Heteroaryl compounds and uses thereof

Abstract

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

We claim: 
     
         1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         Ring A is an optionally substituted group selected from phenyl, an 8-10 membered bicyclic partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         Ring B is phenyl, a 5-6 membered heteroaryl ring having 1-3 heteratoms independently selected from N, O or S, a 5-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from N, O or S, or an 8-10 membered bicyclic partially unsaturated or aryl ring having 1-3 heteroatoms independently selected from N, O or S; 
         R 1  is a warhead group; 
         R y  is hydrogen, halogen, CN, lower alkyl, or lower haloalkyl; 
         G is CH, or N; 
         W is a bivalent C 1-3  alkylene chain wherein one methylene unit of W is optionally replaced by —NR 2 —, —N(R 2 )C(O)—, —C(O)N(R 2 )—, —N(R 2 )SO 2 —, —SO 2 N(R 2 )—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO— or —SO 2 —; 
         R 2  is hydrogen or optionally substituted C 1-6  aliphatic, or:
 R 2  and a substituent on Ring A are taken together with their intervening atoms to form a 4-6 membered saturated ring, or: 
 R 2  and R y  are taken together with their intervening atoms to form a 4-7 membered carbocyclic ring; 
 
         m is 0-4; 
         each R x  is independently selected from —R, halogen, —OR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)NR 2 , —NRSO 2 R, or —N(R) 2 ; or:
 R x  and R 1  are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with a warhead group and 0-3 groups independently selected from oxo, halogen, CN, or C 1-6  aliphatic; and 
 
         each R group is independently hydrogen or an optionally substituted group selected from C 1-6  aliphatic, phenyl, a 4-7 membered heterocylic ring having 1-2 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. 
       
     
     
         2 . The compound according to  claim 1 , wherein the compound is of formula II: 
       
         
           
           
               
               
           
         
         wherein: 
         W is —NR 2 —, —S—, or —O—; 
         R 2  is hydrogen or optionally substituted C 1-6  aliphatic, or:
 R 2  and a substituent on Ring A are taken together with their intervening atoms to form a 4-6 membered saturated ring; and 
 
         G is CH or N. 
       
     
     
         3 . The compound according to  claim 2 , wherein Ring A is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         4 . The compound according to  claim 1 , wherein Ring B is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         5 . The compound according to  claim 2 , wherein m is 1, 2, 3, or 4. 
     
     
         6 . The compound according to  claim 1 , wherein said compound is of formula I-i, I-ii, or I-iii: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The compound according to  claim 1 , wherein said compound is of formula II-i, II-ii, or II-iii: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The compound according to  claim 1 , wherein R 1  is -L-Y, wherein:
 L is a bivalent C 2-8  straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two additional methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—;   Y is hydrogen, C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 R e  groups; and   each R e  is independently selected from -Q-Z, oxo, NO 2 , halogen, CN, a suitable leaving group, or C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, wherein:
 Q is a covalent bond or a bivalent C 1-6  saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and independently replaced by —N(R)—, —S—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —SO—, or —SO 2 —, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, or —SO 2 N(R)—; and 
 Z is hydrogen or C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN. 
   
     
     
         9 . The compound according to  claim 8 , wherein:
 L is a bivalent C 2-8  straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—; and   Y is hydrogen or C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.   
     
     
         10 . The compound according to  claim 9 , wherein L is a bivalent C 2-8  straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—. 
     
     
         11 . The compound according to  claim 9 , wherein L is a bivalent C 2-8  straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —OC(O)—. 
     
     
         12 . The compound according to  claim 9 , wherein L is —NRC(O)CH═CH—, —NRC(O)CH═CHCH 2 N(CH 3 )—, —NRC(O)CH═CHCH 2 O—, —CH 2 NRC(O)CH═CH—, —NRSO 2 CH═CH—, —NRSO 2 CH═CHCH 2 —, —NRC(O)(C═N 2 )—, —NRC(O)(C═N 2 )C(O)—, —NRC(O)CH═CHCH 2 N(CH 3 )—, —NRSO 2 CH═CH—, —NRSO 2 CH═CHCH 2 —, —NRC(O)CH═CHCH 2 O—, —NRC(O)C(═CH 2 )CH 2 —, —CH 2 NRC(O)—, —CH 2 NRC(O)CH═CH—, —CH 2 CH 2 NRC(O)—, or —CH 2 NRC(O)cyclopropylene-; wherein R is H or optionally substituted C 1-6  aliphatic; and Y is hydrogen or C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN. 
     
     
         13 . The compound according to  claim 12 , wherein L is —NHC(O)CH═CH—, —NHC(O)CH═CHCH 2 N(CH 3 )—, —NHC(O)CH═CHCH 2 O—, —CH 2 NHC(O)CH═CH—, —NHSO 2 CH═CH—, —NHSO 2 CH═CHCH 2 —, —NHC(O)(C═N 2 )—, —NHC(O)(C═N 2 )C(O)—, —NHC(O)CH═CHCH 2 N(CH 3 )—, —NHSO 2 CH═CH—, —NHSO 2 CH═CHCH 2 —, —NHC(O)CH═CHCH 2 O—, —NHC(O)C(═CH 2 )CH 2 —, —CH 2 NHC(O)—, —CH 2 NHC(O)CH═CH—, —CH 2 CH 2 NHC(O)—, or —CH 2 NHC(O)cyclopropylene-. 
     
     
         14 . The compound according to  claim 9 , wherein L is a bivalent C 2-8  straight or branched, hydrocarbon chain wherein L has at least one alkylidenyl double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—. 
     
     
         15 . The compound according to  claim 1 , wherein R 1  is -L-Y, wherein:
 L is a bivalent C 2-8  straight or branched, hydrocarbon chain wherein L has at least one triple bond and one or two additional methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—,   Y is hydrogen, C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 R e  groups; and   each R e  is independently selected from -Q-Z, oxo, NO 2 , halogen, CN, a suitable leaving group, or C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, wherein:
 Q is a covalent bond or a bivalent C 1-6  saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and independently replaced by —N(R)—, —S—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —SO—, or —SO 2 —, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, or —SO 2 N(R)—; and 
   Z is hydrogen or C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.   
     
     
         16 . The compound according to  claim 15 , wherein Y is hydrogen or C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN. 
     
     
         17 . The compound according to  claim 16 , wherein L is —C≡C—, —C≡CCH 2 N(isopropyl)-, —NHC(O)C≡CCH 2 CH 2 —, —CH 2 —C≡C—CH 2 —, —C≡CCH 2 O—, —CH 2 C(O)C≡C—, —C(O)C≡C—, or —CH 2 OC(═O)C≡C—. 
     
     
         18 . The compound according to  claim 1 , wherein R 1  is -L-Y, wherein:
 L is a bivalent C 2-8  straight or branched, hydrocarbon chain wherein one methylene unit of L is replaced by cyclopropylene and one or two additional methylene units of L are independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—;   Y is hydrogen, C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 R e  groups; and   each R e  is independently selected from -Q-Z, oxo, NO 2 , halogen, CN, a suitable leaving group, or C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, wherein:
 Q is a covalent bond or a bivalent C 1-6  saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and independently replaced by —N(R)—, —S—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —SO—, or —SO 2 —, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, or —SO 2 N(R)—; and 
 Z is hydrogen or C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN. 
   
     
     
         19 . The compound according to  claim 18 , wherein Y is hydrogen or C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN. 
     
     
         20 . The compound according to  claim 1 , wherein R 1  is -L-Y, wherein:
 L is a covalent bond, —C(O)—, —N(R)C(O)—, or a bivalent C 1-8  saturated or unsaturated, straight or branched, hydrocarbon chain; and   Y is selected from the following (i) through (xvii):
 (i) C 1-6  alkyl substituted with oxo, halogen, NO 2 , or CN; 
 (ii) C 2-6  alkenyl optionally substituted with oxo, halogen, NO 2 , or CN; or 
 (iii) C 2-6  alkynyl optionally substituted with oxo, halogen, NO 2 , or CN; or 
 (iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 R e  groups; or 
 (v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R e  groups; or 
 (vi) 
   
       
         
           
           
               
               
           
         
         
           
             wherein each R, Q, Z; or 
           
           (vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e  groups; or 
           (viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e  groups; or 
           (ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e  groups; 
           (x) 
         
       
       
         
           
           
               
               
           
         
         
           
             or 
           
           (xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e  groups; or 
           (xii) 
         
       
       
         
           
           
               
               
           
         
         
           
             or 
           
           (xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R e  groups; or 
           (xiv) 
         
       
       
         
           
           
               
               
           
         
         
           
             wherein each R e  is as defined above and described herein; or 
           
           (xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 R e  groups; or 
           (xvi) 
         
       
       
         
           
           
               
               
           
         
         
           (xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e  groups; 
         
         wherein: 
         each R group is independently hydrogen or an optionally substituted group selected from C 1-6  aliphatic, phenyl, a 4-7 membered heterocylic ring having 1-2 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 e  is independently selected from -Q-Z, oxo, NO 2 , halogen, CN, a suitable leaving group, or C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, wherein:
 Q is a covalent bond or a bivalent C 1-6  saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and independently replaced by —N(R)—, —S—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —SO—, or —SO 2 —, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, or —SO 2 N(R)—; and 
 Z is hydrogen or C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN. 
 
       
     
     
         21 . The compound according to  claim 20 , wherein L is a covalent bond, —CH 2 —, —NH—, —C(O)—, —CH 2 NH—, —NHCH 2 —, —NHC(O)—, —NHC(O)CH 2 OC(O)—, —CH 2 NHC(O)—, —NHSO 2 —, —NHSO 2 CH 2 —, —NHC(O)CH 2 OC(O)—, or —SO 2 NH—. 
     
     
         22 . The compound according to  claim 21 , wherein L is a covalent bond. 
     
     
         23 . The compound according to any of  claims 20 ,  21 , and  22 , wherein Y is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein each R e  is independently selected from halogen. 
     
     
         24 . The compound according to  claim 1 , wherein R 1  is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein each R e  is independently a suitable leaving group, NO 2 , CN, or oxo. 
     
     
         25 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         26 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         27 . A composition comprising a compound according to  claim 1 , and a pharmaceutically acceptable adjuvant, carrier, or vehicle. 
     
     
         28 . The composition according to  claim 27 , in combination with an additional therapeutic agent. 
     
     
         29 . The composition according to  claim 28 , wherein the additional therapeutic agent is a chemotherapeutic agent. 
     
     
         30 . A method for inhibiting one or more of ErbB1, ErbB2, ErbB3, or ErbB4, 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 according to  claim 1 . 
     
     
         31 . The method according to  claim 30 , wherein the one or more of ErbB1, ErbB2, or ErbB4, or a mutant thereof, activity is inhibited irreversibly. 
     
     
         32 . The method according to  claim 30 , wherein the one or more of ErbB1, ErbB2, or ErbB4, or a mutant thereof, activity is inhibited irreversibly by covalently modifying Cys797 of ErbB1, Cys805 of ErbB2 or Cys803 of ErbB4. 
     
     
         33 . A method for treating an ErbB1-, ErbB2-, ErbB3-, or ErbB4-mediated disorder in a patient in need thereof, comprising the step of administering to said patient a compound according to  claim 1 . 
     
     
         34 . The method according to  claim 33 , wherein the disorder is a carcinoma selected from breast cancer, glioblastoma, lung cancer, cancer of the head and neck, colorectal cancer, bladder cancer, non-small cell lung cancer, squamous cell carcinoma, salivary gland carcinoma, ovarian carcinoma, or pancreatic cancer. 
     
     
         35 . The method according to  claim 34 , wherein the disorder is selected from neurofibromatosis type I (NF1), neurofibromatosis type II (NF2) Schwann cell neoplasms (e.g. MPNST's), or a Schwannoma. 
     
     
         36 . A method for inhibiting one or more TEC-kinases, 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 according to  claim 1 . 
     
     
         37 . The method according to  claim 36 , wherein the TEC-kinase, or a mutant thereof, activity is inhibited irreversibly. 
     
     
         38 . The method according to  claim 37  wherein the TEC-kinase is selected from one or more of TEC, ITK or BMX. 
     
     
         39 . The method according to  claim 38 , where the one or more of TEC, ITK or BMX activity is inhibited irreversibly by covalently modifying Cys 449 of TEC, Cys 442 of ITK or Cys 496 of BMX. 
     
     
         40 . A method for treating a TEC-kinase-mediated disorder in a patient in need thereof, comprising the step of administering to said patient a compound according to  claim 1 . 
     
     
         41 . The method according to  claim 40 , wherein the disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, a hyperproliferative disease, an immunological-mediated diseases, a disease of the respiratory tract, a disease of the bone and joints, a skin disorder, a gastrointestinal disorder, a systemic disease, or allograft rejection. 
     
     
         42 . A method for inhibiting BTK, 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 according to  claim 1 . 
     
     
         43 . The method according to  claim 42 , wherein the BTK, or a mutant thereof, activity is inhibited irreversibly. 
     
     
         44 . The method according to  claim 43 , wherein the BTK, or a mutant thereof, activity is inhibited irreversibly by covalently modifying Cys 481 of BTK. 
     
     
         45 . A method for treating a BTK-mediated disorder in a patient in need thereof, comprising the step of administering to said patient a compound according to  claim 1 . 
     
     
         46 . The method according to  claim 45 , wherein the disorder is an autoimmune disease, a heteroimmune disease, an inflammatory disease, a cancer, or a thromboembolic disorder. 
     
     
         47 . The method according to  claim 46 , wherein the disorder is selected from rheumatoid arthritis, multiple sclerosis, B-cell chronic lymphocytic leukemia, hairy cell leukemia, non-Hodgkin's lymphoma, irritable bowel syndrome, Crohn's disease, lupus or disorders associated with renal transplant. 
     
     
         48 . A method for inhibiting JAK3, 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 according to  claim 1 . 
     
     
         49 . The method according to  claim 48 , wherein the JAK3, or a mutant thereof, activity is inhibited irreversibly. 
     
     
         50 . The method according to  claim 49 , wherein the JAK3, or a mutant thereof, activity is inhibited irreversibly by covalently modifying Cys 909 of JAK3. 
     
     
         51 . A method for treating a JAK3-mediated disorder in a patient in need thereof, comprising the step of administering to said patient a compound according to  claim 1 . 
     
     
         52 . The method according to  claim 51 , wherein the disorder is selected from an autoimmune disorder, an inflammatory disorder, a neurodegenerative disorder, or a solid or hematologic malignancy.