Claims for Patent: 8,735,403

Summary for Patent: 8,735,403

Title:	Inhibitors of Bruton's tyrosine kinase
Abstract:	Disclosed herein are compounds that form covalent bonds with Bruton's tyrosine kinase (Btk). Also described are irreversible inhibitors of Btk. Methods for the preparation of the compounds are disclosed. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the Btk inhibitors are disclosed, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.
Inventor(s):	Lee Honigberg, Erik Verner, Zhengying Pan
Assignee:	Pharmacyclics LLC
Application Number:	US13/249,066
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,735,403
Patent Claims:	1. An irreversible inhibitor of a Bruton's tyrosine kinase (Btk) having the structure of Formula (A): wherein: A is independently selected from N; R1 is L2-(substituted or unsubstituted heteroaryl), or L2-(substituted or unsubstituted aryl), where L2 is a bond, O, S, —S(═O), —S(═O)2, C(═O), -(substituted or unsubstituted C1-C6 alkylene), or -(substituted or unsubstituted C2-C6 alkenylene); R2 and R3 are independently selected from H or lower alkyl; R4 is L3-X-L4-G, wherein, L3 is optional, and when present is a bond, optionally substituted or unsubstituted alkylene, optionally substituted or unsubstituted cycloalkylene, optionally substituted or unsubstituted alkenylene, or optionally substituted or unsubstituted alkynylene; X is optional, and when present is a bond, O, —C(═O), S, —S(═O), —S(═O)2, —NH, —NR9, —NHC(O), —C(O)NH, —NR9C(O), —C(O)NR9, —S(═O)2NH, —NHS(═O)2, —S(═O)2NR9—, —NR9S(═O)2, —OC(O)NH—, —NHC(O)O—, —OC(O)NR9—, —NR9C(O)O—, —CH═NO—, —ON═CH—, —NR10C(O)NR10—, heteroarylene, arylene, —NR10C(═NR11)NR10—, —NR10C(═NR11)—, —C(═NR11)NR10—, —OC(═NR11)—, or —C(═NR11)O—; L4 is optional, and when present is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted heterocyclene; or L3, X and L4 taken together form a nitrogen containing heterocyclic ring; G is wherein, R6, R7 and R8 are independently selected from among H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl; R9 is selected from among H, substituted or unsubstituted lower alkyl, and substituted or unsubstituted lower cycloalkyl; each R10 is independently H, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower cycloalkyl; or two R10 groups can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or R10 and R11 can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or each R11 is selected from H, —S(═O)2R8, —S(═O)2NH2, —C(O)R8, —CN, —NO2, heteroaryl, or heteroalkyl; or a pharmaceutically acceptable solvate, hydrate, or salt thereof, wherein the irreversible Btk inhibitor covalently bonds to cysteine 481 of Btk. 2. The Btk inhibitor of claim 1, wherein the Btk inhibitor has the structure: 3. The Btk inhibitor of claim 1, wherein R1 is L2-substituted aryl; and L2 is a bond. 4. The Btk inhibitor of claim 1, wherein R2 and R3 are independently H. 5. The Btk inhibitor of claim 1, wherein the compound of Formula (A) has the structure of Formula (B): wherein: Y is alkylene or substituted alkylene, or a 4-, 5-, or 6-membered cycloalkylene ring; each Ra is independently H, halogen, —CF3, —CN, —NO2, OH, NH2, -La-(substituted or unsubstituted alkyl), -La-(substituted or unsubstituted alkenyl), -La-(substituted or unsubstituted heteroaryl), or -La-(substituted or unsubstituted aryl), wherein La is a bond, O, S, —S(═O), —S(═O)2, NH, C(O), CH2, —NHC(O)O, —NHC(O), or —C(O)NH; G is wherein, R6, R7 and R8 are independently selected from among H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl; R12 is H or lower alkyl; or Y and R12 taken together form a 4-, 5-, or 6-membered heterocyclic ring; or a pharmaceutically acceptable solvate, hydrate, or salt thereof. 6. The Btk inhibitor of claim 5, wherein Y and R12 taken together form a 6-membered heterocyclic ring. 7. The Btk inhibitor of claim 5, wherein the compound of Formula (B) has the structure of Formula (C): Y is alkylene or substituted alkylene, or a 4-, 5-, or 6-membered cycloalkylene ring; R12 is H or lower alkyl; or Y and R12 taken together form a 4-, 5-, or 6-membered heterocyclic ring; G is wherein, R6, R7 and R8 are independently selected from among H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl; or a pharmaceutically acceptable solvate, hydrate, or salt thereof. 8. The Btk inhibitor of claim 7, wherein Y and R12 taken together form a 4-, 5-, or 6-membered heterocyclic ring. 9. The Btk inhibitor of claim 7, wherein G is or 10. The Btk inhibitor of claim 7, wherein R6, R7, and R8 are independently H. 11. An irreversible inhibitor of a Bruton's tyrosine kinase (Btk) having the structure of Formula (D): wherein La is CH2, O, NH or S; Ar is an optionally substituted aromatic carbocycle or an aromatic heterocycle; Y is an optionally substituted alkyl, heteroalkylene, carbocyclene, heterocyclene, or combination thereof; Z is C(O), OC(O), NHC(O), C(S), S(O)x, OS(O)x, NHS(O)x, where x is 1 or 2; and R6, R7, and R8 are independently selected from H, alkyl, heteroalkyl, carbocycle, heterocycle, or combinations thereof, wherein the irreversible Btk inhibitor covalently bonds to cysteine 481 of Btk. 12. The Btk inhibitor of claim 11, wherein La is O, Ar is an aromatic carbocycle, Y is heterocyclene, Z is C(O), and R6, R7, and R8 are independently H. 13. An oral formulation comprising the BTK inhibitor of claim 1.