PI3K (delta) SELECTIVE INHIBITORS

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.