GLYCINE COMPOUND

TECHNICAL FIELD

The present invention relates to a glycine compound which is useful as an active ingredient of a pharmaceutical composition, in particular, a pharmaceutical composition for preventing and/or treating vascular adhesion protein-1 (which will be hereinafter abbreviated as VAP-1)-related diseases.

BACKGROUND ART

VAP-1 is an amine oxidase (semicarbazide sensitive amine oxidase, SSAO) which is abundant in human plasma (Non-Patent Document 1), and shows remarkably increased expression in vascular endothelium and vascular smooth muscle of the inflammatory region. While the physiological role of VAP-1 has not been clarified until recently, VAP-1 gene was cloned in 1998, and VAP-1 has been reported to be a membrane protein that regulates rolling and migration of lymphocytes and NK cells as an adhesion molecule under regulation of expression by inflammatory cytokines. Although the amine as a substrate is unknown, it is considered to be methylamine generated in any part of biological body. It is also known that hydrogen peroxide and aldehydes produced due to the amine oxidase activity in the molecule are important factors of adhesion activity.

A recent report has documented that the VAP-1 enzyme activity in plasma increases in patients with diabetes mellitus, whether type I or type II, and the increase is particularly remarkable in the patients with diabetes mellitus suffering from retinopathy complications (Non-Patent Documents 2 and 3).

In addition, it has been reported that VAP-1 is related to the following diseases:

(1) cirrhosis, essential stabilized hypertension, diabetes mellitus, and arthrosis (Patent Documents 1 and 2);

(2) endothelium damage (in diabetes mellitus, arteriosclerosis, and hypertension), cardiovascular diseases related to diabetes mellitus and uremia, pain related to gout and arthritis, and retinopathy (in diabetes mellitus patients) (Patent Document 3);

(3) (connective tissue) inflammatory diseases or conditions (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and osteoarthritis or degenerative joint disease, Reiter's syndrome, Sjogren's syndrome, Behcet's syndrome, relapsing polychondritis, systemic lupus erythematosus, discoid lupus erythematosus, systemic sclerosis, eosinophilic fasciitis, polymyositis, dermatomyositis, polymyalgia rheumatica, vasculitis, temporal arteritis, polyarteritis nodosa, Wegener's granulomatosis, mixed connective tissue disease, and juvenile rheumatoid arthritis); gastrointestinal inflammatory diseases or conditions [Crohn's disease, ulcerative colitis, irritable bowel syndrome (spastic colon), fibrotic conditions of the liver, inflammation of the oral mucosa (stomatitis), and recurrent aphtous stomatitis]; central nervous system inflammatory diseases or conditions (multiple sclerosis, Alzheimer's disease, and ischemia-reperfusion injury related to ischemic stroke); pulmonary inflammatory diseases or conditions (asthma, adult respiratory distress syndrome, and chronic obstructive pulmonary disease); (chronic) skin inflammatory diseases or conditions (psoriasis, allergic lesions, lichen planus, pityriasis rosea, contact dermatitis, atopic dermatitis, and pityriasis rubra pilaris); diseases related to carbohydrate metabolism (diabetes mellitus and complications from diabetes mellitus) including microvascular and macrovascular diseases (arteriosclerosis, vascular retinopathies, retinopathy, nephropathy, nephrotic syndrome and neuropathy (polyneuropathy, mononeuropathies and autonomic neuropathy), foot ulcers, joint problems, and increased risk of infection); diseases related to aberrations in adipocyte differentiation or function or smooth muscle cell function (arteriosclerosis and obesity); vascular diseases [atheromatous arteriosclerosis, nonatheromatous arteriosclerosis, ischemic heart disease including myocardial infarction and peripheral arterial occlusion, Raynaud's disease and phenomenon, and thromboangiitis obliterans (Buerger's disease)]; chronic arthritis; inflammatory bowel diseases; and skin dermatoses (Patent Documents 4, 5, and 6, and Non-Patent Documents 4 and 5);

(4) diabetes mellitus (Patent Document 7);

(5) SSAO-mediated complications [diabetes mellitus (insulin dependent diabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus (NIDDM)) and vascular complications (heart attack, angina, strokes, amputations, blindness, and renal insufficiency)], and macular edema (for example, diabetic and non-diabetic macular edema) (Patent Documents 8 and 11); and

(6) hepatitis, transplantation, and the like.

Under the present circumstances, a drug for treating or preventing the above diseases has been demanded.

Furthermore, Patent Document 9 discloses that a compound represented by the formula (A) has a VAP-1 inhibitory activity.

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In addition, Patent Document 10 discloses that a compound represented by the formula (B) has a VAP-1 inhibitory activity.

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RELATED ART
Patent Document

[Patent Document 1] JP-A-61-239891

[Patent Document 2] U.S. Pat. No. 4,888,283

[Patent Document 3] Pamphlet of International Publication WO 93/23023

[Patent Document 4] Pamphlet of International Publication WO 02/02090

[Patent Document 5] Pamphlet of International Publication WO 02/02541

[Patent Document 6] U.S. Unexamined Patent Application Publication No. 2002/0173521

[Patent Document 7] Pamphlet of International Publication WO 02/38152

[Patent Document 8] Pamphlet of International Publication WO 02/38153

[Patent Document 9] Pamphlet of International Publication WO 05/082343

[Patent Document 10] Pamphlet of International Publication WO 09/055,002

[Patent Document 11] Pamphlet of International Publication WO 04/067521

Non-Patent Document

[Non-Patent Document 1] J Neural Transm, Vol. 114, pp. 747-749, 2007

[Non-Patent Document 2] Diabetologia, Vol. 42, pp. 233-237, 1999

[Non-Patent Document 3] Diabetic Medicine, Vol. 16, pp. 514-521, 1999

[Non-Patent Document 4] Diabetologia, Vol. 40, pp. 1243-1250, 1997

[Non-Patent Document 5] J Neural Transm, Vol. 114, pp. 841-843, 2007

DISCLOSURE OF INVENTION
Technical Problem
Problems to Be Solved by the Invention

The present invention provides a compound which is useful as an active ingredient of a pharmaceutical composition, in particular, a pharmaceutical composition for preventing and/or treating VAP-1-related diseases.

Means for Solving the Problems

The present inventors have conducted intensive studies on a compound having a VAP-1 inhibitory activity, and as a result, they have found that a compound of the formula (I) or a salt thereof exhibits an excellent VAP-1 inhibitory activity and is useful for preventing and/or treating VAP-1-related diseases, in particular, diabetic nephropathy or diabetic macular edema, thereby completing the present invention.

That is, the present invention relates to the compound of the formula (I) or a salt thereof, and a pharmaceutical composition comprising the compound of the formula (I) or a salt thereof, and an excipient.

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(wherein

R¹is H or lower alkyl which may be substituted,

R²is halogen,

R³and R⁴are the same as or different from each other, and are H or halogen,

m is 0, 1, 2, 3, or 4,

Y¹and Y²are the same as or different from each other, and are N or CR^Y,

R^Yis H or halogen,

X is H, halogen, Z—(CR¹¹R¹²)_n—, R¹³R¹⁴N—SO₂—, or lower alkenyl which may be substituted,

n is 0 or 1,

R¹¹and R¹²are the same as or different from each other, and are H, or R¹¹and R¹²are combined together to form oxo (═O),

R¹³and R¹⁴are the same as or different from each other, and are H or lower alkyl,

Z is R^Z1R^Z2N—, R^Z3O—, or

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R^Z1and R^Z2are the same as or different from each other, and are H, —C(═O)—R^Z11, —C(═O)—O—R^Z11, —C(═O)—NH₂, —C(═O)—NHR^Z11, —C(═O)—N(R^Z11)₂, —SO₂— (lower alkyl which may be substituted), —SO₂— (aryl which may be substituted), lower alkyl which may be substituted, or a hetero ring group which may be substituted,

R^Z11's are the same as or different from each other, and are lower alkyl which may be substituted, cycloalkyl which may be substituted, or a hetero ring group which may be substituted,

R^Z3is lower alkyl which may be substituted or a hetero ring group which may be substituted,

p is 0, 1, or 2,

q is 1 or 2,

E is CH or N,

G is CR^G1R^G2, NR^G3, O, or SO₂,

R^G1and R^G2are the same as or different from each other, and are H, OH, NH₂, —C(═O)—R^G31, —C(═O)—O—R^G31, —C(═O)—NHR^G31, —C(═O)—N(R^G31)², —SO₂—R^G31, amino which may be substituted, or lower alkyl which may be substituted, cycloalkyl which may be substituted, aryl which may be substituted, or a hetero ring group which may be substituted,

R^G3is H, NH₂, —C(═O)—R^G31, —C(═O)—O—R^G31, —C(═O)—NHR^G31, —C(═O)—N(R^G31), —SO₂—R^G31, or lower alkyl which may be substituted, cycloalkyl which may be substituted, aryl which may be substituted, or a hetero ring group which may be substituted,

R^G31's are the same as or different from each other, and are lower alkyl which may be substituted, cycloalkyl which may be substituted, aryl which may be substituted, or a hetero ring group which may be substituted, and

R²¹, R²², R²³, R²⁴, R²⁵and R²⁶are the same as or different from each other, and are H, OH, halogen, NH₂, amino which may be substituted, or lower alkyl which may be substituted,

in which R^G1or R^G2may be combined with either R²¹or R²²to form a new bond, or

R^G1, R^G2, R²¹, and R²²may be combined together to form a nitrogen-containing hetero ring group which may be substituted, and

R^G3, R²¹, and R²²may be combined together to form a nitrogen-containing hetero ring group which may be substituted.)

Moreover, unless specified otherwise, in the case where the symbols of the chemical formulae in the present specification are also used in other chemical formulae, the same symbols denote the same meanings.

The present invention relates to a pharmaceutical composition comprising the compound of the formula (I) or a salt thereof, and an excipient.

Furthermore, the present invention relates to pharmaceutical composition, in particular, a pharmaceutical composition for preventing and/or treating VAP-1-related diseases, which includes the compound of the formula (I) or a salt thereof, and an excipient.

In addition, the present invention relates to use of the compound of the formula (I) or a salt thereof for the preparation of a pharmaceutical composition for preventing and/or treating VAP-1-related diseases, use of the compound of the formula (I) or a salt thereof for preventing and/or treating VAP-1-related diseases, the compound of the formula (I) or a salt thereof for preventing and/or treating VAP-1-related diseases, and a method for preventing and/or treating VAP-1-related diseases, including administering to a patient an effective amount of the compound of the formula (I) or a salt thereof.

Effects of the Invention

The compound of the formula (I) or a salt thereof has a VAP-1 inhibitory action, and can be used as an agent for preventing and/or treating VAP-1-related diseases.

Further, the VAP-1-related diseases refer to diseases selected from the group consisting of:

(1) cirrhosis, essential stabilized hypertension, diabetes mellitus, and arthrosis;

(4) diabetes mellitus;

(5) SSAO-mediated complications [diabetes mellitus (insulin dependent diabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus (NIDDM)) and vascular complications (heart attack, angina, strokes, amputations, blindness, and renal insufficiency)], macular edema (for example, diabetic and non-diabetic macular edema); and

(6) hepatitis, transplantation, and the like.

EMBODIMENTS FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.

In the present specification, the “lower alkyl” refers to linear or branched alkyl having 1 to 6 carbon atoms (which is hereinafter simply referred to as C_1-6), for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, or the like. In another embodiment, it is C_1-4alkyl, and in a still another embodiment, C_1-3alkyl.

The “lower alkenyl” refers to linear or branched C_2-6alkenyl, for example, vinyl, propenyl, butenyl, pentenyl, 1-methylvinyl, 1-methyl-2-propenyl, 1,3-butadienyl, 1,3-pentadienyl, or the like. In another embodiment, it is C_2-4alkenyl, and in a still embodiment, C_2-3alkenyl.

The “cycloalkyl” refers to a C_3-10saturated hydrocarbon ring group, which may have a bridge. It is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, or the like. In another embodiment, it is C_3-8cycloalkyl, and in a still another embodiment, C_3-6cycloalkyl.

The “aryl” refers to a C_6-14monocyclic to tricyclic aromatic hydrocarbon ring group, and includes a ring group fused with C_5-8cycloalkene at its double bond site. It is, for example, phenyl, naphthyl, 5-tetrahydronaphthyl, 4-indenyl, 1-fluorenyl, or the like. In an embodiment, it is phenyl.

The “hetero ring” means a ring group selected from i) a monocyclic 3- to 8-membered, and in another embodiment, 5- to 7-membered hetero ring, containing 1 to 4 hetero atoms selected from oxygen, sulfur, and nitrogen, and ii) a bi- to tricyclic hetero ring containing 1 to 5 hetero atoms selected from oxygen, sulfur, and nitrogen, formed by condensation with one or two rings in which the monocyclic hetero ring is selected from a monocyclic hetero ring, a benzene ring, C_5-8cycloalkane, and C_5-8cycloalkene. The ring atom, sulfur or nitrogen, may be oxidized to form an oxide or a dioxide.

Examples of the “hetero ring group” include the following embodiments

(1) Monocyclic saturated hetero ring groups

(a) those containing 1 to 4 nitrogen atoms, for example, azepanyl, diazepanyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidyl, pyrazolidinyl, piperazinyl, azocanyl, hexamethyleneimino, homopiperazinyl, and the like;

(b) those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and/or 1 to 2 oxygen atoms, for example, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, morpholinyl, and the like;

(d) those containing 1 to 2 sulfur atoms and 1 to 2 oxygen atoms, for example, oxathiolanyl and the like;

(e) those containing 1 to 2 oxygen atoms, for example, oxiranyl, oxetanyl, dioxolanyl, tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl, and the like;

(2) Monocyclic unsaturated hetero ring groups

(a) those containing 1 to 4 nitrogen atoms, for example, pyrrolyl, 2-pyrrolinyl, imidazolyl, 2-imidazolinyl, pyrazolyl, 2-pyrazolinyl, pyridyl, dihydropyridyl, tetrahydropyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, triazinyl, dihydrotriazinyl, azepinyl, and the like;

(b) those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and/or 1 to 2 oxygen atoms, for example, thiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl, oxazinyl, and the like;

(c) those containing 1 to 2 sulfur atoms, for example, thienyl, thiepinyl, dihydrodithiopyranyl, dihydrodithionyl, 2H-thiopyranyl, and the like;

(d) those containing 1 to 2 sulfur atoms and 1 to 2 oxygen atoms, for example, dihydroxathiopyranyl and the like;

(e) those containing 1 to 2 oxygen atoms, for example, furyl, dihydrofuryl, pyranyl, 2H-pyranyl, oxepinyl, dioxolyl, and the like;

(3) Fused polycyclic saturated hetero ring groups

(a) those containing 1 to 5 nitrogen atoms, for example, quinuclidinyl, 7-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.2.2]nonanyl, and the like;

(b) those containing 1 to 4 nitrogen atoms and 1 to 3 sulfur atoms and/or 1 to 3 oxygen atoms, for example, trithiadiazaindenyl, dioxoloimidazolidinyl, and the like;

(c) those containing 1 to 3 sulfur atoms and/or 1 to 3 oxygen atoms, for example, 2,6-dioxabicyclo[3.2.2]oct-7-yl and the like;

(4) Fused polycyclic unsaturated hetero ring groups

(a) those containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolinyl, indolidinyl, benzoimidazolyl, dihydrobenzoimidazolyl, tetrahydrobenzoimidazolyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, indazolyl, imidazopyridyl, benzotriazolyl, tetrazolopyridazinyl, carbazolyl, acridinyl, quinoxalinyl, dihydroquinoxalinyl, tetrahydroquinoxalinyl, phthalazinyl, dihydroindazolyl, benzopyrimidinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pyridopyrrolidinyl, triazolopiperidinyl, 9,10-dihydroacridine, and the like;

(b) those containing 1 to 4 nitrogen atoms and 1 to 3 sulfur atoms and/or 1 to 3 oxygen atoms, for example, benzothiazolyl, dihydrobenzothiazolyl, benzothiadiazolyl, imidazothiazolyl, imidazothiadiazolyl, benzoxazolyl, dihydrobenzoxazolyl, dihydrobenzoxadinyl, benzoxadiazolyl, benzoisothiazolyl, benzoisoxazolyl, thiazolopiperidinyl, 5,6-dihydro-4H-pyrrolo[3,4-d][1,3]thiazol-2-yl, 10H-phenothiazine, and the like;

(c) those containing 1 to 3 sulfur atoms, for example, benzothienyl, benzodithiopyranyl, chromanyl, dibenzo[b,d]thienyl, and the like;

(d) those containing 1 to 3 sulfur atoms and 1 to 3 oxygen atoms, for example, benzoxathiopyranyl, phenoxazinyl, and the like;

(e) those containing 1 to 3 oxygen atoms, for example, benzodioxolyl, benzofuranyl, dihydrobenzofuranyl, isobenzofuranyl, chromanyl, chromenyl, isochromenyl, dibenzo[b,d]furanyl, methylenedioxyphenyl, ethylenedioxyphenyl, xanthenyl, and the like;

etc.

Further, the “hetero ring group” in (1) to (4) above is described as a monovalent group, but this may represent a divalent or higher group in some cases.

The “monocyclic hetero ring group” refers to a hetero ring group which has one ring structure not fused with other rings as in (1) and (2), among the “hetero ring groups above.

The “nitrogen-containing hetero ring group” refers to one containing at least one nitrogen atom, as in (1)(a), (1)(b), (2)(a), (2)(b), (3)(a), (3)(b), (4)(a), (4)(b), and the like, among the “hetero ring groups” above.

The expression “R^G1, R^G2, R²¹, and R²²are combined together to a form a nitrogen-containing hetero ring group” indicates that R^G1, R^G2, R²¹, and R²²are combined with carbon atoms to which they are bonded to form a nitrogen-containing hetero ring group.

Examples of the nitrogen-containing hetero ring group include:

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(wherein J represents S, O, or NH), and the like, and in another embodiment,

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The expression “R^G3, R²¹, and R²²are combined together to form a nitrogen-containing hetero ring group” indicates that R^G3, R²¹, and R²²are combined with carbon atoms and nitrogen atoms to which they are bonded to form a nitrogen-containing hetero ring group.

Examples of the nitrogen-containing hetero ring group include:

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(wherein J represents S, O, or NH), and the like, and in another embodiment,

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The expression “R^G1or R^G2may be combined with either R²¹or R²²to form a new bond” indicates that R^G1or R^G2of

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is combined with either R²¹or R²²to form a new bond, thereby forming a double bond,

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The “halogen” means F, Cl, Br, or I, and preferably F.

The expression “which may be substituted” represents non-substitution or substitution with 1 to 5 substituents”. Further, if it has a plurality of substituents, the substituents may be the same as or different from one other.

Examples of the substituents in “aryl which may be substituted”, “cycloalkyl which may be substituted”, and “hetero ring group which may be substituted” in R^G3include the groups shown in (a) to (j) below and oxo (═O); in another embodiment, the groups shown in (a) to (j) below; and in a still another embodiment, the groups shown in (a), (b), (d), (g), (f), and (j) below, and oxo (═O).

(a) halogen.

(b) —OH, —O-lower alkyl (in which the lower alkyl may be substituted with 1 to 3 OH, halogen, —O-lower alkyl (in which the lower alkyl may be substituted with one or more —COOH groups), or aryl groups).

(c) amino which may be substituted with one or more lower alkyl groups (in which the lower alkyl may be substituted with one or more aryl groups), or nitro.

(d) —CHO, —CO-lower alkyl (in which the lower alkyl may be substituted with 1 to 3 halogen atoms), —CO-cycloalkyl (in which cycloalkyl may be substituted with one or more —O-lower alkyl groups), —CO-aryl, a —CO-monocyclic saturated hetero ring group, or cyano.

(e) aryl or cycloalkyl; further, these groups may be substituted with 1 to 5 halogen atoms.

(f) a hetero ring group, and in another embodiment, a monocyclic hetero ring group; further, these hetero ring groups and monocyclic hetero ring groups may be substituted with halogen or lower alkyl (in which the lower alkyl may be substituted with one or more aryl groups).

(g) —COOH, —COO-lower alkyl (in which the lower alkyl may be substituted with 1 to 3 halogen atoms).

(h) —CONH₂, —CONH(lower alkyl) (in which the lower alkyl may be substituted with 1 to 3 halogen atoms), —CONH(lower alkyl)₂(in which the lower alkyl may be substituted with 1 to 3 halogen atoms).

(i) —O—CO-lower alkyl (in which the lower alkyl may be substituted with 1 to 3 halogen atoms or aryl groups), —O—CO—O-lower alkyl (in which the lower alkyl may be substituted with 1 to 3 halogen atoms).

(j) lower alkyl or lower alkenyl, which may be each substituted with one or more groups selected from the substituents shown in (a) to (i) above.

The substituents that can be used in the “lower alkyl which may be substituted” in R¹include the groups shown in (a) to (i) above and oxo (═O), and in another embodiment, the groups shown in (a) above.

The substituents that can be used in the “lower alkenyl which may be substituted” in X include the groups shown in (a) to (i) above and oxo (═O), and in another embodiment, the groups shown in (g) above.

The substituents that can be used in the “lower alkyl which may be substituted” in R^Z1and R^Z2include the groups shown in (a) to (i) above and oxo (═O), and in another embodiment, the groups shown in (a) and (b) above.

The substituents that can be used in the “aryl which may be substituted” in R^Z1and R^Z2include the groups shown in (a) to (j) above and oxo (═O), and in another embodiment, the groups shown in (a), (b), and (j) above.

The substituents that can be used in the “hetero ring group which may be substituted” in R^Z1and R^Z2include the groups shown in (a) to (j) above and oxo (═O), and in another embodiment, the groups shown in (j) above and oxo (═O).

The substituents that can be used in the “lower alkyl which may be substituted” in R^Z3include the groups shown in (a) to (i) above and oxo (═O), and in another embodiment, the groups shown in (a) and (b) above.

The substituents that can be used in the “hetero ring group which may be substituted” in R^Z3include the groups shown in (a) to (j) above and oxo (═O), and in another embodiment, the groups shown in (f) and (j) above and oxo (═O).

The substituents that can be used in the “lower alkyl which may be substituted” in R^Z1include the groups shown in (a) to (i) above and oxo (═O), and in another embodiment, the groups shown in (b), (c), (f), and (i) above.

The substituents that can be used in the “cycloalkyl which may be substituted” and the “hetero ring group which may be substituted” in R^Z11include the groups shown in (a) to (j) above and oxo (═O), and in another embodiment, the groups shown in (b), (c), (d), (f), (i), and (j) above and oxo (═O).

The substituents that can be used in the “lower alkyl which may be substituted” in R^G1and R^G2include the groups shown in (a) to (i) above and oxo (═O), and in another embodiment, the groups shown in (a), (b), (c), (g), and (i).

The substituents that can be used in the “amino which may be substituted” in R^G1and R^G2include the groups shown in (j) above.

The substituents that can be used in the “aryl which may be substituted” in R^G1and

R^G2include the groups shown in (a) to (j) above, and in another embodiment, the groups shown in (a), (b), (c), (f), (g), and (j).

The substituents that can be used in the “cycloalkyl which may be substituted”, the “hetero ring group which may be substituted”, “R^G1, R^G2, R²¹, and R²²which may be substituted are combined together to form a nitrogen-containing hetero ring group” and “R^G3, R²¹, and R²²which may be substituted are combined together to form a nitrogen-containing hetero ring group” in R^G1and R^G2include the groups shown in (a) to (j) above and oxo (═O), and in another embodiment, the groups shown in (a), (b), (c), (f), (g), and (j) and oxo (═O).

The substituents that can be used in the “lower alkyl which may be substituted” in R^G3include the groups shown in (a) to (i) above and oxo (═O), and in another embodiment, the groups shown in (a), (c), (b), and (f).

The substituents that can be used in the “lower alkyl which may be substituted” in R^G31include the groups shown in (a) to (i) above and oxo (═O), and in another embodiment, the groups shown in (a), (b), (d), and (g).

The substituents that can be used in the “aryl which may be substituted” in R^G31include the groups shown in (a) to (j) above, and in another embodiment, the groups shown in (a), (b), (d), (g), (f), and (j).

The substituents that can be used in the “cycloalkyl which may be substituted” and the “hetero ring group which may be substituted” in R^G31include the groups shown in (a) to (j) above and oxo (═O), and in another embodiment, the groups shown in (a), (b), (d), (g), (f), and (j), and oxo (═O).

The substituents that can be used in the “lower alkyl which may be substituted” in R²¹, R²², R²³, R²⁴, R²⁵, and R²⁶include the groups shown in (a) to (j) above and oxo (═O), and in another embodiment, the groups shown in (a), (b), (c), (g), and (j).

The substituents that can be used in the “amino which may be substituted” in R²¹, R²², R²³, R²⁴, R²⁵, and R²⁶include the groups shown in (j) above.

Embodiments of the compound (1) include the following compounds or salts thereof.

(1) The compound, wherein Y¹and Y²are both CR^Y, and R^Y's are both H.

(2) The compound, wherein Y¹and Y²are both N.

(3) The compound, wherein Y¹is N, Y²is CR^Y, and R^Yis H.

(4) The compound, wherein R¹is lower alkyl which may be substituted.

(5) The compound, wherein R¹is methyl, ethyl, propyl, or isopropyl.

(6) The compound, wherein X is Z—(CR¹¹R¹²)_n—, n is 0, and Z is

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(7) The compound as described in (6), wherein E is N, G is, CR^G1R^G2, O, or SO₂, p is 1, and q is 1 or 2.

(8) The compound, wherein X is Z—(CR¹¹R¹²)_n—, n is 0, Z is

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G is O or SO₂, and R²¹, R²², R²³, R²⁴, R²⁵, and R²⁶are the same as or different from each other, and are H or lower alkyl which may be substituted.

(9) The compound as described in (8), wherein G is O or SO₂, and R²¹, R²², R²³, R²⁴, R²⁵and R²⁶are the same as or different from each other, and are H, methyl, or hydroxymethyl.

(10) The compound, wherein X is Z—(CR¹¹R¹²)_n—, n is 0, Z is

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(11) The compound as described in (10), wherein R^G1and R^G2are the same as or different from each other, and are H, OH, or a hetero ring group which may be substituted,

- R²¹, R²², R²³, R²⁴, R²⁵, and R²⁶are H, or
- R^G1, R^G2, R²¹, and R²²are combined together to form a nitrogen-containing hetero ring group which may be substituted, and

R^G1or R^G2may be combined with either R²¹or R²²to form a new bond.

(12) The compound as described in (10), wherein R^G1and R^G2are the same as or different from each other, and are H, OH, or pyridine or morpholine which may be substituted,

R²¹, R²², R²³, R²⁴, R²⁵, and R²⁶are H or F, or

R^G1, R^G2, R²¹and R²²are combined together to form pyridine or thiazole which may be substituted, and

R^G1or R^G2may be combined with either R²¹or R²²to form a new bond.

(13) The compound as described in (10), wherein R^G1and R^G2are the same as or different from each other, and are H, OH, pyridin-3-yl or morpholin-4-yl, or, R^G1, R^G2, R²¹and R²²are combined with carbon atoms to which they are bonded to form

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and R²¹, R²², R²³, R²⁴, R²⁵and R²⁶are H or F.

(14) The compound as described in (6), wherein E is, N, G is NR^G3, p is 1, and q is 2.

(15) The compound as described in (6), wherein Z is

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R²¹, R²², R²³, R²⁴, R²⁵and R²⁶are H, Y⁴is N or CR^Y41, Y⁵is N or CR^Y51, R^Y41, R^Y51, and R^G32are H, halogen, —OH, —O-lower alkyl (in which the lower alkyl may be substituted with 1 to 3 OH, halogen, —O-lower alkyl (in which the lower alkyl may be substituted with one or more —COOH groups), or aryl groups), —CHO, —CO-lower alkyl (in which the lower alkyl may be substituted with 1 to 3 halogen atoms), —CO-cycloalkyl (in which cycloalkyl may be substituted with one or more —O-lower alkyl groups), —CO-aryl, a —CO-monocyclic saturated hetero ring group, cyano, —COOH, —COO-lower alkyl (in which the lower alkyl may be substituted with 1 to 3 halogen atoms), lower alkyl which may be substituted with —COOH or —O-lower alkyl (in which the lower alkyl may be substituted with one or more —COOH groups), or lower alkenyl which may be substituted with —COOH or —O-lower alkyl (in which the lower alkyl may be substituted with one or more —COOH groups), and s is 0, 1, 2, or 3.

(16) The compound as described in (6), wherein Z is

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R²¹, R²², R²³, R²⁴, R²⁵and R²⁶are H, and

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is 3-methylpyridin-2-yl, 5-(2-carboxyvinyl)-3-methyl-pyridin-2-yl, 5-(2-carboxyethyl)-3-methyl-pyridin-2-yl, 5-carboxy-3-chloro-pyridin-2-yl, 5-(2-carboxyvinyl)-3-chloro-pyridin-2-yl, 4-carboxy-6-chloro-phenyl, 6-cyanopyridin-3-yl, 2-methylpyridin-3-yl, or 3-chloro-pyridin-2-yl.

(17) The compound, wherein R³and R⁴are H.

(18) The compound, wherein m is 0.

Furthermore, other embodiments of the compound (1) of the present invention include the compounds or salts thereof including the combinations of two or more of the groups as described in (1) to (18), and specifically the following compounds or salts thereof.

(19) The compound as described in (6) to (9) and (14) to (16), wherein Y¹and Y²are both CR^Y, and R^Y's are both H.

(20) The compound as described in (19), wherein m is 0.

(21) The compound as described in (19), wherein R³and R⁴are H.

(22) The compound as described in (19), wherein R³and R⁴are H, and m is 0.

(23) The compound as described in (6) to (16), wherein Y¹and Y²are both N.

(24) The compound as described in (23), wherein m is 0.

(25) The compound as described in (23), wherein R³and R⁴are H.

(26) The compound as described in (23), wherein R³and R⁴are H, and m is 0.

(27) The compound as described in (6) to (9) and (14) to (16), wherein Y′ is N, Y²is CR^Y, and R^Yis H.

(28) The compound as described in (26), wherein m is 0.

(29) The compound as described in (26), wherein R³and R⁴are H.

(30) The compound as described in (26), wherein R³and R⁴are H, and m is O, Still further embodiments of the compound of the present invention are shown below.

(31) The compound as described in (6), wherein Z is

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R²¹, R²², R²³, R²⁴, R²⁵and R²⁶are H, Y⁴is N or CR^Y41, Y⁵is N or CR^Y51, R^Y41, R^Y51, and R^G32are H, halogen, —OH, —O-lower alkyl (in which the lower alkyl may be substituted with 1 to 3 OH, halogen, —O-lower alkyl (in which the lower alkyl may be substituted with one or more —COOH groups), or aryl groups), —CHO, —CO-lower alkyl (in which the lower alkyl may be substituted with 1 to 3 halogen atoms), —CO-cycloalkyl (in which cycloalkyl may be substituted with one or more —O-lower alkyl groups), —CO-aryl, a —CO-monocyclic saturated hetero ring group, cyano, —COOH, —COO-lower alkyl (in which the lower alkyl may be substituted with 1 to 3 halogen atoms), —NH₂, NH(lower alkyl), N(lower alkyl)₂, or lower alkyl which may be substituted with —COOH or —O-lower alkyl (in which the lower alkyl may be substituted with one or more —COOH groups), or lower alkenyl which may be substituted with —COOH or —O-lower alkyl (in which the lower alkyl may be substituted with one or more —COOH groups), and s is 0, 1, 2, or 3.

(32) The compound as described in (31), wherein Y⁴is N or CR^Y41, Y⁵is N or CR^Y51, R^Y41, R^Y51and R^G32are H, halogen, —COOH, lower alkyl, —O-lower alkyl, cyano, —COOH, —COO-lower alkyl, —NH₂, NH(lower alkyl), N(lower alkyl)₂, or lower alkyl which may be substituted with halogen, OH, —COOH, or —O-lower alkyl (in which the lower alkyl may be substituted with —COOH groups), or lower alkenyl which may be substituted with halogen, OH, —COOH, or —O-lower alkyl, and s is 0, 1, 2, or 3.

(33) The compound as described in (31), wherein Y⁴is N or CR^Y41, Y⁵is N or CR^Y51, R^Y41, R^Y51, and R^G32are H, F, Cl, Br, methyl, methoxy, —COOH, —NH₂, —N(CH₃)₂, ethoxycarbonyl, hydroxymethyl, 2-carboxyethyl, trifluoromethyl, carboxymethoxymethyl, or cyano.

(34) The compound as described in (6), wherein Z is

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R²¹, R²², R²³, R²⁴, R²⁵and R²⁶are H, and

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is phenyl, 4-aminophenyl, 4-dimethylaminophenyl, 4-carboxyphenyl, 4-carboxy-6-chloro-phenyl, 4-methylphenyl, 4-fluorophenyl, 4-chlorophenyl, 2-fluorophenyl, 2-methylphenyl, 2,4-difluorophenyl, 2-methoxyphenyl, 3-methylpyridin-2-yl, 3-trifluoromethylpyridin-2-yl, 3-cyano-6-methylpyridin-2-yl, 5-[(E)-2-carboxyvinyl]-3-methylpyridin-2-yl, 5-carboxy-3-chloropyridin-2-yl, 5-[(E)-2-carboxyvinyl]-3-chloropyridin-2-yl, 3-carboxymethoxymethylpyridin-2-yl, 5-(2-carboxyethyl)-3-methylpyridin-2-yl, 5-carboxypyridin-2-yl, pyridin-2-yl, 5-ethoxycarbonylpyridin-2-yl, 5-cyanopyridin-2-yl, 3-cyanopyridin-2-yl, 3-chloropyridin-2-yl, 5-trifluoromethylpyridin-2-yl, 3-fluoropyridin-2-yl, 5-fluoropyridin-2-yl, 5-chloropyridin-2-yl, 5-bromopyridin-2-yl, 3-methoxypyridin-2-yl, 3-hydroxymethylpyridin-2-yl, 5-methylpyridin-2-yl, 4-methylpyridin-2-yl, 5-carboxy-3-methylpyridin-2-yl, 6-methylpyridin-2-yl, 542-carboxyethyl)-3-hydroxymethylpyridin-2-yl, 5-[(E)-2-carboxyvinyl]-3-hydroxymethylpyridin-2-yl, 5-[(E)-2-carboxyvinyl]-pyridin-2-yl, 5-(2-carboxyethyl)pyridin-2-yl, 6-chloropyridin-3-yl, 4-methylpyridin-3-yl, 5-ethoxycarbonylpyridin-3-yl, 5-methylpyridin-3-yl, 2-methylpyridin-3-yl, pyridin-3-yl, 6-aminopyridin-3-yl, 5-chloropyridin-3-yl, 5-carboxypyridin-3-yl, or 6-cyanopyridin-3-yl, 6-chloropyrimidin-3-yl, or pyrimidin-3-yl.

(35) The compound as described in (31), wherein Y⁴is CR^Y41, Y⁵is CR^Y51, R^Y41, R^Y51, and R^G32are H, halogen, —COOH, lower alkyl, —O-lower alkyl, —COOH, —COO-lower alkyl, —NH₂, NH(lower alkyl), or N(lower alkyl)₂, and s is 0, 1, 2, or 3.

(36) The compound as described in (31), wherein Y⁴is CR^Y41, Y⁵is CR^Y51, R^Y41, R^Y51, and R^G32are H, F, Cl, methyl, methoxy, —COOH, —NH₂, or —N(CH₃)₂, and s is 0, 1, 2, or 3.

(37) The compound as described in (34), wherein

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(38) The compound as described in (31), wherein Y⁴is N, Y⁵is CR^Y51, R^Y51and R^G32are H, halogen, —O-lower alkyl (in which the lower alkyl may be substituted with 1 to 3 OH, halogen, —O-lower alkyl (in which the lower alkyl may be substituted with one or more —COOH groups), or aryl groups), cyano, —COOH, —COO-lower alkyl (in which the lower alkyl may be substituted with 1 to 3 halogen atoms), lower alkyl which may be substituted with halogen, OH, —COOH or —O-lower alkyl (in which the lower alkyl may be substituted with one or more —COOH groups), lower alkenyl which may be substituted with halogen, OH, —COOH or —O-lower alkyl (in which the lower alkyl may be substituted with one or more —COOH groups), and s is 0, 1, 2, or 3.

(39) The compound as described in (31), wherein Y⁴is N, Y⁵is CR^Y51, R^Y51and R^G32are H, halogen, —O-lower alkyl, cyano, —COOH, —COO-lower alkyl, lower alkyl which may be substituted with halogen, OH, —COOH, or —O-lower alkyl (in which the lower alkyl may be substituted with —COOH groups), or lower alkenyl which may be substituted with halogen, OH, —COOH, or —O-lower alkyl, and s is 0, 1, 2, or 3.

(40) The compound as described in (31), wherein Y⁴is N, Y⁵is CR^Y51, R^Y51and R^G32are H, F, Cl, Br, methoxy, cyano, —COOH, ethoxycarbonyl, hydroxymethyl, 2-carboxyethyl, trifluoromethyl, carboxymethoxymethyl, or 2-carboxyvinyl, and s is 0, 1, 2, or 3.

(41) The compound as described in (34), wherein

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is 3-methylpyridin-2-yl, 3-trifluoromethylpyridin-2-yl, 3-cyano-6-methylpyridin-2-yl, 5-[(E)-2-carboxyvinyl]-3-methylpyridin-2-yl, 5-carboxy-3-chloropyridin-2-yl, 5-[(E)-2-carboxyvinyl]-3-chloropyridin-2-yl, 3-carboxymethoxymethylpyridin-2-yl, 542-carboxyethyl)-3-methylpyridin-2-yl, 5-carboxypyridin-2-yl, pyridin-2-yl, 5-ethoxycarbonylpyridin-2-yl, 5-cyanopyridin-2-yl, 3-cyanopyridin-2-yl, 3-chloropyridin-2-yl, 5-trifluoromethylpyridin-2-yl, 3-fluoropyridin-2-yl, 5-fluoropyridin-2-yl, 5-chloropyridin-2-yl, 5-bromopyridin-2-yl, 3-methoxypyridin-2-yl, 3-hydroxymethylpyridin-2-yl, 5-methylpyridin-2-yl, 4-methylpyridin-2-yl, 5-carboxy-3-methylpyridin-2-yl, 6-methylpyridin-2-yl, 5-(2-carboxyethyl)-3-hydroxymethylpyridin-2-yl, 5-[(E)-2-carboxyvinyl]-3-hydroxymethylpyridin-2-yl, 5-[(E)-2-carboxyvinyl]-pyridin-2-yl, or 5-(2-carboxyethyl)pyridin-2-yl.

(42) The compound as described in (31), wherein Y⁴is CR^Y41, Y⁵is N, R^Y41and R^G32are H, halogen, cyano, —COOH, —COO-lower alkyl (in which the lower alkyl may be substituted with 1 to 3 halogen atoms), or lower alkyl which may be substituted with —COOH or —O-lower alkyl (in which the lower alkyl may be substituted with one or more —COOH groups), and s is 0, 1, 2, or 3.

(43) The compound as described in (31), wherein Y⁴is CR^Y41, Y⁵is N, R^Y41and R^G32are H, halogen, cyano, —COOH, —COO-lower alkyl, —NH₂, NH(lower alkyl), N(lower alkyl)₂, or lower alkyl, and s is 0, 1, 2, or 3.

(44) The compound as described in (31), wherein Y⁴is CR^Y41, Y⁵is N, R^Y41and R^G32are H, chloro, cyano, —COOH, ethoxycarbonyl, —NH₂, or methyl, and s is 0, 1, 2, or 3.

(45) The compound as described in (34), wherein

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is 6-chloropyridin-3-yl, 4-methylpyridin-3-yl, 5-ethoxycarbonylpyridin-3-yl, 5-methylpyridin-3-yl, 2-methylpyridin-3-yl, pyridin-3-yl, 6-aminopyridin-3-yl, 5-chloropyridin-3-yl, 5-carboxypyridin-3-yl, or 6-cyanopyridin-3-yl.

(46) The compound as described in (31), wherein Y⁴is N, Y⁵is N, R^G32is H, halogen, and s is 0, 1, 2, or 3.

(47) The compound as described in (31), wherein Y⁴is N, Y⁵is N, R^G32is H, Cl, and s is 0, 1, 2, or 3.

(48) The compound as described in (34), wherein

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is 6-chloropyrimidin-3-yl or pyrimidin-3-yl.

(49) The compound as described in (19) to (30), or (31) to (48), wherein R¹is lower alkyl which may be substituted.

(50) The compound as described in (19) to (30), or (31) to (48), wherein R¹is methyl, ethyl, propyl, or isopropyl.

(51) The compound as described in (31) to (50), wherein m is 0.

(52) The compound as described in (31) to (51), wherein R³and R⁴are H.

(53) The compound as described in (31) to (51), wherein R³and R⁴are H, and m is 0.

Specific examples of the compound included in the present invention include the following compounds or salts thereof.

N-methyl-N-[3-(2-morpholin-4-ylpyrimidin-5-yl)benzyl]glycinamide,
N-methyl-N-[3-(2-pyrrolidin-1-ylpyrimidin-5-yl)benzyl]glycinamide,
N-(3-{2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyrimidin-5-yl}benzyl)-N-methylglycinamide,
N-(3-{2-[2-(hydroxymethyl)morpholin-4-yl]pyrimidin-5-yl}benzyl)-N-methylglycinamide,
N-(3-{6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridin-3-yl}benzyl)-N-methylglycinamide,
N-{3-[2-(4-hydroxypiperidin-1-yl)pyrimidin-5-yl]benzyl}-N-methylglycinamide,
N-{3-[2-(1,1-dioxidothiomorpholin-4-yl)pyrimidin-5-yl]benzyl}-N-methylglycinamide,
N-methyl-N-{3-[2-(4-morpholin-4-yl-piperidin-1-yl)pyrimidin-5-yl]benzyl}glycinamide,
N-{3-[2-(3′,6′-dihydro-3,4′-bipyridin-1′ (2′H)-yl)pyrimidin-5-yl]benzyl}-N-methylglycinamide,
N-methyl-N-{3-[2-(4-pyridin-3-ylpiperidin-1-yl)pyrimidin-5-yl]benzyl}glycinamide,
N-methyl-N-(3-{2-[4-(3-methylpyridin-2-yl)piperazin-1-yl]pyrimidin-5-yl}benzyl)glycinamide,
(2E)-3-(6-{4-[5-(3-{[glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}-5-methylpyridin-3-yl)acrylic acid,
3-(6-{-4-[5-(3-{[glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}-5-methylpyridin-3-yl)propionic acid,
5-chloro-6-{4-[5-(3-{glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}nicotinic acid,
(2E)-3-(5-chloro-6-{-4-[5-(3-{[glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}pyridin-3-yl)acrylic acid,
3-chloro-4-{4-[5-(3-{[glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}benzoic acid,
N-(3-{2-[4-(6-cyanopyridin-3-yl)piperidin-1-yl]pyrimidin-5-yl}benzyl)-N-methylglycinamide,
N-methyl-N-(3-{2-[4-(2-methylpyridin-3-yl)piperidin-1-yl]pyrimidin-5-yl}benzyl)glycinamide,
N-(3-{2-[4-(3-chloropyridin-2-yl)piperazin-1-yl]pyrimidin-5-yl}benzyl)-N-methylglycinamide,
N-methyl-N-{3-[2-(2-methyl-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-5(4H)-yl)pyrimidin-5-yl]benzyl}glycinamide,
N-{3-[2-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)pyrimidin-5-yl]benzyl}-N-methylglycinamide, or
N-(3-{2-[(3S)-3-fluoropyrrolidin-1-yl]pyrimidin-5-yl}benzyl)-N-methylglycinamide.

The compound of the formula (I) may exist in the form of tautomers or geometrical isomers depending on the kind of substituents. In the present specification, the compound of the formula (I) shall be described in only one form of isomer, yet the present invention includes other isomers, isolated forms of the isomers, or a mixture thereof.

In addition, the compound of the formula (I) may have asymmetric carbon atoms or axial asymmetry in some cases, and correspondingly, it may exist in the form of optical isomers based thereon. The present invention includes both an isolated form of the optical isomers of the compound of the formula (I) or a mixture thereof.

Moreover, the present invention also includes a pharmaceutically acceptable prodrug of the compound represented by the formula (I). The pharmaceutically acceptable prodrug is a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like through solvolysis or under physiological conditions. Examples of the group forming the prodrug include the groups described in Prog. Med., 5, 2157-2161 (1985) and “Pharmaceutical Research and Development” (Hirokawa Publishing Company, 1990), Vol. 7, Drug Design, 163-198.

Furthermore, the salt of the compound of the formula (I) is a pharmaceutically acceptable salt of the compound of the formula (I) and may form an acid addition salt or a salt with a base depending on the kind of substituents. Specific examples thereof include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditolyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, and the like, and salts with inorganic bases such as sodium, potassium, magnesium, calcium, aluminum, and the like or organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, and the like, salts with various amino acids or amino acid derivatives such as acetylleucine and the like, ammonium salts, etc.

In addition, the present invention also includes various hydrates or solvates, and polymorphic crystalline substances of the compound of the formula (I) and a salt thereof. In addition, the present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.

(Preparation Methods)

The compound of the formula (I) and a salt thereof can be prepared using the characteristics based on the basic structure or the type of substituents thereof and by applying various known synthesis methods. During the preparation, replacing the relevant functional group with a suitable protective group (a group that can be easily converted into the relevant functional group) at the stage from starting material to an intermediate may be effective depending on the type of the functional group in the production technology in some cases. The protective group for such a functional group may include, for example, the protective groups described in “Greene's Protective Groups in Organic Synthesis (4^thEd., 2006)”, P. G. M. Wuts and T. W. Greene, and one of these may be selected and used as necessary depending on the reaction conditions. In this kind of method, a desired compound can be obtained by introducing the protective group, by carrying out the reaction and by eliminating the protective group as necessary.

In addition, the prodrug of the compound of the formula (I) can be prepared by introducing a specific group or by carrying out the reaction using the obtained compound of the formula (I) at the stage from a starting material to an intermediate, just as in the case of the above-mentioned protective group. The reaction can be carried out using methods known to those skilled in the art, such as ordinary esterification, amidation, dehydration, and the like.

Hereinbelow, the representative preparation methods for the compound of the formula (I) will be described. Each of the production processes may also be carried out with reference to the References appended in the present description. Further, the preparation methods of the present invention are not limited to the examples as shown below.

(Production Process 1)

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(wherein W represents a leaving group, and R^Protrepresents a protective group.)

When X is R^Z1R^Z2N—, R^Z3O—, or

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the compound (1a) of the present invention can be obtained by reaction of a compound (6) with X—H (7), followed by a deprotection reaction. Here, examples of the leaving group W include halogen, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a methoxy group, an ethoxy group, and the like, and examples of the protective group R^Protinclude a tert-butoxycarbonyl group, a benzyloxycarbonyl group, and the like.

First, the compound (8) can be obtained by the reaction of the compound (6) with X—H (7).

In this reaction, a mixture of the compound (6) and the compound (7) in an equivalent amount or in an excess amount is stirred in a range of from cooling to heating and refluxing, and preferably at 0° C. to 80° C., usually for 0.1 hours to 5 days in a solvent which is inert to the reaction or without a solvent. The solvent used herein is not particularly limited, but examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, N,N-dimethylformamide, dimethylsulfoxide, ethyl acetate, acetonitrile and a mixture thereof. It may be advantageous in some cases for the smooth progress of the reaction to carry out the reaction in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, and the like, or an inorganic base such as potassium carbonate, sodium carbonate, potassium hydroxide, and the like.

Furthermore, the reaction may be carried out using a catalyst which is not particularly limited, but includes catalysts used for an Ullmann reaction, a Buchwald-Hartwig reaction, or the like. The catalyst as used herein is not particularly limited, but a suitable combination of tris(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine) palladium, or the like with 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene (Xantphos), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos), and the like can be used.

Next, the deprotection reaction of the compound (8) can be carried out with reference to, for example, the method as described in “Greene's Protective Groups in Organic Synthesis (4^thedition, 2006)” above.

[Document]

Synthesis 2006, 4, 629-632

(Production Process 2)

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(wherein U represents a boric ester substituent.)

The compound (1) of the present invention can be obtained by the coupling reaction of a compound (4) with a compound (9), followed by a deprotection reaction.

The present reaction can be carried out under the same reaction condition as for the coupling reaction described in (Starting Material Synthesis 1) as described later.

(Production Process 3)

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The compound (8) can be obtained by the coupling reaction of a compound (3) with a compound (10), followed by a deprotection reaction.

The present reaction can be carried out under the same reaction condition as for the coupling reaction described in (Starting Material Synthesis 1) as described later.

(Starting Material Synthesis 1)

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(wherein P represents a leaving group.)

The compound (6) can be prepared by the compound (1). Herein, examples of the leaving group P include halogen, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and the like.

First, the compound (2) can be obtained by the reaction of the compound (1) with amines (11). The present reaction can be carried out under the same reaction condition for the preparation method (Production Process 1).

Next, the compound (3) can be obtained by the condensation reaction between the compound (2) and carboxylic acid (12).

In the case where the carboxylic acid (12) is used as the carboxylic acid derivative, the step is carried out by using the compound (2) with the carboxylic acid (12) in an equivalent amount or in an excess amount, and stirring the mixture thereof in a range of from cooling to heating, preferably at a temperature from −20° C. to 60° C., usually for about 0.1 hours to 5 days, in a solvent which is inert to the reaction, in the presence of a condensing agent. The solvent as used herein is not particularly limited, but examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and the like, DMF, DMSO, EtOAc, acetonitrile or water, and a mixture thereof. Examples of the condensing agent include, but are not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, dicyclohexylcarbodiimide, carbonyldiimidazole, diphenylphosphonyl azide, and phosphorus oxychloride. It may be sometimes preferable for the reaction to use an additive (for example, 1-hydroxybenzotriazole). It is sometimes advantageous for smooth progress of the reaction to carry out the reaction in the presence of organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, DBU, and the like, or inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide, and the like.

Furthermore, it is also possible to use a method in which a reactive derivative of the carboxylic acid (12) is used, and reacted with the compound (2). Examples of the reactive derivative of the carboxylic acid include acid halides that can be obtained by the reaction with a halogenating agent such as phosphorus oxychloride, thionyl chloride, and the like, mixed acid anhydrides that can be obtained by the reaction with isobutyl chloroformate or the like, active esters that can be obtained by condensation with 1-hydroxybenzotriazole or the like, etc. The reaction of the reactive derivative with the benzyl amine derivative (2) can be carried out in a range of from cooling to heating, and preferably from −20° C. to 60° C., in a solvent which is inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, and the like.

In addition, the compound (4) can be prepared by subjecting the compound (3) to a boronic acid esterification reaction.

In this reaction, a mixture of the compound (3) and a boric ester reagent in an equivalent amount or in an excess amount is stirred in a range of from cooling to heating, and preferably −20° C. to 60° C., in a solvent which is inert to the reaction, usually for 0.1 hours to 5 days, in the presence of an organic metal compound. The solvent as used herein is not particularly limited, but examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform, and the like, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and the like, DMF, DMSO, EtOAc, acetonitrile, or water, and a mixture thereof. Examples of the boronic acid esterification reagent include triisopropyl borate, tributyl borate, and the like. Examples of the organic metal compound used in the present reaction include organic lithium compounds such as n-butyl lithium and the like.

Next, the compound (6) can be obtained by subjecting the compound (4) to a coupling reaction.

In this reaction, a mixture of the compound (4) and the compound (5) in an equivalent amount or in an excess amount is stirred in a range of from cooling to heating under reflux, and preferably 0° C. to 80° C., in a solvent which is inert to the reaction or without a solvent, usually for 0.1 hours to 5 days. The solvent as used herein is not particularly limited, but examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, N,N-dimethylformamide, dimethylsulfoxide, ethyl acetate, acetonitrile and a mixture thereof. It is sometimes advantageous for smooth progress of the reaction to carry out the reaction in the presence of organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, and the like, or inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide, and the like.

Furthermore, the Suzuki-Miyaura cross-coupling reaction can also be carried out using, for example, a catalyst used for the Suzuki-Miyaura cross-coupling reaction, but is not limited thereto. The catalyst as used herein is not particularly limited, but may be tetrakis(triphenylphosphine)palladium(0), palladium(II) acetate, dichloro[1,1′-bis(diphenylphosphenylphosphino)ferrocene]palladium (II), bistriphenylphosphine palladium(II) chloride, or the like. Further, the coupling reaction can also be carried out using metal palladium(0).

[Document]

“Organic Functional Group Preparations”, S. R. Sandler and W. Karo, 2^ndedition, Vol. 1, Academic Press Inc., 1991

The Chemical Society of Japan, “Courses in Experimental Chemistry (5^thedition)” Vol. 14 (2005) (Maruzen)

(Starting Material Synthesis 2)

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The compound (10) can be prepared by the reaction of a compound (7) with a compound (5), followed by a boronic acid esterification reaction.

The present reaction can be carried out by the method as in Starting Material Synthesis 1 as described above.

The compounds of the formula (I) can be isolated and purified as their free compounds, salts, hydrates, solvates, or polymorphic crystalline substances thereof. The salts of the compound of the formula (I) can be prepared by carrying out the treatment of a conventional salt forming reaction.

Isolation and purification are carried out by employing ordinary chemical operations such as extraction, fractional crystallization, various types of fractional chromatography, and the like.

Various isomers can be prepared by selecting an appropriate starting compound or separated by using the difference in the physicochemical properties between the isomers. For example, the optical isomers can be obtained by means of a general method for designing optical resolution of racemic products (for example, fractional crystallization for inducing diastereomer salts with optically active bases or acids, chromatography using a chiral column or the like, and others), and further, the isomers can also be prepared from an appropriate optically active starting compound.

The pharmacological activity of the compound of the formula (I) was confirmed by the tests shown below.

Test Example 1
Inhibitory Effect of Compound on Human VAP-1 Enzyme (SSAO) Activity

A human VAP-1 enzyme (SSAO) activity was measured by a radiochemistry-enzymatic assay using ¹⁴C-benzylamine as an artificial substrate. An enzyme suspension prepared from CHO (Chinese Hamster Ovary) cells stably expressing a human VAP-1 enzyme (SSAO) was preincubated with the compound of the present invention in a 96-well microplate at room temperature for 30 minutes. Subsequently, the enzyme suspension was incubated with ¹⁴C-benzylamine (a final concentration of 1×10⁻⁵mol/L) to a final volume of 50 mL at 37° C. for 1 hour. The enzymatic reaction was stopped by the addition of 2 mol/L (50 μL) of citric acid. The oxidation products were extracted directly in a 200-1 μL toluene scintillator, and the radioactivity was measured with a scintillation spectrometer.

Test Example 2
Inhibitory Effect of Compound on Rat VAP-1 Enzyme (SSAO) Activity

A rat VAP-enzyme 1 (SSAO) activity was measured by a radiochemistry-enzymatic assay using ¹⁴C-benzylamine as an artificial substrate. An enzyme suspension prepared from CHO (Chinese Hamster Ovary) cells stably expressing a rat VAP-enzyme 1 (SSAO) was preincubated with the compound of the present invention in a 96-well microplate at room temperature for 30 minutes. Subsequently, the enzyme suspension was incubated with ¹⁴C-benzylamine (a final concentration of 1×10⁻⁵mol/L) to a final volume of 50 mL at 37° C. for 1 hour. The enzymatic reaction was stopped by the addition of 2 mol/L (50 μL) of citric acid. The oxidation products were extracted directly in a 200-μL toluene scintillator, and the radioactivity was measured with a scintillation spectrometer.

The results are shown in Table 1. In addition, the inhibitory activity is expressed in IC₅₀(nmol/L).

TABLE 1

Human
Rat

Ex
(nM)
(nM)

3
32
22

16
49
7.4

19
6.9
6.9

32
18
10

33
31
21

51
48
21

66
9.4
5.2

69
32
9.8

75
49
3.6

78
61
61

79
66
34

80
81
39

84
140
15

91
18
12

95
11
5.8

102
20
12

147
72
44

190
23
19

191
7
14

261
17
21

216
90
40

263
25
15

From these test, it was confirmed that the compound of the present invention has an extremely high inhibitory activity on human and rat VAP-1. Further, a few of the compounds of the present invention were evaluated for their inhibitory activity on the human platelet MAO, but it became evident that they do not inhibit the enzyme.

Test Example 3

Eight-week to twelve-week Wistar male rats were fasted for 20 hours, and orally administered with a test drug (1 mg/1 kg). Heparin blood collection from the tail vein was performed immediately before the administration, and at 1 h, 3 h, 6 h, and 12 h after the administration. The resulting blood was subjected to centrifugation at 14000 rpm for 5 minutes to separate plasma, and the VAP-1 enzyme activity in the resulting plasma was measured by a radio-enzyme assay method.

For the radio-enzyme assay method, ¹⁴C-benzylamine which is a synthetic substrate (10 μM) was reacted with the resulting plasma at 37° C., and the resulting metabolite was extracted with a mixture of toluene/ethyl acetate. The radioactivity was measured and taken as a VAP-1 enzyme activity in the plasma. The effect of the test drug was calculated from the ratio (%) of the VAP-1 activity after the administration of the test drug relative to the VAP-1 activity in the plasma immediately before the administration (100%).

Reference Document Diabetologia (1997) 40 1243-1250

TABLE 2

Inhibition Ratio (%)

Ex
1 h
3 h
6 h
12 h

3
65
77
71
47

16
83
83
53
42

19
84
79
75
63

32
68
70
58
45

33
84
87
97
83

51
30
37
43
32

66
78
81
74
67

69
72
56
39
24

75
78
58
38
24

78
31
18
3
−4

79
24
21
15
14

80
48
43
26
21

84
16
20
17
NT

91
68
68
68
44

95
70
67
71
21

102
65
62
71
40

147
70
79
75
66

190
42
48
41
11

191
35
43
48
20

216
25
−7
15
25

261
36
44
45
32

263
97
95
80
75

Test Example 4
Effect on Albuminuria in Rats with Diabetes

Seven- to eight-week SD rats (having weights up to 200 to 250 g) during fasting were used and fasted for 20 hours and then intraperitoneally administered with 60 mg/ml/kg of streptozotocin (STZ) prepared from a 2 mmol/l citric acid buffer (pH 4.5). At the same time, the control rats were injected with the same amount of a 2 mmol/l citric acid buffer (pH 4.5). The blood glucose value was measured using a colorimetric method, and the rats that had showed a value of 350 mg/dl blood glucose levels on day 3 after the treatment with STZ was diagnosed with diabetes mellitus.

The test substance was given daily for 4 weeks after the treatment with STZ. After 4 weeks of the treatment with the test substance, 24-hour urine collection was performed using metabolic cages.

Test Example 5
Effect on Eye Permeability in Rats with Diabetes

The test substance was given daily for 4 weeks after the treatment with STZ. After 4 weeks of the treatment with the test substance, the eye vascular permeability was examined after 24 hours from the date of the final administration. The eye permeability was examined on the basis of the colorant leakage into the vitreous body in the eye after 30 minutes from the tail vein administration of 40 mg/ml/kg of a sodium fluorescein solution. The permeability as an index of the evaluation was expressed in the intravitreal concentration/plasma concentration of the fluorescein. Measurement of the fluorescein was carried out using a fluorescent plate reader.

After the result of the tests above, it was confirmed that the compound of the formula (I) constantly exhibits a VAP-1 activity in blood even in the oral administration test with rats. Therefore, the compound can be used for treatment of VAP-1-related diseases or the like.

A pharmaceutical composition containing one or more kinds of the compound of the formula (I) or a salt thereof as an active ingredient can be prepared using excipients that are usually used in the art, that is, excipients for pharmaceutical preparation, carriers for pharmaceutical preparation, and the like according to the methods usually used.

Administration can be accomplished either by oral administration via tablets, pills, capsules, granules, powders, solutions, and the like, or parenteral administration, such as injections such as intraarticular, intravenous, and intramuscular injections, suppositories, ophthalmic solutions, eye ointments, transdermal liquid preparations, ointments, transdermal patches, transmucosal liquid preparations, transmucosal patches, inhalers, and the like.

The solid composition for use in the oral administration is used in the form of tablets, powders, granules, or the like. In such a solid composition, one or more active ingredient(s) are mixed with at least one inactive excipient. In a conventional method, the composition may contain inactive additives, such as a lubricant, a disintegrating agent, a stabilizer, or a solubilization assisting agent. If necessary, tablets or pills may be coated with sugar or a film of a gastric or enteric coating substance.

The liquid composition for oral administration contains pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, or the like, and also contains generally used inert diluents, for example, purified water or ethanol. In addition to the inert diluent, the liquid composition may also contain auxiliary agents, such as a solubilization assisting agent, a moistening agent, and a suspending agent, sweeteners, flavors, aromatics, or antiseptics.

The injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. The aqueous solvent includes, for example, distilled water for injection and physiological saline. Examples of the non-aqueous solvent include alcohols such as ethanol. Such a composition may further contain a tonicity agent, an antiseptic, a moistening agent, an emulsifying agent, a dispersing agent, a stabilizer, or a solubilizing aid. These are sterilized, for example, by filtration through a bacteria retaining filter, blending of a bactericide, or irradiation. In addition, these can also be used by preparing a sterile solid composition, and dissolving or suspending it in sterile water or a sterile solvent for injection prior to its use.

The agent for external use includes ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments, and the like. The agents contain generally used ointment bases, lotion bases, aqueous or non-aqueous liquid preparations, suspensions, emulsions, and the like.

As the transmucosal agents such as an inhaler, a transnasal agent, and the like, those in the form of a solid, liquid, or semi-solid state are used, and can be prepared in accordance with a conventionally known method. For example, a known excipient, and also a pH adjusting agent, an antiseptic, a surfactant, a lubricant, a stabilizer, a thickening agent, or the like may be appropriately added thereto. For their administration, an appropriate device for inhalation or blowing can be used. For example, a compound may be administered alone or as a powder of formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier, using a known device or sprayer, such as a measured administration inhalation device, and the like. A dry powder inhaler or the like may be for single or multiple administration use, and a dry powder or a powder-containing capsule may be used. Alternatively, this may be in a form such as a pressurized aerosol spray which uses an appropriate ejection agent, for example, a suitable gas such as chlorofluoroalkane, carbon dioxide, and the like.

In oral administration, the daily dose is generally from about 0.001 to 100 mg/kg, preferably from 0.1 to 30 mg/kg, and more preferably 0.1 to 10 mg/kg, per body weight, administered in one portion or in 2 to 4 divided portions. In the case of intravenous administration, the daily dose is suitably administered from about 0.0001 to 10 mg/kg per body weight, once a day or two or more times a day. In addition, a transmucosal agent is administered at a dose from about 0.001 to 100 mg/kg per body weight, once a day or two or more times a day. The dose is appropriately decided in response to the individual case by taking the symptoms, the age, and the gender, and the like into consideration.

The compound of the formula (I) can be used in combination with various agents for treating the diseases for which the compound of the formula (I) is considered to be effective. The combined preparation may be administered simultaneously, or separately and continuously, or at a desired time interval. The preparations to be administered simultaneously may be a blend, or may be prepared individually.

EXAMPLES

Hereinbelow, the preparation methods for the compound of the formula (I) will be described in more detail with reference to Examples. Further, the present invention is not limited to only the preparation methods of the specific Examples and Preparation Examples below, but the compound of the formula (I) can be prepared by any combination of the preparation methods or the methods that are apparent to a person skilled in the art.

Furthermore, the following abbreviations may be used in some cases in the Examples, Preparation Examples, and Tables below.

Rf: Preparation Example No.,

Ex: Example No.,

Data: Physicochemical data,

ESI+: representing m/z values in ESI-MS (positive ions), and representing [M+H]⁺ peaks unless otherwise specified,

ESI−: representing m/z values in ESI-MS (negative ions), and representing [M−H]⁻ peaks unless otherwise specified,

APCI+: representing m/z values in APCI-MS (positive ions), and representing [M+H]⁺ peaks unless otherwise specified,

APCI−: representing m/z values in APCI-MS (negative ions), and representing [M−H]⁻ peaks unless otherwise specified,

FAB+: representing m/z values in FAB-MS (positive ions), and representing [M+H]⁺ peaks unless otherwise specified,

FAB−: representing m/z values in FAB-MS (negative ions), and representing [M−H]⁻ peaks unless otherwise specified,

EI+: representing m/z values in EI-MS (positive ions), and representing [M]⁺ peaks unless otherwise specified,

EI−: representing m/z values in EI-MS (negative ions), and representing [M]⁻ peaks unless otherwise specified,

NMR-DMSO-d₆: δ (ppm) in ¹H-NMR in DMSO-d₆,

NMR-CDCl₃: δ (ppm) in ¹H-NMR in CDCl₃,

Powder X-ray diffraction curve using Cu—Kα rays: measured under the condition of using MAC Science MXP18TAHF22, tube: Cu, tube current: 200 mA, tube voltage: 40 kV sampling interval: 0.020°, scanning rate: 3°/min, wavelength: 1.54056 Angstrom, measurement diffraction angle range (2θ): 3 to 40°, or using RIGAKU RINT-TTRII, tube: Cu, tube current: 50 mA, tube voltage: 300 kV, sampling interval: 0.020°, scanning rate: 4°/min, wavelength: 1.54056 Angstrom, measurement diffraction angle range (2θ): 2.5 to 40°,

Structure: Structural formula,

Syn: Preparation method (in which the numeral shows that the compound is prepared by the same preparation method as the compound having the Example No. and R prefixed before the numeral shows that the compound is prepared by the same preparation method as the compound having the Preparation Example No.),

Acid: indicating that the compound represented by a structural formula forms a salt with an acid as described, and the numeral before the acid mean the ratio of the acid. For example, ½FA means formation of a hemifumarate, and 2HCl means formation of dihydrochloride,

L-TA: L-tartaric acid,

OA: oxalic acid,

FA: fumaric acid,

½FA: hemifumaric acid,

SA: succinic acid,

AA: acetic acid,

HCl: hydrochloric acid,

HBr: hydrobromic acid,

Boc: tert-butoxycarbonyl group,

DMSO: dimethylsulfoxide,

THF: tetrahydrofuran,

EtOAc: ethyl acetate,

MgSO₄: anhydrous magnesium sulfate,

DMF: N,N-dimethylformamide,

Na₂SO₄: anhydrous sodium sulfate,

MeOH: methanol,

EtOH: ethanol

CHCl₃: chloroform,

K₂CO₃: potassium carbonate,

NaH: sodium hydride (60% mineral oil suspension),

NMP: N-methyl-2-pyrrolidone,

WSC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide,

HOBt: 1-hydroxybenzotriazole,

TEA: triethylamine,

DIPEA: diisopropylethylamine,

MeCN: acetonitrile,

TFA: trifluoroacetic acid,

DME: 1,2-dimethoxyethane,

M: mol/L.

Preparation Example 1

To 80% ethylamine/MeOH (1.1 g) was added 1-bromo-3-(bromomethyl)benzene (1 g) in five divided portions at room temperature, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to liquid separation with chloroform and a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, and then the aqueous layer was extracted with CHCl₃again. These organic layers were combined, dried over Na₂SO₄, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica, 3% MeOH/CHCl₃) to obtain N-(3-bromobenzyl)ethanamine (610 mg) as a colorless oil.

Preparation Example 2

To a solution of 1-(3-bromophenyl)-N-methylmethanamine (12.0 g) and N-(tert-butoxycarbonyl)glycine (11.5 g) in dichloroethane (80 ml) were added HOBt (9.7 g) and WSC hydrochloride (13.7 g), followed by stirring at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with CHCl₃. The mixture was dried over Na₂SO₄and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH) to obtain tert-butyl {2-[(3-bromobenzyl)amino]-2-oxoethyl}carbamate (21.3 g).

Preparation Example 7

To a solution of tert-butyl {2-[(3-bromobenzyl)amino]-2-oxoethyl}carbamate (1.0 g) and bis(pinacolato)diboron (777 mg) in dioxane (15 ml) were added potassium acetate (858 mg) and dichlorobis(triphenylphosphine)palladium(II) (102 mg), followed by stirring at 80° C. overnight. The reaction mixture was filtrated and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc=10/1 to 1/9) to obtain tert-butyl (2-oxo-2-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]amino}ethyl)carbamate (1.06 g) as a colorless oil.

Preparation Example 10

Under a nitrogen atmosphere, tert-butyl {2-[(3-bromobenzyl)amino]-2-oxoethyl}carbamate (237 mg) and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine (275 mg) were dissolved in DME (3 ml) and water (1.5 ml), and tetrakis(triphenylphosphine)palladium (23 mg) and sodium carbonate (210 mg) were added thereto, followed by stirring at 90° C. for 36 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to liquid separation with CHCl₃and water. The organic layer was separated, and then the aqueous layer was extracted with CHCl₃again. These organic layers were combined and dried over Na₂SO₄, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (2% MeOH/CHCl₃) to obtain tert-butyl (2-{methyl[3-(2-pyrrolidin-1-ylpyrimidin-5-yl)benzyl]amino}-2-oxoethyl)carbamate (260 mg) as a colorless oil.

Preparation Example 16

Under an argon atmosphere, (4-bromophenyl)methanol (3.0 g) and bis(pinacolato)diboron (4.5 g) was dissolved in dioxane (35 ml), and dichlorobis(triphenylphosphine)palladium(II) (567 mg) and potassium acetate (4.7 g) were added thereto, followed by stirring at 80° C. for 1 day. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and concentrated under reduced pressure. The obtained residue was dissolved in DME (35 ml) and water (18 ml), and tert-butyl {2-[(3-bromobenzyl)(methyl)amino]-2-oxoethyl}carbamate (3.5 g) was added thereto under an argon atmosphere. In addition, sodium carbonate (3.1 g) and tetrakis(triphenylphosphine)palladium (339 mg) were added thereto, followed by stirring at 70° C. for 1 day. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl {2-[{[4′-(hydroxymethyl)biphenyl-3-yl]methyl}(methyl)amino]-2-oxoethyl}carbamate (2.8 g).

Preparation Example 50 (2-{[3-(2-Chloropyrimidin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (250 mg) was dissolved in DMF (5 ml), and 4-piperidin-4-ylmorpholine (218 mg) and K₂CO₃(265 mg) were added thereto, followed by stirring at room temperature for 3 days. To the reaction mixture was added water, followed by extraction with EtOAc, and then the organic layer was dried over MgSO₄and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0% to 5% MeOH/CHCl₃) to obtain tert-butyl[2-(methyl {3-[2-(4-morpholin-4-ylpiperidin-1-yl)pyrimidin-5-yl]benzyl}amino)-2-oxoethyl]carbamate (285 mg).
Preparation Example 91

tert-Butyl 4-(2-fluoroethyl)piperazine-1-carboxylate (460 mg) was dissolved in EtOAc (5 ml), and 4 M hydrogen chloride/EtOAc (2.5 ml) was added thereto. After stirring at room temperature for 7 hours, the precipitated solid was collected by filtration to obtain 1-(2-fluoroethyl)piperazine dihydrochloride (406 mg).

Preparation Example 94

3-Bromo-2-methylpyridine (500 mg) and tert-butyl piperazine-1-carboxylate (650 mg) were dissolved in toluene (7.5 ml), and (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one_palladium (3:2) (40 mg), 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphine) (18 mg), and 2-methylpropan-2-ol sodium (391 mg) were added thereto in this order under a nitrogen atmosphere, followed by warming to 100° C. and stirring overnight. The reaction mixture was subjected to liquid separation with CHCl₃and water, the organic layer was dried over Na₂SO₄, and then the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (CHCl₃to 5% MeOH/CHCl₃) to obtain tert-butyl 4-(2-methylpyridin-3-yl)piperazine-1-carboxylate (790 mg) as a pale yellow oil.

Preparation Example 107

Under an argon atmosphere, tert-butyl piperazine-1-carboxylate (10 g) and 2-bromo-3-methylpyridine were dissolved in toluene (150 ml), and tris(dibenzylideneacetone) dipalladium (1.25 g), 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphine) (2.5 g), and 2-methylpropan-2-ol sodium (6.5 g) were added thereto, followed by stirring at 100° C. for 5 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with EtOAc. The organic layer was dried over Na₂SO₄and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc). The product was dissolved in MeOH, and 4 M hydrogen chloride/EtOAc was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then EtOAc was added thereto. The obtained solid was collected by filtration to obtain 1-(3-methylpyridin-2-yl)piperazine dihydrochloride (8.3 g).

Preparation Example 111

5-Bromo-2-fluoropyridine (3.0 g) was dissolved in DMF (18 ml), and K₂CO₃(1.31 g) and tert-butyl piperazine-1-carboxylate (1.76 g) were added thereto, followed by stirring at 130° C. for 3 days. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate (1.21 g).

Preparation Example 112

2-Chloro-3-(trifluoromethyl)pyridine (1.07 g) and tert-butyl piperazine-1-carboxylate (1.0 g) was dissolved in DMF (10 ml), and K₂CO₃(3.0 g) was added thereto, followed by stirring at 80° C. overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc). The product was dissolved in MeOH (16 ml), and 4 M hydrogen chloride/EtOAc (8 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, then EtOAc was added thereto, and the solid was collected by filtration to obtain 1-[3-(trifluoromethyl)pyridin-2-yl]piperazine dihydrochloride (858 mg).

Preparation Example 123

6-[4-(tert-Butoxycarbonyl)piperazin-1-yl]nicotinic acid (934 mg) was dissolved in dioxane (12 ml), and 4 M hydrogen chloride/dioxane (7 ml) was added thereto, followed by stirring at room temperature overnight. The precipitated solid was collected by filtration to obtain 6-piperazin-1-yl nicotinic acid dihydrochloride (850 mg).

Preparation Example 143

tert-Butyl 4-{5-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]-3-methylpyridin-2-yl}piperazine-1-carboxylate (305 mg) was dissolved in EtOH (4 ml), and 4 M hydrogen chloride/EtOAc (2 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure and then suspended in DMF (4 ml), and K₂CO₃(636 mg) and tert-butyl (2-{[3-(2-chloropyrimidin-5-yl)benzyl]methyl)amino}-2-oxoethyl)carbamate (300 mg) were added thereto, followed by stirring at 80° C. overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH) to obtain ethyl (2E)-3-[6-(4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)-5-methylpyridin-3-yl]acrylate (451 mg).

Preparation Example 145

tert-Butyl 3′,6′-dihydro-3,4′-bipyridine-1′(2′H)-carboxylate (606 mg) was dissolved in MeOH (15 ml), and 4 M hydrogen chloride/EtOAc (6 ml) was added thereto, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and then suspended in DMF (8 ml), and K₂CO₃(2.5 g) and 5-bromo-2-fluoropyridine (400 mg) were added thereto, followed by stirring at 80° C. overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH) to obtain 5-bromo-3′,6′-dihydro-2′H-2,1′:4′,3″-terpyridine (170 mg).

Preparation Example 146

tert-Butyl 4-pyridin-3-ylpiperazine-1-carboxylate (680 mg) was dissolved in MeOH (15 ml), and 4 M hydrogen chloride/EtOAc (6.5 ml) was added thereto, followed by stirring at room temperature overnight. Then, the solvent was evaporated under reduced pressure. To a mixture of the obtained residue and DMF (20 ml) was added K₂CO₃(1.8 g), and then 5-bromo-2-fluoropyridine (910 mg) was added thereto. After stirring at 60° C. overnight, water was added thereto, followed by extraction with EtOAc. The organic layer was dried over MgSO₄and then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0% to 5% MeOH/CHCl₃) to obtain 1-(5-bromopyridin-2-yl)-4-pyridin-3-ylpiperazine (173 mg).

Preparation Example 147

Piperazine (1.13 g) and 2-chloro-6-methylnicotinonitrile (500 mg) were dissolved in DMF (15 ml), and K₂CO₃(1.36 g) was added thereto, followed by stirring at 60° C. overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH) to obtain 6-methyl-2-piperazin-1-ylnicotinonitrile (628 mg).

Preparation Example 159

5-Bromo-2-chloropyrimidine (400 mg) was dissolved in DMF (4 ml), and thiomorpholine 1,1-dioxide (308 mg) and K₂CO₃(857 mg) were added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH) to obtain 4-(5-bromopyrimidin-2-yl)thiomorpholine 1,1-dioxide (191 mg).

Preparation Example 160

Under an argon atmosphere, to a solution of tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate (993 mg) and bis(pinacolato)diboron (813 mg) in dioxane (20 ml) were added potassium acetate (1.03 g) and dichlorobis(triphenylphosphine)palladium(II) (102 mg), followed by stirring at 80° C. for 24 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH) to obtain tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate (900 mg).

Preparation Example 162

tert-Butyl {2-[(3-bromobenzyl)amino]-2-oxoethyl}carbamate (274 mg), 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine (222 mg), sodium carbonate (81 mg), tetrakis(triphenylphosphine)palladium (88 mg), DME (5 ml), and water (2.5 ml) were put into a 50-ml recovery flask, followed by stirring at 80° C. for 10 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The obtained residue was subjected to liquid separation with CHCl₃and water. The organic layer was separated, and then the aqueous layer was extracted with CHCl₃again. These organic layers were combined, dried over Na₂SO₄, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (2% MeOH/CHCl₃) to obtain tert-butyl (2-{methyl[(4′-morpholin-4-ylbiphenyl-3-yl)methyl]amino}-2-oxoethyl)carbamate (270 mg) as a pale yellow oil.

Preparation Example 171

rel-(2R,6S)-4-(5-Bromopyrimidin-2-yl)-2,6-dimethylmorpholine (118 mg) and tert-butyl (2-{methyl[3-(4,4,5,5-tetramethyl-1,3,2-dioxabolan-2-yl)benzyl]amino}-2-oxoethyl)carbamate (175 mg) were dissolved in DME (2 ml) and water (1 ml), and tetrakis(triphenylphosphine)palladium (15 mg) and sodium carbonate (137 mg) were added thereto, followed by stirring at 80° C. for 24 hours. The obtained residue was subjected to liquid separation with CHCl₃and water. The organic layer was separated, and then the aqueous layer was extracted with CHCl₃again. These organic layers were combined, dried over Na₂SO₄, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (2% MeOH/CHCl₃) to obtain tert-butyl rel-{2-[(3-{2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyrimidin-5-yl}benzyl)(methyl)amino]-2-oxoethyl}carbamate (190 mg) as a colorless oil.

Preparation Example 200

tert-Butyl (2-{methyl[3-(2-piperazin-1-ylpyrimidin-5-yl)benzyl]amino}-2-oxoethyl)carbamate (200 mg) and ethyl 6-chloronicotinate (169 mg) were dissolved in NMP (4 ml), and N,N-dibutylbutan-1-amine (252 mg) was added thereto, followed by stirring at 100° C. overnight. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with saturated brine and dried over MgSO₄, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0% to 8% CHCl₃/MeOH) to obtain ethyl 6-(4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)nicotinate (100 mg).

Preparation Example 215

1-{5-[3-({[N-(tert-Butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperidine-4-carboxylic acid (200 mg) and N-methylcyclohexanamine (94 mg) were suspended in methylene chloride (4 ml), and WSC hydrochloride (159 mg) and HOBt (112 mg) were added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was subjected to liquid separation with CHCl₃and a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, and then the aqueous layer was extracted with CHCl₃again. These organic layers were combined and dried over Na₂SO₄, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0% to 5% MeOH/CHCl₃) to obtain tert-butyl (2-{[3-(2-{4-[cyclohexyl(methyl)carbamoyl]piperidin-1-yl}pyrimidin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (169 mg).

Preparation Example 228

tert-Butyl (2-{[(4′-aminobiphenyl-3-yl)methyl](methyl)amino}-2-oxoethyl)carbamate (300 mg) was dissolved in DMF (6 ml), and nicotinic acid (150 mg), WSC hydrochloride (233 mg), and HOBt (165 mg) were added thereto, followed by stirring at room temperature for 20 hours. Water was added thereto, followed by extraction with EtOAc. The organic layer was dried over MgSO₄, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH=20/1) to obtain tert-butyl {2-[methyl({4′-[(pyridin-3-ylcarbonyl)amino]biphenyl-3-yl}methyl)amino]-2-oxoethyl}carbamate (328 mg).

Preparation Example 233

tert-Butyl (2-{[(4′-aminobiphenyl-3-yl)methyl](methyl)amino}-2-oxoethyl)carbamate (200 mg) and pyridine (64 mg) were dissolved in methylene chloride (6 ml), followed by ice-cooling. Dimethylcarbamoylchloride (64 mg) was added thereto, followed by warming to room temperature and stirring for 1 hour. The reaction mixture was subjected to liquid separation with CHCl₃and water. The organic layer was separated, and then the aqueous layer was extracted with CHCl₃again. These organic layers were combined and dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (2% MeOH/CHCl₃) to obtain tert-butyl {2-[({4′-[(dimethylcarbamoyl)amino]biphenyl-3-yl}methyl)(methyl)amino]-2-oxoethyl}carbamate (220 mg) as a colorless oil.

Preparation Example 235

To a mixture of 2-(methylamino)ethanol (41 mg), sodium triacetoxyborohydride (166 mg), acetic acid (9 mg), and dichloromethane (4 ml) was added tert-butyl (2-{[(4′-formylbiphenyl-3-yl)methyl](methyl)amino}-2-oxoethyl)carbamate (200 mg), followed by stirring for 5 hours. To the reaction mixture was added CHCl₃-saturated aqueous sodium hydrogen carbonate solution, the organic layer was dried over Na₂SO₄, and then the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (3% MeOH/chloroform) to obtain tert-butyl (2-{[(4′-{[(2-hydroxyethyl)(methyl)amino]methyl}biphenyl-3-yl)methyl](methyl)amino}-2-oxoethyl)carbamate (230 mg) as a colorless oil.

Preparation Example 240

tert-Butyl (2-{methyl[3-(2-piperazin-1-ylpyrimidin-5-yl)benzyl]amino}-2-oxoethyl)carbamate (200 mg) and TEA (92 mg) were dissolved in dichloromethane, followed by ice-cooling. Isopropyl chlorocarbonate (83 mg) was added thereto, followed by stirring at room temperature for 4 hours. Water was added thereto, followed by extraction with chloroform. The organic layer was dried over MgSO₄, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain isopropyl 4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazine-1-carboxylate (155 mg).

Preparation Example 254

Ethyl 4-(4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)benzoate (451 mg) was dissolved in EtOH (5 ml) and THF (5 ml), and a 1 M aqueous NaOH solution (2 ml) was added thereto, followed by stirring at room temperature for 3 hours. After neutralization with 1 M hydrochloric acid (2 ml), water was added thereto, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH) to obtain 4-(4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)benzoic acid (269 mg).

Preparation Example 256

tert-Butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate (800 mg) was dissolved in DMF (4 ml), and ethyl acrylate (368 mg), palladium(II) acetate (27 mg), tris(2-methylphenyl)phosphine (290 mg), and DIPEA (1.26 g) were added thereto, followed by stirring at 100° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and then EtOAc was added thereto. The insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and then the obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl 4-{5-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]pyridin-2-yl}piperazine-1-carboxylate (790 mg).

Preparation Example 257

tert-Butyl (2-{[(4′-cyanobiphenyl-3-yl)methyl](methyl)amino}-2-oxoethyl)carbamate (1.3 g) was dissolved in MeOH (20 ml), and a 28% aqueous ammonia solution (2 ml) was added thereto. Then, Raney nickel (205 mg) was added thereto under an argon atmosphere, followed by stirring at room temperature overnight under a hydrogen atmosphere at 1 atm. The reaction mixture was filtered and washed with water, and then the filtrate was extracted with CHCl₃. The organic layer was concentrated under reduced pressure, and then the obtained residue was purified by silica gel column chromatography (0 to 10% MeOH/CHCl₃) to obtain tert-butyl {2-[{[4′-(aminomethyl)biphenyl-3-yl]methyl}(methyl)amino]-2-oxoethyl}carbamate (900 mg).

Preparation Example 258

Under an argon atmosphere, 1-(4-iodophenyl)azepane (200 mg) and triisopropylborate (162 mg) were dissolved in THF (2 ml), followed by cooling to −78° C. A 1.59 M butyl lithium/hexane solution (0.5 ml) was added thereto, followed by elevating the temperature to 0° C. over 1 hour, and further stirring at the same temperature for 1 hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with EtOAc. The organic layer was dried over Na₂SO₄and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH) to obtain (4-azepan-1-ylphenyl)boronic acid (52 mg).

Preparation Example 259

Under an argon atmosphere, 1,4-diiodiobenzene (2 g), azepane (1.2 g), and 2-(dimethylamino)ethanol (5.3 g) were mixed, and tripotassium phosphate (2.8 g) and copper (77 mg) were added thereto, followed by stirring at 60° C. for 2 days. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 1-(4-iodophenyl)azepane (300 mg).

Preparation Example 260

To a solution of tert-butyl {2-[{[4′-(hydroxymethyl)]biphenyl-3-yl]methyl}(methyl)amino]-2-oxoethyl}carbamate (1.4 g) in 1,2-dichloroethane (15 ml) was added TEA (472 mg), followed by cooling at 0° C. in an ice bath. Methanesulfonyl chloride (518 mg) was added dropwise, followed by warming to room temperature and stirring for 2 hours. To the reaction mixture was added saturated brine, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain [3′-({[N-(tert-butoxycarbonyl)glycyl](methylamino)amino}methyl)biphenyl-4-yl]methylmethanesulfonate (1.0 g).

Preparation Example 264

Under an argon atmosphere, tert-butyl (2-{methyl[3-(2-piperazin-1-ylpyrimidin-5-yl)benzyl]amino}-2-oxoethyl)carbamate (200 mg) and 6-bromonicotinonitrile (124 mg) were dissolved in toluene (6 ml), and tris(dibenzylideneacetone) dipalladium (124 mg), 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphine) (169 mg), and cesium carbonate (222 mg) were added thereto, followed by stirring at 100° C. for 6 hours. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (0% to 7% MeOH/CHCl₃) to obtain tert-butyl {2-[(3-{2-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]pyrimidin-5-yl}benzyl)(methyl)amino]-2-oxoethyl}carbamate (122 mg).

Preparation Example 268

6-Chloronicotinic acid was dissolved in N,N-dimethylacetamide (10 ml), and tert-butyl piperazine-1-carboxylate (1.2 g) and DIPEA (1.6 g) were added thereto, followed by stirring at 130° C. for 3 days. The reaction mixture was concentrated under reduced pressure, and to the obtained residue was added a 1 M aqueous NaOH solution, followed by washing with CHCl₃. The pH of the aqueous layer was adjusted to around 6 to 7 by the addition of 1 M hydrochloric acid, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH) to obtain 6-[4-(tert-butoxycarbonyl)piperazin-1-yl]nicotinic acid (934 mg).

Preparation Example 270

3-Chloro-4-fluorobenzoic acid (1 g) was dissolved in N,N-dimethylacetamide (10 ml), and tert-butyl piperazine-1-carboxylate (1.3 g) and DIPEA (1.9 g) were added thereto, followed by stirring at 130° C. overnight. The reaction mixture was concentrated under reduced pressure, and a 1 M aqueous NaOH solution was added thereto, followed by washing with EtOAc. The pH of the aqueous layer was adjusted to around 6 to 7 by the addition of 1 M hydrochloric acid, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH). The product was dissolved in dioxane (10 ml), and 4 M hydrogen chloride/dioxane (10 ml) was added thereto, followed by stirring at room temperature overnight. The precipitated solid was collected by filtration to obtain 3-chloro-4-piperazin-1-yl benzoic acid hydrochloride (142 mg).

Preparation Example 271

Under ice-cooling, 6-(4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)-5-chloronicotinic acid (303 mg), THF (9 ml), and TEA (65 mg) were mixed, and isobutyl chlorocarbonate (77 mg) was added thereto, followed by stirring at the same temperature for 1.5 hours. The reaction mixture was cooled to −78° C., and a solution of sodium borohydride (77 mg) in water (1.1 ml) was added thereto, followed by warming to 0° C. and stirring for 30 minutes. To the reaction mixture was added water, followed by extraction with EtOAc, and the organic layer was washed with water and saturated brine, and dried over Na₂SO₄. Under reduced pressure, the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (NH silica) to obtain tert-butyl (2-{[3-(2-{4-[3-chloro-5-(hydroxymethyl)pyridin-2-yl]piperazin-1-yl}pyrimidin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (296 mg).

Preparation Example 272

tert-Butyl (2-{[3-(2-{4-[3-chloro-5-(hydroxymethyl)pyridin-2-yl]piperazin-1-yl}pyrimidin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (288 mg) was dissolved in dichloromethane (8 ml), and manganese dioxide (1.16 g) was added thereto, followed by stirring at room temperature for 1.5 hours. Manganese dioxide (220 mg) was added thereto, followed by additionally stirring at room temperature for 1 hour. The reaction mixture was filtered using Celite as a filtration assistant, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH=100/0 to 96/4) to obtain tert-butyl {2-[(3-{2-[4-(3-chloro-5-formylpyridin-2-yl)piperazin-1-yl]pyrimidin-5-yl}benzyl)(methyl)amino]-2-oxoethyl}carbamate (235 mg).

Preparation Example 275

Ethyl (diethylphosphoryl)acetate (471 mg) was dissolved in THF (15 ml), and NaH (98 mg) was added thereto, followed by stirring at room temperature for 30 minutes. A solution of tert-butyl 4-(5-formyl-3-methylpyridin-2-yl)piperazine-1-carboxylate (493 mg) in THF (5 ml) was added thereto, followed by stirring at room temperature for 3 hours. To the reaction mixture was added water, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH) to obtain tert-butyl 4-{5-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]-3-methylpyridin-2-yl}piperazine-1-carboxylate (305 mg).

Preparation Example 276

tert-Butyl 4-(4-nitrophenyl)piperazine-1-carboxylate (500 mg) was dissolved in EtOH (5 ml), and THF (5 ml) and 10% Pd/C (25 mg) was added thereto, followed by stirring for 4 hours under a hydrogen atmosphere. After filtration using Celite as a filtration assistant, the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in MeOH, and 4 M hydrogen chloride/EtOAc (3.8 ml) was added thereto. After stirring at room temperature overnight, the solvent was evaporated under reduced pressure. To a mixture of the obtained residue and DMF (5 ml) was added K₂CO₃(424 mg), and then tert-butyl (2-{[3-(2-chloropyrimidin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (200 mg) was added thereto. After stirring at 60° C. overnight, water was added thereto, followed by extraction with EtOAc. The organic layer was dried over MgSO₄and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0% to 8% MeOH/CHCl₃) to obtain tert-butyl {2-[(3-{2-[4-(4-aminophenyl)piperazin-1-yl]pyrimidin-5-yl}benzyl)(methyl)amino]-2-oxoethyl}carbamate (228 mg).

Preparation Example 277

tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (400 mg) and 3-bromopyridine (226 mg) were dissolved in DMF (4 ml), and K₂CO₃(536 mg) and a 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex were added, followed by stirring at 80° C. overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH) to obtain tert-butyl 3′,6′-dihydro-3,4′-bipyridine-1′(2′H)-carboxylate (249 mg).

Preparation Example 283

Ethyl (2E)-3-[6-(4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)-5-methylpyridin-3-yl]acrylate (250 mg) was dissolved in EtOH (4 ml), and 10% Pd/C (80 mg) was added thereto under a hydrogen atmosphere at 1 atm, followed by stirring at room temperature overnight. The mixture was filtrated using Celite as a filtration assistant to remove the catalyst, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain ethyl 3-[6-(4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)-5-methylpyridin-3-yl]propanoate (163 mg).

Preparation Example 285

tert-Butyl 4-pyrimidin-2-yl-3,6-dihydropyridine-1(2H)-carboxylate (233 mg) was dissolved in EtOH (5 ml), and 10% Pd/C was added thereto, followed by stirring for 4 hours under a hydrogen atmosphere. The mixture was filtered using Celite as a filtration assistant and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc). The obtained oily substance was dissolved in MeOH (5 ml), and 4 M hydrogen chloride/EtOAc (2.2 ml) was added thereto. After stirring at room temperature overnight, the solvent was evaporated under reduced pressure. To a mixture of the obtained residue and DMF (8 ml) was added K₂CO₃(138 mg), and then tert-butyl (2-{[3-(2-chloropyrimidin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (269 mg) was added thereto, followed by stirring at 60° C. overnight. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO₄and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0% to 5% MeOH/CHCl₃) to obtain tert-butyl[2-(methyl{3-[2-(4-pyrimidin-2-ylpiperidin-1-yl)pyrimidin-5-yl]benzyl}amino)-2-oxoethyl]carbamate (361 mg).

Preparation Example 286

tert-Butyl 3′,6′-dihydro-4,4′-bipyridine-1′(2′H)-carboxylate (213 mg) was dissolved in EtOH (4 ml), and 10% Pd/C (20 mg) was added thereto, followed by stirring for 4 hours under a hydrogen atmosphere. The mixture was filtered using Celite as a filtration assistant and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography. The obtained oily substance was dissolved in MeOH (4 ml), and 4 M hydrogen chloride/EtOAc (2 ml) was added thereto. After stirring at room temperature overnight, the solvent was evaporated under reduced pressure. To a mixture of the obtained residue and DMF (4 ml) was added K₂CO₃(904 mg), and then 5-bromo-2-fluoropyridine (432 mg) was added thereto, followed by stirring at 60° C. overnight. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO₄and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 5-bromo-2-(4-pyridin-4-ylpiperidin-1-yl)pyridine (121 mg).

Preparation Example 287

NaH (230 mg) was suspended in DMF (10 ml), and a solution of 5-bromopyrimidine-2-amine in DMF (5 ml) and a solution of cyclohexyl isocyanate (791 mg) in DMF (5 ml) were added dropwise thereto in this order under ice-cooling, followed by stirring at the same temperature for 30 minutes. The obtained solid was collected by filtration and washed with diethyl ether to obtain 1-(5-bromopyrimidin-2-yl)-3-cyclohexylurea (1.47 g).

Preparation Example 289

tert-Butyl (2-{[3-(2-chloropyrimidin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (2.35 g) was dissolved in DMF (50 ml), and piperazine was added thereto, followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extraction with EtOAc, and then the organic layer was dried over MgSO₄and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0% to 10% MeOH/CHCl₃) to obtain tert-butyl (2-{methyl[3-(2-piperazin-1-ylpyrimidin-5-yl)benzyl]amino}-2-oxoethyl)carbamate (1.8 g).

Preparation Example 296

tert-Butyl (2-{[(4′-aminobiphenyl-3-yl)methyl](methyl)amino]-2-oxoethyl}carbamate (240 mg) was dissolved in a mixed solution of EtOAc (10 ml)/saturated aqueous sodium hydrogen carbonate solution (10 ml), followed by ice-cooling. A solution of cyclohexanecarbonyl chloride (142 mg) in EtOAc (5 ml) was added dropwise thereto. The reaction mixture was returned to room temperature and stirred for 24 hours, and then to the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO₄and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane=2/1) to obtain tert-butyl {2-[({4′-[(cyclohexylcarbonyl)amino]biphenyl-3-yl}methyl)(methyl)amino]-2-oxoethyl}carbamate (311 mg).

Preparation Example 301

4-Bromo-3-chloroaniline (500 mg) was dissolved in DMF (10 ml), and bis(2-bromoethyl)ether (1.12 g), K₂CO₃(1.34 g), and potassium iodide (80 mg) were added thereto, followed by stirring at 80° C. for 2 days. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO₄and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0% to 20% EtOAc/hexane) to obtain 4-(4-bromo-3-chlorophenyl)morpholine (263 mg).

Preparation Example 302

1H-Pyrazole (460 mg) was dissolved in DMF (10 ml), and NaH (118 mg) was added thereto. After 10 minutes, tert-butyl 4-{[(4-methylphenyl)sulfonyl]oxy}piperidine-1-carboxylate (800 mg) was added thereto, followed by stirring at 60° C. for 5 hours. To the reaction mixture were added several drops of water, followed by concentration under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc). The product was dissolved in EtOH (15 ml), and 4 M hydrogen chloride/EtOAc (5.6 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure to obtain 4-(1H-pyrazol-1-yl)piperidine dihydrochloride (148 mg).

Preparation Example 303

To an ice-cooled solution of tert-butyl (2-{[(4′-aminobiphenyl-3-yl)methyl](methyl)amino]-2-oxoethyl}carbamate (200 mg) in dichloromethane (4 ml) was added 2-propyl isocyanate (55 mg), followed by stirring at room temperature for 2 hours. To the reaction mixture was added water, followed by stirring, and the organic layer was purified by silica gel column chromatography (2% MeOH/CHCl₃) to obtain tert-butyl {2-[({4′-[(isopropylcarbamoyl)amino]biphenyl-3-yl}methyl)(methyl)amino]-2-oxoethyl}carbamate (240 mg) as a colorless oil.

Preparation Example 305

To a mixture of 4-nitrophenyl(3′-{[{[(tert-butoxycarbonyl)amino]acetyl}(methyl)amino]methyl}biphenyl-4-yl)carbamate (150 mg), DIPEA (36 mg), and dichloromethane (3 ml) was added 1-methylpiperazine (28 mg), followed by stirring at 50° C. for 5 hours. The reaction mixture was subjected to liquid separation with CHCl₃-water, and the aqueous layer was extracted with CHCl₃. The combined organic layer was dried over Na₂SO₄, and then the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (2% MeOH/CHCl₃) to obtain tert-butyl (2-{methyl[(4′-{[(4-methylpiperazin-1-yl)carbonyl]amino}biphenyl-3-yl)methyl]amino}-2-oxoethyl)carbamate (132 mg) as a pale yellow oil.

Preparation Example 306

Pyridin-4-ylmethanol (112 mg) was dissolved in DMF (4 ml), and NaH (45 mg) was added thereto under ice-cooling. After stirring at the same temperature for 30 minutes, tert-butyl (2-{[3-(2-chloropyrimidin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (200 mg) was added thereto, followed by stirring at room temperature for 2 hours. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO₄and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0% to 7% MeOH/CHCl₃) to obtain tert-butyl[2-(methyl{3-[2-(pyridin-4-ylmethoxy)pyrimidin-5-yl]benzyl}amino)-2-oxoethyl]carbamate (237 mg).

Preparation Example 309

2-Fluoroethyl 4-methylbenzenesulfonate (1 g) was dissolved in DMF (20 ml), and tert-butyl piperazine-1-carboxylate (939 mg) and K₂CO₃(1.90 g) were added thereto, followed by stirring at 70° C. overnight. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO₄, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0% to 5% MeOH/CHCl₃) to obtain tert-butyl 4-(2-fluoromethyl)piperazine-1-carboxylate (463 mg).

Preparation Example 313

A mixture of 2-bromo-1-(4-bromophenyl)ethanone (550 mg), pyridine-3-carbothioamide (273 mg), and EtOH (20 ml) was heated under reflux for 2 hours. Thereafter, the mixture was cooled to room temperature, and the precipitated crystal was collected by filtration. This was washed with EtOH to obtain 3-[4-(4-bromophenyl)-1,3-thiazol-2-yl]pyridine hydrochloride (450 mg) as a pale yellow crystal.

Preparation Example 314

tert-Butyl piperazine-1-carboxylate (500 mg) was dissolved in NMP (10 ml), and 4-chloro-2-methylpyridine (685 mg) and tri-n-butylamine (498 mg) were added thereto, followed by stirring at 150° C. overnight. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO₄, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain tert-butyl 4-(2-methylpyridin-4-yl)piperazine-1-carboxylate (667 mg).

Preparation Example 315

Under an argon atmosphere, to a mixture of tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate (1.82 g), pyridin-4-yl boronic acid (473 mg), and DME (35 ml) were added tetrakis(triphenylphosphine)palladium (317 mg), cesium carbonate (5.37 g), and water (9 ml), followed by stirring at 80° C. overnight. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO₄and then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain tert-butyl 3,6-dihydro-4,4′-bipyridine-1(2H)-carboxylate (1.28 g).

Preparation Example 317

To a mixture of tert-butyl 4-(5-bromo-3-formylpyridin-2-yl)piperazine-1-carboxylate (1 g) and MeOH (20 ml) was added sodium borohydride (153 mg). After stirring at room temperature for 2 hours, the solvent was evaporated under reduced pressure. To the obtained residue was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO₄, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain tert-butyl 4-[5-bromo-3-(hydroxymethyl)pyridin-2-yl]piperazine-1-carboxylate (922 mg).

Preparation Example 318

tert-Butyl 4-(6-chloro-5-methylpyrimidin-4-yl)piperazine-1-carboxylate (400 mg) was dissolved in EtOH (8 ml), and 10% Pd/C (40 mg) was added thereto, followed by stirring at room temperature overnight under a hydrogen atmosphere. To the reaction mixture was added TEA (129 mg) and filtered using Celite as a filtration assistant, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (10% to 80% EtOAc/hexane) to obtain tert-butyl 4-(5-methylpyrimidin-4-yl)piperazine-1-carboxylate (255 mg).

Preparation Example 322

tert-Butyl (2-{methyl[3-(2-piperazin-1-ylpyrimidin-5-yl)benzyl]amino}-2-oxoethyl)carbamate (200 mg) was dissolved in DMF (4 ml), and dihydrofuran-2,5-dione (50 mg) and K₂CO₃(125 mg) were added thereto, followed by stirring at room temperature for 1 hour. Water and 1 M hydrochloric acid were added thereto, followed by extraction with EtOAc. The organic layer was dried over MgSO₄, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 4-(4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)-4-oxobutanoic acid (168 mg).

Preparation Example 324

tert-Butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (500 mg) was dissolved in THF (5 ml), and NaH (174 mg) was added thereto under ice-cooling, and subsequently, ethyl iodide (680 mg) was added thereto, followed by elevating the temperature to room temperature and stirring overnight. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO₄and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (5% to 20% EtOAc/hexane) to obtain tert-butyl 4-(2-ethoxyethyl)piperidine-1-carboxylate (496 mg).

Preparation Example 325

tert-Butyl (2-{methyl[(4′-piperazin-1-ylbiphenyl-3-yl)methyl]amino}-2-oxoethyl)carbamate (180 mg) was dissolved in dichloromethane (3.6 ml), and TEA (125 mg) was added thereto under ice-cooling. Subsequently, ethyl iodide (128 mg) was added thereto, followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extraction with CHCl₃. The organic layer was dried over MgSO₄, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (2% MeOH/CHCl₃) to obtain tert-butyl {2-[{[4′-(4-ethylpiperazin-1-yl)biphenyl-3-yl]methyl}(methyl)amino]-2-oxoethyl}carbamate (137 mg).

Preparation Example 326

Under an argon atmosphere, a solution of 2 M isopropylmagnesium chloride in THF (5.5 ml) was cooled to −78° C., and a solution of 2,5-dibromo-3-methylpyridine (2.5 g) in THF (10 ml) was added dropwise. After stirring at the same temperature for 30 minutes, a solution of morpholine-4-carboaldehyde (1.26 g) in THF (5 ml) was added dropwise thereto, followed by elevating the temperature to 0° C. over 30 minutes, followed by stirring at 0° C. for 2 hours. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over Na₂SO₄and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 6-bromo-5-methyl nicotine aldehyde (1.42 g).

Preparation Example 327

tert-Butyl 4-(3-formylpyridin-2-yl)piperazine-1-carboxylate (1.88 g) was dissolved in acetic acid (20 ml), and bromine (1.03 g) was added dropwise thereto, followed by stirring at room temperature for 30 minutes. The solvent was evaporated under reduced pressure. The obtained residue was subjected to liquid separation by the addition of CHCl₃and a 1 M aqueous NaOH solution. The organic layer was dried over MgSO₄and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain tert-butyl 4-(5-bromo-3-formylpyridin-2-yl)piperazine-1-carboxylate (2.05 g).

Preparation Example 328

Ethyl glycolate (116 mg) was dissolved in DMF (4 ml), and NaH (73 mg) was added thereto under ice-cooling. After stirring at the same temperature for 10 minutes, a solution of 4-nitrophenyl 4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazine-1-carboxylate (340 mg) in DMF (3 ml) was added thereto, followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO₄, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2-ethoxy-2-oxoethyl 4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazine-1-carboxylate (35 mg).

Preparation Example 329

tert-Butyl (2-{methyl[3-(2-piperazin-1-ylpyrimidin-5-yl)benzyl]amino}-2-oxoethyl(carbamate (2.18 g) was dissolved in dioxane (50 ml), and a 1 M aqueous sodium hydrogen carbonate solution (19.8 ml) was added thereto. 4-Nitrophenylchlorocarbonate (1.10 g) was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and then the organic layer was extracted by the addition of CHCl₃and water. The organic layer was dried over Na₂SO₄and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 4-nitrophenyl 4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazine-1-carboxylate (2.89 g).

Preparation Example 330

Under an argon atmosphere, a solution of tert-butyl 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylate (400 mg) in THF (8 ml) was cooled to −78° C., and 1.63 M n-butyl lithium (0.9 ml) was added dropwise thereto, followed by stirring at the same temperature for 1 hour. Crushed dry ice was put into another flask, and THF (30 ml) was poured thereinto. The mixture to which n-BuLi had been added dropwise immediately before was added thereto, followed by stirring as it was for 1 hour. To the reaction mixture was added water and 1 M hydrochloric acid, and the pH of the aqueous layer was adjusted to around 5.0. The aqueous layer was extracted with EtOAc, the organic layer was separated, and then the aqueous layer was extracted with CHCl₃again. These organic layers were combined and dried over Na₂SO₄, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH) to obtain 6-[4-(tert-butoxycarbonyl)piperazine-1-yl]-5-methylnicotinic acid (169 mg).

Preparation Example 336

Benzyl 4-phenylpiperazine-1-carboxylate (2.1 g) was dissolved in DMF (80 ml), and N-bromosuccinimide (1.4 g) was added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and subjected to liquid separation by the addition of CHCl₃and a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated and dried over Na₂SO₄, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain benzyl 4-(4-bromophenyl)piperazine-1-carboxylate (2.3 g).

Preparation Example 338

Benzyl 4-[3′-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)biphenyl-4-yl]piperazine-1-carboxylate (1.5 g) was dissolved in a mixed solution of MeOH (15 ml) and THF (15 ml). 10% Pd—C (150 mg) was added thereto, followed by stirring at room temperature for 1 day under a hydrogen atmosphere. The reaction mixture was filtered using Celite as a filtration assistant, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain tert-butyl (2-{methyl [(4′-piperazin-1-ylbiphenyl-3-yl)methyl]amino}-2-oxoethyl)carbamate (860 mg).

The Preparation Example Compounds as shown in Tables below were prepared in the same manner as the methods of Preparation Examples above, using each of the corresponding starting materials. The structures, the preparation methods, and the physicochemical data of Preparation Example Compounds are shown in Tables below.

TABLE 3

Rf
Syn
Structure
Acid

1
R1

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—

2
R2

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—

3
R2

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—

4
R2

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—

5
R2

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—

6
R2

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—

7
R7

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—

TABLE 4

Rf
Syn
Structure
Acid

8
R7

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—

9
R7

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—

10
R10

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—

11
R10

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—

12
R10

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—

TABLE 5

Rf
Syn
Structure
Acid

13
R10

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—

14
R10

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—

15
R10

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—

16
R16

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—

17
R17

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—

TABLE 6

Rf
Syn
Structure
Acid

18
R17

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—

19
R17

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—

20
R17

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—

21
R17

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—

22
R17

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—

TABLE 7

Rf
Syn
Structure
Acid

23
R17

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—

24
R17

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—

25
R17

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—

26
R17

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—

27
R17

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—

TABLE 8

Rf
Syn
Structure
Acid

28
R17

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—

29
R17

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—

30
R17

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—

31
R17

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—

32
R17

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—

TABLE 9

Rf
Syn
Structure
Acid

33
R17

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—

34
R17

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—

35
R17

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—

36
R17

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—

37
R17

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—

TABLE 10

Rf
Syn
Structure
Acid

38
R17

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—

39
R17

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—

40
R17

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—

41
R17

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—

42
R17

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—

TABLE 11

Rf
Syn
Structure
Acid

43
R17

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—

44
R17

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—

45
R17

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—

46
R17

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—

47
R17

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—

TABLE 12

Rf
Syn
Structure
Acid

48
R17

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—

49
R17

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—

50
R17

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—

51
R17

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—

TABLE 13

Rf
Syn
Structure
Acid

52
R17

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—

53
R17

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—

54
R17

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—

55
R17

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—

56
R17

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—

TABLE 14

Rf
Syn
Structure
Acid

57
R17

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—

58
R17

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—

59
R17

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—

60
R17

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—

61
R17

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—

62
R17

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—

TABLE 15

Rf
Syn
Structure
Acid

63
R17

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—

64
R17

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—

65
R17

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—

66
R17

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—

TABLE 16

Rf
Syn
Structure
Acid

67
R17

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—

68
R17

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—

69
R17

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—

70
R17

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—

TABLE 17

Rf
Syn
Structure
Acid

71
R17

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—

72
R17

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—

73
R17

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—

74
R17

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—

TABLE 18

Rf
Syn
Structure
Acid

75
R17

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—

76
R17

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—

77
R17

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—

78
R17

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—

79
R17

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—

TABLE 19

Rf
Syn
Structure
Acid

80
R17

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—

81
R17

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—

82
R17

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—

83
R17

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—

TABLE 20

Rf
Syn
Structure
Acid

84
R17

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—

85
R17

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—

86
R17

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—

87
R17

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—

TABLE 21

Rf
Syn
Structure
Acid

88
R17

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—

89
R17

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—

90
R17

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—

91
R91

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2HCl

92
R92

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—

TABLE 22

Rf
Syn
Structure
Acid

93
R92

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—

94
R92

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—

95
R92

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—

96
R92

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—

97
R92

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—

98
R92

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—

TABLE 23

Rf
Syn
Structure
Acid

99
R92

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—

100
R92

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—

101
R92

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—

102
R92

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—

103
R92

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—

104
R92

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—

TABLE 24

Rf
Syn
Structure
Acid

105
R92

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—

106
R92

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—

107
R107

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2HCl

108
R108

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—

109
R108

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—

110
R108

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—

111
R108

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—

TABLE 25

Rf
Syn
Structure
Acid

112
R112

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2HCl

113
R112

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—

114
R112

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—

115
R115

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—

116
R115

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3HCl

117
R115

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3HCl

TABLE 26

Rf
Syn
Structure
Acid

118
R115

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2HCl

119
R115

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2HCl

120
R115

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2HCl

121
R115

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2HCl

122
R115

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2HCl

TABLE 27

Rf
Syn
Structure
Acid

123
R115

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2HCl

124
R124

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—

125
R124

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—

126
R124

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—

127
R124

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—

TABLE 28

Rf
Syn
Structure
Acid

128
R124

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—

129
R124

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—

130
R124

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—

131
R124

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—

TABLE 29

Rf
Syn
Structure
Acid

132
R124

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—

133
R124

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—

134
R124

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—

135
R124

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—

136
R124

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—

TABLE 30

Rf
Syn
Structure
Acid

137
R124

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—

138
R124

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—

139
R124

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—

140
R124

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—

141
R124

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—

TABLE 31

Rf
Syn
Structure
Acid

142
R124

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—

143
R124

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—

144
R144

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—

145
R144

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—

TABLE 32

Rf
Syn
Structure
Acid

146
R146

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—

147
R147

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—

148
R148

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—

149
R148

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—

150
R148

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—

151
R148

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—

TABLE 33

Rf
Syn
Structure
Acid

152
R148

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—

153
R148

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—

154
R148

embedded image

—

155
R148

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—

156
R148

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—

TABLE 34

Rf
Syn
Structure
Acid

157
R148

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—

158
R148

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—

159
R148

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—

160
R160

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—

161
R161

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—

162
R161

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—

TABLE 35

Rf
Syn
Structure
Acid

163
R161

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—

164
R161

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—

165
R161

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—

166
R161

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—

167
R161

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—

168
R161

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—

TABLE 36

Rf
Syn
Structure
Acid

169
R161

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—

170
R161

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—

171
R171

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—

172
R171

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—

173
R171

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—

174
R171

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—

TABLE 37

Rf
Syn
Structure
Acid

175
R171

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—

176
R171

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—

177
R171

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—

178
R171

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—

179
R171

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—

180
R171

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—

TABLE 38

Rf
Syn
Structure
Acid

181
R171

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—

182
R171

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—

183
R171

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—

184
R171

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—

185
R171

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—

TABLE 39

Rf
Syn
Structure
Acid

186
R171

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—

187
R171

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—

188
R171

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—

189
R171

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—

190
R171

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—

191
R171

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—

TABLE 40

Rf
Syn
Structure
Acid

192
R171

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—

193
R171

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—

194
R171

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—

195
R171

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—

196
R171

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—

TABLE 41

Rf
Syn
Structure
Acid

197
R171

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—

198
R171

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—

199
R171

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—

200
R200

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—

201
R201

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—

TABLE 42

Rf
Syn
Structure
Acid

202
R201

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—

203
R201

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—

204
R201

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—

205
R201

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—

206
R201

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—

TABLE 43

Rf
Syn
Structure
Acid

207
R201

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—

208
R201

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—

209
R201

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—

210
R201

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—

211
R201

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—

212
R201

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—

TABLE 44

Rf
Syn
Structure
Acid

213
R201

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—

214
R201

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—

215
R201

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—

216
R201

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—

217
R201

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—

TABLE 45

Rf
Syn
Structure
Acid

218
R201

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—

219
R201

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—

220
R201

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—

221
R201

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—

222
R222

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—

TABLE 46

Rf
Syn
Structure
Acid

223
R222

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—

224
R222

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—

225
R222

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—

226
R222

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—

227
R222

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—

TABLE 47

Rf
Syn
Structure
Acid

228
R222

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—

229
R222

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—

230
R230

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—

231
R230

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—

232
R230

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—

233
R230

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—

TABLE 48

Rf
Syn
Structure
Acid

234
R234

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—

235
R234

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—

236
R234

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—

237
R237

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—

238
R237

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—

TABLE 49

Rf
Syn
Structure
Acid

239
R237

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—

240
R237

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—

241
R237

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—

242
R237

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—

TABLE 50

Rf
Syn
Structure
Acid

243
R237

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—

244
R237

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—

245
R245

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—

246
R245

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—

TABLE 51

Rf
Syn
Structure
Acid

247
R245

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—

248
R245

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—

249
R245

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—

250
R245

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—

251
R245

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—

TABLE 52

Rf
Syn
Structure
Acid

252
R245

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—

253
R245

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—

254
R245

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—

255
R255

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—

256
R255

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—

TABLE 53

Rf
Syn
Structure
Acid

257
R257

embedded image

—

258
R258

embedded image

—

259
R259

embedded image

—

260
R260

embedded image

—

261
R261

embedded image

—

TABLE 54

Rf
Syn
Structure
Acid

262
R261

embedded image

—

263
R261

embedded image

—

264
R261

embedded image

—

265
R261

embedded image

—

TABLE 55

Rf
Syn
Structure
Acid

266
R266

embedded image

—

267
R266

embedded image

—

268
R266

embedded image

—

269
R266

embedded image

—

270
R270

embedded image

HCl

TABLE 56

Rf
Syn
Structure
Acid

271
R271

embedded image

—

272
R272

embedded image

—

273
R273

embedded image

—

274
R274

embedded image

—

275
R274

embedded image

—

TABLE 57

Rf
Syn
Structure
Acid

276
R276

embedded image

—

277
R277

embedded image

—

278
R278

embedded image

—

279
R278

embedded image

—

280
R278

embedded image

—

281
R278

embedded image

—

TABLE 58

Rf
Syn
Structure
Acid

282
R278

embedded image

—

283
R278

embedded image

—

284
R278

embedded image

—

285
R285

embedded image

—

286
R286

embedded image

—

TABLE 59

Rf
Syn
Structure
Acid

287
R287

embedded image

—

288
R288

embedded image

—

289
R288

embedded image

—

290
R288

embedded image

—

291
R288

embedded image

—

292
R288

embedded image

—

TABLE 60

Rf
Syn
Structure
Acid

293
R288

embedded image

—

294
R288

embedded image

—

295
R288

embedded image

—

296
R296

embedded image

—

297
R297

embedded image

—

298
R297

embedded image

—

TABLE 61

Rf
Syn
Structure
Acid

299
R297

embedded image

—

300
R297

embedded image

—

301
R297

embedded image

—

302
R302

embedded image

2HCl

303
R303

embedded image

—

304
R304

embedded image

—

TABLE 62

Rf
Syn
Structure
Acid

305
R304

embedded image

—

306
R306

embedded image

—

307
R306

embedded image

—

308
R306

embedded image

—

309
R309

embedded image

—

310
R309

embedded image

—

311
R309

embedded image

—

TABLE 63

Rf
Syn
Structure
Acid

312
R309

embedded image

—

313
R313

embedded image

HBr

314
R314

embedded image

—

315
R315

embedded image

—

316
R316

embedded image

—

317
R316

embedded image

—

318
R318

embedded image

—

319
R318

embedded image

—

TABLE 64

Rf
Syn
Structure
Acid

320
R320

embedded image

—

321
R320

embedded image

—

322
R320

embedded image

—

323
R321

embedded image

—

324
R321

embedded image

—

TABLE 65

Rf
Syn
Structure
Acid

325
R325

embedded image

—

326
R326

embedded image

—

327
R327

embedded image

—

328
R328

embedded image

—

329
R329

embedded image

—

330
R330

embedded image

—

TABLE 66

Rf
Syn
Structure
Acid

331
R7

embedded image

—

332
R245

embedded image

—

333
R92

embedded image

—

334
R115

embedded image

3HCl

335
R296

embedded image

—

336
R338

embedded image

—

TABLE 67

Rf
Syn
Structure
Acid

337
R10

embedded image

—

338
R340

embedded image

—

TABLE 68

Rf
Data

1
ESI+: 214

2
FAB+: 357

3
ESI+: 371

4
ESI+: 301

5
ESI+: 302

6
ESI+: 301

7
ESI+: 391

8
ESI+: 419

9
ESI+: 442

10
ESI+: 426

11
ESI+: 441

12
ESI+: 468

13
ESI+: 453

14
ESI+: 370

15
ESI+: 515

16
ESI+: 385

17
ESI+: 532

18
ESI+: 590

19
ESI+: 532

20
ESI+: 532

21
ESI+: 524

22
ESI+: 484

23
ESI+: 509

24
ESI+: 533

25
ESI+: 475

26
ESI+: 512

27
ESI+: 497

28
ESI+: 470

29
ESI+: 484

30
ESI+: 502

31
ESI+: 547

32
ESI+: 616

33
ESI+: 644

34
ESI+: 526

TABLE 69

Rf
Data

35
ESI+: 456

36
ESI+: 470

37
ESI+: 456

38
ESI+: 470

39
ESI+: 454

40
ESI+: 517

41
ESI+: 483

42
ESI+: 477

43
ESI+: 491

44
ESI+: 547

45
ESI+: 561

46
ESI+: 518

47
ESI+: 477

48
ESI+: 463

49
ESI+: 538

50
ESI+: 525

51
ESI+: 519

52
ESI+: 517

53
ESI+: 531

54
ESI+: 535

55
ESI+: 551

56
ESI+: 532

57
ESI+: 485

58
ESI+: 554

59
ESI+: 513

60
ESI+: 488

61
ESI+: 469

62
ESI+: 477

63
ESI+: 532

64
ESI+: 576

65
ESI+: 552

66
ESI+: 532

67
ESI+: 543

68
ESI+: 552

TABLE 70

Rf
Data

69
ESI+: 586

70
ESI+: 531

71
ESI+: 536

72
ESI+: 553

73
ESI+: 546

74
ESI+: 552

75
ESI+: 598

76
ESI+: 484

77
ESI+: 497

78
ESI+: 483

79
ESI+: 523

80
ESI+: 482

81
ESI+: 456

82
ESI+: 456

83
ESI+: 483

84
ESI+: 512

85
ESI+: 498

86
ESI+: 554

87
ESI+: 616

88
ESI+: 589

89
ESI+: 477

90
ESI+: 536

91
ESI+: 133

92
ESI+: 336

93
ESI+: 278

94
ESI+: 278

95
ESI+: 322

96
ESI+: 298

97
ESI+: 292

98
ESI+: 292

99
ESI+: 282

100
ESI+: 282

101
ESI+: 294

102
ESI+: 306

TABLE 71

Rf
Data

103
ESI+: 336

104
ESI+: 278

105
ESI+: 278

106
NMR-CDCl₃: 1.45-1.55 (9H, m), 2.33 (3H, s),

3.32-3.42 (4H, m), 3.50-3.64 (4H, m), 7.82-7.87

(1H, m), 8.51-8.56 (1H, m), 9.91 (1H, s)

107
ESI+: 178

108
ESI+: 236 ([M − tBu + H]+)

109
ESI+: 308

110
ESI+: 313

111
ESI+: 342, 344

112
APCI+: 232

113
ESI+: 199. 201

114
ESI+: 198, 200

115
ESI+: 236

116
ESI+: 178

117
ESI+: 178

118
ESI+: 178

119
ESI+: 222

120
ESI+: 198

121
ESI+: 177

122
ESI+: 262

123
ESI+: 208

124
ESI+: 546

125
ESI+: 546

126
ESI+: 548

127
ESI+: 536

128
ESI+: 561

129
ESI+: 548

130
ESI+: 533

131
ESI+: 568

132
ESI+: 534

133
ESI+: 567

134
ESI+: 620

TABLE 72

Rf
Data

135
ESI+: 498

136
ESI+: 553

137
ESI+: 551

138
ESI+: 537

139
ESI+: 512

140
ESI+: 590

141
ESI+: 646

142
ESI+: 517

143
ESI+: 630

144
ESI+: 316, 318

145
ESI+: 316, 318

146
ESI+: 321

147
APCI+: 203

148
ESI+: 245

149
ESI+: 271

150
ESI+: 274

151
ESI+: 279

152
ESI+: 271

153
ESI+: 320

154
ESI+: 321

155
ESI+: 319

156
ESI+: 319

157
ESI+: 333, 335

158
ESI+: 332, 334

159
ESI+: 293

160
ESI+: 389

161
ESI+: 412

162
ESI+: 440

163
ESI+: 441

164
ESI+: 412

165
ESI+: 370

166
FAB+: 383

167
FAB+: 380

168
ESI+: 427

TABLE 73

Rf
Data

169
ESI+: 261

170
ESI+: 275

171
ESI+: 470

172
ESI+: 472

173
ESI+: 469

174
ESI+: 444

175
ESI+: 470

176
ESI+: 456

177
ESI+: 518

178
ESI+: 519

179
ESI+: 405

180
ESI+: 377

181
ESI+: 518

182
ESI+: 518

183
ESI+: 517

184
APCI+: 458

185
ESI+: 374 ([M − Boc]+)

186
ESI−: 399

187
ESI+: 497

188
ESI+: 391

189
ESI+: 497

190
ESI+: 498

191
ESI+: 358 ([M − Boc]+)

192
ESI+: 454

193
ESI+: 517

194
ESI+: 276

195
NMR-CDCl₃: 1.44 (2.7H, s), 1.47 (6.3H, s), 2.79-2.87

(2H, m), 2.92 (2.1H, s), 3.02 (0.9H, s), 3.92-4.11 (4H, m),

4.24-4.31 (2H, m), 4.52 (0.6H, s), 4.66 (1.4H, s), 5.50-5.63

(1H, m), 6.73-6.82 (2H, m), 7.05-7.20 (2H, m), 7.22-7.31

(1H, m), 7.35-7.51 (3H, m), 7.64-7.76 (2H, m), 8.43-8.48

(1H, m), 8.57-8.62 (1H, m)

TABLE 74

Rf
Data

196
NMR-CDCl₃: 1.44 (2.7H, s), 1.47 (6.3H, s), 2.66-2.73

(2H, m), 2.92 (2.1H, s), 3.02 (0.9H, s), 3.92-4.11 (4H, m),

4.18-4.27 (2H, m), 4.52 (0.6H, s), 4.66 (1.4H, s), 5.50-5.63

(1H, m), 6.24-6.32 (1H, m), 6.75 (1H, d, J = 8.8 Hz),

7.05-7.20 (1H, m), 7.23-7.32 (1H, m), 7.35-7.51 (3H, m),

7.67-7.78 (2H, m), 8.43-8.48 (1H, m), 8.49-8.54 (1H, m),

8.69-8.74 (1H, m)

197
API−: 382

198
ESI+: 518

199
ESI−: 482

200
ESI+: 590

201
ESI+: 557

202
ESI+: 495

203
ESI+: 440

204
ESI+: 496

205
ESI+: 601

206
ESI+: 585

207
ESI+: 496

208
ESI+: 585

209
ESI+: 531

210
ESI+: 496

211
ESI+: 573

212
ESI+: 511

213
ESI+: 551

214
ESI+: 553

215
ESI+: 579

216
ESI+: 539

217
ESI−: 582

218
API+: 496

219
ESI+: 511

220
ESI+: 468

221
ESI+: 496

222
FAB−: 440

223
ESI+: 458

224
ESI−: 494

225
FAB−: 450

TABLE 75

Rf
Data

226
ESI−: 436

227
FAB+: 475

228
ESI−: 473

229
ESI+: 495

230
ESI+: 456

231
ESI+: 440

232
ESI+: 535

233
NMR-CDCl₃: 1.44 (3.6H, s), 1.46 (5.4H, s), 2.80

(1.2H, s), 2.90 (1.8H, s), 3.0-3.1 (6H, m), 3.99-4.09

(2H, m), 4.51 (0.8H, s), 4.66 (1.2H, s), 5.52-5.62 (1H,

br), 7.05-7.55 (8H, m)

234
ESI+: 456

235
NMR-CDCl₃: 1.44 (3.6H, s), 1.46 (5.4H, s), 2.27

(3H, s), 2.64 (2H, t, J = 6 Hz), 2.91 (1.8H, s),

3.02 (1.2H, s), 3.59-3.69 (4H, m), 3.99-4.09 (2H,

m), 4.53 (0.8H, s), 4.67 (1.2H, s), 5.52-5.63 (1H, br),

7.10-7.23 (1H, m),

7.32-7.57 (7H, m)

236
ESI+: 557

237
ESI+: 527

238
ESI+: 499

239
ESI+: 527

240
ESI+: 527

241
ESI+: 541

242
ESI+: 554

243
ESI+: 540

244
ESI+: 552

245
ESI+: 588

246
ESI+: 616

247
ESI+: 512

248
ESI+: 596, 598

249
ESI+: 622, 624

250
ESI+: 606

251
ESI−: 397

252
ESI+: 602

253
ESI+: 604

254
ESI+: 561

TABLE 76

Rf
Data

255
ESI+: 392

256
ESI+: 362

257
FAB+: 384

258
ESI+: 220

259
ESI+: 302

260
ESI+: 463

261
ESI+: 543

262
ESI+: 543

263
ESI+: 552, 554

264
ESI+: 543

265
ESI+: 546

266
ESI+: 624, 626

267
ESI+: 356, 358

268
ESI+: 308

269
ESI+: 562

270
ESI+: 241

271
ESI+: 582, 584

272
ESI+: 580, 582

273
ESI+: 453

274
ESI+: 650, 652

275
ESI+: 376

276
ESI+: 533

277
APCI+: 261

278
ESI+: 278

279
ESI+: 648

280
ESI+: 277

281
ESI+: 263

282
ESI+: 263

283
ESI+: 632

284
ESI+: 618

285
ESI+: 518

286
ESI+: 320

287
ESI+: 301

288
ESI+: 469

TABLE 77

Rf
Data

289
ESI+: 441

290
ESI+: 286

291
ESI+: 189

292
ESI+: 198

293
ESI+: 232

294
ESI+: 198

295
ESI+: 242

296
ESI−: 478

297
ESI+: 258

298
ES+: 262

299
ESI+: 274

300
ESI+: 262

301
ESI+: 278

302
ESI+: 152

303
ESI+: 455

304
NMR-CDCl₃: 1.39-1.55 (11H, m), 1.92-2.03 (2H, m),

2.08-2.20 (2H, m), 2.77-2.87 (2H, m), 2.90 (1.8H, s),

3.01 (1.2H, s), 3.50 (2H, s), 3.67-3.80 (1H, m), 3.99-4.08

(2H, m), 4.50 (0.8H, s), 4.65 (1.2H, s), 4.65-4.72 (1H,

m), 5.52-5.61 (1H, m), 6.39-6.46 (1H, m), 7.06-7.52

(13H, m)

305
ESI+: 496

306
ESI+: 464

307
ESI+: 533

308
ESI+: 486

309
ESI+: 233

310
ESI+: 299

311
ESI+: 297

312
ESI+: 283

313
ESI+: 316

314
ESI+: 278

315
ESI+: 261

316
ESI+: 294

317
ESI+: 375

318
ESI+: 279

319
ESI+: 519

TABLE 78

Rf
Data

320
ESI+: 481

321
ESI+: 495

322
ESI+: 541

323
ESI+: 380

324
EI: 257

325
ESI+: 467

326
ESI+: 201

327
ESI+: 370

328
ESI+: 571

329
ESI+: 606

330
ESI+: 322

331
ESI+: 405

332
ESI+: 595

333
ESI+: 278

334
ESI+: 178

335
ESI+: 297

336
ESI+: 376

337
ESI+: 573

338
ESI+: 439

Example 1

tert-Butyl {2-[(3-bromobenzyl)amino]-2-oxoethyl}carbamate (350 mg) was dissolved in DME (3 ml) and water (1.5 ml), and 1,4-benzodioxane-6-boronic acid (194 mg), sodium carbonate (313 mg), and tetrakis(triphenylphosphine)palladium (34 mg) were added thereto, followed by stirring at 80° C. for 1 day. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH). The product was dissolved in MeOH (3.5 ml), and 4 M hydrogen chloride/EtOAc (2.0 ml) was added thereto, followed by stirring at room temperature for one day. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH). The product was dissolved in EtOH (3 ml), and L-tartaric acid (126 mg) was added thereto, followed by stirring at room temperature for 2 hours. The precipitated solid was collected by filtration to obtain N-[3-(2,3-dihydro-1,4-benzodioxin-6-yl)benzyl]-N-methylglycinamide L-tartrate (453 mg).

Example 2

Azetidine hydrochloride (287 mg) was suspended in DMF (5 ml), and tert-butyl (2-{[3-(2-chloropyrimidin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (300 mg) and K₂CO₃(849 mg) were added thereto, followed by stirring at 80° C. overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc). The product was dissolved in EtOH (4 ml), and 4 M hydrogen chloride/EtOAc (2 ml) was added thereto, followed by stirring at room temperature overnight. The precipitated solid was collected by filtration to obtain N-[3-(2-azetidin-1-ylpyrimidin-5-yl)benzyl]-N-methylglycinamide dihydrochloride (295 mg).

Example 3

1-(3-Methylpyridin-2-yl)piperazine dihydrochloride (3.0 g) and K₂CO₃(8.5 g) were suspended in DMF (100 ml), followed by stirring at 60° C. for 30 minutes. tert-Butyl (2-{[3-(2-chloropyrimidin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (4.0 g) was added thereto, followed by stirring at 60° C. overnight. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄, the solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH). The product was dissolved in EtOH (40 ml), and 4 M hydrogen chloride/EtOAc (20 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH). The product was dissolved in EtOH (40 ml), and L-tartaric acid (960 mg) was added thereto, followed by stirring at room temperature overnight. The precipitated solid was collected by filtration to obtain N-methyl-N-(3-{2-[4-(3-methylpyridin-2-yl)piperazin-1-yl]pyrimidin-5-yl}benzyl)glycinamide L-tartrate (2.9 g).

Example 19

(2E)-3-[6-(4-{5-[3-({[N-(tert-Butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)-5-methylpyridin-3-yl]acrylic acid (147 mg) was dissolved in dioxane (3 ml), and CHCl₃(1 ml) and 4 M hydrogen chloride/dioxane (1 ml) was added thereto, followed by stirring at room temperature overnight. The precipitated solid was collected by filtration to obtain (2E)-3-(6-{-4-[5-(3-{[glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}-5-methylpyridin-3-yl)acrylic acid dihydrochloride (130 mg).

Example 69

To a solution of tert-butyl (2-{methyl[3-(2-morpholin-4-ylpyrimidin-5-yl)benzyl]amino}-2-oxoethyl)carbamate (230 mg) in MeOH (2.3 ml) was added 4 M hydrogen chloride/EtOAc (1 ml), followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to liquid separation with CHCl₃and a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, and then the aqueous layer was extracted with CHCl₃again. These organic layers were combined, dried over Na₂SO₄, and then concentrated under reduced pressure. The obtained residue was purified by flash column chromatography (NH silica 20 ml, 2% MeOH/CHCl₃). The product was dissolved in EtOH (5 ml), and L-tartaric acid was added thereto, followed by stirring for 3 hours. The precipitated solid was collected and washed with EtOH to obtain N-methyl-N-[3-(2-morpholin-4-ylpyrimidin-5-yl)benzyl]glycinamide L-tartrate (191 mg) as a colorless solid.

Example 208

To N-methyl-N-{3-[2-(4-pyridin-3-ylpiperazin-1-yl)pyrimidin-5-yl]benzyl}glycinamide trihydrochloride (140 mg) were added a saturated aqueous sodium hydrogen carbonate solution and CHCl₃, and the organic layer was dried over MgSO₄and concentrated under reduced pressure. The mixture was dissolved in EtOH, and L-tartaric acid (40 mg) was added thereto. After stirring at room temperature for 2 hours, the precipitated solid was collected by filtration to obtain N-methyl-N-{3-[2-(4-pyridin-3-ylpiperazin-1-yl)pyrimidin-5-yl]benzyl}glycinamide L-tartrate (151 mg).

Example 209

tert-Butyl 4-(5-methylpyridin-2-yl)piperazine-1-carboxylate (200 mg) was dissolved in MeOH (4 ml), and 4 M hydrogen chloride/EtOAc (2 ml) was added thereto, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and then suspended in DMF (4 ml), and K₂CO₃(500 mg) was added thereto, followed by stirring at 80° C. for 10 minutes. tert-Butyl (2-{[3-(2-chloropyrimidin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (200 mg) was added thereto, followed by stirring at 80° C. overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH). The product was dissolved in MeOH (3 ml), and 4 M hydrogen chloride/EtOAc (1.5 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH). The product was dissolved in EtOH (3 ml), and L-tartaric acid (35 mg) was added thereto, followed by stirring at room temperature overnight. The precipitated solid was collected by filtration to obtain N-methyl-N-(3-{2-[4-(5-methylpyridin-2-yl)piperazin-1-yl]pyrimidin-5-yl}benzyl)glycinamide L-tartrate (63 mg).

Example 212

6-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-5-methylnicotinic acid (169 mg) was dissolved in dioxane (3.6 ml), and 4 M hydrogen chloride/EtOAc (1.5 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure and then suspended in DMF (3 ml), and tert-butyl (2-{[3-(2-chloropyrimidin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (200 mg) and DIPEA (371 mg) were added thereto, followed by stirring at 130° C. overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH). The product was dissolved in dioxane, and 4 M hydrogen chloride/EtOAc (1.5 ml) was added thereto, followed by stirring at room temperature overnight. The precipitated solid was collected by filtration to obtain 6-{4-[5-(3-{[glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}-5-methylnicotinic acid dihydrochloride (60 mg).

Example 213

To a suspension of tert-butyl {2-[(3-bromobenzyl)(methyl)amino]-2-oxoethyl}carbamate (293 mg) in toluene (4 ml) were added water (2 ml), (4-chlorophenyl) boronic acid (192 mg), sodium carbonate (173 mg), and tetrakis(triphenylphosphine)palladium (28 mg), followed by stirring at 80° C. overnight. The reaction mixture was cooled to room temperature, and then water was added thereto, followed by extraction with EtOAc. The organic layer was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/EtOAc=10/0 to ½). The purified product was dissolved in EtOAc (5 ml), and then 4 M hydrogen chloride/EtOAc (10 ml) was added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and then MeCN was added thereto. The precipitated solid was collected and washed with MeCN to obtain N-[(4′-chlorobiphenyl-3-yl)methyl]-N-methylglycinamide hydrochloride (267 mg).

Example 215

tert-Butyl {2-[(3-bromobenzyl)amino]-2-oxoethyl}carbamate (200 mg) was dissolved in DME (10 ml), and water (5 ml), 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxabolan-2-yl)phenyl]morpholine (219 mg), sodium carbonate (216 mg), and tetrakis(triphenylphosphine)palladium (20 mg) were added thereto, followed by stirring at 80° C. overnight. The reaction mixture was cooled to room temperature, and then water was added thereto, followed by extraction with EtOAc. The organic layer was dried over MgSO₄and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc=2/1). The obtained solid was dissolved in 4 M hydrogen chloride/EtOAc, followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and to the residue was added a 1 M aqueous sodium hydrogen carbonate solution, followed by extraction with CHCl₃. The organic layer was dried over MgSO₄, and then the solvent was evaporated under reduced pressure. The obtained residue was dissolved in EtOH, and oxalic acid (52 mg) was added thereto. The precipitated solid was collected by filtration to obtain N-[(4′-morpholin-4-ylbiphenyl-3-yl)methyl]glycinamide oxalate (126 mg).

Example 217

1-(5-bromopyridin-2-yl)-4-(3-methylpyridin-2-yl)piperazine (280 mg) and tert-butyl (2-{methyl[3-(4,4,5,5-tetramethyl-1,3,2-dioxabolan-2-yl)benzyl]amino}-2-oxoethyl)carbamate (292 mg) was dissolved in DME (4 ml) and water (2 ml), and tetrakis(triphenylphosphine)palladium (41 mg) and sodium carbonate (230 mg) were added thereto, followed by stirring at 80° C. overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄, and then the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc). The product was dissolved in EtOH (4 ml), and 4 M hydrogen chloride/EtOAc (2 ml) was added thereto, followed by stirring at room temperature overnight. The precipitated solid was collected by filtration to obtain N-methyl-N-(3-{6-[4-(3-methylpyridin-2-yl)piperazin-1-yl]pyridin-3-yl}benzyl)glycinamide trihydrochloride (164 mg).

Example 218

Under an argon atmosphere, tert-butyl (2-{methyl[3-(2-piperazin-1-ylpyrimidin-5-yl)benzyl]amino}-2-oxoethyl)carbamate (200 mg) and 2-bromo-6-methylpyridine (94 mg) were dissolved in toluene (3 ml), and tris(dibenzylideneacetone) dipalladium (12 mg), 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphine) (25 mg), and cesium carbonate (444 mg) were added thereto, followed by stirring at 100° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH). The product was dissolved in MeOH (3 ml), and 4 M hydrogen chloride/EtOAc was added thereto, followed by stirring at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH). The product was dissolved in EtOH (2 ml), and L-tartaric acid (15 mg) was added thereto, followed by stirring at room temperature for 1 hour. The precipitated solid was collected by filtration to obtain N-methyl-N-(3-{2-[4-(6-methylpyridin-2-yl)piperazin-1-yl]pyrimidin-5-yl}benzyl)glycinamide L-tartrate (50 mg).

Example 219

3′-({[N-(tert-Butoxycarbonyl)glycyl](methyl)amino}methyl)biphenyl-4-carboxylic acid (400 mg) and 1-benzylpiperidin-4-amine (210 mg) were suspended in methylene chloride (4 ml), and WSC hydrochloride (231 mg) and HOBt (163 mg) were added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was subjected to liquid separation with CHCl₃and water. The organic layer was separated, and then the aqueous layer was extracted with CHCl₃again. These organic layers were combined and dried over Na₂SO₄, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (2% MeOH/CHCl₃). The product was dissolved in MeOH (4 ml), and 4 N hydrogen chloride/EtOAc (1 ml) was added thereto, followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. To the obtained residue were added CHCl₃and an aqueous sodium hydrogen carbonate solution, and the organic layer was dried over Na₂SO₄and then concentrated under reduced pressure. The obtained residue was dissolved in EtOH (3 ml), and oxalic acid (90 mg) was added thereto. The precipitated solid was collected by filtration to obtain N-(1-benzylpiperidin-4-yl)-3′-{[glycyl(methyl)amino]methyl}biphenyl-4-carboxamide oxalate (198 mg) as a colorless solid.

Example 222

tert-Butyl (2-{methyl[3-(2-piperazin-1-ylpyrimidin-5-yl)benzyl]amino}-2-oxoethyl)carbamate (250 mg) was dissolved in dichloroethane (3 ml), and 3-hydroxy-2,2-dimethylpropionic acid (74 mg), WSC hydrochloride (131 mg), and HOBt (92 mg) were added thereto, followed by stirring at 60° C. for 6 hours. To the reaction mixture was added water, followed by extraction with CHCl₃. After drying over Na₂SO₄, the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH). The product was dissolved in EtOH (3 ml), and 4 M hydrogen chloride/EtOAc (1 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH). The product was dissolved in EtOH (3 ml), and L-tartaric acid (27 mg) was added thereto, followed by stirring at room temperature overnight. The precipitated solid was collected by filtration to obtain N-(3-{2-[4-(3-hydroxy-2,2-dimethylpropanoyl)piperazin-1-yl]pyrimidin-5-yl}benzyl)-N-methylglycinamide L-tartrate (62 mg).

Example 226

tert-Butyl {2-[{[4′-(aminomethyl)biphenyl-3-yl]methyl}(methyl)amino]-2-oxoethyl}carbamate (269 mg) was dissolved in THF (4.8 ml), and TEA (85 mg) was added thereto. Acetyl chloride (61 mg) was added thereto, followed by stirring at room temperature for 1 hour. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (NH-silica, hexane/EtOAc=10/0 to 2/8). The purified product was dissolved in EtOAc (5 ml), and then 4 M hydrogen chloride/EtOAc (10 ml) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in EtOH (3 ml), and then added to and suspended in EtOAc (30 ml). The precipitated insoluble material was collected and dried at room temperature under reduced pressure to obtain N-{[4′-(acetamidemethyl)biphenyl-3-yl]methyl}-N-methylglycinamide hydrochloride (146 mg).

Example 228

tert-Butyl (2-{[(4′-aminobiphenyl-3-yl)methyl](methyl)amino]-2-oxoethyl}carbamate (200 mg) was dissolved in CHCl₃(2 ml), and TEA (60 mg) was added thereto. 2,2-Dimethylpropanoyl chloride (73 mg) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and to the residue was added EtOAc. The mixture was washed with 0.5 M hydrochloric acid, a 1 M aqueous sodium hydrogen carbonate solution, and saturated brine in this order, dried over MgSO₄, concentrated under reduced pressure, and then dissolved in EtOAc (5 ml). 4 M hydrogen chloride/EtOAc (10 ml) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. To the obtained residue was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and concentrated under reduced pressure. To the obtained residue was added EtOH, and subsequently, oxalic acid (49 mg) was added thereto. The precipitated solid was collected by filtration to obtain N-(3′-{[glycyl(methyl)amino]methyl}biphenyl-4-yl)-2,2-dimethylpropaneamide oxalate (205 mg).

Example 239

tert-Butyl (2-{[3-(6-formylpyridin-3-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (150 mg) and (2R)-pyrrolidin-2-ylmethanol (59 mg) was dissolved in dichloroethane (1 ml) and acetic acid (1 ml), followed by stirring at 60° C. for 30 minutes. Sodium triacetoxyborohydride (166 mg) was added thereto, followed by stirring at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and to the obtained residue was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH). The product was dissolved in MeOH (3 ml), and 4 M hydrogen chloride/EtOAc (1 ml) was added thereto, followed by stirring at room temperature overnight and concentrating under reduced pressure. Then, EtOH was added thereto, and then the precipitated solid was collected by filtration to obtain N-[3-(6-{[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}pyridin-3-yl)benzyl]-N-methylglycinamide trihydrochloride (43 mg).

Example 244

tert-Butyl (2-{[3-(6-formylpyridin-3-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (300 mg) and 2-piperazin-1-ylpyrimidine (154 mg) was dissolved in dichloroethane (2 ml) and acetic acid (2 ml), followed by stirring at 60° C. for 30 minutes. Sodium triacetoxyborohydride (332 mg) was added thereto, followed by stirring at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH). The product was dissolved in MeOH (5 ml), and 4 M hydrogen chloride/EtOAc (2 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH). The product was dissolved in EtOH (5 ml), and L-tartaric acid (117 mg) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and then EtOAc was added thereto. The precipitated solid was collected by filtration to obtain N-methyl-N-(3-{6-[(4-pyrimidin-2-ylpiperazin-1-yl)methyl]pyridin-3-yl}benzyl)glycinamide L-tartrate (34 mg).

Example 248

Ethyl 3-[6-(4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)-5-(hydroxymethyl)pyridin-3-yl]propanoate (222 mg) was dissolved in EtOH (1 ml) and THF (2 ml), and a 1 M aqueous NaOH solution (1 ml) was added thereto, followed by stirring at room temperature for 5 hours. To the reaction mixture was added 1 M hydrochloric acid (1 ml), and the solvent was evaporated under reduced pressure. To the obtained residue was added water, followed by extraction with CHCl₃. The organic layer was dried over MgSO₄, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH). The product was dissolved in dioxane (2 ml), and 4 M hydrogen chloride/dioxane (0.8 ml) was added thereto. After stirring at room temperature overnight, the precipitated solid was collected by filtration to obtain 3-[6-{4-[5-(3-{[glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}-5-(hydroxymethyl)pyridin-3-yl]propionic acid dihydrochloride (203 mg).

Example 254

To a solution of [3′-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)biphenyl-4-yl]methylmethanesulfonate (163 mg) in DMF (1.6 ml) was added 1-methyl-1,4-diazepane (80 mg), followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then purified by silica gel column chromatography (CHCl₃/MeOH). The product was dissolved in MeOH (1.6 ml), and 4 M hydrogen chloride/EtOAc (0.8 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH). The product was dissolved in EtOH (2 ml), and L-tartaric acid (9 mg) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and then EtOAc was added thereto. The precipitated solid was collected by filtration to obtain N-methyl-N-({4′-[(4-methyl-1,4-diazepan-1-yl)methyl]biphenyl-3-yl}methyl)glycinamide L-tartrate (16 mg).

Example 255

To a solution of [3′-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)biphenyl-4-yl]methylmethanesulfonate (163 mg) in DMF (1.6 ml) was added 1-methylpiperazine (70 mg), followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then purified by silica gel column chromatography (CHCl₃/MeOH). The product was dissolved in MeOH (3 ml), and 4 M hydrogen chloride/EtOAc (1 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then EtOH was added thereto. The precipitated solid was collected by filtration to obtain N-methyl-N-({4′-[(4-methylpiperazin-1-yl)methyl]biphenyl-3-yl}methyl)glycinamide trihydrochloride (168 mg).

Example 261

tert-Butyl {2-[(3-{2-[4-(6-cyanopyridin-3-yl)piperazin-1-yl]pyrimidin-5-yl}benzyl)(methyl)amino]-2-oxoethyl}carbamate (248 mg) was dissolved in dichloromethane (4 ml), and TFA (4.52 g) was added thereto, followed by stirring at room temperature for 3 hours and concentrating under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl₃. The organic layer was purified by silica gel column chromatography (NH silica, CHCl₃/MeOH=100/0 to 96/4). The purified product was dissolved in EtOH (1 ml), and L-tartaric acid (17 mg) was added thereto, followed by stirring at 75° C. for 10 minutes. The precipitated solid was collected by filtration to obtain N-(3-{2-[4-(6-cyanopyridin-3-yl)piperazin-1-yl]pyrimidin-5-yl}benzyl)-N-methylglycinamide L-tartrate (34 mg).

Example 263

3-Chloro-4-piperazin-1-ylboronic acid hydrochloride (142 mg) was suspended in DMF (3 ml), and tert-butyl (2-{[3-(2-chloropyrimidin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (190 mg) and DIPEA (371 mg) were added thereto, followed by stirring at 130° C. overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH). The product was dissolved in dioxane, and 4 M hydrogen chloride/dioxane (1 ml) was added thereto, followed by stirring at room temperature overnight. The precipitated solid was collected by filtration to obtain 3-chloro-4-{4-[5-(3-{[glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}benzoic acid dihydrochloride (72 mg).

Example 264

To a solution of tert-butyl {2-[{([4′-(chloromethyl)biphenyl-3-yl]methyl}(methyl)amino]-2-oxoethyl}carbamate (150 mg) in DMF (2 ml) was added N,N-dimethylpiperidin-4-amine (105 mg), followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH). The product was dissolved in MeOH, and 4 M hydrogen chloride/EtOAc (1 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then EtOH was added thereto. The precipitated solid was collected by filtration to obtain N-[(4′-{[4-(dimethylamino)piperidin-1-yl]methyl}biphenyl-3-yl)methyl]-N-methylglycinamide trihydrochloride (188 mg).

Example 265

To a solution of tert-butyl {2-[{[4′-(chloromethyl)biphenyl-3-yl]methyl}(methyl)amino]-2-oxoethyl}carbamate (150 mg) in DMF (1.4 ml) was added piperidin-4-ylmethanol (81 mg), followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH). The product was dissolved in MeOH (1.4 ml), and 4 M hydrogen chloride/EtOAc (1 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl₃/MeOH). The product was dissolved in EtOH (1.4 ml), and L-tartaric acid (32 mg) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and then EtOAc was added thereto. The precipitated solid was collected by filtration to obtain N-[(4′-{[4-(hydroxymethyl)piperidin-1-yl]methyl}biphenyl-3-yl)methyl]-N-methylglycinamide L-tartrate (69 mg).

Example 270

tert-Butyl (2-{[3-(3′,6′-dihydro-2′H-2,1′:4′,2″-terpyridin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (120 mg) was dissolved in EtOH (3 ml), and 10% Pd/C (40 mg) was added thereto, followed by stirring at room temperature for 5 hours under a hydrogen atmosphere at 1 atm. The catalyst was removed by filtration using Celite as a filtration assistant, and then reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc). The product was dissolved in MeOH, and 4 M hydrogen chloride/EtOAc (1 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and the solvent was concentrated under reduced pressure. The obtained residue was dissolved in EtOH, and L-tartaric acid (13 mg) was added thereto, followed by stirring at room temperature for 5 hours. The precipitated solid was collected by filtration to obtain N-methyl-N-{3-[6-(4-pyridin-2-ylpiperidin-1-yl)pyridin-3-yl]benzyl}glycinamide L-tartrate (24 mg).

Example 272

3-Methoxypropan-1-ol (88 mg) was dissolved in THF (3 ml), and NaH (60 mg) was added thereto, followed by stirring at room temperature for 10 minutes. 4-Nitrophenyl 4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazine-1-carboxylate (250 mg) was added thereto, followed by stirring at room temperature for 1 hour. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over Na₂SO₄and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc). The product was dissolved in EtOH, and 4 M hydrogen chloride/EtOAc was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl₃. The organic layer was dried over Na₂SO₄and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl₃/MeOH). The obtained residue was dissolved in EtOH, and L-tartaric acid (26 mg) was added thereto, followed by stirring at room temperature overnight. The precipitated solid was collected by filtration to obtain 3-methoxypropyl 4-[5-(3-{[glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazine-1-carboxylate L-tartrate (60 mg).

Example 281

To a solution of 3′-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)biphenyl-4-carboxylic acid (9 mg) in DMF (1 ml) was added HOBt (2 mg) and ethylamine (2 mg), and PS-Carbodiimide (manufactured by Biotage AB) (100 mg) was added thereto, followed by shaking overnight. Thereafter, PS-Isocyanate (manufactured by Biotage AB) and MP-Carbonate (manufactured by Biotage AB) were added in an amount of 50 mg, and DMF (0.5 ml) was further added thereto, followed by shaking for 2 hours. The insoluble material was filtered and the filtrate was concentrated. To the obtained residue was added MeOH (0.5 ml), and a 4 M hydrogen chloride/EtOAc solution (0.5 ml) was added thereto, followed by shaking for 1 hour. Thereafter, the reaction mixture was concentrated to obtain N-ethyl-3′-{[glycyl(methyl)amino]methyl}biphenyl-4-carboxamide (15.4 mg).

Example 374

To a mixture of 2-(piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (14 mg), tert-butyl {2-[(3-bromobenzyl)(methyl)amino]-2-oxoethyl}carbamate (9 mg), and DMF (0.2 ml) were added tetrakis(triphenylphosphine)palladium (3 mg), sodium carbonate (5 mg), and water (0.1 ml), followed by stirring at 60° C. overnight. After cooling to room temperature, to the reaction mixture was added CHCl₃(2 ml), and the reaction mixture was filtered in a column preconditioned by the addition of 0.8 ml of water to a diatomaceous earth column (manufactured by Varian Inc., ChemElute 1 ml). The obtained filtrate was concentrated, and then to the residue were added MeOH (0.5 ml) and a 4 M hydrogen chloride/EtOAc solution (0.5 ml), followed by leaving to stand for 30 minutes. Thereafter, the reaction mixture was concentrated and the compound was purified by preparative liquid chromatography (MeOH/0.1% aqueous formic acid solution) to obtain N-methyl-N-{3-[2-(piperidin-1-yl)pyrimidin-5-yl]benzyl}glycinamide (3.8 mg).

Example 417

To 3-chloro-4-{4-[5-(3-{[glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}benzoic acid dihydrochloride (3.0 g) were added THF (30 ml) and H₂O (15 ml). To this mixture was added 1 N sodium hydroxide (10.6 ml), followed by stirring for 30 minutes. The precipitated solid was filtered and washed with water. The obtained product was dried at 50° C. under reduced pressure to obtain 3-chloro-4-{4-[5-(3-{[glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}benzoic acid (2.1 g) as a colorless solid.

Next, 3-chloro-4-{4-[5-(3-{[glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}benzoic acid (2 g) was suspended in THF (40 ml)-H₂O (40 ml), and fumaric acid (938 mg) was added thereto, followed by stirring at 90° C. for 1 hour. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. To the residue was added THF (20 ml)-H₂O (20 ml), followed by stirring at 90° C. for 1 hour as it was suspended. The mixture was cooled to room temperature, followed by stirring overnight. After the mixture was filtered, washed with THF—H₂O (1:1), and then dried at 50° C. for 5 hours under reduced pressure to obtain 3-chloro-4-{4-[5-(3-{[glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}benzoic acid hemifumarate (1.7 g) as a colorless crystal.

Example 418

To N-methyl-N-{[4′-(morpholin-4-yl)biphenyl-3-yl]methyl}glycinamide oxalate (100 mg) were added CHCl₃(10 ml) and a saturated aqueous sodium hydrogen carbonate solution (10 ml), followed by stirring for 10 minutes. The aqueous layer was extracted with chloroform (10 ml). The combined organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was dissolved in EtOH (2 ml), and succinic acid was added thereto, followed by stirring for 3 hours. The resulting crystal was filtered and washed with EtOH. The product residue was dried under reduced pressure and dried to obtain N-methyl-N-{[4′-(morpholin-4-yl)biphenyl-3-yl]methyl}glycinamide hemisuccinate (85 mg) as a colorless crystal.

The Example Compounds as shown in Tables below were prepared in the same manner as the methods of Examples above, using each of the corresponding starting materials. The structures, the preparation methods, and the physicochemical data of Example Compounds are shown in Tables below.

TABLE 79

Ex
Syn
Structure
Acid

1
1

embedded image

L-TA

2
2

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2HCl

3
3

embedded image

L-TA

4
3

embedded image

3HCl

5
3

embedded image

L-TA

TABLE 80

Ex
Syn
Structure
Acid

6
3

embedded image

3HCl

7
3

embedded image

L-TA

8
3

embedded image

L-TA

9
3

embedded image

L-TA

10
3

embedded image

L-TA

TABLE 81

Ex
Syn
Structure
Acid

11
3

embedded image

L-TA

12
3

embedded image

L-TA

13
3

embedded image

L-TA

14
3

embedded image

L-TA

15
3

embedded image

L-TA

16
3

embedded image

L-TA

TABLE 82

Ex
Syn
Structure
Acid

17
3

embedded image

L-TA

18
3

embedded image

HCl

19
19

embedded image

2HCl

20
19

embedded image

HCl

21
19

embedded image

HCl

22
19

embedded image

HCl

TABLE 83

Ex
Syn
Structure
Acid

23
19

embedded image

HCl

24
19

embedded image

2HCl

25
19

embedded image

HCl

26
19

embedded image

HCl

27
19

embedded image

4HCl

28
19

embedded image

4HCl

TABLE 84

Ex
Syn
Structure
Acid

29
19

embedded image

3HCl

30
19

embedded image

2HCl

31
19

embedded image

2HCl

32
19

embedded image

2HCl

33
19

embedded image

2HCl

TABLE 85

Ex
Syn
Structure
Acid

34
19

embedded image

HCl

35
19

embedded image

HCl

36
19

embedded image

2HCl

37
19

embedded image

2HCl

38
19

embedded image

HCl

39
19

embedded image

HCl

TABLE 86

Ex
Syn
Structure
Acid

40
19

embedded image

3HCl

41
19

embedded image

2HCl

42
19

embedded image

2HCl

43
19

embedded image

2HCl

44
19

embedded image

3HCl

TABLE 87

Ex
Syn
Structure
Acid

45
19

embedded image

3HCl

46
19

embedded image

3HCl

47
19

embedded image

3HCl

48
19

embedded image

3HCl

49
19

embedded image

2HCl

50
19

embedded image

2HCl

TABLE 88

Ex
Syn
Structure
Acid

51
19

embedded image

3HCl

52
19

embedded image

4HCl

53
19

embedded image

3HCl

54
19

embedded image

3HCl

55
19

embedded image

3HCl

TABLE 89

Ex
Syn
Structure
Acid

56
19

embedded image

3HCl

57
19

embedded image

3HCl

58
19

embedded image

3HCl

59
19

embedded image

3HCl

60
19

embedded image

2HCl

TABLE 90

Ex
Syn
Structure
Acid

61
19

embedded image

2HCl

62
19

embedded image

2HCl

63
19

embedded image

2HCl

64
19

embedded image

2HCl

65
19

embedded image

2HCl

66
19

embedded image

2HCl

TABLE 91

Ex
Syn
Structure
Acid

67
19

embedded image

3HCl

68
19

embedded image

2HCl

69
69

embedded image

L-TA

70
69

embedded image

OA

71
69

embedded image

OA

72
69

embedded image

TABLE 92

Ex
Syn
Structure
Acid

73
69

embedded image

OA

74
69

embedded image

OA

75
69

embedded image

L-TA

76
69

embedded image

L-TA

77
69

embedded image

L-TA

78
69

embedded image

L-TA

TABLE 93

Ex
Syn
Structure
Acid

79
69

embedded image

L-TA

80
69

embedded image

L-TA

81
69

embedded image

L-TA

82
69

embedded image

L-TA

83
69

embedded image

L-TA

84
69

embedded image

L-TA

TABLE 94

Ex
Syn
Structure
Acid

85
69

embedded image

L-TA

86
69

embedded image

L-TA

87
69

embedded image

L-TA

88
69

embedded image

L-TA

89
69

embedded image

L-TA

TABLE 95

Ex
Syn
Structure
Acid

90
69

embedded image

L-TA

91
69

embedded image

L-TA

92
69

embedded image

L-TA

93
69

embedded image

L-TA

94
69

embedded image

L-TA

TABLE 96

Ex
Syn
Structure
Acid

95
69

embedded image

3HCl

96
69

embedded image

L-TA

97
69

embedded image

L-TA

98
69

embedded image

L-TA

99
69

embedded image

L-TA

100
69

embedded image

L-TA

TABLE 97

Ex
Syn
Structure
Acid

101
69

embedded image

L-TA

102
69

embedded image

L-TA

103
69

embedded image

L-TA

104
69

embedded image

L-TA

105
69

embedded image

L-TA

106
69

embedded image

L-TA

107
69

embedded image

L-TA

TABLE 98

Ex
Syn
Structure
Acid

108
69

embedded image

L-TA

109
69

embedded image

L-TA

110
69

embedded image

L-TA

111
69

embedded image

L-TA

112
69

embedded image

L-TA

113
69

embedded image

L-TA

TABLE 99

Ex
Syn
Structure
Acid

114
69

embedded image

L-TA

115
69

embedded image

L-TA

116
69

embedded image

L-TA

117
69

embedded image

L-TA

118
69

embedded image

L-TA

119
69

embedded image

L-TA

TABLE 100

Ex
Syn
Structure
Acid

120
69

embedded image

L-TA

121
69

embedded image

L-TA

122
69

embedded image

L-TA

123
69

embedded image

L-TA

124
69

embedded image

L-TA

TABLE 101

Ex
Syn
Structure
Acid

125
69

embedded image

L-TA

126
69

embedded image

L-TA

127
69

embedded image

L-TA

128
69

embedded image

L-TA

129
69

embedded image

L-TA

130
69

embedded image

L-TA

131
69

embedded image

L-TA

TABLE 102

Ex
Syn
Structure
Acid

132
69

embedded image

L-TA

133
69

embedded image

L-TA

134
69

embedded image

L-TA

135
69

embedded image

L-TA

136
69

embedded image

L-TA

TABLE 103

Ex
Syn
Structure
Acid

137
69

embedded image

L-TA

138
69

embedded image

L-TA

139
69

embedded image

L-TA

140
69

embedded image

L-TA

TABLE 104

Ex
Syn
Structure
Acid

141
69

embedded image

L-TA

142
69

embedded image

L-TA

143
69

embedded image

L-TA

144
69

embedded image

L-TA

145
69

embedded image

L-TA

TABLE 105

Ex
Syn
Structure
Acid

146
69

embedded image

L-TA

147
69

embedded image

L-TA

148
69

embedded image

L-TA

149
69

embedded image

L-TA

150
69

embedded image

L-TA

TABLE 106

Ex
Syn
Structure
Acid

151
69

embedded image

L-TA

152
69

embedded image

L-TA

153
69

embedded image

L-TA

154
69

embedded image

L-TA

155
69

embedded image

L-TA

TABLE 107

Ex
Syn
Structure
Acid

156
69

embedded image

L-TA

157
69

embedded image

L-TA

158
69

embedded image

L-TA

159
69

embedded image

L-TA

160
69

embedded image

L-TA

TABLE 108

Ex
Syn
Structure
Acid

161
69

embedded image

L-TA

162
69

embedded image

L-TA

163
69

embedded image

L-TA

164
69

embedded image

L-TA

165
69

embedded image

L-TA

TABLE 109

Ex
Syn
Structure
Acid

166
69

embedded image

L-TA

167
69

embedded image

L-TA

168
69

embedded image

L-TA

169
69

embedded image

L-TA

170
69

embedded image

L-TA

TABLE 110

Ex
Syn
Structure
Acid

171
69

embedded image

L—TA

172
69

embedded image

L—TA

173
69

embedded image

L—TA

174
69

embedded image

L—TA

175
69

embedded image

L—TA

TABLE 111

Ex
Syn
Structure
Acid

176
69

embedded image

L—TA

177
69

embedded image

L—TA

178
69

embedded image

L—TA

179
69

embedded image

L—TA

180
69

embedded image

L—TA

TABLE 112

Ex
Syn
Structure
Acid

181
69

embedded image

L—TA

182
69

embedded image

L—TA

183
69

embedded image

L—TA

184
69

embedded image

L—TA

185
69

embedded image

L—TA

TABLE 113

Ex
Syn
Structure
Acid

186
69

embedded image

L—TA

187
69

embedded image

L—TA

188
69

embedded image

L—TA

189
69

embedded image

L—TA

190
69

embedded image

L—TA

TABLE 114

Ex
Syn
Structure
Acid

191
69

embedded image

L—TA

192
69

embedded image

L—TA

193
69

embedded image

L—TA

194
69

embedded image

L—TA

195
69

embedded image

TABLE 115

Ex
Syn
Structure
Acid

196
69

embedded image

HCl

197
69

embedded image

OA

198
69

embedded image

OA

199
69

embedded image

3HCl

200
69

embedded image

OA

201
69

embedded image

TABLE 116

Ex
Syn
Structure
Acid

202
69

embedded image

OA

203
69

embedded image

L—TA

204
69

embedded image

L—TA

205
69

embedded image

L—TA

206
69

embedded image

L—TA

207
69

embedded image

L—TA

TABLE 117

Ex
Syn
Structure
Acid

208
208

embedded image

L—TA

209
209

embedded image

L—TA

210
209

embedded image

L—TA

211
209

embedded image

L—TA

212
212

embedded image

2HCl

TABLE 118

Ex
Syn
Structure
Acid

213
213

embedded image

HCl

214
213

embedded image

HCl

215
215

embedded image

OA

216
11

embedded image

2HCl

217
217

embedded image

3HCl

TABLE 119

Ex
Syn
Structure
Acid

218
218

embedded image

L—TA

219
219

embedded image

OA

220
219

embedded image

OA

221
219

embedded image

HCl

222
222

embedded image

L—TA

223
222

embedded image

L—TA

TABLE 120

Ex
Syn
Structure
Acid

224
222

embedded image

OA

225
222

embedded image

OA

226
226

embedded image

HCl

227
226

embedded image

HCl

228
228

embedded image

OA

229
19

embedded image

3HCl

TABLE 121

Ex
Syn
Structure
Acid

230
228

embedded image

OA

231
228

embedded image

OA

232
228

embedded image

OA

233
228

embedded image

L—TA

234
228

embedded image

L—TA

235
228

embedded image

L—TA

TABLE 122

Ex
Syn
Structure
Acid

236
228

embedded image

L—TA

237
228

embedded image

L—TA

238
228

embedded image

L—TA

239
239

embedded image

3HCl

240
239

embedded image

2HCl

241
239

embedded image

2HCl

TABLE 123

Ex
Syn
Structure
Acid

242
239

embedded image

3HCl

243
239

embedded image

4HCl

244
244

embedded image

L—TA

245
244

embedded image

L—TA

246
244

embedded image

L—TA

247
244

embedded image

L—TA

248
248

embedded image

2HCl

TABLE 124

Ex
Syn
Structure
Acid

249
248

embedded image

2HCl

250
248

embedded image

2HCl

251
248

embedded image

2HCl

252
248

embedded image

2HCl

253
248

embedded image

2HCl

TABLE 125

Ex
Syn
Structure
Acid

254
254

embedded image

L-TA

255
254

embedded image

3HCl

256
254

embedded image

HCl

257
254

embedded image

L-TA

258
254

embedded image

L-TA

259
254

embedded image

L-TA

260
254

embedded image

L-TA

TABLE 126

Ex
Syn
Structure
Acid

261
261

embedded image

L-TA

262
261

embedded image

L-TA

263
263

embedded image

2HCl

264
264

embedded image

3HCl

265
265

embedded image

L-TA

266
265

embedded image

L-TA

TABLE 127

Ex
Syn
Structure
Acid

267
265

embedded image

L-TA

268
265

embedded image

L-TA

269
265

embedded image

L-TA

270
270

embedded image

L-TA

271
270

embedded image

L-TA

272
272

embedded image

L-TA

TABLE 128

Ex
Syn
Structure
Acid

273
272

embedded image

L-TA

274
272

embedded image

L-TA

275
272

embedded image

L-TA

276
272

embedded image

L-TA

277
272

embedded image

L-TA

TABLE 129

Ex
Syn
Structure
Acid

278
272

embedded image

L-TA

279
272

embedded image

L-TA

280
272

embedded image

L-TA

281
281

embedded image

—

282
281

embedded image

—

TABLE 130

Ex
Syn
Structure
Acid

283
281

embedded image

—

284
281

embedded image

—

285
281

embedded image

—

286
281

embedded image

—

287
281

embedded image

—

TABLE 131

Ex
Syn
Structure
Acid

288
281

embedded image

—

289
281

embedded image

—

290
281

embedded image

—

291
281

embedded image

—

292
281

embedded image

—

TABLE 132

Ex
Syn
Structure
Acid

293
281

embedded image

—

294
281

embedded image

—

295
281

embedded image

—

296
281

embedded image

—

297
281

embedded image

—

TABLE 133

Ex
Syn
Structure
Acid

298
281

embedded image

—

299
281

embedded image

—

300
281

embedded image

—

301
281

embedded image

—

302
281

embedded image

—

303
281

embedded image

—

TABLE 134

Ex
Syn
Structure
Acid

304
281

embedded image

—

305
281

embedded image

—

306
281

embedded image

—

307
281

embedded image

—

308
281

embedded image

—

TABLE 135

Ex
Syn
Structure
Acid

309
281

embedded image

—

310
281

embedded image

—

311
281

embedded image

—

312
281

embedded image

—

313
281

embedded image

—

314
281

embedded image

—

TABLE 136

Ex
Syn
Structure
Acid

315
281

embedded image

—

316
281

embedded image

—

317
281

embedded image

—

318
281

embedded image

—

319
281

embedded image

—

TABLE 137

Ex
Syn
Structure
Acid

320
281

embedded image

—

321
281

embedded image

—

322
281

embedded image

—

323
281

embedded image

—

324
281

embedded image

—

TABLE 138

Ex
Syn
Structure
Acid

325
281

embedded image

—

326
281

embedded image

—

327
281

embedded image

—

328
281

embedded image

—

329
281

embedded image

—

TABLE 139

Ex
Syn
Structure
Acid

330
281

embedded image

—

331
281

embedded image

—

332
281

embedded image

—

333
281

embedded image

—

334
281

embedded image

—

TABLE 140

Ex
Syn
Structure
Acid

335
281

embedded image

—

336
281

embedded image

—

337
281

embedded image

—

338
281

embedded image

—

339
281

embedded image

—

TABLE 141

Ex
Syn
Structure
Acid

340
281

embedded image

—

341
281

embedded image

—

342
281

embedded image

—

343
281

embedded image

—

344
281

embedded image

—

345
281

embedded image

—

TABLE 142

Ex
Syn
Structure
Acid

346
281

embedded image

—

347
281

embedded image

—

348
281

embedded image

—

349
281

embedded image

—

350
281

embedded image

—

351
281

embedded image

—

TABLE 143

Ex
Syn
Structure
Acid

352
281

embedded image

—

353
281

embedded image

—

354
281

embedded image

—

355
281

embedded image

—

356
281

embedded image

—

357
281

embedded image

—

TABLE 144

Ex
Syn
Structure
Acid

358
281

embedded image

—

359
281

embedded image

—

360
281

embedded image

—

361
281

embedded image

—

362
281

embedded image

—

363
281

embedded image

—

TABLE 145

Ex
Syn
Structure
Acid

364
281

embedded image

—

365
281

embedded image

—

366
281

embedded image

—

367
281

embedded image

—

368
281

embedded image

—

369
281

embedded image

—

TABLE 146

Ex
Syn
Structure
Acid

370
281

embedded image

—

371
281

embedded image

—

372
281

embedded image

—

373
281

embedded image

—

374
374

embedded image

—

375
374

embedded image

—

TABLE 147

Ex
Syn
Structure
Acid

376
374

embedded image

—

377
374

embedded image

—

378
374

embedded image

—

379
374

embedded image

—

380
374

embedded image

—

381
374

embedded image

—

TABLE 148

Ex
Syn
Structure
Acid

382
374

embedded image

—

383
374

embedded image

—

384
374

embedded image

—

385
374

embedded image

—

386
374

embedded image

—

387
374

embedded image

—

TABLE 149

Ex
Syn
Structure
Acid

388
374

embedded image

—

389
374

embedded image

—

390
374

embedded image

—

391
374

embedded image

—

392
374

embedded image

—

393
374

embedded image

—

TABLE 150

Ex
Syn
Structure
Acid

394
374

embedded image

—

395
374

embedded image

—

396
374

embedded image

—

397
374

embedded image

—

398
374

embedded image

—

399
374

embedded image

—

TABLE 151

Ex
Syn
Structure
Acid

400
374

embedded image

—

401
374

embedded image

—

402
374

embedded image

—

403
374

embedded image

—

404
374

embedded image

—

405
374

embedded image

—

TABLE 152

Ex
Syn
Structure
Acid

406
374

embedded image

—

407
374

embedded image

—

408
374

embedded image

—

409
374

embedded image

—

410
374

embedded image

—

411
374

embedded image

—

TABLE 153

Ex
Syn
Structure
Acid

412
374

embedded image

—

413
374

embedded image

—

414
374

embedded image

—

415
374

embedded image

—

416
374

embedded image

—

TABLE 154

Ex
Data

1
ESI+: 313

2
FAB+: 312

3
ESI+: 432

4
ESI+: 431

5
ESI+: 486

6
ESI+: 430

7
ESI+: 453

8
ESI+: 457

9
ESI+: 452

10
ESI+: 413

11
ESI+: 406

NMR-DMSO-d₆: 1.78-1.93 (2H, m), 2.01-2.14 (2H, m),

2.90 (0.9H, s), 2.96 (2.1H, s), 3.06-3.20 (2H, m),

3.82-4.20 (4H, m), 4.47-4.68 (3H, m), 4.74-4.87 (2H,

m), 6.18-6.26 (1H, m), 7.17-7.26 (1H, m), 7.37-7.52

(3H, m), 7.53-7.65 (1H, m), 7.75-7.83 (1H, m), 8.72

(1.4H, s), 8.75 (0.6H, s)

12
ESI+: 423

13
ESI+: 409

14
FAB+: 340

NMR-DMSO-d₆: 1.22 (3H, d, J = 6.8 Hz), 1.63-1.75

(1H, m), 1.84-2.12 (3H, m), 2.88 (0.9H, s), 2.93 (2.1H, s),

3.39-3.69 (4H, m), 3.70-3.79 (2H, m), 4.18-4.30 (1H, m),

4.58 (0.6H, s), 4.6 (1.4H, s), 7.13-7.22 (1H, m), 7.35-7.49

(2H, m), 7.49-7.60 (1H, m), 8.67 (1.4H, s), 8.69 (0.6H, s)

15
FAB+: 344

NMR-DMSO-d₆: 2.08-2.36 (2H, m), 2.88 (0.9H, s), 2.93

(2.1H, s), 3.38-3.94 (8H, m), 4.56 (0.6H, s), 4.60 (1.4H,

s), 5.34-5.56 (1H, m), 7.13-7.24 (1H, m), 7.34-7.50 (2H,

m), 7.50-7.62 (1H, m), 8.63-8.78 (2H, m)

16
FAB+: 344

NMR-DMSO-d₆: 2.08-2.35 (2H, m), 2.88 (0.9H, s), 2.93

(2.1H, s), 3.38-3.93 (8H, m), 4.57 (0.6H, s), 4.60 (1.4H, s),

5.35-5.56 (1H, m), 7.13-7.23 (1H, m), 7.37-7.50 (2H, m),

7.50-7.62 (1H, m), 8.65-8.76 (2H, m)

TABLE 155

Ex
Data

17
FAB+: 362

NMR-DMSO-d₆: 2.40-2.64 (2H, m), 2.89 (0.9H, s), 2.95

(2.1H, s), 3.70-3.83 (4H, m), 3.83-4.20 (4H, m), 4.58

(0.6H, s), 4.62 (1.4H, s), 7.16-7.26 (1H, m), 7.37-7.52

(2H, m), 7.52-7.64 (1H, m), 8.68-8.81 (2H, m)

18
FAB+: 358

19
FAB+: 502

NMR-DMSO-d₆: 2.39 (3H, s), 2.90 (0.9H, s), 2.97 (2.1H,

s), 3.35-3.52 (4H, m), 3.87-4.04 (6H, m), 4.57-4.66 (2H,

m), 6.56 (1H, d, J = 16.0 Hz), 7.18-7.27 (1H, m),

7.38-7.53 (2H, m), 7.54-7.66 (2H, m), 8.07-8.31 (4H,

m), 8.34-8.41 (1H, m), 8.76 (1.6H, s), 8.79 (0.4H, s)

20
ESI+: 312

21
ESI+: 340

22
ESI+: 355

23
ESI+: 396

24
ESI+: 431

25
ESI+: 356

26
FAB+: 353

27
ESI+: 418

NMR-DMSO-d6: 2.90 (1.2H, s), 2.97 (1.8H, s), 3.78-4.15

(10H, m), 4.61 (0.8H, s), 4.63 (1.2H, s), 7.17-7.65

(6H, m), 8.18-8.33 (5H, m), 8.78 (1.2H, s), 8.80

(0.8H, s)

28
ESI+: 419

NMR-DMSO-d₆: 2.90 (1.2H, s), 2.97 (1.8H, s),

3.50-4.10 (10H, m), 4.60 (0.8H, s), 4.63 (1.2H, s),

6.72 (1H, t, J = 5 Hz), 7.24 (1H, d, J = 7 Hz),

7.40-7.65 (3H, m), 8.07-8.22 (3H, m), 8.44 (2H, d,

J = 5 Hz), 8.75 (1.2H, s), 8.77 (0.8H, s)

29
ESI+: 488

NMR-DMSO-d₆: 2.38 (3H, s), 3.39-3.44 (4H, m),

3.93-4.04 (6H, m), 4.42 (2H, d, J = 6 Hz), 6.54

(1H, d, J = 16 Hz), 7.28 (1H, d, J = 8 Hz),

7.43 (1H, t, J = 8 Hz), 7.54-7.61 (3H, m), 8.37

(1H, d, J = 2 Hz), 8.76 (2H, s), 8.99 (1H, t,

J = 5 Hz)

TABLE 156

Ex
Data

30
ESI+: 516

NMR-DMSO-d₆: 2.38 (3H, s), 3.39-3.44 (4H, m), 3.93-4.04

(6H, m), 4.42 (2H, d, J = 6 Hz), 6.54 (1H, d, J = 16 Hz),

7.28 (1H, d, J = 8 Hz), 7.43 (1H, t, J = 8 Hz), 7.54-7.61

(3H, m), 8.37 (1H, d, J = 2 Hz), 8.76 (2H, s), 8.99 (1H, t,

J = 5 Hz)

31
ESI+: 412

32
ESI+: 496, 498

NMR-DMSO-d₆: 2.90 (0.9H, s), 2.97 (2.1H, s), 3.57-3.62

(4H, m), 3.90-4.02 (6H, m), 4.60 (0.6H, s), 4.63 (1.4H, s),

7.24 (1H, d, J = 7.6 Hz), 7.41-7.65 (3H, m), 8.06-8.17

(3H, br), 8.13 (1H, d, J = 2.0 Hz), 8.69 (1H, d, J = 2.0 Hz),

8.75 (1.4H, s), 8.77 (0.6H, s)

33
ESI+: 522, 524

NMR-DMSO-d₆: 2.90 (0.9H, s), 2.97 (2.1H, s), 3.46-3.51

(4H, m), 3.90-4.02 (6H, m), 4.60 (0.6H, s), 4.63 (1.4H, s),

6.60 (1H, d, J = 16.0 Hz), 7.24 (1H, d, J = 7.6 Hz), 7.41-7.65

(4H, m), 8.07-8.19 (3H, br), 8.27 (1H, d, J = 2.0 Hz), 8.50

(1H, d, J = 2.0 Hz), 8.75 (1.4H, s), 8.77 (0.6H, s)

34
ESI+: 397

35
ESI+: 338

36
ESI+: 375

37
ESI+: 375

38
ESI+: 380

39
ESI+: 396

40
FAB+: 355

41
ESI+: 356

NMR-DMSO-d₆: 1.87-2.11 (4H, m), 2.90 (0.9H, s), 2.97

(2.1H, s), 3.37-3.67 (5H, m), 3.87-4.01 (2H, m), 4.12-4.24

(1H, m), 4.60 (0.6H, s), 4.62 (1.4H, s), 7.21-7.26 (1H, m),

7.40-7.52 (2H, m), 7.54-7.64 (1H, m), 8.15-8.32 (3H, br),

8.73 (1.4H, s), 8.76 (0.6H, s)

42
ESI+: 356

NMR-DMSO-d₆: 1.87-2.12 (4H, m), 2.90 (0.9H, s), 2.97

(2.1H, s), 3.36-3.67 (5H, m), 3.88-4.01 (2H, m), 4.12-4.24

(1H, m), 4.60 (0.6H, s), 4.62 (1.4H, s), 7.21-7.25 (1H, m),

7.39-7.51 (2H, m), 7.54-7.64 (1H, m), 8.73 (1.4H, s),

8.14-8.30 (3H, br), 8.75 (0.6H, s)

TABLE 157

Ex
Data

43
ESI+: 370

NMR-DMSO-d₆: 1.87-2.10 (4H, m), 2.89 (0.9H, s), 2.95

(2.1H, s), 3.28 (3H, s), 3.31-3.37 (1H, m), 3.41-3.52 (1H,

m) 3.54-3.61 (2H, m), 3.88-4.02 (2H, m), 4.23-4.31 (1H,

m), 4.60 (0.6H, s), 4.62 (1.4H, s), 7.20-7.25 (1H, m),

7.39-7.51 (2H, m), 7.53-7.65 (1H, m), 8.07-8.35 (3H, br),

8.72 (1.4H, s), 8.74 (0.6H, s)

44
ESI+: 417

NMR-DMSO-d₆: 2.90 (0.9H, s), 2.98 (2.1H, s), 3.35-3.56

(4H, m), 3.87-4.01 (2H, m), 4.06-4.32 (4H, m), 4.61 (0.6H,

s), 4.63 (1.4H, s), 7.10-7.29 (2H, m), 7.34-7.69 (7H, m),

8.15-8.35 (3H, br), 8.79 (1.4H, s), 8.81 (0.6H, s)

45
ESI+: 461

46
ESI+: 447

47
ESI+: 377

48
ESI+: 391

49
ESI+: 383

50
ESI+: 354

51
ESI+: 425

52
ESI+: 438

53
ESI+: 363

54
ESI+: 377

55
ESI+: 446

56
ESI+: 432

57
ESI+: 460

58
ESI+: 433

59
ESI+: 467

60
ESI+: 397

61
ESI+: 506

NMR-DMSO-d₆: 2.90 (0.9H, s), 2.97 (2.1H, s), 3.25-3.36

(4H, m), 3.87-4.05 (6H, m), 4.19 (2H, s), 4.57-4.66 (4H, m),

7.09-7.16 (1H, m), 7.21-7.26 (1H, m), 7.41-7.52 (2H, m),

7.55-7.65 (1H, m), 7.87-7.94 (1H, m), 8.05-8.19 (3H, br),

8.21-8.26 (1H, m), 8.75 (1.4H, s), 8.77 (0.6H, s)

62
FAB+: 386

63
ESI+: 454

64
FAB+: 452

TABLE 158

Ex
Data

65
ESI+: 441

66
FAB+: 504

NMR-DMSO-d₆: 2.41 (3H, s), 2.57-2.64 (2H, m), 2.78-2.87 (2H, m),

2.90 (0.9H, s), 2.97 (2.1H, s), 3.40-3.53 (4H, m), 3.86-4.03 (6H, m),

4.58-4.66 (2H, m), 7.20-7.28 (1H, m), 7.41-7.53 (2H, m),

7.55-7.66 (1H, m), 7.97-8.07 (2H, m), 8.13-8.30 (3H, m),

8.77 (1.4H, s), 8.80 (0.6H, s)

67
ESI+: 462

NMR-DMSO-d₆: 2.90 (0.9H, s), 2.97 (2.1H, s), 3.79-3.87 (4H, m),

3.89-4.02 (6H, m), 4.55-4.68 (2H, m), 7.04 (1H, d, J = 9.2 Hz),

7.24 (1H, d, J = 7.7 Hz), 7.39-7.53 (2H, m),

7.54-7.66 (1H, m), 7.98-8.07 (1H, m), 8.08-8.27 (3H, m),

8.62 (1H, d, J = 2.3 Hz), 8.76 (1.4H, s), 8.78 (0.6H, s)

68
ESI+: 461

NMR-DMSO-d₆: 2.90 (0.9H, s), 2.97 (2.1H, s), 3.40-3.50 (4H, m),

3.89-4.03 (6H, m), 4.60 (0.6H, s), 4.63 (1.4H, s),

7.03 (2H, d, J = 9.1 Hz), 7.24 (1H, d, J = 7.5 Hz),

7.39-7.53 (2H, m), 7.53-7.65 (1H, m), 7.81 (2H, d, J = 9.0 Hz),

8.10-8.31 (3H, m), 8.75 (1.4H, s), 8.77 (0.6H, s)

69
ESI+: 342

NMR-DMSO-d₆: 2.88 (1.2H, s), 2.93 (1.8H, s), 3.66-3.70 (4H, m),

3.73-3.77 (4H, m), 4.56 (0.8H, s), 4.60 (1.2H, s), 7.18-7.22 (1H, m),

7.40-7.61 (3H, m), 8.72 (1.2H, s), 8.74 (0.8H, s)

70
ESI+: 485

71
ESI+: 485

72
ESI+: 501.3

73
ESI+: 341

74
ESI+: 486

75
ESI+: 326

NMR-DMSO-d₆: 1.85-2.04 (4H, m), 2.89 (1.2H, s), 2.96 (1.8H, s),

3.47-3.60 (4H, m), 3.88 (2H, s), 3.91 (0.8H, s), 3.96 (1.2H, s),

4.58 (0.8H, s), 4.62 (1.2H, s), 7.20 (1H, d, J = 8 Hz),

7.40-7.62 (3H, m), 8.68 (1.2H, s), 8.70 (0.8H, s)

76
ESI+: 341

TABLE 159

Ex
Data

77
ESI+: 368

78
NMR-DMSO-d₆: 1.16 (3H, s), 1.17 (3H, s), 2.54-2.62 (2H, m),

2.89 (1.2H, s), 2.96 (1.8H, s), 3.51-3.61 (2H, m), 3.83 (2H, s),

3.88 (0.8H, s), 3.94 (1.2H, s), 4.55 (2H, d, J = 13 Hz),

4.58 (0.8H, s), 4.62 (1.2H, s), 7.22 (1H, d, J = 8 Hz),

7.39-7.66 (3H, m), 8.70 (1.2H, s), 8.73 (0.8H, s)

79
ESI+: 372

80
ESI+: 369

81
ESI+: 344

82
ESI+: 353

83
ESI+: 370

84
ESI+: 356

85
ESI+: 418

NMR-DMSO-d₆: 2.88 (1.2H, s), 2.93 (1.8H, s), 3.58-3.65 (4H, m),

3.70-3.75 (2H, m), 3.87-3.94 (4H, m), 4.56 (0.8H, s), 4.61 (1.2H, s),

6.64-6.70 (1H, m), 6.89 (1H, d, J = 9 Hz), 7.17-7.24 (1H, m),

7.40-7.63 (4H, m), 8.13-8.16 (1H, m), 8.73 (1.2H, s), 8.75 (0.8H, s)

86
NMR-DMSO-d₆: 2.21 (3H, s), 2.30-2.36 (4H, m), 2.90 (0.8H, s),

2.94 (1.2H, s), 3.43-3.48 (4H, m), 3.80 (2H, s), 3.83 (0.8H, s),

3.89 (1.2H, s), 4.59 (0.8H, s), 4.62 (1.2H, s), 7.16-7.21 (1H, m),

7.37-7.60 (7H, m), 8.60 (0.6H, s), 8.61 (0.4H, s)

87
ESI+: 415

88
FAB+: 432

89
ESI+: 490

90
FAB+: 432

NMR-DMSO-d₆: 2.90 (1.2H, s), 2.96 (1.8H, s), 2.26-2.32 (4H, m),

3.84-3.98 (8H, m), 4.59 (0.8H, s), 4.63 (1.2H, s), 7.20-7.25 (2H, m),

7.41-7.64 (3H, m), 7.88 (1H, s), 8.17 (1H, d, J = 3 Hz),

8.74 (1.2H, s), 8.76 (0.8H, s)

91
ESI+: 432

NMR-DMSO-d₆: 2.90 (1.2H, s), 2.97 (1.8H, s), 2.92-2.99 (4H, m),

3.90-4.00 (6H, m), 4.09 (3H, s), 4.59 (0.8H, s), 4.63 (1.2H, s),

7.16-7.26 (2H, m), 7.40-7.65 (4H, m), 8.16 (1H, dd, J = 2.5 Hz),

8.74 (1.2H, s), 8.77 (0.8H, s)

92
ESI+: 424

TABLE 160

Ex
Data

93
ESI+: 384

94
FAB+: 412

95
ESI+: 375

NMR-DMSO-d₆: 2.91 (1.2H, s), 2.98 (1.8H, s), 3.89-4.04 (2H, m),

4.62 (0.8H, s), 4.64 (1.2H, s), 4.94-5.03 (4H, m), 7.23 (1H, d,

J = 8 Hz), 7.46 (1H, t, J = 8 Hz), 7.49-7.68 (3H, m),

8.15-8.32 (4H, m), 8.68 (1H, d, J = 5 Hz), 8.84 (1.2H, s),

8.87 (0.8H, s)

96
FAB+: 433

NMR-DMSO-d₆: 1.90-1.98 (2H, m), 2.88 (1.2H, s), 2.93 (1.8H, s),

3.64-4.03 (10H, m), 4.56 (0.8H, s), 4.60 (1.2H, s), 7.17-7.22

(1H, m), 7.37-7.58 (3H, m), 7.73 (1H, d, J = 3 Hz),

7.99-8.02 (1H, m), 8.19 (1H, d, J = 2 Hz), 8.66 (1.2H, s),

8.68 (0.8H, s)

97
ESI+: 384

98
FAB+: 402

99
ESI+: 370

NMR-DMSO-d₆: 1.69-1.79 (1H, m), 2.02-2.12 (1H, m),

2.53-2.61 (1H, m), 2.89 (1.2H, s), 2.96 (1.8H, s), 3.24-3.54

(7H, m), 3.61-3.71 (2H, m), 3.84 (2H, s), 3.88 (0.8H, s),

3.95 (1.2H, s), 4.58 (0.8H, s), 4.62 (1.2H, s), 7.20 (1H, d,

J = 8 Hz), 7.38-7.61 (3H, m), 8.68 (1.2H, s), 8.70 (0.8H, s)

100
ESI+: 427

101
FAB+: 397

102
ESI+: 409

103
FAB+: 447

104
ESI+: 343

105
ESI+: 398

106
ESI+: 342

107
ESI+: 358

108
ESI+: 352

109
ESI+: 396

110
ESI+: 396

111
ESI+: 384

112
ESI+: 354

113
FAB+: 395

114
FAB+: 358

TABLE 161

Ex
Data

115
ESI+: 358

116
ESI+: 374

117
ESI+: 397

118
ESI+: 370

NMR-DMSO-d₆: 1.87-2.09 (4H, m), 2.89 (0.9H, s), 2.95

(2.1H, s), 3.28 (3H, s), 3.30-3.37 (1H, m), 3.42-3.51 (1H, m),

3.52-3.61 (2H, m), 3.80 (2H, s), 3.85 (0.6H, s), 3.92 (1.4H, s),

4.23-4.28 (1H, m), 4.58 (0.6H, s), 4.61 (1.4H, s), 7.18-7.24

(1H, m), 7.39-7.50 (2H, m), 7.52-7.61 (1H, m), 8.70 (1.4H, s),

8.72 (0.6H, s)

119
FAB+: 473

120
ESI+: 419

NMR-DMSO-d₆: 2.90 (0.9H, s), 2.97 (2.1H, s), 3.68-3.73 (4H, m),

3.89-4.03 (8H, m), 4.59 (0.6H, s), 4.63 (1.4H, s), 7.21-7.26

(1H, m), 7.41-7.52 (2H, m), 7.55-7.65 (1H, m), 7.86-7.89

(1H, m), 8.10-8.13 (1H, m), 8.37-8.40 (1H, m),

8.75 (1.4H, s), 8.77 (0.6H, s)

121
FAB+: 431

122
FAB+: 435

123
ESI+: 451

124
ESI+: 432

125
ESI+: 454

126
ESI+: 385

127
ESI+: 413

128
ESI+: 433

129
ESI+: 364

130
ESI+: 377

131
ESI+: 369

132
ESI+: 387

133
ESI+: 432

134
ESI+: 490

135
ESI+: 443

TABLE 162

Ex
Data

136
ESI+: 446

NMR-DMSO-d₆: 0.96-1.01 (3H, m), 1.22-1.29 (3H, m),

2.90 (0.9H, s), 2.97 (2.1H, s), 3.26-3.32 (1H, m), 3.41-3.56

(2H, m), 3.89-3.99 (4H, m), 4.20-4.31 (1H, m), 4.47-4.54

(1H, m), 4.59 (0.6H, s), 4.63 (1.4H, s), 4.98-5.08 (1H, m),

7.20-7.25 (2H, m), 7.30-7.35 (1H, m), 7.41-7.51 (2H, m),

7.54-7.64 (1H, m), 7.94-7.98 (1H, m), 8.29-8.33 (1H, m),

8.73 (1.4H, s), 8.75 (0.6H, s)

137
ESI+: 476

138
ESI+: 452

139
ESI+: 432

140
ESI+: 446

141
ESI+: 446

142
ESI+: 417

143
FAB+: 417

144
ESI+: 416

145
FAB+: 418

NMR-DMSO-d₆: 1.66-1.79 (2H, m), 1.98-2.08 (2H, m),

2.90 (0.9H, s), 2.96 (2.1H, s), 3.09-3.24 (3H, m), 3.80 (2H, s),

3.85 (0.6H, s), 3.92 (1.4H, s), 4.58 (0.6H, s), 4.62 (1.4H, s),

4.74-4.83 (2H, m), 7.19-7.24 (1H, m), 7.34-7.37 (1H, m),

7.40-7.51 (1H, m), 7.53-7.63 (1H, m), 8.70 (1.4H, s), 8.73

(0.6H, s), 8.75 (2H, d, J = 4.9 Hz)

146
ESI+: 443

147
ESI+: 452

148
ESI+: 486

149
ESI+: 417

150
ESI+: 417

NMR-DMSO-d₆: 1.52-1.66 (2H, m), 1.86-1.94 (2H, m),

2.85-3.08 (6H, m), 3.82 (2H, s), 3.87 (0.6H, s), 3.94 (1.4H, s),

4.58 (0.6H, s), 4.62 (1.4H, s), 4.84-4.92 (2H, m), 7.19-7.24

(1H, m), 7.28-7.32 (2H, m), 7.40-7.51 (2H, m), 7.54-7.63 (1H,

m), 8.46-8.49 (2H, m), 8.71 (1.4H, s), 8.73 (0.6H, s)

151
ESI+: 436

152
ESI+: 431

153
ESI+: 435

154
ESI+: 453

TABLE 163

Ex
Data

155
ESI+: 436

156
ESI+: 452

157
ESI+: 496, 498

158
ESI+: 448

159
ESI+: 448

160
ESI+: 432

161
ESI+: 419

NMR-DMSO-d₆: 2.90 (0.9H, s), 2.97 (2.1H, s), 3.70-3.76 (4H, m),

3.88-3.99 (8H, m), 4.59 (0.6H, s), 4.63 (1.4H, s), 7.20-7.25

(1H, m), 7.29-7.34 (1H, m), 7.39-7.52 (3H, m), 7.55-7.65

(1H, m), 8.57-8.60 (1H, m), 8.75 (1.4H, s), 8.77 (0.6H, s)

162
ESI+: 467

163
ESI+: 383

164
ESI+: 423

165
ESI+: 382

166
ESI+: 411

167
ESI+: 356

NMR-DMSO-d₆: 2.00-2.14 (2H, m), 2.89 (0.9H, s), 2.96 (2.1H, s),

3.27 (3H, s), 3.45-3.53 (1H, m), 3.55-3.70 (3H, m),

3.85 (2H, s), 3.90 (0.6H, s), 3.96 (1.4H, s), 4.05-4.11

(1H, m), 4.58 (0.6H, s), 4.62 (1.4H, s), 7.17-7.24 (1H,

m), 7.38-7.50 (2H, m), 7.51-7.62 (1H, m), 8.69 (1.4H, s),

8.71 (0.6H, s)

168
ESI+: 356

NMR-DMSO-d₆: 2.00-2.14 (2H, m), 2.89 (0.9H, s), 2.96 (2.1H, s),

3.24 (3H, s), 3.44-3.54 (1H, m), 3.55-3.71 (3H, m), 3.83 (2H, s),

3.88 (0.6H, s), 3.95 (1.4H, s), 4.06-4.11 (1H, m), 4.58 (0.6H, s),

4.62 (1.4H, s), 7.18-7.24 (1H, m), 7.39-7.50 (2H, m), 7.51-7.62

(1H, m), 8.69 (1.4H, s), 8.71 (0.6H, s)

169
ESI+: 398

170
FAB+: 383

171
ESI+: 405

172
ESI+: 399

173
ESI+: 427

174
ESI+: 427

175
ESI+: 441

TABLE 164

Ex
Data

176
ESI+: 439

177
ESI+: 451

178
ESI+: 453

179
ESI+: 479

180
ESI+: 412

181
FAB+: 453

182
FAB+: 451

183
FAB+: 437

184
FAB+: 440

185
ESI+: 412

186
FAB+: 398

187
ESI+: 381

188
ESI+: 395

189
FAB+: 367

190
ESI+: 417

NMR-DMSO-d₆: 1.52-1.72 (2H, m), 1.82-1.95 (2H, m),

2.85-3.09 (6H, m), 3.88-4.03 (4H, m), 4.59 (0.6H, s), 4.63

(1.4H, s), 4.83-4.95 (2H, m), 7.17-7.25 (1H, m), 7.29-7.35

(1H, m), 7.38-7.52 (2H, m), 7.53-7.64 (1H, m), 7.66-7.72

(1H, m), 8.38-8.46 (1H, m), 8.47-8.55 (1H, m), 8.71 (1.4H, s),

8.73 (0.6H, s)

191
ESI+: 415

192
ESI+: 414

193
ESI+: 414

194
ESI+: 377

195
ESI+: 340

196
ESI+: 340

197
ESI+: 356

198
ESI+: 342

199
ESI+: 457

200
ESI+: 457

201
ESI+: 395

202
ESI+: 396

203
FAB+: 438

204
FAB+: 396

205
ESI+ 368

TABLE 165

Ex
Data

206
ESI+: 411

207
ESI+: 452, 454

208
FAB+: 418

NMR-DMSO-d₆: 2.90 (0.9H, s), 2.97 (2.1H, s), 3.26-3.35

(4H, m), 3.90-4.04 (8H, m), 4.59 (0.6H, s), 4.63 (1.4H, s),

7.20-7.28 (2H, m), 7.36-7.52 (3H, m), 7.55-7.65 (1H, m),

8.00-8.05 (1H, m), 8.34-8.39 (1H, m), 8.74 (1.4H, s),

8.77 (0.6H, s)

209
ESI+: 432

210
ESI+: 432

211
ESI+: 417

NMR-DMSO-d₆: 1.59-1.76 (2H, m), 1.84-1.97 (2H, m),

2.85-3.12 (6H, m), 3.81-3.99 (4H, m), 4.59 (0.6H, s),

4.63 (1.4H, s), 4.78-4.91 (2H, m), 7.16-7.25 (2H, m),

7.27-7.33 (1H, m), 7.38-7.51 (2H, m), 7.53-7.64 (1H, m),

7.67-7.76 (1H, m), 8.42-8.52 (1H, m), 8.71 (1.4H, s), 8.73

(0.6H, s)

212
ESI+: 476

213
FAB+: 288

214
FAB+: 298

215
ESI+: 326

216
ESI+: 390

217
FAB+: 431

218
ESI+: 432

219
ESI+: 471

220
FAB+: 354

221
ESI+: 326

222
ESI+: 441

223
ESI+: 410

224
ESI+: 471

225
ESI+: 354

226
ESI+: 366

227
ESI+: 326

228
FAB+: 354

229
ESI+: 418

230
ESI+: 356

231
ESI+: 383

TABLE 166

Ex
Data

232
FAB+: 354

233
ESI+: 397

234
ESI+: 411

235
ESI+: 451

236
FAB+: 411

237
FAB+: 445

238
ESI+: 425

239
FAB+: 369

240
ESI+: 352

241
ESI+: 354

242
FAB+: 403

243
FAB+: 368

244
ESI+: 432

245
ESI+: 431

246
ESI+: 355

247
ESI+: 369

248
ESI+: 520

NMR-DMSO-d₆: 2.55-2.62 (2H, m), 2.82-2.87 (2H, m),

2.90 (0.9H, s), 2.97 (2.1H, s), 3.32-3.45 (4H, m), 3.87-4.02

(6H, m), 4.57 (2H, s), 4.60 (0.6H, s), 4.63 (1.4H, s), 7.21-7.28

(1H, m), 7.40-7.52 (2H, m), 7.55-7.65 (1H, m), 8.00-8.07 (2H, m),

8.08-8.22 (3H, br), 8.75 (1.4H, s), 8.78 (0.6H, s)

249
ESI+: 462

250
ESI+: 518

251
ESI+: 443

252
ESI+: 488

253
ESI+: 490

254
ESI+: 381

255
ESI+ 367

256
ESI+: 402

257
ESI+: 366

258
ESI+: 368

259
ESI+: 368

260
ESI+: 431

261
ESI+: 443

TABLE 167

Ex
Data

262
ESI+: 443

263
ESI+: 495, 497

NMR-DMSO-d₆: 2.90 (0.9H, s), 2.97 (2.1H, s), 3.11-3.22

(4H, m), 3.88-4.02 (6H, m), 4.60 (0.6H, s), 4.63 (1.4H, s),

7.19-7.30 (2H, m), 7.40-7.53 (2H, m), 7.54-7.65 (1H, m),

7.83-8.89 (1H, m), 7.89-7.93 (1H, m), 8.05-8.25 (3H, m),

8.75 (1.4H, s), 8.77 (0.6H, s)

264
FAB+: 395

265
ESI+: 382

266
FAB+: 382

267
FAB+: 368

268
FAB+: 354

269
FAB+: 381

270
ESI+: 416

271
ESI+: 416

NMR-DMSO-d₆: 1.58-1.74 (2H, m), 1.80-1.93 (2H, m), 2.80-3.00

(6H, m), 3.60-3.82 (4H, m), 4.44-4.65 (4H, m), 6.92-7.20 (1H, m),

7.11-7.21 (1H, m), 7.27-7.35 (1H, m), 7.36-7.49 (2H, m),

7.49-7.60 (1H, m), 7.64-7.72 (1H, m), 7.78-7.89 (1H, m),

8.36-8.48 (2H, m), 8.48-8.54 (1H, m)

272
ESI+: 457

273
FAB+: 457

274
FAB+: 455

275
FAB+: 443

276
FAB+: 469

277
FAB+: 469

278
ESI+: 471

279
ESI+: 443

280
ESI+: 455

281
ESI+: 326

282
ESI+: 368

283
ESI+: 356

284
ESI+: 398

285
ESI+: 370

286
ESI+: 398

TABLE 168

Ex
Data

287
ESI+: 342

288
ESI+: 356

289
ESI+: 356

290
ESI+: 370

291
ESI+: 384

292
ESI+: 369

293
ESI+: 383

294
ESI+: 383

295
ESI+: 397

296
ESI+: 411

297
ESI+: 366

298
ESI+: 396

299
ESI+: 395

300
ESI+: 380

301
ESI+: 394

302
ESI+: 382

303
ESI+: 395

304
ESI+: 409

305
ESI+: 453

306
ESI+: 409

307
ESI+: 409

308
ESI+: 409

309
ESI+: 410

310
ESI+: 395

311
ESI+: 409

312
ESI+: 411

313
ESI+: 409

314
ESI+: 423

315
ESI+: 425

316
ESI+: 388

317
ESI+: 402

318
ESI+: 432

319
ESI+: 431

320
ESI+: 431

TABLE 169

Ex
Data

321
ESI+: 406

322
ESI+: 406

323
ESI+: 406

324
ESI+: 418

325
ESI+: 418

326
ESI+: 418

327
ESI+: 389

328
ESI+: 402

329
ESI+: 416

330
ESI+: 420

331
ESI+: 420

332
ESI+: 420

333
ESI+: 432

334
ESI+: 432

335
ESI+: 432

336
ESI+: 403

337
ESI+: 416

338
ESI+: 430

339
ESI+: 414

340
ESI+: 428

341
ESI+: 471

342
ESI+: 352

343
ESI+: 366

344
ESI+: 368

345
ESI+: 384

346
ESI+: 439

347
ESI+: 382

348
ESI+: 423

349
ESI+: 425

350
ESI+: 382

351
ESI+: 382

352
ESI+: 396

353
ESI+: 396

354
ESI+: 396

TABLE 170

Ex
Data

355
ESI+: 410

356
ESI+: 410

357
ESI+: 410

358
ESI+: 395

359
ESI+: 409

360
ESI+: 381

361
ESI+: 425

362
ESI+: 439

363
ESI+: 400

364
ESI+: 414

365
ESI+: 428

366
ESI+: 442

367
ESI+: 443

368
ESI+: 435

369
ESI+: 451

370
ESI+: 443

371
ESI+: 461

372
ESI+: 461

373
ESI+: 461

374
ESI+: 340

375
ESI+: 273

376
ESI+: 289

377
ESI+: 285

378
ESI+: 285

379
ESI+: 280

380
ESI+: 312

381
ESI+: 298

382
ESI+: 340

383
ESI+: 297

384
ESI+: 299

385
ESI+: 333

386
ESI+: 326

387
ESI+: 271

388
ESI+: 361

TABLE 171

Ex
Data

389
ESI+: 299

390
ESI+: 312

391
ESI+: 326

392
ESI+: 352

393
ESI+: 366

394
ESI+: 368

395
ESI+: 348

396
ESI+: 359

397
ESI+: 274

398
ESI+: 286

399
ESI+: 290

400
ESI+: 286

401
ESI+: 299

402
ESI+: 340

403
ESI+: 354

404
ESI+: 288

405
ESI+: 292

406
ESI+: 287

407
ESI+: 300

408
ESI+: 342

409
ESI+: 326

410
ESI+: 341

411
ESI+: 359

412
ESI+: 334

413
ESI+: 424

414
ESI+: 340

415
ESI+: 362

416
ESI+: 313

TABLE 172

Ex
Syn
Structure
Acid

417
417

embedded image

1/2 FA

418
418

embedded image

1/2 SA

419
418

embedded image

1/2 FA

420
418

embedded image

L-TA

TABLE 173

Ex
Data

417
ESI+: 495

NMR-DMSO-d₆: 2.91 (3H, s), 3.18-3.22 (4H, m), 3.56 (2H, s),

3.97-3.99 (4H, m), 4.58 (1H, s), 6.54 (1H, s), 7.19-7.23 (2H, m),

7.40-7.57 (2H, m), 7.52-7.54 (1H, m), 7.83-7.84 (1H, m),

7.89-7.90 (1H, m), 8.69 (2H, s).

Powder X-ray Diffraction using Cu-Kα:

2θ(°): 12.5, 14.8, 17.6, 18.2, 22.0 and 23.4

418
ESI+: 340

NMR-DMSO-d₆: 2.26 (2H, s), 2.89 (1H, s), 2.92 (2H, s),

3.14-3.16 (4H, m), 3.64 (0.7H, s), 3.70 (1.3H, s), 3.74-3.77

(4H, m), 4.57 (0.7H, s), 4.59 (1.3H, s), 7.01-7.36 (2H, m),

7.11-7.16 (1H, m), 7.36-7.56 (5H, m).

Powder X-ray Diffraction using Cu-Kα:

2θ(°): 4.9, 7.4, 15.6, 16.2, 17.7, 20.7 and 22.0

419
ESI+: 340

NMR-DMSO-d₆: 2.88 (1H, s), 2.91 (2H, s), 3.14-3.16 (4H, m),

3.65 (0.7H, s), 3.70 (1.3H, s), 3.74-3.77 (4H, m), 4.56 (0.7H, s),

4.59 (1.3H, s), 6.41 (2H, s), 7.01-7.03 (2H, m), 7.12-7.16

(1H, m), 7.35-7.57 (5H, m).

Powder X-ray Diffraction using Cu-Kα:

2θ(°): 4.9, 7.4, 15.8, 16.4, 17.9, 20.8 and 22.6

420
ESI+: 340

NMR-DMSO-d₆: 2.90 (1H, s), 2.94 (2H, s), 3.14-3.17 (4H, m),

3.75-3.77 (4H, m), 3.83-3.91 (4H, m), 4.58 (0.7H, s), 4.61

(1.3H, s), 6.41 (2H, s), 7.01-7.04 (2H, m), 7.14-7.18

(1H, m), 7.36-7.57 (5H, m).

Powder X-ray Diffraction using Cu-Kα:

2θ(°): 3.9, 18.4, 18.8, 20.0, 21.0 and 21.9

INDUSTRIAL APPLICABILITY

The compound of the formula (I) or a salt thereof has a VAP-1 inhibitory action, and it can be used as an agent for preventing and/or treating VAP-1-related diseases.

GLYCINE COMPOUND

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