Bruton's tyrosine kinase inhibitors

Abstract

The present invention provides compounds useful as inhibitors of Btk, compositions thereof, and methods of using the same.

1 . A compound having the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 X 1  is —O—, —CR 5 R 6 — or —NR 7 —; 
 X 2  is ═CR 8 — or ═N—; 
 p is 0-5; 
 y is 0, 1, or 2; 
 z is 0, 1, or 2, wherein z is 0 or 1 when y is 2, and z is 1 or 2 when y is 0; 
 each R 1  is independently halogen, —NO 2 , —CN, —OR, —SR, —N(R) 2 , —C(O)R, —CO 2 R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —S(O)R, —S(O) 2 R, —C(O)N(R) 2 , —SO 2 N(R) 2 , —OC(O)R, —N(R)C(O)R, —N(R)N(R) 2 , —N(R)C(═NR)N(R) 2 , —C(═NR)N(R) 2 , —C═NOR, —N(R)C(O)N(R) 2 , —N(R)SO 2 N(R) 2 , —N(R)SO 2 R, —OC(O)N(R) 2 , or an optionally substituted group selected from C 1-12  aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
 two R 1  groups on adjacent carbon atoms are taken together with their intervening atoms to form an optionally substituted ring selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or: 
 two R 1  groups on non-adjacent carbon atoms are taken together with their intervening atoms to form an optionally substituted bridge of a bridged bicyclic group, wherein the bridge is a C 1-3  hydrocarbon chain wherein one methylene unit is optionally replaced by —NR—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—S—, or —S—, or: 
 two R 1  groups on the same carbon atom are taken together with their intervening atoms to form an optionally substituted spiro fused ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 
 each R is independently hydrogen or an optionally substituted group selected from C 1-6  aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered heteroaryl ring having 1-3 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 an optionally substituted 3-7 membered saturated, partially unsaturated, or heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 
 each of R 2 , R 3 , R 5 , R 6 , and R 8  is independently R, halogen, —NO 2 , —CN, —OR, —SR, —N(R) 2 , —C(O)R, —CO 2 R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —S(O)R, —S(O) 2 R, —C(O)N(R) 2 , —SO 2 N(R) 2 , —OC(O)R, —N(R)C(O)R, —N(R)N(R) 2 , —N(R)C(═NR)N(R) 2 , —C(═NR)N(R) 2 , —C═NOR, —N(R)C(O)N(R) 2 , —N(R)SO 2 N(R) 2 , —N(R)SO 2 R, or —OC(O)N(R) 2 ; or:
 R 3  and R 4  are optionally taken together with their intervening atoms to form an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 
 each of R 4  and R 7  is independently R, —CN, —C(O)R, —CO 2 R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —C(O)N(R) 2 , —S(O)R, —S(O) 2 R, or —S(O) 2 N(R) 2 ; 
 Ring A 1  is an optionally substituted bivalent ring selected from phenylene, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclylene, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclylene, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic arylene, a 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroarylene ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 Ring A 2  is an optionally substituted ring selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 L is a covalent bond or an optionally substituted, bivalent C 1-7  saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one, two, or three methylene units of L are independently replaced by —Cy—, —CR 2 —, —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—, —SO 2 —, —C(═S)—, —C(═NR)—, —N═N—, or —C(═N 2 )—, wherein at least one methylene unit of L is replaced by —N(R)—; and 
 each Cy is independently an optionally substituted bivalent ring selected from phenylene, a 3-7 membered saturated or partially unsaturated carbocyclylene, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
 
     
     
         2 .- 3 . (canceled) 
     
     
         4 . The compound of  claim 1 , wherein one methylene unit of L is replaced by —C(O)—. 
     
     
         5 . The compound of  claim 1 , wherein L is —NH—C(O)—NH—, —NH—C(O)—, —NH—, or —NHSO 2 —. 
     
     
         6 . (canceled) 
     
     
         7 . The compound of  claim 1 , wherein L is: 
       
         
           
           
               
               
           
         
         wherein s and t are independently 0, 1, or 2, and the sum of s and t is 0-4. 
       
     
     
         8 . (canceled) 
     
     
         9 . The compound of  claim 1 , wherein L is substituted with halogen, —CN, —CF 3 , —OH, —R, —OR, —NH 2 , —N(R) 2 , or —COOH. 
     
     
         10 .- 12 . (canceled) 
     
     
         13 . The compound of  claim 1 , wherein at least one methylene unit of L is replaced by —O—. 
     
     
         14 .- 15 . (canceled) 
     
     
         16 . The compound of  claim 1 , wherein the compound is of formula I-a-i, or I-a-ii: 
       
         
           
           
               
               
           
         
       
     
     
         17 . The compound of  claim 1 , wherein the compound is of formula I-b-i, or I-b-ii: 
       
         
           
           
               
               
           
         
       
     
     
         18 . The compound of  claim 1 , wherein R 3  and R 4  are joined together with their intervening atoms to form an optionally substituted pyrrole or pyrazole. 
     
     
         19 . (canceled) 
     
     
         20 . The compound of  claim 18 , wherein the compound is of formula V-a: 
       
         
           
           
               
               
           
         
       
     
     
         21 .- 27 . (canceled) 
     
     
         28 . The compound of  claim 1 , wherein p is at least two, and:
 two R 1  groups on adjacent carbon atoms are taken together with their intervening atoms to form an optionally substituted ring selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:   two R 1  groups on non-adjacent carbon atoms are taken together with their intervening atoms to form an optionally substituted bridge of a bridged bicyclic group, wherein the bridge is a C 1-3  hydrocarbon chain wherein one methylene unit is optionally replaced by —NR—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—S—, or —S—, or:   two R 1  groups on the same carbon atom are taken together with their intervening atoms to form an optionally substituted spiro fused ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.   
     
     
         29 . The compound of  claim 28 , wherein two R 1  groups are taken together with their intervening atoms to form a bicyclic ring having a formula: 
       
         
           
           
               
               
           
         
         wherein the bicyclic ring is optionally further substituted with one, two, or three R 1  groups. 
       
     
     
         30 . The compound of  claim 29 , wherein R 2  is hydrogen, C 1-6  aliphatic, or —N(R) 2 . 
     
     
         31 .- 41 . (canceled) 
     
     
         42 . The compound of claim  41 , wherein the compound is of formula I-a-iii: 
       
         
           
           
               
               
           
         
       
     
     
         43 . The compound of claim  41 , wherein the compound is of formula I-b-iii: 
       
         
           
           
               
               
           
         
       
     
     
         44 .- 65 . (canceled) 
     
     
         66 . The compound of  claim 1 , wherein the compound is a compound as shown in Table 1. 
     
     
         67 . The compound of  claim 1 , wherein the compound is of formula II-b: 
       
         
           
           
               
               
           
         
       
     
     
         68 . A pharmaceutical formulation comprising a compound of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         69 . (canceled) 
     
     
         70 . A method of treating a disorder responsive to inhibition of Bruton's tyrosine kinase comprising administering to a subject an effective amount of a compound of  claim 1  or a composition thereof. 
     
     
         71 . A method of treating a disorder selected from the group consisting of autoimmune disorders, inflammatory disorders, and cancers comprising administering to a subject an effective amount of a compound of  claim 1  or a composition thereof. 
     
     
         72 .- 74 . (canceled)