Inhibitors of bruton's tyrosine kinase

Abstract

Disclosed herein are amido compounds that form covalent bonds with Bruton's tyrosine kinase (Btk). Also described are irreversible inhibitors of Btk. 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.

1 . A kinase inhibitor which is a compound according to formula (I): 
       
         
           
           
               
               
           
         
         or a stereoisomer thereof; 
         wherein: 
         A is 
       
       
         
           
           
               
               
           
         
         Hy is 2-pyridyl substituted with 1-5 groups independently selected from R 4 , or 
         Hy is imidazolyl, thiazolyl, oxazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, isothiazolyl, or tetrazolyl, each of which substituted with 1-2 groups independently selected from R 4 ; 
         each R 1  and R 2  is independently H, alkyl, or CN; or R 1  and R 2  together form a bond; 
         R 3  is independently H, alkyl, CN, or cycloalkyl; 
         each R 4  is independently H, halo, hydroxyl, CN, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted amido, substituted or unsubstituted sulfonyl, substituted or unsubstituted carboxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two adjacent R 4 s connect together with Hy to form a bicyclic ring; 
         each n is independently 0, 1, or 2; and 
         p is 0, 1 or 2; 
         or a metabolite, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof. 
       
     
     
         2 . A method for treating rheumatoid arthritis or a cancer, comprising administering to a patient in need a therapeutically effective amount of a compound of according to formula (I): 
       
         
           
           
               
               
           
         
         or a stereoisomer thereof; 
         wherein: 
         A is 
       
       
         
           
           
               
               
           
         
         Hy is 2-pyridyl substituted with 1-5 groups independently selected from R 4 , or 
         Hy is imidazolyl, thiazolyl, oxazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, isothiazolyl, or tetrazolyl, each of which substituted with 1-2 groups independently selected from R 4 ; 
         each R 1  and R 2  is independently H, alkyl, or CN; or R 1  and R 2  together form a bond; 
         R 3  is independently H, alkyl, CN, or cycloalkyl; 
         each R 4  is independently H, halo, hydroxyl, CN, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted amido, substituted or unsubstituted sulfonyl, substituted or unsubstituted carboxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two adjacent R 4 s connect together with Hy to form a bicyclic ring; 
         each n is independently 0, 1, or 2; and 
         p is 0, 1 or 2; 
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         3 . The method according to  claim 2 , wherein the compound is according to formula (Ia), (Ib) or (Ic): 
       
         
           
           
               
               
           
         
       
       or a stereoisomer thereof;
 or a pharmaceutically acceptable salt or solvate thereof. 
 
     
     
         4 . The method according to  claim 3 , wherein the compound is according to formula (IIa), (IIb), (IIc), or (IId): 
       
         
           
           
               
               
           
         
       
       or a stereoisomer thereof;
 wherein m is 1, 2, or 3; 
 or a pharmaceutically acceptable salt or solvate thereof. 
 
     
     
         5 . The method of  claim 3 , wherein the compound is according to one of Formulas (IIIa), (IIIb), (IIIc), or (IIId): 
       
         
           
           
               
               
           
         
       
       or a stereoisomer thereof;
 or a pharmaceutically acceptable salt or solvate thereof. 
 
     
     
         6 . The method of  claim 3 , wherein the compound is according to one of Formulas (IIIe), (IIIf), (IIIg), or (IIIh): 
       
         
           
           
               
               
           
         
         or a stereoisomer thereof; 
         or a pharmaceutically acceptable salt or solvate-thereof. 
       
     
     
         7 . The method of  claim 3 , wherein the compound has a structure according to one of Formulas (IVa), (IVb), (IVc) or (IVd): 
       
         
           
           
               
               
           
         
         or a stereoisomer thereof; 
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         8 . The method of  claim 3 , wherein the compound has a structure according to one of Formulas (Va), (Vb), (Vc) or (Vd): 
       
         
           
           
               
               
           
         
         or a stereoisomer thereof; 
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         9 . The method of  claim 2 , wherein R 3  is C 1 -C 4  alkyl or cycloalkyl. 
     
     
         10 . The method of  claim 3 , wherein the compound has a structure according to one of Formulas (VIa), (VIb), (VIc), or (VId): 
       
         
           
           
               
               
           
         
         or a stereoisomer thereof; 
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         11 . The method of  claim 3 , wherein the compound has a structure according to one of Formulas (VIe), (VIf), (VIg) or (VIh): 
       
         
           
           
               
               
           
         
         or a stereoisomer thereof; 
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         12 . The method of  claim 3 , wherein the compound has a structure according to one of Formulas (VIIa), (VIIb), (VIIc), or (VIId): 
       
         
           
           
               
               
           
         
         or a stereoisomer thereof; 
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         13 . The method of  claim 2 , wherein R 4  is H, Me, Et, n-Pr, i-Pr, CF 3  or CN. 
     
     
         14 . The method of  claim 3 , wherein the compound has a structure according to one of Formulas (VIIIa), (VIIIb), (VIIIc) or (VIIId): 
       
         
           
           
               
               
           
         
         or a stereoisomer thereof; 
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         15 . The method of  claim 3 , wherein the compound has a structure according to one of Formulas (VIIIe), (VIIIf), (VIIIg) or (VIIIh): 
       
         
           
           
               
               
           
         
         or a stereoisomer thereof; 
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         16 . The method of  claim 3 , wherein the compound has a structure according to one of Formulas (IXa), (IXb), (IXc) or (IXd): 
       
         
           
           
               
               
           
         
         or a stereoisomer thereof, 
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         17 . The method of  claim 3 , wherein the compound has a structure according to one of Formulas (Xa), (Xb), (Xc) or (Xd): 
       
         
           
           
               
               
           
         
         or a stereoisomer thereof; 
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         18 . The method of  claim 3 , wherein the compound has a structure according to one of Formulas (Xe), (Xf), (Xg), or (Xh): 
       
         
           
           
               
               
           
         
         or a stereoisomer thereof; 
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         19 . The method of  claim 3 , wherein the compound has a structure according to one of Formulas (XIa), (XIb), (XIc), or (XId): 
       
         
           
           
               
               
           
         
         or a stereoisomer thereof; 
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         20 . A method for treating rheumatoid arthritis or a cancer, comprising administering to a patient in need a therapeutically effective amount of a compound selected from:
 (R)-4-(4-amino-1-(1-but-2-ynoylpyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;   (R)-4-(4-amino-1-(1-but-2-ynoylpyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide;   (R)-4-(4-amino-1-(1-but-2-ynoylpyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl)benzamide;   (R)-4-(4-amino-1-(1-but-2-ynoylpyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-isopropylpyridin-2-yl)benzamide;   (R)-4-(4-amino-1-(1-but-2-ynoylpyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-cyanopyridin-2-yl)benzamide;   (R)-4-(4-amino-1-(1-but-2-ynoylpiperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-isopropylpyridin-2-yl)benzamide;   (R)-4-(4-amino-1-(1-pent-2-ynoylpyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide;   (R)-4-(4-amino-1-(1-(3-cyclopropylpropioloyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide;   (R)-4-(4-amino-1-(1-but-2-ynoylpyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-propylpyridin-2-yl)benzamide;   (R)-4-(4-amino-1-(1-but-2-ynoylpiperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl)benzamide;   (R)-4-(4-amino-1-(1-but-2-ynoylpiperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide;   (R)-4-(4-amino-1-(1-but-2-ynoylpiperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;   (R)-4-(4-amino-1-(1-but-2-ynoylpiperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-propylpyridin-2-yl)benzamide;   (R)-4-(4-amino-1-(1-but-2-ynoylpiperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-cyanopyridin-2-yl)benzamide;   (R)-4-(4-amino-1-(1-but-2-ynoylpyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(thiazol-2-yl)benzamide;   (R)-4-(4-amino-1-(1-but-2-ynoylpiperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(thiazol-2-yl)benzamide;   (R)-4-(4-amino-1-(1-but-2-ynoylpiperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(5-methylthiazol-2-yl)benzamide;   (R)-4-(1-(1-acryloylpyrrolidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide;   (R)-4-(1-(1-acryloylpyrrolidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;   (R)-4-(1-(1-acryloylpyrrolidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl)benzamide;   (R)-4-(1-(1-acryloylpyrrolidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-isopropylpyridin-2-yl)benzamide;   R)-4-(1-(1-acryloylpyrrolidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-cyanopyridin-2-yl)benzamide;   (R)-4-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl)benzamide;   (R)-4-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide;   (R)-4-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;   (R)-4-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-isopropylpyridin-2-yl)benzamide;   (R)-4-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-cyanopyridin-2-yl)benzamide;   (R)-4-(1-(1-acryloylpyrrolidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-propylpyridin-2-yl)benzamide;   (R)-4-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-propylpyridin-2-yl)benzamide;   (R,E)-4-(4-amino-1-(1-but-2-enoylpyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide;   (R)-4-(4-amino-1-(1-(3-methylbut-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide;   (R)-4-(1-(1-acryloylpyrrolidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(5-methylthiazol-2-yl)benzamide;   (R)-4-(1-(1-acryloylpyrrolidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(thiazol-2-yl)benzamide;   4-(4-amino-1-((1R,4R)-4-but-2-ynamidocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;   4-(1-((1R,4R)-4-acrylamidocyclohexyl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide;   4-(4-amino-1-((1R,4R)-4-but-2-ynamidocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl)benzamide;   4-(4-amino-1-((1R,4R)-4-but-2-ynamidocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide;   4-(4-amino-1-((1R,4R)-4-but-2-ynamidocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-isopropylpyridin-2-yl)benzamide;   4-(4-amino-1-((1R,4R)-4-but-2-ynamidocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-cyanopyridin-2-yl)benzamide;   4-(4-amino-1-((1R,4R)-4-but-2-ynamidocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(5-methylthiazol-2-yl)benzamide;   4-(4-amino-1-((1R,4R)-4-but-2-ynamidocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(thiazol-2-yl)benzamide;   4-(1-((1R,4R)-4-acrylamidocyclohexyl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(thiazol-2-yl)benzamide;   (R,E)-4-(4-amino-1-(1-pent-2-enoylpyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide;   (R)-4-(4-amino-1-(1-methacryloylpyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide;   (R,Z)-4-(4-amino-1-(1-(2-methylbut-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide;   (R)-4-(4-amino-1-(1-(2-cyano-3-methylbut-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide;   (R)-4-(4-amino-1-(1-(4-hydroxybut-2-ynoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;   (R)-4-(4-amino-1-(1-(4-methoxybut-2-ynoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide; or   (R)-4-(4-amino-1-(1-(1-cyanocyclopropanecarbonyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl)benzamide;   or a solvate or a pharmaceutically acceptable salt thereof.