CYCLOPROPYLAMINES AS LSD1 INHIBITORS

• US 20190211014A1
• Filed: 11/19/2018
• Published: 07/11/2019
• 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, Courter, Joel R., He, Chunhong, Qian, Ding-Quan, Shen, Bo, Wang, Xiaozhao, Yao, Wenqing, Zhang, Fenglei
• Granted Patent: US 10,717,737 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/397 having four-membered rings, e.g. azetidine
• CPC Class Codes: A61K 31/435 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/4468 having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
• CPC Class Codes: A61K 31/4523 containing further heterocyclic ring systems
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• 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: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 Antianaemics
• 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 211/14 with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 211/16 with acylated ring nitrogen atom
• CPC Class Codes: C07D 211/32 by oxygen atoms
• 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 211/58 : attached in position 4
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/10 : Spiro-condensed systems

Abstract

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

Claims

1-67. -67. (canceled)

68. A method of treating a disease, wherein said disease is selected from hematological cancer, sarcoma, liver cancer, lung cancer, nervous system cancer, breast cancer, ovarian cancer, head and neck cancer, myelofibrosis, gastrointestinal cancer, genitourinary tract cancer, skin cancer and thyroid cancer, comprising administering to a patient a therapeutically effective amount of a compound selected from:

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

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

1-{[4-({[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino}methyl)-4-(methoxymethyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid, or

1-{[4-(ethoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl)cyclobutanecarboxylic acid,

or a pharmaceutically acceptable salt thereof.

69. The method of claim 68, wherein the 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.

70. The method of claim 68, wherein the hematological cancer is acute myelogenous leukemia (AML).

71. The method of claim 68, wherein the sarcoma is selected from chondrosarcoma, Ewing'"'"'s sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, harmatoma, and teratoma.

72. The method of claim 68, wherein the lung cancer is selected from non-small cell lung cancer, bronchogenic carcinoma, alveolar carcinoma, bronchial adenoma, chondromatous hamartoma, and mesothelioma.

73. The method of claim 68, wherein the lung cancer is selected from squamous cell carcinoma, undifferentiated large cell carcinoma, and adenocarcinoma.

74. The method of claim 68, wherein the lung cancer is undifferentiated small cell lung cancer.

75. The method of claim 68, wherein the liver cancer is selected from hepatoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

76. The method of claim 75, wherein the liver cancer is hepatocellular carcinoma.

77. The method of claim 68, wherein the nervous system cancer is selected from cancers of the skull, meninges, brain, spinal cord, neuroblastoma and Lhermitte-Duclos disease.

78. The method of claim 77, wherein the nervous system cancer is neuroblastoma.

79. The method of claim 77, wherein the nervous system cancer is glioblastoma.

80. The method of claim 68, wherein the disease is breast cancer.

81. The method of claim 68, wherein the disease is ovarian cancer.

82. The method of claim 68, wherein the disease is head and neck cancer.

83. The method of claim 68, wherein the disease is myelofibrosis.

84. The method of claim 68, wherein the gastrointestinal cancer is selected from cancers of the esophagus, pancreas, small bowel, large bowel, and colorectal cancer.

85. The method of claim 84, wherein the gastrointestinal cancer is colorectal cancer.

86. The method of claim 84, wherein the gastrointestinal cancer is a cancer of the esophagus selected from squamous cell carcinoma, adenocarcinoma, leiomyosarcoma and lymphoma.

87. The method of claim 84, wherein the gastrointestinal cancer is a cancer of the small bowel selected from adenocarcinoma, lymphoma, carcinoid tumors, Kaposi'"'"'s sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma and fibroma.

88. The method of claim 68, wherein the genitourinary tract cancer is selected from cancers of the kidney, bladder and urethra, prostate, and testis.

89. The method of claim 88, wherein the genitourinary tract cancer is a cancer of the bladder and urethra selected from squamous cell carcinoma, transitional cell carcinoma and adenocarcinoma.

90. The method of claim 88, wherein the genitourinary tract cancer is a cancer of the prostate selected from adenocarcinoma and sarcoma.

91. The method of claim 68, wherein the skin cancer is selected from melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi'"'"'s sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids.

92. The method of claim 91, wherein the skin cancer is melanoma.

93. The method of claim 68, wherein the disease is thyroid cancer.

94. The method of claim 68, wherein the compound is 1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopentanecarboxylic acid, or a pharmaceutically acceptable salt thereof.

95. The method of claim 68, wherein the compound is 1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid, or a pharmaceutically acceptable salt thereof.

96. The method of claim 68, wherein the compound is 1-{[4-({[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino}methyl)-4-(methoxymethyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid, or a pharmaceutically acceptable salt thereof.

97. The method of claim 68, wherein the compound is 1-{[4-(ethoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid, or a pharmaceutically acceptable salt thereof.