19(1H, dd, J = 8.9 Hz, 2.3 Hz), 8.28(1H, d, J = 2.3 Hz).

1208
4-CF₃Ph—
—NHCONHPh
mp 240.0-240.5

1209
3,4- Cl₂Ph—

embedded image

¹H NMR (CDCl₃) 1.28(3H, t, J = 7.0 Hz), 1.60- 1.70(2H, m), 1.83(1H, m), 2.03(1H, m), 2.69(1H, m), 2.82(1H, brt, J = 12.0 Hz), 3.03(1H, dd, J = 12.0 Hz, 10.0 Hz), 3.42(1H, brd, J = 12.0 Hz), 3.65(1H, brd, J = 12.0 Hz), 4.17(2H, q, J = 7.0 Hz), 6.90(1H, d, J = 9.0 Hz), 6.97(2H, d, J = 9.0 Hz), 7.03(2H, d, J = 9.0 Hz), 7.58(1H, d, J = 8.5 Hz), 7.70 (IH, dd, J = 8.5 Hz, 2.0 Hz), 7.75(1H, s), 7.97(1H, d, J = 2.0 Hz), 8.14(1H, brd, 3 = 9.0 Hz), 8.23(1H, d, J = 2.5 Hz).

1210
3,4- Cl₂Ph—

embedded image

¹H NMR (DMSO-d₆) 2.33-2.38(4H, m), 2.65- 2.83(2H, m), 3.41(2H, s), 3.45-3.57(4H, m), 3.65-3 75(1H, m), 3.91-4.08(2H, m), 6.00(2H, s), 6.76(1H, dd, J = 1.5 Hz, 8.1 Hz), 6.84- 6.88(2H, m), 7.07(1H, d, J = 8.9 Hz), 7.14(2H, d, J = 8.9 Hz), 7.67(2H, d, J = 9.1 Hz), 7.85(1H, d, J = 8.4 Hz), 7.95(1H, dd, J = 2.0 Hz, 8.4 Hz), 8.19(1H, dd, J = 2.6 Hz, 8.9 Hz), 8.23(1H, d, J = 2.1 Hz), 8.47(1H, d, J = 2.6 Hz), 10.56(1H s).

1211
4-CF₃Ph—

embedded image

¹H NMR (DMSO-d₆) 2.33-2.38(4H, m), 2.65- 2.83(2H, m), 3.41(2H, s), 3.51(4H, brs), 3.65- 3.75(1H, m), 3.91-4.08(2H, m), 5.99(2H, s), 6.76(1H, dd, J = 1.3 Hz, 7.9 Hz), 6.84-6.88(2H, m),), 7.08(1H, d, J = 8.9 Hz), 7.15(2H, d, J = 6.9 Hz), 7.68(2H, d, J = 6.9 Hz), 7.94(2H, d, J = 8 6 Hz), 8.17(2H, d, J = 8.1 Hz), 8.23(1H, dd, J = 2.6 Hz, 8.9 Hz), 8.50(1H, d, J = 2.6 Hz), 10.64(1H, s).

TABLE 264

Example

No.
R₈₂₁

¹H NMR (DMSO-d₆) δppm

1212
3,4-Cl₂Ph—
2.25-2.33(4H, m), 2.92(3H, s), 3.36(2H, s), 3.42(4H, brs), 4.23(2H, s),

5.98(2H, s), 6.29-6.32(2H, m), 6.42-6.45(1H, m), 6.70-6.74(1H, m),

6.80-6.84(2H, m), 6.97(1H, d, J = 8.9 Hz), 7.11-7.17(1H, m),

7.84(1H, d, J = 8.4 Hz), 7.95(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.16-

8.22(2H, m), 8.52(1H, d, J = 2.5 Hz), 10.55(1H, s).

1213
4-CF₃Ph—
2.26-2.33(4H, m), 2.92(3H, s), 3.37-3.41(6H, m), 4.23(2H, s),

5.98(2H, s), 6.29-6.34 (2H, m), 6.42-6.45(1H, m), 6.70-6.74(1H, m),

6.80-6.84(2H, m), 6.98(1H, d, J = 8.9 Hz), 7.11-7.17(1H, m),

7.93(2H, d, J = 8.3 Hz), 8.16(2H, d, J = 8.1 Hz), 8.21(1H, dd, J = 8.9

Hz, 2.6 Hz), 8.54(1H, d, J = 2.3 Hz), 10.63(1H, s).

TABLE 265

Example

No.
R₈₂₂
R₈₂₃
Xb₂₂
M
Form

¹H NMR (solvent) δppm

1214
—CH₃
piperonyl
—N(CH₃)—
1
free
(CDCl₃) 1.90(3H, s), 2.41-2.45(4H, m),

3.03(3H, s), 3.43(2H, s), 3.49(2H, brs),

3.63(2H, brs), 4.09 (2H, s), 4.77(2H, s),

5.95(2H, s), 6.70(2H, d, J = 9.1 Hz),

6.74-6.75(2H, m), 6.81-6.85(2H, m),

7.00(2H, d, J = 9.1 Hz), 7.04(1H, dd,

J = 8.4 Hz, 2.1 Hz), 7.24(1H, dd, J = 8.7

Hz, 2.8 Hz), 7.31(1H, d, J = 2.1 Hz),

7.35(1H, d, J = 8.1 Hz), 7.83(1H, d, J =

2.6 Hz).

1215
—C₂H₅
piperonyl
—N(CH₃)—
1
free
(CDCl₃) 1.08 t, J = 7.4 Hz),

2.07(2H, q, J = 7.4 Hz), 2.41-2.45(4H,

m), 3.03(3H, s), 3.43(2H, s), 3.48(2H,

brs), 3.63(2H, brs), 4.09(2H, s),

4.77(2H, s), 5.95(2H, s), 6.70(2H, d, J =

9.2 Hz), 6.73-6.74(2H, m), 6.82(1H,

d, J = 8.7 Hz), 6.85(1H, brs), 7.00(2H,

d, J = 9.1 Hz), 7.04(1H, dd, J = 8.3 Hz,

2.0 Hz), 7,22(1H, dd, J = 8.7 Hz, 2.8

Hz), 7.30(1H, d, J = 2.0 Hz), 7.34(1H,

d, J = 8.3 Hz), 7.82(1H, d, J = 2.5 Hz).

1216
—CH₃
benzyl
none
0
hydro-
(DMSO-d₆) 1.87(3H, s), 3.14(2H, brs),

chloride
3.37(6H, brs), 4.35(2H, s), 4.85(2H, s),

7.13(1H, d, J = 8.9 Hz), 7.22(2H, d, J =

8.4 Hz), 7.41-7.58(10H, m), 7.80(1H,

dd, J = 8.9 Hz, 2.6 Hz), 8.03(1H, d, J =

2.6 Hz), 10.88(1H, brs).

Example 1217
Production of 1H-indole-2-carboxylic acid {6-[4-(2,4-dioxothiazolidine-5-ylmethyl)-2-methylphenoxy]pyridin-3-yl}amide

To a solution of 5-[4-(5-aminopyridin-2-yloxy)-3-methylbenzyl]thiazolidine-2,4-dione (150 mg, 0.46 mmol) in DMF (5 mL) were added indole-2-carboxylic acid (74 mg, 0.46 mmol), 1-hydroxybenzotriazole monohydrate (70 mg, 0.46 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (110 mg, 0.57 mmol), and the resulting solution was stirred for 5 days at room temperature. This reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, evaporated, and the residue was then purified by silica gel column chromatography (chloroform:methanol=30:1). To the obtained powdery substance was added ethanol, the resulting solution was filtered and the filtrate was washed with ethanol, to thereby yield 100 mg of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 2.10 (3H, s), 3.09 (1H, dd, J=14.2 Hz, 9.7 Hz), 3.40 (1H, dd, J=14.2 Hz, 4.2 Hz), 4.94 (1H, dd, J=9.7 Hz, 4.2 Hz), 6.99 (1H, d, J=Hz), 7.04 (1H, d, J=8.9 Hz), 7.05-7.16 (2H, m), 7.20 (1H, s), 7.24 (18, dd, J=7.0 Hz, 1.0 Hz), 7.39 (1H, d, J=1.6 Hz), 7.46 (1H, d, J=8.2 Hz), 7.68 (1H, d, J=7.7 Hz), 8.21 (1H, dd, J=8.9 Hz, 2.8 Hz), 8.49 (1H, d, J=2.8 Hz), 10.37 (1H, s), 11.80 (1H, s), 12.09 (1H, s).

The following compounds were produced in the same manner as in Example 1217.

TABLE 266

Example

No.
R₈₂₄
R₈₂₅
Form

¹H NMR (solvent) δppm

1218
3,4-(CH₃)₂Ph—
4-CH₃OPhCH₂—
free
(CDCl₃) 2.34(6H, s), 2.45(4H, brs),

3.45(2H, s), 3.47-3.79(4H, m),

3.81(3H, s), 6.83-6.89(2H, m),

6.97(1H, d, J = 8.9 Hz), 7.11-7.16(2H,

m), 7.21-7.26(3H, m), 7.41-7.46(2H,

m), 7.59-7.62 (1H, m), 7.67(1H, d, J =

1.9 Hz), 7.92(1H, brs), 8.23-8.30(1H,

m), 8.31(1H, d, J = 2.4 Hz).

1219
2-(CH₃)₂NPh—
benzyl
trihydro-
(DMSO-d₆) 3.07(6H, s), 3.17-3.48(8H,

chloride
m), 4.35(2H, s), 7.16-7.21(3H, m),

7.41-7.54(6H, m), 7.59-7.70(4H, m),

7.92(1H, d, J = 7.1 Hz), 8.27(1H, dd, J =

Hz), 11.30(1H, s).

1220
3,5-(CH₃)₂Ph—
benzyl
hydro-
(DMSO-d₆) 2.36(6H, s), 3.00-3.20(2H,

chloride
m), 3.20-3.40(2H, m), 3.47(2H, brs),

4.40(2H, brs), 4.33(2H, s), 7.13(1H, d,

J = 8.9 Hz), 7.19(2H, d, J = 8.6 HO,

7.24(1H, s), 7.40-7.70(7H, m),

7.51(2H, d, J = 8.6 Hz), 8.26(1H, dd, J =

8.9 Hz, 2.6 Hz), 8.56(1H, d, J = 2.6

Hz), 10.41(1H, s).

1221
2,3-
benzyl
hydro-
(DMSO-d₆) 3.00-3.65(6H, m), 3.80(3H,

(CH₃O)₂Ph—

chloride
s), 3.86(3H, s), 4.20(2H, brs), 4.33(2H,

brs), 7.09-7.25(6H, m), 7.40-7.80(7H,

m), 8.23(1H, dd, J = 8.9 Hz, 2.3 Hz),

8.52(1H, d, J = 2.3 Hz), 10.43(1H, s).

1222
4-(CH₃)₂NPh—
benzyl
free
(CDCl₃) 2.48(4H, brs), 3.06(6H, s),

3.55(2H, s), 3.70(4H, brs), 6.71(2H, d,

J = 9.0 Hz), 6.96(1H, d, J = 9.6 Hz),

7.13(2H, d, J = 8.7 Hz), 7.20-7.38(5H,

m), 7.43(2H, d, J = 8.7 Hz), 7.71(1H,

brs), 7.78(2H, d, J = 9.0 Hz), 8.20-

8.30(2H, m).

1223
1-naphthyl
benzyl
free
(DMSO-d₆) 2.41(4H, brs), 3.51(4H,

brs), 3.52 (2H, s), 7.17(3H, d, J = 8.7

Hz), 7.21-7.38(5H, m), 7.44(2H, d, J =

8.7 Hz), 7.55-7.69(3H, m), 7.80(1H, d,

J = 6.4 Hz), 7.98-8.06(1H, m), 8.10

(1H, d, J = 8.1 Hz), 8.18-8.27(1H, m),

8.32(1H, dd, J = 8.7 Hz, 2.6 Hz),

8.58(1H, d, J = 2.6 Hz), 10.76(1H, s).

TABLE 267

Example

No.
R₈₂₆
Form
mp (° C.)

1224

embedded image

maleate
172-175

1225

embedded image

maleate
143-146

1226

embedded image

free
187-189

1227

embedded image

free
191-192

1228

embedded image

maleate
180-182

1229
2,5-(CF₃)₂Ph—
dihydrochloride
152-156

1230
2,5-F₂Ph—
maleate
182-184

1231
2,3-Cl₂Ph—
free
195-196

1232
3-PhOPh—
free
171-172

1233
3-CF₃Ph—
dihydrochloride
146-149

TABLE 268

Example

No.
R₈₂₇
R₈₂₈
R₈₂₉
R₈₃₀
MS (M⁺ + H)

1234
—H
—H
—H
—H
532

1235
—H
—H
—OCH₃
—H
562

1236
—H
—H
—Cl
—H
566

1237
—H
—H
—F
—H
550

1238
—CH₃
—H
—H
—H
546

1239
—H
—H
—Br
—H
612

1240
—H
—H
—CH₃
—H
546

1241
—H
—H
—OCF₃
—H
616

1242
—H
—OCH₃
—H
—H
562

1243
—H
—Cl
—H
—H
566

1244
—H
—H
—H
—OCH₃
562

1245
—H
—Cl
—H
—Cl
600

1246
—H
—H
—H
—Cl
566

1247
—H
—H
—OCH₃
—OCH₃
592

TABLE 269

Ex-

ample

MS

No.
R₈₃₁
R₈₃₂
R₈₃₃
R₈₃₄
R₈₃₅
M
(M⁺ + H)

1248
—H
—H
—H
—H
—H
0
532

1249
—H
—H
—H
—H
—H
2
560

1250
—H
—H
—H
—H
—H
1
546

1251
—H
—H
—Cl
—H
—H
1
580

1252
—H
—CH₃
—H
—H
—H
1
560

1253
—H
—CH₃
—CH₃
—H
—H
1
574

1254
—H
—CH₃
—OCH₃
—H
—H
1
590

1255
—H
—CH₃
—F
—H
—H
1
578

1256
—H
—CH₃
—C(CH₃)₃
—H
—H
1
616

1257
—H
—CH₃
—CH₃
—H
—CH₃
1
588

1258
—H
—CH₃
—Br
—H
—F
1
658

1259
—H
—CH₃
—H
—H
—F
1
578

1260
—H
—CH₃
—C₂H₅
—H
—H
1
588

1261
—H
—H
—F
—H
—H
1
564

1262
—H
—H
—H
—F
—H
1
564

1263
—CH₃
—H
—H
—H
—H
1
560

1264
—H
—H
—OCH₃
—H
—H
1
576

1265
—H
—H
—H
—H
—CH₃
1
560

1266
—H
—H
—CH₃
—H
—H
1
560

1267
—H
—H
—H
—H
—H
1
626

TABLE 270

Example

No.
R₈₃₆

¹H NMR (solvent) δppm

1268
3-CNPh—
(CDCl₃) 2.37-2.44(4H, m), 2.57-2.63(2H, m), 2.88-2.95(2H, m),

3.42-3.45(2H, m), 3.55(2H, s), 3.60-3.64(2H, m), 6.90(1H, d, J =

8.9 Hz), 7.00(2H, d, J = 8.6 Hz), 7.16(2H, d, J = 8.6 Hz), 7.25-

7.31(5H, m), 7.54-7.76(1H, m), 7.76-7.80(1H, m), 8.19-8.26(3H,

m), 8.37(1H, d, J = 2.6 Hz), 9.41(1H, brs).

1269
2-CNPh—
(CDCl₃) 2.35-2.45(4H, m), 2.60-2.66(2H, m), 2.95-3.01(2H, m),

3.40-3.44(2H, m), 3.52(2H, s), 3.63-3.67(2H, m), 7.05-7.13(3H, m),

7.23-7.32(8H, m), 7.69-7.80(3H, m), 7.93-7.96(2H, m), 8.23(1H, d,

J = 2.5 Hz).

1270
3-N(CH₃)₂Ph—
(CDCl₃) 2.35-2.44(4H, m), 2.57-2.62(2H, m), 2.91-2.98(8H, m),

3.39-3.43(2H, m), 3.53(2H, s), 3.62-3.65(2H, m), 6.84-6.92(2H, m),

7.02(2H, d, J = 8.6 Hz), 7.11(1H, d, J = 7.9 Hz), 7.19(2H, d, J = 8.6

Hz), 7.25-7.35(7H, m), 8.22-8.37 (3H, m).

1271
3-CH₃Ph—
(CDCl₃) 2.36-2.46(7H, m), 2.57-2.63(2H, m), 2.91-2.97(2H, m),

3.40-3.44(2H, m), 3.56(2H, s), 3.62-3.66(2H, m), 6.91(1H, d, J =

8.9 Hz), 7.00-7.05(2H, m), 7.19(2H, d, J = 8.6 Hz), 7.25-7.35(7H,

m), 7.66-7.71(2H, m), 8.23-8.31(2H, m), 8.43(1H, brs).

1272
3,4-(CH₃)₂Ph—
(CDCl₃) 2.31(3H, s), 2.32(3H, s), 2.36-2.46(4H, m), 2.58-2.64(2H,

m), 2.92-2.98 (2H, m), 3.41-3.44(2H, m), 3.56(2H, s), 3.63-3.67(2H,

m), 6.90-6.94(1H, m), 7.03(2H, d, J = 8.4 Hz), 7.19-7.37(8H, m),

7.58-7.73(2H, m), 8.21-8.28(3H, m).

1273
2-FPh—
(DMSO-d₆) 2.28-2.31(4H, m), 2.59-2.64(2H, m), 2.78-2.84(2H, m),

3.44-3.47 (6H, m), 7.01(2H, d, J = 8.4 Hz), 7.02-7.05(1H, m),

7.26(2H, d, J = 8.4 Hz), 7.31-7.40(7H, m), 7.51-7.61(1H, m), 7.64-

7.72(1H, m), 8.18(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.45(1H, d, J = 2.5

Hz), 10.54(1H, brs).

1274
3-FPh—
(DMSO-d₆) 2.30(4H, brs), 2.62(2H, brs), 2.81(2H, brs), 3.47(6H,

brs), 7.03(3H, brs), 7.25-7.30(7H, m), 7.47(1H, brs), 7.60(1H, d, J =

6.1 Hz), 7.77-7.81(2H, m), 8.20(1H, d, J = 7.6 Hz), 8.49(1H, brs),

10.46(1H, brs).

1275
4-FPh—
(DMSO-d₆) 2.28-2.30(4H, m), 2.58-2.64(2H, m), 2.77-2.83(2H, m),

3.43-3.46 (6H, m), 7.00(2H, d, J = 8.6 Hz), 7.02(1H, d, J = 8.7 Hz),

7.25(2H, d, J = 8.6 Hz), 7.29-7.40(7H, m), 8.01-8.06(2H, m),

8.18(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.46(1H, d, J = 2.5 Hz),

10.39(1H, brs).

1276
4-AcPh—
(DMSO-d₆) 2.28-2.32(4H, m), 2.59-2.65(5H, m), 2.79-2.84(2H, m),

3.44-3.47 (6H, m), 6.99-7.06(3H, m), 7.27-7.36(7H, m), 8.09(4H,

brs), 8.21(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.50(1H, d, J = 2.6 Hz),

10.56(1H, brs).

1277
3,4-F₂Ph—
(DMSO-d₆) 2.28-2.32(4H, m), 2.59-2.65(2H, m), 2.79-2.84(2H, m),

3.44-3.47 (6H, m), 7.01(2H, d, J = 8.4 Hz), 7.04(1H, d, J = 8.7 Hz),

7.27(2H, d, J = 8.4 Hz), 7.31-7.36(5H, m), 7.59-7.69(1H, m), 7.85-

7.89(1H, m), 8.00-8.07(1H, m), 8.18(1H, dd, J = 8.9 Hz, 2.6 Hz),

8.46(1H, d, J = 2.5 Hz), 10.46(1H, brs).

TABLE 271

Example

No.
R₈₃₇
R₈₃₈
R₈₃₉
R₈₄₀
R₈₄₁

¹H NMR (solvent) δppm or MS

1278
—H
—F
—H
—F
—H

¹H NMR (DMSO-d₆) 2.29-

2.32(4H, m), 2.59-2.65(2H, m),

2.79-2.85(2H, m), 3.44-3.48(6H,

m), 7.00-7.06(3H, m), 7.25-

7.36(7H, m), 7.51-7.59(1H, m),

7.67-7.71(2H, m), 8.19(1H, dd, J =

8.7 Hz, 2.6 Hz), 8.48(1H, d, J =

2.5 Hz) 10.51(1H, brs).

1279
—H
—H
—SO₂NH₂
—H
—H

¹H NMR, (DMSO-d₆) 2.25-

2.35(4H, m), 2.60-2.66(2H, m),

2.74-2.85(2H, m), 3.31 (2H, s),

3.40-3.50(4H, m), 7.00-7.06(3H,

m), 7.25-7.34(7H, m), 7.53(2H, s),

7.97 (2H, d, J = 8.6 Hz), 8.12(2H,

d, J = 8.6 Hz), 8.21(1H, dd, J =

8.9 Hz, 2.7 Hz), 8.49 (1H, d, J =

2.7 Hz), 10.56(1H, s).

1280
—H
—H
—NHAc
—H
—H
MS 576(M⁺ − 1)

1281
—F
—H
—CF₃
—H
—H
MS 607(M⁺ + H)

1282
—COOC₂H₅
—H
—H
—H
—H
MS 593(M⁺ + 1)

1283
—Cl
—Cl
—H
—H
—H
MS 590(M⁺ + 2)

1284
—H
—H
—COOCH₃
—H
—H
MS 579(M⁺ + H)

1285
—OCH₃
—H
—OCH₃
—H
—H
MS 580(M⁺)

1286
—Cl
—H
—Cl
—H
—H
MS 589(M⁺)

1287
—CH₃
—H
—CH₃
—H
—H
MS 548(M⁺)

1288
—F
—H
—F
—H
—H
MS 557(M⁺ + H)

1289
—H
—OCH₃
—OCH₃
—H
—H
MS 580(M⁺)

1290
—CF₃
—H
—H
—H
—H
MS 589(M⁺ + 1)

1291
—H
—CF₃
—H
—H
—H
MS 588(M⁺)

1292
—H
—COOCH₃
—H
—H
—H
MS 579(M⁺ + 1)

1293
—F
—H
—H
—H
—F
MS 557(M⁺ + 1)

1294
—F
—F
—H
—H
—H
MS 557(M⁺ + H)

1295
—CF₃
—H
—H
—CF₃
—H
MS 656(M⁺)

1296
—H
—F
—H
—CF₃
—H
MS 606(M⁺)

1297
—F
—CF₃
—H
—H
—H
MS 607(M⁺ + H)

1298
—F
—H
—H
—CF₃
—H
MS 607(M⁺ + 1)

1299
—CH₃
—H
—H
—CH₃
—H
MS 549(M⁺ + 1)

1300
—F
—H
—H
—F
—H
MS 557(M⁺ + H)

1301
—Cl
—H
—F
—H
—H
MS 572(M⁺)

1302
—H
—OAc
—H
—H
—H
MS 579(M⁺ + 1)

1303
—OCF₃
—H
—H
—H
—H
MS 604(M⁺)

TABLE 272

Example

No.
R₈₄₂
R₈₄₃
R₈₄₄
R₈₄₅
R₈₄₆

¹H NMR or MS

1304
—H
—CF₃
—F
—H
—H
MS 607(M⁺ + 1)

1305
—OCH₃
—H
—H
—OCH₃
—H
MS 580(M⁺)

1306
—Cl
—H
—H
—Cl
—H
MS 590(M⁺ + 1)

1307
—CH₃
—H
—H
—F
—H
MS 552(M⁺)

1308
—N(CH₃)₂
—H
—H
—H
—H
MS 564(M⁺ + H)

1309
—OCH₃
—H
—H
—H
—OCH₃
MS 581(M⁺ + H)

1310
—H
—OPh
—H
—H
—H
MS 630(M⁺ + H)

1311
—H
—OCH₃
—H
—OCH₃
—H
MS 581(M⁺ + H)

1312
—H
—Cl
—H
—Cl
—H
MS 589(M⁺ + H)

1313
—H
—CH₃
—H
—CH₃
—H
MS 549(M⁺ + H)

1314
—OCH₃
—OCH₃
—H
—H
—H
MS 581(M⁺ + H)

1315
—CH₃
—CH₃
—H
—H
—H
MS 549(M⁺ + H)

1316
—CH₃
—F
—H
—H
—H
MS 553(M⁺ + H)

1317
—H
—H
—N(CH₃)₂
—H
—H
MS 564(M⁺ + H)

1318
—H
—CF₃
—H
—CF₃
—H
MS 656(M⁺)

1319
—Cl
—H
—H
—CF₃
—H
MS 622(M⁺)

1320
—H
—CH₃
—NHAc
—H
—H
MS 591(M⁺)

1321
—H
—Cl
—NHAc
—H
—H
MS 611(M⁺)

1322
—H
—OCH₃
—NHAc
—H
—H
MS 607(M⁺)

1323
—H
—NHAc
—CH₃
—H
—H
MS 591(M⁺)

1324
—H
—NHAc
—Cl
—H
—H
MS 611(M⁺)

1325
—H
—NHAc
—OCH₃
—H
—H
MS 607(M⁺)

1326
—H
—NHAc
—F
—H
—H
MS 595(M⁺)

1327
—H
—CH₃
—NHCOPh
—H
—H
MS 653(M⁺)

1328
—H
—Cl
—NHCOPh
—H
—H
MS 673(M⁺)

1329
—H
—OCH₃
—NHCOPh
—H
—H
MS 669(M⁺)

1330
—H
—NHCOPh
—CH₃
—H
—H
MS 653(M⁺)

1331
—H
—NHCOPh
—Cl
—H
—H
MS 673(M⁺)

1332
—H
—NHCOPh
—OCH₃
—H
—H
MS 669(M⁺)

1333
—H
—NHCOPh
—F
—H
—H
MS 657(M⁺)

1334
—COOH
—H
—Cl
—Cl
—H

¹H NMR (DMSO-d₆) δ

2.42(4H, brs), 2.62(2H, t, J =

7.1 Hz), 2.81(2H, t, J =

7.1 Hz), 3.33(1H, brs),

3.47(4H, brs), 3.60(2H, s),

7.00(2H, d, J = 8.6 Hz),

7.02(1H, d, J = 4.7 Hz),

7.26(2H, d, J = 8.6 Hz),

7.28-7.38(5H, m), 7.94(1H,

s), 8.05(1H, s), 8.10(1H,

dd, J = 8.7 Hz, 2.8 Hz),

8.36(1H, d, J = 2.8 Hz),

10.68(1H, s).

TABLE 273

Ex-

ample

No.
R₈₄₇
R₈₄₈
R₈₄₉
R₈₅₀
R₈₅₁
MS

1335
—H
—H
—H
—H
—H
546(M⁺)

1336
—H
—OCH₃
—H
—H
—H
577(M⁺ + H)

1337
—Cl
—H
—H
—H
—H
581(M⁺ + H)

1338
—H
—Cl
—H
—H
—H
581(M⁺ + H)

1339
—H
—H
—Cl
—H
—H
581(M⁺ + H)

1340
—F
—H
—H
—H
—H
565(M⁺ + H)

1341
—H
—F
—H
—H
—H
565(M⁺ + H)

1342
—H
—H
—F
—H
—H
565(M⁺ + H)

1343
—H
—H
—N(CH₃)₂
—H
—H
590(M⁺ + 1)

1344
—H
—OCH₃
—OCH₃
—H
—H
606(M⁺)

1345
—Cl
—H
—H
—H
—Cl
615(M⁺ + 1)

1346
—H
—Cl
—Cl
—H
—H
615(M⁺ + H)

1347
—F
—H
—H
—H
—F
583(M⁺ + H)

1348
—H
—F
—H
—F
—H
583(M⁺ + H)

1349
—H
—OCH₂O—
—H
—H
591(M⁺ + H)

1350
—H
—OCH₃
—H
—OCH₃
—H
607(M⁺ + H)

1351
—H
—H
—CH₃
—H
—H
561(M⁺ + H)

1352
—H
—CF₃
—H
—H
—H
615(M⁺ + H)

1353
—H
—H
—OCH₃
—H
—H
577(M⁺ + 1)

1354
—OCH₃
—OCH₃
—H
—H
—H
606(M⁺)

1355
—OCH₃
—H
—H
—OCH₃
—H
607(M⁺ + 1)

1356
—H
—OCH₃
—OCH₃
—OCH₃
—H
637(M⁺ + 1)

TABLE 274

Example

No.
R₈₅₂

¹H NMR (solvent) δppm

1357

embedded image

(CDCl₃) 1.68-1.86(2H, m), 1.91-2.03(2H, m), 2.12(3H, s), 2.34- 2.40(2H, m), 2.40-2.46(2H, m), 2.48-2.56(1H, m), 2.62(2H, t, J = 7.9 Hz), 2.66-2.75(1H, m), 2.96(2H, t, J = 7.9 Hz), 3.08- 3.18(1H, m), 3.38-3.45(2H, m), 3.51(2H, s), 3.59-3.69(2H, m), 3.88-3.97(1H, m), 4.59-4.69(1H, m), 6.89(1H, d, J = 9.7 Hz), 7.02(2H, d, J = 8.4 Hz), 7.22(2H, d, J = 8.4 Hz), 7.25-7.31(1H, m), 7.31-7.38(4H, m), 7.54(1H, brs), 8.08-8.16(2H, m).

1358

embedded image

(CDCl₃) 2.05-2.18(1H, m), 2.32-2.40(2H, m), 2.40-2.47(2H, m), 2.49-2.56 (1H, m), 2.63(2H, t, J = 7.9 Hz), 2.80-2.90(1H, m), 2.90-3.02(3H, m), 3.36-3.46(2H, m), 3.51(2H, s), 3.60-3.70(2H, m), 4.64-4.70(1H, m), 6.88-7.02(3H, m), 7.04(2H, d, J = 8.4 Hz), 7.09-7.15(1H, m), 7.15-7.22(1H, m), 7.22-7.25(1H, m), 7.25-7.30(2H, m), 7.30-7.38(4H, m), 8.14(1H, dd, J = 8.8, 2.8 Hz), 8.25(1H, d, J = 2.8 Hz), 8.54(1H, brs).

1359
—CH₂OCH₃
(CDCl₃) 2.30-2.38(21, m), 2.38-2.45(2H, m), 2.62(2H, t, J = 7.9

Hz), 2.96 (2H, t, J = 7.9 Hz), 3.35-3.43(2H, m), 3.50(2H, s),

3.52(3H, s), 3.58-3.68(2H, m), 4.04(2H, s), 6.90(1H, d, J = 8.8

Hz), 7.03(2H, d, J = 8.4 Hz), 7.22(2H, d, J = 8.4 Hz), 7.25-

7.29(1H, m), 7.29-7.37(4H, m), 8.14(1H, dd, J = 8.8, 2.8 Hz),

8.18-8.25(2H, m).

1360
—CH₃
(CDCl₃) 2.18(3H, s), 2.32-2.39(2H, m), 2.39-2.45(2H, m),

2.61(2H, t, J = 7.9 Hz), 2.95(2H, t, J = 7.9 Hz), 3.36-3.44(2H,

m), 3.50(2H, s), 3.60-3.68(2H, m), 6.85-6.92(1H, m), 7.02(2H,

d, J = 8.4 Hz), 7.21(2H, d, J = 8.4 Hz), 7.25-7.30(1H, m), 7.30-

7.35(4H, m), 7.38(1H, brs), 8.06-8.15(2H, m).

1361
—C(CH₃)₃
(CDCl₃) 1.32(9H, s), 2.32-2.38(2H, m), 2.38-2.44(2H, m),

2.62(2H, t, J = 7.9 Hz), 2.96(2H, t, J = 7.9 Hz), 3.37-3.43(2H,

m), 3.50(2H, s), 3.60-3.69(2H, m), 6.87(1H, d, J = 9.8 Hz),

7.02(2H, d, J = 8.4 Hz), 7.22(2H, d, J = 8.4 Hz), 7.25-7.30(1H,

m), 7.30-7.37(5H, m), 8.07-8.15(2H, m).

1362
—(CH₂)₂OPh
(DMSO-d₆) 2.23-2.33(4H, m), 2.56-2.67(2H, m), 2.73-2.86(4H,

m), 3.37-3.50(6H, m), 4.26(2H, t, J = 6.0 Hz), 6.90-6.96(3H, m),

6.96-7.02(3H, m), 7.20-7.35(9H, m), 8.07(1H, dd, J = 8.8, 2.7

Hz), 8.33(1H, d, J = 2.7 Hz) 10.23(1H, s).

1363
3-CH₃OPhOCH₂—
(DMSO-d₆) 2.23-2.34(4H, m), 2.58-2.68(2H, m), 2.76-2.85(2H,

m), 3.38-3.50(6H, m), 3.74(3H, s), 4.68(2H, s), 6.51-6.62(3H,

m), 6.95-7.04(3H, m), 7.18-7.28(4H, m), 7.28-7.37(4H, m),

8.09(1H, dd, J = 8.9, 2.7 Hz), 8.36 (1H, d, J = 2.7 Hz),

10.22(1H, s).

1364
3-CH₃PhOCH₂—
(DMSO-d₆) 2.23-2.34(7H, m), 2.56-2.66(2H, m), 2.74-2.84(2H,

m), 3.37-3.50(6H, m), 4.67(2H, s), 6.75-6.81(2H, m), 6.81-

6.88(1H, m), 6.96-7.03(3H, m), 7.14-7.21(1H, m), 7.21-7.28(3H,

m), 7.28-7.36(4H, m), 8.09(1H, dd, J = 8.9, 2.7 Hz), 8.36(1H, d,

J = 2.7 Hz), 10.21(1H, s).

1365
4-CH₃PhOCH₂—
(DMSO-d₆) 2.23(3H, s), 2.26-2.32(4H, m), 2.57-2.65(2H, m),

2.73-2.83(2H, m), 3.36-3.50(6H, m), 4.65(2H, s), 6.90(2H, d, J =

8.5 Hz), 6.95-7.02(3H, m), 7.11(2H, d, J = 8.5 Hz),7.20-

7.29(3H, m), 7.29-7.35(4H, m), 8.08(1H, dd, J = 8.9, 2.7 Hz),

8.36(1H, d, J = 2.7 Hz), 10.21(1H, s).

TABLE 275

Example

No.
R₈₅₃

¹H NMR (DMSO-d₆) δppm or MS

1366
PhOCH₂—

¹H NMR 2.23-2.34(4H, m), 2.57-2.65(2H, m), 2.76-

2.85(2H, m), 3.38-3.50(6H, m), 4.70(2H, s), 6.92-

7.05(6H, m), 7.20-7.27(3H, m), 7.27-7.38(6H, m),

8.09(1H, dd, J = 8.9, 2.7 Hz), 8.36(1H, d, J = 2.7 Hz),

10.24(1H, s).

1367
4-CH₃PhCH₂—

¹H NMR 2.21-2.32(7H, m), 2.56-2.65(2H, m), 2.73-

2.82(2H, m), 3.37-3.49(6H, m), 3.58(2H, s), 6.92-

7.00(3H, m), 7.09-7.16(2H, m), 7.19-7.21(2H, m), 7.21-

7.27(3H, m), 7.27-7.35(4H, m), 8.04(1H, dd, J = 8.9, 2.7

Hz), 8.30(1H, d, J = 2.7 Hz). 10.27(1H, s).

1368
4-ClPhCH₂—

¹H NMR 2.21-2.32(4H, m), 2.55-2.65(2H, m), 2.73-

2.82(2H, m), 3.38-3.49(6H, m), 3.66(2H, s), 6.93-

7.00(3H, m), 7.20-7.26(3H, m), 7.26-7.35(6H, m), 7.35-

7.42(2H, m), 8.04(1H, dd, J = 8.9, 2.7 Hz), 8.30 (1H, d, J =

2.7 Hz), 10.33(1H, s).

1369
4-CH₃OPhCH₂—

¹H NMR 2.22-2.33(4H, m), 2.56-2.65(2H, m), 2.75-

2.83(2H, m), 3.38-3.50(6H, m), 3.56(2H, s), 3.73(3H, s),

6.84-6.90(2H, m), 6.92-7.00 (3H, m), 7.19-7.28(5H, m),

7.28-7.36(4H, m), 8.04(1H, dd, J = 8.9, 2.7 Hz),

8.30(1H, d, J = 2.7 Hz), 10.25(1H, s).

1370
4-FPhCH₂—

¹H NMR 2.23-2.32(4H, m), 2.56-2.65(2H, m), 2.75-

2.84(2H, m), 3.39-3.50(6H, m), 3.64(2H, s), 6,93-

7.00(3H, m), 7.11-7.19(2H, m), 7.21-7.29(3H, m), 7.29-

7.40(6H, m), 8.04(1H, dd, J = 8.9, 2.7 Hz), 8.30 (1H, d, J =

2.7 Hz), 10.31(1H, s).

1371
benzyl

¹H NMR 2.22-2.33(4H, m), 2.56-2.67(2H, m), 2.72-

2.84(2H, m), 3.37-3.50(6H, m), 3.64(2H, s), 6.90-

7.00(3H, m), 7.20-7.29(4H, m), 7.29-7.38(8H, m),

8.05(1H, dd, J = 8.8, 2.7 Hz), 8.31(1H, d, J = 2.7 Hz),

10.32(1H, s).

1372
—(CH₂)₃Ph
MS 563(M⁺ + 1)

1373
—(CH₂)₂CH₃
MS 487(M⁺ + 1)

1374
—CH(CH₃)₂
MS 486(M⁺)

1375
cyclopentyl
MS 512(M⁺)

1376

embedded image

MS 630(M⁺)

1377
—(CH₂)₂Ph
MS 549(M⁺ + H)

1378
2-furyl
MS 511(M⁺ + H)

1379
2-thienyl
MS 527(M⁺ + H)

1380
2-thenyl
MS 541(M⁺ + H)

1381
cyclohexyl
MS 527(M⁺ + H)

1382
cycloheptyl
MS 541(M⁺ + H)

1383
cyclopentylmethyl
MS 527(M⁺ + H)

1384
cyclohexylmethyl
MS 541(M⁺ + H)

1385
2-CH₃OPhOCH₂—
MS 581(M⁺ + 1)

TABLE 276

Example

No.
R₈₅₄
MS

1386

embedded image

581(M⁺ + 1)

1387

embedded image

582(M⁺ + 1)

1388

embedded image

587(M⁺ + H)

1389

embedded image

547(M⁺)

1390

embedded image

547(M⁺)

1391

embedded image

561(M⁺ + 1)

1392
2-CH₃PhOCH₂—
565(M⁺ + H)

1393
2-ClPhOCH₂—
585(M⁺)

1394
3-ClPhOCH₂—
585(M⁺ + H)

1395
4-CNPhOCH₂—
575(M⁺)

1396

embedded image

595(M⁺ + H)

1397
3,4,5-(CH₃O)₃PhOCH₂—
641(M⁺ + 1)

1398

embedded image

556(M⁺ + 1)

1399

embedded image

556(M⁺ + H)

1400

embedded image

590(M⁺ + H)

1401

embedded image

567(M⁺)

1402

embedded image

556(M⁺)

TABLE 277

Example

No.
R₈₅₅
MS

1403

embedded image

566(M⁺ − 1)

1404

embedded image

559(M⁺)

1405

embedded image

562(M⁺ + H)

1406

embedded image

528(M⁺ + 1)

1407
2-quinolyl
571(M⁺)

1408
3-quinolyl
572(M⁺ + H)

1409
4-quinolyl
571(M⁺)

1410
6-quinolyl
571(M⁺)

1411
1-isoquinolyl
571(M⁺)

1412
3-isoquinolyl
572(M⁺ + H)

1413

embedded image

560(M⁺)

1414

embedded image

590(M⁺)

1415
3,4-Cl₂PhCH₂—
603(M⁺ + H)

1416
2-CH₃OPhCH₂—
564(M⁺)

1417
—CH(CH₂Ph)NHAc
605(M⁺)

1418

embedded image

557(M⁺)

1419
—CH₂NHAc
515(M⁺)

1420
—CH(CH₃)NHAc
529(M⁺)

1421
—CH(CH₂Ph)NHCOPh
667(M⁺)

1422

embedded image

619(M⁺)

1423
—CH₂NHCOPh
577(M⁺)

TABLE 278

Example

No.
R₈₅₆
MS

1424
—CH(CH₃)NHCOPh
591(M⁺)

1425
2-pyridyl
522(M⁺ + H)

1426
3-pyridyl
522(M⁺ + H)

1427
4-pyridyl
522(M⁺ + H)

1428
1-naphthyl
571(M⁺ + H)

1429

embedded image

551(M⁺)

1430
2-pyrrolyl
509(M⁺)

1431
3-pyridylmethyl
536(M⁺ + H)

1432
3-furyl
510(M⁺)

1433
3-thienyl
526(M⁺)

1434
3-thenyl
541(M⁺ + H)

1435

embedded image

592(M⁺)

1436
3-CH₃PhCH₂—
549(M⁺ + H)

1437
3-ClPhCH₂—
569(M⁺ + H)

1438
2-FPhCH₂—
553(M⁺ + H)

1439
3-FPhCH₂—
553(M⁺ + H)

1440
2,5-(CH₃O)₂PhCH₂—
594(M⁺)

1441
2,4-Cl₂PhCH₂—
603(M⁺ + H)

1442
2,6-Cl₂PhCH₂—
602(M⁺)

1443
3,4,5-(CH₃O)₃PhCH₂—
624(M⁺)

1444
—CH(OCH₃)Ph
564(M⁺)

1445

embedded image

622(M⁺)

1446

embedded image

588(M⁺ + H)

1447

embedded image

659(M⁺)

1448

embedded image

589(M⁺)

TABLE 279

Example

No.
R₈₅₇
MS

1449

embedded image

589(M⁺)

1450

embedded image

590(M⁺ + H)

1451

embedded image

573(M⁺ + H)

1452
4-CH₃OPhO(CH₂)₂—
595(M⁺ + H)

1453
4-CH₂OPh(CH₂)₂—
579(M⁺ + H)

1454
3,4,5-(CH₃O)₃Ph(CH₂)₂—
638(M⁺)

1455
2,4-Cl₂PhOCH₂—
618(M⁺)

1456
PhSCH₂—
567(M⁺ + H)

1457
—(CH₂)₂COPh
577(M⁺ + H)

1458

embedded image

573(M⁺)

1459

embedded image

588(M⁺ + H)

1460

embedded image

590(M⁺ + H)

1461

embedded image

594(M⁺ + H)

1462

embedded image

578(M⁺ + H)

1463

embedded image

573(M⁺)

1464
4-CH₃OPh(CH₂)₃—
593(M⁺ + H)

1465

embedded image

576(M⁺)

TABLE 280

Example

No.
R₈₅₈
mp (° C.) or ¹H NMR (DMSO-d₆) δppm

1466
2,5-F₂Ph—
mp 173-176

1467

embedded image

mp 181-182

1468

embedded image

mp 199-201

1469
2,3-Cl₂Ph—
mp 149-151

1470
2,4-Cl₂Ph—

¹H NMR 2.54(4H, brs), 2.64(2H, t, J = 7.5 Hz), 2.81(2H, t, J =

7.5 Hz), 3.51 (4H, brs), 3.65(2H, brs), 6.01(2H, s), 6.81(1H,

d, J = 8.0 Hz), 6.89(1H, d, J = 8.0 Hz), 6.92(1H, s), 7.01(2H,

d, J = 8.5 Hz), 7.04(1H, d, J = 9.0 Hz), 7.26(2H, d, J = 8.5

Hz), 7.57(1H, dd, J = 8.5 Hz, 2.0 Hz), 7.65(1H, d, J = 8.5

Hz), 7.78 (1H, d, J = 2.0 Hz), 8.15(1H, dd, J = 9.0 Hz, 2.5

Hz) 8.41(1H, d, J = 2.5 Hz), 10.69(1H, s).

1471
2,5-(CF₃)₂Ph—

¹H NMR 2.54(4H, brs), 2.64(2H, t, J = 7.5 Hz), 2.81(2H, t, J =

7.5 Hz), 3.49 (4H, brs), 3.59(2H, brs), 6.00(2H, s), 6.79(1H,

d, J = 8.0 Hz), 6.88(1H, d, J = 8.0 Hz), 6.90(1H, s), 7.02(2H,

d, J = 8.5 Hz), 7.05(1H, d, J = 9.0 Hz), 7.27(2H, d, J = 8.5

Hz), 8.12-8.14(3H, m), 8.21(1H, s), 8.37(1H, d, J = 2.5 Hz),

10.84 (1H, s).

1472
3-CF₃Ph—

¹H NMR 2.54(4H, brs), 2.64(2H, t, J = 7.5 Hz), 2.82(2H, t, J =

7.5 Hz), 3.51 (4H, brs), 3.63(2H, brs), 6.01(2H, s), 6 81(1H,

d, J = 8.0 Hz), 6.89(1H, d, J = 8.0 Hz), 6.92(1H, s), 7.02(2H,

d, J = 8.5 Hz), 7.05(1H, d, J = 9.0 Hz), 7.27(2H, d, J = 8.5

Hz), 7.80(1H, t, J = 8.0 Hz), 7.99(1H, d, J = 8.0 Hz),

8.19(1H, dd, J = 9.0 Hz, 2.5 Hz), 8.27(1H, d, J = 8.0 Hz),

8.30(1H, s), 8.48(1H, d, J = 2.5 Hz), 10.61(1H, s).

1473
2,3-F₂Ph—

¹H NMR 2.54(4H, brs), 2.64(2H, t, J = 7.5 Hz), 2.81(2H, t, J =

7.5 Hz), 3.51 (4H, brs), 3.62(2H, brs), 6.01(2H, s), 6.80(1H,

d, J = 8.0 Hz), 6.89(1H, d, J = 8.0 Hz), 6.92(1H, s), 7.02(2H,

d, J = 8.5 Hz), 7.04(1H, d, J = 9.0 Hz), 7.26(2H, d, J = 8.5

Hz), 7.36(1H, m), 7.50(1H, m), 7.60(1H, m), 8.16(1H, dd, J =

9.0 Hz, 2.5 Hz), 8.43(1H, d, J = 2.5 Hz), 10.67(1H, s).

TABLE 281

Example

No.
R₈₅₉
Xb₂₃
Form
mp (° C.) or ¹H NMR (solvent) δppm

1474

embedded image

—N(Ac)—
free
mp 142-144

1475
3,4-F₂Ph—
—CH₂—
free

¹H NMR (CDCl₃) 2.31-2.40(4H, m), 2.59-

2.65(2H, m), 2.92-2.98(2H, m), 3.38-3.41(4H,

m), 3.60-3.64(2H, m), 5.94(2H, s), 6.70-

6.77(2H, m), 6.84(1H, s), 6.94(1H, d, J = 8.9

Hz), 7.01-7.07(2H, m), 7.19-7.24(2H, m),

7.29-7.33 (1H, m), 7.62-7.68(1H, m), 7.74-

7.81(1H, m), 8.01(1H, brs), 8.16-8.20(1H, m),

8.24(1H, d, J = 2.2 Hz).

1476

embedded image

—CH₂—
hydro- chloride

¹H NMR (DMSO-d₆) 2.60-2.98(6H, m), 3.01- 3.15(1H, m), 3.26(2H, t, J = 15.0 Hz), 3.46- 3.59(1H, m), 4.00-4.11(1H, m), 4.15-4.27(2H, m), 4.30-4.51(1H, m), 6.05(2H, s), 6.97 (1H, d, J = 7.9 Hz), 6.98-7.09(4H, m), 7.20- 7.31(3H, m), 7.97(1H, d, J = 8.4 Hz), 8.11- 8.23(3H, m), 8.50(1H, d, J = 2.7 Hz), 10.78(1H, s), 11.38(1H, brs).

1477

embedded image

—CH₂—
hydro- chloride

¹H NMR (DMSO-d₆) 2.60-2.99(6H, m), 3.01- 3.17(1H, m), 3.25(2H, t, J = 15.0 Hz), 3.48- 3.60(1H, m), 4.00-4.12(1H, m), 4.15-4.28(2H, m), 4.39-4.51(1H, m), 6.05(2H, s), 6.96 (1H, d, J = 8.8 Hz), 6.99-7.08(4H, m), 7.19- 7.31(3H, m), 7.55(1H, t, J = 7.8 Hz), 7.90- 8.04(2H, m), 8.16(1H, dd, J = 8.8 Hz, 2.7 Hz), 8.43(1H, d, J = 2.7 Hz), 10.82(1H, s), 11.44(1H, brs).

1478

embedded image

—CH₂—
hydro- chloride
mp 213-215

1479

embedded image

—CH₂—
trihydro- chloride

¹H NMR (DMSO-d₆) 2.69-3.40(15H, m), 3.99- 4.49(5H, m), 6.07(2H, s), 6.97-7.09(5H, m), 7.21-7.30(3H, m), 7.43-7.47(1H, m), 7.65- 7.70(2H, m), 7.91(1H, d, J = 9.4 Hz), 8.21(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.48(1H, d, J = 2.1 Hz), 11.23(1H, s).

1480
3-PhOPh—
—CH₂—
hydro-

¹H NMR (DMSO-d₆) 2.60-3.09(7H, m). 3.18-

chloride
3.31(2H, m), 3.38-3.50(1H, m), 4.08(1H, d, J =

14.0 Hz), 4.22(2H, brs), 4.45(1H, d, J =

14.0 Hz), 6.07(2H, s), 6.90-7.08(7H, m), 7.15-

7.26(5H,m), 7.44(2H, t, J = 7.9 Hz), 7.56(1H,

t, J = 7.9 Hz), 7.61(1H, s), 7.79(1H, d, J = 7.6

Hz), 8.19(1H, dd, J = 8.9 Hz, 2.6 Hz),

8.45(1H, d, J = 2.6 Hz), 10.45(1H, s), 10.90-

11.20(1H, m).

TABLE 282

Example

No.
R₈₆₀
R₈₆₁
Xb₂₄
Form
mp (°C) or ¹H NMR (solvent) δppm

1481
1-naphthyl
—H
—CH₂—
hydrochloride

¹H NMR (DMSO-d₆) 2.50-3.60(10H, m),

4.00-4.20(1H, m), 4.22(2H, s), 4.35-4.51(1H,

m), 6.07(2H, s), 6.91-7.08(2H, m), 7.04(2H,

d, J = 8.6 Hz), 7.08(1H, d, J = 8.9 Hz), 7.21(1H,

s), 7.39 (2H, d, J = 8.6 Hz), 7.55-7.67(3H, m),

7.79(1H, d, J = 7.1 Hz), 7.98-8.05(1H, m), 8.10

(1H, d, J = 8.2 Hz), 8.16-8.22(1H, m), 8.26(1H,

dd, J = 8.9 Hz, 2.5 Hz), 8.54(1H, d, J = 2.5 Hz),

10.72(1H, s)

1482

embedded image

—CH₃
—N(CH₃)—
free

¹H NMR (CDCl₃) 2.13(3H, s), 2.43(4H, t, J = 4.8 Hz), 3.01(3H, s), 3.44(2H, s), 3.45-3.56 (2H, m), 3.56-3.70(2H, m), 4.08(2H, s), 4.09(3H, s), 5.95(2H, s), 6.51-6.60(2H, m), 6.72-6.76(2H, m), 6.82(1H, d, J = 8.9 Hz), 6.85(1H, s), 6.92(1H, d, J = 8.4 Hz), 7.04(1H, s), 7.14-7.23(1H, m), 7.28-7.40(1H, m), 7.42 (1H, d, J = 7.9 Hz), 7.67(1H, d, J = 7.9 Hz), 7.94(1H, s), 8.14(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.22(1H, d, J = 2.8 Hz).

1483
3,5-(CH₃)₂Ph—
—H
—CH₂—
hydrochloride
H NMR (DMSO-d₆) 2.36(6H, s), 2.60-3.60

(10H, m), 4.00-4.60(2H, m), 4.29(2H, s), 6.07

(2H, s), 6.85-7.10(5H, m), 7.22(2H, s), 7.27

(2H, d, J = 8.5 Hz), 7.57(2H, s), 7.27 (2H, d,

J = 8.5 Hz), 7.57(2H, s), 8.19 (1H, dd, J = 8.9

Hz, 2.7 Hz), 8.48(1H, d, J = 2.7 Hz),

10.34(1H, s).

1484

embedded image

—CH₃
—N(CH₃)—
free
mp 143-144

1485

embedded image

—CH₃
—N(CH₃)—
free
mp 163-165

1486

embedded image

—CH₃
—N(CH₃)—
free
mp 224-227 dec

1487

embedded image

—CH₃—
—N(CH₃)—
free
mp 131-134

TABLE 283

Example

No.
R₈₆₂
R₈₆₃
Xb₂₅
Form

¹H NMR (solvent) δppm

1488
2,3-(CH₃O)₂Ph—
—H
—CH₂—
hydrochloride
(DMSO-d₆) 3.80(3H, s), 3.86(3H, s),

2.60-3.60(10H, m), 4.00-4.20(1H, m),

4.22(2H, s), 4.40-4.55(1H, m), 6.07(2H,

s), 6.90-7.30(11H, m), 8.18(1H, dd, J =

8.8 Hz, 2.6 Hz), 8.45(1H, d, J = 2.6 Hz),

10.37(1H, s).

1489

embedded image

—CH₃—
—N(CH₃)—
free
(CDCl₃) 2.12(3H, s), 2.35-2.50(4H, m), 3.01(3H, s), 3.43(2H, s), 3.45-3.55(2H, m), 3.57-3.70(2H, m), 4.07 (2H, s), 5.95(2H, s), 6.40(2H, t, J = 2.2 Hz), 6.50-6.5 9(2H, m), 6.74(2H, s), 6.81(1H, d, J = 8.9 Hz), 6.85(1H, s), 6.92(1H, d, J = 8.6 Hz), 7.17(2H, t, J = 2.2 Hz), 7.49(2H, d, J = 8.8 Hz), 7.90(1H, brs), 7.95(2H, d, J = 8.8 Hz), 7.90(1H, brs), 7.95(2H, d, J = 8.8 Hz), 8.15(1H, dd, J = 8.9 Hz, 2.3 Hz), 8.22(1H, d, J = 2.3 Hz).

1490

embedded image

—CH₃
—N(CH₃)—
free
(CDCl₃) 2.04(3H, s), 2.39-2.46(4H, m), 2.94(3H, s), 3.43-3.51(4H, m), 3.59-3.63(2H, m), 4.05(2H, s), 5.94 (2H, s), 6.41-6.48(2H, m), 6.67-6.84(6H, m), 7.44(1H, d, J = 4.1 Hz), 8.01(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.17 (1H, d, J = 2.6 Hz), 8.82(1H, brs).

1491

embedded image

—CH₃
—N(CH₃)—
maleate
(DMSO-d₆) 2.01(3H, s), 2.50(4H, brs), 2.93(3H, s), 3.33(4H, brs), 4.03(2H, s), 4.29(2H, s), 6.06(2H, s), 6.10(2H, s), 6.48(1H, dd, J = 8.9 Hz, 2.8 Hz), 6.56(1H, s), 6.81-7.01(6H, m), 7.43-7.53(2H, m), 7.57(1H, dd, J = 5.9 Hz, 3.6 Hz), 7.77(1H, dd, J = 5.8 Hz, 3.6 Hz), 7.88(1H, d, J = 15.7 Hz), 8.11(1H, dd, J = 8.7 Hz, 2.5 Hz), 8.36(1H, d, J = 2.6 Hz), 10.42(1H, s).

1492
4-(CH₃)₂NPh—
—H
—CH₂—
free
(CDCl₃) 2.33(2H, t, J = 5.0 Hz), 2.39(2H, t, J = 5.0 Hz), 2.61(2H, t, J = 7.5 Hz), 2.97(2H, t, J = 7.5 Hz), 3.05(6H, s), 3.32-3.45(2H, m), 3.41(2H, s), 3.63(2H, t, J = 5.0 Hz), 5.94(2H, s), 6.70(2H, d, J = 9.0 Hz), 6.74 (2H, s), 6.85(1H, s), 6.92(1H, d, J = 9.0 Hz), 7.04(2H, d, J = 8.6 Hz), 7.22(2H, d, J = 8.6 Hz), 7.72(1H, s), 7.78(2H, d, J = 9.0 Hz), 8.21(1H, d, J = 2.8 Hz), 8.23 (1H, dd, J = 8.6 Hz, 2.8 Hz).

1493
2,4-Cl₂PhOCH₂—
—CH₃
—N(CH₃)—
free
(CDCl₃) 2.11(3H, s), 2.42(4H, brs), 3.00(3H, s), 3.43 (2H, s), 3.49(2H, brs), 3.63(2H, brs), 4.07(2H, s), 4.62 (2H, s), 5.94(2H, s), 6.54(1H, dd, J = 11.1 Hz, 2.3 Hz), 6.74-6.92(6H, m), 7.24(1H, dd, J = 8.7 Hz, 2.5 Hz), 7.43(1H, d, J = 2.5 Hz), 8.06(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.23(1H, d, J = 2.6 Hz), 8.55(1H, s).

TABLE 284

Example

No.
R₈₆₄
R₈₆₅
Xb₂₆
Xb₂₇
Form
mp (°C) or ¹H NMR (solvent) δppm

1494

embedded image

—CH₃
—N(CH₃)—
—CH₂—
free

¹H NMR (CDCl₃) 2.10(3H, s), 2.45(4H, brs), 3.01(3H, s), 3.45(2H, s), 3.51 (2H, brs), 3.64(2H, brs), 4.08(2H, s), 5.95 (2H, s), 6.51- 6.59(3H, m), 6.75-6.92 (5H, m), 7.33(1H, d, J = 8.3 Hz), 7.45 (1H, d, J = 8.4 Hz), 7.61- 7.76(3H, m), 8.16(1H, d, J = 8.9 Hz), 8.18(1H, s).

1495

embedded image

—CH₃
—N(CH3)—
—CH₂—
free

¹H NMR (CDCl₃) 2.09(3H, s), 2.34-2.48 (4H, m), 2.98(3H, s), 3.42(2H, s), 3.40- 3.55(2H, m), 3.55-3.70(2H, m), 3.84(3H, s), 4.06(2H, s), 5.94(2H, s), 6.46-6.55(2H, m), 6.67-6.76(2H, m), 6.77(1H, d, J = 8.9 Hz), 6.85(1H, s), 6.89(1H, d, J = 8.5 Hz), 6.93-6.98(1H, m), 6.97(1H, dd, J = 8.9 Hz, 2.3 Hz), 7.04(1H, d, J = 2.3 Hz), 7.30(1H, d, J = 8.9 Hz), 8.11(1H, dd, J = 8.9 Hz), 2.5 Hz), 8.22(1H, s), 8.25(1H, d, J = 2.5 Hz), 9.45 (1H, s).

1496
3,4-(CH₃)₂Ph—
—H
—CH₂—
—CH2—
free

¹H, NMR (CDCl₃) 2.31-2.38(10H, m), 2.57-2.63(2H, m), 2.91-2.97(2H, m), 3.37- 3.40(4H, m), 3.59-3.63(2H, m), 5.93(2H, s), 6.70-6.77(2H, m), 6.84(1H, s), 6.91(1H, d, J = 8.9 Hz), 7.00-7.05(2H, m), 7.17-7.22 (3H, m), 7.60(1H, dd, J = 7.8 Hz, 1.9 Hz), 7.66(1H, d, J = 1.9 Hz), 8.16-8.26(3H, m).

1497

embedded image

—H
—CH₂—
—CH₂—
free

¹H NMR (DMSO-d₆) 2.41(4H, brs), 2.62 (2H, t, J = 7.5 Hz), 2.81(2H, t, J = 7.5 Hz), 3.32(1H, brs), 3.47(4H, brs), 3.52 (2H, s), 6.00(2H, s), 6.78(1H, d, J = 8.0 Hz), 6.87(1H, d, J = 8.0 Hz), 6.88(1H, d, J = 2.0 Hz), 7.00(2H, d, J = 8.5 Hz), 7.03(1H, d, J = 8.9 Hz), 7.26(2H, d, J = 8.5 Hz), 7.94(1H, s), 8.05(1H, s), 8.10 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.36(1H, d, J = 2.6 Hz), 8.36(1H, d, J = 2.6 Hz), 10.72(1H, s).

1498

embedded image

—CH₃
—N(CH₃)—
—CH₂—
hydrochloride
mp 145.0-148.0

1499

embedded image

—CH₃
—N(CH₃)—
—CO—
free
mp 269.0-272.0

TABLE 285

Example

No.
R₈₆₈
R₈₆₇
R₈₆₈
Form

¹H NMR (solvent) δppm

1500
3,4-Cl₂Ph—
—CH₃

embedded image

hydrochloride
(DMSO-d₆) 2.08(3H, s), 3.09(1H, dd, J = 14.2 Hz, 9.7 Hz), 3.40(1H, dd, J = 14.2 Hz, 4.2 Hz), 4.93(1H, dd, J = 9.7 Hz, 4.2 Hz), 7.00(1H, d, J = 8.3 Hz), 7.02(1H, d, J = 8.9 Hz), 7.11(1H, dd, J = 8.3 Hz, 2.0 Hz), 7.20 (1H, d, J = 2.0 Hz), 7.83(1H, d, J = 8.4 Hz), 7.95(1H, dd, J = 8.4 Hz, 2.0 Hz), 8.18 (1H, dd, J = 8.9 Hz, 2.5 Hz), 8.23(1H, d, J = 2.0 Hz), 8.44(1H, d, J = 2.5 Hz), 10.57 (1H, s), 12.08(1H, s).

1501
4-CF₃Ph—
—CH₃

embedded image

free
(DMSO-d₆) 2.09(3H, s), 3.09(1H, dd, J = 14.1 Hz, 9.6 Hz), 3.40(1H, dd, J = 14.1 Hz, 4.3 Hz), 4.93(1H, dd, J = 9.6 Hz, 4.3 Hz), 6.99(1H, d, J = 8.2 Hz), 7.03(1H, d, J = 8.9 Hz), 7.12(1H, dd, J = 8.2 Hz, 2.0 Hz), 7.20 (1H, d, J = 2.0 Hz), 7.93(2H, d, J = 8.2 Hz), 8.16(2H, d, J = 8.2 Hz), 8.20(1H, dd, J = 8.9 Hz, 2.5 Hz), 8.45(1H, d, J = 2.5 Hz), 10.60(1H, s), 12.07(1H, s).

1502
3-CF₃Ph—
—H

embedded image

free
(CDCl₃) 1.28(3H, t, J = 7.0 Hz), 1.46(2H, dq, J = 4.0 Hz, 12.5 Hz), 1.85(2H, brd, J = 12.5 Hz), 1.93(1H, m), 2.73(2H, dt, J = 2.5 Hz, 12.0 Hz), 3.61(2H, brd, J = 12.0 Hz), 4.15(2H, q, J = 7.0 Hz), 6.90(1H, d, J = 9.0 Hz), 6.96(2H, d, J = 9.0 Hz), 7.03(2H, d, J = 9.0 Hz), 7.65(1H, t, J = 8.0 Hz), 7.83(1H, d, J = 8.0 Hz), 7.86(1H, brs), 8.07(1H, d, J = 8.0 Hz), 8.14(1H, brs), 8.18(1H, dd, J = 9.0 Hz, 2.5 Hz), 8.27(1H, d, J = 2.5 Hz).

Example 1503
Production of N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide

To a suspension of 1-(4-piperonylpiperazin-1-yl)-2-{methyl-[3-methyl-4-(5-nitropyridin-2-yloxy)phenyl]amino}ethanone (2.65 g, 5.10 mmol) in ethyl acetate (50 mL) was added 5% platinum-carbon (0.20 g) under a nitrogen atmosphere, and the resulting mixture was stirred for 11 hours under a hydrogen atmosphere. The platinum-carbon was separated off by filtration using Celite. To a solution of the resulting filtrate in ethyl acetate was added triethylamine (0.78 mL, 5.61 mmol) under ice cooling, and then to the resulting solution was added 4-(trifluoromethyl)benzoyl chloride (0.80 mL, 5.36 mmol). This reaction solution was stirred for 16 hours, and then added a saturated sodium bicarbonate solution. The resulting solution was stirred at room temperature, and after 20 minutes, extracted with ethyl acetate. The ethyl acetate layer was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from acetone-diethyl ether, to thereby yield 3.03 g of the title compound.

Appearance: Pale yellow powder

Melting point: 153.0-154.5° C.; ¹H NMR (CDCl₃) δ 2.12 (3H, s), 2.31-2.52 (4H, m), 3.01 (3H, s), 3.38-3.72 (6H, m), 4.07 (2H, s), 5.95 (2H, s), 6.49-6.61 (2H, m), 6.69-6.78 (2H, m), 6.79-6.88 (2H, m), 6.92 (1H, d, J=8.6 Hz), 7.76 (2H, d, J=8.3 Hz), 7.81-7.90 (1H, m), 7.99 (2H, d, J=8.3 Hz), 8.13 (1H, dd, J=8.8 Hz, 2.6 Hz), 8.23 (1H, d, J=2.6 Hz).

A crude titled product (5.00 g, 7.6 mmol) obtained using the same procedures was recrystallized from ethanol (15 mL), to thereby yield 3.90 g of the title compound.

Appearance: Pale yellow powder

Melting point: 156-158° C.

The following compounds were produced in the same manner as in Example 1503.

Example 1504
N-{6-[2-methyl-4-(2-oxo-3-piperonylimidazolidin-1-yl)phenoxy]pyridin-3-yl}-4-trifluoromethylbenzamide

mp 188.0-189.0° C.

TABLE 286

Example

No.
R₈₆₉
R₈₇₀
R₈₇₁
R₈₇₂
R₈₇₃
M
form
mp (°C) or ¹H NMR (solvent) δppm

1505
—Cl
—Cl
cyclopentyl
—H
piperonyl
2
oxalate
mp 135-139

1506
—Cl
—Cl
—(CH₂)₂CH₃
—H
piperonyl
2
free

¹H NMR (DMSO-(d₆) 0.86(3H, t, J = 7.5 Hz), 1.56(2H, q, J = 7.5 Hz), 2.27 (2H, brs), 2.64(2H, t, J = 7.4 Hz), 2.83(2H, t, J = 7.4 Hz), 3.37-3.48 (6H, m), 3.84(2H, t, J = 7.5 Hz), 5.98 (2H, s), 6.36(1H, d, J = 9.1 Hz), 6.74 (1H, d, J = 7.9 Hz), 6.83(1H, d, J = 7.9 Hz), 6.86(1H, s), 7.16(2H, d, J = 8.2 Hz), 7.30(2H, d, J = 8.2 Hz), 7.70 (1H, dd, J = 9.1 Hz, 2.6 Hz), 7.81(1H, d, J = 8.4 Hz), 7.93(1H, dd, J = 8.4 Hz, 1.9 Hz), 8.19(1H, d, J = 1.9 Hz), 8.43(1H, d, J = 2.6 Hz), 10.27(1H, s).

1507
—Cl
—Cl
—CH₃
—OCH₃
piperonyl
2
free

¹H NMR (CDCl₃) 2.34-2.41(4H, m), 2.62-2.68(2H, m), 2.95- 3.01(2H, m), 3.34(3H, s), 3.38-3.45(4H, m), 3.62-3.65(2H, m), 3.75(3H, s), 5.94 (2H, s), 6.25(1H, d, J = 9.2 Hz), 6.70-6.84(5H, m), 7.12(1H, d, J = 7.6 Hz), 7.53(1H, d, J = 8.2 Hz), 7.67- 7.72(2H, m), 7.97(2H, d, J = 2.0 Hz), 8.24(1H, d, J = 2.5 Hz).

1508
—CF₃
—H
—CH₃
—OCH₃
piperonyl
2
free

¹H NMR (CDCl₃) 2.36- 2.37(4H, m), 2.62-2.67(2H, m), 2.94-2.99(2H, m), 3.28-3.45(7H, m), 3.60- 3.64(2H, m), 3.74(3H, s), 5.93(2H, s), 6.25(1H, d, J = 9.1 Hz), 6.70- 6.84(5H, m), 7.11(1H, d, J = 7.6 Hz), 7.67-7.75(3H, m), 7.97(2H, d, J = 7.9 Hz), 8.16-8.32(2H, m).

1509
—Cl
—Cl
—CH₃
—H
benzyl
0
oxalate
mp 228-230

TABLE 287

Example

No.
R₈₇₄
R₈₇₅
R₈₇₆
R₈₇₇
R₈₇₈
Form
mp (°C) or ¹H NMR (solvent) δppm

1510
—Cl
—Cl
—H

embedded image

piperonyl
dioxolate

¹H NMR (DMSO-d₆) 2.36-2.50 (4H, m), 2.73(6H, s), 3.42-3.56 (6H, m), 3.94(2H, s), 4.56(2H, s), 5.98(2H, s), 6.76(1H, d, J = 8.0 Hz), 6.85(1H, d, J = 8.0 Hz), 6.88 (1H, s), 7.13(1H, d, J = 8.9 Hz), 7.23(2H, d, J = 8.8 Hz), 7.45(2H, d, J = 8.8 Hz), 7.83(1H, d, J = 8.4 Hz), 7.93(1H, dd, J = 8.4 Hz), 2.0 Hz), 8.20-8.25(2H, m), 8.52(1H, d, J = 2.7 Hz), 10.63(1H, s).

1511
—CF₃
—H
—CH₃
—H
piperonyl
free

¹H NMR (CDCl₃) 2.11(3H, s), 2.42-2.48(4H, m), 3.45-3.48(4H, m), 3.66-3.70(2H, m), 3.86(2H, s), 4.83(1H, brs), 5.96(2H, s), 6.46-6.52(2H, m), 6.71-6.78(2H, m), 6.83-6.91(3H, m), 7.75-7.82 (3H, m), 7.99(2H, d, J = 8.1 Hz), 8.16(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.22(1H, d, J = 2.8 Hz).

1512
—Cl
—Cl
—CH₃
—CH₃
piperonyl
hydrochloride
mp 183-185 dec

1513
—CF₃
—H
—CH₃
—C₂H₅
benzyl
maleate
mp 165-167

1514
—Cl
—Cl
—CH₃
—C₂H₃
benzyl
free
mp 102-105

1515
—CF₃
—H
—CH₃
—CH₃
benzyl
free
mp 110-111

1516
—Cl
—Cl
—CH₃
—CH₃
benzyl
free
mp 111-113

TABLE 288

Example No.
R₈₇₉
Form
mp (°C) or MS

1517
3,4-Cl₂Ph—
maleate
mp 203-205

1518
3-PhOPh—
free
MS 686(M⁺ + H)

1519
3,5-Cl₂Ph—
free
MS 662(M⁺ + H)

1520
3,5-(CH₃)₂Ph—
free
MS 622(M⁺ + H)

1521
2,3-(CH₃)₂Ph—
free
MS 622(M⁺ + H)

1522
2,3-Cl₂Ph—
free
MS 662(M⁺ + H)

1523
1-naphthyl
free
MS 644(M⁺ + H)

1524
2,4-(CH₃)₂Ph—
free
MS 622(M⁺ + H)

1525
3,4-(CH₃)₂Ph—
free
MS 622(M⁺ + H)

1526
3,4-F₂Ph—
free
MS 630(M⁺ + H)

1527
3-CF₃Ph—
free
MS 663(M⁺ + H)

1528
3-CF₃OPh—
free
MS 678(M⁺ + H)

1529
4-CF₃OPh—
free
MS 678(M⁺ + H)

1530
3-ClPhOCH₂—
free
MS 658(M⁺ + H)

1531
2-quinolyl
free
MS 645(M⁺ + H)

1532
4-quinolyl
free
MS 645(M⁺ + H)

1533
1-isoquinolyl
free
MS 645(M⁺ + H)

1534
3-isoquinolyl
free
MS 645(M⁺ + H)

1535
3,4-Cl₂PhCH₂—
free
MS 676(M⁺ + H)

1536
2,4-Cl₂PhCH₂—
free
MS 676(M⁺ + H)

1537
3,5-(CF₃)₂Ph—
free
MS 731(M⁺ + H)

1538
2,4-Cl₂PhOCH₂—
free
MS 691(M⁺ + H)

1539
4-CH₃OPh—
free
MS 624(M⁺ + H)

1540
4-CH₃PhCH₂—
free
MS 622(M⁺ + H)

1541
PhOCH₂—
free
MS 624(M⁺ + H)

1542
3-pyridyl
free
MS 595(M⁺ + H)

1543
—CH(CH₃)₂
free
MS 560(M⁺ + H)

1544
cyclopentyl
free
MS 586(M⁺ + H)

1545
cyclohexyl
free
MS 600(M⁺ + H)

1546
cycloheptyl
free
MS 614(M⁺ + H)

1547
cycloheptylmethyl
free
MS 628(M⁺ + H)

1548
3-CH₃Ph—
free
MS 608(M⁺ + H)

1549
3-(CH₃)₂NPh—
free
MS 637(M⁺ + H)

1550
4-(CH₃)₂NPh—
free
MS 637(M⁺ + H)

1551
2,5-(CH₃)₂Ph—
free
MS 622(M⁺ + H)

1552
—CH(CH₃)Ph
free
MS 622(M⁺ + H)

1553
—C(CH₃)₃
free
MS 574(M⁺ + H)

TABLE 289

Example

No.
R₈₈₀
MS (M⁺ + H)

1554

embedded image

626

1555

embedded image

681

1556

embedded image

681

1557

embedded image

663

1558

embedded image

646

1559

embedded image

677

1560

embedded image

661

1561

embedded image

621

1562

embedded image

601

1563

embedded image

660

1564

embedded image

661

1565

embedded image

702

TABLE 290

Example

No.
R₈₈₁
MS (M⁺ + H)

1566

embedded image

660

1567

embedded image

679

1568

embedded image

672

1569

embedded image

759

1570

embedded image

680

1571

embedded image

651

1572

embedded image

584

1573

embedded image

616

1574

embedded image

601

1575

embedded image

601

1576

embedded image

662

1577

embedded image

704

1578

embedded image

660

TABLE 291

Example

No.
Xb₂₈
R₈₈₂
R₈₈₃
R₈₈₄
R₈₈₅
R₈₈₆
MS (M⁺ + H)

1579
—NH—
—H
—H
—H
—H
—H
634

1580
—O—
—H
—H
—H
—H
—H
634

1581
—O—
—H
—H
—H
—H
—OCH₃
664

1582
—NH—
—H
—H
—OCH₃
—H
—H
663

1583
—NH—
—H
—H
—Cl
—H
—H
667

1584
—NH—
—H
—H
—F
—H
—H
651

1585
—N(CH₃)—
—H
—H
—H
—H
—H
647

1586
—S—
—H
—H
—H
—H
—H
650

1587
—NH—
—H
—H
—Br
—H
—H
711

1588
—NH—
—H
—H
—CH₃
—H
—H
648

1589
—NH—
—H
—H
—OCF₃
—H
—H
717

1590
—NH—
—H
—OCH₃
—H
—H
—H
664

1591
—NH—
—H
—Cl
—H
—H
—H
667

1592
—NH—
—H
—H
—H
—OCH₃
—H
663

1593
—NH—
—H
—Cl
—H
—Cl
—H
701

1594
—NH—
—H
—H
—H
—Cl
—H
667

1595
—NH—
—H
—H
—OCH₃
—OCH₃
—H
693

1596
—O—
—CH³
—H
—H
—H
—H
648

1597
—O—
—H
—H
—OCH₃
—H
—H
664

1598
—O—
—H
—H
—Cl
—H
—H
668

TABLE 292

Example

No.
R₈₈₇
R₈₈₈
R₈₈₉
R₈₉₀
R₈₉₁
MS (M⁺ + H)

1599
—H
—OCH₃
—H
—H
—H
650

1600
—H
—H
—OCH₃
—H
—H
650

1601
—H
—Cl
—H
—H
—H
654

1602
—F
—H
—H
—H
—H
638

1603
—H
—F
—H
—H
—H
638

1604
—OCH₃
—OCH₃
—H
—H
—H
680

1605
—OCH₃
—H
—H
—OCH₃
—H
680

1606
—H
—OCH₃
—OCH₃
—H
—H
680

1607
—Cl
—H
—H
—H
—Cl
688

1608
—H
—Cl
—Cl
—H
—H
688

1609
—F
—H
—H
—H
—F
656

1610
—H
—F
—H
—F
—H
656

1611
—H
—OCH₂O—
—H
—H
664

1612
—H
—OCH₃
—OCH₃
—OCH₃
—H
711

1613
—H
—OCH₃
—H
—OCH₃
—H
681

1614
—H
—CF₃
—H
—H
—H
689

Example 1615
Production of 3,4-dichloro-N-[6-(2-fluoro-4-{methyl[2-oxo-2-(4-piperonylpiperazin-1-yl)ethyl]amino}phenoxy)pyridin-3-yl]benzenesulfonamide

To a solution of 2-{[4-(5-aminopyridin-2-yloxy)-3-fluorophenyl]methylamino}-1-(4-piperonylpiperazin-1-yl)ethanone (15.85 g, 1.9 mmol) in dichloromethane (150 mL) were added 3,4-dichlorobenzenesulfonyl chloride (12.92 g, 1.9 mmol) and pyridine (11 mL, 12.4 mmol), and the resulting solution was stirred for 1 hour at room temperature. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from ethanol, to thereby yield 5.6 g of the title compound.

Appearance: White powder; Melting point: 185.6-187.0° C.;

¹H NMR (CDCl₃) δ 2.45 (4H, t, J=4.6 Hz), 3.01 (3H, s), 3.44 (2H, s), 3.47 (2H, brs), 3.64 (2H, brs), 4.07 (2H, s), 5.95 (2H, s), 6.33-6.44 (2H, m), 6.71-6.78 (2H, m), 6.84-6.87 (2H, m), 6.98 (1H, t, J=9.1 Hz), 7.47 (1H, dd, J=8.4 Hz, 2.0 Hz), 7.51 (2H, dd, J=8.4 Hz, 2.8 Hz), 7.68 (1H, d, J=2.1 Hz), 7.83 (1H, d, J=1.8 Hz); MS 701 (M⁺).

The following compounds were produced in the same manner as in Example 1615.

TABLE 293

Example

No.
R₈₉₂
R₈₉₃
R₈₉₄
R₈₉₅
M

¹H NMR (solvent) δppm

1616
—CH₃
—H
—H
benzyl
2
(CDCl₃) 2.29-2.37(2H, m), 2.37-2.45(5H, m), 2.61(2H, t, J = 7.9 Hz), 2.95(2H, t, J = 7.9 Hz), 3.35-3.42(2H, m), 3.50(2H, s), 3.59-3.68(2H, m), 6.58(1H, brs), 6.83(1H, d, J = 8.8 Hz), 7.00(2H, d, J = 8.4 Hz), 7.18-7.38(9H, m), 7.55-7.63(3H, m), 7.68(1H, d, J = 2.8 Hz).

1617
—CF₃
—H
—H
benzyl
0
(CDCl₃) 2.46(4H, brs), 3.54(2H, s), 3.54(2H, brs), 3.79 (2H, brs), 6.88(1H, d, J = 8.7 Hz), 7.10(2H, d, J = 8.6 Hz), 7.28-7.33(5H, m), 7.42(2H, d, J = 8.6 Hz), 7.59(1H, dd, J = 8.7 Hz, 2.8 Hz), 7.73(2H, d, J = 8.4 Hz), 7.74(1H, s), 7.86(2H, d, J = 8.4 Hz).

1618
—CF₃
—H
—CH₃
piperonyl
2
(DMSO-d₆) 1.96(3H, s), 2.20-2.40(4H, m), 2.56-2.62 (2H, m), 2.73-2.78(2H, m), 3.32(2H, s), 3.37-3.43(4H, m), 5.99(2H, s), 6.74(1H, dd, J = 7.9 Hz, 1.3 Hz), 6.82-6.93(4H, m), 7.05(1H, dd, J = 8.2 Hz, 1.9Hz), 7.12 (1H, s), 7.52(1H, dd, J = 8.8 Hz, 2.7 Hz), 7.73(1H, d, J = 2.7 Hz), 7.89-7.98(4H, m), 10.45(1H, brs).

1619
—Cl
—Cl
—OCH₃
piperonyl
2
(DMSO-d₆) 2.20-2.40(4H, m), 2.58-2.64(2H, m), 2.75-2.81(2H, m), 3.37-3.43(6H, m), 3.60(3H, s), 5.97 (2H, s), 6.70-7.00(7H, m), 7.47(1H, dd, J = 8.8 Hz, 2.8 Hz), 7.61(1H, dd, J = 8.5 Hz, 2.1Hz), 7.68(1H, d, J = 2.6 Hz), 7.82-7.86(2H, m), 10.32(1H, brs).

1620
—CF₃
—H
—OCH₃
piperonyl
2
(DMSO-d₆) 2.20-2.40(4H, m), 2.55-2.70(2H, m), 2.75-2.85(2H, m), 3.30-3.50(6H, m), 3.58(3H, s), 5.97 (2H, s), 6.71-7.00(7H, m), 7.47(1H, dd, J = 8.8 Hz, 2.7 Hz), 7.67(1H, d, J = 2.7 Hz), 7.87-7.98(4H, m), 10.40(1H, brs).

1621
—Cl
—Cl
—CH₃
piperonyl
2
(DMSO-d₆) 1.97(3H, s), 2.20-2.35(4H, m), 2.56-2.62 (2H, m), 2.73-2.79(2H, m), 3.37-3.50(6H, m), 5.98(2H, s), 6.72-6.76(1H, m), 6.82-6.94(4H, m), 7.00-7.13(2H, m), 7.52(1H, dd, J = 8.8 Hz, 2.8 Hz), 7.62(1H, dd, J = 8.4 Hz, J = 2.1 Hz), 7.72(1H, d, J = 2.6 Hz), 7.83(1H, d, J = 2.1 Hz), 7.85(1H, d, J = 8.5 Hz), 10.36(1H, brs).

1622
—CF₃
—H
—F
piperonyl
2
(DMSO-d₆) 2.20-2.35(4H, m), 2.60-2.66(2H, m), 2.78-2.84(2H, m), 3.39(2H, s), 3.42-3.50(4H, m), 5.99(2H, s), 6.72-6.76(1H, m), 6.83-6.86(2H, m), 7.03-7.24(4H, m), 7.55(1H, dd, J = 8.8 Hz, 2.7 Hz), 7.75(1H, d, J = 2.7 Hz), 7.90-7.99(4H, m), 10.52(1H, brs).

TABLE 294

Example

No.
R₈₉₆
R₈₉₇
R₈₉₈
mp (°C) or ¹H NMR (solvent) δppm

1623
—CF₃
—H

embedded image

mp 208.0-209.0

1624
—Cl
—Cl

embedded image

¹H NMR (CDCl₃) 1.70(1H, brs), 2.42(4H, t, J = 5.1 Hz), 3.39(4H, t, J = 5.1 Hz), 3.43(2H, s), 4.38(2H, d, J = 5.4 Hz), 4.80 (1H, t, J = 5.4 Hz), 5.94(2H, s), 6.73(2H, s), 6.84(1H, s), 6.86(1H, d, J = 8.5 Hz), 7.00(2H, d, J = 8.6 Hz), 7.27(2H, d, J = 8.6 Hz), 7.51(2H, d, J = 2.5 Hz), 7.58(1H, dd, J = 8.7 Hz, 2.7 Hz), 7.73(1H, dd, J = 2.7 Hz, 0.7 Hz), 7.83(1H, t, J = 2.5 Hz).

1625
—Cl
—Cl

embedded image

¹H NMR (DMSO-d₆) 2.20-2.35(4H, m), 2.56-2.62(2H, m), 2.77-2.82(2H, m), 3.30-3.50(6H, m). 5.98(2H, s), 6.70-6.80 (1H, m), 6.82-6.90(3H, m), 6.93-6.97(2H, m), 7.05-7.10(1H, m), 7.24-7.35(1H, m), 7.54(1H, dd, J = 8.8 Hz, 2.8 Hz), 7.64(1H, dd, J = 8.5 Hz, 2.0 Hz), 7.80(1H, d, J = 2.8 Hz), 7.86(1H, d, J = 8.4 Hz), 7.89(1H, d, J = 2.0 Hz), 10.43(1H, brs).

1626
—CF₃
—H

embedded image

¹H NMR (DMSO-d₆) 2.20-2.30(4H, m), 2.55-2.61(2H, m), 2.76-2.82(2H, m), 3.30-3.40(6H, m), 5.98(2H, s), 6.70-6.80 (1H, m), 6.82-6.95(5H, m), 7.05(1H, d, J = 7.7 Hz), 7.23-7.30(1H, m), 7.54(1H, dd, J = 8.8 Hz, 2.8 Hz), 7.80(1H, d, J = 2.8 Hz), 7.90-7.99(4H, m), 10.52(1H, brs).

1627
—Cl
—Cl

embedded image

¹H NMR (DMSO-d₆) 2.25-2.45(4H, m), 3.42(2H, s), 3.50-3.75(4H, m), 5.99(2H, s), 6.75-6.80(1H, m), 6.83-6.88(2H, m), 7.00(1H, d, J = 8.8 Hz), 7.05-7.10(1H, m), 7.25-7.29(1H, m), 7.35-7.65(6H, m), 7.8 0(1H, d, J = 2.7 Hz), 7.86(1H, d, J = 8.4 Hz), 7.90(1H, d, J = 2.1 Hz), 10.44 (1H, brs).

TABLE 295

Example

No.
R₈₉₉
R₉₀₀
M
mp (°C) or ¹H NMR (DMSO-d₆) δppm

1628
4-CF₃Ph—
piperonyl
2

¹H NMR 1.89-2.06(5H, m), 3.17-3.31(2H,

m), 3.52-3.71(2H, m), 4.39(2H, s), 5.98(2H,

m), 6.75(1H, dd, J = 1.2 Hz, 7.9 Hz),

6.83(1H, d, J = 1.2 Hz), 6.86(1H, d, J = 7.9

Hz), 6.92(1H, d, J = 8.6 Hz), 6.95(1H, d, J =

8.8 Hz), 7.09(1H, dd, J = 2.5 Hz, 8.6 Hz),

7.18(1H, d, J = 2.5 Hz), 7.53(1H, dd, J = 2.8

Hz, 8.8 Hz), 7.75(1H, d, J = 2.8 Hz),

7.90(2H, d, J = 8.4 Hz), 7.96(2H, d, J = 8.4

Hz), 10.47(1H, s).

1629
3,4-Cl₂Ph—
piperonyl
2

¹H NMR 1.89-2.09(5H, m), 3.19-3.33(2H,

m), 3.50-3.71(2H, m), 4.39(2H, s), 5.98(2H,

s), 6.73-6.78(1H, m), 6.83(1H, d, J = 1.3

Hz), 6.86(1H, d, J = 7.9 Hz), 6.93(1H, d, J =

8.6 Hz), 6.97(1H, d, J = 8.8 Hz), 7.10(1H, d,

J = 2.4 Hz, 8.6 Hz), 7.19(1H, d, J = 2.4 Hz),

7.53(1H, dd, J = 2.7 Hz, 8.8 Hz), 7.62(1H,

dd, J = 2.1 Hz, 8.4 Hz), 7.75(1H, d, J = 2.7

Hz), 7.83(1H, d, J = 2.1 Hz), 7.85(1H, d, J =

8.4 Hz), 10.37(1H, s).

1630

4-CF₃Ph—
piperonyl
1
mp 163.0-164.0

1631
3,4-Cl₂Ph—
piperonyl
1
mp 190.5-191.0

1632

4-CF₃Ph—
3,4-(CH₃O)₂PhCH₂—
2
mp 141.0-143.0

1633
3,4-Cl₂Ph—
3,4-(CH₃O)₂PhCH₂—
2
mp 135.0-136.0

1634
3,4-Cl₂Ph—

embedded image

2
mp 181.0-183.0

TABLE 296

Example

No.
R₉₀₁
R₉₀₂
M

¹H NMR (CDCl₃) δppm

1635
3,4-Cl₂Ph—
—CH₃
0
1.27(3H, t, J = 7.1 Hz), 1.84-2.05(4H, m), 2.06(3H, s),

2.40-2.48(1H, m), 2.71-2.81(2H, m), 3.56-3.61(2H, m

4.16(2H, q, J = 7.1 Hz), 6.74-6.79(3H, m), 6.89(1H, d, J =

8.6 Hz), 7.47-7.57(4H, m) 7.76-7.79(2H, m).

1636
4-CF₃Ph—
—CH₃
0
1.27(3H, t, J = 7.1 Hz), 1.84-2.00(4H, m), 2.03(3H, s),

2.42-2.51(1H, m), 2.70-2.79(2H, m), 3.55-3.60(2H, m),

4.16(2H, q, J = 7.1 Hz), 6.68-6.78(3H, m), 6.87(1H, d, J =

8.6 Hz), 7.55 (1H, dd, J = 8.7 Hz, 2.6 Hz), 7.67(2H, d, J =

8.2 Hz), 7.79-7.84(3H, m), 8.10(1H, s).

1637
3,4-Cl₂Ph—
—H
1
1.27(3H, t, J = 7.1 Hz), 1.39-1.48(2H, m), 1.81-1.92(3H,

m), 2.29(2H, d, J = 6.9 Hz), 2.71(2H, dd, J = 12.2 Hz, 9.9

Hz), 3.59(2H, d, J = 12.4 Hz), 4.15(2H, q, J = 7.3 Hz),

6.78(1H, d, J = 8.7 Hz), 6.90-6.98(4H, m), 7.50(2H, d, J =

1.2 Hz), 7.55(1H, dd, J = 8.7 Hz, 2.6 Hz), 7.78-7.81(3H, m).

1638
4-CF₃Ph—
—H
1
1.27(3H, J = 7.1 Hz), 1.36-1.48(2H, m), 1.81-1.92(3H,

m), 2.29(2H, d, J = 6.9 Hz), 2.70(2H, dd, J = 12.2 Hz, 9.9

Hz), 3.59(2H, d, J = 12.2 Hz), 4.15(2H,

q, J = 7.3 Hz), 6.75(1H, d, J = 8.9 Hz), 6.89-6.97(4H, m),

7.55(1H, dd, J = 8.7 Hz, 2.6 Hz), 7.68(2H, d, J = 8.7 Hz),

7.79-7.85(4H, m).

1639
4-CF₃Ph—
—OCH₃
1
1.27(3H, t, J = 7.1 Hz), 1.30-1.48(2H, m), 1.82-2.05(3H,

m), 2.29(2H, d, J = 6.9 Hz), 2.69-2.77(2H, m), 3.60(2H, d,

J = 12.2 Hz), 3.68(3H, s), 4.15(2H, q, J = 7.1 Hz),

6.48(1H, dd, J = 8.6 Hz, 2.5 Hz), 6.56(1H, d, J = 2.6 Hz),

6.76(1H, d, J = 8.7 Hz), 6.94(1H, d, J = 8.7 Hz), 7.54(1H,

dd, J = 8.7 Hz, 2.8 z), 7.66-7.73(4H, m), 7.83(2H, d, J =

8.2 Hz).

1640
3,4-Cl₂Ph—
—OCH₃
1
1.28(3H, t, J = 7.1 Hz), 1.30-1.48(2H, m), 1.82-2.05(3H,

m), 2.29(2H, d, J = 6.9 Hz), 2.73(2H, t, J = 12.0 Hz),

3.60(2H, d, J = 12.2 Hz), 3.69(3H, s), 4.16(2H, q, J = 7.1

Hz), 5.29(2H s), 6.48(1H, dd, J = 8.7 Hz, 2.6 Hz),

6.56(1H, d, J = 2.6 Hz), 6.77(1H, d, J = 8.7 Hz), 6.94(1H,

d, J = 8.6 Hz), 7.46-7.75(3H, m), 7.79-7.80(3H, m).

1641
4-CF₃Ph—
—H
0
1.27(3H, t, J = 7.1 Hz , 1.81-1.94(2H, m), 2.00-2.05(2H,

m), 2.40-2.54(1H, m), 2.71-2.82(2H, m), 3.56-3.60(2H, m),

4.16(2H, q, J = 7.1 Hz), 6.78(1H, d, J = 8.9 Hz), 6.90-

6.99(5H, m), 7.56(1H, dd, J = 8.9 Hz, 2.8 z), 7.70(2H, d, J =

8.4 Hz), 7.77(1H, d, J = 2.8 Hz), 7.84(2H, d, J = 8.2 Hz).

1642
3,4-Cl₂Ph—
—H
0
1.27(3H, t, J = 7.3 Hz), 1.89-1.94(2H, m), 2.01-2.05(2H,

m), 2.38-2.54(1H, m), 2.72-2.82(2H, m), 3.56-3.61(2H, m),

4.16(2H, q, J = 7.1 Hz), 6.80(1H, d, J = 8.7 Hz), 6.91-

7.00(4H, m), 7.26(1H, brs), 7.51-7.58(3H, m), 7.77(1H, d,

J = 2.8 Hz), 7.82(1H, s).

TABLE 297

Example

No.
R₉₀₃
R₉₀₄
M

¹H NMR (CDCl₃) δppm

1643
4-CF₃Ph—
—CH₃
1
1.27(3H, t, J = 7.1 Hz), 1.38-1.43(2H, m), 1.80-

2.01(3H, m), 2.02(3H, s), 2.29(2H, d, J = 6.9 Hz),

2.69(2H, t, J = 12.0 Hz), 3.58(2H, d, J = 12.0 Hz),

4.15(2H, q, J = 7.3 Hz), 6.67-6.87(4H, m), 7.53-

7.68(3H, m), 7.79-7.84(4H, m).

1644
3,4-Cl₂Ph—
—CH₃
1
1.27(3H, t, J = 7.1 Hz), 1.30-1.48(2H, m), 1.80-

2.04(3H, m), 2.05(3H, s), 2.29(2H, d, J = 6.9 Hz),

2.69(2H, t, J = 12.0 Hz), 3.58(2H, d, J = 12.0 Hz),

4.15(2H, q, J = 7.1 Hz), 6.71-6.79(3H, m), 6.88(1H, d, J =

8.6 Hz), 7.49-7.57(4H, m), 7.77(2H, d, J = 2.8 Hz).

TABLE 298

Example

No.
R₉₀₅
R₉₀₆
R₉₀₇
Form
mp (° C.)

1645
4-CF₃Ph—
—H
—CH₃
hydrochloride
189.0-191.0

1646
3,4-Cl₂Ph—
—H
—CH₃
free
180.0-182.0

1647
4-CF₃Ph—
—CH₃
—H
free
129.5-131.0

1648
3,4-Cl₂Ph—
—CH₃
—H
free
129.0-130.0

TABLE 299

Example

No.
R₉₀₈
R₉₀₉

¹H NMR (DMSO-d₆) δppm

1649

embedded image

—F
2.20-2.35(4H, m), 2.60-2.66(2H, m), 2.77-2.83(2H, m), 3.39(2H, s), 3.39-3.50(4H, m), 5.99(2H, s), 6.65-6.76(1H, m), 6.83-6.86(2H, m), 7.01-7.25(4H, m), 7.30-7.40(1H, m), 7.55(1H, dd, J = 8.8 Hz, 2.8 Hz), 7.72(1H, dd, J = 8.7 Hz, 2.6 Hz), 7.78(1H, d, J = 2.3 Hz), 8.00-8.05(1H, m), 10.65(1H, brs).

1650

embedded image

—CH₃
1.94(3H, s), 2.20-2.35(4H, m), 2.56-2.61(2H, m), 2.72- 2.78(2H, m), 3.38(2H, s), 3.38-3.50(4H, m), 5.98(2H, s), 6.72-6.75(1H, m), 6.82-6.91(4H, m), 7.03-7.12(2H, m), 7.30-7.45(1H, m), 7.52(1H, dd, J = 8.8 Hz, 2.2 Hz), 7.71(1H, dd, J = 8.7 Hz, 2.1 Hz), 7.78(1H, d, J = 2.7 Hz), 7.98-8.04(1H, m), 10.58(1H, brs).

1651
3,4-Cl₂Ph—
—H
2.20-2.35(4H, m), 2.57-2.63(2H, m), 2.76-2.82(2H, m),

3.39(2H, s), 3.39-3.43(4H, m), 5.99(2H, s), 6.70-6.76(1H,

m), 6.82-6.86(2H, m), 6.93-6.98(3H, m), 7.22-7.26(2H, m),

7.51-7.55(1H, m), 7.63(1H, dd, J = 8.5 Hz, 2.0 Hz),

7.79(1H, d, J = 2.7 Hz), 7.86(1H, d, J = 8.5 Hz), 7.88(1H,

d, J = 2.1 Hz), 10.41(1H, brs).

1652
4-CF₃Ph—
—H
2.20-2.35(4H, m), 2.57-2.63(2H, m), 2.76-2.82(2H, m),

3.32(2H, s), 3.32-3.50(4H, m), 5.98(2H, s), 6.70-6.76(1H,

m), 6.82-6.86(2H, m), 6.92-6.98(3H, m), 7.22-7.25(2H, m),

7.52(1H, dd, J = 8.8 Hz, 2.8 Hz), 7.78(1H, d, J = 2.7 Hz),

7.90-7.99(4H, m), 10.50(1H, brs).

1653
3,4-Cl₂Ph—
—F
2.20-2.35(4H, m), 2.60-2.66(2H, m), 2.78-2.84(2H, m),

3.39(2H, s), 3.42-3.50(4H, m), 5.99(2H, s), 6.70-6.76(1H,

m), 6.82-6.86(2H, m), 7.04-7.30(4H, m), 7.55(1H, dd, J =

8.8 Hz, 2.8 Hz), 7.63(1H, dd, J = 8.5 Hz, 2.2 Hz), 7.75(1H,

d, J = 2.6 Hz), 7.85(1H, d, J = 8.5 Hz), 7.88(1H, d, J = 2.1

Hz), 10.43(1H, brs).

TABLE 300

Example

No.
R₉₁₀
R₉₁₁
R₉₁₂
R₉₁₃
mp (° C.) or ¹H NMR (solvent) δppm

1654
4-CF₃Ph—
—F
—H
—CH₃
mp 186.0-188.0

1655
3,4-Cl₂Ph—
—F
—H
—C₂H₅
mp 157.3-160.1

1656
4-CF₃Ph—
—F
—H
—C₂H₅
mp 173.0-176.8

1657
4-CF₃Ph—
—OCH₃
—H
—C₂H₅
mp 179.0-181.0

1658
3,4-Cl₂Ph—
—OCH₃
—H
—C₂H₅
mp 175.0-176.0

1659
4-CF₃Ph—
—CH₃
—H
—CH₃
mp 170.0-172.0

1660
3,4-Cl₂Ph—
—CH₃
—H
—CH₃
mp 170.0-173.0

1661
3,4-Cl₂Ph—
—H
—H
—CH₃
mp 135.0-137.0

1662
4-CF₃Ph—
—H
—H
—CH₃
mp 189.0-190.0

1663
4-CF₃Ph—
—F
—F
—CH₃
mp 159.5-160.0

1664
3,4-Cl₂Ph—
—F
—F
—CH₃
mp 136.0-137.0

1665
Ph—
—H
—H
—CH₃

¹H NMR (CDCl₃) 2.41-2.45(4H, m), 3.01(3H,

s), 3.43 (2H, s), 3.47-3.49(2H, m), 3.63(2H,

brs), 4.07(2H, s), 5.95(2H, s), 6.63(1H, brs),

6.66(2H, d, J = 9.1 Hz), 6.71-6.77(3H, m),

6.85(1H, brs), 6.93(2H, d, J = 9.1 Hz), 7.42-

7.59(4H, m), 7.68-7.73(3H, m).

1666
—(CH₂)₃CH₃
—H
—H
—CH₃

¹H NMR (CDCl₃) 0.93(3H, t, J = 7.3 Hz),

1.36-1.50(2H, m), 1.75-1.87(2H, m), 2.41-

2.45(4H, m), 3.01-3.06(5H, m), 3.44(2H, s),

3.47-3.49(2H, m), 3.63(2H, brs), 4.09(2H, s),

5.95(2H, s), 6.37(1H, brs), 6.69(2H, d, J =

9.1 Hz), 6.72-6.77(2H, m), 6.82-6.96(2H, m),

6.99(2H, d, J = 9.1 Hz), 7.65(1H, dd, J = 8.7

Hz, 2.8 Hz), 8.00(1H, d, J = 2.8 Hz).

1667
4-CH₃Ph—
—H
—H
—CH₃

¹H NMR (CDCl₃) 2.39(3H, s), 2.41-2.44(4H,

m), 3.01(3H, s), 3.43(2H, s), 3.47-3.49(2H,

m), 3.62(2H, brs), 4.07(2H, s), 5.95(2H, s),

6.46-6.51(1H, m), 6.66(2H, d, J = 8.9 Hz),

6.70-6.77(3H, m), 6.85(1H, brs), 6.94(2H, d,

J = 8.9 Hz), 7.23(2H, d, J = 8.1 Hz),

7.50(1H, dd, J = 8.2 Hz, 2.8 Hz), 7.58(2H, d,

J = 8.4 Hz), 7.66(1H, d, J = 2.6 Hz).

1668

embedded image

—F
—H
—CH₃

¹H NMR (DMSO-d₆) 2.25-2.45(4H, m), 2.91(3H, s), 3.42 (6H, brs), 4.26(2H, s), 5.99(2H, s), 6.30-6.40(1H, m), 6.45-6.55(1H, m), 6.74-6.77(1H, m), 6.83-7.05(4H, m), 7.30-7.45(1H, m), 7.51(1H, dd, J = 8.9 Hz, 2.8 Hz), 7.71 (1H, dd, J = 8.7 Hz, 2.5 Hz), 7.79(1H, d, J = 2.7 Hz), 8.02(1H, dd, J = 8.9 Hz, 5.9 Hz), 10.60(1H, brs).

1669
3,4-Cl₂Ph—
—COOCH₃
—H
—C₂H₅

¹H NMR (DMSO-d₆) 1.11(3H, t, J = 7.0 Hz),

2.20-2.5 (4H, m), 3.30-3.50(11H, m),

4.22(2H, s), 5.99(2H, s), 6.75-7.00(7H, m),

7.45-7.55(1H, m), 7.60-7.70 (2H, m), 7.83-

7.87(2H, m), 10.31(1H, brs).

TABLE 301

Example

No.
R₉₁₄
R₉₁₅
R₉₁₆
R₉₁₇

¹H NMR (solvent) δppm

1670

embedded image

—F
—CH₃
—H
(DMSO-d₆) 2.23(3H, s), 2.25-2.45(4H, m), 2.91(3H, s), 3.41(6H, brs), 3.83(3H, s), 4.25(2H, s), 5.99(2H, s), 6.30-6.40(1H, m), 6.45-6.55(1H, m), 6.75-6.77(1H, m), 6.83- 6.99(4H, m), 7.07(1H, d, J = 8.5 Hz), 7.30- 7.40(1H, m), 7.48(1H, d, J = 1.9 Hz), 7.51(1H, dd, J = 8.8 Hz, 2.7 Hz), 7.74(1H, d, J = 2.6 Hz), 9.85(1H, brs).

1671
3,4-Cl₂Ph—
—CH₃
—CH₃
—CH₃
(CDCl₃) 1.28(3H, d, J = 6.6 Hz), 2.05(3H,

s), 2.08-2.21 (1H, m), 2.33(2H, brs),

2.50(1H, brs), 2.75(3H, s), 3.29-3.57(3H,

m), 3.38(2H, s), 3.77(1H, brs), 4.55(1H, q, J =

6.6 Hz), 5.94(2H, s), 6.56-6.59(2H, m),

6.68-6.75(2H, m), 6.79-6.82(2H, m), 6.89-

6.93(1H, m), 7.51-7.52(2H, m), 7.57(1H, dd,

J = 8.9 Hz, 2.8 Hz), 7.71(1H, dd, J = 2.8 Hz,

0.5 Hz), 7.79(1H, dd, J = 1.7 Hz, 0.8 Hz).

1672
4-CF₃Ph—
—CH₃
—CH₃
—CH₃
(CDCl₃) 1.28(3H, d, J = 6.4 Hz), 2.07(3H,

s), 2.17-2.20 (1H, m), 2.33-2.36(2H, m),

2.47-2.49(1H, m), 2.75(3H, s), 3.28-

3.30(1H, m), 3.38(2H, s), 3.38-3.50(1H, m),

3.52-3.56(1H, m), 3.77-3.82(1H, m),

4.55(1H, q, J = 6.6 Hz), 5.94(2H, s), 6.55-

6.59(2H, m), 6.68-6.75(2H, m), 6.78-

6.82(2H, m), 6.89-6.92(1H, m), 7.57(1H, dd,

J = 8.7 Hz, 2.8 Hz), 7.70(1H, dd, J = 2.8 Hz,

0.5 Hz), 7.73(2H, d, J = 8.3 Hz), 7.85(2H, d,

J = 8.3 Hz).

1673

embedded image

—F
—CH₃
—H
(DMSO-d₆) 2.20-2.50(4H, m), 2.91(3H, s), 3.35-3.50 (6H, m), 4.26(2H, s), 5.99(2H, s), 6.20-6.30(1H, m), 6.45-6.55(1H, m), 6.75- 6.80(1H, m), 6.84-7.01(4H, m), 7.52(1H, dd, J = 8.8 Hz, 2.7 Hz), 7.79(1H, d, J = 2.8 Hz), 7.97(1H, dd, J = 8.2 Hz, 1.5 Hz), 8.09(1H, d, J = 8.2 Hz), 8.29(1H, d, J = 1.5 Hz), 10.80(1H, brs).

1674
4-PhOPh—
—F
—CH₃
—H
(DMSO-d₆) 2.20-2.45(4H, m), 2.92(3H, s),

3.35-3.50 (6H, m), 4.26(2H, s), 5.99(2H, s),

6.35-6.45(1H, m), 6.45-6.60(1H, m),

6.76(1H, d, J = 7.9 Hz), 6.83-6.87 (2H, m),

6.93-7.14(6H, m), 7.20-7.30(1H, m), 7.43-

7.55(3H, m), 7.68-7.74(3H, m), 10.17(1H,

brs).

1675
3,4-Cl₂Ph—
—CF₃
—C₂H₅
—H
(DMSO-d₆) 1.11(3H, t, J = 6.9 Hz), 2.25-

2.45(4H, m), 3.35-3.55(8H, m), 4.27(2H, s),

5.99(2H, s), 6.67-6.88(5H, m), 6.94-

7.05(2H, m), 7.52(1H, dd, J = 8.8 Hz, 2.8

Hz), 7.63(1H, dd, J = 8.4 Hz, 2.2 Hz),

7.75(1H, d, J = 2.7 Hz), 7.83-7.87(2H, m),

10.38(1H, brs).

TABLE 302

Example

No.
R₉₁₈
R₉₁₉
R₉₂₀
R₉₂₁
R₉₂₂
Form
Property

1676
4-CF₃Ph—
—F
—F
—H
—CH₃
free
mp 199.0-200.0° C.

1677
3,4-Cl₂Ph—
—F
—F
—H
—CH₃
free
mp 198.0-199.0° C.

1678
4-CF₃Ph—
—F
—H
—F
—CH₃
free
mp 176.0-177.0° C.

1679
3,4-Cl₂Ph—
—F
—H
—F
—CH₃
free
mp 115.0-116.0° C.

1680
4-CF₃Ph—
—F
—H
—F
—C₂H₅
free
mp 173.0-174.0° C.

1681
3,4-Cl₂Ph—
—F
—H
—F
—C₂H₅
free
mp 156.0-157.0° C.

1682
3,4-Cl₂Ph—
—CH₃
—H
—CH₃
—C₂H₅
hydro-

¹H NMR (DMSO-d₆) δ 0.95(3H, t,

chloride
J = 7.0 Hz), 1.97(3H, s), 2.28(3H,

s), 2.70-4.40(14H, m), 6.07(2H, s),

6.86(1H, brs), 6.93-7.10(3H, m),

7.20-7.40(2H, m), 7.56(1H, dd, J =

8.8 Hz, 2.7 Hz), 7.66 (1H, dd, J =

8.5 Hz, 2.1 Hz), 7.78(1H, d, J =

2.6 Hz), 7.85-7.88(2H, m),

10.55(1H, brs), 11.47(1H, brs).

1683
4-CF₃Ph—
—CH₃
—H
—CH₃
—C₂H₅
free

¹H NMR (DMSO-d₆) δ 0.92(3H, t,

J = 7.0 Hz), 1.91(3H, s), 2.16(3H,

s), 2.20-2.40(4H, m), 2.98(2H, q, J =

7.0 Hz), 3.30-3.50(6H, m),

3.77(2H, s), 5.98(2H, s), 6.72-

6.76(2H, m), 6.82-6.90(3H, m),

7.01(1H, s), 7.51(1H, dd, J = 8.8

Hz, 2.8 Hz), 7.75(1H, d, J = 2.7

Hz), 7.89-7.99(4H, m), 10.45(1H,

brs).

1684
3,4-Cl₂Ph—
—F
—H
—H
—H
hydro-

¹H NMR (DMSO-d₆) δ 2.75-

chloride
3.65(7H, m), 3.85-4.55(6H, m),

6.08(2H, s), 6.47-6.50(1H, m),

6.59(1H, dd, J = 13.5 Hz, 2.6 Hz),

6.92-7.01(4H, m), 7.20(1H, s),

7.52(1H, dd, J = 8.7 Hz, 2.6 Hz),

7.64(1H, dd, J = 8.4 Hz, 2.1 Hz),

7.76(1H, d, J = 2.5 Hz), 7.86(1H,

d, J = 8.6 Hz), 7.89(1H, d, J = 2.2

Hz), 10.45(1H, s), 10.90 (1H, brs).

1685
4-
—H
—H
—H
—CH₃
free
MS 646(M⁺ + H)

CH₃OPh—

1686
1-naphthyl
—H
—H
—H
—CH₃
free
MS 666(M⁺ + H)

1687
2-naphthyl
—H
—H
—H
—CH₃
free
MS 666(M⁺ + H)

1688
2-CH₃Ph—
—H
—H
—H
—CH₃
free
MS 630(M⁺ + H)

1689
4-FPh—
—H
—H
—H
—CH₃
free
MS 634(M⁺ + H)

1690
2-CF₃Ph—
—H
—H
—H
—CH₃
free
MS 684(M⁺ + H)

1691
2-ClPh—
—H
—H
—H
—CH₃
free
MS 650(M⁺ + H)

TABLE 303

Example

No.
R₉₂₃
R₉₂₄
MS (M⁺ + H)

1692
2-thienyl
—H
622

1693
2-CF₃OPh—
—H
700

1694
3-CF₃OPh—
—H
700

1695
3-CH₃OPh—
—H
646

1696
3-FPh—
—H
634

1697
2,3-Cl₂Ph—
—H
684

1698
3-CF₃Ph—
—H
684

1699
4-CF₃OPh—
—H
700

1700
4-bipenylyl
—H
692

1701
3,4-(CH₃O)₂Ph—
—H
676

1702
2,5-(CH₃O)₂Ph—
—H
676

1703
3-CH₃Ph—
—H
630

1704
2,5-Cl₂Ph—
—H
684

1705
3-ClPh—
—H
650

1706
2,4-Cl₂Ph—
—H
684

1707
2,3,4-Cl₂Ph—
—H
720

1708
—C₂H₅
—H
568

1709
2,6-Cl₂Ph—
—H
684

1710
4-CH₃OPh—
—F
664

1711
4-ClPh—
—F
668

1712
1-naphthyl
—F
684

1713
2-naphthyl
—F
684

1714
2-CH₃Ph—
—F
648

1715
4-FPh—
—F
652

1716
2-CF₃Ph—
—F
702

1717
2-thienyl
—F
640

1718
2-ClPh—
—F
668

1719
2-CF₃OPh—
—F
718

1720
3-CF₃OPh—
—F
718

1721
2-CNPh—
—F
660

1722
3-CH₃OPh—
—F
664

1723
3-FPh—
—F
652

1724
2,3-Cl₂Ph—
—F
702

1725
3-CF₃Ph—
—F
702

1726
4-CF₃OPh—
—F
718

1727
4-biphenylyl
—F
710

1728
3,4-(CH₃O)₂Ph—
—F
694

1729
2,5-(CH₃O)₂Ph—
—F
694

TABLE 304

Example

No.
R₉₂₅
R₉₂₆
MS (M⁺ + H)

1730
3-CH₃Ph—
—F
648

1731
2,5-Cl₂Ph—
—F
702

1732
3-ClPh—
—F
668

1733
2,4-Cl₂Ph—
—F
702

1734
—CH₃
—F
572

1735
2,3,4-Cl₃Ph—
—F
738

1736
—(CH₂)₃CH₃
—F
614

1737
—C₂H₅
—F
586

1738
2,6-Cl₂Ph—
—F
702

1739
4-CH₃OPh—
—CH₃
660

1740
4-ClPh—
—CH₃
664

1741
1-naphthyl
—CH₃
680

1742
2-naphhyl
—CH₃
680

1743
2-CH₃Ph—
—CH₃
644

1744
4-FPh—
—CH₃
648

1745
2-CF₃Ph—
—CH₃
698

1746
2-thienyl
—CH₃
636

1747
2-ClPh—
—CH₃
664

1748
2-CF₃OPh—
—CH₃
714

1749
2-CNPh—
—CH₃
656

1750
3-CH₃OPh—
—CH₃
660

1751
3-FPh—
—CH₃
648

1752
2,3-Cl₂Ph—
—CH₃
698

1753
3-CF₃Ph—
—CH₃
698

1754
4-CF₃OPh—
—CH₃
714

1755
4-biphenylyl
—CH₃
706

1756
3,4-(CH₃O)₂Ph—
—CH₃
690

1757
2,5-(CH₃O)₂Ph—
—CH₃
690

1758
3-CH₃Ph—
—CH₃
644

1759
2,5-Cl₂Ph—
—CH₃
698

1760
3-ClPh—
—CH₃
664

1761
2,4-Cl₂Ph—
—CH₃
698

1762
—CH₃
—CH₃
568

1763
2,3,4-Cl₃Ph—
—CH₃
734

1764
—(CH₂)₃CH₃
—CH₃
610

1765
—C₂H₅
—CH₃
582

1766
2,6-Cl₂Ph—
—CH₃
698

1767
2,4,5-Cl₃Ph—
—H
719

TABLE 305

Example

No.
R₉₂₇
R₉₂₈
MS (M⁺ + H)

1768
2,4,6-(CH₃)₃Ph—
—H
658

1769
4-C₂H₅Ph—
—H
644

1770
2,5-(CH₃)₂Ph—
—H
644

1771
2-FPh—
—H
634

1772
2,4,6-(CH₃)₃Ph—
—F
676

1773
4-CH₃Ph—
—F
648

1774
4-C₂H₅Ph—
—F
662

1775
2,5-(CH₃)₂Ph—
—F
662

1776
2-FPh—
—F
652

1777
2,4,5-Cl₃Ph—
—CH₃
732

1778
2,4,6-(CH₃)₃Ph—
—CH₃
672

1779
4-CH₃Ph—
—CH₃
644

1780
4-C₂H₅Ph—
—CH₃
658

1781
2,5-(CH₃)₂Ph—
—CH₃
658

1782
2-FPh—
—CH₃
648

1783
4-BrPh—
—H
696

1784
—CH(CH₃)₃
—H
582

1785
8-quinolyl
—H
667

1786
3-CNPh—
—H
641

1787
4-PhOPh—
—H
708

1788
3-BrPh—
—H
696

1789
4-CNPh—
—H
641

1790
2,4-F₂Ph—
—H
652

1791
4-BrPh—
—F
714

1792
—CH(CH₃)₂
—F
600

1793
8-quinolyl
—F
685

1794
3-CNPh—
—F
659

1795
4-CNPh—
—F
659

1796
2,4-F₂Ph—
—F
670

1797
4-BrPh—
—CH₃
710

1798
—CH(CH₃)₂
—CH₃
596

1799
8-quinolyl
—CH₃
681

1800
3-CNPh—
—CH₃
655

1801
3-BrPh—
—CH₃
710

1802
4-CNPh—
—CH₃
655

1803
2,4-F₂Ph—
—CH₃
666

1804
2,4,6-Cl₃Ph—
—H
720

1805
2,4,6-Cl₃Ph—
—F
738

TABLE 306

Example

No.
R₉₂₉
R₉₃₀
MS (M⁺ + H)

1806
2,4,5-Cl₃Ph—
—F
738

1807
2,4,6-Cl₃Ph—
—CH₃
734

1808
Ph—
—F
634

1809
Ph—
—CH₃
630

1810
2,5-F₂Ph—
—F
670

1811
2,5-F₂Ph—
—CH₃
666

1812
2,6-F₂Ph—
—CH₃
666

1813
3,4-F₂Ph—
—CH₃
666

1814
2,6-F₂Ph—
—H
652

1815
3,4-F₂Ph—
—H
652

1816
2,6-F₂Ph—
—F
670

1817
3,4-F₂Ph—
—F
670

1818
—CH₃
—H
554

1819

embedded image

—H
680

1820

embedded image

—H
660

1821

embedded image

—F
698

1822

embedded image

—CH₃
694

1823

embedded image

—CH₃
674

1824

embedded image

—H
718

1825

embedded image

—H
668

1826

embedded image

—H
698

1827

embedded image

—H
718

TABLE 307

Example

No.
R₉₃₁
R₉₃₂
MS (M⁺ + H)

1828

embedded image

—H
675

1829

embedded image

—H
686

1830

embedded image

—H
742

1831

embedded image

—H
672

1832

embedded image

—H
660

1833

embedded image

—H
688

1834

embedded image

—F
716

1835

embedded image

—F
736

1836

embedded image

—F
718

1837

embedded image

—F
678

1838

embedded image

—F
747

1839

embedded image

—F
706

1840

embedded image

—CH₃
712

TABLE 308

Example

No.
R₉₃₃
R₉₃₄
MS (M⁺ + H)

1841

embedded image

—CH₃
732

1842

embedded image

—CH₃
689

1843

embedded image

—CH₃
700

1844

embedded image

—CH₃
714

1845

embedded image

—CH₃
674

1846

embedded image

—CH₃
743

1847

embedded image

—CH₃
702

1848

embedded image

—H
700

1849

embedded image

—H
709

1850

embedded image

—H
680

1851

embedded image

—H
674

1852

embedded image

—H
698

TABLE 309

Example

No.
R₉₃₅
R₉₃₆
MS (M⁺ + H)

1853

embedded image

—H
682

1854

embedded image

—H
710

1855

embedded image

—H
707

1856

embedded image

—F
727

1857

embedded image

—F
698

1858

embedded image

—F
692

1859

embedded image

—F
716

1860

embedded image

—F
700

1861

embedded image

—F
728

1862

embedded image

—F
725

1863

embedded image

—CH₃
723

TABLE 310

Example

No.
R₉₃₇
R₉₃₈
MS (M⁺ + H)

1864

embedded image

—CH₃
694

1865

embedded image

—CH₃
688

1866

embedded image

—CH₃
712

1867

embedded image

—CH₃
696

1868

embedded image

—CH₃
724

1869

embedded image

—CH₃
721

1870

embedded image

—H
730

1871

embedded image

—F
736

1872

embedded image

—F
704

1873

embedded image

—CH₃
732

1874

embedded image

—CH₃
682

1875

embedded image

—H
668

TABLE 311

Example

No.
R₉₃₉
R₉₄₀
MS (M⁺ + H)

1876

embedded image

—H
660

1877

embedded image

—H
664

1878

embedded image

—H
648

1879

embedded image

—H
664

1880

embedded image

—H
714

1881

embedded image

—H
664

1882

embedded image

—F
678

1883

embedded image

—F
682

1884

embedded image

—F
666

1885

embedded image

—F
682

1886

embedded image

—F
686

1887

embedded image

—CH₃
682

1888

embedded image

—F
682

TABLE 312

Example

No.
R₉₄₁
R₉₄₂
MS (M⁺ + H)

1889

embedded image

—CH₃
674

1890

embedded image

—CH₃
678

1891

embedded image

—CH₃
662

1892

embedded image

—CH₃
678

1893

embedded image

—CH₃
728

1894

embedded image

—CH₃
678

1895

embedded image

—F
732

1896

embedded image

—F
760

1897

embedded image

—CH₃
756

1898
3-BrPh—
—F
714

1899
4-PhOPh—
—CH₃
722

1900

embedded image

—F
690

1901

embedded image

—CH₃
686

TABLE 313

Example

No.
R₉₄₃
R₉₄₄
MS (M⁺ + H)

1902

embedded image

—H
678

1903

embedded image

—H
658

1904

embedded image

—H
700

1905

embedded image

—H
700

1906

embedded image

—H
674

1907

embedded image

—H
620

1908

embedded image

—F
696

1909

embedded image

—F
676

1910

embedded image

—F
718

1911

embedded image

—F
718

1912

embedded image

—F
692

1913

embedded image

—F
638

TABLE 314

Example

No.
R₉₄₅
R₉₄₆
MS (M⁺ + H)

1914

embedded image

—CH₃
692

1915

embedded image

—CH₃
672

1916

embedded image

—CH₃
714

1917

embedded image

—CH₃
714

1918

embedded image

—CH₃
688

1919

embedded image

—CH₃
634

1920

embedded image

—H
673

1921
vinyl
—H
566

1922
—(CH₂)₃Cl
—H
616

1923
cyclohexylmethyl
—H
636

1924

embedded image

—F
691

1925
vinyl
—F
584

1926
—(CH₂)₃Cl
—F
634

1927
cyclohexylmethyl
—F
654

1928

embedded image

—CH₃
687

1929
vinyl
—CH₃
580

1930
—(CH₂)₃Cl
—CH₃
630

1931
cyclohexylmethyl
—CH₃
650

1932
2-BrPh—
—H
696

1933

embedded image

—H
656

TABLE 315

Example

No.
R₉₄₇
MS (M⁺ + H)

1934
3,5-Cl₂Ph
684

1935

embedded image

683

1936

embedded image

682

1937

embedded image

702

1938

embedded image

687

1939

embedded image

681

1940

embedded image

723

1941
5-isoquinolyl
667

1942
—CH₂CF₃
622

1943

embedded image

688

1944

embedded image

668

1945

embedded image

635

1946

embedded image

690

1947

embedded image

690

TABLE 316

Example

MS

No.
R₉₄₈
R₉₄₉
(M⁺ + H)

1948
—CH₂Cl
—H
588

1949

embedded image

—H
702

1950

embedded image

—H
660

1951

embedded image

—H
694

1952

embedded image

—H
680

1953

embedded image

—H
726

1954
benzyl
—H
630

1955
PhCH═CH—
—H
642

1956
—(CH₂)₂CH₃
—H
582

1957
2-BrPh—
—F
714

1958

embedded image

—F
674

1959
3,5-Cl₂Ph
—F
702

1960

embedded image

—F
701

1961

embedded image

—F
700

1962

embedded image

—F
720

1963

embedded image

—F
705

1964

embedded image

—F
699

1965

embedded image

—F
741

TABLE 317

Example

No.
R₉₅₀
MS (M⁺ + H)

1966
5-isoquinolyl
685

1967
—CH₂CF₃
640

1968

embedded image

706

1969

embedded image

686

1970

embedded image

653

1971

embedded image

694

1972

embedded image

708

1973

embedded image

708

1974
—CH₂Cl
606

1975

embedded image

720

1976

embedded image

678

1977

embedded image

712

1978

embedded image

698

1979

embedded image

744

1980
benzyl
648

1981
PhCH═CH—
660

TABLE 318

Example

MS

No.
R₉₅₁
R₉₅₂
(M⁺ + H)

1982
—(CH₂)₂CH₃
—F
600

1983
2-BrPh—
—CH₃
710

1984

embedded image

—CH₃
670

1985
3,5-Cl₂Ph
—CH₃
698

1986

embedded image

—CH₃
697

1987

embedded image

—CH₃
696

1988

embedded image

—CH₃
716

1989

embedded image

—CH₃
701

1990

embedded image

—CH₃
695

1991

embedded image

—CH₃
737

1992
5-isoquinolyl
—CH₃
681

1993
—CH₂CF₃
—CH₃
636

1994

embedded image

—CH₃
702

1995

embedded image

—CH₃
682

1996

embedded image

—CH₃
649

TABLE 319

Example

No.
R₉₅₃
R₉₅₄
MS (M⁺ + H)

1997

embedded image

—CH₃
690

1998

embedded image

—CH₃
704

1999

embedded image

—CH₃
704

2000
—CH₂Cl
—CH₃
602

2001

embedded image

—CH₃
716

2002

embedded image

—CH₃
674

2003

embedded image

—CH₃
708

2004

embedded image

—CH₃
694

2005

embedded image

—CH₃
740

2006
benzyl
—CH₃
644

2007
—CHCl₂
—CH₃
636

2008
PhCH═CH—
—CH₃
656

2009
—(CH₂)₂CH₃
—CH₃
596

2010
2,3,4-F₃Ph—
—H
670

2011
2,3,4-F₃Ph—
—F
688

2012
2,3,4-F₃Ph—
—CH₃
684

TABLE 320

Example

No.
R₉₅₅
R₉₅₆
R₉₅₇
Xb₂₉

¹H NMR (solvent) δppm

2013
3,4-Cl₂Ph—
—CH₃
—H
—CO—
(CDCl₃) 2.12(3H, s), 2.50-2.52(4H, m),

3.45(2H, s), 3.72(2H, brs), 4.24(2H, brs),

5.95(2H, s), 6.71-6.78(2H, m), 6.85-6.89(2H,

m), 7.00(1H, d, J = 8.6 Hz), 7.42(1H, dd, J =

8.6 Hz, 2.5 Hz), 7.52-7.55(3H, m), 7.60(1H,

dd, J = 8.7 Hz, 2.8 Hz), 7.70(1H, d, J = 2.6

Hz), 7.79(1H, brs), 9.17(1H, brs).

2014
4-CF₃Ph—
—CH₃
—H
—CO—
(CDCl₃) 2.10(3H, s), 2.50-2.54(4H, m),

3.45(2H, s), 3.70-3.73(2H, m), 4.23(2H, brs),

5.95(2H, s), 6.71-6.78(2H, m), 6.83-6.87(2H,

m), 6.99(1H, d, J = 8.6 Hz), 7.42(1H, dd, J =

8.6 Hz, 2.6 Hz), 7.54(1H, d, J = 2.5 Hz),

7.60(1H, dd, J = 8.7 Hz, 3.3 Hz), 7.70(1H, d,

J = 3.3 Hz), 7.72(2H, d, J = 8.9 Hz), 7.85(2H,

d, J = 8.3 Hz), 9.18(1H, brs).

2015
3,4-Cl₂Ph—
—CH₃
—CH₃
—CO—
(CDCl₃) 2.12(3H, brs), 2.20-2.50(4H, m),

3.27-3.46(9H, m), 5.95-5.96(2H, m), 6.66-

6.77(3H, m), 6.85-7.04(2H, m), 7.08-7.22(2H,

m), 7.51-7.53(2H, m), 7.55-7.72(2H, m), 7.78-

7.80(1H, m).

2016
4-CF₃Ph—
—CH₃
—CH₃
—CO—
(DMSO-d₆) 2.11(3H, s), 2.19-2.51(4H, m),

3.28-3.71(9H, m), 5.96(2H, s), 6.65-6.78(3H,

m), 6.85-7.04(2H, m), 7.08-7.22(2H, m), 7.57-

7.65(1H, m), 7.70-7.73(3H, m), 7.84-7.87(2H,

m).

2017
3,4-Cl₂Ph—
—H
—SO₂CH₃
—CH₂—
(CDCl₃) 2.42(4H, brs), 3.20(3H, s), 3.37-

3.39(2H, m), 3.42(2H, s), 3.61(2H, brs),

4.54(2H, s), 5.95(2H, s), 6.70-6.77(2H, m),

6.83(1H, brs), 6.93(1H, d, J = 8.6 Hz),

7.08(2H, d, J = 8.9 Hz), 7.53-7.54(2H, m),

7.58-7.63(3H, m), 7.77(1H, d, J = 2.6 Hz),

7.88(1H, d, J = 1.0 Hz).

2018
4-CF₃Ph—
—H
—SO₂CH₃
—CH₂—
(CDCl₃) 2.42(4H, brs), 3.19(3H, s), 3.37(2H,

brs), 3.42(2H, s), 3.61(2H, brs), 4.53(2H, s),

5.95(2H, s), 6.73-6.77(2H, m), 6.83(1H, brs),

6.92(1H, d, J = 8.7 Hz), 7.08(2H, d, J = 8.7

Hz), 7. 59(2H, d, J = 8.7 Hz), 7.61(1H, dd, J =

8.7 Hz, 2.8 Hz), 7.73-7.76(3H, m), 7.87(2H,

d, J = 8.6 Hz).

2019
3,4-Cl₂Ph—
—CH₃
—SO₂CH₃
—CH₂—
(CDCl₃) 2.12(3H, s), 2.42(4H, brs), 3.21(3H,

s), 3.38(2H, brs), 3.42(2H, s), 3.61(2H, brs),

4.53(2H, s), 5.95(2H, s), 6.70-6.77(2H, m),

6.83(1H, brs), 6.91(1H, d, J = 8.7 Hz),

6.98(1H, d, J = 8.4 Hz), 7.40-7.50(2H, m),

7.53-7.56(2H, m), 7.60(1H, dd, J = 8.7 Hz,

2.8 Hz), 7.71(1H, d, J = 2.3 Hz), 7.80(1H, dd,

J = 1.7 Hz, 0.8 Hz).

TABLE 321

Example

No.
R₉₅₈
R₉₅₉
R₉₆₀

¹H NMR (solvent) δppm

2020
4-CF₃Ph—
—CH₃
—SO₂CH₃
(CDCl₃) 2.10(3H, s), 2.40-2.42(4H, m), 3.20(3H, s),

3.37(2H, brs), 3.42(2H, s), 3.60(2H, brs), 4.53(2H,

s), 5.94(2H, s), 6.69-6.76(2H, m), 6.83(1H, brs),

6.87(1H, d, J = 8.7 Hz), 6.96(1H, d, J = 8.4 Hz),

7.40(1H, d, J = 8.6 Hz), 7.44(1H, brs), 7.59(1H, dd,

J = 8.7 Hz, 2.8 Hz), 7.72(2H, d, J = 8.2 Hz),

7.73(1H, d, J = 2.8 Hz), 7.86(2H, d, J = 8.2 Hz).

2021
4-CF₃Ph—
—CF₃
—C₂H₅
(DMSO-d₆) 1.11(3H, t, J = 6.9 Hz), 2.25-2.45(4H,

m), 3.35-3.55(8H, m), 4.26(2H, s), 5.99(2H, 8), 6.67-

7.04(7H, m), 7.52(1H, dd, J = 8.8 Hz, 2.8 Hz),

7.74(1H, d, J = 2.6 Hz), 7.88-7.98(4H, m), 10.48(1H,

brs).

2022

embedded image

—CF₃
—C₂H₅
(DMSO-d₆) 1.11(3H, t, J = 6.9 Hz), 2.25-2.45(4H, m), 3.35-3.55(8H, m), 4.26(2H, s), 5.99(2H, s), 6.67- 7.03(7H, m), 7.30-7.45(1H, m), 7.52(1H, dd, J = 8.8 Hz, 2.6 Hz), 7.71(1H, dd, J = 8.7 Hz, 2.5 Hz), 7.79(1H, d, J = 2.7 Hz), 7.99-8.05(1H, m), 10.61(1H, brs).

2023
3,4-Cl₂Ph—
—CF₃
—CH₃
(DMSO-d₆) 2.20-2.45(4H, m), 2.97(3H, s), 3.40-

3.55(6H, m), 4.34(2H, s), 5.99(2H, s), 6.70-6.80(2H,

m), 6.83-6.88(3H m), 6.97(1H, d, J = 8.8 Hz), 7.03-

7.07(1H, m), 7.52(1H, dd, J = 8.8 Hz, 2.8 Hz),

7.63(1H, dd, J = 8.6 Hz, 2.2 Hz), 7.75(1H, d, J = 2.7

Hz), 7.83-7.87(2H, m), 10.39(1H, brs).

2024

embedded image

—CF₃
—CH₃
(DMSO-d₆) 2.25-2.50(4H, m), 2.97(3H, s), 3.35- 3.55(6H, m), 4.34(2H, s), 5.99(2H, s), 6.74-7.05(7H, m), 7.30-7.45(1H, m), 7.52(1H, dd, J = 8.8 Hz, 2.7 Hz), 7.71(1H, dd, J = 8.7 Hz, 2.5 Hz), 7.80(1H, d, J = 2.7 Hz), 8.00-8.06(1H, m), 10.61(1H, brs).

2025
3,4-Cl₂Ph—
—CN
—CH₃
(DMSO-d₆) 2.25-2.50(4H, m), 2.94(3H, s), 3.35-

3.50(6H, m), 4.33(2H, s), 5.99(2H, s), 6.74-7.11(7H,

m), 7.50-7.65(2H, m), 7.78(1H, d, J = 2.6 Hz),

7.83(1H, d, J = 8.5 Hz), 7.89(1H, d, J = 1.5 Hz),

10.45(1H, brs).

2026
4-CF₃Ph—
—OCH₃
—SO₂CH₃
(CDCl₃) 2.43(4H, brs), 3.20(3H, s), 3.38(2H, brs),

3.43(2H, s), 3.61(2H, brs), 3.68(3H, s), 4.54(2H, s),

5.94(2H, s), 6.73-6.76(2H, m), 6.80-6.90(2H, m),

7.04(1H, d, J = 8.4 Hz), 7.15-7.19(1H, m), 7.24-

7.26(1H, m), 7.57(1H, dd, J = 8.7 Hz, 2.8 Hz), 7.70-

7 72(4H, m), 7.85(2H, d, J = 8.2 Hz).

2027
3,4-Cl₂Ph—
—OCH₃
—SO₂CH₃
(CDCl₃) 2.43(4H, brs), 3.21(3H, s), 3.37(2H, brs),

3.43(2H, s), 3.61(2H, brs), 3.71(3H, s), 4.54(2H, s),

5.95(2H, s), 6.73-6.77(2H, m), 6.83(1H, s), 6.92(1H,

d, J = 8.7 Hz), 7.06(1H, d, J = 8.6 Hz), 7.18(1H, dd,

J = 8.4 Hz, 2.3 Hz), 7.25(2H, s), 7.52(2H, s),

7.57(1H, dd, J = 8.7 Hz, 2.8 Hz), 7.70(1H, d, J = 2.6

Hz), 7.81(1H, s).

TABLE 322

Example

No.
R₉₆₁
R₉₆₂
R₉₆₃
R₉₆₄
R₉₆₅

¹H NMR (DMSO-d₆) δppm

2028
3,4-Cl₂Ph—
—CH₃
—H
—CH₃
—CH₃
1.93(3H, s), 2.16(3H, s), 2.20-2.40(4H,

m), 2.63(3H, s), 3.39(2H, s), 3.39-

3.50(4H, m), 3.74(2H, s), 5.99(2H, s),

6.72-6.92(5H, m), 6.98(1H, s), 7.51(1H,

dd, J = 8.8 Hz, 2.4 Hz), 7.63(1H, dd, J =

8.5 Hz, 1.4 Hz), 7.73(1H, d, J = 2.6 Hz),

7.82-7.87(2H, m), 10.35(1H, brs).

2029

embedded image

—CH₃
—H
—CH₃
—CH₃
1.90(3H, s), 2.15(3H, s), 2.25-2.40(4H, m), 2.62(3H, s), 3.38(2H, s), 3.38- 3.50(4H, m), 3.73(2H, s), 5.98(2H, s), 6.72-6.76(2H, m), 6.82-6.88(3H, m), 6.97(1H, s), 7.30-7.45(1H, m), 7.51(1H, dd, J = 8.8 Hz, 2.7 Hz), 7.72(1H, dd, J = 8.7 Hz, 2.6 Hz), 7.78(1H, d, J = 2.8 Hz), 7.98-8.04(1H, m), 10.56(1H, brs).

2030
3,4-Cl₂Ph—
—H
—CF₃
—H
—C₂H₅
0.92(3H, t, J = 7.1 Hz), 2.20-2.40(4H,

m), 3.11(2H, q, J = 7.1 Hz), 3.35-

3.50(6H, m), 3.83(2H, s), 5.98(2H, s),

6.70-6.90(3H, m), 7.05(1H, d, J = 8.8

Hz), 7.32-7.36(2H, m), 7.56-7.75(3H, m),

7.81-7.91(3H, m), 10.48(1H, brs).

Example 2031
N-{4-[4-(4-benzenesulfonylpiperazin-1-yl)phenoxy]phenyl}-3,4-dichlorobenzamide

Melting point: 191-192° C.

The following compounds were produced in the same manner as in Reference Example 292.

TABLE 323

Ex-

ample

No.
R₉₆₆

¹H NMR (CDCl₃) δppm

2032
—CH₃
2.41(4H, brs), 3.20(3H, s), 3.36(2H, brs), 3.42(2H, s),

3.59(2H, brs), 3.66(3H, s), 4.50(2H, s), 5.94(2H, s),

6.70-6.76(2H, m), 6.83(1H, s), 6.93(1H, d, J = 8.7 Hz),

6.99-7.04(2H, m), 7.13(1H, dd, J = 8.4 Hz, 2.1 Hz),

7.51(1H, d, J = 2.3 Hz), 7.69(1H, dd, J = 8.4 Hz, 2.1

Hz), 7.95(1H, d, J = 2.1 Hz), 8.12(1H, dd, J = 8.7 Hz,

2.6 Hz), 8.23(1H, d, J = 2.6 Hz), 8.53(1H, s).

2033
—C₂H₅
1.37(3H, t, J = 7.4 Hz), 2.42(4H, brs), 3.38-3.46(6H,

m), 3.60(2H, brs), 3.71(3H, s), 4.53(2H, s), 5.94(2H,

s), 6.70-6.77(2H, m), 6.84(1H, s), 6.97(1H, d, J = 8.7

Hz), 7.06(1H, d, J = 8.6 Hz), 7.14-7.18(1H, m), 7.26

(1H, s), 7.55(1H, d, J = 8.4 Hz), 7.71(1H, dd, J = 8.4

Hz, 2.1 Hz), 7.98(1H, d, J = 2.1 Hz), 8.16-8.23(3H,

m).

Example 2034
Production of t-butyl 4-{4-[(5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]phenylcarbamoyl}piperidine-1-carboxylate

To a solution of N-[6-(4-aminophenoxy)pyridin-3-yl]-3,4-dichlorobenzamide dihydrochloride (1.0 g, 2.24 mmol) in DMF (15 mL) were added, piperidine-1,4-dicarboxylic acid mono-t-butyl ester (510 mg, 2.22 mmol), triethylamine (0.94 mL, 6.74 mmol), 1-hydroxybenzotriazole monohydrate (350 mg, 2.29 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (514 mg, 2.68 mmol) under ice cooling. The resulting solution was then stirred under ice cooling for 1 hour, and at room temperature for 17 hours. This reaction solution was concentrated under reduced pressure. The residue was diluted with water and ethyl acetate, whereupon a white powder was precipitated. The white powder was filtered, then washed with water, and subsequently washed with ethyl acetate, to thereby yield 1.04 g of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 1.41 (9H, s), 1.35-1.50 (2H, m), 1.70-1.85 (2H, m), 2.40-2.60 (1H, m), 2.63-2.90 (2H, m), 3.90-4.11 (2H, m), 7.03 (1H, d, J=8.9 Hz), 7.06 (2H, d, J=8.9 Hz), 7.62 (2H, d, J=8.9 Hz), 7.84 (1H, d, J=8.5 Hz), 7.94 (1H, dd, J=8.5 Hz, 2.0 Hz), 8.17 (1H, dd, J=8.9 Hz, 2.6 Hz), 8.22 (1H, d, J=2.0 Hz), 8.46 (1H, d, J=2.6 Hz), 9.96 (1H, s), 10.54 (1H, s).

The following compound was produced in the same manner as in Example 2034.

Example 2035
3,4-Dichloro-N-(6-{4-[2-(2,4-dioxothiazolidine-5-yl)acetylamino]phenoxy}pyridin-3-yl)benzamide

¹H NMR (DMSO-d₆) δ 3.07 (1H, dd, J=16.5 Hz, 8.9 Hz), 3.24 (1H, dd, J=16.5 Hz, 4.0 Hz), 4.73 (111, dd, J=9.0 Hz, 4.0 Hz), 7.04 (1H, d, J=8.9 Hz), 7.08 (2H, d, J=8.9 Hz), 7.58 (2H, d, J=8.9 Hz), 7.84 (1H, d, J=8.2 Hz), 7.94 (1H, dd, J=8.2 Hz, 2.0 Hz), 8.18 (1H, dd, J=8.9 Hz, 2.6 Hz), 8.22 (1H, d, J=2.0 Hz), 8.46 (1H, d, J=2.6 Hz), 10.21 (1H, s), 10.53 (1H, s), 12.00 (1H, s).

Example 2036
Production of 3,4-dichloro-N-(6-{4-[(4-piperonylpiperazin-1-ylmethyl]phenoxy}pyridin-3-yl)benzamide

To a solution of 3,4-dichloro-N-[6-(4-piperazin-1-ylmethylphenoxy)pyridin-3-yl]benzamide (300 mg, 0.66 mmol) in DMF (10 mL) were added piperonylic acid (120 mg, 0.72 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (140 mg, 0.73 mmol) and 1-hydroxybenzotriazole monohydrate (100 mg, 0.74 mmol) under ice cooling. The resulting reaction solution was stirred overnight at room temperature. To the residue was added a saturated sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 110 mg of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 2.46 (4H, brs), 3.53 (2H, s), 3.60 (4H, brs), 5.99 (2H, s), 6.79 (1H, d, J=7.9 Hz), 6.85-6.96 (3H, m), 7.08 (2H, d, J=8.6 Hz), 7.33 (2H, d, J=8.3 Hz), 7.54 (1H, d, J=8.3 Hz), 7.69-7.73 (1H, m), 7.99 (1H, d, J=2.3 Hz), 8.16-8.21 (1H, m), 8.27-8.30 (2H, m).

The following compounds were produced in the same manner as in Example 2036.

TABLE 324

Example

No.
R₉₆₇
R₉₆₈
Xb₃₀
R₉₆₉
mp (° C.) or ¹H NMR (solvent) δppm

2037
—CF₃
—H
—CO—

embedded image

¹H NMR (DMSO-d₆) 3.52(4H, brs), 3.60(4H, brs), 5.57(1H, s), 7.17(1H, d, J = 8.9 Hz), 7.20(2H, d, J = 8.9 Hz), 7.51(2H, d, J = 8.4 Hz), 7.95(2H, d, J = 8.1 Hz), 8.17(2H, d, J = 8.1 Hz), 8.27(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.55(1H, d, J = 2.6 Hz), 10.69(1H, brs), 11.18(1H, brs), 11.32(1H, brs).

2038
—Cl
—Cl
—CH₂—

embedded image

mp 250-251

2039
—CF₃
—H
—CH₂—
2-CNPh—
mp 189-192

2040
—CF₃
—H
—CH₂—
4-pyridyl
mp 122-124

2041
—CF₃
—H
—CH₂—
3-pyridyl
mp 167-168

2042
—CF₃
—H
—CH₂—
2-pyridyl
mp 189-191

2043
—CF₃
—H
—CH₂—

embedded image

¹H NMR (DMSO-d₆) 2.45(4H, brs), 3.36(2H, s), 3.54-4.18(4H, m), 7.09(3H, d, J = 8.9 Hz), 7.36(2H, d, J = 8.4 Hz), 7.59(1H, brs), 7.72(1H, s), 7.94(2H, d, J = 8.4 Hz), 8.18(2H, d, J = 8.4 Hz), 8.24(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.53(1H, d, J = 2.6 Hz), 10.67(1H, s), 12.48(1H, brs).

2044
—CF₃
—H
—CH₂—

embedded image

¹H NMR (CDCl₃+ CD₃OD) 2.98- 3.15(5H, m), 3.34-3.47(1H, m), 3.61- 3.76(4H, m), 4.18(2H, s), 4.57(1H, dd, J = 10.2 Hz, 3.1 Hz), 7.04(1H, d, J = 8.7 Hz), 7.19(2H, d, J = 8.6 Hz), 7.49(2H, d, J = 8.6 Hz), 7.79(2H, d, J = 8.3 Hz), 8.11(2H, d, J = 8.1 Hz), 8.25 (1H, dd, J = 8.9 Hz, 2.8 Hz) 8.52(1H, d, J = 2.3 Hz).

2045
—CF₃
—H
—(CH₂)₃—

embedded image

¹H NMR (CDCl₃) 1.81-1.89(2H, m), 2.40- 2.45(6H, m), 2.62-2.68(2H, m), 3.61(4H, brs), 5.98(2H, s), 6.76-6.93(4H, m), 7.03(2H, d, J = 8.4 Hz), 7.19(2H, d, J = 8.4 Hz), 7.68(2H, d, J = 8.4 Hz), 7.99(2H, d, J = 8.3 Hz), 8.18-8.23(1H, m), 8.30(1H, d, J = 2.6 Hz), 8.73(1H, s).

2046
—CF₃
—H
—(CH₂)₃—
3,4-(CH₃O)₂Ph—

¹H NMR (CDCl₃) 1.78-1.89(2H, m), 2.39-

2.45(6H, m), 2.63-2.68(2H, m), 3.62(4H,

brs), 3.85(3H, s), 3.89(3H, s), 6.82-

6.85(1H, m), 6.91-6.95(3H, m), 7.01-

7.06(2H, m), 7.18-7.23(2H, m), 7.70(2H,

d, J = 8.2 Hz), 7.99(2H, d, J = 8.2 Hz),

8.20-8.24(1H, m), 8.29(1H, d, J = 2.6

Hz), 8.51(1H, brs).

TABLE 325

Example

No.
R₉₇₀
R₉₇₁
R₉₇₂
M
Form

¹H NMR (solvent) δppm

2047
—CF₃
—H

embedded image

1
free
(DMSO-d₆) 1.94(6H, s), 2.49- 2.51(4H, m), 2.76-2.93(1H, m), 3.17-3.51(7H, m), 4.20(1H, dd, J = 10.4 Hz, 3.0 Hz), 7.09-7.13(3H, m), 7.42 (2H, brs), 7.94(2H, d, J = 8.4 Hz), 8.16-8.26(3H, m), 8.54(1H, d, J = 2.5 Hz), 10.67(1H, s), 11.68 (1H, brs).

2048
—CF₃
—H

embedded image

1
free
(CDCl₃+ CD₃OD) 2.46-2.59(4H, m), 3.16(1H, dd, J = 14.2 Hz, 9.4 Hz), 3.32(4H, brs), 3.51(1H, dd, J = 14.0 Hz, 3.8 Hz), 3.79(2H, brs), 4.50(1H, dd, J = 9.4 Hz, 4.0 Hz), 6.93(1H, d, J = 8.9 Hz), 7.06(2H, d, J = 8.4 Hz), 7.26-7.46(6H, m), 7.72 (2H, d, J = 8.3 Hz), 8.05(2H, d, J = 8J Hz), 8.27 (1H, d, J = 2.1 Hz), 8.33(1H, dd, J = 8.9 Hz, 2.8 Hz).

2049
—CF₃
—H

embedded image

1
free
(DMSO-d₆) 2.49-2.52(4H, m), 3.34-3.40(4H, m), 3.57(2H, s), 7.06-7.10(3H, m), 7.36(2H, d, J = 8.6 Hz), 754(2H, d, J = 8.1 Hz), 7.67(2H, d, J = 8.4 Hz), 7.79(1H, s), 7.94(2H, d, J = 8.6 Hz), 8.15- 8.25(3H, m), 8.51(1H, d, J = 2.8 Hz), 10.64 (1H, s).

2050
—CF₃
—H
4-pyridyl
3
hydro-
(DMSO-d₆) 2.04(2H, brs), 2.63-

chloride
2.69(2H, m), 3.10-3.59(9H, m),

4.54(1H, brs), 7.05-7.08(3H, m),

7.28(2H, d, J = 8.2 Hz), 7.45(2H,

d, J = 4.9 Hz), 7.94(2H, d, J = 8.2

Hz), 8.18-8.26(3H, m), 8.53(1H, d,

J = 2.3 Hz), 8.70(2H, d, J = 5.4

Hz), 10.72(1H, s), 11.27(1H, brs).

2051
—Cl
—Cl
3,4-F₂Ph—
1
free
(CDCl₃) 2.46(4H, brs), 3.47-

3.72(6H, m), 6.91 (1H, d, J = 8.9

Hz), 7.05-7.33(7H, m), 7.50(1H, d,

J = 8.4 Hz), 7.71(1H, dd, J = 8.4

Hz, 2.1 Hz), 7.97(1H, d, J = 2.1

Hz), 8.14-8.18(1H, m), 8.28 (1H,

d, J = 2.6 Hz), 8.68(1H, s).

TABLE 326

Ex-

ample

No.
Chemical structure
mp (° C.) or ¹H NMR

2052

embedded image

mp 171-173

2053

embedded image

mp 116-118

2054

embedded image

mp 133-135

2055

embedded image

¹H NMR (CDCl₃) δ 2.39 (2H, brs), 2.55 (2H, brs), 3.00 (3H, s), 3.35(2H, brs), 3.51 (2H, s), 3.79(2H, brs), 4.40 (2H, s), 6.82(1H, d, J = 8.9 Hz), 6.99-7.13(4H, m), 7.25- 7.29(5H, m), 7.32 (1H, d, J = 1.8 Hz), 7.39(1H, d, J = 3.3 Hz), 8.68-8.70(2H, m).

Example 2056
Production of N-{6-[4-(4-chloroacetylpiperazino)phenoxy]-3-pyridyl}-4-(trifluoromethyl)benzamide

To a solution of N-[6-(4-piperazinophenoxy)-3-pyridyl]-4-(trifluoromethyl)benzamide (885 mg, 2.00 mmol) in DMF (20 mL) were added triethylamine (0.418 mL, 3.00 mmol) and chloroacetyl chloride (0.191 g, 2.40 mmol), and the resulting reaction solution was stirred for 10 minutes at room temperature. To this reaction solution was added ethyl acetate. The resulting solution was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, to thereby yield 1.00 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 3.17 (2H, t, J=5.0 Hz), 3.22 (2H, t, J=5.0 Hz), 3.70 (2H, t, J=5.0 Hz), 3.80 (2H, t, J=5.0 Hz), 6.95 (1H, d, J=9.0 Hz), 6.97 (2H, d, J=9.0 Hz), 7.08 (2H, d, J=9.0 Hz), 7.77 (1H, brs), 7.78 (2H, d, J=8.0 Hz), 7.99 (2H, d, J=8.0 Hz), 8.20 (1H, dd, J=9.0 Hz, 2.5 Hz), 8.26 (1H, d, J=2.5 Hz).

The following compounds were produced in the same manner as in Example 2056.

TABLE 327

Example

No.
R₉₇₃
R₉₇₄
Xb₃₁
R₉₇₅
mp (° C.) or ¹H NMR (solvent) δppm

2057
—CF₃
—H
—CO—
4-CNPh—

¹H NMR (DMSO-d₆) 3.29 3.69(8H, m), 7.14-

7.20(3H, m), 7.49(2H, d, J = 8.6 Hz),

7.63(2H, d, J = 8.1 Hz), 7.93-7.95(4H, m),

8.17(2H, d, J = 8.1 Hz), 8.27(1H, dd, J = 8.9

Hz, 2.4 Hz), 8.55(1H, d, J = 2.4 Hz),

10.66(1H, s).

2058
—CF₃
—H
—CO—
—CH₃

¹H NMR (CDCl₃) 2.13(3H, s), 3.35-3.90(8H,

m), 7.02(1H, d, J = 8.8 Hz), 7.17(2H, d, J =

8.6 Hz), 7.44(2H, d, J = 8.6 Hz), 7.75(2H, d, J =

8.1 Hz), 8.02(2H, d, J = 8.1 Hz), 8.25(1H,

dd, J = 8.8 Hz, 2.5 Hz), 8.33(1H, d, J = 2.5

Hz), 8.38(1H, brs).

2059
—Cl
—Cl
—CH₂—
—Ph

¹H NMR (CDCl₃) 2.08-2.55(4H, m), 3.43-

3.45(2H, m), 3.55(2H, s), 3.79-3.81 (2H, m),

6.96(1H, d, J = 8.9 Hz), 7.07-7.12(2H, m),

7.33-7.46(7H, m), 7.57(1H, d, J = 8.6 Hz),

7.69-7.73(1H, m), 7.94-7.99(2H, m), 8.17-

8.21(1H, m), 8.27(1H, d, J = 2.6 Hz).

2060
—Cl
—Cl
—CH₂—
4-CNPh—

¹H NMR (CDCl₃) 2.44(2H, brs), 2.58(2H,

brs), 3.39(2H, brs), 3.56(2H, s), 3.81(2H,

brs), 6.96(1H, d, J = 8.9 Hz), 7.08-7.12(2H,

m), 7.34(2H, d, J = 8.4 Hz), 7.48-7.51(2H, m),

7.57(1H, d, J = 8.4 Hz), 7.69-7.77(3H, m),

7.95(1H, brs), 7.98(1H, d, J = 2.0 Hz), 8.14-

8.21(1H, m), 8.27(1H, d, J = 2.3 Hz).

2061
—CF₃
—H
—CH₂—
4-CNPh—
mp 167-168

2062
—CF₃
—H
—CH₂—
—Ph

¹H NMR (CDCl₃) 2.41-2.53(4H, m), 3.43(2H,

brs), 3.53 (2H, s), 3.78(2H, brs), 6.95(1H, d, J =

8.9 Hz), 7.06-7.11 (2H, m), 7.33-7.41(7H,

m), 7.71(2H, d, J = 8.4 Hz), 7.99 (2H, d, J =

8.4 Hz), 8.23(1H, dd, J = 8.9 Hz, 2.7 Hz),

8.31 (1H, d, J = 2.7 Hz), 8.39(1H, s).

2063
—CF₃
—H
—CH₂—
3,4-F₂Ph—
mp 130-133

2064
—CF₃
—H
—CH₂—
3-CNPh—

¹H NMR (CDCl₃) 2.43(2H, brs), 2.56(2H,

brs), 3.39(2H, brs), 3.55(2H, s), 3.79(2H,

brs), 6.97(1H, d, J = 8.9 Hz), 7.07-7.12(2H,

m), 7.32-7.37(2H, m), 7.50-7.77(6H, m),

8.00(2H. d, J = 8.1 Hz), 8.07(1H, brs),

8.23(1H, dd, J = 8.9 Hz, 2.7 Hz), 8.28(1H, d,

J = 2.7 Hz).

2065
—CF₃
—H
—CH₂—
4-CH₃Ph—
mp 193-194

2066
—CF₃
—H
—CH₂—
4-ClPh—
mp 176-178

2067
—CF₃
—H
—CH₂—
4-CH₃OPh—
mp 190-191

TABLE 328

Example

No.
R₉₇₆
R₉₇₇
M

¹H NMR (CDCl₃) δppm

2068
3,4-Cl₂PhCH₂N(CH₃)—
—Ph
1
2.38(2H, brs), 2.53(2H, brs), 2.99(3H, s),

3.42(2H, brs), 3.50(2H, s), 3.79(2H, brs),

4.39(2H, s), 6.81(1H, d, J = 8.9 Hz), 6.99-

7.12(4H, m), 7.26-7.39(9H, m), 7.69(1H, d, J =

3.1 Hz).

2069
3,4-Cl₂PhCH₂N(CH₃)—
4-CNPh—
1
2.39(2H, brs), 2.55(2H, brs), 3.01(3H, s),

3.35(2H, brs), 3.51(2H, s), 3.79(2H, brs),

4.40(2H, s), 6.82(1H, d, J = 8.9 Hz), 6.99-

7.13(4H, m), 7.25-7.33(3H, m), 7.39(1H, d, J =

8.1 Hz), 7.48-7.52(2H, m), 7.69-7.73(3H,

m).

2070
3,4-Cl₂PhCH₂N(CH₃)—
4-ClPh—
1
2.34-2.59(4H, m), 3.00(3H, s), 3.36(2H, brs),

3.52(2H, s), 3.83(2H, brs), 4.40(2H, s),

6.82(1H, d, J = 8.9 Hz), 6.98-7.13(4H, m),

7.25-7.41(8H, m), 7.70(1H, d, J = 3.3 Hz).

2071
3,4-Cl₂PhCH₂N(CH₃)—
3,4-F₂Ph—
1
2.33-2.57(4H, m), 3.00(3H, s), 3.37-3.51(4H,

m), 3.75 (2H, brs), 4.40(2H, s), 6.82(1H, d, J =

8.9 Hz), 7.00-7.32 (10H, m), 7.39(1H, d, J =

8.1 Hz), 7.69(1H, d, J = 3.1 Hz).

2072
4-CF₃PhCONH—
—Ph
3
1.78-1.89(2H, m), 2.39-2.49(6H, m),

2.66(2H, t, J = 7.6 Hz), 3.44(2H, brs),

3.79(2H, brs), 6.94(1H, d, J = 8.7 Hz), 7.02-

7.07(2H, m), 7.18-7.23(2H, m), 7.35-

7.42(5H, m), 7.72(2H, d, J = 8.2 Hz),

7.99(2H, d, J = 8.1 Hz), 8.19-8.29(3H, m).

2073
4-CF₃PhCONH—
4-CNPh—
3
1.79-1.90(2H, m), 2.41-2.69(8H, m),

3.39(2H, brs), 3.81 (2H, brs), 6.95(1H, d, J =

8.9 Hz), 7.02-7.07(2H, m), 7.18-7.23(2H, m),

7.49(2H, d, J = 7.9 Hz), 7.69-7.77(4H, m),

8.00(2H, d, J = 8.1 Hz), 8.06(1H, brs),

8.21(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.28(1H, d,

J = 2.6 Hz).

2074
4-CF₃PhCONH—
3,4-F₂Ph—
3
1.82-1.87(2H, m), 2.41-2.69(8H, m), 3.47-

3.76(4H, m), 6.95(1H, d, J = 8.7 Hz), 7.02-

7.07(2H, m), 7.11-7.28(5H, m), 7.75(2H, d, J =

8.4 Hz), 7.99-8.06(3H, m), 8.19-8.23 (1H,

m), 8.28(1H, d, J = 2.6 Hz).

TABLE 329

Example

No.
Xb₃₂
Xb₃₃
R₉₇₈
mp (° C.) or ¹H NMR (solvent) δppm

2075

embedded image

—COPh
mp 136-138

2076

embedded image

4-CH₃OPhCO—
mp 161-162

2077

embedded image

4-CF₃PhCO—
mp 143-144

2078

embedded image

mp 163-165

2079

embedded image

4-ClPhCO—
mp 147-151

2080

embedded image

—N(CH₃)COPh
mp 231-232

2081

embedded image

—N(CH₃)COCH₂Cl

¹H NMR (CDCl₃) 1.70-1.76(2H, m), 1.80- 1.90(2H, m), 2.80-2.88(2H, m), 2.98(3H, s), 3.56-3.68(2H, m), 4.10 (2H, s), 4.57(1H, m), 6.94-6.99(6H, m), 7.53-7.58(3H, m), 7.69-7.71(2H, m), 7.97(1H, d, J = 2.0 Hz).

2082

embedded image

—COCH₂Cl

¹H NMR (DMSO-d₆) 3.08(2H, m), 3.14(2H, m), 3.61(4H, m), 4.44(2H, s), 6.93- 7.02(6H, m), 7.71(2H, d, J = 9.0 Hz), 7.82(1H, d, J = 8.5 Hz), 7.93(1H, dd, J = 8.5 Hz, 2.0 Hz), 8.21(1H, d, J = 2.0 Hz), 10.39(1H, s).

2083

embedded image

—COCH₂Cl

¹H NMR (CDCl₃) 1.66(1H, m), 1.74(1H, m), 1.91-1.98 (2H, m), 2.72-2.77(2H, m), 3.24(1H, m), 3.99(1H, brd, J = 13.0 Hz), 4.11(2H, s), 4.73(1H, brd, J = 13.0 Hz), 6.96 (2H, d, J = 8.5 Hz), 7.02(2H, d, J = 9.0 Hz), 7.15(2H, d, J = 8.5 Hz), 7.56- 7.79(3H, m), 7.71(1H, dd, J = 8.5 Hz, 2.0 Hz), 7.90(1H, brs), 7.98(1H, d, J = 2.0 Hz).

TABLE 330

Example

No.
R₉₇₉
R₉₈₀
Xb₃₄
Xb₃₅
Xb₃₆
R₉₈₁
mp (° C.) or MS

2084
3,4-Cl₂Ph—
—H
none
none

embedded image

—N(CH₃)COCH₂Ph
MS 616(M⁺)

2085
4-CF₃Ph—
—CH₃
—N(CH₃)—
—CH₂—

embedded image

4-CNPhCO—
mp 131-132

2086
4-CF₃Ph—
—CH₃
—N(CH₃)—
—CH₂—

embedded image

mp 143-145

TABLE 331

Example

No.
R₉₈₂
Xb₃₇
R₉₈₃
Property

2087
—H

embedded image

—Ac
mp 138-140° C.

2088
—F

embedded image

—N(CH₃)COCH₂Ph
MS 661(M⁺)

2089
—H

embedded image

—COCH₂Cl

¹H NMR (CDCl₃) δ 2.62(2H, t, J = 7.6 Hz), 2.95(2H, t, J = 7.6 Hz), 3.31-3.73(8H, m), 4.05(2H, s), 6.91(2H, d, J = 8.5 Hz), 6.97(2H, d, J = 8.9 Hz), 7.15(2H, d, J = 8.5 Hz), 7.49-7.60(3H, m), 7.68(1H, dd, J = 8.3 Hz, 2.1 Hz), 7.91(1H, brs), 7.95(1H, d, J = 2.1 Hz).

TABLE 332

Example

No.
R₉₈₄
mp (° C.)

2090
2-pyridyl
217-218

2091
3-pyridyl
191-192

2092
4-pyridyl
204-205

TABLE 333

Example

No.
R₉₈₅
mp (° C.) or ¹H NMR (CDCl₃) δppm

2093
—Ph
mp 185-186

2094
—CH₂Cl
a mixture of the rotational isomers

¹H NMR 2.57(0.4H, brs), 2.65(0.6H, brs), 3.74(0.6H, t, J =

6.0 Hz), 3.85 (0.4H, t, J = 6.0 Hz), 4.13(0.8H, s),

4.15(1.2H, s), 4.22(1.2H, m), 4.25 (0.8H, m), 5.89(0.4H,

brs), 6.04(0.6H, brs), 6.98(2H, d, J = 8.5 Hz), 7.04 (2H, d,

J = 9.0 Hz), 7.34(2H, dd, J = 8.5 Hz, 4.0 Hz). 7.56-

7.60(3H, m), 7.71(1H, dd, J = 8.5 Hz, 2.0 Hz), 7.89(1H,

brs), 7.89(1H, d, J = 2.0 Hz).

Example 2095
Production of 1-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}-4-benzoyloxypiperidine

To a solution of 1-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}-4-hydroxypiperidine (200 mg, 0.44 mmol) in dichloromethane (8 mL) were added with triethylamine (0.091 mL, 0.65 mmol), benzoyl chloride (74 mg, 0.53 mmol) and 4-(dimethylamino)pyridine (3 mg, 0.025 mmol), and the resulting solution was stirred for 2.5 days at room temperature. This reaction solution was purified by silica gel column chromatography (methanol:dichloromethane=7:93), to thereby yield 80 mg of the title compound.

Appearance: White powder

Melting point: 188-190° C.

Example 2096
Production of 3,4-dichloro-N-(6-{4-[[2-oxo-2-(4-piperonylpiperazin-1-yl)ethyl](2,2,2-trifluoroacetyl)amino]phenoxy}pyridin-3-yl)benzamide

To a solution of 3,4-dichloro-N-(6-{4-[2-oxo-2-(4-piperonylpiperazin-1-yl)ethylamino]phenoxy}pyridin-3-yl)benzamide (0.152 g, 0.239 mmol) in THF (5 mL) were added triethylamine (0.0500 mL, 0.359 mmol) and trifluoroacetic anhydride (0.0410 mL, 0.287 mmol), and the resulting solution was stirred for 6 hours. Water was added to the resulting reaction solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to yield a solid. This solid was recrystallized from methanol, to thereby yield 28.8 mg of the title compound.

Appearance: White powder

Melting point: 211-213° C.

The following compound was produced in the same manner as in Example 2096.

Example 2097
N-[6-(4-Acetyl[2-oxo-2-(4-piperonylpiperazin-1-yl)ethyl]amino)-2-methoxyphenoxy)pyridin-3-yl]-3,4-dichlorobenzamide

¹H NMR (CDCl₃) δ 1.90 (3H, s), 2.28 (2H, brs), 2.38 (2H, brs), 3.37 (4H, brs), 3.49 (2H, brs), 3.67 (3H, s), 4.43 (2H, s), 5.93 (2H, s), 6.68-6.75 (2H, m), 6.82 (1H, s), 6.91-6.97 (2H, m), 7.07-7.10 (2H, m), 7.53 (1H, d, J=8.4 Hz), 7.76 (1H, dd, J=8.4 Hz, 2.0 Hz), 8.05 (1H, d, J=2.0 Hz), 8.20 (1H, dd, J=8.9 Hz, 2.8 Hz), 8.37 (1H, d, J=2.6 Hz), 9.26 (1H, s).

Example 2098
Production of N-[6-(benzoyl{4-[(3-oxo-3-(4-piperonylpiperazin-1-yl)propyl]phenyl}amino)pyridin-3-yl]-3,4-dichlorobenzamide monooxalate

To a solution of 3,4-dichloro-N-(6-{4-[3-oxo-3-(4-piperonylpiperazin-1-yl)propyl]phenylamino}-pyridin-3-yl)benzamide (250 mg, 0.395 mmol) in THF (5 mL) were added triethylamine (0.132 mL, 0.949 mmol) and benzoyl chloride (0.0550 mL, 0.474 mmol), and the resulting solution was stirred for 7 hours at room temperature. Water was added to the resulting reaction solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to yield 0.300 g of a free form. To this free form were added isopropanol (5 mL) and oxalic acid dihydrate (100 mg, 0.793 mmol), and the resulting solution was dissolved under heat. The solvent was evaporated, and the resulting solid was recrystallized from isopropanol, to thereby yield 80.0 mg of the title compound.

Appearance: Yellow powder

Melting point: 140-143° C.

The following compound was produced in the same manner as in Example 2098.

Example 2099
N-[6-(Acetyl{4-[3-oxo-3-(4-piper ylpiperazin-1-yl)propyl]phenyl}amino)pyridin-3-yl]-3,4-dichlorobenzamide

Melting point: 150-165° C.

¹H NMR (DMSO-d₅) δ 1.98 (3H, s), 2.62-2.98 (7H, m), 3.04 (1H, t, J=12.1 Hz), 3.26 (2H, t, J=14.7 Hz), 3.35-3.50 (2H, m), 4.06 (1H, d, J=13.8 Hz), 4.13-4.26 (2H, m), 4.44 (1H, d, J=13.8 Hz), 6.07 (2H, s), 6.95-7.02 (2H, m), 7.20-7.24 (3H, m), 7.28 (2H, d, J=8.3 Hz), 7.52 (1H, d, J=8.9 Hz), 7.85 (1H, d, J=8.4 Hz), 7.96 (1H, dd, J=2.0 Hz, 8.4 Hz), 8.23-8.26 (2H, m), 8.77 (1H, s), 10.77 (1H, s), 11.10 (1H, brs).

Example 2100
Production of 6-{4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenoxy}-N-(3,4-dichlorophenyl)nicotinamide

To a solution of 6-{4-[3-(4-piperonylpiperazin-1-yl)-]-oxopropyl]phenoxy}nicotinic acid (1.23 g, 2.5 mmol) in THF (35 mL) was added N,N′-carbonyldiimidazole (540 mg, 3.3 mmol), and the resulting solution was stirred for 30 minutes at room temperature. The resulting reaction solution was concentrated under reduced pressure, and to the residue was added 3,4-dichloroaniline (4.07 g, 25 mmol). The resulting solution was stirred for 3 days at room temperature. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and the resulting product was recrystallized from diethyl ether, to thereby yield 510 mg of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 2.33 (4H, brs), 2.59-2.65 (2H, m), 2.91-2.97 (2K, m), 3.40 (4H, brs), 3.59 (2H, s), 5.94 (2H, s), 6.70-6.76 (2H, m), 6.83 (1H, s), 6.96-7.06 (3H, m), 7.20-7.26 (2H, m), 7.40 (1H, d, J=8.6 Hz), 7.50-7.54 (1H, m), 7.86 (1H, d, J=1.8 Hz), 8.18-8.22 (1H, m), 8.44 (1H, brs), 8.66 (1H, brs).

The following compounds were produced in the same manner as in Example 2100.

TABLE 334

Example

No.
R₉₈₆
Xb₃₈
Xb₃₉
R₉₈₇
mp (° C.) or ¹H NMR (CDCl₃) δppm

2101
3,4-Cl₂Ph—
none
none
benzyl
mp 206-207

2102
4-CF₃Ph—
none
none
benzyl

¹H NMR 2.44(4H, brs), 3.53-3.70(6H,

m), 6.93(1H, d, J = 8.4 Hz), 7.11-

7.14(2H, m), 7.27-7.40(7H, m),

7.56(2H, d, J = 8.9 Hz), 7.83(2H, d, J =

8.4 Hz), 8.23-8.27(1H, m), 8.71(1H,

d, J = 2.4 Hz), 9.39(1H, brs).

2103
4-CF₃Ph—
—N(CH₃)—
—CH₂—
piperonyl

¹H NMR 2.42(4H, brs), 3.03(3H, s),

3.43-3.52(4H, m), 3.60(2H, brs),

4.10(2H, s), 5.95(2H, s), 6.66-6.77(4H,

m), 6.85(1H, brs), 6.89(1H, d, J = 8.6

Hz), 6.98(2H, d, J = 6.6 Hz), 7.60(2H,

d, J = 8.4 Hz), 7.76(2H, d, J = 8.4 Hz),

8.14(1H, dd, J = 8.6 Hz, 2.6 Hz),

8.33(1H, brs), 8.63(1H, brs).

2104
3,4-Cl₂Ph—
—N(CH₃)—
—CH₂—
piperonyl

¹H NMR 2.42-2.44(4H, m), 3.05(3H,

s), 3.44(2H, brs), 3.47-3.57(2H, m),

3.63(2H, brs), 4.11(2H, s), 5.95(2H, s),

6.68-6.74(4H, m), 6.85(1H, brs), 6.92

(1H, d, J = 8.9 Hz), 7.00(2H, d, J = 8.7

Hz), 7.42-7.44(2H, m), 7.80-7.86(1H,

m), 7.87(1H, d, J = 2.1 Hz), 8.13(1H,

dd, J = 8.7 Hz, 2.6 Hz), 8.63(1H, d, J =

2.1 Hz).

2105
4-CF₃Ph—
none
none
piperonyl

¹H NMR 2.71(4H, brs), 3.46-3.92(6H,

m), 5.91(2H, s), 6.65-6.73(2H, m),

6.81(1H, d, J = 1.5 Hz), 7.01 (1H, d, J =

9.1 Hz), 7.14(2H, d, J = 8.7 Hz),

7.43(2H, d, J = 8.7 Hz), 7.60(2H, d, J =

8.6 Hz), 7.82(2H, d, J = 8.6 Hz),

8.29(1H, dd, J = 2.6 Hz, 8.6 Hz),

8.71(1H, d, J = 2.1 Hz), 8.87(1H, brs).

Example 2106
Production of (4-benzylpiperazin-1-yl){4-[5-(3,4-dichlorophenylsulfanyl)pyridin-2-yloxy]phenyl}methanone

To a solution of [4-(5-aminopyridin-2-yloxy)phenyl](4-benzylpiperazin-1-yl)methanone (0.73 g, 1.88 mmol) in concentrated sulfuric acid (0.38 mL)-water (1.1 mL) were added dropwise a solution of sodium nitrate (0.13 g, 1.88 mmol) in water (0.6 mL) under ice cooling. The reaction mixture was stirred for 10 minutes. This reaction mixture was added to a solution of 3,4-dichlorobenzenethiol (0.24 mL, 1.88 mmol) in 2 N aqueous sodium hydroxide (2 mL) under cooling with ice. Water was added to the resulting reaction solution, and extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel chromatography (dichloromethane:methanol=80:1), to thereby yield 0.1 g of the title compound.

Appearance: Yellow oil

¹H NMR (CDCl₃) δ 2.49 (4H, brs), 3.56 (2H, s), 3.56 (2H, brs), 3.78 (2H, brs), 6.99 (1H, d, J=8.9 Hz), 7.20 (2H, d, J=8.7 Hz), 7.25-7.39 (5H, m), 7.46 (1H, dd, J=8.2 Hz, 2.0 Hz), 7.47 (2H, d, J=8.7 Hz), 7.56 (1H, d, J=8.2 Hz), 7.76 (1H, d, J=2.0 Hz), 7.86 (1H, dd, J=8.9 Hz, 2.5 Hz), 8.50 (1H, d, J=2.5 Hz).

The following compound was produced in the same manner as in Example 2106.

Example 2107
2-({4-[5-(3,4-Dichlorophenylsulfanyl)pyridin-2-yloxy]-3-methoxyphenyl}ethylamino)-1-(4-piperonylpiperazin-1-yl)ethanone

¹H NMR (CDCl₃) δ 1.20 (3H, t, J=7.0 Hz), 2.43 (4H, t, J=4.9 Hz), 3.43 (2H, s), 3.35-3.50 (2H, m), 3.49-3.60 (2H, m), 3.60-3.70 (2H, m), 3.73 (3H, s), 4.05 (2H, s), 5.95 (2H, s), 6.22 (1H, dd, J=8.9 Hz, 2.7 Hz), 6.35 (1H, d, J=2.7 Hz), 6.70-6.76 (2H, m), 6.85 (1H, s), 6.90 (1H, d, J=9.0 Hz), 6.98 (1H, d, J=8.8 Hz), 7.46 (1H, dd, J=8.2 Hz, 2.0 Hz), 7.55 (1H, d, J=8.2 Hz), 7.75 (1H, d, J=2.0 Hz), 7.78 (1H, dd, J=9.0 Hz, 2.5 Hz), 8.49 (1H, d, J=2.5 Hz).

Example 2108
Production of 1-(6-{4-[3-(4-piperonylpiperazin-1-yl)-3-oxopropyl]phenoxy}pyridin-3-yl)-3-(3,4-dichlorophenyl)urea

To a solution of 3-[4-(5-aminopyridin-2-yloxy)phenyl]-1-(4-piperonylpiperazin-1-yl)propane-1-one (600 mg, 1.3 mmol) in toluene (20 mL) were added ethyldiisopropylamine (0.454 mL, 2.6 mmol) and 3,4-dichlorophenylisocyanate (270 mg, 1.4 mmol), and the resulting solution was stirred for 1 day under reflux. The reaction solution was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:chloroform=1:19), and then recrystallized from ethyl acetate to thereby yield 280 mg of the title compound.

Appearance: Pale yellow powder

¹H NMR (CDCl₃) δ 2.37-2.39 (4H, m), 2.61-2.67 (2H, m), 2.89-2.94 (2H, m), 3.41-3.47 (4H, m), 3.61-3.65 (2H, m), 5.94 (2H, s), 6.69-6.83 (4H, m), 6.95 (2H, d, J=8.4 Hz), 7.10-7.26 (4H, m), 7.49 (1H, d, J=2.3 Hz), 7.93-7.96 (2H, m), 8.15 (1H, s), 8.21 (1H, s).

The following compounds were produced in the same manner as in Example 2108.

TABLE 335

Example

No.
R₉₈₈

¹H NMR (solvent) δppm

2109

embedded image

(DMSO-d₆) 1.13(3H, t, J = 6.9 Hz), 2.20-2.60(1H, m), 2.75-3.20(2H, m), 3.20-3.65(7H, m), 3.64(3H, s), 4.05- 4.52(4H, m), 6.07(2H, brs), 6.10(1H, dd, J = 8.8 Hz, 2.7 Hz), 6.27(1H, brs), 6.80(1H, d, J = 8.6 Hz), 6.84(1H, d, J = 8.6 Hz), 7.01(2H, brs), 7.19(1H, brs), 7.33(1H, dd, J = 8.9 Hz, 2.6 Hz), 7.51(1H, d, J = 8.9 Hz), 7.85(1H, dd, J = 8.9 Hz, 2.6 Hz), 7.86(1H, d, J = 2.6 Hz), 8.07(1H, d, J = 2.6 Hz), 8.94(1H, s), 9.28(1H, s).

2110

embedded image

(CDCl₃) 1.14(3H, t, J = 7.0 Hz), 2.35- 2.55(4H, m), 3.38(2H, q, J = 7.0 Hz), 3.44(2H, s), 3.45-3.55(2H, m), 3.60(3H, s), 3.60-3.75(2H, m), 4.02(2H, s), 5.95(2H, s), 6.60-6.80(4H, m), 6.85(1H, s), 6.92(1H, d, J = 8.9 Hz), 7.00- 7.15(2H, m), 7.22(1H, d, J = 8.7 Hz), 7.45(1H, d, J = 2.3 Hz), 7.75-7.85(2H, m), 7.95(1H, s), 7.97(1H, s).

2111

embedded image

(CDCl₃) 1.09(3H, t, J = 7.1 Hz), 2.35- 2.45(4H, m), 3.10(2H, q, J = 7.1 Hz), 3.43(2H, s), 3.55-3.65?(4H, m), 3.85(2H, s), 5.95(2H, s), 6.70-6.80(2H, m), 6.85(1H, s), 6.90(1H, d, J = 8.8 Hz), 7.05-7.35(4H, m), 7.46(1H, d, J = 8.8 Hz), 7.53(1H, d, J = 2.4 Hz), 7.79(1H, brs), 7.85(1H, brs), 7.93(1H, d, J = 2.6 Hz), 7.99(1H, dd, J = 8.8 Hz, 2.8 Hz).

2112

embedded image

(CDCl₃) 1.44(9H, s), 1.96(3H, s), 2.10- 2.30(2H, m), 3.42-3.61(2H, m), 3.62- 3.78(2H, m), 4.04(2H, s), 6.58(1H, d, J = 8.8 Hz), 6.60(1H, d, J = 8.5 Hz), 6.91(1H, dd, J = 2.6 Hz, 8.5 Hz), 7.00(1H, d, J = 2.6 Hz), 7.31(1H, d, J = 8.8 Hz), 7.36(1H, dd, J = 2.3 Hz, 8.8 Hz), 7.69(1H, d, J = 2.3 Hz), 7.79(1H, dd, J = 2.8 Hz, 8.8 Hz), 7.91(1H, d, J = 2.8 Hz), 7.93(1H, s), 8.05(1H, s).

Example 2113
Production of 4-piperonylpiperazine-1-carboxylic acid {4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]phenyl}amide hydrochloride

To a solution of {4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]phenyl}-carbamic acid phenyl ester (320 mg, 0.65 mmol) in DMF (4 mL) was added 1-piperonylpiperazine (285 mg, 1.29 mmol), and the resulting solution was stirred for 17 hours at room temperature. This reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was then purified by silica gel column chromatography (dichloromethane:methanol=25:1). The obtained residue was dissolved in a mixed solvent of ethanol-ethyl acetate. To the resulting solution was added a solution of 4 N hydrogen chloride in ethyl acetate to bring the pH to 3. The precipitated white powder was then filtered off and washed with ethanol, to thereby yield 330 mg of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 2.85-3.09 (2H, m), 3.20-3.50 (4H, m), 4.12-4.38 (4H, m), 6.08 (2H, s), 7.02 (2H, d, J=9.0 Hz), 6.93-7.12 (3H, m), 7.28 (1H, d, 1.5 Hz), 7.49 (2H, d, J=9.0 Hz), 7.83 (1H, d, J=8.5 Hz), 7.97 (1H, dd, 8.5 Hz, 2.0 Hz), 8.19 (1H, dd, J=8.8 Hz, 2.6 Hz), 8.25 (1H, d, J=2.0 Hz), 8.50 (1H, d, J=2.6 Hz), 8.92 (1H, s), 10.63 (1H, s).

The following compound was produced in the same manner as in Example 2113.

Example 2114
4-Benzylpiperazine-1-carboxylic acid {4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]phenyl}amide hydrochloride

¹H NMR (DMSO-d₆) δ 2.90-3.20 (2H, m), 3.22-3.45 (4H, m), 4.27 (2H, d, J=13.6 Hz), 4.35 (2H, d, J=5.0 Hz), 7.02 (1H, d, J=8.9 Hz), 7.03 (2H, d, J=8.9 Hz), 7.41-7.52 (3H, m), 7.48 (2H, d, J=8.9 Hz), 7.55-7.69 (2H, m), 7.84 (1H, d, J=8.4 Hz), 7.97 (1H, dd, J=8.4 Hz, 2.0 Hz), 8.19 (1H, dd, J=8.9 Hz, 2.6 Hz), 8.25 (1H, d, J=2.0 Hz), 8.49 (1H, d, J=2.6 Hz), 8.90 (1H, s), 10.62 (1H, s).

Example 2115
Production of 2-[(4-{5-[(3,4-dichlorobenzylidene)amino]pyridin-2-yloxy}phenyl)methylamino]-1-(4-piperonylpiperazin-1-yl)ethanone

2-{[(4-(5-aminopyridin-2-yloxy)phenyl]methylamino}-1-(4-piperonylpiperazin-1-yl)ethanone (7.80 g, 16.4 mmol) was dissolved in methanol (400 mL), and to the resulting solution was added 3,4-dichlorobenzaldehyde (2.87 g, 16.4 mmol).

This solution was refluxed for 16 hours. The resulting reaction solution was concentrated under reduced pressure, to thereby yield 10.4 g of the title compound.

Appearance: Brown oil

¹H NMR (CDCl₃) δ 2.44 (4H, brs), 3.03 (3H, s), 3.44-3.45 (2H, m), 3.50 (2H, brs), 3.63 (2H, brs), 4.09 (2H, s), 5.94 (2H, s), 6.65-6.77 (4H, m), 6.84-6.88 (2H, m), 7.03 (2H, d, J=9.1 Hz), 7.54 (1H, d, J=8.3 Hz), 7.58 (1H, dd, J=8.9 Hz, 2.8 Hz), 7.70 (1H, dd, J=8.4 Hz, 2.0 Hz), 8.00 (1H, d, J=2.0 Hz), 8.10 (1H, d, J=2.8 Hz), 8.39 (1H, s).

The following compounds were produced in the same manner as in Example 2115.

TABLE 336

Example

No.
R₉₈₉
R₉₀₀
R₉₉₁
Xb₄₀
M

¹H NMR (solvent) δppm

2116
3,4-Cl₂Ph—
—H
benzyl
none
0
(DMSO-d₆) 2.41(4H, brs), 3.34-3.51(6H, m),

7.19 (1H, d, J = 8.7 Hz), 7.20(2H, d, J = 7.9

Hz), 7.29-7.33(5H, m), 7.45(2H, d, J = 7.9

Hz), 7.81(1H, d, J = 8.3 Hz), 7.91-7.96(2H,

m), 8.15(1H, brs), 8.18 (1H, d, J = 2.6 Hz),

8.75(1H, s).

2117
3,4-Cl₂Ph—
—H
benzyl
none
2
(DMSO-d₆) 2.30(4H, brs), 2.60-2.62 (2H,

m), 2.79-2.85(2H, m), 3.44-3.48 (6H, m),

7.05(2H, d, J = 8.4 Hz), 7.09 (1H, d, J = 8.7

Hz), 7.25-7.36 (7H, m), 7.81(1H, d, J = 8.2

Hz), 7.88-7.93(2H, m), 8.13-8.14 (2H, m),

8.74(1H, s).

2118
4-CF₃Ph—
—H
benzyl
none
0
(CDCl₃) 2.47(4H, brs), 3.55(2H, brs),

3.55(2H, s), 3.79(2H, brs), 7.00(1H, d, J =

8.7 Hz), 7.18(2H, d, J = 8.6 Hz), 7.22-

7.40(5H, m), 7.47(2H, d, J = 8.6 Hz),

7.67(1H, dd, J = 8.7 Hz, 2.6 Hz), 7.74(2H,

d, J = 8.1 Hz), 8.03(2H, d, J = 8.1 Hz),

8.14(1H, d, J = 2.6 Hz), 8.54(1H, s).

2119
4-CF₃Ph—
—H
piperonyl
—N(CH₃)—
1
(CDCl₃) 2.45(4H, brs), 3.04(3H, s), 3.45-

3.51(4H, m), 3.65(2H, s), 4.09(2H, s),

5.95(2H, s), 6.71-6.74 (4H, m), 6.86-

6.89(2H, m), 7.04(2H, d, J = 9.1 Hz),

7.61(1H, dd, J = 8.7 Hz, 2.6 Hz), 7.73(2H,

d, J = 8.3 Hz), 8.01(2H, d, J = 8.4 Hz),

8.14(1H, d, J = 2.6 Hz), 8.53(1H, s).

2120
4-CF₃Ph—
—F
benzyl
none
0
(CDCl₃) 2.49(4H, brs), 3.43-3.75(6H, m),

7.07(1H, d, J = 8.6 Hz), 7.29-7.34(8H, m),

7.69(1H, dd, J = 8.7 Hz, 2.8 Hz), 7.74(2H,

d, J = 8.3 Hz), 8.02(2H, d, J = 8.3 Hz),

8.05(1H, d, J = 2.6 Hz), 8.53(1H, s).

2121
3,4-Cl₂Ph—
—H
piperonyl
—N(CH₃)—
2
(CDCl₃) 2.34-2.41(4H, m), 2.55-2.61(2H,

m), 2.95 (3H, s), 3.41(4H, brs), 3.61-

3.65(2H, m), 3.68-3.76 (2H, m), 5.94(2H, s),

6.70-6.77(4H, m), 6.84(1H, d, J = 1.0 Hz),

6.89(1H, dd, J = 8.7 Hz, 0.5 Hz), 7.04(2H,

d, J = 9.2 Hz), 7.55(1H, d, J = 8.3 Hz),

7.60(1H, dd, J = 8.7 Hz, 2.8 Hz), 7.71(1H,

dd, J = 8.3 Hz, 2.0 Hz), 8.01(1H, d, J = 1.8

Hz), 8.11(1H, dd, J = 2.8 Hz, 0.5 Hz),

8.40(1H, brs).

2122
4-CF₃Ph—
—H
piperonyl
—N(CH₃)—
2
(CDCl₃) 2.34-2.41(4H, m), 2.55-2.61 (2H,

m), 2.95 (3H, s), 3.39-3.42(4H, m), 3.61-

3.64(2H, m), 3.68-3.76(2H, m), 5.94(2H, s),

6.70-6.77(4H, m), 6.84(1H, d, J = 0.8 Hz),

6.90(1H, dd, J = 8.7 Hz, 0.7 Hz), 7.05(2H, d, J =

9.2 Hz), 7.63(1H, dd, J = 8.7 Hz, 2.8 Hz),

7.73(2H, d, J = 8.3 Hz), 8.01(2H, d, J = 8.6

Hz), 8.13(1H, dd, J = 2.8 Hz, 0.7 Hz),

8.53(1H, brs).

TABLE 337

Example

No.
R₉₉₂
R₉₉₃

¹H NMR (CDCl₃) δppm

2123
3,4-Cl₂Ph—
—H
2.43(4H, brs), 3.22(3H, s), 3.38(2H, brs), 3.43(2H, s), 3.62(2H,

brs), 4.55(2H, s), 5.95(2H, s), 6.74(2H, brs), 6.84(1H, brs),

7.01(1H, d, J = 8.6 Hz), 7.15(2H, d, J = 8.7 Hz), 7.57(1H, d, J =

8.3 Hz), 7.61-7.68(3H, m), 7.72(1H, dd, J = 8.3 Hz, 1.8 Hz),

8.03(1H, d, J = 1.8 Hz), 8.11(1H, d, J = 2.8 Hz), 8.42(1H, brs).

2124
3,4-Cl₂Ph—
—CH₃
2.20(3H, s), 2.42-2.43(4H, m), 3.23(3H, s), 3.38(2H, brs),

3.43(2H, s), 3.62(2H, brs), 4.54(2H, s), 5.94(2H, s), 6.70-

6.77(2H, m), 6.84(1H, brs), 6.97(1H, dd, J = 8.7 Hz, 0.5 Hz), 7.05

(1H, d, J = 8.6 Hz), 7.43-7.49(2H, m), 7.55(1H, d, J = 8.2

Hz), 7.62-7.66(1H, m), 7.69-7.74(1H, m), 8.01(1H, d, J = 2.0

Hz), 8.07(1H, d, J = 2.1 Hz), 8.40(1H, brs).

2125
4-CF₃Ph—
—CH₃
2.20(3H, s), 2.41-2.43(4H, m), 3.23(3H, s), 3.38(2H, brs),

3.43(2H, s), 3.60(2H, brs), 4.55(2H, s), 5.95(2H, s), 6.73-

6.74(2H, m), 6.84(1H, brs), 6.98(1H, d, J = 8.7 Hz), 7.05(1H, d,

J = 8.4 Hz), 7.43-7.49(2H, m), 7.65-7.75(3H, m), 8.00-8.10(3H,

m), 8.53(1H, brs).

2126
4-CF₃Ph—
—OCH₃
2.43(4H, brs), 3.24(3H, s), 3.39(2H, brs), 3.43(2H, s), 3.63(2H,

brs), 3.77(3H, s), 4.57(2H, s), 5.94(2H, s), 6.73-6.77(2H, m),

6.84(1H, s), 7.02(1H, d, J = 8.6 Hz), 7.13(1H, d, J = 8.4 Hz),

7.22(1H, dd, J = 8.4 Hz, 2.3 Hz), 7.30(1H, d, J = 2.3 Hz),

7.66(1H, dd, J = 8.7 Hz, 2.8 Hz), 7.73(2H, d, J = 8.1 Hz),

8.01(2H, d, J = 8.1 Hz), 8.08(1H, d, J = 2.5 Hz), 8.53(1H, s).

TABLE 338

Example

No.
R₉₉₄
R₉₉₅

¹H NMR (solvent) δppm

2127
3,4-Cl₂Ph—
—H
(CDCl₃) 2.20(3H, s), 2.49-2.55(4H, m), 3.45(2H, s), 3.71-

3.75(2H, m), 4.25-4.29(2H, m), 5.95(2H, s), 6.75(2H, brs),

6.86(1H, brs), 6.92(1H, d, J = 8.6 Hz), 7.06(1H, d, J = 8.6

Hz), 7.44(1H, dd, J = 8.6 Hz, 2.6 Hz), 7.53-7.65(3H, m),

7.70(1H, dd, J = 8.2 Hz, 2.0 Hz), 8.01(1H, d, J = 1.8 Hz),

8.07(1H, d, J = 2.8 Hz), 8.40(1H, brs), 9.17(1H, brs).

2128
4-CF₃Ph—
—H
(CDCl₃) 2.20(3H, s), 2.49-2.55(4H, m), 3.45(2H, s), 3.71-

3.75(2H, m), 4.25-4.28(2H, m), 5.95(2H, s), 6.75(2H, brs),

6.86(1H, brs), 6.93(1H, d, J = 8.7 Hz), 7.07(1H, d, J = 8.7

Hz), 7.45(1H, dd, J = 8.7 Hz, 2.6 Hz), 7.58(1H, d, J = 2.5

Hz), 7.65(1H, dd, J = 8.6 Hz, 2.6 Hz), 7.73(2H, d, J = 8.2

Hz), 8.01(2H, d, J = 8.1 Hz), 8.10(1H, d, J = 2.8 Hz),

8.53(1H, s), 9.19(1H, brs).

2129
3,4-Cl₂Ph—
—CH₃
a mixture of the rotational isomers

(DMSO-d₆) 2.10-2.44(7H, m), 3.16-3.57(9H, m), 5.96-

5.99(2H, m), 6.67-6.89(3H, m), 7.09-7.26(3H, m), 7.29-

7.38(1H, m), 7.81(1H, d, J = 8.41 Hz), 7.89-7.96(2H, m),

8.10-8.15(2H, m), 8.74(1H, s).

2130
4-CF₃Ph—
—CH₃
a mixture of the rotational isomers

(DMSO-d₆) 2.11-2.44(7H, m), 3.18-3.57(9H, m), 5.96-

6.00(2H, m), 6.67-6.90(3H, m), 7.09-7.27(3H, m), 7.29-

7.38(1H, m), 7.90(2H, d, J = 8.24 Hz), 7.95-8.00(1H, m),

8.11-8.16(3H, m), 8.85(1H, s).

TABLE 339

Example

No.
R₉₉₆
R₉₉₇

¹H NMR (CDCl₃) δppm

2131
—H

embedded image

1.46(9H, s), 2.41-2.45(4H, m), 3.43-3.47(4H, m), 3.53(2H, s), 6.96(1H, d, J = 8.7 Hz), 7.08- 7.14(2H, m), 7.36(2H, d, J = 8.4 Hz), 7.55(1H, d, J = 8.2 Hz), 7.63(1H, dd, J = 8.7 Hz, 2.6 Hz), 7.71(1H, dd, J = 8.2 Hz, 2.0 Hz), 8.01(1H, d, J = 1.8 Hz), 8.11-8.12(1H, m), 8.41(1H, s).

2132
—CH₃

embedded image

2.19(3H, s), 3.12(1H, dd, J = 14.0 Hz, 9.9 Hz), 3.55(1H, dd, J = 14.0 Hz, 3.8 Hz), 4.54(1H, dd, J = 9.9 Hz, 3.8 Hz), 6.95(1H, d, J = 8.7 Hz), 7.04(1H, d, J = 8.1 Hz), 7.12(1H, dd, J = 8.1 Hz, 2.1 Hz), 7.16(1H, d, J = 2.1 Hz), 7.56(1H, d, J = 8.4 Hz), 7.64(1H, dd, J = 8.7 Hz, 2.3 Hz), 7.71(1H, dd, J = 8.4 Hz, 1.8 Hz), 8.02(1H, d, J = 1.8 Hz), 8.08(1H, d, J = 2.3 Hz), 8.18 (1H, brs), 8.41(1H, s).

Example 2133
Production of 3-({4-[5-(3,4-dichlorobenzylamino)pyridin-2-yloxy]phenyl}methylamino)-1-(4-piperonylpiperazin-1-yl)propane-1-one

3-[(4-{5-(3,4-dichlorobenzylidene)pyridin-2-yloxy}phenyl)methylamino]-1-(4-piperonylpiperazin-1-yl)propane-1-one (3.88 g, 6.0 mmol) was dissolved in a mixed solvent of methanol (150 mL) and THF (50 mL). To the resulting solution was slowly added odium borohydride (1.13 g, 30.0 mmol) and that resulting solution was stirred for 13 hours at room temperature. This reaction solution was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate, and washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was then purified by silica gel column chromatography (dichloromethane:methanol=40:1), to thereby yield 3.60 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 2.32-2.39 (4H, m), 2.52-2.57 (2H, m), 2.91 (3H, s), 3.36-3.40 (4H, m), 3.59-3.63 (2H, m), 3.66-3.71 (2H, m), 3.97 (1H, brs), 4.27 (2H, d, J=5.0 Hz), 5.94 (2H, s), 6.65-6.76 (5H, m), 6.83 (1H, d, J=1.0 Hz), 6.94 (1H, dd, J=8.9 Hz, 3.0 Hz), 6.97 (2H, d, J=9.2 Hz), 7.18 (1H, dd, J=8.3 Hz, 2.0 Hz), 7.40 (1H, d, J=8.4 Hz), 7.45 (1H, d, J=2.0 Hz), 7.56 (1H, d, J=2.5 Hz); MS 647 (M⁺).

The following compounds were produced in the same manner as in Example 2133.

TABLE 340

Example

No.
R₉₉₈
R₉₉₉
Xb₄₁
M

¹H NMR (solvent) δppm

2134
4-CF₃Ph—
piperonyl
—N(CH₃)—
1
(CDCl₃) 2.42(4H, brs), 2.99(3H, s), 3.43-

3.49(4H, m), 3.62(2H, brs), 4.04(2H, s),

4.37(2H, s), 5.95(2H, s), 6.67-6.75(5H, m),

6.86(1H, brs), 6.92-6.97(3H, m), 7.47(2H, d,

J = 7.9 Hz), 7.58-7.61(3H, m).

2135
4-CF₃Ph—
piperonyl
—N(CH₃)—
2
(CDCl₃) 2.32-2.39(4H, m), 2.52-2.57(2H, m),

2.91(3H, s), 3.36-3.39(4H, m), 3.59-3.63(2H,

m), 3.66-3.71(2H, m), 4.00(1H, brs),

4.37(2H, d, J = 4.3 Hz), 5.94(2H, s), 6.66-

6.76(5H, m), 6.83(1H, d, J = 1.0 Hz),

6.95(1H, dd, J = 8.9 Hz, 3.0 Hz), 6.97(2H, d,

J = 9.1 Hz), 7.46(2H, d, J = 8.1 Hz), 7.57-

7.61(3H, m).

2136
3,4-Cl₂Ph—
piperonyl
—N(CH₃)—
1
(CDCl₃) 2.39-2.43(4H, m), 2.99(3H, s),

3.42(2H, brs), 3.46-3.50(2H, m), 3.60-

3.62(2H, m), 3.97(1H, t, J = 5.8 Hz),

4.05(2H, s), 4.26(2H, d, J = 5.8 Hz),

5.95(2H, s), 6.65-6.77(5H, m), 6.85(1H, brs),

6.93(1H, dd, J = 8.6 Hz, 3.1 Hz), 6.96(2H, d,

J = 9.1 Hz), 7.18(1H, dd, J = 8.3 Hz, 2.1

Hz), 7.40(1H, d, J = 8.3 Hz), 7.45(1H, d, J =

2.1 Hz), 7.57(1H, d, J = 2.8 Hz)

2137
3,4-Cl₂Ph—
benzyl
none
2
(DMSO-d₆) 2.26-2.28(4H, m), 2.57(2H, t, J =

7.9 Hz), 2.76(2H, t, J = 7.9 Hz), 3.40-

3.46(6H, m), 4.28(2H, d, J = 5.9 Hz),

6.36(1H, t, J = 6.1 Hz), 6.77(1H, d, J = 8.7

Hz), 6.85(2H, d, J = 8.3 Hz), 7.09(1H, dd, J =

8.7 Hz, 3.0 Hz), 7.17(2H, d, J = 8.4 Hz),

7.24-7.37(6H, m), 7.50(1H, d, J = 3.0 Hz),

7.58(1H, d, J = 8.3 Hz), 7.62 (1H, d, J = 1.8

Hz).

2138
3,4-Cl₂Ph—
benzyl
none
0
(DMSO-d₆) 2.38(4H, brs), 3.33-3.50(6H, m),

4.30(2H, d, J = 6.3 Hz), 6.47(1H, t, J = 6.3

Hz), 6.87(1H, d, J = 3.7 Hz), 6.97(2H, d, J =

8.6 Hz), 7.12(1H, dd, J = 8.7 Hz, 3.0 Hz),

7.25-7.39(8H, m), 7.56(1H, d, J = 3.0 Hz),

7.58-7.64(2H, m).

2139
4-CF₃Ph—
benzyl
none
0
(CDCl₃) 2.45(4H, brs), 3.52(2H, brs),

3.53(2H, s), 3.73 (2H, brs), 4.16(1H, brs),

4.41(2H, s), 6.80(1H, d, J = 8.7 Hz),

6.99(1H, dd, J = 8.7 Hz, 3.0 Hz), 7.03(2H, d,

J = 8.5 Hz), 7.20-7.37(5H, m), 7.38(2H, d, J =

8.5 Hz), 7.48(2H, d, J = 8.1 Hz), 7.61(2H,

d, J = 8.1 Hz), 7.64 (1H, d, J = 3.0 Hz).

TABLE 341

Example

No.
R₁₀₀₀
R₁₀₀₁

¹H NMR (CDCl₃) δppm

2140
3,4-Cl₂Ph—
—H
2.41(4H, brs), 3.19(3H, s), 3.33-3.35(2H, m), 3.42(2H, s),

3.60(2H, brs), 4.08(1H, brs), 4.30(2H, d, J = 5.3 Hz),

4.50(2H, s), 5.95(2H, s), 6.73-6.74(2H, m), 6.80-6.84(2H,

m), 6.99(1H, dd, J = 8.6 Hz, 3.1 Hz), 7.02(2H, d, J = 8.7

Hz), 7.20(1H, dd, J = 8.3 Hz, 2.0 Hz), 7.42(1H, d, J = 8.3

Hz), 7.66(1H, d, J = 2.1 Hz), 7.54(2H, d, J = 8.9 Hz),

7.60(1H, d, J = 2.8 Hz).

2141
3,4-Cl₂Ph—
—CH₃
2.19(3H, s), 2.41(4H, brs), 3.19(3H, s), 3.35(2H, brs),

3.41(2H, s), 3.60(2H, brs), 4.07-4.15(1H, m), 4.27(2H, s),

4.50(2H, s), 5.93(2H, s), 6.69-6.78(3H, m), 6.83(1H, brs),

6.88(1H, d, J = 8.6 Hz), 6.98(1H, dd, J = 8.7 Hz, 3.0 Hz),

7.17-7.20(1H, m), 7.34-7.44(4H, m), 7.53(1H, d, J = 3.0

Hz).

2142
4-CF₃Ph—
—CH₃
2.20(3H, s), 2.41(4H, brs), 3.19(3H, s), 3.35-3.37(2H, m),

3.41(2H, s), 3.60-3.62(2H, m), 4.15(1H, brs), 4.38(2H, s),

4.50(2H, s), 5.94(2H, s), 6.73(2H, brs), 6.76(1H, d, J = 8.7

Hz), 6.83(1H, brs), 6.88(1H, d, J = 8.6 Hz), 7.00(1H, dd, J =

8.7 Hz, 3.0 Hz), 7.36(1H, dd, J = 8.6 Hz, 2.6 Hz), 7.42(1H,

d, J = 2.5 Hz), 7.47(2H, d, J = 8.1 Hz), 7.56(1H, d, J = 2.8

Hz), 7.59(2H, d, J = 8.1 Hz).

2143
4-CF₃Ph—
—OCH₃
2.41(4H, brs), 3.21(3H, s), 3.36(2H, brs), 3.42(2H, s),

3.60(2H, brs), 3.76(3H, s), 4.09(1H, brs), 4.37(2H, s),

4.52(2H, s), 5.94(2H, s), 6.70-6.83(4H, m), 6.97-7.02(2H,

m), 7.12-7.16 (1H, m), 7.23-7.26(1H, m), 7.44-7.60(5H, m).

TABLE 342

Example

No.
R₁₀₀₂
R₁₀₀₃

¹H NMR (solvent) δ ppm

2144
3,4-Cl₂Ph—
—H
(CDCl₃) 2.17 (3H, s), 2.48-2.53 (4H, m), 3.44 (2H, s), 3.69-

3.73 (2H, m), 3.97 (1H, brs), 4.23-4.27 (4H, m), 5.95 (2H, s),

6.70-6.74 (3H, m), 6.85 (1H, brs), 6.94 (1H, d, J = 8.7 Hz), 6.96 (1H,

dd, J = 8.7 Hz, 3.1 Hz), 7.18 (1H, dd, J = 8.2 Hz, 2.0 Hz),

7.36 (1H, dd, J = 8.7 Hz, 2.5 Hz), 7.40 (1H, d, J = 8.2 Hz),

7.45 (1H, d, J = 2.1 Hz), 7.51 (1H, d, J = 2.3 Hz), 7.55 (1H, d, J =

3.0 Hz), 9.11 (1H, brs).

2145
4-CF₃Ph—
—H
(CDCl₃) 2.19 (3H, s), 2.43-2.53 (4H, m), 3.44 (2H, s), 3.70-

3.73 (2H, m), 4.00 (1H, brs), 4.23-4.27 (2H, m), 4.37 (2H, s),

5.95 (2H, s), 6.72 (1H, d, J = 8.7 Hz), 6.74-6.77 (2H, m), 6.85 (1H,

brs), 6.94 (1H, d, J = 8.7 Hz), 6.97 (1H, dd, J = 8.7 Hz, 3.1 Hz),

7.37 (1H, dd, J = 8.7 Hz, 2.6 Hz), 7.47 (2H, d, J = 8.4 Hz),

7.51 (1H, d, J = 2.5 Hz), 7.57 (1H, d, J = 3.1 Hz), 7.60 (2H, d, J =

8.1 Hz), 9.11 (1H, brs).

2146
3,4-Cl₂Ph—
—CH₃
a mixture of the rotational isomers

(DMSO-d₆) 2.25-2.42 (7H, m), 3.22-3.55 (9H, m), 4.27 (2H, d,

J = 6.27 Hz), 5.77-5.99 (2H, m), 6.38 (1H, t, J = 6.27 Hz), 6.65-

6.90 (5H, m), 7.06-7.14 (2H, m), 7.22-7.28 (1H, m), 7.32-7.36

(1H, m), 7.46 (1H, d, J = 2.80 Hz), 7.56-7.61 (2H, m).

2147
4-CF₃Ph—
—CH₃
a mixture of the rotational isomers

(DMSO-d₆) 2.24-2.41 (7H, m), 3.20-3.54 (9H, m), 4.34-4.36

(2H, m), 5.95-5.98 (2H, m), 6.38-6.41 (1H, m), 6.65-6.88 (5H, m),

7.03-7.13 (2H, m), 7.21-7.27 (1H, m), 7.45 (1H, d, J = 2.64 Hz),

7.55 (2H, d, J = 7.75 Hz), 7.67 (2H, d, J = 7.75 Hz).

TABLE 343

Example

No.
R₁₀₀₄
R₁₀₀₅

¹H NMR (CDCl₃) δ ppm

2148
—H

embedded image

1.45 (9H, s), 2.37-2.40 (4H, m), 3.40-3.44 (4H, m), 3.47 (2H, s), 4.28 (2H, s), 6.77 (1H, d, J = 8.7 Hz), 6.95-7.01 (3H, m), 7.17-7.21 (1H, m), 7.26-7.29 (2H, m), 7.41 (1H, d, J = 8.1 Hz), 7.45 (1H, d, J = 1.8 Hz), 7.60 (1H, d, J = 3.0 Hz).

2149
—CH₃

embedded image

2.19 (3H, s), 3.05 (1H, dd, J = 14.0 Hz, 10.0 Hz), 3.50 (1H, dd, J = 14.0 Hz, 3.8 Hz), 4.02 (1H, brs), 4.27 (2H, s), 4.49 (1H, dd, J = 10.0 Hz, 3.8 Hz), 6.73 (1H, d, J = 8.7 Hz), 6.99 (1H, d, J = 8.2 Hz), 6.97 (1H, dd, J = 8.7 Hz, 2.9 Hz), 7.02 (1H, dd, J = 8.2 Hz, 2.0 Hz), 7.09 (1H, d, J = 2.0 Hz), 7.18 (1H, dd, J = 8.2 Hz, 2.0 Hz), 7.41 (1H, d, J = 8.2 Hz), 7.45 (1H, d, J = 2.0 Hz), 7.55 (1H, d, J = 2.9 Hz), 8.61 (1H, brs).

Example 2150
Production of 1-(4-benzylpiperazin-1-yl)-3-(4-{5-(piperonylamino)pyridin-2-yloxy}phenyl)propane-1-one

3-[4-(5-aminopyridin-2-yloxy)phenyl]-1-(4-piperonylpiperazin-1-yl)propane-1-one (1.04 g, 2.5 mmol) was dissolved in methanol (25 mL). To the resulting solution was added piperonal (0.39 g, 2.63 mmol), and this solution was refluxed overnight. The resulting reaction solution was cooled with ice, and then sodium borohydride (0.28 g, 7.50 mmol) was added. The resulting solution was stirred for 2 hours at room temperature. This reaction solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and washed with water, saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was then purified by silica gel column chromatography (ethyl acetate), to thereby yield 0.80 g of the title compound.

Appearance: Yellow oil

¹H NMR (DMSO-d₆) δ 2.28 (4H, brs), 2.57 (2H, t, J=7.9 Hz), 2.76 (2H, t, J=7.9 Hz), 3.40-3.46 (6H, m), 4.15 (2H, d, J=6.1 Hz), 5.97 (2H, s), 6.21 (1H, t, J=6.1 Hz), 6.76 (1H, d, J=8.6 Hz), 6.82-6.86 (4H, m), 6.92 (1H, brs), 7.08 (1H, dd, J=8.7 Hz, 3.0 Hz), 7.17 (2H, d, J=8.4 Hz), 7.24-7.32 (5H, m), 7.51 (1H, d, J=3.0 Hz).

The following compounds were produced in the same manner as in Example 2150.

TABLE 344

Example

No.
R₁₀₀₆
R₁₀₀₇
R₁₀₀₈
Xb₄₂
M

¹H NMR (solvent) δ ppm

2151
4-CF₃Ph—
—CH₃
piperonyl
—N(C₂H₅)—
1
(CDCl₃) 1.15 (3H, t, J = 7.1 Hz),

2.11 (3H, s), 2.30-2.50 (4H, m),

3.39 (2H, q, J = 7.1 Hz), 3.42 (2H, s),

3.42-3.55 (2H, m), 3.56-3.70 (2H, m),

3.80-4.05 (1H, m), 3.99 (2H, s),

4.36 (2H, s), 5.94 (2H, s), 6.44-

6.55 (2H, m), 6.58-6.64 (1H, m), 6.69-

6.78 (2H, m), 6.80-6.89 (2H, m),

6.94 (1 H, dd, J = 8.8 Hz, 3.1 Hz),

7.46 (2H, d, J = 8.0 Hz), 7.55-

7.63 (3H, m).

2152
3,4-Cl₂Ph—
—CH₃
piperonyl
—N(C₂H₅)—
1
(CDCl₃) 1.15 (3H, t, J = 7.1 Hz),

2.11 (3H, s), 2.32-2.49 (4H, m),

3.39 (2H, q, J = 7.1 Hz), 3.42 (2H, s),

3.44-3.55 (2H, m), 3.56-3.69 (2H, m),

3.79-3.94 (1H, m), 3.99 (2H, s), 4.15-

4.30 (2H, m), 5.94 (2H, s), 6.50 (1H,

dd, J = 8.5 Hz, 3.0 Hz), 6.54 (1H, d,

J = 3.0 Hz), 6.58-6.65 (1H, m), 6.69-

6.78 (2H, m), 6.82-6.88 (2H, m),

6.92 (1H, dd, J = 8.8 Hz, 3.0 Hz),

7.18 (1H, dd, J = 8.2 Hz, 2.0 Hz),

7.40 (1H, d, J = 8.2 Hz), 7.45 (1H, d,

J = 2.0 Hz), 7.57 (1H, d, J = 3.0 Hz).

2153
4-CF₃Ph—
—H
benzyl
none
2
(DMSO-d₆) 2.28 (4H, brs), 2.54-

2.60 (2H, m), 2.73-2.79 (2H, m), 3.42-

3.46 (6H, m), 4.37 (2H, d, J = 5.9 Hz),

6.41 (1H, t, J = 6.1 Hz), 6.77 (1H, d,

J = 8.7 Hz), 6.84 (2H, d, J = 8.6 Hz),

7.08 (1H, dd, J = 8.7 Hz, 3.0 Hz),

7.17 (2H, d, J = 8.6 Hz), 7.22-

7.35 (5H, m), 7.50 (1H, d, J = 3.0 Hz),

7.58 (2H, d, J = 7.9 Hz), 7.69 (2H, d,

J = 7.9 Hz).

2154
4-ClPh—
—H
benzyl
none
2
(DMSO-d₆) 2.28 (4H, t, J = 4.8 Hz),

2.57 (2H, t, J = 7.3 Hz), 2.76 (2H, t,

J = 7.3 Hz), 3.38-3.46 (6H, m),

4.25 (2H, d, J = 6.1 Hz), 6.32 (1H, t,

J = 6.1 Hz), 6.76 (1H, d, J = 8.6 Hz),

6.84 (2H, d, J = 8.6 Hz), 7.07 (1H, dd,

J = 8.7 Hz, 3.1 Hz), 7.17 (2H, d, J =

8.6 Hz), 7.24-7.32 (5H, m), 7.38 (4H,

brs), 7.50 (1H, d, J = 3.1 Hz).

2155
3,4-F₂Ph—
—H
benzyl
none
2
(DMSO-d₆) 2.26-2.28 (4H, m), 2.57-

2.60 (2H, m), 2.73-2.79 (2H, m), 3.37-

3.46 (6H, m), 4.25 (2H, d, J = 5.8 Hz),

6.32 (1H, t, J = 5.8 Hz), 6.77

(1H, d, J = 8.6 Hz), 6.84 (2H, d, J =

8.3 Hz), 7.08 (1H, dd, J = 8.6 Hz,

3.0 Hz), 7.17 (2H, d, J = 8.4 Hz), 7.22-

7.43 (8H, m), 7.50 (1H, d, J = 3.1 Hz).

TABLE 345

Example

No.
R₁₀₀₉
R₁₀₁₀
R₁₀₁₁
Xb₄₃
M
mp (° C.) or ¹H NMR (solvent) δ ppm

2156
4-CF₃Ph—
—CH₃
piperonyl
—N(CH₃)—
1

¹H NMR (CDCl₃) 2.12 (3H, s),

2.42 (4H, t, J = 5.0 Hz), 2.98 (3H,

s), 3.41-3.55 (4H, m), 3.56-

3.67 (2H, m), 3.77-3.99 (1H, m),

4.04 (2H, s), 4.36 (2H, s),

5.94 (2H, s), 6.52 (1H, dd, J = 8.7 Hz,

3.0 Hz), 6.56 (1H, d, J = 3.0 Hz),

6.59-6.64 (1H, m), 6.69-

6.78 (2H, m), 6.85 (1H, s),

6.87 (1H, d, J = 8.7 Hz), 6.93 (1H,

dd, J = 8.8 Hz, 3.0 Hz), 7.46 (2H,

d, J = 8.0 Hz), 7.54-7.63 (3H, m).

2157
3,4-Cl₂Ph—
—CH₃
piperonyl
—N(CH₃)—
1
mp 132-134

2158
4-CF₃Ph—
—CH₃
piperonyl
—N(Ac)—
1

¹H NMR (CDCl₃) 1.94 (3H, s),

2.09 (3H, s), 2.30-2.50 (4H, m),

3.29-3.51 (4H, m), 3.52-3.69 (2H,

m), 3.92-4.17 (1H, m), 4.29-

4.51 (4H, m), 5.94 (2H, s), 6.69-

6.77 (2H, m), 6.78 (1H, d, J =

8.7 Hz), 6.81-6.86 (1H, m), 6.91 (1H,

d, J = 8.5 Hz), 7.01 (1H, dd, J =

8.7 Hz, 3.1 Hz), 7.18 (1H, dd, J =

8.5 Hz, 2.5 Hz), 7.28 (1H, d, J =

2.5 Hz), 7.48 (2H, d, J = 8.1 Hz),

7.56-7.64 (3H, m).

2159
3,4-Cl₂Ph—
—CH₃
piperonyl
—N(Ac)—
1

¹H NMR (CDCl₃) 1.95 (3H, s),

2.07 (3H, s), 2.30-2.51 (4H, m),

3.29-3.50 (4H, m), 3.51-3.71 (2H,

m), 3.92-4.18 (1H, m), 4.29 (2H,

s), 4.42 (2H, s), 5.94 (2H, s), 6.69-

6.78 (3H, m), 6.82-6.87 (1H, m),

6.91 (1H, d, J = 8.5 Hz), 7.00 (1H,

dd, J = 8.7 Hz, 3.0 Hz), 7.14-

7.23 (2H, m), 7.26-7.31 (1H, m),

7.41 (1H, d, J = 8.2 Hz),

7.46 (1H, d, J = 2.0 Hz), 7.57 (1H,

d, J = 3.0 Hz).

2160
Ph—
—H
benzyl
none
2

¹H NMR (DMSO-d₆) 2.27 (4H,

brs), 2.54-2.60 (2H, m), 2.73-

2.79 (2H, m), 3.40-3.46 (6H, m),

4.25 (2H, d, J = 5.9 Hz), 6.28 (1H,

t, J = 5.9 Hz), 6.76 (1H, d, J =

8.7 Hz), 6.84 (2H, d, J = 8.4 Hz), 7.09

(1H, dd, J = 8.7 Hz, 3.0 Hz), 7.17

(2H, d, J = 8.7 Hz), 7.23-7.38

(10H, m), 7.52 (1H, d, J = 3.0 Hz).

2161
4-CF₃Ph—
—OCH₃
piperonyl
—N(CH₃)—
1
mp 102-103

2162
3,4-Cl₂Ph—
—OCH₃
piperonyl
—N(CH₃)—
1
mp 145-146

2163
4-CF₃Ph—
—OCH₃
piperonyl
—N(C₂H₅)—
1
mp 160.0-160.5

2164
3,4-Cl₂Ph—
—OCH₃
piperonyl
—N(C₂H₅)—
1
mp 133-134

2165
3,4-Cl₂Ph—
—F
piperonyl
—N(CH₃)—
1
mp 134-137

TABLE 346

Example

No.
R₁₀₁₂
R₁₀₁₃
Xb₄₄
M
mp (° C.) or ¹H NMR (CDCl₃) δ ppm

2166
4-CF₃Ph—
—OCH₃
none
2

¹H NMR 2.38-2.44 (4H, m), 2.56-2.67 (2H,

m), 2.88-2.99 (2H, m), 3.31-3.45 (2H, m),

3.40 (2H, s), 3.57-3.69 (2H, m), 3.76 (3H,

s), 3.80-4.06 (1H, m), 4.37 (2H, s),

5.94 (2H, s), 6.68-6.81 (4H, m), 6.83-

6.87 (2H, m), 6.96 (1H, d, J = 8.0 Hz),

6.98 (1H, dd, J = 8.7 Hz, 3.0 Hz),

7.46 (2H, d, J = 8.0 Hz), 7.54 (1H, d, J =

2.6 Hz), 7.59 (2H, d, J = 8.0 Hz).

2167
4-CF₃Ph—
—F
—N(C₂H₅)—
1
mp 106-107

2168
4-CF₃Ph—
—F
—N(CH₃)—
1
mp 163-164

2169
3,4-Cl₂Ph—
—F
—N(C₂H₅)—
1
mp 107.5-109.0

2170
4-CF₃Ph—
—H
—N(SO₂CH₃)—
1

¹H NMR 2.41 (4H, brs), 3.18 (3H, s),

3.35 (2H, brs), 3.42 (2H, s), 3.62 (2H, brs),

4.14 (1H, brs), 4.41 (2H, brs), 4.50 (2H, s),

5.94 (2H, s), 6.70-6.76 (2H, m), 6.80-

6.83 (2H, m), 6.98-7.04 (3H, m), 7.47-

7.56 (4H, m), 7.60-7.63 (3H, m).

Example 2171
Production of 1-(4-benzylpiperazin-1-yl)-3-[(4-(5-dibenzylaminopyridin-2-yloxy)phenyl]propane-1-one

3-[4-(5-aminopyridin-2-yloxy)phenyl]-1-(4-benzylpiperazin-1-yl)propane-1-one (1.0 g, 2.4 mmol) was dissolved in DMF (30 mL). To this solution were added potassium carbonate (0.73 g, 5.28 mmol), sodium iodide (0.76 g, 5.04 mmol) and benzyl bromide (0.60 mL, 5.04 mmol), and the resulting solution was stirred at room temperature overnight. This reaction solution was concentrated under reduced pressure. The residue was diluted with chloroform, and washed with water, saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was then purified by silica gel column chromatography (chloroform:methanol=80:1), to thereby yield 0.67 g of the title compound.

Appearance: Yellow oil

¹H NMR (DMSO-d₆) δ 2.27 (4H, brs), 2.50-2.59 (2H, m), 2.73-2.78 (2H, m), 3.37-3.45 (6H, m), 4.68 (4H, s), 6.78 (1H, d, J=8.9 Hz), 6.85 (2H, d, J=8.4 Hz), 7.17 (2H, d, J=8.6 Hz), 7.20-7.36 (16H, m), 7.54 (1H, d, J=3.1 Hz).

Example 2172
Production of 2-[(4-{5-[(3,4-dichlorobenzyl)ethylamino]pyridin-2-yloxy}phenyl)methylamino]-1-(4-piperonylpiperazin-1-yl)ethanone

2-({4-[5-(3,4-dichlorobenzylamino)pyridin-2-yloxy]phenyl}methylamino)-1-(4-piperonylpiperazin-1-yl)ethanone (1.59 g, 2.5 mmol) was dissolved in dichloroethane (80 mL). To this solution were added acetoaldehyde (1.40 mL, 25.0 mmol) and sodium triacetyloxy borohydride (1.59 mL, 7.5 mmol) under ice cooling. To the resulting solution was added dropwise acetic acid (0.43 mL, 7.5 mmol), and this solution was stirred at room temperature for 16 hours. The resulting reaction solution was washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was then purified by silica gel column chromatography (chloroform:methanol=50:1). The obtained solid was recrystallized from ethanol, to thereby yield 0.65 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 1.17 (3H, t, J=7.1 Hz), 2.41 (4H, brs), 2.99 (3H, s), 3.36-3.44 (4H, m), 3.48 (2H, brs), 3.62 (2H, brs), 4.04 (2H, s), 4.35 (2H, s), 5.95 (2H, s), 6.67-6.77 (5H, m), 6.85 (1H, brs), 6.97 (2H, d, J=9.1 Hz), 7.01 (1H, dd, J=8.9 Hz, 3.1 Hz), 7.07 (1H, dd, J=8.2 Hz, 2.0 Hz), 7.32 (1H, d, J=2.0 Hz), 7.37 (1H, d, 8.3 Hz), 7.63 (1H, d, J=3.0 Hz); MS 661 (M⁺).

The following compounds were produced in the same manner as in Example 2172.

TABLE 347

Example

No.
R₁₀₁₄
R₁₀₁₅
R₁₀₁₆
Xb₄₅
M

¹H NMR (CDCl₃) δ ppm

2173
4-CF₃Ph—
—H
piperonyl
—N(CH₃)—
1
2.44 (4H, brs), 2.99 (6H, s), 3.39-

3.62 (6H, m), 4.04 (2H, s), 4.48 (2H,

s), 5.95 (2H, s), 6.62-6.78 (5H, m),

6.86 (1H, brs), 6.97 (2H, d, J =

9.1 Hz), 7.08 (1H, dd, J = 8.9 Hz,

3.1 Hz), 7.34 (2H, d, J = 7.9 Hz),

7.57 (2H, d, J = 8.1 Hz), 7.69 (1H, d,

J = 3.1 Hz).

2174
3,4-Cl₂Ph—
—H
piperonyl
—N(CH₃)—
2
2.32-2.40 (4H, m), 2.53-2.58 (2H, m),

2.92 (3H, s), 2.97 (3H, s), 3.37-

3.40 (4H, m), 3.59-3.63 (2H, m), 3.66-

3.72 (2H, m), 4.37 (2H, s), 5.94 (2H,

s), 6.66-6.76 (5H, m), 6.83 (1H, d, J =

1.0 Hz), 6.98 (2H, d, J = 9.1 Hz),

7.04-7.11 (2H, m), 7.32 (1H, d, J =

2.0 Hz), 7.38 (1H, d, J = 8.3 Hz),

7.67 (1H, d, J = 3.1 Hz).

2175
4-CF₃Ph—
—H
piperonyl
—N(CH₃)—
2
2.32-2.39 (4H, m), 2.52-2.57 (2H, m),

2.92 (3H, s), 2.99 (3H, s), 3.36-

3.40 (4H, m), 3.59-3.63 (2H, m), 3.66-

3.72 (2H, m), 4.48 (2H, s), 5.94 (2H,

s), 6.67-6.76 (5H, m), 6.83 (1H, d, J =

1.0 Hz), 6.98 (2H, d, J = 9.2 Hz),

7.09 (1H, dd, J = 9.1 Hz, 3.1 Hz),

7.34 (2H, d, J = 7.9 Hz), 7.57 (2H, d,

J = 8.1 Hz), 7.68 (1H, d, J = 2.8 Hz).

2176
3,4-Cl₂Ph—
—H
piperonyl
—N(CH₃)—
1
2.40-2.44 (4H, m), 2.96 (3H, s),

3.00 (3H, s), 3.43 (2H, brs), 3.49 (2H,

brs), 3.62 (2H, brs), 4.05 (2H, s),

4.36 (2H, s), 5.95 (2H, s), 6.67-

6.77 (5H, m), 6.85 (1H, brs), 6.97 (2H,

d, J = 9.1 Hz), 7.06 (1H, dd, J =

8.3 Hz, 1.7 Hz), 7.07 (1H, dd, J =

8.9 Hz, 3.1 Hz), 7.32 (1H, d, J =

2.0 Hz), 7.38 (1H, d, J = 8.3 Hz), 7.69

(1H, d, J = 3.1 Hz).

2177
4-CF₃Ph—
—F
benzyl
none
0
2.46 (4H, brs), 3.02 (3H, s), 3.54 (6H,

brs), 4.52 (2H, s), 6.89 (1H, d, J =

8.9 Hz), 7.14 (1H, dd, J = 8.9 Hz,

3.1 Hz), 7.17-7.21 (2H, m), 7.28-7.35

(8H, m), 7.58 (2H, d, J = 8.1 Hz),

7.62 (1H, d, J = 2.8 Hz).

2178
3,4-Cl₂Ph—
—F
benzyl
none
0
2.47 (4H, brs), 3.00 (3H, s), 3.55-

3.73 (6H, m), 4.40 (2H, s), 6.89 (1H, d,

J = 8.9 Hz), 7.06 (1H, dd, J = 8.2 Hz,

1.7 Hz), 7.14 (1H, dd, J = 8.9 Hz,

3.1 Hz), 7.17-7.22 (3H, m), 7.28-7.33

(6H, m), 7.39 (1H, d, J = 8.3 Hz), 7.61

(1H, d, J = 3.3 Hz).

TABLE 348

Example

mp (° C.) or ¹H NMR

No.
R₁₀₁₇
R₁₀₁₈
R₁₀₁₉
Form
(DMSO-d₆) δ ppm

2179
4-CF₃Ph—
—CH₃
—C₂H₅
fumarate
mp 157-159 dec

2180
3,4-Cl₂Ph—
—CH₃
—C₂H₅
fumarate
mp 148-151 dec

2181
4-CF₃Ph—
—CH₃
—CH₃
fumarate
mp 151-154

2182
3,4-Cl₂Ph—
—CH₃
—CH₃
hydrochloride
mp 139-142

2183
4-CF₃Ph—
—CH₃
—Ac
hydrochloride
mp 199.5-201.5

2184
3,4-Cl₂Ph—
—CH₃
—Ac
hydrochloride
mp 188.5-190.0

2185
4-CF₃Ph—
—OCH₃
—CH₃
oxalate

¹H NMR 2.48-2.81 (4H, m),

2.93 (3H, s), 2.94 (3H, s), 3.36-

3.85 (9H, m), 4.25 (2H, s), 4.56

(2H, s), 6.0 (2H, s), 6.12 (1H, dd,

J = 8.8 Hz, 2.8 Hz), 6.29 (1H, d,

J = 2.8 Hz), 6.66 (1H, d, J =

9.0 Hz), 6.77 (1H, d, J = 8.8 Hz),

6.79-6.98 (3H, m), 7.22 (1H, dd,

J = 9.0 Hz, 3.2 Hz), 7.42 (2H, d,

J = 8.1 Hz), 7.52 (1H, d, J =

3.2 Hz), 7.67 (2H, d, J = 8.1 Hz).

2186
3,4-Cl₂Ph—
—OCH₃
—CH₃
hydrochloride

¹H NMR 2.75-3.18 (8H, m), 3.21-

3.42 (2H, m), 3.63 (3H, s), 3.83-

4.52 (10H, m), 6.06 (2H, s),

6.16 (1H, dd, J = 8.8 Hz, 2.7 Hz),

6.34 (1H, d, J = 2.7 Hz), 6.68 (1H,

d, J = 9.0 Hz), 6.79 (1H, d, J =

8.8 Hz), 6.94-7.06 (2H, m), 7.16-

7.24 (2H, m), 7.27 (1H, dd, J =

9.0 Hz, 3.2 Hz), 7.47 (1H, d, J =

2.0 Hz), 7.53 (1H, d, J = 3.2 Hz),

7.56 (1H, d, J = 8.2 Hz), 10.91-

11.26 (1H, m).

2187
4-CF₃Ph—
—OCH₃
—C₂H₅
fumarate
mp 159-162

2188
3,4-Cl₂Ph—
—OCH₃
—C₂H₅
fumarate
mp 154-157

2189
4-CF₃Ph—
—F
—CH₃
hydrobromide
mp 211-212

2190
3,4-Cl₂Ph—
—F
—CH₃
hydrobromide
mp 206.5-207.0

2191
4-CF₃Ph—
—F
—C₂H₅
hydrobromide
mp 151.0-152.5

2192
3,4-Cl₂Ph—
—F
—C₂H₅
hydrobromide
mp 172.5-174.5

TABLE 349

Example

No.
R₁₀₂₀
R₁₀₂₁
R₁₀₂₂
M
Form

¹H NMR (DMSO-d₆) δ ppm

2193
Ph—
—CH₃
—H
2
dihydro-
2.50-3.07 (10H, m), 3.22-3.31 (2H, m),

chloride
3.45-3.50 (1H, m), 4.03-4.08 (1H, m),

4.30 (2H, d, J = 3.8 Hz), 4.42-4.55 (3H,

m), 6.85-6.92 (3H, m), 7.19-7.26 (5H, m),

7.30-7.35 (3H, m), 7.45-7.47 (3H, m),

7.58-7.60 (2H, m), 7.66 (1H, d, J =

2.8 Hz), 11.33 (2H, brs).

2194
3,4-Cl₂Ph—
—CH₃
—H
0
dihydro-
2.50-2.51 (2H, m), 3.03 (3H, s), 3.13-

chloride
3.48 (6H, m), 4.34-4.37 (2H, m), 4.58

(2H, s), 6.97 (1H, d, J = 8.9 Hz), 7.04 (2H,

d, J = 8.4 Hz), 7.23 (1H, dd, J = 8.4 Hz,

1.5 Hz), 7.34 (1H, dd, J = 8.9 Hz, 3.1 Hz),

7.44-7.47 (5H, m), 7.51 (1H, d, J =

1.5 Hz), 7.58-7.61 (3H, m), 7.70 (1H, d,

J = 3.3 Hz), 11.52 (2H, brs).

2195
4-CF₃Ph—
—CH₃
—H
0
dihydro-
3.06 (3H, s), 3.00-3.20 (2H, m), 3.20-

chloride
3.40 (2H, m), 3.45 (2H, brs), 4.20-

4.50 (2H, m), 4.34 (2H, s), 4.69 (2H, s),

6.97 (1H, d, J = 8.9 Hz), 7.04 (2H, d, J =

8.8 Hz), 7.33 (1H, dd, J = 8.9 Hz,

3.1 Hz), 7.41-7.49 (7H, m), 7.55-7.68

(2H, m), 7.70 (1H, d, J = 3.1 Hz), 7.71

(2H, d, J = 8.0 Hz).

2196
3,4-Cl₂Ph—
—CH₃
—H
2
dihydro-
2.49-3.07 (10H, m), 3.23-3.27 (2H, m),

chloride
3.45-3.55 (1H, m), 4.03-4.08 (1H, m),

4.30 (2H, d, J = 4.3 Hz), 4.42-4.47 (1H,

m), 4.54 (2H, s), 6.87 (1H, d, J = 9.1 Hz),

6.90 (2H, d, J = 8.6 Hz), 7.19-7.23 (3H,

m), 7.32 (1H, dd, J = 8.9 Hz, 3.3 Hz),

7.45-7.50 (4H, m), 7.57-7.64 (4H, m),

11.33 (2H, brs).

2197
4-CF₃Ph—
—C₂H₅
—F
0
hydro-
1.21 (3H, t, J = 6.9 Hz), 2.50-2.51 (2H,

chloride
m), 3.14-3.38 (6H, m), 3.49 (2H, q, J =

6.9 Hz), 4.34 (2H, brs), 4.61 (2H, brs),

6.98 (1H, d, J = 8.9 Hz), 7.25-7.29 (3H,

m), 7.42-7.50 (7H, m), 7.58 (2H, brs),

7.69 (2H, d, J = 8.1 Hz), 11.12 (1H, brs).

2198
3,4-Cl₂Ph—
—C₂H₅
—F
0
hydro-
1.10 (3H, t, J = 7.0 Hz), 2.49-2.52 (2H,

chloride
m), 3.13 (2H, brs), 3.32-3.58 (6H, m),

4.33 (2H, brs), 4.50 (2H, brs), 6.99 (1H, d,

J = 9.1 Hz), 7.20-7.31 (4H, m), 7.42-7.57

(6H, m), 7.58-7.60 (3H, m), 11.14 (1H,

brs).

TABLE 350

Example

No.
R₁₀₂₃
R₁₀₂₄
R₁₀₂₅
M
Form
mp (° C.) or ¹H NMR (solvent) δ ppm

2199
3,4-Cl₂Ph—
—H
—CH₃
2
free

¹H NMR (CDCl₃) 1.17 (3H, t, J =

7.1 Hz), 2.32-2.39 (4H, m), 2.52-

2.57 (2H, m), 2.91 (3H, s), 3.36-

3.44 (6H, m), 3.59-3.63 (2H, m),

3.66-3.71 (2H, m), 4.35 (2H, s), 5.95

(2H, s), 6.67-6.76 (5H, m), 6.83 (1H,

d, J = 1.0 Hz), 6.98 (2H, d, J =

9.1 Hz), 7.03 (1H, dd, J = 9.1 Hz,

3.3 Hz), 7.07 (1H, dd, J = 8.9 Hz,

2.1 Hz), 7.32 (1H, d, J = 2.0 Hz),

7.47 (1H, d, J = 8.3 Hz), 7.62 (1H, d,

J = 3.1 Hz).

2200
4-CF₃Ph—
—H
—CH₃
2
free

¹H NMR (CDCl₃) 1.19 (3H, t, J =

7.1 Hz), 2.32-2.38 (4H, m), 2.52-

2.57 (2H, m), 2.91 (3H, s), 3.36-

3.47 (6H, m), 3.59-3.63 (2H, m),

3.66-3.71 (2H, m), 4.47 (2H, s), 5.94

(2H, s), 6.67-6.76 (5H, m), 6.83 (1H,

d, J = 1.0 Hz), 6.97 (2H, d, J =

9.2 Hz), 7.03 (1H, dd, J = 9.1 Hz,

3.1 Hz), 7.35 (2H, d, J = 7.9 Hz),

7.56 (2H, d, J = 7.9 Hz), 7.63 (1H, d,

J = 2.8 Hz).

2201
3,4-Cl₂Ph—
—CH₃
—CH₃
1
hydrochloride
mp 167-170 dec

2202
3,4-CF₃Ph—
—CH₃
—Ac
1
hydrochloride
mp 186-189

2203
3,4-Cl₂Ph—
—CH₃
—Ac
1
hydrochloride
mp 188.5-191.0

2204
4-CF₃Ph—
—OCH₃
—CH₃
1
oxalate

¹H NMR (DMSO-d₆) 1.08 (3H, t, J =

7.0 Hz), 2.50-2.81 (4H, m), 2.93 (3H,

s), 3.41 (2H, q, J = 7.0 Hz), 3.33-

3.72 (7H, m), 3.77 (2H, s), 4.25 (2H,

s), 4.52 (2H, s), 6.0 (2H, s),

6.12 (1H, dd, J = 8.8 Hz, 2.7 Hz),

6.28 (1H, d, J = 2.7 Hz), 6.64 (1H,

d, J = 9.0 Hz), 6.76 (1H, d, J =

8.7 Hz), 6.80-6.94 (2H, m), 6.97 (1H,

brs), 7.15 (1H, dd, J = 9.0 Hz,

3.2 Hz), 7.34-7.50 (3H, m), 7.66 (2H,

d, J = 8.1 Hz).

2205
3,4-Cl₂Ph—
—OCH₃
—CH₃
1
hydrochloride

¹H NMR (DMSO-d₆) 1.06 (3H, t, J =

6.9 Hz), 2.75-3.16 (5H, m), 3.21-

3.48 (4H, m), 3.62 (3H, s), 3.71-

4.52 (10H, m), 6.06 (2H, s), 6.16 (1H,

dd, J = 8.8 Hz, 2.7 Hz), 6.34 (1H, d,

J = 2.7 Hz), 6.67 (1H, d, J = 8.9 Hz),

6.78 (1H, d, J = 8.8 Hz), 6.94-7.06

(2H, m), 7.13-7.28 (3H, m), 7.41-

7.52 (2H, m), 7.56 (1H, d, J = 8.3 Hz),

10.83-11.19 (1H, m).

TABLE 351

Example

No.
R₁₀₂₆
R₁₀₂₇
R₁₀₂₈
Form
mp (° C.)

2206
4-CF₃Ph—
—CH₃
—C₂H₅
oxalate
126-128

2207
3,4-Cl₂Ph—
—CH₃
—C₂H₅
oxalate
111-113

2208
4-CF₃Ph—
—CH₃
—C₂H₅
oxalate
120-123

2209
4-CF₃Ph—
—OCH₃
—CH₃
hydrobromide
205-208

2210
3,4-Cl₂Ph—
—OCH₃
—C₂H₅
hydrobromide
133-135

2211
4-CF₃Ph—
—F
—CH₃
hydrobromide
203-205

2212
3,4-Cl₂Ph—
—F
—CH₃
hydrobromide
185-188

2213
4-CF₃Ph—
—F
—C₂H₅
oxalate
121.0-122.5

2214
3,4-Cl₂Ph—
—F
—C₂H₅
hydrobromide
165.0-166.5

TABLE 352

Example

No.
R₁₀₂₉
R₁₀₃₀

¹H NMR (CDCl₃) δ ppm

2215
—H

embedded image

1.45 (9H, s), 2.39-2.43 (4H, m), 3.01 (3H, s), 3.41-3.44 (4H, m), 3.50 (2H, s), 4.41 (2H, s), 6.82 (1H, d, J = 8.9 Hz), 7.01 (2H, d, J = 8.4 Hz), 7.08-7.13 (2H, m), 7.27-7.41 (4H, m), 7.70 (1H, d, J = 8.6 Hz).

2216
—CH₃

embedded image

2.20 (3H, s), 2.98 (3H, s), 3.06 (1H, dd, J = 14.0 Hz, 10.1 Hz), 3.52 (1H, dd, J = 14.0 Hz, 3.8 Hz), 4.38 (2H, s), 4.50 (1H, dd, J = 10.1 Hz, 3.8 Hz), 6.77 (1H, d, J = 8.9 Hz), 6.91 (1H, d, J = 8.3 Hz), 7.03 (1H, dd, J = 8.3 Hz, 2.1 Hz), 7.05-7.16 (3H, m), 7.32 (1H, d, J = 2.1 Hz), 7.39 (1H, d, J = 8.3 Hz), 7.67 (1H, d, J = 3.1 Hz).

TABLE 353

Example

No.
R₁₀₃₁
R₁₀₃₂
R₁₀₃₃

¹H NMR (CDCl₃) δppm

2217
3,4-Cl₂Ph—
—CH₃
—H
2.41 (4H, brs), 3.02 (3H, s), 3.19 (3H, s), 3.36

(2H, brs), 3.42 (2H, s), 3.60 (2H, brs), 4.41 (2H, s),

4.51 (2H, s), 5.95 (2H, s), 6.73-6.77 (2H, m),

6.84-6.87 (2H, m), 7.03 (2H, d, J = 8.9 Hz), 7.07

(1H, dd, J = 8.3 Hz, 2.0 Hz), 7.12 (1H, dd, J =

8.9 Hz, 3.1 Hz), 7.33 (1H, d, J = 2.0 Hz), 7.40 (1H,

d, J = 8.3 Hz), 7.59 (2H, d, J = 8.9 Hz), 7.69 (1H,

d, J = 3.1 Hz).

2218
3,4-Cl₂Ph—
—C₂H₅
—H
1.21 (3H, t, J = 7.1 Hz), 2.41 (4H, brs), 3.18 (3H,

s), 3.36 (2H, brs), 3.42 (2H, s), 3.46 (2H, q, J =

7.1 Hz), 3.60 (2H, brs), 4.40 (2H, s), 4.50 (2H, s),

5.94 (2H, s), 6.73-6.77 (2H, m), 6.81-6.84 (2H,

m), 7.01-7.10 (4H, m), 7.33 (1H, d, J = 2.0 Hz),

7.39 (1H, d, J = 8.3 Hz), 7.54 (2H, d, J = 9.1 Hz),

7.64 (1H, d, J = 3.0 Hz).

2219
4-CF₃Ph—
—CH₃
—H
2.41 (4H, brs), 3.05 (3H, s), 3.19 (3H, s), 3.34-

3.36 (2H, m), 3.42 (2H, s), 3.60 (2H, brs), 4.50

(2H, s), 4.54 (2H, s), 5.95 (2H, s), 6.73-6.74 (2H,

m), 6.83 (1H, brs), 6.85 (1H, d, J = 8.9 Hz), 7.03

(2H, d, J = 8.9 Hz), 7.13 (1H, dd, J = 8.9 Hz,

3.3 Hz), 7.34 (2H, d, J = 7.9 Hz), 7.54 (2H, d, J =

8.9 Hz), 7.59 (2H, d, J = 8.1 Hz), 7.70 (1H, d, J =

3.1 Hz).

2220
4-CF₃Ph—
—C₂H₅
—H
1.22 (3H, t, J = 7.1 Hz), 2.41 (4H, brs), 3.19 (3H,

s), 3.35 (2H, brs), 3.42 (2H, s), 3.48 (2H, q, J =

7.1 Hz), 3.60 (2H, brs), 4.50 (2H, s), 4.52 (2H, s),

5.95 (2H, s), 6.70-6.77 (2H, m), 6.82 (1H, d, J =

8.7 Hz), 6.84 (1H, brs), 7.02 (2H, d, J = 8.9 Hz),

7.07 (1H, dd, J = 8.9 Hz, 3.1 Hz), 7.36 (2H, d, J =

7.9 Hz), 7.54 (2H, d, J = 8.9 Hz), 7.58 (2H, d, J =

8.1 Hz), 7.65 (1H, d, J = 3.0 Hz).

2221
3,4-Cl₂Ph—
—CH₃
—CH₃
2.21 (3H, s), 2.42 (4H, brs), 3.00 (3H, s), 3.21 (3H,

s), 3.34-3.38 (2H, m), 3.42 (2H, s), 3.59-3.62 (2H,

m), 4.39 (2H, s), 4.51 (2H, s), 5.95 (2H, s), 6.73-

6.77 (2H, m), 6.80-6.83 (2H, m), 6.91 (1H, d, J =

8.6 Hz), 7.06 (1H, dd, J = 8.2 Hz, 2.1 Hz),

7.12 (1 H, dd, J = 8.9 Hz, 3.1 Hz), 7.32-7.44 (4H,

m), 7.65 (1H, d, J = 3.1 Hz).

2222
4-CF₃Ph—
—CH₃
—CH₃
2.21 (3H, s), 2.42 (4H, brs), 3.02 (3H, s), 3.20 (3H,

s), 3.34-3.38 (2H, m), 3.42 (2H, s), 3.58-3.62

(2H, m), 4.51 (4H, brs), 5.94 (2H, s), 6.70-6.76 (2H,

m), 6.79-6.83 (2H, m), 6.90 (1H, d, J = 8.6 Hz),

7.12 (1H, dd, J = 8.9 Hz, 3.3 Hz), 7.32-7.39 (3H,

m), 7.43 (1H, d, J = 2.5 Hz), 7.58 (2H, d, J =

8.1 Hz), 7.66 (1H, d, J = 3.0 Hz).

TABLE 354

Example

No.
R₁₀₃₄
R₁₀₃₅
R₁₀₃₆

¹H NMR (CDCl₃) δ ppm

2223
3,4-Cl₂Ph—
—C₂H₅
—CH₃
1.19 (3H, t, J = 7.1 Hz), 2.21 (3H, s), 2.41 (4H, brs),

3.20 (3H, s), 3.34-3.37 (2H, m), 3.42 (2H, s),

3.43 (2H, q, J = 7.1 Hz), 3.58-3.62 (2H, m),

4.38 (2H, s), 4.50 (2H, s), 5.95 (2H, s), 6.70-

6.77 (2H, m), 6.79 (1H, d, J = 8.9 Hz), 6.83 (1H, d,

J = 0.8 Hz), 6.91 (1H, d, J = 8.6 Hz), 7.04-7.09 (2H,

m), 7.32-7.43 (4H, m), 7.60 (1H, d, J = 3.0 Hz).

2224
4-CF₃Ph—
—C₂H₅
—CH₃
1.21 (3H, t, J = 7.1 Hz), 2.21 (3H, s), 2.41 (4H, brs),

3.20 (3H, s), 3.34-3.37 (2H, m), 3.42 (2H, s),

3.46 (2H, q, J = 7.1 Hz), 3.58-3.62 (2H, m),

4.50 (4H, brs), 5.94 (2H, s), 6.70-6.74 (2H, m),

6.78 (1H, d, J = 9.2 Hz), 6.83 (1H, brs), 6.90 (1H, d,

J = 8.6 Hz), 7.04-7.08 (1H, m), 7.34-7.43 (4H, m),

7.57 (2H, d, J = 8.1 Hz), 7.60 (1H, d, J = 3.0 Hz).

2225
4-CF₃Ph—
—CH₃
—OCH₃
2.42 (4H, brs), 3.01 (3H, s), 3.21 (3H, s), 3.37 (2H,

brs), 3.42 (2H, s), 3.61 (2H, brs), 3.78 (3H, s),

4.27 (2H, s), 4.53 (2H, s), 5.94 (2H, s), 6.72-

6.76 (2H, m), 6.84 (2H, d, J = 8.4 Hz), 7.00 (1H, d,

J = 8.4 Hz), 7.10-7.16 (2H, m), 7.24-7.26 (1H, m),

7.33 (2H, d, J = 8.1 Hz), 7.57 (2H, d, J = 7.9 Hz),

7.62 (1H, d, J = 3.0 Hz).

2226
4-CF₃Ph—
—C₂H₅
—OCH₃
1.20 (3H, t, J = 6.9 Hz), 2.42 (4H, brs), 3.21 (3H, s),

3.36 (2H, brs), 3.40-3.43 (4H, m), 3.61 (2H, brs),

3.77 (3H, s), 4.48 (2H, s), 4.52 (2H, s), 5.94 (2H, s),

6.73-6.76 (2H, m), 6.81-6.85 (2H, m), 6.99 (1H, d,

J = 8.6 Hz), 7.07 (1H, dd, J = 9.1 Hz, 3.3 Hz),

7.14 (1H, dd, J = 8.4 Hz, 2.3 Hz), 7.24 (1H, d, J =

2.5 Hz), 7.34 (2H, d, J = 8.1 Hz), 7.54-7.57 (3H, m).

TABLE 355

Example

No.
R₁₀₃₇
R₁₀₃₈
R₁₀₃₉

¹H NMR (solvent) δ ppm

2227
3,4-Cl₂Ph—
—CH₃
—H
(CDCl₃) 2.20 (3H, s), 2.48-2.54 (4H, m), 2.97 (3H, s),

3.44 (2H, s), 3.70-3.73 (2H, m), 4.23-4.27 (2H, m),

4.37 (2H, s), 5.95 (2H, s), 6.73-6.77 (3H, m), 6.85 (1H,

brs), 6.95 (1H, d, J = 8.6 Hz), 7.06 (1lH, dd, J =

8.2 Hz, 2.0 Hz), 7.10 (1H, dd, J = 8.9 Hz, 3.1 Hz),

7.32 (1H, d, J = 2.0 Hz), 7.37 (1H, dd, J = 8.6 Hz,

2.6 Hz), 7.38 (1H, d, J = 8.2 Hz), 7.52 (1H, d, J =

2.5 Hz), 7.66 (1H, d, J = 2.8 Hz), 9.12 (1H, brs).

2228
4-CF₃Ph—
—CH₃
—H
(CDCl₃) 2.20 (3H, s), 2.48-2.54 (4H, m), 3.00 (3H, s),

3.44 (2H, s), 3.72 (2H, t, J = 5.0 Hz), 4.23-4.27 (2H,

m), 4.49 (2H, s), 5.95 (2H, s), 6.73-6.77 (3H, m),

6.85 (1H, brs), 6.95 (1H, d, J = 8.7 Hz), 7.10 (1H, dd,

J = 8.9 Hz, 3.3 Hz), 7.32-7.39 (3H, m), 7.52 (1H, d,

J = 2.5 Hz), 7.57 (2H, d, J = 8.1 Hz), 7.67 (1H, d, J =

3.3 Hz), 9.12 (1H, brs).

2229
3,4-Cl₂Ph—
—C₂H₅
—H
(CDCl₃) 1.18 (3H, t, J = 7.1 Hz), 2.20 (3H, s), 2.48-

2.53 (4H, m), 3.41 (2H, q, J = 7.1 Hz), 3.44 (2H, s),

3.70-3.73 (2H, m), 4.23-4.27 (2H, m), 4.36 (2H, s),

5.95 (2H, s), 6.72-6.77 (3H, m), 6.85 (1H, brs),

6.95 (1H, d, J = 8.6 Hz), 7.02-7.09 (2H, m), 7.32-

7.39 (3H, m), 7.51 (1H, d, J = 2.6 Hz), 7.60 (1H, d,

J = 3.1 Hz), 9.12 (1H, brs).

2230
4-CF₃Ph—
—C₂H₅
—H
(CDCl₃) 1.19 (3H, t, J = 7.1 Hz), 2.20 (3H, s), 2.48-

2.53 (4H, m), 3.43 (2H, q, J = 7.1 Hz), 3.44 (2H, s),

3.70-3.73 (2H, m), 4.23-4.27 (2H, m), 4.48 (2H, s),

5.95 (2H, s), 6.71-6.77 (3H, m), 6.85 (1H, brs),

6.95 (1H, d, J = 8.7 Hz), 7.04 (1H, dd, J = 8.9 Hz,

3.1 Hz), 7.32-7.38 (3H, m), 7.51 (1H, d, J = 2.5 Hz),

7.56 (2H, d, J = 8.1 Hz), 7.61 (1H, d, J = 3.1 Hz).

9.11 (1H, brs).

2231
3,4-Cl₂Ph—
—C₂H₅
—CH₃
a mixture of the rotational isomers

(DMSO-d₆) 1.09 (3H, t, J = 6.93 Hz), 2.29-2.42 (7H,

m), 3.22-3.54 (11H, m), 4.48 (2H, s), 5.97-5.99 (2H,

m), 6.64-6.94 (5H, m), 7.07-7.27 (4H, m), 7.46-

7.59 (3H, m).

2232
4-CF₃Ph—
—C₂H₅
—CH₃
a mixture of the rotational isomers

(DMSO-d₆) 1.12 (3H, t, J = 6.93 Hz), 2.07-2.42 (7H,

m), 3.22-3.55 (11H, m), 4.59 (2H, s), 5.97-5.99 (2H,

m), 6.65-6.94 (5H, m), 7.07-7.18 (1H, m), 7.23-

7.29 (2H, m), 7.44 (2H, d, J = 8.08 Hz), 7.53 (1H, d,

J = 3.13 Hz), 7.67 (2H, d, J = 8.41 Hz).

TABLE 356

Example

No.
R₁₀₄₀

¹H NMR (DMSO-d₆) δ ppm

2233
3,4-Cl₂Ph—
a mixture of the rotational isomers

2.09-2.12 (3H, m), 2.66-4.53 (18H, m), 6.05-6.08 (2H, m), 6.88-

6.93 (2H, m), 6.96-7.11 (3H, m), 7.19-7.25 (3H, m), 7.32-7.36 (1H,

7.48 (1H, d, J = 2.1 Hz), 7.55-7.60 (2H, m), 11.35 (1H, brs).

2234
4-CF₃Ph—
a mixture of the rotational isomers

2.10-2.12 (3H, m), 2.66-4.64 (18H, m), 6.05-6.08 (2H, m), 6.87-

6.92 (2H, m), 6.96-7.11 (3H, m), 7.18-7.25 (2H, m), 7.30-7.35 (1H,

m), 7.43 (2H, d, J = 8.1 Hz), 7.60-7.61 (1H, m), 7.68 (2H, d,

J = 8.2 Hz), 11.27 (1H, brs).

Example 2235
Production of (4-{5-[benzyl-(3,4-dichlorobenzyl)amino]pyridin-2-yloxy}(4-benzylpiperazin-1-yl)methanone

(4-benzylpiperazin-1-yl){4-[5-(3,4-dichlorobenzylamino)pyridin-2-yloxy]phenyl}methanone (1.09 g, 2.0 mmol) was dissolved in DMF (30 mL). To this solution were added potassium carbonate (0.28 g, 2.0 mmol) and benzyl bromide (0.24 mL, 2.0 mmol), and the resulting solution was stirred at room temperature for 2 hours, then subsequently stirred for 1 hour at 70° C. To the resulting solution were further added potassium carbonate (0.03 g, 0.2 mmol) and benzyl bromide (0.02 mL, 0.2 mmol), and this solution was stirred for 3 hours at 70° C. To the resulting solution were again added potassium carbonate (0.03 g, 0.2 mmol), benzyl bromide (0.02 mL, 0.2 mmol) and sodium iodide (0.15 g, 1.0 mmol), and this solution was stirred for overnight at 70° C. The resulting reaction solution was concentrated under reduced pressure. The residue was diluted with chloroform, and this solution was washed with water, saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was then purified by silica gel column chromatography (ethyl acetate), to thereby yield 0.64 g of the title compound.

Appearance: Pale yellow oil

¹H NMR (CDCl₃) δ 2.37 (4H, brs), 3.28-3.50 (6H, m), 4.71 (2H, s), 4.73 (2H, s), 6.90 (1H, d, J=8.9 Hz), 6.99 (2H, d, J=8.6 Hz), 7.22-7.37 (14H, m), 7.52 (1H, d, J=2.0 Hz), 7.58-7.61 (2H, m).

The following compounds were produced in the same manner as in Example 2235.

TABLE 357

Example

No.
R₁₀₄₁
R₁₀₄₂
R₁₀₄₃

¹H NMR (CDCl₃) δppm

2236
3,4-Cl₂PhCON(CH₃)—
—OCH₃
—C₂H₅
1.19 (3H, t, J = 7.1 Hz), 2.42 (4H, t, J = 4.8

Hz), 3.30-3.55 (4H, m), 3.43 (2H, s),

3.44 (3H, s), 3.58-3.70 (2H, m), 3.67 (3H, s),

4.03 (2H, s), 5.95 (2H, s), 6.19 (1H, dd, J =

8.8 Hz, 2.8 Hz), 6.30 (1H, d, J = 2.8 Hz),

6.70-6.75 (2H, m), 6.79 (1H, d, J = 8.9 Hz),

6.85 (1H, s), 6.92 (1H, d, J = 8.8 Hz), 7.05

(1H, dd, J = 8.1 Hz, 2.0 Hz), 7.27 (1H, d, J =

8.1 Hz), 7.35 (1H, dd, J = 8.9 Hz, 2.6

Hz), 7.41 (1H, d, J = 2.0 Hz), 7.80 (1H, d, J =

2.6 Hz).

2237
4-CF₃PhCON(CH₃)—
—CH₃
—CH₃
1.97 (3H, s), 2.43 (4H, t, J = 5.0 Hz),

3.00 (3H, s), 3.44 (2H, s), 3.47 (3H, s), 3.42-

3.57 (2H, m), 3.63 (2H, brs), 4.06 (2H, s),

5.95 (2H, s), 6.44-6.55 (2H, m), 6.67-

6.79 (3H, m), 6.82-6.90 (2H, m), 7.40-

7.47 (1H, m), 7.37 (2H, d, J = 8.1 Hz), 7.48

(2H, d, J = 8.1 Hz), 7.81 (1H, brs).

2238
4-CF₃PhCON(CH₃)—
—OCH₃
—C₂H₅
1.18 (3H, t, J = 7.1 Hz), 2.41 (4H, t, J = 4.9

Hz), 3.40 (2H, q, J = 7.1 Hz), 3.42 (2H, t, J =

3.5 Hz), 3.47 (3H, s), 3.42-3.59 (2H, m),

3.63 (5H, s), 4.02 (2H, s), 5.95 (2H, s),

6.18 (1H, dd, J = 8.7 Hz, 2.8 Hz), 6.28 (1H,

d, J = 2.8 Hz), 6.69-6.78 (2H, m), 6.77 (1H,

d, J = 8.8 Hz), 6.85 (1H, s), 6.90 (1H, d, J =

8.7 Hz), 7.35 (1H, d, J = 8.8 Hz), 7.38 (2H,

d, J = 8.4 Hz), 7.48 (2H, d, J = 8.4 Hz),

7.79 (1H, brs).

2239
3,4-Cl₂PhN(CH₃)CO—
—OCH₃
—C₂H₅
1.18 (3H, t, J = 7.1 Hz), 2.42 (4H, t, J = 5.0

Hz), 3.42 (2H, s), 3.43 (2H, q, J = 7.1 Hz),

3.45 (3H, s), 3.55 (2H, brs), 3.65 (5H, brs),

4.02 (2H, s), 5.95 (2H, s), 6.19 (1H, dd, J =

8.7 Hz, 2.8 Hz), 6.29 (1H, d, J = 2.8 Hz),

6.71-6.74 (3H, m), 6.85 (1H, brs), 6.87 (1H,

dd, J = 8.6 Hz, 2.5 Hz), 6.92 (1H, d, J =

8.7 Hz), 7.20 (1H, d, J = 2.5 Hz), 7.32 (1H,

d, J = 8.4 Hz), 7.64 (1H, dd, J = 8.6 Hz,

2.3 Hz), 8.05 (1H, d, J = 1.8 Hz).

2240
3,4-Cl₂PhSO₂N(CH₃)—
—F
—CH₃
2.44 (2H, brs), 3.03 (3H, s), 3.19 (3H, s),

3.44 (2H, brs), 3.47 (2H, brs), 3.62 (2H,

brs), 4.08 (2H, brs), 4.08 (2H, s), 5.95 (2H,

s), 6.41 (1H, dd, J = 8.2 Hz, 3.1 Hz), 6.42-

6.50 (1H, m), 6.70-6.79 (2H, m), 6.85 (1H,

brs), 6.90 (1H, d, J = 8.7 Hz), 7.04 (1H, t, J =

7.8 Hz), 7.34 (1H, dd, J = 8.4 Hz, 2.2

Hz), 7.50 (1H, dd, J = 8.7 Hz, 2.8 Hz),

7.56 (1H, d, J = 8.4 Hz), 7.72 (1H, d, J =

2.2 Hz), 7.77 1H, d, J = 2.8 Hz).

TABLE 358

Example

No.
R₁₀₄₄
R₁₀₄₅
Xb₄₆
Form
mp (° C.) or ¹H NMR

2241
4-CH₃PhCON(CH₃)—
—CH₃
—N(SO₂CH₃)—
free

¹H NMR (CDCl₃) δ

2.05 (3H, s), 2.42 (4H, brs),

3.20 (3H, s), 3.34-3.37 (2H,

m), 3.42 (2H, s), 3.48 (3H

s), 3.59-3.61 (2H, m),

4.52 (2H, s), 5.95 (2H, s),

6.70-6.77 (2H, m), 6.84 (1H,

brs), 6.86 (1H, d, J = 8.7

Hz), 6.97 (1H, d, J = 8.1

Hz), 7.37-7.51 (7H, m),

7.79 (1H, brs).

2242
3,4-Cl₂PhCON(CH₃)—
—CH₃
—N(SO₂CH₃)—
free

¹H NMR (CDCl₃) δ

2.09 (3H, s), 2.42 (4H, brs),

3.21 (3H, s), 3.37 (2H, brs),

3.43 (2H, s), 3.46 (3H, s),

3.61 (2H, brs), 4.52 (2H, s),

5.95 (2H, s), 6.70-6.80 (2H,

m), 6.84 (1H, brs), 6.89 (1H,

d, J = 8.7 Hz), 6.99 (1H, d,

J = 8.4 Hz), 7.09 (1H, dd, J =

8.2 Hz, 1.8 Hz), 7.29 (1H,

d, J = 8.2 Hz), 7.38 (1H, d,

J = 2.0 Hz), 7.42-7.46 (3H,

m), 7.80 (1H, d, J = 2.5

Hz).

2243

embedded image

—H
—CH₂—
free
mp 133.0-134.0

2244

embedded image

—H
—CH₂—
free
mp 117.0-118.0

2245
4-CF₃PhN(CH₃)SO₂—
—H
—CH₂—
free

¹H NMR (CDCl₃) δ 2.33-

2.41 (4H, m), 2.63 (2H, t, J =

7.3 Hz), 2.99 (2H, t, J =

7.3 Hz), 3.22 (3H, s),

3.40 (4H, brs), 3.61-

3.64 (2H, m), 5.93 (2H, s),

6.69-6.76 (2H, m), 6.84 (1H,

s), 6.94 (1H, d, J = 8.7 Hz),

7.06 (2H, d, J = 8.6 Hz),

7.27-7.31 (4H, m), 7.59 (2H,

d, J = 8.4 Hz), 7.71 (1H, dd,

J = 8.7 Hz, 2.6 Hz),

8.37 (1H, d, J = 2.6 Hz).

2246
F₃CCH═CHCON(CH₃)—
—CH₃
—N(CH₃)—
hydro-
mp 161.0-164.0

chloride

TABLE 359

Example

No.
R₁₀₄₆

¹H NMR (solvent) δppm

2247
3,4-Cl₂PhCON(CH₃)—
a mixture of the rotational isomers

(DMSO-d₆) 1.93 (3H, brs), 2.08-2.42 (4H, m), 3.21-

3.56 (12H, m), 5.97-5.99 (2H, m), 6.66-6.89 (3H, m),

6.90-7.07 (2H, m), 7.13-7.32 (3H, m), 7.48-7.54

(2H, m), 7.85-7.89 (2H, m).

2248
4-CF₃PhCON(CH₃)—
a mixture of the rotational isomers

(DMSO-d₆) 1.87 (3H, brs), 2.07-2.41 (4H, m), 3.20-

3.55 (12H, m), 5.97-5.99 (2H, m), 6.66-6.89 (3H, m),

6.98-7.04 (2H, m), 7.12-7.21 (1H, m), 7.24-7.30 (1H,

m), 7.47 (2H, brs), 7.61-7.64 (2H, m), 7.86-7.89 (2H, m).

2249
3,4-Cl₂PhSO₂N(CH₃)—
(CDCl₃) 2.17 (3H, s), 2.23-2.53 (4H, m), 3.21(3H, brs),

3.32-3.82 (9H, m), 5.93-5.95 (2H, m), 6.65-6.78 (3H,

m), 6.85-6.95 (1H, m), 7.02-7.06 (1H, m), 7.07-

7.18 (2H, m), 7.38-7.42 (1H, m), 7.53-7.58 (2H, m),

7.67-7.68 (1H, m), 7.78-7.80 (1H, m).

2250
4-CF₃PhSO₂N(CH₃)—
a mixture of the rotational isomers

(DMSO-d₆) 2.07-2.43 (7H, m), 3.16-3.56 (12H, m),

6.67-6.70 (2H, m), 6.76-6.89 (3H, m), 7.05-7.36 (4H, m),

7.61-7.66 (1H, m), 7.77-7.80 (2H, m), 7.91-7.80 (3H, m).

2251
4-CF₃PhSO₂N(C₂H₅)—
(CDCl₃) 1.13 (3H, t, J = 7.1 Hz), 2.18 (3H, s), 2.23-2.52

(4H, m), 3.32-3.66 (11H, m), 5.93-5.95 (2H, m), 6.66-

6.95 (4H, m), 7.04-7.19 (3H, m), 7.46 (1H, dd, J = 8.7

Hz, 2.6 Hz), 7.73-7.80 (5H, m).

TABLE 360

Example

No.
R₁₀₄₇
R₁₀₄₈
R₁₀₄₉

¹H NMR (CDCl₃) δppm

2252
4-CF₃Ph—
—H
benzyl
1.34-1.46 (2H, m), 1.85-2.03 (3H, m), 2.29 (2H, d

J = 6.8 Hz), 2.43 (4H, brs), 2.73 (2H, t, J = 12.0

Hz), 3.19 (3H, s), 3.47-3.65 (8H, m), 6.83 (1H, d,

J = 8.7 Hz), 6.92-7.03 (4H, m), 7.26-7.33 (5H, m),

7.48 (1H, dd, J = 8.9 Hz, 2.8 Hz), 7.70-7.78 (5H,

m).

2253
3,4-Cl₂Ph—
—H
piperonyl
1.33-1.46 (2H, m), 1.85-2.04 (3H, m), 2.29 (2H, d,

J = 6.8 Hz), 2.39-2.42 (4H, m), 2.74 (2H, t, J =

12.2 Hz), 3.19 (3H, s), 3.43 (2H, s), 3.46-3.64 (6H,

m), 5.94 (2H, s), 6.70-6.77 (2H, m), 6.83 (2H, d,

J = 8.9 Hz), 6.92-7.03 (4H, m), 7.38 (1H, dd, J =

8.4 Hz, 2.1 Hz), 7.49 (1H, dd, J = 8.9 Hz, 2.8 Hz),

7.56 (1H, d, J = 8.4 Hz), 7.70 (1H, d, J = 2.1 Hz),

7.81 (1H, d, J = 2.3 Hz).

2254
4-CF₃Ph—
—H
piperonyl
1.34-1.46 (2H, m), 1.85-2.02 (3H, m), 2.28 (2H, d,

J = 6.8 Hz), 2.39-2.42 (4H, m), 2.74 (2H, t, J =

12.0 Hz), 3.20 (3H, s), 3.43 (2H, s), 3.46-3.64 (6H,

m), 5.94 (2H, s), 6.70-6.77 (2H, m), 6.81-7.03 (6H,

m), 7.49 (1H, dd, J = 8.7 Hz, 2.8 Hz), 7.71-

7.78 (5H, m).

2255
4-CF₃Ph—
—OCH₃
benzyl
1.31-1.42 (2H, m), 1.86-2.00 (3H, m), 2.29 (2H, d,

J = 6.8 Hz), 2.42-2.45 (4H, m), 2.76 (2H, t, J =

12.0 Hz), 3.19 (3H, s), 3.49-3.69 (8H, m), 3.75 (3H,

s), 6.51 (1H, dd, J = 8.7 Hz, 2.5 Hz), 6.59 (1H, d,

J = 2.5 Hz), 6.83 (1H, d, J = 8.7 Hz), 6.98 (1H, d,

J = 8.7 Hz), 7.26-7.33 (5H, m), 7.47 (1H, dd, J =

8.9 Hz, 2.8 Hz), 7.69-7.75 (5H, m).

2256
3,4-Cl₂Ph—
—H
benzyl
1.39-1.42 (2H, m), 1.84-2.02 (3H, m), 2.28 (2H, d,

J = 6.8 Hz), 2.41-2.45 (4H, m), 2.73 (2H, t, J =

12.2 Hz), 3.19 (3H, s), 3.48-3.95 (8H, m), 6.83 (1H,

d, J = 8.7 Hz), 6.92-7.03 (4H, m), 7.27-7.39 (6H,

m), 7.48 (1H, dd, J = 8.7 Hz, 2.8 Hz), 7.55 (1H, d,

J = 8.4 Hz), 7.70 (1H, d, J = 2.1 Hz), 7.81 (1H, d,

J = 2.3 Hz).

2257
3,4-Cl₂Ph—
—OCH₃
benzyl
1.34-1.42 (2H, m), 1.82-2.00 (3H, m), 2.29 (2H, d,

J = 6.8 Hz), 2.41-2.45 (4H, m), 2.76 (2H, t, J =

12.2 Hz), 3.19 (3H, s), 3.49-3.65 (8H, m), 3.75 (3H,

s), 6.51 (1H, dd, J = 8.7 Hz, 2.6 Hz), 6.58 (1H, d,

J = 2.6 Hz), 6.84 (1H, d, J = 8.7 Hz), 6.98 (1H, d,

J = 8.6 Hz), 7.26-7.39 (6H, m), 7.46 (1H, dd, J =

8.7 Hz, 2.6 Hz), 7.54 (1H, d, J = 8.4 Hz), 7.69 (1H,

d, J = 2.0 Hz), 7.78 (1H, d, J = 2.5 Hz).

TABLE 361

Example

No.
R₁₀₅₀
R₁₀₅₁

¹H NMR (CDCl₃) δppm

2258
4-CF₃PhN(CH₃)SO₂—
—H
1.34-1.46 (2H, m), 1.85-2.00 (3H, m), 2.28 (2H, d,

J = 6.8 Hz), 2.39-2.43 (4H, m), 2.75 (2H, t, J = 12.2

Hz), 3.21 (3H, s), 3.43 (2H, s), 3.46-3.64 (6H, m),

5.94 (2H, s), 6.70-6.77 (2H, m), 6.85-7.02 (6H, m),

7.26-7.31 (2H, m), 7.59 (2H, d, J = 8.6 Hz), 7.67 (1H,

dd, J = 8.7 Hz, 2.6 Hz), 8.39 (1H, d, J = 2.1 Hz).

2259
4-CF₃PhSO₂N(C₂H₅)—
—OCH₃
1.11 (3H, t, J = 7.1 Hz), 1.30-1.42 (2H, m), 1.85-

2.00 (3H, m), 2.29 (2H, d, J = 6.8 Hz), 2.39-2.44 (4H,

m), 2.76 (2H, t, J = 12.2 Hz), 3.40-3.70 (10H, m),

3.75 (3H, s), 5.94 (2H, s), 6.51 (1H, dd, J = 8.7 Hz,

2.6 Hz), 6.59 (1H, d, J = 2.6 Hz), 6.74-6.87 (4H, m),

6.99 (1H, d, J = 8.7 Hz), 7.37-7.48 (2H, m), 7.54 (1H,

d, J = 8.4 Hz), 7.73-7.75 (2H, m).

2260
4-CF₃PhSO₂N(C₂H₅)—
—H
1.11 (3H, t, J = 7.1 Hz), 1.35-1.47 (2H, m), 1.85-

2.00 (3H, m), 2.29 (2H, d, J = 6.8 Hz), 2.40-2.42 (4H,

m), 2.74 (2H, t, J = 12.0 Hz), 3.42-3.48 (4H, m),

3.57-3.64 (6H, m), 5.94 (2H, s), 6.74-6.77 (2H, m),

6.82-7.04 (6H, m), 7.41 (1H, dd, J = 8.7 Hz, 2.8 Hz),

7.72-7.94 (5H, m).

2261
4-CF₃PhSO₂N(CH₃)—
—OCH₃
1.39-1.47 (2H, m), 1.86-2.00 (3H, m), 2.29 (2H, d,

J = 6.8 Hz), 2.41 (4H, brs), 2.76 (2H, t, J = 12.0 Hz),

3.19 (3H, s), 3.43 (2H, s), 3.48 (2H, brs), 3.60 (4H,

brs), 3.64 (3H, s), 5.93 (2H, s), 6.51 (1H, dd, J = 8.7

Hz, 2.5 Hz), 6.59 (1H, d, J = 2.5 Hz), 6.74-6.84 (4H,

m), 6.98 (1H, d, J = 8.6 Hz), 7.46 (1H, dd, J = 8.7

Hz, 2.6 Hz), 7.69-7.76 (5H, m).

2262
4-CF₃PhN(CH₃)SO₂—
—CH₃
1.34-1.45 (2H, m), 1.85-2.01 (3H, m), 2.07 (3H, s),

2.29 (2H, d, J = 6.8 Hz), 2.41-2.43 (4H, m), 2.73 (2H,

t, J = 12.0 Hz), 3.22 (3H, s), 3.43 (2H, s), 3.46-

3.77 (6H, m), 5.94 (2H, s), 6.74-6.94 (7H, m),

7.29 (2H, d, J = 8.2 Hz), 7.58 (2H, d, J = 8.4 Hz),

7.68 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.38 (1H, d, J =

2.5 Hz).

2263
3,4-Cl₂PhSO₂N(CH₃)—
—CH₃
1.38-1.41 (2H, m), 1.84-1.98 (3H, m), 2.11 (3H, s),

2.29 (2H, d, J = 6.8 Hz), 2.41 (4H, brs), 2.72 (2H, t,

J = 12.0 Hz), 3.19(3H, s), 3.43-3.64 (8H, m), 5.94 (2H,

s), 6.74-6.85 (6H, m), 6.93 (1H, d, J = 8.6 Hz),

7.39 (1H, dd, J = 8.4 Hz, 2.1 Hz), 7.49 (1H, dd, J =

8.7 Hz, 2.8 Hz), 7.56(1H, d, J = 8.4 Hz), 7.67 (1H,

d, J = 2.0 Hz), 7.78 (1H, d, J = 2.3 Hz).

2264
3,4-Cl₂PhSO₂N(CH₃)—
—OCH₃
1.39-1.47 (2H, m), 1.85-2.02 (3H, m), 2.29 (2H, d,

J = 6.8 Hz), 2.39-2.44 (4H, m), 2.76 (2H, t, J = 12.2

Hz), 3.19 (3H, s), 3.43 (2H, s), 3.49 (2H, brs), 3.59-

3.73 (4H, m), 3.75 (3H, s), 5.94 (2H, s), 6.51 (1H, dd,

J = 8.7 Hz, 2.6 Hz), 6.59 (1H, d, J = 2.6 Hz), 6.74-

6.85 (4H, m), 6.98 (1H, d, J = 8.6 Hz), 7.38 (1H, dd,

J = 8.2 Hz, 2.0 Hz), 7.46 (1H, dd, J = 8.7 Hz, 2.8

Hz), 7.55 (1H, d, J = 8.4 Hz), 7.69 (1H, d, J = 2.1

Hz), 7.78 (1H, d, J = 2.8 Hz).

TABLE 362

Example

No.
Xb₄₇
R₁₀₅₂

¹H NMR (CDCl₃) δppm

2265
—CO—

embedded image

2.33 (2H, d, J = 5.1 Hz), 2.38 (2H, d, J = 5.1 Hz), 2.60 (2H, t, J = 5.1 Hz), 2.96 (2H, t, J = 8.0 Hz), 3.33-3.46 (2H, m), 3.40 (2H, s), 3.47 (3H, s), 3.62 (2H, t, J = 2.0 Hz), 5.94 (2H, s), 6.67- 6.79 (2H, m), 6.83 (1H, d, J = 8.7 Hz), 6.84 (1H, s), 6.99 (2H, d, J = 8.4 Hz), 7.22 (2H, d, J = 8.4 Hz), 7.34-7.45 (1H, m), 7.40 (2H, d, J = 8.2 Hz), 7.50 (2H, d, J = 8.2 Hz), 7.85 (1 H, brs).

2266
—CO—

embedded image

3.17 (3H, s), 3.21 (3H, s), 3.48 (3H, s), 6.70 (1H, d, J = 8.7 Hz), 6.72-6.84 (6H, m), 6.95 (1H, t, J = 7.4 Hz), 7.07 (2H, t, J = 7.8 Hz), 7.31-7.45 (3H, m), 7.46- 7.58 (2H, m), 7.79-7.92 (1H, m).

2267
—SO₂—

embedded image

1.78-2.04 (4H, m), 2.11 (3H, s), 2.44 (4H, brs), 2.53-2.76 (3H, m), 3.19 (3H, s), 3.53 (4H, brs), 3.67 (4H, brs), 6.76- 6.81 (3H, m), 6.93 (1H, d, J = 8.6 Hz), 7.26-7.33 (5H, m), 7.49 (1H, dd, J = 8.9 Hz, 2.8 Hz), 7.70-7.79 (5H, m).

TABLE 363

Example

No.
R₁₀₅₃
Form

¹H NMR (DMSO-d₆) δppm

2268
—CH₃
free
2.39 (4H, brs), 3.32-3.51 (9H, m), 7.08 (1H, d, J = 8.7 Hz),

7.09 (2H, d, J = 8.4 Hz), 7.25-7.31 (6H, m), 7.41 (2H, d, J =

8.6 Hz), 7.55-7.58 (2H, m), 7.87 (1H, dd, J = 8.7 Hz, 2.8 Hz),

8.03 (1H, brs).

2269
benzyl
hydro-
3.12-3.43 (8H, m), 4.33(2H, s), 5.09 (2H, s), 7.02 (1H, d, J =

chloride
8.7 Hz), 7.07 (2H, d, J = 7.8 Hz), 7.26-7.33 (6H, m), 7.45-

7.48 (5H, m), 7.55-7.58 (3H, m), 7.67 (1H, brs), 7.77 (1H, d,

J = 8.7 Hz), 7.85 (1H, brs), 11.09 (1H, brs).

Example 2270
Production of 1-(t-butoxycarbonyl)-4-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}-4-hydroxypiperidine

To a solution of N-[4-(4-bromophenoxy)phenyl]-3,4-dichlorobenzamide (4.94 g, 11.3 mmol) in THF (100 mL) was stirred at −85° C., and added a solution of 2.46 M n-butyl lithium hexane (9.65 mL, 23.7 mmol) dropwise over 10 minutes. Upon stirring for 20 minutes at the same temperature, crystals were precipitated. To this reaction solution was added a solution of 1-(t-butoxycarbonyl)-4-piperidone (2.48 g, 12.4 mmol) in THF (20 mL). The temperature of the solution was raised over 3 hours to −40° C., and then aqueous saturated ammonium chloride was added to the solution. The resulting reaction solution was extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was then evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:3 to 1:1), to yield 2.30 g of a white powder. These crystals were washed with ether, to thereby yield 1.80 g of the title compound.

Appearance: White powder

Melting point: 208-209° C.

Example 2271
Production of 1-(t-butoxycarbonyl)-4-(4-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}-1,2,5,6-tetrahydropyridine

To a solution of 1-(t-butoxycarbonyl)-4-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}-4-hydroxypiperidine (1.56 g, 2.80 mmol) in toluene (32 mL) was added p-toluenesulfonic acid hydrate (53 mg, 0.28 mmol), and the resulting solution was refluxed for 18 hours. The resulting reaction solution was purified by silica gel column chromatography (dichloromethane:methanol=20:1), to thereby yield 1.35 g of the title compound.

Appearance: White powder

Melting point: 173-174° C.

Example 2272
Production of 1-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}-4-hydroxypiperidine

To a solution of 1-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}-4-(methoxymethoxy)piperidine (5.50 g, 11.0 mmol) in ethanol (110 mL) was added 2 M hydrochloric acid (55 mL, 110 mmol), and the resulting solution was stirred for 8 hours at 60° C. To the resulting reaction solution was added potassium carbonate (16 g) at room temperature, and the solvent was evaporated under reduced pressure. Water (200 mL) was added to the residue. Precipitated crystals were collected by filtration, to thereby yield 5.0 g of the title compound.

Appearance: Pale brown powder

Melting point: 178-180° C.

Example 2273
Production of 1-(3-{4-[(4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}propionyl)piperazine monohydrochloride

To a solution of 1-(t-butoxycarbonyl)-4-(3-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}-propionyl)piperazine (2.40 g, 4.01 mmol) in dichloromethane (24 mL) was added trifluoroacetic acid (12 mL) under ice cooling, and the resulting solution was stirred for 3 hours at the same temperature. The solvent was evaporated. To the residue was added acetone (5 mL), and then added a saturated sodium bicarbonate solution to make the solution basic. The formed solids were collected by filtration and dried, whereby 2.00 g of a white powder free form was obtained. This free form (0.500 g) was dissolved in ethanol (10 mL) and 5 M hydrochloric acid (0.4 mL) by heating. The solvent was then evaporated, and the obtained solid was recrystallized from isopropanol, to thereby yield 0.388 g of the title compound.

Appearance: White powder

Melting point: 127-130° C.

The following compounds were produced in the same manner as in Example 2273.

TABLE 364

Example

No.
R₁₀₅₄
R₁₀₅₅
Form
mp (° C.) or ¹H NMR (solvent) δppm

2274
—F

embedded image

hydro- chloride
mp 149-151

2275
—H

embedded image

free
mp 198-199

2276
—H

embedded image

free
mp 170-174

2277
—H

embedded image

free

¹H NMR (CDCl₃) 2.43-2.46 (2H, m), 3.11 (2H, t, J = 5.5 Hz), 3.53 (2H, q, J = 3 Hz), 6.10 (1H, m), 6.97 (2H, d, J = 8.5 Hz), 7.04 (2H, d, J = 9.0 Hz), 7.36 (2H, d, J = 8.5 Hz), 7.56-7.59 (3H, m), 7.68-7.69 (2H, m) 7.97 (1H, d, J = 2.0 Hz).

2278
—H

embedded image

free

¹H NMR (DMSO-d₆) 1.32-1.36 (2H, m), 1.85-1.91 (2H, m), 2.32 (3H, s), 2.45 (1H, m), 2.66-2.71 (2H, m), 3.54-3.56 (2H, m), 4.13 (1H, m), 6.89-6.97 (6H, m), 7.65- 7.71 (3H, m), 7.82 (1H, d, J = 8.5 Hz), 7.93 (1H, dd, J = 8.5 Hz, 2.0 Hz), 8.21 (1H, d, J = 2.0 Hz), 10.36 (1H, s).

2279
—H

embedded image

free

¹H NMR (CDCl₃) 1.63 (2H, m), 1.83 (2H, brd, J = 14.0 Hz), 2.61 (1H, m), 2.75 (2H, dt, J = 2.5 Hz, 12.0 Hz), 3.20 (2H, brd, J = 12.0 Hz), 6.95 (2H, d, J = 8.5 Hz), 7.03 (2H, d, J = 9.0 Hz), 7.19 (2H, d, J = 8.5 Hz), 7.55 (1H, d, J = 8.0 Hz), 7.58 (2H, d, J = 8.5 Hz), 7.69 (1H, dd, J = 8.0 Hz, 2.0 Hz), 7.69 (1H, brs), 7.97 (1H, d, J = 2.0 Hz).

TABLE 365

Example

No.
R₁₀₅₆
Xb₄₈
Xb₄₉
Form

¹H NMR (solvent) δppm

2280
3,4-Cl₂Ph—
none
—CO—
trifluoro-
(DMSO-d₆) 3.56 (2H, brs), 3.87 (2H, m),

acetate
3.92(2H, brs), 7.14 (1H, d, J = 8.8 Hz),

7.20 (2H, dd, J = 6.7 Hz, 2.2 Hz),

7.35 (2H, dd, J = 6.7 Hz, 2.2 Hz),

7.85 (1H, d, J = 8.4 Hz), 7.95 (1H, dd, J =

8.4 Hz, 2.1 Hz), 8.22 (1H, dd, J = 8.8

Hz, 2.7 Hz), 8.23 (1H, d, J = 2.1 Hz),

8.51 (1H, d, J = 2.7 Hz), 9.30 (2H, brs),

10.59 (1H, s).

2281
4-CF₃Ph—
none
—CH₂—
free
(CDCl₃) 3.07 (4H, t, J = 5.0 Hz),

3.15 (4H, t, J = 5.0 Hz), 6.92 (1H, d, J =

9.0 Hz), 6.96(2H, d, J = 9.0 Hz),

7.06 (2H, d, J = 9.0 Hz), 7.77 (1H, brs),

7.78 (2H, d, J = 8.0 Hz), 7.99 (2H, d, J =

8.0 Hz), 8.19 (1H, brd, J = 9.0 Hz),

8.25 (1H, d, J = 2.5 Hz).

2282
3,4-Cl₂Ph—
none
—CH₂—
free
(CDCl₃) 3.18 (4H, dd, J = 5.5 Hz, 2.5

Hz), 3.16 (4H, dd, J = 5.5 Hz, 2.5 Hz),

6.90 (1H, d, J = 9.0 Hz), 6.95 (2H, d, J =

9.0 Hz), 7.05 (2H, d, J = 9.0 Hz),

7.58 (1H, d, J = 8.5 Hz), 7.71 (1H, dd, J =

8.5 Hz, 2.0 Hz), 7.88 (1H, brs),

7.98 (1H, d, J = 2.0 Hz), 8.16 (1H, dd, J =

9.0 Hz, 2.5 Hz), 8.24 (1H, d, J = 2.5 Hz).

2283
3,4-Cl₂Ph—
—CH₂—
—CH₂—
free
(DMSO-d₆) 2.45-2.47 (4H, m), 2.88-

2.92 (4H, m), 3.49 (2H, s), 7.05-

7.09 (3H, m), 7.33 (2H, d, J = 8.6 Hz),

7.84 (1H, d, J = 8.6 Hz), 7.95-7.99 (1H,

m), 8.18-8.25 (2H, m), 8.51 (1H, d, J =

2.6 Hz), 10.62 (1H, s).

2284
3,4-Cl₂Ph—
—CO—
—CH₂—
free
(DMSO-d₆) 2.69 (4H, brs), 3.40 (4H,

brs), 7.12-7.17 (3H, m), 7.41-7.44 (2H,

m), 7.84 (1H, d, J = 8.4 Hz), 7.96 (1H,

dd, J = 8.4 Hz, 2.2 Hz), 8.21-8.26 (2H,

m), 8.52 (1H, d, J = 2.7 Hz), 10.62 (1H,

brs).

2285
4-CF₃Ph—
—CH₂—
—CH₂—
free
(DMSO-d₆) 2.44-2.46 (4H, m), 2.89-

2.92 (4H, m), 3.49 (2H, s), 4.79 (1H,

brs), 7.06-7.09 (3H, m), 7.33 (2H, d, J =

8.6 Hz), 7.94 (2H, d, J = 8.1 Hz). 8.16-

8.25 (3H, m), 8.52 (1H, d, J = 2.7 Hz),

10.65 (1H, s).

2286
3,4-(CH₃)₂Ph—
—CO—
—CH₂—
free
(DMSO-d₆) 2.29 (3H, s), 2.30 (3H, s),

2.73 (4H, brs), 3.44 (4H, brs), 7.09-

7.16 (3H, m), 7.29 (1H, d, J = 7.9 Hz),

7.40-7.44 (2H, m), 7.69-7.72 (1H, m),

7.75 (1H, brs), 8.22-8.26 (1H, m),

8.53 (1H, d, J = 2.8 Hz), 10.31 (1H, s).

TABLE 366

Example

No.
R₁₀₅₇
Xb₅₀
M

¹H NMR (solvent) δppm

2287
3,4-Cl₂PhCH₂N(CH₃)—
none
1
(DMSO-d₆) 2.51-2.54 (4H, m), 3.00 (3H, s),

3.06-3.08 (4H, m), 3.50 (2H, s), 4.55 (2H, s),

6.88 (1H, d, J = 8.9 Hz), 6.94 (2H, d, J =

8.4 Hz), 7.19-7.32 (4H, m), 7.49 (1H, d, J =

1.5 Hz), 7.58 (1H, d, J = 8.2 Hz), 7.64 (1H,

d, J = 3.1 Hz), 8.73 (1H, brs).

2288
4-CF₃PhCONH—
none
3
(CDCl₃) 1.77-1.96 (6H, m), 2.35-2.44 (6H,

m), 2.61-2.66 (2H, m), 6.92 (1H, d, J = 8.6

Hz), 7.01-7.05 (2H, m), 7.17-7.23 (2H, m),

7.74 (2H, d, J = 8.4 Hz), 8.00 (2H, d, J = 8.4

Hz), 8.21 (1H, dd, J = 8.6 Hz, 2.6 Hz), 8.27-

8.28 (2H, m).

2289
3,4-Cl₂PhCONH—
—CO—
2
(DMSO-d₆) 2.59-2.69 (6H, m), 2.79-

2.85 (2H, m), 3.37-3.43 (4H, m), 4.31 (1H,

brs), 7.00-7.06 (3H, m), 7.27 (2H, d, J = 8.6

Hz), 7.84 (1H, d, J = 8.4 Hz), 7.95 (1H, dd,

J = 8.4 Hz, 2.1 Hz), 8.16-8.22 (2H, m),

8.46 (1H, d, J = 2.3 Hz), 10.54 (1H, s).

2290
4-CF₃PhCONH—
—COCO—
1
(CDCl₃) 1.69 (1H, brs), 2.51 (2H, t, J = 5.1

Hz), 2.77 (2H, t, J = 5.1 Hz), 3.15 (2H, t, J =

5.1 Hz), 3.53 (2H, t, 5.1 Hz), 4.05 (2H, s),

6.98 (1H, d, J = 8.7 Hz), 7.11 (2H, d, J = 8.5

Hz), 7.29 (2H, d, J = 8.5 Hz), 7.76 (2H, d, J =

8.2 Hz), 7.99 (2H, d, J = 8.2 Hz),

8.01 (1H, brs), 8.21 (1H, dd, J = 8.7 Hz, 2.7

Hz), 8.25 (1H, d, J = 2.7 Hz).

Example 2291
[3-(4-{5-[3-(3,4-Dichlorophenyl)ureido]pyridin-2-yloxy}-3-methylphenyl)-2-oxotetrahydropyrimidin-1-yl]acetic acid

¹H NMR (DMSO-d₆) δ 1.87-2.15 (5H, m), 3.25-3.47 (2H, m), 3.58-3.75 (2H, m), 3.95 (2H, s), 6.82-7.00 (2H, m), 7.01-7.12 (1H, m), 7.17 (1H, d, J=2.4 Hz), 7.29-7.32 (1H, m), 7.50 (1H, d, J=8.8 Hz), 7.85 (1H, d, J=2.4 Hz), 7.89-8.02 (1H, m), 8.11 (1H, d, J=2.7 Hz), 8.95 (1H, s), 9.17 (1H, s), 12.50 (1H, s).

The following compounds were produced in the same manner as in Reference Example 922.

TABLE 367

Example

No.
R₁₀₅₈
R₁₀₅₉

¹H NMR (DMSO-d₆) δppm

2292
3,4-Cl₂Ph—

embedded image

1.40-1.65 (2H, m), 1.95-2.18 (2H, m), 2.40- 2.65 (3H, m), 3.00 (2H, brs), 3.25 (1H, brs), 3.85 (1H, brs), 4.40 (1H, brs), 7.15 (1H, d, J = 9.0 Hz), 7.19 (2H, d, J = 8.7 Hz), 7.43 (2H, d, J = 8.7 Hz), 7.84 (1H, d, J = 8.4 Hz), 7.99 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.22-8.30 (2H, m), 8.56 (1H, d, J = 2.0 Hz), 10.71 (1H, s).

2293
3,4-Cl₂Ph—

embedded image

1.70-2.05 (4H, m), 2.60-2.80 (1H, m), 2.80- 3.05 (2H, m), 3.44 (2H, d, J = 7.1 Hz), 7.03 (1H, d, J = 8.7 Hz), 7.07 (2H, d, J = 8.9 Hz), 7.65 (2H, d, J = 8.9 Hz), 7.84 (1H, d, J = 8.4 Hz), 7.98 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.20 (1H, dd, J = 8.7 Hz, 2.7 Hz), 8.26 (1H, d, J = 2.0 Hz), 8.50 (1H, d, J = 2.7 Hz), 10.22 (1H, s), 10.65 (1H, s).

2294
4-CF₃Ph—

embedded image

1.75-1.90 (2H, m), 1.95-2.30 (2H, m), 2.84 (3H, s), 2.70-3.15 (2H, m), 3.20-3.42 (2H, m), 4.55 (1H, brs), 6.51 (1H, brs), 7.16 (1H, d, J = 8.8 Hz), 7.17 (2H, d, J = 8.4 Hz), 7.47 (2H, d, J = 8.4 Hz), 7.94 (2H, d, J = 8.1 Hz), 8.22 (2H, d, J = 8.1 Hz). 8.31 (1H, dd, J = 8.8 Hz, 2.6 Hz), 8.60 (1H, d, J = 2.6 Hz), 10.84 (1H, s).

TABLE 368

Example

No.
R₁₀₆₀
R₁₀₆₁
Xb₅₁
M
Form

¹H NMR (solvent) δppm

2295
—H
—H
none
0
dihydro-
(DMSO-d₆) 3.16 (4H, brs), 3.75 (4H,

chloride
brs), 7.16 (1H, d, J = 8.9 Hz),

7.19 (2H, d, J = 8.7 Hz), 7.53 (2H, d,

J = 8.7 Hz), 7.93 (2H, d, J = 8.1 Hz),

8.21 (2H, d, J = 8.1 Hz), 8.30 (1H, dd,

J = 8.9 Hz, 2.5 Hz), 8.60 (1H, d, J =

2.5 Hz), 10.81 (1H, s).

2296
—H
—H
none
2
dihydro-
(DMSO-d₆) 2.68 (1H, d, J = 6.5 Hz),

chloride
2.71 (1H, d, J = 8.4 Hz), 2.82 (1H, d,

J = 8.4 Hz), 2.84 (1H, d, J = 6.5 Hz),

3.04 (4H, brs), 3.70 (4H, t, J = 5.0

Hz), 7.03 (2H, d, J = 8.6 Hz),

7.05 (1H, d, J = 8.9 Hz), 7.29 (2H, d,

J = 8.6 Hz), 7.41 (1H, brs), 7.92 (2H,

d, J = 8.5 Hz), 8.21 (2H, d, J = 8.5 Hz),

8.25 (1H, dd, J = 8.9 Hz, 2.8 Hz),

8.54 (1H, d, J = 2.8 Hz), 10.80 (1H, s).

2297
—CH₃
—H
—N(CH₃)—
1
free
(CDCl₃) 2.11 (3H, s), 2.74-2.96 (4H,

m), 3.01 (3H, s), 3.39-3.70 (4H, m),

4.08 (2H, s), 6.54 (1H, dd, J = 8.6 Hz,

3.0 Hz), 6.57 (1H, d, J = 3.0 Hz), 6.81

(1H, d, J = 8.9 Hz), 6.91 (1H, d, J =

8.6 Hz), 7.75 (2H, d, J = 8.2 Hz),

7.93-8.02 (3H, m), 8.13 (1H, dd, J =

8.9 Hz, 2.7 Hz), 8.24 (1H, d, J = 2.7 Hz).

2298
—H
—CH₂CONHNH₂
none
0
trihydro-
(DMSO-d₆) 3.42 (4H, brs), 3.75 (4H,

chloride
brs), 4.21 (2H, s), 7.17 (1H, d, J = 8.8

Hz), 7.21 (2H, d, J = 8.6 Hz), 7.53

(2H, d, J = 8.6 Hz), 7.94 (2H, d, J =

8.1 Hz), 8.22 (2H, d, J = 8.1 Hz),

8.31 (1H, dd, J = 8.8 Hz, 2.6 Hz),

8.62 (1H, d, J = 2.6 Hz), 10.87 (1H, s).

Example 2299
Production of 1-(3-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}propionyl)-4-piperonylpiperazine monohydrochloride

To a suspension consisting of 1-(3-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}propionyl)piperazine (0.500 g, 1.00 mmol) and diisopropylethylamine (0.262 mL, 1.50 mmol) in acetonitrile (12 mL) was added piperonyl chloride (0.188 g, 1.10 mmol), and the resulting solution was heated to reflux for 1.5 hours. Water was added to this reaction solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1), to thereby yield 0.486 g of a free form. This free form was dissolved in ethanol (10 mL) and 5 M hydrochloric acid (0.3 mL) by heating. The solvent was then evaporated, and the obtained solid was recrystallized from 90% ethanol (17.5 mL), to thereby yield 0.322 g of the title compound.

Appearance: White powder

Melting point: 221-224° C.

A crude titled product (9.95 g, 14.9 mmol) obtained using the same procedures was recrystallized from 80% ethanol (350 mL), to thereby yield 9.37 g of the title compound.

Appearance: White powder

Melting point: 232-234

The following compounds were produced in the same manner as in Example 2299.

TABLE 369

Example

No.
R₁₀₆₂
Xb₅₂
Xb₅₃
R₁₀₆₃
Form
mp (° C.) or ¹H NMR (CDCl₃) δppm

2300
—H
—(CH₂)₂—
—CO—
—(CH₂)₂Ph
hydro-
mp 205-207

chloride

2301
—H
—(CH₂)₂—
—CO—
—(CH₂)₂OH
hydro-
mp 101-105

chloride

2302
—H
—(CH₂)₂—
—CO—
—(CH₂)₃Ph
½
mp 156-159

fumarate

2303
—F
—(CH₂)₂—
—CO—
4-CH₃PhCH₂—
free
mp 105-107

2304
—F
—(CH₂)₂—
—CO—
4-CH₃OPhCH₂—
free
mp 137-139

2305
—F
—(CH₂)₂—
—CO—
2-CF₃PhCH₂—
free
mp 130-132

2306
—F
—(CH₂)₂—
—CO—
2-naphthyl-
hydro-
mp 172-175

methyl
chloride

2307
—H
—(CH₂)₂—
—CO—
—CH₂COOC₂H₅
free

¹H NMR 1.25 (3H, t, J = 7.1

Hz), 2.39-2.53 (4H, m), 2.58 (2H,

t, J = 7.8 Hz), 2.90 (2H. t, J = 7.8

Hz), 3.19 (2H, s), 3.36-3.48 (2H,

m), 3.58-3.69 (2H, m), 4.16 (2H,

q, J = 7.1 Hz), 6.89 (2H, d, J = 8.6

Hz), 6.96 (2H, d, J = 8.9 Hz), 7.12

(2H, d, J = 8.6 Hz), 7.47-7.59 (3H,

m), 7.69 (1H, dd, J = 8.3 Hz, 2.1

Hz), 7.96 (1H, d, J = 2.1 Hz), 8.14

(1H, brs).

2308
—H
none
—CO—
—(CH₂)₂Ph
hydro-
mp 210-218

chloride

2309
—H
none
none
—(CH₂)₂Ph
free
mp 214-215

2310
—H
none
none
benzyl
free
mp 189-190

2311
—H
none
none
—(CH₂)₃Cl
free

¹H NMR 2.00 (2H, m),

2.56 (2H, t, J = 7.0 Hz), 2.62-2.64

(4H, m), 3.16-3.18 (4H, m),

3.64 (2H, t, J = 7.0 Hz), 6.92 (2H,

d, J = 7.0 Hz), 6.95-6.98 (4H, m),

7.52 (2H, d, J = 9.0 Hz), 7.57 (1H,

d, J = 8.0 Hz), 7.69 (1H, dd, J =

8.0 Hz, 2.0 Hz), 7.70 (1H, s), 7.96

(1H, d, J = 2.0 Hz).

2312
—H
none
none
—CH₂COOC₂H₅
free

¹H NMR 1.30 (3H, t, J = 7.0

Hz), 2.76 (4H, t, J = 5.0 Hz),

3.21 (4H, t, J = 5.0 Hz),

3.28 (2H, s), 4.21 (2H, q, J =

7.0 Hz), 6.91-6.98 (6H, m), 7.52

(2H, d, J = 9.0 Hz), 7.57 (1H,

d, J =8.5 Hz), 7.69 (1H, dd, J = 8.5

Hz, 2.0 Hz), 7.72 (1H, brs), 7.96

(1H, d, J = 2.0 Hz).

TABLE 370

Example

No.
R₁₀₆₄
mp (° C.) or ¹H NMR (CDCl₃) δppm

2313

embedded image

mp 189-195

2314

embedded image

¹H NMR 2.60 (2H, brs), 2.85 (2H, m), 3.31 (2H, m), 3.39 (2H, s), 3.76 (3H, s), 6.00 (1H, brs), 6.95 (2H, d, J = 8.5 Hz), 7.03 (2H, d, J = 8.5 Hz), 7.34 (2H, d, J = 8.5 Hz), 7.57 (2H, d, J = 8.5 Hz), 7.57 (1H, brs), 7.70 (1H, d, J = 7.0 Hz), 7.75 (1H, brs), 7.97 (1H, s).

2315

embedded image

¹H NMR 1.28 (3H, t. J = 7.0 Hz), 1.60-1.70 (2H, m), 1.93-1.96 (2H, m), 2.46 (3H, s), 2.60-2.72 (3H, m), 3.37 (2H, s), 3.64-3.66 (2H, m), 4.20 (2H, q, J = 7.0 Hz), 6.93-6.98 (6H, m), 7.52 (2H, m), 7.57 (1H, d, J = 8.5 Hz), 7.68-7.70 (2H, m), 7.96 (1H, d, J = 2.0 Hz).

2316

embedded image

¹H NMR 1.29 (3H, t, J = 7.0 Hz), 1.81-1.88 (4H, m), 2.30 (2H, brt, J = 11.0 Hz), 2.49 (1H, m), 3.06 (2H, brd, J = 11.0 Hz), 4.21 (2H, q, J = 7.0 Hz), 6.94 (2H, d, J = 8.5 Hz), 7.01 (2H, d, J = 9.0 Hz), 7.18 (2H, d, J = 8.5 Hz), 7.55-7.68 (3H, m), 7.69 (1H, d, J = 2.0 Hz), 7.75 (1H, brs), 7.97 (1H, d, J = 2.0 Hz).

2317

embedded image

¹H NMR 2.04 (2H, m), 2.56 (2H, brs), 2.62 (2H, t, J = 7.0 Hz), 2.72 (2H, t, J = 5.5 Hz), 3.17 (2H, brs), 3.64 (2H, t, J = 6.5 Hz), 6.02 (1H, brs), 6.96 (2H, d, J = 9.0 Hz), 7.04 (2H, d, J = 9.0 Hz), 7.36 (2H, d, J = 9.0 Hz), 7.58 (3H, m), 7.70 (1H, dd, J = 8.5 Hz, 2.0 Hz), 7.77 (1H, brs), 7.98 (1H, d, J = 2.0 Hz).

TABLE 371

Example

No.
R₁₀₆₅
R₁₀₆₆

¹H NMR (solvent) δppm

2318
4-CF₃Ph—
—(CH₂)₂Ph
(DMSO-d₆) 2.31-2.60 (6H, m), 2.67-2.81 (2H,

m), 3.51 (4H, brs), 7.16 (1H, d, J = 8.8 Hz),

7.17 (2H, d, J = 8.5 Hz), 7.10-7.33 (5H, m),

7.44 (2H, d, J = 8.5 Hz), 7.94 (2H, d, J = 8.2 Hz),

8.17 (2H, d, J = 8.2 Hz), 8.26 (1H, dd, J = 8.8

Hz, 2.6 Hz), 8.55 (1H, d, J = 2.6 Hz), 10.67 (1H, s).

2319
3,4-Cl₂Ph—
4-CNPhCH₂—
(CDCl₃) 2.46 (4H, brs), 3.59 (2H, s), 3.75 (4H,

brs), 6.97 (1H, d, J = 8.9 Hz), 7.11-7.14 (2H, m),

7.40-7.43 (2H, m), 7.46 (2H, d, J = 7.8 Hz),

7.56-7.65 (3H, m), 7.72-7.76 (1H, m), 8.02 (1H,

d, J = 2.2 Hz), 8.16 (1H, dd, J = 8.9 Hz, 2.7 Hz),

8.27 (1H, brs), 8.30 (1H, d, J = 2.7 Hz).

2320
3,4-Cl₂Ph—
—(CH₂)₂COPh
(CDCl₃) 2.65 (4H, brs), 3.60-3.82 (4H, m),

3.89 (2H, s), 6.99 (1H, d, J = 8.7 Hz), 7.15 (2H,

d, J = 8.6 Hz), 7.43-7.50 (4H, m), 7.56-7.60 (2H,

m), 7.72-7.76 (1H, m), 7.97-8.02 (3H, m), 8.13-

8.21 (2H, m), 8.30 (1H, d, J = 2.5 Hz).

2321
3,4-Cl₂Ph—
3,4-(CH₃)₂PhCH₂—
(CDCl₃) 2.25 (3H, s), 2.26 (3H, s), 2.44 (4H, brs),

3.47 (2H, s), 3.73 (4H, brs), 6.89 (1H, d, J = 8.9

Hz), 7.01-7.10 (5H, m), 7.32-7.36 (2H, m),

7.51 (1H, d, J = 8.4 Hz), 7.74-7.78 (1H, m),

8.05 (1H, d, J = 8.1 Hz), 8.09 (1H, dd, J = 8.8

Hz, 2.7 Hz), 8.30 (1H, d, J = 2.7 Hz), 9.06 (1H, brs).

2322
3,4-Cl₂Ph—
4-C(CH₃)₃COPhCH₂—
(CDCl₃) 1.36 (9H, s), 2.48 (4H, brs), 3.58 (2H, s),

3.70 (4H, brs), 6.96 (1H, d, J = 8.7 Hz), 7.11-

7.14 (2H, m), 7.39-7.43 (4H, m), 7.57 (1H, d, J =

8.4 Hz), 7.69 (2H, d, J = 8.3 Hz), 7.73-7.77 (1H,

m), 8.03 (1H, d, J = 2.0 Hz), 8.15 (1H, dd, J =

8.9 Hz, 2.7 Hz), 8.30 (1H, d, J = 2.7 Hz),

8.37 (1H, brs).

2323
3,4-Cl₂Ph—
4-PhCH₂OPhCH₂—
(CDCl₃) 2.45 (4H, brs), 3.49 (2H, s), 3.73 (4H,

brs), 5.06 (2H, s), 6.92-6.98 (3H, m), 7.11-

7.15 (2H, m), 7.23 (2H, d, J = 8.6 Hz), 7.32-

7.46 (7H, m), 7.57 (1H, d, J = 8.1 Hz), 7.75 (1H,

dd, J = 8.4 Hz, 2.2 Hz), 8.03 (1H, d, J = 2.2 Hz),

8.16 (1H, dd, J = 8.9 Hz, 2.7 Hz), 8.26 (1H, brs),

8.29 (1H, d, J = 2.7 Hz).

2324
3,4-Cl₂Ph—
4-C(CH₃)₃PhCH₂—
(CDCl₃) 1.32 (9H, s), 2.48 (4H, brs), 3.53 (2H, s),

3.70 (4H, brs), 6.98 (1H, d, J = 8.4 Hz), 7.13 (2H,

d, J = 8.6 Hz), 7.21-7.27 (2H, m), 7.36 (2H, d, J =

8.4 Hz), 7.43 (2H, d, J = 8.6 Hz), 7.59 (1H, d, J =

8.1 Hz), 7.72-7.76 (1H, m), 8.02 (1H, d, J = 2.2

Hz), 8.13 (1H, brs), 8.16-8.20 (1H, m), 8.30 (1H,

d, J = 2.2 Hz).

2325
3,4-Cl₂Ph—
3-CH₃PhCH₂—
(CDCl₃) 2.36 (3H, s), 2.47 (4H, brs), 3.52 (2H, s),

3.74 (4H, brs), 6.97 (1H, d, J = 8.7 Hz), 7.08-

7.26 (6H, m), 7.41-7.44 (2H, m), 7.58 (1H, d, J =

8.4 Hz), 7.76 (1H, dd, J = 8.4 Hz, 2.1 Hz),

8.04 (1H, d, J = 2.1 Hz), 8.14-8.19 (1H, m),

8.26 (1H, brs), 8.30 (1H, d, J = 2.2 Hz).

TABLE 372

Example No.
R₁₀₆₇
R₁₀₆₈

¹H NMR (CDCl₃) δ ppm

2326
3,4-Cl₂Ph—
4-CH(CH₃)₂PhCH₂—
1.25 (6H, d, J = 7.3 Hz), 2.46 (4H, brs), 2.85-

2.96 (1H, m), 3.52 (2H, s), 3.75 (4H, brs),

6.95 (1H, d, J = 8.9 Hz), 7.10-7.13 (2H, m), 7.17-

7.26 (4H, m), 7.38-7.42 (2H, m), 7.57 (1H, d, J =

8.1 Hz), 7.75 (1H, dd, J = 8.4 Hz, 2.2 Hz),

8.04 (1H, d, J = 2.2 Hz), 8.14 (1H, dd, J = 8.9 Hz,

2.7 Hz), 8.30 (1H, d, J = 2.7 Hz), 8.41 (1H, brs).

2327
3,4-Cl₂Ph—
4-CH₃PhCH₂—
2.34 (3H, s), 2.45 (4H, brs), 3.51 (2H, s), 3.73 (4H,

brs), 6.93 (1H, d, J = 8.7 Hz), 7.07-7.22 (6H, m),

7.35-7.38 (2H, m), 7.54 (1H, d, J = 8.4 Hz),

7.77 (1H, dd, J = 8.4 Hz, 2.2 Hz), 8.05 (1H, d, J =

2.2 Hz), 8.12 (1H, dd, J = 8.9 Hz, 2.7 Hz),

8.30 (1H d, J = 2.7 Hz) 8.82 (1H, s).

2328
3,4-Cl₂Ph—
3,4-F₂PhCH₂—
2.45 (4H, brs), 3.49-3.73 (6H, m), 6.96 (1H, d, J =

8.7 Hz), 7.01-7.23 (5H, m), 7.39-7.42 (2H, m),

7.56 (1H, d, J = 8.4 Hz), 7.76 (1H, dd, J =8.4 Hz

2.1 Hz), 8.03 (1H, d, J = 2.1 Hz), 8.17 (1H, dd, J =

8.7 Hz, 2.7 Hz), 8.30 (1H, d, J = 2.7 Hz),

8.50 (1H, s).

2329
3,4-Cl₂Ph—
4-CH₃OPhCH₂—
2.43 (4H, brs), 3.48 (2H, s), 3.73 (4H, brs),

3.81 (3H, s), 6.85-6.93 (3H, m), 7.06-7.10 (2H, m),

7.21-7.24 (2H, m), 7.34-7.37 (2H, m), 7.53 (1H, d,

J = 8.4 Hz), 7.77 (1H, dd, J = 8.4 Hz, 2.1 Hz),

8.05 (1H, d, J = 2.1 Hz), 8.10 (1H, dd, J = 8.9 Hz,

2.7 Hz), 8.30 (1H, d, J = 2.7 Hz) 8.90 (1H, s).

2330
4-CF₃Ph—
4-CF₃PhCH₂—
2.48 (4H, brs), 3.60 (2H, s), 3.70 (4H, brs),

7.00 (1H, d, J = 8.9 Hz), 7.12-7.17 (2H, m), 7.41-

7.48 (4H, m), 7.60 (2H, d, J = 7.9 Hz), 7.77 (2H,

d, J = 8.1 Hz), 8.02 (2H, d, J = 8.1 Hz), 8.14 (1H,

brs), 8.19-8.24 (1H, m), 8.32 (1H, d, J = 2.3 Hz).

2331
4-CF₃Ph—
3,4-(CH₃)₂PhCH₂—
2.25 (3H, s), 2.26 (3H, s), 2.45 (4H, brs), 3.47 (2H,

s), 3.40-3.90 (4H, m), 6.98 (1H, d, J = 8.7 Hz),

6.97-7.10 (3H, m), 7.13 (2H, d, J = 8.7 Hz),

7.42 (2H, d, J = 8.7 Hz), 7.76 (2H, d, J = 8.1 Hz),

8.02 (2H, d, J = 8.1 Hz), 8.18 (1H, brs), 8.20 (1H,

dd, J = 8.7 Hz, 2.5 Hz), 8.31 (1H, d, J = 2.5 Hz).

2332
4-CF₃Ph—
3-CH₃PHCH₂—
2.35 (3H, s), 2.46 (4H, brs), 3.35-3.90 (4H, m),

3.50 (2H, s), 6.98 (1H, d, J = 8.9 Hz), 7.12 (2H, d,

J = 8.6 Hz), 7.05-7.30 (4H, m), 7.41 (2H, d, J =

8.6 Hz), 7.76 (2H, d, J = 8.1 Hz), 8.02 (2H, d, J =

8.1 Hz), 8.19 (1H, dd, J = 8.9 Hz, 2.6 Hz),

8.28 (1H, brs), 8.31 (1H, d, J = 2.6 Hz).

2333
4-CF₃Ph—
4-CH₃PhCH₂—
2.34 (3H, s), 2.44 (4H, brs), 3.50 (2H, s), 3.35-

3.85 (4H, m), 6.97 (1H, d, J = 8.9 Hz), 7.12 (2H,

d, J = 8.8 Hz), 7.12 (2H, d, J = 8.1 Hz), 7.20 (2H,

d, J = 8.1 Hz), 7.40 (2H, d, J = 8.8 Hz), 7.75 (2H,

d, J = 8.1 Hz), 8.02 (2H, d, J = 8.1 Hz), 8.18 (1H,

dd, J = 8.9 Hz, 2.5 Hz), 8.32(1H, d, J = 2.5 Hz),

8.38 (1H, s).

TABLE 373

Example

No.
R₁₀₆₉
R₁₀₇₀

¹H NMR (CDCl₃) δ ppm

2334
3,4-Cl₂Ph—
3-CH₃OPhCH₂—
2.47 (4H, brs), 3.46-3.82 (6H, m), 3.86 (3H, s),

6.80-6.84 (1H, m), 6.88-6.92 (2H, m), 6.95 (1H, d,

J = 8.8 Hz), 7.10-7.13 (2H, m), 7.23 (1H, d, J = 8.1

Hz), 7.38-7.41 (2H, m), 7.56 (1H, d, J = 8.3 Hz),

7.73-7.77 (1H, m), 8.04 (1H, d, J = 2.1 Hz), 8.12-

8.16 (1H, m), 8.29 (1H, d, J = 2.7 Hz), 8.44 (1H,

brs).

2335
3,4-Cl₂Ph—
2-quinolylmethyl
2.58 (4H, brs), 3.58-3.76 (4H, m), 3.88 (2H, s),

6.94 (1H, d, J = 8.8 Hz), 7.11 (2H, d, J = 8.4 Hz),

7.40 (2H, d, J = 8.6 Hz), 7.51-7.57 (2H, m),

7.62 (1H, d, J = 8.4 Hz), 7.68-7.84 (3H, m),

8.04 (1H, d, J = 2.1 Hz), 8.07 (1H, d, J = 8.6 Hz),

8.12-8.17 (2H, m), 8.29 (1H, d, J = 2.5 Hz),

8.65 (1H, brs).

2336
3,4-Cl₂Ph—
4-CF₃PhCH₂—
2.47 (4H, brs), 3.44-3.85 (6H, m), 6.98 (1H, d, J =

8.9 Hz), 7.11-7.16 (2H, m), 7.39-7.48 (4H, m),

7.56-7.61 (3H, m), 7.75 (1H, dd, J = 8.4 Hz, 2.1

Hz), 8.02 (1H, d, J = 2.1 Hz), 8.14-8.18 (1H, m),

8.24 (1H, brs), 8.30 (1H, d, J = 2.6 Hz).

2337
3,4-Cl₂Ph—
4-CF₃OPhCH₂—
2.46 (4H, brs), 3.46-3.84 (6H, m), 6.96 (1H, d, J =

8.9 Hz), 7.10-7.20 (4H, m), 7.34-7.41 (4H, m),

7.56 (1H, d, J = 8.4 Hz), 7.76 (1H, dd, J = 8.4 Hz,

2.1 Hz), 8.03 (1H, d, J = 2.1 Hz), 8.11-8.16 (1H,

m), 8.30 (1H, d, J = 2.5 Hz), 8.49 (1H, brs).

2338
3,4-Cl₂Ph—
PhO(CH₂)₂—
2.60 (4H, brs), 2.85 (2H, t, J = 5.4 Hz), 3.53-

3.75 (4H, m), 4.12 (2H, t, J = 5.4 Hz), 6.88-

6.99 (4H, m), 7.06-7.13 (2H, m), 7.25-7.37 (4H, m),

7.51 (1H, d, J = 8.4 Hz), 7.77 (1H, dd, J = 8.4 Hz,

2.1 Hz), 8.05 (1H, d, J = 2.1 Hz), 8.07-8.12 (1H,

m), 8.32 (1H, d, J = 2.6 Hz), 9.10 (1H, brs).

2339
4-CF₃Ph—
4-CNPhCH₂—
2.45 (4H, brs), 3.58 (2H, s), 3.63 (4H, brs),

6.98 (1H, d, J = 8.8 Hz), 7.13 (2H, d, J = 8.7 Hz),

7.41 (2H, d, J = 8.7 Hz), 7.46 (2H, d, J = 8.1 Hz),

7.62 (2H, d, J = 8.1 Hz), 7.75 (2H, d, J = 8.1 Hz),

8.01 (2H, d, J = 8.1 Hz), 8.20 (1H, dd, J = 8.8 Hz,

2.6 Hz), 8.28 (1H, brs), 8.33 (1H, d, J = 2.6 Hz).

2340
4-CF₃Ph—
3,4-F₂PhCH₂—
2.44 (4H, brs), 3.48 (2H, s), 3.64 (4H, brs),

6.98 (1H, d, J = 8.9 Hz), 6.97-7.25 (3H, m),

7.12 (2H, d. J = 8.7 Hz), 7.41 (2H, d, J = 8.7 Hz),

7.75 (2H, d, J = 8.0 Hz), 8.01 (2H, d, J = 8.0 Hz),

8.19 (1H, dd, J = 8.9 Hz, 2.3 Hz), 8.30 (1H, brs),

8.32 (1H, d, J = 2.3 Hz).

2341
4-CF₃Ph—
4-CH₃OPhCH₂—
2.43 (4H, brs), 3.48 (2H, s), 3.60 (4H, brs),

3.80 (3H, s), 6.86 (2H, d, J = 8.7 Hz), 6.96 (1H, d,

J = 8.7 Hz), 7.11 (2H, d, J = 8.7 Hz), 7.22 (2H, d,

J = 8.7 Hz), 7.38 (2H, d, J = 8.7 Hz), 7.74 (2H, d,

J = 8.1 Hz), 8.02 (2H, d, J = 8.1 Hz), 8.17 (1H, dd,

J = 8.7 Hz, 2.4 Hz), 8.32 (1H, d, J = 2.4 Hz),

8.52 (1H, s).

TABLE 374

Example

No.
R₁₀₇₁
R₁₀₇₂
mp (° C.) or ¹H NMR (CDCl₃) δ ppm

2342
3,4-(CH₃)₂Ph—
4-CNPhCH₂—

¹H NMR 2.33 (6H, s), 2.45 (4H, brs), 3.58 (2H,

s), 3.64 (4H, brs), 6.97 (1H, d, J = 8.7 Hz),

7.11-7.16 (2H, m), 7.24 (1H, d, J = 7.6 Hz),

7.41-7.47 (4H, m), 7.58-7.67 (4H, m), 7.94

(1H, brs), 8.24 (1H, dd, J = 8.7 Hz, 2.7 Hz),

8.31 (1H, d, J = 2.7 Hz).

2343
3,4-(CH₃)₂Ph—
3,4-F₂PhCH₂—

¹H NMR 2.34 (6H, s), 2.45 (4H, brs), 3.48 (2H,

s), 3.65 (4H, brs), 6.98 (1H, d, J = 8.9 Hz),

7.03-7.23 (6H, m), 7.41-7.46 (2H, m), 7.59-

7.62 (1H, m), 7.67 (1H, d, J = 1.8 Hz), 7.95

(1H, brs), 8.26 (1H, dd, J = 8.9 Hz, 2.7 Hz),

8.31 (1H, d, J = 2.7 Hz).

2344
4-CF₃Ph—
3-CH₃OPhCH₂—
mp 118-120

2345
4-CF₃Ph—
2-quinolylmethyl

¹H NMR 2.56 (4H, brs), 3.43-3.81 (4H, m),

3.87 (2H, s), 6.94 (1H, d, J = 8.9 Hz), 7.08-

7.13 (2H, m), 7.35-7.40 (2H, m), 7.51-7.57 (1H,

m), 7.61 (1H, d, J = 8.4 Hz), 7.68-7.74 (3H,

m), 7.81-7.84 (1H, m), 8.01-8.20 (5H, m),

8.33 (1H, d, J = 2.7 Hz), 8.94 (1H, s).

2346
4-CF₃Ph—
PHO(CH₂)₂—
mp 161-162

2347
4-CF₃Ph—

embedded image

¹H NMR 2.48 (4H, brs), 3.55 (2H, brs), 3.66 (2H, s), 3.75 (2H, brs), 6.97 (1H, d, J = 8.7 Hz), 7.12 (2H, d, J = 8.4 Hz), 7.32- 7.43 (1H, m), 7.41 (2H, d, J = 8.4 Hz), 7.55 (1H, d, J = 8.4 Hz), 7.70-7.80 (1H, m), 7.75 (2H, d, J = 8.1 Hz), 8.02 (2H, d, J = 8.1 Hz), 8.10 (1H, s), 8.20 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.32 (1H, d, J = 2.6 Hz), 8.41 (1H, s).

TABLE 375

Example

No.
R₁₀₇₃
R₁₀₇₄

¹H NMR (CDCl₃) δ ppm

2348
3,4-Cl₂Ph—
2,6-F₂PhCH₂—
2.42 (4H, brs), 2.54-2.60 (2H, m), 2.83-2.88 (2H,

m), 3.38-3.42 (2H, m), 3.55-3.58 (2H, m),

3.69 (2H, s), 6.85-6.98 (5H, m), 7.12 (2H, d, J =

8.6 Hz), 7.19-7.31 (1H, m), 7.48 (1H, d, J = 8.4

Hz), 7.74 (1H, dd, J = 8.4 Hz, 2.1 Hz), 7.99 (1H,

d, J = 2.1 Hz), 8.14-8.18 (1H, m), 8.30 (1H, d, J =

2.8 Hz), 9.19 (1H, brs).

2349
3,4-Cl₂Ph—
4-CF₃PhCH₂—
2.33-2.41 (4H, m), 2.59-2.65 (2H, m), 2.92-

2.97 (2H, m), 3.40-3.44 (2H, m), 3.55 (2H, s),

3.61-3.64 (2H, m), 6.93 (1H, d, J = 8.8 Hz),

7.02-7.06 (2H, m), 7.20 (2H, d, J = 8.6 Hz),

7.44 (2H, d, J = 8.4 Hz), 7.54-7.60 (3H, m),

7.74 (1H, dd, J = 8.4 Hz, 2.2 Hz), 8.01 (1H, d,

J = 2.2 Hz), 8.17-8.21 (1H, m), 8.28 (1H, d, J =

2.6 Hz), 8.44 (1H, brs).

2350
4-CF₃Ph—

embedded image

2.28 (2H, t, J = 4.9 Hz), 2.43 (2H, t, J = 4.9 Hz), 2.61 (2H, t, J = 7.5 Hz), 2.96 (2H, t, J = 7.5 Hz), 3.30 (2H, t, J = 4.9 Hz), 3.59 (2H, s), 3.63 (2H, t, J = 4.9 Hz), 6.96 (1H, d, J = 8.3 Hz), 7.04 (2H, d, J = 8.5 Hz), 7.21 (2H, d, J = 8.5 Hz), 7.36 (1H, dd, J = 8.5 Hz, 1.5 Hz), 7.53 (1H, d, J = 8.4 Hz), 7.73 (1H, brs), 7.75 (2H, d, J = 8.3 Hz), 8.01 (1H, s), 8.02 (2H, d, J = 8.3 Hz), 8.25 (1H, s), 8.27 (1H, dd, J = 8.3 Hz, 2.6 Hz), 8.58 (1H, s).

2351
3,4-Cl₂Ph—
3,4-F₂PhCH₂—
2.31-2.40 (4H, m), 2.60-2.65 (2H, m), 2.93-

2.99 (2H, m), 3.39-3.45 (4H, m), 3.61-3.65 (2H,

m), 6.95 (1H, d, J = 8.8 Hz), 7.03-7.24 (7H, m),

7.57 (1H, d, J = 8.3 Hz), 7.73 (1H, dd, J = 8.4

Hz, 2.1 Hz), 8.00 (1H, d, J = 2.1 Hz), 8.10 (1H,

brs), 8.16-8.20 (1H, m), 8.26 (1H, d, J = 2.3

Hz).

2352
3,4-Cl₂Ph—
3,5-F₂PhCH₂—
2.32-2.38 (4H, m), 2.58-2.64 (2H, m), 2.89-

2.94 (2H, m), 3.40-3.46 (4H, m), 3.59-3.62 (2H,

m), 6.66-6.74 (1H, m), 6.85-7.03 (5H, m),

7.17 (2H, d, J = 8.6 Hz), 7.52 (1H, d, J = 8.2

Hz), 7.71-7.75 (1H, m), 7.99 (1H, d, J = 2.0 Hz),

8.16-8.20 (1H, m), 8.28 (1H, d, J = 2.6 Hz),

8.77 (1H, brs).

TABLE 376

Example

No.
R₁₀₇₅
Xb₅₄
R₁₀₇₆

¹H NMR (CDCl₃) δ ppm

2353
3,4-Cl₂Ph—
—CO—
—CH₃—
3.03 (2H, t, J = 5.2 Hz), 3.39 (2H, s), 3.51 (2H, s),

3.76 (2H, t, J = 5.2 Hz), 3.77 (3H, s), 6.98 (1H, d,

J = 8.9 Hz), 7.15 (2H, dd, J = 8.8 Hz, 2.1 Hz),

7.30 (2H, dd, J = 8.8 Hz, 2.1 Hz), 7.59 (1H, d, J =

8.4 Hz), 7.72 (1H, dd, J = 8.4 Hz, 2.1 Hz),

7.99 (1H, d, J = 2.1 Hz), 8.15 (1H, dd, J = 8.9 Hz,

2.7 Hz), 8.29 (1H, d, J = 2.7 Hz).

2354
3,4-Cl₂Ph—
—CH₂—
—CH₃—
2.75 (4H, t, J = 5.0 Hz), 3.23 (4H, t, J = 5.0 Hz),

3.30 (2H, s), 3.75 (3H, s), 6.90 (1H, d, J = 9.0 Hz),

6.95 (2H, d, J = 9.0 Hz), 7.04 (2H, d, J = 9.0 Hz),

7.58 (1H, d, J = 8.5 Hz), 7.70 (1H, dd, J = 8.5 Hz,

2.0 Hz), 7.76 (1H, brs), 7.98 (1H, d, J = 2.0 Hz),

8.15 (1H, dd, J = 9.0 Hz, 3.0 Hz), 8.23 (1H, d, J =

3.0 Hz).

2355
3,4-Cl₂Ph—
—CH₂—
—C₂H₅—
1.31 (3H, t, J = 7.0 Hz), 2.75 (4H, t, J = 5.0 Hz),

3.23 (4H, t, J = 5.0 Hz), 3.28 (2H, s), 4.21 (2H, q, J =

7.0 Hz), 6.90 (1H, d, J = 9.0 Hz), 6.95 (2H, d, J =

9.0 Hz), 7.04 (2H, d, J = 9.0 Hz), 7.57 (1H, d, J =

8.5 Hz), 7.71 (1H, dd, J = 8.5 Hz, 2.0 Hz),

7.88 (1H, brs), 7.98 (1H, d, J = 2.0 Hz), 8.15 (1H,

dd, J = 9.0 Hz, 2.5 Hz), 8.24 (1H, d, J = 2.5 Hz).

2356
4-CF₃Ph—
—CH₂—
—CH₃—
2.75 (4H, t, J = 5.0 Hz), 3.24 (4H, t, J = 5.0 Hz),

3.30 (2H, s), 3.75 (3H, s), 6.92 (1H, d, J = 9.0 Hz),

6.96 (2H, d, J = 9.0 Hz), 7.06 (2H, d, J = 9.0 Hz),

7.74 (1H, brs), 7.78 (2H, d, J = 8.0 Hz), 7.99 (2H, d,

J = 8.0 Hz), 8.19 (1H, dd, J = 9.0 Hz, 2.5 Hz), 8.25

(1H, d, J = 2.5 Hz).

Example 2357
Production of 3,4-dichloro-N-[6-(4-{4-[(3,4-difluorobenzyl)methylamino]piperidine-1-carbonyl}phenoxy)pyridin-3-yl]benzamide

3,4-dichloro-N-{6-[4-(4-methylamino-piperidine-1-carbonyl)phenoxy]pyridin-3-yl}benzamide dihydrochloride (114 mg, 0.2 mmol) was dissolved in DMF (3 mL). To the resulting solution were added 4-bromomethyl-1,2-difluorobenzene (31 μl, 0.24 mmol) and potassium carbonate (111 mg, 0.8 mmol), and this solution was stirred for 4 hours at room temperature. The resulting reaction solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. This residue was purified by silica gel column chromatography (chloroform:methanol=50:1), to thereby yield 60 mg of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 1.64 (4H, brs), 1.84 (2H, brs), 2.20 (3H, s), 2.65-2.90 (3H, m), 3.54 (2H, s), 6.95-7.08 (4H, m), 7.13 (2H, d, J=9.3 Hz), 7.41 (2H, d, J=9.2 Hz), 7.57 (1H, d, J=8.4 Hz), 7.75 (1H, dd, J=8.4 Hz, 2.0 Hz), 8.03 (1H, d, J=2.0 Hz), 8.15 (1H, dd, J=8.9 Hz, 2.8 Hz), 8.30 (1H, brs), 8.31 (1H, d, J=2.2 Hz).

The following compounds were produced in the same manner as in Example 2357.

TABLE 377

Example

No.
R₁₀₇₇

¹H NMR (CDCl₃) δ ppm

2358
2,4-F₂Ph—
1.66 (4H, brs), 1.91 (2H, brs), 2.25 (3H, s), 2.73-3.08 (3H, m),

3.63 (2H, s), 6.75-6.89 (3H, m), 6.97 (1H, d, J = 8.7 Hz), 7.13 (2H,

d, J = 9.2 Hz), 7.42 (2H, d, J = 9.2 Hz), 7.57 (1H, d, J = 8.3 Hz),

7.76 (1H, dd, J = 8.3 Hz, 2.1 Hz), 8.04 (1H, d, J = 2.1 Hz),

8.16 (1H, dd, J = 8.9 Hz, 2.8 Hz), 8.31 (1H, d, J = 2.3 Hz), 8.37

(1H, brs).

2359
2,5-F₂Ph—
1.72 (4H, brs), 1.88 (2H, brs), 2.25 (3H, s), 2.67-2.96 (3H, m),

3.62 (2H, s), 6.85-7.02 (3H, m), 7.09-7.23 (3H, m), 7.39 (2H, d,

J = 8.9 Hz), 7.55 (1H, d, J = 8.3 Hz), 7.77 (1H, dd, J = 8.4 Hz, 2.1

Hz), 8.05 (1H, d, J = 2.1 Hz), 8.12 (1H, dd, J = 8.9 Hz, 2.8 Hz),

8.31 (1H, d, J = 2.6 Hz), 8.66 (1H, brs).

2360
4-CH(CH₃)₂Ph—
1.25(6H, d, J = 6.9 Hz), 1.57-2.21 (7H, m), 2.66-3.07 (4H, m),

3.56 (2H, s), 3.90 (1H, brs), 4.66 (1H, brs), 6.90 (1H, d, J = 8.9

Hz), 7.04-7.10 (2H, m), 7.16-7.25 (4H, m), 7.31-7.36 (2H, m),

7.50 (1H, d, J = 8.4 Hz), 7.77 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.06-

8.10 (2H, m), 8.33 (1H, d, J = 2.5 Hz), 9.37 (1H, s).

2361
4-C(CH₃)₃Ph—
1.32 (9H, s), 1.58 (2H, brs), 1.89 (2H, brs), 2.22 (3H, s), 2.62-

3.10 (3H, m), 3.57 (2H, s), 3.92 (1H, brs), 4.69 (1H. brs),

6.92 (1H, d, J = 8.6 Hz), 7.06-7.11 (2H, m), 7.22-7.25 (2H, m),

7.32-7.37 (4H, m), 7.53 (1H, d, J = 8.6 Hz), 7.78 (1H, dd, J = 8.4

Hz, 2.2 Hz), 8.07 (1H, d, J = 2.2 Hz), 8.11 (1H, d, J = 2.7 Hz),

8.32 (1H, d, J = 2.7 Hz), 9.07 (1H, brs).

TABLE 378

Example

No.
R₁₀₇₈

¹H NMR (CDCl₃) δ ppm

2362
4-CNPh—
1.54 (1H, brs), 1.86 (3H, brs), 2.20 (3H, s), 2.64-3.04 (3H, m), 3.64 (2H,

s), 3.91 (1H, brs), 4.69 (1H, brs), 6.91 (1H, d, J = 8.9 Hz), 7.05-7.10 (2H,

m), 7.32-7.37 (2H, m), 7.45 (2H, d, J = 8.4 Hz), 7.50 (1H, d, J = 8.4 Hz),

7.59-7.62 (2H, m), 7.75-7.79 (1H, m), 8.05 (1H, d, J = 2.0 Hz), 8.10 (1H,

dd, J = 8.9 Hz, 2.7 Hz), 8.35 (1H, d, J = 2.7 Hz), 9.31(1H, brs).

2363
Ph—
1.55 (2H, brs), 1.87 (2H, brs), 2.22 (3H, s), 2.61-2.80 (2H, m), 2.90 (1H,

brs), 3.60 (2H, s), 3.93 (1H, brs), 4.72 (1H, brs), 6.98 (1H, d, J = 8.9 Hz),

7.14 (2H, d, J = 8.7 Hz), 7.18-7.37 (5H, m), 7.43 (2H, d, J = 8.7 Hz),

7.58 (1H, d, J = 8.4 Hz), 7.75 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.02 (1H, d,

J = 2.0 Hz), 8.16 (1H, dd, J = 8.9 Hz, 2.4 Hz), 8.19 (1H, brs), 8.30 (1H, d,

J = 2.4 Hz).

2364
2-ClPh—
1.50 (2H, brs), 1.90 (2H, brs), 2.26 (3H, s), 2.68-2.85 (2H, m), 2.98 (1H,

brs), 3.70 (2H, s), 3.95 (1H, brs), 4.75 (1H, brs), 6.98 (1H, d, J = 8.7 Hz),

7.14 (2H, d, J = 8.5 Hz), 7.15-7.30 (2H, m), 7.34 (1H, dd, J = 7.2 Hz, 2.0

Hz), 7.43 (2H, d, J = 8.5 Hz), 7.47 (1H, dd, J = 7.2 Hz, 2.0 Hz),

7.58 (1H, d, J = 8.4 Hz), 7.75 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.04 (1H, d, J =

2.0 Hz), 8.16 (1H, dd, J = 8.7 Hz, 2.8 Hz), 8.31 (1H, d, J = 2.8 Hz),

8.32 (1H, brs).

2365
3-ClPh—
1.50 (2H, brs), 1.87 (2H, brs), 2.21 (3H, s), 2.55-3.20 (3H, m), 3.57 (2H,

s), 3.95 (1H, brs), 4.70 (1H, brs), 6.99 (1H, d, J = 8.8 Hz), 7.14 (2H, d, J =

8.7 Hz), 7.15-7.28 (3H, m), 7.33 (1H, brs), 7.44 (2H, d, J = 8.7 Hz),

7.59 (1H, d, J = 8.4 Hz), 7.74 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.02 (1H, d,

J = 2.0 Hz), 8.09 (1H, brs), 8.17 (1H, dd, J = 8.8 Hz, 2.8 Hz), 8.30 (1H, d,

J = 2.8 Hz).

2366
3,4-Cl₂Ph—
1.50 (2H, brs), 1.85 (2H, brs), 2.20 (3H, s), 2.60-3.15 (3H, m), 3.54 (2H,

s), 3.95 (1H, brs), 4.70 (1H, brs), 6.97 (1H, d, J = 8.9 Hz), 7.13 (2H, d, J =

8.6 Hz), 7.10-7.19 (1H, m), 7.36 (1H, s), 7.41 (2H, d, J = 8.6 Hz), 7.35-

7.47 (1H, m), 7.57 (1H, d, J = 8.4 Hz), 7.75 (1H, dd, J = 8.4 Hz, 2.1 Hz),

8.03 (1H, d, J = 2.1 Hz), 8.14 (1H, dd, J = 8.9 Hz, 2.5 Hz), 8.30 (1H, d, J =

2.5 Hz), 8.40 (1H, s).

2367
2,3-Cl₂Ph—
1.60 (2H, brs), 1.90 (2H, brs), 2.26 (3H, s), 2.65-3.20 (3H, m), 3.72 (2H,

s), 3.90 (1H, brs), 4.72 (1H, brs), 6.97 (1H, d, J = 8.8 Hz), 7.13 (2H, d, J =

8.6 Hz), 7.20 (1H, d, J = 8.0 Hz), 7.36 (1H, dd, J = 8.0 Hz, 1.5 Hz),

7.42 (2H, d, J = 8.6 Hz), 7.37-7.46 (1H, m), 7.57 (1H, d, J = 8.2 Hz),

7.75 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.04 (1H, d, J = 2.0 Hz), 8.14 (1H, dd,

J = 8.8 Hz, 2.7 Hz), 8.30 (1H, d, J = 2.7 Hz), 8.38 (1H, brs).

2368
2-FPh—
1.55 (2H, brs), 1.85 (2H, brs), 2.25 (3H, s), 2.50-3.20 (3H, m), 3.65 (2H,

s), 3.95 (1H, brs), 4.70 (1H, brs), 6.97 (1H, d, J = 8.8 Hz), 6.95-7.17 (2H,

m), 7.13 (2H, d, J = 8.7 Hz), 7.18-7.29 (1H, m), 7.32-7.45 (1H, m),

7.42 (2H, d, J = 8.7 Hz), 7.57 (1H, d, J = 8.2 Hz), 7.75 (1H, dd, J = 8.2

Hz, 2.1 Hz), 8.04 (1H, d, J = 2.1 Hz), 8.14 (1H, dd, J = 8.8 Hz, 2.5 Hz),

8.30 (1H, d, J = 2.5 Hz), 8.34 (1H, brs).

2369
2-CH₃Ph—
1.67 (4H, brs), 1.89 (2H, brs), 2.19 (3H, s), 2.36 (3H, s), 2.67-2 96 (3H,

m), 3.57 (2H, s), 6.96 (1H, d, J = 8.7 Hz), 7.07-7.26 (6H, m), 7.41 (2H, d,

J = 8.1 Hz), 7.57 (1H, d, J = 8.4 Hz), 7.77 (1H, dd, J = 8.4 Hz, 2.0 Hz),

8.05 (1H, d, J = 2.0 Hz), 8.14 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.31 (1H, d,

J = 2.6 Hz), 8.51 (1H, brs).

TABLE 379

Example

No.
R₁₀₇₉
Form

¹H NMR (solvent) δ ppm

2370
3,5-(CH₃O)₂Ph—
hydro-
(DMSO-d₆) 1.67-1.93 (2H, m), 2.08-2.30 (2H, m),

chloride
2.61 (3H, d, J = 4.8 Hz), 2.95 (1H, brs), 3.31-3.75 (4H,

m), 3.77 (6H, s), 4.02-4.18 (1H, m), 4.31-4.45 (1H, m),

6.57 (1H, t, J = 2.0 Hz), 6.83 (2H, d, J = 2.0 Hz),

7.16 (1H, d, J = 8.7 Hz), 7.20 (2H, d, J = 8.6 Hz),

7.49 (2H, d, J = 8.6 Hz), 7.85 (1H, d, J = 8.4 Hz),

7.97 (1H, dd, J = 8.4 Hz, 2.1 Hz), 8.24 (1H, d, J = 2.1

Hz), 8.24 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.55 (1H, d, J =

2.6 Hz), 10.64 (1H, brs).

2371
3-CH₃OPh—
free
(CDCl₃) 1.60 (2H, brs), 1.87 (2H, brs), 2.23 (3H, s), 2.52

3.20 (3H, m), 3.58 (2H, s), 3.81 (3H, s), 3.95 (1H, brs),

4.70 (1H, brs), 6.75-6.90 (3H, m), 6.97 (1H, d, J = 8.9

Hz), 7.13 (2H, d, J = 8.6 Hz), 7.21 (1H, d, J = 8 0 Hz),

7.41 (2H, d, J = 8.6 Hz), 7.57 (1H, d, J = 8.4 Hz),

7.75 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.04 (1H, d, J = 2.0

Hz), 8.14 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.30 (1H, d, J =

2.6 Hz), 8.36 (1H, brs).

2372
3-CH₃Ph—
free
(CDCl₃) 1.61 (4H, brs), 1.88 (2H, brs), 2.22 (3H, s),

2.35 (3H, s), 2.68-3.01 (3H, m), 3.56 (2H, s), 6.98 (1H, d,

J = 8.9 Hz), 7.06-7.29 (6H, m), 7.42 (2H, d, J = 8.6 Hz),

7.58 (1H, d, J = 8.2 Hz), 7.76 (1H, dd, J = 8.3 Hz, 2.0

Hz), 8.04 (1H, d, J = 2.0 Hz), 8.16 (1H, dd, J = 8.9 Hz,

2.6 Hz), 8.31 (1H, d, J = 2.3 Hz), 8.38 (1H, brs).

2373
3,5-F₂Ph—
free
(CDCl₃) 1.42-1.96 (4H, m), 2.21 (3H, s), 2.65-3.10 (3H,

m), 3.56 (2H, s), 3.90 (1H, brs), 4.68 (1H, brs), 6.64-

6.70 (1H, m), 6.85-6.92 (3H, m), 7.04-7.09 (2H, m), 7.31-

7.36 (2H, m), 7.50 (1H, d, J = 8.4 Hz), 7.74-7.79 (1H,

m), 8.05-8.10 (2H, m), 8.33 (1H, d, J = 2.5 Hz), 9.30

(1H, brs).

2374
3,4-(CH₃)₂Ph—
free
(CDCl₃) 1.59 (4H, brs), 1.90-1.98 (2H, m), 2.22 (3H, s),

2.25 (3H, s), 2.26 (3H, s), 2.67-2.97 (3H, m), 3.59 (2H, s),

6.99 (1H, d, J = 8.7 Hz), 7.05-7.10 (3H, m), 7.15 (2H, d,

J = 9.4 Hz), 7.44 (2H, d, J = 9.4 Hz), 7.59 (1H, d, J =

8.3 Hz), 7.74 (1H, dd, J = 8.3 Hz, 2.2 Hz), 8.02 (1H, d, J =

2.0 Hz), 8.03 (1H, brs), 8.18 (1H, dd, J = 8.7 Hz, 2.8

Hz), 8.31 (1H, d, J = 2.8 Hz).

2375
3-FPh—
free
(CDCl₃) 1.59-1.85 (6H, m), 2.22 (3H, s), 2.67-2.99 (3H,

m), 3.59 (2H, s), 6.94-6.97 (2H, m), 7.05-7.13 (5H, m),

7.39 (2H, d, J = 8.4 Hz), 7.56 (1H, d, J = 8.4 Hz),

7.77 (1H, dd, J = 8.4 Hz, 2.0 Hz), 8.05 (1H, d, J = 2.0

Hz), 8.13 (1H, dd, J = 8.7 Hz, 2.6 Hz), 8.31 (1H, d, J =

2.5 Hz), 8.63 (1H, brs).

2376
2,6-F₂Ph—
free
(CDCl₃) 1.65 (4H, brs), 1.81-1.91 (2H, m), 2.28 (3H, s),

2.69-3.03 (3H, m), 3.69 (2H, s), 6.83-6.92 (3H, m),

6.99 (1H, d, J = 8.9 Hz), 7.15 (2H, d, J = 9.2 Hz),

7.44 (2H, d, J = 9.2 Hz), 7.59 (1H, d, J = 8.4 Hz),

7.75 (1H, dd, J = 8.4 Hz, 2.2 Hz), 8.03 (1H, d, J = 2.2

Hz), 8.17 (1H, brs), 8.18 (1H, dd, J = 8.7 Hz, 2.8 Hz),

8.31 (1H, d, J = 2.6 Hz).

TABLE 380

Example

No.
R₁₀₈₀
mp (° C.) or MS

2377
4-CF₃OPh—
mp 180-181

2378
2-NO₂Ph—
MS 634 (M⁺ + H)

2379
3-NO₂Ph—
MS 634 (M⁺ + H)

2380
4-NO₂Ph—
MS 634 (M⁺ + H)

2381
2-CF₃Ph—
MS 657 (M⁺ + H)

2382
3-CF₃Ph—
MS 657 (M⁺ + H)

2383
4-CF₃Ph—
MS 657 (M⁺ + H)

2384
2-CF₃OPh—
MS 673 (M⁺ + H)

2385

embedded image

MS 647 (M⁺ + H)

2386
4-biphenylyl
MS 665 (M⁺ + H)

2387

embedded image

MS 647 (M⁺ + H)

2388

embedded image

MS 699 (M⁺ + H)

2389
2-pyridyl
MS 590 (M⁺ + H)

2390
2-quinolyl
MS 640 (M⁺ + H)

2391

embedded image

MS 671 (M⁺ + H)

2392

embedded image

MS 609 (M⁺ + H)

2393
2,4-Cl₂Ph—
MS 657 (M⁺ + H)

2394
2,5-Cl₂Ph—
MS 657 (M⁺ + H)

2395
2,6-Cl₂Ph—
MS 657 (M⁺ + H)

TABLE 381

Example

No.
R₁₀₈₁
Xb₅₅
Xb₅₆
R₁₀₈₂
mp (° C.) or MS

2396
—H
none
none
Ph—
mp 155-158

2397
—F
—(CH₂)₂—
—CO—
Ph—
MS 634 (M⁺ + H)

2398
—F
—(CH₂)₂—
—CO—
2-ClPh—
MS 668 (M⁺ + 1)

2399
—F
—(CH₂)₂—
—CO—
3-ClPh—
MS 668 (M⁺ + H)

2400
—F
—(CH₂)₂—
—CO—
4-ClPh—
MS 668 (M⁺ + H)

2401
—F
—(CH₂)₂—
—CO—
2,3-Cl₂Ph—
MS 702 (M⁺ + 1)

2402
—F
—(CH₂)₂—
—CO—
2,4-Cl₂Ph—
MS 701 (M⁺)

2403
—F
—(CH₂)₂—
—CO—
2,5-Cl₂Ph—
MS 702 (M⁺ + 1)

2404
—F
—(CH₂)₂—
—CO—
2,6-Cl₂Ph—
MS 702 (M⁺ + H)

2405
—F
—(CH₂)₂—
—CO—
3,4-Cl₂Ph—
MS 703 (M⁺)

2406
—F
—(CH₂)₂—
—CO—
3-pyridyl
MS 634 (M⁺)

2407
—F
—(CH₂)₂—
—CO—
2-quinolyl
MS 685 (M⁺ + H)

2408
—F
—(CH₂)₂—
—CO—

embedded image

MS 716 (M⁺ + H)

2409
—F
—(CH₂)₂—
—CO—

embedded image

MS 654 (M⁺ + H)

2410
—F
—(CH₂)₂—
—CO—

embedded image

MS 730 (M⁺ + H)

2411
—F
—(CH₂)₂—
—CO—
3-CH₃OPh—
MS 662 (M⁺ − 1)

2412
—F
—(CH₂)₂—
—CO—
3,5-(CH₃O)₂Ph—
MS 693 (M⁺)

2413
—F
—(CH₂)₂—
—CO—
2-CH₃Ph—
MS 648 (M⁺ + H)

2414
—F
—(CH₂)₂—
—CO—
3-CH₃Ph—
MS 648 (M⁺ + H)

2415
—F
—(CH₂)₂—
—CO—
4-CH₃Ph—
MS 648 (M⁺ + H)

2416
—F
—(CH₂)₂—
—CO—
3,4-(CH₃)₂Ph—
MS 662 (M⁺ + 1)

2417
—F
—(CH₂)₂—
—CO—
2-FPh—
MS 652 (M⁺ + H)

2418
—F
—(CH₂)₂—
—CO—
3-FPh—
MS 652 (M⁺ + H)

2419
—F
—(CH₂)₂—
—CO—
4-FPh—
MS 652 (M⁺ + 1)

2420
—F
—(CH₂)₂—
—CO—
2 4 F₂Ph—
MS 670 (M⁺ + H)

2421
—F
—(CH₂)₂—
—CO—
2,5-F₂Ph—
MS 670 (M⁺ + H)

2422
—F
—(CH₂)₂—
—CO—
2,6-F₂Ph—
MS 671 (M⁺ + 2)

2423
—F
—(CH₂)₂—
—CO—
3,4-F₂Ph—
MS 670 (M⁺ + H)

2424
—F
—(CH₂)₂—
—CO—
3,5-F₂Ph—
MS 670 (M⁺ + H)

TABLE 382

Example

No.
R₁₀₈₃
MS

2425
2-NO₂Ph—
679 (M⁺ + H)

2426
3-NO₂Ph—
678 (M⁺)

2427
4-NO₂Ph—
679 (M⁺ + H)

2428
2-CF₃Ph—
701 (M⁺)

2429
3-CF₃Ph—
702 (M⁺ + H)

2430
4-CF₃Ph—
701 (M⁺)

2431
4-CNPh—
659 (M⁺ + H)

2432
2-CF₃OPh—
718 (M⁺ + H)

2433
3-CF₃OPh—
718 (M⁺ + H)

2434
4-CF₃OPh—
718 (M⁺ + H)

2435

embedded image

692 (M⁺ + H)

2436
4-biphenylyl
710 (M⁺ + H)

2437

embedded image

692 (M⁺ + H)

2438
4-C₂H₅Ph—
662 (M⁺ + H)

2439
4-CH(CH₃)₂Ph—
676 (M⁺ + H)

2440
4-C(CH₃)₃Ph—
690 (M⁺ + H)

2441

embedded image

744 (M⁺ + H)

2442
2-naphthyl
684 (M⁺ + H)

2443
2-pyridyl
635 (M⁺ + H)

Example 2444
Production of 1-(4-piperonylpiperazin-1-yl)-2-{4-[5-(4-trifluoromethylphenoxymethyl)pyridin-2-yloxy]-phenylamino}ethanone

4-[5-(4-trifluoromethylphenoxymethyl)pyridin-2-yloxy]phenylamine (4.50 g, 12.5 mmol) was dissolved in DMF (150 mL). To the resulting solution were added potassium carbonate (2.60 g, 18.8 mmol) and sodium iodide (1.87 g, 12.5 mmol), and then to this solution was added 2-chloro-1-(4-piperonylpiperazin-1-yl)ethanone (4.21 g, 12.5 mmol). The resulting solution was stirred for 11 hours under a nitrogen atmosphere at 80° C. The resulting reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate and washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=80:1), to thereby yield 5.2 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 2.44-2.46 (4H, m), 3.43-3.47 (4H, m), 3.69 (2H, t, J=5.0 Hz), 3.86 (2H, s), 4.91 (1H, brs), 5.02 (2H, s), 5.94 (2H, s), 6.64 (2H, d, J=8.9 Hz), 6.74-6.75 (2H, m), 6.85-6.89 (2H, m), 6.96-7.03 (4H, m), 7.55 (2H, d, J=8.4 Hz), 7.72 (1H, dd, J=8.4 Hz, 2.5 Hz), 8.22 (1H, d, J=2.0 Hz).

Example 2445
Production of N-{6-[4-(4-thiazole-2-ylmethylpiperazine-1-carbonyl)phenoxy]pyridin-3-yl}-4-trifluoromethylbenzamide

To a suspension of N-{6-[4-(piperazine-1-carbonyl)phenoxy]pyridin-3-yl}-4-trifluoromethylbenzamide dihydrochloride (400 mg, 0.74 mmol) in 1,2-dichloroethane (20 mL) were added 2-formylthiazole (125 mg, 1.10 mmol) and triethylamine (0.21 mL, 1.50 mmol). After the resulting solution was stirred at room temperature for 30 minutes, sodium triacetyloxy borohydride (312 mg, 1.47 mmol) was added under ice cooling. The reaction mixture was stirred at the same temperature for 30 minutes and at room temperature for 1 hour. Acetic acid (0.085 mL, 1.48 mmol) was added to the reaction mixture, and stirred at room temperature for 17 hours. The reaction mixture was poured into ice water, and extracted with chloroform. The chloroform layer was washed with a saturated sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate. A significant part of the solvent was evaporated. The white precipitate was then filtered off and washed with ethyl acetate, to thereby yield 293 mg of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 2.55 (4H, brs), 3.55 (4H, brs), 3.90 (2H, s), 7.15 (1H, d, J=8.7 Hz), 7.16 (2H, d, J=8.6 Hz), 7.45 (2H, d, J=8.6 Hz), 7.68 (1H, d, J=3.2 Hz), 7.73 (1H, d, J=3.2 Hz), 7.94 (2H, d, J=8.1 Hz), 8.17 (2H, d, J=8.1 Hz), 8.26 (1H, dd, J=8.7 Hz, 2.3 Hz), 8.55 (1H, d, J=2.3 Hz), 10.68 (1H, s).

The following compounds were produced in the same manner as in Example 2445.

TABLE 383

Example

No.
R₁₀₈₄
R₁₀₈₅

¹H NMR (solvent) δ ppm

2446
3,4-Cl₂Ph—
3,4-(CH₃)₂Ph—
(CDCl₃) 2.27 (3H, s), 2.29 (3H, s), 2.42 (4H, brs),

3.49 (2H, s), 3.70 (4H, brs), 6.90 (1H, d, J = 8.9 Hz),

7.05-7.10 (5H, m), 7.34-7 36 (2H, m), 7.50 (1H, d, J =

8.4 Hz), 7.75-7.79 (1H, m), 8.00-8.14 (2H, m),

8.33 (1H, d, J = 2.7 Hz), 9.30 (1H, brs).

2447
4-CF₃Ph—
2-FPh—
(CDCl₃) 2.50 (4H, brs), 3.55 (2H, brs), 3.70 (2H, brs),

3.62 (2H, s), 6.98 (1H, d, J = 8.8 Hz), 6.95-7.17 (2H, m),

7.12 (2H, d, J = 8.7 Hz), 7.20-7.41 (2H, m), 7.40 (2H, d,

J = 8.7 Hz), 7.76 (2H, d, J = 8.2 Hz), 8.02 (2H, d, J =

8.2 Hz), 8.19 (1H, dd, J = 8.8 Hz, 2.8 Hz), 8.31 (1H, s),

8.32 (1H, d, J = 2.8 Hz).

2448
4-CF₃Ph—
3-pyridyl
(CDCl₃) 2.46 (4H, brs), 3.55 (2H, s), 3.58-3.73 (4H, m),

6.97 (1H, d, J = 8.7 Hz), 7.10-7.15 (2H, m), 7.25-

7.30 (1H, m), 7.38-7.43 (2H, m), 7.65-7.69 (1H, m),

7.74 (2H, d, J = 8.1 Hz), 8.03 (2H, d, J = 8.1 Hz) 8.19-

8.23 (1H, m), 8.32 (1H, d, J = 2.3 Hz), 8.51-8.53 (1H,

m), 8.54 (1H, d, J = 1.5 Hz), 8.62 (1H, brs).

2449
4-CF₃Ph—
cyclohexyl
(DMSO-d₆) 0.60-1.90 (11H, m), 2.10 (2H, d, J = 7.2

Hz), 2.34 (4H, brs), 3.50 (4H, brs), 7.15 (1H, d, J = 8.8

Hz), 7.16 (2H, d, J = 8.7 Hz), 7.43 (2H, d, J = 8.7 Hz),

7.94 (2H, d, J = 8.1 Hz), 8.17 (2H, d, J = 8.1 Hz),

8.26 (1H, dd, J = 8.8 Hz, 2.7 Hz), 8.55 (1H, d, J = 2.7

Hz), 10.66 (1H, s).

2450
4-CF₃Ph—
3-furyl
(CDCl₃) 2.46 (4H, brs), 3.42 (2H, s), 3.40-3.90 (4H, m),

6.39 (1H, brs), 6.98 (1H, d, J = 8.9 Hz), 7.13 (2H, d, J =

8.7 Hz), 7.34 (1H, brs), 7.33-7.42 (1H, m), 7.41 (2H, d,

J = 8.7 Hz), 7.76 (2H, d, J = 8.1 Hz), 8.02 (2H, d, J = 8.1

Hz), 8.20 (1H, dd, J = 8.9 Hz, 2.5 Hz), 8.29 (1H, s),

8.32 (1H, d, J = 2.5 Hz).

2451
4-CF₃Ph—
4-pyridyl
(CDCl₃) 2.45 (4H, brs), 3.41-3.81 (6H, m), 6.95 (1H, d,

J = 8.9 Hz), 7.08-7.13 (2H, m), 7.28 (2H, d, J = 5.9 Hz),

7.35-7.40 (2H, m), 7.70 (2H, d, J = 8.4 Hz), 8.02 (2H, d,

J = 8.4 Hz), 8.21 (1H, dd, J = 8.9 Hz, 2.7 Hz), 8.33 (1H,

d, J = 2.7 Hz), 8.53-8.55 (2H, m), 9.02 (1H, s).

2452
4-CF₃Ph—
2-furyl
(CDCl₃) 2.50 (4H, brs), 3.59 (2H, s), 3.73 (4H, brs),

6.23 (1H, d, J = 3.0 Hz), 6.33 (1H, dd, J = 3.0 Hz, 2.0

Hz), 6.99 (1H, d, J = 8.9 Hz), 7.13 (2H, d, J = 8.8 Hz)

7.41 (2H, d, J = 8.8 Hz), 7.35-7.48 (1H, m) 7.76 (2H, d,

J = 8.1 Hz), 8.02 (2H, d, J = 8.1 Hz), 8.20 (1H, dd, J =

8.9 Hz, 2.5 Hz), 8.24 (1H, brs), 8.32 (1H, d, J = 2.5 Hz)

2453
4-CF₃Ph—
4-NO₂Ph—
(CDCl₃) 2.48 (4H, brs), 3.63 (2H, s), 3.73 (4H, brs),

7.00 (1H, d, J = 8.8 Hz), 7.14 (2H, d, J = 8.7 Hz),

7.43 (2H, d, J = 8.7 Hz), 7.53 (2H, d, J = 8.4 Hz),

7.76 (2H, d, J = 8.0 Hz), 8.01 (2H, d, J = 8.0 Hz),

8.15 (1H, brs), 8.20 (2H, d, J = 8.4 Hz), 8.21 (1H, dd,

J = 8.8 Hz, 2.5 Hz), 8.32 (1H, d, J = 2.5 Hz).

TABLE 384

Example

No.
R₁₀₈₆
R₁₀₈₇
mp (° C.) or ¹H NMR (solvent) δ ppm

2454
4-CF₃Ph—

¹H NMR (CDCl₃) 2.43 (4H, brs), 3.46 (2H, s) 3.55 (4H, brs), 3.65 (3H, s), 5.95-6.08 (2H, m), 6.61 (1H, t, J = 2.2 Hz), 6.98 (1H, d, J = 8.9 Hz), 7.13 (2H, d, J = 8.8 Hz), 7.41 (2H, d, J = 8.8 Hz), 7.76 (2H, d, J = 8.1 Hz), 8.02 (2H, d J = 8.1 Hz), 8.20 (1H, dd, J = 8 9 Hz, 2.5 Hz), 8.25 (1H, brs), 8.31 (1H, d, J = 2.5 Hz).

2455
4-CF₃Ph—
2-pyridyl
mp 175-176

2456
4-CF₃Ph—
4-OHPh—

¹H NMR (DMSO-d₆) 2.36 (4H, brs), 3.32 (2H, s),

3.49 (4H, brs), 6.70 (2H, d, J = 8.4 Hz), 7.09 (2H, d, J =

8.4 Hz), 7.15 (1H, d, J = 8.9 Hz), 7.16 (2H, d, J = 8.6

Hz) 7.43 (2H, d, J = 8.6 Hz), 7.94 (2H, d, J = 8.0 Hz),

8.17 (2H, d, J = 8.0 Hz), 8.26 (1H, dd, J = 8.9 Hz, 2.5

Hz), 8.54 (1H, d, J = 2.5 Hz), 9.27 (1H, s), 10.66 (1H, s).

2457
4-CF₃Ph—
2-OHPh—

¹H NMR (CDCl₃) 2.59 (4H, brs), 3.68 (4H, brs), 3.75 (2H,

s), 6.72-6.88 (2H, m), 6.92-710 (1H, m), 7.01(1H, d, J = 8.8

Hz), 7.15 (2H, d, J = 8.8 Hz), 7.10-7.25 (1H, m), 7.44

(2H, d, J = 8.8 Hz), 7.76 (2H, d, J = 8.1 Hz), 8.01 (2H, d, J =

8.1 Hz), 8.12 (1H, brs), 8.22 (1H, dd, J = 8.8 Hz, 2.3 Hz),

8.31 (1H, d, J = 2.3 Hz).

2458
4-CF₃Ph—
4-AcNHPh—

1H NMR (DMSO-d₆) 2.02 (3H, s), 2.38 (4H, brs),

3.45 (2H, s), 3.45 (4H, brs), 7.15 (1H, d. J = 8.9 Hz),

7.16 (2H, d, J = 8.6 Hz), 7.22 (2H, d, J = 8.4 Hz),

7.44 (2H, d, J = 8.6 Hz), 7.52 (2H, d, J = 8.4 Hz),

7.94 (2H, d, J = 8.1 Hz), 8.17 (2H, d, J = 8.1 Hz),

8.26 (1H, dd, J = 8.9 Hz, 2.6 Hz), 8.54 (1H, d, J = 2.6

Hz), 9.90 (1H, s), 10.66 (1H, s).

2459
4-CF₃Ph—
2,3-(CH₃)₂Ph—

¹H NMR (CDCl₃) 2.25 (3H, s), 2.28 (3H, s), 2.42 (4H,

brs), 3.47 (2H, s), 3.67 (4H, brs), 6.95 (1H, d, J = 8.7

Hz), 6.95-7.12 (3H, m), 7.10 (2H, d, J = 8.6 Hz),

7.38 (2H, d, J = 8.6 Hz), 7.73 (2H, d, J = 8.1 Hz),

8.00 (2H, d, J = 8.1 Hz), 8.17 (1H, dd, J = 8.7 Hz, 2.7

Hz), 8.30 (1H, d, J = 2.7 Hz), 8.43 (1H, s).

2460
4-CF₃Ph—
3-thienyl

¹H NMR (CDCl₃) 2.45 (4H, brs), 3.55 (2H, brs),

3.56 (2H, s), 3.72 (2H, brs), 6.97 (1H, d, J = 8.9 Hz),

7.05 (1H, dd, J = 5.0 Hz, 1.1 Hz), 7.08-7.17 (1H, m),

7.12 (2H, d, J = 8.7 Hz), 7.29 (1H, dd, J = 5.0 Hz, 3.0

Hz), 7.39 (2H, d, J = 8.7 Hz), 7.75 (2H, d, J = 8.1 Hz),

8.02 (2H, d, J = 8.1 Hz), 8.19 (1H, dd, J = 8.9 Hz, 2.8

Hz), 8.32 (1H, d, J = 2.8 Hz), 8.41 (1H, brs).

2461
3,4-Cl₂PH—
3-pyridyl

¹H NMR (CDCl₃) 2.46 (4H, brs), 3.46 (2H, s), 3.55-

3.80 (4H, m), 6.96 (1H, d, J = 8.9 Hz), 7.12 (2H, d, J =

8.4 Hz), 7.26-7.30 (1H, m), 7.40 (2H, d, J = 8.4 Hz),

7.56 (1H, d, J = 8.4 Hz), 7.65-7.78 (2H, m), 8.04 (1H, d,

J = 2.2 Hz), 8.16 (1H, dd, J = 8.9 Hz, 2.7 Hz), 8.29 (1H,

d, J = 2.2 Hz), 8.51-8.56 (2H, m), 8.61 (1H, brs).

brs), 3.47 (2H, s), 3.67 (4H, brs), 6.95 (1H, d, J = 8.7

Hz), 6.95-7.12 (3H, m), 7.10 (2H, d, J = 8.6 Hz),

7.38 (2H, d, J = 8.6 Hz), 7.73 (2H, d, J = 8.1 Hz),

8.00 (2H, d, J = 8.1 Hz), 8.17 (1H, dd, J =8.7 Hz, 2.7

Hz), 8.30 (1H, d, J = 2.7 Hz), 8.43 (1H, s).

TABLE 385

Example

No.
R₁₀₈₈
R₁₀₈₉
Form

¹H NMR (solvent) ppm

2462
4-CF₃Ph—
cyclopropyl
free
(CDCl₃) 0.11 (2H, dd, J = 10.5 Hz, 4.5

Hz), 0.54 (2H, dd, J = 12.5 Hz, 6.5 Hz),

0.77-0.93 (1H, m), 2.29 (2H, d, J = 6.5 Hz),

2.52 (4H, brs), 3.55 (2H, brs), 3.75 (2H,

brs), 6.98 (1H, d, J = 8.9 Hz), 7.14 (2H, d,

J = 8.7 Hz), 7.42 (2H, d, J = 8.7 Hz),

7.76 (2H, d, J = 8.1 Hz), 8.03 (2H, d, J =

8.1 Hz), 8.20 (1H, dd, J = 8.9 Hz, 2.5 Hz),

8.33 (1H,d, J = 2.5 Hz), 8.36 (1H, brs).

2463
4-CF₃Ph—
3-OHPh—
hydro-
(DMSO-d₆) 2.90-3.70 (6H, m), 3.90-

chloride
4.20 (2H, m), 4.24 (2H, d, J = 3.9 Hz),

6.86 (1H, dd, J = 8.1 Hz, 1.7 Hz), 6.97

(1H, brs), 7.01 (1H, d, J = 7.7 Hz),

7.16 (1H, d, J = 8.9 Hz), 7.20 (2H, d, J =

8.6 Hz), 7.25 (1H, t, J = 7.7 Hz), 7.52 (2H,

d, J = 8.6 Hz). 7.94 (2H, d, J = 8.1 Hz),

8.20 (2H, d, J = 8.1 Hz), 8.29 (1H, dd, J =

8.9 Hz, 2.5 Hz), 8.58 (1H, d, J = 2.5 Hz),

10.77 (1H, s).

2464
4-CF₃Ph—
—C(CH₃)₃
free
(CDCl₃) 0.88 (9H, s), 2.09 (2H, s), 2.52 (4H,

brs), 3.49 (2H, brs), 3.68 (2H, brs),

6.97 (1H, d, J = 8.8 Hz), 7.12 (2H, d, J =

8.5 Hz), 7.39 (2H, d, J = 8.5 Hz), 7.75 (2H,

d, J = 8.1 Hz), 8.03 (2H, d, J = 8.1 Hz),

8.19 (1H, dd, J = 8.8 Hz, 2.5 Hz), 8.33 (1H,

d, J = 2.5 Hz), 8.47 (1H, s).

2465
4-CF₃Ph—

free
(CDCl₃) 2.42 (3H, s) 2.59 (4H, brs), 348- 3.76 (4H, m), 3.91 (2H, s), 4.56 (2H, s), 7.00 (1H, d, J = 8.9 Hz), 7.13 (2H, d, J = 8.7 Hz), 7.39 (2H, d, J = 8.6 Hz), 7.71 (2H, d, J = 8.3 Hz), 7.79 (1H, s), 8.00 (2H, d, J = 8.1 Hz), 8.22-8.29 (2H, m), 8.81 (1H, brs).

2466
4-CF₃Ph—

free
(CDCl₃) 2.55 (3H, s), 2.35-2.70 (4H, m), 3.66 (2H, s), 3.40-3.95 (4H, m), 6.93 (1H, d, J = 8.7 Hz), 7.05 (1H, d, J = 7.6 Hz), 7.12 (2H, d, J = 8.5 Hz), 7.22 (1H, d, J = 7.6 Hz), 7.42 (2H, d, J = 8.5 Hz), 7.56 (1H, t, J = 7.6 Hz), 7.75 (2H, d, J = 8.2 Hz), 8.02 (2H, d, J = 8.2 Hz), 8.21 (1H, dd, J = 8.7 Hz, 2.8 Hz), 8.31 (1H, d, J = 2.8 Hz), 8.38 (1H, s).

2467
4-Cl₂Ph—
4-AcNHPh—
free
(DMSO-d₆) 2.02 (3H, s), 2.38 (4H, brs),

3.44 (2H, s), 3.55 (4H, brs), 7.14 (1H, d,

J = 8.8 Hz), 7.16 (2H, d, J = 8.7 Hz),

7.21 (2H, d, J = 8.4 Hz), 7.43 (2H, d, J =

8.7 Hz), 7.52 (2H, d, J = 8.4 Hz), 7.84 (1H,

d, J = 8.4 Hz), 7.95 (1H, dd, J = 8.4 Hz,

2.0 Hz), 8.22 (1H, d, J = 2.0 Hz), 8.23 (1H,

dd, J = 8.8 Hz, 2.6 Hz), 8.51 (1H, d, J =

2.6 Hz), 9.90 (1H, s), 10.59 (1H, s).

TABLE 386

Example

No.
Xb₅₇
R₁₀₉₀
R₁₀₉₁
Xb₅₈
Form

¹H NMR (solvent) δ ppm

2468
—NH—
—H

embedded image

—CH₂—
trihydro- chloride
(DMSO-d₆) 2.60-3.20 (7H, m), 3.22-3.60 (3H, m), 3.71 (3H, s), 4.10 (1H, d, J = 13.2 Hz), 4.30 (2H, d, J = 4.8 Hz), 4.48 (1H, d, J = 13.2 Hz). 6.05 (1H, t, J = 2.5 Hz), 6.32 (1H, dd, J = 3.6 Hz, 1.9 Hz), 6.87 (1H, t, J = 2.5 Hz), 7.04 (2H, d, J = 8.4 Hz), 7.06 (1H, d, J = 8.8 Hz), 7.29 (2H, d, J = 8.4 Hz), 7.93 (2H, d, J = 8.5 Hz), 8.19 (2H, d, J =8.5 Hz), 8.22 (1H, dd, J = 8.8 Hz, 2.6 Hz), 8.51 (1H, d, J = 2.6 Hz), 10.70 (1H, s).

2469
—NH—
—H
3-furylmethyl
—CH₂—
free
(CDCl₃) 2.25-2.45 (4H, m),

2.60 (2H, t, J = 7.7 Hz),

2.93 (2H, t, J = 7.7 Hz), 3.37

(2H, s), 3.40 (2H, t, J = 5.0 Hz),

3.60 (2H, t, J = 5.0 Hz), 6.37

(1H, d, J = 1.5 Hz), 6.93 (1H, d,

J = 8.8 Hz), 7.02 (2H, d, J = 8.6

Hz), 7.19 (2H, d, J = 8.6 Hz),

7.33 (1H, s), 7.39 (1H, t, J = 1.5

Hz), 7.73 (2H, d, J = 8.1 Hz),

8.01 (2H, d, J = 8.1 Hz),

8.21 (1H, dd, J = 8.8 Hz, 2.6

Hz), 8.28 (1H, d, J = 2.6 Hz),

8.46 (1H, s).

2470
—NH—
—H
furfuryl
—CH₂—
free
(CDCl₃) 2.31-2.52 (4H, m),

2.60 (2H, t, J = 7.2 Hz),

2.93 (2H, t, J = 7.2 Hz), 3.43

(2H, t, J = 5.0 Hz), 3.55 (2H, s),

3.63 (2H, t, J = 5.0 Hz),

6.21 (1H, d, J = 2.6 Hz),

6.32 (1H, d, J = 3.0 Hz),

6.94 (1H, d, J = 8.9 Hz),

7.02 (2H, d, J = 8.5 Hz),

7.19 (2H, d, J = 8.5 Hz),

7.38 (1H, d, J = 2.8 Hz),

7.74 (2H, d, J = 8.0 Hz), 8.00

(2H, d, J = 8.0 Hz), 8.21 (1H, dd,

J = 8.9 Hz, 2.5 Hz), 8.28 (1H, d,

J = 2.5 Hz), 8.35 (1H, s).

2471
none
—CH₃
piperonyl
—N(CH₃)—
free
(CDCl₃) 2.12 (3H, s), 2.42-

2.45 (4H, m), 3.03 (3H, s),

3.44 (2H, s), 3.47-3.52 (2H, m),

3.62-3.65 (2H, m), 4.09 (2H, s),

5.95 (2H, s), 6.54-6.59 (2H, m),

6.71-6.77 (2H, m), 6.85 (1H, s),

6.92-6.96 (2H, m), 7.75 (2H, d, J =

8.4 Hz), 7.87 (2H, d, J = 8.1

Hz), 8.17 (1H, dd, J = 8.6 Hz,

2.5 Hz), 8.58 (1H, d, J = 2.1 Hz).

TABLE 387

Example

No.
R₁₀₉₂
Xb₅₉
Xb₆₀
R₁₀₉₃

¹H NMR (DMSO-d₆) δppm

2472
3,4-Cl₂Ph—
—NH—
none
benzyl
1.55-1.82(4H, m), 1.96(2H, t, J =

10.5 Hz), 2.21-2.40(1H, m),

2.87(2H, d, J = 10.5 Hz), 3.47(2H,

s), 7.02(1H, d, J = 8.9 Hz),

7.05(2H, d, J = 9.1 Hz), 7.18-

7.42(5H, m), 7.62(2H, d, J = 9.1

Hz), 7.84(1H, d, J = 8.4 Hz),

7.94(1H, dd, J = 8.4 Hz, 2.0 Hz),

8.17(1H, dd, J = 8.9 Hz, 2.6 Hz),

8.22(1H, d, J = 2.0 Hz), 8.46(1H,

d, J = 2.6 Hz), 9.89(1H, s),

10.53(1H, s).

2473
3,4-Cl₂Ph—
—NH—
none
3-furylmethyl
1.55-1.85(4H, m), 1.85-2.07(2H,

m), 2.18-2.40(1H, m), 2.80-

3.00(2H, m), 3.32(2H, s), 6.44(1H,

s), 7.02(1H, d, J = 8.9 Hz),

7.05(2H, d, J = 8.9 Hz), 7.57(1H,

s), 7.57-7.66(1H, m), 7.62(2H, d, J =

8.9 Hz), 7.84(1H, d, J = 8.4 Hz),

7.94(1H, dd, J = 8.4 Hz, 2.0 Hz),

8.17(1H, dd, J = 8.9 Hz, 2.6 Hz),

8.22(1H, d, J = 2.0 Hz), 8.45(1H,

d, J = 2.6 Hz), 9.89(1H, s),

10.54(1H, s).

2474
4-CF₃Ph—
none
—N(CH₃)—
benzyl
1.50-2.30(6H, m), 2.84(5H, brs),

3.44(2H, brs), 4.27(1H, brs),

7.16(3H, d, J = 8.6 Hz), 7.18-

7.39(5H, m), 7.41(2H, d, J =

Hz), 7.95(2H, d, J = 8.1 Hz),

8.17(2H, d, J = 8.1 Hz), 8.27(1H,

dd, J = 8.9 Hz, 2.5 Hz), 8.56 (1H,

d, J = 2.5 Hz), 10.68(1H, s).

2475
4-CF₃Ph—
none
—N(CH₃)—
3-furylmethyl
1.50-2.20(6H, m), 2.83(3H, s),

2.72-3.02(2H, m), 3.30(2H, d, J =

3.5 Hz), 4.28(1H, brs), 6.41(1H, s),

7.15(1H, d, J = 8.8 Hz), 7.16(2H,

d, J = 8.4 Hz), 7.41(2H, d, J = 8.4

Hz)7.53 (1H, s) 7.60(1H, s),

7.95(2H, d, J = 8.1 Hz), 8.17(2H,

d, J = 8.1 Hz), 8.27(1H, dd, J = 8.8

Hz, 2.5 Hz), 8.55(1H, d, J = 2.5

Hz), 10.68 (1H, s).

TABLE 388

Example

No.
R₁₀₉₄

¹H NMR (CDCl₃) δppm

2476
cyclohexyl
1.00-1.40(5H, m), 1.52-1.70(1H, m), 1.70-1.92(4H, m), 2.21-2.40(1H,

m), 2.57 (4H, brs), 3.52(2H, brs), 3.73(2H, brs), 6.98(1H, d, J = 8.9

Hz), 7.13(2H, d, J = 8.8 Hz), 7.41(2H, d, J = 8.8 Hz), 7.76(2H, d, J =

8.2 Hz), 8.03(2H, d, J = 8.2 Hz), 8.19 (1H, dd, J = 8.9 Hz, 2.5 Hz),

8.33(1H, d, J = 2.5 Hz), 8.36(1H, brs).

2477

embedded image

1.40-1.85(4H, m), 2.38-2.60(1H, m), 2.57(4H, brs), 3.38(2H, t, J = 11.0 Hz), 3.72 (4H, brs), 4.03(2H, dd, J = 11.0 Hz, 3.5 Hz), 7.00(1H, d, J = 8.7 Hz), 7.15(2H, d, J = 8.7 Hz), 7.43(2H, d, J = 8.7 Hz), 7.77(2H, d, J = 8.5 Hz), 8.02(2H, d, J = 8.5 Hz), 8.16(1H, brs), 8.21(1H, dd, J = 8.7 Hz, 2.5 Hz), 8.32(1H, d, J = 2.5 Hz).

2478
cyclopropyl
0.33-0.58(4H, m), 1.45-1.72(1H, m), 2.62(4H, brs), 3.49(2H, brs),

3.68(2H, brs), 7.00(1H, d, J = 8.9 Hz), 7.15(2H, d, J = 8.4 Hz),

7.43(2H, d, J = 8.4 Hz), 7.77(2H, d, J = 8.4 Hz), 8.02(2H, d, J = 8.4

Hz), 8.21(1H, s), 8.21(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.33(1H, d, J = 2.6

Hz).

TABLE 389

Ex-

ample

¹H NMR

No.
Chemical structure
(solvent) δppm

2479

embedded image

(DMSO-d₆) 2.77-3.10 (2H, m), 3.17-3.63(4H, m), 3.71-3.89(1H, m), 4.18(2H, s), 4.24(2H, s), 4.27-4.44(1H, m), 6.07 (2H, s), 6.92-7.06(2H, m), 7.09(3H, d, J = 8.6 Hz), 7.22(1H, s), 7.28(2H, d, J = 8.6 Hz), 7.92(2H, d, J = 8.0 Hz), 8.18(2H, d, J = 8.0 Hz), 8.24(1H, dd, J = 8.8 Hz, 2.5 Hz), 8.53(1H, d, J = 2.5 Hz), 10.69(1H, s).

2480

embedded image

(CDCl₃) 2.25-2.52(4H, m), 2.77-2.95 (2H, m), 3.12-3.29(1H, m), 3.29- 3.46 (1H, m), 3.41(2H, s), 3.43-3.59(1H, m), 3.65-3.84(2H, m), 5.30 (1H, brs), 5.92 (2H, s), 6.73(2H, s), 6.84(1H, s), 6.95 (1H, d, J = 9.0 Hz), 7.05(2H, d, J = 8.4 Hz), 7.23(2H, d, J = 8.4 Hz), 7.75(2H, d, J = 8.1 Hz), 7.98(2H, d, J = 8.1 Hz), 8.03(1H, brs), 8.20(1H, dd, J = 9.0 Hz, 2.5 Hz), 8.22(1H, s).

2481

embedded image

(CDCl₃) 1.32-1.44(2H, m), 1.83-2.02 (3H, m), 2.30(2H, d, J = 6.8 Hz), 2.42-2.47(4H, m), 2.69 (2H, t, J = 12.0 Hz), 3.48-3.66(8H, m), 6.86- 6.99(6H, m), 7.25-7.32 (7H, m), 7.50(2H, d, J = 8.6 Hz), 7.98(1H, dd, J = 8.7 Hz, 2.6 Hz), 8.59 (1H, d, J = 2.0 Hz).

Example 2482
Production of N-(6-{4-[4-((1S,2S)-2-hydroxycyclohexyl)piperazine-1-carbonyl]phenoxy}pyridin-3-yl)-4-trifluoromethylbenzamide

To a solution of N-{6-[4-(piperazine-1-carbonyl)phenoxy]-pyridin-3-yl}-4-trifluoromethylbenzamide (430 mg, 0.91 mmol) in methanol was added 1,2-epoxycyclohexane (180 mg, 1.83 mmol), and the resulting solution was stirred for 1 day under reflux. The resulting reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=35:1), and then ethyl acetate was added. The precipitated white powder was filtered off and washed with ethyl acetate, to thereby yield 284 mg of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 1.03-1.38 (4H, m), 1.42-1.88 (3H, 2.06-2.35 (2H, m), 2.31 (2H, brs), 2.74 (2H, brs), 3.30-4.00 (6H, m), 7.00 (1H, d, J=8.9 Hz), 7.15 (2H, d, J=8.7 Hz), 7.43 (2H, d, J=8.7 Hz), 7.77 (2H, d, J=8.1 Hz), 8.02 (2H, d, J=8.1 Hz), 8.21 (1H, brs), 8.22 (1H, dd, J=8.9 Hz, 2.7 Hz), 8.33 (1H, d, J=2.7 Hz).

Example 2483
Production of 3,4-dichloro-N-[6-({4-[3-oxo-3-(4-piperonylpiperazin-1-yl)propyl]phenyl}methylamino)pyridin-3-yl]benzamide dioxalate

To a solution of 3,4-dichloro-N-(6-{4-[3-oxo-3-(4-piperonylpiperazin-1-yl)propyl]phenylamino}-pyridin-3-yl)benzamide (250 mg, 0.395 mmol) in methanol (3 mL) were added acetic acid (0.500 mL) and 37% aqueous formaldehyde (0.640 mL, 7.89 mmol), and the resulting solution was stirred for 30 minutes at 50° C. To the reaction solution was added sodium cyanoborohydride (0.160 g, 2.55 mmol) at room temperature, and stirred for 8 hours at 50° C. Water was added to the reaction solution and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=10:1), to yield a free form. This free form was dissolved in isopropanol (5 mL) and oxalic acid dihydrate (70 mg, 0.555 mmol) by heating. The solvent was evaporated, and the resulting solid was recrystallized from isopropanol, to thereby yield 0.193 g of the title compound.

Appearance: Pale yellow powder

Melting point: 127-129° C.

The following compound was produced in the same manner as in Example 2483.

Example 2484
2-(Ethyl{4-[5-(4-trifluoromethylphenoxymethyl)pyridin-2-yloxy]phenyl}amino)-1-(4-piperonylpiperazin-1-yl)ethanone

¹H NMR (CDCl₃) δ 1.18 (3H, t, J=7.1 Hz), 2.41-2.44 (4H, m), 3.39-3.47 (4H, m), 3.51 (2H, brs), 3.64 (2H, brs), 4.03 (2H, s), 5.03 (2H, s), 5.94 (2H, s), 6.68 (2H, d, J=9.1 Hz), 6.73-6.74 (2H, m), 6.85-6.88 (2H, m), 6.99 (2H, d, J=9.1 Hz), 7.01 (2H, d, J=8.4 Hz), 7.55 (2H, d, J=8.7 Hz), 7.71 (1H, dd, J=8.6 Hz, 2.5 Hz), 8.22 (1H, d, J=2.3 Hz).

Example 2485
Production of 3,4-dichloro-N-[6-(4-thiomorpholine-4-ylmethylphenoxy)pyridin-3-yl]benzamide monohydrochloride

3,4-dichloro-N-[6-(4-chloromethylphenoxy)pyridin-3-yl]benzamide (0.61 g, 1.5 mmol) was dissolved in DMF (5 mL). To the resulting solution were added triethylamine (0.84 mL, 6.0 mmol) and thiomorpholine (0.15 mL, 1.5 mmol), and this solution was stirred overnight at 40° C. The resulting reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate and washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate and evaporated. This residue was purified by silica gel column chromatography (chloroform:methanol=80:1). The obtained solid (0.56 g, 1.18 mmol) was dissolved in ethyl acetate (50 mL), and a solution of 4 N hydrogen chloride in ethyl acetate (0.295 mL, 1.18 mmol) was added, and this solution was stirred for 1 hour at room temperature. The precipitated crystals were collected by suction filtration, and recrystallized from methanol, to thereby yield 0.38 g of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 2.80-2.83 (2H, m), 3.09-3.17 (4H, m), 3.61 (2H, m), 4.35 (2H, s), 7.14 (1H, d, J=8.9 Hz), 7.21 (2H, d, J=8.3 Hz), 7.60 (2H, d, J=8.3 Hz), 7.85 (1H, d, J=8.6 Hz), 7.96 (1H, dd, J=8.3 Hz, 2.0 Hz), 8.23 (1H, dd, J=8.9 Hz, 2.6 Hz), 8.24 (1H, d, J=2.0 Hz), 8.53 (1H, d, J=2.6 Hz), 10.45 (1H, brs), 10.62 (1H, brs).

The following compounds were produced in the same manner as in Example 2485.

Example 2486
3,4-Dichloro-N-(4-{4-[1-(3-imidazole-1-ylpropyl)-1,2,3,6-tetrahydropyridine-4-yl]phenoxy}phenyl)benzamide

Melting point: 169-171° C.

TABLE 390

Ex-

ample

mp

No.
R₁₀₉₅
Xb₆₁
R₁₀₉₆
Form
(° C.)

2487
—F
—CH₂—
benzyl
dihydro-
178-179

chloride

2488
—F
—CH₂—
piperonyl
dihydro-
192-195

chloride

2489
—F
—(CH₂)₂—
benzyl
dihydro-
208-210

chloride

2490
—F
—(CH₂)₂—
piperonyl
dihydro-
202-205

chloride

2491
—F
—(CH₂)₃—
benzyl
dihydro-
260-262

chloride

2492
—F
—(CH₂)₃—
piperonyl
dihydro-
258-260

chloride

2493
—F
—(CH₂)₄—
benzyl
dihydro-
245-248

chloride

2494
—F
—(CH₂)₄—
piperonyl
dihydro-
256-258

chloride

2495
—H
none

embedded image

free
172-173

2496
—H
none

embedded image

free
131-134

TABLE 391

Example

No.
M
Form
mp (° C.)

2497
1
hydrochloride
165-168

2498
2
free
143-144

2499
3
oxalate
173-175

2500
4
hydrochloride
226-228

TABLE 392

Example

No.
M
mp (° C.)

2501
1
183-185

2502
4
141-143

TABLE 393

Example

No.
R₁₀₉₇
R₁₀₉₈
M
Form

¹H NMR (solvent) δppm

2503
3,4-Cl₂Ph—
piperidino
1
free
(CDCl₃) 1.42-1.58(6H, m), 2.36-2.38(4H,

m), 3.44(2H, s), 6.86(1H, d, J = 8.9 Hz),

6.99(2H, dd, J = 6.6 Hz, 2.0 Hz), 7.26-

7.31(2H, m), 7.47(1H, d, J = 8.3 Hz),

7.67(1H, dd, J = 8.3 Hz, 2.0 Hz),

7.94(1H, d, J = 2.3 Hz), 8.10(1H, dd, J =

8.9 Hz, 2.6 Hz), 8.21(1H, d, J = 2.6 Hz),

8.69(1H, brs).

2504
3,4-Cl₂Ph—
piperidino
3
dihydro-
(DMSO-d₆) 1.67-1.77(6H, m), 1.99-2.10

chloride
(2H, m), 2.61-3.05 (6H, m), 3.40-3.43(2H,

m), 6.01(1H, brs), 7.04-7.08(3H, m),

7.28(2H, d, J = 8.6 Hz), 7.84(1H, d, J =

8.4 Hz), 7.96-8.00 (1H, m), 8.19-8.23(1H,

m), 8.26(1H, d, J = 1.9 Hz), 8.51 (1H, d, J =

2.7 Hz), 10.24(1H, brs), 10.67(1H, s).

2505
3,4-Cl₂Ph—
piperidino
4
free
(CDCl₃) 1.40-1.50(2H, m), 1.50-1.75(8H,

m), 2.25-2.50 (6H, m), 2.63(2H, t, J = 7.0

Hz), 6.93(1H, d, J = 9.0 Hz), 7.03(2H, d,

J = 8.5 Hz), 7.19(2H, d, J = 8.5 Hz),

7.58(1H, d, J = 8.5 Hz), 7.71(1H, dd, J =

8.5 Hz, 2.0 Hz), 7.82(1H, s), 7.98(1H, d, J =

2.0 Hz), 8.16(1H, dd, J = 9.0 Hz, 3.0

Hz), 8.25(1H, d, J = 3.0 Hz).

2506
3,4-Cl₂Ph—
piperidino
5
free
(CDCl₃) 1.20-1.80(12H, m), 2.31(2H, t, J =

7.8 Hz), 2.40 (4H, brs), 2.61(2H, t, J =

7.8 Hz), 6.94(1H, d, J = 8.8 Hz), 7.04(2H,

d, J = 8.4 Hz), 7.20(2H, d, J = 8.4 Hz),

7.71(1H, dd, J = 8.2 Hz, 2.0 Hz),

7.98(1H, d, J = 2.3 Hz), 8.16(1H, dd, J =

8.8 Hz, 2.8 Hz), 8.24(1H, d, J = 2.8 Hz).

2507
4-CF₃Ph—
morpholino
1
free
(DMSO-d₆) 2.37(4H, t, J = 4.6 Hz), 3.46

(2H, s), 3.59(4H, t, J = 4.6 Hz), 7.07(3H,

d, J = 8.6 Hz), 7.33(2H, d, J = 8.6 Hz),

7.93(2H, d, J = 8.6 Hz), 8.15-8.24(3H, m),

8.51(1H, d, J = 2.6 Hz), 10.63(1H, s).

2508
3,4-Cl₂Ph—
morpholino
1
free
(CDCl₃) 2.56(4H, t, J = 4.6 Hz), 3.60(2H,

s), 3.82(4H, t J = 4.6 Hz), 7.05(1H, d, J =

8.6 Hz), 7.18(2H, dd, J = 6.6 Hz, 2.0 Hz),

7.45(2H, d, J = 8.6 Hz), 7.67(1H, d, J =

8.6 Hz), 7.80(1H, dd, J = 83 Hz, 2.0 Hz),

7.99(1H, brs), 8.07(1H, d, J = 2.0 Hz),

8.25-8.29(1H, m), 8.35(1H, d, J = 2.6 Hz).

2509
3,4-Cl₂Ph—
morpholino
2
free
(CDCl₃) 2.54-2.85(8H, m), 3.74-3.78(4H,

m), 6.95(1H, d, J = 8.9 Hz), 7.04-7.07(2H,

m), 7.22-7.26(2H, m), 7.58(1H, d, J = 8.6

Hz), 7.68-7.72(1H, m), 7.79(1H, brs),

7.98(1H, d, J = 2.0 Hz), 8.17(1H, dd, J =

8.9 Hz, 2.6 Hz), 8.24(1H, d, J = 2.6 Hz).

2510
3,4-Cl₂Ph—
morpholino
3
free
(CDCl₃) 1.78-1.83(2H, m), 2.34-2.45(6H,

m), 2.60-2.66 (2H, m), 3.70-3.73(4H, m),

6.88(1H, d, J = 8.6 Hz), 7.00 (2H, d, J =

8.6 Hz), 7.18(2H, d, J = 8.6 Hz), 7.51(1H,

d, J = 8.6 Hz), 7.66-7.70(1H, m), 7.94(1H,

d, J = 2.2 Hz), 8.10-8.14(1H, m), 8.22(1H,

d, J = 2.7 Hz), 8.40(1H, brs).

TABLE 394

Example

No.
R₁₀₉₉
M
Form

¹H NMR (solvent) δppm

2511
morpholino
4
dihydro-
(DMSO-d₆) 1.55-1.90(4H, m), 2.63(2H, t, J = 7.2 Hz),

chloride
2.90-3.20(4H, m), 3.30-3.50(2H, m), 3.79(2H, t, J = 11.2

Hz) 3.93(2H, s), 7 04(2H, d, J = 8.2 Hz), 7.05(1H, d, J =

9.0 Hz), 7.26(2H, d, J = 8.2 Hz), 7.84(1H, d, J = 8.2 Hz),

7.98(1H, dd, J = 8.2 Hz, 2.0 Hz), 8.20(1H, dd, J = 9.0

Hz, 2.7 Hz), 8.25(1H, d, J = 2.0 Hz), 8.50(1H, d, J = 2.7

Hz), 10.65(1H, s).

2512
morpholino
5
free
(CDCl₃) 1.30-1.45(2H, m), 1.45-1.75(4H, m), 2.33(2H, t,

J = 7.2 Hz), 2.44(4H, t, J = 4.6 Hz), 2.62(2H, t, J = 7.7

Hz), 3.72(4H, t, J = 4.6 Hz), 6.94(1H, d, J = 9.0 Hz),

7.04(2H, d, J = 8.5 Hz), 7.20(2H, d, J = 8.5 Hz),

7.58(1H, d, J = 8.2 Hz), 7.65-7.75(2H, m), 7.98(1H, d, J =

2.0 Hz), 8.16 (1H, dd, J = 9.0 Hz, 2.6 Hz), 8.24(1H, d,

J = 2.6 Hz).

2513

embedded image

3
free
(CDCl₃) 1.97-2.03(2H, m), 2.67(2H, t, J = 7.6 Hz), 3.68- 3.73(2H, m), 3.88(2H, s), 6.95(1H, d, J = 8.9 Hz), 7.05(2H, d, J = 8.6 Hz), 7.21(2H, d, J = 8.6 Hz), 7.56(1H, d, J = 8.3 Hz), 7.69-7.74(2H, m), 7.98(1H, d, J = 2.3 Hz), 8.14-8.18(1H, m), 8.23(1H, d, J = 3.0 Hz).

2514

embedded image

1
free
(DMSO-d₆) 5.20(2H, s), 6.91(1H, s), 7.07(1H, d, J = 8.6 Hz), 7.10(2H, d, J = 8.6 Hz), 7.22(1H, s), 7.31(2H, d, J = 8.6 Hz), 7.77(1H, s), 7.84 (1H, d, J = 8.6 Hz), 7.94(1H, dd, J = 8.6 Hz, 2.0 Hz), 8.19(1H, dd, J = 8.6 Hz, 2.3 Hz), 8.22(1H, d, J = 2.0 Hz), 8.46(1H, d, J = 2.3 Hz), 10.57 (1H, s).

2515

embedded image

1
hydro- chloride
(DMSO-d₆) 5.48(2H, s), 7.09(1H, d, J = 8.5 Hz), 7.12(2H, d, J = 8.6 Hz), 7.38(2H, d, J = 8.6 Hz), 7.83(1H, d, J = 8.5 Hz), 7.98(1H, dd, J = 8.5 Hz, 2.0 Hz), 8.23(1H, dd, J = 8.5 Hz, 2.3 Hz), 8.26(1H, s), 8.26(1H, d, J = 2.0 Hz), 8.51(1H, d, J = 2.3 Hz), 9.05(1H, s), 10.70(1H, s).

2516

embedded image

1
free
(DMSO-d₆) 5.63(2H, d, J = 8.6 Hz), 7.09(1H, d, J = 8.6 Hz), 7.11(2H, d, J = 8.6 Hz), 7.36(2H, d, J = 8.6 Hz), 7.76(1H, d, J = 1.0 Hz), 7.84(1H, d, J = 8.3 Hz), 7.94(1H, dd, J = 8.3 Hz, 2.0 Hz), 8.20(1H, dd, J = 8.6 Hz, 2.6 Hz), 8.23(2H, s), 8.46(1H, d, J = 2.6 Hz), 10.55(1H, s).

2517

embedded image

1
hydro- chloride
(DMSO-d₆) 5.66(2H, s), 7.09(1H, d, J = 8.6 Hz), 7.10(2H, d, J = 8.6 Hz), 7.32(2H, d, J = 8.6 Hz), 7.83(2H, s), 7.83(1H, d, J = 8.5 Hz), 7.96 (1H, dd, J = 8.5 Hz, 2.0 Hz), 8.21(1H, dd, J = 8.5 Hz, 2.3 Hz), 8.23(1H, d, J = 2.0 Hz), 8.47(1H, d, J = 2.3 Hz), 10.61(1H, s).

2518

embedded image

1
hydro- chloride
(DMSO-d₆) 5.34(2H, s), 6.28(1H, t, J = 2.0 Hz), 7.06(1H, d, J = 9.0 Hz), 7.07(2H, d, J = 8.6 Hz), 7.26(2H, d, J = 8.6 Hz), 7.47(1H, d, J = 2.0 Hz), 7.83(1H, d, J = 8.6 Hz), 7.85(1H, d, J = 2.0 Hz), 7.96(1H, dd, J = 8.6 Hz, 2.0 Hz), 8.20(1H, dd, J = 9.0 Hz, 2.6 Hz), 8.23(1H, d, J = 2.0 Hz), 8.47(1H, d, J = 2.6 Hz,) 10.61(1H, s),

2519

embedded image

2
free
(CDCl₃) 3.04(2H, t, J = 7.0 Hz), 4.17(2H, t, J = 7.0 Hz), 6.87(1H, t, J = 1.3 Hz), 6.94(1H, d, J = 8.7 Hz), 7.02(1H, brs), 7.05(4H, s), 7.30(1H, brs), 7.56(1H, d, J = 8.3 Hz), 7.75(1H, dd, J = 8.3 Hz, 2.1 Hz), 8.03(1H, d, J = 2.1 Hz), 8.17(1H, dd, J = 8.7 Hz, 2.3 Hz), 8.23(1H, d, J = 2.3 Hz), 8.61(1H, brs).

TABLE 395

Example

No.
R₁₁₀₀
R₁₁₀₁

¹H NMR (solvent) δppm

2520
4-ClPh—
piperonyl
(CDCl₃) 2.48(8H, brs), 3.42(2H, s), 3.50(2H, s), 5.93(2H,

s), 6.74 (2H, s), 6.85(1H, s), 6.94(1H, d, J = 8.6 Hz),

7.07(2H, d, J = 8.6 Hz), 7.33(2H, d, J = 8.6 Hz), 7.49(2H,

d, J = 8.6 Hz), 7.73(1H, brs), 7.82(2H, d, J = 8.6 Hz),

8.18-8.24(2H, m).

2521
4-CNPh—
piperonyl
(CDCl₃) 2.48(8H, brs), 3.42(2H, s), 3.51(2H, s), 5.93(2H,

s), 6.73-6.74(2H, m), 6.85(1H, s), 6.96(1H, d, J = 8.9 Hz),

7.07(2H, d, J = 8.6 Hz), 7.34(2H, d, J = 8.6 Hz), 7.79-

7.82(3H, m), 7.99(2H, d, J = 8.2 Hz), 8.19(1H, dd, J =

8.9 Hz, 2.6 Hz), 8.26(1H, d, J = 2.6 Hz).

2522
3,4-Cl₂Ph—
benzyl
(CDCl₃) 2.51(8H, brs), 3.52(2H, s), 3.53(2H, s)6.95(1H,

d, J = 8.9 Hz), 7.07(2H, d, J = 8.2 Hz), 7.26-7.36(7H, m),

7.59(1H, d, J = 8.6 Hz), 7.69-7.73(2H, m), 7.99(1H, d, J =

2.0 Hz), 8.18(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.25(1H, d, J =

2.6 Hz).

2523
3,4-Cl₂Ph—
—COOC(CH₃)₃
(CDCl₃) 1.46(9H, s), 2.40(4H, t, J = 5.0 Hz), 3.43(4H, t, J =

5.0 Hz), 3.50(2H, s), 6.95(1H, d, J = 8.9 Hz), 7.08(2H,

d, J = 8.6 Hz), 7.34 (2H, d, J = 8.6 Hz), 7.57(1H, d, J =

8.3 Hz), 7.70-7.74(1H, m), 8.00 (1H, d, J = 2.0 Hz),

8.07(1H, brs), 8.17-8.21(1H, m), 8.27(1H, d, J = 2.6 Hz).

2524
3,4-Cl₂Ph—
—C₂H₅
(CDCl₃) 1.08(3H, t, J = 7.3 Hz), 2.38-2.49(10H, m),

3.48(2H, s), 6.88(1H, d, J = 8.9 Hz), 7.01(2H, d, J = 8.3

Hz), 7.30(2H, d, J = 8.6 Hz), 7.49(1H, d, J = 8.3 Hz),

7.66-7.70(1H, m), 7.95(1H, d, J = 2.0 Hz), 8.13(1H, dd, J =

8.9 Hz, 2.6 Hz), 8.23(1H, d, J = 2.6 Hz), 8.58 (1H, brs).

2525
3,4-Cl₂Ph—
—Ph
(CDCl₃) 2.64(4H, t, J = 5.0 Hz), 3.22(4H, t, J = 5.0 Hz),

3.57(2H, s), 6.83-6.88(1H, m), 6.92-6.99(3H, m),

7.10(2H, d, J = 8.6 Hz), 7.23-7.29(2H, m), 7.39(2H, d, J =

8.6 Hz), 7.59(1H, d, J = 8.6 Hz), 7.71(1H, dd, J = 8.3

Hz, 2.0 Hz), 7.76(1H, s), 7.99(1H, d, J = 2.0 Hz),

8.19(1H, dd, J = 8.6 Hz, 2.6 Hz), 8.26(1H, d, J = 2.6 Hz).

2526
4-CF₃Ph—
—COOC(CH₃)₃
(DMSO-d₆) 1.40(9H, s), 2.32-2.36(4H, m), 3.30-3.35(4H,

m), 3.49 (2H, s), 7.06-7.09(3H, m), 7.32-7.36(2H, m),

7.94(2H, d, J = 8.4 Hz), 8.18(2H, d, J = 8.1 Hz), 8.24(1H,

dd, J = 8.9 Hz, 2.7 Hz), 8.52 (1H, d, J = 2.7 Hz),

10.64(1H, s).

2527
3,4-Cl₂Ph—
—CH₃
(CDCl₃) 2.27(3H, s), 2.45(8H, brs), 3.47(2H, s), 6.87(1H,

d, J = 8.9 Hz), 6.99-7.03(2H, m), 7.27-7.31(2H, m),

7.48(1H, dd, J = 8.3 Hz, 2.6 Hz), 7.68(1H, dd, J = 8.6

Hz, 2.0 Hz), 7.94(1H, d, J = 2.0 Hz), 8.12(1H, dd, J = 8.9

Hz, 2.6 Hz), 8.23(1H, d, J = 2.6 Hz), 8.76(1H, brs).

2528
3,4-Cl₂Ph—
piperonyl
(CDCl₃) 2.47(8H, brs), 3.42(2H, s), 3.49(2H, s), 5.93(2H,

s), 6.73 (2H, d, J = 0.7 Hz), 6.84(1H, s), 6.91(1H, d, J =

8.9 Hz), 7.04(2H, d, J = 8.6 Hz), 7.31(2H, d, J = 8.6 Hz),

7.53(1H, d, J = 8.2 Hz), 7.70 (1H, dd, J = 8.3 Hz, 2.0

Hz), 7.97(1H, d, J = 2.3 Hz), 8.13-8.18(1H, m), 8.24(2H,

d, J = 2.6 Hz).

TABLE 396

Example

No.
R₁₁₀₂
Xb₆₂
R₁₁₀₃
Form

¹H NMR (solvent) δppm

2529
3,4-Cl₂Ph—
—(CH₂)₂—
piperonyl
free
(CDCl₃) 1.97-2.01(2H, m), 2.85-

2.90(8H, m), 3.68(2H, s),

3.75(2H, s), 5.95(2H, s), 6.74-

6.84(2H, m), 6.94-6.97(2H, m),

7.08(2H, d, J = 8.6 Hz),

7.41(2H, d, J = 8.6 Hz),

7.57(1H, d, J = 8.6 Hz),

7.75(1H, dd, J = 8.6 Hz, 2.3

Hz), 8.01-8.02(2H, m), 8.20(1H,

dd, J = 8.9 Hz, 2.6 Hz),

8.31(1H, d, J = 2.6 Hz).

2530
3,4-Cl₂Ph—
—(CH₂)₂—
benzyl
trihydro-
(DMSO-d₆) 2.25(2H, brs), 3.38

chloride
(4H, brs), 3.78(4H, brs), 4.38

(4H, s), 7.12-7.22(3H, m), 7.46-

7.48(3H, m), 7.62-7.67 (4H, m),

7.84(1H, d, J = 8.6 Hz), 7.98

(1H, dd, J = 8.6 Hz, 2.0 Hz),

8.22-8.27(2H, m), 8.55 (1H, d, J =

2.6 Hz), 10.68(1H, s).

2531
3,4-Cl₂Ph—
—CO—
benzyl
free
(CDCl₃) 2.66(2H, t, J = 5.9 Hz),

3.22-3.25(4H, m), 3.55(2H, s),

4.60(2H, s), 6.95(1H, d, J = 8.9

Hz), 7.08(2H, d, J = 8.6 Hz),

7.23-7.35(7H, m), 7.56(1H, d, J =

8.3 Hz), 7.72(1H, dd, J = 2.0

Hz, 8.6 Hz), 8.00(1H, d, J = 2.0

Hz), 8.10(1H, s), 8.18(1H, dd, J =

2.6 Hz, 8.6 Hz), 8.28 (1H, d, J =

2.6 Hz).

2532
4-CF₃Ph—
—CH₂—

embedded image

free
(CDCl₃) 2.61(4H, brs), 3.38(4H, brs), 3.55(2H, s), 6.85-6.94(3H, m), 7.06-7.14 (4H, m), 7.36(2H, d, J = 8.3 Hz), 7.64(2H, d, J = 8.3 Hz), 7.70-7.75(4H, m), 7.99 (2H, t, J = 8.3 Hz), 8.24(1H, dd, J = 8.7 Hz, 2.5 Hz), 8.40(1H, d, J = 2.6 Hz), 9.19 (1H, s).

2533
4-CF₃Ph—
—CH₂—

embedded image

free
(CDCl₃) 2.58-2.62(4H, m), 3.14- 3.17(4H, m), 3.54(2H, s), 3.86(2H, s), 6.83-7.14 (11H, m), 7.36(2H, d, J = 8.4 Hz), 7.71 (2H, d, J = 8.3 Hz), 7.96(2H, d, J = 8.1 Hz), 8.15-8.26(3H, m).

TABLE 397

Example

No.
R₁₁₀₄
R₁₁₀₅
M

¹H NMR (CDCl₃) δppm

2534
3,4-Cl₂Ph—
CH₃
2
2.30(3H, s), 2.50-2.81(12H, m), 6.86(1H, d, J =

8.6 Hz), 6.98 (2H, d, J = 8.6 Hz), 7.18(2H, d, J =

8.3 Hz), 7.47(1H, d, J = 8.3 Hz), 7.67(1H, dd, J =

8.3 Hz, 2.0 Hz), 7.94(1H, d, J = 2.0 Hz), 8.11(1H,

dd, J = 8.9 Hz, 2.6 Hz), 8.21(1H, d, J = 2.6 Hz),

8.66 (1H, brs).

2535
3,4-Cl₂Ph—
piperonyl
2
2.51-2.83(12H, m), 3.43(2H, s), 5.93(2H, s) 6.74

(2H, d, J = 1.0 Hz), 6.86-7.03(4H, m), 7.20(2H, d,

J = 8.3 Hz), 7.53(1H, d, J = 8.6 Hz), 7.68-

7.72(1H, m), 7.97(1H, d, J = 2.0 Hz), 8.15(1H, dd,

J = 8.9 Hz, 2.6 Hz), 8.23(2H, d, J = 2.6 Hz).

2536
3,4-Cl₂Ph—
—CH₃
3
1.78-1.84(2H, m), 2.29(3H, s), 2.36-2.48(10H, m),

2.59-2.65 (2H, m), 6.89(1H, d, J = 8.4 Hz),

(2H, d, J = 8.4 Hz), 7.18 (2H, d, J = 8.4 Hz),

7.00(2H, d, J = 8.4 Hz), 7.18 (2H, d, J = 8.4 Hz),

7.52(1H, d, J = 8.6 Hz), 7.67-7.71(1H, m),

7.96(1H, d, J = 2.2 Hz), 8.11-8.15(1H, m),

8.23(1H, d, J = 2.7 Hz), 8.31(1H, brs).

2537
3,4-Cl₂Ph—
piperonyl
3
1.78-1.84(2H, m), 2.36-2.47(10H, m), 2.60-2.65

(2H, m), 3.41 (2H, s), 5.93(2H, s), 6.73(2H, d, J =

0.8 Hz), 6.85(1H, s), 6.91 (1H, d, J = 8.9 Hz),

7.02(2H, d, J = 8.4 Hz), 7.19(2H, d, J = 8.6 Hz),

7.55(1H, d, J = 8.1 Hz), 7.68-7.71(1H, m), 7.96-

7.97(2H, m), 8.I4-8.17(1H, m), 8.23(1H, d, J =

2.7 Hz).

2538
4-CF₃Ph—
—COOC(CH₃)₃
3
1.46(9H, s), 1.78-1.89(2H, m), 2.36-2.42(6H, m),

2.62-2.68 (2H, m), 3.42-3.45(4H, m), 6.94(1H, d,

J = 8.9 Hz), 7.01-7.06 (2H, m), 7.18-7.23(2H, m),

7.76(2H, d, J = 8.2 Hz), 7.99-8.03 (3H, m),

8.22(1H, dd, J = 8.9 Hz, 2.6 Hz), 8.28(1H, d, J =

2.6 Hz).

2539
3,4-Cl₂Ph—
—CH₃
4
1.50-1.80(4H, m), 2.32(3H, s), 2.38(2H, t, J = 7.3

Hz), 2.30-2.70(8H, m), 2.64(2H, t, J = 7.3 Hz),

6.94(1H, d, J = 8.8 Hz), 7.03(2H, d, J = 8.2 Hz),

7.19(2H, d, J = 8.2 Hz), 7.58(1H, d, J = 8.2 Hz),

7.72(1H, dd, J = 8.2 Hz, 2.0 Hz), 7.84(1H, s),

8.00(1H, d, J = 2.0 Hz), 8.18(1H, dd, J = 8.8 Hz,

2.6 Hz), 8.26 (1H, d, J = 2.6 Hz).

2540
3,4-Cl₂Ph—
benzyl
4
1.45-1.75(4H, m), 2.36(2H, t, J = 7.5 Hz), 2.30-

2.65(8H, m), 2.62(2H, t, J = 7.7 Hz), 3.51(2H, s),

6.92(1H, d, J = 8.6 Hz), 7.03(2H, d, J = 8.6 Hz),

7.19(2H, d, J = 8.6 Hz), 7.15-7.40(5H, m),

7.57(1H, d, J = 8.2 Hz), 7.71(1H, dd, J = 8.2 Hz,

2.0 Hz), 7.85(1H, s), 7.98(1H, d, J = 2.0 Hz),

8.16(1H, dd, J = 8.6 Hz, 2.5 Hz), 8.24(1H, d, J =

2.5 Hz).

2541
3,4-Cl₂Ph—
benzyl
5
1.25-1.45(2H, m), 1.45-1.75(4H, m), 2.34(2H, t, J =

7.7 Hz), 2.30-2.70(8H, m), 2.61(2H, t, J = 7.7

Hz), 3.51(2H, s), 6.93(1H, d, J = 8.7 Hz),

7.03(2H, d, J = 8.6 Hz) 7.19(2H, d, J = 8.6 Hz),

7.20-7.40(5H, m), 7.58(1H, d, J = 8.3 Hz),

7.70(1H, dd, J = 8.3 Hz, 2.0 Hz), 7.71(1H, d, J =

2.0 Hz), 7.98(1H, d, J = 2.0 Hz), 8.16(1H, dd, J =

8.7 Hz 2.6 Hz) 8.24(1H, d, J = 2.6 Hz).

TABLE 398

Example

No.
R₁₁₀₆
R₁₁₀₇
Form

¹H NMR (DMSO-d₆) δppm

2542
3,4-Cl₂Ph—
—H
hydro-
1.12(3H, d, J = 6.3 Hz), 2.75-3.03(2H,

chloride
m), 3.24-3.39(2H, m), 3.78-3.98(3H, m),

4.31(2H, brs), 7.13(1H, d, J = 8.6 Hz),

7.20 (2H, d, J = 8.3 Hz), 7.63(2H, d, J =

8.3 Hz) 7.84(1H, d, J = 8.2 Hz),

7.98(1H, dd, J = 8.2 Hz, 2.6 Hz),

8.24(1H, dd, J = 8.9 Hz, 2.6 Hz),

8.25(1H, d, J = 2.0 Hz), 8.55(1H, d, J =

2.6 Hz), 10.67(1H, brs), 11.10(1H, brs).

2543
3,4-Cl₂Ph—
—O(CH₂)₃CH₃
hydro-
0.87(3H, t, J = 7.3 Hz), 1.22-1.36(2H,

chloride
m), 1.41-1.51(2H, m), 2.90-3.07(2H, m),

3.23-3.50(6H, m), 3.80-3.88(1H, m),

3.99-4.02(2H, m), 4.35(2H, brs),

7.13(1H, d, J = 8.9 Hz), 7.21 (2H, d, J =

8.6 Hz), 7.63(2H, d, J = 8.3 Hz),

7.84(1H, d, J = 8.6 Hz), 7.97(1H, dd, J =

8.3 Hz 2.0 Hz), 8.24(1H, dd, J = 8.9 Hz,

2.6 Hz), 8.25(1H, d, J = 2.0 Hz),

8.54(1H, d, J = 2.6 Hz), 10.66(1H, brs),

11.17(1H, brs).

2544
3,4-Cl₂Ph—
piperidino
dihydro-
1.38-1.77(6H, m), 2.92-3.10(5H, m),

chloride
3.22-3.33(4H, m), 3.47-3.51(1H, m),

3.97-4.06(2H, m), 4.27-4.55(3H, m), 7.13

(1H, d, J = 8.9 Hz), 7.21(2H, d, J = 8.6

Hz), 7.67(2H, d, J = 8.6 Hz), 7.84(1H, d,

J = 8.6 Hz), 7.99(1H, dd, J = 8.2 Hz, 2.0

Hz), 8.26(1H, dd, J = 8.6 Hz, 3.0 Hz),

8.28(1H, d, J = 2.3 Hz), 8.57(1H, d, J =

2.6 Hz), 10.27(1H, brs), 10.74(1H, brs),

11.91 (1H, brs).

2545
4-CF₃Ph—
—H
hydro-
1.12(3H, d, J = 6.1 Hz), 2.68-2.80(1H,

chloride
m), 2.98-3.06(1H, m), 3.24-3.28(2H, m),

3.80-3.90(3H, m), 4.31(2H, brs),

7.14(1H, d, J = 8.7 Hz), 7.21(2H, d, J =

8.4 Hz), 7 64(2H, d, J = 8.1 Hz),

7.93(2H, d, J = 8.4 Hz), 8.19(2H, d, J =

8.2 Hz), 8.27(1H, dd, J = 8.9 Hz, 2.6

Hz), 8.57(1H, d, J = 2.6 Hz), 10.75(1H,

brs), 11.19(1H, brs).

2546
4-CF₃Ph—
—OCH₃
hydro-
2.92-3.12(2H, m), 3.26(3H, s), 3.34.

chloride
3.47(4H, m), 3.80-4.02 (3H, m), 4.34(2H,

brs), 7.14(1H, d, J = 8.9 Hz), 7.21(2H, d,

J = 8.6 Hz), 7.63(2H, d, J = 8.2 Hz),

7.94(2H, d, J = 8.4 Hz), 8.18 (2H, d, J =

8.1 Hz), 8.27(1H, dd, J = 8.7 Hz, 2.6

Hz), 8.57(1H, d, J = 2.6 Hz), 10.73(1H,

brs), 11.13(1H, brs).

2547
3,4-Cl₂Ph—
—OCH₃
hydro-
2.92-3.11(2H, m), 3.26(3H, s), 3.31-

chloride
3.52(4H, m), 3.79-3.87 (1H, m), 3.95-

4.04(2H, m), 4.34(2H, brs), 714(1H, d, J =

8.9 Hz), 7.21(2H, d, J = 8.6 Hz),

7.62(2H, d, J = 8.6 Hz), 7.84(1H, d, J =

8.4 Hz), 7.97(1H, dd, J = 8.4 Hz, 2.2

Hz), 8.24-8.26(2H, m), 8.54(1H, d, J =

2.6 Hz), 10.66(1H, brs), 11.02(1H, brs).

TABLE 399

Example

No.
R₁₁₀₈
M
Form

¹H NMR (solvent) δppm

2548

embedded image

5
free
(CDCl₃) 1.30-1.45(2H, m), 1.45-1.75(4H, m), 2.30(3H, s), 2.25-2.40 (2H, m), 2.49(8H, brs), 2.62(2H, t, J = 7.5 Hz), 6.94(1H, d, J = 8.9 Hz), 7.04(2H, d, J = 8.6 Hz), 7.20(2H, d, J = 8.6 Hz), 7.59(1H, d, J = 8.2 Hz), 7.65-7.75(2H, m), 7.98(1H, d, J = 2.0 Hz), 8.17(1H, dd, J = 8.9 Hz, 3.0 Hz), 8.24(1H, d, J = 3.0 Hz).

2549

embedded image

1
hydro- chloride
(DMSO-d₆) 1.13(6H, d, J = 6.6 Hz), 2.66-2.76(2H, m), 3.25-3.34 (2H, m), 3.91-3.99(2H, m), 4.30(2H, s), 7.14(1H, d, J = 8.6 Hz), 7.21 (2H, d, J = 8.6 Hz), 7.62(2H, d, J = 8.3 Hz), 7.85(1H, d, J = 8.6 Hz), 7.97(1H, dd, J = 8.6 Hz, 2.0 Hz), 8.24(1H, dd, J = 8.6 Hz, 3.0 Hz), 8.25(1H, d, J = 2.3 Hz), 8.55(1H, d, J = 2.6 Hz), 10.65(1H, brs), 10.96(1H, brs).

2550

embedded image

1
hydro- chloride
(DMSO-d₆) 1.11(3H, d, J = 6.3 Hz), 1.40(3H, d, J = 6.9 Hz), 2.67-2.75(1H, m), 3.10(2H, m), 3.25- 3.33(1H, m), 4.02-4.32(4H, m), 7.14(1H, d, J = 8.9 Hz), 7.21(2H, d, J = 8.3 Hz), 7.65(2H, d, J = 8.6 Hz), 7.85(1H, d, J = 8.2 Hz), 7.97(1H, dd, J = 8.6 Hz, 2.0 Hz), 8.21-8.26(2H, m), 8.54(1H, d, J = 2.3 Hz), 10.46(1H, brs), 10.64(1H, brs).

Example 2551
Production of 1-(3-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}propionyl)-4-[2-(morpholino)acetyl]-piperazine

To a solution of 1-chloroacetyl-4-(3-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}propionyl)piperazine (0.515 g, 0.896 mmol) and diisopropylethylamine (0.234 ml, 1.34 mmol) in acetonitrile (11 mL) was added morpholine (0.117 mL, 1.34 mmol), and the resulting solution was refluxed for 1 hour. This reaction solution was concentrated under reduced pressure. To the residue was added a saturated sodium bicarbonate solution, and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, and evaporated. The obtained solid was recrystallized from water-containing acetone, to thereby yield 0.441 g of the title compound.

Appearance: White powder

Melting point: 187-190° C.

The following compounds were produced in the same manner as in Example 2551.

TABLE 400

Example

No.
R₁₁₀₉
Form
mp (° C.) or ¹H NMR

2552
—COCH₂N(C₂H₅)₂
3/2 oxalate
mp 107-118

2553
—COCH₂NHCH₂Ph
hydrochloride
mp 199-202

2554
—COCH₂N(C₂H₅)CH₂Ph
fumarate

¹H NMR (DMSO-d₆) δ 0.99(3H, t, J =

7.1 Hz), 2.56-2.70(2H, m), 2.73-

2.86(2H, m), 3.09-3.50 (12H, m),

3.59(2H, s), 6.61(2H, s), 6.91(2H, d, J =

8.0 Hz), 6.98(2H, d, J = 9.0 Hz),

7.14-7.37(7H, m), 7.74(2H, d, J = 9.0

Hz), 7.81(1H, d, J = 8.4 Hz), 7.92(1H,

dd, J = 8.4 Hz, 2.1 Hz), 8.20(1H, d, J =

2.1 Hz), 10.39(1H, s), 13.09(2H,

brs).

2555

embedded image

dihydrochloride
mp 173-176

2556
—COCH₂N(C₂H₅)Ph
free
mp 140-143

TABLE 401

Example

No.
R₁₁₁₀
mp (° C.)

2557

embedded image

206-210

2558

embedded image

154-156

2559
morpholino
177-178

2560

embedded image

204-206

2561
—N(CH₃)CH₂Ph
182-184

TABLE 402

Example No.
R₁₁₁₁
mp (° C.)

2562

embedded image

151-152

2563
morpholino
177-178

2564

embedded image

146-147

TABLE 403

Example No.
R₁₁₁₂
mp (° C.)

2565
morpholino
195-197

2566

embedded image

146-148

2567

embedded image

173-176

2568

embedded image

150-153

TABLE 404

Example No.
R₁₁₁₃
Form
mp (° C.)

2569

embedded image

dihydrochloride
152-155

2570

embedded image

dihydrochloride
181-185

2571
morpholino
hydrochloride
146-150

TABLE 405

Example No.
R₁₁₁₄
mp (° C.)

2572
morpholino
157-160

2573

embedded image

241-243

2574

embedded image

193-196

2575

embedded image

180-182

TABLE 406

Example No.
R₁₁₁₅
Xb₆₃
R₁₁₁₆
mp (° C.) or ¹H NMR

2576
3,4-Cl₂Ph—
none
morpholino

¹H NMR (DMSO-d₆δ 2.50-

2.53 (4H, m), 3.55-3.61 (4H,

m), 3.82 (2H, s), 7.20 (1H, d, J =

8.7 Hz), 7.21 (2H, d, J = 8.1

Hz), 7.85 (1H, d, J = 8.4 Hz),

7.96 (1H, dd, J = 8.4 Hz, 1.2

Hz), 8.06 (2H, d, J = 8.4 Hz),

8.23 (1H, d, J = 1.5 Hz),

8.27 (1H, dd, J = 8.9 Hz, 2.8

Hz), 8.55 (1H, d, J = 2.8 Hz),

10.61 (1H, brs).

2577
4-CF₃Ph—

embedded image

mp 179-181

2578
4-CF₃Ph—

embedded image

mp 172-174

2579
4-CF₃Ph—

embedded image

morpholino
mp 144-146

2580
4-CF₃Ph—

embedded image

—N(CH)CH₂Ph
mp 188-190

2581
4-CF₃Ph—

embedded image

mp 192-193

The following compound was produced in the same manner as in Reference Example 860.

Example 2582
1-{4-[5-(3,4-Dichlorobenzoylamino)pyridin-2-yloxy]benzyl}piperazine-4-carboxylic acid ethyl ester

Appearance: Pale yellow oil

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7.0 Hz), 1.76 (2H, m), 1.77 (2H, m), 2.03 (2H, t, J=11.5 Hz), 2.28 (1H, m), 2.87 (2H, brd, J=11.5 Hz), 3.48 (2H, s), 4.13 (2H, q, 7.0 Hz), 6.94 (1H, d, J=9.0 Hz), 7.06 (2H, d, J=8.5 Hz), 7.33 (2H, d, J=9.0 Hz), 7.57 (1H, d, J=8.5 Hz), 7.70 (1H, dd, J=8.5 Hz, 2.0 Hz), 7.88 (1H, brs), 7.97 (1H, d, J=2.0 Hz), 8.17 (1H, dd, J=9.0 Hz, 3.0 Hz), 8.24 (1H, d, J=3.0 Hz).

Example 2583
Production of 3,4-dichloro-N-{6-[4-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)phenoxy]pyridin-3-yl}benzamide

To uracil (200 mg, 1.8 mmol) was added hexamethyldisilazane (5 mL), and the resulting solution was stirred for 5.5 hours at 150′C. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in a solution of acetonitrile (10 mL)-THF (5 mL), and to this solution were added 3,4-dichloro-N-[6-(4-chloromethylphenoxy)pyridin-3-yl]benzamide (500 mg, 1.2 mmol) and tin tetrachloride (3 drops). The resulting solution was refluxed for 2.5 hours. To this reaction solution was added methanol (1 mL), and the resulting solution was stirred for 30 minutes at room temperature. The resulting reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol:chloroform=1:99→3:97), to thereby yield 20 mg of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 4.88 (2H, s), 5.61 (1H, dd, J=7.9 Hz, 2.3 Hz), 7.07-7.13 (3H, m), 7.35 (2H, d, J=8.6 Hz), 7.79-7.85 (2H, m), 7.95 (1H, dd, J=8.6 Hz, 2.0 Hz), 8.18 (1H, d, J=2.6 Hz), 8.22 (1H, d, J=2.0 Hz), 8.47 (1H, d, J=2.6 Hz), 10.55 (1H, s), 11.33 (1H, s);

MS: m/z 482 (M⁺).

Example 2584
Production of N-{6-[4-(4-benzyl-2-oxopiperazin-1-ylmethyl)phenoxy]pyridin-3-yl}-3,4-dichlorobenzamide dihydrochloride

To a solution of 4-benzylpiperazin-2-one (0.56 g, 2.95 mmol) in DMF (10 mL) was added 60% sodium hydride (0.12 g, 2.95 mmol), and this solution was stirred at room temperature for 30 minutes. 2-(4-chloromethylphenoxy)-5-nitropyridine (0.78 g, 2.95 mmol) was added to the reaction mixture, and the mixture was stirred for 1 hour at room temperature. To this mixture was added brine (50 mL), and extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The remaining oil was dissolved in ethyl acetate (5 mL), and to the resulting solution was added iron powder (0.33 g, 5.89 mmol). This solution was stirred for 2 hours at room temperature. The resulting reaction solution was concentrated under reduced pressure, and a saturated sodium bicarbonate solution (50 mL) was added to the residue. The obtained mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated. The remaining oil was dissolved in THF (10 mL). To the resulting solution were added triethylamine (0.21 mL, 1.47 mmol) and 3,4-dichlorobenzoyl chloride (0.31 mL, 1.47 mmol), and this solution was stirred at room temperature for 2 hours. A saturated sodium bicarbonate solution (50 mL) was added to the solution, and extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=40:1). The obtained oil was dissolved in ethyl acetate (5 mL), and to the resulting solution was added a solution of 4 N hydrogen chloride in ethyl acetate (1.5 mL, 6 mmol). The formed white powder was collected by suction filtration, to thereby yield 0.045 g of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 3.54 (4H, m), 3.86 (2H, brs), 4.42 (2H, s), 4.59 (2H, brs), 7.06-7.12 (3H, m), 7.34 (2H, d, J=8.6 Hz), 7.48-7.51 (3H, m), 7.57-7.60 (2H, m), 7.84 (1H, d, J=8.6 Hz), 7.97 (1H, dd, J=2.0 Hz, 8.3 Hz), 8.18-8.24 (2H, m), 8.49 (1H, d, J=2.6 Hz), 10.61 (1H, s).

The following compound was produced in the same manner as in Reference Example 656.

Example 2585
2-({4-[(5-(3,4-Dichlorophenylamino)pyridin-2-yloxy]-2-trifluoromethylphenyl}ethylamino)-1-(4-piperonylpiperazin-1-yl)ethanone

¹H NMR (CDCl₃) δ 1.02 (3H, J=7.1 Hz), 2.30-2.45 (4H, m), 3.22 (2H, q, J=7.1 Hz), 3.40 (2H, s), 3.45-3.65 (4H, m), 3.85 (2H, s), 5.57 (1H, brs), 5.94 (2H, s), 6.65-6.80 (3H, m), 6.85 (1H, s), 6.95 (1H, d, J=8.7 Hz), 7.00 (1H, d, J=2.7 Hz), 7.29-7.31 (2H, m), 7.39 (1H, d, J=2.7 Hz), 7.53 (1H, dd, J=8.7 Hz, 2.9 Hz), 7.64 (1H, d, J=8.8 Hz), 7.99 (1H, d, J=2.7 Hz).

The following compounds were produced in the same manner as in Reference Example 658.

TABLE 407

Example No.
R₁₁₁₇
R₁₁₁₈
M
mp (° C.) or ¹H NMR (DMSO-d₆) δppm

2586
4-CF₃Ph—
—H
2

¹H NMR 2.14-2.30 (2H, m), 2.62-3.12 (7H, m), 3.20-

3.58 (3H, m), 3.77 (2H, t, J =5.9 Hz), 3.81-4.15 (3H,

m), 4.16-4.32 (2H, m), 4.49-4.57 (1H, m), 6.08 (2H, a),

6.96-7.09 (5H, m), 7.21 (1H, s), 7.29 (2H, d, J = 8.5

Hz), 7.58 (2H, d, J = 8.5 Hz), 7.70 (2H, d, J = 8.8 Hz),

7.86 (1H, dd, J = 2.8 Hz, 8.8 Hz, 8.13 (1H, d, J = 2.8

Hz), 10.78-11.01 (1H, m).

2587
3,4-Cl₂Ph—
—H
2
mp 182.0-183.0

2588
3-CF₃Ph—
—H
1
mp 200.0-203.0

2589
4-CF₃Ph—
—OCH₃
1
mp 153.0-154.0

2590
3,4-Cl₂Ph—
—OCH₃
1
mp 169.0-171.0

2591
4-CF₃Ph—
—OCH₃
2
mp 134.0-136.0

2592
3,4-Cl₂Ph—
—OCH₃
2
mp 130.0-132.0

TABLE 408

Example No.
R₁₁₁₉
M
mp (° C.) or ¹H NMR (DMSO-d₆) δppm

2593
4-CF₃Ph—
1

¹H NMR 1.90-2.06 (2H, m), 2.07 (3H, s), 3.18-3.32 (2H, m),

3.55-3.70 (2H, m), 3.73 (3H, s), 3.74 (3H, s), 3.91-4.12 (4H, m),

4.43 (2H, s), 4.49-4.93 (1H, m), 6.81 (1H, dd, J = 1.8 Hz, 8.1

Hz), 6.88 (1H, d, J = 1.8 Hz), 6.92 (1H, d, J = 8.1 Hz),

6.97 (1H, d, J = 8.5 Hz), 7.06 (1H, d, J = 9.0 Hz), 7.12 (1H, dd,

J = 2.4 Hz, 8.5 Hz), 7.21 (1H, d, J = 2.4 Hz), 7.71 (2H, d, J =

8.9 Hz), 7.83 (2H, d, J = 8.9 Hz), 8.19 (1H, dd, J = 2.9 Hz, 9.0

Hz), 8.27 (1H, d, J = 2.9 Hz).

2594
3,4-Cl₂Ph—
1
mp 146.0-148.0

2595
3,4-Cl₂Ph—
2

¹H NMR 1.91-2.11 (5H, m), 2.12-2.24 (2H, m), 3.19-3.32 (2H,

m), 3.58-3.83 (10H, m), 3.85-4.22 (3H, m), 4.42 (2H, s),

6.81 (1H, dd, J = 1.8 Hz, 8.1 Hz), 6.87 (1H, d, J = 1.8 Hz),

6.91 (1H, d, J = 8.1 Hz), 6.94-7.02 (2H, m), 7.12 (1H, dd, J = 2.5

Hz, 8.6 Hz), 7.21 (1H, d, J = 2.5 Hz), 7.35 (1H, dd, J = 2.5 Hz,

8.8 Hz), 7.57 (1H, d, J = 8.8 Hz), 7.66 (1H, d, J = 2.5 Hz),

7.82 (1H, dd J = 2.5 Hz 8.8 Hz), 8.07 (1H d J = 2.5 Hz).

Example 2596
Production of 3-(4-{5-[4-(3,4-dichlorophenyl)piperazin-1-yl]pyridin-2-yloxy}phenyl)-1-(4-piperonylpiperazin-1-yl)propane-1-one

To a solution of 3-[4-(5-bromopyridin-2-yloxy)phenyl]-1-(4-piperonylpiperazin-1-yl)propane-1-one (359 mg, 0.69 mmol) and 1-(3,4-dichlorophenyl)piperazine (206 mg, 0.89 mmol) in toluene (16 mL) were added with Pd₂(dba)₃(25 mg, 0.027 mmol), Xantphos (32 mg, 0.055 mmol) and sodium t-butoxide (99 mg, 1.03 mmol), and the resulting solution was refluxed under an argon atmosphere for 3 hours. The solution was left to cool, water was added to this reaction mixture. The resulting solution was extracted with dichloromethane, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1), to thereby yield 236 mg of the title compound.

Appearance: Pale yellow powder

¹H NMR (CDCl₃) δ 2.31-2.40 (4H, m), 2.58-2.64 (2H, m), 2.92-2.98 (2H, m), 3.23-3.38 (8H, m), 3.41 (4H, brs), 3.63 (2H, t, J=4.9 Hz), 5.94 (2H, s), 6.72-6.73 (2H, m), 6.78 (1H, dd, J=8.9 Hz, 2.8 Hz), 6.84-6.90 (2H, m), 6.99-7.06 (3H, m), 7.19-7.24 (3H, m), 7.32 (1H, dd, J=9.4 Hz, 3.1 Hz), 7.88 (1H, d, J=3.0 Hz). Tris(dibenzylideneacetone)dipalladium is abbreviated to Pd₂(dba)₃. Hereinafter, the same. 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene is abbreviated to Xantphos. Hereinafter the same.

The following compounds were produced in the same manner as in Example 2596.

TABLE 409

Example No.
R₁₁₂₀
R₁₁₂₁
Xb₆₄

¹H NMR (CDCl₃) δppm

2597
4-CF₃PhCH₂—
—H
—CH₂—
2.31-2.38 (4H, m), 2.60-2.64 (6H, m), 2.95 (2H, t, J =

7.3 Hz), 3.11-3.15 (4H, m), 3.40 (4H, brs),

3.61 (4H, brs), 5.93 (2H, s), 6.73 (2H, s), 6.83 (2H,

d, J = 9.1 Hz), 6.99 (2H, d, J = 8.4 Hz), 7.19 (2H,

d, J = 8.4 Hz), 7.29 (1H, dd, J = 8.9 Hz, 3.1 Hz),

7.47 (2H, d, J = 8.2 Hz), 7.58 (2H, d, J = 8.1 Hz),

7.83 (1H, d, J = 3.0 Hz).

2598
3,4-Cl₂Ph—
—CH₃
—N(CH₃)—
2.13 (3H, s), 2.40-2.44 (4H, m), 3.00 (3H, s), 3.18-

3.38 (8H, m), 3.43 (2H, s), 3.49 (2H, brs), 3.63 (2H,

brs), 4.06 (2H, s), 5.94 (2H, s), 6.52-6.57 (2H, m),

6.69-6.91 (6H, m), 7.00 (1H, d, J = 3.0 Hz), 7.26-

7.32 (2H, m), 7.86 (1H, d, J = 2.8 Hz).

2599
4-CF₃Ph—
—CH₃
—N(CH₃)—
2.13 (3H, s), 2.41-2.44 (4H, m), 3.00 (3H, s), 3.20-

3.24 (4H, m), 3.34-3.43 (6H, m), 3.49 (2H, brs),

3.63 (2H, brs), 4.06 (2H, s), 5.94 (2H, s), 6.52-

6.58 (2H, m), 6.70-6.77 (3H, m), 6,85-6.98 (4H, m),

7.31 (1H, dd, J = 9.1 Hz, 3.1 Hz), 7.50 (2H, d, J =

8.6 Hz), 7.87 (1H, d, J = 2.6 Hz).

2600
4-CF₃Ph—
—H
—CH₂—
2.31-2.40 (4H, m), 2.61 (2H, t, J = 7.3 Hz),

2.96 (2H, t, J = 7.3 Hz), 3,23-3.27 (4H, m), 3.38-

3.45 (8H, m), 3.63 (2H, t, J = 4.8 Hz), 5.94 (2H, s),

6.70-6.76 (2H. m), 6.84-7.06 (6H, m), 7.19-

7.26 (2H, m), 7.36 (1H, dd, J = 8.9 Hz, 3.1 Hz),

7.51 (2H, d, J = 8,9 Hz), 7.89 (1H, d. J = 3.0 Hz).

The following compounds were produced in the same manner as in Reference Example 659.

TABLE 410

Example No.
R₁₁₂₂
Xb₆₅
Xb₆₆
R₁₁₂₃

¹H NMR (CDCl₃) δppm

2601
4-CF₃Ph—
—N(CH₃)—
—CH₂—
piperonyl
2.41-2.44 (4H, m), 3.03 (3H, s), 3.43 (2H,

s), 3.47-3.50 (2H, m), 3.61-3.65 (2H, m),

4.09 (2H, s), 5.93 (2H, s), 6.68-6.77 (4H,

m), 6.83-6.86 (2H, m), 6.90 (1H, d, J =

16.5 Hz), 7.00-7.06 (2H, m), 7.10 (1H, d,

J = 16.5 Hz), 7.54-7.61 (4H, m), 7.84 (1H,

dd, J = 8.6 Hz, 2.5 Hz), 8.26 (1H, d, J =

2.5 Hz).

2602
3,4-Cl₂Ph—
—N(CH₃)—
—CH₂—
piperonyl
2.42-2.45 (4H, m), 3.04 (3H, s), 3.44 (2H,

s), 3.48-3.52 (2H, m), 3.62-3.66 (2H, m),

4.09 (2H, s), 5.95 (2H, s), 6.68-6.86 (6H,

m), 6.94 (1H, d, J = 17.3 Hz), 6.99-

7.04 (3H, m), 7.31 (1H, dd, J = 8.4 Hz, 2.0

Hz), 7.42 (1H, d. J = 8.4 Hz), 7.57 (1H, d,

J = 2.0 Hz), 7.82 (1H, d, J = 8.4 Hz),

8.24 (1H, brs).

2603
4-CF₃Ph—
—CH₂—
—CH₂—
piperonyl
2.32-2.41 (4H, m), 2.60-2.66 (2H, m),

2.96-3.01 (2H, m), 3.39-3.43 (4H, m),

3.62-3.66 (2H, m), 5.95 (2H, s), 6.70-

6.77 (2H, m), 6.84-6.85 (1H, m), 6.93 (1H,

d, J = 8.6 Hz), 7.00-7.09 (3H, m),

7.12 (1H, d, J = 16.5 Hz), 7.23-7.27 (2H,

m), 7.56-7.64 (4H, m), 7.90 (1H, dd, J =

8.7 Hz, 2.6 Hz), 8.27 (1H, d, J = 2.6 Hz).

2604
4-CF₃Ph—
none
none
benzyl
2.47 (4H, brs), 3.55-3.77 (6H, m),

6.97 (1H, d, J = 8.6 Hz), 7.05 (1H, d, J =

16.3 Hz), 7.10-7.27 (3H, m), 7.28-

7.34 (5H, m), 7.45-7.50 (2H, m), 7.57-

7.64 (4H, m), 7.93 (1H, dd, J = 8.6 Hz, 2.4

Hz), 8.29 (1H, d, J = 2.4 Hz).

2605
3,4-Cl₂Ph—
none
none
benzyl
2.52 (4H, brs), 3.49-3.90 (6H, m), 6.89-

6.98 (2H, m), 7.03 (1H, d, J = 16.5 Hz),

7.15-7.20 (2H, m), 7.30-7.50 (9H, m),

7.58 (1H, d, J = 2.1 Hz), 7.90 (1H, dd, J =

8.7 Hz, 2.5 Hz), 8.26 (1H, d, J = 2.5 Hz).

TABLE 411

Example No.
R₁₁₂₄
Form

¹H NMR (solvent) δppm

2606
piperonyl
hydrobromide
(DMSO-d₆) 1.89-2.06 (2H, m), 2.06 (3H, s),

3.18-3.35 (2H, m), 3.57-3.71 (2H, m), 4.40 (2H,

s), 4.42-4.80 (1H, m, 5.99 (2H, s), 6.77 (1H, dd,

J = 1.6 Hz, 7.9 Hz), 6.84 (1H, d, J = 1.6 Hz),

6.87 (1H, d, J = 7.9 Hz), 7.01 (1H, d, J = 8.6

Hz), 7.07 (1H, d, J = 8.6 Hz), 7.13 (1H, dd, J =

2.5 Hz, 8.6 Hz), 7.23 (1H, d, J = 2.5 Hz),

7.32 (1H, d, J = 16.5 Hz), 7.42 (1H, d, J = 16.5

Hz), 7.72 (2H, d, J = 8.5 Hz), 7.79 (2H, d, J =

8.5 Hz), 8.19 (1H, dd, J = 2.4 Hz, 8.6 Hz),

8.30 (1H, d, J = 2.4 Hz).

2607
3,4-
free
(CDCl₃) 1.99-2.14 (2H, m), 2.18 (3H, s), 3.22-

(CH₃O)₂PhCH₂—

3.38 (2H, m), 3.63-3.79 (2H, m), 3.89 (3H, s),

3.90 (3H, s), 4.57 (2H, s), 6.76-6.95 (4H, m),

6.97-7.20 (4H, m), 7.51-7.67 (4H, m), 7.88 (1H,

dd, J = 2.5 Hz, 8.6 Hz), 8.27 (1H, d, J = 2.5

Hz).

Example 2608
Production of 1-(3,4-dimethoxybenzyl)-3-{3-methyl-4-[5-(4-trifluoromethylphenylethynyl)pyridin-2-yloxy]phenyl}tetrahydropyrimidin-2-one

To a solution of 1-[4-(5-bromopyridin-2-yloxy)-3-methylphenyl]-3-(3,4-dimethoxybenzyl)tetrahydropyrimidin-2-one (0.3 g, 0.59 mmol) in N-methylpyrrolidone (10 mL) were added bis(triphenylphosphine)palladium dichloride (20 mg, 0.03 mmol), copper iodide (11 mg, 0.059 mmol), 4-ethynyl-α,α,α-trifluorotoluene (0.14 mL, 0.88 mmol) and triethylamine (0.14 mL, 10 mmol) under a nitrogen atmosphere. The resulting solution was stirred for 3 hours at 110 to 120° C. After being left to cool, water was added to the reaction solution. The resulting solution was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then evaporated, and the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1→1:1), to thereby yield 0.28 g of the title compound.

Appearance: Pale brown amorphous powder

¹H NMR (CDCl₃) δ 1.97-2.15 (2H, m), 2.16 (3H, s), 3.31 (2H, t, J=6.0 Hz), 3.72 (2H, t, J=6.0 Hz), 3.88 (3H, s), 3.89 (3H, s), 4.57 (2H, s), 6.72-6.95 (5H, m), 7.04 (1H, d, J=8.6 Hz), 7.17 (1H, dd, J=2.6 Hz, 8.6 Hz), 7.55-7.68 (4H, m), 7.78 (1H, dd, J=2.3 Hz, 8.6 Hz), 8.36 (1H, d, J=2.3 Hz).

Example 2609
Production of 3-(3-methyl-4-{5-[2-oxo-2-(4-trifluoromethylphenyl)ethyl]pyridin-2-yloxy}phenyl)-1-piperonyltetrahydropyrimidin-2-one hydrobromide

To a solution of 3-[4-(5-bromopyridin-2-yloxy)-3-methylphenyl]-1-piperonyltetrahydropyrimidin-2-one (0.11 g, 0.22 mmol) in toluene (10 mL) were added Pd₂(dba)₃(10 mg, 0.01 mmol) and Xantphos (15 mg, 0.03 mmol) under a nitrogen atmosphere. The resulting solution was stirred for 5 minutes, and then 4′-(trifluoromethyl)acetophenone (63 mg, 0.33 mmol) and potassium bis(trimethylsilyl)amide (66 mg, 0.33 mmol) were added to the reaction solution. The resulting solution was stirred at 70 to 80° C. for 30 minutes, and left to cool. Water was added to the reaction solution, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→1:1), to yield 50 mg of a free form. To this free form was added an equivalent amount of hydrobromic acid, to thereby yield 50 mg of the title compound.

Appearance: Colorless amorphous powder

¹H NMR (DMSO-d₆) δ 1.85-2.10 (2H, m), 2.06 (3H, s), 3.14-3.47 (2H, m), 3.50-3.76 (2H, m), 4.40 (2H, s), 4.49 (2H, s), 4.70-5.40 (1H, m), 5.98 (2H, s), 6.70-6.80 (1H, m), 6.81-6.90 (2H, m), 6.90-7.04 (2H, m), 7.12 (1H, d, J=2.2 Hz, 8.6 Hz), 7.18-7.26 (1H, m), 7.72 (1H, dd, J=2.2 Hz, 8.5 Hz), 7.93 (2H, d, J=8.2 Hz), 7.95-8.02 (1H, m), 8.24 (2H, d, J=8.2 Hz).

The following compounds were produced in the same manner as in Example 2609.

TABLE 412

Example No.
R₁₁₂₅
R₁₁₂₆

¹H NMR (CDCl₃) δppm

2610
3,4-Cl₂Ph—
piperonyl
1.82-2.10 (2H, m), 2.07 (3H, s), 3.12-3.32 (2H, m),

3.53-3.72 (2H, m), 4.40 (2H, s), 4.45 (2H, s), 4.80-

5.40 (1H, m), 5.99 (2H, s), 6.71-6.80 (1H, m), 6.81-

6.90 (2H, m), 6.98 (2H, dd, J = 2.4 Hz, 8.5 Hz),

7.12 (1H, dd, J = 2.4 Hz, 8.5 Hz), 7.21 (1H, d, J = 2.4

Hz), 7.70 (1H, dd, J = 2.2 Hz, 8.4 Hz), 7.84 (1H, d, J =

8.4 Hz), 7.96 (1H, d, J = 2.2 Hz), 8.00 (1H, dd, J =

2.0 Hz, 8.4 Hz), 8.25 (1H, d, J = 2.0 Hz).

2611
4-CF₃Ph—
3,4-(CH₃O)₂Ph—
1.87-2.11 (5H, m), 3.15-3.32 (2H, m), 3.43-3.71 (3H,

m), 3.74 (3H, s), 3.75 (3H, s), 4.44 (2H, s), 4.51 (2H, s),

6.78-6.86 (1H, m), 6.87-6.91 (1H, m), 6.93 (1H, d, J =

8.5 Hz), 6.99 (1H, d, J = 8.5 Hz), 7.00 (1H, d, J = 8.5

Hz), 7.14 (1H, dd, J = 2.4 Hz, 8.5 Hz), 7.19-7.25 (1H,

m), 7.73 (1H, dd J = 2.4 Hz, 8.5 Hz), 7.94 (1H, d, J =

8.3 Hz), 7.97-8.01 (1H, m), 8.25 (1H, d, J = 8.3 Hz).

TABLE 413

Example No.
R₁₁₂₇
mp (° C.) or ¹H NMR (solvent) δppm

2612

embedded image

¹H NMR (CDCl₃) 2.44 (4H, brs), 3.44 (2H, s), 3.54 (2H, brs), 3.73 (2H, brs), 4.29 (2H, s), 5.94 (2H, s), 6.74 (2H, s), 6.85 (1H, s), 6.94 (1H, d, J = 8.4 Hz), 7.16 (2H, d, J = 8.6 Hz), 7.45 (2H, d, J = 8.6 Hz), 7.63 (1H, dd, J = 8.4 Hz, 2.5 Hz), 7.76 (2H, d, J = 8.1 Hz), 8.07 (1H, d, J = 2.5 Hz), 8.11 (2H, d, J = 8.1 Hz).

2613

embedded image

¹H NMR (DMSO-d₆) 2.31 (3H, s), 2.76- 3.45 (9H, m), 3.69-4.57 (8H, m), 6.07 (2H, s), 6.81-7.22 (6H, m), 7.74 (1H, dd, J = 2.2 Hz, 8.4 Hz), 7.89-8.00 (2H, m), 8.24 (1H, d, J = 8.4 Hz), 9.49-9.79 (1H, m).

2614

embedded image

mp 164.0-166.0

The following compounds were produced in the same manner as in Reference Example 111.

TABLE 414

Example No.
Xb₆₇

¹H NMR (solvent) δppm

2615
—N(CH₃)—
2.42-2.45 (4H, m), 3.05 (3H, s), 3.44 (2H, s), 3.47-3.51 (2H, m), 3.62-

3.65 (2H, m), 4.11 (2H, s), 5.95 (2H, s), 6.69-6.77 (4H, m), 6.85 (1H,

s), 6.97 (1H, d, J = 8.7 Hz), 7.01-7.07 (2H, m), 7.75 (2H, d, J = 8.4

Hz), 7.87 (2H, d, J = 8.1. Hz), 8.17 (1H, dd, J = 8.7 Hz, 2.3 Hz),

8.58 (1H, d, J = 2.3 Hz).

2616
—CH₂—
2.32-2.41 (4H, m), 2.61-2.67 (2H, m), 2.97-3.03 (2H, m), 3.41-

3.43 (4H, m), 3.62-3.66 (2H, m), 5.95 (2H, s), 6.70-6.77 (2H, m),

6.84 (1H, s), 7.03-7.13 (3H, m), 7.28-7.32 (2H, m), 7.76 (2H, d, J = 8.1

Hz), 7.88 (2H, d, J = 8.1 Hz), 8.22 (1H, dd, J = 8.6 Hz, 2.4 Hz),

8.58 (1H, d, J = 2.4 Hz).

TABLE 415

Example No.
R₁₁₂₈
R₁₁₂₉

¹H NMR CDCl₃) δppm

2617
—H
—CH₂COOC₂H₅
1.27 (3H, t, J = 7.1 Hz), 1.34-1.48 (2H, m), 1.81-1.99 (3H,

m), 2.29 (2H, d, J = 6.9 Hz), 2.73 (2H, t, J = 12.2 Hz),

3.63 (2H, d, J = 12.2 Hz), 4.15 (2H, q, J =7.3 Hz), 6.91-

7.01 (4H, m), 7.18-7.26 (3H, m), 7.54 (2H, d, J = 8.9 Hz),

8.26 (1H, d, J = 2.3 Hz), 8.43 (1H, d, J = 2.3 Hz).

2618
—CH₃
—CH₂COOC₂H₅
1.28 (3H, t, J = 7.1 Hz), 1.30-1.39 (2H, m), 1.80-1.96 (3H,

m), 2.07 (3H, s), 2.29 (2H, d, J = 6.9 Hz), 2.70 (2H, t, J =

12.0 Hz), 3.61 (2H d, J = 12.4 Hz), 4.17 (2H, q, J = 7.3

Hz), 6.74-6.78 (2H, m), 6.92 (1H, d, J = 8.6 Hz), 7.20-

7.26 (3H, m), 7.52 (2H, d, J = 8.4 Hz), 8.28 (1H, d, J = 2.3

Hz), 8.41 (1H, d, J = 2.3 Hz).

2619
—H
—COOC₂H₅
1.27 (3H, t, J = 7.1 Hz), 1.92-2.00 (2H, m), 2.01-2.05 (2H,

m), 2.38-2.47 (1H, m), 2.74-2.84 (2H, m), 3.59-3.63 (2H,

m), 4.15 (2H, q, J = 7.1 Hz), 6.93-7.02 (4H, m), 7.17-

7.26 (3H, m), 7.54 (2H, d, J = 8.4 Hz), 8.26 (1H, d, J = 2.3

Hz), 8.43 (1H, d, J = 2.3 Hz).

TABLE 416

Example No.
R₁₁₃₀
R₁₁₃₁
mp (° C.) or ¹H NMR (DMSO-d₆) δppm

2620
4-CF₃Ph—
piperonyl
mp 129.0-130.5

2621
4-CF₃Ph—
3,4-(CH₃O)₂PhCH₂—
mp 130.0-132.0

2622
3,4-Cl₂Ph—
3,4-(CH₃O)₂PhCH₂—

¹H NMR 1.85-2.14 (5H, m), 3.13-3.33 (2H,

m), 3.58-3.71 (2H, m), 3.73 (3H, s), 3.74 (3H,

s), 4.12-4.78 (3H, m), 6.73-6.94 (3H, m),

7.04 (1H, d, J = 8.6 Hz), 7.11-7.20 (2H, m),

7.25 (1H, d, J = 2.4 Hz), 7.61 (1H, d, J = 8.8

Hz), 7.71 (1H, dd, J = 2.4 Hz, 8.8 Hz),

8.11 (1H, d, J = 2.4 Hz), 8.34 (1H, dd J = 2.4

Hz, 8.8 Hz), 8.66 (1H, d, J = 2.4 Hz),

10.53 (1H, s).

Example 2623
Production of 2-[4-(3-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}propionyl)piperazin-1-yl]acetic acid hydrochloride

To a solution of ethyl 2-[4-(3-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}propionyl)piperazin-1-yl]acetate (0.493 g, 0.843 mmol) in THF (5 mL) and ethanol (5 mL) were added 5 M aqueous sodium hydroxide (0.253 mL, 1.27 mmol) and water (1 mL), and the resulting solution was refluxed for 1 hour. This reaction solution was concentrated under reduced pressure, and the residue was dissolved in 50% aqueous ethanol. To the resulting solution was added 5 M hydrochloric acid (0.253 mL, 1.27 mmol), and the obtained solid was collected by filtration. To this solid was dissolved in ethanol (10 mL) and 5 M hydrochloric acid (0.3 mL) by heating. The solvent was then evaporated, and the obtained solid was recrystallized from ethanol-diethyl ether, to thereby yield 0.381 g of the title compound.

Appearance: White powder

Melting point: 215-218° C.

The following compounds were produced in the same manner as in Example 2623.

TABLE 417

Ex-

ample

No
R₁₁₃₂

¹H NMR (solvent) δppm

2624

embedded image

(DMSO-d₆) 2.71-2.73(4H, m), 3.12-3.14(4H, m), 3.21(2H, s), 6.91-6.98 (6H, m), 7.71(2H, dd, J = 7.0 Hz, 2.0 Hz), 7.82(1H, d, J = 8.0 Hz), 7.93(1H, dd, J = 8.0 Hz, 2.0 Hz), 8.21(1H, d, J = 2.0 Hz), 10.38(1H, s).

2625

embedded image

(CDCl₃) 2.68(2H, m), 3.05(2H, m), 3.35(2H, s), 3.49(2H, m), 6.00(1H, m), 6.98(2H, d, J = 8.5 Hz), 7.05(2H, d, J = 8.5 Hz), 7.35(2H, d, J = 8.5 Hz), 7.58(2H, d, J = 8.5 Hz), 7.58(1H, brs), 7.77(2H, m), 7.97(1H, s).

2626

embedded image

DMSO-d₆)7.60-1.70(2H, m), 1.85-1.90(2H, m), 2.50(1H, m), 2.65-2.73(2H, m), 3.55(2H, brd, J = 12.5 Hz), 6.90-6.98(6H, m), 7.71(2H, d, J = 9.0 Hz), 7.81(1H, d, J = 8.5 Hz), 7.93(1H, dd, J = 8.5 Hz, 2.0 Hz), 8.21(1H, d, J = 2.0 Hz), 10.37(1H, s), 12.20(1H, brs).

2627

embedded image

(DMSO-d₆) 1.51-1.58(2H, m), 1.90-1.95(2H, m), 2.78-2.82(2H, m), 3.43(2H, m), 3.52(1H, m), 3.92(2H, s), 6.89-6.98(6H, m), 7.70(2H, d, J = 9.0 Hz), 7.82(1H, d, J = 8.5 Hz), 7.93(1H, dd, J = 8.5 Hz, 2.0 Hz) 8.21(1H, d, J = 2.0 Hz), 10.40(1H, s).

2628

embedded image

(DMSO-d₆) 1.59-1.66(2H, m), 1.94-1.97(2H, m), 2.54(3H, s), 3.62(2H, t, J = 11.0 Hz), 2.98(1H, m), 3.29(2H, s), 3.67- 3.70(2H, m), 6.90-6.99(6H, m), 7.71(2H, d, J = 9.0 Hz), 7.82(1H, d, J = 8.5 Hz), 7.93(1H, dd, J = 8.5 Hz, 2.0 Hz), 8.21(1H, d, J = 2.0 Hz), 10.39(1H, s).

2629

embedded image

(CDCl₃) 1.80-1.83(4H, m), 2.61-2.65(3H, m), 3.24(2H, s), 3.25(2H, brd, J = 11.0 Hz), 6.94(2H, d, J = 8.5 Hz), 7.03(2H, d, J = 9.0 Hz), 7.25(2H, d, J = 8.5 Hz), 7.03(2H, Hz), 7.83(1H, d, J = 8.5 Hz), 7.94(1H, dd, J = 8.5 Hz, 2.0 Hz), 8.21(1H, d, J = 2.0 Hz), 10.41(1H, s).

TABLE 418

Ex-

ample

No
R₁₁₃₃
Xb₆₈
Xb₆₉
M

¹H NMR (DMSO-d₆) δppm

2630
4-CF₃Ph—
—N(CH₃)—
none
1
1.20-1.45(2H, m), 1.70-1.95(3H, m),

2.20(2H, d, J = 6.6 Hz), 2.67(2H, t, J = 12.4

Hz), 3.32(3H, s), 3.67(2H, d, J = 12.4 Hz),

6.42(1H, d, J = 9.1 Hz), 6.99(2H, d, J = 8.9

Hz), 7.11(2H, d, J = 8.9 Hz), 7.73(1H, dd, J =

9.1 Hz, 2.3 Hz), 7.90(2H, d, J = 8.2 Hz),

8.15(2H, d, J = 8.2 Hz), 8.46(1H, d, J = 2.3

Hz), 10.33(1H, s).

2631
3,4-Cl₂Ph—
—O—
—CH₂—
0
1.57(2H, brs), 1.81(2H, brs), 2.00(2H, brs),

2.23(1H, brs), 2.77(2H, brs), 3.44(2H, brs),

7.05(1H, d, J = 9.0 Hz), 7.07(2H, d, J = 8.5

Hz), 7.35(2H, d, J = 8.5 Hz), 7.84(1H, d, J =

8.5 Hz), 7.95(1H, d, J = 8.5 Hz), 8.20 (1H,

dd, J = 9.0 Hz, 3.0 Hz), 8.22(1H, d, J = 2.0

Hz), 8.49(1H, d, J = 3.0 Hz), 10.56(1H, s),

12.15(1H, brs).

2632
3,4-Cl₂Ph—
—O—
—CO—
0
1.52(2H, m), 1.86(2H, brs), 2.52(1H, m),

3.10(2H, brs), 3.65(1H, brs), 4.31(1H, brs),

7.15(1H, d, J = 9.0 Hz), 7.16(2H, d, J = 8.5

Hz), 7.43(2H, d, J = 8.5 Hz), 7.84(2H, d, J =

8.5 Hz), 7.95(1H, dd, J = 8.5 Hz, 2.0 Hz),

8.23(1H, d, J = 2.0 Hz), 8.24(1H, dd, J = 9.0

Hz, 3.0 Hz), 8.52(1H, d, J =3.0 Hz),

10.60(1H, s).

2633
4-CF₃Ph—
—O—
—CO—
0
1.52(2H, m), 1.86(2H, brs), 2.54(1H, m),

3.05(2H, brs), 3.63(1H, brs), 4.31(1H, brs),

7.15(1H, d, J = 9.0 Hz), 7.16(2H, d, J = 8.5

Hz), 7.44(2H, d, J = 8.5 Hz), 7.94 (2H, d, J =

8.5 Hz), 8.17(2H, d, J = 8.5 Hz), 8.27(1H,

dd, J = 9.0 Hz, 2.5 Hz), 8.55(1H, d, J = 2.5

Hz), 10.67(1H, s).

2634
3,4-Cl₂Ph—
—O—
none
0
1.63-1.71(2H, m), 1.92(2H, brd, J = 10.0

Hz), 2.74(2H, t, J = 11.5 Hz), 3.58(2H, brd,

J = 12.5 Hz), 6.96(1H, d, J = 9.0 Hz),

6.98(4H, s), 7.83(1H, d, J = 8.5 Hz),

7.94(1H, dd, J = 8.5 Hz, 2.0 Hz), 8.14(1H,

dd, J = 9.0 Hz, 2.5 Hz), 8.21(1H, d, J = 2.0

Hz), 8.44(1H, d, J = 2.5 Hz), 10.50(1H, s),

12.20(1H, brs).

2635
3,4-Cl₂Ph—
—O—
none
1
1.31-1.34(2H, m), 1.77(2H, brd, J = 11.5

Hz), 2.20(2H, t, J = 6.5 Hz), 2.64(2H, brt, J =

10.5 Hz), 3.61(2H, brd, J =12.5 Hz),

6.96(1H, J = 9.0 Hz), 6.96(4H, s), 7.83

(1H, d, J = 8.5 Hz), 7.94(1H, dd, J = 8.5 Hz,

2.0 Hz), 8,14(1H, dd, J = 9.0 Hz, 2.5 Hz),

8.21(1H, d, J = 2.0 Hz), 8.44(1H, d, J = 2.5

Hz), 10.50(1H, s), 12.06(1H, brs).

TABLE 419

Ex-

ample

No.
R₁₁₃₄
Xb₇₀
Xb₇₁
Xb₇₂

¹H NMR (DMSO-d₆) δppm

2636
4-CF₃Ph—
—O—
—CO—
—CH₂—
3.30(4H, brs), 3.77(4H, brs), 3.99(2H,

s), 7.17(1H, d, J = 8.8 Hz), 7.21(2H, d,

J = 8.6 Hz), 7.51(2H, d, J = 8.6 Hz),

7.94(2H, d, J = 8.0 Hz), 8.20(2H, d, J =

8.0 Hz), 8.29(1H, dd, J = 8.8 Hz, 2.6

Hz), 8.59(1H, d, J = 2.6 Hz), 10.79(1H,

s).

2637
3,4-Cl₂Ph—
—O—
none
—CH₂—
2.71(4H, t, J = 5.0 Hz), 3.13(2H, s),

3.14(4H, t, J = 5.0 Hz), 6.96-7.00(5H,

m), 7.82(1H, d, J = 8.5 Hz), 7.96(1H,

dd, J = 8.5 Hz, 2.0 Hz), 8.16(1H, dd, J =

9.0 Hz, 2.5 Hz), 8.24(1H, d, J = 2.0

Hz), 8.37(1H, s), 8.46(1H, d, J = 2.5

Hz), 10.62(1H, brs).

2638
4-CF₃Ph—
—N(CH₃)—
none
—CH₂—
2.64(4H, brs), 2.95(2H, s), 3.15(4H,

brs), 3.33(3H, s), 6.42(1H, d, J = 9.1

Hz), 6.99(2H, d, J = 8.9 Hz), 7.13(2H,

d, J = 8.9 Hz), 7.75(1H, dd, J = 9.1 Hz,

2.5 Hz), 7.89(2H, d, J = 8.2 Hz),

8.17(2H, d, J = 8.2 Hz), 8.49(1H, d, J =

2.5 Hz), 10.46(1H, s).

2639
4-CF₃Ph—
—O—
none
—CH₂—
2.72(4H, t, 3 = 5.0 Hz), 3.15(4H, t, J =

5.0 Hz), 3.20(2H, s), 6.96-7.01(5H,

m), 7.93(2H, d, J = 8.5 Hz), 8.16(2H, d,

J = 8.5 Hz), 8.18(1H, dd, J = 9.0 Hz, 2.5

Hz), 8.46(1H, d, J = 2.5 Hz), 10.60(1H,

s).

2640
3,4-Cl₂Ph—
—O—
none
—CO—
3.13(2H, brs), 3.17(2H, s), 3.48(2H,

brs), 3.71(2H, brs), 7.12(1H, d, J = 8.9

Hz), 7.15(2H, dd, J = 6.8 Hz, 2.1 Hz),

7.36(2H, dd, J = 6.8 Hz, 2.1 Hz),

7.84(1H, d, J = 8.4 Hz), 7.95(1H, dd, 3

Hz, 2.7 Hz), 8.23(1H, d, J = 2.1 Hz),

8.49 (1H, d, 3 = 2.7 Hz), 10.58(1H, s).

TABLE 420

Ex-

ample

¹H NMR (solvent)

No
R₁₁₃₅
Xb₇₃
Xb₇₄
Xb₇₅
R₁₁₃₆
δppm

2641
4-CF₃PhCO—
none
none
none
benzyl
(CD₃OD) 3.47(8H,

brs), 4.43(2H, s), 6.96

(1H, d, J = 8.9 Hz),

7.14(1H, d, J = 8.9

Hz), 7.30(1H, dd, J =

8.9 Hz, 3.0 Hz), 7.51-

7.59(6H, m), 7.82(2H,

d, J = 8.3 Hz), 8.12-

8.18(3H, m), 8.36(1H,

d, J = 2.5 Hz).

2642
3,4-Cl₂PhSO₂—
—N(C₂H₅)—
—CH₂—
—CO—
piperonyl
(DMSO-d₆) 1.11(3H, t,

J = 7.0 Hz), 2.20-2.45

(4H, m), 3.30-3.55(8H,

m), 4.22(2H, s), 5.99

(2H, s), 6.70-7.00(7H,

m) 7.40-7.50(1H, m),

7.55-7.60(1H, m),

7.66(1H, d, J = 2.7

Hz), 7.84(1H, d, J

8.4 Hz), 7.88(1H, d, J =

2.1 Hz), 10.27(1H,

brs), 12.51(1H, brs).

2643
3,4-Cl₂PhNHCO—
—N(C₂H₅)—
—CH₂—
—CO—
piperonyl
(DMSO-d₆) 1.13(3H, t,

J = 7.0 Hz), 2.20-2.50

(4H, m), 3.30-3.60(8H,

m), 4.21(2H, s), 5.99

(2H, s), 6.60-7.05(7H,

m) 7.30-7.40(1H, m)

7.47(1H,

Hz), 7.65-7.85(1H, m),

7.90(1H, d, J = 2.3

Hz), 8.06(1H, d, J =

2.6 Hz), 9.80(2H, brs),

12.40(1H, brs).

TABLE 421

Ex-

ample

No.
R₁₁₃₇
R₁₁₃₈
R₁₁₃₉
R₁₁₄₀

¹H NMR (solvent) δppm

2644
3,4-Cl₂Ph—
—H
—H
—COOH
(CDCl₃) 1.80(1H, m), 1.86-1.94(3H,

m), 2.82(1H, m), 3.14(2H, m), 3.32

(2H, m), 6.94(1H, d, J = 9.0 Hz),

7.06(4H, s), 7.57(1H, d, J = 8.5 Hz),

7.72(1H, d, J = 8.5 Hz), 7.93(1H,

brs), 7.99(1H, s), 8.18(1H, brd, J =

9.0 Hz), 8.26(1H, d, J = 2.5 Hz).

2645
4-CF₃Ph—
—H
—CH₂COOH
—H
(CDCl₃) 1.44-1.50(2H, m), 1.90(2H,

brd, J = 13.5 Hz), 1.94(1H, m), 2.36

(2H, d, J = 7.0 Hz), 2.75(2H, dt, J =

2.5 Hz, 12.0 Hz), 3.63(2H, brd, J =

12.0 Hz), 6.92(1H, d, J = 9.0 Hz),

6.97(2H, d, J = 9.0 Hz), 7.04(2H, d,

J = 9.0 Hz), 7.72(1H, s), 7.78(2H, d,

J = 8.0 Hz), 7.99(2H, d, J = 8.0 Hz),

8.19 (1H, dd, J = 9.0 Hz, 2.5 Hz),

8.25(1H, d, J = 2.5 Hz).

2646
3-CF₃Ph—
H
—CH₂COOH
—H
(CDCl₃) 1.46-1.49(2H, m), 1.89(2H,

brd, J = 15.0 Hz), 1.95(1H, m),

2.36(2H, d, J = 7.0 Hz), 2.74(2H, dt,

J = 2.0 Hz, 12.0 Hz), 3.63(2H, brd,

J = 12.0 Hz), 6.92(1H, d, J = 9.0

Hz), 6.97(2H, d, J = 9.0 Hz), 7.05

(2H, d, J = 9.0 Hz), 7.66(1H, t, J =

7.5 Hz), 7.73(2H, brs), 7.84(1H, d, J =

7.5 Hz), 8.07(1H, d, J = 7.5 Hz),

8.14(1H, brs), 8.17(1H, dd, J = 9.0

Hz, 2.5 Hz), 8.27(1H, d, J = 2.5 Hz).

2647
4-CF₃Ph—
—OCH₃
—CH₂COOH
—H
(DMSO-d₆1.31-1.36 2H, m, 1.77-

1.81(3H, m), 2.21(2H, d, J = 7.4

Hz), 2.68-2.75(2H, m), 3.64(2H,

brs), 3.68(3H, s), 6.52(1H, brs),

6.68(1H, brs), 6.89-6.96(2H, m),

7.92(2H, d, J = 8.4 Hz), 8.09

8.17(3H, m), 8.38(1H, d, J = 2.5

Hz), 10.54(1H, s), 12.10(1H, brs).

2648
4-CF₃Ph—
—H
—COOH
—H
(CDCl₃+ CD₃OD) 1.82-1.96(2H, m),

2.04-2.09(2H, m), 2.38-2.48(1H,

m), 2.74-2.84(2H, m), 3.52-3.61(2H,

m), 6.86(1H, dd, J = 8.9 Hz, 0.5

Hz), 6.96-7.05(4H, m), 7.69-

7.76(2H, m), 8.06(2H, d, J = 8.1

Hz), 8.16(1H, d, J = 8.1 Hz), 8.23-

8.33(2H, m).

TABLE 422

Ex-

ample

No.
R₁₁₄₁
R₁₁₄₂

¹H NMR (DMSO-d₆) δppm

2649
4-CF₃Ph—
—CH₃
1.41(2H, brs), 1.84-1.96(3H, m), 1.97(3H, s), 2.22(2H, d, J =

6.6 Hz), 2.55-2.75(2H, m), 3.58(2H, d, J = 11.9 Hz), 6.72-

7.11(4H, m), 7.52(1H, dd, J = 8.9 Hz, 2.8 Hz), 7.74(1H, d, J =

2.6 Hz), 7.89-7.99(4H, m), 10.49(1H, s), 12.14(1H, brs).

2650
3,4-Cl₂Ph—
—CH₃
1.38(2H, brs), 1.82-1.96(3H, m), 1.97(3H, s), 2.22(2H, d, J =

6.4 Hz), 2.55-2.75(2H, m), 3.59(2H, d, J = 11.9 Hz), 6.88-

6.91(4H, m), 7.51(1H, dd, J = 8.7 Hz, 2.5 Hz), 7.63(1H, dd, J =

8.4 Hz, 2.1 Hz), 7.74(1H, d, J = 2.8 Hz), 7.83-7.87(2H, m),

10.38(1H, s), 12.12(1H, brs).

2651
3,4-Cl₂Ph—
—H
1.30-1.37(2H, m), 1.75-1.91(3H, m), 2.20(2H, d, J = 6.9 Hz),

2.51-2.62(2H, m), 3.60(2H, d, J = 12.0 Hz), 6.87-6.94(5H,

m), 7.50(1H, dd, J = 8.7 Hz, 2.8 Hz), 7.62(1H, dd, J = 8.6

Hz, 2.3 Hz), 7.77(1H, d, J = 2.8 Hz), 7.84-7.89(2H, m),

10.39(1H, s), 12.09(1H, brs).

2652
4-CF₃Ph—
—H
1.29-1.33(2H, m), 1.74-1.91(3H, m), 2.19(2H, d, J = 6.8 Hz),

2.63-2.75(2H, m), 3.59(2H, d, J = 12.2 Hz), 6.86-6.93(5H,

m), 7.50(1H, dd, J = 8.9 Hz, 2.8 Hz), 7.77(1H, d, J = 2.6 Hz),

7.89-7.99(4H, m), 10.47(1H, s), 12.09(1H, brs).

2653
4-CF₃Ph—
—OCH₃
1.41(2H, brs), 1.81-1.85(3H, m), 2.25(2H, d, J = 6.4 Hz),

2.55-2.79(2H, m), 3.64(3H, s), 3.68(2H, brs), 6.73-6.95(4H,

m), 7.51(1H, dd, J = 8.7 Hz, 2.5 Hz), 7.73(1H, d, J = 2.6 Hz),

7.92-8.02(4H, m), 10.45(1H, s), 12.14(1H, brs).

2654
3,4-Cl₂Ph—
—OCH₃
1.42(2H, brs), 1.79-1.91(3H, m), 2.23(2H, d, J = 6.6 Hz),

2.76-2.83(2H, m), 3.63(5H, brs), 6.63-6.98(4H, m), 7.48(1H,

dd, J = 8.7 Hz, 2.6 Hz), 7.63(1H, dd, J = 8.4 Hz, 2.0 Hz),

7.71(1H, d, J = 2.8 Hz), 7.85-7.88(2H, m), 10.36(1H, s),

12.33(1H, brs).

TABLE 423

Ex-

ample

No.
R₁₁₄₃
R₁₁₄₄

¹H NMR (DMSO-d₆) δppm

2655
4-CF₃Ph—
—CH₃
1.81-1.99(4H, m), 2.00(3H, s), 2.41-2.44(1H, m), 2.75(2H,

brs), 3.58(2H, d, J = 12.2 Hz), 6.91-7.20(4H, m), 7.53(1H,

dd, J = 8.9 Hz, 2.6 Hz), 7.75(1H, d, J = 2.6 Hz), 7.90-

7.99(4H, m), 10.52(1H, s), 12.41(1H, brs).

2656
3,4-Cl₂Ph—
—CH₃
1.63-1.71(2H, m), 1.91-1.94(2H, m), 1.95(3H, s), 2.41-

2.48(1H, m), 2.75-2.80(2H, m), 3.58(2H, d, J = 12.9 Hz),

6.85-6.89(3H, m), 7.50(1H, dd, J = 8.7 Hz, 2.6 Hz), 7.68-

7.79(2H, m), 7.81-7.98(4H, m), 10.43(1H, s), 12.35(1H,

brs).

2657
3,4-Cl₂Ph—
—H
1.74(2H, brs), 1.93-1.98(2H, m), 2.49-2.51(2H, m),

2.88(1H, brs), 3.55-3.60(2H, m), 6.90-7.01(5H, m), 7.50-

7.89(5H, m), 10.41(1H, s), 12.13(1H, brs).

2658
4-CF₃Ph—
—H
1.66-1.71(2H, m), 1.88-1.92(2H, m), 2.34-2.42(1H, m),

2.68-2.76(2H, m), 3.56(2H, d, J = 12.4 Hz), 6.85-6.92(5H,

m), 7.48(1H, d, J = 2.8 Hz), 7.51(1H, d, J = 2.8 Hz), 7.77-

7.99(4H, m), 10.47(1H, s), 12.21(1H, s).

TABLE 424

Ex-

ample

No.
R₁₁₄₅
R₁₁₄₆

¹H NMR (DMSO-d₆) δppm

2659
—H
—CH₂COOH
1.26-1.32(2H, m), 1.74-1.91(3H, m), 2.20(2H, d, J = 6.6

Hz), 2.66(2H, t, J = 11.0 Hz), 3.63(2H, d, J = 12.5 Hz),

6.93-7.03(4H, m), 7.13-7.35(2H, m), 7.65(2H, d, J = 8.6

Hz), 8.42(1H, d, J = 2.3 Hz), 8.47(1H, d, J = 2.3 Hz),

11.00(1H, s), 12.07(1H, brs).

2660
—CH₃
—CH₂COOH
1.30-1.41(2H, m), 1.80-2.00(3H, m), 1.99(3H, s), 2.20(2H,

d, J = 6.6 Hz), 2.68-2.76(2H, m), 3.62(2H, d, J = 12.2 Hz),

6.88-6.96(3H, m), 7.33(2H, d, J = 8.2 Hz), 7.65(2H, d, J =

8.6 Hz), 8.44(2H, s), 11.00(1H, s), 12.10(1H, brs).

2661
—H
—COOH
1.63-1.70(2H, m), 1.88-1.92(2H, m), 2.41-2.45(1H, m),

2.71-2.79(2H, m), 3.61(2H, d, J = 12.5 Hz), 6.93-7.00(4H,

m), 7.31(2H, d, J = 8.6 Hz), 7.63(2H, d, J = 8.7 Hz), 8.40-

8.47(2H, m), 10.63(1H, s), 12.21(1H, s).

TABLE 425

Example

No.
R₁₁₄₇

¹H NMR (DMSO-d₆) δppm

2662
4-CF₃PhCO—
2.08(3H, s), 2.09-2.32(2H, m), 3.65-3.93(4H, m), 7.01(1H, d, J =

8.6 Hz), 7.06(1H, d, J = 8.9 Hz), 7.19(1H, dd, J = 2.6 Hz, 8.6 Hz),

7.29(1H, d, J = 2.6 Hz), 7.42-7.51(2H, m), 7.81-7.98(4H, m),

8.10-8.18(2H, m), 8.21(1H, dd, J = 2.6 Hz, 8.9 Hz), 8.43(1H, d, J =

2.6 Hz), 10.60(1H, s), 12.60-12.91(1H, m).

2663
3,4-Cl₂PhSO₂—
1.99(3H, s), 2.07-2.31(2H, m), 3.60-3.91(4H, m), 6.97(H, d, J =

8.5 Hz), 6.98(1H, d, J = 8.8 Hz), 7.16(1H, dd, J = 2.4 Hz, 8.5 Hz),

7.25(1H, d, J = 2.2 Hz), 7.40-7.51(2H, m), 7.54(1H, dd, J = 2.8

Hz, 8.8 Hz), 7.62(1H, dd, J = 2.2 Hz, 8.5 Hz), 7.75(1H, d, J = 2.8

Hz), 7.79-7.93(4H, m).

Example 2664
Production of (4-{5-[(4-trifluoromethylphenylamino)methyl]-pyridin-2-yloxy}phenyl)(4-piperonylpiperazin-1-yl)methanone

Methanesulfonic acid 6-[4-(4-piperonylpiperazine-1-carbonyl)phenoxy]pyridin-3-yl ester (0.433 g, 0.824 mmol) and 4-trifluoromethyl phenylamine (0.310 mL, 2.47 mmol) were mixed together, and the resulting mixture was stirred for 2 hours at 100° C. The formed yellow mass was stirred together with a saturated sodium bicarbonate solution, ethyl acetate and THF (20 ml of each). The organic layer was collected, washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica g column chromatography (dichloromethane:methanol=50:1), to thereby yield 0.236 g of the title compound.

Appearance: Pale yellow amorphous powder

¹H NMR (CDCl₃) δ 2.44 (4H, brs), 3.45 (2H, s), 3.57 (2H, brs), 3.75 (2H, brs), 4.30-4.35 (1H, m), 4.36 (2H, s), 5.95 (2H, s), 6.63 (2H, d, J=8.7 Hz), 6.74-6.77 (2H, m), 6.85 (1H, s), 6.93 (1H, d, J=8.4 Hz), 7.15 (2H, d, 8.4 Hz), 7.39-7.47 (4H, m), 7.71 (1H, dd, J=2.5 Hz, 8.4 Hz), 8.18 (1H, d, J=2.3 Hz).

The following compounds were produced in the same manner as in Example 2664.

TABLE 426

Example

No.
R₁₁₄₈
Xb₇₆
Xb₇₇
Form

¹H NMR (solvent) δppm

2665
3,4-Cl₂Ph—
—N(CH₃)—
CH₂
free
(CDCl₃) 2.42-2.44(4H, m), 3.03(3H, s),

3.43(2H, brs), 3.49-3.50(2H, m),

3.63(2H, brs), 4.08(2H, s), 4.94(2H, s),

5.94(2H, s), 6.70(2H, d, J = 9.2 Hz),

6.74(2H, brs), 6.80(1H, dd, J = 8.9 Hz,

2.8 Hz), 6.83-6.86(2H) 7.01(2H, d

J = 9.1 Hz), 7.05(1H, d, J = 2.8 Hz),

7.32(1H, d, J = 8.9 Hz), 7.86(1H, dd, J =

8.6 Hz, 2.5 Hz), 8.19(1H, d, J = 1.8

Hz).

2666
4-CF₃Ph—
—N(CH₃)—
—CH₂—
free
(CDCl₃) 2.41-2.44(4H, m), 3.03(3H, s),

3.43(2H, brs), 3.49(2H, brs), 3.63(2H,

brs), 4.08(2H, s), 5.02(2H, s), 5.95(2H,

s), 6.69-6.74(4H, m), 6.85-6.88(2H, m),

7.00-7.03(4H, m), 7.56(2H, d, J = 8.6

Hz), 7.72(1H, dd, J = 8.6 Hz, 2.5 Hz),

8.22(1H, d, J = 2.3 Hz).

2667
4-CF₃Ph—
none
none
hydro-
(DMSO-d₆) 3.10-3.42(8H, m), 4.24(2H,

chloride
brs), 5.20(2H, s), 6.07(2H, s), 6.97-

m), 7.15(1H, d, J = 8.6 Hz),

7.21-7.24(1H, m), 7.52(2H, d, J = 8.6

HO, 7.68(2H, d, J = 8.7 Hz), 8.01(1H,

dd, J = 2.5 Hz, 8.4 Hz), 8.29(1H, d, J =

2.3 Hz), 11.00(1H, brs).

Example 2668
Production of 2-(methyl-{4-[5-(5-trifluoromethylpyridin-2-yloxymethyl)pyridin-2-yloxy]phenyl}amino)-1-(4-piperonylpiperazin-1-yl)ethanone

2-{[4-(5-hydroxymethylpyridin-2-yloxy)phenyl]methylamino}-1-(4-piperonylpiperazin-1-yl)ethanone (0.98 g, 2.0 mmol) was dissolved in DMF (30 mL). To the resulting solution was added 60% sodium hydride (60%, 88 mg, 2.2 mmol) under ice cooling, and this solution was stirred for 30 minutes at 0° C. To the reaction solution was added 2-chloro-5-(trifluoromethyl)pyridine (0.36 g, 2.0 mol), and this solution was stirred under a nitrogen atmosphere for 3 hours at 60° C. The resulting reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate, and this solution was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:5), to thereby yield 0.68 g of the title compound.

Appearance: White powder

¹H NMR (CDCl₃) δ 2.41-2.44 (4H, m), 3.02 (3H, s), 3.43 (2H, s), 3.48 (2H, brs), 3.63 (2H, brs), 4.08 (2H, s), 5.37 (2H, s), 5.94 (2H, s), 6.68-6.77 (4H, m), 6.81-6.84 (3H, m), 7.00 (2H, d, J=9.1 Hz), 7.72-7.79 (2H, m), 8.27 (1H, d, J=2.3 Hz), 8.44 (1H, brs).

The following compounds were produced in the same manner as in Example 2668.

TABLE 427

Example

No.
R₁₁₄₉
mp (° C.)

2669
4-CF₃Ph—
165.0-166.0

2670
3-CF₃Ph—
163.0-165.0

2671
3,4-Cl₂Ph—
160.0-161.5

Example 2672
3,4-dichloro-N-{6-[4-(3,5-dioxoisoxazolidine-4-ylidenemethyl)phenoxy]pyridin-3-yl}benzamide

TO a solution of hydroxylamine hydrochloride (500 mg, 1.0 mmol) in water (0.2 mL) were added sodium carbonate (1.05 g, 9.91 mmol) and a solution of 2-{4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]benzylidene}malonic acid dimethyl ester (500 mg, 1.0 mmol) in THF (5 mL). To the resulting solution was subsequently added methanol (5 mL) and stirred for 8 hours at 60° C. The reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1). To the resulting white precipitate was added ethyl acetate, filtered, and the filtrate was washed with diethyl ether, to thereby yield 105 mg of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 7.12 (1H, d, J=8.9 Hz), 7.14 (2H, d, J=8.8 Hz), 7.63 (2H, d, J=8.8 Hz), 7.84 (1H, d, J=8.4 Hz), 7.95 (1H, dd, J=8.4 Hz, 2.0 Hz), 8.15 (1H, s), 8.22 (1H, dd, J=8.9 Hz, 2.6 Hz), 8.22 (1H, d, J=2.0 Hz), 8.51 (1H, d, J=2.6 Hz), 10.57 (1H, s), 11.16 (1H,

Example 2673
Production of 3,4-dichloro-N-{6-[4-(5-methyl-[1,2,4]oxadiazol-3-ylmethyl)phenoxy]pyridin-3-yl}benzamide monohydrochloride

To 3,4-dichloro-N-{6-[4-(N-acetoxycarbamimidoylmethyl)phenoxy]pyridin-3-yl}benzamide (340 mg, 0.788 mmol) was added acetic acid (4 mL), and the resulting solution was stirred under reflux for 10 minutes. This reaction solution was concentrated under reduced pressure. To the residue was added a saturated sodium bicarbonate solution, and the resulting solution was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=40:1), and the obtained reside was dissolved in ethyl acetate (5 mL). To this solution was added a solution of 4 N hydrogen chloride in ethyl acetate until the compound no longer precipitated out. The obtained white powder was filtered, and washed with diethyl ether, to thereby yield 154 mg of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 2.55 (3H, s), 4.05 (2H, s), 7.07 (1H, d, J=8.7 Hz), 7.07 (2H, d, J=8.6 Hz), 7.33 (2H, d, 8.6 Hz), 7.83 (1H, d, J=8.4 Hz), 7.96 (1H, dd, J=8.4 Hz, 2.0 Hz), 8.21 (1H, dd, J=8.7 Hz, 2.6 Hz), 8.24 (1H, d, J=2.0 Hz), 8.48 (1H, d, J=2.6 Hz), 10.62 (1H, s).

Example 2674
Production of 1-(3-{4-[5-(3,4-dichlorobenzoylamino)-2-pyridylmethyl]phenyl}propionyl)-4-piperonylpiperazine monohydrochloride

To a solution of ethyl 3-(4-{5-[bis(3,4-dichlorobenzoyl)amino]2-pyridylmethyl}phenyl) propionate (177 mg, 0.281 mmol) in THF (5 mL) and ethanol (5 mL) were added 5 M aqueous sodium hydroxide (0.0929 mL, 0.463 mmol) and water (1 mL), and the resulting solution was refluxed for 1 hour. To this reaction solution was added 5 M hydrochloric acid (0.12 mL), and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was dissolved in DMF (3 mL), and to the resulting solution were then added 1-piperonylpiperazine (102 mg, 0.463 mmol), triethylamine (0.137 mL, 0.983 mmol) and diethyl cyanophosphonate (0.0703 mL, 463 mmol), and stirred for 1.5 hours at room temperature. Water was added to the resulting reaction solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=70:1→40:1→20:1), to thereby yield 44.1 mg of a free form. This free form was dissolved in ethanol (5 mL) and 5 M hydrochloric acid (0.03 mL) by heating. The solvent was then evaporated, and the obtained solid was recrystallized from water-containing isopropanol, to thereby yield 19.6 mg of the title compound.

Appearance: Pale yellow powder

Melting point: 181-183° C.

Example 2675
Production of N-(6-{4-[4-(5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-ylmethyl)piperazine-1-carbonyl]-phenoxy}pyridin-3-yl)-4-trifluoromethylbenzamide monooxalate

To a suspension of N-{6-[4-(4-hydrazinocarbonylmethylpiperazine-1-carbonyl)phenoxy]pyridin-3-yl}-4-trifluoromethylbenzamide trihydrochloride (300 mg, 0.46 mmol) in THF (7 mL) was added triethylamine (0.29 mL, 2.08 mmol), and the resulting solution was stirred for 10 minutes at room temperature. To the solution was added N,N′-carbonyldiimidazole (97 mg, 0.60 mmol) under ice cooling, and the resulting solution was stirred for 1 hour at room temperature. The reaction solution was concentrated under reduced pressure. To the residue was added a saturated sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was then purified by silica gel column chromatography (chloroform:methanol=15:1). The obtained residue was dissolved in ethanol, and to the resulting solution was added oxalic acid. Ethanol was evaporated under reduced pressure, after which the solidified white substance was filtered, and washed with diethyl ether, to thereby yield 140 mg of the title compound.

Appearance: White powder

¹H NMR (DMSO-d₆) δ 2.31-2.69 (4H, m), 3.53 (2H, s), 3.53 (4H, brs), 7.16 (1H, d, J=8.9 Hz), 7.17 (2H, d, J=8.5 Hz), 7.45 (2H, d, J=8.5 Hz), 7.94 (2H, d, J=8.1 Hz), 8.17 (2H, d, J=8.1 Hz), 8.26 (1H, dd, J=8.9 Hz, 2.7 Hz), 8.55 (1H, d, J=2.7 Hz), 10.67 (1H, s), 12.27 (1H, s).

Example 2676
Production of 4-(4-{4-[4-(3,4-dichlorobenzoylamino)-2-fluorophenoxy]phenyl}-4-hydroxybutyryl)morpholine

To a suspension of 4-(4-{4-[4-(3,4-dichlorobenzoylamino)-2-fluorophenoxy]phenyl}-4-oxobutyryl)morpholine (1.00 g, 1.83 mmol) in THF (20 mL) and methanol (5 mL) was added sodium borohydride (0.0694 g, 1.83 mmol), and the resulting solution was stirred for 1 hour at room temperature. To this reaction solution were added water and saturated aqueous ammonium chloride, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1). The obtained solid was recrystallized from water-containing isopropanol, to thereby yield 0.850 g of the title compound.

Appearance: White powder

Melting point: 108-111° C.

The following compounds were produced in the same manner as in Example 2676.

TABLE 428

Ex-

ample

No.
R₁₁₅₀
Form
mp (° C.)

2677
morpholino
free
142-145

2678

embedded image

free
150-152

2679

embedded image

hydro- chloride
197-199

2680

embedded image

hydro- chloride
222-225

TABLE 429

Ex-

ample

No.
Xb₇₈
R₁₁₅₁
Form
mp (° C.) or ¹H NMR

2681
—O—

embedded image

free

¹H NMR (DMSO-d₆) δ 2.38- 2.54(6H, m), 3.58(4H, t, J = 4.5 Hz), 4.73-4.77(1H, m), 5.06 (1H, d, J = 3.8 Hz), 7.04-7.07(3H, m), 7.38(2H, d, J = 8.4 Hz), 7.84 (1H, d, J = 8.4 Hz), 7.95(1H, dd, J = 8.4 Hz, 1.2 Hz), 8.22(1H, d, J = 2.0 Hz), 8.19(1H, dd, J = 8.9 Hz, 2.8 Hz), 8.48(1H, d, J = 2.6 Hz), 10.55(1H, brs).

2682
—CH(OH)—

embedded image

oxalate
mp 102-108

TABLE 430

Example

No.
R₁₁₅₂
Xb₇₉

¹H NMR (CDCl₃) δppm

2683
—OCH₃
—CH₂—
2.30-2.39(4H, m), 2.57-2.62(2H, m), 2.90-2.95(2H, m), 3.36-

3.43(4H, m), 3.58-3.61(2H, m), 3.70(3H, s), 5.83(1H, s),

5.93(2H, s), 6.69-6.88(6H, m), 6.99(1H, d, J = 8.1 Hz), 7.47-

7.62(5H, m), 8.07(1H, d, J = 2.3 Hz).

2684
—H
—N(CH₃)—
2.38-2.43(4H, m), 2.99(3H, s), 3.42-3.60(6H, m), 4.05(2H, s),

5.77(1H, s), 5.94(2H, s), 6.64-6.84(6H, m), 6.93-6.99(2H, m),

7.47(2H, d, J = 8.1 Hz), 7.53-7.59(3H, m), 8.10(1H, d, J = 2.1

Hz).

Example 2685
Production of {6-[4-(4-piperonylpiperazin-1-ylmethyl)phenoxy]pyridin-3-ylmethyl}-(4-trifluoromethylphenyl)amine

To a suspension of lithium aluminum hydride (0.106 g, 2.80 mmol) in THF (10 mL) was added dropwise a solution of 6-[4-(4-piperonylpiperazine-1-carbonyl)phenoxy]-N-(4-trifluoromethylphenyl)nicotinamide (0.423 g, 0.700 mmol) in THF (10 mL) under ice cooled stirring. Once the entire amount was added dropwise, the solution temperature was slowly raised, and stirred under reflux for 2 hours. After cooling, ice water (50 mL) was added to the solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=40:1), to thereby yield 0.125 g of the title compound.

Appearance: Pale Yellow oil

MS 576 (M⁺)

The following compounds were produced in the same manner as in Example 2685.

Example 2686
N-[6-(2-fluoro-4-{methyl[2-(4-piperonylpiperazin-1-yl)ethyl]amino}phenoxy)pyridin-3-yl]-3,4-dichlorobenzenesulfonamide

¹H NMR (CDCl₃) δ 2.50-2.55 (10H, m), 2.92 (3H, s), 3.41-3.45 (4H, m), 5.93 (2H, s), 6.39-6.49 (2H, m), 6.73-6.74 (2H, m), 6.84-6.89 (2H, m), 6.99 (1H, t, J=9.1 Hz), 7.42-7.70 (4H, m), 7.81 (1H, brs).

Example 2687
Production of 3-(3-methyl-4-{5-[2-(4-trifluoromethylphenyl)ethyl]pyridin-2-yloxy}phenyl)-1-piperonyltetrahydropyrimidin-2-one hydrobromide

To a solution of 3-(3-methyl-4-{5-[(E)-2-(4-trifluoromethylphenyl)vinyl]pyridin-2-yloxy}phenyl)-1-piperonyltetrahydropyrimidin-2-one (0.16 g, 6.27 mmol) in ethyl acetate (15 mL) was added 5% platinum-carbon (0.05 g) under a nitrogen atmosphere, and the resulting solution was then stirred under a hydrogen atmosphere for 4.5 hours at room temperature. The resulting reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:=n-hexane 1:4-1:2), and to the resulting product was added hydrobromide, to thereby yield 50 mg of the title compound.

Appearance: Colorless amorphous powder

¹H NMR (DMSO-d₆) δ 1.85-2.09 (5H, m), 2.77-3.02 (4H, m), 3.15-3.33 (2H, m), 3.55-3.70 (2H, m), 3.75-4.15 (1H, m), 4.40 (2H, s), 5.99 (2H, s), 6.76 (1H, dd, J=1.5 Hz, 7.8 Hz), 6.80-6.98 (4H, m), 7.10 (1H, dd, J=2.6 Hz, 8.5 Hz), 7.19 (1H, d, J=2.6 Hz), 7.44 (2H, d, J=8.1 Hz), 7.62 (2H, d, J=8.1 Hz), 7.71 (1H, dd, J=2.4 Hz, 8.4 Hz), 7.91 (1H, d, J=2.4 Hz).

The following compounds were produced in the same manner as in Reference Example 673.

TABLE 431

Example

No.
R₁₁₅₃
R₁₁₅₄
M

¹H NMR (CDCl₃) δppm

2688
—H
piperonyl
1
1.31-1.45(2H, m), 1.84-2.02(3H, m), 2.30(2H, d, J =

6.8 Hz), 2.41-2.43(4H, m), 2.72(2H, t, J = 12.2 Hz),

3.43(2H, s), 3.44-3.65(6H, m), 5.95(2H, s), 6.71-

6.77(2H, m), 6.85-7.00(6H, m), 7.21-7.26(3H, m),

7.51(2H, d, J = 8.6 Hz), 7.98(1H, dd, J = 8.7 Hz, 2.6

Hz), 8.60(1H, d, J = 2.6 Hz).

2689
—H
—H
1
1.38-1.46(2H, m), 1.84-2.00(3H, m), 2.31(2H, d, J =

6.8 Hz), 2.71(2H, t, J = 12.2 Hz), 2.86-2.89(4H, m),

3.48-3.63(7H, m), 6.86-6.99(5H, m), 7.23-7.29(3H,

m), 7.49(2H, d, J = 8.4 Hz), 7.97(1H, dd, J = 8.9 Hz,

2.6 Hz), 8.60(1H, d, J = 2.1 Hz).

2690
—CH₃
piperonyl
1
1.36-1.40(2H, m), 1.82-2.02(3H, m), 2.03(3H, s),

2.30(2H, d, J = 6.8 Hz), 2.41-2.43(4H, m), 2.68(2H,

t, J = 12.0 Hz), 3.43(2H, s), 3.49-3.65(6H, m),

5.94(2H, s), 6.74-6.89(8H, m), 7.24(2H, d, J = 8.2

Hz), 7.49(2H, d, J = 8.6 Hz), 7.99(1H, dd, J = 8.7

Hz, 2.5 Hz), 8.58(1H, d, J = 2.1 Hz).

2691
—H
piperonyl
0
1.78-2.03(4H, m), 2.46(4H, brs), 2.55-2.77(3H, m),

3.46(2H, s), 3.55(2H, brs), 3.67(4H, brs), 5.95(2H,

s), 6.75-6.78(2H, m), 6.85-7.01(6H, m), 7.21-

7.26(3H, m), 7.52(2H, d, J = 8.6 Hz), 7.98(1H, dd, J =

8.7 Hz, 2.6 Hz), 8.60(1H, d, J = 2.5 Hz).

Example 2692
Production of 1-[3-(4-{1-[5-(3,4-dichlorobenzoylamino)-2-pyridyl]-1-hydroxyimino}methylphenyl)propionyl]-4-piperonylpiperazine

To a solution of 1-(3-{4-[5-(3,4-dichlorobenzoylamino)pyridine-2-carbonyl]phenyl}propionyl)-4-piperonylpiperazine (0.330 g, 0.511 mmol) in pyridine (7 mL) was added hydroxylamine hydrochloride (53.3 mg, 0.767 mmol), and the resulting solution was refluxed for 0.5 hours. The reaction solution was concentrated under reduced pressure, and to the residue was added brine. This solution was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=15:1), whereby 0.225 g of the title compound was obtained as a mixture of the syn form and the anti form (1:1) of the oxime.

Appearance: Colorless amorphous powder

¹H NMR (CDCl₃) δ 2.21-2.39 (4H, m), 2.49-2.60 (2H, m), 2.78-2.90 (2H, m), 3.29-3.44 (4H, m), 3.55 (2H, s), 5.90 (2H, s), 6.62-6.73 (2H, m), 6.80 (1H, s), 7.07 (1H, d, J=7.7 Hz), 7.12 (1H, d, J=7.7 Hz), 7.15-7.30 (2.5H, m), 7.39 (0.5H, d, J=8.4 Hz), 7.42 (0.5H, d, J=8.4 Hz), 7.45-7.51 (0.5H, m), 7.62-7.74 (1H, m), 7.94 (0.5H, d, J=2.0 Hz), 7.99 (0.5H, d, J=2.0 Hz), 8.09-8.28 (1H, m), 8.62 (0.5H, s), 8.85 (0.5H, s), 9.40 (0.5H, brs), 9.62 (0.5H, brs), 10.21 (0.5H, brs), 13.85 (0.5H, brs).

Example 2693
Production of 4-(2-oxo-3-{4-[5-(4-trifluoromethylbenzoylamino)pyridin-2-yloxy]phenyl}propionyl)piperazine-1-carboxylic acid t-butyl ester

To a solution of 4-(2-hydroxy-3-{4-[5-(4-trifluoromethylbenzoylamino)pyridin-2-yloxy]phenyl}propionyl)piperazine-1-carboxylic acid butyl ester (0.58 g, 0.94 mmol) in dichloromethane (4 mL) was added a Dess-Martin reagent (0.8 g, 1.89 mmol), and the resulting solution was then stirred under a nitrogen gas flow for 4 hours at room temperature. The reaction solution was concentrated under reduced pressure. To the residue was added 1 N aqueous sodium hydroxide (50 mL), and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel chromatography (dichloromethane:methanol=50:1), to thereby yield 0.31 g of the title compound.

Appearance: Yellow powder

¹H NMR (CDCl₃) δ 1.41 (9H, s), 2.99-3.22 (4H, m), 3.25-3.41 (2H, m), 3.42-3.60 (2H, m), 4.04 (2H, s), 6.97 (1H, d, J=8.9 Hz), 7.10 (2H, d, J=8.4 Hz), 7.27 (2H, d, J=8.4 Hz), 7.73 (2H, d, J=8.0 Hz), 7.99 (2H, d, J=8.0 Hz), 8.13 (1H, d, J=2.8 Hz), 8.30 (18, dd, J=8.9 Hz, 2.8 Hz), 8.45 (1H, brs).

Example 2694
Production of 3,4-dichloro-N-{3-fluoro-4-[4-(1-hydroxy-2-morpholine-4-ylethyl)phenoxy]phenyl}benzamide

3,4-Dichloro-N-{3-fluoro-4-[4-(1-hydroxy-2-morpholine-4-ylethyl)phenoxy]phenyl}benzamide (37.4 g) was recrystallized from ethanol (700 mL) to yield 34.34 g of the title compound.

Appearance: White powder

Melting point: 175-176° C.

Example 2695
Production of N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-fluorophenoxy)pyridin-3-yl]-3,4-dichlorobenzenesulfonamide

N-[6-(4-{[2-(4-Piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-fluorophenoxy)pyridin-3-yl]-3,4-dichlorobenzenesulfonamide (8.15 g) was recrystallized from ethanol (60 mL) to yield 7.78 g of the title compound.

Appearance: White powder

Melting point: 163-166° C.

Example 2696
Production of N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide

N-[6-(4-{[2-(4-Piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide (5.1 g, 7.7 mmol) was recrystallized from acetone (15 mL) to yield 3.7 g of the title compound.

Appearance: White powder

Melting point: 128-131° C.

Example 2697
Production of N-{6-[4-(4-benzylpiperazine-1-carbonyl)phenoxy]pyridin-3-yl}-4-trifluoromethylbenzamide

N-{6-[4-(4-Benzylpiperazine-1-carbonyl)phenoxy]pyridin-]-yl}-4-trifluoromethylbenzamide (78.86 g) was recrystallized from ethanol (530 mL) to yield 96.66 g of the title compound.

Appearance: White needles

Melting point: 177.6-179.2° C.

Example 2698
Production of N-(6-{4-[4-(2-oxo-1,2,3,4-tetrahydroquinoline-6-ylmethyl)piperazine-1-carbonyl]phenoxy}-pyridin-3-yl)-4-trifluoromethylbenzamide

To a solution of 4-[5-(4-trifluoromethylbenzoylamino)pyridin-2-yloxy]benzoic acid (4.30 g, 10.7 mmol) in DMF (150 mL) were added 1-(2-oxo-1,2,3,4-tetrahydroquinoline-6-ylmethyl)piperazine (2.6 g, 10.7 mmol), 1-hydroxybenzotriazole monohydrate (1.64 g, 10.7 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.46 g, 12.8 mmol) under ice cooling, and the resulting solution was stirred for 1 hour under ice cooling and for 17 hours at room temperature. This reaction solution was concentrated under reduced pressure. To the residue was added a saturated sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was recrystallized from ethyl acetate, to thereby yield 5.24 g of the title compound.

Appearance: White powder

Melting point: 250.5-252.5° C.

Example 2699
Production of N-(6-{4-[4-(4-benzylpiperidine-1-carbonyl)piperazine-1-carbonyl]phenoxy}pyridin-3-yl)-3,4-dichlorobenzamide

To a solution of 1-{4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]benzoyl}piperidine-4-carboxylic acid (4.5 g, 8.8 mmol) in DMF (88 mL) were added 1-benzylpiperazine (1.83 mL, 10.5 mmol), 1-hydroxybenzotriazole monohydrate (1.61 g, 10.5 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.02 g, 10.5 mmol) under ice cooling, and the resulting solution was stirred overnight at room temperature. To this reaction solution was added a saturated sodium bicarbonate solution, and the resulting solution was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was recrystallized from isopropyl alcohol (700 mL), to thereby yield 3.2 g of the title compound.

Appearance: White powder

Melting point: 223-225° C.

Example 2700
Production of N-[6-(4-{[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide

To a suspension of 1-(4-benzylpiperazin-1-yl)-2-{methyl[3-methyl-4-(5-nitropyridin-2-yloxy)phenyl]amino}ethanone (2.85 g, 6.0 mmol) in ethyl acetate (30 mL) was added 5% platinum-carbon (0.30 g) under a nitrogen atmosphere, and the resulting solution was stirred for 3 hours at 40° C. under a hydrogen atmosphere. The platinum-carbon was separated off with Celite, and the filtrate was concentrated. The residue was dissolved in THF (30 mL), and to this solution was added triethylamine (1.26 mL, 9.1 mmol) under ice cooling. To the resulting solution was then added dropwise 4-(trifluoromethyl)benzoyl chloride (1.16 mL, 7.8 mmol). This reaction solution was stirred overnight, then a saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1). The resulting product was then recrystallized from a mixed solvent consisting of diisopropyl ether-acetone, to thereby yield 1.37 g of the title compound.

Appearance: White powder

Melting point: 112-113° C.

Example 2701
Production of (4-benzylpiperazin-1-yl)(4-{5-[methyl(4-trifluoromethylbenzyl)amino]pyridin-2-yloxy}phenyl)methanone

To a solution of (4-benzylpiperazin-1-yl){4-[5-(4-trifluoromethylbenzylamino)pyridin-2-yloxy]phenyl}methanone (5.40 g, 9.88 mmol) in methanol (150 mL) were added 37% aqueous formaldehyde (2.8 mL), sodium cyanoborohydride (1.86 g, 29.6 mmol) and acetic acid (1.7 mL) under ice cooling, and the resulting solution was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. Water was added to the residue, and this solution was neutralized with a saturated sodium bicarbonate solution, and extracted with chloroform. The organic layer was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform:methanol=60:1). To the resulting product was then added a solution of 4 M hydrogen chloride in ethyl acetate until the resulting solution had a pH of 1. The precipitates were collected by filtration and recrystallized from ethanol (80 mL), to thereby yield 2.5 g of the title compound.

Appearance: White powder

Melting point: 180-183.5° C.

Example 2702
Production of 4-piperonylpiperazine-1-carboxyl 4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]benzylamide hydrochloride

To a solution of 4-piperonylpiperazine-1-carboxyl 4-(5-aminopyridin-2-yloxy)benzylamide (2.48 g, 5.4 mmol) in THF (50 mL) were added triethylamine (0.9 mL, 6.5 mmol) and 3,4-dichlorobenzoyl chloride (1.13 g, 5.4 mmol) under ice cooling, and the resulting solution was stirred under ice cooling for 10 minutes. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=25:1) to yield 2.97 g of a white powder. This white powder was dissolved in ethanol (45 mL), and to the resulting solution was added a solution of 4 M hydrogen chloride in ethyl acetate until the solution had a pH of 1. The precipitates were collected by filtration and recrystallized from 83% ethanol (36 mL), to thereby yield 2.72 g of the title compound.

Appearance: White powder

Melting point: 243.5-246.5° C.

Example 2703
Production of N-[6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzenesulfonamide

N-[6-(4-{4-[2-(4-Piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzenesulfonamide (1.35 g) was recrystallized from ethanol (20 mL) to yield 1.23 g of the title compound.

Appearance: White powder

Melting point: 156-158° C.

Example 2704
Production of N-(6-{4-[4-(4-piperonylpiperazine-1-carbonyl)piperidin-1-yl]phenoxy}pyridin-3-yl)-3,4-dichlorobenzenesulfonamide

N-(6-{4-[(4-(4-Piperonylpiperidine-1-carbonyl)piperidin-1-yl]phenoxy}pyridin-3-yl)-3,4-dichlorobenzenesulfonamide (1.95 g) was recrystallized from ethanol (35 mL) to yield 1.70 g of the title compound.

Appearance: White powder

Melting point: 130-133° C.

Example 2705
Production of N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide

N-[6-(4-{[2-(4-Piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide (0.86 g, 1.30 mmol) was recrystallized from a mixed solvent of acetone (3 mL) diethyl ether (4 mL) and n-hexane (1 mL) to yield 0.72 g of the title compound.

Appearance: Pale yellow powder

Melting point: 154-155° C.

Example 2706
Production of N-(6-{4-[4-(4-benzylpiperazine-1-carbonyl)piperidin-1-yl]phenoxy}pyridin-3-yl)-4-trifluoromethylbenzensulfonamide

N-(6-{4-[4-(4-Benzylpiperidin-1-carbonyl)piperidin-1-yl]phenoxy}pyridin-3-yl)-4-trifluoromethylbenzensulfonamide (1.55 g) was recrystallized from ethanol (60 mL) to yield 1.41 g of the title compound.

Appearance: White powder

Melting point: 199-201° C.

Example 2707
Production of N-[6-(4-{4-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}-2-methylphenoxy)pyridin-3-yl]-3,4-dichlorobenzenesulfonamide

To a solution of (1-{4-[5-(3,4-dichlorobenzenesulfonylamino)pyridin-2-yloxy]-3-methylphenyl}piperidine-4-yl)acetic acid (1.70 g, 3.1 mmol) and 1-benzylpiperazine (0.71 g, 4.0 mmol) in DMF (40 mL) were added triethylamine (1.08 mL, 7.8 mmol) and diethyl cyanophosphonate (0.76 g, 4.3 mmol) under ice cooling, and the resulting solution was stirred for 1 hour under ice cooling. To this reaction solution was added a saturated sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=40:1), after which the resulting product was recrystallized from ethanol, to thereby yield 1.61 g of the title compound.

Appearance: White needles

Melting point: 151-155° C.

Example 2708
Production of N-[6-(4-{[2-(4-benzothiazole-6-ylmethylpiperazin-1-yl)-2-oxoethyl]methylamino}-phenoxy)pyridin-3-yl]-3,4-dichlorobenzamide dihydrochloride

To a solution of ({4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]phenyl}methylamino)acetic acid (1.02 g, 2.3 mmol) and 1-(benzothiazole-6-ylmethyl)piperazine (0.58 g, 2.5 mmol) in DMF (15 mL) were added triethylamine (0.95 mL, 6.9 mmol) and diethyl cyanophosphonate (0.447 mL, 2.7 mmol) under ice cooling, and the resulting solution was stirred for 30 minutes under ice cooling and for 45 minutes at room temperature. Water was added to the solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1) to obtain 1.28 g of a white powder. This white powder was dissolved in ethanol (15 mL), and to the resulting solution was added a solution of 4 M hydrogen chloride in ethyl acetate until the resulting solution had a pH of 1. The precipitates were collected by filtration and recrystallized from 85% ethanol (30 mL), to thereby yield 1.06 g of the title compound.

Appearance: White powder

Melting point: 202-223° C.

Example 2709
Production of 3,4-dichloro-N-{6-[4-({2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)piperazin-1-yl]-2-oxoethyl}methylamino)phenoxy]pyridin-3-yl}benzamide maleate

To a solution of ({4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]phenyl}methylamino)acetic acid (2.50 g, 5.6 mmol) in DMF (55 mL) were added 1-(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)piperazine (1.7 g, 7.3 mmol), 1-hydroxybenzotriazole monohydrate (0.86 g, 5.6 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.29 g, 6.7 mmol) under ice cooling, and the resulting solution was stirred for 30 minutes under ice cooling and for 17 hours at room temperature. This reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was dissolved in ethanol (30 mL). To the resulting solution was added maleic acid (0.32 g, 2.7 mmol), and this solution was left to stand. The precipitates were collected by filtration, to thereby yield 1.45 g of the title compound.

Appearance: Pale yellow powder

Melting point: 188-190° C.

Example 2710
Production of N-(6-{4-[4-(4-benzylpiperazine-1-carbonyl)piperidin-1-yl]phenoxy}pyridin-3-yl)-3,4-dichlorobenzenesulfonamide

N-(6-{4-[4-(4-Benzylpiperazine-1-carbonyl)piperidin-1-yl]phenoxy}pyridin-3-yl)-3,4-dichlorobenzenesulfonamide (0.79 g) was recrystallized from ethanol (15 mL) to yield 0.67 g of the title compound.

Appearance: White powder

Melting point: 185-189° C.

Example 2711
Production of N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-pyrrole-1-ylbenzamide

N-[6-(4-{[2-(4-Piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-pyrrole-1-ylbenzamide (2.49 g) was recrystallized from a mixed solvent consisting of acetone (20 mL) and diethyl ether (30 mL) to yield 2.26 g of the title compound.

Appearance: Pale yellow powder

Melting point: 163.1-166.5° C.

Example 2712
Production of N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-fluorophenoxy)pyridin-3-yl]-4-trifluoromethylbenzenesulfonamide

N-[6-(4-{[2-(4-Piperonylpiperazin-1-yl)-2-oxoethyl]ethylamino}-2-fluorophenoxy)pyridin-3-yl]-4-trifluoromethylbenzenesulfonamide (8.18 g) was recrystallized from a mixed solvent consisting of ethyl acetate (70 mL) and n-hexane (20 mL) to yield 6.93 g of the title compound.

Appearance: White powder

Melting point: 177.8-180.1° C.

Example 2713
Production of 6-(4-{4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl]-2-methylphenoxy}pyridine-3-sulfonyl-(4-trifluoromethylphenyl)amide

6-(4-{4-[2-(4-Piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl]-2-methylphenoxy}pyridine-3-sulfonyl-(4-trifluoromethylphenyl)amide (1.50 g) was recrystallized from ethanol (20 mL) to yield 1.40 g of the title compound.

Appearance: White powder

Melting point: 156-160° C.

Example 2714
Production of N-[6-(4-{[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide

N-[6-(4-{[2-(4-Piperonylpiperazin-1-yl)-2-oxoethyl]methylamino}-2-methylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide (2.1 g, 3.2 mmol) was heated to dissolve in acetone (5 mL), and to the resulting solution was then added diethyl ether (10 mL), whereby recrystallization yielded 2.0 g of the title compound.

Appearance: White powder

Melting point: 113-116° C.

Example 2715
Production of 3,4-dichloro-N-{3-fluoro-4-[4-(1-hydroxy-2-morpholine-4-ylethyl)phenoxy]phenyl}benzamide

3,4-Dichloro-N-{3-fluoro-4-[4-(1-hydroxy-2-morpholine-4-ylethyl)phenoxy]phenyl}benzamide (5 g) was recrystallized from ethyl acetate-n-hexane to yield 4.73 g of the title compound.

Appearance: White powder

Melting point: 169-170° C.

Example 2716
Production of N-(6-{4-[4-(4-piperonylpiperazine-1-carbonyl)piperidine-1-carbonyl]phenoxy}pyridin-3-yl)-3,4-dichlorobenzamide

To a solution of 1-{4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]benzoyl}piperidine-4-carboxylic acid (7.96 g, 15.5 mmol) in DMF (160 mL) were added 1-piperonylpiperazine (3.75 g, 17.6 mmol), 1-hydroxybenzotriazole monohydrate (2.85 g, 18.6 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.56 g, 18.6 mmol) under ice cooling, and the resulting solution was stirred for overnight at room temperature. This reaction solution was concentrated under reduced pressure. To the residue were added water and ethyl acetate, and the resulting solution was vigorously stirred. The resulting precipitates were collected by filtration and recrystallized from a dichloromethane-methanol mixed solvent, to thereby yield 7.36 g of the title compound.

Appearance: White powder

Melting point: 236-238° C.

Example 2717
Production of N-{6-[(4-[4-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenyl)methylamino]-pyridin-3-yl]-4-trifluoromethylbenzamide

To a solution of [1-(4-{methyl[5-(4-trifluoromethylbenzoylamino)pyridin-2-yl]amino}phenyl)piperidine-4-yl]acetic acid (0.80 g, 1.6 mmol) in DMF (10 mL) were added 1-piperonylpiperazine (0.41 g, 1.9 mmol), 1-hydroxybenzotriazole monohydrate (0.24 g, 1.6 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.39 g, 2.0 mmol) under ice cooling, and the resulting solution was stirred for 3 hours at room temperature. This reaction solution was concentrated under reduced pressure. To the residue was added a saturated sodium bicarbonate solution, and extracted with dichloromethane. The dichloromethane layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1). The resulting product was then recrystallized from a mixed solvent consisting of 95% ethanol-dichloromethane, to thereby yield 1.05 g of the title compound.

Appearance: White powder

Melting point: 210-212° C.

Formulation Example 1

100 g of the N-[6-(4-{4-[2-(piperonylpiperazin-1-yl)-2-oxoethyl]piperidin-1-yl}phenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide obtained in Example 319, 40 g of Avicel (Tradename, manufactured by Asahi Kasei Corporation), 30 g of cornstarch and 2 g of magnesium stearate were mixed and ground together. The resulting mixture was then formed into a sugar-coated R 10-mm-tablets using a pestle. The obtained tablets were coated with a film coating agent containing 10 g of TC-5 (Tradename, manufactured by Shin-Etsu Chemical Co., Ltd., hydroxypropylmethyl cellulose), 3 g of polyethylene glycol 6000, 40 g of castor oil and a suitable amount of ethanol, to thereby prepare a film-coated tablet.

Pharmacological Test

LI90 cells, a human stellate cell line, were seeded on 12-well plastic plates in DMEM (DULBECCO'S modified eagle medium) supplemented with 10% fetal bovine serum, and were cultured for 24 hours in a carbon dioxide (CO₂) incubator (set temperature: 37° C., set CO₂concentration: 5%). The cultured cells were then washed with D-PBS(−) (DULBECCO's phosphate buffered saline), and subsequently further cultured for 3 days in MEM (Eagle's minimum essential medium) supplemented with 0.1% fetal bovine serum. The cultured cells were again washed with D-PBS(−), and cultured for 16 hours in MEM (0.1% fetal bovine serum with respect to a total MEM volume) which contained a test compound and 10 pM h-TGF-β1 (human transforming growth factor β1). Next, the cultured LI90 cells were washed with D-PBS(−), and cultured for 24 hours in MEM containing ³H-proline (radioactive labelled compound) and 0.25 mM ascorbic acid. The produced collagen was labelled with RI (radioactive isotope). From this culture supernatant, an acid-soluble fraction was extracted. Radioactivity was measured for this fraction. The measured value was taken to be the collagen synthesis activity.

Radioactivity of the culture supernatant cultured with the test compound was compared with that of the culture supernatant cultured without the test compound to calculate a collagen synthesis inhibitory activity (T/C) and determine a concentration (μM) at which collagen synthesis was inhibited by 50% (IC50=a concentration of the test compound at which T/C corresponded to 0.5).

T/C=(Radioactivity of culture supernatant cultured with the test compound)/(radioactivity of culture supernatant cultured without the test compound)

These results are shown in Table 432.

TABLE 432

Collagen synthesis inhibitory activity

Text compound
IC50 (μM)

Example No. 148
0.0230

Example No. 305
0.0069

Example No. 319
0.0019

Example No. 433
0.0130

Example No. 582
0.0370

Example No. 590
0.0380

Example No. 592
0.0950

Example No. 768
0.0860

Example No. 790
0.0055

Example No. 800
0.0290

Example No. 1039
0.0220

Example No. 1049
0.0490

Example No. 1110
0.0390

Example No. 1503
0.0078

Example No. 2063
0.0300

Example No. 2100
0.0790

Example No. 2322
0.0640

Example No. 2362
0.0440

Example No. 2600
0.0220

Example No. 2601
0.0260

Number	Date	Country	Kind
2004-230092	Aug 2004	JP	national
2005-090149	Mar 2005	JP	national

	Number	Date	Country
Parent	11659689	Feb 2007	US
Child	13409090		US

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