Novel compounds and methods of treating or ameliorating an il-1r-mediated disease or disorder using same

Abstract

The present invention provides compounds useful for treating or preventing an IL-1R-mediated disease or disorder. In certain embodiments, the disease or disorder comprises scleroderma.

1 . A compound, or a salt, tautomer or solvate thereof, selected from the group consisting of:
 (i) a compound of formula (I):   
       
         
           
           
               
               
           
         
          wherein in (I),
 ring A is selected from the group consisting of: 
 
       
       
         
           
           
               
               
           
         
         
           
             wherein in ring A one occurrence of R 1  is CR 6  and the other occurrence of R 1  is N or CR 7  and the furan rings are independently optionally substituted with R 7 ; 
           
           R 2  is selected from the group consisting of bond, —CH 2 S—, —SCH 2 —, —CH 2 O—, —OCH 2 —, —(CH 2 ) 1-6 —, arylene, heteroarylene, and combinations thereof; 
           R 3  is selected from the group consisting of —C 1 -C 6  alkyl, —C 2 -C 6  alkenyl, —C 1 -C 6  heteroalkyl, —(C 0 -C 3  alkyl)-(C 3 -C 8  cycloalkyl), —(C 0 -C 3  alkyl)-(C 4 -C 10  heterocyclyl), —(C 0 -C 3  alkyl)-(C 6 -C 10  aryl) and —(C 0 -C 3  alkyl)-(C 5 -C 10  heteroaryl), wherein the alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is independently optionally substituted; 
           R 4  is selected from the group consisting of —C 1 -C 6  alkyl, —C 1 -C 6  heteroalkyl, —(C 0 -C 3  alkyl)-(C 3 -C 8  cycloalkyl), —(C 0 -C 3  alkyl)-(C 4 -C 10  heterocyclyl), —(C 0 -C 3  alkyl)-(C 6 -C 10  aryl), —(C 0 -C 3  alkyl)-(C 5 -C 10  heteroaryl), —(CH 2 ) 1-3 —C(═O)NH 2 , —(CH 2 ) 1-3 —C(═O)NHNHC(═O)R 5 , —S(CH 2 ) 1-3 —C(═O)NH 2 , —S(CH 2 ) 1-3 —C(═O)NHR 8 , —S(CH 2 ) 1-3 —C(═O)OR 3  and —S(CH 2 ) 1-3 —C(═O)NHNHC(═O)R 5 , wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is independently optionally substituted; 
           each occurrence of R 5  is independently —C 4 -C 10  heterocyclyl, —C 6 -C 10  aryl or —C 5 -C 10  heteroaryl, wherein the heterocyclyl, aryl or heteroaryl group is independently optionally substituted; 
           each occurrence of R 6  is independently selected from the group consisting of —NHR 8 , —C(═O)OH, —C(═O)OR 8  and —C(═O)NHR 8 ; 
           each occurrence of R 7  is independently H, halo, —C 1 -C 6  alkyl or —C 3 -C 10  cycloalkyl, wherein the alkyl or cycloalkyl group is independently optionally substituted; and,
 each occurrence of R 8  is independently selected from the group consisting of —C 1 -C 6  alkyl, —C 1 -C 6  heteroalkyl, —(C 0 -C 3  alkyl)-(C 3 -C 8  cycloalkyl), —(C 0 -C 3  alkyl)-(C 4 -C 10  heterocyclyl), —(C 0 -C 3  alkyl)-(C 6 -C 10  aryl) and —(C 0 -C 3  alkyl)-(C 5 -C 10  heteroaryl), wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is independently optionally substituted; 
 
         
         (ii) a compound of formula (II): 
       
       
         
           
           
               
               
           
         
          wherein in (II):
 R 1  and R 3  are independently selected from the group consisting of —(C 0 -C 3  alkyl)-(C 0 -C 10  aryl), and —(C 0 -C 3  alkyl)-(C 5 -C 10  heteroaryl), wherein the alkyl, aryl or heteroaryl group is independently optionally substituted; 
 R 2  is S, S(═O) or S(═O) 2 ; 
 R 4  is selected from the group consisting of —(CH 2 ) 1-3 C(═O)OH, —(CH 2 ) 1-3 C(═O)OR 5  and —(CH 2 ) 1-3 C(═O)NHR 5 ; and, 
 each occurrence of R 5  is independently selected from the group consisting of —C 1 -C 6  alkyl, —C 1 -C 6  heteroalkyl, —(C 0 -C 3  alkyl)-(C 3 -C 8  cycloalkyl), —(C 0 -C 3  alkyl)-(C 4 -C 10  heterocyclyl), —(C 0 -C 3  alkyl)-(C 6 -C 10  aryl) and —(C 0 -C 3  alkyl)-(C 5 -C 10  heteroaryl), wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is independently optionally substituted; 
 
         (iii) a compound of formula (III): 
       
       
         
           
           
               
               
           
         
          wherein in (III),
 each occurrence of R 1  is independently N or CR 6 ; 
 R 2  is selected from the group consisting of —(C 0 -C 3  alkyl)-(C 4 -C 10  heterocyclyl), —(C 0 -C 3  alkyl)-(C 6 -C 10  aryl) and —(C 0 -C 3  alkyl)-(C 5 -C 10  heteroaryl), wherein the alkyl, heterocyclyl, aryl or heteroaryl group is independently optionally substituted; 
 R 3  and R 4  are independently selected from the group consisting of —(CH 2 ) 1-3 —C(═O)OR 5 , —(CH 2 ) 1-3 —C(═O)NH 2 , —(CH 2 ) 1-3 —C(═O)NHR 5 , —S(CH 2 ) 1-3 —C(═O)NH 2 , —S(CH 2 ) 1-3 —C(═O)OR 5  and —S(CH 2 ) 1-3 —C(═O)NHR 5 ; 
 each occurrence of R 5  is independently H, —C 1 -C 6  alkyl, —C 3 -C 10  cycloalkyl, —C 6 -C 10  aryl, or heteroaryl, wherein the alkyl, cycloalkyl, aryl or heteroaryl group is independently optionally substituted; and, 
 each occurrence of R 6  is independently H, halo, —C 1 -C 6  alkyl, —C 3 -C 10  cycloalkyl, —C 6 -C 10  aryl, or heteroaryl, wherein the alkyl, cycloalkyl, aryl or heteroaryl group is independently optionally substituted; 
 
         (iv) a compound of formula (IV): 
       
       
         
           
           
               
               
           
         
          wherein in (IV),
 R 1  is selected from the group consisting of —(C 0 -C 3  alkyl)-(C 4 -C 10  heterocyclyl), —(C 0 -C 3  alkyl)-(C 6 -C 10  aryl) and —(C 0 -C 3  alkyl)-(C 5 -C 10  heteroaryl), wherein the alkyl, heterocyclyl, aryl or heteroaryl group is independently optionally substituted; 
 R 2  is selected from the group consisting of —(CH 2 ) 1-3 —C(═O)OR 4 , —(CH 2 ) 1-3 —C(═O)NH 2 , and —(CH 2 ) 1-3 —C(═O)NHR 4 ; 
 R 3  is —C(═O)OR 4 , —C(═O)NHR 4  or —S(═O) 2 NHR 4 ; 
 each occurrence of R 4  is independently H, —C 1 -C 6  alkyl, —C 3 -C 10  cycloalkyl, —C 6 -C 10  aryl, or heteroaryl, wherein the alkyl, cycloalkyl, aryl or heteroaryl group is independently optionally substituted; and, 
 A ring is optionally further substituted; 
 
         (v) a compound of formula (V): 
       
       
         
           
           
               
               
           
         
          wherein in (V),
 R 1  is selected from the group consisting of O, NH and N(C 1 -C 6  alkyl), wherein the alkyl group is optionally substituted; 
 R 2  is selected from the group consisting of H and —(C 1 -C 6  alkyl), wherein the alkyl group is optionally substituted; 
 R 3  is selected from the group consisting of H, —(C 1 -C 6  alkyl) and aryl, wherein the alkyl or aryl group is optionally substituted; 
 R 4  is optionally substituted aryl; 
 R 5  is selected from the group consisting of —CN, —C(═O)OH and —C(═O)O(C 1 -C 6  alkyl), wherein the alkyl group is optionally substituted; and 
 R 6  is methyl or NH 2 ; 
 
         (vi) the compound of formula (VI), 3-(furan-2-ylmethyl)-8-(naphthalen-1-yl)-6-oxo-3,4,7,8-tetrahydro-2H,6H-pyrido[2,1-b][1,3,5]thiadiazine-9-carbonitrile: 
       
       
         
           
           
               
               
           
         
         (vii) the compound of formula (VII), 6-amino-4-(2-hydroxynaphthalen-1-yl)-3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile: 
       
       
         
           
           
               
               
           
         
         (viii) the compound of formula (VIII), 2-((3-cyano-4-(naphthalen-1-yl)-6-oxo-1,4,5,6-tetrahydropyridin-2-yl)thio)-N-phenylacetamide: 
       
       
         
           
           
               
               
           
         
         (ix) the compound of formula (IX), methyl 6-amino-5-cyano-2-(methoxymethyl)-4-(naphthalen-1-yl)-4H-pyran-3-carboxylate: 
       
       
         
           
           
               
               
           
         
         (x) the compound of formula (X), 2-amino-4-(naphthalen-1-yl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile: 
       
       
         
           
           
               
               
           
         
         (xi) a compound of formula (XI): 
       
       
         
           
           
               
               
           
         
          wherein in (XI):
 each occurrence of R 1  is independently selected from the group consisting of H and methyl; 
 R 2  is O or —NH; and 
 R 3  is optionally substituted phenyl or naphthyl; 
 
         (xii) a compound of formula (XII): 
       
       
         
           
           
               
               
           
         
          wherein in (XII):
 R 1  is phenyl or benzyl, wherein the phenyl or benzyl group is optionally substituted; 
 R 2  is H or methyl; and, 
 R 3  is optionally substituted phenyl; 
 
         (xiii) a compound of formula (XIII): 
       
       
         
           
           
               
               
           
         
          wherein in (XIII):
 R 1  is optionally substituted phenyl; 
 R 2  is optionally substituted phenyl; and, 
 R 3  is optionally substituted phenyl or heteroaryl; 
 
         and any mixtures thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein in (I) ring A is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , wherein in (I) at least one of the following applies:
 (a) in ring A one occurrence of R 1  is CR 6  and the other occurrence of R 1  is CR 7 ;   (b) R 2  is selected from the group consisting of —CH 2 S—, —SCH 2 — and —(CH 2 ) 1-6 —;   (c) R 3  is selected from the group consisting of —C 1 -C 6  alkyl, —C 2 -C 6  alkenyl, —C 3 -C 8  cycloalkyl, —(C 0 -C 3  alkyl)-(C 6 -C 10  aryl) and —(C 0 -C 3  alkyl)-(C 5 -C 10  heteroaryl), wherein the alkyl, alkenyl cycloalkyl, aryl or heteroaryl group is independently optionally substituted;   (d) R 4  is selected from the group consisting of C 1 -C 6  alkyl, —(C 0 -C 3  alkyl)-(C 6 -C 10  aryl), —(C 0 -C 3  alkyl)-(C 5 -C 10  heteroaryl), —(CH 2 ) 1-3 —C(═O)NH 2 , —S(CH 2 ) 1-3 —C(═O)NH 2 , —S(CH 2 ) 1-3 —C(═O)OR 3  and —S(CH 2 ) 1-3 —C(═O)NHNHC(═O)R 5 ;   (e) R 5  is C 6 -C 10  aryl or C 5 -C 10  heteroaryl, wherein the aryl or heteroaryl group is independently optionally substituted;   (f) R 6  is selected from the group consisting of —NHR 8  and —C(═O)NHR 8 ;   (g) R 7  is H, halo or C 1 -C 6  alkyl, wherein the alkyl group is optionally substituted; or   (h) R 8  is selected from the group consisting of —(C 0 -C 3  alkyl)-(C 3 -C 8  cycloalkyl), —(C 0 -C 3 alkyl)-(C 6 -C 10  aryl) and —(C 0 -C 3  alkyl)-(C 5 -C 10  heteroaryl), wherein the alkyl, heteroalkyl, cycloalkyl, aryl or heteroaryl group is independently optionally substituted.   
     
     
         4 - 10 . (canceled) 
     
     
         11 . The compound of  claim 1 , wherein in (II) at least one of the following applies:
 (a) R 1  and R 3  are independently selected from the group consisting of —(C 6 -C 10  aryl) and —(C 5 -C 10  heteroaryl), wherein the aryl or heteroaryl group is independently optionally substituted;   (b) R 2  is —S(═O)— or —S(═O) 2 —;   (c) R 4  is —(CH 2 ) 1-3 C(═O)NHR 5 ; or   (d) R 5  is selected from the group consisting of —C 1 -C 6  alkyl, —(C 0 -C 3  alkyl)-(C 3 -C 8  cycloalkyl), —(C 0 -C 3  alkyl)-(C 4 -C 10  heterocyclyl), —(C 0 -C 3  alkyl)-(C 6 -C 10  aryl), and —(C 0 -C 3 alkyl)-(C 5 -C 10  heteroaryl), wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is independently optionally substituted.   
     
     
         12 - 14 . (canceled) 
     
     
         15 . The compound of  claim 1 , wherein in (III) at least one of the following applies:
 (a) each occurrence of R 1  is N;   (b) R 3  is selected from the group consisting of —S(CH 2 ) 1-3 —C(═O)NH 2 , —S(CH 2 ) 1-3 —C(═O)OR 5  and —S(CH 2 ) 1-3 —C(═O)NHR 5 ; or   (c) R 4  is selected from the group consisting of —(CH 2 ) 1-3 —C(═O)OR 5 , —(CH 2 ) 1-3 —C(═O)NH 2 , and —(CH 2 ) 1-3 —C(═O)NHR 5 .   
     
     
         16 - 17 . (canceled) 
     
     
         18 . The compound of  claim 1 , wherein in (IV) at least one of the following applies:
 (a) R 1  is selected from the group consisting of —CH 2 —(C 4 -C 10  heterocyclyl), —CH 2 —(C 6 -C 10  aryl) and —CH 2 —(C 5 -C 10  heteroaryl);   (b) R 2  is —(CH 2 ) 1-3 —C(═O)NHR 4 ; or   (c) R 3  is —S(═O) 2 NHR 4 .   
     
     
         19 - 20 . (canceled) 
     
     
         21 . The compound of  claim 1 , which is at least one selected from the group consisting of: cyclohexyl 2-((5-((2-((3-chlorophenyl)amino)thiazol-4-yl)methyl)-4-(furan-2-yl methyl)-4H-1,2,4-triazol-3-yl)thio)acetate; 3-(4-(furan-2-ylmethyl)-5-(((2-(phenylamino)thiazol-4-yl)methyl)thio)-4H-1,2,4-triazol-3-yl)propanamide; ethyl 2-(((4-(3-chlorophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)methyl) thiazole-4-carboxylate; 2-(((4-(3-chlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl)thio)methyl)-N-(furan-2-yl methyl)thiazole-4-carboxamide; N′-(2-((4-butyl-5-((2-((3-chlorophenyl)amino)thiazol-4-yl)methyl)-4H-1,2,4-triazol-3-yl)thio)acetyl)furan-2-carbohydrazide; 2-((5-((2-((4-fluorophenyl)amino)thiazol-4-yl)methyl)-4-(furan-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio)acetamide; 2-(((4-(3-chlorophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)methyl)-N-cyclohexylthiazole-4-carboxamide; 2-((4-allyl-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)-N-(benzo[d]thiazol-2-yl) acetamide; N-(4,5-dimethylthiazol-2-yl)-2-((4-ethyl-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)acetamide; 2-((5-((2-((4-ethoxyphenyl)amino)thiazol-4-yl)methyl)-4-ethyl-4H-1,2,4-triazol-3-yl)thio)-N-(furan-2-ylmethyl)acetamide; N-(2-(cyclohexylamino)-2-oxoethyl)-2-((2-((4-fluorophenyl)amino)-2-oxoethyl) sulfinyl)-N-(naphthalen-1-yl)acetamide; (N-cyclohexyl-N2-[({2-[(4-fluorophenyl)amino]-2-oxoethyl}sulfinyl)acetyl]-N 2 -1-naphthylglycinamide); (N 2 -({[2-(1,3-benzodioxol-5-ylamino)-2-oxoethyl]sulfinyl}acetyl)-N 2 -(2-chlorobenzyl)-N-cyclopentylglycinamide); N-(2-(tert-butylamino)-2-oxoethyl)-2-((2-((4-fluorophenyl)amino)-2-oxoethyl) sulfinyl)-N-(m-tolyl)acetamide; (2-[5-{[2-(cyclopentylamino)-2-oxoethyl]sulfanyl}-3-(4-pyridinyl)-1H-1,2,4-triazol-1-yl]-N-(3-methoxy phenyl)acetamide); N 2 -(1,3-benzodioxol-5-ylmethyl)-N 2 -{[4-(cyclopentylsulfamoyl)phenyl]sulfonyl}-N-phenylglycinamide; 2-amino-4-(2,7-diethoxynaphthalen-1-yl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile; ethyl 2-methyl-4-(naphthalen-1-yl)-5-oxo-7-phenyl-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate; methyl 7-(3,4-dimethoxyphenyl)-2-methyl-4-(naphthalen-1-yl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate; 2-methoxyethyl 2-methyl-4-(naphthalen-1-yl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate; methyl 7-(4-methoxyphenyl)-2-methyl-4-(naphthalen-1-yl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate; ethyl 4-(anthracen-9-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (KA820); 3-(furan-2-ylmethyl)-8-(naphthalen-1-yl)-6-oxo-3,4,7,8-tetrahydro-2H,6H-pyrido[2,1-b][1,3,5]thiadiazine-9-carbonitrile; 6-amino-4-(2-hydroxynaphthalen-1-yl)-3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile; 2-((3-cyano-4-(naphthalen-1-yl)-6-oxo-1,4,5,6-tetrahydropyridin-2-yl)thio)-N-phenylacetamide; methyl 6-amino-5-cyano-2-(methoxymethyl)-4-(naphthalen-1-yl)-4H-pyran-3-carboxylate; 2-amino-4-(naphthalen-1-yl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile; 1,3-dimethyl-5-(naphthalen-1-yl)-5,11-dihydro-1H-indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine-2,4,6(3H)-trione; 2-amino-5-(naphthalen-1-yl)-5,11-dihydro-1H-indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine-4,6-dione; 3-(4-chlorophenyl)-7-(4-fluorophenyl)-3H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-c]pyrimidine; 3-(2-chlorobenzyl)-7-(4-fluorophenyl)-5-methyl-3H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-c]pyrimidine; 7-(4-(1H-tetrazol-1-yl)phenyl)-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-c]pyrimidine; 4-(5-(4-butoxyphenyl)-4-phenyl-4H-1,2,4-triazol-3-yl)-2-(p-tolyl)quinolone; 4-(5-(4-(tert-butyl)phenyl)-4-(p-tolyl)-4H-1,2,4-triazol-3-yl)pyridine; 3-(5-(4-butoxyphenyl)-4-phenyl-4H-1,2,4-triazol-3-yl)aniline; or a salt, tautomer or solvate thereof. 
     
     
         22 . A pharmaceutical composition comprising at least one compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         23 . The pharmaceutical composition of  claim 22 , further comprising at least one additional therapeutic agent selected from the group consisting of anakinra, rilonacept, azathioprine, methotrexate, bosentan, etanercept, halofuginone, iloprost, cyclophosphamide, cyclosporin A, mycophenolate mofetil, intravenous immunoglobulin, pirfenidone, prednisone, rituximab, beta-glycan peptides, basiliximab, sirolimus, alefacept, terguride, pomalidomide, and a tyrosine kinase inhibitor. 
     
     
         24 . A method of treating or ameliorating an IL-1R-mediated disease or disorder in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of at least one compound of  claim 1 , whereby the disease or disorder is treated or ameliorated. 
     
     
         25 . The method of  claim 24 , wherein the disease or disorder is an infectious, inflammatory or autoimmune disease or disorder. 
     
     
         26 . The method of  claim 24 , wherein the disease or disorder is selected from the group consisting of scleroderma, inflammation in general, systemic lupus erythematosus (lupus), Sjogren's syndrome, arthritis, myositis, Behcet's disease, inflammatory bowel disease, colitis, septic shock, chronic myelogenous leukemia, acute myelogenous leukemia, multiple myeloma, non-blood cancers, psoriasis, type I and type II diabetes, asbestosis, idiopathic pulmonary fibrosis, graft-versus-host disease, familial Mediterranean fever, stroke, epilepsy, and cryopyrin-associated periodic syndromes (CAPS). 
     
     
         27 . The method of  claim 26 , wherein the non-blood cancer comprises at least one selected from the group consisting of glioma, metastatic breast cancer, interleukin-1-producing cancer, pancreatic ductal adenocarcinoma, colorectal, melanoma, gastric carcinoma, cervical cancer, lung carcinoma, and ovarian carcinoma. 
     
     
         28 . The method of  claim 24 , wherein the compound is selected from the group consisting of cyclohexyl 2-((5-((2-((3-chlorophenyl)amino)thiazol-4-yl)methyl)-4-(furan-2-yl methyl)-4H-1,2,4-triazol-3-yl)thio)acetate; 3-(4-(furan-2-ylmethyl)-5-(((2-(phenylamino) thiazol-4-yl)methyl)thio)-4H-1,2,4-triazol-3-yl)propanamide; ethyl 2#(4-(3-chlorophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)methyl) thiazole-4-carboxylate; 2-(((4-(3-chlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl)thio)methyl)-N-(furan-2-yl methyl)thiazole-4-carboxamide; N′-(2-((4-butyl-5-((2-((3-chlorophenyl)amino)thiazol-4-yl)methyl)-4H-1,2,4-triazol-3-yl)thio) acetyl)furan-2-carbohydrazide; 2-((5-((2-((4-fluorophenyl)amino)thiazol-4-yl)methyl)-4-(furan-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio)acetamide; 2-(((4-(3-chlorophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)methyl)-N-cyclohexylthiazole-4-carboxamide; 2-((4-allyl-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)-N-(benzo[d]thiazol-2-yl) acetamide; N-(4,5-dimethylthiazol-2-yl)-2-((4-ethyl-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)acetamide; 2-((5-((2-((4-ethoxyphenyl)amino)thiazol-4-yl)methyl)-4-ethyl-4H-1,2,4-triazol-3-yl)thio)-N-(furan-2-ylmethyl)acetamide; N-(2-(cyclohexylamino)-2-oxoethyl)-2-((2-((4-fluorophenyl)amino)-2-oxoethyl) sulfinyl)-N-(naphthalen-1-yl)acetamide; (N-cyclohexyl-N 2 -[({2-[(4-fluorophenyl)amino]-2-oxoethyl}sulfinyl)acetyl]-N 2 -1-naphthylglycinamide); (N 2 -({[2-(1,3-benzodioxol-5-ylamino)-2-oxoethyl]sulfinyl}acetyl)-N 2 -(2-chlorobenzyl)-N-cyclopentylglycinamide); N-(2-(tert-butylamino)-2-oxoethyl)-2-((2-((4-fluorophenyl)amino)-2-oxoethyl) sulfinyl)-N-(m-tolyl)acetamide; (2-[5-{[2-(cyclopentylamino)-2-oxoethyl]sulfanyl}-3-(4-pyridinyl)-1H-1,2,4-triazol-1-yl]-N-(3-methoxy phenyl)acetamide); N 2 -(1,3-benzodioxol-5-ylmethyl)-N 2 -{[4-(cyclopentylsulfamoyl)phenyl]sulfonyl}-N-phenylglycinamide; 2-amino-4-(2,7-diethoxynaphthalen-1-yl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile; ethyl 2-methyl-4-(naphthalen-1-yl)-5-oxo-7-phenyl-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate; methyl 7-(3,4-dimethoxyphenyl)-2-methyl-4-(naphthalen-1-yl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate; 2-methoxyethyl 2-methyl-4-(naphthalen-1-yl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate; methyl 7-(4-methoxyphenyl)-2-methyl-4-(naphthalen-1-yl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate; ethyl 4-(anthracen-9-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (KA820); 3-(furan-2-ylmethyl)-8-(naphthalen-1-yl)-6-oxo-3,4,7,8-tetrahydro-2H,6H-pyrido[2,1-b][1,3,5]thiadiazine-9-carbonitrile; 6-amino-4-(2-hydroxynaphthalen-1-yl)-3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile; 2-((3-cyano-4-(naphthalen-1-yl)-6-oxo-1,4,5,6-tetrahydropyridin-2-yl)thio)-N-phenylacetamide; methyl 6-amino-5-cyano-2-(methoxymethyl)-4-(naphthalen-1-yl)-4H-pyran-3-carboxylate; 2-amino-4-(naphthalen-1-yl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile; 1,3-dimethyl-5-(naphthalen-1-yl)-5,11-dihydro-1H-indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine-2,4,6(3H)-trione; 2-amino-5-(naphthalen-1-yl)-5,11-dihydro-1H-indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine-4,6-dione; 3-(4-chlorophenyl)-7-(4-fluorophenyl)-3H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-c]pyrimidine; 3-(2-chlorobenzyl)-7-(4-fluorophenyl)-5-methyl-3H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-c]pyrimidine; 7-(4-(1H-tetrazol-1-yl)phenyl)-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-c]pyrimidine; 4-(5-(4-butoxyphenyl)-4-phenyl-4H-1,2,4-triazol-3-yl)-2-(p-tolyl)quinolone; 4-(5-(4-(tert-butyl)phenyl)-4-(p-tolyl)-4H-1,2,4-triazol-3-yl)pyridine; 3-(5-(4-butoxyphenyl)-4-phenyl-4H-1,2,4-triazol-3-yl)aniline; or a salt, tautomer or solvate thereof. 
     
     
         29 . The method of  claim 24 , wherein the mammal is further administered at least one additional therapeutic agent. 
     
     
         30 . The method of  claim 29 , wherein the additional therapeutic agent comprises at least one selected from the group consisting of anakinra, rilonacept, azathioprine, methotrexate, bosentan, etanercept, halofuginone, iloprost, cyclophosphamide, cyclosporin A, mycophenolate mofetil, intravenous immunoglobulin, pirfenidone, prednisone, rituximab, beta-glycan peptides, basiliximab, sirolimus, alefacept, terguride, pomalidomide, and a tyrosine kinase inhibitor. 
     
     
         31 . The method of  claim 30 , wherein the mammal and the additional therapeutic agent are co-administered to the mammal. 
     
     
         32 . The method of  claim 30 , wherein the compound is administered to the mammal a given period of time before or after the additional therapeutic agent is administered to the mammal. 
     
     
         33 . The method of  claim 24 , wherein the compound is formulated as a pharmaceutical composition. 
     
     
         34 . The method of  claim 24 , wherein the mammal is human.