Patent NZ-602313-A (NZ)
Title: Piperidin-4-yl azetidine derivatives as jak1 inhibitors
Inventor: YAO WENQING
IPC: A61K31/397
Filed: 2011-03-09
Abstract: Disclosed are 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidine and 3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidine derivatives of formula (I), wherein X is N or CR2; Y is N or CR3; Z is H, cyano, halo, alkyl, or haloalkyl; L is C(R4)2, C(=O), C(=O)N(R4a), C(=O)C(R4b)2, S(=O)2, C(=O)O, C(=O)OC(R4b)2 or C(=O)N(R4a)C(R4b)2; A is optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R1 is, independently alkyl, hydroxyl, alkoxy, fluoro, hydroxyalkyl, or alkoxyalkyl; or two R1 groups together form a 2- or 3-carbon bridge or a bridge of formula -CH2-O-CH2-; and wherein the remaining substituents are as defined herein. Particularly preferred compounds include: { 1-{ 1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl} -3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl} acetonitrile, propyl 4-{ 3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl} piperidine-1-carboxylate, benzyl 4-{ 3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl} piperidine-1-carboxylate, { 1-(1-{ [6-[(isopropylamino)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl} piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl} acetonitrile, { 1-(1-{ [6-(hydroxymethyl)-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl} piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl} acetonitrile, 2,4-difluorobenzyl 4-{ 3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl} piperidine-1-carboxylate, cyclopentylmethyl 4-{ 3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl} piperidine-1-carboxylate and { 1-{ 1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl} -3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl} acetonitrile. Further disclosed is a composition comprising a compound or salt as defined above and a pharmaceutically acceptable carrier, for modulating an activity of JAK1, and particularly for treating an autoimmune disease (including skin disorders, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, type I diabetes, lupus, inflammatory bowel disease, Crohn’s disease, myasthenia gravis, immunoglobulin nephropathies, myocarditis, or autoimmune thyroid disorder), a cancer (including solid tumor, prostate cancer, renal cancer, hepatic cancer, breast cancer, lung cancer, thyroid cancer, Kaposi’s sarcoma, Castleman’s disease, pancreatic cancer, lymphoma, leukemia, or multiple myeloma), a myeloproliferative disorder (including polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), primary myelofibrosis (PMF), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), idiopathic myelofibrosis (IMF), or systemic mast cell disease (SMCD)), an inflammatory disease, a bone resorption disease (including osteoporosis, osteoarthritis, bone resorption associated with hormonal imbalance, bone resorption associated with hormonal therapy, bone resorption associated with autoimmune disease, or bone resorption associated with cancer), or organ transplant rejection in a patient in need thereof.