CYCLOPROPYLAMINES AS LSD1 INHIBITORS

• US 20170158633A1
• Filed: 11/18/2016
• Published: 06/08/2017
• Est. Priority Date: 02/13/2014
• Status: Active Grant

• Current Assignee: Incyte Corporation, Incyte Holdings Corporation (Incyte Corporation)
• Original Assignee: Incyte Corporation
• Inventors: Wu, Liangxing, Qian, Ding-Quan, Yao, Wenqing, Shen, Bo, He, Chunhong
• Granted Patent: US 10,513,493 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/397 having four-membered rings, e.g. azetidine
• CPC Class Codes: A61K 31/4427 containing further heterocyclic ring systems
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 205/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 211/34 with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C12N 9/0022 with oxygen as acceptor (1.4.3)
• CPC Class Codes: C12Y 104/03004 Monoamine oxidase (1.4.3.4)

Abstract

The present invention is directed to cyclopropylamine derivatives which are LSD1 inhibitors useful in the treatment of diseases such as cancer.

Claims

1-37. -37. (canceled)

38. A method of treating a disease comprising administering to a patient a therapeutically effective amount of a compound of Formula I,

39. The method of claim 38 wherein said cancer is a hematological cancer.

40. The method of claim 39 wherein said hematological cancer is selected from acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma, Hodgkin lymphoma, primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasia syndrome (MDS), or multiple myeloma.

41. The method of claim 38 wherein said cancer is a sarcoma, lung cancer, gastrointestinal cancer, genitourinary tract cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, or skin cancer.

42. A method of treating a disease comprising administering to a patient a therapeutically effective amount of a compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein said disease is a viral disease or a beta-globinopathy.

43. The method of claim 38, wherein ring B is monocyclic 4-7 membered heterocycloalkyl having carbon and 1, 2, or 3 heteroatoms selected from N, O, and S.

44. The method of claim 38, where the compound is a compound having Formula II:

45. The method of claim 38, wherein the compound is a compound having Formula IIIa or IIIb:

46. The method of claim 45, wherein the compound is a compound having Formula IVa or IVb:

47. The method of claim 38, wherein the compound is a compound having Formula Va or Vb:

48. The method of claim 38, wherein q is 0.

49. The method of claim 38, wherein q is 1.

50. The method of claim 38, wherein ring A is phenyl.

51. The method of claim 38, wherein n is 0.

52. The method of claim 38, wherein both R⁵ and R⁶ are H.

53. The method of claim 38, wherein ring C is phenyl.

54. The method of claim 38, wherein ring C is monocyclic 5-6 membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S.

55. The method of claim 38, wherein ring C is phenyl, pyridyl, piperazinyl, pyrazinyl, pyrimidinyl, or pyrazolyl.

56. The method of claim 38, wherein ring C is phenyl, pyridyl, piperazinyl, pyrazinyl, or pyrazolyl.

57. The method of claim 38, wherein R⁴ is C_1-6 alkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, 4-10 membered heterocycloalkyl, CN, NR^c3R^d3, C(O)OR^a3, or C(O)NR^c3R^d3, wherein said C_1-6 alkyl, C_3-10 cycloalkyl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, C(═

NR^e3)NR^c3R^d3, NR^c3C(═

NR^e3)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3.

58. The method of claim 38, wherein R⁴ is C_1-6 alkyl, C_1-6 haloalkyl, 4-10 membered heterocycloalkyl, CN, or C(O)NR^c3R^d3, wherein said C_1-6 alkyl and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, C(═

NR^e3)NR^c3R^d3, NR^c3C(═

NR^e3)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3.

59. The method of claim 38, wherein each R³ is independently selected from halo, C_1-6 alkyl, C_1-6 haloalkyl, CN, OR^a2, and C(O)NR^c2R^d2, wherein said C_1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 cyanoalkyl, CN, NO₂, OR^a2, SR^a, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, C(═

NR^e2)NR^c2R^d2, NR^c2C(═

NR^e2)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2 NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2.

60. The method of claim 38, wherein each R³ is independently selected from halo, C_1-6 alkyl, C_1-6 haloalkyl, CN, OR^a2, and C(O)NR^c2R^d2.

61. The method of claim 38, wherein p is 0.

62. The method of claim 38, wherein p is 1.

63. The method of claim 38, wherein p is 2.

64. The method of claim 38, wherein m is 0.

65. The method of claim 38, wherein m is 1.

66. The method of claim 38, wherein R^z is C_1-4 alkyl or C_6-10 aryl-C_1-4 alkyl-, wherein said C_1-4 alkyl and C_6-10 aryl-C_1-4 alkyl- are each optionally substituted by halo, CN, or OR^a4.

67. The method of claim 38, wherein R^z is C_1-4 alkyl.

68. The method of claim 38, wherein R^z is C_1-4 alkyl substituted by CN or methoxy.

69. The method of claim 38, wherein R^z is C_6-10 aryl-C_1-4 alkyl-substituted by fluoro.

70. The method of claim 38, wherein R^z is methyl, cyanomethyl, methoxymethyl, or 4-fluorophenylmethyl.

71. The method of claim 38, wherein R^z is C_1-4 alkyl substituted by CN.

72. The method of claim 38, wherein R^z is cyanomethyl.

73. The method of claim 38, wherein R^z is H.

74. The method of claim 38, wherein the compound is a compound having a trans configuration with respect to the di-substituted cyclopropyl group depicted in Formula I.

75. The method of claim 38, wherein the compound is selected from:

3-Fluoro-4-[3-({[trans-2-phenylcyclopropyl]amino}methyl)azetidin-1-yl]benzonitrile;

3,5-Difluoro-4-[3-({[trans-2-phenylcyclopropyl]amino}methyl)azetidin-1-yl]benzonitrile;

2,5-Difluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide;

2-Methyl-6-[3-({[trans-2-phenylcyclopropyl]amino}methyl)azetidin-1-yl]nicotinonitrile;

N-Ethyl-5-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)pyrazine-2-carboxamide;

3,5-Difluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide;

2,6-Difluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide;

2,3-Difluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide;

2-Chloro-5-fluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}-azetidin-1-yl)benzamide;

3-Fluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide;

2-Fluoro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide;

2-Fluoro-N-isopropyl-5-methyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}-azetidin-1-yl)benzamide;

N-Isopropyl-2-methoxy-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide;

3-Chloro-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)benzamide;

5-(3-{[(trans-2-Phenylcyclopropyl)amino]methyl}azetidin-1-yl)-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide;

N-({1-[6-(4-Methylpiperazin-1-yl)pyrimidin-4-yl]azetidin-3-yl}methyl)-trans-2-phenylcyclopropanamine;

trans-N-{[1-(1-Methyl-1H-pyrazol-4-yl)azetidin-3-yl]methyl}-2-phenylcyclopropanamine;

2-Chloro-6-(4-(cyanomethyl)-4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)benzonitrile; and

{4-{[(trans-2-Phenylcyclopropyl)amino]methyl})-1-[3-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}acetonitrile;

or a pharmaceutically acceptable salt of any of the aforementioned.

76. The method of claim 38, wherein the compound is selected from:

6-[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylic acid;

5-[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylic acid;

1-{4-[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]phenyl})cyclopropanecarboxylic acid;

4-[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylic acid;

6-[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylic acid;

5-[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylic acid;

6-[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylic acid;

4-[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxylic acid;

N,N-dimethyl-5-[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxamide;

N-methyl-5-[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]pyridine-2-carboxamide;

2-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)pyrimidin-4-amine;

2-(4-{[(1S,2R)-2-phenylcyclopropyl]amino}piperidin-1-yl)pyrimidin-4-amine;

or a pharmaceutically acceptable salt of any of the aforementioned.