PI3K (delta) SELECTIVE INHIBITORS

Abstract

Novel PI3K, especially PI3K delta isoform, selective inhibitors are disclosed. The compounds are useful in treating disorders related to abnormal PI3K or PI3Kδ activities such as cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine disorders and neurological disorders.

We claim: 
     
         1 . A compound of Formula IVa or IVb: 
       
         
           
           
               
               
           
         
       
       or a salt thereof; or a prodrug, or a salt of a prodrug thereof; or a hydrate, solvate, or polymorph thereof; wherein X is N or CR; A and B are each independently CH, N, NH, O or S, where A and B together with the carbon atoms they are attached to form a five or six-membered aryl or heteroaryl, which is optionally substituted with Z 1 , Z 2  and Z 3 ; R, R 1 , and R 2  are each independently hydrogen, alkyl, alkoxy, cycloalkyl, or heterocyclo, each optionally substituted with Z 1 , Z 2  and Z 3 ; 
       Z 1 , Z 2  and Z 3  are each independently:
 (1) hydrogen, or Z 6 , where Z 6  is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; (ii) a group (i) which is substituted by one or more groups selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; or (iii) a group (i) or (ii) which is substituted by one or more of the following groups (2) to (12); 
 (2) —OH or —OZ 16 ; 
 (3) —SH or —SZ 16 ; 
 (4) —C(O) 2 H, C(O) q Z 16 , C(O) q O—Z 16 , —C(O)NZ 17 Z 18 , —C(O)C(O)NZ 17 Z 18 , or —O—C(O) q Z 16 , where each q is independently 1 or 2; 
 (5) —SO 3 H, —S(O) q Z 16 , or —S(O) q NZ 17 Z 18 ; 
 (6) halo; 
 (7) cyano; 
 (8) nitro; 
 (9) —Z 4 —NZ 17 Z 18 ; 
 (10) —Z 4 —N(Z 18 )—Z 5 —NZ 19 Z 20 ; 
 (11) oxo; 
 (12) —O—C(O)—Z 16 ; or 
 (13) any two of Z 1 , Z 2 , and Z 3  may together be alkylene, alkenylene, aryl, heteroaryl, or heterocyclo completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; 
 Z 4  and Z 5  are each independently 
 (1) a single bond; 
 (2) —Z 11 —S(O) q —Z 12 —; 
 (3) —Z 11 —C(O)—Z 12 —; 
 (4) —Z 11 —O—Z 12 —; 
 (5) —Z 11 —S—Z 12 —; 
 (6) —Z 11 —O—C(O)—Z 12 —; or 
 (7) —Z 11 —C(O)—O—Z 12 ; 
 Z 11  and Z 12  are each independently 
 (1) a single bond; 
 (2) alkylene; 
 (3) alkenylene; or 
 (4) alkynylene; 
 each Z 16  is independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl, each optionally substituted with one or more of the following groups: 
 (1) hydrogen or alkyl; 
 (2) —OH or —OZ 21 ; 
 (3) —SH or —SZ 21 ; 
 (4) —C(O) 2 H, C(O) q Z 21 , —C(O)NZ 17 Z 18 , —C(O)C(O)NZ 17 Z 18 , or —O—C(O) q Z 21 , 
 where each q is independently 1 or 2: 
 (5) —SO 3 H, —S(O) q Z 21 , or —S(O) q NZ 17 Z 18 ; 
 (6) halo; 
 (7) cyano; 
 (8) nitro; 
 (9) —Z 4 —NZ 17 Z 18 ; 
 (10) —Z 4 —N(Z 18 )—Z 5 —NZ 19 Z 20 ; 
 (11) oxo; or 
 (12) —O—C(O)—Z 21 ; 
 each Z 17  is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; 
 each Z 18  is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; 
 each Z 19  is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; 
 each Z 20  is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; 
 each Z 21  is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; 
 each Z 22  is independently, 
 (1) hydrogen; 
 (2) —OH or —OZ 21 ; 
 (3) —SH or —SZ 21 ; 
 (4) —C(O) 2 H, C(O) q Z 21 , —C(O)NZ 21 Z 21 , —C(O)C(O)NZ 21 Z 21 , or —O—C(O) q Z 21 , 
 where q is 1 or 2; 
 (5) —SO 3 H, —S(O) q Z 21 , or —S(O) q NZ 21 Z 21 ; 
 (6) halo; 
 (7) cyano; 
 (8) nitro; 
 (9) —Z 4 —NZ 21 Z 21 ; 
 (10) —Z 4 —N(Z 21 )—Z 5 —NZ 21 Z 21 ; 
 (11) oxo; or 
 (12) —O—C(O)—Z 21 ; 
 where Z 17 , Z 18 , Z 19  or Z 20  may be substituted with 1, 2, or 3 independent Z 22 ; 
 where Z 17  and Z 18 , or Z 19  and Z 20 , together with the nitrogen atom to which they are attached may be a heterocycle which is unsubstituted or substituted with 1, 2, or 3 independent Z 22 ; and 
 where any two of Z 18 , Z 19  or Z 20  together with the nitrogen atoms to which they are attached may be a 3- to 12-membered saturated or unsaturated mono-, bi-, or tri-heterocyclic ring which is unsubstituted or substituted with 1, 2, or 3 independent Z 22 . 
 
     
     
         2 . The compound of  claim 1 , wherein the compound is of Formula IVc: 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 3  and R 4  are each independently hydrogen, alkyl, alkoxy, cycloalkyl, or heterocyclo, each optionally substituted with Z 1 , Z 2  and Z 3 . 
     
     
         3 . The compound of  claim 1 , wherein the compound is of Formula IVd: 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 3  and R 4  are each independently hydrogen, alkyl, alkoxy, cycloalkyl, or heterocyclo, each optionally substituted with Z 1 , Z 2  and Z 3 . 
     
     
         4 . The compound of  claim 1 , wherein the compound is of Formula IVe: 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and R 3  are each independently hydrogen, alkyl, alkoxy, cycloalkyl, or heterocyclo, each optionally substituted with Z 1 , Z 2  and Z 3 . 
     
     
         5 . The compound of  claim 1 , wherein the compound is of Formula IVf: 
       
         
           
           
               
               
           
         
       
       wherein X is N or CR; R, R 1 , R 2 , R 3  and R 4  are each independently hydrogen, alkyl, alkoxy, cycloalkyl, or heterocyclo, each optionally substituted with Z 1 , Z 2  and Z 3 . 
     
     
         6 . The compound of  claim 1 , wherein the compound is of Formula IVg: 
       
         
           
           
               
               
           
         
       
       wherein X is N or CR; R, R 1 , R 2 , and R 3  are each independently hydrogen, alkyl, alkoxy, cycloalkyl, or heterocyclo, each optionally substituted with Z 1 , Z 2  and Z 3 . 
     
     
         7 . The compound of any of  claims 1 ,  5 , or  6 , wherein X is N. 
     
     
         8 . The compound of  claim 1 , wherein the compound is one of
 2-(2-Difluoromethyl-benzoimidazol-1-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine;   6-(2-Difluoromethyl-benzoimidazol-1-yl)-4-morpholin-4-yl-1-(tetrahydro-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine;   2-(2-Difluoromethyl-4-methoxy-benzoimidazol-1-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine; or   6-(2-Difluoromethyl-4-methoxy-benzoimidazol-1-yl)-4-morpholin-4-yl-1-(tetrahydro-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine.   
     
     
         9 . The compound of  claim 1 , wherein the compound is one of 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 1 , wherein the compound is one of
 6-(2-difluoromethyl-benzoimidazol-1-yl)-9-[2-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-2-morpholin-4-yl-9H-purine;   2-{6-[2-(difluoromethyl)benzimidazol-1-yl]-2-morpholin-4-ylpurin-9-yl}ethan-1-ol;   6-(2-Difluoromethyl-benzoimidazol-1-yl)-2-morpholin-4-yl-9-(tetrahydro-pyran-4-yl)-9H-purine;   9-sec-Butyl-6-(2-difluoromethyl-benzoimidazol-1-yl)-2-morpholin-4-yl-9H-purine;   2-[6-(2-Difluoromethyl-benzoimidazol-1-yl)-2-morpholin-4-yl-purin-9-yl]-propan-1-ol;   2-[6-(2-Difluoromethyl-benzoimidazol-1-yl)-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-purin-9-yl]-propan-1-ol;   4-{1-(2H-3,4,5,6-tetrahydropyran-4-yl)-4[2-(difluoromethyl)benzimidazolyl]pyrazolo[5,4-d]pyrimidin-6-yl})morpholine; or   4-{4-[2-(difluoromethyl)benzimidazolyl]-6-morpholin-4-ylpyrazolo[5,4-d]pyrimidinyl}piperidyl 4-methylpiperazinyl ketone.   
     
     
         11 . The compound of  claim 1 , wherein the compound is one of
 1-(2-{4-[2-(difluoromethyl)benzimidazolyl]-6-morpholin-4-ylpyrazolo[5,4-d]pyrimidinyl)ethyl}-4-(methylsulfonyl)piperazine;   4-{6-[2-(difluoromethyl)benzimidazolyl]-2-morpholin-4-ylpurin-9-yl}piperidyl 4-methylpiperazinyl ketone;   [4-[6-[2-(difluoromethyl)benzimidazol-1-yl]-2-morpholino-purin-9-yl]-1-piperidyl]-(4-fluorophenyl)methanone;   [4-[6-[2-(difluoromethyl)benzimidazol-1-yl]-2-morpholino-purin-9-yl]-1-piperidyl]-(4-pyridyl)methanone;   [4-[6-[2-(difluoromethyl)benzimidazol-1-yl]-2-morpholino-purin-9-yl]-1-piperidyl]-(3-pyridyl)methanone;   (4-{6-[2-(difluoromethyl)benzimidazolyl]-2-morpholin-4-ylpurin-9-yl}piperidyl)-N,N-dimethylcarboxamide;   methyl 4-{6-[2-(difluoromethyl)benzimidazolyl]-2-morpholin-4-ylpurin-9-yl}piperidinecarboxylate;   4-{6-[2-(difluoromethyl)benzimidazolyl]-2-morpholin-4-ylpurin-9-yl}-1-(methylsulfonyl)piperidine;   (2R)-1-(4-{6-[2-(difluoromethyl)benzimidazolyl]-2-morpholin-4-ylpurin-9-yl}piperidyl)-2-hydroxypropan-1-one;   4-{6-[2-(difluoromethyl)benzimidazolyl]-2-morpholin-4-ylpurin-9-yl}piperidyl pyrrolidinyl ketone;   4-{6-[2-(difluoromethyl)-4-methoxybenzimidazolyl]-2-morpholin-4-ylpurin-9-yl}piperidyl 4-methylpiperazinyl ketone;   4-{6-[2-(difluoromethyl)-4-methoxybenzimidazolyl]-2-morpholin-4-ylpurin-9-yl}-1-(methylsulfonyl)piperidine;   1-(9-(2H-3,4,5,6-tetrahydropyran-4-yl)-2-morpholin-4-ylpurin-6-yl)-2-(difluoromethyl)-4-methoxybenzimidazole;   (3-{6-[2-(difluoromethyl)benzimidazolyl]-2-morpholin-4-ylpurin-9-yl}pyrrolidinyl)-N,N-dimethylcarboxamide;   4-{3-(2H-3,4,5,6-tetrahydropyran-4-yl)-7-[2-(difluoromethyl)benzimidazolyl]-1,2,3-triazolo[5,4-d]pyrimidin-5-yl}morpholine.   
     
     
         12 . A method of treating a disease in a subject comprising administering to the subject a compound of  claim 1 . 
     
     
         13 . A method of treating a disease in a subject comprising administering to the subject a composition comprising a compound of  claim 1 . 
     
     
         14 . The method of  claim 12 , wherein the disease is mediated by the PI-3 kinases. 
     
     
         15 . A method of treating a disease in a subject comprising administering to the subject a compound of any one of  claims 1 ,  2 ,  3 ,  4 ,  5 ,  6 ,  7 ,  8 ,  9 ,  10 , or  11 . 
     
     
         16 . A method of treating a disease in a subject comprising administering to the subject a composition comprising a compound of any one of  claims 1 ,  2 ,  3 ,  4 ,  5 ,  6 ,  7 ,  8 ,  9 ,  10 , or  11 . 
     
     
         17 . The method of  claim 16 , wherein the disease is mediated by the PI3Kδ. 
     
     
         18 . The method of  claim 16 , wherein the disease is mediated by one or more of the PI3K isoforms. 
     
     
         19 . The method of  claim 16 , wherein the disease is cancer, immune disorder, cardiovascular disease, viral infection, inflammation, metabolism/endocrine disorder or neurological disorder.