Heteroaryl compounds and uses thereof

Abstract

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

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 X 1  is —CR 4 ; 
 X 2  is —CR 5 ; 
 X 3  is N; 
 X 4  is N; 
 X 5  is C; 
 G is H, O, OR, or N(R)(R); 
 Ring A is an optionally substituted group selected from phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10 membered bicyclic saturated, partially unsaturated or aryl ring; 
 each R is independently hydrogen or an optionally substituted group selected from C 1-6  aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 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; or 
 two R groups on the same nitrogen are taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocylic ring having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 4-7 membered heteroaryl ring having 0-4 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 R 1  is a warhead group -L-Y; wherein R 1  is attached to an atom adjacent to the atom where T is attached, wherein:
 R 1  is selected from 
 
 
       
         
           
           
               
               
           
         
         
           L is a bivalent C 2-8  straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two 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)—; or 
           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 additional methylene unit of L is optionally replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—; or 
           L is a bivalent C 2-8  straight or branched, hydrocarbon chain wherein one methylene unit of L is replaced by cyclopropylene and one additional methylene unit of L is 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—; or 
           L is a bivalent C 2-8  straight or branched, hydrocarbon chain wherein L has at least one triple bond and one or two 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—; and 
           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; or 
           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 —, or —SO 2 NH—, and Y is selected from:
 (i) C 1-6  alkyl substituted with oxo, halogen, NO 2 , or CN; or 
 (ii) C2-6 alkenyl substituted with oxo, halogen, NO 2 , or CN; or 
 (iii) C2-6 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 
 
         
       
       
         
           
           
               
               
           
         
         
           
             (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; or 
           
         
       
       
         
           
           
               
               
           
         
         
           
              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 
           
         
       
       
         
           
           
               
               
           
         
         
           
             (xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R e  groups; or 
           
         
       
       
         
           
           
               
               
           
         
         
           
              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 
           
         
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
              or 
             (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; or 
           
           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:
 (i) C 1-6  alkyl substituted with oxo, halogen, NO 2 , or CN; or 
 (ii) C2-6 alkenyl optionally substituted with oxo, halogen, NO 2 , or CN; or 
 (iii) C2-6 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 
 
         
       
       
         
           
           
               
               
           
         
         
           
              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; or 
           
         
       
       
         
           
           
               
               
           
         
         
           
              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 
           
         
       
       
         
           
           
               
               
           
         
         
           
              or 
             (xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R e  groups or 
           
         
       
       
         
           
           
               
               
           
         
         
           
              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 
           
         
       
       
         
           
           
               
               
           
         
         
           
              or 
             (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: 
           
           each R e  is independently selected from -Q-Z, oxo, NO 2 , halogen, CN, C 1-6  aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, or a suitable leaving group selected from alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyl, or diazonium, wherein:
 Q is 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—, —SO 2 —, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, or —SO 2 N(R)—; and 
 each Z is independently hydrogen or C 1-6  aliphatic substituted with oxo, halogen, NO 2 , or CN; 
 
         
         each R 2  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 3  is hydrogen, C2-6 alkenyl, —W-Cy, or C 1-6  alkyl, wherein the C 1-6  alkyl is optionally substituted with 1-3 groups independently selected from halogen, —CN, oxo, —OR′, or —C(O)O(C 1-6  alkyl); 
         W is absent or is a bivalent C1-3 alkylene chain optionally substituted with one or more R″ and wherein one methylene unit of W is optionally replaced with —O—, —S—, or —NR′—; 
         each R′ is independently hydrogen or C 1-6  alkyl; 
         each R″ is independently halogen or C 1-6  alkyl, wherein the C 1-6  alkyl is optionally substituted with 1-3 groups independently selected from halogen, —CN, oxo, or —OR′; 
         Cy is phenyl, C3-7 cycloalkyl, or a 3-7 membered monocyclic or 5-10 membered bicyclic saturated, partially unsaturated, or heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy is optionally substituted with 1-3 R x ; 
         each R x  is independently H, —CN, oxo, —NH 2 , C 1-6  alkyl, halogen, —OR′, —N(R′) 2 , —NHC(O)(C 1-6  alkyl), —C(O)N(R′) 2 , —C(O)O(C 1-6  alkyl), —NHSO 2 (C 1-6  alkyl), or —SO 2 N(R′) 2 ; 
         or R 3  is absent if not allowed by valence; 
         R 4  is hydrogen or an optionally substituted group selected from C 1-6  aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring which is optionally bridged, a 4-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10 membered bicyclic saturated, partially unsaturated or aryl ring, which is optionally bridged; 
         R 5  is independently —R, halogen, —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 ; 
         Y is O or NR a ; 
         R a  is hydrogen or an optionally substituted C 1-6  aliphatic group; 
         T is a covalent bond or a bivalent straight or branched, saturated or unsaturated C 1-6  hydrocarbon chain wherein one or more methylene units are optionally replaced by —O—, —S—, —N(R)—, —C(O)—, —OC(O)—, —C(O)O—, —C(O)N(R)—, —N(R)C(O)—, —N(R)C(O)N(R)—, —S(O)—, —SO 2 —, —SO 2 N(R)—, —N(R)SO 2 —, or —N(R)SO 2 N(R)—; and 
         q is 0-6. 
       
     
     
         2 - 68 . (canceled) 
     
     
         69 . The compound of  claim 1 , wherein G is H. 
     
     
         70 . The compound of  claim 69 , wherein Ring A is phenyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclobutyl, cyclopropyl, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, piperidine, piperidin-one, pyrrolidine, tetrahydropyran, tetrahydrofuran, tetrahydrothiophene dioxide, or cyclobutene dione. 
     
     
         71 . The compound of  claim 70 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
     
     
         72 . The compound of  claim 71 , wherein R 3  is hydrogen. 
     
     
         73 . The compound of  claim 72 , wherein R 4  is ethyl, phenyl, cyclohexyl, 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         74 . The compound of  claim 73 , wherein R 4  is 
       
         
           
           
               
               
           
         
       
     
     
         75 . The compound of  claim 74 , wherein R 4  is 
       
         
           
           
               
               
           
         
       
     
     
         76 . The compound of  claim 74 , wherein R 5  is H. 
     
     
         77 . The compound of  claim 76 , wherein Y is NR a . 
     
     
         78 . The compound of  claim 77 , wherein R a  is hydrogen. 
     
     
         79 . The compound of  claim 78 , wherein T is a covalent bond. 
     
     
         80 . The compound of  claim 79 , wherein q is 0. 
     
     
         81 . The compound of  claim 1 , where the compound is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         82 . A composition comprising a compound according to  claim 1 , and a pharmaceutically acceptable adjuvant, carrier, or vehicle. 
     
     
         83 . A method for inhibiting activity of FGFR4, or a mutant thereof, 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 . 
     
     
         84 . The method according to  claim 83 , wherein the activity of FGFR4, or a mutant thereof, is inhibited irreversibly. 
     
     
         85 . The method according to  claim 84 , wherein the activity of FGFR4, or a mutant thereof, is inhibited irreversibly by covalently modifying Cys 552 of FGFR4. 
     
     
         86 . A method for treating a FGFR4-mediated disorder in a patient in need thereof, comprising the step of administering to said patient a compound according to  claim 1 . 
     
     
         87 . The method according to  claim 86 , wherein the disorder is hepatocellular carcinoma or rhabdomyosarcoma.