EA045243B1 - ANTAGONISTS OF MELANOCORTIN RECEPTOR 2 SUBTYPE (MC2R) AND THEIR ROUTES OF APPLICATION - Google Patents

Description

Field of technology to which the present invention relates

Disclosed herein are compounds that modulate the activity of one or more melanocortin receptors, methods for preparing such compounds, pharmaceutical compositions and drugs containing such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from modulation. melanocortin receptor subtype 2 (MC2R) activity.

BACKGROUND OF THE INVENTION

Melanocortin receptors form a family of G protein-coupled receptors (GPCRs) (MC1R, MC2R, MC3R, MC4R, and MC5R) that are selectively activated by various melanocortin peptides of adrenocorticotropic hormone (ACTH) and melanocortin peptides of α-, β-, and γmelanocyte-stimulating hormone (α -MSH, β-MSH and γ-MSH), all of which are proteolytically derived from the hormone proopiomelanocortin or POMC. ACTH is a 39 amino acid peptide that is a major regulator of adrenal glucocorticoid synthesis and secretion and has affinity only for MC2R. As a central actor in this hypothalamic-pituitary-adrenal (HPA) axis, ACTH is secreted by the pituitary gland in response to stress stimuli and acts on the adrenal glands to stimulate the synthesis and secretion of cortisol. Modulation of MC2R holds promise for the treatment of conditions, diseases, or disorders that would benefit from modulation of melanocortin receptor activity.

Summary of the present invention

The compounds described in the present invention are melanocortin receptor modulator compounds. In some embodiments, the compounds described herein modulate one or more melanocortin subtype protein receptors. In some embodiments, the compounds described herein modulate two or more melanocortin subtype protein receptors. In some embodiments, compounds described herein modulate MC2R.

In one aspect, the present invention provides a compound of formula (IX) or a pharmaceutically acceptable salt thereof:

where V represents CH or N;

R ^a is selected from the group consisting of hydrogen, halogen, -OR ⁸ , -CN, -N(R ⁷ ) ₂ , C ₁ -C6 alkyl, C1C6fluoroalkyl and C ₁ -C ₆ heteroalkyl;

R ^b and R ^c are each independently selected from the group consisting of hydrogen, halogen, -OR ⁸ , -CN, N(R ⁷ ) ₂ and C ₁ -C ₆ alkyl;

R ^B represents

where Z represents CH or N;

or R ^B is unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, unsubstituted or substituted cyclopentenyl or unsubstituted or substituted cyclohexyl, wherein if R ^B is substituted then R ^B is substituted with R ^d , R ^e and R ^f ;

or R ^B represents

- 1 045243, where m is 0, 1, 2 or 3.

R ^d is selected from the group consisting of hydrogen, halogen, -OR ⁸ , -CN, -N(R ⁷ ) ₂ , C _{1 -C} 6 alkyl, C 1 -C 6 fluoroalkyl and C ₁ -C ₆ heteroalkyl;

R ^e and R ^f are each independently selected from the group consisting of hydrogen, halogen, -OR ⁸ , -CN, N(R ⁷ ) ₂ and C ₁ -C ₆ alkyl;

X ¹ represents N or CR ⁶ ;

R ⁶ represents H or F;

R ² and R ³ represent hydrogen;

or R ² and R ³ are taken together with the carbon atom to which they are attached to form -C(=O)-;

R ⁴ represents -CH2CH2NH2, -CH ₂ (CH ₂ ) ₂ NH ₂ ,

each R ⁷ is independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl and C ₁ -C ₆ fluoroalkyl; or two R ⁷ taken together with the nitrogen atom to which they are attached to form unsubstituted or substituted pyrrolidinyl, unsubstituted or substituted oxazolidinyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted morpholinyl, unsubstituted or substituted thiomorpholinyl, unsubstituted or substituted piperazinyl, substituted or substituted aziridinyl, unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrazolidinyl, or unsubstituted or substituted imidazolidinyl; and each R ⁸ is independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl and C 1 C ₆ fluoroalkyl;

wherein the term substituted, unless specifically defined, means that said group is replaced by one or two additional groups individually and independently selected from halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3;

wherein the term heteroalkyl means an alkyl group in which one or two skeletal carbon atoms of the alkyl are independently selected from oxygen, -NH-, -N(C ₁ -C ₄ alkyl)- or sulfur.

In some embodiments, R ^a is -OR ⁸ ; and R ^b and R ^c each represent hydrogen.

In some embodiments, R ^a is -OCH ₂ CH ₃ .

In some embodiments, R ⁴ is

In some embodiments, R ⁴ is -CH2CH2NH2, -CH ₂ (CH ₂ ) ₂ NH ₂ ,

- 2 045243

In some embodiments, R ^B is

In some embodiments, R ⁴ is

where Z represents CH or N.

In some embodiments, R ^B is unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, unsubstituted or substituted cyclopentenyl, or unsubstituted or substituted cyclohexyl, wherein if R ^B is substituted then R ^B is substituted with R ^d , R ^e and R ^f .

In some embodiments, R ^B is

where m is 0, 1, 2 or 3.

In some embodiments, each R ¹⁰ is independently selected from the group consisting of unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3C6 cycloalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, and unsubstituted or substituted phenyl. In some embodiments, each R ¹⁰ is independently selected from the group consisting of unsubstituted or substituted C1-C ₆ alkyl and unsubstituted or substituted phenyl.

In some embodiments, R ^B is

- 3 045243

In some embodiments, R ^B is

- 4 045243

In some embodiments, R ^B is

In some embodiments, R ^B is

In some embodiments, R ^B is

- 5 045243

In some embodiments, R ² and R ³ are taken together with the carbon atom to which they are attached to form -C(=O)-.

In some embodiments, a compound of formula (IX) has the structure of formula (IXa), or a pharmaceutically acceptable salt thereof:

Formula (IXa).

In some embodiments, the connection is:

1-1: T\[-(2-aminoethyl)-4-[(2K)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2ethylpiperazin 1 -yl]-2',3'-difluoro -[1,1'-biphenyl]-3-carboxamide;

1-2: N(2-aminoethyl)-4-[(2K)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2ethylpiperazin 1 -yl]-2'-methoxy-[1,1' -biphenyl]-3-carboxamide;

1-3: N(2-aminoethyl)-4-[(2K)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2ethylpiperazin1 -yl]-2'-ethoxy-[1, G-biphenyl] -3-carboxamide;

1-4: N(2-aminoethyl)-4-[(2K)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2ethylpiperazin 1-yl]-2'-fluoro-[1,G- biphenyl]-3-carboxamide;

1-5: N(2-aminoethyl)-4-[(2К)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2ethylpiperazin 1 -yl]-2'-ethyl-[1,1 - biphenyl]-3-carboxamide;

1-6: N-(2-aminoethyl)-2'-chloro-4-[(2R)-4-[2-chloro-4-(τpiφτopmethyl)benzoyl]

2ethylpiperazin-1-yl]-[1,1'-biphenyl]-3-carboxamide;

1-7: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(τpiφΊΌpmethyl)benzoyl]-2ethylπipyrazine 1 -yl]-2'-cyano-[1,1' -biphenyl]-3-carboxamide;

1-8: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(τpiφτopmethyl)benzoyl]-2ethylπiperazine 1 -yl]-2'-methyl-[1,1' -biphenyl]-3-carboxamide;

1-9: N-(2-aminoethyl)-2'-chloro-4-[(2R)-4-[2-chloro-4-(τpiφτopmethyl)benzoyl]

2ethylpiperazin-1-yl]-3'-fluoro-[1,1'-biphenyl]-3-carboxamide;

1-10: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(τpiφτopmethyl)benzoyl]

2ethylpiperazin-1-yl]-3'-ethoxy-[1, G-biphenyl]-3-carboxamide;

1-11: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(τpiφτopmethyl)benzoyl]

2ethylpiperazin-1-yl]-2'-propoxy-[1,G-biphenyl]-3-carboxamide;

1-12: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(τpiφτopmethyl)benzoyl]

2ethylpiperazin-1-yl]-2'-(propan-2-yloxy)-[1,1'-biphenyl]-3-carboxamide;

1-13: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(τpiφτopmethyl)benzoyl]

2ethylpiperazin-1-yl]-2'-hydroxy-[1,G-biphenyl]-3-carboxamide;

1-14: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(τpiφτopmethyl)benzoyl]

2ethylpiperazin-1-yl]-2'-cyclopropoxy-[1,1'-biphenyl]-3-carboxamide;

1-23: N-(3-aminopropyl)-4-[(2R)-4-[2-chloro-4-(τpiφτopmethyl)benzoyl]

2ethylpiperazin-1-yl]-2'-ethoxy-[1,G-biphenyl]-3-carboxamide;

1-25: N-(2-aminoethyl)-4-[(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]

2ethylpiperazin-1-yl]-2'-ethoxy-[1,G-biphenyl]-3-carboxamide;

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1-28: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(τpiφτopmethyl)benzoyl]2ethylpiperazin-1 -yl]-2'-propyl-[1,1' -biphenyl]-3-carboxamide;

1-29: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(τpiφτopmethyl)benzoyl]2ethylpiperazin-1 -yl]-4'-propyl-[1,1' -biphenyl]-3-carboxamide;

1-31: N-(2-aminoethyl)-2-[(2R)-4-[2-chloro-4-(τpiφτopmethyl)benzoyl]2ethylpiperazin-1 -yl]-5 -(pyridin-3 -yl)benzamide ;

1-34: N-(2-aminoethyl)-2-[(2R)-4-[2-chloro-4-(τpiφτopmethyl)benzoyl]2ethylpiperazin-1 -yl]-5 -(2-ethoxypyride in-3 -yl)benzamide;

1-35: N-(2-aminoethyl)-2-[(2R)-4-[2-chloro-4-(τpiφτopmethyl)benzoyl]2ethylpiperazin-1 -yl]-5 -(4-ethoxypyride in-3 -yl)benzamide;

1-37: N-(2-aminoethyl)-2-[(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]2ethylpiperazin-1 -yl]-5 -(2-ethoxypyride in-3 -yl)benzamide;

1-38: N-(2-aminoethyl)-2-[(2R)-4-(2-chloro-4-φτopbenzoyl)-2-ethylpiperazin-l-yl]-5(2-ethoxypyr idin-3 -yl )benzamide;

1-42: N-(2-aminoethyl)-2-[(2R)-4-(2,4-dichlorobenzoyl)-2-ethylpypiperazin-l-yl]-5(2ethoxypyridin-3-yl)benzamide;

1-43: N-(2-aminoethyl)-2-[(2R)-4-(2-chloro-4-methylbenzoyl)-2-ethylpiperazin-l-yl]-5(2-ethoxypyr idin-3 -yl )benzamide;

1-45: 2-[(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]-2-ethylπpiperazin-l-yl]-5(2ethylpyridin-3-yl)-N-[(ЗR) -πppolidin-3-yl]benzamide;

1-46: 2-[(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]-2-ethylπpiπerazin-l-yl]-5(2ethoxypyridin-3-yl)-M-[2-( methylamino)ethyl]benzamide;

1-47: 2-[(2R)-4-[4-chloro-2-(τpiτopmethyl)benzoyl]-2-ethylπpiperazin-l-yl]-N-[2(dimethylamino)ethyl]-5-(2- ethoxypyridin-3-yl)benzamide;

1-48: 2-[(2R)-4-[4-chloro-2-(τpiτopmethyl)benzoyl]-2-ethylπpiperazin-l-yl]-5(2ethoxypyr idin-3-yl)-M-[(3R )-1-methylpyrrolid in-3-yl]benzamide;

1-49: 2-[(2R)-4-[4-chloro-2-(τpiτopmethyl)benzoyl]-2-ethylπpiperazin-l-yl]-5(2ethoxypyridin-3-yl)-M-[2-( pyrrolidin-1-yl)ethyl]benzamide;

1-52: N-(2-aminoethyl)-2-[(2R)-4-[2-(4-aminopipiridin-l-yl)-4-chlorobenzoyl]2ethylpiperazin-1 -yl] -5 -(2- ethoxypyride in-3-yl)benzamide;

1-53: N-(2-aminoethyl)-2-[(2R)-4-(3,5-dichloropyridin-2-carbonyl)-2-ethylpypiperazin1-yl]-5-(2-ethoxypyridin-3-yl )benzamide;

1-54: N-(2-aMHHO3T№i)-2-[(2R)-4-(4-xnop-2-MeTOKCH6eH3O№i)-2-3T№inHnepa3HH-l-№i]5 -(2 -ethoxypyride in-3 -yl)benzamide;

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1-55: N-(2-aminoethyl)-2-[(2R)-4-(2-chloro-4-cyanobenzoyl)-2-ethylpiperazin-l-yl]-5(2-ethoxypyridin-3-yl )benzamide;

1-57: N-(2-aminoethyl)-2-[(2R)-4-{2-[(3S)-3-aminopyrrolidin-1-yl]-4chlorobenzoyl} 2-ethylpiperazin-1-yl] - 5 -(2-ethoxypyridin-3-yl)benzamide;

1-58: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-φτop-2(trifluoromethyl)benzoyl]piperazin- 1-yl]benzamide;

1-59: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-methyl-2(trifluoromethyl)benzoyl]piperazin- 1-yl]benzamide;

1-60: N-(2-aminoethyl)-2-[(2R)-4-(2,4-dimethylbenzoyl)-2-ethylpypiperazin-l-yl]-5(2ethoxypyridin-3-yl)benzamide;

1-61: N-(2-aminoethyl)-2-[(2R)-4-[4-chloro-2-(πppolidin-l-yl)benzoyl]2ethylpiperazin-1 -yl]-5 -(2-ethoxypyr id in-3 -yl)benzamide;

1-62: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[2(trifluoromethyl)benzoyl]piperazin-1-yl] benzamide;

1-64: 2-[(2R)-4-[4-chloro-2-(τpiτopmethyl)benzoyl]-2-ethylπpiperazin-l-yl]-5(2ethoxypyridin-3-yl)-M-[(pyridin- 2-yl)methyl]benzamide;

1-65: 2-[(2R)-4-[4-chloro-2-(τpiτopmethyl)benzoyl]-2-ethylπpiperazin-l-yl]-5(2ethoxypyridin-3-yl)-M-[(pyridine -3 -yl)methyl]benzamide;

1-66: 2-[(2R)-4-[4-chloro-2-(τpiτopmethyl)benzoyl]-2-ethylπpiperazin-l-yl]-5(2ethoxypyridin-3-yl)-M-[(pyridin- 4-yl)methyl]benzamide;

1-67: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-{4-methyl-2-[(3S)3 - (methylamino)pyrrolid in-1 -yl] benzoyl } piperazin-1 -yl] benzamide;

1-68: N-(2-aminoethyl)-2-[(2R)-4-{2-[(3S)-3-(dimethylamino)πppolidin-l-yl]4methylbenzoyl} -2-ethylpiperazin-1 -yl ] -5 -(2-ethoxypyridin-3-yl)benzamide;

1-69: N-(2-aminoethyl)-6-[(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]2ethylpiperazin-1 -yl]-3 -(2-ethoxypyride in-3 -yl)-2-fluorobenzamide;

1-70: 2-[(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]-2-ethylπpiπerazin-l-yl]-5(2ethoxypyridin-3-yl)-M-(pyridin-4 -yl)benzamide;

1-71: N-(2-aminoethyl)-2-[(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]2ethylpiperazin-1 -yl]-5-(2-methoxypyr idin-3 - yl)benzamide;

1-72: 6-[(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]-2-ethylpiperazin-1 -yl]-3(2ethoxypyridin-3-yl)-2-φτop-N- [(3R)-πpyrrolidin-3-yl]benzamide;

1-73: 6-[(2R)-4-(2-chloro-4-φτopbenzoyl)-2-ethylπpiperazin-l-yl]-3-(2-ethoxypyridin3-yl)-2-φτop-N-[( 3R)-πppolidin-3-yl]benzamide;

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1-76: M-(2-aminoethyl)-2-[(2К)-4-[2-(dimethylamino)-6-(trifluoromethyl)pyridin3 carbonyl]-2-ethylpiperazin-1 -yl]-5-(2 -ethoxypyridin-3-yl)benzamide;

1-77: M-(2-aminoethyl)-2-[(2I.)-4-(2,6-dimethylpyridin-3-carbonyl)2ethylpiperazin-1-yl]-5 -(2-ethoxypyridin-3 -yl)benzamide;

1-78: M-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2K)-2-ethyl-4-(4-fluoro2methylbenzoyl)piperazin-1-yl]benzamide;

1-79: M-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2I.)-2-ethyl-4-(4-fluoro2methoxybenzoyl)piperazin-1-yl]benzamide ;

1-80: M-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2K)-2-ethyl-4-(2-methoxy4methylbenzoyl)piperazin-1-yl]benzamide;

1-81: T\G-(2-aminoethyl)-2-[(2K)-4-(4-tert-butylbenzoyl)-2-ethylpiperazin-1-yl]-5(2ethoxypyridin-3-yl)benzamide ;

1-82: 2-[(2K)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin3-yl)-N-[(3R)-πippolidine -3-yl]benzamide;

1-83: 2-[(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]-2-ethylπpiπerazin-l-yl]-5(2ethoxypyridin-3-yl)-M-[(1H- imidazol-5-yl)methyl]benzamide;

1-84: 2-[(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]-2-ethylπpiperazin-l-yl]-5(2ethoxypyridin-3-yl)-M-[2-( 1H-imidazol-5-yl)ethyl]benzamide;

1-86: M-(2-aminoethyl)-2-[(2I.)-4-(4,6-dimethylpyridin-3-carbonyl)2ethylpiperazin-1-yl]-5 -(2-ethoxypyridin-3 -yl)benzamide;

1-87: N-(2-aminoethyl)-2-[(2R)-4-(4-chloro-2-methylbenzoyl)-2-ethylpiperazin-l-yl]-5(2-ethoxypyr idin-3 -yl )benzamide;

1-89: N-(2-aminoethyl)-2-[(2R)-4-(3-chloro-5-φτopπridin-2-carbonyl)2ethylpiperazin-1-yl]-5 -(2-ethoxypyridin- 3-yl)benzamide;

1-90: 2-[(2R)-4-[4-chloro-2-(piperazin-1-yl)benzoyl]-2-ethylpiperazin-1-yl]-5(2ethoκcypyridin-3-yl)-N- [(3R)-πpyrrolidin-3-yl]benzamide;

1-91: 2-[(2R)-4-[4-chloro-2-(dimethylamino)benzoyl]-2-ethylpiperazin-l-yl]-5(2ethoxypyridin-3-yl)-N-[(ЗR) -πppolidin-3-yl]benzamide;

1-92: 2-[(2R)-4-[4-chloro-2-(τpiτopmethyl)benzoyl]-2-ethylπpiπerazin-l-yl]-5(2ethoxypyridin-3-yl)^- [(3 8 )-pyrrolidin-3-yl]benzamide;

1-93: 2-[(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]-2-ethylπpiπerazin-l-yl]-5(2ethoxypyridin-3-yl)-M-[2-( 1 H-imidazol-2-yl)ethyl]benzamide;

1-94: 5 -(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4- { 4-methyl-2-[(3 S)-3 (methylamino)πpyrrolidine- l-yl]benzoyl}piperazin-l-yl]-N-[(3R)-πpyrrolid inZyl]benzamide;

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1-95: 6-[(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]-2-ethylπpiπerazin-l-yl]-3(2ethoxypyridin-3-yl)-2-fluoro^-[ 2-(methylamino)ethyl]benzamide;

1-96: 6-[(2R)-4-(2-chloro-4-φτopbenzoyl)-2-ethylpypiperazin-l-yl]-3-(2-ethoxypyridin3-yl)-2-fluoro-KG-[2 -(methylamino)ethyl]benzamide;

1-97: N-{[(2 8)-azetide in-2-yl]methyl}-2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]2-ethylpiperazine-1- yl]-5-(2-ethoxypyridin-3-yl)benzamide;

1-98: 2-[(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]-2-ethylπpiperazin-l-yl]-5(2ethoxypyr idin-3 -nn)-N- {[( 2 8)-pyrrolidin-2-yl]methyl } benzamide;

1-99: 2-[(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]-2-ethylπpiperazin-l-yl]-5(2ethylpyridin-3-yl)-N-[(ЗR) -pipiridin-3-yl]benzamide;

1-100: 2-[(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]-2-ethylπpiperazin-l-yl]-5(2ethoxypyridin-3-yl)-K-[(3 8)-piper idin-3-yl]benzamide;

1-101: 5 -(2-ethoxypyridin-3-yl)-2-[(2R)-2-3Tnn-4- { 4-fluoro-2-[(3 S)-3 (methylamino)pyrrolidine- 1 -yl]benzoyl } piperazin-1 -yl]-N-[(3R)-πpyrrolidin3 yl]benzamide;

1-102: N-{[(2R)-azetidin-2-yl]methyl}-2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]2-ethylpiperazin-1 -yl] -5 -(2-ethoxypyridin-3-yl)benzamide;

1-103: 5 -(2-ethoxypyridin-3-yl)-2-[(2R)-2-3Tnn-4- { 2-fluoro-4-[(3 S)-3 (methylamino)pyrrolidin- 1 -yl]benzoyl } piperazin-1 -yl]-N-[(3R)-πpyrrolidin3 yl]benzamide;

1-105: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[2-(morpholin4yl)-6-(trifluoromethyl)pyridine -3-carbonyl]piperazin-1-yl]benzamide;

1-106: N-(2-aminoethyl)-2-[(2R)-4-[3-(dimethylamino)-5-(τpiφτopmethyl)πpyridin2carbonyl]-2-ethylpiperazin-1-yl]-5-(2- ethoxypyridin-3-yl)benzamide;

1-107: N-(2-aminoethyl)-2-[(2R)-4-[2-(dimethylamino)-4-(τpiφτopmethyl)benzoyl]2ethylpiperazin-1 -yl]-5 -(2-ethoxypyride in -3-yl)benzamide;

1-108: 2-[(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]-2-ethylπpiperazin-l-yl]-5(2ethoxypyr idin-3 -ππ)-Ν- {[( 2R)-πpyrrolidin-2-yl] methyl } benzamide;

1-109: 2-[(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]-2-ethylπpiperazin-l-yl]-5(2ethoxypyridin-3-yl)-KG-{[(28 )-morpholin-2-yl]methyl} benzamide;

1-110: 6-[(2R)-4-(2-xnop-4-MeTnn6eH3onn)-2-3THnnHnepa3HH-l-Hn]-3(2ethoxypyridin-3-yl)-2-φτop-N-[(ЗR )-πpyrrolidin-3-yl]benzamide;

1-111: 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-φτop-2(τpiφτopmethyl)benzoyl]πpiperazin-l-yl]-2-φτop -N-[(ЗR)-πpyrrolidine-zyl]benzamide;

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1-112: N-{[(2S)-azetidin-2-yl]methyl}-6-[(2R)-4-[4-chloro-2-(τpiτopmethyl)benzoyl]2-ethylpiperazin-1 -yl] -3 -(2-ethoxypyridin-3-yl)-2-fluorobenzamide;

1-113: 6-[(2R)-4-(2-chloro-4-methylbenzoyl)-2-ethylpypiperazin-l-yl]-3(2ethoxypyridin-3-yl)-2-fluoro-X-[2- (methylamino)ethyl]benzamide;

1-114: 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-φτop-2(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluoro -M-[2-(methylamino)ethyl]benzamide;

1-115: 2-[(2R)-4- { 4-chloro-2- [(3 S)-3 -(d imethylamino)pyrrolid in-1 -yl] benzoyl } 2ethylpiperazin-l-yl]-5- (2-ethoxypyridin-3-yl)-N-[(3R)-πpyrrolidin-zyl]benzamide;

1-116: 6-[(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]-2-ethylπpiperazin-l-yl]-3(2ethoxypyridin-3-yl)-2-fluoro-M- [2-(1H-imidazol-2-yl)ethyl]benzamide;

1-117: N-(2-aminoethyl)-2-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-l-yl]5 -(2-ethoxypyride in-3 - yl)benzamide;

1-118: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[5-φτop-3(trifluoromethyl)pyridin-2- carbonyl]piperazin-1-yl]benzamide;

1-119: X-(2-aminoethyl)-5 -(2-ethoxypyrid in-3-yl)-2-[(2R)-2-ethyl-4-[2(methylamino)6-(trifluoromethyl)pyr idin-3-carbonyl]piperazin-1-yl]benzamide;

1-120: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[2-(pyrrolidin1 -yl)-6-(trifluoromethyl )pyr idin-3 -carbonyl]piperazin-1 -yl]benzamide;

1-121: 3 -(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[2(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluoro-M -[2-(methylamino)ethyl]benzamide;

1-122: 3 -(2-ethoxypyrid in-3-yl)-6-[(2К)-2-ethyl-4-[2(τττφφττττι)benzoyl]πipπerazin-l-yl]-2-φτop-N -[(ЗR)-πpyrrolidine-zyl]benzamide;

1-123: N-{[(2R)-aseTHflin-2-yl]methyl}-6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]2-ethylpiperazin-1-yl] -3 -(2-ethoxypyridin-3-yl)-2-fluorobenzamide;

1-124: 6-[(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]-2-ethylπpiperazin-l-yl]-3(2ethoxypyridin-3-yl)-2-fluoro-M -{ [(2R)-πpyrrolidin-2-yl]methyl } benzamide;

1-125: 2-[(2R)-4-[4-chloro-2-(τpiτopmethyl)benzoyl]-2-ethylπpiperazin-l-yl]-N[ (4,5dihydro-1H-imidazol-2-yl) methyl]-5-(2-ethoxypyridin-3-yl)benzamide;

1-126: 2-[(2R)-4-[2-amino-6-(τpiφτopmethyl)pyridin-3-κapbonyl]-2-ethylπpiperazin1-yl]-M-(2-aminoethyl)-5-(2- ethoxypyridin-3-yl)benzamide;

1-127: N-(2-aminoethyl)-2-[(2R)-4-[6-(dimethylamino)-2-(τpiφτopmethyl)πpyridin3 carbonyl]-2-ethylpiperazin-1 -yl]-5-(2 -ethoxypyridin-3-yl)benzamide;

1-128: 2-[(2R)-4-[4-chloro-2-(diφτopmethyl)benzoyl]-2-ethylπipiperazin-l-yl]-5(2ethoxypyridin-3-yl)-M-[2-( methylamino)ethyl]benzamide;

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1-132: 2-[(2R)-4-[4-chloro-2-(τpiτopmethyl)benzoyl]-2-ethylπpiperazin-l-yl]-5(2ethoxypyridin-3-yl)-H-[(1H- imidazol-2-yl)methyl]benzamide; 1-133: 5 -(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[5-(trifluoromethyl)pyridin2κapbonyl]πipepazin-l-yl]-N-[(ЗR )-πpyrrolidin-3-yl]benzamide;

1-134: 2-[(2R)-4-[3-chloro-5-(τpiφτopmethyl)pyridin-2-carbonyl]-2-ethylπipiperazinl-yl]-5-(2-ethoxypyridin-3-yl)-N -[(3R)-πpyrrolidin-3-yl]benzamide;

1-135: 5 - [(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]-2-ethylpiperazin-1 -yl] 2'ethoxy-M-[2-(methylamino)ethyl]-[ 2,3'-bipyridine]-6-carboxamide;

1-136: 2'-ethoxy-5 - [(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl] piperazin1 yl] -K-[2-(methylamino)ethyl]- [ 2,3'-bipyridine]-6-carboxamide;

1-137: 2'-ethoxy-5-[(2R)-4-[4-ethoxy-2-(τpiφτopmethyl)benzoyl]-2-ethylπpyπerazin1 yl]-N-[2-(methylamino)ethyl]-[ 2,3'-bipyridine]-6-carboxamide;

1-138: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5(2ethoxypyridin-3-yl)-M-{ [(3 8)-morpholin-3-yl]methyl } benzamide;

1-139: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5 (2ethoxypyridin-3-yl)-M-[ 2-(1H-1,2,4-triazol-1 -yl)ethyl]benzamide;

1-140: 6-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-3 (2ethoxypyridin-3-yl)-2-fluoro-M-[2- (1H-imidazol-2-yl)ethyl]benzamide;

1-141: 6-[(2R)-4-(4-chloro-2-ethoxybenzoyl)-2-ethylpiperazin-l-yl]-3(2ethoxypyridin-3-yl)-2-fluoro-M-[2- (1H-imidazol-2-yl)ethyl]benzamide;

1-142: 2-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpypiperazin-1-yl]-5 (2ethoxypyridin-3-yl)-N-[(3R)-pyrrolidin- 3-yl]benzamide;

1-143: 5 -(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-methoxy-2(τpiφτopmethyl)benzoyl]πpiperazin-l-yl]-N- [(3R)-πpyrrolidin-3-yl]benzamide;

1-144: 2-[(2R)-4-[4-cyano-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5(2ethoxypyridin-3-yl)-M-[( ZK.)-pyrrolidin-3-yl]benzamide;

1-145: 2-[(2R)-4-[6-amino-2-(τpiφτopmethyl)pyridin-3-κapbonyl]-2-ethylpiperazin1-yl]-M-(2-aminoethyl)-5-(2- ethoxypyridin-3-yl)benzamide;

1-146: N-(2-aminoethyl)-2-[(2R)-4-[4-(dimethylamino)-6-(τpiφτopmethyl)pyridin3 carbonyl]-2-ethylpiperazin-1 -yl]-5-(2 -ethoxypyridin-3-yl)benzamide;

1-147: 2-[(2I)-4-[2-(d imethylamino)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-N-[2(dimethylamino)ethyl]-5-(2- ethoxypyridin-3-yl)benzamide;

1-148: 2-[(2R)-4-[2-(3-aminoazetidin-1-yl)-4-fluorobenzoyl]-2-ethylpiperazin-1 -yl] M-[2-(dimethylamino)ethyl]- 5-(2-ethoxypyridin-3-yl)benzamide;

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1-149: 3-[(2R)-4-[4-chloro-2-(τpiτopmethyl)benzoyl]-2-ethylπpiperazin-l-yl]-N[2(dimethylamino)ethyl]-6-(2-ethoxyphenyl )pyridine-2-carboxamide;

1-150: 5 - [(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2(dimethylamino)ethyl]-2'- ethoxy-[2,3'-bipyridine]-6-carboxamide;

1-151: 5 - [(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]-2-ethylpiperazin-1-yl] 2'ethoxy-N-[(3R)-πpyrrolidin-3-yl ]-[2,3'-bipyridine]-6-capboamide;

1-152: 5 - [(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]-2-ethylpiperazin-1 -yl] 2'ethoxy-N-[(ЗR)-l-methylpyrrolidin-3 -yl]-[2,3'-bipyridine]-6-carboxamide;

1-153: 6-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-3 (2ethoxypyridin-3-yl)-2-fluoro-M-[2- (methylamino)ethyl]benzamide;

1-154: 6-[(2R)-4-[4-cyano-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3 (2ethoxypyridin-3-yl)-2-fluoro- HCH-[2-(methylamino)ethyl]benzamide;

1-155: 3 -(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-methoxy-2(trifluoromethyl)benzoyl]piperazin-1-yl]-2- fluoro-M-[2-(methylamino)ethyl]benzamide;

1-156: 6-[(2R)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-l-yl]-3-(2-ethoxypyridinZyl)-2-fluoro^-[2-(methylamino) ethyl]benzamide;

1-157: 6-[(2R)-4-[2-cyano-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3 (2ethoxypyridin-3-yl)-2-fluoro- M-[2-(methylamino)ethyl]benzamide;

1-158: 5 - [(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylπpiperazin-1 -yl]-N-[2(dimethylamino)ethyl]-2'-ethoxy-[2, 3'-bipyridine]-6-carboxamide;

1-159: ?<-(2-ami noethyl)-5 -(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[2-methoxy-6(trifluoromethyl)pyride in-3-carbonyl]piperazin-1-yl]benzamide;

1-160: N-(2-aminoethyl)-2-[(2R)-4-[2-(dimethylamino)-6-methylpyridin-3-carbonyl]2-ethylpiperazin-1 -yl] -5 -(2- ethoxypyr idin-3-yl)benzamide;

1-161: 2-[(2R)-4-[2-(azeτid in-1 -yl)-4-fluorobenzoyl]-2-ethylpiperazin-1 -yl]-N-[2(dimethylamino)ethyl]-5 -(2-ethoxypyridin-3-yl)benzamide;

1-162: N-[2-(dimethylamino)ethyl]-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4[4fluoro-2-(pyrrolide in-1 - yl)benzoyl]piperazin-1-yl]benzamide;

1-163: 3 -(2-ethoxypyridin-3-yl)-6-[(2E)-2-ethyl-4-[6-(methylamino)-2(trifluoromethyl)pyridin-3-carbonyl]piperazine-1 -yl]-2-fluoro-M-[2(methylamino)ethyl]benzamide;

1-164: 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[6-methoxy2(trifluoromethyl)pyridin-3-carbonyl]piperazin-1-yl]-2 -fluoro-M-[2(methylamino)ethyl]benzamide;

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1-165: 6-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridin-3-carbonyl]-2ethylpiperazin1-yl]-3-(2-ethoxypyridin-3-yl)-2- fluoro-M-[2-(methylamino)ethyl]benzamide;

1-166: 3 -(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[2-methoxy6(τpiφτopmethyl)πpyridin-3-carbonyl]πpiperazin-l-yl]- 2-φτop-N-[2(methylamino)ethyl]benzamide;

1-167: 2'-ethoxy-5-[(2R)-2-ethyl-4-[4-methoxy-2-(τpiτopmethyl)benzoyl]piperazin1-yl]-M-[2-(methylamino)ethyl]- [2,3'-bipyridine]-6-carboxamide;

1-168: N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4[4methoxy-2-(trifluoromethyl)benzoyl]piperazine -1-yl]-2-fluorobenzamide;

1-169: N-[2-(dimethylamino)ethyl]-2'-ethoxy-5-[(2R)-2-ethyl-4-[4-methoxy2(trifluoromethyl)benzoyl]piperazin-1-yl]-[ 2,3'-bipyridine]-6-carboxamide;

1-170: N-[(4,5-dihydro-1 H-imidazol-2-yl)methyl]-3 -(2-ethoxypyrid in-3 -yl)-6 [(2R)2-ethyl-4 -[4-methoxy-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2fluorobenzamide;

1-171: 5 - [(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylπpiperazin-1 -yl]-2'-ethoxy-M-[2(methylamino)ethyl] - [2, 3'-bipyridine]-6-carboxamide;

1-173: 6-[(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2(dimethylamino)ethyl]-3 -(2- ethoxypyr idin-3-yl)-2-fluorobenzamide;

1-174: N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4[4fluoro-2-(trifluoromethyl)benzoyl ]piperazin-1-yl]-2-fluorobenzamide;

1-175: 6-[(2R)-4-[4-cyano-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2(dimethylamino)ethyl]-3 -(2- ethoxypyr idin-3-yl)-2-fluorobenzamide;

1-176: 6-[(2R)-4-[2-^ iforomethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1 -yl]-N-[2(dimethylamino)ethyl]-3-(2-ethoxypyr idin-3-yl)-2-fluorobenzamide;

1-177: 6-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-3 (2ethoxypyridin-3-yl)-2-fluoro-M-[ 2-(methylamino)ethyl]benzamide;

1-178: 6-[(2K.)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl]-X-[(4,5-dihydro1 Nimidazol-2-yl)methyl] -3 -(2-ethoxypyrid in-3-yl)-2-fluorobenzamide;

1-179: 6-[(2R)-4-(2,4-d chlorobenzoyl)-2-ethylpiperazin-1-yl]-N-[2(dimethylamino)ethyl]-3-(2-ethoxypyridin-3 -yl)-2-fluorobenzamide;

1-180: 6-[(2R)-4- { 4-chloro-2- [(3 S)-3 -(d imethylamino)pyrrolid in-1 -yl] benzoyl } 2ethylpiperazin-1 -yl] - M- [2-(d imethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)2fluorobenzamide;

1-181: 2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(τpiφτopmethyl)pyridin-3-carbonyl]2ethylpiperazin-1-yl]-M-[2-(methylamino)ethyl ]-[2,3'-bipyridine]-6-carboxamide;

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1-182: N-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-3-(2-ethoxypyridin-3-yl)-6 [(2R)2-ethyl-4 -[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluorobenzamide;

1-183: 6-[(2R)-4-[4-chloro-2-(diφτopmethyl)benzoyl]-2-ethylπipπerazin-l-yl]-3(2ethoxypyridin-3-yl)-2-fluoro-M- [2-(methylamino)ethyl]benzamide;

1-184: 6-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2(dimethylamino)ethyl]-3 -(2- ethoxypyr idin-3-yl)-2-fluorobenzamide;

1-185: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methyl-2-(τpiφτopmethyl)πpyridinZcarbonyl]piperazin-1-yl]-M-[2-(methylamino)ethyl ]-[2,3'-bipyridine]-6carboxamide;

1-186: 6-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylπpiperazin-1 -yl]-N-[2(dimethylamino)ethyl]-3-(2-ethoxypyr idin- 3-yl)-2-fluorobenzamide;

1-187: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(τpiφτopmethyl)pyridineZcarbonyl]piperazin-1-yl]-M-[2-(methylamino)ethyl ]-[2,3'-bipyridine]-6carboxamide;

1-188: 6-[(2R)-4-[4-chloro-2-(τpiτopmethyl)benzoyl]-2-ethylπpiperazin-l-yl]-N[(4,5 dihydro-1H-imidazol-2- yl)methyl]-3 -(2-ethoxypyrid in-3 -yl)-2-fluorobenzamide;

1-189: 6-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-3 (2ethoxypyridin-3-yl)-2-φτop-N-[ (3R)-πpyrrolidin-3-yl]benzamide;

1-190: 6-[(2R)-4-[4-chloro-2-(diφτopmethyl)benzoyl]-2-ethylπipiperazin-l-yl]-3(2ethoxypyridin-3-yl)-2-φτop-N- [(3R)-πpyrrolidin-3-yl]benzamide;

1-191: N-[2-(dimethylamino)ethyl]-5 -(2-ethoxypyridin-3 - yl)-2-[(2I)-2-ethyl-4- { 2[ethyl(methyl)amino] - 4-fluorobenzoyl } piperazin-1 -yl] benzamide;

1-194: 5-[(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]-2-ethylpiperazin-l-yl]-2'-ethylN-[2-(methylamino)ethyl] - [ 2,3'-bipyridine]-6-carboxamide;

1-195: 5 - [(2R)-4-(2-chloro-4-ethox ibenzoyl)-2-ethylpiperase in-1 -yl]-2'-ethoxy-M-[2(methylamino)ethyl] - [ 2,3'-bipyridine]-6-carboxamide;

1-196: 5 - [(2R)-4-(2-chloro-4-ethoxybenzoyl)-2-ethylpipiperazin-1-yl]-N-[2(dimethylamino)ethyl]-2'-ethoxy-[2, 3'-bipyridine]-6-carboxamide;

1-197: 6-[(2R)-4- { 4-chloro-2- [(3 S)-3 -(d imethylamino)pyrrolid in-1 -yl] benzoyl } 2ethylpiperazin-1 -yl] -3 - (2-ethoxypyr id in-3 - yl)-2-φτορ-Ν-[2(methylamino)ethyl]benzamide;

1-198: N-(azetidin-3 -yl)-6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl] 2ethylpiperazin-1 -yl]-3 -(2-ethoxypyr idin- 3-yl)-2-fluorobenzamide;

1-199: 6-[(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]-2-ethylπpiperazin-l-yl]-3(2ethoxypyridin-3-yl)-2-φτop-N -[(3R)-1-methylpyrrolidin-3-yl]benzamide;

1-200: 6-[(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]-2-ethylπpiperazin-l-yl]-3(2ethoxypyridin-3-yl)-2-fluoro-M- [(38)-pyrrolidin-3-yl]benzamide;

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1-201: 6-[(2K)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3(2ethoxypyridin-3-yl)-2-fluoro-M -[(3S)-1-methylpyrrolidin-3-yl]benzamide;

1-202: T4-(azetidin-3-yl)-3-(2-ethoxypyridin-3-yl)-6-[(2K)-2-ethyl-4-[4-methoxy-2(trifluoromethyl)benzoyl] piperazin-1-yl]-2-fluorobenzamide;

1-203: 3 -(2-ethoxypyridin-3-yl)-6-[(2K)-2-ethyl-4-[4-methoxy2(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluoro- M-(1-methylase etidin-3yl)benzamide;

1-204: 6-[(2K)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3(2ethoxypyridin-3 -yl)-2-fluoro^- (1-methylazetidin-3-yl)benzamide;

1-205: 5-[(2K)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2(dimethylamino)ethyl]-2'-ethyl- [2,3'-bipyridine]-6-carboxamide;

1-206: 3-[(2K)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6(2ethoxyphenyl)-M-[(3R)-1-methylpyrrolidine -3-yl]pyr idin-2-carboxamide;

1-207: N-[2-(dimethylamino)ethyl]-2'-ethoxy-5-[(2R)-4-[6-ethoxy-2(trifluoromethyl)pyridin-3-carbonyl]-2-ethylpiperazine-1 -yl]-[2,3'-bipyridine]bcarboxamide;

1-208: 3-[(2K)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6(2ethoxyphenyl)-M-[2-(methylamino)ethyl] pyridine-2-carboxamide;

1-209: 3-[(2R)-4-[4-chloro-2-(τpiτopmethyl)benzoyl]-2-ethylπpiperazin-l-yl]-6(2ethoxyphenyl)-M-[(ZK)-pyrrolidine-3 -yl]pyridine-2-carboxamide;

1-210: 5 - [(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-N-[2(dimethylamino)ethyl]-2'-ethoxy- [2,3'-bipyridine]-6-carboxamide;

1-211: N-(azetidin-3-yl)-5 -[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]2ethylpiperazin-1-yl]-2'-ethoxy-[2, 3'-bipyridine]-6-carboxamide;

1-212: 5 - [(2K)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl] 2'ethoxy-M-(1-methylazetidin-3-yl)- [2,3'-bipyridine]-6-carboxamide;

1-213: 5-[(2К)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'ethoxyN-[2-(methylamino)ethyl] - [2 ,3'-bipyridine]-6-carboxamide;

1-214: 5 - [(2K)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl] 2'ethoxy-M-[(38)-pyrrolidin-3-yl ]-[2,3'-bipyridine]-6-carboxamide;

1-215: 5 - [(2K)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl] 2'ethoxy-M-[(38)-1-methylpyrrolidin-3 -yl]-[2,3'-bipyridine]-6-carboxamide;

1-216: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5(2ethoxypyridin-3-yl)-M-(1-methylazetidine -3-yl)benzamide;

1-218: 5-[(2K)-4-(2-chloro-4-cyclopropoxybenzoyl)-2-ethylpiperazin-1-yl]-2'ethoxyN-[2-(methylamino)ethyl] - [2,3' -bipyridine]-6-carboxamide;

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1-219: 6-[(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]-2-ethylπpiperazin-l-yl]-N[2(4,5-dihydro-1 N-imide azole -2-yl)ethyl]-3 -(2-ethoxypyrid in-3 -yl)-2-fluorobenzamide;

1-220: N-(azetidin-3-yl)-3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]2ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)pyridine -2-carboxamide;

1-221: 3-[(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]-2-ethylπpiperazin-l-yl]-6(2ethoxyphenyl)-T4-(1-methylazetidin-3-yl )pyridine-2-carboxamide. 1-222: N-[(azetidin-3yl)methyl]-5-[(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]-2ethylpiperazin-l-yl]-2'-ethoxy[2 ,3'-bipyridine]-6-carboxamide;

1-223: 5-[(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]-2-ethylpiperazin-1 -yl] 2'ethoxy-M-[(1-methylazetidin-3-yl) methyl]-[2,3'-bipyridine]-6-carboxamide;

1-224: 2'-ethoxy-5 - [(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl] piperazin1 yl]-bTs2-(1 H-imidazol-2-yl) ethyl]-[2,3'-bipyridine]-6-carboxamide;

1-225: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-(ethylamino)-2-(τpiφτopmethyl)pyridineZcarbonyl]piperazin-1-yl]-M-[2-(methylamino )ethyl]-[2,3'-bipyridine]-6carboxamide;

1-226: 5-[(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]-2-ethylπpiperazin-l-yl]-N[(4,5dihydro-1H-imidazol-2-yl) methyl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxamide;

1-227: 5-[(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]-2-ethylpiperazin-1 -yl] 2'ethoxy-M-[( 1 -methyl-4,5 - dihydro-1 H-imidazol-2-yl)methyl]-[2,3'-bipyridine] bcarboxamide;

1-228: 2-[(2R)-4-[4-chloro-2-(τpiτopmethyl)benzoyl]-2-ethylπpiperazin-l-yl]-5(2ethoxypyridin-3-yl)-N-[[(2К )-1-methylazetidin-2-yl]methyl [benzamide;

1-229: 6-[(2R)-4-[4-chloro-2-(τpiτopmethyl)benzoyl]-2-ethylπpiperazin-l-yl]-3(2ethoxypyridin-3-yl)-2-fluoro-M- {[(28)-1-methylazetidin-2-yl]methyl}benzamide. 1-230: 2'ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(τpiφτopmethyl)pyridin-Zarbonyl]piπerazin-lyl]-N-(1-methylazetidin-3 -yl )-[2,3'-bipyridine]-bcarboxamide;

1-231: 5 - [(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]-2-ethylpiperazin-1 -yl] 2'3tokch-N- {[(2R)-1-methyl azetide in -2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide;

1-232: 5-[(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]-2-ethylpiperazin-1-yl] 2'ethoxy-M-{[(28)-1-methylazetidin- 2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide;

1-233: 2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(τpiφτopmethyl)pyridin-3-carbonyl]2ethylpiperazin-1-yl]-M-(1-methylazetidine-3- yl)-[2,3'-bipyridine]-6-carboxamide;

1-234: 5-[(2R)-4-[4-chloro-2-(τpiφτopmethyl)benzoyl]-2-ethylpiperazin-1 -yl] 2'ethoxy-M-[2-(1-methyl-1H -imidazol-2-yl)ethyl]-[2,3'-bipyridine]-6-carboxamide;

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1-235: 2'-ethoxy-5-[(2K)-2-ethyl-4-[1(trifluoromethyl)cyclopropanecarbonyl]piperazin-1 -yl]-N-(1 -methylazetidin-3 -yl)-[2 ,3'bipyridine]-6-carboxamide;

1-236: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[6-methocyclic-2-(τpiφτopmethyl)pyridine3 carbonyl]piperazine-1 -ηπ]-Ν-( 1 - methylazetidin-3-yl)pyridin-2-carboxamide;

1-237: 3-[(2R)-4-[6-ethoxy-2-(τpiφτopmethyl)pyridin-3-κcarbonyl]-2ethylπipiperazin1-yl]-6-(2-ethoxyphenyl)-M-(1-methylazetidine- 3-yl)pyridin-2carboxamide;

1-239: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(τpiφτopmethyl)pyridineZcarbonyl]piperazin-1-yl]-K-[(ZK)-1- methylpyrrolidin-3-yl]-[2,3'-bipyridine]bcarboxamide;

1-240: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(τpiφτopmethyl)pyridineZcarbonyl]piperazin-1-yl]-M-[(ZK)-pyrrolidin- 3-yl]-[2,3'-bipyridine]-6carboxamide;

1-241: 2'-ethoxy-5 - [(2R)-2-ethyl-4-[1 (trifluoromethyl)cyclopentanecarbonyl]piperazin-1 -yl]-N-(1-methylazetidin-3 -yl)- [2 ,3'bipyridine]-6-carboxamide;

1-242: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(τpiφτopmethyl)pyridineZcarbonyl]piperazin-1-yl]-K-[(1-methylazetidine-3 -yl)methyl]-[2,3'-bipyridine]bcarboxamide;

1-243: 2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(τpiφτopmethyl)pyridin-3-carbonyl]2ethylpiperazin-1-yl]-M-[(ZK)-1- methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6carboxamide;

1-244: N-{[(2 8)-azetide in-2-yl]methyl}-2'-ethoxy-5-[(2K)-2-ethyl-4-[6-methoxy2(trifluoromethyl)pyridin- 3-carbonyl]piperazin-1-yl]-[2,3'-bipyridine]-6carboxamide;

1-245: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(τpiφτopmethyl)pyridineZcarbonyl]piperazin-1-yl]-X-{[(28)-1 -methylazetidin-2-yl]methyl}-[2,3'bipyridine]-6carboxamide;

1-246: 5-[(2R)-2-ethyl-4-[6-methoxy-2-(τpiφτopmethyl)pyridin-3carbonyl]piperazin-1-yl]-2'-methoxy-M-(1-methylazetidine- 3-yl)-[2,3'-bipyridine]-6carboxamide;

1-247: 5-[(2R)-4-[6-ethoxy-2-(τpiφτopmethyl)pyridin-3-carbonyl]-2ethylπpiπerazin1-yl]-2'-methoxy-M-(1-methylazetidin-3-yl )-[2,3'-bipyridine]-6carboxamide;

1-248: 5-[(2R)-4-[1-(2,2-difluoroethyl)cyclobutanecarbonyl]-2-ethylpiperazin-1-yl]2'-3tokch-N-(1-methylase etidin-3-yl )-[2,3'-bipyridine]-6-carboxamide;

1-249: 2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(τpiφτopmethyl)pyridin-3-carbonyl]2ethylpiperazin-1-yl]-M-[(1-methylase ethidin- 3-yl)methyl]-[2,3'-bipyride in]-6carboxamide;

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1-250: 2'-ethoxy-5-[(2R)-2-ethyl-4-(l-ethylcyclobutancarbonyl)piperazin-l-yl]-N[2-(methylamino)ethyl]-[2,3'- bipyridine]-6-carboxamide;

1-251: 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[g/is-4(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-2- fluoro^-[2(methylamino)ethyl]benzamide; 1-252: 3 -(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[trans4(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-2-fluoro-M -[2(methylamino)ethyl]benzamide;

1-253: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[6-methoxy-2-(τpiφτopmethyl)pyridine3 carbonyl] piperazine-1 -Hn]-N-[(3R )-1-methylpyrrolidin-3-yl]pyridin-2carboxamide;

1-254: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[6-methoxy-2-(τpiφτopmethyl)pyridineZcarbonyl]piperazin-1-yl]-M-[(ZK) -pyrrolidin-3-yl]pyridin-2-carboxamide;

1-255: 2'-ethoxy-5 - [(2R)-2-ethyl-4-[ 1 (τpiφτopmethyl)cyclophenentanocarbonyl]πipiperazin-l-yl]-N-[(ЗR)-lmethylpyrrolidin-3-yl][ 2,3'-bipyridine]-6-carboxamide; 1-256: N-{[(2S)-azetidin-2-yl]methyl}-2'-ethoxy-5-[(2R)-4-[6-ethoxy2(trifluoromethyl)pyridin-3-carbonyl]-2 -ethylpiperazin-1-yl]-[2,3'-bipyridine]bcarboxamide;

1-257: 2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(τpiφτopmethyl)pyridin-3-carbonyl]2ethylpiperazin-1-yl]-T4-{[(28)-1 -methylazetidin-2-yl]methyl}-[2,3'-bipyridine]bcarboxamide;

1-258: 2'-ethoxy-5 - [(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl] piperazinyl]-N-[(3R)-l-methylpyppolidin-3- yl]-[2,3'-bipyridine]-6-carboxamide;

1-259: 5-[(2R)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-l-yl]-2'-ethoxy-N-[(3R)1methylpyrrolidin-3-yl]-[2 ,3'-bipyridine]-6-carboxamide;

1-260: 5-[(2K)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-M-[(3K.)1-methylpyrrolidin-3- yl]-[2,3'-bipyridine]-6-carboxamide;

1-261: 5-[(2R)-4-(2-chloro-4-φτopbenzoyl)-2-ethylπpyperazin-l-yl]-2'-ethoxy-N-[(3R)1-methylpyrrolidin-3-yl ]-[2,3'-bipyridine]-6-carboxamide;

1-262: 5-[(2R)-4-[4-chloro-2-(diφτopmethyl)benzoyl]-2-ethylπipiperazin-l-yl]-2'ethoxyN-[(ЗR)-l-methylπppolidin-3- yl]-[2,3'-bipyridine]-6-carboxamide;

1-263: 2'-ethoxy-5-[(2R)-2-ethyl-4-[l(τpiφτopmethyl)cyclophenancarbonyl]piperazin-l-yl]-N-[(3R)-pyrrolidin-3-yl][ 2,3'bipyridine]-6-carboxamide;

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1-264: 2'-ethoxy-5-[(2H)-2-ethyl-4-(1-ethylcyclopentanecarbonyl)piperazin-1-yl]-H[2-(methylamino)ethyl]-[2,3'- bipyridine]-6-carboxamide;

1-265: 5-[(2K)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'ethoxyN-[(3K)-pyrrolidin-3-yl] -[2,3'-bipyridine]-6-carboxamide;

1-266: 2'-ethoxy-5 - [(2I)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin1yl]-H-[(3K)-pyrrolidine-3- yl]-[2,3'-bipyridine]-6-carboxamide;

1-267: 5-[(2K)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-H[(3K)pyrrolidin-3-yl]-[2, 3'-bipyridine]-6-carboxamide;

1-270: 3-(2-ethoxypyridin-3-yl)-6-[(2K)-2-ethyl-4-[6-methoxy2(trifluoromethyl)pyridin-3-carbonyl]piperazin-1-yl]-2 -fluoro-T4-[(3K)1 methylpyrrolidin-3-yl]benzamide;

1-271: 3 -(2-ethoxypyridin-3-yl)-6-[(2K)-2-ethyl-4-[6-methoxy-2(trifluoromethyl)pyridin-3-carbonyl]piperazin-1-yl ]-2-fluoro-M-[(3K)-pyrrolidin-3yl]benzamide;

1-273: 2'-ethoxy-5-[(2K)-2-ethyl-4-[1(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-M-[(3K)-pyrrolidin-3-yl]- [2,3'bipyridine]-6-carboxamide;

1-275: 5-[(2K)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]2'ethoxy-M-[(38.4K)-4-fluoropyrrolidine -3-yl]-[2,3'-bipyridine]-6-carboxamide;

1-276: 5-[(2K)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl] 2'ethoxy-M-[(3K,4K)-4-fluoropyrrolidine -3-yl]-[2,3'-bipyridine]-6-carboxamide;

1-277: 5-[(2K)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-M[(3K)pyrrolidin-3-yl]-[ 2,3'-bipyridine]-6-carboxamide;

1-278: 5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2'ethoxyN-[(3H)-pyrrolidin-3-yl]- [2,3'-bipyridine]-6-carboxamide;

1-279: 5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2'ethoxyN-[(3H)-1-methylpyrrolidin-3-yl ]-[2,3'-bipyridine]-6-carboxamide;

1-280: 2'-ethoxy-5-[(2H)-2-ethyl-4-[1(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3R)-p yrrol id in-3 -yl]-[2,3 bipyridine]-6-carboxamide;

1-283: 2'-ethoxy-5-[(2H)-2-ethyl-4-[1(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl ] [2,3'-bipyridine]-6-carboxamide;

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1-286: 2'-ethoxy-5-[(2R)-2-ethyl-4-[g/wc-4(τpiφτopmethyl)cyclogecancancarbonyl]piperazin-l-yl]-N-[(ЗR)-l methylpyrrolidin- 3-yl][2,3'-bipyridine]-6-carboxamide;

1-287: 3-[(2R)-4-[4-chloro-2-(diφτopmethyl)benzoyl]-2-ethylπipiperazin-l-yl]-6(2ethoxyphenyl)-N-[(3R)-l-methylpyrpolidine -3-yl]pyridin-2-capboxamide;

1-288: 3-[(2R)-4-[4-chloro-2-(diφτopmethyl)benzoyl]-2-ethylπipπerazin-l-yl]-6(2ethoxyphenyl)-N-[(3R)-πpyrrolidin-3 -yl]pyridin-2-κapboxamide;

1-289: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(τpiφτopmethyl)pyridineZarbonyl]piperazin-l-yl]-N-[(ЗR,4R)- 4-φτopπppolidin-3-yl]-[2,3'-bipyridine]bcarboxamide;

1-290: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(τpiφτopmethyl)pyridineZarbonyl]piperazin-l-yl]-N-[(ЗR,4R)- 4-φτop-l-methylpyrrolidin-3-yl]-[2,3'bipyridine]6-carboxamide;

1-291: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(τpiτopmethyl)pyridine3 carbonyl] piperazine-1 -nn]-N-[(3S, 4R) -4-φτopπppolidin-3-yl]-[2,3'-bipyridine]bcarboxamide;

1-292: 3-[(2R)-4-[2-(diφτopmethyl)-4-φopbenzoyl]-2-ethylπpiπerazin-l-yl]-6(2ethoκcyphenyl)-N-[(ЗR)-πpyrrolidin-3- yl]pyridin-2-κapboxamide;

1-293: 3-[(2R)-4-[2-(diτopmethyl)-4-φopbenzoyl]-2-ethylπpiperazin-l-yl]-6(2ethoκcyphenyl)-N-[(ЗR)-l-methylpyppolidin- 3-yl]pyridin-2-capboxamide;

1-295: 5-[(2R)-4-[1-(difluoromethyl)-3,3-difluorocyclobutanecarbonyl] 2ethylpiperazin-l-yl]-2'-ethoxy-N-[(3R)-πpyrrolidin-3- yl]-[2,3'-bipyridine]bcarboxamide;

1-296: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(τpiφτopmethyl)pyridineZarbonyl]piperazin-l-yl]-N-[(3S,4R)- 4-φτop-l-methylpyrrolidin-3-yl]-[2,3'bipyridine]6-carboxamide;

1-298: 5-[(2R)-4-[3,3-difluoro-1-(trifluoromethyl)cyclobutanecarbonyl]2ethylpiperazin-1-yl]-2'-ethoxy-N-[(3K)-pyrrolidine-3 -yl]-[2,3'-bipyridine]bcarboxamide;

1-299: 2'-ethoxy-5-[(2R)-2-ethyl-4-[g/wc-4(τpiφτopmethyl)cyclogecancancarbonyl]piperazin-l-yl]-N-[(3R)-pyrrolidin-3 -yl]-[2,3'bipyridine]-6-carboxamide;

1-300: 2'-ethoxy-5-[(2R)-2-ethyl-4-[g/wc-3(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3R)-πpropolid in- 3-yl]-[2,3'bipyridine]-6-carboxamide;

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1-301: 2'-ethoxy-5-[(2R)-2-ethyl-4-[m/?α//c-3(τpiφτopmethyl)cyclobutanecarbonyl]piperazin-l-yl]-N-[(ЗR) -πpyrrolidin-3-yl]-[2,3'bipyridine]-6-carboxamide; 1-303: 5-[(2R)-4-(2-chloro-4-φτopbenzoyl)-2-ethylπpiperazin-l-yl]-2'-ethoxy-N[(3R)πpyrrolidin-3-yl]-[ 2,3'-bipyridine]-6-carboxamide; 1-304: 6-(2-ethoxyphenyl)-3 - [(2R)-2-3thh-4-[ 1 (τpiφτopmethyl)cyclophenancarbonyl]piperazin-l-yl]-N-[(3R)-πpyrrolidin-Zyl] πpyridine2-carboxamide;

1-305: 3 -[(2R)-4-(2-τpeτ-bytylpyppolidin-1-carbonyl)-2-ethylpiperazin-1-yl]-6(2ethoκciphenyl)-N-[(3R)-πpyrrolidin-3- yl]pyridin-2-κapboxamide;

1-306: 2'-ethoxy-5 - [(2R)-2-3thh-4- [(2 8)-2-(trifluoromethyl)pyrrolidine1 carbonyl] piperazin-1 -yl]-N-[(3R)- pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide;

1-307: 2'-ethoxy-5-[(2R)-2-ethyl-4-[l(trifluoromethyl)cyclopentanecarbonyl]piperazine-1-hh]-N-[(3R)-1-[(5-methyl -2-oxo-2H-1,3d ioxol4-yl)methyl]pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide;

1-310: 2'-ethyl-5-[(2R)-2-ethyl-4-[(2R)-2-(τpiφτopmethyl)πpyrrolidine1 carbonyl] piperazin-1 -yl]-N-[(3R)-πpyrrolidine -3-yl]-[2,3'-bipyridine]-6carboxamide;

1-313: 2'-ethoxy-5 - [(2K)-2-ethyl-4-[1 (trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]^-[(1 -methylase etidin-3 yl)methyl][ 2,3'-bipyridine]-6-carboxamide;

1-315: 3 - [(2R)-4-[(2 8)-2-tert-butylpyrrolide in-1-carbonyl]-2-ethylpiperazin-1 yl] 6-(2-methoκciphenyl)-N-[( 3R)-πpyrrolidin-3-yl]πpyridin-2-carboxamide;

1-316: 3 - [(2R)-4-[(2R)-2-τpeτ-byτpeτ-pyrpolide in-1-carbonyl]-2-ethylpiperazin-1 yl] 6-(2-methoκciphenyl)-N-[(ЗR )-πpyrrolidin-3-yl]πpyridin-2-carboxamide;

1-318: 2'-ethoxy-5 - [(2R)-2-ethyl-4-[1 (trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-M-[(3-fluoroazetidin-Zyl)methyl][2 ,3'-bipyridine]-6-carboxamide;

1-319: 2'-ethoxy-5-[(2R)-2-ethyl-4-[l(trifluoromethyl)cyclopentanecarbonyl]piperazin-1 -yl]-M-[(3-fluoro-1 methylazetidin-3 yl) methyl]-[2,3'-bipyridine]-6-carboxamide;

1-320: 2'-ethoxy-5 - [(2R)-2-ethyl-4-[(2S)-2-(2-τopπpopan-2-yl)πppolidinI carbonyl]piperazin-1-yl]-H- [(3K)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6carboxamide;

1-321: 2'-3tokch-5-[(2R)-2-3TНi-4-[1(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-M-[(38)-pyrrolidin-3-yl ]-[2,3'bipyridine]-6-carboxamide;

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1-322: 2'-ethoxy-5-[(2K)-2-ethyl-4-[g/is-4(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-M-[(1-methylazetidine-Zyl) methyl][2,3'-bipyridine]-6-carboxamide;

1-323: 5-[(2R)-4-(2,2-d ethylpyrrolid in-1-carbonyl)-2-ethylpiperazin-1-yl] 2'ethoxy-N-[(3R)-πpyrrolidin-3- yl]-[2,3'-bipyridine]-6-carboxamide;

1-324: 2'-ethoxy-5-[(2R)-2-ethyl-4-[l(τpiφτopmethyl)cyclophenancarbonyl]piperazin-l-yl]-N-{[(2R)-pyrrolidin-2yl]methyl} [2,3'-bipyridine]-6-carboxamide;

1-325: 2'-ethoxy-5-[(2R)-2-ethyl-4-[l(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-{[(2 8)-pyrrolidin-2yl]methyl } [2,3'-bipyridine]-6-carboxamide;

1-326: 2'-ethoxy-5-[(2R)-2-ethyl-4-[2-methyl-2-(τpiφτopmethyl)πppolidinlκapbonyl]πipiperazin-l-yl]-N-[(ЗR)-pyrrolidin- 3-yl]-[2,3'-bipyridine]-6carboxamide;

1-327: X-{[(2K)-azetidin-2-yl]methyl}-2'-ethoxy-5-[(2K)-2-ethyl-4[1(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl ]-[2,3'-bipyridine]-6carboxamide;

1-328: 5-[(2R)-4-[1-(2,2-difluoroethyl)cyclobutanecarbonyl]-2-ethylpiperazin-1-yl] 2'-ethoxy-N-[(3R)-πppolidin-3- yl]-[2,3'-bipyridine]-6-carboxamide;

1-329: N-{[(2S)-azetidin-2-yl]methyl}-2'-ethoxy-5-[(2R)-2-ethyl-4[1(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl ]-[2,3'-bipyridine]-6carboxamide;

1-330: 2'-ethoxy-5-[(2R)-2-ethyl-4-[l(τpiφτopmethyl)cyclophenancarbonyl]piperazin-l-yl]-N-{[(2R)-l-methylazetidin-2yl] methyl }-[2,3'-bipyridine]-6-carboxamide;

1-331: 2'-ethoxy-5-[(2R)-2-ethyl-4-[l(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-{ [(2S)-1-methyl azetide in-2yl ]methyl }-[2,3'-bipyridine]-6-carboxamide;

1-332: 2'-ethoxy-5-[(2R)-2-ethyl-4-[l(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-X-{ [(2S)-1 methylpyrrolidin-2yl]methyl } - [2,3'-bipyridine]-6-carboxamide;

1-333: 2'-ethoxy-5-[(2R)-2-ethyl-4-[l(τpiφτopmethyl)cyclophenancarbonyl]piperazin-l-yl]-N-{[(2R)-lmethylπpyropolidin-2yl]methyl } - [2,3'-bipyridine]-6-carboxam;

1-334: 2'-ethoxy-5-[(2R)-2-ethyl-4-[l(trifluoromethyl)cyclopentanecarbonyl]piperazin-1 -yl]-M-[(3-methoxy-1 methylazetidin-3 yl) methyl]-[2,3'-bipyridine]-6-carboxamide;

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1-335: 6-(2-ethoxyphenyl)-3-[(2K)-2-ethyl-4-[g/is-4(τpiφτopmethyl)cyclohecancancarbonyl]πiperazin-l-yl]-N-[(ЗR)- πpyrrolidine-Zyl]πpyridine2-carboxamide;

1-336: 6-(2-ethoxyphenyl)-3-[(2K)-2-ethyl-4-[g/is-4(trifluoromethyl)cyclohexanecarbonyl] piperazine-1 -hh]-N-[(3R)- 1 methylpyrrolidin-3yl]pyridin-2-carboxamide;

1-337: N-[2-(azetidin-1-yl)ethyl]-2'-ethoxy-5-[(2R)-2-ethyl-4-[1 (trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl] -[2,3'-biiridine]-6carboxamide;

1-340: 6-(2-ethoxyphenyl)-3 - [(2R)-2-ethyl-4-[1 (trifluoromethyl)cyclopentanecarbonyl]piperazin-1 -yl]-M-[(1-methylazetidin3 yl)methyl] pyridine-2-carboxamide;

1-341: 6-(2-ethoxyphenyl)-3 - [(2R)-2-ethyl-4-[1 (trifluoromethyl)cyclopentanecarbonyl]piperazine-1 -nn]-N-[(3R)-1 methylpyrrolidine-3 yl]pyridine-2-carboxamide;

1-342: 6-(2-ethoxyphenyl)-3-[(2K)-2-ethyl-4-[(28)-2-(trifluoromethyl)pyrrolidine1 carbonyl]piperazin-1 -yl]-M-[(3K )-pyrrolidin-3-yl]pyridin-2-carboxamide;

1-343: 6-(2-ethoxyphenyl)-3-[(2K)-2-ethyl-4-[(28)-2-(trifluoromethyl)pyrrolidineI carbopyl]piperazip-1-yl]-M-[(38 )-pyrrolidip-3-yl]pyridip-2-carboxamide;

1-344: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1 (trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidine - 3 yl]pyridine-2-carboxamide;

1-349: 6-(2-ethoxyphenyl)-3-[(2K)-2-ethyl-4-[1-(2,2,2trifluoroethyl)cyclobutanecarbonyl]piperazin-1-yl]^-[(3K)- 1-methylpyrrolidin3 yl]pyridine-2-carboxamide;

1-355: 3 - [(2R)-4-[(2 8)-2-tert-butylpyrrolide in-1-carbonyl]-2-ethylpiperazin-1-yl] 6-(2-ethoxyphenyl)-M-[ (3K)-pyrrolidin-3-yl]pyridin-2-carboxamide;

1-356: 3-[(2K)-4-[(2K)-2-tert-butylpyrrolidine-1-carbonyl]-2-ethylpiperazin-1 yl]6-(2-ethoxyphenyl)-M-[(3K) -pyrrolidin-3-yl]pyridin-2-carboxamide;

1-357: 5-[(2K)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]2'ethoxy-M-[2-(3-fluoroazetidin-1- yl)ethyl]-[2,3'-bipyridine]-6-carboxamide;

1-359: 2'-ethoxy-5-[(2K)-2-ethyl-4-[1-(2,2,2τpiφτopethyl)cyclophenancarbonyl]piperazin-l-yl]-N-[(ЗR)-l- methylpyrrolidin-3-yl][2,3'-bipyridine]-6-carboxamide;

1-362: 6-(2-ethoxyphenyl)-3 - [(2R)-2-ethyl-4-[(2 8)-2-(trifluoromethyl)pyrrolidine1 carbonyl]piperazin-1 -yl]-M-[( 1-methylazetidin-3-yl)methyl]pyridine-2carboxamide;

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1-363: 2'-ethoxy-5-[(2R)-2-ethyl-4-[l(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-M-[(3S)-l methylpyrrolidin-3-yl ] [2,3'-bipyridine]-6-carboxamide;

1-364: 2'-ethoxy-5-[(2R)-2-ethyl-4-[l(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3S)-1-methylpyrrolidin-3- yl][2,3'-bipyridine]-6-carboxamide;

1-372: 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(τpiφτopmethyl)πppolidinlocapbonyl]piperazin-l-yl]-N-[(ЗR)-l- methylpyrrolidin-3-yl]-[2,3'-bipyridine]bcarboxamide;

1-373: 2'-ethyl-5-[(2R)-2-ethyl-4-[(2S)-2-(τpiφτopmethyl)pyrrolidine1 carbonyl]piperazin-1 -yl]-M-[(3S)- 1-methylpyrrolidin-3-yl]-[2,3'-bipyridin]bcarboxamide;

1-374: 6-(2-ethoxyphenyl)-3 - [(2R)-2-ethyl-4-[(2 8)-2-(trifluoromethyl)pyrrolidine1 carbonyl]piperazine-1 -hh]-N-[( 3R)-1-methylpyrrolidin-3-yl]pyridin-2carboxamide;

1-375: 6-(2-ethoxyphenyl)-3 - [(2R)-2-ethyl-4-[(2 8)-2-(trifluoromethyl)pyrrolidine1 carbonyl]piperazine-1 -hh]-N-[( 3 S)-1 -methylpyrrolidin-3-yl]pyr idin-2carboxamide;

1-386: 2'-ethoxy-5 - [(2R)-2-ethyl-4-[(2 8)-2-(trifluoromethyl)pyrrolidine1 carbonyl] piperazin-1 -yl] -N- {[ (2R) -1-methyl azetide in-2-yl]methyl}-[2,3'bipyridine]-6carboxamide;

1-387: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(τpiφτopmethyl)πppolidine1 carbonyl] piperazine-1 -ηπ]-Ν-{ [( 2 S)-1 -methylazetidin-2-yl]methyl }pyridine 2carboxamide;

1-390: 2'-ethoxy-5 - [(2R)-2-ethyl-4-[1 (trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-M-{[(28)-1-methyl azetidin2yl]methyl } - [2,3'-bipyridine]-6-carboxamide;

1-391: 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(τpiφτopmethyl)πppolidin1carbonyl]piperazin-1-yl]-M-{[(28)-1 -methylase etidin-2-yl]methyl }-[2,3'bipyridine]-6carboxamide;

1-398: N-[(3S)-l-azabicyclo[2.2.2]okτan-3-yl]-5-[(2R)-4-[4-chloro-2(trifluoromethyl)benzoyl]-2-ethylpiperazine -1-yl]-2'-ethoxy-[2,3'-bipyridine]-6carboxamide;

1-399: 6-(2-ethoxyphenyl)-3 - [(2R)-2-ethyl-4-[1 (trifluoromethyl)cyclopentanecarbonyl]piperazin-1 -yl]-N-(1 -methylazetidin-3 yl)pyridine2 -carboxamide;

1-400: N-[(3S)-l-azabicyclo[2.2.2]octan-3-yl]-2'-ethoxy-5-[(2R)-2-ethyl-4[1(trifluoromethyl)cyclopentanecarbonyl] piperazin-1-yl]-[2,3'-bipyridine]-6carboxamide;

- 25 045243

1-401: 6-(2-ethoxyphenyl)-3 -[(2K)-2-ethyl-4-[1 (trifluoromethyl)cyclopentanecarbonyl]piperazin-1 -yl]-X-[(3 S)-1 methylpyrrolidin- 3yl]pyridine-2-carboxamide;

1-405: X-{1-azabicyclo[2.2L]ber1an-4-yl}-2'-ethoxy-5-[(2K)-2-ethyl-4[1(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl ]-[2,3'-bipyridine]-6carboxamide;

1-410: N-[(3S)-l-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4[ 1 -( trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide;

1-411: N-[(3 8)-1-azabicyclo[2.2.2]octan-3-yl]-2'-ethoxy-5-[(2К)-2-ethyl-4[1(trifluoromethyl)cyclobutanecarbonyl ]piperazin-1-yl]-[2,3'-bipyridine]-6carboxamide;

1-412: 6-(2-ethoxyphenyl)-3 - [(2R)-2-ethyl-4-[(2 8)-2-(2-fluoropropan-2yl)pyrrolidin 1 -carbonyl] piperazin-1 -yl ]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridin2carboxamide;

1-413: 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(2-φτopπpopan-2-yl)πppolidinlκapbonyl]piperazin-l-yl]-N-[ (3R)-l-methylpyrrolidin-3-yl]-[2,3'-bipyridine]bcarboxamide;

1-415: 2'-ethoxy-5-[(2R)-2-ethyl-4-[l(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-M-[(1-methyl-4,5-dihydro- 1Nimidazol-2-yl)methyl]-[2,3'-bipyridine]-6-carboxamide;

1-416: 5 -[(2R)-4- [1 -(difluoromethyl)cyclopentanecarbonyl]-2-ethylpiperazin-1 -yl] 2'ethoxy-N-[(3R)-l-methylpyrrolidin-3-yl]- [2,3'-bipyridine]-6-carboxamide;

1-417: 3 - [(2R)-4-[ 1 -(difluoromethyl)cyclopentanecarbonyl]-2-ethylpiperazin-1 -yl]-6(2-ethoκciphenyl)-N-[(3R)-l-methylpyrrolidin-3 -yl]pyridine-2-carboxamide;

1-427: 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(τpiφτopmethyl)πpipiridinlκcapbonyl]piperazin-l-yl]-N-[(ЗR)-l- methylpyrrolidin-3-yl]-[2,3'-bipyridine]bcarboxamide;

1-433: 6-(2-ethoxyphenyl)-3 - [(2R)-2-ethyl-4-[(2 8)-2-(trifluoromethyl)piperidine1 carbonyl]piperazin-1 -yl]-M-[( 3 R)-1-methylpyrrolidin-3-yl]pyridin-2carboxamide;

1-434: 2'-ethoxy-5 - [(2R)-2-ethyl-4-[(2 8)-2-(trifluoromethyl)piperidine1 carbonyl]piperazin-1 -yl]-M-[(3 S) -1-methylpyrrolidin-3-yl]-[2,3'-bipyr idin]bcarboxamide;

1-435: 6-(2-ethoxyphenyl)-3 - [(2R)-2-ethyl-4-[(2 8)-2-(trifluoromethyl)piperidine1 carbonyl]piperazin-1 -yl]-M-[( 3 S)-1-methylpyrrolidin-3-yl]pyridin-2carboxamide;

2-21: {[5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-φτop-2(trifluoromethyl)benzoyl]piperazin-1 -yl]phenyl] methyl } [2-(methylamino)ethyl]amine; or a pharmaceutically acceptable salt thereof.

In some embodiments, the connection is:

- 26 045243

or a pharmaceutically acceptable salt thereof.

In some embodiments, the connection

- 27 045243 has the following structure:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound has the following structure:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound has the following structure:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound has the following structure:

or a pharmaceutically acceptable salt thereof.

In one aspect, the compounds described herein are in the form of pharmaceutically acceptable salts. Moreover, the active metabolites of such compounds, which exhibit the same type of activity, are included within the scope of the present invention.

As used herein, pharmaceutically acceptable refers to a substance, such as a carrier or diluent, that does not remove the biological activity or properties of the compound and is relatively non-toxic, i.e. the substance was administered to a subject without causing adverse biological effects or interacting inappropriately with any component of the composition in which it is contained.

The term pharmaceutically acceptable salt refers to a form of a therapeutically effective agent that consists of a cationic form of a therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of a therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim/Zurich:Wiley-VCH/VHCA, 2002. Pharmaceutical salts are typically more soluble and more readily soluble in the stomach and gastric juices than nonionic species , and are thus useful in solid dosage forms. Moreover, since their solubility is often a function of pH, selective dissolution in one or another part of the gastrointestinal tract is possible and this ability can be controlled as one aspect of extended and sustained release regimens. Also, since the salt-forming molecule can be in equilibrium with the neutral form, passage through biological membranes can be regulated.

In some embodiments, pharmaceutically acceptable salts are prepared by reacting a compound of formula (IX) with an acid. In some embodiments, the compound of formula (IX) (ie, the base form) is basic and reacts with an organic acid or an inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and metaphosphoric acid. Organic acids include, but are not limited to, 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid);

- 28 045243 carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (-L); malonic acid; mandelic acid (DL); methanesulfonic acid; naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; butyric acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; propionic acid; pyroglutamic acid (-L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L); thiocyanic acid; toluenesulfonic acid (para) and undecenoic acid.

In some embodiments, the compound of formula (IX) is prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt, or phosphate salt.

In some embodiments, pharmaceutically acceptable salts are prepared by reacting a compound of formula (IX) with a base. In some embodiments, the compound of formula (IX) is acidic and reacts with a base. In such cases, the acidic proton of the compound of formula (IX) is replaced by a metal ion, for example a lithium, sodium, potassium, magnesium, calcium or aluminum ion. In some cases, the compounds described herein are reacted with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, the compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Suitable inorganic bases used to form salts with compounds that include an acidic proton include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds of the present invention are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, Nmethylglucamine salt, or ammonium salt.

In some embodiments, compounds of formula (IX) have one or more stereocenters and each stereocenter exists independently in either an R or S configuration. In some embodiments, the compound of formula (IX) exists in the R configuration. In some embodiments, the compound of formula (IX) exists in the S configuration. The compounds provided herein include all diastereomeric, individual enantiomeric, atropiomeric and epimeric forms, as well as appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, opposite (E) and adjacent (Z) isomers, as well as appropriate mixtures thereof.

The individual stereoisomers are obtained, if necessary, by methods such as stereoselective synthesis and/or separation of stereoisomers using chiral chromatography columns or separation of diastereomers using either non-chiral or chiral chromatography columns or crystallization and recrystallization in a suitable solvent or mixture of solvents. In certain embodiments, compounds of formula (IX) are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a diastereomeric compound/salt pair, resolving the diastereomers and reducing the optically pure individual enantiomers. In some embodiments, resolution of the individual enantiomers is accomplished using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation/resolution techniques based on differences in solubility. In other embodiments, the separation of stereoisomers is carried out by chromatography or by the formation of diastereomeric salts and separation by recrystallization or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley and Sons, Inc., 1981. In some embodiments, stereoisomers are prepared by stereoselective synthesis.

Synthesis of compounds.

The compounds of formula (IX) described in the present invention were synthesized using standard synthetic procedures or using methods known in the art in combination with the methods described in the present invention.

Unless otherwise noted, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology were used.

The compounds were prepared using standard organic chemistry techniques such as those described, for example, in March's Advanced Organic Chemistry, ^6th Edition, John Wiley and Sons, Inc. They can

- 29 045243 alternative reaction conditions described in the present invention for synthesis transformations, such as variations in solvent, reaction temperature, reaction time, as well as various chemical reagents and other reaction conditions, can be used.

In some embodiments, the compounds described herein are prepared as described in Scheme A.

Scheme A

a) DMSO, Et ₃ N, 100°C; b) Fe, NH ₄ CI, EtOH/H ₂ O, 70°C; c) n-Butyl nitrite, CuBr ₂ . ACN, 70°C;

d) R ^a B(OH) ₂ . Pd ₂ (dba) ₃ HCI ₃ P(t-Bu) ₃ HBF ₄ , K ₃ PO ₄ . toluene, 70°C; e) LiOH.H ₂ O, H ₂ O/MeOH/THF; f) TFA, DCM.

Compound I was prepared by heating methyl 2-fluoro-5-nitrobenzoate or methyl 2,6-difluoro-3-nitrobenzoate with monoprotected substituted piperazine in the presence of an organic base such as N,N-diisopropylethylamine. Iron-catalyzed reduction of the nitro group produced arylamine, which was subsequently converted to aryl bromide (II) by producing a diazonium salt and subsequent substitution with the Br anion catalyzed by copper (IX). Compound II was subjected to an organometallic coupling reaction such as the Suzuki-Miyaura reaction with R ^A B(OH) ₂ or its corresponding ester, followed by standard hydrolysis to form compound III. Compound IV was converted to intermediate V by iron-catalyzed nitro reduction followed by a Sandmeyer reaction on aniline. Alternatively, Compound V can also be prepared from standard deprotection of Compound II.

In some embodiments, the compounds described herein are prepared as described in Scheme B.

Scheme B

Compound V was converted to intermediate VI by treatment with an activated carboxylic acid using HATU and triethylamine or acyl chloride in the presence of triethylamine or other bases. Compound VII was prepared from aryl bromide (VI) by organometallic coupling reactions such as the Suzuki-Miyaura reaction with boronic acid R ^A B(OH)2 or its ester, or Still's coupling with R ^A SnBu3. The direct conversion of carboxylic acid ester (VII) to amide (VIII) was carried out by heating it with a diamine in a polar protic solvent. Alternatively, compound VI was converted to the corresponding boronic acid ester intermediate (IX), which was sequentially subjected to a coupling reaction, such as the SuzukiMiyaura reaction, with an aryl halide such as R ^A -Br, and then the ester was converted to an amide to give compound VIII.

In some embodiments, the compounds described herein are prepared as described in Scheme C.

- 30 045243

Scheme C

a) R ⁴ R ⁵ NH, HATU, Et3N; b) TFA, DCM; c) R ^B CO2H, HATU, Et ₃ N or R ^B COCI, Et ₃ N; d) deprotection (optical).

Compound III was reacted with an amine (R ⁴ R ⁵ NH) in the presence of HATU and triethylamine to yield intermediate X. Compound X was subjected to Boc removal with TFA or another acid and then amide formation with RACO2H or RACOCl to yield compound XI. If R ⁴ or R ⁵ contains a protecting group, then an additional deprotection step occurs to obtain compound XI. Alternatively, intermediate XII was prepared by deprotecting III with TFA and converted to XIII by treatment with preactivated RBCO2H. Compound XIII was used to prepare the corresponding amides (XI) in a similar manner.

In some embodiments, the compounds described herein are prepared as described in Scheme D.

Scheme D

a) R ^a B(OH) ₂ , Pd ₂ (dba) ₃ HCI ₃ P(t-Bu) ₃ HBF _4i K ₃ PO ₄ . toluene, 70°C; b) NaBH ₄ MeOH, 50°C;

c) IBX; d) R ⁴ R ⁵ NH, NaBH(OAc)3; e) TFA, DCM; f) R ^B CO2H, HATU, Et ₃ N; g) deprotection (if necessary)

Compound II was subjected to Suzuki coupling with boronic acid R ^B B(OH)2 in the presence of a transition metal catalyst to give intermediate (XIV). The carboxylic acid ester on XIV was reduced to an alcohol using NaBH4 followed by oxidation with 2-iodooxybenzoic acid to give benzaldehyde XV, which was subjected to a ^reductive amination reaction with the appropriate amine ( ^R4R5NH ) and a reducing agent such as NaBH(OAc)3 , to obtain compound XVI. Subsequent Boc deprotection and then amide formation with R ^B CO2H afforded compound XVII. If R ⁴ contains a protecting group, then an additional deprotection step occurs to obtain compound XVII.

In some embodiments, the compounds described herein are prepared as described in Scheme E.

- 31 045243

Scheme E

a) R ^a B(OH)2. PdCl2(t-Bu2PPhNMe2)2, K2CO3, dioxane/H2O; b) DMSO, DIEA, 140°C; c) TRA or HCI d) R ^b CO ² H, HATU, Et3N or R ^B COCI, Et3N; e) KOH, EtOH/H2O, 100°C; f) R ⁴ R ⁵ NH, HATU, Et3N; g) NiCI ₂ . _NaBH4 ; h) Cbz-CI, DIPEA DCM or CbzOSu, DCM; i) TFA, 70°C.

Compound XVIII was prepared by Suzuki Miyaura coupling with boronic acid R ^A B(OH)2 or Still coupling with R ^A SnBu3, which reacted with a monoprotected substituted piperazine in the presence of an organic base such as DIEA to give compound XIX. The Boc group is then removed with acid and the corresponding amide is formed by a standard amide formation reaction with RBCO2H to give compound XX. Benzylamine analogues (XXII-B) were prepared by nickel(II)-catalyzed reduction of carbonitrile. Hydrolysis of -CN on compound XX with a strong inorganic base such as KOH provided the carboxylic acid intermediate (XXI), which was converted to compound XXII-A by coupling with R ⁴ R ⁵ NH. If R ⁴ contains a protecting group, then an additional deprotection step occurs to obtain compound XXII. Alternatively, compound XXII-A was prepared by a 4-step synthesis, starting with compound XIX by first hydrolyzing the cyano group to a carboxylic acid and then amide formation with R4R5NH to form compound XXIII, then the Boc group was removed and RBCO2H or RBCOCl was used to obtain compound XXII-A . If R ⁴ contains a protecting group, then a suitable deprotection step to remove the protecting group was carried out to obtain compound XXII. In some embodiments, compound XXII-B was alternatively prepared from compound XIX by the following method: the cyano group was reduced with NaBH ₄ in the presence of MCl ₂ . The new amine formed was then protected with a Cbz group. Subsequently, the Boc group was removed, followed by amide formation with RBCO2H. Finally, the Cbz group was removed by stirring in hot TFA to give Compound XXXII-B.

In some embodiments, the compounds described herein are prepared as described in Scheme F.

Scheme F

Vos

a) DMSO, DIEA, 120°C; b) R ^A B(OH)2 PdCI2(t-Bu2PPhNMe2)2, K2CO3, dioxane/H2O, 100°C; c) LiOH.H2O, MeOH/H2O/THF; d) TFA, DCM, e) R ^B CO2H, HATU, Et3N;

f) HATU, R ⁴ R ⁵ NH; g) deprotection (if necessary)

Heating methyl 6-bromo-3-chloropyrazine-2-carboxylate with monoprotected substituted piperazine gave compound XXIV, which was subsequently subjected to Suzuki Miyaura coupling with R ^a B(OH) ₂ and then hydrolysis of the ester to acid and standard de-Boc procedure to obtain compound XXV. Compound XXVI was prepared from a coupling reaction with pre-activated RBCO2H and an additional reaction with R4R5NH in the presence of HATU to obtain compound XXVII. If R ⁴ or R ⁵ contains a protecting group, then an additional deprotection step occurs to obtain compound XXII.

- 32 045243

In some embodiments, the compounds described herein are prepared as described in Scheme G. Scheme G

and XXVIH XXIX

R ⁵ XXXI ^xxx

a) TFA, DCM; b) R ^B -CI (or F), DIEA, DMSO; c) NON.H ₂ O, H ₂ O/MeOH/THF;

d) R ⁴ R ⁵ NH, HATU. Et3N; e) R ^A B(OH)2 Pd (II), K ₂ CO ₃ dioxane/H ₂ O; f) deprotection

The Boc group on compound II was removed to give compound XXVIII, which was treated with R ^B Cl or RB-F followed by saponification of the ester to give compound XXIX. The coupling of compound XXIX with R4R5NH gave compound XXX, which underwent a Suzuki-Miyaura reaction with boronic acid R ^A B(OH) ₂ to give compound XXXI. Additional deprotection occurs if R ⁴ or R ⁵ contains a protecting group on compound XXXI.

In some embodiments, the compounds described herein are prepared as described in Scheme H. Scheme H

The Boc group of compound X was removed to form compound XXXII, which was reacted with arylsulfonyl chloride in the presence of an organic base to give compound XXXIII. Similarly, urea analogues (XXXIV) were prepared either by reaction with isocyanates (R ^B NCO), or by the reaction of R ^B R ⁷ CO ₂ Ph, or by the reaction of compound XXXII with triphosgene and then with RBR7NH. In addition, the efficient synthesis of carbamate derivatives (XXXV) was carried out by reacting compound XXXII with CDI-activated alcohols. If R ⁴ contains a protecting group, then it is removed sequentially with suitable conditions from compound XXXIII, XXXIV or XXXV.

In some embodiments, the compounds described herein are synthesized as set forth in the Examples.

Certain terminology

Unless otherwise noted, the following terms used in the present invention are characterized by the definitions provided below. The use of the term including, as well as other forms such as include, includes and included, is not limited. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

As used herein, C1-C _x includes Ci-C ₂ , C1-C ₃ . . . Ci-C _x . By way of example only, a group designated C1-C6 means that there are from one to six carbon atoms in the fragment, i.e., groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, by way of example only, C1-C4 alkyl means that there are from one to four carbon atoms in the alkyl group, i.e. the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

An alkyl group refers to an aliphatic hydrocarbon group. An alkyl group is a branched or straight chain. According to some embodiments

- 33 045243 nium alkyl group contains from 1 to 10 carbon atoms, i.e. C1-C ₁₀ alkyl. In all cases where it occurs, the range of numeric values, such as 1-10, refers to each integer in the range represented; for example, 1-10 carbon atoms means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers occurrences of the term alkyl where not The area of numerical values is indicated. In some embodiments, alkyl is _C1C6 alkyl. In one aspect, alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

The alkylene group refers to a divalent alkyl radical. Any of the above monovalent alkyl groups can be made alkylene by abstraction of the second hydrogen atom from the alkyl. In some embodiments, the alkylene is C1C ₆ alkylene. In other embodiments, the alkylene is C1- _C4 alkylene. Typical alkylene groups include, but are not limited to, _-CH2- , _-CH2CH2- , _-CH2CH2CH2- , _{CH2CH2CH2CH2CH2- ,} etc. In some embodiments, the alkylene is CH2-.

An alkoxy group refers to an (alkyl)O-group, where alkyl is defined herein.

The term alkylamine refers to the -N(alkyl) _x H _y group where x is 0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.

Hydroxyalkyl refers to an alkyl in which one hydrogen atom is replaced by hydroxyl. In some embodiments, the hydroxyalkyl is a C1- _C4 hydroxyalkyl. Typical hydroxyalkyl groups include, but are not limited to -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, and the like.

Aminoalkyl refers to an alkyl in which one hydrogen atom is replaced by amino. In some embodiments, the aminoalkyl is a C1- _C4 aminoalkyl. Exemplary aminoalkyl groups include _, but _are not _{limited to , -CH2NH2} , -CH2CH2NH2, _{-CH2CH2CH2NH2} , _{-CH2CH2CH2CH2NH2 ,} and the like.

The term alkenyl refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, the alkenyl group is characterized by the formula -C(R)=CR ₂ , where R refers to the remaining portions of the alkenyl group, which may be the same or different. In some embodiments, R is H or alkyl. In some embodiments, alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of the alkenyl group include -CH= _CH2 , -C( _CH3 )= _CH2 , -CH= _CHCH3 , -C( _CH3 )= _CHCH3 and -CH2CH=CH2.

The term alkynyl refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, the alkynyl group is characterized by the formula -C^CR, where R refers to the remaining portions of the alkynyl group. In some embodiments, R is H or alkyl. In some embodiments, the alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of the alkynyl group include -C^CH, -C^CH ₃ -C^CCH ₂ CH ₃ , -CH ₂ C^CH.

The term heteroalkyl refers to an alkyl group in which one or more skeletal alkyl atoms are selected from atoms other than carbon, such as oxygen, nitrogen (eg, -NH-, -N(alkyl)-), sulfur, or combinations thereof. The heteroalkyl is attached to the remainder of the molecule at the carbon atom of the heteroalkyl. In one aspect, heteroalkyl is C ₁ -C ₆ heteroalkyl.

The term aromatic refers to a planar ring with a delocalized π electron system containing 4n+2 π electrons, where n is an integer. The term aromatic includes both carbocyclic aryl (aryl, eg phenyl) and heterocyclic aryl (or heteroaryl or heteroaromatic) groups (eg pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups.

The term carbocyclic or carbocycle refers to a ring or ring system where the atoms forming the framework of the ring are all carbon atoms. Thus, the term distinguishes carbocyclic from heterocyclic rings or heterocycles in which the ring framework contains at least one atom that is different from a carbon atom. In some embodiments, the carbocycle is a monocyclic carbocycle or a bicyclic carbocycle. In some embodiments, the carbocycle is a monocyclic carbocycle. Carbocycles are non-aromatic or aromatic. Non-aromatic carbocycles are saturated or partially unsaturated. In some embodiments, the carbocycle is a bicyclic carbocycle. In some embodiments, at least one of the two rings of the bicyclic carbocycle is aromatic. In some embodiments, both rings of the bicyclic carbocycle are aromatic. Carbocycles include aryls and cycloalkyls.

As used herein, the term aryl refers to an aromatic ring where each of the atoms forming the ring is a carbon atom. In one aspect, aryl is phenyl or naphthyl. In some embodiments, aryl is phenyl. In some embodiments, aryl is phenyl, naphthyl, indanyl, indenyl, or tetrahydronaphthyl. In some embodiments, aryl is C ₆ -C ₁₀ aryl. Depending on the structure, an aryl group is monoradical or diradical (i.e., an arylene group).

The term cycloalkyl refers to a monocyclic, bicyclic or polycyclic aliphatic, non-aromatic radical where each of the atoms forming the ring (ie, the backbone atoms) is a carbon atom. In some embodiments, the cycloalkyls are spirocyclic or bridged compounds. In some embodiments, the cycloalkyls are optionally fused to an aromatic ring and the point of attachment is at a carbon atom that is not an aromatic ring carbon atom. Cycloalkyl groups include groups containing from 3 to 10 ring atoms. In some embodiments, the cycloalkyl groups are selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl, norbornenyl, bicyclo[1.1.1]pentyl, adamantyl, norbornyl, norbornenyl, decalinyl, or 7,7-dimethylbicyclo[2.2.1]heptanyl. In some embodiments, the cycloalkyl is C ₃ -C ₆ cycloalkyl. In some embodiments, the cycloalkyl is a monocyclic cycloalkyl. Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl (ie, bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethylbicyclo[2.2.1]heptanyl, and the like.

The term halo or alternatively halogen or halide means fluorine, chlorine, bromine or iodine. In some embodiments, the halogen is fluorine, chlorine, or bromine.

The term fluoroalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. In one aspect, the fluoroalkyl is a C ₁ -C ₆ fluoroalkyl.

The term heterocycle or heterocyclic refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings containing from one to four heteroatoms in the ring(s), wherein each heteroatom in the ring(s) is selected from O, S and N, each heterocyclic group contains from 3 to 10 atoms in its ring system, and provided that any ring does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings containing from 3 to 10 atoms in its ring system system, and aromatic heterocyclic groups include rings containing from 5 to 10 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetane yl, tietanil, homopiperidinil, oxepanil, tiepanil, oxazepinil, diazepinil, thiazepinil , 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl , dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1onyl, isoindolin-1,3-dionyl, 3 ,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindolin-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[ d]imidazol-2(3H)-onyl, benzo[d]thiazol2(3H)-onyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolyl zinil, phthalazinil , pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanil, benzofurazanil, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl. The above groups are either C-linked (or C-linked) or N-linked where possible. For example, the group derived from pyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). In addition, the group derived from imidazole includes imidazol1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached ). Heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least

- 35 045243 one of the two rings of the bicyclic heterocycle is aromatic. In some embodiments, both rings of the bicyclic heterocycle are aromatic.

The terms heteroaryl or, alternatively, heteroaromatic refer to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl and furazanyl. Monocyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolysine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8naphthyridine and pteridine. In some embodiments, the heteroaryl contains 0-4 N ring atoms. In some embodiments, the heteroaryl contains 1-4 N ring atoms. In some embodiments, heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms on the ring. In some embodiments, the heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms on the ring. In some embodiments, the heteroaryl is C1C ₉ heteroaryl. In some embodiments, the monocyclic heteroaryl is C1- _C5 heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl is a C ₆ -C ₉ heteroaryl.

A heterocycloalkyl group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, the heterocycloalkyl is fused with aryl or heteroaryl. In some embodiments, heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidin-2,5-dithionyl, pyrrolidin-2,5-dionyl , pyrrolidinonyl , imidazolidinyl, imidazolidin-2-onyl or thiazolidin-2-onyl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including without limitation monosaccharides, disaccharides and oligosaccharides. In one aspect, heterocycloalkyl is C ₂ C ₁₀ heterocycloalkyl. In another aspect, heterocycloalkyl is C ₄ C ₁₀ heterocycloalkyl. In some embodiments, the heterocycloalkyl contains 0-2 N ring atoms. In some embodiments, the heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms, and 0-1 S atom on the ring.

The term bond or single bond refers to a chemical bond between two atoms or two fragments if the atoms connected by the bond are considered as part of a larger substructure. In one aspect, if a group described in the present invention is a link, the control group is omitted, thereby allowing the formation of a link between the remaining established groups.

The term fragment refers to a specific segment or functional group of a molecule. Chemical moieties are often shown as chemical units embedded in or attached to a molecule.

The term optionally substituted or substituted means that the control group is optionally substituted with one or more additional group(s) separately and independently selected from halogen, -CN, -NH2, -NH(alkyl), -N(alkyl) ₂ . -OH, -CO ₂ H, -CO ₂ alkyl, -C(=O)NH ₂ , -C(=O)NH(alkyl), -C(=O)N(alkyl) ₂ , -S(=O ) ₂ NH ₂ , -S(=O) ₂ NH(alkyl), -S(=O) ₂ N(alkyl) ₂ , alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkyl sulfoxide, arylsulfoxide, alkyl sulfone and arylsulfone. In some other embodiments, the optional substituents are independently selected from halogen, -CN, -NH2, -NH(alkyl), -N(alkyl) ₂ , -OH, _-CO2H , _-CO2alkyl , -C(=O) NH ₂ , -C(=O)NH(alkyl), C(=O)N(alkyl) ₂ , -S(=O) ₂ NH ₂ , -S(=O) ₂ NH(alkyl), -S( =O) ₂ N(alkyl) ₂ , alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkyl sulfoxide, arylsulfoxide, alkyl sulfone and arylsulfone. In some other embodiments, the optional substituents are independently selected from halogen, -CN, -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , -OH, -CO ₂ H, -CO ₂ (C1-C ₄ alkyl), -C(=O)NH ₂ , -C(=O)NH(C ₁ -C ₄ alkyl), -C(=O)N(C1C ₄ alkyl) ₂ , -S(=O) ₂ NH ₂ , -S(=O) ₂ NH(C ₁ -C ₄ alkyl), -S(=O) ₂ N(C ₁ -C ₄ alkyl) ₂ , C1-C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C1-C ₄ fluoroalkyl, C1-C ₄ heteroalkyl, C1-C ₄ alkoxy, C1-C ₄ fluoroalkoxy, -SC ₁ -C ₄ alkyl, -S(=O)C1C ₄ alkyl and -S(=O) ₂ C ₁ -C ₄ αlkyl. In some other embodiments, the optional substituents are independently selected from halogen, -CN, -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , -OH, -CO ₂ H, -CO ₂ (C1C4alkyl), - C(=O)NH2, -C(=O)NH(C1-C4αalkyl), -C(=O)N(C1-C4alkyl)2, -S(=O)2NH2, -S(=O) ₂ NH (CiC ₄ alkyl), -S(=O) ₂ N(C ₁ -C ₄ alkyl) ₂ , C1-C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ heterocycloalkyl, C1C ₄ fluoroalkyl, C1- C ₄ heteroalkyl, C1-C ₄ alkoxy, C1-C ₄ fluoroalkoxy, -SC ₁ -C ₄ αlkyl, -S(=O)C ₁ -C ₄ αlkyl and -S(=O) ₂ C ₁ -C ₄ alkyl . In some embodiments, the optional substituents are independently selected from halogen, -CN, -NH2, -OH, -NH(CH ₃ ), -N(CH ₃ ) ₂ , -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , - OCH ₃ and -OCF ₃ .

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In some embodiments, the substituted groups are replaced by one or two preceding groups. In some embodiments, the optional substituent on the aliphatic carbon atom (acyclic or cyclic) includes oxo (=O).

As used herein, the term acceptable in relation to a formulation, composition or ingredient means that it does not have a persistent adverse effect on the general health of the subject being treated.

As used herein, the term modulate means interacting with a target, either directly or indirectly by changing the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.

As used herein, the term modulator refers to a molecule that interacts with a target either directly or indirectly. Interactions include, but are not limited to, agonist, partial agonist, inverse agonist, antagonist, disruptor, or combinations thereof. In some embodiments, the modulator is an agonist.

As used herein, the terms introduce, administration process, introduction, etc. refer to methods that can be used to effect delivery of compounds or compositions to the desired site of biological action. Such methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those skilled in the art will know administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

As used herein, the terms co-administration or the like cover the administration of selected therapeutic agents to a single patient and include treatment regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

As used herein, the terms effective amount or therapeutically effective amount refer to a sufficient amount of an agent or compound to be administered that will alleviate to some extent one or more symptoms of the disease or condition being treated. The result includes a reduction and/or attenuation of signs, symptoms or causes of disease or some other desired change in a biological system. For example, an effective amount for therapeutic applications is the amount of a composition containing a compound disclosed herein necessary to provide a clinically significant reduction in the symptoms of a disease. The appropriate effective amount in any particular case is not necessarily determined using techniques such as dose escalation studies.

As used herein, the terms enhance or enhance mean increasing or prolonging either the effectiveness or duration of a desired effect. Thus, with respect to the enhancing effect of therapeutic agents, the term enhancement refers to the ability to increase or prolong either the effectiveness or duration of effect of other therapeutic agents in the system. As used herein, the term enhancing effective amount refers to an amount suitable to enhance the effect of another therapeutic agent in the desired system.

As used herein, the term pharmaceutical combination means a product that is the result of mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients. The term fixed combination means that the active ingredients, for example, both the compound of formula (IX) or a pharmaceutically acceptable salt thereof, and the co-drug, are administered to the patient simultaneously in the form of a single substance or dosage. The term "unfixed combination" means that the active ingredients, for example, a compound of formula (IX) or a pharmaceutically acceptable salt and co-agent thereof, are administered to a patient in the form of separate substances either simultaneously, in parallel or sequentially without any specific time intervals, wherein such administration provides effective content of two compounds in the patient's body. The latter also applies to cocktail therapy, such as the administration of three or more active ingredients.

The terms product and set are used interchangeably.

The term subject or patient includes mammals. Examples of mammals include, without limitation, any member of the class Mammals: humans, non-human primates such as chimpanzees and other monkeys, as well as other monkey species; farm animals such as cattle, horses, sheep, goats, pigs; pets such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice, guinea pigs, etc. In one aspect, the mammal is a human.

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As used herein, the terms treat, treatment process, or treatment include reducing, alleviating, or alleviating at least one symptom of a disease or condition, preventing additional symptoms, suppressing a disease or condition, e.g., delaying the progression of a disease or condition, alleviating a disease or condition, providing regression of a disease or condition, alleviation of a condition caused by a disease or condition, or suspension of symptoms of a disease or condition, either prophylactically and/or therapeutically.

Pharmaceutical compositions.

In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into pharmaceutically usable preparations. The appropriate composition depends on the chosen route of administration. Brief descriptions of the pharmaceutical compositions described herein are found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), incorporated herein by reference for such disclosure.

In some embodiments, the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents in a pharmaceutical composition. Administration of the compounds and compositions described herein can be accomplished by any method that provides delivery of the compounds to the site of action. These methods include, but are not limited to, delivery by enteral routes (including oral, gastric or duodenal feeding tubes, rectal suppositories, and rectal enema), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal and local (including cutaneous, cutaneous, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most appropriate route may depend, for example, on the condition and disorder of the recipient. By way of example only, the compounds described herein can be administered locally to the site in need of treatment, for example, by local infusion during surgery, topical application, such as creams or ointments, injection, catheter or implant. Administration can also be accomplished by direct injection into the affected tissue or organ.

In some embodiments, pharmaceutical compositions suitable for oral administration are presented in discrete units, such as capsules, sachets, or tablets, each containing a predetermined amount of the active ingredient, as a powder or granule, or as a solution or suspension in an aqueous medium. , or a non-aqueous medium, or in the form of an oil-in-water liquid emulsion, or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented in the form of a bolus, electuary, or paste.

Pharmaceutical compositions that can be administered orally include tablets, hard capsules made from gelatin, and soft, sealed capsules made from gelatin and a plasticizer such as glycerin or sorbitol. Tablets may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in bulk form such as powder or granules, optionally mixed with binders, inert diluents or lubricants, surfactants or dispersants. Molded tablets can be prepared by molding in a suitable machine a mixture of a powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and formulated to provide a slow or controlled release of the active ingredient therein. All formulations for oral administration must be in dosages suitable for such administration. Hard capsules may contain the active ingredients in admixture with excipients such as lactose, binders such as starches and/or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin or liquid polyethylene glycols. In some embodiments, stabilizers are added. The pellet cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain acacia gum, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, varnish solutions and suitable organic solvents or mixtures of solvents. Dyes or pigments may be added to tablets or dragee coatings to identify or characterize different dosage combinations of the active compound.

In some embodiments, the pharmaceutical compositions are formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Injectable formulations may be presented in unit dosage form, such as ampoules or multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous carrier vehicles, and may contain auxiliary agents such as suspending, stabilizing and/or dispersing agents. The compositions may be presented in single-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) state requiring only the addition of a sterile liquid carrier, such as saline or sterile pyrogen-free solution. water immediately before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the previously described type.

Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injectable solutions of the active compounds, which may contain antioxidants, buffers, bacteriostatics and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. Suitable lipophilic solvents or carrier media include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to provide highly concentrated solutions.

Pharmaceutical compositions can also be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (eg, as an emulsion in a suitable oil), or ion exchange resins, or as sparingly soluble derivatives, eg, as a sparingly soluble salt.

For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, lozenges or gels formulated by conventional means. Such compositions may contain the active ingredient in a flavor base such as sucrose and acacia gum or gum tragacanth.

Pharmaceutical compositions can be administered topically, that is, by non-systemic administration. This involves applying a compound of the present invention externally to the epidermis or buccal cavity and instilling such compound into the ear, eye and nose such that the compound does not enter the bloodstream to a significant extent. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

Pharmaceutical compositions suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin into the site of inflammation, such as gels, liniments, lotions, creams, ointments or patches and drops suitable for administration to the eye, ear or nose. . For topical administration, the active ingredient may be from 0.001 to 10% w/w, for example 1 to 2% by weight of the formulation.

Pharmaceutical compositions for administration by inhalation are conveniently delivered by insufflator, pressurized aerosol cans, or other suitable aerosol spray delivery means. The pressurized cylinders may contain a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver the metered amount. Alternatively, for administration by inhalation or insufflation, the pharmaceutical preparations may take the form of a dry powder composition, for example, a powder mixture of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, for example, in capsules, cartridges, gelatin or blister packs, from which the powder can be administered by means of an inhaler or insufflator.

It should be appreciated that, in addition to the ingredients specifically mentioned above, the compounds and compositions described herein may include other agents conventional in the art relevant to the composition of the type in question, for example, agents suitable for oral administration, may include flavoring agents.

Methods of dosing and treatment regimens.

In one embodiment, the compounds of formula (IX) or pharmaceutically acceptable salts thereof are used in the preparation of medicinal products for the treatment of diseases or conditions in a mammal for which modulation of melanocortin receptor activity would be effective. Methods of treating any of the diseases or conditions described herein in a mammal in need of such treatment comprise administering to said mammal pharmaceutical compositions that include at least one compound of formula (IX) or a pharmaceutically acceptable salt thereof, the active a metabolite, prodrug, or pharmaceutically acceptable solvate, in therapeutically effective amounts.

In certain embodiments, compositions containing compound(s) described herein are administered for prophylactic and/or therapeutic treatments. In some therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially relieve at least one of the symptoms of the disease or condition. Amounts effective for such use depend on the severity and course of the disease or condition, pretreatment, the medical condition of the patient, weight and response to drugs, and the judgment of the attending physician. Therapeutically effective amounts are not necessarily determined by methods involving, but not limited to, dose escalation and/or dose varying clinical testing.

In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk for a particular disease, disorder or condition. Such amount is defined as a prophylactically effective amount or dose. When used in this way, the exact quantities also depend on the patient's health, weight, etc. When used in patients, effective amounts for such use will depend on the severity and course of the disease, disorder or condition, prior therapy, the patient's health status and response to drugs, and the judgment of the attending physician. In one aspect, the prophylactic treatments comprise administering to a mammal that has previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition containing a compound of formula (IX) or a pharmaceutically acceptable salt thereof to prevent relapse symptoms of a disease or condition.

In certain embodiments, if the patient's condition does not improve, at the physician's discretion, the compounds are administered chronically, that is, over an extended period of time, including throughout the patient's life, to alleviate or otherwise control or limit the symptoms of the patient's disease or condition.

After the patient's condition improves, a maintenance dose is administered if necessary. Then, in certain embodiments, the dosage or frequency of administration, or both, is reduced as a function of symptoms to a level at which improvement in the disease, disorder, or condition is maintained. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis for any recurrence of symptoms.

The amount of a given agent that corresponds to such an amount varies depending on factors such as the particular compound, the disease state and its severity, the characteristics (eg, weight, gender) of the subject or recipient in need of treatment, but is nevertheless determined in accordance with the specific circumstances surrounding the case, including, for example, the specific agent to be administered, route of administration, condition to be treated, and subject or recipient to be treated.

However, typically the doses used to treat an adult typically range from 0.01 mg to 2000 mg per day. In one embodiment, the desired dose is conventionally provided as a single dose or divided doses administered simultaneously or at appropriate intervals, for example, two, three, four or more sub-doses per day.

In one embodiment, daily dosages suitable for a compound of formula (IX) or a pharmaceutically acceptable salt thereof are from about 0.01 to about 50 mg/kg body weight. In some embodiments, the daily dosage or amount of active ingredient in dosage form is lower or higher than the ranges specified herein, depending on a number of variables in the individual treatment regimen. In various embodiments, daily and unit dosages vary depending on a number of variables, including, without limitation, the activity of the compound used, the disease or condition being treated, the route of administration, the requirement of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner. .

The toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determination of LD ₅₀ and ED ₅₀ . The relationship of dose to toxic and therapeutic effects is the therapeutic index and is expressed as the ratio of LD ₅₀ to ED ₅₀ . In certain embodiments, data obtained from cell culture assays and animal studies are used in formulating a range of therapeutically effective

- 40 045243 daily dosages and/or a therapeutically effective amount of unit dosages for use in mammals, including humans. In some embodiments, the daily dosage amount for the compounds described herein is within a range of circulating concentrations that include the ED ₅₀ with minimal toxicity. In certain embodiments, the daily dosage range and/or the number of dosage units varies within the range depending on the dosage form used and the route of administration used.

According to any of the above aspects, further embodiments are provided wherein an effective amount of a compound of formula (IX) or a pharmaceutically acceptable salt thereof: (a) is administered to a mammal systemically; and/or (b) administered orally to the mammal; and/or (c) administered intravenously to the mammal; and/or (d) administered to a mammal by injection; and/or (e) administered topically to the mammal; and/or (f) administered non-systemically or locally to a mammal.

In accordance with any of the foregoing aspects, additional embodiments are provided that provide single administrations of an effective amount of the compound, including additional embodiments in which (i) the compound is administered once daily; or (ii) the compound is administered to a mammal several times over the course of one day.

According to any of the foregoing aspects, additional embodiments are provided that provide multiple administrations of an effective amount of a compound, including additional embodiments in which (i) the compound is administered continuously or intermittently as a single dose; (ii) the time intervals between multiple administrations are 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. In additional or alternative embodiments, the method includes a drug holiday in which the administration of the compound is temporarily suspended or the dose of the compound to be administered is temporarily reduced; at the end of the drug holiday, the dose of the compound is resumed. According to one embodiment, the duration of the drug holiday varies from 2 days to 1 year.

Combined treatment.

In some cases, it is advisable to administer at least one compound of formula (IX) or a pharmaceutically acceptable salt thereof in combination with one or more other therapeutic agents.

In one embodiment, the therapeutic efficacy of one of the compounds described herein is enhanced by administration of an excipient (i.e., the excipient alone has minimal therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, in some embodiments, the benefit experienced by a patient is enhanced by administering one of the compounds described herein with another agent (which also includes a therapeutic regimen) that also has a therapeutic benefit.

In one specific embodiment, a compound of formula (IX) or a pharmaceutically acceptable salt thereof is co-administered with a second therapeutic agent, wherein the compound of formula (IX) or a pharmaceutically acceptable salt thereof and the second therapeutic agent modulate various aspects of the disease, disorder or condition being treated, thereby providing greater overall benefit than administering either therapeutic agent alone.

In any case, with respect to the disease, disorder or condition being treated, the overall benefit experienced by the patient may be additive from the two therapeutic agents, or the patient may experience a synergistic effect.

For the combination therapeutic agents described herein, the dosages of the co-administered compounds vary depending on the type of drug used together, the specific drug used, the disease or condition being treated, and the like. In additional embodiments, when administered in conjunction with one or more other therapeutic agents, a compound provided herein is administered either simultaneously with one or more other therapeutic agents or sequentially.

In the case of combination therapeutic agents, multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If the administration is simultaneous, then multiple therapeutic agents are provided, by way of example only, in a single unit form or in multiple forms (eg, as a single pill or as two separate pills).

The compounds of formula (IX) or a pharmaceutically acceptable salt thereof, as well as combination therapeutic agents, are administered before, during or after the onset of a disease or condition, and the time of administration of the composition containing the compound varies. Thus, in one embodiment, the compounds described herein are used prophylactically and are administered chronically to subjects with a predisposition to developing conditions or diseases to prevent

- 41 045243 before the onset of a disease or condition. In another embodiment, the compounds and compositions are administered to the subject during or as soon as possible after the onset of symptoms. In certain embodiments, a compound described herein is administered as soon as possible after the onset of a disease or condition, known or suspected, and for a period of time necessary to treat the disease. In some embodiments, the length of time required for treatment varies and the duration of treatment is adjusted to meet the specific needs of each subject.

Abbreviations:

DIEA: N,N-diisopropylethylamine;

DMSO: dimethyl sulfoxide;

Pd(PPh ₃ ) ₄ : tetrakis(triphenylphosphine)palladium (0);

Pd(dppf)Cl ₂ : [1,1'-bis(diphenylphosphino)ferrocene]palladium(P) dichloride;

CuI: copper(I) iodide;

TBAF: tetra-n-butylammonium fluoride;

P(t-Bu) ₃ : tri-tert-butylphosphine;

HBF4: tetrafluoroboric acid;

DBU: 1,8-diazabicyclo[5,4,0]undec-7-ene;

prep-HPLC: preparative high-performance liquid chromatography;

TFA: trifluoroacetic acid;

CH ₃ CN, MeCN or ACN: acetonitrile;

MeOD: deuterated methanol;

CDCl ₃ : deuterated chloroform;

DME: 1,2-dimethoxyethanol;

DMF: N,N-dimethylformamide;

DCM: dichloromethanol;

H ₂ O: water;

KOAc: potassium acetate;

NaOAc: sodium acetate;

Cs ₂ CO ₃ : cesium carbonate;

p-TsOH: p-toluenesulfonic acid;

NaNO ₂ : sodium nitrite;

THF: tetrahydrofuran;

NBS: N-bromosuccinimide;

Br ₂ : bromine;

AgF: silver fluoride;

LiAlH ₄ : lithium aluminum hydride;

IBX: 2-iodoxybenzoic acid;

TEA: trimethylamine;

DMAP: N,N-dimethylpyridin-4-amine;

HOBT: hydroxybenzotriazole;

EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide;

Pd(PPh ₃ ) ₂ Cl ₂ : bis(triphenylphosphine) palladium(P) dichloride;

PdAMphos or Pd (amphos)Cl ₂ or: bis(di-tert-butyl(4dimethylaminophenyl)phosphine)dichloropalladium(P);

Pd(DTBPF)Cl ₂ : [1,1'-bis(di-dareda-butylphosphino)ferrocene]dichloropalladium(II);

cc: column chromatography;

room temperature: room temperature;

h: hour or hours.

Examples

The following examples are provided for illustrative purposes only and do not limit the scope of the presented claims.

Synthesis of compounds.

Example 1: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]2',3'-difluoro-[ 1,1'-biphenyl]-3-carboxamide (compound 1-1)

F

Step 1-1, preparation of tert-butyl(3R)-3-ethyl-4-[2-(methoxycarbonyl)-4-nitrophenyl]piperazine-1carboxylate: methyl 2-fluoro-5-nitrobenzoate was placed in a 40 ml round bottom flask (2.2 g, 0.01

- 42 045243 mmol, 1.2 eq.), tert-butyl(3R)-3-ethylpiperazine-1-carboxylate (2.0 g, 9.33 mmol), TEA (2.8 g, 0.03 mmol, 3.0 eq.) and DMSO (20 ml). The resulting solution was stirred at 100°C for 2 hours and cooled to room temperature. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine (2x50 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by a silica gel column eluting with ethyl acetate/petroleum ether (1:3) to give 3.3 g (90%) of the title compound as a brown oil. LCMS (M+H)+: 394.2.

Step 1-2, preparation of methyl 2-[(2R)-2-ethylpiperazin-1-yl]-5-nitrobenzoate: tert-butyl(3R)-3-ethyl-4-[2-(methoxycarbonyl)-4-nitrophenyl solution ]piperazine-1-carboxylate (3.3 g, 8.39 mmol) in TFA (3 ml)/DCM (6 ml) was stirred at 30°C for 2 hours. The resulting mixture was concentrated in vacuo. This resulted in 3.3 g (97%) of the title compound as a brown oil. LCMS (M+H)+: 294.1.

Step 1-3, preparation of tert-butyl(3R)-4-[4-bromo-2-(methoxycarbonyl)phenyl]-3-ethylpiperazine-1carboxylate: 2-chloro-4-(trifluoromethyl)benzoic acid (860 mg, 3 .83 mmol, 1.2 eq.) and HATU (1.46 g, 3.83 mmol, 1.2 eq.) were dissolved in DMF (20 ml). After stirring for 5 min at room temperature, the resulting solution was treated with methyl 2-[(2R)-2-ethylpiperazin-1-yl]-5-nitrobenzoate trifluoroacetate (1.3 g, 3.19 mmol) and DIEA ( 1.23 g, 9.57 mmol, 3.0 eq.). The reaction mixture was stirred for 1 hour at room temperature, diluted with water (50 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine (2x50 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified on a silica gel column, eluting with ethyl acetate/petroleum ether (1:1). 1.8 g (83%) of the title compound was obtained as a yellow oil. LCMS (M+H)+: 500.1.

Step 1-4, preparation of 5-amino-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1yl]benzoate: methyl-2 was placed in a 40 ml round bottom flask -[(2R)-4-[2-chloro-4(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-nitrobenzoate (1.8 g, 3.60 mmol), Fe (1 g, 18 .00 mmol, 5.0 eq.), NH ₄ Cl (963 mg, 18.00 mmol, 5.0 eq.) and EtOH (20 ml)/H ₂ O (4 ml). The resulting solution was stirred at 70°C for 1 hour and cooled to room temperature. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (3x60 ml). The combined organic layers were dried and concentrated in vacuo. The residue was purified on a silica gel column, eluting with ethyl acetate/petroleum ether (1:1). 1.1 g (65%) of the title compound was isolated as a yellow oil. LCMS (M+H)+: 470.1.

Step 1-5, preparation of methyl 5-bromo-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin1-yl]benzoate: CuBr was placed in a 40 ml round bottom flask ₂ (1.31 g, 5.85 mmol, 2.5 eq.), nbutyl nitrite (482 mg, 4.68 mmol, 2.0 eq.) and ACN (20 ml). The resulting solution was stirred for 5 min at 0°C and treated with a solution of methyl 5-amino-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2ethylpiperazin-1-yl]benzoate ( 1.1 g, 2.34 mmol) in ACN (5 ml) dropwise at 0°C. The resulting solution was stirred at 50°C for 1 hour. The reaction mixture was cooled to room temperature and diluted with water (50 ml). The resulting solution was extracted with ethyl acetate (3x50 ml). The combined organic layers were dried and concentrated in vacuo. The residue was purified on a silica gel column, eluting with ethyl acetate/petroleum ether (1:1). 520 mg (42%) of the title compound was isolated as a light yellow oil. LCMS (M+H)+: 533.0.

Step 1-6, preparation of methyl 4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]2',3'-difluoro-[1,1 '-biphenyl]-3-carboxylate: methyl 5bromo-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl was placed in a test tube under pressure of 8 ml ]benzoate (30 mg, 0.06 mmol), 2,3difluorophenylboronic acid (13.3 mg, 0.08 mmol), Pd ₂ (dba) ₃ CHCl ₃ (5.8 mg, 0.01 mmol), P( tBu) ₃ .HBF ₄ (1.6 mg, 0.01 mmol), K3PO4 (35.8 mg, 0.17 mmol) and toluene/H ₂ O (1 ml/0.1 ml). The resulting solution was degassed for 5 minutes with N2, sealed and stirred at 70°C for 2 hours in an oil bath. The resulting mixture was cooled to room temperature and concentrated in vacuo. The residue was applied to a silica gel column, eluting with ethyl acetate/petroleum ether (1:3) to obtain 20 mg (63%) of the title compound. LCMS (M+H)+: 567.1.

Step 1-7, preparation of N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2ethylpiperazin-1-yl]-2',3'-difluoro -[1,1'-biphenyl]-3-carboxamide: methyl-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazine- 1-yl]-2',3'-difluoro[1,1'-biphenyl]-3-carboxylate (20 mg, 0.04 mmol), ethanol-1,2-diamine (0.5 ml) and IPA ( 0.5 ml). The resulting solution was sealed and stirred at 70°C for 16 hours. The resulting mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by prep-HPLC under the following conditions: SunFire Prep C18 OBD column; mobile phase, phase A: water (0.05% TFA); phase B: ACN (30% up to 45% in 6 min); flow rate: 20 ml/min; detector, 220 and 254 nm, 7.4 mg (30%) of the title compound was obtained. LCMS (M+H)+: 595.2.

The following compounds were prepared similarly to Example 1 with appropriate substitution reagents and substrates at various stages. In some examples, additional functional group modifications may be necessary to introduce an appropriate substituent on the aryl rings.

- 43 045243

Example 2: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'cyclopropoxy-[1,1 '-biphenyl]-3-carboxamide (compound 1-14)

Step 2-1, preparation of methyl 2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)benzoate: methyl 5-bromo-2-[(2R)-4-[2- was placed in an 8 ml pressurized test tube, purged and maintained under an inert nitrogen atmosphere. chloro-4(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]benzoate from example 1, step 1-5 (250 mg, 0.47 mmol), 4,4,5,5-tetramethyl-2-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (178 mg, 0.70 mmol), Pd(DTBPF)Cl ₂ (25 mg, 0 .04 mmol), KOAc (138 mg, 1.4 mmol) and dioxane (5 ml). The resulting solution was degassed for 10 minutes with _N2 , sealed and stirred at 90°C for 3 hours in an oil bath. The resulting mixture was cooled to room temperature and concentrated in vacuo. The residue was applied to a silica gel column, eluting with ethyl acetate/petroleum ether (1:3). This resulted in 120 mg (44%) of the title compound. LCMS (M+H)+: 581.2.

Step 2-2, preparation of methyl 4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]2'-cyclopropoxy-[1,1'-biphenyl ]-3-carboxylate: 2[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(4,4 ,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)benzoate (43 mg, 0.07 mmol), 1-bromo-2-cyclopropoxybenzene (28 mg, 0.13 mmol), Pd(DTBPF)Cl ₂ (2 mg, 0.003 mmol), K ₂ CO ₃ (20 mg, 0.14 mmol) and dioxane/H ₂ O (2 ml/0.2 ml). The resulting solution was degassed for 10 minutes with _N2 , sealed and stirred at 90°C for 2 hours in an oil bath. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by pre-TLC with ethyl acetate/petroleum ether (1:3) to obtain 25 mg (57%) of the title compound. LCMS (M+H) ⁺ : 587.0.

Step 2-3, preparation of N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2ethylpiperazin-1 -yl]-2'-cyclopropoxy-[1 ,1'-biphenyl]-3-carboxamide: methyl 4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl was placed in a test tube under pressure of 8 ml ]-2'cyclopropoxy-[1,1'-biphenyl]-3-carboxylate (25 mg, 0.04 mmol), ethanol-1,2-diamine (2 ml) and IPA (2 ml). The resulting solution was sealed and stirred at 70°C for 16 hours. The resulting mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by prep-HPLC under the following conditions: SunFire Prep C18 OBD column; mobile phase, phase A: water (0.05% TFA); phase B: ACN (21% up to 38% in 6 min); flow rate: 20 ml/min; detector, 220 and 254 nm, obtaining 10.7 mg (34%) of the title compound. LCMS (M+H) ⁺ : 615.2.

The following compounds were prepared similarly to Example 2 with appropriate substitution reagents and substrates at various stages:

Connection no. MS (M+N) ⁺ 1-32 604.2 1-33 604.2 1-35 604.2

Example 3: 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin- 44 045243

3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide (compound 1-95)

Step 3-1, preparation of tert-butyl(3R)-3-ethyl-4-[3-fluoro-2-(methoxycarbonyl)-4nitrophenyl]piperazine-1-carboxylate: to a solution of tert-butyl-(3R)-3- ethylpiperazine-1-carboxylate (555 mg, 2.59 mmol) and methyl 2,6-difluoro-3-nitrobenzoate (843 mg, 3.89 mmol) in DMSO (2 ml) was added DIEA (0.90 ml, 5 .2 mmol). The mixture was heated at 130°C for 1 hour. The mixture was purified by C18 reverse phase column chromatography to give the title compound (813 mg, 76% yield) as a tan gum. LCMS (M+H)+: 412.3.

Step 3-2, preparation of tert-butyl(3R)-4-[4-amino-3-fluoro-2-(methoxycarbonyl)phenyl]-3ethylpiperazine-1-carboxylate: to a solution of tert-butyl(3R)-3-ethyl -4-[3-fluoro-2-(methoxycarbonyl)-4nitrophenyl]piperazine-1-carboxylate (813 mg, 1.98 mmol) in MeOH (30 ml) was added with 10% Pd/C (213 mg, 0.0941 mmol ) and NH ₄ Cl (1.188 g, 18.83 mmol). The mixture was heated at 80°C for 20 minutes. The mixture was filtered through celite and the filtrate was concentrated and purified by C18 reverse phase column chromatography to give the title compound (612 mg, 81% yield) as a reddish brown gum. LCMS (M+H) ⁺ : 382.3.

Step 3-3, preparation of tert-butyl(3R)-4-[4-bromo-3-fluoro-2-(methoxycarbonyl)phenyl]-3ethylpiperazine-1-carboxylate: to a solution of tert-butyl(3R)-4-[ 4-amino-3-fluoro-2(methoxycarbonyl)phenyl]-3-ethylpiperazine-1-carboxylate (612 mg, 1.60 mmol) in MeCN (10 ml) was added under nitrogen atmosphere with CuBr ₂ (197 mg, 0.882 mmol) and 90% tert-butyl nitrite (0.24 ml, 1.8 mmol). The mixture was heated at 70°C for 30 minutes. The mixture was quenched with ice water and extracted with DCM (3x). The combined organic layers were washed with saturated NaHCP ₃ (aq), concentrated and purified by C18 reverse phase column chromatography to give the title compound (267 mg, 0.600 mmol, 38% yield) as a brown gum. LCMS (M+H) ⁺ : 445.2.

Step 3-4, preparation of tert-butyl(3R)-4-[4-(2-ethoxypyridin-3-yl)-3-fluoro-2(methoxycarbonyl)phenyl]-3-ethylpiperazine-1-carboxylate: to a mixture of tert -butyl(3R)-4-[4-bromo-3-fluoro-2(methoxycarbonyl)phenyl]-3-ethylpiperazine-1-carboxylate (267 mg, 0.600 mmol), (2-ethoxypyridin-3yl)boronic acid (150 mg, 0.900 mmol), Pd[t-Bu ₂ P(4-NMe ₂ C ₆ H ₄ )] ₂ Cl ₂ ) (42.5 mg, 0.0600 mmol) and K ₂ CO ₃ (249 mg, 1. 80 mmol) dioxane (4 ml) and H ₂ O (0.4 ml) were added in a stoppered test tube. The resulting solution was degassed with N ₂ (gas) for 10 min, sealed and stirred at 100°C for 30 min. The reaction was treated with additional (2-ethoxypyridin-3-yl)boronic acid (37.8 mg, 0.226 mmol), Pd[t-Bu2P(4-NMe2CH4)]2Cl2) (13.4 mg, 0.0189 mmol) and K2CO3 (78.3 mg, 0.567 mmol) and stirred at 100°C for an additional 30 minutes. The mixture was concentrated and purified by C18 reverse phase column chromatography to give the title compound (255 mg, 87% yield) as a brown gum. LCMS (M+H) ⁺ : 488.4.

Step 3-5, preparation of 6-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-3-(2ethoxypyridin-3-yl)-2-fluorobenzoic acid: to solution tert-butyl(3R)-4-[4-(2-ethoxypyridin-3-yl)3-fluoro-2-(methoxycarbonyl)phenyl]-3-ethylpiperazine-1-carboxylate (255 mg, 0.523 mmol) in THF/ MeOH/H ₂ O (4.5/1.5/1.5 ml) was added LiOH-H ₂ O (220 mg, 5.24 mmol). The mixture was heated at 60°C overnight. Approximately 50% of the reaction was complete. After adding additional LiOH-H ₂ O (220 mg, 5.24 mmol), the mixture was continued to be heated at 70°C for 2 days. After removing the volatile solvent, the aqueous residue was diluted with ice water and acidified with 1 N HCl (aq) to pH 4. The solid was collected by vacuum filtration and dried to give the title compound (239 mg, 97% yield) as a brown solid. LCMS (M+H) ⁺ : 474.2.

Step 3-6, preparation of 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethylpiperazin-1-yl]-2-fluorobenzoic acid dihydrochloride: to a solution of 6-[(2R)-4 -[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-3-(2ethoxypyridin-3-yl)-2-fluorobenzoic acid (100 mg, 0.211 mmol) in DCM (0.3 ml) was added 4 n HCl in dioxane (0.30 ml, 1.2 mmol). The mixture was stirred at RT for 1 hour. The solution was decanted and the residue was washed with DCM (3x) and dried under vacuum to give the title compound as a medium brown solid. LCMS (M+H) ⁺ : 374.3.

Step 3-7, preparation of 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2ethoxypyridin-3-yl)-2-fluorobenzoic acid acids: to a solution of 4-chloro-2-(trifluoromethyl)benzoic acid (94.9 mg, 0.423 mmol) and HATU (145 mg, 0.381 mmol) in DMF (0.5 ml) was added DIEA (0.073 ml, 0.42 mmol). After stirring at room temperature for 5 minutes, the resulting solution was added to a solution of 3-(2ethoxypyridin-3-yl)-6-[(2R)-2-ethylpiperazin-1-yl]-2-fluorobenzoic acid dihydrochloride (0.211 mmol ) and DIEA (0.11 ml, 0.42 mmol) in DMF (0.2 ml). The mixture was stirred at room temperature for 10 minutes. The reaction mixture was immediately purified by C18 reverse phase column chromatography to obtain the title compound (69.8 mg, 57% yield) as a white solid. LCMS (M+H) ⁺ :

- 45 045243

580.3.

Step 3-8, obtaining tert-butyl-N-[2-({6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2ethylpiperazin-1-yl]-3-(2 -ethoxypyridin-3-yl)-2-fluorophenyl}formamido)ethyl]-N-methylcarbamate: to a solution of 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazine-1 -yl]-3-(2-ethoxypyridin-3-yl)2-fluorobenzoic acid (35.0 mg, 0.06 mmol) and HATU (34.4 mg, 0.091 mmol) in DMF (0.2 ml) were added DIEA (0.021 ml, 0.12 mmol). After stirring at RT for 5 min, the reaction mixture was treated with tert-butyl-N-(2-aminoethyl)-N-methylcarbamate (21.0 mg, 0.121 mmol) and stirred at RT for 5 min. The mixture was purified by C18 reverse phase column chromatography to obtain the title compound (35.6 mg, 80% yield) as an off-white solid. LCMS (M+H)+: 736.4.

Step 3-9, preparation of 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2ethoxypyridin-3-yl)-2-fluoro -N-[2-(methylamino)ethyl]benzamide: to a solution of tert-butyl-N-[2-({6-[(2R)-4[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazine -1-yl]-3-(2-ethoxypyridin-3-yl)-2fluorophenyl}formamido)ethyl]-N-methylcarbamate (35.6 mg, 0.0484 mmol) in DCM (0.1 ml) was added 4 N HCl in dioxane (0.10 ml, 0.40 mmol). The mixture was stirred at room temperature for 10 minutes. The solution was decanted and the residue was washed with DCM (3x) and dried under vacuum. The HCl salt of the product was triturated with saturated NaHCO ₃ (aq) and dried to give the title compound (24.6 mg, 80% yield) as an off-white solid. LCMS (M+H) ⁺ : 636.3.

The following compounds were prepared similarly to Example 3 with appropriate substitution reagents and substrates at various stages. In some examples, additional functional group modifications may be necessary to introduce an appropriate substituent on the aryl rings. In some examples, the final deprotection step may not be required:

Connection no. MS (M+N) ⁺ 1-15 569.2 1-19 617.2 1-20 616.2 1-21 630.2 1-25 603.3 1-45 630.4 1-46 618.3 1-48 644.5 1-49 658.5 1-69 622.3 1-92 630.5 1-97 630.5 1-98 644.5 1-99 644.5 1-100 644.4 1-102 630.6 1-108 644.4 1-109 660.2 1-112 648.3 1-123 648.4 1-124 662.3 1-138 660.3 1-198 634.3 1-199 662.3 1-200 648.4 1-201 662.3 1-202 630.4 1-203 644.5 1-204 648.5 3-5 604.2 3-6 590.3 1-216 630.5 1-217 659.2

Example 4: 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2(dimethylamino)ethyl]-3-(2-ethoxypyridine -3-yl)-2-fluorobenzamide (compound 1-173)

Step 4-1, preparation of tert-butyl(3R)-4-(2-{[2-(dimethylamino)ethyl]carbamoyl}-4-(2ethoxypyridin-3-yl)-3-fluorophenyl)-3-ethylpiperazine-1 -carboxylate: to a solution of 6-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzoic acid from example 3, step 3-5 (1.000 g, 2.111 mmol) and HATU (963 mg, 2.53 mmol) in DMF (1 ml) was added DIEA (0.92 ml, 5.3 mmol). After stirring at RT for 5 min, the resulting solution was treated with (2-aminoethyl)dimethylamine (0.35 ml, 3.1 mmol) and stirred at RT for 10 min. The reaction mixture was purified by C18 reverse phase column chromatography to obtain the title compound (973.7 mg, 85% yield) as a light yellow solid. LCMS (M+H)+: 544.4.

Step 4-2, preparation of N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-6-[(2R)-2ethylpiperazin-1-yl]-2-fluorobenzamide trihydrochloride: to solution tert-butyl(3R)-4-(2-{[2(dimethylamino)ethyl]carbamoyl}-4-(2-ethoxypyridin-3-yl)-3-fluorophenyl)-3-ethylpiperazine-1carboxylate (973.7 mg , 1.791 mmol) to DCM (2 ml) was added 4 N HCl in dioxane (2.3 ml, 9.2 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was treated with additional 4N HCl in dioxane (2.0 mL, 8.0 mmol) and continued stirring for 2 hours. The solution was decanted and the residue was washed with DCM (3x) and dried under vacuum to give the title compound as a light yellow solid matter. LCMS (M+H)+: 444.3.

Step 4-3, preparation of 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2(dimethylamino)ethyl]-3-( 2-ethoxypyridin-3-yl)-2-fluorobenzamide: to a solution of 4-chloro-2(trifluoromethyl)benzoic acid (40.6 mg, 0.181 mmol) and HATU (61.9 mg, 0.163 mmol) in DMF (0. 2 ml) DIEA (0.047 ml, 0.27 mmol) was added. After stirring at room temperature for 5 minutes, the resulting solution was added to a solution of N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-6-[(2R)-2ethylpiperazin-1- yl]-2-fluorobenzamide trihydrochloride (40.0 mg, 0.0723 mmol) and DIEA (0.110 ml, 0.631 mmol) in DMF (0.2 ml). After stirring at RT for 10 minutes, the reaction mixture was purified by C18 reverse phase column chromatography to give the title compound (35.3 mg, 75% yield) as an off-white solid. LCMS (M+H)+: 650.3.

The following compounds were prepared similarly to Example 4 with appropriate substitution reagents and substrates at various stages. In some examples, additional functional group modifications may be necessary to introduce an appropriate substituent on the aryl rings. In some examples, additional deprotection is necessary at the final stage:

Connection no. MS (M+N) ⁺ 1-37 604.4 1-38 554.2 1-39 597.3 1-42 570.2 1-43 550.2 1-47 632.4 1-53 571.2 1-54 566.3 1-55 561.2 1-58 588.3 1-59 584.0 1-60 530.3 1-61 605.3 1-62 570.4 1-63 542.4 1-71 590.3 1-72 648.3 1-73 598.2

- 47 045243

1-74 603.4 1-76 614.4 1-77 531.5 1-78 534.3 1-79 550.3 1-80 546.3 1-81 558.4 1-82 580.3 1-86 531.4 1-87 550.3 1-88 556.4 1-89 555.5 1-91 605.4 1-96 586.2 1-105 656.4 1-106 614.4 1-107 613.4 1-110 594.3 1-111 632.3 1-113 582.2 1-114 620.4 1-117 561.3 1-118 589.4 1-119 600.2 1-120 640.4 1-121 602.5 1-122 614.4 1-126 586.3 1-127 614.3 1-129 614.3 1-130 613.3 1-131 614.3 1-133 597.4 1-134 631.5 1-142 587.3 1-143 626.5 1-144 621.5 1-145 586.3 1-146 614.3 1-147 591.4 1-153 593.2 1-154 627.2 1-155 632.4 1-156 602.4 1-157 627.4 1-159 601.3 1-160 560.4 1-161 603.3 1-162 617.4 1-163 632.3 1-164 633.3 1-165 647.3 1-166 633.3 1-168 646.4 1-174 634.4 1-175 641.4 1-179 616.3 1-186 607.1 1-191 605.3 1-192 585.2 1-193 571.2 1-228 644.5 1-229 662.2 1-270 659.4 1-271 645.5

Example 5: 6-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2(dimethylamino)ethyl]-3-(2-ethoxypyridine -3-yl)-2-fluorobenzamide (compound 1-184)

Step 5-1, preparation of 4-chloro-2-(difluoromethyl)benzoic acid: to a mixture of 4-chloro-2methylbenzoic acid (0.460 g, 2.70 mmol), Selectfluor (2.697 g, 7.612 mmol) and Na ₂ S ₂ O ₈ (0.365 g, 1.53 mmol) MeCN (2 ml) and water (2 ml) were added to a stoppered tube. N ₂ (gas) was bubbled in and then the mixture was cooled to -78° C. under nitrogen and AgNO ₃ (51.8 mg, 0.305 mmol) was added. After addition, the mixture was heated to room temperature under a nitrogen atmosphere and then heated at 80°C for 3 hours, filtered

- 48 045243 through celite and washed with EtOAc. The filtrate was washed with saturated NaHCO ₃ (aq) (3x25 ml). The combined basic aqueous solution was acidified with 1 N HCl (aq) to pH 2-3 and extracted

EtOAc (2x). The combined organic layers were concentrated and purified by C18 reverse phase column chromatography to give the title compound (128.8 mg, 23% yield) as an off-white solid.

Step 5-2, preparation of 6-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2(dimethylamino)ethyl]-3-( 2-ethoxypyridin-3-yl)-2-fluorobenzamide: to a solution of 4-chloro-2(difluoromethyl)benzoic acid (37.3 mg, 0.181 mmol) and HATU (61.9 mg, 0.163 mmol) in DMF (0. 2 ml) DIEA (0.047 ml, 0.27 mmol) was added. After stirring at room temperature for 5 minutes, the resulting solution was added to a solution of N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-6-[(2R)-2ethylpiperazin-1- yl]-2-fluorobenzamide trihydrochloride from Example 4, Step 4-2 (43.0 mg, 0.0778 mmol) and DIEA (0.110 ml, 0.631 mmol) in DMF (0.2 ml). The mixture was stirred at room temperature for 10 minutes. The mixture was purified by C18 reverse phase column chromatography to obtain the title compound (20.6 mg, 0.0326 mmol, 41.9% yield) as an off-white solid. LCMS (M+H)+: 632.3.

The following compounds were prepared similarly to Example 5 with appropriate substitution reagents and substrates at various stages. In some examples, additional deprotection is necessary at the final stage:

Example 6: 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[(4,5-dihydro-1Nimidazol-2-yl) methyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide (compound 1-188)

Step 6-1 Preparation of 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[(4,5dihydro-1H-imidazol-2- yl)methyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide: to a solution of 6-[(2R)-4-[4chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl ]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzoic acid from example 3, step 3-7 (48 mg, 0.082 mmol) in ACN (1 ml) was added HATU (31 mg, 0.082 mmol) and Et ₃ N (17 µl, 0.12 mmol). After stirring for 5 min at RT, the resulting solution was treated with (4,5-dihydro-1H-imidazol-2-yl)methylamine dihydrochloride (14 mg, 0.081 mmol), which was previously neutralized with Et ₃ N (34 μl, 0 .24 mmol) in ACN (1 ml). The reaction mixture was stirred at RT for 20 min, diluted with DCM and washed with H ₂ O and brine. The organic layer was dried with anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography eluting with DCM/MeOH (100/0 - 85/15) to give the title compound (21 mg, 39%). LCMS (M+H) ⁺ : 661.2.

The following compounds were prepared similarly to Example 6 with appropriate substitution reagents and substrates at various stages:

- 49 045243

Connection no. MS (M+N) ⁺ 1-64 652.4 1-65 652.4 1-66 652.4 1-70 638.2 1-83 641.4 1-84 655.6 1-93 655.1 1-116 673.4 1-125 643.4 1-132 641.3 1-139 656.6 1-140 630.6 1-141 649.5 1-170 657.5 1-178 627.3 1-182 645.4 1-219 675.2 1-224 640.3 1-226 644.5 1-227 658.4 1-234 670.4

Example 7: N-(2-aminoethyl)-2-[(2R-4-{2-[(3 S)-3-aminopyrrolidin-1-yl]-4-chlorobenzoyl}-2ethylpiperazin-1 -yl]-5 -(2-ethoxypyridin-3-yl)benzamide (compound 1-57)

Step 7-1 preparation of 2-[(3S)-3-{[(tert-butoxy)carbonyl]amino}pyrrolidin-1-yl]-4chlorobenzoic acid: a solution of 4-chloro methyl ester was placed in a 15 ml pressure test tube -2-fluorobenzoic acid (80 mg, 0.42 mmol), pyrrolidin-3-ylcarbamic acid tert-butyl ester (118 mg, 0.63 mmol) and DIEA (0.11 mL, 0.63 mmol) in DMSO (2 ml). The resulting solution was stirred at 140°C for 2.5 hours in an oil bath. The progress of the reaction was monitored using LCMS. The resulting mixture was cooled to room temperature and purified by C18 reverse phase column chromatography with 0.1% TFA-ACN/0.1% TFA-H2O to give the methyl ester 2-[(3S)-3-{[( tert-butoxy)carbonyl]amino}pyrrolidin-1-yl]-4-chlorobenzoic acid (150 mg, 100%). LCMS (M+H)+: 355.3.

A solution of 2-[(3S)-3{[(tert-butoxy)carbonyl]amino}pyrrolidin-1-yl]-4-chlorobenzoic acid methyl ester (150 mg, 0.42 mmol) was placed in a 25 ml round bottom flask. in H ₂ O/MeOH/THF (0.6/0.6/1.8 ml). The resulting solution was treated with LiOH monohydrate (170 mg, 4.2 mmol) and stirred overnight at 70°C. The reaction mixture was cooled to room temperature, concentrated, and then diluted with H ₂ O (~2 ml). The resulting solution was acidified with 1 N HCl and then extracted with EtOAc (2x). The combined organic layers were washed with brine, dried and concentrated to give 2-[(3S)-3-{[(tert-butoxy)carbonyl]amino}pyrrolidin-1-yl]-4-chlorobenzoic acid (110 mg, 82%) . LCMS (M+H) ⁺ : 341.1.

Stage 7-2. preparation of beyuyl-N-[2-({2-[(2R)-4-{2-[(3S)-3-{[(tertbutoxy)carbonyl]amino}pyrrolidin-1-yl]-4-chlorobenzoyl}- 2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin3-yl)phenyl}formamido)ethyl]carbamate: a solution of 2[(3S)-3-{[(tert-butoxy)carbonyl was placed in a 10 ml round bottom flask ]amino}pyrrolidin-1-yl]-4-chlorobenzoic acid (25 mg, 0.073 mmol) in ACN (1.0 ml). The solution was treated with HATU (30 mg, 0.079 mmol) and Et ₃ N (11 μl, 0.079 mmol). After stirring for 5 min, the resulting solution was treated with benzyl-N-(2-{[5-(2ethoxypyridin-3-yl)-2-[(2R)-2-ethylpiperazin-1-yl]phenyl]formamido}ethyl)carbamate (40 mg, 0.073 mmol) and stirred at room temperature for 20 minutes. The resulting mixture was immediately purified by C18 reverse phase column chromatography with 0.1% TFA-ACN/0.1% TFA-H2O to give benzyl-N[2-( {2-[(2R)-4- {2-[ (3S)-3-{[(tert-butoxy)carbonyl]amino}pyrrolidin-1-yl]-4-chlorobenzoyl}-2ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)phenyl}formamido )ethyl]carbamate (30 mg, 48%). LCMS (M+H) ⁺ : 854.5.

Step 7-3, preparation of N-2-aminoethyl)-2-[(2R)-4-{2-[(3S)-3-aminopyrrolidin-1-yl]-4chlorobenzoyl}-2-ethylpiperazin-1-yl] -5-(2-ethoxypyridin-3-yl)benzamide: solution of benzyl-N-[2-({2[(2R)-4-{2-[(3S)-3-{[(tert-butoxy)carbonyl ]amino}pyrrolidin-1-yl]-4-chlorobenzoyl}-2-ethylpiperazin1-yl]-5-(2-ethoxypyridin-3-yl)phenyl}formamido)ethyl]carbamate (28 mg, 0.032 mmol) and catalytic amount thioanisole (1~2 drops) in TFA (0.5 ml) was stirred at 60°C for 30 min. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by C18 reverse phase column chromatography with 0.1% TFA-ACN/0.1% TFA-H2O to give N-(2-aminoethyl)-2-[(2R)-4{2- [(3S)-3-aminopyrrolidin-1-yl]-4-chlorobenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3yl)benzamide (13 mg, 65%). LCMS (M+H)+: 620.5.

The following compounds were prepared similarly to Example 7 with appropriate substitution reagents and substrates at various stages. In some examples, additional functional group modifications may be necessary to introduce an appropriate substituent on the aryl rings. In some examples, acid-catalyzed deprotection is not required in the final step:

Connection no. MS (M+N) ⁺ 1-40 634.3 1-41 634.2 1-50 668.3 1-51 618.3 1-52 634.3 1-56 618.4 1-67 614.4 1-68 628.6 1-90 646.5 1-94 640.3 1-101 644.6 1-103 644.7 1-104 614.4 1-115 674.4 1-148 618.6 1-180 694.5 1-197 680.4

Example 8: N-(2-aminoethyl)-4-[(2R)-4-[4'-(aminomethyl)-5-fluoro-[1,1'-biphenyl]-2-carbonyl]-2ethylpiperazine-1 - yl]-2'-ethoxy-[1,1'-biphenyl]-3-carboxamide (compound 1-17)

Step 8-1, preparation of benzyl-N-[2-({4-[(2R)-4-(2-bromo-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2'ethoxy-[1, 1'-Biphenyl]-3-yl}formamido)ethyl]carbamate: A solution of 2-bromo-4-fluorobenzoic acid (40 mg, 0.18 mmol) in ACN (2.0 mL) was placed in a 10 mL round bottom flask. The solution was treated with HATU (76 mg, 0.2 mmol) and Et ₃ N (36 μl, 0.27 mmol). After stirring for 5 min, the resulting solution was treated with benzyl-N-[2-({2'-ethoxy-4-[(2R)-2-ethylpiperazin-1-yl]-[1,1'-biphenyl]-3 yl }formamido)ethyl]carbamate with trifluoroacetate (120 mg, 0.18 mmol) and stirred at room temperature for 20 minutes. The resulting mixture was immediately purified by C18 reverse phase column chromatography eluting with 0.1% TFA-ACN/0.1% TFA-H2O to give benzyl-N-[2-({4-[(2R)-4-(2 -bromo-4fluorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-[1,1'-biphenyl]-3-yl}formamido)ethyl]carbamate (54 mg, 41%). LCMS (M+H) ⁺ : 731.5.

Stage 8-2. preparation of benzyl-N-[2-({4-[(2R)-4-[4'-({[(tert-butoxy)carbonyl]amino}methyl)-5-fluoro[1,1'-biphenyl]- 2-carbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[1,1'-biphenyl]-3yl}formamido)ethyl]carbamate: benzyl-N-[2] was placed in a 15 ml pressure test tube -({4[(2R)-4-(2-bromo-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-[1,1'-biphenyl]-3yl}formamido)ethyl] carbamate (50 mg, 0.068 mmol), [4-({[(tert-butoxy)carbonyl]amino}methyl)phenyl]boronic acid (35 mg, 0.14 mmol), PdCl ₂ (t-Bu ₂ PPhNMe ₂ ) ₂ ( 5 mg, 0.007 mmol), K ₂ CO ₃ (19 mg, 0.14 mmol) and dioxane/H ₂ O (2 ml/0.2 ml). The resulting solution was degassed with N2 for 5 min and then stoppered. The reaction mixture was stirred at 85 °C for 2 hours in an oil bath. The resulting mixture was cooled to room temperature, diluted with ESO Ac and washed with 1 N HCl and saline. The organic layer was dried over anhydrous MgSO ₄ and concentrated. The residue was purified by C18 reverse phase column chromatography eluting with 0.1% TFA-ACN/0.1% TFA-H2O to give benzyl-N-[2-( {4-[(2R)-4-[4'- ( {[(tert-butoxy)carbonyl]amino}methyl)-5-fluoro-[1,1'-biphenyl]-2-carbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy[1,1'- biphenyl]-3-yl}formamido)ethyl]carbamate (43 mg, 74%). LCMS (M+H) ⁺ : 858.8.

Step 8-3, preparation of N-(2-aminoethyl)-4-[(2R)-4-[4'-(aminomethyl)-5-fluoro-[1,1'-biphenyl]-2carbonyl]-2-ethylpiperazine -1-yl]-2'-ethoxy-[1,1'-biphenyl]-3-carboxamide: benzyl-N-[2-({4[(2R)-4-[4'-( {[( tert-butoxy)carbonyl]amino}methyl)-5-fluoro-[1,1'-biphenyl]-2-carbonyl]-2ethylpiperazin-1-yl]-2'-ethoxy-[1,1'-biphenyl]- 3-yl}formamido)ethyl]carbamate (43 mg, 0.050 mmol) and a catalytic amount of thioanisole (1~2 drops) in TFA (0.5 ml) were stirred at 60°C for 30

- 51 045243 min. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by C18 reverse phase column chromatography eluting with 0.1% TFA-ACN/0.1% TFA-H2O to give N-(2-aminoethyl)-4-[(2R)-4-[4'-( aminomethyl)-5-fluoro-[1,1'-biphenyl]-2-carbonyl]-2-ethylpiperazin-1yl]-2'-ethoxy-[1,1'-biphenyl]-3-carboxamide (22 mg, 71 %). LCMS (M+H)+: 624.4.

The following compounds were prepared similarly to Example 8 with appropriate substitution reagents and substrates at various stages. In some examples, CN reduction may be necessary to introduce benzylamine in the final step:

Example 9 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[2(methylamino)ethyl]-[ 2,3'-bipyridine]-6-carboxamide (compound 1-135)

Step 9-1, preparation of 2'-ethoxy-5-fluoro-[2,3'-bipyridine]-6-carbonitrile: to a solution of a mixture of 6-bromo3-fluoropyridine-2-carbonitrile and 6-chloro-3-fluoropyridine-2 -carbonitrile (4:1 ratio, 1.0 equiv., 1.0 mmol, 200 mg) in dioxane (4 ml) was added Pd(Amphos)Cl ₂ (0.025 equiv., 0.025 mmol, 18 mg), 2ethoxypyridine-3 -ylboronic acid (2.0 equiv., 2.0 mmol, 334 mg), K ₂ CO ₃ (2.2 equiv., 2.2 mmol, 304 mg) and water (0.4 ml). The resulting solution was purged with nitrogen and heated at 100°C for 1 hour. Complete consumption of the starting material and formation of the desired product were observed using LCMS. This reaction was repeated on a 5.0 mmol scale under similar conditions. The two batches of the reaction mixture were combined, diluted with ethyl acetate (50 ml), washed with water and brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated. The remaining residue was purified by silica gel chromatography eluting with EtOAc/hexane (0-50%) to obtain 1.7 g (>100%) of the desired product containing unidentified impurities. LCMS (M+H)+ = 244.1.

Step 9-2, preparation of tert-butyl(3R)-4-{6-cyano-2'-ethoxy-[2,3'-bipyridin]-5-yl}-3ethylpiperazine-1-carboxylate: to a solution of 2'- ethoxy-5-fluoro-[2,3'-bipyridine]-6-carbonitrile (1.0 equiv., 6.0 mmol, 1.7 g) in DMSO (10 ml) was added tert-butyl(3R)-3 -ethylpiperazine-1-carboxylate (1.5 equiv., 9.0 mmol, 1.9 g) and DIEA (2.0 equiv., 12 mmol, 2.0 ml). The resulting solution was purged with nitrogen and heated at 140°C for 2 days. The desired product was observed to be formed by LCMS, but the Boc protecting group was partially lost. Thus, the reaction mixture was cooled to room temperature and then DIPEA (2.0 equiv., 12 mmol, 2.0 ml) and di-tert-butyl dicarbonate (2.0 equiv., 12 mmol, 2.75 mmol) and stirred for 1 hour. The reaction solution was then diluted with ethyl acetate (50 ml), washed with water and brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by C18 reverse phase column chromatography eluting with MeCN/water (5-100%). The pure fractions were combined, neutralized with saturated NaHCO ₃ and extracted with ethyl acetate. The combined organic layers were dried with MgSO ₄ , concentrated and dried under high vacuum to obtain 1.20 g (46%) of the desired product. LCMS (M+H)+ = 438.3.

Step 9-3, preparation of 2'-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-[2,3'-bipyridine]-6-carbonitrile trifluoroacetate: to a solution of tert-butyl(3R)- 4-{6-cyano-2'-ethoxy-[2,3'-bipyridin]-5-yl}-3ethylpiperazine-1-carboxylate (1.0 equiv., 0.73 mmol, 320 mg) in DCM (3 .0 ml) TFA (1.0 ml) was added. The resulting mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated in vacuo to give the crude product (560 mg) as the TFA salt. This substance was used in the next step without further purification. LCMS (M+H)+ = 338.4.

Step 9-4, preparation of 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'ethoxy-[2,3'-bipyridine]- 6-carbonitrile: to a solution of 2'-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-[2,3'bipyridine]-6-carbonitrile trifluoroacetate (560 mg crude, 0.73 mmol) in DMF (3.0 ml) added DIEA (1.06 ml, 4.38 mmol, 6.0 eq), HATU (570 mg, 1.5 mmol, 2.0 eq) and 2-trifluoromethyl-4chlorobenzoic acid (224 mg, 1.0 mmol, 1.35 eq.). The resulting mixture was stirred at room temperature for 10 min and the complete consumption of the starting material was observed using LCMS. Reaction solution

- 52 045243 diluted with ethyl acetate (50 ml), washed with water and brine, anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by chromatography on silica gel, eluting

EtOAc/hexane (0-50%) to obtain 230 mg (58%) of the desired product. LCMS (M+H)+ = 544.3.

Step 9-5, preparation of 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperαzin-1-yl]-2'ethoxy-[2,3'-bipyridine]- 6-carboxylic acid: to a solution of 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridine] -6-carbonitrile (27 mg, 0.05 mmol) in EtOH (0.25 ml) was added KOH (85%, 28 mg, 0.50 mmol, 10 eq.) and water (0.25 ml). The resulting mixture was heated at 100°C overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), washed with saturated NaHSO ₄ (5.0 mL) and brine, dried and concentrated to give 26 mg of the crude title compound. This substance was used in the next step without further purification. LCMS (M+H) ⁺ = 563.3.

Step 9-6, preparation of tert-butyl-N-[2-({5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2ethylpiperazin-1-yl]-2'-ethoxy -[2,3'-bipyridin]-6-yl}formamido)ethyl]-N-methylcarbamate: N to a solution of 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2- ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6carboxylic acid (26 mg, 0.05 mmol) in DMF (0.5 ml) was added DIEA (0.10 ml, 0. 55 mmol, 11 eq.), HATU (38 mg, 0.10 mmol, 2.0 eq.) and 1-boc-1-methylethylenediamine (19 mg, 0.10 mmol, 2.0 eq.). The resulting mixture was stirred at ambient temperature for 0.5 h. The crude reaction solution was purified by C18 reverse phase column chromatography eluting with MeCN/water (5-100%). The pure fractions were combined, neutralized with saturated NaHCO ₃ and NaCl, extracted with ethyl acetate and dried with MgSO ₄ . The organic layer was concentrated and dried under high vacuum to obtain 15 mg (47%) of the desired product. LCMS (M+H) ⁺ = 719.3.

Step 9-7 Preparation of 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'ethoxy-N-[2-(methylamino)ethyl] -[2,3'-bipyridine]-6-carboxamide: to a solution of tert-butyl-N-[2-({5-[(2R)4-[4-chloro-2-(trifluoromethyl)benzoyl]-2- ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridin]-6yl}formamido)ethyl]-N-methylcarbamate (15 mg, 0.021 mmol) in DCM (0.5 ml) added TFA (0 ,2 ml). The resulting mixture was stirred at ambient temperature for 0.5 h. The reaction mixture was concentrated and purified by C18 reverse phase column chromatography eluting with MeCN/water (5-60%). The pure fractions were combined, neutralized with saturated NaHCO ₃ and NaCl, extracted with ethyl acetate and dried with MgSO ₄ . The organic layer was concentrated and dried under high vacuum to obtain 9 mg (70%) of the desired product. LCMS (M+H) ⁺ = 619.4.

The following compounds were prepared similarly to Example 9 with appropriate substitution reagents and substrates at various stages. In some examples, additional functional group modifications may be necessary to introduce an appropriate substituent on the aryl rings. In some examples, additional deprotection is not required in the final stages.

Connection no. MS (M+N) ⁺ 1-136 602.6 1-137 629.6 1-149 632.3 1-151 631.4 1-167 615.4 1-171 576.4 1-172 594.5 1-181 630.6 1-185 600.4 1-187 616.6 1-194 603.4 1-195 595.3 1-205 617.4 1-206 644.4 1-208 618.6 1-209 630.5 1-211 617.5

- 53 045243

1-214 631.4 1-215 645.5 1-218 607.3 1-220 616.3 1-221 630.5 1-222 631.3 1-223 645.4 1-230 628.4 1-231 645.3 1-232 645.5 1-233 642.4 1-236 627.4 1-237 641.4 1-239 642.5 1-240 628.5 1-242 642.5 1-243 656.5 1-244 628.4 1-245 642.4 1-246 614.3 1-247 628.4 1-249 656.6 1-256 642.4 1-257 656.6 1-268 646.3 1-269 632.3 1-272 632.1 1-275 649.3 1-276 649.5 1-289 646.4 1-290 660.5 1-291 646.5 1-296 660.3 1-303 581.2

Example 10 2,3'-bipyridine]-6-carboxamide acetate (compound 1-150)

Step 10-1, preparation of 5-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'bipyridine]-6-carboxylic acid : to the solution of tert-butyl(3R)-4-{6-cyano-2'-ethoxy-[2,3'-bipyridin]-5yl}-3-ethylpiperazine-1-carboxylate from example 9, step 9-2 ( 271 mg, 0.62 mmol) in EtOH (3 ml) was added KOH (85%, 409 mg, 6.2 mmol, 10 eq.) and water (3.0 ml). The resulting mixture was heated at 100°C overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), washed with saturated NaHSO ₄ (10 mL) and brine, dried and concentrated to give 283 mg of the crude title compound. This substance was used in the next step without further purification. LCMS (M+H)+ = 457.3.

Stage 10-2. preparation of tert-butyl(3R)-4-(6-{[2-(dimethylamino)ethyl]carbamoyl}-2'-ethoxy-[2,3'bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate : to a solution of 5-[(2R)-4-[(tert-butoxy)carbonyl]-2ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxylic acid (283 mg, 0.619 mmol) in DMF (5.0 ml) was added HATU (353 mg, 0.93 mmol, 1.5 eq), DIEA (0.31 ml, 1.86 mmol, 3.0 eq) and N, Ndimethylethylenediamine (84 mg, 0.93 mmol, 1.5 eq.). The resulting mixture was stirred at 50°C for 0.5 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried with Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel chromatography eluting with MeOH/DCM (0-15%) to give 396 mg of the desired product as a brown oil. LCMS (M+H) ⁺ = 527.4.

Step 10-3, preparation of N-[2-(dimethylamino)ethyl]-2'-ethoxy-5-[(2R)-2-ethylpiperαzin-1-yl]-[2,3'bipyridine]-6-carboxamide: to a solution of tert-butyl(3R)-4-(6-{[2-(dimethylamino)ethyl]carbamoyl}-2'ethoxy-[2,3'-bipyridin]-5-yl)-3-ethylpiperazin-1- carboxylate (396 mg, 0.75 mmol) in DCM (4.0 ml) was added TFA (2.0 ml). The resulting mixture was stirred at ambient temperature for 0.5 h and concentrated in vacuo. The residue was neutralized with saturated NaHCO ₃ , extracted with ethyl acetate, dried with Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel chromatography eluting with MeOH/DCM (0-20%) to give 201 mg (64%) of the desired product as a brown oil. LCMS (M+H)+= 427.4.

Step 10-4, preparation of 5-[(2R-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2(dimethylamino)ethyl]-2'-ethoxy -[2,3'-bipyridine]-6-carboxamide acetate: to a solution of N-[2(dimethylamino)ethyl]-2'-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-[2 ,3'-bipyridine]-6-carboxamide (89 mg,

- 54 045243

0.20 mmol) in DMF (2 ml) was added HATU (91 mg, 0.24 mmol, 1.2 eq.), DIEA (0.092 ml, 0.50 mmol, 2.5 eq.) and 2-trifluoromethyl- 4-chlorobenzoic acid (45 mg, 0.20 mmol, 1.0 eq.). The resulting mixture was heated at 50°C for 0.5 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried with Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel chromatography eluting with MeOH/DCM (0-9%). The pure fractions were combined and concentrated with HOAc (0.1 ml) to obtain 90 mg (64%) of the desired product. LCMS (M+H)+ = 633.4.

The following compounds were prepared similarly to Example 10 with appropriate substitution reagents and substrates at various stages. In some examples, additional deprotection was required at the final stage.

Example 11: 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2ethoxypyridin-3-yl)-^[2-(methylamino )ethyl]pyrazine-2-carboxamide (compound 3-8)

Step 11-1, preparation of methyl 6-bromo-3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1yl]pyrazin-2-carboxylate: placed in a 15 ml pressure test tube 6-bromo-3-chloropyrazine-2-carboxylic acid methyl ester (300 mg, 1.19 mmol), tert-butyl(3R)-3ethylpiperazine-1-carboxylate (370 mg, 1.72 mmol, 1.4 equiv .), DIEA (0.3 ml, 1.78 mmol, 1.5 equiv.) and DMSO (6 ml). The resulting solution was stirred at 140°C for 1 hour, cooled to room temperature and diluted with EtOAc (~15 ml). The organic layer was washed with 1 N HCl (2x) and brine (1x), dried with anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by C18 reverse phase column chromatography eluting with 0.1% TFA-ACN/0.1% TFA-H ₂ O. 140 mg (27%) of methyl-6-bromo-3[(2R)-4- [(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]pyrazin-2-carboxylate. LCMS (M+H) ⁺ : 429.3.

Step 11-2, preparation of methyl 3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-6-(2ethoxypyridin-3-yl)pyrazin-2-carboxylate: 66bromo-3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]pyrazin-2-carboxylate (100 mg, 0.23 mmol) was placed in a 15 ml pressure test tube. , 2-ethoxypyridine-3-boronic acid (78 mg, 0.46 mmol), PdCl ₂ (t-Bu ₂ PPhNMe ₂ ) ₂ (24 mg, 0.033 mmol), K ₂ CO ₃ (64 mg, 0.46 mmol ) and dioxane/H ₂ O (2.5 ml/0.25 ml). The resulting solution was degassed with N ₂ for 5 min and then sealed with a stopper. The reaction mixture was stirred at 100°C for 1 hour in an oil bath. The resulting mixture was cooled to room temperature, diluted with EtOAc, and washed with 1 N HCl and brine. The organic layer was dried with anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by C18 reverse phase column chromatography eluting with 0.1% TFAACN/0.1% TFA-H2O to give methyl-3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazine- 1-yl]-6(2-ethoxypyridin-3-yl)pyrazin-2-carboxylate (85 mg, 77%). LCMS(M+H) ⁺ : 472.3.

Step 11-3, preparation of 3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-6-(2ethoxypyridin-3-yl)pyrazin-2-carboxylic acid: to solution of methyl 3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)pyrazin-2-carboxylate (85 mg, 0. 18 mmol) in MeOH/H ₂ O/THF (1/1/3 ml) was added lithium hydroxide hydrate (108 mg, 15 eq.). The resulting solution was stirred at room temperature for 3 hours. After removing the volatile solvent, the aqueous residue was diluted with H ₂ O (~3 ml) and then acidified with 1 N HCl. The resulting aqueous layer was extracted with DCM (3x). The combined organic layers were washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give 3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-6(2 -ethoxypyridin-3-yl)pyrazin-2-carboxylic acid (75 mg, 91%). LCMS (M+H) ⁺ : 458.3.

- 55 045243

Step 11-4, preparation of 6-(2-ethoxypyridin-3-yl)-3-[(2R)-2-ethylpiperazin-1-yl]pyrazin-2-carboxylic acid: solution of 3-[(2R)-4-[( tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-6-(2ethoxypyridin-3-yl)pyrazin-2-carboxylic acid (75 mg, 0.16 mmol) in TFA (0.2 ml)/DCM (0.6 ml) was stirred at room temperature for 1.5 hours. The resulting mixture was concentrated in vacuo. The residue (~100%) was diluted with ACN (1 ml) and neutralized with Et ₃ N, which was used in the next step without further purification. LCMS (M+H)+: 358.2.

Stage 11-5. preparation of 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2ethoxypyridin-3-yl)pyrazin-2-carboxylic acid: to solution 4-Chloro-2-(trifluoromethyl)benzoic acid (45 mg, 0.2 mmol, 1.33 eq.) in ACN (1 ml) was added with HATU (75 mg, 0.2 mmol) followed by Et ₃ N ( 40 µl, 0.35 mmol). The resulting solution was stirred for 5 min at room temperature and treated with 6-(2ethoxypyridin-3-yl)-3-[(2R)-2-ethylpiperazin-1-yl]pyrazin-2-carboxylic acid (~55 mg, 0.15 mmol, 1 eq.) obtained from the previous step. The resulting solution was stirred for 20 minutes at room temperature and concentrated in vacuo. The residue was purified by C18 reverse phase column chromatography eluting with 0.1% TFA-ACN/0.1% TFA-H2O to give 3-[(2R)-4[4-chloro-2-(trifluoromethyl)benzoyl]-2 -ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)pyrazin-2-carboxylic acid (55 mg, 64%). LCMS (M+H) ⁺ : 564.5.

Step 11-6, preparation of tert-butyl-N-[2-({3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2ethylpiperazin-1-yl]-6-(2 -ethoxypyridin-3-yl)pyrazin-2-yl}formamido)ethyl]-N-methylcarbamate: 3-[(2K)-4-[4-chloro-2-(trifluoromethyl)benzoyl]- was placed in a 10 ml vessel 2-ethylpiperazin-1-yl]-6-(2ethoxypyridin-3-yl)pyrazin-2-carboxylic acid (30 mg, 0.053 mmol, 1.00 eq.), HATU (21 mg, 0.056 mmol), Et ₃ N (11 µl, 0.08 mmol) and ACN (1 ml). The resulting solution was stirred for 5 min at room temperature and treated with tert-butyl-N-(2-aminoethyl)-N-methylcarbamate (11 mg, 0.063 mmol, 1.2 eq.). The reaction mixture was stirred for 20 min at room temperature and concentrated in vacuo. The residue was purified by C18 reverse phase column chromatography eluting with 0.1% TFA-ACN/0.1% TFA-H2O to give tert-butyl-N-[2-({3-[(2R)-4-[4 -chloro-2(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)pyrazin-2yl}formamido)ethyl]-N-methylcarbamate (18 mg, 47%). LCMS (M+H) ⁺ : 720.3.

Stage 11-7. preparation of 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2ethoxypyridin-3-yl)-N-[2-(methylamino) ethyl]pyrazin-2-carboxamide: solution of tert-butyl-N-[2-({3[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]- 6-(2-ethoxypyridin-3-yl)pyrazin-2yl}formamido)ethyl]-N-methylcarbamate (18 mg, 0.025 mmol) in TFA (0.2 ml)/DCM (0.6 ml) was stirred at room temperature. t. for 1.5 hours. The resulting mixture was concentrated in vacuum. The residue was purified by C18 reverse phase column chromatography eluting with 0.1% TFA-ACN/0.1% TFA-H2O to give 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]- 2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)-N[2-(methylamino)ethyl]pyrazin-2-carboxamide (10 mg, 67%). LCMS (M+H) ⁺ : 620.4.

The following compounds were prepared similarly to Example 11 with appropriate substitution reagents and substrates at various stages. In some examples, additional deprotection is not required at the final stage.

Connection no. MS (M+N) ⁺ 3-7 634.2

Example 12: 1-{5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'bipyridine]- 6-yl}methanolamine (compound 2-13)

About CF ₃

Step 12-1, preparation of 1-{5-[(2K)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'ethoxy-[2,3'- bipyridin]-6-yl}methanolamine: to a solution of 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2ethylpiperazin-1-yl]-2'-ethoxy-[2,3' -bipyridine]-6-carbonitrile from example 9, step 9-4 (65 mg, 0.12 mmol) in MeOH (1.0 ml) was added NiCl ₂ (8.0 mg, 0.06 mmol, 0.5 equiv .) and NaBH ₄ (36 mg, 0.96 mmol, 8.0 eq.) at 0°C. The resulting mixture was stirred at the same temperature for 15 minutes and approximately 40% conversion to the desired product was observed by LCMS analysis. At 0°C, additional NiCl ₂ (0.5 equiv., 0.06 mmol, 8.0 mg) and NaBH ₄ (8.0 equiv., 0.96 mmol, 36 mg) was added and the resulting mixture was stirred for another 15 min. The reaction mixture was diluted with ethyl acetate and washed with saturated NH ₄ Cl. The organic layer was dried and concentrated. The residue was purified by C18 reverse phase column chromatography eluting with MeCN/water (5-60%). The pure fractions were combined, neutralized with saturated NaHCO ₃ and NaCl, extracted with ethyl acetate and dried with MgSO ₄ . The organic layer was concentrated and dried under high vacuum to obtain 8 mg (12%) of the desired product. LCMS (M+H) ⁺ = 548.3.

- 56 045243

The following compounds were prepared similarly to Example 12 with appropriate substitution reagents and substrates at various stages. In some examples, additional functional group modifications may be necessary to introduce an appropriate substituent on the aryl rings.

Example 13: 2-[({4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[1,1'biphenyl ]-3-yl}methyl)amino]ethan-1-ol (compound 2-1)

Step 13-1, preparation of tert-butyl(3R)-4-[2'-ethoxy-3-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl]-3ethylpiperazine-1-carboxylate: in a test tube under tert-butyl(3K)-4-[4bromo-2-(methoxycarbonyl)phenyl]-3-ethylpiperazine-1-carboxylate from example 1, step 1.3 (80 mg, 0.19 mmol) was placed under a pressure of 8 ml. (2-ethoxyphenyl)boronic acid (46.6 mg, 0.28 mmol), Pd ₂ (dba) ₃ CHCl ₃ (19.4 mg, 0.02 mmol), P(t-Bu) ₃ .HBF ₄ ( 5.4 mg, 0.02 mmol), K ₃ PO ₄ (119.2 mg, 0.56 mmol) and toluene/H ₂ O (1 ml/0.1 ml). The resulting solution was degassed for 5 minutes with N ₂ , sealed and stirred at 70°C for 2 hours in an oil bath. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was applied to a silica gel column, eluting with ethyl acetate/petroleum ether (1:1). 80 mg (91%) of the desired product was isolated. LCMS (M+H)+ = 469.1.

Step 13-2, preparation of tert-butyl(3R)-4-[2'-ethoxy-3-(hydroxymethyl)-[1,1'-biphenyl]-4-yl]-3ethylpiperazine-1-carboxylate: to heterogeneous solution tert-butyl(3K)-4-[2'-ethoxy-3(hydroxymethyl)-[1,1'-biphenyl]-4-yl]-3-ethylpiperazine-1-carboxylate (60 mg, 0.13 mmol) and NiCl ₂ (16.6 mg, 0.13 mmol) in MeOH (1.0 ml), NaBH ₄ (48.4 mg, 1.28 mmol, 10 eq.) was added at room temperature. The resulting mixture was stirred at 50 °C for 1 hour. The reaction mixture was cooled to room temperature, diluted with H ₂ O and extracted with ethyl acetate (3x). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated to obtain 60 mg (~100%) of the desired product. LCMS (M+H) ⁺ = 441.3.

Step 13-3, preparation of tert-butyl(3R)-4-{2'-ethoxy-3-formyl-[1,1'-biphenyl]-4-yl}-3ethylpiperazine-1-carboxylate: solution of tert-butyl( 3K)-4-[2'-ethoxy-3-(hydroxymethyl)-[1,1'-biphenyl]-4yl]-3-ethylpiperazine-1-carboxylate (90 mg, 0.2 mmol) and IBX (171, 6 mg, 0.62 mmol) in ACN (2 ml) was stirred at RT for 1 hour. After removal of solids by filtration, the filtrate was concentrated in vacuo to give the crude desired product (90 mg, ~100%) which was used at the next stage without additional purification. LCMS (M+H) ⁺ = 439.3.

Step 13-4, preparation of tert-butyl(3K)-4-[3-({[2-(benzyloxy)ethyl]amino}methyl)-2'-ethoxy-[1,1'biphenyl]-4-yl] -3-ethylpiperazine-1-carboxylate: to a solution of tert-butyl(3K)-4-{2'-ethoxy-3-formyl-[1,1'biphenyl]-4-yl}-3-ethylpiperazine-1-carboxylate (30 mg, 0.07 mmol) and 2-(benzyloxy)ethanol-1-amine (21 mg, 0.14 mmol) in DCM (2.0 ml) was added NaBH(OAc) ₃ (44 mg, 0.21 mmol, 3 eq.). The resulting mixture was stirred at RT for 30 min and diluted with H ₂ O (20 ml). The resulting solution was extracted with EtOAc (3x). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated to give the desired product (25 mg, 64%). LCMS (M+H) ⁺ = 574.4.

Step 13-5, preparation of [2-(benzyloxy)ethyl]({2'-ethoxy-4-[(2K)-2-ethylpiperazin-1-yl]-[1,1'- 57 045243 biphenyl]-3- yl}methyl)aminetrifluoroacetate: to a solution of tert-butyl(3R)-4-[3-({[2(benzyloxy)ethyl]amino}methyl)-2'-ethoxy-[1,1'-biphenyl]-4- yl]-3-ethylpiperazine-1-carboxylate (25 mg,

0.04 mmol) in DCM (2.0 ml) was added TFA (1 ml). The resulting mixture was stirred at room temperature for an hour and concentrated in vacuo. This resulted in the desired product (25 mg, 98%) as the TFA salt.

LCMS (M+H)+ = 474.3.

Step 13-6, preparation of [2-(benzyloxy)ethyl]({4-[(2K)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2ethylpiperazin-1-yl]-2'-ethoxy- [1,1'-biphenyl]-3-yl}methyl)amine: to a solution of 2-chloro-4(trifluoromethyl)benzoic acid (2 mg, 0.01 mmol, 0.3 eq.), HATU (5.7 mg, 0.01 mmol. 0.3 eq.) and [2(benzyloxy)ethyl]({2'-ethoxy-4-[(2K)-2-ethylpiperazin-1-yl]-[1,1'- biphenyl]-3yl}methyl)amine trifluoroacetate (17.5 mg, 0.03 mmol) in DMF (2 ml) was added DIEA (11.6 mg, 0.09 mmol, 3 eq.). The resulting mixture was stirred at room temperature for 1 hour and diluted with H ₂ O (20 ml). The resulting solution was extracted with EtOAc (3x). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography eluting with DCM/MeOH (10/1) to give the desired product (20 mg, 38%). LCMS (M+H) ⁺ = 680.2.

Step 13-7, preparation of 2-[({4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'ethoxy-[1,1 '-biphenyl]-3-yl}methyl)amino]ethan-1-ol trifluoroacetate: solution of [2-(benzyloxy)ethyl]({4[(2K)-4-[2-chloro-4-(trifluoromethyl)benzoyl ]-2-ethylpiperazin-1-yl]-2'-ethoxy-[1,1'-biphenyl]-3yl}methyl)amine (20 mg, 0.03 mmol) in TFA (1.0 ml) was stirred at 80 °C for 3 hours. The resulting mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by prep-HPLC under the following conditions: SunFire Prep C18 OBD column; mobile phase, phase A: water (0.05% TFA); phase B: ACN (31% up to 45% in 6 min); flow rate: 20 ml/min; detector, 220 and 254 nm. 3.9 mg (19%) of the desired product was isolated as the TFA salt. LCMS (M+H) ⁺ = 590.2.

The following compounds were prepared similarly to Example 13 with appropriate substitution reagents and substrates at various stages. In some examples, additional deprotection was not required at the final stage.

Connection no. MS (M+N) ⁺ 2-2 604.3 2-21 588.4

Example 14: N-(3-aminopropyl)-4-{4-[2-cyano-4-(trifluoromethyl)phenyl]piperazin-1-yl}-2'-ethoxy[1,1'-biphenyl]-3- carboxamide (compound 3-2)

Step 14-1, preparation of tert-butyl 4-[4-bromo-2-(methoxycarbonyl)phenyl]piperazine-1-carboxylate: to a solution of tert-butylpiperazine-1-carboxylate (1.600 g, 8.588 mmol) and methyl 4-bromo -2fluorobenzoate (1.000 g, 4.292 mmol) in DMSO (5 ml) was added DIEA (2.20 ml, 12.6 mmol). The mixture was heated at 130°C for 1 day. The mixture was partitioned between water and DCM and the organic layer was separated and concentrated. The residue was purified by C18 reverse phase column chromatography to give the title compound (0.5088 g, 30% yield) as a medium brown solid. MS (M+H) ⁺ : 399.2. The hydrolyzed acid (0.7537 g, 46% yield) was also isolated as a light brown solid. LCMS (M+H) ⁺ = 385.3.

Step 14-2, preparation of methyl 5-bromo-2-(piperazin-1-yl)benzoate hydrochloride: to a solution of tert-butyl 4-[4-bromo-2-(methoxycarbonyl)phenyl]piperazin-1-carboxylate (508, 8 mg, 1.274 mmol) in DCM (2 ml) was added 4 N HCl in dioxane (2.0 ml, 8.0 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness to obtain the title compound as a light yellow solid. LCMS (M+H) ⁺ = 299.2.

Step 14-3, preparation of methyl 5-bromo-2-{4-[2-cyano-4-(trifluoromethyl)phenyl]piperazin-1yl}benzoate: to a solution of methyl 5-bromo-2-(piperazin-1- yl)benzoate hydrochloride (0.4538 g, 1.352 mmol) and 2-fluoro-5-(trifluoromethyl)benzonitrile (353.0 mg, 1.867 mmol) in DMSO (3 mL) was added DIEA (0.81 mL, 4.7 mmol). The mixture was heated at 130°C overnight. The mixture was purified by C18 reverse phase column chromatography to obtain the title compound (453 mg, 72% yield) as a yellow solid. LCMS (M+H) ⁺ = 468.3.

Step 14-4, preparation of 5-bromo-2-{4-[2-cyano-4-(trifluoromethyl)phenyl]piperazin-1-yl}benzoic acid: to a solution of methyl-5-bromo-2-{4-[ 2-cyano-4-(trifluoromethyl)phenyl]piperazin-1-yl}benzoate (453 mg, 0.967 mmol) in a solvent mixture of THF:MeOH:H ₂ O (6:2:2 ml) was added LiOH-H ₂ O ( 406 mg, 9.67 mmol).

The mixture was stirred at room temperature for 4 hours. After removing the volatile solvent, the aqueous residue was diluted with water and acidified with 1 N HCl (aq) to pH 2-3. The solid was collected by vacuum

- 58 045243 by filtration and washed with water and dried to obtain the title compound (421 mg, 96% yield) as a yellow solid. LCMS (M+H)+ = 454.1.

Step 14-5, preparation of tert-butyl-N-{3-[(5-bromo-2-{4-[2-cyano-4(trifluoromethyl)phenyl]piperazin-1-yl}phenyl)formamido]propyl}carbamate : to a solution of 5-bromo-2-{4-[2cyano-4-(trifluoromethyl)phenyl]piperazin-1-yl}benzoic acid (201.9 mg, 0.4444 mmol) and HATU (220 mg, 0.579 mmol) DIEA (0.15 mL, 0.86 mmol) was added to DMF (1 mL). After stirring at room temperature for 5 minutes, the resulting solution was treated with tert-butyl-N-(3-aminopropyl)carbamate (126.5 mg, 0.7262 mmol) and stirred at room temperature for 5 minutes. The reaction mixture was purified by C18 reverse phase column chromatography to obtain the title compound (198.7 mg, 73% yield) as an off-white solid. LCMS (M+H) ⁺ = 610.3.

Step 14-6, preparation of tert-butyl-N-{3-[(4-{4-[2-cyano-4-(trifluoromethyl)phenyl]piperazin-1-yl}2'-ethoxy-[1,1' -biphenyl]-3-yl)formamido]propyl}carbamate: to a mixture of tert-butyl-N-{3-[(5-bromo-2-{4-[2cyano-4-(trifluoromethyl)phenyl]piperazine-1- yl}phenyl)formamido]propyl}carbamate (20.0 mg, 0.0328 mmol), 2-ethoxyphenylboronic acid (10.9 mg, 0.0657 mmol), Pd[t-Bu ₂ P(4-NMe ₂ C ₆ H ₄ )] ₂ Cl ₂ ) (9.2 mg, 0.013 mmol) and K ₂ CO ₃ (27.2 mg, 0.197 mmol) dioxane (2 ml) and H ₂ O (0.2 ml) were added to a sealed test tube ). The resulting mixture was degassed with N ₂ for 10 min and stirred at 100°C for 30 min. The mixture was concentrated and purified by C18 reverse phase column chromatography to give the title compound (18.5 mg, 87% yield) as a white solid. LCMS (M+H) ⁺ = 652.5.

Step 14-7, preparation of N-(3-aminopropyl)-4-{4-[2-cyano-4-(trifluoromethyl)phenyl]piperazin-1yl}-2'-ethoxy-[1,1'-biphenyl]- 3-carboxamide: to a solution of tert-butyl-N-{3-[(4-{4-[2-cyano-4(trifluoromethyl)phenyl]piperazin-1 -yl}-2'-ethoxy-[1,1' -biphenyl]-3-yl)formamido]propyl} carbamate (18.5 mg, 0.0284 mmol) in DCM (0.1 ml) was added 4 N HCl in dioxane (0.1 ml, 0.4 mmol). The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated to dryness to give the 1 HCl salt of the title compound, which was triturated with saturated NaHCO ₃ (aq) to give the title compound (12.9 mg, 82% yield) as an off-white solid. LCMS (M+H) ⁺ = 552.2.

The following compounds were prepared similarly to Example 14 with appropriate substitution reagents and substrates at various stages:

E# of MS connection (M+H) ⁺

544.3

Example 15: 6-[(2R)-4-(2,4-dichlorobenzenesulfonyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3yl)-2-fluoro-N-[2-(methylamino )ethyl-1-benzamide (compound 3-3)

Stage 15-1. Preparation of benzyl-N-[2-([6-[(2R)-4-(2,4-dichlorobenzenesulfonyl)-2-ethylpiperazin-1yl]-3-(2-ethoxypyridin-3-yl)-2-fluorophenyl] formamido)ethyl]-N-methylcarbamate: benzyl-N-(2-[[3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethylpiperazin-1-yl) was placed in an 8 ml vessel ]-2fluorophenyl]formamido]ethyl)-N-methylcarbamate trifluoroacetate (30 mg, 0.027 mmol), which was prepared in a similar manner as described in Example 4, steps 1 and 2, TEA (8 mg, 0.079 mmol, 2.98 eq.) , 2,4dichlorobenzene-1-sulfonyl chloride (8 mg, 0.033 mmol, 1.23 eq.) and DCM (2 ml). The resulting solution was stirred for 2 hours at 25°C. The reaction mixture was diluted with DCM (10 ml) and washed with H ₂ O (2x20 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 20 mg of (crude) title compound as an off-white oil. LCMS (M+H) ⁺ = 772.2.

Step 15-2, preparation of 6-[(2R)-4-(2,4-dichlorobenzenesulfonyl)-2-ethylpiperazin-1-yl]-3-(2ethoxypyridine in-3-yl)-2-fluoro-N-[ 2-(methylamino)ethyl]benzamide: benzyl-N-[2-([6-[(2R)-4-(2,4-dichlorobenzenesulfonyl)-2-ethylpiperazin-1-yl]- was placed in an 8 ml vessel 3-(2-ethoxypyridin-3-yl)-2fluorophenyl]formamido)ethyl]-R-methylcarbamate (20 mg, 0.021 mmol) and trifluoroacetic acid (2 ml). The resulting solution was stirred for 3 hours at 60°C, cooled to room temperature and concentrated in vacuo. The residue was dissolved in DMF (4 ml) and purified by reverse phase HPLC to give 7.9 mg (56%) of the title compound as the formic acid salt. LCMS (M+H) ⁺ = 638.2

Example 16: (3R)-N-(2,4-dichlorophenyl)-4-[4-(2-ethoxypyridin-3-yl)-3-fluoro-2-{[2(methylamino)ethyl]carbamoyl}phenyl] -3-ethylpiperazine-1-carboxamide (compound 3 -4)

- 59 045243

Step 16-1, preparation of phenyl-N-(2,4-dichlorophenyl)carbamate: 2,4dichloroaniline (200 mg, 1.23 mmol) and THF (5 ml) were placed in an 8 ml vessel. The resulting solution was treated with NaH (59 mg, 1.47 mmol, 1.19 eq., 60% purity) and stirred for 20 min at 0°C. The reaction mixture was treated with phenylchloroformate (232 mg, 1.48 mmol, 1.2 eq.), stirred for an additional 3 hours at 0°C and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with ethyl acetate/petroleum ether (1:5). This resulted in 120 mg (34%) of the title compound as a yellow oil. LCMS (M+H)+= 282.0.

Step 16-2, preparation of benzyl-N-2-([6-[(2R)-4-[(2,4-dichlorophenyl)carbamoyl]-2-ethylpiperazin-1yl]-3-(2-ethoxypyridine-3- yl)-2-fluorophenyl]formamido)ethyl]-N-methylcarbamate: benzyl-N-(2-[[3-(2-ethoxypyridin-3-yl)-6-[(2R)- 2-ethylpiperazin-1-yl]-2fluorophenyl]formamido]ethyl)-N-methylcarbamate trifluoroacetate (36 mg, 0.053 mmol), DCM (2 ml), TEA (16 mg, 0.158 mmol, 2.97 eq.) and phenyl -N-(2,4-dichlorophenyl)carbamate (15 mg, 0.053 mmol). The resulting solution was stirred for 2 hours at 25°C, diluted with DCM (10 ml) and washed with water (2x20 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 30 mg (crude) of the title compound as a yellow oil. LCMS (M+H) ⁺ = 751.2.

Step 16-3, preparation of (3R)-N-(2,4-dichlorophenyl)-4-[4-(2-ethoxypyridin-3-yl)-3-fluoro-2-[[2(methylamino)ethyl]carbamoyl ]phenyl]-3-ethylpiperazine-1-carboxamide: benzyl-N-[2-([6-[(2R)-4-[(2,4-dichlorophenyl)carbamoyl]-2-ethylpiperazine was placed in an 8 ml vessel -1-yl]-3-(2-ethoxypyridin-3-yl)2-fluorophenyl]formamido)ethyl]-N-methylcarbamate (30 mg, 0.04 mmol) and TFA (2 ml). The resulting solution was stirred for 2 hours at 60°C, cooled to room temperature and concentrated in vacuo. The residue was dissolved in DMF (4 ml) and purified by prep-HPLC under the following conditions (prep-HPLC-013): column, Atlantis Prep T3 OBD column, 19x150 mm, 5 µm; mobile phase, water (0.1% FA) and ACN (24% phase B up to 53% in 6 min); 20 ml/min. Detector, UV 220, 254 nm. This resulted in 5.6 mg (21%) of the title compound as the formic acid salt. LCMS (M+H) ⁺ = 617.2.

Example 17: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)1-methylpyrrolidin-3 -yl]-[2,3'-bipyridine]-6-carboxamide (compound 1-152)

Step 17-1, preparation of 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'ethoxy-N-[(3R)-1- methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide: to a solution of 5-[(2R)-4-[4chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl] -2'-ethoxy-[2,3'-bipyridine]-6-carboxylic acid from example 9, step 5 (40 mg, 0.071 mmol) in ACN (0.5 ml) was added HATU (30 mg, 0.078 mmol, 1 .1 eq.) and Et ₃ N (19 µl, 2.0 eq.). The resulting solution was stirred at room temperature for 5 min and treated with (R)-1-methylpyrrolidin-3-ylamine (10.6 mg, 0.106 mmol, 1.5 eq.). The reaction mixture was stirred at room temperature for 0.5 h. The crude reaction solution was purified by C18 reverse phase column chromatography eluting with MeCN/water (5-100%). The combined pure fractions were neutralized with saturated NaHCO ₃ , the volatile solvent was removed and extracted with DCM (3x). The combined organic layer was dried with anhydrous Na ₂ SO ₄ , concentrated and dried under high vacuum to obtain 25 mg (55%) of the title compound. LCMS (M+H) ⁺ = 645.5.

Example 18: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-(1methylazetidin-3-yl)-[ 2,3'-bipyridine]-6-carboxamide (compound 1-212)

Step 18-1, preparation of 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'ethoxy-N-(1-methylazetidin-3- yl)-[2,3'-bipyridine]-6-carboxamide: this compound was prepared in a manner similar to that described in Example 17, starting with 40 mg (0.071 mmol) of 5-[(2R)-4-[4-chloro-2 (trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxylic acid. 20 mg (45%) of the title compound were isolated. LCMS (M+H) ⁺ = 631.4.

The following compounds were prepared similarly to Example 18 with appropriate substitution reagents and substrates at various stages:

Connection no. MS (M+N) ⁺ 1-359 663.3 1-398 671.4

Example 19: 1-{2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridin-3-carbonyl]-2ethylpiperazin-1-yl]-[2,3'- bipyridin]-6-yl}methanolamine (compound 2-30)

About CF ₃

Step 19-1, preparation of 5-[(2R)-4-[6-chloro-2-(trifluoromethyl)pyridin-3-carbonyl]-2-ethylpiperazin1-yl]-2'-ethoxy-[2,3'- bipyridine]-6-carbonitrile: to DMF (3.0 ml) 2'-ethoxy-5-[(2R)-2-ethylpiperazin-1yl]-[2,3'-bipyridine]-6-carbonitrile (step 9- 3, 1.0 equiv., 0.26 mmol, 87 mg) added DIPEA (2.5 equiv., 0.65 mmol, 0.1 ml), HATU (1.2 equiv., 0.39 mmol, 118 mg) and 6-chloro-2-(trifluoromethyl)pyridine-3carboxylic acid (1.0 equiv., 0.26 mmol, 61 mg). The resulting mixture was stirred at room temperature for 0.5 h and the complete consumption of the starting material was observed using LCMS. The reaction solution was diluted with ethyl acetate (50 ml), washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The remaining residue was purified by silica gel chromatography eluting with EtOAc/hexane (0-50%) to obtain 104 mg of the title compound. LCMS (M+H)+ = 545.3.

Stage 19-2. preparation of 2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridin-3-carbonyl]-2ethylpiperazin-1-yl]-[2,3'-bipyridine]-6- carbonitrile: to EtOH (0.5 ml) solution of 5-[(2R)-4-[6-chloro-2(trifluoromethyl)pyridin-3-carbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy- [2,3'-bipyridine]-6-carbonitrile (1.0 equiv., 0.05 mmol, 28 mg) was added with NaOEt (21% w/w in EtOH, 2.5 equiv., 0.13 mmol, 0 .05 ml). The resulting mixture was heated at 70°C for 0.5 h. The reaction solution was diluted with ethyl acetate (20 ml), washed with saturated NH ₄ Cl and brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain 25 mg of crude product. This substance was used in the next step without purification. LCMS (M+H)+ = 555.2.

Step 19-3, preparation of tert-butyl-N-((2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridin-3carbonyl]-2-ethylpiperazin-1-yl ]-[2,3'-bipyridin]-6-yl}methyl)carbamate: to MeOH (1.0 ml) solution of 2'ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl )pyridin-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3'bipyridine]-6-carbonitrile (1.0 equiv., 0.05 mmol, 25 mg) was added NiCl ₂ (0.5 equiv., 0.025 mmol, 3.3 mg) and di-tert-butyl dicarbonate (2.0 equiv., 0.10 mmol, 0.023 ml).NaBH ₄ (7.0 equiv., 0.023 ml) was added portionwise at 0°C. 35 mmol, 13.5 mg) and the resulting mixture was stirred at the same temperature for 0.5 h. The reaction mixture was filtered and the filtrate was concentrated. The remaining residue was purified by silica gel chromatography eluting with EtOAc/hexane (0-50%) to give 24 mg of the indicated compound LCMS (M+H)+ = 659.4.

Step 19-4 Preparation of 1-(2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridin-3-carbonyl]-2ethylpiperazin-1-yl]-[2,3 '-bipyridin]-6-yl}methanol amine: to DCM (0.5 ml) tert-butyl-H-({2'-ethoxy-5[(2R)-4-[6-ethoxy-2-(trifluoromethyl )pyridin-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3'-bipyridin]-6yl}methyl)carbamate (1.0 equiv., 0.036 mmol, 24 mg) was added TFA (0.10 ml) The resulting mixture was stirred at ambient temperature for 0.5 h. The reaction solution was concentrated and the resulting residue was purified by C18 reverse phase chromatography eluting with MeCN/water (5-50%).Pure fractions were combined, neutralized with saturated NaHCO ₃ and NaCl, extracted with ethyl acetate and dried with MgSO _4. The organic layer was concentrated and dried under high vacuum to obtain 6 mg of the title compound. LCMS (M+H)+ = 559.2.

The following compounds were prepared similarly to Example 19 with appropriate substitution reagents and substrates at various stages:

F# connection MS (M+H) ⁺

2-31 545.4

Example 20: 5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1methylpyrrolidin-3 -yl ]-[2,3'-bipyridine]-6-carboxamide (compound 1-279)

Step 20-1, preparation of 2-(difluoromethyl)-4-fluorobenzoic acid: to a mixture of 4-fluoro-2methylbenzoic acid (1.000 g, 6.49 mmol), Selectfluor (6.895 g, 19.46 mmol) and sodium persulfate

- 61 045243 (0.772 g, 3.24 mmol) MeCN (3.2 ml) and water (3.2 ml) were added under nitrogen atmosphere. The mixture was cooled to 78°C under nitrogen and silver nitrate (110.2 mg, 0.649 mmol) was added. The frozen mixture was degassed under vacuum and filled with nitrogen (repeated 3·). The mixture was heated to room temperature under atmosphere and then heated at 80°C for 7 hours. The reaction was not completed, so more Selectfluor (2.298 g, 6.49 mmol), sodium persulfate (0.257 g, 1.08 mmol) and silver nitrate (36.7 mg, 0.216 mmol) was added under nitrogen and the reaction mixture was continued heat at 80°C for 6 hours. The mixture was filtered through celite and washed with EtOAc. The filtrate was washed with saturated NaHCO ₃ (aq) (5·25 ml). The combined basic aqueous solution was acidified with 1 N HCl (aq) to pH 2-3 to form a solid. The solid was collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (484.1 mg). The filtrate was extracted with EtOAc (1·) and the organic layer was concentrated and purified by C18 reverse phase column chromatography to obtain more product (314.4 mg). Complete reaction provided the title compound (798.5 mg, 4.20 mmol, 64.7% yield) as an off-white solid.

Step 20-2, preparation of tert-butyl(3R)-4-(2'-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}[2,3'-bipyridine]-5- yl)-3-ethylpiperazin-1-carboxylate: to a solution of 5-[(2R)-4-[(tert-butoxy)carbonyl]2-ethylpiperazin-1-yl]-2'-ethoxy-[2,3'- bipyridine]-6-carboxylic acid (400 mg, 0.876 mmol) from step 10-1 in DMF (2.0 ml) was added HATU (500 mg, 1.31 mmol), DIEA (0.46 ml, 2.63 mmol ). After stirring at room temperature for 5 min, (3R)-1-methylpyrrolidin-3-amine (176 mg, 1.75 mmol) was added. The resulting mixture was stirred at room temperature for 10 minutes. The reaction mixture was purified by C18 reverse phase column chromatography to obtain the title compound (284.6 mg, 0.53 mmol, 60.3% yield) as a light brown solid. LCMS (M+H)+ = 539.5.

Step 20-3, preparation of 2'-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl][2,3'-bipyridine] -6-carboxamide tris(2,2,2-trifluoroacetate): to a solution of tert-butyl(3R)-4-(2'-ethoxy-6{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}- [2,3'-Bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate (268.8 mg, 0.50 mmol) in DCM (1.5 ml) was added with TFA (0.76 ml). The resulting mixture was stirred at RT for 30 min and concentrated in vacuo to dryness to give the title compound (389.5 mg, 0.50 mmol, 100% yield) as a brown gum, which was used in the next step without further purification. LCMS (M+H) ⁺ = 439.1.

Step 20-4, preparation of 5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2'ethoxy-N-[(3R)-1-methylpyrrolidine -3-yl]-[2,3'-bipyridine]-6-carboxamide: to a solution of 2-(difluoromethyl)4-fluorobenzoic acid (142.3 mg, 0.75 mmol) in DMF (0.5 ml) was added HATU (265.6 mg, 0.70 mmol) and DIEA (0.26 ml, 1.50 mmol). After stirring at room temperature for 5 min, this HATU-activated solution was added to the 2'-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-N-[(3R)-1methylpyrrolidin-3-yl solution ]-[2,3'-bipyridine]-6-carboxamide tris(2,2,2-trifluoroacetate) (389.5 mg, 0.50 mmol) and DIEA (0.52 ml, 3.00 mmol) in DMF (0.5 ml). The resulting mixture was stirred at room temperature for 10 minutes. The reaction mixture was purified by C18 reverse phase column chromatography to obtain the title compound (245.0 mg, 0.40 mmol, 80.4% yield) as a light brown solid. LCMS (M+H) ⁺ = 611.3.

The following compounds were prepared similarly to Example 20 with appropriate substitution reagents and substrates at various stages:

Connection no. MS (M+N) ⁺ 1-262 627.3 1-287 626.5 1-293 610.4

Example 21: 5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)pyrrolidin-3 -yl] -[2,3'-bipyridine]-6-carboxamide (compound 1-278)

Step 21-1, preparation of tert-butyl(3R)-4-(6-{[(3R)-1-[(benzyloxy)carbonyl]pyrrolidin-3yl]carbamoyl}-2'-ethoxy-[2.3'-bipyridine] -5-yl)-3-ethylpiperazin-1-carboxylate: to a solution of 5-[(2R)-4[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-[2, 3'-bipyridine]-6-carboxylic acid (300 mg, 0.657 mmol) from step 10-1 in DMF (1.0 ml) was added HATU (325 mg, 0.854 mmol), DIEA (0.23 ml, 1.3 mmol). After stirring at room temperature for 5 min, benzyl(3R)-3-aminopyrrolidine-1carboxylate (217 mg, 0.986 mmol) was added. The resulting mixture was stirred at room temperature for 10 minutes. The reaction mixture was purified by C18 reverse phase column chromatography to obtain the title compound (270.8 mg, 0.411 mmol, 62.6% yield) as a brown solid. LCMS

- 62 045243 (M+H)+ = 659.5.

Step 21-2, preparation of benzyl(3R)-3-{2'-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-[2,3'-bipyridine]-6amido}pyrrolidine-1- carboxylate bis(2,2,2-trifluoroacetate): to a solution of tert-butyl(3R)-4-(6-{[(3R)-1[(benzyloxy)carbonyl]pyrrolidin-3-yl]carbamoyl}-2'-ethoxy-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine 1-carboxylate (90.0 mg, 0.137 mmol) in DCM (0.4 ml) was added with TFA (0.2 ml). The resulting mixture was stirred at RT for 30 min and concentrated in vacuo to dryness to give the title compound (107 mg, 0.137 mmol, 100% yield) as a brown gum, which was used in the next step without further purification. LCMS (M+H) ⁺ = 559.4.

Step 21-3, preparation of benzyl(3R)-3{5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin1-yl]-2'-ethoxy-[2.3'- bipyridine]-6-amido}pyrrolidine-1-carboxylate: HATU (72, 4 mg, 0.190 mmol) and DIEA (0.071 ml, 0.41 mmol). After stirring at room temperature for 5 min, this HATU-activated solution was added to a solution of benzyl(3R)-3-{2'-ethoxy-5-[(2R)-2-ethylpiperαzin-1-yl][2,3' -bipyridine]-6-amido}pyrrolidine-1-carboxylate bis(2,2,2-trifluoroacetate) (107 mg, 0.136 mmol) and DIEA (0.14 ml, 0.80 mmol) in DMF (0.2 ml ). The resulting mixture was stirred at room temperature for 10 minutes. The reaction mixture was purified by C18 reverse phase column chromatography to obtain the title compound (63.0 mg, 0.0862 mmol, 63.4% yield) as a light yellow solid. LCMS (M+H) ⁺ = 731.3.

Step 21-4, preparation of 5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperαzin-1-yl]-2'ethoxy-N-[(3R)-pyrrolidin-3 -yl]-[2,3'-bipyridine]-6-carboxamide: to benzyl(3R)-3 {5-[(2R)-4-[2(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazine-1 -yl]-2'-ethoxy-[2,3'-bipyridine]-6-amido}pyrrolidine 1-carboxylate (63.0 mg, 0.0862 mmol) was added (methylsulfanyl)benzene (0.050 ml) and TFA (0. 25 ml). The resulting mixture was heated at 60°C for 30 minutes. The reaction mixture was purified by C18 reverse phase column chromatography to obtain the title compound (39.9 mg, 0.0669 mmol, 77.6% yield) as an off-white solid. LCMS (M+H) ⁺ = 597.4.

The following compounds were prepared similarly to Example 21 with appropriate substitution reagents and substrates at various stages:

Connection no. MS (M+N) ⁺ 1-265 613.3 1-288 612.1 1-292 596.4

Example 22: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N[(3R)-pyrrolidin-3-yl]-[ 2,3'-bipyridine]-6-carboxamide (compound 1 -263)

Step 22-1, preparation of benzyl(3R)-3-(2'-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-[2,3'-bipyridine]-6amido}pyrrolidine-1- carboxylate: to a solution of tert-butyl(3R)-4-(6-{[(3R)-1[(benzyloxy)carbonyl]pyrrolidin-3-yl]carbamoyl}-2'-ethoxy-[2,3'-bipyridine ]-5-yl)-3-ethylpiperazine 1-carboxylate from Example 21, Step 1 (27 mg, 0.041 mmol) in DCM (0.4 ml) was added TFA (0.1 ml) The resulting solution was stirred at room temperature. for 1 h and concentrated in vacuo to remove volatile solvent. The residue was dissolved in ACN (0.3 ml) and neutralized with TEA (16 µl, ~3 eq.), which was used in the next step without further purification. LCMS (M+H ) ⁺ = 559.3.

Stage 22-2. preparation of benzyl(3R)-3-{2'-ethoxy-5-[(2R)-2-ethyl-4-[1(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-[2,3'-bipyridine]- 6-amido}pyrrolidine-1-carboxylate: To a solution of 1-(trifluoromethyl)cyclopentane-1-carboxylic acid (11 mg, 0.06 mmol) in ACN (0.5 ml) was added HATU (22 mg, 0.06 mmol) and TEA (11 µl, 0.08 mmol). After stirring at room temperature for 5 min, the resulting solution was treated with benzyl(3R)-3-{2'-ethoxy-5-[(2R)-2ethylpiperazin-1-yl]-[2,3'-bipyridine]- 6-amido}pyrrolidine-1-carboxylate from step 1 (22 mg, 0.039 mmol). The reaction mixture was stirred at RT for 30 min and immediately purified by C18 reverse phase column chromatography to give the title compound (21 mg, 74% yield). LCMS (M+H) ⁺ = 723.8.

Step 22-3, preparation of 2'-ethoxy-5-[(2R)-2-ethyl-4-[1(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidine-3 - yl]-[2,3'-bipyridine]-6carboxamide: to a solution of benzyl(3R)-3-{2'-ethoxy-5-[(2R)-2-ethyl-4-[1(trifluoromethyl)cyclopentanecarbonyl]piperazine -1-yl]-[2,3'-bipyridine]-6-amido}pyrrolidine-1carboxylate (21 mg, 0.029 mmol) in TFA (0.5 ml) was added one drop of methyl(phenyl)sulfane. The resulting mixture was stirred at 60°C for 1 hour and cooled to room temperature. After removal of the volatile solvent, the residue was purified by C18 reverse phase column chromatography to obtain

- 63 045243 of the indicated compound (14 mg, 82% yield) in the form of a white powder. LCMS (M+H)+ = 589.4.

The following compounds were prepared similarly to Example 22 with appropriate substitution reagents and substrates at various stages:

Connection no. MS (M+N) ⁺ 1-250 523.6 1-251 608.3 1-252 608.3 1-264 537.6 1-273 603.5 1-274 629.5 1-280 575.5 1-285 641.4 1-294 613.4 1-295 593.4 1-297 615.5 1-298 611.3 1-299 603.3 1-300 575.3 1-301 575.3 1-302 563.3 1-304 588.4 1-308 577.6 1-314 575.5 1-318 607.5 1-321 589.3 1-324 603.5 1-325 603.5 1-327 589.3 1-328 571.4 1-329 589.4 1-335 602.5 1-352 597.4 1-353 583.4 1-354 611.4 1-368 603.3

Example 23: 2*-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N[(3K)-1-methylpyrrolidin-3-yl] -[2,3'-bipyridine]-6-carboxamide (compound 1-255)

Step 23-1, preparation of 2'-ethoxy-5-[(2R)-2-ethyl-4-[1(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-M-[(3K)-1-methylpyrrolidine-3 -yl]-[2,3'bipyridine]-6-carboxamide: to a solution of 1-(trifluoromethyl)cyclopentane-1-carboxylic acid (13 mg, 0.071 mmol) in ACN (0.5 ml) was added HATU (27 mg, 0.071 mmol) and TEA (19 µl, 0.14 mmol). After stirring at room temperature for 5 min, the resulting solution was treated with neutral 2'-ethoxy-5[(2R)-2-ethylpiperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl] -[2,3'-bipyridine]-6-carboxamide from Example 20, Step 3 (20 mg, 0.045 mmol). The reaction mixture was stirred at RT for 30 min and immediately purified by C18 reverse phase column chromatography to give the title compound (19 mg, 70% yield). LCMS (M+H)+ = 603.6.

The following compounds were prepared similarly to Example 23 with appropriate substitution reagents and substrates at various stages. In some examples, reductive amination with the introduction of a tert-amine moiety as a final step may be necessary:

Connection no. MS (M+N) ⁺ 1-235 561.4 1-238 587.3 1-241 589.5 1-248 571.5 1-281 629.5 1-282 643.5 1-284 655.4 1-286 617.6 1-313 603.6

- 64 045243

1-319 621.5 1-322 617.4 1-330 603.5 1-331 603.5 1-332 617.5 1-333 617.6 1-334 633.4 1-336 616.6 1-337 603.6 1-339 629.4 1-340 602.6 1-341 602.4 1-359 617.4 1-363 603.4 1-378 617.2 1-379 601.4 1-380 617.3 1-382 617.5 1-385 629.5 1-388 628.5 1-394 615.4 1-395 629.5 1-399 588.4 1-400 629.5 1-401 602.4 1-405 615.5 1-415 616.4 1-416 585.3 1-417 584.4

Example 24: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N[(3K)-1-methylpyrrolidin-3-yl] -[2,3'-bipyridine]-6-carboxamide (compound 1-283)

Step 24-1, preparation of 2'-ethoxy-5-[(2R)-2-ethyl-4-[1(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidine-3 -yl]-[2,3'bipyridine]-6-carboxamide: To a solution of 1-(trifluoromethyl)cyclobutane-1-carboxylic acid (632 mg, 3.76 mmol) in DMF (5.0 ml) was added HATU (1 .43 g, 3.76 mmol) and TEA (0.67 ml, 5.02 mmol). After stirring at room temperature for 5 min, the resulting solution was treated with 2'-ethoxy-5-[(2R)-2ethylpiperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[ 2,3'-bipyridine]-6-carboxamide from Example 20, Step 3 (1.10 g, 2.51 mmol). The reaction mixture was stirred at room temperature for 30 minutes and immediately purified by C18 reverse phase column chromatography to give the title compound (0.85 g, 58% yield). LCMS (M+H)+ = 589.4.

The following compounds were prepared similarly to Example 24 with appropriate substitution reagents and substrates at various stages. In some examples, reductive amination with the introduction of a tert-amine moiety as a final step may be necessary:

Example 25: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidin-1carbonyl]piperazin-1-yl]-N-[(3R )-1-methylpyrrolidin-3-yl]pyridin-2-carboxamide (compound 1-374)

Step 25-1, preparation of tert-butyl(3R)-4-(6-bromo-2-cyanopyridin-3-yl)-3-ethylpiperazine-1carboxylate: 6-bromo-3-fluoropicolinonitrile was placed in a 1000 ml round bottom flask 50.0 g, 249 mmol), tert-butyl(R)-3-ethylpiperazine-1-carboxylate (59 g, 275 mmol), DIEA (97 g, 750 mmol) and DMSO (500 ml). The resulting reaction mixture was stirred for 24 hours at 90°C. Reactionary

- 65 045243 the mixture was cooled at room temperature and quenched with water (1000 ml). The resulting solution was extracted with ethyl acetate (3-1000 ml). The organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in the title compound (100 g, 66%) as a yellow oil.

LCMS (M+H)+ = 395.1.

Step 25-2, preparation of tert-butyl(3R)-4-[2-cyano-6-(2-ethoxyphenyl)pyridin-3-yl]-3ethylpiperazine-1-carboxylate: into a 250 mL round bottom flask, purged and maintaining an inert nitrogen atmosphere, tert-butyl(3R)-4-(6-bromo-2-cyanopyridin-3-yl)-3-ethylpiperazine 1-carboxylate (5.0 g, 13 mmol), (2-ethoxyphenyl)boronic acid was added acid (4.0 g, 26 mmol), potassium carbonate (5.0 g, 36 mmol), Pd(DtBPF)Cl ₂ (0.4 g, 0.62 mmol) and dioxane/water (50 ml/5 ml ). The resulting solution was stirred at 80°C for 1 hour and cooled to room temperature. The inorganic solid was filtered off and the filtrate was concentrated. The residue was purified on a silica gel column, eluting with ethyl acetate/petroleum ether (1:3). This resulted in the title compound (4.0 g, 67%) as a yellowish oil. LCMS (M+H)+ = 437.2.

Step 25-3, preparation of 3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-6-(2ethoxyphenyl)pyridine-2-carboxylic acid: in a purged round bottom flask with a volume 250 ml were placed tert-butyl(3R)-4-[2-cyano-6-(2-ethoxyphenyl)pyridin-3-yl]-3-ethylpiperazine-1-carboxylate (4.0 g, 9.2 mmol), EtOH (40 ml) and water (40 ml). This resulting solution was treated with KOH (5.3 g, 94 mmol) at room temperature and then stirred at 100°C for 50 hours. The reaction mixture was cooled to room temperature and concentrated to give EtOH. The pH value of the aqueous layer was adjusted to 6-7 using 3 N HCl. The resulting solution was extracted with ethyl acetate (3-50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give the title compound (2.3 g, 55%) as a yellow solid. LCMS (M+H)+ = 456.2.

Step 25-4, preparation of ethyl 6-(2-ethoxyphenyl)-3-[(2R)-2-ethylpiperazin-1-yl]pyridin-2-carboxylate: 3-[(2R)-4 was placed in a 50 ml round bottom flask -[(tert-butoxy)carbonyl]-2ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)pyridine-2-carboxylic acid (1.0 g, 2.2 mmol), EtOH (10 ml) and sulfuric acid (0.5 ml). The resulting reaction mixture was stirred at 80°C for 3 hours and cooled to room temperature. The reaction mixture was diluted with water (50 ml) and then adjusted to pH 6~7 with sodium bicarbonate. The resulting solution was extracted with EtOAc (3-10 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (400 mg, 48%) as a yellow oil. LCMS (M+H)+ = 384.2.

Step 25-5, preparation of ethyl 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2(trifluoromethyl)pyrrolidin-1-carbonyl]piperazin-1-yl] pyridine-2-carboxylate: (S)-2-(trifluoromethyl)pyrrolidine (75 mg, 0.54 mmol), DIEA (210 mg, 1.62 mmol) and DCM (1 ml) were placed in an 8 ml vessel. The reaction mixture was cooled to 0°C and treated with bis(trichloromethyl)carbonate (64 mg, 0.22 mmol). The resulting mixture was stirred at 0°C for 3 hours, quenched with water (20 ml) and extracted with DCM (3-20 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The activated pyrrolidine was used immediately in the next step without further purification. Ethyl 6-(2-ethoxyphenyl)-3-[(2R)-2-ethylpiperazin-1-yl]pyridine-2-carboxylate (210 mg, 5.43 mmol), activated pyrrolidine described above, and potassium carbonate ( 750 mg, 5.43 mmol) and ACN (2 ml) were placed in an 8 ml vessel. The resulting reaction mixture was stirred at 30°C for 2 hours and cooled to room temperature. The crude product was purified by C18 reverse phase column chromatography to give the title compound (200 mg, 68%) as a yellow oil. LCMS (M+H)+ = 549.4.

Step 25-6, preparation of 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1carbonyl]piperazin-1-yl]pyridin-2 -carboxylic acid: ethyl 6-(2ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazine-1 was placed in a vessel with a volume of 8 ml -yl]pyridine 2-carboxylate (200 mg, 0.365 mmol), LiOH (88 mg, 3.7 mmol), EtOH (2 ml) and water (1 ml). The resulting reaction mixture was stirred at 60°C for 1 hour and cooled to room temperature. The reaction mixture was diluted with water (10 ml) and then adjusted to pH 6~7 with 3 N HCl. The resulting solution was extracted with EtOAc (3-10 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give the title compound (170 mg, 90%) as a yellow oil. LCMS (M+H)+ = 521.6.

Step 25-7, preparation of 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidin-1carbonyl]piperazin-1-yl]-N- [(3R)-1-methylpyrrolidin-3-yl]pyridin-2-carboxamide formate: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S) was placed in a 50 ml round bottom flask )-2(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]pyridine-2-carboxylic acid (80 mg, 0.15 mmol), HATU (58 mg, 0.15 mmol), DIEA (40 mg, 0.30 mmol) and DMF (1 ml). The resulting reaction mixture was stirred for 10 min at room temperature and then treated with (R)-1-methylpyrrolidin-3-amine (20 mg, 0.20 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour. The crude product was purified by prep-HPLC under the following conditions (Prep-HPLC-013): column, Atlantis Prep T3 OBD column, 19x150 mm 5 μm; mobile phase, water (0.1% FA) and ACN (30% phase B up to

- 66 045243

90% in 8 minutes); total flow 20 ml/min. Detector, UV 220 nm. This resulted in the title compound (62 mg, 62%) as a white solid. LCMS (M+H)+ = 603.4.

The following compounds were prepared similarly to Example 25 with appropriate substitution reagents and substrates at various stages. In some examples, chiral resolution may be necessary to obtain optically pure compounds, but their absolute stereochemistry has not been determined. In some examples, additional deprotection is necessary at the final stage:

Connection no. MS (M+N) ⁺ 1-305 577.4 1-306 590.3 1-310 590.4 1-311 562.4 1-315 563.4 1-316 563.4 1-317 570.5 1-320 582.2 1-323 578.4 1-326 604.4 1-342 589.4 1-343 589.4 1-345 598.4 1-346 604.5 1-347 604.4 1-350 588.4 1-355 577.4 1-356 577.4 1-360 584.3 1-361 638.3 1-362 603.3 1-365 595.3 1-372 604.4 1-373 604.3 1-375 603.4 1-381 630.6 1-383 609.3 1-386 604.4 1-387 603.4 1-389 652.5 1-391 604.4 1-393 608.2 1-402 651.5 1-404 609.3 1-409 595.5 1-412 595.6 1-413 596.6 1-414 594.5 1-418 638.5 1-419 636.4 1-420 622.3 1-421 635.3 1-422 613.4 1-423 627.4 1-424 612.3 1-426 626.4 1-427 618.4 1-433 617.4 1-434 618.4 1-435 617.3

Example 26: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N[(3K)-1-[(5-methyl- 2-oxo-2H-1,3-dioxol-4-yl)methyl]pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide (compound 1-307)

Step 26-1, preparation of 2'-ethoxy-5-[(2R)-2-ethyl-4-[1(trifluoromethyl)cyclopentαncarbonyl]piperazin-1-yl]-N-[(3R)-1-[(5 -methyl-2-oxo-2H-1,3-dioxol-4yl)methyl]pyrrolidin-3-yl]-[2,3'-bipyridine1-6-carboxamide: to a heterogeneous solution of the compound of example 22 (50 mg, 0.085 mmol ) and potassium bicarbonate (10 mg, 0.10 mmol) in DMF (1.5 ml), 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one (20 mg, 0.10 mmol) was slowly added ) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 hours. The inorganic solid was filtered, and then the filtrate was purified by C18 reverse phase column chromatography to obtain the title compound (18 mg, 30%). LCMS (M+H)+ = 701.4.

Example 27: (2S*)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl-(3R)-4-(2'-ethoxy-6-{[(3R)-pyrrolidin-3- 67 045243 yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate (compound 1-367) [^absolute stereochemistry not determined]

Step 27-1, preparation of (2S*)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl-1H-imidazol-1-carboxylate: to a solution of 1,1,1-trifluoro-3,3 -dimethylbutan-2-ol (100 mg, 0.640 mmol) in THF (3.0 ml) was added 1-(1Himidazol-1-carbonyl)-1H-imidazole (156 mg, 0.961 mmol). The mixture was stirred at room temperature for 2.5 days. The mixture was concentrated to dryness and the residue was purified by silica gel column chromatography to obtain a racemic mixture of the title compound (145 mg, 0.578 mmol, 90.3% yield) as a white solid. LCMS (M+H)+ = 251.1. The racemic mixture was purified under the following conditions to obtain enantiomerically pure title compound ( ^2nd enantiomer: preliminary determination).

Conditions for chiral cleavage:

column: Daicel Chiralpak ID normal phase column, 20 mm ID x 250 mm L, particle size 5 µm;

gradient: isocratic 5% EtOH in hexanes;

flow rate: 20 ml/min;

retention time: ^1st enantiomer: 1.22 min (absolute stereochemistry not determined; tentatively identified as compound 1-366); ^2nd enantiomer: 1.52 min (absolute stereochemistry not determined; tentatively identified as compound 1-367).

Step 27-2, preparation of benzyl(3R)-3-{2'-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-[2,3'-bipyridine]-6amido}pyrrolidine-1- carboxylate: to a solution of tert-butyl(3R)-4-(6-{[(3R)-1[(benzyloxy)carbonyl]pyrrolidin-3-yl]carbamoyl}-2'-ethoxy-[2,3'-bipyridine ]-5-yl)-3-ethylpiperazine 1-carboxylate (181 mg, 0.274 mmol) from step 21-1 in DCM (0.7 ml) was added TFA (0.38 ml, 4.9 mmol). The resulting mixture was stirred at room temperature for 30 minutes and concentrated in vacuo to dryness. The crude TFA salt was neutralized with saturated NaHCO ₃ (aq) to obtain the title compound (153 mg, 0.274 mmol, 100% yield) as a brown solid. LCMS (M+H)+ = 559.3.

Step 27-3, preparation of benzyl(2S*)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl-(3R)-4-(6-{[3R)-1[(benzyloxy)carbonyl ]pyrrolidin-3-yl]carbamoyl}-2'-ethoxy-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine 1-carboxylate: to a solution of benzyl(3R)-3-{2'-ethoxy- 5-[(2R)-2-ethylpiperazin-1-yl]-[2,3'-bipyridine]-6amido}pyrrolidine-1-carboxylate (110 mg, 0.197 mmol) in THF (5.0 mL) was added to DIEA (0.270 ml, 1.55 mmol) and (2S)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl-1H-imidazol-1-carboxylate (75 mg, 0.30 mmol) in a stopper test tube The mixture was heated at 100°C for 24 hours. The mixture was concentrated to dryness and the residue was purified by C18 reverse phase column chromatography to give the title compound (120 mg, 0.162 mmol, 82.2% yield) as a yellow oil. LCMS (M+H)+ = 741.4.

Step 27-4, preparation of (2S*)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl-(3R)-4-(2'-ethoxy-6-{[(3R)pyrrolidin- 3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate formate: to benzyl(2S*)-1,1,1-trifluoro-3,3-dimethylbutane- 2-yl-(3R)-4-(6- {[(3R)- 1-[(benzyloxy)carbonyl] pyrrolide in3-yl]carbamoyl}-2'-ethoxy-[2,3'-bipyridine in]- 5-yl)-3-ethylpiperazine-1-carboxylate (120 mg, 0.162 mmol) was added with TFA (2.0 ml). The resulting mixture was heated at 60°C for 2 hours. The reaction mixture was purified by C18 reverse phase column chromatography to obtain the title compound (72.0 mg, 0.110 mmol, 67.9% yield) as a white solid. LCMS (M+H)+ = 597.4.

The following compounds were prepared similarly to Example 27 with appropriate substitution reagents and substrates at various stages. Some examples of absolute stereochemistry have not been established. In some examples, additional deprotection was not required at the final stage:

- 68 045243 * absolute stereochemistry not determined

Example 28: (2S*)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl-(3R)-4-(2'-ethoxy-6-{[(3R)-1methylpyrrolidin-3- yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate (compound

1-392) [*absolute stereochemistry not determined]

Step 28-1, preparation of (2S*)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl-(3R)-4-(2'-ethoxy-6-{[(3R)-1methylpyrrolidine -3-yl]carbamoyl}-[2,3'-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate: to a solution of (2S*)-1,1,1-trifluoro-3,3-dimethylbutane -2-yl-(3R)-4-(2'-ethoxy-6-{[(3R)-pyrrolidin-3-yl]carbamoyl} [2,3'-bipyridin]-5-yl)-3-ethylpiperazine -1-carboxylate formate (40.0 mg, 0.0613 mmol) in MeOH (3.0 ml) was added with paraformaldehyde (38.5 mg) and sodium cyanoborohydride (38.5 mg, 0.613 mmol). The resulting mixture was stirred at RT for 1 hour. The reaction mixture was quenched with TFA (0.1 ml) and re-basified with saturated NaHCO ₃ (aq). The mixture was extracted with DCM and the organic layer was concentrated to dryness in vacuo. The residue was purified by C18 reverse phase column chromatography to give the title compound (26.1 mg, 0.0420 mmol, 68.5% yield) as an off-white solid. LCMS (M+H)+ = 621.5.

The following compounds were prepared similarly to Example 28 with appropriate substitution reagents and substrates at various stages. Some examples of absolute stereochemistry have not been established:

* absolute stereochemistry not determined.

Example 29: 5-[(2R)-4-(7-cyano-5-fluoro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N[(3R)- 1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide (compound 1-438)

Step 29-1, preparation of 5-fluoro-1I-indole-7-carbonitrile: to a mixture of 7-bromo-5-fluoro-1I-indole (920 mg, 4.30 mmol), dicyanozinc (1.514 g, 12.89 mmol ) and Pd(PPh ₃ ) ₄ (993 mg, 0.860 mmol) DMF (10 ml) was added to a stoppered tube. Nitrogen (gas) was bubbled through the reaction mixture. The resulting mixture was heated at 120°C for 16 hours. The mixture was quenched with water and extracted with DCM (3x). The combined organics were concentrated to dryness and the residue was purified by C18 reverse phase column chromatography to give the title compound (676 mg, 4.22 mmol, 98% yield) as an off-white solid.

Step 29-2, preparation of 4-nitrophenyl-7-cyano-5-fluoro-III-indole-1-carboxylate: to a suspension of 5fluoro-1H-indole-7-carbonitrile (306 mg, 1.91 mmol) and 4-nitrophenylchloroformate (463 mg, 2.30 mmol) in THF (20 ml) were added TEA (0.80 ml, 5.74 mmol) and DMAP (23.4 mg, 0.191 mmol). The resulting mixture was stirred at room temperature for 2 hours, but the reaction was not complete. More 4nitrophenyl chloroformate (463 mg, 2.30 mmol) and triethylamine (0.80 mL, 5.73 mmol) were added and the reaction was continued for 2 hours. The mixture was concentrated to dryness and the residue was purified by silica gel column chromatography to give the title compound (411 mg, 1.26 mmol, 66% yield) as an off-white solid.

Step 29-3, preparation of 5-[(2R)-4-(7-cyano-5-fluoro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2'ethoxy-N-[ (3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide: to a solution of 2'-ethoxy-5-[(2R)2-ethylpiperazin-1-yl]-N- [(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide from Example 20, Step 3 (50.0 mg, 0.114 mmol) and 4-nitrophenyl-7-cyano- 5-fluoro-1H-indole-1-carboxylate (44.5 mg, 0.137 mmol) in MeCN (1 ml) was added with DMAP (34.8 mg, 0.285 mmol). The mixture was heated at 50°C for 1 hour. The mixture was purified by C18 reverse phase column chromatography to give the title compound (14.5 mg, 0.023 mmol, 20% yield) as a light yellow solid. LCMS (M+H)+ = 625.4.

The following compounds were prepared similarly to Example 29 with appropriate substitution reagents and substrates at various stages.

Example 30: 5-[(2R)-4-[2-chloro-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1methylpyrrolidin-3-yl]- [2,3'-bipyridine]-6-carboxamide (compound 1-261)

Step 30-1, preparation of 5-[(2R)-4-[2-chloro-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)1-methylpyrrolidin-3 -yl]-[2,3'-bipyridine]-6-carboxamide: to a solution of 2-chloro-4-fluorobenzoic acid (35.9 mg, 0.206 mmol) and HATU (73.0 mg, 0.192 mmol) in DMF ( 0.2 mL) DIEA (0.072 mL, 0.41 mmol) was added. After stirring at room temperature for 5 minutes, this HATU-activated solution was added to a solution of 2'-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-N-[(3R)-1-methylpyrrolidine -3-yl]-[2,3'-bipyridine]6-carboxamide tris(2,2,2-trifluoroacetate) from example 20, step 3 (107 mg, 0.137 mmol) and DIEA (0.072 ml, 0.41 mmol ) in DMF (0.2 ml). The resulting mixture was stirred at room temperature for 10 minutes. The reaction mixture was purified by C18 reverse phase column chromatography to obtain the title compound (39.4 mg, 0.0645 mmol, 47% yield) as a light yellow solid. LCMS (M+H) ⁺ = 595.5.

Example 31: N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1(trifluoromethyl )cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide (compound 1-410)

Step 31-1, preparation of 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxylic acid: to solution 3 [(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)pyridine-2-carboxylic acid (450 mg, 0.98 mmol) from Example 25 , step 3 in DCM (5.0 ml) was added TFA (1.14 ml, 14.8 mmol) at RT. The resulting solution was stirred at RT for 1 hour and concentrated in vacuo to give 6-( 2-ethoxyphenyl)-3-[(2R)-2-ethylpiperazin-1-yl]pyridine-2-carboxylic acid. This residue was dissolved in ACN (2 ml) and neutralized with Et ₃ N (~0.3 ml). The solution was used in the next HATU coupling step without further purification.

To a solution of 1-(trifluoromethyl)cyclobutane-1-carboxylic acid (332 mg, 1.98 mmol) in ACN (5 ml) was added HATU (751 mg, 1.98 mmol) followed by Et ₃ N (0.26 ml , 1.98 mmol) at room temperature. After stirring at room temperature for 5 minutes, this HATU-activated solution was treated with a solution of 6-(2ethoxyphenyl)-3-[(2R)-2-ethylpiperazin-1-yl] pyridine-2-carboxylic acid described above. The resulting mixture was stirred at room temperature for 30 minutes and concentrated in vacuo. The residue was purified by C18 reverse phase column chromatography to give the title compound (290 mg, 58% yield). LCMS (M+H) ⁺ = 506.3.

Step 31-2, preparation of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4[1 -(trifluoromethyl)cyclobutancarbonyl]piperazin-1-yl]pyridin-2-carboxamide: to a solution of 6-(2ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazine-1 -yl]pyridin-2carboxylic acid (70 mg, 0.14 mmol) and HATU (58.0 mg, 0.15 mmol) in DMF (1.5 ml) was added Et ₃ N (0.074 ml, 0.55 mmol) . After stirring at room temperature for 5 min, the resulting solution was treated with (8)-quinuclidine-3-amine dihydrochloride (33 mg, 0.17 mmol). The resulting mixture was stirred at room temperature for 1 hour and immediately purified by C18 reverse phase column chromatography with

- 70 045243 obtaining the specified compound (40 mg, 47% yield). LCMS (M+H)+ = 614.3.

Example A-1. Parenteral pharmaceutical composition.

To prepare a parenteral pharmaceutical composition suitable for injection (subcutaneous, intravenous), 1-100 mg of a water-soluble salt of a compound of formula (IX) or a pharmaceutically acceptable salt thereof was dissolved in sterile water and then mixed with 10 ml of 0.9% sterile saline solution. Optionally, a suitable buffer is added, as well as an optional acid or base to adjust the pH. The mixture was included in a unit dosage form suitable for injection.

Example A-2. Oral solution.

To prepare a pharmaceutical composition for oral delivery, a sufficient amount of a compound of formula (IX) or a pharmaceutically acceptable salt thereof is added to water (with optional solubilizer(s), optional buffer(s) and taste-masking auxiliaries) to provide a solution 20 mg/ml.

Example A-3. Oral tablet.

A tablet was prepared by mixing 20-50% by weight of a compound of formula (IX) or a pharmaceutically acceptable salt thereof, 20-50% by weight microcrystalline cellulose, 1-10% by weight low-substituted hydroxypropylcellulose and 1-10% by weight magnesium stearate or other suitable auxiliary means. The tablets were obtained by direct compression. The total weight of the compressed tablets was maintained at 100-500 mg.

Example A-4. Oral capsule.

To prepare a pharmaceutical composition for oral delivery, 10-500 mg of a compound of formula (IX) or a pharmaceutically acceptable salt thereof is mixed with starch or other suitable powder mixture. The mixture is included in an oral dosage unit, such as a hard gelatin capsule, which is suitable for oral administration.

In another embodiment, 10-500 mg of a compound of formula (IX) or a pharmaceutically acceptable salt thereof is placed in a size 4 capsule or size 1 capsule (hypromellose or hard gelatin) and the capsule is closed.

Example A-5. Local gel composition.

To prepare a pharmaceutical topical gel composition, a compound of formula (IX) or a pharmaceutically acceptable salt thereof was mixed with hydroxypropylcellulose, propylene glycol, isopropyl myristate and USP purified alcohol. The resulting gel mixture was then placed in containers, such as tubes, that are suitable for topical application.

Example B-16. MC2R analyses. Membrane preparation.

Crude membrane fractions were prepared from CRE-bla-CHO-K1 cells stably expressing the hMC2 receptor and hMRAP accessory protein (Thermo Fisher). Cells were grown to 85-100% confluency in standard Petri dishes in GlutaMax DMEM growth medium (Gibco) with the following additives: 10% dialyzed FBS (Gemini), 0.1 mM NEAA (Gibco), 25 mM HEPES (Gibco), 5 μg/ ml blasticidin (Goldbio), 100 µg/ml zeocin (Invitrogen), 600 µg/ml hygromycin (Goldbio). To prepare the membranes, cells were scraped and collected in 1× Dulbecco's phosphate-buffered saline (Corning) and then pelleted at 1000 rpm. The cell pellet was reconstituted in membrane preparation buffer (20 mM HEPES, 6 mM MgCl ₂ and 1 mM EGTA, protease inhibitor tablets (Pierce), adjusted to pH 7.4), homogenized using a Dounce homogenizer, and the resulting membrane fraction was pelleted by centrifugation at 12000 rpm The membrane pellet was resuspended in membrane preparation buffer, flash frozen, and stored at -80°C for later use.

Protocol for hMC2 antagonist binding assay.

The following components were used in the hMC2 membrane binding assay: radiolabeled [ ¹²⁵ 1]ACTH(1-39) Tyr23 (PerkinElmer), PVT SPA beads coated with wheat germ agglutinin (PerkinElmer), crude hMC2R membranes and compounds. Briefly, hMC2R membranes were incubated with SPA beads in binding assay buffer (50 mM HEPES, 5 mM MgCl ₂ , 1 mM CaCl ₂ , 0.2% BSA, protease inhibitor tablets (Pierce), adjusted to pH 7.4) before starting analysis. Dose-response compound (final compound concentration typically ranges from 0-10,000 nM), SPA membranes and [ ¹²⁵ 1]ACTH(1-39)Tyr23 at a final concentration of 0.2 nM were placed in a 96-well assay plate and incubated for 1.5 hours at room temperature. Assay plates were read using Top Count NXT, and Ki values for compounds were determined using GraphPad Prism 6 nonlinear regression analysis.

Exemplary binding affinities of selective compounds are described in Table. A. The types of activities are divided into four criteria: + means that Ki is from 1000 to 10000 nM; ++ means Ki is between 100 nM and 1000 nM; +++ means Ki is between 10 nM and 100 nM; ++++ means Ki is below 10 nM.

- 71 045243

Table A

Connection no. MC2R binding activity 1-1 +++ 1-2 ++++ 1-3 ++++ 1-4 +++ 1-5 +++ 1-6 +++ 1-7 +++ 1-8 +++ 1-9 +++ 1-11 +++ 1-15 ++++ 1-16 +++ 1-17 ++++ 1-18 ++++ 1-19 +++ 1-20 +++ 1-23 +++ 1-24 ++++ 1-25 ++++ 1-26 ++++ 1-27 ++++ 1-32 +++ 1-33 +++ 1-34 ++++ 1-35 ++++ 1-36 ++++ 1-37 ++++ 1-38 ++++ 1-40 ++++ 1-41 ++++ 1-42 ++++ 1-43 ++++ 1-44 ++++ 1-45 ++++

- 72 045243

1-46 ++++ 1-47 ++++ 1-48 ++++ 1-49 ++++ 1-50 ++++ 1-51 ++++ 1-52 ++++ 1-54 ++++ 1-57 ++++ 1-58 ++++ 1-59 ++++ 1-60 ++++ 1-62 ++++ 1-67 ++++ 1-68 ++++ 1-69 ++++ 1-71 ++++ 1-72 ++++ 1-73 ++++ 1-76 ++++ 1-82 ++++ 1-84 ++++ 1-87 ++++ 1-88 ++++ 1-90 ++++ 1-91 ++++ 1-92 ++++ 1-93 ++++ 1-94 ++++ 1-95 ++++ 1-96 ++++ 1-97 ++++ 1-98 ++++ 1-99 ++++ 1-100 ++++ 1-101 ++++ 1-102 ++++ 1-104 ++++ 1-107 ++++ 1-108 ++++ 1-109 ++++ 1-110 ++++ 1-111 ++++ 1-112 ++++ 1-113 ++++ 1-114 ++++ 1-115 ++++

- 73 045243

1-116 ++++ 1-117 ++++ 1-123 ++++ 1-124 ++++ 1-125 ++++ 1-136 ++++ 1-137 ++++ 1-138 ++++ 1-142 ++++ 1-143 ++++ 1-148 ++++ 1-149 ++++ 1-150 ++++ 1-151 ++++ 1-152 ++++ 1-155 ++++ 1-156 ++++ 1-163 ++++ 1-164 ++++ 1-165 ++++ 1-167 ++++ 1-168 ++++ 1-169 ++++ 1-170 ++++ 1-171 ++++ 1-173 ++++ 1-174 ++++ 1-176 ++++ 1-177 ++++ 1-178 ++++ 1-181 ++++ 1-182 ++++ 1-183 ++++ 1-184 ++++ 1-187 ++++ 1-188 ++++ 1-189 ++++ 1-190 ++++ 1-198 ++++ 1-199 ++++ 1-200 ++++ 1-201 ++++ 1-202 ++++ 1-203 ++++ 1-206 ++++ 1-207 ++++ 1-208 ++++ 1-209 ++++

- 74 045243

1-210 ++++ 1-211 ++++ 1-212 ++++ 1-213 ++++ 1-214 ++++ 1-215 ++++ 1-216 ++++ 1-219 ++++ 1-220 ++++ 1-221 ++++ 1-222 ++++ 1-223 ++++ 1-224 ++++ 1-225 ++++ 1-226 ++++ 1-227 ++++ 1-228 ++++ 1-229 ++++ 1-230 ++++ 1-231 ++++ 1-232 ++++ 1-233 ++++ 1-234 ++++ 1-236 ++++ 1-237 ++++ 1-238 ++++ 1-239 ++++ 1-240 ++++ 1-241 ++++ 1-242 ++++ 1-243 ++++ 1-244 ++++ 1-245 ++++ 1-246 ++++ 1-247 ++++ 1-249 ++++ 1-253 ++++ 1-254 ++++ 1-255 ++++ 1-256 ++++ 1-257 ++++ 1-258 ++++ 1-259 ++++ 1-260 ++++ 1-261 ++++ 1-262 ++++ 1-263 ++++ 1-264 ++++

- 75 045243

- 76 045243

- 77 045243

1-393 ++++ 1-394 ++++ 1-395 ++++ 1-396* ++++ 1-397 ++++ 1-398 ++++ 1-399 ++++ 1-400 ++++ 1-401 ++++ 1-402 ++++ 1-403* ++++ 1-404 ++++ 1-405 ++++ 1-406* ++++ 1-407* ++++ 1-408 ++++ 1-409 ++++ 1-410 ++++ 1-411 ++++ 1-412 ++++ 1-413 ++++ 1-414 ++++ 1-415 ++++ 1-416 ++++ 1-417 ++++ 1-418 ++++ 1-419 ++++ 1-420 ++++ 1-421 ++++ 1-422 ++++ 1-423 ++++ 1-424 ++++ 1-425 ++++ 1-426 ++++ 1-427 ++++ 1-428 ++++ 1-429 ++++ 1-430 ++++ 1-431 ++++ 1-432 ++++ 1-433 ++++ 1-434 ++++ 1-435 ++++ 1-436 ++++ 1-437 ++++ 1-438 ++++ 1-439 ++++ 2-2 ++++ 2-3 +++ 2-13 ++++ 2-16 ++++ 2-20 ++++ 2-21 ++++ 2-25 ++++ 2-30 ++++ 2-31 ++++

* absolute stereochemistry not determined.

The examples and embodiments described herein are presented for illustrative purposes only, and various modifications or changes suggested by those skilled in the art are intended to be encompassed within the spirit and scope of the present invention and within the scope of the appended claims.

Claims (26)

1. A compound of formula (IX) or a pharmaceutically acceptable salt thereof: pb Formula (IX) where: V represents CH or N; R ^a is selected from the group consisting of hydrogen, halogen, -OR ⁸ , -CN, -N(R ⁷ ) ₂ , C ₁ -C ₆ alkyl, C ₁ O ₆ fluoroalkyl and C ₁ -C ₆ heteroalkyl; R ^b and R ^c are each independently selected from the group consisting of hydrogen, halogen, -OR ⁸ , -CN, -N(R ⁷ ) ₂ - 78 045243 and C ₁ -C6 alkyl; R ^B represents where Z represents CH or N; or R ^B is unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, unsubstituted or substituted cyclopentenyl or unsubstituted or substituted cyclohexyl, wherein if R ^B is substituted then R ^B is substituted with R ^d , R ^e and R ^f ; or R ^B represents where m is 0, 1, 2 or 3. R ^d is selected from the group consisting of hydrogen, halogen, -OR ⁸ , -CN, -N(R ⁷ ) ₂ , C ₁ -C ₆ alkyl, C1C ₆ fluoroalkyl and C ₁ -C ₆ heteroalkyl; R ^e and R ^f are each independently selected from the group consisting of hydrogen, halogen, -OR ⁸ , -CN, -N(R ⁷ ) ₂ and C1-C6 alkyl; X ¹ represents N or CR ⁶ ; R ⁶ represents H or F; R ² and R ³ represent hydrogen; or R ² and R ³ are taken together with the carbon atom to which they are attached to form -C(=O)-; R ⁴ represents -CH2CH2NH2, -C^CH^NHi, ^H O1 each R ⁷ is independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl and C ₁ -C ₆ fluoroalkyl; or two R ⁷ taken together with the nitrogen atom to which they are attached to form unsubstituted or substituted pyrrolidinyl, unsubstituted or substituted oxazolidinyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted morpholinyl, unsubstituted or substituted thiomorpholinyl, unsubstituted or substituted piperazinyl, substituted or substituted aziridinyl, unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrazolidinyl, or unsubstituted or substituted imidazolidinyl; and each R ⁸ is independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl and C 1 C ₆ fluoroalkyl; wherein the term substituted, unless specifically defined, means that said group is replaced by one or two additional groups individually and independently selected from halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3; wherein the term heteroalkyl means an alkyl group in which one or two skeletal carbon atoms of the alkyl are independently selected from oxygen, -NH-, -N(C ₁ -C ₄ alkyl)- or sulfur. 2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, where: R ^a represents -OR ⁸ ; And - 79 045243 R ^b and R ^c each represent hydrogen. 3. A compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R ^a represents -OSH2CH3. 4. A compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, where: R ⁴ represents 5. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, where: R ⁴ represents -CH2CH2NH2, -CH ₂ (CH ₂ ) ₂ NH ₂ , 6. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, where: R ⁴ represents 7. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, where: R ^B represents where Z represents CH or N. 8. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, where: R ^B represents unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, unsubstituted or substituted cyclopentenyl or unsubstituted or substituted cyclohexyl, and if R ^B is substituted, then R ^B is substituted by R ^d , R ^e and R ^f . 9. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, where: R ^B represents where m is 0, 1, 2 or 3. 10. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, where: R ^B represents - 80 045243 11. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, where: R ^B represents - 81 045243 12. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, where: R ^B represents 13. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, where: R ^B represents 14. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, where: - 82 045243 R ^B represents 15. A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, where: R ² and R ³ are taken together with the carbon atom to which they are attached to form -C(=O)-. 16. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (IX) has the structure of formula (IXa), or a pharmaceutically acceptable salt thereof: Formula (IXa). 17. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: 1-1: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2',3'difluoro- [1,1'-biphenyl]-3-carboxamide; 1-2: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'methoxy-[1, 1'-biphenyl]-3-carboxamide; 1 -3: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-2'-ethoxy[1, 1'-biphenyl]-3-carboxamide; 1-4: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-fluoro[1, 1'-biphenyl]-3-carboxamide; 1-5: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethyl[1, 1'-biphenyl]-3-carboxamide; 1-6: N-(2-aminoethyl)-2'-chloro-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl][1, 1'-biphenyl]-3-carboxamide; 1-7: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-cyano[1, 1'-biphenyl]-3-carboxamide; 1-8: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-methyl[1, 1'-biphenyl]-3-carboxamide; 1-9: N-(2-aminoethyl)-2'-chloro-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3' fluoro-[1,1'-biphenyl]-3-carboxamide; 1-10: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3'ethoxy-[1, 1'-biphenyl]-3-carboxamide; 1-11: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'propoxy-[1, 1'-biphenyl]-3-carboxamide; 1-12: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'(propan-2- yloxy)-[1,1'-biphenyl]-3-carboxamide; 1-13: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'hydroxy-[1, 1'-biphenyl]-3-carboxamide; 1-14: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'cyclopropoxy-[1, 1'-biphenyl]-3-carboxamide; 1-23: N-(3-aminopropyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'ethoxy-[1, 1'-biphenyl]-3-carboxamide; 1-25: N-(2-aminoethyl)-4-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'ethoxy-[1, 1'-biphenyl]-3-carboxamide; 1-28: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'propyl-[1, 1'-biphenyl]-3-carboxamide; 1-29: N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-4'propyl-[1, 1'-biphenyl]-3-carboxamide; 1-31: N-(2-aminoethyl)-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5(pyridin-3-yl )benzamide; 1-34: N-(2-aminoethyl)-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2ethoxypyridin-3- yl)benzamide; 1-35: N-(2-aminoethyl)-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(4- 83 045243 ethoxypyridin-3-yl)benzamide; 1-37: N-(2-aminoethyl)-2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2ethoxypyridin-3 - yl)benzamide; 1-38: N-(2-aminoethyl)-2-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1 -yl]-5-(2ethoxypyridin-3 -yl)benzamide ; 1-42: N-(2-aminoethyl)-2-[(2R)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3yl)benzamide; 1-43: N-(2-aminoethyl)-2-[(2R)-4-(2-chloro-4-methylbenzoyl)-2-ethylpiperazin-1-yl]-5-(2ethoxypyridin-3-yl)benzamide ; 1-45: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-5-(2-ethoxypyridin-3 yl)-N-[( 3R)-pyrrolidin-3-yl]benzamide; 1-46: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-5-(2-ethoxypyridin-3 yl)-N-[2 -(methylamino)ethyl]benzamide; 1-47: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-N-[2(dimethylamino)ethyl]-5 -(2- ethoxypyridin-3-yl)benzamide; 1-48: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-5-(2-ethoxypyridin-3yl)-N-[(3R )-1-methylpyrrolidin-3-yl]benzamide; 1-49: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-5-(2-ethoxypyridin-3 yl)-N-[2 -(pyrrolidin-1-yl)ethyl]benzamide; 1-52: N-(2-aminoethyl)-2-[(2R)-4-[2-(4-aminopiperidin-1-yl)-4-chlorobenzoyl]-2-ethylpiperazin-1yl]-5-(2 -ethoxypyridin-3-yl)benzamide; 1-53: N-(2-aminoethyl)-2-[(2R)-4-(3,5-dichloropyridin-2-carbonyl)-2-ethylpiperazin-1-yl]-5-(2ethoxypyridin-3 -yl )benzamide; 1-54: N-(2-aminoethyl)-2-[(2R)-4-(4-chloro-2-methoxybenzoyl)-2-ethylpiperazin-1-yl]-5-(2ethoxypyridin-3-yl)benzamide ; 1-55: N-(2-aminoethyl)-2-[(2R)-4-(2-chloro-4-cyanobenzoyl)-2-ethylpiperazin-1-yl]-5-(2ethoxypyridin-3-yl)benzamide ; 1-57: N-(2-aminoethyl)-2-[(2R)-4-{2-[(3S)-3-aminopyrrolidin-1-yl]-4-chlorobenzoyl}-2ethylpiperazin-1 -yl] - 5-(2-ethoxypyridin-3-yl)benzamide; 1-58: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-fluoro-2(trifluoromethyl)benzoyl]piperazin- 1-yl]benzamide; 1-59: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-methyl-2(trifluoromethyl)benzoyl]piperazine- 1-yl]benzamide; 1-60: N-(2-aminoethyl)-2-[(2R)-4-(2,4-dimethylbenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin3-yl)benzamide; 1-61: N-(2-aminoethyl)-2-[(2R)-4-[4-chloro-2-(pyrrolidin-1 -yl)benzoyl]-2-ethylpiperazin-1 -yl]-5-( 2ethoxypyridin-3-yl)benzamide; 1-62: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[2(trifluoromethyl)benzoyl]piperazin-1-yl] benzamide; 1 -64: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-5-(2-ethoxypyridin-3 yl)-N-[( pyridin-2-yl)methyl]benzamide; 1-65: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-5-(2-ethoxypyridin-3 yl)-N-[( pyridin-3-yl)methyl]benzamide; 1-66: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-5-(2-ethoxypyridin-3 yl)-N-[( pyridin-4-yl)methyl]benzamide; 1-67: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-{4-methyl-2-[(3S)-3 (methylamino)pyrrolidin-1 -yl] benzoyl} piperazin-1 -yl] benzamide; 1-68: N-(2-aminoethyl)-2-[(2R)-4-{2-[(3 S)-3-(dimethylamino)pyrrolidin-1-yl]-4-methylbenzoyl}-2ethylpiperazine-1 -yl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-69: N-(2-aminoethyl)-6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2ethoxypyridin-3- yl)-2-fluorobenzamide; 1-70: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3yl)-N-(pyridin- 4-yl)benzamide; 1-71: N-(2-aminoethyl)-2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2methoxypyridin-3 - yl)benzamide; 1-72: 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-3-(2-ethoxypyridin-3 yl)-2-fluoro- N-[(3R)-pyrrolidin-3-yl]benzamide; 1-73: 6-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N[ (3R)-pyrrolidin-3-yl]benzamide; 1-76: N-(2-aminoethyl)-2-[(2R)-4-[2-(dimethylamino)-6-(trifluoromethyl)pyridin-3-carbonyl]-2ethylpiperazin-1 -yl]-5-( 2-ethoxypyridin-3-yl)benzamide; 1-77: N-(2-aminoethyl)-2-[(2R)-4-(2,6-dimethylpyridin-3-carbonyl)-2-ethylpiperazin-1-yl]-5-(2-84 045243 ethoxypyridine -3-yl)benzamide; 1-78: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-(4-fluoro-2methylbenzoyl)piperazin-1 -yl] benzamide; 1-79: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-(4-fluoro-2methoxybenzoyl)piperazin-1-yl] benzamide; 1-80: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-(2-methoxy-4methylbenzoyl)piperazin-1-yl] benzamide; 1-81: N-(2-aminoethyl)-2-[(2R)-4-(4-tert-butylbenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin3-yl)benzamide; 1-82: 2-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R) pyrrolidin-3-yl]benzamide; 1-83: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3yl)-K-[(1H -imidazol-5-yl)methyl]benzamide; 1-84: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-5-(2-ethoxypyridin-3 yl)-N-[2 -(1H-imidazol-5-yl)ethyl]benzamide; 1-86: N-(2-aminoethyl)-2-[(2R)-4-(4,6-dimethylpyridin-3-carbonyl)-2-ethylpiperazin-1-yl]-5-(2ethoxypyridin-3-yl )benzamide; 1-87: N-(2-aminoethyl)-2-[(2R)-4-(4-chloro-2-methylbenzoyl)-2-ethylpiperazin-1-yl]-5-(2ethoxypyridin-3-yl)benzamide ; 1-89: N-(2-aminoethyl)-2-[(2R)-4-(3-chloro-5-fluoropyridin-2-carbonyl)-2-ethylpiperazin-1-yl]-5-(2ethoxypyridin-3 -yl)benzamide; 1 -90: 2-[(2R)-4-[4-chloro-2-(piperazin-1 -yl)benzoyl]-2-ethylpiperazin-1 -yl]-5-(2-ethoxypyridin-3yl)-N -[(3R)-pyrrolidin-3-yl]benzamide; 1-91: 2-[(2R)-4-[4-chloro-2-(dimethylamino)benzoyl]-2-ethylpiperazin-1 -yl]-5-(2-ethoxypyridin-3 yl)-N-[( 3R)-pyrrolidin-3-yl]benzamide; 1 -92: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-5-(2-ethoxypyridin-3ul)-N- [( 3 S)-pyrrolidin-3-yl]benzamide; 1-93: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3ul)-N-[2- (1 H-imidazol-2-yl)ethyl]benzamide; 1-94: 5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-{4-methyl-2-[(3S)-3-(methylamino)pyrrolidin-1yl] benzoyl}piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]benzamide; 1-95: 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-3-(2-ethoxypyridin-3 yl)-2-fluoro- K-[2-(methylamino)ethyl]benzamide; 1-96: 6-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N[ 2-(methylamino)ethyl]benzamide; 1-97: N-{[(2S)-azetidin-2-yl]methyl}-2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin1 -yl] - 5 -(2-ethoxypyridin-3-yl)benzamide; 1-98: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-5-(2-ethoxypyridin-3yl)-N-{[( 2S)-pyrrolidin-2-yl]methyl}benzamide; 1-99: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-5-(2-ethoxypyridin-3 yl)-N-[( 3R)-piperidin-3-yl]benzamide; 1-100: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-5-(2-ethoxypyridin-3 yl)-N-[( 3S)-piperidin-3-yl]benzamide; 1-101: 5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-{4-fluoro-2-[(3 S)-3-(methylamino)pyrrolidine-1 yl]benzoyl}piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]benzamide; 1-102: N-{[(2R)-azetidin-2-yl]methyl}-2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2ethylpiperazin-1 -yl] - 5-(2-ethoxypyridin-3-yl)benzamide; 1-103: 5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-{2-fluoro-4-[(3S)-3-(methylamino)pyrrolidin-1yl] benzoyl}piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]benzamide; 1-105: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[2-(morpholin-4-yl)-6( trifluoromethyl)pyridin-3-carbonyl]piperazin-1-yl]benzamide; 1-106: N-(2-aminoethyl)-2-[(2R)-4-[3-(dimethylamino)-5-(trifluoromethyl)pyridin-2-carbonyl]-2ethylpiperazin-1 -yl]-5-( 2-ethoxypyridin-3-yl)benzamide; 1-107: N-(2-aminoethyl)-2-[(2R)-4-[2-(dimethylamino)-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1yl]-5-(2-ethoxypyridin- 3-yl)benzamide; 1-108: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3 yl)-N-{[ (2R)-pyrrolidin-2-yl]methyl}benzamide; 1-109: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3 yl)-N-{[ (2S)-morpholin-2-yl]methyl}benzamide; 1-110: 6-[(2R)-4-(2-chloro-4-methylbenzoyl)-2-ethylpiperazin-1 -yl]-3-(2-ethoxypyridin-3 -yl)-2-fluoroN-[( 3R)-pyrrolidin-3-yl]benzamide; 1-111: 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-85 045243 yl] - 2-fluoro-N-[(3R)-pyrrolidin-3-yl]benzamide; 1-112: N-{[(2S)-azetidin-2-yl]methyl}-6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2ethylpiperazin-1 -yl] - 3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 1-113: 6-[(2R)-4-(2-chloro-4-methylbenzoyl)-2-ethylpiperazin-1 -yl]-3-(2-ethoxypyridin-3 -yl)-2-fluoroN-[2 -(methylamino)ethyl]benzamide; 1-114: 3 -(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1 yl]-2-fluoro -N-[2-(methylamino)ethyl]benzamide; 1-115: 2-[(2R)-4-{4-chloro-2-[(3 S)-3-(dimethylamino)pyrrolidin-1 -yl]benzoyl}-2-ethylpiperazin-1 yl]-5- (2-ethoxypyridin-3-yl)-N-[(3R)-pyrrolidin-3-yl]benzamide; 1-116: 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-3-(2-ethoxypyridin-3 yl)-2-fluoro- N-[2-(1H-imidazol-2-yl)ethyl]benzamide; 1-117: N-(2-aminoethyl)-2-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1 -yl]-5-(2ethoxypyridin-3 -yl)benzamide ; 1-118: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[5-fluoro-3(trifluoromethyl)pyridin-2- carbonyl]piperazin-1-yl]benzamide; 1-119: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[2(methylamino)-6(trifluoromethyl)pyridin-3 -carbonyl]piperazin-1-yl]benzamide; 1-120: N-(2-aminoethyl)-5 -(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[2-(pyrrolidin-1 -yl)-6( trifluoromethyl)pyridin-3-carbonyl]piperazin-1-yl]benzamide; 1-121: 3 -(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[2-(trifluoromethyl)benzoyl]piperazin-1 -yl]-2fluoro-N-[2 -(methylamino)ethyl]benzamide; 1-122: 3 -(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[2-(trifluoromethyl)benzoyl]piperazin-1 -yl]-2fluoro-N-[( 3R)-pyrrolidin-3-yl]benzamide; 1-123: N-{[(2R)-azetidin-2-yl]methyl}-6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2ethylpiperazin-1 -yl] - 3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 1-124: 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-3-(2-ethoxypyridin-3 yl)-2-fluoro- N-{[(2R)-pyrrolidin-2-yl]methyl}benzamide; 1-125: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[(4,5-dihydro-1Himidazol-2-yl )methyl]-5-(2-ethoxypyridin-3-yl)benzamide; 1-126: 2-[(2R)-4-[2-amino-6-(trifluoromethyl)pyridin-3-carbonyl]-2-ethylpiperazin-1 -yl]-N-(2aminoethyl)-5-(2- ethoxypyridin-3-yl)benzamide; 1-127: N-(2-aminoethyl)-2-[(2R)-4-[6-(dimethylamino)-2-(trifluoromethyl)pyridin-3-carbonyl]-2ethylpiperazin-1 -yl]-5-( 2-ethoxypyridin-3-yl)benzamide; 1-128: 2-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-5-(2-ethoxypyridin-3 yl)-N-[2 -(methylamino)ethyl]benzamide; 1-132: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-5-(2-ethoxypyridin-3 yl)-N-[( 1 H-imidazol-2-yl)methyl]benzamide; 1-133: 5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[5-(trifluoromethyl)pyridin-2carbonyl]piperazin-1-yl]-N-[( 3R)-pyrrolidin-3-yl]benzamide; 1-134: 2-[(2R)-4-[3-chloro-5-(trifluoromethyl)pyridin-2-carbonyl]-2-ethylpiperazin-1-yl]-5-(2ethoxypyridin-3-yl)-N -[(3R)-pyrrolidin-3-yl]benzamide; 1-135: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-2'-ethoxy-N-[2(methylamino)ethyl]- [2,3'-bipyridine]-6-carboxamide; 1-136: 2'-ethoxy-5-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-N-[2(methylamino)ethyl] -[2,3'-bipyridine]-6-carboxamide; 1-137: 2'-ethoxy-5-[(2R)-4-[4-ethoxy-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-N-[2(methylamino)ethyl]- [2,3'-bipyridine]-6-carboxamide; 1-138: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3 yl)-N-{[ (3S)-morpholin-3-yl]methyl}benzamide; 1-139: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-5-(2-ethoxypyridin-3 yl)-N-[2 -(1H-1,2,4-triazol-1-yl)ethyl]benzamide; 1-140: 6-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1 -yl]-3-(2-ethoxypyridin-3 -yl)-2-fluoroN-[2 -(1H-imidazol-2-yl)ethyl]benzamide; 1-141: 6-[(2R)-4-(4-chloro-2-ethoxybenzoyl)-2-ethylpiperazin-1 -yl]-3-(2-ethoxypyridin-3 -yl)-2-fluoroN-[2 -(1H-imidazol-2-yl)ethyl]benzamide; 1-142: 2-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R) pyrrolidin-3-yl]benzamide; 1-143: 5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-methoxy-2-(trifluoromethyl)benzoyl]piperazin1 -yl]-N-[( 3R)-pyrrolidin-3-yl]benzamide; 1-144: 2-[(2R)-4-[4-cyano-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-5-(2-ethoxypyridin-3 yl)-N-[( 3R)-pyrrolidin-3-yl]benzamide; 1-145: 2-[(2R)-4-[6-amino-2-(trifluoromethyl)pyridin-3-carbonyl]-2-ethylpiperazin-1-yl]-N-(2-86 045243 aminoethyl)-5 -(2-ethoxypyridin-3-yl)benzamide; 1-146: N-(2-aminoethyl)-2-[(2R)-4-[4-(dimethylamino)-6-(trifluoromethyl)pyridin-3-carbonyl]-2ethylpiperazin-1 -yl]-5-( 2-ethoxypyridin-3-yl)benzamide; 1-147: 2-[(2R)-4-[2-(dimethylamino)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-N-[2(dimethylamino)ethyl]-5 -(2-ethoxypyridine -3-yl)benzamide; 1-148: 2-[(2R)-4-[2-(3-aminoazetidin-1-yl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-N-[2(dimethylamino)ethyl] - 5 -(2-ethoxypyridin-3-yl)benzamide; 1-149: 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2(dimethylamino)ethyl]-6-(2- ethoxyphenyl)pyridine-2-carboxamide; 1-150: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2(dimethylamino)ethyl]-2'-ethoxy- [2,3'-bipyridine]-6-carboxamide; 1-151: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)pyrrolidin-3- yl]-[2,3'-bipyridine]-6-carboxamide; 1-152: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1methylpyrrolidin-3 -yl]-[2,3'-bipyridine]-6-carboxamide; 1-153: 6-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1 -yl]-3-(2-ethoxypyridin-3 -yl)-2-fluoroN-[2 -(methylamino)ethyl]benzamide; 1-154: 6-[(2R)-4-[4-cyano-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-3-(2-ethoxypyridin-3 yl)-2-fluoro- N-[2-(methylamino)ethyl]benzamide; 1-155: 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-methoxy-2-(trifluoromethyl)benzoyl]piperazin1-yl]-2-fluoro- N-[2-(methylamino)ethyl]benzamide; 1-156: 6-[(2R)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2 (methylamino)ethyl]benzamide; 1-157: 6-[(2R)-4-[2-cyano-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-3-(2-ethoxypyridin-3 yl)-2-fluoro- N-[2-(methylamino)ethyl]benzamide; 1-158: 5-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1 -yl]-N-[2-(dimethylamino)ethyl]-2'ethoxy-[2, 3'-bipyridine]-6-carboxamide; 1-159: N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[2-methoxy-6(trifluoromethyl)pyridin-3 - carbonyl]piperazin-1-yl]benzamide; 1-160: N-(2-aminoethyl)-2-[(2R)-4-[2-(dimethylamino)-6-methylpyridin-3-carbonyl]-2ethylpiperazin-1 -yl]-5-(2-ethoxypyridine -3-yl)benzamide; 1-161: 2-[(2R)-4-[2-(azetidin-1 -yl)-4-fluorobenzoyl]-2-ethylpiperazin-1 -yl]-N-[2(dimethylamino)ethyl] -5 - (2-ethoxypyridin-3-yl)benzamide; 1-162: N-[2-(dimethylamino)ethyl]-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-fluoro-2(pyrrolidin-1 -yl)benzoyl]piperazin-1 -yl]benzamide; 1-163: 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[6-(methylamino)-2-(trifluoromethyl)pyridin-3carbonyl]piperazin-1 -yl ]-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 1-164: 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[6-methoxy-2(trifluoromethyl)pyridin-3carbonyl]piperazin-1 -yl]-2 -fluoro-N-[2-(methylamino)ethyl]benzamide; 1-165: 6-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridin-3-carbonyl]-2-ethylpiperazin-1-yl]-3-(2ethoxypyridin-3-yl)-2 -fluoro-N-[2-(methylamino)ethyl]benzamide; 1-166: 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[2-methoxy-6(trifluoromethyl)pyridin-3carbonyl]piperazin-1 -yl]-2 -fluoro-N-[2-(methylamino)ethyl]benzamide; 1-167: 2'-ethoxy-5-[(2R)-2-ethyl-4-[4-methoxy-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-N-[2(methylamino)ethyl] -[2,3'-bipyridine]-6-carboxamide; 1-168: N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-methoxy-2(trifluoromethyl)benzoyl ]piperazin-1-yl]-2-fluorobenzamide; 1-169: N-[2-(dimethylamino)ethyl]-2'-ethoxy-5-[(2R)-2-ethyl-4-[4-methoxy-2(trifluoromethyl)benzoyl]piperazin-1 -yl] -[2,3'-bipyridine]-6-carboxamide; 1-170: N-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-3-(2-ethoxypyridin-3-yl)-6[(2R)-2-ethyl-4-[ 4methoxy-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluorobenzamide; 1-171: 5-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[2-(methylamino)ethyl][2, 3'-bipyridine]-6-carboxamide; 1-173: 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2(dimethylamino)ethyl]-3 -(2- ethoxypyridin-3-yl)-2-fluorobenzamide; 1-174: N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-fluoro-2(trifluoromethyl)benzoyl ]piperazin-1-yl]-2-fluorobenzamide; 1-175: 6-[(2R)-4-[4-cyano-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-N-[2(dimethylamino)ethyl]-3 -(2- ethoxypyridin-3-yl)-2-fluorobenzamide; 1-176: 6-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-N-[2(dimethylamino)ethyl]-3-(2-ethoxypyridine -3-yl)-2-fluorobenzamide; 1-177: 6-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1 -yl]-3-(2-ethoxypyridin-3 - 87 045243 yl)-2- fluoro-N-[2-(methylamino)ethyl]benzamide; 1-178: 6-[(2R)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl]-N-[(4,5-dihydro-1H-imidazol-2yl)methyl]-3 -(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 1-179: 6-[(2R)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-3-(2ethoxypyridin-3-yl) -2-fluorobenzamide; 1-180: 6-[(2R)-4-{4-chloro-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]benzoyl}-2-ethylpiperazin-1 yl]-N- [2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 1-181: 2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridin-3-carbonyl]-2-ethylpiperazin-1 -yl] N-[2-(methylamino )ethyl]-[2,3'-bipyridine]-6-carboxamide; 1-182: N-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-3-(2-ethoxypyridin-3-yl)-6[(2R)-2-ethyl-4-[ 4fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluorobenzamide; 1-183: 6-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-3-(2-ethoxypyridin-3 yl)-2-fluoro- N-[2-(methylamino)ethyl]benzamide; 1-184: 6-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-N-[2(dimethylamino)ethyl]-3 -(2- ethoxypyridin-3-yl)-2-fluorobenzamide; 1-185: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methyl-2-(trifluoromethyl)pyridin-3-carbonyl]piperazin-1-yl] N-[2-( methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 1-186: 6-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-3 -(2ethoxypyridin-3- yl)-2-fluorobenzamide; 1-187: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1yl]-N-[2-(methylamino )ethyl]-[2,3'-bipyridine]-6-carboxamide; 1-188: 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[(4,5dihydro-1Nimidazol-2-yl)methyl ]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 1-189: 6-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3 yl)-2-fluoro-N -[(3R)-pyrrolidin-3-yl]benzamide; 1-190: 6-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-3-(2-ethoxypyridin-3 yl)-2-fluoro- N-[(3R)-pyrrolidin-3-yl]benzamide; 1-191: N-[2-(dimethylamino)ethyl]-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-{2[ethyl(methyl)amino]- 4-fluorobenzoyl}piperazin-1-yl]benzamide; 1-194: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-2'-ethyl-N-[2(methylamino)ethyl]- [2,3'-bipyridine]-6-carboxamide; 1-195: 5-[(2R)-4-(2-chloro-4-ethoxybenzoyl)-2-ethylpiperazin-1 -yl]-2'-ethoxy-N-[2(methylamino)ethyl]-[2, 3'-bipyridine]-6-carboxamide; 1-196: 5-[(2R)-4-(2-chloro-4-ethoxybenzoyl)-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-2'ethoxy-[2, 3'-bipyridine]-6-carboxamide; 1-197: 6-[(2R)-4-{4-chloro-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]benzoyl}-2-ethylpiperazin-1 yl]-3- (2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide; 1-198: N-(azetidin-3 -yl)-6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-3-(2ethoxypyridin- 3-yl)-2-fluorobenzamide; 1-199: 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-3-(2-ethoxypyridin-3 yl)-2-fluoro- N-[(3R)-1-methylpyrrolidin-3-yl]benzamide; 1 -200: 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-3-(2-ethoxypyridin-3 yl)-2-fluoro- N-[(3S)-pyrrolidin-3-yl]benzamide; 1 -201: 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-3-(2-ethoxypyridin-3 yl)-2-fluoro- N-[(3S)-1-methylpyrrolidin-3-yl]benzamide; 1-202: N-(azetidin-3-yl)-3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-methoxy-2(trifluoromethyl)benzoyl] piperazin-1-yl]-2-fluorobenzamide; 1-203: 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-methoxy-2(trifluoromethyl)benzoyl]piperazin1-yl]-2-fluoro-N -(1-methylazetidin-3-yl)benzamide; 1 -204: 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-3-(2-ethoxypyridin-3 yl)-2-fluoro- N-(1-methylazetidin-3-yl)benzamide; 1 -205: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2(dimethylamino)ethyl]-2'-ethyl- [2,3'-bipyridine]-6-carboxamide; 1-206: 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N[(3R)-1 -methylpyrrolidin-3-yl]pyridin-2-carboxamide; 1-207: N-[2-(dimethylamino)ethyl]-2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3carbonyl]-2-ethylpiperazine-1 - yl]-[2,3'-bipyridine]-6-carboxamide; 1-208: 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[2(methylamino) ethyl]pyridine-2-carboxamide; 1-209: 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N[(3R)-pyrrolidine -3-yl]pyridin-2-carboxamide; 1-210: 5-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-N-[2- 88 045243 (dimethylamino)ethyl]-2' -ethoxy-[2,3'-bipyridine]-6-carboxamide; 1-211: N-(azetidin-3-yl)-5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'ethoxy-[ 2,3'-bipyridine]-6-carboxamide; 1-212: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-(1methylazetidin-3-yl)- [2,3'-bipyridine]-6-carboxamide; 1-213: 5-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-2'-ethoxy-N-[2(methylamino)ethyl]- [2,3'-bipyridine]-6-carboxamide; 1-214: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3S)pyrrolidin-3- yl]-[2,3'-bipyridine]-6-carboxamide; 1-215: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-2'-ethoxy-N-[(3 S)-1 methylpyrrolidine -3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-216: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-5-(2-ethoxypyridin-3 yl)-N-( 1 -methylazetidin-3-yl)benzamide; 1-218: 5-[(2R)-4-(2-chloro-4-cyclopropoxybenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[2(methylamino)ethyl]-[2, 3'-bipyridine]-6-carboxamide; 1-219: 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2(4,5-dihydro-1Nimidazol-2- yl)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide; 1 -220: N-(azetidin-3 -yl)-3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-6-(2ethoxyphenyl) pyridine-2-carboxamide; 1 -221: 3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-6-(2-ethoxyphenyl)-N-(1 methylazetidine-3 -yl)pyridin-2-carboxamide; 1-222: N-[(azetidin-3-yl)methyl]-5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1yl]-2'-ethoxy -[2,3'-bipyridine]-6-carboxamide; 1-223: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(1methylazetidin-3-yl) methyl]-[2,3'-bipyridine]-6-carboxamide; 1-224: 2'-ethoxy-5-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-N-[2-(1Himidazol-2 -yl)ethyl]-[2,3'-bipyridine]-6-carboxamide; 1-225: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-(ethylamino)-2-(trifluoromethyl)pyridin-3-carbonyl]piperazin1 -yl]-N-[2- (methylamino)ethyl]-[2,3'-bipyridine]-6-carboxamide; 1-226: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[(4,5-dihydro-1Himidazol-2-yl )methyl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxamide; 1-227: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(1-methyl4,5- dihydro-1H-imidazol-2-yl)methyl]-[2,3'-bipyridine]-6-carboxamide; 1 -228: 2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-5-(2-ethoxypyridin-3yl)-N-{[( 2R)-1-methylazetidin-2-yl]methyl}benzamide; 1 -229: 6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-3-(2-ethoxypyridin-3 yl)-2-fluoro- N-{[(2S)-1-methylazetidin-2-yl]methyl}benzamide; 1-230: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1yl]-N-(1-methylazetidin- 3-yl)-[2,3'-bipyridine]-6-carboxamide; 1-231: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-{[(2R)-1methylazetidin- 2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 1-232: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-{[(2S)-1methylazetidin- 2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 1-233: 2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridin-3-carbonyl]-2-ethylpiperazin-1-yl]N-(1-methylazetidin- 3-yl)-[2,3'-bipyridine]-6-carboxamide; 1-234: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[2-(1-methyl1H -imidazol-2-yl)ethyl]-[2,3'-bipyridine]-6-carboxamide; 1-235: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopropanecarbonyl]piperazin-1-yl]-N-(1methylazetidin-3-yl)-[2, 3'-bipyridine]-6-carboxamide; 1-236: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridin-3carbonyl]piperazin-1-yl]-N-(1 -methylazetidin-3-yl)pyridin-2-carboxamide; 1-237: 3-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridin-3-carbonyl]-2-ethylpiperazin-1-yl]-6-(2ethoxyphenyl)-N-(1 - methylazetidin-3-yl)pyridin-2-carboxamide; 1-239: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1yl]-N-[(3R)- 1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1 -240: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridin-3-carbonyl]piperazin-1 yl]-N-[(3R) -pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1 -241: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-(1methylazetidin-3-yl)-[2, 3'-bipyridine]-6-carboxamide; 1 -242: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridin-3-carbonyl]piperazin-1 yl]-N-[(1- methylazetidin-3-yl)methyl]-[2,3'-bipyridine]-6-carboxamide; 1 -243: 2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridin-3-carbonyl]-2-ethylpiperazin-1-yl] - 89 045243 N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-244: N-{[(2S)-azetidin-2-yl]methyl}-2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2(trifluoromethyl)pyridin- 3-carbonyl]piperazin-1-yl]-[2,3'-bipyridine]-6-carboxamide; 1-245: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1yl]-N-{[(2S) -1-methylazetidin-2-yl]methyl}-[2,3'bipyridine]-6-carboxamide; 1-246: 5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-2'MemoKcu-N-(1-methylazetidine -3-yl)-[2,3'-bipyridine]-6-carboxamide; 1-247: 5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridin-3-carbonyl]-2-ethylpiperazin-1-yl]-2'MemoKcu-N-( 1-methylazetidine- 3-yl)-[2,3'-bipyridine]-6-carboxamide; 1 -248: 5-[(2R)-4-[1 -(2,2-difluoroethyl)cyclobutanecarbonyl]-2-ethylpiperazin-1 -yl]-2'-ethoxy-N-(1methylazetidin-3-yl)- [2,3'-bipyridine]-6-carboxamide; 1 -249: 2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1 -yl] N-[(1-methylazetidine -3-yl)methyl]-[2,3'-bipyridine]-6-carboxamide; 1-250: 2'-ethoxy-5-[(2R)-2-ethyl-4-(1-ethylcyclobutanecarbonyl)piperazin-1-yl]-N-[2(methylamino)ethyl]-[2,3'- bipyridine]-6-carboxamide; 1-251: 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[cis-4(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-2-fluoro-N -[2-(methylamino)ethyl]benzamide; 1-252: 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[trans-4(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-2-fluoro-N -[2-(methylamino)ethyl]benzamide; 1-253: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridin-3carbonyl]piperazin-1-yl]-N-[( 3R)-1-methylpyrrolidin-3-yl]pyridin-2carboxamide; 1-254: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridin-3carbonyl]piperazin-1-yl]-N-[( 3R)-pyrrolidin-3-yl]pyridin-2-carboxamide; 1-255: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)1-methylpyrrolidin-3-yl ] -[2,3'-bipyridine]-6-carboxamide; 1-256: N-{[(2S)-azetidin-2-yl]methyl}-2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridin-3carbonyl] - 2-ethylpiperazin-1-yl]-[2,3'-bipyridine]-6-carboxamide; 1-257: 2'-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridin-3-carbonyl]-2-ethylpiperazin-1-yl]N-{[(2S) -1-methylazetidin-2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 1-258: 2'-ethoxy-5-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-N-[(3R)-1methylpyrrolidin- 3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-259: 5-[(2R)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1-methylpyrrolidin3-yl]-[ 2,3'-bipyridine]-6-carboxamide; 1-260: 5-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1methylpyrrolidin-3-yl] -[2,3'-bipyridine]-6-carboxamide; 1-261: 5-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1methylpyrrolidin-3-yl] -[2,3'-bipyridine]-6-carboxamide; 1-262: 5-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'ethoxy-N-[(3R)-1methylpyrrolidin-3- yl]-[2,3'-bipyridine]-6-carboxamide; 1-263: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)pyrrolidin-3-yl][ 2,3'-bipyridine]-6-carboxamide; 1-264: 2'-ethoxy-5-[(2R)-2-ethyl-4-(1-ethylcyclopentanecarbonyl)piperazin-1-yl]-N-[2(methylamino)ethyl]-[2,3'- bipyridine]-6-carboxamide; 1-265: 5-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'ethoxy-N-[(3R)pyrrolidin-3-yl ]-[2,3'-bipyridine]-6-carboxamide; 1-266: 2'-ethoxy-5-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-N-[(3R)pyrrolidine-3 -yl]-[2,3'-bipyridine]-6-carboxamide; 1-267: 5-[(2R)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)pyrrolidin-3-yl][2, 3'-bipyridine]-6-carboxamide; 1-270: 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridin-3carbonyl]piperazin-1 -yl] - 2-fluoro-N-[(3R)-1-methylpyrrolidin-3-yl]benzamide; 1-271: 3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridin-3carbonyl]piperazin-1 -yl] - 2-fluoro-N-[(3R)-pyrrolidin-3-yl]benzamide; 1-273: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-N-[(3R)pyrrolidin-3-yl]- [2,3'-bipyridine]-6-carboxamide; 1 -275: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1 -yl]-2'-ethoxy-N-[(3S,4R)- 4fluoropyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-276: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R,4R)-4fluoropyrrolidine -3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-277: 5-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)pyrrolidin-3yl]-[2 ,3'-bipyridine]-6-carboxamide; 1-278: 5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)- 90 045243 pyrrolidin- 3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-279: 5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)-1methylpyrrolidin-3- yl]-[2,3'-bipyridine]-6-carboxamide; 1-280: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3R)pyrrolidin-3-yl]- [2,3'-bipyridine]-6-carboxamide; 1-283: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3R)1-methylpyrrolidin-3-yl ] -[2,3'-bipyridine]-6-carboxamide; 1-286: 2'-ethoxy-5-[(2R)-2-ethyl-4-[cis-4-(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-N[(3R)-1-methylpyrrolidine-3 -yl]-[2,3'-bipyridine]-6-carboxamide; 1-287: 3-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N[(3R)-1 -methylpyrrolidin-3-yl]pyridin-2-carboxamide; 1-288: 3-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N[(3R)-pyrrolidine -3-yl]pyridin-2-carboxamide; 1-289: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1yl]-N-[(3R,4R )-4-fluoropyrrolidin-3-yl]-[2,3'-bipyridine]-6carboxamide; 1-290: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1yl]-N-[(3R,4R )-4-fluoro-1-methylpyrrolidin-3-yl]-[2,3'bipyridine]-6-carboxamide; 1-291: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1yl]-N-[(3S,4R )-4-fluoropyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-292: 3-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N[(3R)-pyrrolidin- 3-yl]pyridin-2-carboxamide; 1-293: 3-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N[(3R)-1 - methylpyrrolidin-3-yl] pyridin-2-carboxamide; 1-295: 5-[(2R)-4-[1-(difluoromethyl)-3,3-difluorocyclobutanecarbonyl]-2-ethylpiperazin-1-yl]-2'ethoxy-N-[(3R)-pyrrolidine-3 -yl]-[2,3'-bipyridine]-6-carboxamide; 1-296: 2'-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1yl]-N-[(3S,4R )-4-fluoro-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-298: 5-[(2R)-4-[3,3-difluoro-1-(trifluoromethyl)cyclobutanecarbonyl]-2-ethylpiperazin-1-yl]-2'ethoxy-N-[(3R)-pyrrolidin- 3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-299: 2'-ethoxy-5-[(2R)-2-ethyl-4-[cis-4-(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-N[(3R)-pyrrolidin-3-yl ]-[2,3'-bipyridine]-6-carboxamide; 1-300: 2'-ethoxy-5-[(2R)-2-ethyl-4-[cis-3-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N[(3R)-pyrrolidin-3-yl ]-[2,3'-bipyridine]-6-carboxamide; 1-301: 2'-ethoxy-5-[(2R)-2-ethyl-4-[trans-3-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N[(3R)-pyrrolidin-3-yl ]-[2,3'-bipyridine]-6-carboxamide; 1-303: 5-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)pyrrolidin-3-yl][ 2,3'-bipyridine]-6-carboxamide; 1-304: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1yl]-N-[(3R)-pyrrolidin-3-yl ]pyridine-2-carboxamide; 1-305: 3-[(2R)-4-(2-tert-butylpyrrolidine-1-carbonyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)N-[(3R)-pyrrolidin- 3-yl]pyridin-2-carboxamide; 1-306: 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidin-1-carbonyl]piperazin-1-yl]N-[(3R) -pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-307: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)1-[(5-methyl -2-oxo-2H-1,3-dioxol4-yl)methyl]pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-310: 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2R)-2-(trifluoromethyl)pyrrolidin-1-carbonyl]piperazin-1-yl]N-[(3R) -pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-313: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(1methylazetidin-3-yl)methyl]- [2,3'-bipyridine]-6-carboxamide; 1-315: 3-[(2R)-4-[(2S)-2-tert-butylpyrrolidine-1-carbonyl]-2-ethylpiperazin-1-yl]-6-(2methoxyphenyl)-N-[(3R) -pyrrolidin-3-yl]pyridin-2-carboxamide; 1-316: 3-[(2R)-4-[(2R)-2-tert-butylpyrrolidine-1-carbonyl]-2-ethylpiperazin-1-yl]-6-(2methoxyphenyl)-N-[(3R) -pyrrolidin-3-yl]pyridin-2-carboxamide; 1-318: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3fluoroazetidin-3-yl)methyl]- [2,3'-bipyridine]-6-carboxamide; 1-319: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3fluoro-1-methylazetidin-3 -yl )methyl]-[2,3'-bipyridine]-6-carboxamide; 1-320: 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(2-fluoropropan-2-yl)pyrrolidin-1-carbonyl]piperazin-1yl]-N -[(3R)-pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-321: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3S)pyrrolidin-3-yl]- [2,3'-bipyridine]-6-carboxamide; 1-322: 2'-ethoxy-5-[(2R)-2-ethyl-4-[cis-4-(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-N- 91 045243 [(1-methylazetidin-3-yl)methyl]-[2,3'-bipyridine]-6-carboxamide; 1-323: 5-[(2R)-4-(2,2-diethylpyrrolidin-1-carbonyl)-2-ethylpiperazin-1-yl]-2'ethoxy-N-[(3R)pyrrolidin-3-yl] -[2,3'-bipyridine]-6-carboxamide; 1-324: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N{[(2R)-pyrrolidin-2-yl] methyl}-[2,3'-bipyridine]-6-carboxamide; 1-325: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N {[(2S)-pyrrolidin-2-yl] methyl}-[2,3'-bipyridine]-6-carboxamide; 1-326: 2'-ethoxy-5-[(2R)-2-ethyl-4-[2-methyl-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1yl]-N-[(3R)- pyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-327: N-{[(2R)-azetidin-2-yl]methyl}-2'-ethoxy-5-[(2R)-2-ethyl-4-[1(trifluoromethyl)cyclopentanecarbonyl]piperazine-1- yl]-[2,3'-bipyridine]-6-carboxamide; 1-328: 5-[(2R)-4-[1-(2,2-difluoroethyl)cyclobutanecarbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)pyrrolidine-3- yl]-[2,3'-bipyridine]-6-carboxamide; 1-329: N-{[(2S)-azetidin-2-yl]methyl}-2'-ethoxy-5-[(2R)-2-ethyl-4-[1(trifluoromethyl)cyclopentanecarbonyl]piperazine-1- yl]-[2,3'-bipyridine]-6-carboxamide; 1-330: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N{[(2R)-1-methylazetidin-2- yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 1-331: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N{[(2S)-1-methylazetidin-2- yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 1-332: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N{[(2S)-1-methylpyrrolidin-2- yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 1-333: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N {[(2R)-1-methylpyrrolidin-2- yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 1-334: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3methoxy-1-methylazetidin-3 -yl )methyl]-[2,3'-bipyridine]-6-carboxamide; 1-335: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[cis-4-(trifluoromethyl)cyclohexanecarbonyl]piperazin1-yl]-N-[(3R)-pyrrolidine-3 -yl]pyridine-2-carboxamide; 1-336: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[cis-4-(trifluoromethyl)cyclohexanecarbonyl]piperazin1-yl]-N-[(3R)-1-methylpyrrolidine -3-yl]pyridin-2-carboxamide; 1-337: N-[2-(azetidin-1-yl)ethyl]-2'-ethoxy-5-[(2R)-2-ethyl-4-[1(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl] -[2,3'-bipyridine]-6-carboxamide; 1-340: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1yl]-N-[(1-methylazetidin-3-yl) methyl]pyridine-2-carboxamide; 1-341: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1 yl]-N-[(3R)-1-methylpyrrolidin- 3-yl]pyridin-2-carboxamide; 1-342: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidin-1carbonyl]piperazin-1-yl]-N-[( 3R)-pyrrolidin-3-yl]pyridin-2-carboxamide; 1-343: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidin-1carbonyl]piperazin-1-yl]-N-[( 3S)-pyrrolidin-3-yl]pyridin-2-carboxamide; 1-344: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]N-[(3R)-1-methylpyrrolidin- 3-yl]pyridin-2-carboxamide; 1-349: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1 -(2,2,2-trifluoroethyl)cyclobutanecarbonyl]piperazin-1 yl]-N-[(3R )-1-methylpyrrolidin-3-yl]pyridin-2-carboxamide; 1-355: 3-[(2R)-4-[(2S)-2-tert-butylpyrrolidine-1-carbonyl]-2-ethylpiperazin-1-yl]-6-(2ethoxyphenyl)-N-[(3R) -pyrrolidin-3-yl]pyridin-2-carboxamide; 1-356: 3-[(2R)-4-[(2R)-2-tert-butylpyrrolidine-1-carbonyl]-2-ethylpiperazin-1-yl]-6-(2ethoxyphenyl)-N-[(3R) -pyrrolidin-3-yl]pyridin-2-carboxamide; 1-357: 5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2'ethoxy-N-[2-(3fluoroazetidin-1 -yl) )ethyl]-[2,3'-bipyridine]-6-carboxamide; 1-359: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1 -(2,2,2-trifluoroethyl)cyclopentanecarbonyl]piperazin-1 -yl]-N [(3R)-1 -methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-362: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidin-1carbonyl]piperazin-1-yl]-N-[( 1-methylazetidin-3-yl)methyl]pyridine-2-carboxamide; 1-363: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3S)1-methylpyrrolidin-3-yl ] -[2,3'-bipyridine]-6-carboxamide; 1-364: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobuganecarbonyl]piperazin-1-yl]-N-[(3S)1-methylpyrrolidin-3-yl ] -[2,3'-bipyridine]-6-carboxamide; 1-372: 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidin-1-carbonyl]piperazin-1-yl]N-[(3R) -1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-373: 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidin-1-carbonyl]piperazin-1-yl]N-[(3S) -1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-374: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidin-1-92 045243 carbonyl]piperazin-1-yl]- N-[(3R)-1-methylpyrrolidin-3-yl]pyridin-2-carboxamide; 1-375: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidin-1carbonyl]piperazin-1-yl]-N-[( 3S)-1-methylpyrrolidin-3-yl]pyridin-2-carboxamide; 1-386: 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidin-1-carbonyl]piperazin-1-yl]N-{[(2R )-1-methylazetidin-2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 1-387: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidin-1carbonyl]piperazin-1-yl]-N-{[ (2S)-1-methylazetidin-2-yl]methyl}pyridine-2-carboxamide; 1-390: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-{[(2S)1-methylazetidin-2- yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 1-391: 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidin-1-carbonyl]piperazin-1-yl]N-{[(2S )-1-methylazetidin-2-yl]methyl}-[2,3'-bipyridine]-6-carboxamide; 1-398: N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2ethylpiperazin- 1-yl]-2'-ethoxy-[2,3'-bipyridine]-6-carboxamide; 1-399: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1yl]-N-(1-methylazetidin-3-yl)pyridine -2-carboxamide; 1-400: N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-2'-ethoxy-5-[(2R)-2-ethyl-4-[1(trifluoromethyl)cyclopentanecarbonyl ]piperazin-1-yl]-[2,3'-bipyridine]-6-carboxamide; 1 -401: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1 yl]-N-[(3S)-1-methylpyrrolidin- 3-yl]pyridin-2-carboxamide; 1-405: N-{1-azabicyclo[2.2.1]heptan-4-yl}-2'-ethoxy-5-[(2R)-2-ethyl-4-[1(trifluoromethyl)cyclopentanecarbonyl]piperazine-1 -yl]-[2,3'-bipyridine]-6-carboxamide; 1-410: N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1( trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide; 1-411: N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-2'-ethoxy-5-[(2R)-2-ethyl-4-[1(trifluoromethyl)cyclobutanecarbonyl ]piperazin-1-yl]-[2,3'-bipyridine]-6-carboxamide; 1-412: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(2-fluoropropan-2-yl)pyrrolidin1carbonyl]piperazin-1-yl]- N-[(3R)-1-methylpyrrolidin-3-yl]pyridin-2-carboxamide; 1-413: 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(2-fluoropropan-2-yl)pyrrolidin-1-carbonyl]piperazin-1yl]-N -[(3R)-1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-415: 2'-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(1methyl-4,5-dihydro-1 N-imidazol-2-yl)methyl]-[2,3'-bipyridine]-6-carboxamide; 1-416: 5-[(2R)-4-[1-(difluoromethyl)cyclopentanecarbonyl]-2-ethylpiperazin-1-yl]-2'-ethoxy-N-[(3R)1-methylpyrrolidin-3-yl] -[2,3'-bipyridine]-6-carboxamide; 1-417: 3-[(2R)-4-[1-(difluoromethyl)cyclopentanecarbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)N-[(3R)-1-methylpyrrolidin-3 -yl]pyridine-2-carboxamide; 1-427: 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)piperidin-1-carbonyl]piperazin-1-yl]-N[(3R) -1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-433: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)piperidin-1carbonyl]piperazin-1-yl]-N-[( 3R)-1-methylpyrrolidin-3-yl]pyridin-2-carboxamide; 1-434: 2'-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)piperidin-1-carbonyl]piperazin-1-yl]-N[(3S) -1-methylpyrrolidin-3-yl]-[2,3'-bipyridine]-6-carboxamide; 1-435: 6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)piperidin-1carbonyl]piperazin-1-yl]-N-[( 3S)-1-methylpyrrolidin-3-yl]pyridin-2-carboxamide; 2-21: {[5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1yl]phenyl]methyl }[2-(methylamino)ethyl]amine; or a pharmaceutically acceptable salt thereof. 18. The connection according to claim 1, wherein the connection is: - 93 045243 or a pharmaceutically acceptable salt thereof. 19. A compound according to claim 1, wherein the compound has the following structure: - 94 045243 or a pharmaceutically acceptable salt thereof. 20. A compound according to claim 1, wherein the compound has the following structure: or a pharmaceutically acceptable salt thereof. 21. Connection by π. 1, and the connection has the following structure: or a pharmaceutically acceptable salt thereof. 22. A compound according to claim 1, wherein the compound has the following structure: or a pharmaceutically acceptable salt thereof. 23. A pharmaceutical composition containing a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable auxiliary agent. 24. A method of treating a disease or condition in a mammal for which modulation of the activity of the melanocortin subtype 2 receptor (MC2R) would be effective, comprising administering a compound according to any one of claims. 1-22 or a pharmaceutically acceptable salt thereof to a mammal in need thereof. 25. The method of claim 24, wherein the disease or condition is increased fat deposits in the collarbone, back of the neck, face and torso, excessive sweating, dilated capillaries, thinning skin, muscle weakness, hirsutism, depression/anxiety, hypertension, osteoporosis , insulin resistance, hyperglycemia and heart disease. 26. The method of claim 24, wherein the disease is Cushing's syndrome, Cushing's disease, ectopic ACTH syndrome, or congenital adrenal hyperplasia (CAH).