TRIAZOLOPYRIDINES AND TRIAZOLOPYRAZINES AS LSD1 INHIBITORS

• US 20190119272A1
• Filed: 09/27/2018
• Published: 04/25/2019
• Est. Priority Date: 07/10/2014
• Status: Abandoned Application

• Current Assignee: Incyte Corporation, Incyte Holdings Corporation (Incyte Corporation)
• Original Assignee: Incyte Corporation
• Inventors: Wu, Liangxing, Wang, Xiaozhao, Yao, Wenqing, Zhang, Colin
• Application Number:
  US16/144,365
• Publication Number:
  US 20190119272A1
• Time in Patent Office: Days
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

The present invention is directed to [1,2,4]triazolo[1,5-a]pyridine and [1,2,4]triazolo[1,5-a]pyrazine derivatives which are LSD1 inhibitors useful in the treatment of diseases such as cancer.

Claims

1-45. -45. (canceled)

46. A method of treating a disease, wherein said disease is selected from leukemia, lung cancer, Ewing'"'"'s sarcoma, prostate cancer, and myelofibrosis, comprising administering to a patient a therapeutically effective amount of a compound of Formula I:

47. The method of claim 46, wherein X is N.

48. The method of claim 46, wherein X is CR^X.

49. The method of claim 46, wherein R¹ is halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, Cy¹, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, S(O)₂R^b1, or S(O)₂NR^c1R^d1;

wherein said C_1-6 alkyl, C_2-6 alkenyl, and C_2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹, halo, CN, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1.

50. The method of claim 46, wherein R¹ is pyrrolidin-3-ylmethoxy, 2-pyrrolidin-3-ylethyl, (1-methylpyrrolidin-3-yl)ethyl, 3-[(methylamino)methyl]phenyl, 3-aminopyrrolidin-1-yl)methyl]phenyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-yl)methyl, 3-(dimethylamino)pyrrolidin-1-yl, 3-(methylamino)pyrrolidin-1-yl, or (1-methylpyrrolidin-3-yl)methoxy.

51. The method of claim 46, wherein each Cy¹ is independently selected from phenyl, C_3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^Cy.

52. The method of claim 46, wherein each Cy¹ is phenyl, pyrrolidinyl, or piperazinyl, each optionally substituted with 1 or 2 substituents independently selected from C_1-4 alkyl and NR^c6R^d6, wherein said C_1-4 alkyl is optionally substituted with NR^c6R^d6.

53. The method of claim 46, wherein R^Cy is C_1-4 alkyl and NR^c6R^d6, wherein said C_1-4 alkyl is optionally substituted with NR^c6R^d6.

54. The method of claim 46, wherein each R^a1 is independently selected from H, C_1-6 alkyl, and Cy⁴;

wherein said C_1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy⁴, halo, CN, OR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, NR^c3R^d3, NR^c3C(O)R^b3, S(O)₂R^b3, and S(O)₂NR^c3R^d3.

55. The method of claim 46, wherein each R^a1 is pyrrolidinylmethyl optionally substituted by 1 C_1-4 alkyl.

56. The method of claim 46, wherein the compound is a compound having Formula IIa:

57. The method of claim 46, wherein the compound is a compound having Formula IIb:

58. The method of claim 46, wherein the compound is a compound having Formula IIIa:

59. The method of claim 46, wherein the compound is a compound having Formula

60. The method of claim 46, wherein the compound is selected from:

4-{5-(4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy][1,2,4]triazolo[1,5-a]pyridin-6-yl}benzonitrile;

4-[5-(4-methylphenyl)-8-(2-pyrrolidin-3-ylethyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile;

4-{5-(4-methylphenyl)-8-[2-(1-methylpyrrolidin-3-yl)ethyl][1,2,4]triazolo[1,5-a]pyridin-6-yl}benzonitrile;

4-[8-{3-[(methylamino)methyl]phenyl)}-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile;

4-[8-{3-[(3-aminopyrrolidin-1-yl)methyl]phenyl}-5-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile;

4-[5-(4-methylphenyl)-8-(piperazin-1-ylmethyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile;

4-{5-(4-methylphenyl)-8-[(4-methylpiperazin-1-yl)methyl][1,2,4]triazolo[1,5-a]pyridin-6-yl}benzonitrile;

4-[8-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]methyl}-5-(4-methylphenyl)-[1,2,4]triazolo-[1,5-a]pyridin-6-yl]benzonitrile;

4-[8-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]methyl}-5-(4-methylphenyl)-[1,2,4]triazolo-[1,5-a]pyridin-6-yl]benzonitrile;

4-[8-{[(3S)-3-(methylamino)pyrrolidin-1-yl]methyl}-5-(4-methylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile;

4-[8-{[(3R)-3-(methylamino)pyrrolidin-1-yl]methyl}-5-(4-methylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]benzonitrile;

4-{5-(4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy][1,2,4]triazolo[1,5-a]pyrazin-6-yl}benzonitrile; and

4-(5-(4-methylphenyl)-8-{[(3R)-1-methylpyrrolidin-3-yl]methoxy}[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile,

or a pharmaceutically acceptable salt of any of the aforementioned.

61. The method of claim 46, wherein said disease is leukemia.

62. The method of claim 61, wherein said leukemia is acute myelogenous leukemia.

63. The method of claim 61, wherein said leukemia is acute lymphoblastic leukemia.

64. The method of claim 61, wherein said leukemia is acute promyelocytic leukemia.

65. The method of claim 61, wherein said leukemia is chronic lymphocytic leukemia.

66. The method of claim 61, wherein said leukemia is chronic myelogenous leukemia.

67. The method of claim 46, wherein said lung cancer is undifferentiated small cell lung cancer.

68. The method of claim 46, wherein said lung cancer is non-small cell lung cancer.

69. The method of claim 46, wherein said lung cancer is bronchogenic carcinoma.

70. The method of claim 46, wherein said lung cancer is alveolar carcinoma.

71. The method of claim 46, wherein said lung cancer is bronchial adenoma.

72. The method of claim 46, wherein said lung cancer is chondromatous hamartoma.

73. The method of claim 46, wherein said lung cancer is mesothelioma.

74. The method of claim 46, wherein said lung cancer is squamous cell carcinoma.

75. The method of claim 46, wherein said lung cancer is undifferentiated large cell lung cancer.

76. The method of claim 46, wherein said lung cancer is adenocarcinoma.

77. The method of claim 46, wherein said disease is Ewing'"'"'s sarcoma.

78. The method of claim 46, wherein said disease is prostate cancer.

79. The method of claim 46, wherein said disease is myelofibrosis.