AZETIDINYL PHENYL, PYRIDYL OR PYRAZINYL CARBOXAMIDE DERIVATIVES AS JAK INHIBITORS

• US 20170253598A1
• Filed: 02/17/2017
• Published: 09/07/2017
• Est. Priority Date: 06/20/2011
• Status: Active Grant

• Current Assignee: Incyte Corporation, Incyte Holdings Corporation (Incyte Corporation)
• Original Assignee: Incyte Corporation, Incyte Holdings Corporation (Incyte Corporation)
• Inventors: Yao, Wenqing, Burns, David M., Zhuo, Jincong
• Granted Patent: US 10,513,522 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

The present invention provides azetidinyl phenyl, pyridyl, or pyrazinyl carboxamide derivatives, as well as their compositions and methods of use, that modulate the activity of Janus kinase (JAKs) and are useful in the treatment of diseases related to the activity of JAK including, for example, inflammatory disorders, autoimmune disorders, cancer, and other diseases.

Claims

1-49. -49. (canceled)

50. A compound, which is 5-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropylpyrazine-2-carboxamide, or a pharmaceutically acceptable salt thereof.

51. A composition comprising a compound according to claim 50, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

52. A method of inhibiting an activity of JAK1 comprising contacting JAK1 with a compound according to claim 50, or a pharmaceutically acceptable salt thereof.

53. The method according to claim 52, wherein said compound, or pharmaceutically acceptable salt thereof, is selective for JAK1 over JAK2.

54. A method of treating an autoimmune disease, a cancer, a myeloproliferative disorder, an inflammatory disease, a bond resorption disease, or organ transplant rejection in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 50, or a pharmaceutically acceptable salt thereof.

55. The method according to claim 54, wherein the autoimmune disease is a skin disorder.

56. The method according to claim 55, wherein the skin disorder is atopic dermatitis, psoriasis, skin sensitization, skin irritation, skin rash, contact dermatitis or allergic contact sensitization.

57. The method according to claim 54, wherein the autoimmune disease is multiple sclerosis.

58. The method according to claim 54, wherein the autoimmune disease is rheumatoid arthritis, psoriatic arthritis, or juvenile arthritis.

59. The method according to claim 54, wherein the autoimmune disease is type I diabetes.

60. The method according to claim 54, wherein the autoimmune disease is lupus.

61. The method according to claim 54, wherein the autoimmune disease is inflammatory bowel disease.

62. The method according to claim 54, wherein the autoimmune disease is Crohn'"'"'s disease.

63. The method according to claim 54, wherein the autoimmune disease is myasthenia gravis.

64. The method according to claim 54, wherein the autoimmune disease is immunoglobulin nephropathies.

65. The method according to claim 54, wherein the autoimmune disease is myocarditis.

66. The method according to claim 54, wherein the autoimmune disease is autoimmune thyroid disorder.

67. The method according to claim 54, wherein the cancer is a solid tumor.

68. The method according to claim 54, wherein the cancer is prostate cancer, renal cancer, hepatic cancer, breast cancer, lung cancer, thyroid cancer, Kaposi'"'"'s sarcoma, Castleman'"'"'s disease, pancreatic cancer, colorectal cancer, lymphoma, or leukemia.

69. The method according to claim 68, wherein the leukemia is acute myelogenous leukemia.

70. The method according to claim 68, wherein the leukemia is acute lymphoblastic leukemia.

71. The method according to claim 54, wherein the cancer is multiple myeloma.

72. The method according to claim 54, wherein the myeloproliferative disorder is polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), idiopathic myelofibrosis (IMF), or systemic mast cell disease (SMCD).

73. The method according to claim 54, wherein the myeloproliferative disorder is myelofibrosis.

74. The method according to claim 54, wherein the myeloproliferative disorder is post polycythemia vera myelofibrosis (Post-PV MF).

75. The method according to claim 54, wherein the myeloproliferative disorder is post-essential thrombocythemia myelofibrosis (Post-ET MF).

76. The method according to claim 54, wherein the bone resorption disease is osteoporosis, osteoarthritis, bone resorption associated with hormonal imbalance, bone resorption associated with hormone therapy, bone resorption associated with autoimmune disease, or bone resorption associated with cancer.

77. A method of treating allograft rejection in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 50, or a pharmaceutically acceptable salt thereof.

78. A method of treating graft-versus-host disease in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 50, or a pharmaceutically acceptable salt thereof.

79. A method of treating lupus erythematosus, sarcoidosis, cutaneous t-cell lymphoma, mycosis fungoides, ankylosing spondylitis, ulcerative colitis, chronic obstructive pulmonary disease, asthma, rhinitis, sinusitis, or cachexia in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 50, or a pharmaceutically acceptable salt thereof.