Irak inhibitors and uses thereof

Abstract

The present invention provides compounds, compositions thereof, and methods of using the same.

We claim: 
     
         1 - 20 . (canceled) 
     
     
         21 . A method of treating a disorder mediated by one or more IRAK protein kinases in a patient in need thereof, comprising the step of administering to said patient a compound represented by formula 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         Ring A is a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         n is 0-4; 
         each R 1  is independently —R, halogen, —CN, —NO 2 , —OR, —CH 2 OR, —SR, —N(R) 2 , —SO 2 R, —SO 2 N(R) 2 , —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —C(O)N(R)—OR, —NRC(O)R, —NRC(O)N(R) 2 , Cy, or —NRSO 2 R; or R 1  is selected from one of the following formulas: 
       
       
         
           
           
               
               
           
         
       
       or
 two R 1  groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered fused, spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each Cy is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each R is independently hydrogen or an optionally substituted group selected from C 1-6  aliphatic, aryl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or: 
 two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, or sulfur; 
 R z  is —R, —CN, —NO 2 , halogen, —C(O)N(R) 2 , —C(O)OR, —C(O)R, —N(R) 2 , —OR, or —SO 2 N(R) 2 ; 
 Ring B is an unsubstituted 4-8 membered partially unsaturated carbocyclic fused ring; and 
 L is a C 1-6  bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, —SO 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO— or —SO 2 —; 
 or a pharmaceutically acceptable composition thereof. 
 
     
     
         22 . The method of  claim 21 , wherein the disorder is a proliferative disorder. 
     
     
         23 . The method of  claim 22 , wherein the proliferative disorder is selected from a benign or malignant tumor, lymphoma, Hodgkin's and Non-Hodgkin's lymphoma, multiple myeloma, smoldering or indolent multiple myeloma, Waldenström's macroglobulinemia, carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, or gastrointestinal cancer, colon carcinoma or colorectal adenoma or a tumor of the neck and head, an epidermal hyperproliferation, prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small-cell lung carcinoma, a mammary carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, or a leukemia. 
     
     
         24 . The method of  claim 21 , wherein the disorder is mediated by one or more of IRAK-1, IRAK-2, or IRAK-4, or a mutant thereof. 
     
     
         25 . The method of  claim 21 , wherein the disorder is selected from acute and chronic gout, chronic gouty arthritis, psoriasis, contact dermatitis, atopic dermatitis alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, rheumatoid arthritis, Juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), Cryopyrin-Associated Periodic Syndrome (CAPS), systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, Crohn's disease, an ulcerative colitis, an inflammatory condition of the eye, Sjogren's syndrome, allergic disorders, osteoarthritis, ocular allergy, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis, an inflammatory condition of the nasal passages, allergic rhinitis, an inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, an autoimmune hematological disorder, hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia, polychondritis, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, sepsis, Type 1 diabetes, Type 2 diabetes, metabolic syndrome, obesity, HIV infection, epilepsy, atherosclerosis, heart disease, chronic heart failure, ischemia/reperfusion, stroke, asthma, chronic obstructive pulmonary disease, gut diseases, inflammatory neuropathy, organ transplantation, or graft versus host disease. 
     
     
         26 . The method of  claim 21 , further comprising administering to the patient an additional therapeutic agent. 
     
     
         27 . The method of  claim 21 , wherein the compound has the formula III-g or IV-g: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         28 . The method of  claim 21 , wherein the compound has the formula III-h or IV-h: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         29 . The method of  claim 21 , wherein the compound has the formula III-i or IV-i: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         30 . The method of  claim 28 , wherein n is 1, and R 1  is of one the following formulas: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         31 . The method of  claim 28 , wherein n is 1 and R 1  is —N(CH 3 ) 2 . 
     
     
         32 . The method of  claim 28 , wherein n is 1 and R 1  is Cy. 
     
     
         33 . The method of  claim 32 , wherein the compound has the formula III-j or IV-j: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         34 . The method of  claim 21 , wherein L is —O—. 
     
     
         35 . The method of  claim 21 , wherein L is —NR—. 
     
     
         36 . The method of  claim 21 , wherein L is —NH—. 
     
     
         37 . The method of  claim 21 , wherein L is —S—. 
     
     
         38 . The method of  claim 21 , wherein said compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         39 . The method of  claim 21 , wherein said compound is selected from: