Aminopyrimidine derivatives as phosphatidylinositol phosphate kinase inhibitors

Abstract

The invention relates to inhibitors of PI5P4K inhibitors useful in the treatment of cancers, neurodegenerative diseases, inflammatory disorders, and metabolic diseases, having the Formula: where A, B, R 1 , X 1 , X 2 , and W are described herein.

1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof,
 wherein: 
 A is aryl; 
 B is heteroaryl, substituted with one or more R 8 , provided that when B is heteroaryl, B is not bonded through its heteroatom; 
 X 1  is C(R 5 ); 
 X 2  is C(R 5 ) or N; 
 W is C(R 6 ); 
 R 1  is —N(R 2 )C(O)R 3 , —C(O)N(R 2 )(R 3 ), —P(O)(R 2 )(R 3 ), or heteroaryl, wherein the heteroaryl is optionally substituted with one or more R 7 ; 
 R 2  is independently, at each occurrence, C 1-6  alkyl; 
 R 3  is independently, at each occurrence, C 1-6  alkyl or C 3-8  cycloalkyl; or 
 R 2  and R 3  when taken together with the atom to which they are each attached form a heterocycle optionally substituted with one or more R 4 ; 
 R 4  is independently —H or C 1-6  alkyl; 
 R 5  is independently —H; 
 R 6  is —H, —N(R 26 )(R 27 ), C 1-6  alkoxy, heterocyclyl, C 1-6  alkenyl, C 1-6  haloalkyl, or C 1-6  alkyl, wherein the alkyl, alkenyl, alkoxy, or heterocyclyl, is optionally substituted with one or more —OH, —CN, C 1-6  alkyl, or heterocyclyl; 
 R 7  is C 1-6  alkyl; 
 R 8  is heterocyclyl, —N(R 9 )(R 10 ), or —OR 10 , wherein the heterocyclyl is optionally substituted with one or more R 15 ; or 
 two R 8  groups, together with the atoms to which they are attached, form a heterocyclyl, optionally substituted with one or more R 15 ; 
 each R 9  or R 10  is independently, at each occurrence, C 1-6  alkyl optionally substituted with one or more R 11 ; 
 R 11  is —OH, heterocyclyl, —C(O)R 17 , or —C(O)N(R 23 )(R 23 ), wherein the heterocyclyl is optionally substituted with one or more R 17 ; 
 R 15  is —N(C 1-6  alkyl) 2 , C 1-6  alkyl, —C(O)N(R 21 )(R 23 ), —(CH 2 ) o —C(O)R 23 , or —C(O)OR 23 , wherein the alkyl, is optionally substituted with one or more R 23 ; or 
 two R 15  groups, together with the atoms to which they are attached, form a heterocyclyl optionally substituted with one or more R 20 ; 
 R 17  is halogen or C 1-6  alkyl; 
 R 20  is independently oxo or C 1-6  alkyl, wherein the C 1-6  alkyl is substituted with heterocyclyl; 
 R 21  is —H or C 1-6  alkyl; 
 each R 23  is independently C 1-6  alkyl, optionally substituted with one or more —N(C 1-6  alkyl) 2 ; or 
 two R 23  together form a heterocyclyl, wherein the heterocyclyl is optionally substituted by C 1-6  alkyl; 
 R 26  is —H or C 1-6  alkyl; 
 R 27  is C 1-6  alkyl, heterocyclyl, or cycloalkyl, wherein the alkyl, heterocyclyl, or cycloalkyl is optionally substituted with one or more halogen, —CN, —C(O)OH, —OH, or —NH 2 ; and 
 each o is independently 0-4, 
 provided that R 8  is not methoxy. 
 
     
     
         2 . The compound of  claim 1  having the Formula (Ia): 
       
         
           
           
               
               
           
         
         wherein X 2  is C(R 5 ) or N and W is C(R 6 ). 
       
     
     
         3 . The compound of  claim 1  having the Formula (Ib): 
       
         
           
           
               
               
           
         
       
       wherein X 2  is C(R 5 ) or N and W is C(R 6 ). 
     
     
         4 . The compound of  claim 1  having the Formula (Ic): 
       
         
           
           
               
               
           
         
         wherein X 2  is C(R 5 ) or N and W is C(R 6 ). 
       
     
     
         5 . The compound of  claim 1  having the Formula (Id): 
       
         
           
           
               
               
           
         
       
       wherein X 2  is C(R 5 ) or N and W is C(R 6 ). 
     
     
         6 . The compound of  claim 1  having the Formula (Ie): 
       
         
           
           
               
               
           
         
       
       wherein X 2  is C(R 5 ) or N and W is C(R 6 ). 
     
     
         7 . The compound of  claim 1  having the Formula (If): 
       
         
           
           
               
               
           
         
       
       wherein X 2  is C(R 5 ) or N and W is C(R 6 ). 
     
     
         8 . The compound of  claim 1  selected from the group consisting of:
 2-[(2-{[(6S)-3-oxo-8-oxa-2,10-diazatricyclo[7.4.0.0 2,6 ]trideca-1(9),10,12-trien-12-yl]amino}-5-[4-(2-oxopyrrolidin-1-yl)phenyl]pyrimidin-4-yl)amino]acetic acid; 
 (6S)-12-[(4-{methyl[(3S)-oxolan-3-yl]amino}-5-[4-(2-oxopyrrolidin-1-yl)phenyl]pyrimidin-2-yl)amino]-8-oxa-2,10-diazatricyclo[7.4.0.0 2,6 ]trideca-1(13),9,11-trien-3-one; 
 (6S)-12-({4-[methyl(oxolan-3-yl)amino]-5-[4-(2-oxopyrrolidin-1-yl)phenyl]pyrimidin-2-yl}amino)-8-oxa-2,10-diazatricyclo[7.4.0.0 2,6 ]trideca-1(13),9,11-trien-3-one; 
 (6S)-12-[(4-{methyl[(1r,3r)-3-hydroxycyclobutyl]amino}-5-[4-(2-oxopyrrolidin-1-yl)phenyl]pyrimidin-2-yl)amino]-8-oxa-2,10-diazatricyclo[7.4.0.0 2,6 ]trideca-1(13),9,11-trien-3-one; 
 2-(dimethylamino)ethyl 7-({4-methoxy-5-[4-(2-oxopyrrolidin-1-yl)phenyl]pyrimidin-2-yl}amino)-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate; 
 (6S)-12-({4-[2-(morpholin-4-yl)ethoxy]-5-[4-(2-oxopyrrolidin-1-yl)phenyl]pyrimidin-2-yl}amino)-8-oxa-2,10-diazatricyclo[7.4.0.0 2,6 ]trideca-1(9),10,12-trien-3-one; 
 (6S)-12-[(4-{methyl[(3R)-oxolan-3-yl]amino}-5-[4-(2-oxopyrrolidin-1-yl)phenyl]pyrimidin-2-yl)amino]-8-oxa-2,10-diazatricyclo[7.4.0.0 2,6 ]trideca-1(13),9,11-trien-3-one; 
 (6S)-12-({5-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]-4-(prop-1-en-2-yl)pyridin-2-yl}amino)-8-oxa-2,10-diazatricyclo[7.4.0.0 2,6 ]trideca-1(13),9,11-trien-3-one; 
 N-cyclopropyl-4-(4-methoxy-2-{[(6S)-3-oxo-8-oxa-2,10-diazatricyclo[7.4.0.0 2,6 ]trideca-1(9),10,12-trien-12-yl]amino}pyrimidin-5-yl)-N-methylbenzamide; 
 3-methyl-1-(2-{[(6S)-3-oxo-8-oxa-2,10-diazatricyclo[7.4.0.0 2,6 ]trideca-1(13),9,11-trien-12-yl]amino}-5-[4-(2-oxopyrrolidin-1-yl)phenyl]pyrimidin-4-yl)azetidine-3-carbonitrile; 
 12-({4-methoxy-5-[4-(2-oxopyrrolidin-1-yl)phenyl]pyrimidin-2-yl}amino)-4-[2-(morpholin-4-yl)ethyl]-8-oxa-2,4,10-triazatricyclo[7.4.0.0 2,6 ]trideca-1(9),10,12-trien-3-one; 
 1-{4-[2-({2H,3H-[1,4]dioxino[2,3-b]pyridin-7-yl}amino)-4-{methyl[(1r,3r)-3-hydroxycyclobutyl]amino}pyrimidin-5-yl]phenyl}pyrrolidin-2-one; 
 2-(dimethylamino)ethyl 7-({5-[4-(5-methyl-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-2-yl}amino)-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate; 
 (6S)-12-({5-[4-(2-oxopyrrolidin-1-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-yl}amino)-8-oxa-2,10-diazatricyclo[7.4.0.0 2,6 ]trideca-1(9),10,12-trien-3-one; 
 2-(dimethylamino)ethyl 7-({5-[4-(dimethylcarbamoyl)phenyl]-4-methoxypyrimidin-2-yl}amino)-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate; 
 1-{4-[2-({5-[4-(dimethylamino)piperidin-1-yl]pyridin-3-yl}amino)-4-methoxypyrimidin-5-yl]phenyl}pyrrolidin-2-one; 
 N-{5-[4-(dimethylamino)piperidin-1-yl]pyridin-3-yl}-4-methoxy-5-[4-(4-methylpyridazin-3-yl)phenyl]pyrimidin-2-amine; 
 4-[2-({2H,3H-[1,4]dioxino[2,3-b]pyridin-7-yl}amino)-4-{methyl[(1s,3s)-3-hydroxycyclobutyl]amino}pyrimidin-5-yl]-N,N-dimethylbenzamide; 
 1-{4-[2-({1-[2-(dimethylamino)acetyl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}amino)-4-methoxypyrimidin-5-yl]phenyl}pyrrolidin-2-one; 
 2-(dimethylamino)-1-[7-({5-[4-(5-methyl-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-2-yl}amino)-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-1-yl]ethan-1-one; 
 (6S)-12-({5-[3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl]-4-[(3-hydroxyoxetan-3-yl)methyl]pyrimidin-2-yl}amino)-8-oxa-2,10-diazatricyclo[7.4.0.0 2,6 ]trideca-1(9),10,12-trien-3-one; 
 2-(diethylamino)ethyl 7-[(5-{4-[(2R)-2-methyl-5-oxopyrrolidin-1-yl]phenyl}pyrimidin-2-yl)amino]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate; 
 2-(diethylamino)ethyl 7-({5-[4-(2-oxopyrrolidin-1-yl)phenyl]pyrimidin-2-yl}amino)-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate; 
 N-[2-(diethylamino)ethyl]-7-[(4-methoxy-5-{4-[(2R)-2-methyl-5-oxopyrrolidin-1-yl]phenyl}pyrimidin-2-yl)amino]-N-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxamide; 
 N-[2-(diethylamino)ethyl]-N-methyl-7-[(5-{4-[(2R)-2-methyl-5-oxopyrrolidin-1-yl]phenyl}pyrimidin-2-yl)amino]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxamide; 
 1-{4-[2-({1-[2-(diethylamino)ethyl]-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}amino)-4-methoxypyrimidin-5-yl]phenyl}pyrrolidin-2-one; 
 (6S)-12-({5-[4-(dimethylphosphoryl)phenyl]pyridin-2-yl}amino)-8-oxa-2,10-diazatricyclo[7.4.0.0 2,6 ]trideca-1(9),10,12-trien-3-one; 
 2-{4-[5-({4-methoxy-5-[4-(4-methylpyridazin-3-yl)phenyl]pyrimidin-2-yl}amino)pyridin-3-yl]piperazin-1-yl}ethan-1-ol; 
 N-[2-(diethylamino)ethyl]-7-[(5-{4-[(2R)-2-methyl-5-oxopyrrolidin-1-yl]phenyl}pyrimidin-2-yl)amino]-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxamide; 
 1-(4-{2-[(5-{[2-(4-ethylpiperazin-1-yl)-2-oxoethyl](methyl)amino}pyridin-3-yl)amino]-4-methoxypyrimidin-5-yl}phenyl)pyrrolidin-2-one; 
 N3-[2-(3,3-difluoropyrrolidin-1-yl)ethyl]-N5-{4-methoxy-5-[4-(4-methylpyridazin-3-yl)phenyl]pyrimidin-2-yl}-N3-methylpyridine-3,5-diamine; 
 1-(4-{2-[(5-{[2-(4,4-difluoropiperidin-1-yl)ethyl](methyl)amino}pyridin-3-yl)amino]-4-methoxypyrimidin-5-yl}phenyl)pyrrolidin-2-one; 
 1-(4-{2-[(5-{[2-(3,3-difluoropyrrolidin-1-yl)ethyl](methyl)amino}pyridin-3-yl)amino]-4-methoxypyrimidin-5-yl}phenyl)pyrrolidin-2-one; 
 N-{5-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]pyridin-3-yl}-4-methoxy-5-[4-(4-methylpyridazin-3-yl)phenyl]pyrimidin-2-amine; 
 1-{4-[2-({5-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]pyridin-3-yl}amino)-4-methoxypyrimidin-5-yl]phenyl}pyrrolidin-2-one; 
 1-(4-{4-methoxy-2-[(5-{methyl[2-oxo-2-(piperazin-1-yl)ethyl]amino}pyridin-3-yl)amino]pyrimidin-5-yl}phenyl)pyrrolidin-2-one; 
 N-{5-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]pyridin-3-yl}-4-methoxy-5-[4-(4-methylpyridazin-3-yl)phenyl]pyrimidin-2-amine; 
 1-{4-[2-({5-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]pyridin-3-yl}amino)-4-methoxypyrimidin-5-yl]phenyl}pyrrolidin-2-one; 
 1-(4-{4-methoxy-2-[(5-{methyl[3-oxo-3-(piperazin-1-yl)propyl]amino}pyridin-3-yl)amino]pyrimidin-5-yl}phenyl)pyrrolidin-2-one; 
 N-{5-[2-(3,3-difluoropyrrolidin-1-yl)ethoxy]pyridin-3-yl}-4-methoxy-5-[4-(4-methylpyridazin-3-yl)phenyl]pyrimidin-2-amine; and 
 1-{4-[2-({5-[2-(3,3-difluoropyrrolidin-1-yl)ethoxy]pyridin-3-yl}amino)-4-methoxypyrimidin-5-yl]phenyl}pyrrolidin-2-one. 
 
     
     
         9 . A pharmaceutical composition comprising a compound of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         10 . A method of treating a disease or disorder associated with modulation of phosphatidylinositol-5-phosphate-4-kinase (PI5P4K) comprising administering to a patient in need thereof an effective amount of a compound of  claim 1 . 
     
     
         11 . The method of  claim 10 , wherein the disease or disorder associated with modulation of (PI5P4K) is a cancer or cell proliferative disorder, a metabolic disorder, a neurodegenerative disease, or an inflammatory disease. 
     
     
         12 . A method of inhibiting PI5P4K comprising administering to a patient in need thereof an effective amount of a compound of  claim 1 . 
     
     
         13 . A method of treating cancer or a cell proliferative disorder, the method comprising administering to a patient in need thereof an effective amount of a compound of  claim 1 . 
     
     
         14 . The method of  claim 13 , wherein the cancer or cell proliferative disorder is leukemia (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (Hodgkin's disease, non-Hodgkin's disease), Waldenstrom's macroglobulinemia, heavy chain disease, or solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcorna, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendothelioma sarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcorna, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodenroglioma, schwannoma, meningioma, melanoma, neuroblastoma, and retinoblastoma). 
     
     
         15 . A method of treating a neurodegenerative disease comprising administering to a patient in need thereof an effective amount of a compound of  claim 1 . 
     
     
         16 . The method of  claim 15 , wherein the neurodegenerative disease is brain trauma, spinal cord trauma, trauma to the peripheral nervous system, Alzheimer's disease, Pick's disease, diffuse Lewy body disease, progressive supranuclear palsy (Steel-Richardson syndrome), multisystem degeneration (Shy-Drager syndrome), motor neuron diseases including amyotrophic lateral sclerosis, degenerative ataxias, cortical basal degeneration, ALS-Parkinson's-Dementia complex of Guam, subacute sclerosing panencephalitis, Huntington's disease, Parkinson's disease, synucleinopathies, primary progressive aphasia, striatonigral degeneration, Machado-Joseph disease/spinocerebellar ataxia type 3 and olivopontocerebellar degenerations, Gilles De La Tourette's disease, bulbar and pseudobulbar palsy, spinal and spinobulbar muscular atrophy (Kennedy's disease), primary lateral sclerosis, familial spastic paraplegia, Werdnig-Hoffman disease, Kugelberg-Welander disease, Tay-Sach's disease, Sandhoff disease, familial spastic disease, Wohlfart-Kugelberg-Welander disease, spastic paraparesis, progressive multifocal leukoencephalopathy, and prion diseases (including Creutzfeldt-Jakob, Gerstmann-Straussler-Scheinker disease, Kuru and fatal familial insomnia, age-related dementia, vascular dementia, diffuse white matter disease (Binswanger's disease), dementia of endocrine or metabolic origin, dementia of head trauma and diffuse brain damage, dementia pugilistica or frontal lobe dementia, neurodegenerative disorders resulting from cerebral ischemia or infarction including embolic occlusion and thrombotic occlusion as well as intracranial hemorrhage of any type, intracranial and intravertebral lesions, hereditary cerebral angiopathy, normeuropathic hereditary amyloid, Down's syndrome, macroglobulinemia, secondary familial Mediterranean fever, Muckle-Wells syndrome, multiple myeloma, pancreatic- and cardiac-related amyloidosis, chronic hemodialysis arthropathy, or Finnish and Iowa amyloidosis. 
     
     
         17 . A method of treating an inflammatory disease, the method comprising administering to a patient in need thereof an effective amount of a compound of  claim 1 . 
     
     
         18 . The method of  claim 17 , wherein the inflammatory disease is associated with a metabolic disorder. 
     
     
         19 . The method of  claim 18 , wherein the metabolic disorder is Type II diabetes, insulin resistance cardiovascular disease, arrhythmia, atherosclerosis, coronary artery disease, hypertriglyceridemia, dyslipidemia, retinopathy, nephropathy, neuropathy, or macular edema. 
     
     
         20 . The method of  claim 17 , wherein the inflammatory disease is associated with an inflammatory bowel disease. 
     
     
         21 . The method of  claim 20 , wherein the inflammatory bowel disease is ileitis, ulcerative colitis, Barrett's syndrome, or Crohn's disease. 
     
     
         22 . The method of  claim 10 , wherein administering is performed orally, parentally, subcutaneously, by injection, or by infusion. 
     
     
         23 . The method of  claim 10 , wherein the patient is selected for treatment based on gene amplification and/or elevated tumor expression of PI5P4K. 
     
     
         24 . The method of  claim 23 , wherein the gene amplified and/or expressed is PI5P4Kα gene, PI5P4Kβ gene, or PI5P4Kγ gene. 
     
     
         25 . The method of  claim 10 , wherein the patient is selected for the treatment based on tumor expression of p53 mutations. 
     
     
         26 . The method of  claim 10 , wherein administration of the compound induces a change in the cell cycle or cell viability. 
     
     
         27 . A method of inducing cell cycle arrest, apoptosis in tumor cells, and/or enhanced tumor specific T-cell immunity, comprising contacting the cells with an effective amount of a compound of  claim 1 . 
     
     
         28 .- 29 . (canceled)