Chemical compounds as inhibitors of interleukin-1 activity

Abstract

The present disclosure relates to novel sulfonylurea and sulfonyl thiourea compounds and related compounds and their use in treating a disease or condition responsive to modulation of cytokines such as IL-1β and IL-18, modulation of NLRP3 or inhibition of the activation of NLRP3 or related components of the inflammatory process.

1 - 99 . (canceled) 
     
     
         100 . A method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering an effective amount of a compound of formula (Ib), or a pharmaceutically acceptable salt, solvate, or tautomer thereof, to the subject in need thereof, wherein formula (Ib) is: 
       
         
           
           
               
               
           
         
       
       wherein:
 X 1  is O or S; 
 R 1  is selected from the group consisting of 
 
       
         
           
           
               
               
           
         
            represents a single bond or a double bond provided that the ring comprising one or more A 2  is a non-aromatic ring; 
         each A is independently CR 5a  or N; 
         each A 2  is independently CR 5a , C(R 5a ) 2 , N, NR 5a , O, S, or S(O) 2 ; 
         R 2  is 
       
       
         
           
           
               
               
           
         
         X 2  is N or CR 5b ; 
         R 3  and R 4  are H; 
         each R 5a  is independently H, D, halogen, —OH, —CN, —NO 2 , —SR 6 , —OR 6 , —NHR 6 , —NR 6 R 7 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, or —CH 2 —C 3 -C 8 cycloalkyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, and —CH 2 —C 3 -C 8 cycloalkyl are optionally substituted with D, halogen, C 1 -C 6 alkyl, —OR 6 , —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ; or 
         two R 5a  together with the atoms to which they are attached can form C 3 -C 8 cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; wherein the C 3 -C 8 cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C 1 -C 6 alkyl, —OR 6 , —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ; or 
         two geminal R 5a  can form an oxo group; 
         each R 5b  is independently H, D, halogen, —OH, —CN, —NO 2 , —SR 6 , —OR 6 , —NHR 6 , —NR 6 R 7 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, or C 2 -C 6 alkynyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, and C 2 -C 6 alkynyl are optionally substituted with D, halogen, —OR 6 , —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ; 
         R 6  and R 7  are independently, at each occurrence, H, D, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P and O; wherein the C 1 -C 6 alkyl, C 2 -C 8 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with D, halogen, C 1 -C 6 alkyl, —OH, —O—C 1 -C 6 alkyl, —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ; or 
         R 6  and R 7  together with the atom to which they are attached can form heterocyclyl or heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, S, P, and O; and 
         n is an integer from 0 to 5; 
         provided that when the ring comprising A is an imidazole, then at least one A 2  is N, NR 5a , O, S, or S(O) 2 . 
       
     
     
         101 . The method of  claim 100 , wherein the disease, disorder, or condition is of the liver, of the cardiovascular system, of the renal system, of the gastro-intestinal tract, of the respiratory system, of the endocrine system, of the central nervous system (CNS), is an inflammatory disease, disorder, or condition, or is an autoimmune disease, disorder, or condition. 
     
     
         102 . The method of  claim 100 , wherein the disease, disorder, or condition is selected from the group consisting of Muckle-Wells syndrome (MWS); familial cold autoinflammatory syndrome (FCAS); neonatal-onset multisystem inflammatory disease (NOMID); familial Mediterranean fever (FMF); TNF receptor associated periodic syndrome (TRAPS); mevalonate kinase deficiency (MKD); hyperimmunoglobulinemia D and periodic fever syndrome (HIDS); deficiency of interleukin 1 receptor (DIRA) antagonist; Majeed syndrome; pyogenic arthritis, pyoderma gangrenosum and acne (PAPA); haploinsufficiency of A20 (HA20); pediatric granulomatous arthritis (PGA); PLCG2-associated antibody deficiency and immune dysregulation (PLAID); PLCG2-associated autoinflammation, antibody deficiency and immune dysregulation (APLAID); sideroblastic anemia with B-cell immunodeficiency, periodic fevers, developmental delay (SIFD); Sweet's syndrome; chronic nonbacterial osteomyelitis (CNO); chronic recurrent multifocal osteomyelitis (CRMO); synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome (SAPHO); multiple sclerosis (MS); type-1 diabetes; psoriasis; rheumatoid arthritis; Behcet's disease; Sjogren's syndrome; Schnitzler syndrome; idiopathic pulmonary fibrosis (IPF); chronic obstructive pulmonary disorder (COPD); steroid-resistant asthma; asbestosis; silicosis; cystic fibrosis; Parkinson's disease; Alzheimer's disease; motor neuron disease; Huntington's disease; cerebral malaria; brain injury from pneumococcal meningitis; Type 2 diabetes; atherosclerosis; obesity; gout; pseudo-gout; disease of the ocular epithelium; age-related macular degeneration (AMD); corneal infection; uveitis; dry eye; chronic kidney disease; oxalate nephropathy; diabetic nephropathy; non-alcoholic steatohepatitis (NASH); alcoholic liver disease; fatty liver disease; liver fibrosis; non-alcoholic fatty liver disease (NAFLD); inflammatory bowel disease; celiac disease; intestinal hyperplasia; contact hypersensitivity; sunburn; osteoarthritis; systemic juvenile idiopathic arthritis; adult-onset Still's disease; relapsing polychondritis; alpha virus infection; Chikungunya virus infection; Ross River virus infection; flavivirus infection; Dengue virus infection; Zika virus infection; flu; HIV infection; hidradenitis suppurativa (HS); cyst-causing skin diseases; lung cancer metastasis; pancreatic cancers; gastric cancers; myelodisplastic syndrome; leukemia; polymyositis; stroke; myocardial infarction; Graft versus Host Disease; hypertension; colitis; helminth infection; bacterial infection; abdominal aortic aneurism; wound healing; depression; psychological stress; pericarditis; Dressler's syndrome; ischaemia reperfusion injury; and any disease where an individual has been determined to carry a germ line or somatic non-silent mutation in NLRP3. 
     
     
         103 . The method of  claim 100 , wherein the compound is of formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein:
 X 1  is O or S; 
 R 1  is selected from the group consisting of 
 
       
         
           
           
               
               
           
         
            represents a single bond or a double bond provided that the ring comprising one or more A 2  is a non-aromatic ring; 
         each A is independently CR 5  or N; 
         each A 2  is independently CR 5 , C(R 5 ) 2 , N, NR 5 , O, S, or S(O) 2 ; 
         R 2  is 
       
       
         
           
           
               
               
           
         
         X 2  is N or CR 5 ; 
         R 3  and R 4  are H; 
         each R 5  is independently H, D, halogen, —OH, —CN, —NO 2 , —SR 6 , —OR 6 , —NHR 6 , —NR 6 R 7 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, or C 2 -C 6 alkynyl; 
         R 6  and R 7  are independently, at each occurrence, H, D, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P and O; or 
         R 6  and R 7  together with the atom to which they are attached can form heterocyclyl or heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, S, P, and O; and 
         n is an integer from 0 to 5; 
       
       provided that when the ring comprising A is an imidazole, then at least one A 2  is N, NR 5 , O, S, or S(O) 2 . 
     
     
         104 . The method of  claim 103 , wherein the disease, disorder, or condition is of the liver, of the cardiovascular system, of the renal system, of the gastro-intestinal tract, of the respiratory system, of the endocrine system, of the central nervous system (CNS), is an inflammatory disease, disorder, or condition, or is an autoimmune disease, disorder, or condition. 
     
     
         105 . The method of  claim 103 , wherein the disease, disorder, or condition is selected from the group consisting of Muckle-Wells syndrome (MWS); familial cold autoinflammatory syndrome (FCAS); neonatal-onset multisystem inflammatory disease (NOMID); familial Mediterranean fever (FMF); TNF receptor associated periodic syndrome (TRAPS); mevalonate kinase deficiency (MKD); hyperimmunoglobulinemia D and periodic fever syndrome (HIDS); deficiency of interleukin 1 receptor (DIRA) antagonist; Majeed syndrome; pyogenic arthritis, pyoderma gangrenosum and acne (PAPA); haploinsufficiency of A20 (HA20); pediatric granulomatous arthritis (PGA); PLCG2-associated antibody deficiency and immune dysregulation (PLAID); PLCG2-associated autoinflammation, antibody deficiency and immune dysregulation (APLAID); sideroblastic anemia with B-cell immunodeficiency, periodic fevers, developmental delay (SIFD); Sweet's syndrome; chronic nonbacterial osteomyelitis (CNO); chronic recurrent multifocal osteomyelitis (CRMO); synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome (SAPHO); multiple sclerosis (MS); type-1 diabetes; psoriasis; rheumatoid arthritis; Behcet's disease; Sjogren's syndrome; Schnitzler syndrome; idiopathic pulmonary fibrosis (IPF); chronic obstructive pulmonary disorder (COPD); steroid-resistant asthma; asbestosis; silicosis; cystic fibrosis; Parkinson's disease; Alzheimer's disease; motor neuron disease; Huntington's disease; cerebral malaria; brain injury from pneumococcal meningitis; Type 2 diabetes; atherosclerosis; obesity; gout; pseudo-gout; disease of the ocular epithelium; age-related macular degeneration (AMD); corneal infection; uveitis; dry eye; chronic kidney disease; oxalate nephropathy; diabetic nephropathy; non-alcoholic steatohepatitis (NASH); alcoholic liver disease; fatty liver disease; liver fibrosis; non-alcoholic fatty liver disease (NAFLD); inflammatory bowel disease; celiac disease; intestinal hyperplasia; contact hypersensitivity; sunburn; osteoarthritis; systemic juvenile idiopathic arthritis; adult-onset Still's disease; relapsing polychondritis; alpha virus infection; Chikungunya virus infection; Ross River virus infection; flavivirus infection; Dengue virus infection; Zika virus infection; flu; HIV infection; hidradenitis suppurativa (HS); cyst-causing skin diseases; lung cancer metastasis; pancreatic cancers; gastric cancers; myelodisplastic syndrome; leukemia; polymyositis; stroke; myocardial infarction; Graft versus Host Disease; hypertension; colitis; helminth infection; bacterial infection; abdominal aortic aneurism; wound healing; depression; psychological stress; pericarditis; Dressler's syndrome; ischaemia reperfusion injury; and any disease where an individual has been determined to carry a germ line or somatic non-silent mutation in NLRP3. 
     
     
         106 . The method of  claim 100 , wherein:
 X 1  is O;   R 1  is selected from the group consisting of   
       
         
           
           
               
               
           
         
            represents a single bond; 
         each A 2  is independently C(R 5a ) 2  or O; 
         X 2  is CR 5b ; 
         each R 5a  is independently H, halogen, —OH, —OR 6 , —NHR 6 , —NR 6 R 7 , C 1 -C 6 alkyl, or heterocyclyl; wherein the C 1 -C 6 alkyl and heterocyclyl are optionally substituted with D, halogen, —OR 6 , —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ; or 
         two R 5a  together with the atoms to which they are attached can form C 3 -C 8 cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P, and O; wherein the C 3 -C 8 cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C 1 -C 6 alkyl, —OR 6 , —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ; or 
         two geminal R 5a  can form an oxo group; 
         each R 5b  is independently H, D, halogen, —CN, —OR 6 , or C 1 -C 6 alkyl; wherein the C 1 -C 6 alkyl is optionally substituted with D, halogen, —OR 6 , —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ; and 
         R 6  and R 7  are independently, at each occurrence, H, D, C 1 -C 8 alkyl, C 2 -C 8 alkynyl, or aryl; wherein C 1 -C 6 alkyl, C 2 -C 6 alkynyl, and aryl are optionally substituted with D, halogen, or C 1 -C 6 alkyl. 
       
     
     
         107 . The method of  claim 100 , wherein:
 R 1  is   
       
         
           
           
               
               
           
         
         R 5a1a  is H, D, halogen, —OH, —CN, —NO 2 , —SR 6 , —OR 6 , —NHR 6 , —NR 6 R 7 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, or —CH 2 —C 3 -C 8 cycloalkyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, and —CH 2 —C 3 -C 8 cycloalkyl are optionally substituted with D, halogen, C 1 -C 6 alkyl, —OR 6 , —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ; 
         R 5a2c  and R 5a2d  are each independently H, D, halogen, —OH, —CN, —NO 2 , —SR 6 , —OR 6 , —NHR 6 , —NR 6 R 7 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, or —CH 2 —C 3 -C 8 cycloalkyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, and —CH 2 —C 3 -C 8 cycloalkyl are optionally substituted with D, halogen, C 1 -C 6 alkyl, —OR 6 , —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ; or 
         R 5a2c  and R 5a2d  together with the atom to which they are attached can form C 3 -C 8 cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; wherein the C 3 -C 8 cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C 1 -C 6 alkyl, —OR 6 , —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ; or 
         R 5a2c  and R 5a2d  can form an oxo group. 
       
     
     
         108 . The method of  claim 100 , wherein:
 R 1  is   
       
         
           
           
               
               
           
         
         R 5a2a  and R 5a2b  are each independently H, D, halogen, —OH, —CN, —NO 2 , —SR 6 , —OR 6 , —NHR 6 , —NR 6 R 7 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, or —CH 2 —C 3 -C 8 cycloalkyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, and —CH 2 —C 3 -C 8 cycloalkyl are optionally substituted with D, halogen, C 1 -C 6 alkyl, —OR 6 , —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ; or 
         R 5a2a  and R 5a2b  together with the atom to which they are attached can form C 3 -C 8 cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; wherein the C 3 -C 8 cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C 1 -C 6 alkyl, —OR 6 , —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ; or 
         R 5a2a  and R 5a2b  can form an oxo group. 
       
     
     
         109 . The method of  claim 100 , wherein:
 R 1  is   
       
         
           
           
               
               
           
         
         R 5a2e  and R 5a2f  are each independently H, D, halogen, —OH, —CN, —NO 2 , —SR 6 , —OR 6 , —NHR 6 , —NR 6 R 7 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, or —CH 2 —C 3 -C 8 cycloalkyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, and —CH 2 —C 3 -C 8 cycloalkyl are optionally substituted with D, halogen, C 1 -C 6 alkyl, —OR 6 , —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ; or 
         R 5a2e  and R 5a2f  together with the atom to which they are attached can form C 3 -C 8 cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; wherein the C 3 -C 8 cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C 1 -C 6 alkyl, —OR 6 , —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ; or 
         R 5a2e  and R 5a2f  can form an oxo group. 
       
     
     
         110 . The method of  claim 100 , wherein R 2  is 
       
         
           
           
               
               
           
         
       
       X 2  is CR 5b , and R 5b  is H, fluoro, chloro, or methyl. 
     
     
         111 . The method of  claim 100 , wherein R 2  is 
       
         
           
           
               
               
           
         
       
       and each R 5b  is independently selected from the group consisting of H, D, halogen, —OH, —CN, —NO 2 , —OR 6 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 4 -C 8 cycloalkenyl. 
     
     
         112 . The method of  claim 100 , wherein X is O, R 1  is 
       
         
           
           
               
               
           
         
       
       and R 2  is 
       
         
           
           
               
               
           
         
       
     
     
         113 . The method of  claim 101 , wherein X is O, R 1  is 
       
         
           
           
               
               
           
         
       
       and R 2  is 
       
         
           
           
               
               
           
         
       
     
     
         114 . The method of  claim 100 , wherein R 1  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         115 . The method of  claim 100 , wherein the compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, or tautomer thereof. 
     
     
         116 . The method of  claim 100 , wherein the compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, or tautomer thereof. 
     
     
         117 . The method of  claim 100 , wherein the compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, or tautomer thereof. 
     
     
         118 . The method of  claim 100 , wherein the compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, or tautomer thereof. 
     
     
         119 . The method of  claim 100 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, or tautomer thereof. 
     
     
         120 . The method of  claim 100 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, or tautomer thereof. 
     
     
         121 . The method of  claim 100 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, or tautomer thereof. 
     
     
         122 . The method of  claim 100 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, or tautomer thereof. 
     
     
         123 . The method of  claim 100 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, or tautomer thereof. 
     
     
         124 . The method of  claim 100 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, or tautomer thereof. 
     
     
         125 . The method of  claim 100 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, or tautomer thereof. 
     
     
         126 . The method of  claim 100 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, or tautomer thereof. 
     
     
         127 . The method of  claim 100 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, or tautomer thereof. 
     
     
         128 . The method of  claim 100 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, or tautomer thereof. 
     
     
         129 . The method of  claim 100 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, or tautomer thereof.