Kinase inhibitors and methods for making and using

Abstract

Disclosed embodiments concern kinase inhibitors, such as interleukin receptor associated kinases (IRAK) inhibitors, and compositions comprising such inhibitors. Also disclosed are methods of making and using the compounds and compositions. The disclosed compounds and/or compositions may be used to treat or prevent a kinase-associated disease or condition, particularly an IRAK-associated disease or condition.

We claim: 
     
         1 . A method for treating a disease or condition in a subject, comprising administering to the subject an effective amount of a compound having a formula 1 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, N-oxide, or solvate thereof, wherein:
 Het-1 is a 5- or 6-membered heteroaryl comprising at least one carbon atom and at least one heteroatom selected from N, O or S; 
 R 1  is H or alkyl; 
 R 2  is —N(R c ) 2 ; 
 each R 3  independently is C 1-6 alkyl, C 1-3 haloalkyl, or halo; 
 m is 0, 1 or 2; 
 each R 4  independently is C 1-6 alkyl; 
 k is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; 
 A is N or CR h ; 
 R h  is H, R 3  or the 
 
       
         
           
           
               
               
           
         
       
       moiety;
 R 5  is H, aliphatic, phosphonooxyalkyl, phosphonoalkyl, or acyl; 
 each of R 6  and R 7  independently is H, aliphatic, or halo; 
 X is O or NR 9 ; 
 R 9  is R a , C(O)C 1-6 aliphatic, C(O)N(R c ) 2 , or CO 2 R a ; 
 Y is N or CH; 
 Linker is a bond, —(C(R 10 ) 2 ) n —, —(C(R 10 ) 2 ) n —O—, —C(O)—(C(R 10 ) 2 ) p —, or —(C(R 10 ) 2 ) p —N(R a )—; 
 each R 10  independently is R a  or R b ; 
 n is 1, 2, 3, 4, 5, or 6; 
 p is 0, 1, or 2; 
 R a  is independently for each occurrence H, D, C 1-6 alkyl, or C 3-6 cycloalkyl; 
 R b  is independently for each occurrence —OH, —OR a , or halo; and 
 R c  is independently for each occurrence R a , or two R c  groups together with the nitrogen bound thereto form a C 3-7 heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents selected from C 1-6 alkyl, C 1-3 haloalkyl, —OH, or halo, and optionally interrupted with one or two additional heteroatoms selected from O, —N(R g )—, or S, where R g  is R a , —C(O)R a , —C(O)OR a  or —C(O)N(R a ) 2 ; or 
 the compound is selected from 
 I-39: N-(2-methoxy-5-morpholinophenyl)-6-(1H-pyrazol-4-yl)picolinamide; 
 I-40: N-(2-methoxy-5-morpholinophenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; or 
 I-41: N-(2-methoxy-5-morpholinophenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide. 
 
     
     
         2 . The method of  claim 1 , wherein Het-1 is pyridinyl, furanyl or thiazolyl. 
     
     
         3 . The method of  claim 1 , wherein:
 R 2  has a formula   
       
         
           
           
               
               
           
         
         Z is a bond, O, —NR a , —NC(O)R a , or C(R 8 ) 2 ; and 
         each R 8  independently is H, C 1-6 alkyl, C 1-3 haloalkyl, —OH, or halo. 
       
     
     
         4 . The method of  claim 3 , wherein R 2  is 
       
         
           
           
               
               
           
         
       
     
     
         5 . The method of  claim 1 , wherein m is 1 or 2 and each R 3  independently is F, Cl, Br, or I. 
     
     
         6 . The method of  claim 1 , wherein k is 0. 
     
     
         7 . The method of  claim 1 , wherein:
 each of R 6  and R 7  independently is H, halo, or C 1-6  alkyl;   R 5  is H, C 1-6 alkyl, —CH 2 OP(O)(R d ) 2 , —CH 2 P(O)(R d ) 2 , or acyl, where each R d  is independently for each occurrence —OR a , —O − M +  where each M +  independently is an alkali metal ion or an ammonium ion;   R 6  is H;   R 7  is H;   R 9  is H or C 1-6 alkyl; or   a combination thereof.   
     
     
         8 . The method of  claim 7 , wherein R 5  is H. 
     
     
         9 . The method of  claim 1 , wherein the 
       
         
           
           
               
               
           
         
       
       moiety is 
       
         
           
           
               
               
           
         
       
     
     
         10 . The method of  claim 1 , wherein the compound has a formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, N-oxide, or solvate thereof. 
     
     
         11 . The method of  claim 1 , wherein m is 1; and
 R 3  is para to the amide; or   R 3  is para to R 2 .   
     
     
         12 . The method of  claim 1 , the compound having a structure according to formula 2 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, N-oxide, or solvate thereof, wherein:
 Het-1 is pyridinyl, furanyl or thiazolyl; 
 R 2  is —N(R c ) 2 ; 
 each R 3  independently is halo; 
 m is 0 or 1; 
 each of R 5 , R 6  and R 7  is H; 
 A is N or CR h ; 
 R h  is H, R 3  or the 
 
       
         
           
           
               
               
           
         
       
       moiety;
 X is O or NR 9 ; 
 R 9  is R a ; 
 Y is N or CH; 
 Linker is a bond, —(C(R 10 ) 2 ) n —, —(C(R 10 ) 2 ) n —O—, —C(O)—(C(R 10 ) 2 ) p —, or —(C(R 10 ) 2 ) p —N(R a )—; 
 each R 10  independently is R a  or R b ; 
 n is 1 or 2; and 
 p is 0 or 1. 
 
     
     
         13 . The method of  claim 12 , wherein the compound has a general formula selected from 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, N-oxide, or solvate thereof. 
     
     
         14 . The method of  claim 1 , wherein the compound is selected from:
 I-1: N-(4-(4-methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;   I-2: N-(4-(4-methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;   I-3: N-(4-(4-methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;   I-4: N-(2-(4-fluoropiperidin-1-yl)-4-morpholinophenyl)-6-(1H-pyrazol-4-yl)picolinamide;   I-5: N-(2-(4-fluoropiperidin-1-yl)-4-morpholinophenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;   I-6: N-(2-(4-fluoropiperidin-1-yl)-4-morpholinophenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;   I-7: N-(2-(4-fluoropiperidin-1-yl)-4-(4-methylpiperazin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;   I-8: N-(2-(4-fluoropiperidin-1-yl)-4-(4-methylpiperazin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;   I-9: N-(2-(4-fluoropiperidin-1-yl)-4-(4-methylpiperazin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;   I-10: N-(2-(4-hydroxypiperidin-1-yl)-4-morpholinophenyl)-6-(1H-pyrazol-4-yl)picolinamide;   I-11: N-(2-(4-hydroxypiperidin-1-yl)-4-morpholinophenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;   I-12: N-(2-(4-hydroxypiperidin-1-yl)-4-morpholinophenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;   I-13: N-(2,4-dimorpholinophenyl)-6-(1H-pyrazol-4-yl)picolinamide;   I-14: N-(2,4-dimorpholinophenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;   I-15: N-(2,4-dimorpholinophenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;   I-16: N-(2-(4-hydroxy-4-methylpiperidin-1-yl)-4-morpholinophenyl)-6-(1H-pyrazol-4-yl)picolinamide;   I-17: N-(2-(4-hydroxy-4-methylpiperidin-1-yl)-4-morpholinophenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;   I-18: N-(2-(4-hydroxy-4-methylpiperidin-1-yl)-4-morpholinophenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;   I-19: N-(2-(4,4-difluoropiperidin-1-yl)-4-morpholinophenyl)-6-(1H-pyrazol-4-yl)picolinamide;   I-20: N-(2-(4,4-difluoropiperidin-1-yl)-4-morpholinophenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;   I-21: N-(2-(4,4-difluoropiperidin-1-yl)-4-morpholinophenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;   I-22: N-(4-morpholino-2-(pyrrolidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;   I-23: N-(4-morpholino-2-(pyrrolidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;   I-24: N-(4-morpholino-2-(pyrrolidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;   I-25: N-(5-morpholino-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;   I-26: N-(5-morpholino-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;   I-27: N-(5-(2-morpholinoethoxy)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;   I-28: N-(5-(2-morpholinoethoxy)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;   I-29: N-(5-(2-morpholinoethoxy)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;   I-30: N-(4-fluoro-5-(2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;   I-31: N-(4-fluoro-5-(2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;   I-32: N-(4-fluoro-5-(2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;   I-33: N-(5-(1,1-difluoro-2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;   I-34: N-(5-(1,1-difluoro-2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;   I-35: N-(5-(1,1-difluoro-2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;   I-36: N-(4-morpholino-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;   I-37: N-(4-morpholino-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;   I-38: N-(4-morpholino-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;   I-39: N-(2-methoxy-5-morpholinophenyl)-6-(1H-pyrazol-4-yl)picolinamide;   I-40: N-(2-methoxy-5-morpholinophenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;   I-41: N-(2-methoxy-5-morpholinophenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;   I-42: N-(6-morpholino-4-(piperidin-1-yl)pyridin-3-yl)-6-(1H-pyrazol-4-yl)picolinamide;   I-43: N-(6-morpholino-4-(piperidin-1-yl)pyridin-3-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;   I-44: N-(6-morpholino-4-(piperidin-1-yl)pyridin-3-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;   I-45: N-(4-(morpholine-4-carbonyl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;   I-46: N-(4-(morpholine-4-carbonyl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;   I-47: N-(4-(morpholine-4-carbonyl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;   I-48: N-(4-(morpholinomethyl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;   I-49: N-(4-(morpholinomethyl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;   I-50: N-(4-(morpholinomethyl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;   I-51: N-(4-(2-morpholino-2-oxoethyl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;   I-52: N-(4-(2-morpholino-2-oxoethyl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;   I-53: N-(4-(2-morpholino-2-oxoethyl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;   I-54: N-(4-(2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;   I-55: N-(4-(2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;   I-56: N-(4-(2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;   I-57: N-(5-(morpholine-4-carbonyl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;   I-58: N-(5-(morpholine-4-carbonyl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;   I-59: N-(5-(morpholine-4-carbonyl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;   I-60: N-(5-(morpholinomethyl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;   I-61: N-(5-(morpholinomethyl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;   I-62: N-(5-(morpholinomethyl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;   I-63: N-(5-(2-morpholino-2-oxoethyl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;   I-64: N-(5-(2-morpholino-2-oxoethyl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;   I-65: N-(5-(2-morpholino-2-oxoethyl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;   I-66: N-(5-(2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;   I-67: N-(5-(2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;   I-68: N-(5-(2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;   I-69: N-(4-(methyl(2-morpholinoethyl)amino)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;   I-70: N-(4-(methyl(2-morpholinoethyl)amino)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;   I-71: N-(4-(methyl(2-morpholinoethyl)amino)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;   I-72: N-(4-((2-morpholinoethyl)amino)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;   I-73: N-(4-((2-morpholinoethyl)amino)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;   I-74: N-(4-((2-morpholinoethyl)amino)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; or   I-75: N-(5-morpholino-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide.   
     
     
         15 . The method of  claim 1 , wherein the disease or condition is a disease or condition for which an IRAK inhibitor is indicated. 
     
     
         16 . The method of  claim 1 , wherein the disease is an auto-immune disease, inflammatory disorder, cardiovascular disease, neurodegenerative disorder, allergic disorder, multi-organ failure, kidney disease, platelet aggregation, cancer, transplantation, sperm motility, erythrocyte deficiency, graft rejection, lung injury, respiratory disease, ischemic condition, bacterial infection, viral infection, immune regulatory disorder or a combination thereof. 
     
     
         17 . The method of  claim 16 , wherein the disease or condition is an auto-immune disease, inflammatory disorder, cardiovascular disease, cancer, ischemic condition, immune regulatory disorder or a combination thereof. 
     
     
         18 . The method of  claim 16 , wherein the disease or condition is an auto-immune disease or inflammatory disorder. 
     
     
         19 . The method of  claim 17 , wherein the cancer is breast cancer, lung cancer, melanoma, leukemia, large B-cell lymphoma, Waldenström's macroglobulinemia, myelodysplastic syndromes, Kaposi's sarcoma, or a combination thereof. 
     
     
         20 . The method of  claim 17 , wherein the disease is an inflammatory or immune regulatory disorder. 
     
     
         21 . The method of  claim 20 , wherein the disorder comprises transplant or tissue rejection, a graft-versus-host disease, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, myasthenia gravis, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, postinfectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrhoeic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedemas, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus, Mooren's ulcer, scleritis, Graves' opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergies, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or inveterate asthma, late asthma and airway hyper-responsiveness, bronchitis, gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel diseases, inflammatory bowel diseases, necrotizing enterocolitis, intestinal lesions associated with thermal burns, celiac diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture's syndrome, hemolytic-uremic syndrome, diabetic nephropathy, multiple myositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthyroidism, Basedow's disease, pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis, fibroid lung, idiopathic interstitial pneumonia, dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity, cutaneous T cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, myocardosis, scleroderma, Wegener's granuloma, Sjögren's syndrome, adiposis, eosinophilic fascitis, lesions of gingiva, periodontium, alveolar bone, substantia ossea dentis, glomerulonephritis, male pattern alopecia or alopecia senilis by preventing epilation or providing hair germination and/or promoting hair generation and hair growth, muscular dystrophy, pyoderma and Sezary's syndrome, Addison's disease, ischemia-reperfusion injury of organs which occurs upon preservation, transplantation or ischemic disease, endotoxin-shock, pseudomembranous colitis, colitis caused by drug or radiation, ischemic acute renal insufficiency, chronic renal insufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer, pulmonary emphysema, cataracta, siderosis, retinitis pigmentosa, senile macular degeneration, vitreal scarring, corneal alkali burn, dermatitis erythema multiforme, linear IgA ballous dermatitis and cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenesis, metastasis of carcinoma and hypobaropathy, disease caused by histamine or leukotriene-C4 release, Behcet's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial liver resection, acute liver necrosis, necrosis caused by toxin, viral hepatitis, shock, or anoxia, B-virus hepatitis, non-A/non-B hepatitis, cirrhosis, alcoholic liver disease, including alcoholic cirrhosis, non-alcoholic steatohepatitis (NASH), hepatic failure, fulminant hepatic failure, late-onset hepatic failure, “acute-on-chronic” liver failure, augmentation of chemotherapeutic effect, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, Parkinson's disease, trauma, chronic bacterial infection, or a combination thereof. 
     
     
         22 . The method of  claim 20 , wherein the disorder is an inflammatory skin disease, psoriasis, palmoplantar psoriasis, primary biliary cirrhosis, sclerosing cholangitis, or systemic juvenile idiopathic arthritis.