Btk inhibitors with improved dual selectivity

Abstract

Disclosed herein is a tri-substituted phenyl Btk inhibitors with improved dual selectivity, a method and a composition for inhibiting Btk and treating disease associated with undesirable Btk activity (Btk-related diseases).

1 - 25 . (canceled) 
     
     
         26 . A method of treating a disease associated with undesirable Btk activity in a subject comprising administering to the subject, a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
 L is a bond, CH 2 , NR 12 , O, or S; 
 R 1  is halogen, heteroalkyl, alkyl, alkenyl, cycloalkyl, aryl, saturated or unsaturated heterocyclyl, heteroaryl, alkynyl, —CN, —NR 13 R 14 , —OR 13 , —COR 13 , —CO 2 R 13 , —CONR 13 R 14 , —C(═NR 13 )NR 14 R 15 , —NR 13 COR 14 , —NR 13 CONR 14 R 15 , —NR 13 CO 2 R 14 , —SO 2 R 13 , —NR 13 SO 2 NR 14 R 15 , or —NR 13 SO 2 R 4 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and saturated or unsaturated heterocyclyl are optionally substituted with at least one substituent R 16 ; 
 n is an integer of 2, 3 or 4; 
 each R 2  is independently halogen, alkyl, —S-alkyl, —CN, —NR 13 R 14 , —OR 13 , —COR 13 , —CO 2 R 13 , —CONR 13 R 14 , —C(═NR 13 )NR 14 R, —NR 13 COR 14 , —NR 13 CONR 14 R 15 , —NR 13 CO 2 R 1 , —SO 2 R 13 , —NR 13 SO 2 NR 14 R 15 , or —NR 13 SO 2 R 14 , wherein R 2  is, optionally, partially or fully deuterated; 
 R 4a  and R 4b  are each independently hydrogen, halogen, heteroalkyl, alkyl, alkenyl, cycloalkyl, saturated or unsaturated heterocyclyl, heteroaryl, alkynyl, —CN, —NR 13 R 14 , —OR 13 , —COR 13 , —CO 2 R 13 , —CONR 13 R 14 , —C(═NR 13 )NR 14 R, —NR 13 COR 14 , —NR 13 CONR 14 R 13 , —NR 13 CO 2 R 14 , —SO 2 R 13 , —NR 13 SO 2 NR 14 R 15 , or —NR 13 SO 2 R 14 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and saturated or unsaturated heterocyclyl are optionally substituted with at least one substituent R 16 ; 
 R 5a  and R 5b  are each independently hydrogen, halogen, heteroalkyl, alkyl, alkenyl, cycloalkyl, aryl, saturated or unsaturated heterocyclyl, heteroaryl, alkynyl, —CN, —NR 13 R 14 , —OR 13 , —COR 13 , —CO 2 R 13 , —CONR 13 R 14 , —C(═NR 13 )NR 14 R 15 , —NR 13 COR 4 , —NR 13 CONR 4 R 1 , —NR 13 CO 2 R 4 , —SO 2 R 13 , —NR 13 SO 2 NR 14 R 15 , or —NR 13 SO 2 R 14 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and saturated or unsaturated heterocyclyl are optionally substituted with at least one substituent R 16 ; 
 R 6a  and R 6b  are each independently hydrogen, halogen, heteroalkyl, alkyl, alkenyl, cycloalkyl, aryl, saturated or unsaturated heterocyclyl, heteroaryl, alkynyl, —CN, —NR 13 R 14 , —OR 13 , —COR 13 , —CO 2 R 13 , —CONR 13 R 14 , —C(═NR 13 )NR 14 R 15 , —NR 13 COR 4 , —NR 13 CONR 4 R 1 , —NR 13 CO 2 R 4 , —SO 2 R 13 , —NR 13 SO 2 NR 14 R 15 , or —NR 13 SO 2 R 14 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and saturated or unsaturated heterocyclyl are optionally substituted with at least one substituent R 16 ; or 
 wherein (R 4a  and R 5a ), or (R 4a  and R 5b ), or (R 4b  and R 5a ), or (R 4b  and R 5b ), or (R 5a  and R 6a ), or (R 5a  and R 6b ), or (R 5b  and R 6a ), or (R 5b  and R 6b ), together with the atoms to which they are attached, may form a fused ring selected from cycloalkyl, saturated or unsaturated heterocycle, aryl, and heteroaryl rings, optionally substituted with at least one substituent R 16 ; 
 R 12  is H or alkyl; 
 R 13 , R 14  and R 15  are each independently H, heteroalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, saturated or unsaturated heterocyclyl, aryl, or heteroaryl; wherein (R 13  and R 14 ), and/or (R 14  and R 15 ) together with the atom(s) to which they are attached, each can form a ring selected from cycloalkyl, saturated or unsaturated heterocycle, aryl, and heteroaryl rings optionally substituted with at least one substituent R 16 ; and 
 R 16  is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, oxo, —CN, —OR a , —NR a R b , —COR a , —CO 2 R a , —CONR a R b , —C(═NR a )NR b R c , —NR a COR b , —NR a CONR a R b , —NR a CO 2 R b , —SO 2 R a , —SO 2 aryl, —N a SO 2 NR b R c , or —NR a SO 2 R b , wherein R a , R b , and R c  are independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, wherein (R a  and R b ), and/or (R a  and R b ) together with the atoms to which they are attached, can form a ring selected from cycloalkyl, saturated or unsaturated heterocycle, aryl, and heteroaryl rings. 
 
       
     
     
         27 . The method of  claim 26 , wherein L is a bond. 
     
     
         28 . The method of  claim 26 , wherein R 1  is halogen, alkyl, alkenyl, cycloalkyl, aryl, saturated heterocyclyl, heteroaryl, or —OR 13 , wherein the alkyl, alkenyl, cycloalkyl, and heteroaryl are optionally substituted with at least one substituent R 16 . 
     
     
         29 . The method of  claim 26 , wherein n is 2. 
     
     
         30 . The method of  claim 29 , wherein one of R 2  is at position 3 of the phenyl ring, and the other R 2  is at position 5 of the phenyl ring, wherein R 2  is optionally partially or fully deuterated. 
     
     
         31 . The method of  claim 30 , wherein R 2 , at each of its occurrence, is halogen, alkyl or —O-alkyl, wherein the alkyl group or moiety is optionally partially or fully deuterated. 
     
     
         32 . The method of  claim 26 , wherein R 4a , R 5a , R 5b , R 6a  and R 6b  are hydrogen; and R 4b  is alkyl, or saturated heterocyclyl, wherein the alkyl and saturated heterocyclyl are optionally substituted with at least one substituent R 16 . 
     
     
         33 . The method of  claim 32 , wherein R 4a , R 5a , R 5b , R 6a  and R 6b  are hydrogen; and R 4b  is a saturated heterocyclyl containing a nitrogen atom which is optionally substituted with acryloyl or propiolyl. 
     
     
         34 . The method of  claim 33 , wherein the saturated heterocyclyl in the definition of R 4b  is a monocyclic ring selected from an azetidine, pyrrole, piperidine, azapane or azocane ring; or a spiro or bridged bicyclic ring selected from azabicyclooctanyl, azaspirononanyl or azaspiroheptanyl. 
     
     
         35 . The method of  claim 26 , wherein (R 4a  and R 5a ), or (R 4a  and R 5b ), or (R 4b  and R 5a ) or (R 4b  and R 5b ), or (R 5a  and R 6a ), or (R 5a  and R 6b ), or (R 5b  and R 6a ), or (R 5b  and R 6b ), together with the atoms to which they are attached, form a fused ring selected from cycloalkyl, saturated or unsaturated heterocycle, aryl, and heteroaryl rings, optionally substituted with at least one substituent R 16 . 
     
     
         36 . The method of  claim 35 , wherein the fused saturated or unsaturated heterocycle ring is an azetidine, pyrrole, piperidine, azapane or azocane ring optionally substituted with a substituent R 16  at the nitrogen atom of the fused ring, wherein the substituent R 16  is acryloyl or propiolyl. 
     
     
         37 . A method of treating a disease associated with undesirable Btk activity in a subject comprising administering to the subject, a compound of formula (II): 
       
         
           
           
               
               
           
         
         or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
 R x  is halogen, alkyl, or —O-alkyl, wherein the alkyl group or moiety is optionally partially or fully deuterated; 
 R y  is halogen, alkyl optionally substituted with at least substituents selected from hydroxy, halogen, or cycloalkyl; and 
 R z  is halogen, alkyl, or —O-alkyl, wherein the alkyl group or moiety is optionally partially or fully deuterated. 
 
       
     
     
         38 . The method of  claim 37 , wherein
 R x  is methoxy, ethoxy, methyl, ethyl or chloro, wherein the methoxy, ethoxy, methyl, ethyl is optionally partially or fully deuterated;   R y  is 2-hydroxylethyl, trifluoromethyl, isopropyl, cyclopropyl, methyl, chloro, bromo, or iodo; and   R z  is methoxy, methyl, or chloro, wherein the methoxy or methyl is optionally partially or fully deuterated.   
     
     
         39 . The method of  claim 37 , wherein
 R x  is methoxy, ethoxy, methyl, chloro, CD 3 , -CD 2 CD 3 , OCD 3 , or —O-CD 2 CD 3 ;   R y  is 2-hydroxylethyl, CF 3 , isopropyl, cyclopropyl, methyl, chloro, bromo, or iodo; and   R z  is ethoxy, methoxy, methyl, ethyl, chloro, or CD 3 , -CD 2 CD 3 , OCD 3 , or —O-CD 2 CD 3 .   
     
     
         40 . The method of  claim 37 , wherein
 R x  is methoxy, ethoxy, methyl, ethyl, chloro, or OCD 3 ;   R y  is 2-hydroxylethyl, CF 3 , isopropyl, cyclopropyl, methyl, chloro, bromo, or iodo; and   R z  is methoxy, methyl, chloro, or OCD 3 .   
     
     
         41 . The method of  claim 37 , wherein the compound is in (S)-configuration of the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         42 . The method of  claim 26 , which is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         pharmaceutically acceptable salt thereof. 
       
     
     
         43 . The method of  claim 28 , wherein R 1  is alkyl or cycloalkyl. 
     
     
         44 . The method of  claim 26 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         45 . The method of  claim 26 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         46 . The method of  claim 26 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 
     
     
         47 . The method of  claim 26 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 
     
     
         48 . The method of  claim 26 , wherein the disease is a B-cell malignancy. 
     
     
         49 . The method of  claim 48 , wherein the B-cell malignancy is selected from lymphoma, non-Hodgkin's lymphoma (NHL), diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia (WM), marginal zone lymphoma (MZL), Hairy cell leukemia (HCL), Burkitt's-like leukemia (BL), or a combination of two or more thereof. 
     
     
         50 . The method of  claim 37 , wherein the disease is a B-cell malignancy. 
     
     
         51 . The method of  claim 50 , wherein the B-cell malignancy is selected from lymphoma, non-Hodgkin's lymphoma (NHL), diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia (WM), marginal zone lymphoma (MZL), Hairy cell leukemia (HCL), Burkitt's-like leukemia (BL), or a combination of two or more thereof.