Heteroaryl compounds as irak inhibitors and uses thereof

Abstract

The present invention relates to compounds of Formula I and pharmaceutically acceptable compositions thereof, useful as IRAK inhibitors.

We claim: 
     
         1 . A compound of formula I, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
       
       
         
           
           
               
               
           
         
       
       is a C 3-10  aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
 each R a  is independently —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ; 
 R b  is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ; or R b  is absent; 
 Ring X is a C 3-10  aryl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a fused C 3-10  aryl, a fused 5-10 membered saturated or partially unsaturated carbocyclic ring, a fused 5-10 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a fused 5-10 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; 
 R 1  is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ; 
 R 2  is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ; 
 R 3  is —R or -haloalkyl; 
 R 4  is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ; 
 each R is independently hydrogen, C 1-6  aliphatic, C 3-10  aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or 
 two R groups on the same atom are taken together with the atom to which they are attached to form a C 3-10  aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; and 
 p is 0, 1, 2, 3, 4, or 5. 
 
     
     
         2 . The compound of  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       is cyclohexanone, furanone, piperidinone, pyridinone, pyrimidinone, pyrrolidinone, or oxetanyl. 
     
     
         3 . The compound of  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein Ring X is an optionally substituted C 3-10  aryl; an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an optionally substituted fused C 3-10  aryl; or an optionally substituted fused 5-10 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     
     
         5 . The compound of  claim 4 , wherein Ring X is phenyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; 1,2,5oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, tetrazole, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, or 1,3,4-triazolyl; each of which is optionally substituted. 
     
     
         6 . The compound of  claim 5 , wherein Ring X is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 4 , wherein Ring X is: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 1 , wherein R 3  is C 1-6  aliphatic, a 3-8 membered saturated or partially unsaturated carbocyclic ring, or a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted. 
     
     
         9 . The compound of  claim 8 , wherein R 3  is methyl, ethyl, propyl, i-propyl, n-butyl, s-butyl, t-butyl, a straight chain or branched pentyl, or a straight chain or branched hexyl; each of which is optionally substituted. 
     
     
         10 . The compound of  claim 9 , wherein R 3  is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 1 , of formula I-a, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         12 . The compound of  claim 1 , of formula I-b, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         13 . The compound of  claim 1 , of formula I-c, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         14 . The compound of  claim 1 , selected from Table 1. 
     
     
         15 . A pharmaceutical composition comprising a compound of  claim 1 , and a pharmaceutically acceptable adjuvant, carrier, or vehicle. 
     
     
         16 . A method for inhibiting IRAK, or a mutant thereof, activity in a patient or in a biological sample, comprising the step of administering to said patient or contacting said biological sample with a compound of  claim 1  or a physiologically acceptable salt thereof. 
     
     
         17 . A method for treating an IRAK-mediated disorder in a patient in need thereof, comprising the step of administering to said patient a compound of  claim 1 . 
     
     
         18 . The method of  claim 17 , wherein the disorder is selected from Rheumatoid Arthritis, Psoriatic arthritis, Osteoarthritis, Systemic Lupus Erythematosus, Lupus nephritis, Ankylosing Spondylitis, Osteoporosis, Systemic sclerosis, Multiple Sclerosis, Psoriasis, Type I diabetes, Type II diabetes, Inflammatory Bowel Disease (Cronh's Disease and Ulcerative Colitis), Hyperimmunoglobulinemia D and periodic fever syndrome, Cryopyrin-associated periodic syndromes, Schnitzler's syndrome, Systemic juvenile idiopathic arthritis, Adult's onset Still's disease, Gout, Pseudogout, SAPHO syndrome, Castleman's disease, Sepsis, Stroke, Atherosclerosis, Celiac disease, DIRA (Deficiency of IL-1 Receptor Antagonist), Alzheimer's disease, Parkinson's disease, and Cancer. 
     
     
         19 . A method for treating cancer in a subject, comprising the step of administering to said subject a compound of  claim 1  or a physiologically acceptable salt thereof. 
     
     
         20 . The method of  claim 18 , wherein the disorder is selected from Rheumatoid Arthritis, Systemic Lupus Erythematosus, Lupus nephritis, and Multiple Sclerosis.