Heterocyclic compounds as btk inhibitors

Abstract

The present invention relates to heterocyclic compounds or their pharmaceutically acceptable salts thereof as inhibitors of Bruton's tyrosine kinase (BTK) and its C481 mutant. The present invention relates to compounds shown in Formula (I) and their pharmaceutically acceptable salts thereof. The present invention also relates to methods for preparing compounds or their pharmaceutically acceptable salts thereof. Compounds of the present invention can be used to treat and/or prevent related diseases mediated by BTK or its C481 mutant, especially cancer and autoimmune diseases.

What is claimed is: 
     
         1 . A compound represented by general formula (I), or a pharmaceutically acceptable salt, stable isotope derivative, or stereo isomer thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         A is 
       
       
         
           
           
               
               
           
         
         where → indicates that A is connected to the benzene ring, and   indicates that A is connected to E; 
         Ring K is phenyl or pyridyl, where phenyl and pyridyl are optionally substituted by one or more substituents selected from halogen, cyano, C 1-6  alkyl or —OR a ; 
         E is C 1-6  alkyl, C 3-10  cycloalkyl, 3-10 membered heterocyclyl, C 6-10  aryl or 5-10 membered heteroaryl, where the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more substituents selected from D, halogen, cyano, —OR b , —NR b R c , —COOR b , —C(O)R b , —C(O)NR b R c , or R e ; 
         R e  is C 1-6  alkyl, C 3-10  cycloalkyl or 3-10 membered heterocyclyl, where the alkyl, cycloalkyl and heterocyclyl are optionally substituted by halogen, cyano, —OR b , —NR b R c , —COOR b , —C(O)R b  or —C(O)NR b R c ; 
         R 1  is H, halogen, —OR a  or C 1-6  alkyl; 
         R a  is C 1-6  alkyl, where one or more hydrogens of the alkyl are optionally substituted by D or fluorine; and 
         R b  and R c  are each independently selected from H, C 1-6  alkyl, C 3-6  cycloalkyl, or 4-6 membered heterocyclyl, 
         wherein the compound is a CNS penetrant having a Kp, CSF value of at least 0.15. 
       
     
     
         2 . The compound according to  claim 1 , or a pharmaceutically acceptable salt, stable isotope derivative, or a stereo isomer thereof, wherein E is a C 1-6  alkyl group, wherein one or more hydrogens of the alkyl group are optionally substituted by D or fluorine. 
     
     
         3 . The compound according to  claim 1 , or a pharmaceutically acceptable salt, stable isotope derivative, or a stereo isomer thereof, wherein E is C 3-7  monocyclic cycloalkyl or 4-8 membered monocyclic heterocyclyl containing N and/or O, the monocyclic cycloalkyl and the monocyclic heterocyclyl are optionally substituted by one or more substituents selected from D, halogen, —OR b , —NR b R c , —COOR b , —C(O)R b , —C(O)NR b R c  or C 1-6  alkyl, where one or more hydrogens of the alkyl group are further optionally substituted by halogen, —OR b  or —NR b R c ; R b  and R c  are each independently selected from H, C 1-6  alkyl, C 3-6  cycloalkyl or N and/or O containing 4-6-membered heterocyclyl. 
     
     
         4 . The compound according to  claim 1 , or a pharmaceutically acceptable salt, stable isotope derivative, or a stereo isomer thereof, wherein E is cyclopropanyl, cyclobutanyl, cyclopentyl, cyclohexane, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl, the cycloalkyl and heterocyclic groups are optionally selected from one or more D, fluorine, —OR b , —NR b R c , —COOR b , —C(O)R b , —C(O)NR b R c  or C 1-2  alkyl substituent substituted, wherein one or more hydrogens of the alkyl substituents are further optionally substituted by fluorine, —OH or —NH 2 ; R b  and R c  are each independently selected from H, C 1-2  alkyl, C 3-6  cycloalkyl, or 4-6 membered heterocyclyl containing N and/or O (for example, morpholinyl). 
     
     
         5 . The compound according to  claim 1 , or a pharmaceutically acceptable salt, stable isotope derivative, or a stereo isomer thereof, wherein E is a C 5-10  polycyclic cycloalkyl group or an 0-containing 5-10 membered polycyclic heterocyclic group, the polycyclic cycloalkyl and polycyclic heterocyclic groups are optionally substituted by one or more substituents selected from D, halogen, —OR b , —NR b R c , —COOR b , —C(O)R b , —C(O)NR b R c  or C 1-6  alkyl substituents, wherein one or more hydrogens of the alkyl substituents are further optionally substituted by halogen, —OR b  or —NR b R c ; R b  and R c  are each independently selected from H, C 1-6  alkyl, C 3-6  cycloalkyl or 4-6 membered heterocyclic group containing N and/or O. 
     
     
         6 . The compound according to  claim 1 , or a pharmaceutically acceptable salt, stable isotope derivative, or a stereo isomer thereof,
 wherein E is   
       
         
           
           
               
               
           
         
          G is H, fluorine, —OR b , —NR b R c , —COOR b , —C(O)R b , —C(O)NR b R c  or C 1-2  alkyl, wherein one or more hydrogens of the alkyl are optionally substituted by fluorine, —OH or —NH 2 ; R b  and R c  are each independently selected from H, C 1-2  alkyl, C 3-6  cycloalkyl or 4-6 membered heterocyclic group containing N and/or O (for example, morpholinyl). 
       
     
     
         7 . The compound according to  claim 1 , or a pharmaceutically acceptable salt, stable isotope derivative, or a stereo isomer thereof, wherein ring K is a phenyl group, wherein the phenyl group is optionally selected from halogen or —OR a  by one or two groups. 
     
     
         8 . The compound according to  claim 1 , or a pharmaceutically acceptable salt, stable isotope derivative, or a stereo isomer thereof, wherein ring K is 
       
         
           
           
               
               
           
         
         R a  is C 1-2  alkyl, wherein one or more hydrogens of the alkyl group are optionally substituted by D. 
       
     
     
         9 . The compound according to  claim 1 , or its pharmaceutically acceptable salt, stable isotope derivative and isomer thereof, wherein R 1  is H or fluorine. 
     
     
         10 . A compound having the following structure, or its pharmaceutically acceptable salt, stable isotope derivative, and stereoisomer thereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 10 , which is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 10 , which is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         13 . A pharmaceutical composition comprising the compound according to  claim 10 , or a pharmaceutically acceptable salt, stable isotope derivative, or a stereoisomer thereof, and a pharmaceutically acceptable carrier. 
     
     
         14 . A method for preventing or treating related diseases mediated by BTK or its C481 mutant, the method comprising administering to a patient in need a therapeutically effective amount of the compound according to  claim 10  or a pharmaceutically acceptable salt, stable isotope derivative, or a stereoisomer thereof, wherein the diseases mediated by BTK and its C481 mutant are cancer, lymphoma, leukemia, an autoimmune disease or an inflammatory disease. 
     
     
         15 . The method according to  claim 14 , wherein the disease is B-cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, Waldenstrom's macroglobulinemia, marginal zone lymphoma, follicular lymphoma, central nervous system lymphoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, multiple myeloma, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, lupus nephritis, Sjogren's syndrome, IgG4-related diseases, idiopathic thrombocytopenic purpura, immune thrombocytopenia, or pemphigus.