HETEROCYCLIC COMPOUNDS FOR THE TREATMENT OF STRESS-RELATED CONDITIONS

TECHNICAL FIELD

The present invention relates to a novel heterocyclic compound.

BACKGROUND ART

In the modern society, people are exposed to various physical or psychosocial stresses in living environments and complicated human relations. It is known that when such stress is build up to the extent that an individual person cannot cope with, the homeostatic function of the body and mind is destroyed and an extremely wide variety of diseases thus develop, including a neurotic disorder such as depression, panic disorder, post-traumatic stress disorder and anxiety disorder; an eating disorder such as bulimia and anorexia; gastric and duodenal ulcer, irritable bowel syndrome, hypertension, ischemic heart disease, hyperventilation (hyperventilation syndrome), asthma, urticaria, alopecia areata, frequent urination, ringing in the ears and dizziness.

The hypothalamus-pituitary gland-adrenal system (HPA-axis) or the sympathetic nerve-adrenal medulla system is activated by stress stimuli. Likewise, the neuroendocrine system responds to stress.

It has been elucidated that a biological reaction to stress is controlled by stress hormones represented by corticotropin releasing hormone (CRH), neurotransmitters such as noradrenaline, serotonin and dopamine, and other various neuropeptides. Of them, CRH is a main stress hormone mediating a stress response through the HPA-axis. Clinical studies have been conducted on a CRH receptor antagonist in expectation of a therapeutic effect on various stress-related diseases; however, a sufficient therapeutic effect has not yet been observed.

A prolactin-releasing peptide (PrRP) was identified as an endogenous ligand of orphan G-protein coupled receptor, GPR10 (Nature 393 (1998) 272-276). PrRP is expressed primarily in the hypothalamus of the brain, the medulla oblongata and the intestine, and PrRP-producing nerve cells are present in the solitary nucleus of the medulla oblongatas, the ventrolateral reticular formation of the medulla oblongata and the hypothalamus. A PrRP receptor, GPR10, is present in the area postrema, the amygdala, the paraventricular nucleus and the supraoptic nucleus of hypothalamus in large amounts. Based on the nerve function of the sites at which GPR10 is expressed, it is suggested that a receptor antagonist may be useful as a therapeutic agent for various disorders including stress-related disorders (U.S. Pat. No. 6,383,764 B1). The PrRP nerve cells of the medulla oblongata are A1 and A2 noradrenaline nerve cells and it is suggested that the CRH nerve cells and oxytocin nerve cells are activated by projecting the PrRP nerve cells in the paraventricular nucleus (Neuroscience Research 38 (2000) 223-230). When PrRP is administered into the cerebral ventricle, the CRH nerve cells of the paraventricular nucleus are activated (Neuroscience Letter 285 (2000) 234-238) and release of adrenocorticotropic hormone (ACTH) and oxytocin from the pituitary gland is accelerated. Furthermore, the PrRP nerve cells of the medulla oblongata and the hypothalamus are activated by stress stimuli (Endocrinology 142 (2001) 2032-2038). These suggest that PrRP is deeply involved in the stress response of the neuroendocrine system. On the other hand, in extensive wide-genome quantitative trait loci (QTL) analysis of the obesity, dyslipemia and diabetes model rat, namely, OLETF rat (Otsuka•Long-Evans•Tokushima fatty•rat), Dmo 1 was identified as one of the gene loci significantly related to pathologic phenotypes. As a result of detailed analysis, a GPR10 gene was found. It was found that a part of the GPR10 gene was mutated in the OLETF rat and the mutation was related to obesity and dyslipemia in the obese diabetic strain rat. In order to analyze the function of the GPR10 gene, a congenic BN (Brown-Norway) rat was prepared by introducing a mutant GPR10 domain, which is defective in PrRP signal transmission, to a normal BN rat background. The mutant GPR10 congenic rat did not exhibit obesity or dyslipemia as compared to the normal BN rat, while the mutant rat expressed a resistant phenotype to stress and anxiety. The anti-stress and anti-anxiety-like behaviors of the mutant GPR10 congenic rat support involvement of the GPR10 receptor in stress response, which is estimated from the aforementioned histochemical analysis, and also supports the possibility that a GPR10 antagonist serves as a therapeutic agent for depression, anxiety disorder or various types of stress-related disorders (US 2004216177 A1, Brain Research 1178 (2007) 114-124).

SUMMARY OF THE INVENTION
Problem to be Solved by the Invention

An object of the present invention is to provide a therapeutic agent for various types of stress-related disorders having a novel mechanism of action for suppressing an excessive stress response in a central nervous system, having few adverse drug reactions compared to known antidepressants and anxiolytic drugs, and being excellent in safety.

Means for Solving the Problems

The present inventors have repeatedly conducted intensive studies with a view toward solving the aforementioned problem. As a result, they succeeded in synthesizing a novel compound having a GPR10 receptor antagonist effect. The present invention was accomplished based on this finding.

The present invention provides a heterocyclic compound shown in the following Items or a salt thereof and a method for producing the same.

Item 1. A heterocyclic compound represented by general formula (1)

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wherein, R₁and R₂each independently represent hydrogen; a phenyl lower alkyl group that may have a substituent(s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen atom, a halogen-substituted lower alkyl group, a halogen-substituted lower alkoxy group, a cyclo C3-C8 alkyl group and a cyano group, on a benzene ring and/or a lower alkyl group; a cyclo C3-C8 alkyl lower alkyl group; a cyclo C3-C8 alkyl group that may have a halophenyl group(s); or R₁and R₂may form a pyrrolidine ring together with nitrogen adjacent to R₁and R₂, and the pyrrolidine ring may have a substituent(s) selected from the group consisting of a halophenyl group and a phenyl group having a halogen-substituted lower alkyl group(s);

R₃represents a lower alkynyl group; an amino group that may have a lower alkyl group(s); a lower alkoxy group; a piperazinyl group that may have a lower alkyl group(s); a phenyloxy group; a morpholinyl group or a pyrrolidinyl group;

R₄represents any one of groups represented by the following (1) to (91):

(1) a phenyl group

(2) a naphthyl group

(3) a dihydroindenyl group

(4) a phenyl lower alkyl group

(5) a pyridyl group

(6) a pyridazinyl group

(7) a triazolyl group

(8) a pyrimidinyl group

(9) an imidazolyl group

(10) a dihydropyridyl group

(11) a quinolyl group

(12) an isoquinolyl group

(13) a tetrahydroquinolyl group

(14) a dihydroquinolyl group

(15) an imidazopyridyl group

(16) a pyrazolopyridyl group

(17) an indolinyl group

(18) a naphthyridinyl group

(19) a benzoimidazolyl group

(20) an indolizinyl group

(21) a thienyl group

(22) a benzothienyl group

(23) a benzodioxolyl group

(24) a benzofuryl group

(25) a thienopyridyl group

(26) a thienopyrrolyl group

(27) a dihydrobenzothiazinyl group

(28) an isoxazolyl group

(29) a tetrahydrobenzoxazepinyl group

(30) an indolyl group

(31) a benzothiazolyl group

(32) a dihydrothienodioxinyl group

(33) a pyrrolidinyl group

(34) a dihydrobenzoxazinyl group

(35) a tetrahydroquinazolinyl group

(36) a tetrahydroquinoxalinyl group

(37) a dihydrobenzodioxinyl group

(38) a chromanyl group

(39) a dihydropyridooxazinyl group

(40) a tetrahydronaphthyl group

(41) a dihydrobenzofuryl group

(42) a dihydrobenzoxazolyl group

(43) a tetrahydrobenzothienyl group

(44) a tetrahydrocyclopentapyrazolyl group

(45) a benzotriazolyl group

(46) a dihydrobenzoimidazolyl group

(47) a dihydrobenzothiazolyl group

(48) an isoindolinyl group

(49) a tetrahydrobenzodiazepinyl group

(50) a dihydrobenzodioxepinyl group

(51) a quinoxalinyl group

(52) an indazolyl group

(53) a cinnolinyl group

(54) a dihydrophthalazinyl group

(55) a dihydronaphthyridinyl group

(56) a hexahydroquinolinyl group

(57) a furopyrrolyl group

(58) a thienopyrazinyl group

(59) an imidazothiazolyl group

(60) a xanthenyl group

(61) a piperidinyl group

(62) a pyrrolyl group

(63) a pyrazolyl group

(64) a thiazolyl group

(65) a furyl group

(66) a pyrazinyl group

(67) a dihydropyrazolyl group

(68) a thiazolidinyl group

(69) a tetrahydrofuranyl group

(70) a tetrahydropyranyl group

(71) a thiadiazolyl group

(72) a dihydropyridazinyl group

(73) a thienyl lower alkyl group

(74) a cyclo C3-C8 alkyl group

(75) a lower alkyl group

(76) a benzodioxolyloxy group

(77) a phenylthio lower alkyl group

(78) a phenylcyclo C3-C8 alkyl group

(79) a phenoxy lower alkyl group

(80) a phenyl lower alkenyl group

(81) a cyclo C3-C8 alkyl lower alkenyl group

(82) a pyridyl lower alkyl group

(83) a benzofuryl lower alkenyl group

(84) a dihydrobenzofuryl lower alkenyl group

(85) a dihydrobenzodioxinyl lower alkenyl group

(86) a dihydrobenzodioxinyloxy lower alkyl group

(87) an oxazolyl group

(88) a dihydroindenyloxy lower alkyl group

(89) a dihydropyrimidinyl group

(90) a pyridyloxy lower alkyl group

(91) a lower alkoxy lower alkyl group;

wherein on the lower alkyl group, cycloalkyl ring, aromatic ring or heterocyclic ring, one or more substituent(s) selected from the following (1-1) to (1-46) may be present:

(1-1) a halogen atom

(1-2) a lower alkyl group

(1-3) a lower alkanoyl group

(1-4) a halogen-substituted lower alkyl group

(1-5) a halogen-substituted lower alkoxy group

(1-6) a cyano group

(1-7) a lower alkoxy group

(1-8) a lower alkylthio group

(1-9) an imidazolyl group that may have a lower alkyl group(s)

(1-10) an oxazolyl group

(1-11) an oxadiazolyl group that may have a lower alkyl group(s)

(1-12) a triazolyl group

(1-13) a benzoyl group

(1-14) a pyridyl group

(1-15) an oxo group

(1-16) a phenyl group that may have a substituent(s) selected from the group consisting of a lower alkyl group, a halogen-substituted lower alkoxy group, a halogen-substituted lower alkyl group and a halogen atom

(1-17) a thienyl group

(1-18) a furyl group

(1-19) a thiazolyl group

(1-20) a triazolyl lower alkyl group

(1-21) a cyclo C3-C8 alkyloxy group

(1-22) a phenyl lower alkyl group

(1-23) a phenoxy group

(1-24) a cyclo C3-C8 alkyl group

(1-25) a pyrazolyl group

(1-26) a pyrrolyl group

(1-27) a lower alkenyl group

(1-28) a pyrrolidinyl group that may have an oxo group(s)

(1-29) a dihydropyrazolyl group that may have a substituent(s) selected from the group consisting of an oxo group and a lower alkyl group

(1-30) a hydroxy group

(1-31) a tetrazolyl group

(1-32) a morpholinyl group

(1-33) a pyrimidinyl group

(1-34) a homo-piperazinyl group that may have a lower alkyl group(s)

(1-35) a lower alkanoylamino group

(1-36) a cyclo C3-C8 alkylcarbonylamino group

(1-37) a phenoxy lower alkyl group

(1-38) a thiomorpholino group

(1-39) a piperidinyl group

(1-40) a lower alkoxy lower alkyl group

(1-41) an amino group that may have a substituent(s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group and a cyclo C3-C8 alkyl group

(1-42) a morpholinyl lower alkyl group

(1-43) a piperidinyl lower alkyl group

(1-44) a lower alkylsulfonyl group

(1-45) an adamantyl lower alkyl group

(1-46) a carbamoyl group that may have a lower alkyl group(s)

or a salt thereof.

Item 2. The heterocyclic compound according to (1) represented by general formula (1), wherein, R₁and R₂each independently represent hydrogen; a phenyl lower alkyl group that may have 1 to 3 substituent(s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen atom, a halogen-substituted lower alkyl group, a halogen-substituted lower alkoxy group, a cyclo C3-C8 alkyl group and a cyano group, on a benzene ring and/or a lower alkyl group; a cyclo C3-C8 alkyl lower alkyl group; a cyclo C3-C8 alkyl group that may have a single halophenyl group; or R₁and R₂may form a pyrrolidine ring together with nitrogen adjacent to R₁and R₂, and the pyrrolidine ring may have a single substituent selected from the group consisting of a halophenyl group and a phenyl group having a single halogen-substituted lower alkyl group;

R₃represents a lower alkynyl group; an amino group that may have 1 to 2 lower alkyl group(s); a lower alkoxy group; a piperazinyl group that may have a single lower alkyl group; a phenyloxy group; a morpholinyl group or a pyrrolidinyl group;

R₄represents any one of groups represented by the following (1) to (91):

wherein, on the lower alkyl group, cycloalkyl ring, aromatic ring or heterocyclic ring, 1 to 4 substituent(s) selected from the following (1-1) to (1-46) may be present:

(1-1) a halogen atom

(1-2) a lower alkyl group

(1-3) a lower alkanoyl group

(1-4) a halogen-substituted lower alkyl group

(1-5) a halogen-substituted lower alkoxy group

(1-6) a cyano group

(1-7) a lower alkoxy group

(1-8) a lower alkylthio group

(1-9) an imidazolyl group that may have a single lower alkyl group

(1-10) an oxazolyl group

(1-11) an oxadiazolyl group that may have a single lower alkyl group

(1-12) a triazolyl group

(1-13) a benzoyl group

(1-14) a pyridyl group

(1-15) an oxo group

(1-16) a phenyl group that may have a single substituent selected from the group consisting of a lower alkyl group, a halogen-substituted lower alkoxy group, a halogen-substituted lower alkyl group and a halogen atom

(1-17) a thienyl group

(1-18) a furyl group

(1-19) a thiazolyl group

(1-20) a triazolyl lower alkyl group

(1-21) a cyclo C3-C8 alkyloxy group

(1-22) a phenyl lower alkyl group

(1-23) a phenoxy group

(1-24) a cyclo C3-C8 alkyl group

(1-25) a pyrazolyl group that may have a single lower alkyl group

(1-26) a pyrrolyl group

(1-27) a lower alkenyl group

(1-28) a pyrrolidinyl group that may have a single oxo group

(1-29) a dihydropyrazolyl group that may have 1 to 2 substituent(s) selected from the group consisting of an oxo group and a lower alkyl group

(1-30) a hydroxy group

(1-31) a tetrazolyl group

(1-32) a morpholinyl group

(1-33) a pyrimidinyl group

(1-34) a homo-piperazinyl group that may have a single lower alkyl group

(1-35) a lower alkanoylamino group

(1-36) a cyclo C3-C8 alkylcarbonylamino group

(1-37) a phenoxy lower alkyl group

(1-38) a thiomorpholino group

(1-39) a piperidinyl group

(1-40) a lower alkoxy lower alkyl group

(1-41) an amino group that may have 1 to 2 substituent(s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group and a cyclo C3-C8 alkyl group

(1-42) a morpholinyl lower alkyl group

(1-43) a piperidinyl lower alkyl group

(1-44) a lower alkylsulfonyl group

(1-45) an adamantyl lower alkyl group

(1-46) a carbamoyl group that may have 1 to 2 lower alkyl group(s)

or a salt thereof.

Item 3. The heterocyclic compound according to (2) represented by general formula (1), wherein, R₁and R₂each independently represent hydrogen; a phenyl lower alkyl group that may have 1 to 2 substituent(s) selected from the group consisting of a lower alkoxy group, a halogen atom and a halogen-substituted lower alkyl group on a benzene ring and/or a lower alkyl group; a cyclo C3-C8 alkyl lower alkyl group; a cyclo C3-C8 alkyl group that may have a single monohalophenyl group; or R₁and R₂may form a pyrrolidine ring together with nitrogen adjacent to R₁and R₂, and the pyrrolidine ring may have a single substituent selected from the group consisting of a halophenyl group and a phenyl group having a single halogen-substituted lower alkyl group;

R₃represents a lower alkynyl group; an amino group that may have 1 to 2 lower alkyl group(s); a lower alkoxy group; a morpholinyl group or a pyrrolidinyl group;

R₄represents any one of groups represented by the following (1) to (90):

(1) a phenyl group

(4) a phenyl lower alkyl group

(5) a pyridyl group

(11) a quinolyl group

(12) a isoquinolyl group

(13) a tetrahydroquinolyl group

(16) a pyrazolopyridyl group

(19) a benzoimidazolyl group

(21) a thienyl group

(22) a benzothienyl group

(23) a benzodioxolyl group

(24) a benzofuryl group

(25) a thienopyridyl group

(30) an indolyl group

(37) a dihydrobenzodioxinyl group

(40) a tetrahydronaphthyl group

(57) a furopyrrolyl group

(63) a pyrazolyl group

(65) a furyl group

(77) a phenylthio lower alkyl group

(79) a phenoxy lower alkyl group

(80) a phenyl lower alkenyl group

(88) a dihydroindenyloxy lower alkyl group

(90) a pyridyloxy lower alkyl group;

wherein, on the lower alkyl group, cycloalkyl ring, aromatic ring or heterocyclic ring, 1 to 3 substituent(s) selected from the following (1-1) to (1-46) may be present:

(1-1) a halogen atom

(1-2) a lower alkyl group

(1-5) a halogen-substituted lower alkoxy group

(1-6) a cyano group

(1-7) a lower alkoxy group

(1-9) an imidazolyl group that may have a single lower alkyl group

(1-10) an oxazolyl group

(1-15) an oxo group

(1-17) a thienyl group

(1-27) a lower alkenyl group

(1-46) a carbamoyl group that may have 1 to 2 lower alkyl group(s)

or a salt thereof.

Item 4. The heterocyclic compound according to (3) represented by general formula (1), wherein, R₄represents any one of groups (1) to (90) below:

(1) a phenyl group that may have 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a lower alkyl group, a halogen-substituted lower alkoxy group, a cyano group, a lower alkoxy group, a lower alkenyl group, an oxazolyl group, a carbamoyl group that may have 1 to 2 lower alkyl group(s) and an imidazolyl group

(4) a phenyl lower alkyl group that may have a single halogen atom

(5) a pyridyl group that may have 1 to 2 substituent(s) selected from the group consisting of a cyano group and a lower alkoxy group

(11) a quinolyl group that may have a single halogen atom

(13) a tetrahydroquinolyl group that may have 1 to 2 substituent(s) selected from the group consisting of a lower alkyl group and an oxo group.

(16) a pyrazolopyridyl group

(19) a benzimidazolyl group that may have 1 to 2 substituent(s) selected from the group consisting of a halogen atom and a lower alkyl group

(21) a thienyl group that may have a single substituent selected from the group consisting of a lower alkyl group, a lowe alkoxy group and a halogen atom

(22) a benzothienyl group

(23) a benzodioxolyl group

(24) a benzofuryl group that may have a single substituent selected from the group consisting of a halogen atom and a lower alkoxy group

(25) a thienopyridyl group

(30) an indolyl group that may have 1 to 2 substituent(s) selected from the group consisting of a halogen atom and a lower alkyl group

(37) a dihydrobenzodioxinyl group

(40) a tetrahydronaphthyl group

(57) a furopyrrolyl group that may have a single lower alkyl group

(63) a pyrazolyl group that may have 1 to 2 substituent(s) selected from the group consisting of a thienyl group and a lower alkyl group

(65) a furyl group that may have a single halogen atom

(77) a phenylthio lower alkyl group that may have a single halogen atom

(79) a phenoxy-lower alkyl group that may have 1 to 2 substituent(s) selected from the group consisting of a halogen atom and a cyano group

(80) a phenyl lower alkenyl group that may have a single halogen atom

(88) a dihydroindenyloxy lower alkyl group

(90) a pyridyloxy lower alkyl group

or a salt thereof.

Item 5. Use of the heterocyclic compound according to any one of (1) to (4) represented by general formula (1) or a salt thereof as a pharmaceutical agent.

Item 6. Use of the heterocyclic compound according to any one of (1) to (4) or a salt thereof for the manufacture of a medicament for preventing or treating stress-related diseases.

Item 7. Use of the heterocyclic compound according to any one of (1) to (4) represented by general formula (1) or a salt thereof as a GPR10 antagonist.

Item 8. A method of treating or preventing stress-related diseases, comprising administering to a human or animal the heterocyclic compound according to any one of (1) to (4) represented by general formula (1) or a salt thereof.

Item 9. A pharmaceutical composition comprising the heterocyclic compound according to any one of (1) to (4) or a salt thereof as an active ingredient and a pharmaceutically acceptable carrier.

Item 10. The pharmaceutical composition according to (9) for preventing or treating stress-related diseases.

Item 11. The pharmaceutical composition according to (10) for preventing or treating stress-related diseases selected from the group consisting of respiratory system disorders, gastrointestinal disorders, cardiovascular system disorders, endocrine and metabolic disorders, nervous system disorders, eating disorders, done and muscle disorders, dermatopathy, urinary system disorders, otorhinolaryngological disorders, oral cavity disorders, ophthalmic disorders and gynecologic disorders.

Item 12. The pharmaceutical composition according to (11) for treating or preventing eating disorders.

Item 13. A method of producing a pharmaceutical composition, comprising blending the heterocyclic compound according to any one of (1) to (4) represented by general formula (1) or a salt thereof and a pharmaceutically acceptable carrier.

Item 14. The heterocyclic compound according to any one of (1) to (4) or a salt thereof for preventing or treating stress-related diseases.

Item 15. A method of producing a heterocyclic compound represented by general formula (1)

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wherein R₁, R₂, R₃and R₄are the same as those in formula (1) of claim 1 or a salt thereof, comprising reacting a compound (2) or a reactive derivative thereof represented by general formula (2)

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wherein R₁, R₂and R₃are the same as those in formula (1) of claim 1, or a salt thereof with a compound (3) or a reactive derivative thereof represented by general formula (3)

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wherein R₄is the same as that in formula (1) of claim 1, or a salt thereof.

Specific examples of individual groups shown in the general formula are as follows. The term “lower” is intended to mean a group having 1 to 6 (preferably 1 to 4, more preferably 1 to 3) carbon atom(s), unless otherwise provided.

Examples of the lower alkyl group include, unless otherwise specified, a straight or branched alkyl groups having 1 to 6 carbon atoms (preferably, 1 to 4 carbon atoms), and more specifically, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-ethylpropyl, isopentyl, neopentyl, n-hexyl, 1,2,2-trimethylpropyl, 3,3-dimethylbutyl, 2-ethylbutyl, isohexyl and 3-methylpentyl groups, etc.

Examples of the lower alkoxy group include, unless otherwise specified, straight or branched alkoxy groups having 1 to 6 carbon atoms (preferably, 1 to 4 carbon atoms), and more specifically, include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy and 3-methylpentyloxy groups, etc.

Examples of the halogen atom include, unless otherwise specified, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Examples of the halogen-substituted lower alkyl group include, unless otherwise specified, the lower alkyl groups exemplified above that are substituted with 1 to 7, more preferably, 1 to 3 halogen atoms, and more specifically, include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, dichlorofluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2-fluoroethyl, 2-chloroethyl, 3,3,3-trifluoropropyl, heptafluoropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoroisopropyl, 3-chloropropyl, 2-chloropropyl, 3-bromopropyl, 4,4,4-trifluorobutyl, 4,4,4,3,3-pentafluorobutyl, 4-chlorobutyl, 4-bromobutyl, 2-chlorobutyl, 5,5,5-trifluoropentyl, 5-chloropentyl, 6,6,6-trifluorohexyl, 6-chlorohexyl and perfluorohexyl groups, etc.

Examples of the cyclo C3-C8 alkyl group may include, unless otherwise specified, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups, etc.

Examples of the phenyl lower alkyl group include, unless otherwise specified, the lower alkyl groups exemplified above (straight or branched alkyl groups having preferably 1 to 6 carbon atoms (more preferably, 1 to 4 carbon atoms)) having 1 to 3 phenyl groups, preferably a single phenyl group; and more specifically, include benzyl, phenethyl, 3-phenylpropyl, benzhydryl, trityl, 4-phenylbutyl, 5-phenylpentyl and 6-phenylhexyl groups, etc.

Examples of the lower alkynyl group may include, unless otherwise specified, straight or branched alkynyl groups having 2 to 6 carbon atoms (preferably, 2 to 4 carbon atoms), and more specifically, include ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 2-hexynyl, and 3,3-dimethyl-1-butynyl groups, etc.

Examples of the lower alkanoyl group may include, unless otherwise specified, straight or branched alkanoyl groups having 1 to 6 carbon atoms (preferably, 1 to 4 carbon atoms), and more specifically, include formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butyl carbonyl and hexanoyl groups, etc.

Examples of the halogen-substituted lower alkoxy group may include, unless otherwise specified, the lower alkoxy groups exemplified above and substituted with 1 to 7, preferably, 1 to 3 halogen atoms, and more specifically, include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, bromomethoxy, dibromomethoxy, dichlorofluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 2-chloroethoxy, 3,3,3-trifluoropropoxy, heptafluoropropoxy, heptafluoroisopropoxy, 3-chloropropoxy, 2-chloropropoxy, 3-bromopropoxy, 4,4,4-trifluorobutoxy, 4,4,4,3,3-pentafluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy, 2-chlorobutoxy, 5,5,5-trifluoropentoxy, 5-chloropentoxy, 6,6,6-trifluorohexyloxy and 6-chlorohexyloxy groups, etc.

Examples of the halophenyl group may include, unless otherwise specified, a phenyl group substituted with 1 to 5 halogen atoms, preferably 1 to 3 halogen atoms, and further preferably, a single halogen atom.

Examples of the lower alkylthio group may include, unless otherwise specified, thio groups substituted with straight or branched alkyl having 1 to 6 carbon atoms (preferably, 1 to 4 carbon atoms), and more specifically, include, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, sec-butylthio, n-pentylthio, 1-ethylpropylthio, isopentylthio, neopentylthio, n-hexylthio, 1,2,2-trimethylpropylthio, 3,3-dimethylbutylthio, 2-ethylbutylthio, isohexylthio and 3-methylpentylthio groups.

Examples of the lower alkenyl group may include, unless otherwise specified, a straight or branched alkenyl group having 2 to 6 carbon atoms (preferably, 2 to 4 carbon atoms) and having 1 to 3 double bonds, which includes both trans-form and cis-form; and more specifically include, vinyl, 1-propenyl, 2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-propenyl, 2-butenyl, 1-butenyl, 3-butenyl, 2-pentenyl, 1-pentenyl, 3-pentenyl, 4-pentenyl, 1,3-butadienyl, 1,3-pentadienyl, 2-penten-4-yl, 2-hexenyl, 1-hexenyl, 5-hexenyl, 3-hexenyl, 4-hexenyl, 3,3-dimethyl-1-propenyl, 2-ethyl-1-propenyl, 1,3,5-hexatrienyl, 1,3-hexadienyl and 1,4-hexadienyl groups, etc.

Examples of the dihydroindenyl group may include a (1-, 2-, 4-, or 5-)-1,2-dihydroindenyl group, etc.

Examples of the triazolyl group may include 1,2,4-triazolyl, 1,3,5-triazolyl and 1,2,3-triazolyl groups, etc.

Examples of the imidazolyl group may include a (1-, 2-, 4-, or 5-)imidazolyl group, etc.

Examples of the dihydropyridyl group may include 1,2-dihydropyridyl, 1,4-dihydropyridyl, 3,4-dihydropyridyl, 5,6-dihydropyridyl and 3,6-dihydropyridyl groups, etc.

Examples of the quinolyl group may include 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl and 8-quinolyl groups, etc.

Examples of the isoquinolyl group may include 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl and 8-isoquinolyl groups, etc.

Examples of the tetrahydroquinolyl group may include a (1-, 2-, 4-, 5-, 6-, or 8-)(1,2,3,4-tetrahydroquinolyl group, etc.

Examples of the dihydroquinolyl group may include 1,2-dihydroquinolyl, 3,4-dihydroquinolyl, 1,4-dihydroquinolyl, 4a,8a-dihydroquinolyl, 5,6-dihydroquinolyl, 7,8-dihydroquinolyl and 5,8-dihydroquinolyl groups, etc.

Examples of the imidazopyridyl group may include imidazo[1,2-a]pyridyl and imidazo[1,5a]pyridyl groups, etc.

Examples of the pyrazolopyridyl group may include a pyrazolo[1,5a]pyridyl group.

Examples of the indolinyl group may include a (1-, 2-, 3-, 4-, 5-, 6- or 7-)indolinyl group.

Examples of the naphthyridinyl group may include 1,8-naphthyridinyl, 1,7-naphthyridinyl, 1,6-naphthyridinyl, 1,5-naphthyridinyl, 2,7-naphthyridinyl, 2,6-naphthyridinyl and 2,5-naphthyridinyl groups.

Examples of the benzoimidazolyl group may include 1H-benzo[d]imidazolyl, 2H-benzo[d]imidazolyl and 3aH-benzo[d]imidazolyl groups.

Examples of the benzothienyl group may include benzo[b]thienyl and benzo[c]thienyl groups.

Examples of the benzodioxolyl group may include benzo[d][1,3]dioxolyl and 3H-benzo[c][1,2]dioxolyl groups.

Examples of the benzofuryl group may include a (2-, 3-, 4-, 5-, 6- or 7-)benzofuryl group.

Examples of the thienopyridyl group may include thieno[2,3-b]pyridyl, thieno[2,3-c]pyridyl, thieno[3,2-b]pyridyl, thieno[3,4-b]pyridyl and thieno[3,4-c]pyridyl groups, etc.

Examples of the thienopyrrolyl group may include 4H-thieno[3,2-b]pyrrolyl, 6H-thieno[2,3-b]pyrrolyl, 4H-thieno[2,3-b]pyrrolyl, 4H-thieno[2,3-c]pyrrolyl, 6aH-thieno[2,3-b]pyrrolyl, 3H-thieno[3,4-b]pyrrolyl, 4H-thieno[3,4-c]pyrrolyl and 1H-thieno[3,4-b]pyrrolyl groups, etc.

Examples of the dihydrobenzothiazinyl group may include 3,4-dihydro-2H-benzo[b][1,4]thiazinyl, 3,4-dihydro-2H-benzo[e][1,2]thiazinyl, 3,4-dihydro-2H-benzo[e][1,3]thiazinyl, 3,4-dihydro-1H-benzo[d][1,2]thiazinyl, 2,4-dihydro-1H-benzo[d][1,3]thiazinyl and 3,4-dihydro-1H-benzo[c][1,2]thiazinyl groups, etc.

Examples of the isoxazolyl group may include a (3-, 4-, or 5-)isoxazolyl group.

Examples of the tetrahydrobenzoxazepinyl group may include 1,2,3,5-tetrahydrobenzo[e][1,4]oxazepinyl, 1,3,4,5-tetrahydrobenzo[c][1,2]oxazepinyl and 1,2,4,5-tetrahydrobenzo[d][1,3]oxazepinyl, etc.

Examples of the indolyl group may include a 1H-indolyl and 3H-indolyl groups.

Examples of the benzothiazolyl group may include a benzo[d]thiazolyl group.

Examples of the dihydrothienodioxinyl group may include 2,3-dihydrothieno[3,4-b][1,4]dioxinyl, 3,4-dihydrothieno[3,4-c][1,2]dioxinyl, 2,3-dihydrothieno[3,4-b][1,4]dioxinyl, 2,3-dihydrothieno[3,2-b][1,4]dioxinyl, 3,4-dihydrothieno[3,2-c][1,2]dioxinyl and 3,4-dihydrothieno[2,3-c][1,2]dioxinyl groups, etc.

Examples of the pyrrolidinyl group may include a (1-, 2- or 3-)pyrrolidinyl group.

Examples of the dihydrobenzoxazinyl group may include (2-, 3-, 4-, 5-, 6-, 7-, or 8-)3,4-dihydro-2H-benzo[b][1.4]oxazinyl and (1-, 2-, 4-, 5-, 6-, 7-, or 8-)2,4-dihydro-1H-benzo[d][1.3]oxazinyl groups, etc.

Examples of the tetrahydroquinazolinyl group may include (1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-)1,2,3,4-tetrahydroquinazolinyl and (1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-)5,6,7,8-tetrahydroquinazolinyl groups, etc.

Examples of the tetrahydroquinoxalinyl group may include (1-, 2-, 5-, or 6-)1,2,3,4-tetrahydroquinoxalinyl and (1-, 2-, 5-, or 6-)5,6,7,8-tetrahydroquinoxalinyl groups, etc.

Examples of the dihydrobenzodioxinyl group may include 2,3-dihydrobenzo[b][1,4]dioxinyl and 3,4-dihydrobenzo[c][1,2]dioxinyl groups, etc.

Examples of the dihydropyridodioxinyl group may include 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 3,4-dihydro-1H-pyrido[2,3-c][1,2]oxazinyl, 6,8-dihydro-5H-pyrido[3,2-d][1,4]oxazinyl, 7,8-dihydro-5H-pyrido[2,3-b][1,2]oxazinyl and 3,4-dihydro-2H-pyrido[2,3-e][1,3]oxazinyl groups, etc.

Examples of the tetrahydronaphthyl group may include a (1- or 2-)1,2,3,4-tetrahydronaphthyl group, etc.

Examples of the dihydrobenzofuryl group may include a 2,3-dihydro-(2-, 3-, 4-, 5-, 6-, or 7-)benzofuryl group, etc.

Examples of the dihydrobenzoxazolyl group may include a (2-, 3-, 4-, 5-, 6-, or 7-)2,3-dihydrobenzoxazolyl group, etc.

Examples of the tetrabenzothienyl group may include 4,5,6,7-tetrabenzo[c]thienyl and 4,5,6,7-tetrabenzo[b]thienyl groups, etc.

Examples of the tetrahydrocyclopentapyrazolyl group may include 1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl and 2,4,5,6-tetrahydrocyclopenta[c]pyrazolyl groups.

Examples of the benzotriazolyl group may include a 1H-benzo[d][1,2,3]triazolyl group.

Examples of the dihydrobenzoimidazolyl group may include a (1-, 2-, 4-, or 5-)2,3-dihydro-1H-benzoimidazolyl group, etc.

Examples of the dihydrobenzothiazolyl group may include a (2-, 3-, 4-, 5-, 6-, or 7-)2,3-dihydrobenzothiazolyl group, etc.

Examples of the tetrahydrobenzodiazepinyl group may include (1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-)2,3,4,5-tetrahydro-1H-benzo[b][1.4]diazepinyl and (1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-)2,3,4,5-tetrahydro-1H-benzo[e][1.4]diazepinyl groups, etc.

Examples of the dihydrobenzodioxepinyl may include 3,4-dihydro-2H-1,5-benzodioxepinyl, 4,5-dihydro-3H-1,2-benzodioxepinyl and 3,5-dihydro-2H-1,4-benzodioxepinyl groups, etc.

Examples of the indazolyl group may include a (1-, 3-, 4-, 5-, 6-, or 7-)indazolyl group, etc.

Examples of the dihydrophthalazinyl group may include 1,2-dihydrophthalazinyl, 1,4-dihydrophthalazinyl and 3,4-dihydrophthalazinyl groups, etc.

Examples of the dihydronaphthylidyl group may include 7,8-dihydro-1,8-naphthyridinyl, 5,6-dihydro-1,8-naphthyridinyl, 5,8-dihydro-1,8-naphthyridinyl, 1,4-dihydro-1,7-naphthyridinyl, 3,4-dihydro-1,7-naphthyridinyl, 1,2-dihydro-1,7-naphthyridinyl, 5,6-dihydro-1,5-naphthyridinyl, 5,8-dihydro-1,5-naphthyridinyl, and 7,8-dihydro-1,5-naphthyridinyl groups, etc.

Examples of the hexahydroquinolinyl group may include a 1,2,5,6,7,8-hexahydroquinolinyl group, a 1,4,5,6,7,8-hexahydroquinolinyl group, a 1,5,6,7,8,8a-hexahydroquinolinyl group, a 1,4,6,7,8,8a-hexahydroquinolinyl group, a 1,4,4a,7,8,8a-hexahydroquinolinyl group, a 1,4,4a,5,8,8a-hexahydroquinolinyl group, a 1,4,4a,5,6,8a-hexahydroquinolinyl group and a 1,4,4a,5,6,7-hexahydroquinolinyl group, etc.

Examples of the furopyrrolyl group may include a 4H-furo[3,2-b]pyrrolyl group, a 5H-furo[2,3-c]pyrrolyl group and a 6H-furo[2,3-b]pyrrolyl group, etc.

Examples of the thienopyrazinyl group may include a thieno[3,2-b]pyrazinyl group, a thieno[3,4-b]pyrazinyl group and a thieno[2,3-b]pyrazinyl group, etc.

Examples of the imidazothiazolyl group may include a (2-, 3-, 5-, or 6-)imidazo[2,1-b]thiazolyl group, etc.

Examples of the xanthenyl group may include a (1-, 2-, 3- or 4-)9H-xanthenyl group, etc.

Examples of the piperidinyl group may include a (1-, 2-, 3- or 4-)piperidinyl group.

Examples of the pyrrolyl group may include a (1-, 2- or 3-)pyrrolyl group.

Examples of the pyrazolyl group may include a 1H-pyrazolyl group, a 3H-pyrazolyl group and a 4H-pyrazolyl group.

Examples of the thiazolyl group may include a (2-, 4-, or 5-)thiazolyl group.

Examples of the furyl group may include a (2- or 3-)furyl group.

Examples of the pyrazinyl group may include a 2-pyrazinyl group.

Examples of the dihydropyrazolyl group may include a 2,3-dihydropyrazolyl group or a 4,5-dihydro pyrazolyl group.

Examples of the thiazolidinyl group may include a (2-, 3-, 4-, or 5-)thiazolidinyl group.

Examples of the tetrahydrofuranyl group may include 2-tetrahydrofuranyl and 3-tetrahydrofuranyl groups.

Examples of the tetrahydropyranyl group may include a tetrahydro-2H-pyranyl group.

Examples of the thiadiazolyl group may include 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl or 1,3,4-thiadiazolyl group.

Examples of the dihydropyridazinyl group may include 1,6-dihydropyridazinyl, 1,4-dihydropyridazinyl or 4,5-dihydropyridazinyl group.

Examples of the thienyl lower alkyl group may include, unless otherwise specified, a lower alkyl group as exemplified above (preferably a straight or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms, and most preferably 1 to 3 carbon atoms) having 1 to 2 thienyl groups (preferably a single thienyl group); and more specifically include (2- or 3-)thienylmethyl, 2-[(2- or 3-)thienyl]ethyl, 1-[(2- or 3-)thienyl]ethyl, 3-[(2- or 3-)thienyl]propyl, 4-[(2- or 3-)thienyl]butyl, 5-[(2- or 3-)thienyl]pentyl, 6-[(2- or 3-)thienyl]hexyl, 1,1-dimethyl-2-[(2- or 3)-thienyl]ethyl and 2-methyl-3-[(2- or 3-)thienyl]propyl groups, etc.

Examples of the benzodioxolyloxy group may include benzo[d][1,3]dioxolyloxy and 3H-benzo[c][1,2]dioxolyloxy groups, etc.

Examples of the phenylthio lower alkyl group may include, unless otherwise specified, a lower alkyl group as exemplified above (straight or branched alkyl groups having 1 to 6 carbon atoms (more preferably, 1 to 4 carbon atoms, and most preferably 1 to 3 carbon atoms)) having 1 to 2 phenylthio groups (preferably a single phenylthio group).

Examples of the phenylcyclo C3-C8 alkyl group may include, unless otherwise specified, C3-C8 alkyl group as exemplified above having 1 to 2 phenyl groups (preferably a single phenyl group); and more specifically include phenylcyclopropyl, phenylcyclobutyl, phenylcyclopentyl, phenylcyclohexyl, phenylcycloheptyl and phenylcyclooctyl groups, etc.

Examples of the phenoxy lower alkyl group may include, unless otherwise specified, a lower alkyl group as exemplified above (preferably a straight or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms, and most preferably 1 to 3 carbon atoms) having 1 to 3 phenoxy groups (preferably a single phenoxy group); and more specifically include, phenoxymethyl, 1-phenoxyethyl, 2-phenoxyethyl, 3-phenoxypropyl, 2-phenoxypropyl, 4-phenoxybutyl, 5-phenoxypentyl, 4-phenoxypentyl, 6-phenoxyhexyl, 2-methyl-3-phenoxypropyl and 1,1-dimethyl-2-phenoxyethyl, etc.

Examples of the phenyl lower alkenyl group may include, unless otherwise specified, a lower alkenyl group as exemplified above (more preferably a straight or branched alkyl group having 2 to 6 carbon atoms (most preferably 2 to 4-carbon atoms) having 1 to 3 phenyl groups (preferably a single phenyl group); and more specifically include, styryl, 3-phenyl-2-propenyl (trivial name: cinnamyl), 4-phenyl-2-butenyl, 4-phenyl-3-butenyl, 5-phenyl-4-pentenyl, 5-phenyl-3-pentenyl, 6-phenyl-5-hexenyl, 6-phenyl-4-hexenyl, 6-phenyl-3-hexenyl, 4-phenyl-1,3-butadienyl and 6-phenyl-1,3,5-hexatrienyl groups, etc.

Examples of the cyclo C3-C8 alkyl lower alkenyl group may include, unless otherwise specified, a lower alkenyl group as exemplified above (more preferably a straight or branched alkyl group having 2 to 6 carbon atoms (most preferably 2 to 4-carbon atoms) having 1 to 3 cyclo C3-C8 alkyl groups (preferably a single cyclo C3-C8 alkyl group); and more specifically include, 2-cyclopropylethenyl, 1-cyclobutylethenyl, 3-cyclopentylpropenyl, 4-cyclohexylbutenyl, 5-cycloheptylpentenyl and 6-cyclooctylhexenyl groups, etc.

Examples of the pyridyl lower alkyl group may include, unless otherwise specified, a lower alkyl group as exemplified above (preferably a straight or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms, and most preferably 1 to 3 carbon atoms) having 1 to 2 pyridyl groups (preferably a single pyridyl group); and more specifically include (2-, 3-, or 4-)pyridylmethyl, 2-[(2-, 3-, or 4-)pyridyl]ethyl, 1-[(2-, 3-, or 4-)pyridyl]ethyl, 3-[(2-, 3-, or 4-)pyridyl]propyl, 4-[(2-, 3-, or 4-)pyridyl]butyl, 1,1-dimethyl-2-[(2-, 3-, or 4-)pyridyl]ethyl, 5-[(2-, 3-, or 4-)pyridyl]pentyl, 6-[(2-, 3,- or 4-)pyridyl]hexyl, 1-[(2-, 3-, or 4-)pyridyl]isopropyl and 2-methyl-3-[(2-, 3-, or 4-)pyridyl]propyl groups, etc.

Examples of the benzofuryl lower alkenyl group may include, unless otherwise specified, a lower alkenyl group as exemplified above (more preferably a straight or branched alkyl group having 2 to 6 carbon atoms (most preferably 2 to 4-carbon atoms) having 1 to 2 benzofuryl groups (preferably a single benzofuryl group); and more specifically include, 2-(4-benzofuryl)ethenyl, 1-(4-benzofuryl)ethenyl, 3-(4-benzofuryl)propenyl, 4-(4-benzofuryl)butenyl, 5-(4-benzofuryl)pentenyl and 6-(4-benzofuryl)hexenyl groups, etc.

Examples of the dihydrobenzofuryl lower alkenyl group may include, unless otherwise specified, a lower alkenyl group as exemplified above (more preferably a straight or branched alkyl group having 2 to 6 carbon atoms (most preferably 2 to 4-carbon atoms) having 1 to 2 dihydrobenzofuryl groups (preferably a single dihydrobenzofuryl group); and more specifically include, a 2-(2,3-dihydrobenzofuryl)vinyl group, a 1-(2,3-dihydrobenzofuryl)vinyl group, a 3-(2,3-dihydrobenzofuryl)propenyl group, a 4-(2,3-dihydrobenzofuryl)butenyl group, a 5-(2,3-dihydrobenzofuryl)pentenyl group and a 6-2,3-dihydrobenzofuryl)hexenyl group, etc.

Examples of the dihydrobenzodioxinyl lower alkenyl group may include, unless otherwise specified, a lower alkenyl group as exemplified above (more preferably a straight or branched alkyl group having 2 to 6 carbon atoms (most preferably 2 to 4-carbon atoms) having 1 to 2 dihydrobenzodioxinyl groups (preferably a single dihydrobenzodioxinyl group); and more specifically include a 2-(2,3-dihydrobenzo[b][1,4]dioxinyl)vinyl group, a 1-(2,3-dihydrobenzo[b][1,4]dioxinyl)vinyl group, a 3-(2,3-dihydrobenzo[b][1,4]dioxinyl)propenyl group, a 4-(2,3-dihydrobenzo[b][1,4]dioxinyl)butenyl group, a 5-(2,3-dihydrobenzo[b][1,4]dioxinyl)pentenyl group and a 6-(2,3-dihydrobenzo[b][1,4]dioxinyl)hexenyl group, etc.

Examples of the dihydrobenzodioxinyloxy group may include, unless otherwise specified, the dihydrobenzodioxinyl group exemplified above that are substituted with oxy groups; and more specifically include 2,3-dihydrobenzo[b][1,4]dioxinyloxy and 3,4-dihydrobenzo[c][1,2]dioxinyloxy groups, etc.

Examples of the dihydrobenzodioxinyloxy lower alkyl group may include, unless otherwise specified, a lower alkyl group as exemplified above (preferably a straight or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms, and most preferably 1 to 3 carbon atoms) having 1 to 2 dihydrobenzodioxinyloxy groups (preferably a single dihydrobenzodioxinyloxy group); and more specifically include (2,3-dihydrobenzo[b][1,4]dioxinyloxy)methyl, 2-(2,3-dihydrobenzo[b][1,4]dioxinyloxy)ethyl, 3-(2,3-dihydrobenzo[b][1,4]dioxinyloxy)propyl, 2-(2,3-dihydrobenzo[b][1,4]dioxinyloxy)propyl, 4-(2,3-dihydrobenzo[b][1,4]dioxinyloxy)butyl, 5-(2,3-dihydrobenzo[b][1,4]dioxinyloxy)pentyl and 6-(2,3-dihydrobenzo[b][1,4]dioxinyloxy)hexyl groups, etc.

Examples of the oxazolyl group may include a (2-, 4- or 5-)oxazolyl group.

Examples of the dihydroindenyloxy group may include, unless otherwise specified, the dihydroindenyl group exemplified above that are substituted with oxy groups; and more specifically include a (1-, 2-, 4- or 5-)-1,2-dihydroindenyloxy group.

Examples of the dihydroindenyloxy lower alkyl group may include, unless otherwise specified, a lower alkyl group as exemplified above (preferably a straight or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms, and most preferably 1 to 3 carbon atoms) having 1 to 2 dihydroindenyloxy groups (preferably a single dihydroindenyloxy group); and more specifically include (2,3-dihydro-1H-indenyloxy)methyl, 2-(2,3-dihydro-1H-indenyloxy)ethyl, 3-(2,3-dihydro-1H-indenyloxy)propyl, 4-(2,3-dihydro-1H-indenyloxy)butyl, 5-(2,3-dihydro-1H-indenyloxy)pentyl and 6-(2,3-dihydro-1H-indenyloxy)hexyl groups, etc.

Examples of the dihydropyrimidinyl group may include 2,3-dihydropyrimidinyl, 4,5-dihydropyrimidinyl and 2,5-dihydropyrimidinyl groups, etc.

Examples of the pyridyloxy lower alkyl group may include, unless otherwise specified, a lower alkyl group as exemplified above (preferably a straight or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms, and most preferably 1 to 3 carbon atoms) having 1 to 2 pyridyloxy groups (preferably a single pyridyloxy group); and more specifically include (pyridyloxy)methyl, 2-(pyridyloxy)ethyl, 1-(pyridyloxy)ethyl, 3-(pyridyloxy)propyl, 4-(pyridyloxy)butyl, 5-(pyridyloxy)pentyl and 6-(pyridyloxy)hexyl groups, etc.

Examples of the lower alkoxy lower alkyl group may include, unless otherwise specified, a lower alkyl group as exemplified above (preferably a straight or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms, and most preferably 1 to 3 carbon atoms) having 1 to 3 (preferably a single lower alkoxy group)lower alkoxy group as exemplified above groups (preferably a straight or branched alkyl group having 1 to 6 carbon atoms); and more specifically include methoxymethyl, 2-methoxyethyl, 1-ethoxyethyl, 2-ethoxyethyl, 2-isobutoxyethyl, 2,2-dimethoxyethyl, 2-methoxy-1-methylethyl, 2-methoxy-1-ethylethyl, 3-methoxypropyl, 3-ethoxypropyl, 3-isobutoxypropyl, 3-n-butoxypropyl, 4-n-propoxybutyl, 1-methyl-3-isobutoxypropyl, 1,1-dimethyl-2-n-pentyloxyethyl, 5-n-hexyloxypentyl, 6-methoxyhexyl, 1-ethoxyisopropyl and 2-methyl-3-methoxypropyl groups.

Examples of the imidazolyl group that may have a lower alkyl group may include an imidazolyl group that may have 1 to 2 lower alkyl groups as exemplified above (preferably a single lower alkyl group); and more specifically include 2-methyl-1H-imidazolyl, 2-ethyl-1H-imidazolyl, 2-propyl-1H-imidazolyl, 2-butyl-1H-imidazolyl, 2-pentyl-1H-imidazolyl and 2-hexyl-1H-imidazolyl groups, etc.

Examples of the oxadiazolyl group that may have a lower alkyl group may include an oxadiazolyl group that may have 1 to 2 lower alkyl groups as exemplified above (preferably a single lower alkyl group); and more specifically include 5-methyl-1,3,4-oxadiazolyl, 5-ethyl-1,3,4-oxadiazolyl, 5-propyl-1,3,4-oxadiazolyl, 5-butyl-1,3,4-oxadiazolyl, 5-pentyl-1,3,4-oxadiazolyl and 5-hexyl-1,3,4-oxadiazolyl groups, etc.

Examples of a triazolyl lower alkyl group may include, unless otherwise specified, a lower alkyl group (preferably a straight or branched alkyl group having 1 to 6 chain atoms) as exemplified above and having a 1 to 2 (preferably 1) triazolyl groups as exemplified above; and more specifically include [1,2,4-triazol-(3- or 5-)yl]methyl, [1,2,3-triazol-(4- or 5-)yl]methyl, 2-[1,2,4-triazol-(3- or 5-)yl]ethyl, 1-[1,2,4-triazol-(3- or 5-)yl]ethyl, 3-[1,2,4-triazol-(3- or 5-)yl]propyl, 4-[1,2,4-triazol-(3- or 5-)yl]butyl, 1,1-dimethyl-2-[1,2,4-triazol-(3- or 5-yl]ethyl, 5-[1,2,4-triazol-(3- or 5-)yl]pentyl, 6-[1,2,4-triazol-(3- or 5-)yl]hexyl, 1-[1,2,4-triazol-(3- or 5-)yl]isopropyl and 2-methyl-3-[1,2,4-triazol-(3- or 5)-yl]propyl groups, etc.

Examples of the cyclo C3-C8 alkyloxy group may include, unless otherwise specified, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy groups, etc.

Examples of the pyrrolidinyl group that may have an oxo group may include, unless otherwise specified, a pyrrolidinyl group having 1 to 2 (preferably 1) oxo groups; and more specifically may include (1-, 2-, or 3-)pyrrolidinyl, (2- or 3-)oxo-1-pyrrolidinyl, (3-, 4-, or 5-)oxo-2-pyrrolidinyl and (2-, 4-, or 5-)oxo-3-pyrrolidinyl groups.

Examples of the dihydropyrazolyl group that may have a substituent selected from the group consisting of an oxo group and a lower alkyl group may include, unless otherwise specified, dihydropyrazolyl group having 2 to 3 substituent groups (preferably 2 substituent groups) selected from the group consisting of an oxo group and a lower alkyl group (preferably a straight or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms, and most preferably 1 to 3 carbon atoms); and more specifically include a 3-methyl-5-oxo-4,5-dihydro-1H-pyrazolyl group, a 3-ethyl-5-oxo-4,5-dihydro-1H-pyrazolyl group, a 5-oxo-3-propyl-4,5-dihydro-1H-pyrazolyl group, a 3-butyl-5-oxo-4,5-dihydro-1H-pyrazolyl group, a 5-oxo-3-pentyl-4,5-dihydro-1H-pyrazolyl group and a 3-hexyl-5-oxo-4,5-dihydro-1H-pyrazolyl group, etc.

Examples of the tetrazolyl group may include a (1- or 5-)tetrazolyl group.

Examples of the homopiperazinyl group that may have a lower alkyl group may include, unless otherwise specified, a homopiperazinyl group having 1 to 2 (preferably a single lower alkyl group) lower alkyl group as exemplified above (preferably a straight or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms, and most preferably 1 to 3 carbon atoms) groups; and more specifically include, a 1-homopiperazinyl group, a 2-homopiperazinyl group, a 3-homopiperazinyl group, a 4-homopiperazinyl group, a 5-homopiperazinyl group, a 6-homopiperazinyl group, a 7-homopiperazinyl group, a 4-methyl-1-homopiperazinyl group, a 4-ethyl-1-homopiperazinyl group, a 4-n-propyl-1-homo piperazinyl group, a 4-tert-butyl-1-homopiperazinyl group, a 4-n-pentyl-1-homopiperazinyl group and a 4-n-hexyl-1-homopiperazinyl group.

Examples of the lower alkanoyl amino group may include, unless otherwise specified, a amino group that are substituted with lower alkanoyl group as exemplified above (straight or branched lower alkanoyl groups having 1 to 6 carbon atoms (more preferably, 1 to 4 carbon atoms, and most preferably 1 to 3 carbon atoms)); and more specifically include, acetylamino, propionylamino, butyrylamino, pentanoylamino, 2-methylpropionylamino and hexanoylamino groups, etc.

Examples of the cycloC3-C8alkyl carbonyl amine group may include, unless otherwise specified, a amino group having cycloC3-C8alkyl carbonyl groups as exemplified above (preferably a single cycloC3-C8alkyl carbonyl group); and more specifically include, cyclopropylcarbonylamino, cyclobutylcarbonylamino, cyclopentylcarbonylamino, cyclohexylcarbonylamino, cycloheptylcarbonylamino and cyclooctylcarbonylamino, etc.

Examples of the morpholinyl lower alkyl group may include, unless otherwise specified, a lower alkyl group as exemplified above (preferably a straight or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms, and most preferably 1 to 3 carbon atoms) having 1 to 2 morpholinyl groups (preferably a single morpholinyl); and more specifically include 2-morpholinylmethyl, 3-morpholinylmethyl, 4-morpholinylmethyl, 2-(2-morpholinyl)ethyl, 2-(3-morpholinyl)ethyl, 2-(4-morpholinyl)ethyl, 1-(2-morpholinyl)ethyl, 1-(3-morpholinyl)ethyl, 1-(4-morpholinyl)ethyl, 3-(2-morpholinyl)propyl, 3-(3-morpholinyl)propyl, 3-(4-morpholinyl)propyl, 4-(2-morpholinyl)butyl, 4-(3-morpholinyl)butyl, 4-(4-morpholinyl)butyl, 5-(2-morpholinyl)pentyl, 5-(3-morpholinyl)pentyl, 5-(4-morpholinyl)pentyl, 6-(2-morpholinyl)hexyl, 6-(3-morpholinyl)hexyl, 6-(4-morpholinyl)hexyl, 3-methyl-3-(2-morpholinyl)propyl, 3-methyl-3-(3-morpholinyl)propyl, 3-methyl-3-(4-morpholinyl)propyl, 1,1-dimethyl-2-(2-morpholinyl)ethyl, 1,1-dimethyl-2-(3-morpholinyl)ethyl and 1,1-dimethyl-2-(4-morpholinyl)ethyl groups.

Examples of the piperidinyl lower alkyl group may include, unless otherwise specified, a lower alkyl group as exemplified above (preferably a straight or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms, and most preferably 1 to 3 carbon atoms) having 1 to 2 piperidinyl groups (preferably a single piperidinyl); and more specifically include [(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 and 2-methyl-3-[(1,2,3 or 4-)piperidinyl]propyl.

Examples of the lower alkylsulfonyl group may include unless otherwise specified, a sulfonyl group having lower alkyl group as exemplified above (preferably a straight or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms, and most preferably 1 to 3 carbon atoms) groups; and more specifically include, sulfonyl group having a lower alkyl group (preferably a straight or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)) having an lower alkyl moiety as exemplified above; and more specifically include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl, sec-butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, n-hexylsulfonyl, isohexylsulfonyl and 3-methylpentylsulfonyl groups, etc.

Examples of the adamantyl lower alkyl group may include unless otherwise specified, a lower alkyl group (preferably a straight or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)) as exemplified above and having 1 to 3 (preferably 1) adamantyl groups.

Examples of the cyclo C3-C8 alkyl lower alkyl group may include, unless otherwise specified, a lower alkyl group as exemplified above (straight or branched alkyl groups having 1 to 6 carbon atoms (more preferably, 1 to 4 carbon atoms, and most preferably 1 to 3 carbon atoms)) having 1 to 3 cyclo C3-C8 alkyl groups (preferably a single cyclo C3-C8 alkyl group), and more specifically include cyclopropylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 1-cyclobytylethyl, cyclopentylmethyl, 3-cyclopentylpropyl, cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl, 4-cyclohexylbutyl, 5-cycloheptylpentyl, 6-cyclooctylhexyl, 1,1-dimethyl-2-cyclohexylethyl and 2-methyl-3-cyclopropylpropyl, etc.

A heterocyclic compound represented by the general formula (1) is produced by various methods, for example, produced in accordance with the following reaction formulas-1 and 2.

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[in the formula, R₁, R₂, R₃, R₄are the same as defined above.]

A compound (1) is produced by reacting a compound (3) or a reactive derivative thereof modified at the carboxy group and a compound (2) or a reactive derivative thereof modified at the imino group.

Examples of a preferable reactive derivative of the compound (3) modified at the carboxy group include an acid halide, an acid anhydride, an activated amide and an activated ester, etc. As a preferable example of the reactive derivative, mention may be made of an acid chloride; an acid azide; a mixed anhydride with an acid such as a substituted phosphoric acid, such as dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid and halogenated phosphoric acid, dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, a sulfonic acid such as methanesulfonic acid, an aliphatic carboxylic acid such as acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentane acid, isopentane acid, 2-ethylbutyric acid and trichloro acetic acid or an aromatic carboxylic acid such as benzoic acid; a symmetric anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or activated ester such as cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester and mesylphenyl ester, or an ester with an N-hydroxy compound such as N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide and 1-hydroxy-1H-benzotriazole, etc. These reactive derivatives can be arbitrarily selected from the above examples depending upon the compound (3) to be used.

In the aforementioned reaction, when the compound (3) is used in the form of a free acid or a salt thereof, the reaction is desirably conducted in the presence of a condensing agent. As the condensing agent, a wide variety of condensing agents known in this field can be used. Examples thereof include N,N′-dicyclohexyl carbodiimide; N-cyclohexyl-N′-morpholinoethyl carbodiimide; N-cyclohexyl-N′-(4-diethylaminocyclohexyl)carbodiimide; N,N′-diethyl carbodiimide; N,N′-diisopropyl carbodiimide; N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide or a hydrochloride thereof; N,N-carbonylbis(2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene, 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; diphenyl phosphorylazide; thionyl chloride; oxalyl chloride; lower alkyl haloformate such as ethyl chloroformate and isopropyl chloroformate; triphenyl phosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide internal salt; benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; and a so-called Vilsmeier reagent prepared by the reaction between N,N-dimethyl formamide and thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride or the like. Furthermore, the reaction is further desirably conducted in the copresence of the condensing agent and an esterification activating agent such as N-hydroxysuccinimide and N-hydroxyphthalimide and 1-hydroxy-1H-benzotriazole, etc.

Examples of a preferable reactive derivative of a compound (2) modified at the imino group include a Schiff base imino, which is produced by the reaction between a compound (2) and a carbonyl compound such as aldehyde, ketone or an enamine tautomer; a silyl derivative, which is produced by the reaction between a compound (2) and a silyl compound such as bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide, bis(trimethylsilyl)urea; and a derivative which is produced by the reaction between a compound (2) and phosphorus trichloride, phosgene or the like.

This reaction is usually conducted in a customary solvent having no adverse effect on the reaction. As the solvent, for example, mention is made of water; an alcohol solvent such as methanol, ethanol, isopropanol, n-butanol, trifluoroethanol and ethylene glycol; a ketone solvent such as acetone and methylethyl ketone; an ether solvent such as tetrahydrofuran, dioxane, diethylether, diisopropyl ether and diglyme; an ester solvent such as methyl acetate and ethyl acetate; a nonprotonic polar solvent such as acetonitrile, N,N-dimethylformamide and dimethylsulfoxide; a hydrocarbon solvent such as n-pentane, n-hexane, n-heptane and cyclohexane; a halogenated hydrocarbon solvent such as methylene chloride and ethylene chloride; or an organic solvent other than these, or solvent mixtures of these, etc.

This reaction may be conducted in the presence of a base. As the base, a wide variety of inorganic bases and organic bases known in the art can be used. Examples of the inorganic base include an alkali metal (e.g., sodium, potassium), a hydrogen carbonate of an alkali metal (e.g., lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate), a hydroxide of an alkali metal (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide), a carbonate of an alkali metal (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate), a lower alkoxide of an alkali metal (e.g., sodium methoxide, sodium ethoxide) and a hydride of an alkali metal (e.g., sodium hydride, potassium hydride). Examples of the organic base include a trialkylamine (e.g., trimethylamine, triethylamine, N-ethyldiisopropylamine), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc. Furthermore, when these bases are in a liquid state, they can be also used as a solvent. These bases are used singly or as a mixture of two or more types. The amount of the base(s) to be used is usually 0.1 to 10 moles and preferably 0.1 to 3 moles based on 1 mole of a compound (3).

With respect to the ratio of a compound (3) relative to a compound (2) used in reaction formula 2 above, the former is usually used in an amount of at least 1 mole and preferably about 1 to 5 moles relative to 1 mole of the latter.

The reaction temperature is not particularly limited; however, the reaction is conducted usually under any one of cooling, room temperature and heating. Preferably, the reaction is conducted under temperature conditions of room temperature to 100° C. for 30 minutes to 30 hours, preferably, for 30 minutes to 5 hours.

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[in the formula, R₁, R₂, R₃, R₄are the same as defined above.]

A compound (1) can be produced by the reaction between a compound (4) and a compound (5). The reaction is conducted in the absence of a solvent or in an inert solvent, in the presence or absence of a basic compound and in the presence of a condensing agent.

Examples of the inert solvent may include water; ethers such as dioxane, tetrahydrofuran, diethylether, diethylene glycol methyl ether and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene and xylene; lower alcohols such as methanol, ethanol and isopropanol; ketones such as acetone and methyl ethyl ketone; and polar solvents such as N,N-dimethyl formide (DMF), dimethylsulfoxide (DMSO), hexamethylphosphoric acid triamide and acetonitrile, etc.

As the basic compound, a wide variety of basic compounds known in the art can be used. Examples thereof may include a hydroxide of an alkali metal such as sodium hydroxide, potassium hydroxide, cesium hydroxide and lithium hydroxide, a carbonate of an alkali metal such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; an alkali metal such as sodium and potassium; an inorganic base such as sodium amide, sodium hydride and potassium hydride, and alkali metal alcoholates such as sodium methoxide, sodium ethoxide, potassium methoxide and potassium ethoxide; an organic base such as triethylamine, tripropylamine, pyridine, quinoline, piperidine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazacyclo[4.3.0]nonene-5 (DBN), 1,8diazabicyclo[5.4.0]undecene-7 (DBU) and 1,4-diazabicyclo[2.2.2]octane (DABCO), etc.

These basic compounds are used singly or as a mixture of two or more types.

The amount of the basic compound(s) to be used, usually 0.5 to 10 fold by mole of a compound represented by the general formula (4), and preferably, 0.5 to 6 fold by mole.

The reaction may be conducted by adding, if necessary, an alkali metal iodide such as potassium iodide and sodium iodide as a reaction accelerator.

With respect to the ratio of a compound of the general formula (4) relative to a compound of the general formula (5) in reaction formula 3 above, the latter may be used at least 0.5 fold by mole, preferably, about 0.5 to 5 fold by mole relative to the former.

The reaction is usually conducted under temperature conditions of 0° C. to 200° C., preferably, room temperature to 150° C., and generally completed in about 1 to 30 hours.

As the condensing agent, for example, hexafluoro phosphoric acid benzotriazol-1-yloxy-tris(dimethylamino)phosphonium and bromotriphenylpyrrolidinophosphonium hexafluorophosphate are mentioned.

A compound of the general formula (2) to be used as a starting material is produced, for example, through the step of the following reaction formula-3→4→5→6, and a compound of the general formula (4) is produced, for example, through the step of the following reaction formula-3→4→7→8 or through the step of the following reaction formula-9→10→11, respectively.

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In reaction formulas 3 to 11, R₁, R₂, R₃and R₄are the same as defined above, R₅represents a lower alkoxy, R₆phenoxy, R₇an N-protecting group and X a halogen atom, etc. The lower alkoxy group represented by R₅and the halogen atom represented by X are the same as defined above.

Examples of the N-protecting group may include a lower alkoxycarbonyl group, a lower alkanoyl group and an aryl-substituted lower alkyl group, etc.

Examples of the lower alkoxycarbonyl group include a straight or branched alkoxycarbonyl group having 1 to 6 carbon atoms. Specific examples thereof may include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl groups, etc.

Examples of the lower alkanoyl group include straight or branched alkanoyl group having 1 to 6 carbon atoms. Specific examples thereof include formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butyl carbonyl and hexanoyl groups, etc.

Examples of the aryl-substituted lower alkyl group may include a straight or branched alkyl group having 1 to 6 carbon atoms that is substituted with 1 to 3 phenyl groups, such as benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, diphenylmethyl and trityl, etc. As the substituents on the phenyl group, mention can be made of a straight or branched alkyl group having 1 to 6 carbon atoms and optionally having 1 to 3 groups selected from the group consisting of a halogen atom and a hydroxy group as substituents, such as methyl, ethyl, propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, 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, 5-chloropentyl, 3-chloro-2-methylpropyl, 5-bromohexyl, 5,6-dichlorohexyl and 3-hydroxy-2-chloropropyl group; a straight or branched alkoxy group having 1 to 6 carbon atoms and optionally having 1 to 3 groups selected from the group consisting of a halogen atom and a hydroxy group as substituents, such as methoxy, ethoxy, propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, hydroxymethoxy, 2-hydroxyethoxy, 1-hydroxyethoxy, 3-hydroxypropoxy, 2,3-dihydroxypropoxy, 4-hydroxybutoxy, 1,1-dimethyl-2-hydroxyethoxy, 5,5,4-trihydroxypentyloxy, 5-hydroxypentyloxy, 6-hydroxyhexyloxy, 1-hydroxyisopropoxy, 2-methyl-3-hydroxypropoxy, 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, 5-bromohexyloxy, 5,6-dichlorohexyloxy and 3-hydroxy-2-chloropropoxy groups; and halogen atoms such as a fluorine atom, a bromine atom, a chlorine atom and an iodine atom, etc. When the number of substituents is 2 or more, these substituents may be of the same or different types.

The individual reaction formulas will be more specifically described below.

Reaction Formula 3

A compound (8) can be produced by the reaction between a compound (6) and a compound (7). The reaction is conducted in the absence of a solvent or in an inert solvent and in the presence or absence of a basic compound.

Examples of the inert solvent may include, water; ethers such as dioxane, tetrahydrofuran, diethylether, diethylene glycol methyl ether and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene and xylene; lower alcohols such as methanol, ethanol and isopropanol; ketones such as acetone and methyl ethyl ketone; and polar solvents such as N,N-dimethyl formide (DMF), dimethylsulfoxide (DMSO), hexamethylphosphoric acid triamide and acetonitrile, etc.

These basic compounds are used singly or as a mixture of two or more types.

The amount of the basic compound(s) to be used, usually 0.5 to 10 fold by mole of a compound represented by the general formula (6), and preferably, 0.5 to 6 fold by mole.

The reaction may be conducted by adding, if necessary, an alkali metal iodide such as potassium iodide and sodium iodide as a reaction accelerator.

With respect to the ratio of a compound of the general formula (6) relative to a compound of the general formula (7) in reaction formula 4 above, the latter may be used at least 0.5 fold by mole of the former, preferably, about 0.5 to 5 fold by mole.

The reaction is usually conducted under temperature conditions of 0° C. to 200° C., preferably, room temperature to 150° C. and generally completed in about 1 to 30 hours.

Reaction Formula 4

A compound (11) can be produced by reacting a compound (8) and a compound (9) to obtain a compound (10) and subjecting the compound (10) to a cyclization reaction. The reaction is conducted in the absence of a solvent or in an inert solvent and in the presence or absence of a basic compound.

These basic compounds are used singly or as a mixture of two or more types.

The amount of the basic compound(s) to be used, usually 0.5 to 10 fold by mole of a compound of the general formula (8), and preferably, 0.5 to 6 fold by mole.

The reaction may be conducted by adding, if necessary, an alkali metal iodide such as potassium iodide and sodium iodide as a reaction accelerator.

With respect to the ratio of a compound of the general formula (8) relative to a compound of the general formula (9) in reaction formula 3 above, the latter may be used at least 0.5 fold by mole of the former, preferably, about 0.5 to 5 fold by mole.

The reaction is usually conducted under temperature conditions of 0° C. to 200° C., preferably, room temperature to 150° C. and generally completed in about 1 to 30 hours.

Reaction Formula 5

A compound (12) can be produced by reacting a compound (11) and a compound (5). The reaction is conducted in the same reaction conditions as in reaction formula 2 above.

Reaction Formula 6

The compound (2) can be produced by subjecting compound (12) to a reaction of eliminating an N-protecting group.

To the elimination reaction of an N-protecting group, a customary method such as hydrolysis and hydrogenolysis can be applied.

The elimination reaction is usually conducted in a customary solvent having no adverse effect on the reaction. As the solvent, for example, mention is made of water; an alcohol solvent such as methanol, ethanol, isopropanol, n-butanol, trifluoroethanol and ethylene glycol; a ketone solvent such as acetone and methylethyl ketone; an ether solvent such as tetrahydrofuran, dioxane, diethylether, dimethoxyethane and diglyme; an ester solvent such as methyl acetate and ethyl acetate; a nonprotonic polar solvent such as acetonitrile, N,N-dimethylformamide, dimethylsulfoxide and N-methylpyrrolidone; a halogenated hydrocarbon solvent such as methylene chloride and ethylene chloride; or an organic solvent other than these, etc.

(i) Hydrolysis:

Hydrolysis is preferably performed in the presence of a base or an acid (including Lewis acid).

As the base, a wide variety of inorganic bases and organic bases known in the art can be used. As the inorganic base preferably used, for example, mention is made of an alkali metal (e.g., sodium, potassium), an alkaline-earth metal (e.g., magnesium, calcium), hydroxides, carbonates or hydrogen carbonates of these. As the organic base preferably used, for example, mention is made of trialkyl amine (e.g., trimethylamine, triethylamine), picoline and 1,5-diazabicyclo[4,3,0]non-5-ene, etc.

As the acid, a wide variety of inorganic acids and organic acids known in the art can be used. As the inorganic acid preferably used, for example, mention is made of a fatty acid such as formic acid, acetic acid and propionic acid; and a trihaloacetic acid such as trichloroacetic acid and trifluoroacetic acid, etc. As the inorganic base preferably used, for example, mention is made of hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride and hydrogen bromide. As the Lewis acid, for example, mention is made of a boron trifluoride ether complex, boron tribromide, aluminum chloride and ferric chloride, etc.

When a trihaloacetic acid or a Lewis acid is used as the acid, hydrolysis is preferably performed in the presence of a cation trapping agent (e.g., anisole, phenol).

The amount of the base or acid to be used is not particularly limited as long as it is required for hydrolysis.

The reaction temperature is usually 0 to 120° C., preferably, room temperature to 100° C., and more preferably room temperature to 80° C. The reaction time is usually 30 minutes to 24 hours, preferably, 30 minutes to 12 hours, and more preferably, 1 to 8 hours.

(ii) Hydrogenolysis:

To hydrogenolysis, a wide variety of hydrogenolysis methods known in the art can be applied. As the hydrogenolysis method, for example, chemical reduction and catalytic reduction are mentioned.

Examples of the reducing agent preferably used for chemical reduction include a hydride (e.g., hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium boron hydride, sodium cyanoborohydride) or a combination of a metal (e.g., tin, zinc, iron) or a metal compound (e.g., chromium chloride, chromium acetate) and an organic acid or an inorganic acid (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid).

Examples of the catalyst preferably used for catalytic reduction include a platinum catalyst (e.g., platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire), a palladium catalyst (e.g., spongy palladium, palladium black, palladium oxide, palladium carbon, palladium/barium sulfate, palladium/barium carbonate), a nickel catalyst (e.g., reduced nickel, nickel oxide, Raney nickel), a cobalt catalyst (e.g., reduced cobalt, Raney cobalt) and an iron catalyst (e.g., reduced iron), etc.

Note that the aforementioned acids to be used in chemical reduction are in a liquid state, they can be also used as a solvent.

The amount of the reducing agent to be used for chemical reduction and the amount of the catalyst to be used as catalytic reduction are not particularly limited and the amounts usually used may be employed.

Furthermore, the elimination reaction of the N-protecting group mentioned above is not limited to the aforementioned reaction conditions, for example, the reaction described in T. W. Green, P. G. M. Wuts, “Protective Groups in Organic Synthesis”, the 4th edition and John Wiley & Sons; New York, 1991, P. 309 can be also applied to the step of the elimination reaction.

Reaction Formula 7

The compound (13) can be produced by subjecting a compound (11) to a reaction of eliminating an N-protecting group. The elimination reaction can be conducted in the same reaction conditions as in the reaction represented by the above reaction formula-6.

Reaction Formula 8

The compound (4) is produced by reacting a compound (3) or its reactive derivative modified at a carboxy group and a compound (13) or its reactive derivative modified at an imino group. The reaction is conducted in the same reaction conditions as in the reaction represented by the above reaction formula-1.

Reaction Formula 9

The compound (15) is produced by amination of a compound (14). The reaction is conducted in the same reaction conditions as in the reaction of Reference Example 21 (described later).

Reaction Formula 10

The compound (16) can be produced by the reaction between a compound (15) and a compound (7). The reaction can be conducted in the same reaction conditions as in the reaction of reaction formula-3.

Reaction Formula 11

The compound (4) can be produced by obtaining a compound (17) formed through the reaction between a compound (16) and a compound (9) and subjecting the compound (17) to a cyclization reaction. The reaction is conducted in the same reaction conditions as in the reaction of reaction formula-4.

The raw material compounds used in each of the reaction formulas may be a salt preferably used, and a desired compound obtained in each reaction may form also a salt preferably used. Examples of the salt preferably used include preferable salts of the compound (1) as exemplified below.

A preferable salt of the compound (1) is a pharmacologically acceptable salt. Examples thereof include a metal salt such as an alkali metal salt (e.g., sodium salt, potassium salt), an alkaline-earth metal salt (e.g., a calcium salt, a magnesium salt), a salt of an inorganic base such as an ammonium salt, a carbonate of an alkali metal (e.g., lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate), a hydrogen carbonate of an alkali metal (e.g., lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate), a hydroxide of an alkali metal (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide); a salt of an organic base such as tri(lower)alkylamine (e.g., trimethylamine, triethylamine, N-ethyldiisopropylamine), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-(lower)alkyl-morpholine (e.g., N-methylmorpholine), 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,4-diazabicyclo[2.2.2]octane (DABCO); a salt of an inorganic acid such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate and phosphate; and a salt of an organic acid such as formic acid, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, picrate, methanesulfonate, ethanesulfonate, p-toluenesulfonate and glutamate, etc.

Furthermore, compounds formed by adding a solvate (e.g., hydrate, ethanolate) to a raw material and a desired compound shown in each reaction formula are also included in each of the general formulas. As a preferable solvate, a hydrate is mentioned.

The desired compound obtained in each of the reaction formulas above can be isolated from a reaction mixture and purified, for example, by cooling the reaction mixture, subjecting it to an isolation operation such as filtration, concentration and extraction to separate a crude reaction product and subjecting to a customary purification operation such as column chromatography and recrystallization.

The compounds represented by the general formula (1) of the present invention, as a matter of course, include isomers such as a geometric isomer, a stereoisomer and an optical isomer.

Furthermore, the present invention may include an isotope-labeled compound, which is identical with a compound represented by the general formula (1) except that one or more atoms are substituted with one or more atoms having a specific atomic mass or mass number. Examples of the isotope to be integrated into a compound according to the present invention may include hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine isotopes such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ¹⁸F and ³⁶Cl, respectively. A compound according to the present invention labeled with a specific isotope, which includes the aforementioned isotopes and/or other isotopes of other atoms, for example, a compound according to the present invention labeled with a radio isotope such as ³H and ¹⁴C, is useful in a drug tissue-distribution assay and/or a substrate tissue-distribution assay. Tritiated (that is, ³H) isotope and carbon-14 (that is ¹⁴C) isotope are particularly preferable since it is easily prepared and detected. Furthermore, if a heavier isotope such as heavy hydrogen (that is, ²H) is used in place, metabolic stability is improved, for example, in-vivo half time is increased or a requisite dose is reduced. Due to these, specific therapeutic benefits can be expected. An isotope labeled compound according to the present invention generally can be prepared in accordance with the aforementioned reaction formula and/or the method disclosed in Examples below by replacing a non-isotope labeled reagent with an easily available isotope-labeled reagent.

A compound of the general formula (1) and a salt thereof are used in the form of a general pharmaceutical preparation. The preparation is prepared using a diluent or an excipient usually used such as a filler, an extending agent, a binder, a moisturing agent, a disintegrator, a surfactant and a lubricant. The dosage form of the pharmaceutical preparation can be selected from various forms depending upon the purpose of therapy. Typical examples thereof include a tablet, a pill, a powder, a liquid, a suspension, an emulsion, a grain, a capsule, a suppository and an injection (liquid, suspension, etc.), etc.

When the preparation is formed into a tablet, a wide variety of carriers conventionally known in this field can be used. Examples thereof that can be used may include an excipient such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystal cellulose and silica, a binder such as water, ethanol, propanol, simple syrup, a glucose solution, a starch solution, a gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate and polyvinyl pyrrolidone, a disintegrator such as dry starch, sodium alginate, powdered agar, powdered laminaran, sodium hydrogen carbonate, calcium carbonate, a polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch and lactose, a disintegration suppressing agent such as white sugar, stearin, cacao butter and hydrogenated oil, an absorption promoter such as a quaternary ammonium base and sodium lauryl sulfate, a moisturizing agent such as glycerin and starch, an adsorbent such as starch, lactose, kaolin, bentonite, colloidal silica, and a lubricant such as purified talc, a stearate, powdered boric acid and polyethylene glycol. Furthermore, a tablet may be coated with a film usually used and formed into a sugar coating tablet, gelatin encapsulated tablet, an enteric coated tablet, a film coated tablet, or a double-layer tablet and a multi-layer tablet, etc.

When a preparation is formed into a pill, a wide variety of carriers conventionally known in this field can be used. For example, an excipient such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin and talc, a binder such as powdered gum Arabic, powdered tragacanth, gelatin and ethanol, and a disintegrator such as laminaran and agar, can be used.

When a preparation is formed into a suppository, a wide variety of carriers conventionally known in this field can be used. As examples thereof, polyethylene glycol, cacao butter, a higher alcohol, an ester of a higher alcohol, gelatin and a semi-synthesized glyceride may be mentioned.

A capsule can be prepared usually by mixing an active-ingredient compound with a carrier as exemplified above and filling a capsule such as a hard gelatin capsule and a soft capsule with the mixture in accordance with a customary method.

When a preparation is prepared as an injection, a liquid, an emulsion and a suspension are preferably sterilized and rendered isotonic with blood. When a preparation is formed into these forms, all diluents customarily used in this field can be used. For example, water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol and polyoxyethylene sorbitan fatty acid ester can be used.

Note that, in this case, a sufficient amount of salt, glucose or glycerin for preparing an isotonic solution may be contained in a pharmaceutical preparation or a general solubilization agent, a buffer and a soothing agent, etc. may be added. Furthermore, if necessary, a colorant, a preservative, a flavor and a sweetener, etc. and other medical drugs may be contained in a pharmaceutical preparation.

The amount of the compound of the general formula (1) or a salt thereof to be contained in a pharmaceutical preparation of the present invention is not particularly limited and may be appropriately selected from a broad range; however, it is usually about 1 to 70 wt %, and preferably, about 1 to 30 wt % in a preparation composition.

The method for administering a pharmaceutical preparation of the present invention is not particularly limited. The preparation is administered by a method selected in accordance with the dosage form, the age and gender of the patient, other conditions and the extent of the disease. For example, in the case of a tablet, a pill, a liquid, a suspension, an emulsion, a grain and a capsule, the preparation is orally administered. In the case of an injection, the preparation is intravenously injected singly or as a mixture with a fluid replacement usually used such as glucose and amino acid. Further, if necessary, the preparation is singly injected intramuscularly, subcutaneously, or intraperitoneally. In the case of a suppository, the preparation is administered intrarectally.

The dose of the pharmaceutical preparation of the present invention is appropriately selected depending upon the dosage form, the age and gender of the patient, other conditions and the extent of the disease; however, it may be usually about 0.1 to 10 mg per weight (kg) per day in terms of amount of active-ingredient compound. Furthermore, it is desirable to contain an active-ingredient compound in an amount within the range of about 1 to 200 mg in a dose unit of a preparation.

A compound according to the present invention can be used in combination with a medical drug (hereinafter, simply referred to as a concomitant drug) such as a therapeutic agent for diabetes, a therapeutic agent for a diabetic complication, a hypolipidemic agent, an antihypertensive agent, an anti-obesity agent and a diuretic agent for augmentation of the effect. The time for administrating a compound according to the present invention and a concomitant drug is not limited and they may be administered to a subject to be administered at the same time and at a time interval. Furthermore, a compound according to the present invention and a concomitant drug may be integrated into a combination drug. The dose of the concomitant drug can be appropriately selected based on the clinical dosage. Furthermore, the blending ratio of a compound according to the present invention and a concomitant drug can be appropriately selected depending upon the subject to be administered, administration route, target disease, symptom and combination, etc. For example, when a human is a subject to be administered, a concomitant drug may be used in an amount of 0.01 to 100 parts by weight based on the compound according to the present invention (1 part by weight).

Note that examples of the therapeutic agent for diabetes include an insulin preparation (e.g., an animal insulin preparation extracted from bovine and swine pancreas, human insulin preparation synthesized in a genetic engineering process using Escherichia coli or a yeast), an insulin-resistance improving agent (e.g., pioglitazone or a hydrochloride thereof, troglitazone, rosiglitazone or a maleate thereof, GI-262570, JTT-501, MCC-555, YM-440, KRP-297, CS-011), an α-glucosidase inhibitor (e.g., voglibose, acarbose, miglitol, emiglitate), a biguanide agent (e.g., metformin), an insulin-secretion accelerating agent (e.g., a sulfonylurea agent such as tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide and glimepiride; repaglinide, senaglinide, nateglinide, mitiglinide), a dipeptidylpeptidase IV (DPP-IV) inhibitor (e.g., sitagliptin or a phosphate thereof, vildagliptin, alogliptin or a benzoate thereof, denagliptin or a tosyl acid salt), GLP-1, a GLP-1 analogue (exenatide, liraglutide, SUN-E7001, AVE010, BIM-51077, CJC1131), a protein tyrosine phosphate inhibitor (e.g., vanadium acid), and a β3 agonist (e.g., GW-427353B, N5984).

Examples of the therapeutic agent for a diabetic complication include an aldose reductase inhibitor (e.g., tolrestat, epalrestat, zenarestat, zopolrestat, minarestat, fidarestat, ranirestat, SK-860, CT-112); a neurotrophic factor (e.g., NGF, NT-3, BDNF), a PKC inhibitor (e.g., LY-333531), an AGE inhibitor (e.g., ALT946, pimagedine, piratoxathin, N-phenacylthiazolium bromide (ALT766)), an active oxygen eliminating agent (e.g., thioctic acid) and a cerebral vasodilator (e.g., tiapride, mexiletine). Examples of the hypolipidemic agent include a HMG-CoA reductase inhibitor (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin or sodium salts thereof), a squalene synthase inhibitor and an ACAT inhibitor. Examples of the antihypertensive agent include an angiotensin-converting enzyme inhibitor (e.g., captopril, enalapril, alacepril, delapril, lisinopril, imidapril, benazepril, cilazapril, temocapril, trandolapril), an angiotensin II antagonist (e.g., olmesartan, medoxomil, candesartan, cilexetil, losartan, eprosartan, valsartan, telmisartan, irbesartan, tasosartan), a calcium antagonist (e.g., nicardipine hydrochloride, manidipine hydrochloride, nisoldipine, nitrendipin, nilvadipine, amlodipine).

Examples of the anti-obesity agent include a centrally-acting anti-obesity agent (e.g., phentermine, sibutramine, amfepramone, dexamfetamin, mazindol, SR-141716A), a pancreatic lipase inhibitor (e.g., orlistat), a peptidic appetite suppressor (e.g., leptin, CNTF (ciliary body neurotrophic factor)), a cholecystokinin agonist (e.g., lintitript, FPL-15849). Examples of the diuretic agent include a xanthine derivative (e.g., theobromine sodium salicylate, theobromine calcium salicylate), a thiazide preparation (e.g., ethiazide, cyclopenthiazide, trichlormethiazide, hydrochlorthiazide, hydroflumethiazide, bentyl hydrochlorothiazide, penflutizide, polythiazide, methyclothiazide), an antialdosterone preparation (e.g., spironolactone, triamterene), a carbonic anhydrase inhibitor (e.g., acetazolamide), a chlorobenzene sulfoneamide preparation (e.g., chlorthalidone, mefruside, indapamide), azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide and furosemide.

Preferable examples of the concomitant drug include GLP-1, a GLP-1 analogue, an α-glucosidase inhibitor, a biguanide agent, an insulin-secretion accelerating agent and an insulin-resistance improver. The concomitant drugs may be used in appropriate combination of two or more.

When a compound according to the present invention is used in combination with a concomitant drug, the dose of these medical drugs can be reduced within the safe range in view of adverse drug reactions of the medical drugs. Particularly, the biguanide agent can be reduced than a general dose. Accordingly, adverse drug reactions that will be caused by these medical drugs can be safely prevented. In addition, the dosages of e.g., a diabetic complication agent, a hypolipidemic agent, an antihypertensive agent can be reduced. As a result, adverse drug reactions that will be caused by these medical drugs can be effectively prevented.

Advantages of the Invention

The compound of the present invention has a human GPR10 receptor antagonist effect.

The compound of the present invention has a strong suppression effect on stress-induced defecation in a restraint stress-induced defecation rat, which is used as a model of irritable bowel syndrome known as one of the stress-related diseases. Furthermore, the compound of the present invention, has a strong suppression effect on stress-induced eating behavior in a tale-pinch stress induced eating behavior rat used as a model of a stress induced bulimia.

The compound of the present invention effectively works on a stress-related disease caused by excessive stress load, for example, including a disorder of the respiratory system (e.g., bronchial asthma; hyperventilation syndrome), a gastrointestinal disorder (e.g., irritable bowel syndrome; gastric atony; gastric ulcer; duodenum ulcer; gastritis; ulcerative colitis), a cardiovascular system disorder (e.g., essential hypertension; orthostatic hypotension; arrhythmia; myocardial infarction; angina pectoris), an endocrine/metabolic disorder (e.g., obesity; diabetes; hyperthyroidism), a nervous system disorder (e.g., major depression; generalized anxiety disorder; panic disorder; obsessive-compulsive disorder; phobia; conversion disorder; dissociative disorder; posttraumatic stress syndrome; migraine headache; autonomic dysregulation), an eating disorder (e.g., bulimia nervosa; anorexia nervosa), a bone/muscle disorder (e.g., chronic rheumatoid arthritis; systemic myalgia; spinal irritation; tic syndrome; traumatic neurosis), dermatopathy (e.g., atopic dermatitis; chronic urticaria; alopecia areata; cutaneous pruritus), a urinary system disorder (e.g., enuresis; impotency; hypersensitive cystitis), an otorhinolaryngological disorder (e.g., Meniere syndrome; pharyngolaryngeal paresthesia; hearing loss; ringing in the ears; loss of voice; stutter), an oral cavity disorder (stomatitis; oral dysodia; abnormal salivation; dental prothesis neurotic disorder), an ophthalmic disorder (e.g., primary glaucoma; eyestrain; eyelid twitching) and a gynecologic disorder (e.g., dysmenorrhea; amenorrhea; menstrual disorder; menopausal disorder; frigidity).

EXAMPLES

For a better understanding of the present invention, Reference Examples, Examples and Pharmacological Tests will be described below.

Reference Example 1
Synthesis of ethyl-4-phenoxycarbonylamino-1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxylate

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Ethyl-4-amino-1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxylate (23.6 g) was dissolved in methylene chloride (460 ml), and pyridine (13 ml) and phenyl chlorocarbonate (15 ml) were added under ice cooling and the resultant mixture was stirred for one hour at the same temperature. To the reaction solution, water was added and the mixture was extracted with methylene chloride. After the organic layer was washed sequentially with 1 N hydrochloric acid and saturated saline solution in this order, the organic layer was dried over sodium sulfate, filtrated and concentrated under reduced pressure. To the resultant residue, diethyl ether was added to obtain a precipitate by filtration. The titled compound (10.57 g) was obtained as a colorless solid substance. Furthermore, the filtrate was concentrated under reduced pressure. Thereafter, the resultant residue was purified by medium-pressure silica gel column (solvent; ethyl acetate:hexane=10:90 to 50:50). The resultant crude crystal was washed with a solvent mixture of diethyl ether-hexane to obtain the titled compound (11.10 g) as a slightly yellow solid substance.

¹H-NMR (CDCl₃) δ ppm: 1.32 (t, J=7.1 Hz, 3H), 1.48 (s, 9H), 3.02 (t, J=5.9 Hz, 2H), 3.52 (t, J=5.9 Hz, 2H), 4.18 (brs, 2H), 4.24 (q, J=7.1 Hz, 2H), 7.13 (t, J=7.8 Hz, 2H), 7.19-7.25 (m, 1H), 7.37 (t, J=7.8 Hz, 2H), 11.36 (s, 1H).

Reference Example 2
Synthesis of 6-(tert-butoxycarbonyl)-3-propargyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-dione

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Ethyl-4-phenoxycarbonylamino-1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxylate (5.0 g) was dissolved in THF (50 ml), and propargylamine (1.32 ml) and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) (0.2 ml) were added and the resultant mixture was stirred at room temperature for 2 hours. After production of an intermediate (urea) was confirmed by TLC, a 5 N aqueous sodium hydroxide solution (5 ml) was added and the resultant mixture was further stirred at room temperature for 2 hours. To the reaction solution, 6 N hydrochloric acid was added to neutralize and the resultant mixture was then concentrated. To the residue, water was added and the mixture was extracted with ethyl acetate. After the organic layer was washed with a saturated saline solution, the organic layer was dried over sodium sulfate, filtrated and concentrated under reduced pressure. A precipitate was obtained by filtration. The titled compound (3.78 g) was obtained as a white powder.

¹H-NMR (CDCl₃) 5 ppm: 1.48 (s, 9H), 2.18 (t, J=2.4 Hz, 1H), 2.54 (t, 5.7 Hz, 2H), 3.68 (t, J=5.7 Hz, 2H), 4.24 (s, 2H), 4.69 (d, J=2.4 Hz, 2H), 9.82 (brs, 1H).

Reference Example 3
Synthesis of 6-(tert-butoxycarbonyl)-2-(S)-{1-[4-(trifluoromethyl)phenyl]ethylamino}-3-propargyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4-(3H)-one

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6-(tert-Butoxycarbonyl)-3-propargyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-dione (1.0 g) was dissolved in tetrahydrofuran (20 ml) and 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (2.17 g) and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) (0.76 ml) were added and the resultant mixture was stirred at room temperature. At 10 minutes later, (S)-1-[4-(trifluoromethyl)phenyl]ethylamine (0.93 ml) was added and the resultant mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure and a saturated aqueous sodium hydrogen carbonate solution was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and thereafter dried over sodium sulfate, filtrated and concentrated under reduced pressure. The resultant residue was purified by medium-pressure silica gel column (solvent; ethyl acetate:hexane=20:80 to 90:10). The titled compound (520 mg) was obtained as a colorless amorphous substance.

¹H-NMR (CDCl₃) δ ppm: 1.46 (s, 9H), 1.60 (d, J=6.7 Hz, 3H), 2.30-2.61 (m, 3H), 3.44-3.71 (m, 2H), 4.15-4.36 (m, 2H), 4.88 (d, J=2.6 Hz, 2H), 5.21-5.40 (m, 2H), 7.48 (d, J=8.2 Hz, 2H), 7.60 (d, J=8.2 Hz, 2H).

Reference Example 4
Synthesis of 6-(tert-butoxycarbonyl)-3-propargyl-2-(S)-[1-(4-chlorophenyl)ethylamino]-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(3H)-one

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Synthesis was performed in the same manner as in Reference Example 3.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.47 (s, 9H), 1.57 (d, J=6.9 Hz, 3H), 2.35-2.60 (m, 3H), 3.50-3.70 (m, 2H), 4.15-4.35 (m, 2H), 4.85 (d, J=2.5H, 2H), 5.20-5.25 (m, 2H), 7.31 (s, 4H).

Reference Example 5
Synthesis of 6-(tert-butoxycarbonyl)-3-dimethylamino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-dione

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Ethyl-4-phenoxycarbonylamino-1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxylate (5.0 g) was dissolved in THF (50 ml) and dimethyl hydrazine (1.46 ml) and DBU (0.2 ml) were added and the resultant mixture was stirred at room temperature for 2 hours. Dimethylhydrazine (0.73 ml) and DBU (0.2 ml) were added and the resultant mixture was further stirred at room temperature for 2 hours. After production of an intermediate (urea) was confirmed by TLC, a 5 N aqueous sodium hydroxide solution (5 ml) was added and the resultant mixture was further stirred at room temperature overnight. To the reaction solution, 6 N hydrochloric acid was added to neutralize and the resultant mixture was then concentrated. To the residue, water was added and the mixture was extracted with ethyl acetate. After the organic layer was washed with a saturated saline solution, the organic layer was dried over sodium sulfate, filtrated and concentrated. The resultant residue was purified by medium-pressure silica gel column chromatography (solvent; ethyl acetate:hexane=50:50 to 100:0). To the resultant amorphous substance, diethyl ether was added to obtain a precipitate by filtration. The titled compound (3.34 g) was obtained as a white powder.

¹H-NMR (CDCl₃) δ ppm: 1.48 (s, 9H), 2.48 (t, J=5.7 Hz, 2H), 2.97 (s, 6H), 3.65 (t, J=5.7 Hz, 2H), 4.21 (s, 2H), 9.20 (brs, 1H).

Reference Example 6
Synthesis of 6-(tert-butoxycarbonyl)-2-(S)-{1-[4-(trifluoromethyl)phenyl]ethylamino}-3-dimethylamino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(3H)-one

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6-(tert-Butoxycarbonyl)-3-dimethylamino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-dione (1.0 g) was dissolved in tetrahydrofuran (20 ml) and 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (2.17 g) and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) (0.76 ml) were added and the resultant mixture was stirred at room temperature. At 10 minutes later, (S)-1-[4-(trifluoromethyl)phenyl]ethylamine (0.93 ml) was added and the resultant mixture was further stirred at room temperature overnight. The reaction solution was distilled away under reduced pressure. To the residue, a saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. After the organic layer was washed with a saturated saline solution, the organic layer was dried over sodium sulfate, filtrated and concentrated. The resultant residue was purified by medium-pressure silica gel column chromatography (solvent; ethyl acetate:hexane=20:80 to 70:30). The titled compound (990 mg) was obtained as a colorless amorphous substance.

¹H-NMR (CDCl₃) δ ppm: 1.46 (s, 9H), 1.56 (d J=7.0 Hz, 3H), 2.30-2.57 (m, 2H), 2.93-3.11 (m, 6H), 3.45-3.70 (m, 2H), 4.10-4.30 (m, 2H), 5.11-5.28 (m, 1H), 6.85 (d, J=8.0 Hz, 1H), 7.44 (d, J=8.1 Hz, 2H), 7.59 (d, J=8.1 Hz, 21-1).

Reference Example 7
Synthesis of 6-(tert-butoxycarbonyl)-3-dimethylamino-2-[3-fluoro-4-(trifluoromethyl)benzylamino]-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(3H)-one

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Synthesis was performed in the same manner as in Reference Example 6.

Colorless amorphous.

¹H-NMR (CDCl₃) δ ppm: 1.48 (s, 9H), 2.40-2.52 (m, 2H), 3.02 (s, 6H), 3.59 (t, J=5.7 Hz, 2H), 4.20-4.25 (m, 2H), 4.63 (d, J=6.2 Hz, 2H), 7.01 (t, J=6.2 Hz, 1H), 7.15-7.19 (m, 2H), 7.57 (t, J=7.6 Hz, 1H).

Reference Example 8
Synthesis of 6-(tert-butoxycarbonyl)-2-(S)-[1-(4-chlorophenyl)ethylamino]-3-dimethylamino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(3H)-one

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Synthesis was performed in the same manner as in Reference Example 6.

Colorless amorphous.

¹H-NMR (CDCl₃) δ ppm: 1.47 (s, 9H), 1.53 (d, J=6.9 Hz, 3H), 2.41-2.51 (m, 2H), 2.98 (s, 3H), 3.02 (s, 3H), 3.50-3.60 (m, 2H), 4.18-4.25 (m, 2H), 5.11-5.15 (m, 1H), 6.79 (d, J=8.1 Hz, 1H), 7.25-7.32 (m, 4H).

Reference Example 9
Synthesis of 6-(tert-butoxycarbonyl)-3-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-dione

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Ethyl-4-phenoxycarbonylamino-1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxylate (3.0 g) was dissolved in THF (30 ml) and O-methylhydroxylamine hydrochloride (3.2 g), triethylamine (5.35 ml) and DBU (0.3 ml) were added to the solvent, and the resultant mixture was stirred at room temperature overnight. O-methylhydroxylamine hydrochloride (3.2 g) and triethylamine (5.35 ml) were added and the resultant mixture was further stirred at room temperature for 6 hours. After production of an intermediate (urea) was confirmed by TLC, a 5 N sodium hydroxide solution (5 ml) was added and the resultant mixture was further stirred at room temperature overnight. To the reaction solution, 6 N hydrochloric acid was added, and the resultant mixture was neutralized and concentrated to obtain a precipitate by filtration. The resultant crude crystal was dissolved in methylene chloride-methanol and ethyl acetate was added to obtain a precipitate by filtration. The resultant crude crystal was purified by medium-pressure silica gel column chromatography (solvent; methanol:ethyl acetate=0:100 to 10:90). The titled compound (2.21 g) was obtained as a white powder.

¹H-NMR (CDCl₃) δ ppm: 1.48 (s, 9H), 2.53 (t, J=5.7 Hz, 2H), 3.67 (t, J=5.7 Hz, 2H), 4.00 (s, 3H), 4.25 (s, 2H), 9.56 (brs, 1H).

Reference Example 10
Synthesis of 6-(tert-butoxycarbonyl)-2-(S)-{1-[4-(trifluoromethyl)phenyl]ethylamino}-3-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(3H)-one

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6-(tert-Butoxycarbonyl)-3-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-dione (1.0 g) was dissolved in tetrahydrofuran (20 ml) and 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (2.17 g), and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) (0.76 ml) were added and the resultant mixture was stirred at room temperature. At 10 minutes later, (S)-1-[4-(trifluoromethyl)phenyl]ethylamine (0.93 ml) was added and the resultant mixture was further stirred at room temperature overnight. The reaction solution was distilled away under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue and the mixture was extracted with ethyl acetate. After the organic layer was washed with a saturated saline solution, the organic layer was dried over sodium sulfate, filtrated and concentrated. The resultant residue was purified by medium-pressure silica gel column chromatography (solvent; ethyl acetate:hexane=20:80 to 90:10). The titled compound (788 mg) was obtained as a slightly yellow amorphous substance. ¹H-NMR (CDCl₃) δ ppm: 1.43 (s, 9H), 1.61 (d, J=7.0 Hz, 3H), 2.31-2.60 (m, 2H), 3.39-3.64 (m, 2H), 3.85-4.40 (m, 5H), 5.13-5.31 (m, 1H), 5.61-6.00 (m, 1H), 7.40-7.58 (m, 2H), 7.61 (d, J=8.3 Hz, 2H).

Reference Example 11
Synthesis of 6-(tert-butoxycarbonyl)-3-methoxy-2-(S)-[1-(4-chlorophenyl)ethylamino]-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(3H)-one

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Synthesis was performed in the same manner as in Reference Example 10.

Colorless amorphous.

¹H-NMR (CDCl₃) δ ppm: 1.47 (s, 9H), 1.57 (d, J=6.9 Hz, 3H), 2.35-2.60 (m, 2H), 3.50-3.70 (m, 2H), 4.04 (s, 3H), 4.15-4.35 (m, 2H), 5.15-5.25 (m, 1H), 5.55-5.75 (m, 1H), 7.20-7.40 (m, 4H).

Reference Example 12
Synthesis of 2-(S)-{1-[4-(trifluoromethyl)phenyl]ethylamino}-3-dimethylamino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(3H)-one

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6-(tert-Butoxycarbonyl)-2-(S)-{1-[4-(trifluoromethyl)phenyl]ethylamino}-3-dimethylamino-5,6,7,8-tetrahydropyrido[4,3-D]pyrimidin-4-(3H)-one (990 mg) was dissolved in methylene chloride (10 ml), trifluoroacetic acid (3 ml) was added under ice cooling and the resultant mixture was stirred at room temperature overnight. Under ice cooling, the reaction mixture was alkalified with sodium hydroxide solution, and the mixture was extracted with methylene chloride. After the organic layer was washed with a saturated saline solution, the organic layer was dried over sodium sulfate, filtrated and concentrated to obtain the titled compound (733 mg) as a colorless amorphous substance. The resultant compound was used in a next reaction without further purifying.

¹H-NMR (CDCl₃) δ ppm: 1.56 (d, J=7.0 Hz, 3H), 2.25-2.50 (m, 2H), 2.92-3.12 (m, 8H), 3.57-3.73 (m, 2H), 5.12-5.29 (m, 2H), 6.83 (d, J=8.0 Hz, 1H), 7.45 (d, J=8.2 Hz, 2H), 7.59 (d, J=8.2 Hz, 2H).

Reference Example 13
Synthesis of 2-(S)-{1-[4-(trifluoromethyl)phenyl]ethylamino}-3-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(3H)-one

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6-(tert-Butoxycarbonyl)-2-(S)-{1-[4-(trifluoromethyl)phenyl]ethylamino}-3-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(3H)-one (788 mg) was dissolved in methylene chloride (5 ml), trifluoroacetic acid (2 ml) was added under ice cooling and the resultant mixture was stirred at room temperature overnight. Under ice cooling, the reaction mixture was alkalified with sodium hydroxide solution, and the mixture was extracted with methylene chloride. After the organic layer was washed with a saturated saline solution, the organic layer was dried over sodium sulfate, filtrated and concentrated to obtain the titled compound (310 mg) as a colorless amorphous substance. The resultant compound was used in a next reaction without further purifying.

¹H-NMR (CDCl₃) δ ppm: 1.60 (d, J=7.0 Hz, 3H), 2.28-2.42 (m, 2H), 2.93-3.11 (m, 2H), 3.60-3.80 (m, 2H), 4.06 (s, 3H), 5.18-5.35 (m, 1H), 5.61 (d, J=7.7 Hz, 1H), 7.47 (d, J=8.2 Hz, 2H), 7.61 (d, J=8.2 Hz, 2H). Amine H was not observed.

Reference Example 14
Synthesis of tert-butyl-2,4-dioxo-3-(pyrrolidin-1-yl)-1,2,3,4,7,8-hexahydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate

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Under nitrogen, 1-tert-butyl 3-ethyl 4-(phenoxycarbonylamino)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (6.14 g) was dissolved in THF (50 ml) and 1-aminopyrrolidine hydrochloride (2.31 g), triethylamine (6.58 ml) and 1,8-diazabicyclo[5.4.0]und-7-ene (0.24 ml) were added, and the resultant mixture was stirred at room temperature for 2 hours. Thereafter, the reaction solution was stirred at 50° C. for 2 hours and 68° C. for 3 hours. After consumption of the raw materials was confirmed by TLC or LC/MS, to the reaction mixture 2 N sodium hydroxide solution (15.7 ml) was added at 0° C., and the resultant mixture was stirred at room temperature for two days. Thereafter, the solution was stirred at 50° C. for 3 hours and further 2 N sodium hydroxide solution (10 ml) was added at the same temperature. The reaction mixture was stirred at 68° C. for 2 hours. After the completion of the reaction was confirmed by TLC or LC/MS, the solution was cooled to room temperature, 2 N hydrochloric acid (30 ml) and a saturated ammonium chloride solution were added, the resultant mixture was extracted with ethyl acetate and dried over sodium sulfate. The solution was filtrated, concentrated and purified by silica gel chromatography to obtain desired tert-butyl-2,4-dioxo-3-(pyrrolidin-1-yl)-1,2,3,4,7,8-hexahydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate in an amount of 3.19 g (yield 60%).

¹H-NMR (DMSO-d₆) δ ppm: 11.10 (brs, 1H), 4.02 (brs, 2H), 3.50 (brt, J=5.68 Hz, 4H), 3.11 (brt, J=6.52 Hz, 2H), 2.37 (brt, J=5.68 Hz, 2H), 1.84 (m, 4H), 1.41 (s, 9H).

Reference Example 15
Synthesis of 2-(S)-{1-[4-(trifluoromethyl)phenyl]ethylamino}-3-propargyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(3H)-one

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6-(tert-Butoxycarbonyl)-2-(S)-{1-[4-(trifluoromethyl)phenyl]ethylamino}-3-propargyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(3H)-one (520 mg) was dissolved in methylene chloride (10 ml), trifluoroacetic acid (3 ml) was added under ice cooling and the resultant mixture was stirred at room temperature overnight. Under ice cooling, the reaction mixture was alkalified with sodium hydroxide solution, and the mixture was extracted with methylene chloride. After the organic layer was washed with saturated saline solution, the organic layer was dried over sodium sulfate, filtrated and concentrated to obtain the titled compound (402 mg) as a colorless amorphous substance. The resultant compound was used in a next reaction without further purifying.

¹H-NMR (CDCl₃) δ ppm: 1.60 (d, J=6.8 Hz, 3H), 2.30-2.57 (m, 3H), 2.96-3.18 (m, 2H), 3.63-3.79 (m, 2H), 4.87 (d, J=2.4 Hz, 2H), 5.18-5.41 (m, 2H), 7.48 (d, J=8.0 Hz, 2H), 7.59 (d, J=8.0 Hz, 2H). Amine H was not observed.

Reference Example 16
Synthesis of 3-propargyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-dione hydrochloride

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6-(tert-Butoxycarbonyl)-3 propargyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-dione (1.0 g) was suspended in 4 N hydrochloric acid in ethyl acetate (10 ml) and the resultant mixture was stirred at room temperature for 3 hours. A precipitate was obtained by filtration and dissolved in ethanol and the solvent was distilled away under reduced pressure. This was repeated three times to obtain the titled compound (790 mg) as a colorless amorphous substance. The resultant compound was subjected to a next reaction without further purifying. ¹H-NMR (DMSO-d₆) δ ppm: 2.60-2.74 (m, 2H), 3.08-3.11 (m, 1H), 3.21-3.35 (m, 2H), 3.77 (s, 2H), 4.41-4.52 (m, 2H), 9.38 (brs, 2H), 11.61 (s, 1H).

Reference Example 17
Synthesis of 6-(4-chlorobenzoyl)-3-propargyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-dione

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3-propargyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-dione hydrochloride (790 mg) was suspended in methylene chloride, triethylamine (0.95 ml) and 4-chlorobenzoyl chloride (0.42 ml) were added under ice cooling and the resultant mixture was stirred at the same temperature for 30 minutes. To the reaction solution, water was added and the resultant mixture was concentrated. To the residue, diethyl ether was added and insoluble matter was separated by filtration to obtain the titled compound (894 mg) as a white powder. The resultant compound was used in a next reaction without further purifying.

¹H-NMR (DMSO-d₆) δ ppm: 2.46-2.60 (m, 2H), 2.90-3.12 (m, 1H), 3.41-3.92 (m, 2H), 3.94-4.38 (m, 2H), 4.38-4.64 (m, 2H), 7.43-7.58 (m, 4H), 11.41 (brs, 1H).

Reference Example 18
Synthesis of 3-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-dione hydrochloride

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6-(tert-Butoxycarbonyl)-3-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-dione (1.0 g) was suspended in 4 N hydrochloric acid in ethyl acetate (10 ml) and the resultant mixture was stirred at room temperature for 3 hours. The reaction solution was distilled away under reduced pressure. To the residue, methanol was added and the solvent was distilled away under reduced pressure. This was repeated three times to obtain the titled compound (790 mg) as a white powder. The resultant compound was used in a next reaction without further purifying.

¹H-NMR (DMSO-d₆) δ ppm: 2.62-2.72 (m, 2H), 3.22-3.35 (m, 2H), 3.68-3.79 (m, 2H), 3.81 (s, 3H), 9.56 (brs, 2H), 11.72 (brs, 1H).

Reference Example 19
Synthesis of 6-(4-chlorobenzoyl)-3-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-dione

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3-Methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-dione hydrochloride (790 mg) was suspended in methylene chloride, and triethylamine (1.17 ml) and 4-chlorobenzoyl chloride (0.43 ml) were added under ice cooling and the resultant mixture was stirred at the same temperature for 1.5 hours. To the reaction solution, water was added and the resultant mixture was concentrated. To the residue, diethyl ether was added and insoluble matter was obtained by filtration. The titled compound (684 mg) was obtained as a white powder. The resultant compound was used in a next reaction without further purifying.

¹H-NMR (DMSO-d₆) δ ppm: 2.40-2.55 (m, 2H), 3.39-3.92 (m, 5H), 3.92-4.40 (m, 2H), 7.48 (d J=8.5 Hz, 2H), 7.54 (d, J=8.5 Hz, 2H), 11.45 (brs, 1H).

Reference Example 20
Synthesis of ethyl 1-(4-chlorobenzoyl)-4-piperidone-3-carboxylate

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Ethyl 4-piperidone-3-carboxylate hydrochloride (10 g) was suspended in methylene chloride (250 ml), triethylamine (16 ml) and 4-chlorobenzoyl chloride (7.2 ml) were added and the resultant mixture was stirred one hour under ice cooling. To the reaction solution, water was added and the mixture was extracted with methylene chloride. After the organic layer was washed with a saturated saline solution, the organic layer was dried over sodium sulfate, filtrated and concentrated. The resultant residue was purified by medium-pressure silica gel column chromatography (solvent; ethyl acetate:hexane=33:67 to 50:50). The titled compound (15.95 g) was obtained as a colorless solid substance.

¹H-NMR (CDCl₃) δ ppm: 1.20-1.40 (m, 3H), 2.30-2.71 (m, 2H), 3.42-4.00 (m, 2H), 4.00-4.51 (m, 4H), 7.29-7.48 (m, 4H), 12.1 (s, 1H).

Reference Example 21
Synthesis of ethyl-4-amino-1-(4-chlorobenzoyl)-1,2,5,6-tetrahydropyridine-3-carboxylate

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Ethyl 1-(4-chlorobenzoyl)-4-piperidone-3-carboxylate (15.9 g) was dissolved in toluene (200 ml), ammonium acetate (12.0 g) and acetic acid (3.0 ml) were added and the resultant mixture was heated to reflux for 5 hours by use of Dean-Stark apparatus. To the reaction solution, a saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. After the organic layer was washed with a saturated saline solution, the organic layer was dried over sodium sulfate, filtrated and concentrated. The resultant residue was subjected to medium-pressure column fractionation (solvent; ethyl acetate:hexane=33:67 to 50:50). A crude crystal was washed with diethyl ether to obtain the titled compound (13.97 g) as a white powder.

¹H-NMR (CDCl₃) δ ppm: 1.07-1.36 (m, 3H), 2.25-2.52 (m, 2H), 3.31-3.98 (m, 2H), 4.01-4.49 (m, 4H), 7.30-7.48 (m, 4H). Amine H was not observed.

Reference Example 22
Synthesis of ethyl-4-phenoxycarbonylamino-1-(4-chlorobenzoyl)-1,2,5,6-tetrahydropyridine-3-carboxylate

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Ethyl-4-amino-1-(4-chlorobenzoyl)-1,2,5,6-tetrahydropyridine-3-carboxylate (7.0 g) was dissolved in methylene chloride (140 ml), pyridine (6.0 ml) and phenyl chlorocarbonate (6.0 ml) were added under ice cooling, and the resultant mixture was stirred at room temperature for 2 hours. To the reaction solution, water was added and the mixture was extracted with methylene chloride. After the organic layer was washed with citric acid solution and a saturated saline solution, the organic layer was dried over sodium sulfate, filtrated and concentrated. The resultant residue was subjected to medium-pressure column fractionation (solvent; ethyl acetate:hexane=20:80 to 60:40). The titled compound (8.35 g) was obtained as a white powder.

¹H-NMR (CDCl₃) δ ppm: 1.20-1.44 (m, 3H), 2.98-3.23 (m, 2H), 3.38-3.94 (m, 2H), 4.06-4.54 (m, 4H), 7.13 (d, J=5.5 Hz, 2H), 7.20-7.25 (m, 1H), 7.29-7.47 (m, 6H), 11.4 (brs, 1H).

Reference Example 23
Synthesis of 6-(4-chlorobenzoyl)-3-dimethylamino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-dione

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Ethyl-4-phenoxycarbonylamino-1-(4-chlorobenzoyl)-1,2,5,6-tetrahydropyridine-3-carboxylate (200 mg) was dissolved in THF (2 ml), N,N-dimethylhydrazine (142 μl) and DBU (10 μl) were added and the resultant mixture was shaken at 50° C. for 3 hours. 5 N sodium hydroxide solution (200 μl) was added and the resultant mixture was further shaken at 50° C. overnight. To the reaction solution, acetic acid (300 μl) was added to neutralize, and the reaction solution was then concentrated. The resultant residue was subjected to medium-pressure column fractionation (solvent; methanol:methylene chloride=0:100 to 7:93). The titled compound (105 mg) was obtained as a white powder.

¹H-NMR (CDCl₃) δ ppm: 2.47-2.69 (m, 2H), 2.94 (s, 6H), 3.53-4.02 (m, 2H), 4.04-4.51 (m, 2H), 7.29-7.46 (m, 4H), 9.03 (brs, 1H).

Reference Example 24
Synthesis of (S)-tert-butyl-4-oxo-3-(pyrrolidin-1-yl)-2-{1-[4-(trifluoromethyl)phenyl]ethylamino}-3,4,7,8-tetrahydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate

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Under nitrogen, tert-butyl 2,4-dioxo-3-(pyrrolidin-1-yl)-1,2,3,4,7,8-hexahydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (1.5 g) was dissolved in THF (50 ml), and 1,8-diazabicyclo[5.4.0]unde-7-ene (1 ml) and benzotriazol-1-yloxy-tris-(dimethylamino)phosphonium hexafluorophosphate (2.96 g) were added at room temperature. After the reaction solution was stirred at room temperature for a while, (S)-1-(4-trichlorophenyl)ethylamine (1.25 ml) was added. The reaction solution was stirred at room temperature. Saturated sodium hydrogen carbonate solution was added, and the resultant mixture was extracted with ethyl acetate, washed with a saturated saline solution, dried over sodium sulfate, filtrated, concentrated and purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain a desired compound (1.91 g, yield 84%).

¹H-NMR (DMSO-d₆) δ ppm: 7.60 (d, J=8.24 Hz, 2H), 7.45 (d, J=8.24 Hz, 2H), 6.88 (d, J=8.24 Hz, 1H), 5.22 (dt, J=8.24, 7.00 Hz, 1H), 4.22-4.15 (m, 2H), 3.63-3.48 (m, 4H), 3.14-3.07 (m, 2H), 2.45 (m, 2H), 2.20 (m, 2H), 1.87 (m, 2H), 1.57 (d, J=7.00 Hz, 3H), 1.46 (s, 9H).

Reference Example 25
Synthesis of 3-(pyrrolidin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-(1H,5H)-dione hydrochloride

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tert-Butyl 2,4-dioxo-3-(pyrrolidin-1-yl)-1,2,3,4,7,8-hexahydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (1.690 g) was dissolved in methylene chloride (50 ml), 4 N HCl in ethyl acetate (10 ml) was added and the resultant mixture was stirred under room temperature, overnight. A solid substance was precipitated, filtrated off, dried to quantitatively obtain the desired compound.

¹H-NMR (DMSO-d₆) δ ppm: 11.40 (brs, 1H), 9.30 (brs, 2H), 4.00-3.50 (br, 2H), 3.28 (br, 2H), 3.12 (brt, J=6.54 Hz, 4H), 2.62 (br, 2H), 1.85 (m, 4H).

Reference Example 26
Synthesis of 6-(4-chlorobenzoyl)-3-(pyrrolidin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-(1H,3H)-dione

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Under nitrogen, 3-(pyrrolidin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-(1H,5H)-dione hydrochloride (1.370 g) was dissolved in methylene chloride (20 ml), and pyridine (1 ml) and 4-chlorobenzoyl chloride (0.64 ml) were added at 0° C. After the solution was stirred at 0° C. for 45 minutes, the temperature was raised up to room temperature and the solution was stirred for one hour and a half. Methylene chloride (10 ml) and pyridine (1 ml) were added and the resultant mixture was stirred overnight at room temperature. Thereafter, the reaction solution was cooled to 0° C. and pyridine (1 ml) and 4-chlorobenzoyl chloride (0.6 ml) were added, and the resultant mixture was stirred at the same temperature for 2 hours for 50 minutes, and heated to reflux further one hour. After consumption of the raw materials was confirmed by TLC and LC/MS, water was added. The mixture was extracted with methylene chloride. The organic layer was dried over sodium sulfate, filtrated and concentrated. Thereafter, the resultant solid substance was washed with diethyl ether and ethyl acetate. The solid substance was recovered and dried to obtain a desired compound in an amount of 1.03 g (yield 55%).

¹H-NMR (DMSO-d₆) δ ppm: 11.2 (s, 1H), 7.54 (d, J=8.36 Hz, 2H), 7.48 (d, J=8.36 Hz, 2H), 4.24 (br, 1H), 4.04 (br, 1H), 3.79 (br, 1H), 3.46 (br, 1H), 3.10 (br, 4H), 2.50 (br, 2H), 1.84 (br, 4H).

Reference Example 27
Synthesis of tert-butyl 3-ethoxy-2,4-dioxo-1,2,3,4,7,8-hexahydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate

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The titled compound was obtained in the same manner as in Reference Example 14.

¹H-NMR (DMSO-d₆) δ ppm: 11.6-11.4 (brs, 1H), 4.03 (q, J=7.08 Hz, 2H), 4.02 (br, 2H), 3.50 (t, J=5.68 Hz, 2H), J=5.68 Hz, 2H), 1.41 (s, 9H), 1.22 (t, J=7.08 Hz, 3H).

Reference Example 28
Synthesis of (S)-tert-butyl 3-ethoxy-4-oxo-2-{1-[4-(trifluoromethyl)phenyl]ethylamino}-3,4,7,8-tetrahydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate

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The titled compound was obtained in the same manner as in Reference Example 24.

¹H-NMR (DMSO-d₆) δ ppm: 7.61 (d, J=8.16 Hz, 2H), 7.46 (d, J=8.16 Hz, 2H), 5.62 (d, J=7.68 Hz, 1H), 5.25 (dt, J=7.68, 5.36 Hz, 1H), 4.34 (m, 2H), 4.24 (q, J=7.14 Hz, 2H), 3.60-3.49 (m, 2H), 2.52-2.40 (m, 2H), 3.11 (d, J=5.36 Hz, 1H), 1.61 (d, J=5.36 Hz, 3H), 1.47 (s, 9H), 1.41 (t, J=7.14 Hz, 3H).

Reference Example 29
Synthesis of 3-ethoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-(1H,5H)-dione hydrochloride

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The titled compound was obtained in the same manner as in Reference Example 25.

¹H-NMR (DMSO-d₆) δ ppm: 9.20 (brs, 2H), 4.05 (q, J=7.04 Hz, 2H), 3.78 (brs, 2H), 3.29 (t, J=5.92 Hz, 2H), 2.64 (brt, J=5.92 Hz, 2H), 1.23 (t, J=7.04 Hz, 3H). Amine H was not observed.

Reference Example 30
Synthesis of 3-dimethylamino-2-(3-fluoro-4-trifluoromethylbenzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(3H)-one

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The titled compound was obtained in the same manner as in Reference Example 12. Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 2.41-2.45 (m, 2H), 3.03 (s, 6H), 3.04-3.06 (m, 3H), 3.68-3.69 (m, 2H), 4.63 (d, J=6.2 Hz, 2H), 6.98 (t, J=6.0 Hz, 1H), 7.16-7.20 (m, 2H), 7.57 (t, J=8.0 Hz, 1H).

Reference Example 31
Synthesis of 2-(S)-[1-(4-chlorophenyl)ethylamino]-3-dimethylamino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(3H)-one

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The titled compound was obtained in the same manner as in Reference Example 12. Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.53 (d, J=6.9 Hz, 3H), 2.35-2.48 (m, 3H), 2.96 (s, 3H), 3.00 (s, 3H), 3.03-3.09 (m, 2H), 3.63-3.72 (m, 2H), 5.09-5.17 (m, 1H), 6.78 (d, J=8.1 Hz, 1H), 7.26-7.31 (m, 4H).

Reference Example 32

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3-(2-Butynyl)-4-oxo-2-[(S)-1-(4-trifluoromethyl-phenyl)-ethylamino]-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester

Synthesis was performed in the same manner as in Reference Example 10.

¹H-NMR (CDCl₃) δ ppm: 7.43 (d, J=8.22 Hz, 2H), 7.49 (d, J=8.22 Hz, 2H), 5.45 (d, J=6.84 Hz, 1H), 5.35 (qd, J=6.92, 6.84 Hz, 1H), 4.91 (dd, J=17.6, 2.42 Hz, 1H), 4.71 (dd, J=17.6, 2.42 Hz, 1H), 4.28 (d, J=17.12 Hz, 1H), 4.20 (d, J=17.12 Hz, 1H), 3.60 (br, 1H), 3.53 (m, 1H), 2.47 (brm, 2H), 1.80 (t, J=2.42 Hz, 3H), 1.60 (d, J=6.92 Hz, 3H), 1.46 (s, 9H).

Reference Example 33

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3-Morpholin-4-yl-4-oxo-2-[(S)-1-(4-trifluoromethyl-phenyl)-ethylamino]-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester

Synthesis was performed in the same manner as in Reference Example 10.

¹H-NMR (CDCl₃) δ ppm: 1.48 (s, 9H), 1.57 (d, J=7.0 Hz, 3H), 2.32-2.56 (m, 2H), 2.66-2.83 (m, 2H), 3.45-3.76 (m, 4H), 3.95-4.04 (m, 2H), 4.17-4.35 (m, 4H), 5.13-5.24 (m, 1H), 6.89 (d, J=8.0 Hz, 1H), 7.42 (d, J=8.0 Hz, 2H), 7.61 (d, J=8.0 Hz, 2H).

Reference Example 34

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3-(3-Butynyl)-4-oxo-2-[(S)-1-(4-trifluoromethyl-phenyl)-ethylamino]-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester

Synthesis was performed in the same manner as in Reference Example 10.

¹H-NMR (CDCl₃) δ ppm: 7.59 (d, J=8.24 Hz, 2H), 7.49 (d, J=8.24 Hz, 2H), 5.46 (d, J=6.0 Hz, 1H), 5.29 (m, 1H), 4.30-4.05 (m, 4H), 3.63 (br, 1H), 3.57-3.50 (m, 1H), 2.73-2.68 (m, 2H), 2.60-2.40 (br, 2H), 1.98 (t, J=2.66 Hz, 1H), 1.57 (d, J=6.36 Hz, 3H), 1.47 (s, 9H),

Reference Example 35

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3-Isopropoxy-4-oxo-2-[(S)-1-(4-trifluoromethyl-phenyl)-ethylamino]-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester

Synthesis was performed in the same manner as in Reference Example 10.

¹H-NMR (CDCl₃) δ ppm: 1.31 (d, J=6.5 Hz, 3H), 1.37 (d, J=6.5 Hz, 3H), 1.47 (s, 9H), 1.59 (d, J=7.0 Hz, 3H), 2.35-2.58 (m, 2H), 3.47-3.68 (m, 2H), 4.15-4.32 (m, 2H), 4.84-4.97 (m, 1H), 5.17-5.30 (m, 1H), 5.62 (d, J=7.5 Hz, 1H), 7.46 (d, J=8.5 Hz, 2H), 7.61 (d, J=8.5 Hz, 2H).

Reference Example 36

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4-oxo-3-phenoxy-2-[(S)-1-(4-trifluoromethyl-phenyl)-ethylamino]-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester

Synthesis was performed in the same manner as in Reference Example 10.

¹H-NMR (CDCl₃) δ ppm: 1.46 (s, 9H), 1.52 (d, J=7.0 Hz, 3H), 2.38-2.62 (m, 2H), 3.46-3.69 (m, 2H), 4.14-4.32 (m, 2H), 5.16-5.32 (m, 1H), 5.55 (d, J=7.5 Hz, 1H), 7.00 (d, J=8.0 Hz, 2H), 7.17 (dd, J=7.0 Hz, 7.0 Hz, 1H), 7.27-7.43 (m, 4H), 7.54 (d, J=8.0 Hz, 2H).

Reference Example 37

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2-[1-(4-Chloro-phenyl)-propylamino]-3-methoxy-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester

Synthesis was performed in the same manner as in Reference Example 10.

¹H-NMR (CDCl₃) δ ppm: 0.94 (t, J=7.4 Hz, 3H), 1.47 (s, 9H), 1.84-1.94 (m, 2H), 2.35-2.58 (m, 2H), 3.47-3.69 (m, 2H), 4.05 (s, 3H), 4.11-4.30 (m, 2H), 4.89-4.96 (m, 1H), 5.62 (d, J=8.0 Hz, 1H), 7.24-7.33 (m, 4H).

Reference Example 38

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3-(4-Methyl-piperazin-1-yl)-4-oxo-2-[(S)-1-(4-trifluoromethyl-phenyl)-ethylamino]-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester

Synthesis was performed in the same manner as in Reference Example 10.

¹H-NMR (CDCl₃) δ ppm: 1.46 (s, 9H), 1.56 (d, J=7.0 Hz, 3H), 2.13-2.26 (m, 2H), 2.34 (s, 3H), 2.37-2.54 (m, 2H), 2.68-2.86 (m, 2H), 2.88-2.95 (m, 2H), 3.43-3.65 (m, 2H), 4.12-4.27 (m, 4H), 5.10-5.22 (m, 1H), 6.95 (d, J=8.0 Hz, 1H), 7.42 (d, J=8.0 Hz, 2H), 7.61 (d, J=8.0 Hz, 2H).

Reference Example 39

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2-[2-(4-Chloro-phenyl)-pyrrolidin-1-yl]-3-methoxy-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester

Synthesis was performed in the same manner as in Reference Example 10.

¹H-NMR (CDCl₃) δ ppm: 1.46 (s, 9H), 1.78-2.02 (m, 2H), 2.06-2.14 (m, 1H), 2.23-2.45 (m, 2H), 2.46-2.60 (m, 1H), 3.40-3.57 (m, 1H), 3.58-3.69 (m, 1H), 3.71-3.86 (m, 4H), 3.90-4.00 (m, 1H), 4.15-4.37 (m, 2H), 5.12-5.21 (m, 1H), 7.17-7.32 (m, 4H).

Reference Example 40

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2-[(R)-1-(4-Chloro-phenyl)-propylamino]-3-methoxy-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester

Synthesis was performed in the same manner as in Reference Example 10.

Reference Example 41

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4-Oxo-3-(2-propynyl)-2-[1-(4-trifluoromethyl-phenyl)-ethylamino]-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester

Synthesis was performed in the same manner as in Reference Example 10.

Reference Example 42

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3-Dimethylamino-4-oxo-2-[1-(4-trifluoromethyl-phenyl)-ethylamino]-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester

Synthesis was performed in the same manner as in Reference Example 10.

Reference Example 43

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2-[1-(4-Chloro-phenyl)-ethylamino]-3-dimethylamino-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester

Synthesis was performed in the same manner as in Reference Example 10.

Reference Example 44

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2-[1-(4-Chloro-phenyl)-2-methyl-propylamino]-3-methoxy-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester

Synthesis was performed in the same manner as in Reference Example 10.

¹H-NMR (CDCl₃) δ ppm: 0.87 (d, J=6.7 Hz, 3H), 1.03 (d, J=6.7 Hz, 3H), 1.46 (s, 9H), 2.00-2.14 (m, 1H), 2.27-2.53 (m, 2H), 3.40-3.69 (m, 2H), 4.07 (s, 3H), 4.10-4.30 (m, 2H), 4.77 (dd, J=7.7, 7.7 Hz, 1H), 5.71 (d, J=8.6 Hz, 1H), 7.12-7.35 (m, 4H).

Reference Example 45

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2-[(S)-1-(4-Chloro-phenyl)-propylamino]-3-methoxy-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester

Synthesis was performed in the same manner as in Reference Example 10.

Reference Example 46

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2-[1-(4-Chloro-phenyl)-4,4,4-trifluoro-butylamino]-3-methoxy-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester

Synthesis was performed in the same manner as in Reference Example 10.

¹H-NMR (CDCl₃) δ ppm: 1.47 (s, 9H), 2.00-2.28 (m, 4H), 2.35-2.56 (m, 2H), 3.44-3.63 (m, 2H), 4.04 (s, 3H), 4.16-4.32 (m, 2H), 5.01-5.15 (m, 1H), 5.65 (d, 8.1 Hz, 1H), 7.20-7.38 (m, 4H).

Reference Example 47

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2-[1-(4-Cyano-phenyl)-ethylamino]-3-methoxy-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester

Synthesis was performed in the same manner as in Reference Example 10.

¹H-NMR (CDCl₃) δ ppm: 1.47 (s, 9H), 1.61 (d, J=7.0 Hz, 3H), 2.30-2.53 (m, 2H), 3.42-3.63 (m, 2H), 4.05 (s, 3H), 4.07-4.24 (m, 2H), 5.15-5.29 (m, 1H), 5.80 (bs, 1H), 7.48 (d, J=8.3 Hz, 2H), 7.63 (d, 8.3 Hz, 2H).

Reference Example 48

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2-(4-Chloro-benzylamino)-3-methoxy-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester

Synthesis was performed in the same manner as in Reference Example 10.

¹H-NMR (CDCl₃) δ ppm: 1.48 (s, 9H), 2.54 (brt, J=5.5 Hz, 2H), 3.61 (t, J=6.0 Hz, 2H), 4.04 (s, 3H), 4.27 (s, 2H), 4.58 (d, J=6.0 Hz, 2H), 5.75 (brt, J=6.0 Hz, 1H), 7.26-7.35 (m, 4H).

Reference Example 49

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3-Methoxy-4-oxo-2-(4-trifluoromethyl-benzylamino)-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester

Synthesis was performed in the same manner as in Reference Example 10.

¹H-NMR (CDCl₃) δ ppm: 1.48 (s, 9H), 2.53 (t, J=6.0 Hz, 2H), 3.61 (t, J=6.0 Hz, 2H), 4.07 (s, 3H), 4.28 (s, 2H), 4.69 (d, J=6.0 Hz, 2H), 5.83 (t, J=6.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 2H), 7.62 (d, J=8.0 Hz, 2H).

Reference Example 50

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3-Methoxy-2-[(S)-1-(4-methoxy-phenyl)-ethylamino]-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester

Synthesis was performed in the same manner as in Reference Example 10.

¹H-NMR (CDCl₃) δ ppm: 1.47 (s, 9H), 1.58 (d, J=7.0 Hz, 3H), 2.41-2.59 (m, 2H), 3.49-3.68 (m, 2H), 3.80 (s, 3H), 4.00 (s, 3H), 4.14-4.30 (m, 2H), 5.11-5.23 (m, 1H), 5.60 (d, J=8.0 Hz, 1H), 6.86-6.91 (m, 2H), 7.28-7.32 (m, 2H).

Reference Example 51

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2-(4-Cyano-benzylamino)-3-methoxy-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester

Synthesis was performed in the same manner as in Reference Example 10.

¹H-NMR (CDCl₃) δ ppm: 1.47 (s, 9H), 2.50 (t, J=5.5 Hz, 2H), 3.59 (t, J=5.5 Hz, 2H), 4.06 (s, 3H), 4.26 (s, 2H), 4.70 (d, J=6.0 Hz, 2H), 6.18 (t, J=6.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 2H), 7.63 (d, J=8.0 Hz, 2H).

Reference Example 52

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2-[(S)-1-(4-Chloro-phenyl)-2-methyl-propylamino]-3-methoxy-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester

Synthesis was performed in the same manner as in Reference Example 10.

¹H-NMR (CDCl₃) δ ppm: 0.87 (d, J=6.6 Hz, 3H), 1.03 (d, J=6.6 Hz, 3H), 1.46 (s, 9H), 2.00-2.17 (m, 1H), 2.29-2.55 (m, 2H), 3.40-3.69 (m, 2H), 4.07 (s, 3H), 4.10-4.30 (m, 2H), 4.77 (dd, J=7.7, 7.7 Hz, 1H), 5.71 (d, J=8.4 Hz, 1H), 7.14-7.37 (m, 4H).

Reference Example 53

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3-Methoxy-4-oxo-2-[(S)-1-(4-trifluoromethyl-phenyl)-propylamino]-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester

Synthesis was performed in the same manner as in Reference Example 10.

¹H-NMR (CDCl₃) δ ppm: 0.97 (t, J=7.3 Hz, 3H), 1.46 (s, 9H), 1.79-2.00 (m, 2H), 2.24-2.56 (m, 2H), 3.36-3.62 (m, 2H), 4.07 (s, 3H), 4.10-4.33 (m, 2H), 4.90-5.07 (m, 1H), 5.69 (d, J=7.8 Hz, 1H), 7.43 (d, J=8.1 Hz, 2H), 7.60 (d, J=8.0 Hz, 2H).

Reference Example 54

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3-(2-Butynyl)-2-[(S)-1-(4-chloro-phenyl)-2-methyl-propylamino]-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester

Synthesis was performed in the same manner as in Reference Example 10.

¹H-NMR (CDCl₃) δ ppm: 0.91 (d, J=6.7 Hz, 3H), 1.03 (d, J=6.7 Hz, 3H), 1.45 (s, 9H), 1.84 (s, 3H), 1.95-2.16 (m, 1H), 2.26-2.52 (m, 2H), 3.39-3.65 (m, 2H), 4.07-4.36 (m, 2H), 4.78-4.84 (m, 2H), 4.92 (dd, J=7.3, 7.3 Hz, 1H), 5.58 (d, J=7.4 Hz, 1H), 7.16-7.32 (m, 4H).

Reference Example 55

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2-{[(4-Chloro-phenyl)-cyclopropyl-methyl]-amino}-3-methoxy-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester

Synthesis was performed in the same manner as in Reference Example 10.

¹H-NMR (CDCl₃) δ ppm: 0.37-0.56 (m, 2H), 0.58-0.71 (m, 2H), 1.41-1.27 (m, 1H), 1.47 (s, 9H), 2.29-2.52 (m, 2H), 3.42-3.66 (m, 2H), 4.08 (s, 3H), 4.12-4.31 (m, 2H), 4.37-4.46 (m, 1H), 5.85 (d, J=7.5 Hz, 1H), 7.26-7.38 (m, 4H).

Reference Example 56

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2-(4-Ethoxy-benzylamino)-3-methoxy-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester

Synthesis was performed in the same manner as in Reference Example 10.

¹H-NMR (CDCl₃) δ ppm: 1.39-1.43 (m, 3H), 1.48 (s, 9H), 2.56 (bs, 2H), 3.54-3.67 (m, 2H), 3.96-4.06 (m, 5H), 4.23-4.33 (m, 2H), 4.48-4.53 (m, 2H), 5.56-5.65 (m, 1H), 6.88 (d, J=5.2 Hz, 2H), 7.26 (d, J=5.2 Hz, 2H).

Reference Example 57

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3-Pyrrolidin-1-yl-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

The titled compound was obtained in the same manner as in Reference Example 12.

¹H-NMR (CDCl₃) δ ppm: 7.59 (d, J=8.26 Hz, 2H), 7.45 (d, J=8.26 Hz, 2H), 6.85 (d, J=8.16 Hz, 1H), 5.22 (m, 1H), 3.70-3.50 (m, 4H), 3.16-2.96 (m, 5H), 2.46-2.31 (m, 2H), 2.24-2.10 (m, 2H), 1.89-1.80 (m, 2H), 1.57 (d, J=7.0 Hz, 3H).

Reference Example 58

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3-Ethoxy-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

The titled compound was obtained in the same manner as in Reference Example 12.

¹H-NMR (CDCl₃) δ ppm: 7.61 (d, J=8.32 Hz, 2H), 7.46 (d, J=8.32 Hz, 2H), 5.59 (d, J=7.72 Hz, 1H), 5.25 (m, 1H), 4.33 (q, J=7.6 Hz, 2H), 3.70 (m, 2H), 3.05-3.00 (m, 2H), 2.44-2.37 (m, 2H), 1.41 (t, J=7.16 Hz, 3H), 1.60 (d, J=6.96 Hz, 3H).

Reference Example 59

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3-(2-Butynyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

The titled compound was obtained in the same manner as in Reference Example 12.

¹H-NMR (CDCl₃) δ ppm: 7.59 (d, J=8.16 Hz, 2H), 7.49 (dd, J=8.16, 2.44 Hz, 2H), 5.42 (dd, J=6.8, 2.44 Hz, 1H), 5.32 (m, 1H), 4.90 (d, J=17.3 Hz, 1H), 4.71 (d, J=17.3 Hz, 1H), 3.72 (d, J=16.1 Hz, 1H), 3.67 (d, J=16.1 Hz, 1H), 3.03 (m, 2H), 2.48-2.33 (m, 2H), 1.80 (t, J=2.44 Hz, 3H), 1.60 (d, J=6.8 Hz, 3H).

Reference Example 60

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3-Isobutoxy-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

The titled compound was obtained in the same manner as in Reference Example 12.

¹H-NMR (CDCl₃) δ ppm: 1.05 (d, J=6.7 Hz, 6H), 1.59 (d, J=6.9 Hz, 3H), 2.08-2.23 (m, 1H), 2.28-2.52 (m, 2H), 2.95-3.10 (m, 2H), 3.64-3.77 (m, 2H), 3.90-4.08 (m, 2H), 5.16-5.28 (m, 1H), 5.60 (d, J=7.6 Hz, 1H), 7.46 (d, J=8.3 Hz, 2H), 7.61 (d, J=8.3 Hz, 2H).

Reference Example 61

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2-[1-(4-Chlorophenyl)propylamino]-3-methoxy-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

The titled compound was obtained in the same manner as in Reference Example 12.

¹H-NMR (CDCl₃) δ ppm: 0.94 (t, J=7.3 Hz, 3H), 1.78-2.00 (m, 2H), 2.28-2.44 (m, 2H), 2.90-3.10 (m, 2H), 3.55-3.77 (m, 2H), 4.05 (s, 3H), 4.82-5.03 (m, 1H), 5.50-5.61 (m, 1H), 7.18-7.38 (m, 4H).

Reference Example 62

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2-[(S)-1-(4-Chlorophenyl)ethylamino]-3-methoxy-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

The titled compound was obtained in the same manner as in Reference Example 12.

¹H-NMR (CDCl₃) δ ppm: 1.58 (d, J=6.9 Hz, 3H), 2.32-2.53 (m, 2H), 2.95-3.13 (m, 2H), 3.61-3.80 (m, 2H), 4.03 (s, 3H), 5.11-5.26 (m, 1H), 5.56 (d, J=7.8 Hz, 1H), 7.26-7.40 (m, 4H).

Reference Example 63

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2-[2-(4-Chlorophenyl)pyrrolidin-1-yl]-3-methoxy-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

The titled compound was obtained in the same manner as in Reference Example 12.

MS [M+H]⁺=361

Reference Example 64

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2-[(R)-1-(4-Chlorophenyl)propylamino]-3-methoxy-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

The titled compound was obtained in the same manner as in Reference Example 12.

¹H-NMR (CDCl₃) δ ppm: 0.94 (t, J=7.4 Hz, 3H), 1.78-2.00 (m, 2H), 2.29-2.52 (m, 2H), 2.91-3.11 (m, 2H), 3.59-3.79 (m, 2H), 4.04 (s, 3H), 4.88-4.99 (m, 1H), 5.59 (d, J=8.0 Hz, 1H), 7.18-7.37 (m, 4H).

Reference Example 65

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2-[1-(4-Chlorophenyl)cyclopropylamino]-3-methoxy-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

The titled compound was obtained in the same manner as in Reference Example 12.

¹H-NMR (CDCl₃) δ ppm: 1.30-1.39 (m, 4H), 2.44 (t, J=5.9 Hz, 2H), 3.03 (t, J=5.9 Hz, 2H), 3.70 (s, 2H), 4.03 (s, 3H), 6.08 (s, 1H), 7.20-7.31 (m, 4H).

Reference Example 66

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3-Methoxy-2-[1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

The titled compound was obtained in the same manner as in Reference Example 12.

Reference Example 67

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2-[(S)-1-(4-Chlorophenyl)ethylamino]-3-(2-propynyl)-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

The titled compound was obtained in the same manner as in Reference Example 12.

¹H-NMR (CDCl₃) δ ppm: 1.57 (d, J=6.5 Hz, 3H), 2.37-2.70 (m, 3H), 3.02-3.20 (m, 2H), 3.68-3.85 (m, 2H), 4.84 (d, J=2.2 Hz, 2H), 5.17-5.32 (m, 2H), 7.28-7.37 (m, 4H).

Reference Example 68

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3-(3-Butynyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

The titled compound was obtained in the same manner as in Reference Example 12.

¹H-NMR (CDCl₃) δ ppm: 1.57 (d, J=6.9 Hz, 3H), 1.92-1.98 (m, 1H), 2.28-2.54 (m, 2H), 2.57-2.77 (m, 2H), 2.92-3.08 (m, 2H), 3.57-3.74 (m, 2H), 3.97-4.19 (m, 2H), 5.17-5.32 (m, 1H), 5.40 (d, J=6.0 Hz, 1H), 7.41-7.63 (m, 4H).

Reference Example 69

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2-[1-(4-Chlorophenyl)-2-methylpropylamino]-3-methoxy-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

The titled compound was obtained in the same manner as in Reference Example 12.

¹H-NMR (CDCl₃) δ ppm: 0.87 (d, J=6.7 Hz, 3H), 1.03 (d, J=6.7 Hz, 3H), 2.00-2.17 (m, 1H), 2.25-2.52 (m, 2H), 2.90-3.10 (m, 2H), 3.60-3.78 (m, 2H), 4.06 (s, 3H), 4.78 (dd, J=8.3, 8.3 Hz, 1H), 5.69 (d, J=8.5 Hz, 1H), 7.11-7.34 (m, 4H).

Reference Example 70

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2-[(S)-1-(4-Chlorophenyl)propylamino]-3-methoxy-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

The titled compound was obtained in the same manner as in Reference Example 12.

¹H-NMR (CDCl₃) δ ppm: 0.94 (t, J=7.4 Hz, 3H), 1.78-2.01 (m, 2H), 2.27-2.52 (m, 2H), 2.90-3.11 (m, 2H), 3.59-3.76 (m, 2H), 4.04 (s, 3H), 4.85-4.99 (m, 1H), 5.60 (d, J=8.0 Hz, 1H), 7.18-7.36 (m, 4H).

Reference Example 71

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2-[1-(4-Chlorophenyl)-4,4,4-trifluorobutylamino]-3-methoxy-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

The titled compound was obtained in the same manner as in Reference Example 12.

¹H-NMR (CDCl₃) δ ppm: 1.91-2.29 (m, 4H), 2.29-2.53 (m, 2H), 2.90-3.10 (m, 2H), 3.58-3.77 (m, 2H), 4.02 (s, 3H), 5.01-5.16 (m, 1H), 5.58 (d, 8.3 Hz, 1H), 7.16-7.41 (m, 4H).

Reference Example 72

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4-[1-(3-Methoxy-4-oxo-3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidin-2-ylamino)ethyl]-benzonitrile

The titled compound was obtained in the same manner as in Reference Example 12.

¹H-NMR (CDCl₃) δ ppm: 1.59 (d, J=7.0 Hz, 3H), 2.21-2.51 (m, 2H), 3.58-3.76 (m, 2H), 4.07 (s, 3H), 4.27-4.45 (m, 2H), 5.14-5.28 (m, 1H), 5.56-5.72 (m, 1H), 7.40-7.50 (m, 2H), 7.54-7.70 (m, 2H).

Reference Example 73

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2-[(S)-1-(4-Chlorophenyl)-2-methylpropylamino]-3-methoxy-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

The titled compound was obtained in the same manner as in Reference Example 12.

¹H-NMR (CDCl₃) δ ppm: 0.87 (d, J=6.7 Hz, 3H), 1.03 (d, J=6.7 Hz, 3H), 1.97-2.16 (m, 1H), 2.24-2.48 (m, 2H), 2.88-3.08 (m, 2H), 3.57-3.77 (m, 2H), 4.06 (s, 3H), 4.78 (dd, J=8.3, 8.3 Hz, 1H), 5.69 (d, J=8.5 Hz, 1H), 7.11-7.35 (m, 4H).

Reference Example 74

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3-Methoxy-2-[(S)-1-(4-trifluoromethylphenyl)propylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

The titled compound was obtained in the same manner as in Reference Example 12.

¹H-NMR (CDCl₃) δ ppm: 0.97 (t, J=7.3 Hz, 3H), 1.81-2.00 (m, 2H), 2.22-2.52 (m, 2H), 2.88-3.11 (m, 2H), 3.60-3.75 (m, 2H), 4.06 (s, 3H), 4.92-5.08 (m, 1H), 5.64 (d, J=7.7 Hz, 1H), 7.43 (d, J=8.0 Hz, 2H), 7.60 (d, J=8.0 Hz, 2H).

Reference Example 75

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3-(2-Butynyl)-2-[(S)-1-(4-chlorophenyl)-2-methylpropylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

The titled compound was obtained in the same manner as in Reference Example 12.

¹H-NMR (CDCl₃) δ ppm: 0.91 (d, J=6.7 Hz, 3H), 1.02 (d, J=6.7 Hz, 3H), 1.84 (s, 3H), 2.00-2.17 (m, 1H), 2.17-2.47 (m, 2H), 2.87-3.06 (m, 2H), 3.54-3.73 (m, 2H), 4.77-4.86 (m, 2H), 4.93 (dd, J=7.3, 7.3 Hz, 1H), 5.54 (d, J=7.1 Hz, 1H), 7.16-7.34 (m, 4H).

Reference Example 76

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2-(4-Ethoxybenzylamino)-3-methoxy-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

The titled compound was obtained in the same manner as in Reference Example 12.

¹H-NMR (CDCl₃) δ ppm: 1.42 (t, J=7.0 Hz, 3H), 2.42-2.60 (m, 2H), 2.96-3.13 (m, 2H), 3.74 (s, 2H), 3.94-4.11 (m, 5H), 4.52 (d, J=5.4 Hz, 2H), 5.50-5.65 (m, 1H), 6.80-6.92 (m, 2H), 7.18-7.32 (m, 2H).

Reference Example 77

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3-Isobutoxy-4-oxo-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester

Synthesis was performed in the same manner as in Reference Example 10.

¹H-NMR (CDCl₃) δ ppm: 7.61 (d, J=8.26 Hz, 2H), 7.45 (d, J=8.26 Hz, 2H), 5.63 (d, J=7.6 Hz, 1H), 5.23 (dq, J=7.6, 6.92 Hz, 1H), 4.24 (q, J=17.3 Hz, 2H), 4.07-3.98 (m, 2H), 3.61-3.45 (m, 2H), 2.60-2.45 (m, 2H), 2.19-2.12 (m, 1H), 1.59 (d, J=6.92 Hz, 3H), 1.46 (s, 9H), 1.07 (d, J=6.06 Hz, 6H).

Reference Example 78

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2-((S)-1-Cyclohexylethylamino)-3-methoxy-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester

Synthesis was performed in the same manner as in Reference Example 10.

¹H-NMR (CDCl₃) δ ppm: 0.88-1.31 (m, 9H), 1.48 (s, 9H), 1.62-1.85 (m, 5H), 2.45-2.60 (m, 2H), 3.60 (t, J=5.7 Hz, 2H), 3.90-4.02 (m, 1H), 4.06 (s, 3H), 4.26 (s, 2H), 5.22 (d, J=9.0 Hz, 1H).

Reference Example 79

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2-((S)-1-Cyclohexylethylamino)-3-methoxy-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

The titled compound was obtained in the same manner as in Reference Example 12.

¹H-NMR (CDCl₃) δ ppm: 0.90-1.55 (m, 9H), 1.64-2.00 (m, 5H), 2.47 (t, J=5.8 Hz, 2H), 3.07 (t, J=5.8 Hz, 2H), 3.73 (s, 2H), 3.90-4.01 (m, 1H), 4.03 (s, 3H), 5.21 (d, J=8.9 Hz, 1H).

Reference Example 80

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2-((R)-1-Cyclohexylethylamino)-3-methoxy-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester

Synthesis was performed in the same manner as in Reference Example 10.

¹H-NMR (CDCl₃) δ ppm: 0.88-1.31 (m, 9H), 1.48 (s, 9H), 1.62-1.85 (m, 5H), 2.45-2.60 (m, 2H), 3.60 (t, J=5.7 Hz, 2H), 3.90-4.02 (m, 1H), 4.06 (s, 3H), 4.26 (s, 2H), 5.22 (d, J=9.0 Hz, 1H).

Reference Example 81

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2-((R)-1-Cyclohexylethylamino)-3-methoxy-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

The titled compound was obtained in the same manner as in Reference Example 12.

¹H-NMR (CDCl₃) δ ppm: 0.90-1.55 (m, 9H), 1.64-2.00 (m, 5H), 2.47 (t, J=5.8 Hz, 2H), 3.07 (t, J=5.8 Hz, 2H), 3.73 (s, 2H), 3.90-4.01 (m, 1H), 4.03 (s, 3H), 5.21 (d, J=8.9 Hz, 1H).

Reference Example 82

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3-Methoxy-2-[2-(4-trifluoromethylphenyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

The titled compound was obtained in the same manner as in Reference Example 12.

MS [M+H]+=359

Example 1
Synthesis of 6-(4-cyano-2-fluorobenzoyl)-3-propargyl-2-(S)-{1-[4-(trifluoromethyl)phenyl]ethylamino}-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(3H)-one hydrochloride

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Under nitrogen atmosphere, 4-cyano-2-fluoro benzoate (658 mg) was dissolved in DMF (20 ml), and to the solution 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) (930 mg) and 1-hydroxybenzotriazole (637.8 mg) were added at 0° C. After the reaction solution was stirred at 0° C. for a while, 2-(S)-{1-[4-(trifluoromethyl)phenyl]ethylamino}-3-propargyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(3H)-one (1 g) was added. The temperature was raised to room temperature and the resultant mixture was stirred for 5 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate. Thereafter, filtration and concentration were performed and purification was performed by column chromatography (hexane:ethyl acetate=1:1). The purified substance was dissolved in methylene chloride (5 ml), 1 N hydrogen chloride in ethanol (2 ml) was added, and the resultant mixture was concentrated. The residue was washed with diethyl ether:methylene chloride (1:1) to obtain the titled compound in an amount of 902.5 mg (yield 61%) as a white solid substance. The melting point: 136-138° C.

Example 2
Synthesis of 6-(4-chlorobenzoyl)-3-propargyl-2-(S)-{1-[4-(trifluoromethyl)phenyl]ethylamino}-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(3H)-one hydrochloride

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Under nitrogen atmosphere, 2-(S)-{1-[4-(trifluoromethyl)phenyl]ethylamino}-3-propargyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(3H)-one (830 mg) was dissolved in methylene chloride (40 ml) at 0° C. To the solution, triethylamine (0.46 ml) and 4-chlorobenzoyl chloride (0.28 ml) were added. After stirred at 0° C. for 30 minutes, water and saturated sodium hydrogen carbonate solution were added and the resultant mixture was extracted with methylene chloride and dried over sodium sulfate. After filtration and concentration were performed, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1). The purified substance was dissolved in methylene chloride (10 ml), 1 N hydrogen chloride in ethanol (2 ml) was added and the resultant mixture was concentrated. The residue was washed with diethyl ether:methylene chloride (1:1) to obtain the titled compound in an amount of 755.9 mg (67%) as a white solid substance. The melting point: 173-174° C.

Example 3
Synthesis of 6-(4-chlorobenzoyl)-3-propargyl-2-(S)-{1-[4-chloro phenyl]ethylamino}-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(3H)-one

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Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.57 (d, J=1.8 Hz, 3H), 2.35-2.75 (m, 3H), 3.45-4.70 (m, 4H), 4.75-4.95 (m, 2H), 5.20-5.30 (m, 2H), 7.20-7.50 (m, 8H).

Example 4
Synthesis of 6-(4 chlorobenzoyl)-2-(3-fluoro-4-trifluorobenzylamino)-3-propargyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(3H)-one

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6-(4-Chlorobenzoyl)-3-propargyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-dione (800 mg) was dissolved in tetrahydrofuran (16 ml), 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (1.85 g) and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) (0.71 ml) were added and the resultant mixture was stirred at room temperature. At 10 minutes later, 3-fluoro-4-trifluoromethylbenzylamine (0.90 ml) was added and the resultant mixture was further stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. To the residue, saturated sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution and thereafter dried over sodium sulfate, filtrated and concentrated. The resultant residue was purified by medium-pressure silica gel column chromatography (solvent; ethyl acetate:hexane=50:50 to 80:20) to obtain a colorless amorphous substance (460 mg). A substance (860 mg) separately synthesized was combined and dissolved in ethanol (15 ml) and 1 N hydrochloric acid in ethanol (2.50 ml) was added. After concentration, diisopropyl ether was added to the resultant residue to form a crystal. The resultant crude crystal was recrystallized from isopropyl alcohol. The titled compound (367 mg) was obtained as a white powder.

¹H-NMR (CDCl₃) δ ppm: 2.36-2.46 (m, 1H), 2.46-2.75 (m, 2H), 3.35-4.06 (m, 2H), 4.16-4.66 (m, 2H), 4.72-4.76 (m, 2H), 4.85 (brs, 2H), 5.39-5.57 (m, 1H), 7.11-7.25 (m, 2H), 7.39 (s, 4H), 7.59 (t, 7.6 Hz, 1H).

Example 5
Synthesis of 6-(4-cyano-2-fluorobenzoyl)-3-dimethylamino-2-(S)-{1-[4-(trifluoromethyl)phenyl]ethylamino}-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(3H)-one hydrochloride

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¹H-NMR (DMSO-d₆) δ ppm: 1.52 (d, J=6.9 Hz, 3H), 2.27-2.67 (m, 2H), 2.85-2.95 (m, 6H), 3.33-3.37 (m, 1H), 3.58-4.10 (m, 2H), 4.16-4.44 (m, 1H), 5.01-5.36 (m, 1H), 7.56-7.73 (m, 5H), 7.76-7.86 (m, 1H), 7.96-7.86 (m, 1H), 8.06-8.17 (m, 1H). HCl was not observed.

Example 6
Synthesis of 6-(4-chlorobenzoyl)-3-dimethylamino-2-(S)-{1-[4-(trifluoromethyl)phenyl]ethylamino}-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(3H)-one hydrochloride

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Slightly yellow powder, melting point 116-118° C. (ether-ethyl acetate)

¹H-NMR (DMSO-d₆) δ ppm: 1.54 (d, J=7.0 Hz, 3H), 2.33-2.52 (m, 2H), 2.86 (s, 3H), 2.93 (s, 3H), 3.35-3.50 (m, 1H), 3.70-3.85 (m, 1H), 4.00-4.15 (m, 1H), 4.25-4.40 (m, 1H), 5.25-5.50 (m, 1H), 7.45-7.53 (m, 4H), 7.63 (d, J=8.3 Hz, 2H), 7.70 (d, J=8.3 Hz, 2H), 8.20-8.40 (m, 1H). HCl was not observed.

Example 7
Synthesis of 6-(4-chlorobenzoyl)-3-dimethylamino-2-(3-fluoro-4-trifluoromethylbenzylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(3H)-one hydrochloride

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Slightly yellow powder, melting point 122-124° C. (ether-ethyl acetate)

¹H-NMR (DMSO-d₆) δ ppm: 2.40-2.55 (m, 2H), 2.87 (s, 3H), 2.95 (s, 3H), 3.40-3.60 (m, 1H), 3.70-3.80 (m, 1H), 4.00-4.20 (m, 1H), 4.25-4.40 (m, 1H), 4.65-4.80 (m, 2H), 7.38 (d, J=8.0 Hz, 1H), 7.46-7.58 (m, 5H), 7.74 (t, J=7.9 Hz, 1H), 8.70-9.00 (m, 1H). HCl was not observed.

Example 8
Synthesis of 6-(4-chlorobenzoyl)-2-(S)-[1-(4-chlorophenyl)ethylamino]-3-dimethylamino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(3H)-one hydrochloride

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Slightly yellow powder, melting point 121-123° C. (ether-ethyl acetate)

¹H-NMR (DMSO-d₆) δ ppm: 1.50 (d, J=7.0 Hz, 3H), 2.37-2.55 (m, 2H), 2.85 (s, 3H), 2.91 (s, 3H), 3.35-3.50 (m, 1H), 3.70-3.85 (m, 1H), 4.00-4.15 (m, 1H), 4.25-4.40 (m, 1H), 5.20-5.30 (m, 1H), 7.37-7.39 (m, 2H), 7.44-7.58 (m, 6H), 8.10-8.40 (m, 1H). HCl was not observed.

Example 9
Synthesis of 6-(4-chlorobenzoyl)-3-methoxy-2-(S)-[1-(4-chlorophenyl)ethylamino]-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(3H)-one

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Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.56 (d, J=1.8 Hz, 3H), 2.35-2.75 (m, 2H), 3.45-4.70 (m, 7H) 5.10-5.30 (m, 1H), 5.55-5.70 (m, 1H), 7.20-7.50 (m, 8H).

Example 10
Synthesis of 6-(4-chlorobenzoyl)-3-methoxy-2-(S)-{1-[4-(trifluoromethyl)phenyl]ethylamino}-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(3H)-one hydrochloride

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Under nitrogen atmosphere, 3-methoxy-2-(S)-{1-[4-(trifluoromethyl)phenyl]ethylamino}-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(3H)-one (0.75 g) was dissolved in methylene chloride (7 ml), and diisopropylmethylamine (0.45 ml) and 4-chlorobenzoyl chloride (0.32 ml) were added while stirring under ice cooling. The reaction mixture was stirred under nitrogen atmosphere at room temperature for 18 hours. To the reaction solution, saturated saline solution was added and the mixture was extracted with methylene chloride. The organic layer was dried over sodium sulfate, filtrated and concentrated. The resultant residue was subjected to medium-pressure silica gel column chromatography (solvent; ethyl acetate:hexane=0:100 to 50:50) to obtain a white amorphous substance (0.57 g).

The resultant compound was dissolved in ethanol and 1 N hydrochloric acid in ethanol (1.5 ml) was added and the resultant mixture was concentrated. The resultant residue was dissolved in a small amount of ethanol and ether was added to form a crystal. The titled compound (0.49 g) was obtained as a white powdery crystal.

Melting point 123 to 126° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.54 (d, J=7.0 Hz, 3H), 2.24-2.52 (m, 2H), 3.34-3.50 (m, 1H), 3.61-3.97 (m, 5H), 4.00-4.13 (m, 1H), 5.19-5.33 (m, 1H), 7.46 (d, J=8.5 Hz, 2H), 7.52 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 2H), 7.70 (d, J=8.5 Hz, 2H), 8.21 (d, J=8.5 Hz, 1H). HCl was not observed.

Example 11
Synthesis of 6-(4-cyano-2-fluorobenzoyl)-3-methoxy-2-(S)-{1-[4-(trifluoromethyl)phenyl]ethylamino}-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(3H)-one hydrochloride

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Under nitrogen atmosphere, to 3-methoxy-2-(S)-{1-[4-(trifluoromethyl)phenyl]ethylamino}-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(3H)-one (0.75 g) and 4-cyano-2-fluoro benzoate (0.40 g) in DMF (7 ml), diisopropylmethylamine (0.45 ml) was added. Under ice cooling while stirring, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium hexafluorophosphate (HATU) (0.92 g) was added. The reaction mixture was stirred under nitrogen atmosphere at room temperature for 18 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtrated and concentrated. The resultant residue was purified by medium-pressure silica gel column chromatography (solvent; ethyl acetate:hexane=0:100 to 50:50). A white amorphous substance (1.04 g) was obtained.

The resultant compound was dissolved in ethanol, 1 N hydrochloric acid in ethanol (2.5 ml) was added and the resultant mixture was concentrated. The resultant residue was dissolved in a small amount of ethanol and ether was added to form a crystal. The titled compound (0.85 g) was obtained as a white powdery crystal. Melting point 120 to 122° C.

¹H-NMR (DMSO-d₆) δ ppm: 1.54 (d, J=7.0 Hz, 3H), 2.24-2.45 (m, 2H), 3.30-3.39 (m, 1H), 3.67-3.91 (m, 2H), 3.94 (s, 3H), 4.27-4.39 (m, 1H), 5.20-5.33 (m, 1H), 7.58-7.72 (m, 5H), 7.76-7.84 (m, 1H), 7.97-8.50 (m, 1H), 8.24 (d, J=8.5 Hz, 1H). HCl was not observed.

Appropriate corresponding starting materials were used to produce compounds of Examples 12-2384 shown in the following table in the same manner as the above Reference Examples and the above Examples.

TABLE 1

Example
R21
R22
R23
R24
R25
MS(M + 1)

12
—H
—H
—OCH₃
—H
—H
468

13
—H
—H
—Cl
—H
—H
472

14
—H
—H
—CF₃
—H
—H
506

15
—H
—H
—CN
—H
—H
463

16
—H
—H
—OCF₃
—H
—H
522

17
—H
—H
—CH₃
—H
—H
452

18
—H
—H
—F
—H
—H
456

19
—H
—F
—CF₃
—H
—H
524

20
—H
—Cl
—Cl
—H
—H
506

TABLE 2

Example
R21
R22
R23
R24
R25
MS(M + 1)

21
—H
—H
—Cl
—H
—H
486

22
—H
—H
—CF₃
—H
—H
520

23
—H
—H
—CH₃
—H
—H
466

24
—H
—H
—OCH₃
—H
—H
482

25
—H
—H
—F
—H
—H
470

26
—H
—H
—OCF₃
—H
—H
536

TABLE 3

Example
R21
R22
R23
R24
R25
MS(M + 1)

27
—H
—H
—Cl
—H
—H
459

28
—H
—H
—CF₃
—H
—H
493

29
—H
—H
—OCF₃
—H
—H
509

30
—H
—H
—CH₃
—H
—H
439

31
—H
—H
—F
—H
—H
443

32
—H
—F
—CF₃
—H
—H
511

TABLE 4

Example
R21
R22
R23
R24
R25
MS(M + 1)

33
—H
—H
—Cl
—H
—H
473

34
—H
—H
—CF₃
—H
—H
507

35
—H
—H
—CH₃
—H
—H
453

36
—H
—H
—OCH₃
—H
—H
469

37
—H
—H
—F
—H
—H
457

38
—H
—H
—OCF₃
—H
—H
523

TABLE 5

Example
R21
R22
R23
R24
R25
MS(M + 1)

39
—H
—H
—Cl
—H
—H
467

40
—H
—H
—CF₃
—H
—H
501

41
—H
—H
—OCF₃
—H
—H
517

42
—H
—H
—CH₃
—H
—H
447

43
—H
—H
—F
—H
—H
451

44
—H
—F
—CF₃
—H
—H
519

TABLE 6

Example
R21
R22
R23
R24
R25
MS(M + 1)

45
—H
—H
—Cl
—H
—H
481

46
—H
—H
—CF₃
—H
—H
515

47
—H
—H
—CH₃
—H
—H
461

48
—H
—H
—OCH₃
—H
—H
477

49
—H
—H
—F
—H
—H
465

50
—H
—H
—OCF₃
—H
—H
531

TABLE 7

Example
R26
R27
R28
R29
R210
MS(M + 1)

51
—H
—H
—CN
—H
—H
511

52
—F
—H
—CN
—H
—H
529

53
—H
—H
—CH₃
—H
—H
500

54
—H
—H
—COCH₃
—H
—H
528

55
—H
—H
—CF₃
—H
—H
554

56
—H
—H
—OCF₃
—H
—H
570

57
—H
—H

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—H
—H
553

TABLE 8

Example
R26
R27
R28
R29
R210
MS(M + 1)

58
—H
—H
—CN
—H
—H
498

59
—F
—H
—CN
—H
—H
516

60
—H
—H
—CH₃
—H
—H
487

61
—H
—H
—COCH₃
—H
—H
515

62
—H
—H
—CF₃
—H
—H
541

63
—H
—H
—OCF₃
—H
—H
557

64
—H
—H

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—H
—H
540

TABLE 9

Example
R26
R27
R28
R29
R210
MS(M + 1)

65
—H
—H
—CN
—H
—H
506

66
—F
—H
—CN
—H
—H
524

67
—H
—H
—CH₃
—H
—H
495

68
—H
—H
—COCH₃
—H
—H
523

69
—H
—H
—CF₃
—H
—H
549

70
—H
—H
—OCF₃
—H
—H
565

71
—H
—H

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—H
—H
548

TABLE 10

Example
R211
R212
MS(M + 1)

72

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—N(CH₃)₂
536

73

embedded image

—CH₂C≡CH
531

74

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—CH₂C≡CH
537

75

embedded image

—OCH₃
523

76

embedded image

—OCH₃
529

77

embedded image

—N(CH₃)₂
506

78

embedded image

—CH₂C≡CH
501

79

embedded image

—OCH₃
493

TABLE 11

Example
R212
R213
MS(M + 1)

80
—N(CH₃)₂

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512

81
—CH₂C≡CH

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507

82
—OCH₃

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499

83
—OCH₃

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485

TABLE 12

Example
R26
R27
R28
R29
R210
MS(M + 1)

84
—H
—H
—H
—H
—H
487

85
—H
—H
—CH₃
—H
—H
501

86
—H
—H
—Cl
—H
—H
521

87
—H
—H
—F
—H
—H
505

88
—H
—H
—OCH₃
—H
—H
517

89
—H
—H
—CF₃
—H
—H
555

90
—H
—Cl
—H
—H
—H
521

91
—H
—CH₃
—H
—H
—H
501

92
—H
—H
—CN
—H
—H
512

93
—H
—CH₃
—CH₃
—H
—H
515

94
—H
—H
—OCF₃
—H
—H
571

95
—F
—H
—CN
—H
—H
530

96
—H
—CH₃
—Cl
—H
—H
535

97
—H
—Cl
—CH₃
—H
—H
535

98
—H
—H
—OC₂H₅
—H
—H
531

99
—H
—H
—SCH₃
—H
—H
533

100
—H
—H
—OCH(CH₃)₂
—H
—H
545

TABLE 13

Exam-

MS(M +

ple
R26
R27
R28
R29
R210
1)

101
—H
—H

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—H
—H
554

102
—H
—H

embedded image

—H
—H
553

103
—H
—H

embedded image

—H
—H
554

104
—H
—H

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—H
—H
554

105
—H
—H

embedded image

—H
—H
569

TABLE 14

Example
R211
MS(M + 1)

106

embedded image

537

107

embedded image

537

108

embedded image

531

109

embedded image

538

110

embedded image

538

111

embedded image

556

112

embedded image

586

TABLE 15

Example
R211
MS(M + 1)

113

embedded image

561

114

embedded image

561

115

embedded image

543

116

embedded image

554

117

embedded image

554

118

embedded image

561

119

embedded image

527

TABLE 16

Example
R211
MS(M + 1)

120

embedded image

507

121

embedded image

544

122

embedded image

527

123

embedded image

543

124

embedded image

554

125

embedded image

489

126

embedded image

538

TABLE 17

Example
R211
MS(M + 1)

127

embedded image

570

128

embedded image

572

129

embedded image

478

130

embedded image

542

131

embedded image

556

132

embedded image

489

133

embedded image

540

TABLE 18

Example
R211
MS(M + 1)

134

embedded image

502

135

embedded image

502

136

embedded image

523

137

embedded image

526

138

embedded image

555

139

embedded image

527

140

embedded image

532

TABLE 19

Example
R211
MS(M + 1)

141

embedded image

551

142

embedded image

539

143

embedded image

542

144

embedded image

542

145

embedded image

489

146

embedded image

588

147

embedded image

538

TABLE 20

Example
R211
MS(M + 1)

148

embedded image

544

149

embedded image

538

150

embedded image

526

151

embedded image

477

152

embedded image

584

153

embedded image

518

154

embedded image

518

TABLE 21

Example
R26
R27
R28
R29
R210
MS(M + 1)

155
—H
—H
—H
—H
—H
512

156
—H
—H
—CH₃
—H
—H
526

157
—H
—H
—Cl
—H
—H
546

158
—H
—H
—F
—H
—H
530

159
—H
—H
—OCH₃
—H
—H
542

160
—H
—H
—CF₃
—H
—H
580

161
—H
—Cl
—H
—H
—H
546

162
—H
—CH₃
—H
—H
—H
526

163
—H
—H
—CN
—H
—H
537

164
—H
—CH₃
—CH₃
—H
—H
540

165
—H
—H
—OCF₃
—H
—H
596

166
—F
—H
—CN
—H
—H
555

167
—H
—CH₃
—Cl
—H
—H
560

168
—H
—Cl
—CH₃
—H
—H
560

169
—H
—H
—OC₂H₅
—H
—H
556

170
—H
—H
—SCH₃
—H
—H
558

171
—H
—H
—OCH(CH₃)₂
—H
—H
570

TABLE 22

Example
R26
R27
R28
R29
R210
MS(M + 1)

172
—H
—H

embedded image

—H
—H
579

173
—H
—H

embedded image

—H
—H
578

174
—H
—H

embedded image

—H
—H
579

175
—H
—H

embedded image

—H
—H
579

176
—H
—H

embedded image

—H
—H
594

TABLE 23

Example
R211
MS(M + 1)

177

embedded image

562

178

embedded image

562

179

embedded image

556

180

embedded image

563

181

embedded image

563

182

embedded image

581

183

embedded image

611

TABLE 24

Example
R211
MS(M + 1)

184

embedded image

586

185

embedded image

586

186

embedded image

568

187

embedded image

579

188

embedded image

579

189

embedded image

586

190

embedded image

552

TABLE 25

Example
R211
MS(M + 1)

191

embedded image

532

192

embedded image

569

193

embedded image

564

194

embedded image

552

195

embedded image

568

196

embedded image

579

197

embedded image

514

TABLE 26

Example
R211
MS(M + 1)

198

embedded image

563

199

embedded image

595

200

embedded image

597

201

embedded image

567

202

embedded image

581

203

embedded image

514

204

embedded image

565

TABLE 27

Example
R211
MS(M + 1)

205

embedded image

527

206

embedded image

527

207

embedded image

548

208

embedded image

551

209

embedded image

580

210

embedded image

552

211

embedded image

557

TABLE 28

Example
R211
MS(M + 1)

212

embedded image

576

213

embedded image

564

214

embedded image

567

215

embedded image

567

216

embedded image

514

217

embedded image

613

218

embedded image

563

TABLE 29

Example
R211
MS(M + 1)

219

embedded image

569

220

embedded image

563

221

embedded image

551

222

embedded image

502

223

embedded image

609

224

embedded image

543

225

embedded image

543

TABLE 30

Example
R21
R22
R23
R24
R25
MS(M + 1)

226
—H
—H
—H
—H
—H
466

227
—H
—H
—CH₃
—H
—H
480

228
—H
—H
—OCH₃
—H
—H
496

229
—H
—H
—CN
—H
—H
490

230
—H
—H
—CF₃
—H
—H
534

231
—H
—H
—Cl
—H
—H
500

232
—H
—H
—OCF₃
—H
—H
550

233
—H
—Cl
—Cl
—H
—H
536

234
—H
—F
—CF₃
—H
—H
552

TABLE 31

Example
R21
R22
R23
R24
R25
MS(M + 1)

235
—H
—H
—F
—H
—H
498

236
—H
—H
—Cl
—H
—H
514

237
—H
—H
—CF₃
—H
—H
548

238
—H
—H
—OCH₃
—H
—H
510

239
—H
—CF₃
—H
—CF₃
—H
616

TABLE 32

Example
R21
R22
R23
R24
R25
MS(M + 1)

240
—H
—H
—H
—H
—H
453

241
—H
—H
—CH₃
—H
—H
467

242
—H
—H
—OCH₃
—H
—H
483

243
—H
—H
—CN
—H
—H
478

244
—H
—H
—CF₃
—H
—H
521

245
—H
—H
—Cl
—H
—H
487

246
—H
—H
—OCF₃
—H
—H
537

247
—H
—Cl
—Cl
—H
—H
523

248
—H
—F
—CF₃
—H
—H
539

TABLE 33

Example
R21
R22
R23
R24
R25
MS(M + 1)

249
—H
—H
—F
—H
—H
485

250
—H
—H
—Cl
—H
—H
501

251
—H
—H
—CF₃
—H
—H
535

252
—H
—H
—OCH₃
—H
—H
497

253
—H
—CF₃
—H
—CF₃
—H
603

TABLE 34

Example
R21
R22
R23
R24
R25
MS(M + 1)

254
—H
—H
—H
—H
—H
461

255
—H
—H
—CH₃
—H
—H
475

256
—H
—H
—OCH₃
—H
—H
491

257
—H
—H
—CN
—H
—H
486

258
—H
—H
—CF₃
—H
—H
529

259
—H
—H
—Cl
—H
—H
495

260
—H
—H
—OCF₃
—H
—H
545

261
—H
—Cl
—Cl
—H
—H
531

262
—H
—F
—CF₃
—H
—H
547

TABLE 35

Example
R21
R22
R23
R24
R25
MS(M + 1)

263
—H
—H
—F
—H
—H
493

264
—H
—H
—Cl
—H
—H
509

265
—H
—H
—CF₃
—H
—H
543

266
—H
—H
—OCH₃
—H
—H
505

267
—H
—CF₃
—H
—CF₃
—H
611

TABLE 36

Example
R212
R213
MS(M + 1)

268
—CH₂C≡CH

embedded image

467

269
—N(CH₃)₂

embedded image

472

270
—OCH₃

embedded image

459

271
—CH₂C≡CH

embedded image

569

272
—N(CH₃)₂

embedded image

574

273
—OCH₃

embedded image

561

TABLE 37

MS

Example
R212
R213
(M + 1)

274
—CH₂C≡CH

embedded image

551

275
—OCH₃

embedded image

543

276
—CH₂C≡CH

embedded image

535

277
—N(CH₃)₂

embedded image

540

278
—OCH₃

embedded image

527

279
—CH₂C≡CH

embedded image

601

TABLE 38

MS

Example
R212
R213
(M + 1)

280
—N(CH₃)₂

embedded image

606

281
—OCH₃

embedded image

593

282
—CH₂C≡CH

embedded image

537

283
—N(CH₃)₂

embedded image

542

284
—OCH₃

embedded image

529

TABLE 39

Example
R212
R213
MS(M + 1)

285
—CH₂C≡CH

embedded image

591

286
—CH₂C≡CH

embedded image

569

287
—N(CH₃)₂

embedded image

574

288
—OCH₃

embedded image

561

289
—CH₂C≡CH

embedded image

535

TABLE 40

Example
R212
R213
MS(M + 1)

290
—N(CH₃)₂

embedded image

540

291
—OCH₃

embedded image

527

TABLE 41

Example
R26
R27
R28
R29
R210
MS(M + 1)

292
—H
—H
—H
—H
—H
515

293
—H
—H
—CH₃
—H
—H
529

294
—H
—H
—Cl
—H
—H
549

295
—H
—H
—F
—H
—H
533

296
—H
—H
—OCH₃
—H
—H
545

297
—H
—H
—CF₃
—H
—H
583

298
—H
—Cl
—H
—H
—H
549

299
—H
—CH₃
—H
—H
—H
529

300
—H
—H
—CN
—H
—H
540

301
—H
—H
—OCF₃
—H
—H
599

302
—F
—H
—CN
—H
—H
558

303
—H
—CH₃
—Cl
—H
—H
563

304
—H
—Cl
—CH₃
—H
—H
563

305
—H
—H
—OC₂H₅
—H
—H
559

306
—H
—H
—SCH₃
—H
—H
561

307
—H
—H
—OCH(CH₃)₂
—H
—H
573

308
—H
—H

embedded image

—H
—H
582

309
—H
—H

embedded image

—H
—H
581

310
—H
—H

embedded image

—H
—H
582

311
—H
—H

embedded image

—H
—H
582

312
—H
—H

embedded image

—H
—H
597

TABLE 42

Example
R211
MS(M + 1)

292

embedded image

565

293

embedded image

565

294

embedded image

559

295

embedded image

566

296

embedded image

566

297

embedded image

584

298

embedded image

614

299

embedded image

589

300

embedded image

589

301

embedded image

571

302

embedded image

582

303

embedded image

582

304

embedded image

589

305

embedded image

555

306

embedded image

535

307

embedded image

572

308

embedded image

567

309

embedded image

555

310

embedded image

571

311

embedded image

582

312

embedded image

517

313

embedded image

566

314

embedded image

598

315

embedded image

600

316

embedded image

506

317

embedded image

570

318

embedded image

584

319

embedded image

517

320

embedded image

568

321

embedded image

530

322

embedded image

530

323

embedded image

551

324

embedded image

554

325

embedded image

583

326

embedded image

555

327

embedded image

560

328

embedded image

579

329

embedded image

567

330

embedded image

570

331

embedded image

570

332

embedded image

517

333

embedded image

616

334

embedded image

566

335

embedded image

572

336

embedded image

566

337

embedded image

554

338

embedded image

505

339

embedded image

612

340

embedded image

546

341

embedded image

546

TABLE 43

Example
R26
R27
R28
R29
R210
MS(M + 1)

363
—H
—H
—H
—H
—H
495

364
—H
—H
—CH₃
—H
—H
509

365
—H
—H
—Cl
—H
—H
529

366
—H
—H
—F
—H
—H
513

367
—H
—H
—OCH₃
—H
—H
525

368
—H
—H
—CF₃
—H
—H
563

369
—H
—Cl
—H
—H
—H
529

370
—H
—CH₃
—H
—H
—H
509

371
—H
—H
—CN
—H
—H
520

372
—H
—CH₃
—CH₃
—H
—H
523

373
—H
—H
—OCF₃
—H
—H
579

374
—F
—H
—CN
—H
—H
538

375
—H
—CH₃
—Cl
—H
—H
543

376
—H
—Cl
—CH₃
—H
—H
543

377
—H
—H
—OC₂H₅
—H
—H
539

378
—H
—H
—SCH₃
—H
—H
541

379
—H
—H
—OCH(CH₃)₂
—H
—H
553

380
—H
—H

embedded image

—H
—H
562

381
—H
—H

embedded image

—H
—H
561

382
—H
—H

embedded image

—H
—H
562

383
—H
—H

embedded image

—H
—H
562

384
—H
—H

embedded image

—H
—H
577

TABLE 44

Example
R211
MS(M + 1)

385

embedded image

545

386

embedded image

545

387

embedded image

539

388

embedded image

546

389

embedded image

546

390

embedded image

564

391

embedded image

594

392

embedded image

569

393

embedded image

569

394

embedded image

551

395

embedded image

562

396

embedded image

562

397

embedded image

569

398

embedded image

535

399

embedded image

515

400

embedded image

552

401

embedded image

547

402

embedded image

535

403

embedded image

551

404

embedded image

562

405

embedded image

497

406

embedded image

546

407

embedded image

578

408

embedded image

580

409

embedded image

486

410

embedded image

550

411

embedded image

564

412

embedded image

497

413

embedded image

548

414

embedded image

510

415

embedded image

510

416

embedded image

531

417

embedded image

534

418

embedded image

563

419

embedded image

535

420

embedded image

540

421

embedded image

559

422

embedded image

547

423

embedded image

550

424

embedded image

550

425

embedded image

497

426

embedded image

596

427

embedded image

546

428

embedded image

552

429

embedded image

546

430

embedded image

534

431

embedded image

485

432

embedded image

592

433

embedded image

526

434

embedded image

526

TABLE 45

Ex-

MS

amp-

(M +

le
R26
R27
R28
R29
R210
1)

435
—H
—H
—H
—H
—H
528

436
—H
—H
—CH₃
—H
—H
542

437
—H
—H
—Cl
—H
—H
562

438
—H
—H
—F
—H
—H
546

439
—H
—H
—OCH₃
—H
—H
558

440
—H
—H
—CF₃
—H
—H
596

441
—H
—Cl
—H
—H
—H
562

442
—H
—CH₃
—H
—H
—H
542

443
—H
—H
—CN
—H
—H
553

444
—H
—CH₃
—CH₃
—H
—H
556

445
—H
—H
—OCF₃
—H
—H
612

446
—F
—H
—CN
—H
—H
571

447
—H
—CH₃
—Cl
—H
—H
576

448
—H
—Cl
—CH₃
—H
—H
576

449
—H
—H
—OC₂H₅
—H
—H
572

450
—H
—H
—SCH₃
—H
—H
574

451
—H
—H
—OCH(CH₃)₂
—H
—H
586

452
—H
—H

embedded image

—H
—H
595

453
—H
—H

embedded image

—H
—H
594

454
—H
—H

embedded image

—H
—H
595

455
—H
—H

embedded image

—H
—H
595

456
—H
—H

embedded image

—H
—H
610

TABLE 46

Example
R211
MS(M + 1)

457

embedded image

578

458

embedded image

578

459

embedded image

572

460

embedded image

579

461

embedded image

579

462

embedded image

597

463

embedded image

627

464

embedded image

602

465

embedded image

602

466

embedded image

584

467

embedded image

595

468

embedded image

595

469

embedded image

602

470

embedded image

568

471

embedded image

548

472

embedded image

585

473

embedded image

580

474

embedded image

568

475

embedded image

584

476

embedded image

595

477

embedded image

530

478

embedded image

579

479

embedded image

611

480

embedded image

613

481

embedded image

519

482

embedded image

583

483

embedded image

597

484

embedded image

530

485

embedded image

581

486

embedded image

543

487

embedded image

543

488

embedded image

564

489

embedded image

567

490

embedded image

596

491

embedded image

568

492

embedded image

573

493

embedded image

592

494

embedded image

580

495

embedded image

583

496

embedded image

583

497

embedded image

530

498

embedded image

629

499

embedded image

579

500

embedded image

585

501

embedded image

579

502

embedded image

567

503

embedded image

518

504

embedded image

625

505

embedded image

559

506

embedded image

559

TABLE 47

Example
R26
R27
R28
R29
R210
MS(M + 1)

507
—H
—H
—H
—H
—H
473

508
—H
—H
—CH₃
—H
—H
487

509
—H
—H
—F
—H
—H
491

510
—H
—H
—OCH₃
—H
—H
503

511
—H
—H
—NHCOCH₃
—H
—H
530

512
—H
—Cl
—Cl
—H
—H
541

513
—F
—H
—CF₃
—H
—H
559

514
—Cl
—H
—H
—H
—H
507

515
—Cl
—H
—H
—H
—Cl
541

516
—H
—OCH₃
—H
—H
—H
503

517
—H
—Cl
—H
—H
—H
507

518
—H
—CH₃
—H
—H
—H
487

519
—H
—CN
—H
—H
—H
498

520
—H
—F
—H
—H
—H
491

521
—H
—N(CH₃)₂
—H
—H
—H
516

522
—H
—OC₆H₅
—H
—H
—H
565

523
—H
—Cl
—H
—Cl
—H
541

524
—H
—CH₃
—H
—CH₃
—H
501

525
—CH₃
—CH₃
—H
—H
—H
501

526
—Cl
—Cl
—H
—H
—H
541

527
—H
—H
—CN
—H
—H
498

528
—H
—H
—N(CH₃)₂
—H
—H
516

529
—Cl
—H
—Cl
—H
—H
541

530
—CH₃
—H
—CH₃
—H
—H
501

531
—F
—H
—F
—H
—H
509

532
—H
—OCH₃
—OCH₃
—H
—H
533

533
—H
—CH₃
—CH₃
—H
—H
501

534
—H
—F
—F
—H
—H
509

535
—H
—CF₃
—F
—H
—H
559

536
—F
—H
—F
—H
—F
527

537
—H
—OCH₃
—OCH₃
—OCH₃
—H
563

538
—H
—F
—F
—F
—H
527

539
—H
—CF₃
—H
—H
—H
541

540
—H
—H
—OC₆H₅
—H
—H
565

541
—CN
—H
—H
—H
—H
498

542
—F
—H
—H
—H
—F
509

543
—F
—F
—H
—H
—H
509

544
—H
—F
—H
—F
—H
509

545
—Cl
—H
—F
—H
—H
525

546
—F
—F
—F
—H
—H
527

547
—H
—OCF₃
—H
—H
—H
557

548
—H
—C₆H₅
—H
—H
—H
549

549
—H
—OH
—NHCOCH₃
—H
—H
546

550
—F
—H
—OCH₃
—H
—H
521

551
—F
—H
—H
—Cl
—H
525

552
—CF₃
—H
—F
—H
—H
559

553
—H
—H
—OC₂H₅
—H
—H
517

554
—H
—H
—SCH₃
—H
—H
519

555
—SCH₃
—H
—H
—H
—H
519

556
—H
—H
—OCH(CH₃)₂
—H
—H
531

557
—OCH₃
—CH₃
—OC₆H₅
—H
—CH₃
623

558
—H
—H
—C₆H₅
—H
—H
549

559
—OCH₃
—H
—Cl
—H
—H
537

560
—OCH₃
—H
—H
—Cl
—H
537

561
—H
—Cl
—OCH₃
—H
—CH₃
551

562
—H
—H
—SO₂CH₃
—H
—H
551

563
—H
—F
—CF₃
—H
—H
559

564
—Cl
—H
—F
—F
—H
543

565
—Cl
—H
—Cl
—F
—H
559

566
—Cl
—H
—OCH₃
—OCH₃
—H
567

567
—Cl
—H
—H
—SCH₃
—H
553

568
—Cl
—H
—H
—F
—H
525

569
—H
—H
—N(C₂H₅)₂
—H
—H
544

570
—CH₃
—H
—OCH₃
—H
—H
517

571
—H
—F
—Cl
—H
—H
525

572
—H
—H
—CH═CH₂
—H
—H
499

573
—H
—H
—(CH₂)₃CH₃
—H
—H
529

574
—H
—H
—C(CH₃)₃
—H
—H
529

575
—H
—OCH₃
—CH₃
—H
—H
517

576
—H
—F
—CH₃
—H
—H
505

577
—H
—CH₃
—Cl
—H
—H
521

578
—H
—Cl
—CH₃
—H
—H
521

579
—H
—H
—CH₂OC₆H₅
—H
—H
579

580
—H
—H
—(CH₂)₂CH₃
—H
—H
515

581
—H
—H
—OCH₂C₆H₅
—H
—H
579

582
—CH₃
—OCH₃
—H
—H
—H
517

583
—F
—H
—H
—H
—OCH₃
521

584
—H
—F
—OCH₃
—H
—H
521

585
—F
—H
—Cl
—H
—H
525

586
—F
—H
—CH₃
—H
—H
505

587
—H

embedded image

—H
—H
—H
550

588
—H

embedded image

—H
—H
—H
550

589

embedded image

—H
—H
—H
—H
550

590

embedded image

—H
—H
—H
—H
550

591
—H

embedded image

—H
—H
—H
550

592
—H

embedded image

—H
—H
—H
554

593
—H

embedded image

—H
—H
—H
540

594
—CH3
—H

embedded image

—H
—H
585

595
—H

embedded image

—H
—H
—H
553

596
—H

embedded image

—H
—H
—H
551

597
—H

embedded image

—H
—H
—H
556

598
—CH3
—H

embedded image

—H
—H
583

599
—H
—H

embedded image

—H
—H
612

600
—H
—H

embedded image

—H
—H
556

601
—H
—H

embedded image

—H
—H
538

602
—H
—H

embedded image

—H
—H
539

603
—H
—H

embedded image

—H
—H
540

604
—H
—H

embedded image

—H
—H
539

605
—H
—H

embedded image

—H
—H
540

606
—H
—H

embedded image

—H
—H
574

607
—H
—H

embedded image

—H
—H
558

608
—H
—H

embedded image

—H
—H
569

609
—H
—H

embedded image

—H
—H
541

610
—H
—H

embedded image

—H
—H
550

611
—H
—H

embedded image

—H
—H
550

612
—H
—H

embedded image

—H
—H
550

613
—H
—H

embedded image

—H
—H
555

614
—H
—H

embedded image

—H
—H
553

615

embedded image

—H
—H
—H
—H
553

616
—H

embedded image

—H
—H
—H
553

617
—H
—H

embedded image

—H
—H
551

618

embedded image

—H
—H
—H
—H
585

619
—H
—H

embedded image

—H
—H
542

620
—H

embedded image

—H
—H
—H
539

621
—H
—H

embedded image

—H
—H
540

622
—H
—H

embedded image

—H
—H
570

623
—H
—H

embedded image

—H
—H
555

624
—H

embedded image

—H
—H
—H
613

625
—H

embedded image

—H
—H
—H
627

626
—H

embedded image

—H
—H
—H
538

627

embedded image

—H
—H
—H
—H
539

628

embedded image

—H
—H
—H
—H
539

629
—H

embedded image

—H
—H
—H
539

630

embedded image

—H
—H
—H
—H
538

631
—H
—H

embedded image

—H
—H
539

632
—H

embedded image

—H
—H
—H
540

633
—H

embedded image

—H
—H
—H
539

634

embedded image

—H
—H
—H
—H
539

635
—H
—H

embedded image

—H
—H
556

636
—H
—H

embedded image

—H
—H
572

TABLE 48

Example
R26
R27
R28
R29
R210
MS(M + 1)

637
—H
—H
—CH₃
—H
—H
501

638
—H
—H
—Cl
—H
—H
521

639
—H
—H
—F
—H
—H
505

640
—H
—H
—OCH₃
—H
—H
517

641
—H
—Cl
—Cl
—H
—H
555

TABLE 49

Example
R21
MS(M + 1)

642

embedded image

493

643

embedded image

493

644

embedded image

545

645

embedded image

488

646

embedded image

488

647

embedded image

553

TABLE 50

Example
R26
R27
R28
R29
R210
MS(M + 1)

648
—H
—H
—H
—H
—H
503

649
—H
—H
—CH₃
—H
—H
517

650
—H
—H
—Cl
—H
—H
537

651
—H
—H
—F
—H
—H
521

652
—H
—H
—OCH₃
—H
—H
533

653
—H
—H
—CN
—H
—H
528

654
—H
—F
—H
—H
—H
521

TABLE 51

Example
R21
MS(M + 1)

655

embedded image

547

656

embedded image

561

657

embedded image

504

658

embedded image

543

TABLE 52

Ex-

MS

ample
R26
R27
R28
R29
R210
(M + 1)

659
—H
—H
—Cl
—H
—H
533

660
—H
—OC₂H₅
—OC₂H₅
—H
—H
587

661
—H
—H
—NHCOCH₃
—H
—H
556

662
—H
—H
—SO₂CH₃
—H
—H
577

663
—H
—H

embedded image

—H
—H
568

664
—H
—H

embedded image

—H
—H
564

665
—H
—H

embedded image

—H
—H
565

666
—H
—H

embedded image

—H
—H
565

TABLE 53

Example
R21
MS(M + 1)

667

embedded image

539

668

embedded image

569

669

embedded image

557

670

embedded image

541

TABLE 54

Example
R27
R28
R29
R210
MS(M + 1)

671
—H
—H
—H
—H
474

672
—C₆H₅
—H
—H
—H
550

673
—CH₃
—H
—H
—H
488

674
—H
—H
—H
—CH₃
488

675
—H
—H
—H
—F
492

676
—H
—C₆H₅
—H
—H
550

677
—H
—CH₃
—H
—H
488

678
—H
—OCH₃
—H
—H
504

679
—H
—F
—H
—H
492

680
—H
—Cl
—H
—H
508

681
—H
—CN
—H
—H
499

682

embedded image

—H
—H
—H
543

683
—H

embedded image

—H
—H
543

684
—H

embedded image

—H
—H
540

TABLE 55

Example
R27
R28
R29
R210
MS(M + 1)

685
—H
—H
—H
—H
474

686
—OCH₃
—H
—H
—H
504

687
—H
—Cl
—H
—H
508

688
—H
—Cl
—Cl
—H
542

689
—C₆H₅
—H
—H
—H
550

690
—H
—C₆H₅
—H
—H
550

691
—H
—H
—C₆H₅
—H
550

692
—H
—H
—H
—CH₃
488

693
—H
—CH₃
—H
—H
488

694
—Cl
—Cl
—H
—H
542

695
—H
—CF₃
—H
—H
542

696
—H
—OH
—Cl
—H
524

697
—H
—H
—CH₃
—H
488

698
—H
—OH
—H
—H
490

699
—OH
—CH₃
—H
—H
504

700
—OH
—H
—Cl
—H
524

701
—H
—OCH₃
—H
—H
504

702
—H

embedded image

—H
—H
539

703
—H

embedded image

—H
—H
551

704

embedded image

—H
—H
—H
551

705
—H
—H

embedded image

—H
556

706

embedded image

—H
—H
—H
543

TABLE 56

Example
R27
R28
R29
R210
MS(M + 1)

707
—H
—H
—H
—H
474

708
—H
—Cl
—H
—H
508

709
—H
—C₆H₅
—H
—H
550

710
—F
—H
—H
—H
492

711
—H
—OH
—CH₃
—H
504

712
—CH₃
—H
—H
—H
488

713
—CH₃

embedded image

—H
—H
606

714
—H

embedded image

—H
—H
559

TABLE 57

Example
R21
MS(M + 1)

715

embedded image

523

716

embedded image

553

717

embedded image

537

718

embedded image

541

719

embedded image

527

720

embedded image

527

721

embedded image

513

722

embedded image

513

TABLE 58

Example
R21
MS(M + 1)

723

embedded image

524

724

embedded image

524

725

embedded image

524

726

embedded image

524

727

embedded image

524

728

embedded image

524

729

embedded image

554

730

embedded image

554

731

embedded image

524

732

embedded image

538

733

embedded image

554

TABLE 59

Example
R23
R24
R25
R26
R27
MS(M + 1)

734
—H
—H
—H
—H
—H
513

735
—H
—H
—Cl
—H
—OCH₃
577

736
—H
—H
—H
—H
—OCH₃
543

737
—CH₃
—H
—H
—H
—H
527

738
—H
—H
—OCH₃
—H
—H
543

739
—H
—H
—Cl
—H
—H
547

740
—CH₃
—H
—H
—OCH₃
—H
557

TABLE 60

Example
R21
MS(M + 1)

741

embedded image

513

742

embedded image

569

743

embedded image

527

744

embedded image

527

745

embedded image

513

746

embedded image

557

TABLE 61

Example
R23
R24
R25
R26
R27
MS(M + 1)

747
—H
—H
—CH₃
—H
—H
543

748
—Cl
—H
—H
—H
—H
563

749
—CH₃
—H
—H
—H
—H
543

750
—H
—H
—CF₃
—H
—H
597

751
—H
—F
—H
—H
—H
547

752
—H
—H
—H
—H
—H
529

753
—H
—H
—H
—F
—H
547

754
—H
—H
—H
—OCH₃
—H
559

755
—H
—H
—H
—Cl
—H
563

TABLE 62

Example
R21
MS(M + 1)

756

embedded image

529

757

embedded image

529

758

embedded image

563

759

embedded image

529

TABLE 63

Example
R23
R24
R25
R26
R27
MS(M + 1)

760
—H
—H
—H
—H
—H
512

761
—H
—H
—OCH₃
—H
—H
542

762
—H
—H
—Cl
—H
—H
546

763
—H
—H
—F
—H
—H
530

764
—H
—H
—H
—H
—H
526

765
—H
—H
—CH₃
—H
—H
526

766
—H
—H
—OCF₃
—H
—H
596

767
—H
—OCH₃
—H
—H
—H
542

768
—H
—Cl
—H
—H
—H
546

769
—H
—H
—H
—OCH₃
—H
542

770
—H
—H
—H
—Cl
—H
546

771
—H
—H
—OCH₃
—OCH₃
—H
572

772
—H
—CH₃
—H
—H
—H
526

773
—H
—H
—H
—CH₃
—H
526

774
—H
—H
—H
—OCH₃
—H
556

775
—H
—H
—H
—N(CH₃)₂
—H
555

776
—H
—H
—Cl
—H
—H
560

777
—H
—H
—F
—H
—H
544

778
—H
—H
—OCH₃
—H
—H
556

779
—H
—OCH₃
—H
—H
—H
556

TABLE 64

Example
R21
MS(M + 1)

780

embedded image

512

781

embedded image

526

782

embedded image

526

783

embedded image

526

784

embedded image

512

785

embedded image

512

786

embedded image

512

787

embedded image

526

788

embedded image

526

789

embedded image

542

TABLE 65

Example
R23
R24
R25
MS(M + 1)

790
—H
—H
—H
463

791
—H
—CH₃
—CH₃
491

792
—H
—H
—CH₃
477

793
—H
—H

embedded image

573

794
—H
—H

embedded image

562

795
—H
—H

embedded image

560

TABLE 66

MS

Example
R23
R24
R25
(M + 1)

796
—H
—H
—H
463

797
—CH₃
—H
—C₆H₅
553

798
—CF₃
—H
—C₆H₅
607

799
—CH₃
—H
—H
477

800
—CF₃
—H
—CH₃
545

801
—CH₃
—H
—CH₃
491

802
—CH₃
—H

embedded image

587

803

embedded image

—H
—H
560

TABLE 67

Example
R23
R24
R25
MS(M + 1)

804
—H
—H
—H
479

805
—CH₃
—H
—H
493

806
—Cl
—H
—H
513

807
—H
—H
—Cl
513

808
—H
—H
—C₆H₅
555

809
—OCH₃
—H
—H
509

810
—Cl
—Cl
—Cl
581

811
—H
—CH₃
—H
493

812
—H
—H
—COCH₃
521

813
—H
—H
—OCH₃
509

814
—H
—H

embedded image

556

815
—H
—H

embedded image

556

TABLE 68

Example
R23
R24
R25
MS(M + 1)

816
—H
—H
—H
479

817
—H
—OCH₃
—H
509

818
—Cl
—H
—Cl
547

819
—H
—H
—Cl
513

TABLE 69

Example
R21
MS(M + 1)

820

embedded image

540

821

embedded image

540

822

embedded image

540

823

embedded image

540

824

embedded image

540

825

embedded image

570

826

embedded image

584

827

embedded image

540

828

embedded image

568

829

embedded image

584

830

embedded image

584

831

embedded image

554

Example
R21
MS(M + 1)

832

embedded image

542

833

embedded image

556

834

embedded image

542

835

embedded image

556

836

embedded image

586

837

embedded image

542

838

embedded image

556

839

embedded image

556

840

embedded image

582

841

embedded image

556

842

embedded image

570

843

embedded image

572

TABLE 71

Example
R22
R24
MS(M + 1)

844
—H
—H
480

845
—H
—CH₃
494

846
—CH₃
—CH₃
508

847
—C₆H₅
—CH₃
570

848

embedded image

—CH₃
638

849

embedded image

—H
565

850

embedded image

—H
563

851

embedded image

—H
549

TABLE 72

Example
R22
R24
MS(M + 1)

852
—H
—H
480

853
—C₆H₅
—H
556

854
—CH₃
—H
494

855

embedded image

—H
557

856

embedded image

—H
590

857

embedded image

—H
562

858

embedded image

—H
570

TABLE 73

Example
R21
MS(M + 1)

859

embedded image

544

860

embedded image

530

861

embedded image

530

862

embedded image

524

863

embedded image

524

864

embedded image

524

865

embedded image

475

866

embedded image

475

867

embedded image

557

868

embedded image

551

869

embedded image

544

TABLE 74

Example
R21
MS(M + 1)

870

embedded image

477

871

embedded image

477

872

embedded image

477

873

embedded image

463

874

embedded image

463

TABLE 75

Example
R22
R24
MS(M + 1)

875
—CH₃
—CF₃
546

876
—CH₃
—H
478

877
—H
—C₆H₅
540

878
—CH₃
—CH₃
492

879
—C₆H₅
—CH₃
554

880
—H
—H
464

881
—H

embedded image

570

TABLE 76

Example
R21
MS(M + 1)

882

embedded image

478

883

embedded image

554

884

embedded image

590

885

embedded image

464

886

embedded image

540

TABLE 77

Example
R22
R24
MS(M + 1)

887
—H
—CH₃
478

888
—CH₃
—CH₃
492

889
—CH₃
—H
478

890
—C₆H₅
—CH₃
554

TABLE 78

Example
R22
R24
MS(M + 1)

891
—H
—CH(CH3)2
506

892
—H
—CH3
478

893
—H
—C6H5
540

TABLE 79

Example
R21
R24
R25
MS(M + 1)

894
—CH₃
—H
—C₆H₅
553

895
—CH₃
—H
—H
477

896
—H
—H
—H
463

897
—CH₃
—H
—CH₃
491

898
—CH3
—H

embedded image

543

899
—CH3
—H

embedded image

559

TABLE 80

Example
R21
R24
R25
MS(M + 1)

900
—CH₃
—H
—C₆H₅
553

901
—CH₃
—H
—H
477

902
—C₂H₅
—H
—CH₃
505

903
—C₆H₅
—H
—H
539

904
—CH₃
—H
—CH₃
491

905
—C(CH₃)₃
—H
—CH₃
533

906
—CH₃
—H
—C(CH₃)₃
533

907
—CH₃
—H

embedded image

559

908
—CH₃
—H

embedded image

543

TABLE 81

Example
R21
R24
R25
MS(M + 1)

909
—CH₃
—H
—H
477

910
—C₆H₅
—H
—CH₃
553

911
—CH₃
—H
—C₆H₅
553

912
—CH₃
—CF₃
—H
545

TABLE 82

Example
R21
MS(M + 1)

913

embedded image

525

914

embedded image

525

915

embedded image

525

916

embedded image

553

917

embedded image

525

918

embedded image

544

919

embedded image

544

920

embedded image

544

921

embedded image

558

922

embedded image

544

923

embedded image

544

924

embedded image

544

925

embedded image

544

926

embedded image

560

927

embedded image

574

928

embedded image

585

929

embedded image

557

930

embedded image

557

931

embedded image

554

932

embedded image

570

933

embedded image

542

934

embedded image

568

935

embedded image

555

TABLE 83

Example
R21
MS(M + 1)

936

embedded image

462

937

embedded image

462

938

embedded image

476

939

embedded image

478

940

embedded image

554

941

embedded image

568

942

embedded image

492

943

embedded image

464

944

embedded image

554

945

embedded image

481

946

embedded image

504

947

embedded image

504

948

embedded image

504

949

embedded image

505

950

embedded image

581

951

embedded image

475

952

embedded image

475

953

embedded image

475

954

embedded image

489

TABLE 84

Example
R21
MS(M + 1)

955

embedded image

514

956

embedded image

528

957

embedded image

528

958

embedded image

528

959

embedded image

542

960

embedded image

528

961

embedded image

528

962

embedded image

542

963

embedded image

542

964

embedded image

584

965

embedded image

528

966

embedded image

514

967

embedded image

527

968

embedded image

513

969

embedded image

581

970

embedded image

529

971

embedded image

557

972

embedded image

527

973

embedded image

513

974

embedded image

581

975

embedded image

561

976

embedded image

530

977

embedded image

530

978

embedded image

530

979

embedded image

544

980

embedded image

546

981

embedded image

527

982

embedded image

513

983

embedded image

513

984

embedded image

513

985

embedded image

527

TABLE 85

Example
R21
MS(M + 1)

986

embedded image

517

987

embedded image

517

988

embedded image

531

989

embedded image

531

990

embedded image

545

991

embedded image

545

992

embedded image

529

993

embedded image

529

994

embedded image

529

995

embedded image

529

996

embedded image

515

997

embedded image

543

998

embedded image

515

TABLE 86

Example
R21
MS(M + 1)

999

embedded image

584

1000

embedded image

522

1001

embedded image

640

1002

embedded image

558

1003

embedded image

480

1004

embedded image

570

1005

embedded image

556

1006

embedded image

556

1007

embedded image

494

1008

embedded image

570

1009

embedded image

584

TABLE 87

Example
R21
MS(M + 1)

1010

embedded image

437

1011

embedded image

513

1012

embedded image

543

1013

embedded image

547

1014

embedded image

527

1015

embedded image

451

1016

embedded image

505

1017

embedded image

569

1018

embedded image

513

1019

embedded image

479

1020

embedded image

561

1021

embedded image

451

1022

embedded image

465

1023

embedded image

541

1024

embedded image

479

1025

embedded image

555

1026

embedded image

555

1027

embedded image

493

1028

embedded image

547

1029

embedded image

589

1030

embedded image

547

1031

embedded image

547

1032

embedded image

493

1033

embedded image

439

1034

embedded image

565

1035

embedded image

469

1036

embedded image

555

1037

embedded image

491

1038

embedded image

563

1039

embedded image

557

1040

embedded image

481

1041

embedded image

467

1042

embedded image

467

TABLE 88

Example
R21
MS(M + 1)

1043

embedded image

516

1044

embedded image

531

1045

embedded image

547

1046

embedded image

527

1047

embedded image

513

1048

embedded image

518

1049

embedded image

532

1050

embedded image

537

1051

embedded image

525

1052

embedded image

579

1053

embedded image

512

1054

embedded image

498

1055

embedded image

541

1056

embedded image

513

1057

embedded image

519

1058

embedded image

513

1059

embedded image

513

1060

embedded image

545

1061

embedded image

577

1062

embedded image

530

1063

embedded image

533

1064

embedded image

513

1065

embedded image

558

1066

embedded image

585

1067

embedded image

527

1068

embedded image

544

TABLE 89

Example
R26
R27
R28
R29
R210
MS(M + 1)

1069
—H
—H
—H
—H
—H
501

1070
—H
—H
—CH₃
—H
—H
515

1071
—H
—H
—Cl
—H
—H
535

1072
—H
—H
—F
—H
—H
519

1073
—H
—H
—OCH₃
—H
—H
531

1074
—H
—H
—CF₃
—H
—H
569

1075
—H
—Cl
—H
—H
—H
535

1076
—H
—CH₃
—H
—H
—H
515

1077
—H
—H
—CN
—H
—H
526

1078
—H
—H
—OCF₃
—H
—H
585

1079
—F
—H
—CN
—H
—H
544

1080
—H
—CH₃
—Cl
—H
—H
549

1081
—H
—Cl
—CH₃
—H
—H
549

1082
—H
—H
—OC₂H₅
—H
—H
545

1083
—H
—H
—SCH₃
—H
—H
547

1084
—H
—H
—OCH(CH₃)₂
—H
—H
559

1085
—H
—H

embedded image

—H
—H
568

1086
—H
—H

embedded image

—H
—H
567

1087
—H
—H

embedded image

—H
—H
568

1088
—H
—H

embedded image

—H
—H
568

1089
—H
—H

embedded image

—H
—H
583

TABLE 90

Example
R211
MS(M + 1)

1090

embedded image

551

1091

embedded image

551

1092

embedded image

545

1093

embedded image

552

1094

embedded image

552

1095

embedded image

570

1096

embedded image

600

1097

embedded image

575

1098

embedded image

575

1099

embedded image

557

1100

embedded image

568

1101

embedded image

568

1102

embedded image

575

1103

embedded image

541

1104

embedded image

521

1105

embedded image

558

1106

embedded image

553

1107

embedded image

541

1108

embedded image

557

1109

embedded image

568

1110

embedded image

503

1111

embedded image

552

1112

embedded image

584

1113

embedded image

586

1114

embedded image

556

1115

embedded image

570

1116

embedded image

503

1117

embedded image

554

1118

embedded image

516

1119

embedded image

516

1120

embedded image

537

1121

embedded image

540

1122

embedded image

569

1123

embedded image

541

1124

embedded image

546

1125

embedded image

565

1126

embedded image

553

1127

embedded image

556

1128

embedded image

556

1129

embedded image

503

1130

embedded image

602

1131

embedded image

552

1132

embedded image

558

1133

embedded image

552

1134

embedded image

540

1135

embedded image

491

1136

embedded image

598

1137

embedded image

532

1138

embedded image

532

TABLE 91

Example
R26
R27
R28
R29
R210
MS(M + 1)

1139
—H
—H
—CH₃
—H
—H
549

1140
—H
—H
—Cl
—H
—H
569

1141
—H
—H
—CN
—H
—H
560

1142
—F
—H
—CN
—H
—H
578

1143
—H
—H

embedded image

—H
—H
601

TABLE 92

Example
R21
MS(M + 1)

1144

embedded image

586

1145

embedded image

609

1146

embedded image

609

1147

embedded image

592

1148

embedded image

586

TABLE 93

Example
R26
R27
R28
R29
R210
MS(M + 1)

1149
—H
—H
—H
—H
—H
495

1150
—H
—H
—CH₃
—H
—H
509

1151
—H
—H
—Cl
—H
—H
529

1152
—H
—H
—F
—H
—H
513

1153
—H
—H
—OCH₃
—H
—H
525

1154
—H
—H
—CF₃
—H
—H
563

1155
—H
—Cl
—H
—H
—H
529

1156
—H
—CH₃
—H
—H
—H
509

1157
—H
—H
—CN
—H
—H
520

1158
—H
—CH₃
—CH₃
—H
—H
523

1159
—H
—H
—OCF₃
—H
—H
579

1160
—F
—H
—CN
—H
—H
538

1161
—H
—CH₃
—Cl
—H
—H
543

1162
—H
—Cl
—CH₃
—H
—H
543

1163
—H
—H
—OC₂H₅
—H
—H
539

1164
—H
—H
—SCH₃
—H
—H
541

1165
—H
—H
—OCH(CH₃)₂
—H
—H
553

1166
—H
—H

embedded image

—H
—H
562

1167
—H
—H

embedded image

—H
—H
561

1168
—H
—H

embedded image

—H
—H
562

1169
—H
—H

embedded image

—H
—H
562

1170
—H
—H

embedded image

—H
—H
577

TABLE 94

Example
R211
MS(M + 1)

1171

embedded image

545

1172

embedded image

545

1173

embedded image

539

1174

embedded image

546

1175

embedded image

546

1176

embedded image

564

1177

embedded image

594

1178

embedded image

569

1179

embedded image

569

1180

embedded image

551

1181

embedded image

562

1182

embedded image

562

1183

embedded image

569

1184

embedded image

535

1185

embedded image

515

1186

embedded image

552

1187

embedded image

547

1188

embedded image

535

1189

embedded image

551

1190

embedded image

562

1191

embedded image

497

1192

embedded image

546

1193

embedded image

578

1194

embedded image

580

1195

embedded image

550

1196

embedded image

564

1197

embedded image

497

1198

embedded image

548

1199

embedded image

510

1200

embedded image

510

1201

embedded image

531

1202

embedded image

534

1203

embedded image

563

1204

embedded image

535

1205

embedded image

540

1206

embedded image

559

1207

embedded image

547

1208

embedded image

550

1209

embedded image

550

1210

embedded image

497

1211

embedded image

596

1212

embedded image

546

1213

embedded image

552

1214

embedded image

546

1215

embedded image

534

1216

embedded image

485

1217

embedded image

592

1218

embedded image

526

1219

embedded image

526

TABLE 95

MS

Example
R26
R27
R28
R29
R210
(M + 1)

1220
—H
—H
—H
—H
—H
481

1221
—H
—H
—CH₃
—H
—H
495

1222
—H
—H
—OCH₃
—H
—H
511

1223
—H
—Cl
—Cl
—H
—H
549

1224
—F
—H
—CF₃
—H
—H
567

1225
—H
—CN
—H
—H
—H
506

1226
—H
—N(CH₃)₂
—H
—H
—H
524

1227
—H
—CH₃
—CH₃
—H
—H
509

1228
—F
—H
—F
—H
—F
535

1229
—F
—H
—H
—H
—F
517

1230
—OCH₃
—H
—Cl
—H
—H
545

1231
—H
—H
—N(C₂H₅)₂
—H
—H
552

1232
—F
—H
—OCH₃
—H
—H
529

1233
—H
—F
—CH₃
—H
—H
513

1234
—H
—CH₃
—Cl
—H
—H
529

1235
—H
—Cl
—CH₃
—H
—H
529

1236
—H
—H
—OC₂H₅
—H
—H
525

1237
—H
—H
—SCH₃
—H
—H
527

1238
—H
—H

embedded image

—H
—H
547

1239
—H
—H

embedded image

—H
—H
548

1240
—H
—H

embedded image

—H
—H
473

1241
—H
—H

embedded image

—H
—H
558

1242
—H

embedded image

—H
—H
—H
558

1243
—H
—H

embedded image

—H
—H
548

TABLE 96

MS

Example
R26
R27
R28
R29
R210
(M + 1)

1244
—H
—H
—CH₃
—H
—H
525

1245
—H
—H
—Cl
—H
—H
545

1246
—H
—H
—F
—H
—H
529

1247
—H
—H
—CN
—H
—H
536

TABLE 97

MS

Example
R21
(M + 1)

1248

embedded image

537

1249

embedded image

541

1250

embedded image

550

1251

embedded image

520

1252

embedded image

532

1253

embedded image

532

1254

embedded image

532

1255

embedded image

521

1256

embedded image

538

1257

embedded image

537

1258

embedded image

550

1259

embedded image

576

1260

embedded image

564

1261

embedded image

578

1262

embedded image

550

1263

embedded image

550

1264

embedded image

535

1265

embedded image

551

1266

embedded image

555

1267

embedded image

538

1268

embedded image

523

1269

embedded image

533

1270

embedded image

539

1271

embedded image

552

1272

embedded image

568

1273

embedded image

561

1274

embedded image

564

1275

embedded image

524

1276

embedded image

539

1277

embedded image

555

1278

embedded image

514

1279

embedded image

551

1280

embedded image

567

1281

embedded image

537

1282

embedded image

548

1283

embedded image

564

1284

embedded image

534

1285

embedded image

548

1286

embedded image

571

1287

embedded image

551

1288

embedded image

555

1289

embedded image

561

1290

embedded image

571

1291

embedded image

535

1292

embedded image

521

1293

embedded image

538

1294

embedded image

533

1295

embedded image

521

1296

embedded image

532

1297

embedded image

566

1298

embedded image

521

1299

embedded image

535

1300

embedded image

534

1301

embedded image

533

1302

embedded image

582

1303

embedded image

532

1304

embedded image

538

1305

embedded image

520

1306

embedded image

538

1307

embedded image

552

1308

embedded image

538

TABLE 98

MS

Example
R26
R27
R28
R29
R210
(M + 1)

1309
—H
—H
—H
—H
—H
486

1310
—H
—H
—CH₃
—H
—H
500

1311
—H
—H
—OCH₃
—H
—H
516

1312
—H
—Cl
—Cl
—H
—H
554

1313
—F
—H
—CF₃
—H
—H
572

1314
—H
—CN
—H
—H
—H
511

1315
—H
—CH₃
—CH₃
—H
—H
514

1316
—F
—H
—F
—H
—F
540

1317
—OCH₃
—H
—Cl
—H
—H
550

1318
—H
—H
—CH═CH₂
—H
—H
512

1319
—F
—H
—OCH₃
—H
—H
534

1320
—H
—F
—CH₃
—H
—H
518

1321
—H
—CH₃
—Cl
—H
—H
534

1322
—H
—Cl
—CH₃
—H
—H
534

1323
—H
—H
—OC₂H₅
—H
—H
530

1324
—H
—H
—SCH₃
—H
—H
532

1325
—H
—H

embedded image

—H
—H
553

1326
—H
—H

embedded image

—H
—H
554

1327
—H
—H

embedded image

—H
—H
563

1328
—H

embedded image

—H
—H
—H
563

TABLE 99

MS

Example
R21
(M + 1)

1329

embedded image

546

1330

embedded image

555

1331

embedded image

525

1332

embedded image

537

1333

embedded image

537

1334

embedded image

537

1335

embedded image

526

1336

embedded image

543

1337

embedded image

542

1338

embedded image

555

1339

embedded image

581

569

1341

embedded image

583

1342

embedded image

555

1343

embedded image

555

1344

embedded image

560

1345

embedded image

528

1346

embedded image

526

1347

embedded image

538

1348

embedded image

544

1349

embedded image

557

1350

embedded image

573

1351

embedded image

566

1352

embedded image

559

1353

embedded image

569

1354

embedded image

529

1355

embedded image

544

1356

embedded image

560

1357

embedded image

519

1358

embedded image

556

1359

embedded image

572

1360

embedded image

542

1361

embedded image

553

1362

embedded image

553

1363

embedded image

569

1364

embedded image

553

1365

embedded image

576

1366

embedded image

556

1367

embedded image

560

1368

embedded image

566

1369

embedded image

576

1370

embedded image

540

1371

embedded image

526

1372

embedded image

543

1373

embedded image

538

1374

embedded image

527

1375

embedded image

537

1376

embedded image

571

1377

embedded image

526

1378

embedded image

540

1379

embedded image

539

1380

embedded image

538

1381

embedded image

587

1382

embedded image

537

1383

embedded image

525

1384

embedded image

543

1385

embedded image

557

1386

embedded image

542

TABLE 100

MS

Example
R26
R27
R28
R29
R210
(M + 1)

1387
—H
—H
—H
—H
—H
541

1388
—H
—H
—CH₃
—H
—H
555

1389
—H
—H
—OCH₃
—H
—H
571

1390
—H
—Cl
—Cl
—H
—H
609

1391
—F
—H
—CF₃
—H
—H
627

1392
—H
—CN
—H
—H
—H
566

1393
—H
—N(CH₃)₂
—H
—H
—H
584

1394
—H
—CH₃
—CH₃
—H
—H
569

1395
—F
—H
—F
—H
—F
595

1396
—F
—H
—H
—H
—F
577

1397
—OCH₃
—H
—Cl
—H
—H
605

1398
—H
—H
—N(C₂H₅)₂
—H
—H
612

1399
—H
—H
—CH═CH₂
—H
—H
567

1400
—F
—H
—OCH₃
—H
—H
589

1401
—H
—F
—CH₃
—H
—H
573

1402
—H
—CH₃
—Cl
—H
—H
589

1403
—H
—Cl
—CH₃
—H
—H
589

1404
—H
—H
—OC₂H₅
—H
—H
585

1405
—H
—H
—SCH₃
—H
—H
587

1406
—H
—H

embedded image

—H
—H
607

1407
—H
—H

embedded image

—H
—H
608

1408
—H
—H

embedded image

—H
—H
642

1409
—H
—H

embedded image

—H
—H
609

1410
—H
—H

embedded image

—H
—H
618

1411
—H
—H

embedded image

—H
—H
618

1412
—H

embedded image

—H
—H
—H
618

1413
—H
—H

embedded image

—H
—H
608

TABLE 101

MS

Example
R26
R27
R28
R29
R210
(M + 1)

1414
—H
—H
—CH₃
—H
—H
585

1415
—H
—H
—Cl
—H
—H
605

1416
—H
—H
—F
—H
—H
589

1417
—H
—H
—CN
—H
—H
596

TABLE 102

MS

Example
R21
(M + 1)

1418

embedded image

597

1419

embedded image

601

1420

embedded image

610

1421

embedded image

580

1422

embedded image

592

1423

embedded image

592

1424

embedded image

592

1425

embedded image

581

1426

embedded image

598

1427

embedded image

597

1428

embedded image

610

1429

embedded image

638

1430

embedded image

640

1431

embedded image

610

1432

embedded image

610

1433

embedded image

595

1434

embedded image

611

1435

embedded image

615

1436

embedded image

598

1437

embedded image

583

1438

embedded image

581

1439

embedded image

593

1440

embedded image

599

1441

embedded image

612

1442

embedded image

584

1443

embedded image

599

1444

embedded image

615

1445

embedded image

574

1446

embedded image

611

1447

embedded image

627

1448

embedded image

597

1449

embedded image

608

1450

embedded image

608

1451

embedded image

594

1452

embedded image

608

1453

embedded image

631

1454

embedded image

611

1455

embedded image

615

1456

embedded image

631

1457

embedded image

595

1458

embedded image

581

1459

embedded image

598

1460

embedded image

593

1461

embedded image

581

1462

embedded image

592

1463

embedded image

626

1464

embedded image

581

1465

embedded image

595

1466

embedded image

594

1467

embedded image

593

1468

embedded image

642

1469

embedded image

592

1470

embedded image

598

1471

embedded image

580

1472

embedded image

598

1473

embedded image

612

1474

embedded image

597

TABLE 103

Example
R21
MS(M + 1)

1475
—CH₂C≡CCH₃
495

1476
—(CH₂)₂C≡CH
495

1477
—OC₂H₅
487

1478
—OCH₂CH(CH₃)₂
515

1479

embedded image

512

TABLE 104

Example
R21
MS(M + 1)

1480
—(CH₂)₂C≡CH
525

1481
—OC₂H₅
517

1482
—OCH₂CH(CH₃)₂
545

TABLE 105

Example
R21
MS(M + 1)

1483
—CH₂C≡CCH₃
521

1484
—(CH₂)₂C≡CH
521

1485

embedded image

513

TABLE 106

Example
R21
MS(M + 1)

1486
—CH₂C≡CCH₃
472

1487
—OC₂H₅
464

1488
—OCH₂CH(CH₃)₂
492

1489
—OCH(CH₃)₂
478

1490

embedded image

489

TABLE 107

Example
R26
R27
R28
R29
R210
MS(M + 1)

1491
—H
—H
—H
—H
—H
439

1492
—H
—H
—CH₃
—H
—H
453

1493
—H
—H
—OCH₃
—H
—H
469

1494
—H
—Cl
—Cl
—H
—H
508

1495
—F
—H
—CF₃
—H
—H
525

1496
—H
—CN
—H
—H
—H
464

1497
—H
—N(CH₃)₂
—H
—H
—H
482

1498
—H
—CH₃
—CH₃
—H
—H
467

1499
—F
—H
—F
—H
—F
493

1500
—F
—H
—H
—H
—F
475

1501
—OCH₃
—H
—Cl
—H
—H
503

1502
—H
—H
—N(C₂H₅)₂
—H
—H
510

1503
—H
—H
—CH═CH₂
—H
—H
465

1504
—F
—H
—OCH₃
—H
—H
487

1505
—H
—F
—CH₃
—H
—H
471

1506
—H
—CH₃
—Cl
—H
—H
487

1507
—H
—Cl
—CH₃
—H
—H
487

1508
—H
—H
—OC₂H₅
—H
—H
483

1509
—H
—H
—SCH₃
—H
—H
485

1510
—H
—H

embedded image

—H
—H
505

1511
—H
—H

embedded image

—H
—H
506

1512
—H
—H

embedded image

—H
—H
507

1513
—H
—H

embedded image

—H
—H
516

1514
—H
—H

embedded image

—H
—H
516

1515
—H

embedded image

—H
—H
—H
516

1516
—H
—H

embedded image

—H
—H
506

TABLE 108

Example
R26
R27
R28
R29
R210
MS(M + 1)

1517
—H
—H
—CH₃
—H
—H
483

1518
—H
—H
—Cl
—H
—H
503

1519
—H
—H
—F
—H
—H
487

1520
—H
—H
—CN
—H
—H
494

TABLE 109

Example
R21
MS(M + 1)

1521

embedded image

495

1522

embedded image

499

1523

embedded image

509

1524

embedded image

478

1525

embedded image

490

1526

embedded image

490

1527

embedded image

490

1528

embedded image

479

1529

embedded image

496

1530

embedded image

495

1531

embedded image

508

1532

embedded image

534

1533

embedded image

522

1534

embedded image

536

1535

embedded image

538

1536

embedded image

508

1537

embedded image

508

1538

embedded image

493

1539

embedded image

509

1540

embedded image

513

1541

embedded image

496

1542

embedded image

481

1543

embedded image

479

1544

embedded image

491

1545

embedded image

497

1546

embedded image

510

1547

embedded image

526

1548

embedded image

519

1549

embedded image

512

1550

embedded image

522

1551

embedded image

482

1552

embedded image

497

1553

embedded image

513

1554

embedded image

472

1555

embedded image

509

1556

embedded image

525

1557

embedded image

495

1558

embedded image

506

1559

embedded image

506

1560

embedded image

522

1561

embedded image

492

1562

embedded image

506

1563

embedded image

529

1564

embedded image

509

1565

embedded image

519

1566

embedded image

529

1567

embedded image

493

1568

embedded image

479

1569

embedded image

496

1570

embedded image

491

1571

embedded image

479

1572

embedded image

490

1573

embedded image

524

1574

embedded image

479

1575

embedded image

493

1576

embedded image

492

1577

embedded image

491

1578

embedded image

540

1579

embedded image

490

1580

embedded image

496

1581

embedded image

478

1582

embedded image

496

1583

embedded image

510

1584

embedded image

495

TABLE 110

Ex-

MS

ample
R26
R27
R28
R29
R210
(M + 1)

1585
—H
—H
—H
—H
—H
467

1586
—H
—H
—CH₃
—H
—H
481

1587
—H
—H
—OCH₃
—H
—H
497

1588
—H
—H
—Cl
—Cl
—H
535

1589
—H
—H
—CF₃
—H
—F
553

1590
—H
—H
—H
—CN
—H
492

1591
—H
—H
—H
—N(CH₃)₂
—H
510

1592
—H
—H
—CH₃
—CH₃
—H
495

1593
—F
—H
—F
—H
—F
521

1594
—F
—H
—H
—H
—F
503

1595
—H
—H
—Cl
—H
—OCH₃
531

1596
—H
—H
—N(C₂H₅)₂
—H
—H
538

1597
—H
—H
—CH═CH₂
—H
—H
493

1598
—H
—H
—OCH₃
—H
—F
515

1599
—H
—H
—CH₃
—F
—H
499

1600
—H
—H
—Cl
—CH₃
—H
515

1601
—H
—H
—CH₃
—Cl
—H
515

1602
—H
—H
—OC₂H₅
—H
—H
511

1603
—H
—H
—SCH₃
—H
—H
513

1604
—H
—H

embedded image

—H
—H
533

1605
—H
—H

embedded image

—H
—H
534

1606
—H
—H

embedded image

—H
—H
568

1607
—H
—H

embedded image

—H
—H
535

1608
—H
—H

embedded image

—H
—H
544

1609
—H
—H

embedded image

—H
—H
544

1610
—H

embedded image

—H
—H
—H
544

1611
—H
—H

embedded image

—H
—H
534

TABLE 111

Example
R26
R27
R28
R29
R210
MS(M + 1)

1612
—H
—H
—CH₃
—H
—H
511

1613
—H
—H
—Cl
—H
—H
531

1614
—H
—H
—F
—H
—H
515

1615
—H
—H
—CN
—H
—H
522

TABLE 112

Example
R21
MS(M + 1)

1616

embedded image

523

1617

embedded image

527

1618

embedded image

537

1619

embedded image

506

1620

embedded image

518

1621

embedded image

518

1622

embedded image

518

1623

embedded image

507

1624

embedded image

524

1625

embedded image

523

1626

embedded image

536

1627

embedded image

562

1628

embedded image

550

1629

embedded image

564

1630

embedded image

566

1631

embedded image

536

1632

embedded image

536

1633

embedded image

521

1634

embedded image

537

1635

embedded image

541

1636

embedded image

524

1637

embedded image

509

1638

embedded image

507

1639

embedded image

519

1640

embedded image

525

1641

embedded image

538

1642

embedded image

554

1643

embedded image

547

1644

embedded image

540

1645

embedded image

550

1646

embedded image

510

1647

embedded image

525

1648

embedded image

541

1649

embedded image

500

1650

embedded image

537

1651

embedded image

553

1652

embedded image

523

1653

embedded image

534

1654

embedded image

534

1655

embedded image

550

1656

embedded image

520

1657

embedded image

534

1658

embedded image

557

1659

embedded image

537

1660

embedded image

541

1661

embedded image

547

1662

embedded image

557

1663

embedded image

521

1664

embedded image

507

1665

embedded image

524

1666

embedded image

519

1667

embedded image

507

1668

embedded image

518

1669

embedded image

552

1670

embedded image

507

1671

embedded image

521

1672

embedded image

520

1673

embedded image

519

1674

embedded image

568

1675

embedded image

518

1676

embedded image

506

1677

embedded image

524

1678

embedded image

538

1679

embedded image

523

TABLE 113

Ex-

ample
R26
R27
R28
R29
R210
MS(M + 1)

1680
—H
—H
—H
—H
—H
435

1681
—H
—H
—CH₃
—H
—H
449

1682
—H
—H
—OCH₃
—H
—H
465

1683
—H
—Cl
—Cl
—H
—H
503

1684
—F
—H
—CF₃
—H
—H
521

1685
—H
—CN
—H
—H
—H
460

1686
—H
—N(CH₃)₂
—H
—H
—H
478

1687
—H
—CH₃
—CH₃
—H
—H
463

1688
—F
—H
—F
—H
—F
489

1689
—F
—H
—H
—H
—F
471

1690
—OCH₃
—H
—Cl
—H
—H
499

1691
—H
—H
—N(C₂H₅)₂
—H
—H
506

1692
—H
—H
—CH═CH₂
—H
—H
461

1693
—F
—H
—OCH₃
—H
—H
483

1694
—H
—F
—CH₃
—H
—H
467

1695
—H
—CH₃
—Cl
—H
—H
483

1696
—H
—Cl
—CH₃
—H
—H
483

1697
—H
—H
—OC₂H₅
—H
—H
479

1698
—H
—H
—SCH₃
—H
—H
481

1699
—H
—H

embedded image

—H
—H
501

1700
—H
—H

embedded image

—H
—H
502

1701
—H
—H

embedded image

—H
—H
536

1702
—H
—H

embedded image

—H
—H
503

1703
—H
—H

embedded image

—H
—H
512

1704
—H
—H

embedded image

—H
—H
512

1705
—H

embedded image

—H
—H
—H
512

1706
—H
—H

embedded image

—H
—H
501

1707
—H
—H

embedded image

—H
—H
502

TABLE 114

Example
R26
R27
R28
R29
R210
MS(M + 1)

1708
—H
—H
—CH₃
—H
—H
479

1709
—H
—H
—Cl
—H
—H
499

1710
—H
—H
—F
—H
—H
483

1711
—H
—H
—CN
—H
—H
490

TABLE 115

Example
R21
MS(M + 1)

1712

embedded image

491

1713

embedded image

495

1714

embedded image

504

1715

embedded image

474

1716

embedded image

486

1717

embedded image

486

1718

embedded image

486

1719

embedded image

475

1720

embedded image

492

1721

embedded image

491

1722

embedded image

504

1723

embedded image

530

1724

embedded image

518

1725

embedded image

532

1726

embedded image

534

1727

embedded image

504

1728

embedded image

504

1729

embedded image

489

1730

embedded image

505

1731

embedded image

509

1732

embedded image

492

1733

embedded image

477

1734

embedded image

475

1735

embedded image

487

1736

embedded image

493

1737

embedded image

506

1738

embedded image

522

1739

embedded image

515

1740

embedded image

508

1741

embedded image

518

1742

embedded image

478

1743

embedded image

493

1744

embedded image

509

1745

embedded image

468

1746

embedded image

505

1747

embedded image

521

1748

embedded image

491

1749

embedded image

502

1750

embedded image

518

1751

embedded image

488

1752

embedded image

502

1753

embedded image

525

1754

embedded image

505

1755

embedded image

509

1756

embedded image

515

1757

embedded image

525

1758

embedded image

489

1759

embedded image

475

1760

embedded image

492

1761

embedded image

487

1762

embedded image

475

1763

embedded image

486

1764

embedded image

520

1765

embedded image

475

1766

embedded image

489

1767

embedded image

488

1768

embedded image

487

1769

embedded image

536

1770

embedded image

486

1771

embedded image

492

1772

embedded image

474

1773

embedded image

492

1774

embedded image

506

1775

embedded image

491

TABLE 116

Example
R26
R27
R28
R29
R210
MS(M + 1)

1776
—H
—H
—H
—H
—H
416

1777
—H
—H
—CH₃
—H
—H
430

1778
—H
—H
—OCH₃
—H
—H
446

1779
—H
—Cl
—Cl
—H
—H
484

1780
—F
—H
—CF₃
—H
—H
502

1781
—H
—CN
—H
—H
—H
441

1782
—H
—N(CH₃)₂
—H
—H
—H
459

1783
—H
—CH₃
—CH₃
—H
—H
444

1784
—F
—H
—F
—H
—F
470

1785
—F
—H
—H
—H
—F
452

1786
—OCH₃
—H
—Cl
—H
—H
480

1787
—H
—H
—N(C₂H₅)₂
—H
—H
487

1788
—H
—H
—CH═CH₂
—H
—H
442

1789
—H
—H
—Cl
—H
—H
450

1790
—F
—H
—OCH₃
—H
—H
464

1791
—H
—F
—CH₃
—H
—H
448

1792
—H
—CH₃
—Cl
—H
—H
464

1793
—H
—Cl
—CH₃
—H
—H
464

1794
—H
—H
—OC₂H₅
—H
—H
460

1795
—H
—H
—SCH₃
—H
—H
462

1796
—H
—H

embedded image

—H
—H
482

1797
—H
—H

embedded image

—H
—H
483

1798
—H
—H

embedded image

—H
—H
484

1799
—H
—H

embedded image

—H
—H
493

1800
—H
—H

embedded image

—H
—H
493

1801
—H

embedded image

—H
—H
—H
493

1802
—H
—H

embedded image

—H
—H
483

TABLE 117

Example
R26
R27
R28
R29
R210
MS(M + 1)

1803
—H
—H
—CH₃
—H
—H
460

1804
—H
—H
—Cl
—H
—H
480

1805
—H
—H
—F
—H
—H
464

1806
—H
—H
—CN
—H
—H
471

TABLE 118

Example
R21
MS(M + 1)

1807

embedded image

472

1808

embedded image

476

1809

embedded image

485

1810

embedded image

455

1811

embedded image

467

1812

embedded image

467

1813

embedded image

467

1814

embedded image

456

1815

embedded image

473

1816

embedded image

472

1817

embedded image

485

1818

embedded image

511

1819

embedded image

499

1820

embedded image

513

1821

embedded image

515

1822

embedded image

485

1823

embedded image

485

1824

embedded image

470

1825

embedded image

486

1826

embedded image

490

1827

embedded image

473

1828

embedded image

458

1829

embedded image

456

1830

embedded image

468

1831

embedded image

474

1832

embedded image

487

1833

embedded image

503

1834

embedded image

496

1835

embedded image

489

1836

embedded image

499

1837

embedded image

459

1838

embedded image

574

1839

embedded image

490

1840

embedded image

449

1841

embedded image

486

1842

embedded image

502

1843

embedded image

472

1844

embedded image

499

1845

embedded image

469

1846

embedded image

483

1847

embedded image

506

1848

embedded image

486

1849

embedded image

490

1850

embedded image

496

1851

embedded image

506

1852

embedded image

470

1853

embedded image

456

1854

embedded image

473

1855

embedded image

468

1856

embedded image

456

1857

embedded image

467

1858

embedded image

501

1859

embedded image

456

1860

embedded image

470

1861

embedded image

469

1862

embedded image

468

1863

embedded image

517

1864

embedded image

467

1865

embedded image

473

1866

embedded image

455

1867

embedded image

473

1868

embedded image

487

1869

embedded image

472

TABLE 119

Ex-

ample
R26
R27
R28
R29
R210
MS(M + 1)

1870
—H
—H
—H
—H
—H
425

1871
—H
—H
—CH₃
—H
—H
439

1872
—H
—H
—OCH₃
—H
—H
455

1873
—H
—Cl
—Cl
—H
—H
494

1874
—F
—H
—CF₃
—H
—H
511

1875
—H
—CN
—H
—H
—H
450

1876
—H
—N(CH₃)₂
—H
—H
—H
468

1877
—H
—CH₃
—CH₃
—H
—H
453

1878
—F
—H
—F
—H
—F
479

1879
—F
—H
—H
—H
—F
461

1880
—OCH₃
—H
—Cl
—H
—H
489

1881
—H
—H
—N(C₂H₅)₂
—H
—H
496

1882
—H
—H
—CH═CH₂
—H
—H
451

1883
—F
—H
—OCH₃
—H
—H
473

1884
—H
—F
—CH₃
—H
—H
457

1885
—H
—CH₃
—Cl
—H
—H
473

1886
—H
—Cl
—CH₃
—H
—H
473

1887
—H
—H
—OC₂H₅
—H
—H
469

1888
—H
—H
—SCH₃
—H
—H
471

1889
—H
—H

embedded image

—H
—H
491

1890
—H
—H

embedded image

—H
—H
492

1891
—H
—H

embedded image

—H
—H
502

1892
—H
—H

embedded image

—H
—H
502

1893
—H

embedded image

—H
—H
—H
502

1894
—H
—H

embedded image

—H
—H
491

1895
—H
—H

embedded image

—H
—H
492

TABLE 120

Example
R26
R27
R28
R29
R210
MS(M + 1)

1896
—H
—H
—CH₃
—H
—H
469

1897
—H
—H
—Cl
—H
—H
489

1898
—H
—H
—F
—H
—H
473

1899
—H
—H
—CN
—H
—H
480

TABLE 121

Example
R21
MS(M + 1)

1900

embedded image

481

1901

embedded image

485

1902

embedded image

495

1903

embedded image

464

1904

embedded image

476

1905

embedded image

476

1906

embedded image

476

1907

embedded image

465

1908

embedded image

482

1909

embedded image

481

1910

embedded image

494

1911

embedded image

520

1912

embedded image

508

1913

embedded image

522

1914

embedded image

524

1915

embedded image

494

1916

embedded image

494

1917

embedded image

479

1918

embedded image

495

1919

embedded image

499

1920

embedded image

482

1921

embedded image

493

1922

embedded image

467

1923

embedded image

465

1924

embedded image

477

1925

embedded image

483

1926

embedded image

496

1927

embedded image

512

1928

embedded image

505

1929

embedded image

498

1930

embedded image

508

1931

embedded image

468

1932

embedded image

483

1933

embedded image

499

1934

embedded image

458

1935

embedded image

495

1936

embedded image

511

1937

embedded image

481

1938

embedded image

492

1939

embedded image

508

1940

embedded image

478

1941

embedded image

492

1942

embedded image

515

1943

embedded image

495

1944

embedded image

499

1945

embedded image

505

1946

embedded image

515

1947

embedded image

479

1948

embedded image

465

1949

embedded image

482

1950

embedded image

477

1951

embedded image

465

1952

embedded image

476

1953

embedded image

510

1954

embedded image

465

1955

embedded image

479

1956

embedded image

478

1957

embedded image

477

1958

embedded image

526

1959

embedded image

482

1960

embedded image

464

1961

embedded image

482

1962

embedded image

496

1963

embedded image

481

TABLE 122

Ex-

ample
R26
R27
R28
R29
R210
MS(M + 1)

1964
—H
—H
—H
—H
—H
459

1965
—H
—H
—CH₃
—H
—H
473

1966
—H
—H
—OCH₃
—H
—H
489

1967
—H
—Cl
—Cl
—H
—H
527

1968
—F
—H
—CF₃
—H
—H
545

1969
—H
—CN
—H
—H
—H
484

1970
—H
—N(CH₃)₂
—H
—H
—H
502

1971
—H
—CH₃
—CH₃
—H
—H
487

1972
—F
—H
—F
—H
—F
513

1973
—F
—H
—H
—H
—F
495

1974
—OCH₃
—H
—Cl
—H
—H
523

1975
—H
—H
—N(C₂H₅)₂
—H
—H
530

1976
—H
—H
—CH═CH₂
—H
—H
485

1977
—F
—H
—OCH₃
—H
—H
507

1978
—H
—F
—CH₃
—H
—H
491

1979
—H
—CH₃
—Cl
—H
—H
507

1980
—H
—Cl
—CH₃
—H
—H
507

1981
—H
—H
—OC₂H₅
—H
—H
503

1982
—H
—H
—SCH₃
—H
—H
505

1983
—H
—H

embedded image

—H
—H
525

1984
—H
—H

embedded image

—H
—H
526

1985
—H
—H

embedded image

—H
—H
560

1986
—H
—H

embedded image

—H
—H
527

1987
—H
—H

embedded image

—H
—H
536

1988
—H
—H

embedded image

—H
—H
536

1989
—H

embedded image

—H
—H
—H
536

1990
—H
—H

embedded image

—H
—H
525

1991
—H
—H

embedded image

—H
—H
526

TABLE 123

Ex-

MS

ample
R26
R27
R28
R29
R210
(M + 1)

1992
—H
—H
—CH₃
—H
—H
503

1993
—H
—H
—Cl
—H
—H
523

1994
—H
—H
—F
—H
—H
507

1995
—H
—H
—CN
—H
—H
514

TABLE 124

Example
R21
MS (M + 1)

1996

embedded image

515

1997

embedded image

519

1998

embedded image

528

1999

embedded image

498

2000

embedded image

510

2001

embedded image

510

2002

embedded image

510

2003

embedded image

499

2004

embedded image

516

2005

embedded image

515

2006

embedded image

528

2007

embedded image

554

2008

embedded image

542

2009

embedded image

556

2010

embedded image

558

2011

embedded image

528

2012

embedded image

528

2013

embedded image

513

2014

embedded image

529

2015

embedded image

533

2016

embedded image

516

2017

embedded image

501

2018

embedded image

499

2019

embedded image

511

2020

embedded image

517

2021

embedded image

530

2022

embedded image

546

2023

embedded image

539

2024

embedded image

532

2025

embedded image

542

2026

embedded image

502

2027

embedded image

517

2028

embedded image

533

2029

embedded image

492

2030

embedded image

529

2031

embedded image

545

2032

embedded image

515

2033

embedded image

.526

2034

embedded image

542

2035

embedded image

512

2036

embedded image

526

2037

embedded image

549

2038

embedded image

529

2039

embedded image

533

2040

embedded image

539

2041

embedded image

549

2042

embedded image

513

2043

embedded image

499

2044

embedded image

516

2045

embedded image

511

2046

embedded image

499

2047

embedded image

510

2048

embedded image

544

2049

embedded image

499

2050

embedded image

513

2051

embedded image

512

2052

embedded image

511

2053

embedded image

560

2054

embedded image

510

2055

embedded image

516

2056

embedded image

498

2057

embedded image

516

2058

embedded image

530

2059

embedded image

515

TABLE 125

MS

Example
R26
R27
R28
R29
R210
(M + 1)

2060
—H
—H
—H
—H
—H
465

2061
—H
—H
—CH₃
—H
—H
479

2062
—H
—H
—Cl
—H
—H
499

2063
—H
—H
—OCH₃
—H
—H
495

2064
—H
—Cl
—Cl
—H
—H
535

2065
—F
—H
—CF₃
—H
—H
551

2066
—H
—CN
—H
—H
—H
490

2067
—H
—N(CH₃)₂
—H
—H
—H
508

2068
—H
—CH₃
—CH₃
—H
—H
493

2069
—F
—H
—F
—H
—F
519

2070
—F
—H
—H
—H
—F
501

2071
—OCH₃
—H
—Cl
—H
—H
529

2072
—H
—H
—N(C₂H₅)₂
—H
—H
536

2073
—H
—H
—CH═CH₂
—H
—H
491

2074
—F
—H
—OCH₃
—H
—H
513

2075
—H
—F
—CH₃
—H
—H
497

2076
—H
—CH₃
—Cl
—H
—H
523

2077
—H
—Cl
—CH₃
—H
—H
513

2078
—H
—H
—OC₂H₅
—H
—H
509

2079
—H
—H
—SCH₃
—H
—H
511

2080
—H
—F
—OCH₃
—H
—H
513

2081
—F
—H
—Cl
—H
—H
517

2082
—F
—H
—CH₃
—H
—H
497

2083
—H
—CN
—H
—F
—H
508

2084
—H
—F
—CN
—H
—H
508

2085
—H
—CN
—F
—H
—H
508

2086
—H
—H

embedded image

—H
—H
531

2087
—H
—H

embedded image

—H
—H
532

2088
—H
—H

embedded image

—H
—H
566

2089
—H
—H

embedded image

—H
—H
533

2090
—H
—H

embedded image

—H
—H
542

2091
—H
—H

embedded image

—H
—H
542

2092
—H

embedded image

—H
—H
—H
542

2093
—H
—H

embedded image

—H
—H
532

TABLE 126

MS

Example
R26
R27
R28
R29
R210
(M + 1)

2094
—H
—H
—CH₃
—H
—H
509

2095
—H
—H
—Cl
—H
—H
529

2096
—H
—H
—F
—H
—H
513

2097
—H
—H
—CN
—H
—H
520

TABLE 127

Example
R21
MS (M + 1)

2098

embedded image

521

2099

embedded image

525

2100

embedded image

535

2101

embedded image

504

2102

embedded image

516

2103

embedded image

516

2104

embedded image

516

2105

embedded image

505

2106

embedded image

522

2107

embedded image

521

2108

embedded image

534

2109

embedded image

560

2110

embedded image

548

2111

embedded image

562

2112

embedded image

564

2113

embedded image

534

2114

embedded image

534

2115

embedded image

519

2116

embedded image

535

2117

embedded image

539

2118

embedded image

522

2119

embedded image

507

2120

embedded image

505

2121

embedded image

517

2122

embedded image

523

2123

embedded image

536

2124

embedded image

552

2125

embedded image

545

2126

embedded image

538

2127

embedded image

548

2128

embedded image

508

2129

embedded image

523

2130

embedded image

539

2131

embedded image

498

2132

embedded image

535

2133

embedded image

551

2134

embedded image

521

2135

embedded image

548

2136

embedded image

518

2137

embedded image

532

2138

embedded image

555

2139

embedded image

535

2140

embedded image

539

2141

embedded image

545

2142

embedded image

555

2143

embedded image

519

2144

embedded image

505

2145

embedded image

522

2146

embedded image

517

2147

embedded image

505

2148

embedded image

516

2149

embedded image

550

2150

embedded image

505

2151

embedded image

519

2152

embedded image

518

2153

embedded image

517

2154

embedded image

566

2155

embedded image

516

2156

embedded image

522

2157

embedded image

504

2158

embedded image

522

2159

embedded image

536

2160

embedded image

521

2161

embedded image

520

2162

embedded image

536

2163

embedded image

480

2164

embedded image

496

2165

embedded image

519

2166

embedded image

491

2167

embedded image

501

2168

embedded image

548

2169

embedded image

550

2170

embedded image

550

TABLE 128

Example
R26
R27
R28
R29
R210
MS (M + 1)

2171
—H
—H
—H
—H
—H
465

2172
—H
—H
—CH₃
—H
—H
479

2173
—H
—H
—OCH₃
—H
—H
495

2174
—H
—Cl
—Cl
—H
—H
534

2175
—F
—H
—CF₃
—H
—H
551

2176
—H
—CN
—H
—H
—H
490

2177
—H
—N(CH₃)₂
—H
—H
—H
508

2178
—H
—CH₃
—CH₃
—H
—H
493

2179
—F
—H
—F
—H
—F
519

2180
—F
—H
—H
—H
—F
501

2181
—OCH₃
—H
—Cl
—H
—H
529

2182
—H
—H
—N(C₂H₅)₂
—H
—H
536

2183
—H
—H
—CH═CH₂
—H
—H
491

2184
—F
—H
—OCH₃
—H
—H
513

2185
—H
—F
—CH₃
—H
—H
497

2186
—H
—CH₃
—Cl
—H
—H
513

2187
—H
—Cl
—CH₃
—H
—H
513

2188
—H
—H
—OC₂H₅
—H
—H
509

2189
—H
—H
—SCH₃
—H
—H
511

2190
—H
—H

embedded image

—H
—H
531

2191
—H
—H

embedded image

—H
—H
532

2192
—H
—H

embedded image

—H
—H
533

2193
—H
—H

embedded image

—H
—H
542

2194
—H
—H

embedded image

—H
—H
542

2195
—H

embedded image

—H
—H
—H
542

2196
—H
—H

embedded image

—H
—H
532

TABLE 129

Example
R26
R27
R28
R29
R210
MS (M + 1)

2197
—H
—H
—CH₃
—H
—H
509

2198
—H
—H
—Cl
—H
—H
529

2199
—H
—H
—F
—H
—H
513

2200
—H
—H
—CN
—H
—H
520

TABLE 130

Example
R21
MS (M + 1)

2201

embedded image

521

2202

embedded image

525

2203

embedded image

535

2204

embedded image

504

2205

embedded image

516

2206

embedded image

516

2207

embedded image

516

2208

embedded image

505

2209

embedded image

522

2210

embedded image

521

2211

embedded image

534

2212

embedded image

560

2213

embedded image

548

2214

embedded image

562

2215

embedded image

564

2216

embedded image

534

2217

embedded image

534

2218

embedded image

519

2219

embedded image

535

2220

embedded image

539

2221

embedded image

522

2222

embedded image

507

2223

embedded image

505

2224

embedded image

517

2225

embedded image

523

2226

embedded image

536

2227

embedded image

552

2228

embedded image

545

2229

embedded image

538

2230

embedded image

548

2231

embedded image

508

2232

embedded image

523

2233

embedded image

539

2234

embedded image

498

2235

embedded image

535

2236

embedded image

551

2237

embedded image

521

2238

embedded image

532

2239

embedded image

548

2240

embedded image

518

2241

embedded image

532

2242

embedded image

555

2243

embedded image

535

2244

embedded image

539

2245

embedded image

545

2246

embedded image

555

2247

embedded image

519

2248

embedded image

505

2249

embedded image

522

2250

embedded image

517

2251

embedded image

505

2252

embedded image

516

2253

embedded image

550

2254

embedded image

505

2255

embedded image

519

2256

embedded image

518

2257

embedded image

517

2258

embedded image

566

2259

embedded image

516

2260

embedded image

522

2261

embedded image

504

2262

embedded image

522

2263

embedded image

536

2264

embedded image

521

TABLE 131

Example
R21
MS (M + 1)

2265
—CH₂C≡CCH₃
453

2266
—(CH₂)₂C≡CH
453

2267
—OC₂H₅
445

2268
—OCH₂CH(CH₃)₂
473

2269
—OCH(CH₃)₂
459

2270
—CH₂C≡CH
439

2271
—N(CH₃)₂
444

2272

embedded image

470

TABLE 132

Example
R21
MS (M + 1)

2273
—CH₂C≡CCH₃
447

2274
—(CH₂)₂C≡CH
447

2275
—OCH(CH₃)₂
453

2276
—CH₂C≡CH
433

2277
—N(CH₃)₂
438

2278

embedded image

464

TABLE 133

Example
R21
MS (M + 1)

2279
—CH₂C≡CCH₃
479

2280
—(CH₂)₂C≡CH
479

2281
—OC₂H₅
471

2282
—OCH₂CH(CH₃)₂
499

2283
—OCH(CH₃)₂
485

2284

embedded image

496

2285

embedded image

525

TABLE 134

Example
R21
MS (M + 1)

2286

embedded image

529

2287

embedded image

458

2288

embedded image

511

2289

embedded image

509

2290

embedded image

541

2291

embedded image

477

2292

embedded image

507

2293

embedded image

523

2294

embedded image

583

TABLE 135

Example
R21
MS (M + 1)

2295

embedded image

534

2296

embedded image

463

2297

embedded image

516

2298

embedded image

514

2299

embedded image

546

2300

embedded image

482

2301

embedded image

568

2302

embedded image

512

2303

embedded image

528

2304

embedded image

588

TABLE 136

Example
R26
R27
R28
R29
R210
MS (M + 1)

2305
—H
—CN
—H
—F
—H
482

2306
—H
—F
—CN
—H
—H
482

2307
—H
—CN
—F
—H
—H
482

2308
—F
—H
—H
—H
—Cl
491

TABLE 137

Example
R21
MS (M + 1)

2309

embedded image

470

2310

embedded image

522

2311

embedded image

526

2312

embedded image

493

2313

embedded image

509

2314

embedded image

526

2315

embedded image

464

2316

embedded image

475

2317

embedded image

524

2318

embedded image

524

2319

embedded image

528

2320

embedded image

524

TABLE 138

Example
R26
R27
R28
R29
R210
MS (M + 1)

2321
—H
—CN
—H
—F
—H
495

2322
—H
—F
—CN
—H
—H
495

2323
—H
—CN
—F
—H
—H
495

2324
—F
—H
—H
—H
—Cl
504

TABLE 139

Example
R21
MS (M + 1)

2325

embedded image

483

2326

embedded image

506

2327

embedded image

522

2328

embedded image

478

2329

embedded image

488

2330

embedded image

535

2331

embedded image

537

2332

embedded image

537

2333

embedded image

541

2334

embedded image

537

2335

embedded image

539

2336

embedded image

540

TABLE 140

Example
R26
R27
R28
R29
R210
MS (M + 1)

2337
—H
—CN
—H
—F
—H
529

2338
—H
—F
—CN
—H
—H
529

2339
—H
—CN
—F
—H
—H
529

2340
—F
—H
—H
—H
—Cl
538

TABLE 141

Example
R21
MS (M + 1)

2341

embedded image

517

2342

embedded image

540

2343

embedded image

556

2344

embedded image

512

2345

embedded image

522

2346

embedded image

569

2347

embedded image

571

2348

embedded image

571

2349

embedded image

571

2350

embedded image

573

2351

embedded image

574

2352

embedded image

575

TABLE 142

Example
R26
R27
R28
R29
R210
MS (M + 1)

2353
—H
—CN
—H
—F
—H
515

2354
—H
—F
—CN
—H
—H
515

2355
—H
—CN
—F
—H
—H
515

2356
—F
—H
—H
—H
—Cl
542

TABLE 143

Example
R21
MS (M + 1)

2357

embedded image

559

2358

embedded image

503

2359

embedded image

526

2360

embedded image

542

2361

embedded image

498

2362

embedded image

508

2363

embedded image

552

2364

embedded image

557

2365

embedded image

557

2366

embedded image

561

2367

embedded image

557

2368

embedded image

560

TABLE 144

Example
R26
R27
R28
R29
R210
MS (M + 1)

2369
—F
—H
—H
—H
—Cl
525

2370
—H
—CN
—H
—F
—H
515

2371
—H
—F
—CN
—H
—H
515

2372
—H
—CN
—F
—H
—H
515

TABLE 145

Example
R21
MS (M + 1)

2373

embedded image

504

2374

embedded image

527

2375

embedded image

543

2376

embedded image

509

2377

embedded image

556

2378

embedded image

558

2379

embedded image

558

2380

embedded image

559

2381

embedded image

560

2382

embedded image

498

2383

embedded image

561

2384

embedded image

557

Example 2385
Synthesis of 6-(4-chlorobenzoyl)-3-methoxy-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

embedded image

Using an appropriate starting material and following the procedure of Example 11, the object compound was synthesized.

White powder (ether-ethyl acetate)

Melting Point 208-209° C.

Example 2386
Synthesis of 4-{3-methoxy-4-oxo-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carbonyl}benzonitrile

embedded image

Using an appropriate starting material and following the procedure of Example 2, the object compound was synthesized.

White powder

¹H-NMR (CDCl₃) δ ppm: 1.61 (d, J=7.0 Hz, 3H), 2.31-2.79 (m, 2H), 3.40-4.06 (m, 5H), 4.15-4.68 (m, 2H), 5.12-5.30 (m, 1H), 5.70 (d, J=7.4 Hz, 1H), 7.47 (d, J=8.1 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 7.62 (d, J=8.1 Hz, 2H), 7.71 (d, J=8.1 Hz, 2H).

Example 2387
Synthesis of 4-{4-oxo-3-pyrrolidin-1-yl-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carbonyl}benzonitrile hydrochloride

embedded image

Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

White solid (salt)

Melting Point 173.7° C.

Example 2388
Synthesis of 3-fluoro-4-{4-oxo-3-pyrrolidin-1-yl-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carbonyl}benzonitrile hydrochloride

embedded image

Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Solid

Melting Point 124.3° C.

Example 2389
Synthesis of 6-[2-(4-chlorophenoxy)acetyl]-3-methoxy-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

embedded image

Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.61 (d, J=6.8 Hz, 3H), 2.35-2.66 (m, 2H), 3.57-3.93 (m, 2H), 4.08 (s, 3H), 4.25-4.53 (m, 2H), 4.73 (s, 2H), 5.16-5.32 (m, 1H), 5.60-5.82 (m, 1H), 6.88 (d, J=8.9 Hz, 2H), 7.22 (d, J=8.9 Hz, 2H), 7.47 (d, J=8.2 Hz, 2H), 7.62 (d, J=8.2 Hz, 2H).

Example 2390
Synthesis of 6-[2-(4-chlorophenylsulfanyl)acetyl]-3-methoxy-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

embedded image

Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.53-1.70 (m, 3H), 2.31-2.69 (m, 2H), 3.50-3.87 (m, 4H), 4.00-4.11 (m, 3H), 4.14-4.53 (m, 2H), 5.17-5.28 (m, 1H), 5.58-5.75 (m, 1H), 7.04-7.21 (m, 2H), 7.31-7.40 (m, 2H), 7.47 (d, J=7.9 Hz, 2H), 7.62 (d, J=8.3 Hz, 2H).

Example 2391
Synthesis of 6-[3-(4-chlorophenyl)propionyl]-3-methoxy-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

embedded image

Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.60 (d, J=6.9 Hz, 3H), 2.30-2.55 (m, 2H), 2.60-2.81 (m, 2H), 2.86-3.02 (m, 2H), 3.47-3.70 (m, 1H), 3.77-3.94 (m, 1H), 4.07 (s, 3H), 4.11-4.52 (m, 2H), 5.15-5.32 (m, 1H), 5.68 (d, J=7.5 Hz, 1H), 7.10-7.22 (m, 4H), 7.48 (d, J=8.0 Hz, 2H), 7.62 (d, J=8.0 Hz, 2H).

Example 2392
Synthesis of 6-[(E)-3-(4-chlorophenyl)acryloyl]-3-methoxy-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

embedded image

Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.61 (d, J=7.0 Hz, 3H), 2.44-2.69 (m, 2H), 3.68-4.02 (m, 2H), 4.09 (s, 3H), 4.40-4.62 (m, 2H), 5.20-5.34 (m, 1H), 5.72 (d, J=7.6 Hz, 1H), 6.95 (d, J=15.6 Hz, 1H), 7.34 (d, J=6.6 Hz, 2H), 7.38-7.46 (m, 4H), 7.60-7.67 (m, 3H).

Example 2393
Synthesis of 6-(4-chlorobenzoyl)-3-ethoxy-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one hydrochloride

embedded image

Using an appropriate starting material and following the procedure of Example 2, the object compound was synthesized.

White solid

¹H-NMR (DMSO-d₆) δ ppm: 7.97 (d, J=7.92 Hz, 1H), 7.70 (d, J=8.32 Hz, 2H), 7.63 ((d, J=8.32 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H), 7.46 (J=8.4 Hz, 2H), 5.30 (m, 1H), 4.29-4.08 (m, 4H), 3.74 (br, 1H), 3.00 (br, 1H), 2.51-2.48 (m, 2H), 1.54 (d, J=7.12 Hz, 3H), 1.32 (br, 3H). H of HCl sat was not observed.

Example 2394
Synthesis of 3-methoxy-6-(4-methylbenzoyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

embedded image

Using an appropriate starting material and following the procedure of Example 2, the object compound was synthesized.

White powder

¹H-NMR (CDCl₃) δ ppm: 1.61 (d, J=6.9 Hz, 3H), 2.37 (s, 3H), 2.43-2.75 (m, 2H), 3.51-4.17 (m, 5H), 4.18-4.71 (m, 2H), 5.16-5.37 (m, 1H), 5.70 (d, J=7.5 Hz, 1H), 7.19 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 7.47 (d, J=8.0 Hz, 2H), 7.61 (d, J=8.0 Hz, 2H).

Example 2395
Synthesis of 3-methoxy-6-(4-trifluoromethoxybenzoyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

embedded image

Using an appropriate starting material and following the procedure of Example 2, the object compound was synthesized.

White powder

¹H-NMR (CDCl₃) δ ppm: 1.61 (d, J=7.0 Hz, 3H), 2.34-2.77 (m, 2H), 3.52-4.14 (m, 5H), 4.18-4.70 (m, 2H), 5.16-5.36 (m, 1H), 5.71 (d, J=7.9 Hz, 1H), 7.24 (d, J=8.1 Hz, 2H), 7.38-7.56 (m, 4H), 7.62 (d, J=8.1 Hz, 2H).

Example 2396
Synthesis of 6-(4-chloro-3-methylbenzoyl)-3-methoxy-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

embedded image

Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

White powder

¹H-NMR (CDCl₃) δ ppm: 1.61 (d, J=7.0 Hz, 3H), 2.38 (s, 3H), 2.43-2.73 (m, 2H), 3.34-4.15 (m, 5H), 4.17-4.70 (m, 2H), 5.17-5.35 (m, 1H), 5.68 (d, J=7.6 Hz, 1H), 7.19 (dd, J=1.8 Hz, 8.2 Hz, 1H), 7.28-7.40 (m, 2H), 7.47 (d, J=8.2 Hz, 2H), 7.62 (d, J=8.2 Hz, 2H).

Example 2397
Synthesis of 6-(4-chloro-2-methylbenzoyl)-3-methoxy-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

embedded image

Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

White powder

¹H-NMR (CDCl₃) δ ppm: 1.61 (d, J=7.0 Hz, 3H), 2.22-2.28 (m, 3H), 2.32-2.73 (m, 2H), 3.25-4.90 (m, 7H), 5.15-5.36 (m, 1H), 5.69 (d, J=7.5 Hz, 1H), 7.06-7.11 (m, 1H), 7.15-7.29 (m, 2H), 7.44-7.49 (m, 2H), 7.61-7.64 (d, J=8.3 Hz, 2H).

Example 2398
Synthesis of 3-ethoxy-6-(thieno[2,3-b]pyridine-2-carbonyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one dihydrochloride

embedded image

Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

White solid

Melting Point 155-156.5° C.

Example 2399
Synthesis of 4-{3-ethoxy-4-oxo-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carbonyl}-3-fluorobenzonitrile hydrochloride

embedded image

Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

White solid

Melting Point 121-122.1° C.

Example 2400
Synthesis of 3-ethoxy-6-(4-oxazol-5-ylbenzoyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one hydrochloride

embedded image

Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

White solid

free form: ¹H-NMR (CDCl₃) δ ppm: 7.95 (s, 1H), 7.69 (d, J=8.22 Hz, 2H), 7.62 (d, J=8.18 Hz, 2H), 7.51 (d, J=8.22 Hz, 2H), 7.46 (d, J=8.18 Hz, 2H), 7.41 (s, 1H), 5.66 (brd, J=7.52 Hz, 1H), 5.27 (m, 1H), 4.70-4.20 (br, 3H), 4.00-3.80 (br, 2H), 3.58 (br, 1H), 2.60 (br, 2H), 1.61 (d, J=6.96 Hz, 3H), 1.39 (br, 3H).

Example 2401
Synthesis of 4-{3-ethoxy-4-oxo-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carbonyl}benzonitrile hydrochloride

embedded image

Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

White amorphous

free form: ¹H-NMR (CDCl₃) δ ppm: 7.71 (brd, J=8.02 Hz, 2H), 7.59 (d, J=8.3 Hz, 2H), 7.53 (d, J=8.3 Hz, 2H), 7.46 (d, J=8.02 Hz, 2H), 5.68 (brd, J=7.24 Hz, 1H), 5.25 (br, 1H), 4.59-4.10 (br, 3H), 4.00-3.80 (br, 2H), 3.49 (br, 2H), 2.63-2.48 (br, 2H), 1.61 (d, J=7.00 Hz, 3H), 1.40 (br, 3H).

Example 2402
Synthesis of 3-(2-butynyl)-6-(4-imidazol-1-ylbenzoyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one dihydrochloride

embedded image

Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

White amorphous

free form: ¹H-NMR (CDCl₃) δ ppm: 7.88 (s, 1H), 7.62-7.56 (m, 4H), 7.52 (m, 4H), 7.30-7.23 (m, 2H, overlapping CHCl3), 5.50 (d, J=6.68 Hz, 1H), 5.36 (m, 1H), 4.88-4.83 (br, 1H), 4.69-4.65 (br, 1H), 4.32 (br, 1H), 4.00 (br, 1H), 3.85 (br, 1H), 3.60 (br, 1H), 2.65-2.50 (br, 2H), 1.79 (brs, 3H), 1.61 (d, J=6.92 Hz, 3H).

Example 2403
Synthesis of 6-(5-chlorobenzofuran-2-carbonyl)-3-methoxy-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

embedded image

Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Beige amorphous

¹H-NMR (DMSO-d₆) δ ppm: 1.54 (d, J=7.1 Hz, 3H), 2.32-2.61 (m, 2H), 3.70-4.04 (m, 5H), 4.15-4.62 (m, 2H), 5.24-5.38 (m, 1H), 7.42 (s, 1H), 7.47 (dd, J=2.2, 8.8 Hz, 1H), 7.63 (d, J=8.3 Hz, 2H), 7.69 (d, J=8.3 Hz, 2H), 7.73 (d, J=8.8 Hz, 1H), 7.84 (brs, 1H), 8.20 (d, J=8.2 Hz, 1H).

Example 2404
Synthesis of 3-methoxy-6-(5-methyl-thiophene-2-carbonyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

embedded image

Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Beige amorphous

¹H-NMR (CDCl₃) δ ppm: 1.61 (d, J=7.0 Hz, 3H), 2.49 (s, 3H), 2.51-2.72 (m, 2H), 3.71-3.85 (m, 1H), 3.85-3.94 (m, 1H), 4.05 (s, 3H), 4.47-4.71 (m, 2H), 5.15-5.36 (m, 1H), 5.69 (d, J=7.4 Hz, 1H), 6.71 (d, J=3.6 Hz, 1H), 7.21 (d, J=3.6 Hz, 1H), 7.47 (d, J=8.3 Hz, 2H), 7.62 (d, J=8.3 Hz, 2H).

Example 2405
Synthesis of 6-(5-chlorothiophene-2-carbonyl)-3-methoxy-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

embedded image

Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Beige amorphous

¹H-NMR (CDCl₃) δ ppm: 1.61 (d, J=7.0 Hz, 3H), 2.45-2.71 (m, 2H), 3.72-3.85 (m, 1H), 3.86-3.97 (m, 1H), 4.06 (s, 3H), 4.46-4.69 (m, 2H), 5.18-5.35 (m, 1H), 5.71 (d, J=7.7 Hz, 1H), 6.88 (d, J=3.9 Hz, 1H), 7.18 (d, J=3.9 Hz, 1H), 7.47 (d, J=8.1 Hz, 2H), 7.61 (d, J=8.1 Hz, 2H).

Example 2406
Synthesis of 4-{3-(2-butynyl)-4-oxo-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carbonyl}-3-fluorobenzonitrile hydrochloride

embedded image

Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

White amorphous

free form: ¹H-NMR (CDCl₃) δ ppm: 7.62-7.59 (m, 2H), 7.54-7.40 (m, 5H), 5.52 (d, J=6.92 Hz, 1H), 5.40-5.30 (m, 1H), 4.97-4.57 (m, 3H), 4.17-4.10 (m, 1H), 4.00-3.70 (br, 1H), 3.43 (br, 1H), 2.70-2.46 (m, 2H), 1.81-1.79 (m, 3H), 1.61 (d, J=6.92 Hz, 3H). Two isomers were observed due to the amide rotamers.

Example 2407
Synthesis of 4-{3-(2-butynyl)-4-oxo-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carbonyl}benzonitrile hydrochloride

embedded image

Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

White solid

free form: ¹H-NMR (CDCl₃) δ ppm: 7.70 (brd, J=7.64 Hz, 2H), 7.61 (d, J=8.2 Hz, 2H), 7.53-7.48 (m, 4H), 5.51 (d, J=6.8 Hz, 1H), 5.36 (m, 1H), 5.00-4.50 (br, 2H), 4.21 (br, 1H), 4.00 (br, 1H), 3.90-3.80 (br, 1H), 3.60-3.40 (br, 1H), 2.80-2.40 (br, 2H), 1.79 (brs, 3H), 1.61 (d, J=6.96 Hz, 3H). Salt form: ¹H NMR was observed as broad peaks.

Example 2408
Synthesis of 3-(2-butynyl)-6-(4-methylbenzoyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one hydrochloride

embedded image

Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

White solid

free form: ¹H-NMR (CDCl₃) δ ppm: 7.60 (d, J=8.16 Hz, 2H), 7.49 (d, J=8.16 Hz, 2H), 7.32 (d, J=7.64 Hz, 2H), 7.18 (d, J=7.64 Hz, 2H), 5.47 (d, J=6.28 Hz, 1H), 5.36 (m, 1H), 4.88-4.82 (br, 1H), 4.67 (br, 1H), 4.32 (br, 1H), 3.98 (br, 1H), 3.81 (br, 1H), 3.56 (br, 1H), 2.65-2.46 (br, 2H), 2.36 (brs, 3H), 1.78 (s, 3H), 1.60 (d, J=6.92 Hz, 3H).

Example 2409
Synthesis of 3-(2-butynyl)-6-(4-chlorobenzoyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one hydrochloride

embedded image

Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

White solid

free form: ¹H-NMR (CDCl₃) δ ppm: 7.61 (d, J=8.20 Hz, 2H), 7.49 (d, J=8.20 Hz, 2H), 7.37 (s, 4H), 5.49 (d, J=6.84 Hz, 1H), 5.35 (m, 1H), 4.89-4.83 (br, 1H), 4.72-4.65 (br, 1H), 4.27 (br, 1H), 3.96 (br, 1H), 3.82 (br, 1H), 3.54 (br, 1H), 2.70-2.40 (br, 2H), 1.79 (s, 3H), 1.60 (d, J=6.96 Hz, 3H).

Example 2410
Synthesis of 3-(2-butynyl)-6-(4-oxazol-5-ylbenzoyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one hydrochloride

embedded image

Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

White solid

free form: ¹H-NMR (CDCl₃) δ ppm: 7.94 (s, 1H), 7.69 (d, J=8.16 Hz, 2H), 7.61 (d, J=8.16 Hz, 2H), 7.52-7.48 (m, 4H), 7.41 (s, 1H), 5.49 (d, J=6.68 Hz, 1H), 5.36 (m, 1H), 4.94-4.83 (br, 1H), 4.66 (br, 1H), 4.31 (br, 1H), 4.00 (br, 1H), 3.84 (br, 1H), 3.58 (br, 1H), 2.58 (br, 2H), 1.79 (br, 3H), 1.61 (d, J=6.92 Hz, 3H).

Example 2411
Synthesis of 3-(2-butynyl)-6-(pyrazolo[1,5-a]pyridine-2-carbonyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one hydrochloride

embedded image

Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

White solid

¹H-NMR (CDCl₃) δ ppm: 8.43 (d, J=7.04 Hz, 1H), 7.71-7.52 (m, 5H), 7.29-7.15 (m, 1H), 7.00-6.84 (m, 2H), 6.50 (br, 1H), 6.00-5.80 (br, 1H), 4.97-4.58 (m, 4H), 4.27-3.98 (m, 2H), 3.37 (br, 1H), 3.20-2.70 (m, 1H), 2.00-1.50 (br, 6H). Two isomers were observed due to the amide rotamers. H of HCl sat was not observed.

Example 2412
Synthesis of 3-(2-butynyl)-6-(2-oxo-1,2,3,4-tetrahydro-quinoline-6-carbonyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one hydrochloride

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Yellow solid

Free form: ¹H-NMR (CDCl₃) δ ppm: 7.61 (d, J=8.15 Hz, 3H), 7.49 (d, J=8.15 Hz, 2H), 7.31-7.25 (m, 2H), 6.72 (d, J=8.04 Hz, 1H), 5.48 (d, J=6.80 Hz, 1H), 5.36 (m, 1H), 4.86 (brd, J=17.14 Hz, 1H), 4.68 (brd, J=17.14 Hz, 1H), 4.35 (br, 2H), 4.00-3.70 (br, 2H), 2.98 (t, J=7.50 Hz, 2H), 2.65 (t, J=7.50 Hz, 2H), 2.65-2.49 (br, 2H), 1.79 (brs, 3H), 1.60 (d, J=6.92 Hz, 3H).

Example 2413
Synthesis of 6-(4-chloro-3-methoxybenzoyl)-3-methoxy-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

White powder

¹H-NMR (CDCl₃) δ ppm: 1.61 (d, J=7.1 Hz, 3H), 2.31-2.83 (m, 2H), 3.43-3.97 (m, 5H), 4.04 (s, 3H), 4.19-4.75 (m, 2H), 5.18-5.34 (m, 1H), 5.71 (d, J=7.8 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 7.03 (s, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.47 (d, J=8.2 Hz, 2H), 7.62 (d, J=8.2 Hz, 2H).

Example 2414
Synthesis of 6-(4-chloro-2-methoxybenzoyl)-3-methoxy-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

White powder

¹H-NMR (CDCl₃) δ ppm: 1.61 (d, J=7.1 Hz, 3H), 2.18-2.80 (m, 2H), 3.27-3.91 (m, 5H), 4.00-4.78 (m, 5H), 5.10-5.37 (m, 1H), 5.58-5.81 (m, 1H), 6.79-7.04 (m, 2H), 7.07-7.23 (m, 1H), 7.37-7.55 (m, 2H), 7.56-7.74 (m, 2H).

Example 2415
Synthesis of 3-methoxy-6-(thieno[2,3-b]pyridine-2-carbonyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Beige powder

¹H-NMR (CDCl₃) δ ppm: 1.62 (d, J=7.0 Hz, 3H), 2.52-2.75 (m, 2H), 3.76-4.12 (m, 5H), 4.49-4.74 (m, 2H), 5.14-5.38 (m, 1H), 5.71 (d, J=7.8 Hz, 1H), 7.35 (dd, J=4.6, 8.1 Hz, 1H), 7.42-7.55 (m, 3H), 7.62 (d, J=8.2 Hz, 2H), 8.10 (dd, J=1.6, 8.1 Hz, 1H), 8.62 (dd, J=1.6, 4.6 Hz, 1H).

Example 2416
Synthesis of 3-fluoro-4-{3-isobutoxy-4-oxo-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carbonyl}benzonitrile

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.06-1.15 (m, 6H), 1.60 (d, J=6.9 Hz, 3H), 1.95-2.27 (m, 1H), 2.31-2.80 (m, 2H), 3.40-4.77 (m, 6H), 5.09-5.33 (m, 1H), 5.59-5.78 (m, 1H), 7.35-7.57 (m, 5H), 7.62 (d, J=8.2 Hz, 2H).

Example 2417
Synthesis of 3-(2-butynyl)-6-(quinoline-7-carbonyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one dihydrochloride

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Yellow solid

free form: ¹H-NMR (CDCl₃) δ ppm: 8.96 (br, 1H), 8.17 (brd, J=6.24 Hz, 1H), 8.13 (s, 1H), 7.87 (br, 1H), 7.61 (d, J=8.14 Hz, 3H), 7.50 (d, J=8.14 Hz, 2H), 7.46 (m, 1H), 5.48 (br, 1H), 5.37 (br, 1H), 5.00-4.80 (br, 1H), 4.63 (br, 1H), 4.33 (br, 1H), 4.04 (br, 1H), 3.91 (br, 1H), 3.61 (br, 1H), 2.58 (br, 2H), 1.78 (br, 3H), 1.61 (d, J=6.92 Hz, 3H).

Example 2418
Synthesis of 3-methoxy-6-(quinoline-3-carbonyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Beige powder

¹H-NMR (CDCl₃) δ ppm: 1.59 (d, J=7.0 Hz, 3H), 2.37-2.91 (m, 2H), 3.45-4.22 (m, 5H), 4.26-4.82 (m, 2H), 5.18-5.37 (m, 1H), 5.72 (d, J=7.6 Hz, 1H), 7.47 (d, J=8.1 Hz, 2H), 7.55-7.70 (m, 3H), 7.73-7.83 (m, 1H), 7.90 (d, J=7.9 Hz, 1H), 8.13 (d, J=8.6 Hz, 1H), 8.26 (s, 1H), 8.98 (d, J=2.0 Hz, 1H).

Example 2419
Synthesis of 6-(2,6-dimethoxypyridine-3-carbonyl)-3-methoxy-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

White powder

¹H-NMR (CDCl₃) δ ppm: 1.61 (d, J=7.0 Hz, 3H), 2.27-2.83 (m, 2H), 3.24-4.11 (m, 1H), 4.12-4.79 (m, 2H), 5.09-5.37 (m, 1H), 5.68 (d, J=7.4 Hz, 1H), 6.22-6.44 (m, 1H), 7.40-7.69 (m, 5H).

Example 2420
Synthesis of 6-(4-chlorobenzoyl)-2-[1-(4-chlorophenyl)propylamino]-3-methoxy-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 2, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 0.95 (t, J=7.4 Hz, 3H), 1.79-2.00 (m, 2H), 2.35-2.70 (m, 2H), 3.48-4.16 (m, 5H), 4.16-4.63 (m, 2H), 4.82-5.01 (m, 1H), 5.65 (d, J=8.3 Hz, 1H), 7.18-7.41 (m, 8H).

Example 2421
Synthesis of 6-(4-chlorobenzoyl)-2-[1-(4-chlorophenyl)propylamino]-3-methoxy-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one hydrochloride

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White solid

Melting Point 118.1-123.7° C.

Example 2422
Synthesis of 6-(4-chlorobenzoyl)-2-[(R)-1-(4-chlorophenyl)propylamino]-3-methoxy-5,6,7,8-tetrahydro-31′-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 2, the object compound was synthesized.

Colorless solid

¹H-NMR (CDCl₃) δ ppm: 0.95 (t, J=7.4 Hz, 3H), 1.79-2.00 (m, 2H), 2.32-2.71 (m, 2H), 3.50-4.17 (m, 5H), 4.17-4.66 (m, 2H), 4.81-5.01 (m, 1H), 5.65 (d, J=8.3 Hz, 1H), 7.18-7.41 (m, 8H).

Example 2423
Synthesis of 6-(4-chlorobenzoyl)-2-[(R)-1-(4-chlorophenyl)propylamino]-3-methoxy-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one hydrochloride

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White solid

Melting Point 127-129.5° C.

Example 2424
Synthesis of 6-(4-chlorobenzoyl)-3-(2-propynyl)-2-[1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 2, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.60 (d, J=6.6 Hz, 3H), 2.39-2.72 (m, 3H), 3.40-4.10 (m, 2H), 4.17-4.67 (m, 2H), 4.70-4.95 (m, 2H), 5.25-5.41 (m, 2H), 7.30-7.40 (m, 4H), 7.48 (d, J=8.1 Hz, 2H), 7.60 (d, J=8.1 Hz, 2H).

Example 2425
Synthesis of 6-(4-chlorobenzoyl)-3-dimethylamino-2-[1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 2, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.57 (d, J=7.0 Hz, 3H), 2.30-2.68 (m, 2H), 2.81-3.14 (m, 6H), 3.37-4.05 (m, 2H), 4.09-4.57 (m, 2H), 5.11-5.28 (m, 1H), 6.89 (d, J=7.9 Hz, 1H), 7.32-7.41 (m, 4H), 7.44 (d, J=8.1 Hz, 2H), 7.60 (d, J=8.1 Hz, 2H).

Example 2426
Synthesis of 6-(4-chlorobenzoyl)-2-[1-(4-chlorophenyl)ethylamino]-3-dimethylamino-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 2, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.54 (d, J=7.0 Hz, 3H), 2.37-2.70 (m, 2H), 2.82-3.12 (m, 6H), 3.39-4.02 (m, 2H), 4.10-4.66 (m, 2H), 5.06-5.18 (m, 1H), 6.83 (d, J=8.2 Hz, 1H), 7.20-7.33 (m, 4H), 7.36-7.44 (m, 4H).

Example 2427
Synthesis of 6-(4-chlorobenzoyl)-3-methoxy-2-[1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 2, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.60 (d, J=7.0 Hz, 3H), 2.32-2.75 (m, 2H), 3.30-4.15 (m, 5H), 4.17-4.70 (m, 2H), 5.12-5.32 (m, 1H), 5.72 (d, J=7.5 Hz, 1H), 7.28-7.40 (m, 4H), 7.47 (d, J=8.2 Hz, 2H), 7.62 (d, J=8.2 Hz, 2H).

Example 2428
Synthesis of 3-fluoro-4-{3-methoxy-4-oxo-2-[1-(4-trifluoromethylphenyl)ethylamino]-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carbonyl}benzonitrile

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.61 (d, J=7.0 Hz, 3H), 2.36-2.77 (m, 2H), 3.32-4.71 (m, 7H), 5.16-5.35 (m, 1H), 5.60-5.79 (m, 1H), 7.35-7.58 (m, 5H), 7.62 (d, J=8.3 Hz, 2H).

Example 2429
Synthesis of 3-(2-butynyl)-6-(1-methyl-2-oxo-1,2-dihydropyridine-3-carbonyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one hydrochloride

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

White solid

¹H-NMR (DMSO-d₆) δ ppm: 7.81 (m, 1H), 7.69 (d, J=8.28 Hz, 2H), 7.64 (d, J=8.28 Hz, 2H), 7.49-7.44 (m, 2H), 6.27 (t, J=6.8 Hz, 1H), 5.37 (m, 1H), 4.99-4.69 (m, 2H), 4.24 (brd, J=4.72 Hz, 1H), 3.94 (brs, 1H), 3.76 (br, 1H), 3.46 (s, 3H), 3.34 (brt, J=5.72 Hz, 1H), 2.50-2.28 (brm, 2H), 1.81 (d, J=9.12 Hz, 3H), 1.53 (d, J=7.04 Hz, 3H).

Example 2430
Synthesis of 6-[2-(4-chlorophenoxy)acetyl]-2-[(S)-1-(4-chlorophenyl)ethylamino]-3-methoxy-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

White powder

¹H-NMR (CDCl₃) δ ppm: 1.49-1.61 (m, 3H), 2.37-2.64 (m, 2H), 3.57-3.93 (m, 2H), 3.97-4.12 (m, 3H), 4.25-4.56 (m, 2H), 4.63-4.81 (m, 2H), 5.07-5.27 (m, 1H), 5.55-5.74 (m, 1H), 6.78-6.96 (m, 2H), 7.10-7.42 (m, 6H).

Example 2431
Synthesis of 6-[2-(4-chlorophenoxy)acetyl]-2-[(S)-1-(4-chlorophenyl)ethylamino]-3-dimethylamino-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Pale pink powder

Melting Point 141.6-144.0° C.

Example 2432
Synthesis of 4-{3-morpholin-4-yl-4-oxo-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carbonyl}benzonitrile hydrochloride

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Using an appropriate starting material and following the procedure of Example 11, the object compound was synthesized.

Pale yellow powder (ethanol-ether)

Melting Point 126-129° C.

Example 2433
Synthesis of 4-{3-(3-butynyl)-4-oxo-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carbonyl}benzonitrile

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Using an appropriate starting material and following the procedure of Example 2, the object compound was synthesized.

Yellow amorphous

¹H-NMR (CDCl₃) δ ppm: 1.58 (d, J=6.9 Hz, 3H), 1.99 (s, 1H), 2.26-2.82 (m, 4H), 3.32-4.68 (m, 6H), 5.18-5.38 (m, 1H), 5.55 (d, J=6.1 Hz, 1H), 7.37-7.80 (m, 8H).

Example 2434
Synthesis of 3-(3-butynyl)-6-(4-imidazol-1-ylbenzoyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.58 (d, J=7.0 Hz, 3H), 1.99 (s, 1H), 2.29-2.83 (m, 4H), 3.39-4.19 (m, 4H), 4.19-4.69 (m, 2H), 5.19-5.40 (m, 1H), 5.57 (d, J=5.9 Hz, 1H), 7.10-7.35 (m, 2H), 7.35-7.67 (m, 8H), 7.89 (s, 1H).

Example 2435
Synthesis of 4-{3-(3-butynyl)-4-oxo-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carbonyl}-3-fluorobenzonitrile

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

White solid

¹H-NMR (CDCl₃) δ ppm: 7.62-7.41 (m, 7H), 5.53 (d, J=6.12 Hz, 1H), 5.29 (m, 1H), 4.70-4.40 (br, 1H), 4.21-3.87 (m, 4H), 3.45 (br, 1H), 2.76-2.48 (m, 4H), 1.98 (m, 1H), 1.58 (d, J=6.96 Hz,

Example 2436
Synthesis of 6-[2-(4-chlorophenoxy)acetyl]-3-(2-propynyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Beige powder

Melting Point 202.6-204.2° C.

Example 2437
Synthesis of 6-[2-(4-chlorophenoxy)acetyl]-2-[(S)-1-(4-chlorophenyl)ethylamino]-3-(2-propynyl)-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

White powder

Melting Point 185.2-186.8° C.

Example 2438
Synthesis of 3-(3-butynyl)-6-(4-oxazol-5-ylbenzoyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

White solid

¹H-NMR (CDCl₃) δ ppm: 7.94 (s, 1H), 7.69 (brd, J=7.76 Hz, 2H), 7.60 (d, J=8.24 Hz, 2H), 7.52 (d, J=8.24 Hz, 2H), 7.50 (d, J=7.76 Hz, 2H), 7.41 (s, 1H), 5.51 (d, J=5.92 Hz, 1H), 5.29 (br, 1H), 4.57-4.48 (br, 2H), 4.31-3.58 (br, 4H), 2.82-2.46 (br, 4H), 1.98 (br, 1H), 1.58 (d, J=7.64 Hz, 3H).

Example 2439
Synthesis of 3-(3-butynyl)-6-(4-chlorobenzoyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 2, the object compound was synthesized.

White solid

¹H-NMR (CDCl₃) δ ppm: 1.58 (d, J=6.9 Hz, 3H), 1.98 (s, 1H), 2.25-2.80 (m, 4H), 3.35-4.66 (m, 6H), 5.16-5.38 (m, 1H), 5.54 (d, J=6.0 Hz, 1H), 7.27-7.66 (m, 8H).

Example 2440
Synthesis of 6-(4-chlorobenzoyl)-2-[(S)-1-(4-chlorophenyl)propylamino]-3-methoxy-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 2, the object compound was synthesized.

White solid

¹H-NMR (CDCl₃) δ ppm: 0.95 (t, J=7.3 Hz, 3H), 1.74-1.97 (m, 2H), 2.57 (brs, 2H), 3.31-4.12 (m, 5H), 4.12-4.67 (m, 2H), 4.81-4.99 (m, 1H), 5.67 (d, J=7.6 Hz, 1H), 7.15-7.51 (m, 8H).

Example 2441
Synthesis of 6-(4-chlorobenzoyl)-2-[1-(4-chlorophenyl)-2-methylpropylamino]-3-methoxy-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 2, the object compound was synthesized.

Yellow amorphous

¹H-NMR (CDCl₃) δ ppm: 0.87 (d, J=6.7 Hz, 3H), 1.03 (d, J=6.7 Hz, 3H), 1.97-2.19 (m, 1H), 2.55 (brs, 2H), 3.30-4.64 (m, 7H), 4.77 (dd, J=8.3, 8.3 Hz, 1H), 5.78 (d, J=8.5 Hz, 1H), 7.13-7.44 (m, 8H).

Example 2442
Synthesis of 6-[2-(4-chlorophenoxy)acetyl]-3-dimethylamino-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one hydrochloride

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

White powder

¹H-NMR (DMSO-d₆) δ ppm: 1.53 (d, J=7.0 Hz, 3H), 2.13-2.47 (m, 2H), 2.84-3.03 (m, 6H), 3.30-3.70 (m, 2H), 4.01-4.28 (m, 2H), 4.89 (s, 2H), 5.12-5.36 (m, 1H), 6.93 (d, J=8.7 Hz, 2H), 7.19-7.38 (m, 2H), 7.61 (d, J=8.2 Hz, 2H), 7.69 (d, J=8.2 Hz, 2H), 8.16 (d, J=8.7 Hz, 1H).

Example 2443
Synthesis of 3-(3-butynyl)-6-(4-methylbenzoyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 2, the object compound was synthesized.

White amorphous

¹H-NMR (CDCl₃) δ ppm: 1.57 (d, J=6.9 Hz, 3H), 1.97 (s, 1H), 2.36 (s, 3H), 2.42-2.80 (m, 4H), 3.31-4.69 (m, 6H), 5.15-5.35 (m, 1H), 5.54 (d, J=6.1 Hz, 1H), 7.19 (d, J=7.9 Hz, 2H), 7.33 (d, J=7.9 Hz, 2H), 7.49 (d, J=8.3 Hz, 2H), 7.59 (d, J=8.3 Hz, 2H).

Example 2444
Synthesis of 6-(benzo[1,3]dioxole-5-carbonyl)-3-(2-butynyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 2, the object compound was synthesized.

White amorphous

¹H-NMR (CDCl₃) δ ppm: 1.60 (d, J=6.9 Hz, 3H), 1.79 (s, 3H), 2.34-2.74 (m, 2H), 3.49-4.03 (m, 2H), 4.37 (brs, 2H), 4.52-4.73 (m, 1H), 4.97-4.95 (m, 1H), 5.24-5.42 (m, 1H), 5.50 (d, J=6.8 Hz, 1H), 6.00 (s, 2H), 6.80 (d, J=7.9 Hz, 1H), 6.86-7.03 (m, 2H), 7.49 (d, J=8.2 Hz, 2H), 7.60 (d, J=8.2 Hz, 2H).

Example 2445
Synthesis of 3-(2-butynyl)-6-(4-fluorobenzoyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 2, the object compound was synthesized.

White amorphous

¹H-NMR (CDCl₃) δ ppm: 1.60 (d, J=7.0 Hz, 3H), 1.79 (s, 3H), 2.33-2.72 (m, 2H), 3.33-4.04 (m, 2H), 4.17-5.00 (m, 4H), 5.25-5.44 (m, 1H), 5.50 (d, J=6.8 Hz, 1H), 7.00-7.16 (m, 2H), 7.38-7.55 (m, 4H), 7.61 (d, J=8.2 Hz, 2H).

Example 2446
Synthesis of 3-(2-butynyl)-6-(quinoline-3-carbonyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

White solid

¹H-NMR (CDCl₃) δ ppm: 1.61 (d, J=7.0 Hz, 3H), 1.78 (s, 3H), 2.35-2.79 (m, 2H), 3.40-4.20 (m, 2H), 4.20-5.01 (m, 4H), 5.24-5.41 (m, 1H), 5.51 (d, J=6.8 Hz, 1H), 7.49 (d, J=8.1 Hz, 2H), 7.53-7.68 (m, 3H), 7.68-7.90 (m, 2H), 8.13 (d, J=8.3 Hz, 1H), 8.26 (s, 1H), 8.97 (d, J=2.1 Hz, 1H).

Example 2447
Synthesis of 3-(2-butynyl)-6-(3,4-dimethylbenzoyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

White solid

¹H-NMR (CDCl₃) δ ppm: 7.60 (d, J=8.24 Hz, 2H), 7.49 (d, J=8.24 Hz, 2H), 7.20 (s, 1H), 7.13 (s, 2H), 5.46 (d, J=6.6 Hz, 1H), 5.36 (m, 1H), 5.00-4.50 (br, 2H), 4.36-4.26 (br, 1H), 3.96 (br, 1H), 3.85-3.50 (br, 2H), 2.70-2.40 (br, 2H), 2.26 (s, 6H), 1.78 (s, 3H), 1.60 (d, J=6.92 Hz, 3H).

Example 2448
Synthesis of 3-(2-butynyl)-6-(4-methoxybenzoyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 2, the object compound was synthesized.

White amorphous

¹H-NMR (CDCl₃) δ ppm: 1.60 (d, J=6.9 Hz, 3H), 1.79 (s, 3H), 2.37-2.73 (m, 2H), 3.53-4.00 (m, 5H), 4.39 (brs, 2H), 4.54-4.94 (m, 2H), 5.25-5.42 (m, 1H), 5.49 (d, J=6.8 Hz, 1H), 6.89 (d, J=8.7 Hz, 2H), 7.41 (d, J=8.7 Hz, 2H), 7.49 (d, J=8.2 Hz, 2H), 7.60 (d, J=8.2 Hz, 2H).

Example 2449
Synthesis of 3-(2-butynyl)-6-(quinoline-2-carbonyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Yellow amorphous

¹H-NMR (CDCl₃) δ ppm: 1.50-1.70 (m, 3H), 1.70-1.88 (m, 3H), 2.50-2.84 (m, 2H), 3.68-4.18 (m, 2H), 4.39-5.03 (m, 4H), 5.26-5.57 (m, 2H), 7.40-7.92 (m, 8H), 8.00-8.18 (m, 1H), 8.18-8.32 (m, 1H).

Example 2450
Synthesis of 6-(4-chlorobenzoyl)-2-[1-(4-chlorophenyl)-4,4,4-trifluorobutylamino]-3-methoxy-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 2, the object compound was synthesized.

White solid

¹H-NMR (CDCl₃) δ ppm: 1.92-2.29 (m, 4H), 2.60 (brs, 2H), 3.37-4.10 (m, 2H), 4.01 (s, 3H), 4.18-4.66 (m, 2H), 5.02-5.20 (m, 1H), 5.63 (d, J=8.7 Hz, 1H), 7.18-7.33 (m, 4H), 7.33-7.46 (m, 4H).

Example 2451
Synthesis of 6-(4-ethoxybenzoyl)-3-methoxy-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.42 (t, J=7.0 Hz, 3H), 1.60 (d, J=7.0 Hz, 3H), 2.34-2.72 (m, 2H), 3.52-3.93 (m, 2H), 3.93-4.20 (m, 5H), 4.41 (brs, 2H), 5.17-5.38 (m, 1H), 5.79 (d, J=7.2 Hz, 1H), 6.88 (d, J=8.7 Hz, 2H), 7.41 (d, J=8.7 Hz, 2H), 7.47 (d, J=8.2 Hz, 2H), 7.61 (d, J=8.2 Hz, 2H).

Example 2452
Synthesis of 6-(3,4-dimethylbenzoyl)-3-methoxy-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.61 (d, J=7.0 Hz, 3H), 2.26 (s, 3H), 2.27 (s, 3H), 2.37-2.75 (m, 2H), 3.33-4.14 (m, 2H), 4.03 (s, 3H), 4.14-4.69 (m, 2H), 5.18-5.35 (m, 1H), 5.75 (d, J=7.5 Hz, 1H), 7.05-7.18 (m, 2H), 7.21 (s, 1H), 7.47 (d, J=8.2 Hz, 2H), 7.61 (d, J=8.2 Hz, 2H).

Example 2453
Synthesis of 4-{1-[6-(4-chlorobenzoyl)-3-methoxy-4-oxo-3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidin-2-ylamino]-ethyl}benzonitrile

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Using an appropriate starting material and following the procedure of Example 2, the object compound was synthesized.

White solid

¹H-NMR (CDCl₃) δ ppm: 1.60 (d, J=7.0 Hz, 3H), 2.52 (brs, 2H), 3.31-4.14 (m, 5H), 4.14-4.75 (m, 2H), 5.11-5.32 (m, 1H), 5.75 (d, J=7.2 Hz, 1H), 7.38 (s, 4H), 7.46 (d, J=8.3 Hz, 2H), 7.65 (d, J=8.3 Hz, 2H).

Example 2454
Synthesis of 6-(5-chloro-furan-2-carbonyl)-3-methoxy-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Pale yellow amorphous

¹H-NMR (CDCl₃) δ ppm: 1.61 (d, J=7.0 Hz, 3H), 2.43-2.75 (m, 2H), 3.70-4.03 (m, 2H), 4.07 (s, 3H), 4.44-4.74 (m, 2H), 5.18-5.34 (m, 1H), 5.72 (d, J=7.6 Hz, 1H), 6.28 (d, J=3.5 Hz, 1H), 7.00 (d, J=3.5 Hz, 1H), 7.47 (d, J=8.2 Hz, 2H), 7.62 (d, J=8.2 Hz, 2H).

Example 2455
Synthesis of 4-{1-[6-(2,6-difluorobenzoyl)-3-methoxy-4-oxo-3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidin-2-ylamino]ethyl}benzonitrile

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.61 (d, J=7.0 Hz, 3H), 2.28-2.70 (m, 2H), 3.37-3.56 (m, 1H), 3.72-3.93 (m, 1H), 3.93-4.21 (m, 4H), 4.50-4.74 (m, 1H), 5.13-5.36 (m, 1H), 5.78 (d, J=7.1 Hz, 1H), 6.83-7.04 (m, 2H), 7.29-7.51 (m, 3H), 7.57-7.71 (m, 2H).

Example 2456
Synthesis of 3-methoxy-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-6-(4-vinylbenzoyl)-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.61 (d, J=7.0 Hz, 3H), 2.57 (brs, 2H), 3.30-4.68 (m, 7H), 5.12-5.38 (m, 2H), 5.72 (d, J=7.4 Hz, 1H), 5.75 (dd, J=17.6, 0.5 Hz, 1H), 6.72 (dd, J=17.6, 10.9 Hz, 1H), 7.29-7.52 (m, 6H), 7.62 (d, J=8.2 Hz, 2H).

Example 2457
Synthesis of 6-(3-fluoro-4-methylbenzoyl)-3-methoxy-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.58-1.70 (m, 3H), 2.30 (s, 3H), 2.56 (brs, 2H), 3.35-4.16 (m, 5H), 4.16-4.68 (m, 2H), 5.12-5.38 (m, 1H), 5.72 (d, J=7.5 Hz, 1H), 6.98-7.30 (m, 3H), 7.47 (d, J=8.1 Hz, 2H), 7.62 (d, J=8.1 Hz, 2H).

Example 2458
Synthesis of 6-(1H-benzoimidazole-2-carbonyl)-3-(3-butynyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.47-1.63 (m, 3H), 1.99 (t, J=2.6 Hz, 1H), 2.41-2.88 (m, 4H), 3.80-4.27 (m, 3H), 4.51-4.73 (m, 1H), 4.73-4.98 (m, 1H), 5.18-5.65 (m, 3H), 7.19-7.42 (m, 2H), 7.42-7.67 (m, 5H), 7.75-7.90 (m, 1H), 10.74-11.21 (m, 1H).

Example 2459
Synthesis of 6-(2,3-dihydrobenzo[1,4]dioxine-6-carbonyl)-3-methoxy-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.61 (d, J=7.0 Hz, 3H), 2.33-2.69 (m, 2H), 3.32-4.08 (m, 5H), 4.17-4.62 (m, 6H), 5.13-5.34 (m, 1H), 5.72 (dd, J=7.3, 7.3 Hz, 1H), 6.78-7.03 (m, 3H), 7.47 (d, J=8.3 Hz, 2H), 7.62 (d, J=8.3 Hz, 2H).

Example 2460
Synthesis of 3-methoxy-6-(5-methoxybenzofuran-2-carbonyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.62 (d, J=7.0 Hz, 3H), 2.42-2.77 (m, 2H), 3.71-4.11 (m, 8H), 4.70 (brs, 2H), 5.16-5.35 (m, 1H), 5.74 (d, J=7.6 Hz, 1H), 6.94-7.09 (m, 2H), 7.28 (s, 1H), 7.42-7.54 (m, 3H), 7.62 (d, J=8.2 Hz, 2H).

Example 2461
Synthesis of 3-methoxy-6-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinoline-6-carbonyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.61 (d, J=7.0 Hz, 3H), 2.31-2.72 (m, 4H), 2.79-3.04 (m, 2H), 3.34 (s, 3H), 3.45-4.18 (m, 5H), 4.18-4.70 (m, 2H), 5.15-5.37 (m, 1H), 5.74 (d, J=7.6 Hz, 1H), 6.91-7.11 (m, 2H), 7.18 (d, J=7.9 Hz, 1H), 7.47 (d, J=8.2 Hz, 2H), 7.62 (d, J=8.2 Hz, 2H).

Example 2462
Synthesis of 6-(4-chlorobenzoyl)-2-(4-chlorobenzylamino)-3-methoxy-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one hydrochloride

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Using an appropriate starting material and following the procedure of Example 2, the object compound was synthesized.

White powder (ethanol-ether)

Melting Point 113-117° C.

Example 2463
Synthesis of 3-fluoro-4-{3-morpholin-4-yl-4-oxo-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carbonyl}benzonitrile hydrochloride

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Using an appropriate starting material and following the procedure of Example 11, the object compound was synthesized.

White powder (ether-ethyl acetate)

Melting Point 132-135° C.

Example 2464
Synthesis of 3-methoxy-6-(1-methyl-5-thiophen-2-yl-1H-pyrazole-3-carbonyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.61 (d, J=6.9 Hz, 3H), 2.41-2.75 (m, 2H), 3.68-4.25 (m, 8H), 4.42-4.93 (m, 2H), 5.13-5.34 (m, 1H), 5.70 (d, J=7.5 Hz, 1H), 6.66-6.88 (m, 1H), 7.03-7.23 (m, 2H), 7.34-7.52 (m, 3H), 7.61 (d, J=8.2 Hz, 2H).

Example 2465
Synthesis of 3-methoxy-6-(4-methyl-4H-furo[3,2-b]pyrrole-5-carbonyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Pale yellow amorphous

¹H-NMR (CDCl₃) δ ppm: 1.61 (d, J=7.0 Hz, 3H), 2.44-2.70 (m, 2H), 3.71-3.99 (m, 5H), 4.05 (s, 3H), 4.43-4.73 (m, 2H), 5.17-5.34 (m, 1H), 5.73 (d, J=7.7 Hz, 1H), 6.34 (s, 1H), 6.40-6.48 (m, 1H), 7.43 (d, J=2.2 Hz, 1H), 7.48 (d, J=8.3 Hz, 2H), 7.62 (d, J=8.3 Hz, 2H).

Example 2466
Synthesis of 3-(3-butynyl)-6-(4-fluorobenzoyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 2, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.58 (d, J=6.9 Hz, 3H), 1.98 (t, J=2.6 Hz, 1H), 2.30-2.79 (m, 4H), 3.34-4.70 (m, 6H), 5.16-5.37 (m, 1H), 5.53 (d, J=5.9 Hz, 1H), 7.07 (d, J=8.6 Hz, 1H), 7.10 (d, J=8.6 Hz, 1H), 7.34-7.54 (m, 4H), 7.60 (d, J=8.2 Hz, 2H).

Example 2467
Synthesis of 6-(4-chlorobenzoyl)-3-methoxy-2-[(S)-1-(4-methoxyphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one hydrochloride

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Using an appropriate starting material and following the procedure of Example 4, the object compound was synthesized.

White powder (ethanol-ether)

Melting Point 105-108° C.

Example 2468
Synthesis of 4-(2-{3-methoxy-4-oxo-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidin-6-yl}-2-oxo-ethoxy)benzonitrile

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.48-1.73 (m, 3H), 2.34-2.63 (m, 2H), 3.50-3.93 (m, 2H), 4.09 (s, 3H), 4.19-4.57 (m, 2H), 4.82 (s, 2H), 5.09-5.35 (m, 1H), 5.60-5.81 (m, 1H), 6.91-7.11 (m, 2H), 7.47 (d, J=7.9 Hz, 2H), 7.52-7.72 (m, 4H).

Example 2469
Synthesis of 4-[2-((S)-1-cyclohexylethylamino)-3-methoxy-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carbonyl]-3-fluorobenzonitrile

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 0.85-1.52 (m, 9H), 1.63-1.87 (m, 5H), 2.43-2.73 (m, 2H), 3.37-4.85 (m, 8H), 5.29 (d, J=9.0 Hz, 1H), 7.36-7.48 (m, 1H), 7.48-7.61 (m, 2H).

Example 2470
Synthesis of 6-(4-chlorobenzoyl)-2-((S)-1-cyclohexyl-ethylamino)-3-methoxy-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 2, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 0.85-1.52 (m, 9H), 1.53-1.92 (m, 5H), 2.35-2.79 (m, 2H), 3.38-4.14 (m, 6H), 4.16-4.73 (m, 2H), 5.28 (d, J=8.9 Hz, 1H), 7.29-7.51 (m, 4H).

Example 2471
Synthesis of 6-(4-chlorobenzoyl)-3-methoxy-2-[(R)-2-(4-trifluoromethylphenyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 2, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.77-2.23 (m, 3H), 2.23-2.75 (m, 3H), 3.39-4.07 (m, 7H), 4.12-4.67 (m, 2H), 5.26 (t, J=7.1 Hz, 1H), 7.30-7.46 (m, 6H), 7.56 (d, J=8.2 Hz, 2H).

Example 2472
Synthesis of 4-[2-((R)-1-cyclohexyl-ethylamino)-3-methoxy-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carbonyl]-3-fluorobenzonitrile

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 0.85-1.52 (m, 9H), 1.63-1.87 (m, 5H), 2.43-2.73 (m, 2H), 3.37-4.85 (m, 8H), 5.29 (d, J=9.0 Hz, 1H), 7.36-7.48 (m, 1H), 7.48-7.61 (m, 2H).

Example 2473
Synthesis of 6-(4-chlorobenzoyl)-2-(R)-1-cyclohexyl-ethylamino)-3-methoxy-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 2, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 0.85-1.52 (m, 9H), 1.53-1.92 (m, 5H), 2.35-2.79 (m, 2H), 3.38-4.14 (m, 6H), 4.16-4.73 (m, 2H), 5.28 (d, J=8.9 Hz, 1H), 7.29-7.51 (m, 4H).

Example 2474
Synthesis of 6-(benzo[b]thiophene-2-carbonyl)-3-methoxy-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

White solid

¹H-NMR (CDCl₃) δ ppm: 1.61 (d, J=7.0 Hz, 3H), 2.47-2.74 (m, 2H), 3.75-4.03 (m, 2H), 4.05 (s, 3H), 4.47-4.74 (m, 2H), 5.16-5.35 (m, 1H), 5.76 (d, J=7.7 Hz, 1H), 7.30-7.50 (m, 4H), 7.50-7.66 (m, 3H), 7.73-7.90 (m, 2H).

Example 2475
Synthesis of 6-(4-chlorobenzoyl)-3-methoxy-2-[2-(4-trifluoromethylphenyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 2, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.77-2.23 (m, 3H), 2.23-2.75 (m, 3H), 3.39-4.07 (m, 7H), 4.12-4.67 (m, 2H), 5.26 (t, J=7.1 Hz, 1H), 7.30-7.46 (m, 6H), 7.56 (d, J=8.2 Hz, 2H).

Example 2476
Synthesis of 3-{4-oxo-3-(2-propynyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carbonyl}benzonitrile

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.61 (d, J=6.6 Hz, 3H), 2.26-2.80 (m, 3H), 3.31-4.63 (m, 4H), 4.83 (brs, 2H), 5.18-5.43 (m, 2H), 7.34-7.80 (m, 8H).

Example 2477
Synthesis of 6-(4-chlorobenzoyl)-3-methoxy-2-(4-trifluoromethylbenzylamino)-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one hydrochloride

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Using an appropriate starting material and following the procedure of Example 2, the object compound was synthesized.

White powder (ethanol-ether)

Melting Point 109-112° C.

Example 2478
Synthesis of 6-(2,6-difluorobenzoyl)-3-(2-propynyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.50-1.70 (m, 3H), 2.33-2.77 (m, 3H), 3.39-3.59 (m, 1H), 3.72-3.91 (m, 1H), 4.01-4.27 (m, 2H), 4.43-4.95 (m, 2H), 5.19-5.45 (m, 2H), 6.79-7.01 (m, 2H), 7.27-7.45 (m, 1H), 7.45-7.56 (m, 2H), 7.56-7.78 (m, 2H).

Example 2479
Synthesis of 2-[(S)-1-(4-chlorophenyl)-2-methylpropylamino]-6-(2,3-dihydrobenzo[1,4]dioxine-6-carbonyl)-3-methoxy-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 0.87 (d, J=6.7 Hz, 3H), 1.03 (d, J=6.7 Hz, 3H), 1.99-2.20 (m, 1H), 2.33-2.72 (m, 2H), 3.46-3.95 (m, 2H), 4.04 (s, 3H), 4.15-4.58 (m, 5H), 4.77 (dd, J=8.3, 8.3 Hz, 1H), 5.73 (d, J=8.6 Hz, 1H), 6.89-7.03 (m, 4H), 7.10-7.38 (m, 4H).

Example 2480
Synthesis of 4-(2-{2-[(S)-1-(4-chlorophenyl)-2-methylpropylamino]-3-methoxy-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidin-6-yl}-2-oxo-ethoxy)benzonitrile

embedded image

Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 0.87 (d, J=6.7 Hz, 3H), 1.02 (d, J=6.7 Hz, 3H), 1.98-2.20 (m, 1H), 2.31-2.63 (m, 2H), 3.47-3.92 (m, 2H), 4.08 (s, 3H), 4.18-4.54 (m, 2H), 4.62-4.86 (m, 3H), 5.62-5.86 (m, 1H), 6.88-7.08 (m, 2H), 7.10-7.38 (m, 4H), 7.48-7.65 (m, 2H).

Example 2481
Synthesis of 2-[(S)-1-(4-chlorophenyl)-2-methylpropylamino]-6-(4-imidazol-1-ylbenzoyl)-3-methoxy-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

embedded image

Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 0.87 (d, J=6.7 Hz, 3H), 1.04 (d, J=6.7 Hz, 3H), 1.96-2.20 (m, 1H), 2.31-2.73 (m, 2H), 3.30-4.17 (m, 5H), 4.17-4.66 (m, 2H), 4.78 (dd, J=8.4, 8.4 Hz, 1H), 5.80 (d, J=8.6 Hz, 1H), 7.07-7.38 (m, 6H), 7.43 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H), 7.89 (s, 1H).

Example 2482
Synthesis of 3-fluoro-4-{3-methoxy-4-oxo-2-[(S)-1-(4-trifluoromethylphenyl)propylamino]-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carbonyl}benzonitrile

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 0.97 (t, J=7.3 Hz, 3H), 1.88-1.99 (m, 2H), 2.26-2.73 (m, 2H), 3.24-3.52 (m, 1H), 3.62-4.20 (m, 5H), 4.39-4.74 (m, 1H), 4.88-5.08 (m, 1H), 5.60-5.80 (m, 1H), 7.34-7.56 (m, 5H), 7.56-7.79 (m, 2H).

Example 2483
Synthesis of 2-[(S)-1-(4-chlorophenyl)-2-methylpropylamino]-3-methoxy-6-(pyrazolo[1,5-a]pyridine-2-carbonyl)-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

embedded image

Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 0.87 (d, J=6.7 Hz, 3H), 1.03 (d, J=6.7 Hz, 3H), 1.98-2.20 (m, 1H), 2.44-2.76 (m, 2H), 3.70-4.20 (m, 5H), 4.45-4.88 (m, 3H), 5.63-5.84 (m, 1H), 6.71-6.92 (m, 2H), 7.03-7.37 (m, 5H), 7.54 (d, J=8.7 Hz, 1H), 8.43 (d, J=6.7 Hz, 1H).

Example 2484
Synthesis of 3-dimethylamino-6-(2,4,6-trifluorobenzoyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one hydrochloride

embedded image

Using an appropriate starting material and following the procedure of Example 11, the object compound was synthesized.

White powder (ethanol-ether)

Melting Point 104-106° C.

Example 2485
Synthesis of 3-dimethylamino-6-(4-methylbenzoyl)-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one hydrochloride

embedded image

Using an appropriate starting material and following the procedure of Example 11, the object compound was synthesized.

White powder (ethanol-ether)

Melting Point 106-109° C.

Example 2486
Synthesis of 4-{3-(2-butynyl)-2-[(S)-1-(4-chlorophenyl)-2-methylpropylamino]-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carbonyl}-3-fluorobenzonitrile

embedded image

Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 0.91 (d, J=6.7 Hz, 3H), 1.03 (d, J=6.7 Hz, 3H), 1.70-1.90 (m, 3H), 1.90-2.21 (m, 1H), 2.21-2.77 (m, 2H), 3.20-4.28 (m, 3H), 4.38-4.97 (m, 4H), 5.66 (d, J=7.4 Hz, 1H), 7.12-7.35 (m, 4H), 7.35-7.58 (m, 3H).

Example 2487
Synthesis of 2-[(S)-1-(4-chlorophenyl)-2-methylpropylamino]-3-methoxy-6-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinoline-6-carbonyl)-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 0.87 (d, J=6.7 Hz, 3H), 1.04 (d, J=6.7 Hz, 3H), 2.00-2.18 (m, 1H), 2.39-2.73 (m, 4H), 2.80-3.00 (m, 2H), 3.37 (s, 3H), 3.50-4.20 (m, 5H), 4.20-4.63 (m, 2H), 4.77 (dd, J=8.4, 8.4 Hz, 1H), 5.75 (d, J=8.4 Hz, 1H), 6.97 (d, J=8.3 Hz, 1H), 7.21 (d, J=8.5 Hz, 2H), 7.24-7.41 (m, 4H).

Example 2488
Synthesis of 3-(2-butynyl)-6-(4-chlorobenzoyl)-2-[(S)-1-(4-chlorophenyl)-2-methylpropylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 2, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 0.91 (d, J=6.7 Hz, 3H), 1.03 (d, J=6.7 Hz, 3H), 1.83 (s, 3H), 2.00-2.20 (m, 1H), 2.28-2.78 (m, 2H), 3.27-4.61 (m, 4H), 4.79 (brs, 2H), 4.92 (dd, J=7.3, 7.3 Hz, 1H), 5.63 (d, J=7.2 Hz, 1H), 7.10-7.30 (m, 4H), 7.37 (s, 4H).

Example 2489
Synthesis of 2-[(S)-1-(4-chlorophenyl)-2-methylpropylamino]-6-(isoquinoline-3-carbonyl)-3-methoxy-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Pale yellow amorphous

¹H-NMR (CDCl₃) δ ppm: 0.89 (d, J=6.7 Hz, 3H), 1.05 (d, J=6.7 Hz, 3H), 1.97-2.22 (m, 1H), 2.47-2.80 (m, 2H), 3.56-4.20 (m, 5H), 4.30-4.70 (m, 2H), 4.80 (dd, J=8.3, 8.3 Hz, 1H), 5.58-5.84 (m, 1H), 7.10-7.39 (m, 4H), 7.58-7.80 (m, 2H), 7.80-8.18 (m, 3H), 9.25 (s, 1H).

Example 2490
Synthesis of 4-[2-(4-ethoxybenzylamino)-3-methoxy-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carbonyl]-3-fluorobenzonitrile

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.42 (t, J=7.0 Hz, 3H), 2.45-2.76 (m, 2H), 3.35-3.56 (m, 1H), 3.84-4.21 (m, 7H), 4.38-4.72 (m, 3H), 5.58-5.78 (m, 1H), 6.76-6.96 (m, 2H), 7.12-7.32 (m, 2H), 7.34-7.61 (m, 3H).

Example 2491
Synthesis of 6-(4-chlorobenzoyl)-2-(4-ethoxybenzylamino)-3-methoxy-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 2, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.42 (t, J=7.0 Hz, 3H), 2.67 (brs, 2H), 3.30-4.18 (m, 7H), 4.18-4.72 (m, 4H), 5.52-5.70 (m, 1H), 6.79-6.97 (m, 2H), 7.18-7.34 (m, 2H), 7.34-7.44 (m, 4H).

Example 2492
Synthesis of 4-(2-{2-[(S)-1-(4-chlorophenyl)-2-methylpropylamino]-3-methoxy-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidin-6-yl}-1,1-dimethyl-2-oxo-ethoxy)benzonitrile

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 0.86 (d, J=6.7 Hz, 3H), 1.03 (d, J=6.7 Hz, 3H), 1.68 (s, 6H), 1.97-2.20 (m, 1H), 2.20-2.52 (m, 2H), 3.35-3.76 (m, 1H), 3.86-4.16 (m, 4H), 4.16-4.39 (m, 1H), 4.43-4.74 (m, 2H), 5.59-5.78 (m, 1H), 6.88 (d, J=8.8 Hz, 2H), 7.18 (d, J=8.3 Hz, 2H), 7.21-7.59 (m, 4H).

Example 2493
Synthesis of 4-{3-(3-butynyl)-4-oxo-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carbonyl}benzoic acid methyl ester

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Using an appropriate starting material and following the procedure of Example 1, the object compound was synthesized.

Colorless amorphous

¹H-NMR (CDCl₃) δ ppm: 1.58 (d, J=6.9 Hz, 3H), 1.98 (s, 1H), 2.28-2.80 (m, 4H), 3.30-3.68 (m, 1H), 3.68-4.37 (m, 7H), 4.37-4.75 (m, 1H), 5.13-5.40 (m, 1H), 5.51 (d, J=5.9 Hz, 1H), 7.49 (d, J=8.2 Hz, 4H), 7.60 (d, J=8.2 Hz, 2H), 8.07 (d, J=7.8 Hz, 2H).

Example 2494
Synthesis of 4-{3-(3-butynyl)-4-oxo-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carbonyl}-N,N-dimethylbenzamide

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4-{3-(3-Butynyl)-4-oxo-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carbonyl}benzoic acid methyl ester (360 mg) was dissolved in MeOH (6 ml), and 5N NaOH solution (0.65 ml) was added. The reaction mixture was stirred at room temperature for 20 hr. The reaction mixture was acidified with aqueous ammonium chloride. The mixture was extracted with methylene chloride and ethyl acetate successively, and the organic layer was dried over sodium sulfate. The organic layer was filtrated and concentrated under reduced pressure to afford the crude acid (0.40 g). The crude acid was suspended in methylene chloride (12 ml), and to the suspension HOBT (0.15 g), WSC (0.19 g), dimethylamine hydrochloride (0.11 g) and triethylamine (0.18 ml) were added. The reaction mixture was stirred at room temperature for 12 hr. The reaction solution was quenched with aqueous NaHCO₃, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified medium-pressure silica gel column chromatography (solvent; ethyl acetate:hexane=2:3 to 0:100). The titled compound (0.24 g) was obtained as a colorless amorphous substance.

¹H-NMR (CDCl₃) δ ppm: 1.58 (d, J=6.9 Hz, 3H), 1.98 (s, 1H), 2.27-2.83 (m, 4H), 2.97 (s, 3H), 3.12 (s, 3H), 3.34-3.70 (m, 1H), 3.70-4.70 (m, 5H), 5.18-5.37 (m, 1H), 5.56 (d, J=6.1 Hz, 1H), 7.34-7.56 (m, 6H), 7.60 (d, J=8.2 Hz, 2H).

Example 2495
Synthesis of 2-[(S)-1-(4-chlorophenyl)ethylamino]-3-methoxy-6-(thieno[2,3-b]pyridine-2-carbonyl)-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one hydrochloride

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Using an appropriate starting material and following the procedure of Example 11, the object compound was synthesized.

White powder (ethanol-ether)

Melting Point 125-129° C.

Example 2496
Synthesis of 4-(2-{2-[(S)-1-(4-chlorophenyl)ethylamino]-3-methoxy-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidin-6-yl}-2-oxoethoxy)-benzonitrile hydrochloride

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Using an appropriate starting material and following the procedure of Example 11, the object compound was synthesized.

White powder (ethanol-ether)

Melting Point 102-105° C.

Example 2497
Synthesis of 6-(3-chloro-4-methylbenzoyl)-2-[(S)-1-(4-chlorophenyl)ethylamino]-3-methoxy-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one

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Using an appropriate starting material and following the procedure of Example 11, the object compound was synthesized.

White powder (ethanol-ether)

Melting Point 111-114° C.

Example 2498
Synthesis of 4-[2-(4-chlorobenzylamino)-3-dimethylamino-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carbonyl]-3-fluorobenzonitrile hydrochloride

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Using an appropriate starting material and following the procedure of Example 11, the object compound was synthesized.

White powder (ethanol-ether)

Melting Point 128-132° C.

Example 2499
Synthesis of 4-[2-(4-chloro-benzylamino)-3-dimethylamino-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carbonyl]-benzonitrile hydrochloride

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Using an appropriate starting material and following the procedure of Example 11, the object compound was synthesized.

White powder (ethanol-ether)

Melting Point 124-127° C.

Example 2500
Synthesis of 2-[(S)-1-(4-chlorophenyl)ethylamino]-3-dimethylamino-6-(2,4,6-trifluorobenzoyl)-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one hydrochloride

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Using an appropriate starting material and following the procedure of Example 11, the object compound was synthesized.

White powder (ethanol-ether)

Melting Point 113-117° C.

Example 2501
Synthesis of 4-{2-[(S)-1-(4-chlorophenyl)ethylamino]-3-dimethylamino-4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carbonyl}-3-fluorobenzonitrile hydrochloride

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Using an appropriate starting material and following the procedure of Example 11, the object compound was synthesized.

White powder (ethanol-ether)

Melting Point 122-126° C.

Example 2502
Synthesis of 4-[3-dimethylamino-4-oxo-2-(4-trifluoromethylbenzylamino)-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carbonyl]-3-fluorobenzonitrile hydrochloride

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Using an appropriate starting material and following the procedure of Example 11, the object compound was synthesized.

White powder (ethanol-ether)

Melting Point 127-130° C.

Example 2503
Synthesis of 4-[3-dimethylamino-4-oxo-2-(4-trifluoromethylbenzylamino)-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6-carbonyl]benzonitrile hydrochloride

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Using an appropriate starting material and following the procedure of Example 11, the object compound was synthesized.

White powder (ethanol-ether)

Melting Point 127-131° C.

Example 2504
Synthesis of 3-dimethylamino-6-(2,4,6-trifluorobenzoyl)-2-(4-trifluoromethylbenzylamino)-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one hydrochloride

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Using an appropriate starting material and following the procedure of Example 11, the object compound was synthesized.

White powder (ethanol-ether)

Melting Point 119-121° C.

Example 2505
Synthesis of 6-(4-chlorobenzoyl)-2-{[(4-chlorophenyl)cyclopropyl-methyl]amino}-3-dimethylamino-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one hydrochloride

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Using an appropriate starting material and following the procedure of Example 4, the object compound was synthesized.

White powder (ethanol-ether)

Melting Point 115-119° C.

Example 2506
Synthesis of 6-(4-chlorobenzoyl)-3-pyrrolidin-1-yl-2-[(S)-1-(4-trifluoromethylphenyl)ethylamino]-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one hydrochloride

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Using an appropriate starting material and following the procedure of Example 4, the object compound was synthesized.

White powder (ethanol-ether)

Melting Point 110-113° C.

Example 2507
Synthesis of 6-(4-chlorobenzoyl)-2-[(S)-1-(4-chlorophenyl)ethylamino]-3-pyrrolidin-1-yl-5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one hydrochloride

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Using an appropriate starting material and following the procedure of Example 4, the object compound was synthesized.

White powder (ethanol-ether)

Melting Point 106-110° C.

Pharmacological Study 1

Inhibitory Activity on Binding of [³H]-PrRP to GPR10

Human GPR10 receptor expressing human embryonic kidney cells, HEK 293 cells, were cultured in Dulbecco's Modified Eagle's medium supplemented with 10% fetal bovine serum and 1% penicilline-streptmycin at 37° C., in 5% carbon dioxide gas conditions. The medium was removed and the cells were recovered in a phosphate buffer to prepare a cell suspension. The cell suspension was homogenated on ice by an ultrasonic cell homogenizer (Microson™ type XL200) and centrifuged at 40,000 g for 10 minutes at 4° C. After the supernatant was discarded, Buffer A (20 mM HEPES, 10 mM EDTA, 1 μl/ml protease inhibiting cocktail, pH 7.4) was added to the pellet. The pellet was suspended by the ultrasonic cell homogenizer, then the suspension was centrifuged at 40,000 g, for 10 minutes at 4° C. After this operation was repeated once again, the supernatant was discarded, Buffer B (20 mM HEPES, 0.1 mM EDTA, pH 7.4) was added to the pellet, and the pellet was suspended by the ultrasonic homogenizer. This was stored at a freezer of −80° C. as a cell membrane fraction until use in a binding test.

Receptor-expressing HEK 293 cell membrane fraction was analyzed by modifying the methods of C. J. Langmead et al. (see Langmead C J, Szekeres P G; Chambers J K, Ratcliffe S J, Jones D N C, Hirst W D, et al. Characterization of the binding of [¹²⁵1]-human prolactin releasing peptide (PrRP) to GPR10, a novel G protein coupled receptor. Br J Pharmacol 2000; 131: 683-688.). To each well of a 96-well plate, 150 μl of assay buffer (20 mM HEPES, 10 mM EDTA, 1 μl/ml protease inhibiting agent cocktail, pH 7.4), 20 μl of cell membrane fraction, 10 μl of test compound and [³H]-PrRP (final concentration 1 nM) were added and incubated at room temperature for 90 minutes. After completion of the reaction, using a cell harvester, the cell-membrane fraction sample product was filtered under aspiration by a glass fiber filter plate (Unifilter; GF/B) previously treated with 0.5% polyethylene imine. The filter was washed with a 50 mM Tris hydrochloric acid buffer (pH 7.4) three times. After the filter was dried in a dryer (50° C.) for about 3 hours, 40 μl of liquid scintillation cocktail (MicroScint-O) was added to each well and radio activity was measured by a scintillation counter (Packard Topcount). The radio activity in the presence of an excessive amount of non-labeled PrRP (final concentration: 100 nM) was regarded as non-specific binding.

The binding inhibition rate was calculated based on calculating formula:

100−(radio activity when a compound is added−radio activity of non-specific binding)÷(radio activity when a solvent is added−radio activity of non-specific binding)×100.

An IC₅₀value was calculated based on the concentration dependent reaction using a non-linear analysis program and a Ki value was calculated using Cheng-Prussoff formula.

The results are shown in Table 146.

TABLE 146

Results of pharmacological Test 1

Test Compounds
Ki value (nM)

Compound of Example 1
5

Compound of Example 2
29

Compound of Example 3
42

Compound of Example 5
8

Compound of Example 6
17

Compound of Example 8
25

Compound of Example 9
28

Compound of Example 10
17

Compound of Example 11
15

Compound of Example 63
16

Compound of Example 86
25

Compound of Example 92
11

Compound of Example 95
5

Compound of Example 104
20

Compound of Example 121
17

Compound of Example 163
10

Compound of Example 166
6

Compound of Example 2386
2

Compound of Example 2389
8

Compound of Example 2390
8

Compound of Example 2391
134

Compound of Example 2392
12

Compound of Example 2396
20

Compound of Example 2402
6

Compound of Example 2403
12

Compound of Example 2404
10

Compound of Example 2405
15

Compound of Example 2406
2

Compound of Example 2407
8

Compound of Example 2409
16

Compound of Example 2410
10

Compound of Example 2411
20

Compound of Example 2412
8

Compound of Example 2414
18

Compound of Example 2415
9

Compound of Example 2416
33

Compound of Example 2417
17

Compound of Example 2418
8

Compound of Example 2419
7

Compound of Example 2421
44

Compound of Example 2430
15

Compound of Example 2431
207

Compound of Example 2432
36

Compound of Example 2433
5

Compound of Example 2434
9

Compound of Example 2435
2

Compound of Example 2438
26

Compound of Example 2441
37

Compound of Example 2442
140

Compound of Example 2443
41

Compound of Example 2444
42

Compound of Example 2446
28

Compound of Example 2447
41

Compound of Example 2448
23

Compound of Example 2449
24

Compound of Example 2450
121

Compound of Example 2451
9

Compound of Example 2452
4

Compound of Example 2454
48

Compound of Example 2456
6

Compound of Example 2457
8

Compound of Example 2458
245

Compound of Example 2459
10

Compound of Example 2460
14

Compound of Example 2461
16

Compound of Example 2462
98

Compound of Example 2463
3

Compound of Example 2464
20

Compound of Example 2465
10

Compound of Example 2468
6

Compound of Example 2469
56

Compound of Example 2470
108

Compound of Example 2472
61

Compound of Example 2474
15

Compound of Example 2475
34

Compound of Example 2476
9

Compound of Example 2477
39

Compound of Example 2478
9

Compound of Example 2479
42

Compound of Example 2481
31

Compound of Example 2482
8

Compound of Example 2483
13

Compound of Example 2484
6

Compound of Example 2487
24

Compound of Example 2489
26

Compound of Example 2490
237

Compound of Example 2494
201

Compound of Example 2495
3

Pharmacological Test 2
Antagonistic Activity on GPR10 Using Human GPR10-Expressing HEK293 Cells.

Antagonistic activity of test compounds on PrRP-induced intracellular calcium mobilization was evaluated using GPR10-expressing HEK293 cells.

HEK293 cells expressing human GPR10 were maintained in Dulbecco's Modified Eagles' medium supplemented with 10% fetal bovine serum, 1% penicillin-streptomycin and 20 mM HEPES at 37° C. in a 5% CO₂incubator. GPR10-expressing HEK293 cells were placed in poly-D-lysine coated 96-well culture plates and cultured for 18-24 hr before the test at a density of 3×10⁴cells/well. The cells were incubated with 2.5 nM Fluo-8 for 1 hr at room temperature in Recording Buffer containing 1% bovine serum albumin, 0.01% pluronic F-127 and 20 mM HEPES, Hanks Balanced Buffered Saline, pH 7.4. The cells were incubated with test compounds for 15 min at room temperature, and then PrRP (the final concentration, 1 nM) was added into the medium. The changes in intracellular calcium-dependent fluorescence were monitored using a fluorescence imaging plate reader (FDSS3000, Hamamatsu Photonics K.K.). Fluo-8 fluorescence was measured with excitation at 490 nm and emission at 520 nm. The calcium-dependent fluorescence intensity was calculated by subtracting basal intensity (average intensity for 30 sec before agonist stimulation) from peak intensity for 60 sec after PrRP-stimulation, and then IC₅₀values were determined by nonlinear curve-fitting program, GraphPad Prism 5.

The test compounds were proved from the values of IC₅₀that they have the antagonist activity to GPR10 receptor.

The results are shown in Table 147.

TABLE 147

Results of pharmacological Test 2

Test Compounds
IC₅₀(nM)

Compound of Example 1
42

Compound of Example 2
378

Compound of Example 3
1722

Compound of Example 5
46

Compound of Example 6
187

Compound of Example 8
253

Compound of Example 9
204

Compound of Example 10
140

Compound of Example 11
34

Compound of Example 63
686

Compound of Example 86
3710

Compound of Example 92
156

Compound of Example 95
227

Compound of Example 104
158

Compound of Example 121
1684

Compound of Example 163
648

Compound of Example 166
298

Compound of Example 2386
140

Compound of Example 2389
678

Compound of Example 2390
1140

Compound of Example 2391
3896

Compound of Example 2392
5793

Compound of Example 2396
2225

Compound of Example 2402
99

Compound of Example 2403
824

Compound of Example 2404
1128

Compound of Example 2405
8793

Compound of Example 2406
78

Compound of Example 2407
207

Compound of Example 2409
2440

Compound of Example 2410
665

Compound of Example 2411
776

Compound of Example 2412
259

Compound of Example 2417
780

Compound of Example 2418
286

Compound of Example 2419
228

Compound of Example 2421
1570

Compound of Example 2430
1183

Compound of Example 2431
3600

Compound of Example 2432
238

Compound of Example 2433
62

Compound of Example 2435
68

Compound of Example 2441
4494

Compound of Example 2446
2794

Compound of Example 2449
3350

Compound of Example 2451
1285

Compound of Example 2452
1031

Compound of Example 2463
187

Compound of Example 2484
216

Pharmacological Test 3
Inhibition Activity of Restraint Stress-Induced Rat Defecation.

Male Wistar rats (8-10 week old, Japan SLC Co., Ltd.) were used for the test. Rats were housed n several groups, five in each group, under a 12 h light-dark cycle (lights on from 07:00-19:00), with free access to food and water in the house cages. All experiments were carried out in a soundproof room. The rats were transported to a soundproof room for adaptation at least 1 hour before the experiment. Restraint stress-induced defecation test was conducted using a modified method described by K. Miyata et al (Keiji Miyata, Takeshi Kamato, Akito Nishida, Hiroyuki Ito, Hidenobu Yuki, Mayumi Yamano, et al. Role of the serotonin3 receptor in stress-induced defecation. J of Pharmacology and Experimental Therapeutics. 1992; 261 (1); 297-303.). The rats were stressed by placing them in individual compartments of stainless resistant cage (Natsume Seisakusho Co., Ltd.; KN-468, W265×L95×H200 mm) for 1 hr. Test compounds were freshly prepared by suspending in 5% arabic gum/saline using an agate morter, and orally administered (5 mL/kg body weight) 1 or 2 hr prior to resistant stimulus. Fecal pellet induced by restraint stress was collected and counted. The inhibition rate of test compounds (%) was calculated as 1−(stools in test group−average number of stools in vehicle group)×100.

The test compounds were confirmed that they had the inhibition activity for the restraint stress-induced rat defecation.

Pharmacological Test 4
Inhibition Activity of Tail-Pinch Stress-Induced Feeding Behavior in Rat

Male Wistar rats (7-9 week old, Japan SLC Co., Ltd.) were used for the test. Rats were housed in several groups, five in each groups, under a 12 h light-dark cycle (lights on from 07:00-19:00), with free access to food and water in the home cages. All experiments were conducted in a soundproof room. The rats were transported to a soundproof room for adaptation at least 1 hour before the experiment. Tail-pinch-induced feeding behavior test was conducted using a partly modified methods described by D. A. Czech et al (D. A. Czech, A. E. Klosterman and K. T. Le Sueur, NG-nitro-L-arginine methyl ester reduces stress-related feeding in the rat tail-pinch model. Pharmacology Biochemistry and Behavior, 60 (1), pp 91-96, 1998). Pre-weighed pelleted foods (Oriental Yeast Co., Ltd., CRF-1) were generously scattered on the floor, and the rats were then gently placed into the center of the cage individually. Tail of the rat was hold with urethane pad, and the tail-pinch stimulus was then applied for 5-10 min with the constant pressure at 3 cm from the tip of the tail by the pressure stimulus control system (Yamashita Technology Science Co., Ltd.).

At the end of the test, the rat was removed from the cage and then all remaining food was weighed. Amount of food intake was calculated by subtracting the food weight from pre-weighed food in each cage.

Test compounds were freshly prepared by suspending in 5% arabic gum/water, and orally administered (5 mL/kg body weight) 1 or 2 hr prior to tail-pinch stimulus.

The test compounds were confirmed that they have the inhibition activity for the tail-pinch stress-induced feeding behavior in rat.

HETEROCYCLIC COMPOUNDS FOR THE TREATMENT OF STRESS-RELATED CONDITIONS

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