Therapeutically active pyrazolo-pyrimidine derivatives

Abstract

A series of pyrazolo[3,4-d]pyrimidine derivatives that are substituted at the 4-position by a diaza monocyclic, bridged bicyclic or spirocyclic moiety, are beneficial in the treatment and/or prevention of various human ailments, including inflammatory, autoimmune and oncological disorders; viral diseases and malaria; and organ and cell transplant rejection.

Claims

1. A compound represented by formula (IA), or a pharmaceutically acceptable salt or solvate thereof: ##STR00014## wherein R.sup.12 represents hydrogen, trifluoromethyl or C.sub.1-6 alkyl; Q is ##STR00015## in which the asterisk (*) represents the point of attachment to the remainder of the molecule; Y represents C(O)N(R.sup.4) or C(O)C(O); Z represents C.sub.3-7 cycloalkyl, C.sub.3-7 heterocycloalkyl, aryl, or heteroaryl any of which groups is optionally substituted by one or more substituents independently selected from halogen, cyano, C.sub.1-6 alkyl, trifluoromethyl, (C.sub.3-7)-heterocycloalkyl, dihalo(C.sub.3-7)heterocycloalkyl, hydroxy, oxo, C.sub.1-6 alkoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, C.sub.1-6 alkylsulfonyl, C.sub.1-6 alkylamino and di(C.sub.1-6)alkylamino; A.sup.1 represents hydrogen, methyl, ethyl, isopropyl, isobutyl, trifluoromethyl, trifluoroethyl, CH.sub.2OR.sup.a or CH.sub.2CH.sub.2OR.sup.a; A.sup.2 represents hydrogen or C.sub.1-6 alkyl; R.sup.4 represents hydrogen or C.sub.1-6 alkyl; R.sup.a represents hydrogen or C.sub.1-6 alkyl; and R.sup.13 represents C.sub.1-6 alkyl.

2. A compound as claimed in claim 1 wherein Q represents a group of formula (Qa-1), (Qa-2) or (Qa-3): ##STR00016## in which the asterisk (*) represents the point of attachment to the remainder of the molecule.

3. A compound as claimed in claim 1 represented by formula (IIA), or a pharmaceutically acceptable salt or solvate thereof: ##STR00017## wherein A.sup.11 represents hydrogen, methyl, ethyl, isopropyl, isobutyl, trifluoromethyl, CH.sub.2CF.sub.3, hydroxymethyl, or hydroxyethyl; and R.sup.12 represents hydrogen, trifluoromethyl or C.sub.1-6 alkyl.

4. A compound as claimed in claim 1 represented by formula (IIB), or a pharmaceutically acceptable salt or solvate thereof: ##STR00018## wherein R.sup.12 represents hydrogen, trifluoromethyl or C.sub.1-6 alkyl; and A.sup.11 represents hydrogen, methyl, ethyl, isopropyl, isobutyl, trifluoromethyl, CH.sub.2CF.sub.3, hydroxymethyl, or hydroxyethyl.

5. A compound as claimed in claim 3 wherein A.sup.11 represents methyl, ethyl, hydroxymethyl or hydroxyethyl.

6. A compound as claimed in claim 1 wherein Z represents C.sub.3-7 cycloalkyl, C.sub.3-7 heterocycloalkyl, aryl or heteroaryl, any of which groups is optionally substituted by one, two or three substituents independently selected from halogen, cyano, C.sub.1-6 alkyl, trifluoromethyl, (C.sub.3-7)heterocycloalkyl, dihalo(C.sub.3-7)-heterocycloalkyl, hydroxy, oxo, C.sub.1-6 alkoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, C.sub.1-6 alkylsulfonyl, C.sub.1-6 alkylamino and di(C.sub.1-6)alkylamino.

7. A compound as claimed in claim 6 wherein Z represents (methoxy)(methyl)-phenyl, (methyl)(trifluoromethoxy)phenyl, (methoxy)(methyl)pyridinyl, (ethyl)-(methoxy)pyridinyl, (ethoxy)(methyl)pyridinyl or dimethoxypyridinyl.

8. A compound as claimed in claim 1 wherein R.sup.12 represents hydrogen or methyl.

9. A compound as claimed in claim 1 wherein R.sup.13 represents methyl.

10. A compound of formula (IA) as claimed in claim 1 which is 6-Amino-4-{4-[(4-methoxy-2-methylphenyl)carbamyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine; 6-Amino-4-{4-[(4-methoxyphenyl)carbamyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]-pyrimdine; 6-Amino-4-{4-[(4-methoxy-2-methylphenyl)carbamyl]-2-(S)-methylpiperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine; 6-Amino-4-{4-[(4-methoxyphenyl)carbamyl]-2-(S)-methylpiperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine; 6-Amino-4-{4-[(4-methoxy-2-methylphenyl)carbamyl]-2-(S)-methylpiperazin-1-yl}-1-methylpyrazolo[3,4-d]pyrimidine; 6-Amino-4-{4-[(4-methoxyphenyl)carbamyl]-2-(S)-methylpiperazin-1-yl}-1-methylpyrazolo[3,4-d]pyrimidine; 6-Amino-4-[4-(indan-5-ylcarbamyl)-2-(S)-methylpiperazin-1-yl]-1-methylpyrazolo[3,4-d]pyrimidine; 6-Amino-4-(4-{[4-(dimethylamino)phenyl]carbamyl}-2-(S)-methylpiperazin-1-yl)-1-methylpyrazolo[3,4-d]pyrimidine; (3S)-4-(6-Amino-1,3-dimethylpyrazolo[3,4-d]pyrimidin-4-yl)-N-[6-(3,3-difluoroazetidin-1-yl)-2-methylpyridin-3-yl]-3-methylpiperazine-1-carboxamide; (3S)-4-(6-Amino-1,3-dimethylpyrazolo[3,4-d]pyrimidin-4-yl)-N-(4-methoxy-2-methyl-phenyl)-3-methylpiperazine-1-carboxamide; (3S)-4-(6-Amino-1,3-dimethylpyrazolo[3,4-d]pyrimidin-4-yl)-N-(6-methoxy-2-methyl-pyridin-3-yl)-3-methylpiperazine-1-carboxamide; (3R)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-N-[6-(3,3-difluoroazetidin-1-yl)-2-methylpyridin-3-yl]-3-(hydroxymethyl)piperazine-1-carboxamide; (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-N-[6-(3,3-difluoroazetidin-1-yl)-2-methylpyridin-3-yl]-3-methylpiperazine-1-carboxamide; (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-N-(6-methoxy-2-methyl-pyridin-3-yl)-3-methylpiperazine-1-carboxamide; (3R)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-N-(4-methoxy-2-methyl-phenyl)-3-methylpiperazine-1-carboxamide; (3S)-4-[6-Amino-1-methyl-3-(trifluoromethyl)pyrazolo[3,4-d]pyrimidin-4-yl]-N-[6-(3,3-difluoroazetidin-1-yl)-2-methylpyridin-3-yl]-3-methylpiperazine-1-carboxamide; (3S)-4-[6-Amino-1-methyl-3-(trifluoromethyl)pyrazolo[3,4-d]pyrimidin-4-yl]-N-(6-methoxy-2-methylpyridin-3-yl)-3-methylpiperazine-1-carboxamide; (3S)-4-[6-Amino-1-methyl-3-(trifluoromethyl)pyrazolo[3,4-d]pyrimidin-4-yl]-N-(4-methoxy-2-methylphenyl)-3-methylpiperazine-1-carboxamide; (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-N-(2, 1,3-benzothiadiazol-4-yl)-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-N-(1H-indazol-7-yl)-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-N-(2, 1,3-benzothiadiazol-5-yl)-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-N-(1H-indol-7-yl)-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-N-(1H-indol-4-yl)-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-3-methyl-N-(2-methyl-1H-benzimidazol-4-yl)piperazine-1-carboxamide (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-3-methyl-N-(1-methylindazol-7-yl)piperazine-1-carboxamide (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-3-methyl-N-(4-methyl-1H-indazol-7-yl)piperazine-1-carboxamide (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-N-(6-hydroxy-2-methylpyridin-3-yl)-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-3-methyl-N-[2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-piperazine-1-carboxamide (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-N-(1,2-dimethyl-6-oxopyridin-3-yl)-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-3-methyl-N-[2-methyl-6-(methylamino)pyridin-3-yl]-piperazine-1-carboxamide (3S)-4-(6-Amino-1-methylpyrazolo-[3,4-d]pyrimidin-4-yl)-N-[2-(3,3-difluoroazetidin-1-yl)-4-methyl-pyrimidin-5-yl]-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methylpyrazolo-[3,4-d]pyrimidin-4-yl)-N-[4-(difluoro-methoxy)-2-methylphenyl]-3-methyl-piperazine-1-carboxamide (3S)-4-(6-Amino-1-methylpyrazolo-[3,4-d]pyrimidin-4-yl)-N-[2-(dimethyl-amino)-4-methylpyrimidin-5-yl]-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methylpyrazolo-[3,4-d]pyrimidin-4-yl)-N-[6-(azetidin-1-yl)-2-methylpyridin-3-yl]-3-methyl-piperazine-1-carboxamide (3S)-4-(6-Amino-1-methylpyrazolo-[3,4-d]pyrimidin-4-yl)-N-[6-(3,3-difluoroazetidin-1-yl)-4-methylpyridin-3-yl]-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methylpyrazolo-[3,4-d]pyrimidin-4-yl)-N-[6-(dimethyl-amino)-2-methylpyridin-3-yl]-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methylpyrazolo-[3,4-d]pyrimidin-4-yl)-N-[6-(dimethyl-amino)-methylpyridin-3-yl]-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1,3-dimethyl-pyrazolo[3,4-d]pyrimidin-4-yl)-N-[6-(azetidin-1-yl)-2-methylpyridin-3-yl]-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1,3-dimethyl-pyrazolo[3,4-d]pyrimidin-4-yl)-N-[6-(dimethylamino)-4-methylpyridin-3-yl]-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1,3-dimethyl-pyrazolo[3,4-d]pyrimidin-4-yl)-N-[6-(dimethylamino)-2-methylpyridin-3-yl]-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1,3-dimethylpyrazolo[3,4-d]pyrimidin-4-yl)-N-(4-methoxyphenyl)-3-methylpiperazine-1-carboxamide; [(3S)-4-(6-Amino-1-methylpyrazolo-[3,4-d]pyrimidin-4-yl)-3-methyl-piperazin-1-yl](2,3-dihydrobenzo-furan-2-yl)methanone 1-[(3S)-4-(6-Amino-1-methylpyrazolo-[3,4-d]pyrimidin-4-yl)-3-methyl-piperazin-1-yl]-2-phenylethane-1,2-dione [(3S)-4-(6-Amino-1-methylpyrazolo-[3,4-d]pyrimidin-4-yl)-3-methyl-piperazin-1-yl](5-methoxybenzofuran-2-yl)methanone (3S)-N-(4-Methoxy-2-methylphenyl)-3-methyl-4-[1-methyl-6-(methylsulfanyl)-pyrazolo[3,4-d]pyrimidin-4-yl]piperazine-1-carboxamide; (3S)-N-(Indan-5-yl)-3-methyl-4-[1-methyl-6-(methylsulfonyl)pyrazolo[3,4-d]pyrimidin-4-yl]piperazine-1-carboxamide; (3S)-N-(Indan-5-yl)-4-(6-methoxy-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-3-methyl-piperazine-1-carboxamide; (3S)-4-(6-Cyano-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-N-(indan-5-yl)-3-methyl-piperazine-1-carboxamide; (3S)-4-[6-(2-Hydroxyethylamino)-1-methylpyrazolo[3,4-d]pyrimidin-4-yl]-N-(4-methoxy-2-methylphenyl)-3-methylpiperazine-1-carboxamide; (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-3-methyl-N-[2-methyl-4-(trifluoromethoxy)phenyl]piperazine-1-carboxamide; (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-[2-fluoro-4-(trifluoromethoxy)-phenyl]-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-[2-chloro-4-(trifluoromethoxy)-phenyl]-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-[3-methoxy-5-(trifluoromethyl)-phenyl]-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(1-ethyl-1H-indazol-3-yl)-3-methyl-piperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-[6-(difluoromethoxy)-2-methyl-pyridin-3-yl]-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(6-ethoxy-5-fluoropyridin-3-yl)-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(2-chloro-4-fluoro-5-methylphenyl)-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(5-fluoro-6-methoxypyridin-3-yl)-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(6-ethoxy-2-methylpyridin-3-yl)-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-3-methyl-N-[1-methyl-5-(trifluoro-methyl)-1H-indazol-3-yl]piperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(6-fluoro-1-methyl-1H-indazol-3-yl)-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(5-fluoro-1-methyl-1H-indazol-3-yl)-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(imidazo[1,2-a]pyridin-8-yl)-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-3-methyl-N-(5-methyl-1,2-oxazol-3-yl)-piperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(1,2-benzoxazol-3-yl)-3-methyl-piperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-3-methyl-N-(1-methyl-1H-indazol-3-yl)piperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(6-cyano-2-methylpyridin-3-yl)-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-3-methyl-N-[2-methyl-4-(methyl-sulfonyl)phenyl]piperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-[6-(difluoromethoxy)-4-methyl-pyridin-3-yl]-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(6-methoxy-5-methylpyridin-3-yl)-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(6-methoxy-4-methylpyridin-3-yl)-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(5-methoxy-2-methylphenyl)-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(3-chloro-4-methylphenyl)-3-methyl-piperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(2,5-dichlorophenyl)-3-methyl-piperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(4-cyano-2-methylphenyl)-3-methyl-piperazine-1-carboxamide (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-3-ethyl-N-(6-methoxy-2-methylpyridin-3-yl)piperazine-1-carboxamide; (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-N-(6-ethoxy-2-methylpyridin-3-yl)-3-ethylpiperazine-1-carboxamide; (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-N-(2,6-dimethoxypyridin-3-yl)-3-ethylpiperazine-1-carboxamide; (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-3-ethyl-N-(4-methoxy-2-methylphenyl)piperazine-1-carboxamide; (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-N-[6-(3,3-difluoroazetidin-1-yl)-2-methylpyridin-3-yl]-3-ethylpiperazine-1-carboxamide; (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-3-ethyl-N-[2-methyl-4-(trifluoromethoxy)phenyl]piperazine-1-carboxamide; (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-3-ethyl-N-(4-methoxy-3-methylphenyl)piperazine-1-carboxamide; (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(1,2-benzoxazol-3-yl)-3-ethyl-piperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-3-ethyl-N-(1-methyl-1H-indazol-3-yl)-piperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-[6-(difluoromethoxy)-4-methyl-pyridin-3-yl]-3-ethylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-3-ethyl-N-(6-methoxy-5-methyl-pyridin-3-yl)piperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-3-ethyl-N-[2-methyl-4-(methyl-sulfonyl)phenyl]piperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-3-ethyl-N-(6-methoxy-4-methyl-pyridin-3-yl)piperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-3-ethyl-N-[1-methyl-5-(trifluoro-methyl)-1H-indazol-3-yl]piperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-3-ethyl-N-(6-fluoro-1-methyl-1H-indazol-3-yl)piperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-3-ethyl-N-(5-fluoro-1-methyl-1H-indazol-3-yl)piperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-[6-(difluoromethoxy)-2-methyl-pyridin-3-yl]-3-ethylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-3-ethyl-N-(imidazo[1,2-a]pyridin-8-yl)piperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(6-ethoxy-5-fluoropyridin-3-yl)-3-ethylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(2-chloro-4-fluoro-5-methyl-phenyl)-3-ethylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-3-ethyl-N-(5-fluoro-6-methoxy-pyridin-3-yl)piperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(6-cyano-2-methylpyridin-3-yl)-3-ethylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(4-cyano-2-methylphenyl)-3-ethyl-piperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-[4-(difluoromethoxy)-2-methyl-phenyl]-3-ethylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-[5-(dimethylamino)-3-methyl-pyrazin-2-yl]-3-ethylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methyl-N-(1-methyl-1H-indazol-4-yl)-piperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-(2-methoxy-6-methylpyridin-3-yl)-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methyl-N-(1-methyl-1H-indol-4-yl)piperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methyl-N-(1-methyl-1H-benzotriazol-4-yl)piperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-(imidazo[1,2-a]pyridin-5-yl)-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-(imidazo[1,2-a]pyridin-3-yl)-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-3-methyl-N-(1-methyl-1H-pyrazolo-[4,3-c]pyridin-4-yl)piperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(3-chloro-5-methoxypyridin-2-yl)-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(2-chloro-4-methoxyphenyl)-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-[6-methoxy-2-(trifluoromethyl)-pyridin-3-yl]-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(6-fluoro-1-methyl-1H-indazol-4-yl)-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(2-ethyl-6-methoxypyridin-3-yl)-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-[5-(dimethylamino)-3-methyl-pyrazin-2-yl]-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-3-ethyl-N-(1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)piperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(2-chloro-4-methoxyphenyl)-3-ethylpiperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-3-ethyl-N-(6-fluoro-1-methyl-1H-indazol-4-yl)piperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-3-ethyl-N-[6-methoxy-2-(trifluoro-methyl)pyridin-3-yl]piperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-3-ethyl-N-(2-ethyl-6-methoxypyridin-3-yl)piperazine-1-carboxamide (3S)-4-(6-Amino-1,3-dimethyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-[2-(dimethylamino)-4-methyl-pyrimidin-5-yl]-3-methylpiperazine-1-carboxamide 4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-3-(2-hydroxyethyl)-N-[2-methyl-4-(trifluoromethoxy)phenyl]piperazine-1-carboxamide; (3R)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-(hydroxymethyl)-N-[2-methyl-4-(trifluoromethoxy)phenyl]piperazine-1-carboxamide; (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(6-methoxy-2-methylpyridin-3-yl)-3-(propan-2-yl)piperazine-1-carboxamide (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(6-methoxy-2-methylpyridin-3-yl)-3-(2-methylpropyl)piperazine-1-carboxamide 4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(6-methoxy-2-methylpyridin-3-yl)-3-(2,2,2-trifluoroethyl)piperazine-1-carboxamide 4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(imidazo[1,2-a]pyridin-8-yl)-3-(2,2,2-trifluoroethyl)piperazine-1-carboxamide (3S,5S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(1-ethyl-1H-indazol-3-yl)-3,5-dimethylpiperazine-1-carboxamide (3S,5S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-3,5-dimethyl-N-(1-methyl-1H-indazol-3-yl)piperazine-1-carboxamide (3S,5S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-[5-(dimethylamino)-3-methyl-pyrazin-2-yl]-3,5-dimethylpiperazine-1-carboxamide (3S,5S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(imidazo[1,2-a]pyridin-8-yl)-3, 5-dimethylpiperazine-1-carboxamide (3S,5S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-3,5-dimethyl-N-[2-methyl-4-(trifluoromethoxy)phenyl]piperazine-1-carboxamide (3S,5S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(6-methoxy-2-methylpyridin-3-yl)-3,5-dimethylpiperazine-1-carboxamide 4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(6-methoxy-2-methylpyridin-3-yl)-3-(trifluoromethyl)piperazine-1-carboxamide 4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(4-methoxy-2-methylphenyl)-3-(trifluoromethyl)piperazine-1-carboxamide (3S)-4-(6-Amino-1,3-dimethyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(6-fluoro-1-methyl-1H-indazol-3-yl)-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1,3-dimethyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-(5-fluoro-1-methyl-1H-indazol-3-yl)-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1,3-dimethyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-[6-(difluoromethoxy)-2-methyl-pyridin-3-yl]-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1,3-dimethyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-[5-(dimethylamino)-3-methyl-pyrazin-2-yl]-3-methylpiperazine-1-carboxamide (3S)-4-(6-Amino-1,3-dimethyl-1H-pyrazolo[3,4-d]-pyrimidin-4-yl)-N-[4-(difluoromethoxy)-2-methyl-phenyl]-3-methylpiperazine-1-carboxamide (3S)-4-[6-Amino-3-(4-fluorophenyl)-1-methylpyrazolo[3,4-d]pyrimidin-4-yl]-N-(4-methoxy-2-methylphenyl)-3-methylpiperazine-1-carboxamide; or (3S)-4-[6-Amino-1-methyl-3-(pyridin-3-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-N-(4-methoxy-2-methylphenyl)-3-methylpiperazine-1-carboxamide; or a pharmaceutically acceptable salt of one of the foregoing.

11. A pharmaceutical composition comprising a compound of formula (IA) as defined in claim 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

12. A method for the treatment of organ or cell transplant rejection, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (IA) as defined in claim 1, or a pharmaceutically acceptable salt or solvate thereof.

Description

EXAMPLES

Abbreviations

(1) TABLE-US-00001 THF: tetrahydrofuran MeOH: methanol DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide DCM: dichloromethane DIPEA: N,N-diisopropylethylamine TFA: trifluoroacetic acid EtOAc: ethyl acetate MCPBA: 3-chloroperoxybenzoic DMAP: 4-(dimethylamino)pyridine acid IPA: isopropyl alcohol IMS: industrial methylated spirit HATU: O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate Pd(dppf)Cl.sub.2: [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) h: hour MS: Mass Spectrometry M: mass RT: retention time r.t.: room temperature LCMS: Liquid Chromatography Mass Spectrometry HPLC: High Performance Liquid Chromatography
Analytical Methods
Method 1
High pH (approximately pH 9.5)
Column: Waters XBridge, C18, 2.120 mm, 2.5 m
Solvent A: 10 mM ammonium formate in water+0.1% ammonia solution
Solvent B: acetonitrile+5% solvent A+0.1% ammonia solution
Gradient Program:

(2) TABLE-US-00002 Time A % B % 0.00 95.0 5.0 1.50 5.0 95.0 2.50 5.0 95.0 3.00 95.0 5.0
Method 2
High pH (approximately pH 9.5)
Column: Waters XBridge, C18, 2.120 mm, 2.5 m
Solvent A: 10 mM ammonium formate in water+0.1% ammonia solution
Solvent B: acetonitrile+5% solvent A+0.1% ammonia solution
Gradient Program:

(3) TABLE-US-00003 Time A % B % 0.00 95.0 5.0 4.00 5.0 95.0 5.00 5.0 95.0 5.10 95.0 5.0
Method 3
Low pH (approximately pH 3)
Column: Waters XBridge, C18, 2.120 mm, 2.5 m
Solvent A: 10 mM ammonium formate in water+0.1% formic acid solution
Solvent B: acetonitrile+5% solvent A+0.1% formic acid solution
Gradient Program:

(4) TABLE-US-00004 Time A % B % 0.00 95.0 5.0 1.50 5.0 95.0 2.50 5.0 95.0 3.00 95.0 5.0
Method 4
Low pH (approximately pH 3)
Column: Waters XBridge, C18, 2.120 mm, 2.5 m
Solvent A: 10 mM ammonium formate in water+0.1% formic acid solution
Solvent B: acetonitrile+5% solvent A+0.1% formic acid solution
Gradient Program:

(5) TABLE-US-00005 Time A % B % 0.00 95.0 5.0 4.00 5.0 95.0 5.00 5.0 95.0 5.10 95.0 5.0
Method 5
High pH (approximately pH 9.5)
Column: Waters XBridge, C18, 2.120 mm, 2.5 m
Solvent A: 10 mM ammonium formate in water+0.1% ammonia solution
Solvent B: acetonitrile+5% solvent A+0.1% ammonia solution
Gradient Program:

(6) TABLE-US-00006 Time A % B % 0.00 95.0 5.0 3.00 5.0 95.0 4.00 5.0 95.0 5.00 95.0 5.0
Method 6
Waters Acquity-SQD
Solvent A: 10 mM ammonium formate+0.1% ammonia
Solvent B: 95% acetonitrile+5% water+0.1% ammonia
Gradient Program:

(7) TABLE-US-00007 Time A % B % 0.00 95.0 5.0 0.50 95.0 5.0 1.75 5.0 95.0 2.00 5.0 95.0 2.25 95.0 5.0

Intermediate 1

6-Amino-4-chloro-1H-pyrazolo[3,4-d]pyrimidine

(8) To a suspension of 2-amino-4,6-dichloropyrimidine-5-carbaldehyde (1.92 g, 10 mmol) and triethylamine (1.59 mL, 11.5 mmol) in a mixture of THF (40 mL) and H.sub.2O (4 mL) was added hydrazine (64%, 486 L, 10 mmol) dropwise at r.t. The reaction mixture was continuously stirred for 4 h, then the volatile material was removed under vacuum. The residue was precipitated with H.sub.2O. The precipitate was washed with H.sub.2O, and dried under vacuum to provide the title compound (1.8 g, quantitative) as a yellow solid. .sup.13C NMR (DMSO-d.sub.6, 75 MHz) 161.5 (C-2), 157.5 (C-4), 153.2 (C-7a), 132.7 (C-5), 105.8 (C-4a). MS (m/z) 170 [M+H].sup.+.

Intermediate 2

6-Amino-4-(piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine

(9) To a suspension of Intermediate 1 (169 mg, 1 mmol) and piperazine (86 mg, 1 mmol) in DMF (4 mL) was added DIPEA (345 L, 2 mmol) at r.t., and the reaction mixture was continuously stirred overnight. The volatile material was evaporated under reduced pressure, and the residue was precipitated in cold DCM, to provide the title compound (240 mg, quantitative) as a yellow solid. .sup.13C NMR (DMSO-d.sub.6, 75 MHz) 161.4 (C-2), 158.7 (C-4), 156.9 (C-7a), 133.4 (C-5), 94.3 (C-4a), 42.6 (NCH.sub.2), 42.8 (NCH.sub.2). MS (m/z) 220 [M+H].sup.+.

Intermediate 3

6-Amino-4-[2-(S)-methyl-4-(tert-butoxycarbonyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]-pyrimidine

(10) To a suspension of Intermediate 1 (804 mg, 4.74 mmol) and 2-(S)-methyl-4-(tertbutoxycabonyl)piperazine (949 mg, 4.74 mmol) in DMF (10 mL) was added DIPEA (1.2 mL, 7.11 mmol) at r.t., and the reaction mixture was heated at 100 C. for 36 h. The volatile material was evaporated under reduced pressure, and the residue was precipitated in water, to provide the title compound (1.2 g, 76%) as a yellow solid. .sub.H (DMSO-d.sub.6, 300 MHz) 1.16 (d, J 6 Hz, 3H), 1.43 (s, 9H), 3.01-3.22 (m, 3H), 3.79-3.94 (m, 2H), 4.39-4.77 (m, 2H), 6.03 (s, 2H), 7.91 (s, 1H), 12.58 (s, 1H). MS (m/z) 334 [M+H].sup.+.

Intermediate 4 (Method A)

6-Amino-4-[2-(S)-methylpiperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine

(11) A solution of Intermediate 3 (193 mg, 0.58 mmol) in a mixture of DCM (3 mL) and trifluoroacetic acid (3 mL) was stirred at r.t. for 1 h. The reaction mixture was evaporated in vacuo and co-evaporated with NH.sub.3-MeOH solution to dryness. The title compound was obtained as a crude product that was utilised in subsequent reactions without further purification. MS (m/z) 234 [M+H].sup.+.

Intermediate 5

2-Amino-6-chloro-4-[2-(S)-methyl-4-(tert-butoxycarbonyl)piperazin-1-yl]pyrimidine-5-carbaldehyde

(12) To a suspension of 2-amino-4,6-dichloropyrimidine-5-carbaldehyde (1.92 g, 10 mmol) and DIPEA (3.4 mL, 20 mmol) in DMF (30 mL) was added 2-(S)-methyl-4-(tertbutoxycabonyl)piperazine (2 g, 10 mmol), and the reaction mixture was stirred at r.t. for 24 h. The volatile material was evaporated, and the residue was precipitated in water, to provide the title compound (3.37 g, 94%) as a yellow solid. .sup.13C NMR (DMSO-d.sub.6, 75 MHz) 183.5 (CHO), 166.6 (C-6), 162.9 (C-4), 161.2 (C-2), 154.3 (CO), 103.7 (C-5), 78.9 (OC), 50.6 (NCH), 43.4 (NCH), 27.9 (Me), 14.8 (Me). MS (m/z) 356 [M+H].sup.+.

Intermediate 6

6-Amino-4-[2-(S)-methyl-4-(tert-butoxycarbonyl)piperazin-1-yl]-1-methylpyrazolo[3,4-d]pyrimidine

(13) To a solution of Intermediate 3 (662 mg, 1.98 mmol) in dry DMF (10 mL) was added NaH (96 mg, 2.38 mmol) at 0 C. The resulting solution was stirred at 0 C. for 15 minutes, then iodomethane (149 L, 2.38 mmol) was added. The reaction mixture was slowly warmed to room temperature and continuously stirred for 3.5 h. The reaction mixture was concentrated and purified by silica gel chromatography (DCM:MeOH 50:1) to provide the title compound (492 mg, 47%) as a white solid. .sup.13C NMR (DMSO-d.sub.6, 75 MHz) 161.1 (C-2), 157.6 (C-4), 156.9 (C-7a), 155.1 (CO), 132.5 (C-5), 96.1 (C-4a), 80.2 (OC(CH.sub.3).sub.3), 48.6 (NCH.sub.2), 39.6 (NCH.sub.2), 33.5 (NMe), 28.4 (Me), 15.3 (Me). MS (m/z) 348 [M+H].sup.+.

Alternative Preparation

(14) To a solution of Intermediate 5 (356 mg, 1 mmol) and triethylamine (166 L, 1.2 mmol) in THF (6 mL) at 0 C. was added methylhydrazine (108 L, 2 mmol). The reaction mixture was slowly warmed to r.t. and continuously stirred for 42 h. The volatile material was evaporated, and the residue was purified by silica gel chromatography (DCM:MeOH 50:1), to provide the title compound (240 mg, 69%) as a white solid.

Intermediate 7

6-Amino-4-[2-(S)-methylpiperazin-1-yl]-1-methylpyrazolo[3,4-d]pyrimidine

(15) Prepared via Method A using Intermediate 6 (87 mg, 0.25 mmol), TFA (3 mL) and DCM (3 mL). The title compound was obtained as a crude product that was utilised in subsequent reactions without further purification. MS (m/z) 248 [M+H].sup.+.

Alternative Preparation

(16) Intermediate 6 (6.5 g, 19 mmol) in 4N HCl in 1,4-dioxane (20 mL) was stirred overnight. The reaction mixture was concentrated in vacuo, then triturated with diethyl ether, to yield the title compound dihydrochloride (5.2 g, 98%) as a yellow solid. LCMS (ES+) [M+H].sup.+ 248, RT 1.40 minutes (method 2).

Intermediate 8

1-(2-Amino-4,6-dichloropyrimidin-5-yl)ethanol

(17) To 2-amino-4,6-dichloropyrimidine-5-carbaldehyde (0.93 g, 4.65 mmol) was added THF (34 mL) and the mixture was cooled to 78 C. under nitrogen. To the mixture was slowly added methylmagnesium chloride (4.8 mL of a 3.0M solution in THF). A further aliquot of methylmagnesium chloride (2.4 mL) was added slowly and the mixture was stirred at 78 C. for 30 minutes before being quenched with water (20 mL). A partial solid formed. The mixture was neutralised and diluted with water, then extracted with EtOAc (100 mL). The solid was discarded, and the aqueous layer was further extracted (10% MeOH/DCM, 3100 mL). The organic layers were combined and dried over sodium sulfate. Concentration in vacuo gave the title compound (0.45 g, 46.8%) as a pale yellow solid, which was used crude without further purification. .sub.H (DMSO-d.sub.6, 300 MHz) 8.49 (br s, 1H), 7.38 (br s, 2H), 5.21-5.11 (m, 2H), 1.42 (d, J 6.9 Hz, 3H).

Intermediate 9

1-(2-Amino-4,6-dichloropyrimidin-5-yl)ethanone

(18) To Intermediate 8 (0.45 g, 2.18 mmol) were added manganese dioxide (1.90 g, 21.9 mmol) and DCM (50 mL). The mixture was heated at 40 C. for 2.5 h before cooling to r.t. overnight. To the mixture was added further manganese dioxide (2.9 g, 34.2 mmol) and the mixture was heated at 40 C. for 3 h. The mixture was cooled to r.t. and filtered through celite. The solvent was removed in vacuo to yield the title compound (0.29 g, 65.3%) as a pale yellow solid. .sub.H (DMSO-d.sub.6) 7.90 (br s, 2H), 3.34 (s, 3H).

Intermediate 10

tert-Butyl (3S)-4-(5-acetyl-2-amino-6-chloropyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

(19) To Intermediate 9 (0.29 g, 1.42 mmol) was added 2-(S)-methyl-4-(tert-butoxycarbonyl)piperazine (0.33 g, 1.6 mmol) and the solids were dissolved in 1,4-dioxane (10 mL). To this was added DIPEA (0.3 mL, 2 mmol) and the mixture was heated at 80 C. for 5 h before cooling to r.t. overnight. The solvent was removed in vacuo and the yellow oil was purified by flash column chromatography on silica [Biotage SNAP 25 g, Isolera, gradient elution (100% isohexane to 50% EtOAc/isohexane)] to yield the title compound (0.47 g, 89.9%) as a white foam. LCMS (ES+) 370.2 [M+H].sup.+, RT 1.35 minutes (method 3).

Intermediate 11

tert-Butyl (3S)-4-(6-amino-1,3-dimethylpyrazolo[3,4-d]pyrimidin-4-yl)-3-methyl-piperazine-1-carboxylate

(20) To Intermediate 10 (0.46 g, 1.25 mmol) in THF (15 mL) were added methylhydrazine (0.08 mL, 2 mmol) and triethylamine (0.35 mL, 2.5 mmol). The mixture was heated at 68 C. overnight whilst stirring under nitrogen. The mixture was concentrated in vacuo. The resulting off-white solid was purified by flash column chromatography on silica [Biotage SNAP 25 g, Isolera, gradient elution (20% EtOAc/isohexane to 100% EtOAc)], yielding the title compound as a white solid. LCMS (ES+) 362.2 [M+H].sup.+, RT 1.21 minutes (method 3).

Intermediate 12

1,3-Dimethyl-4-[(2S)-2-methylpiperazin-1-yl]pyrazolo[3,4-d]pyrimidin-6-amine hydrochloride

(21) To Intermediate 11 (0.31 g, 0.86 mmol) was added 4N HCl in 1,4-dioxane (10 mL) and the mixture was stirred at r.t. DCM (10 mL) was added to aid solubility. The mixture was stirred at r.t. for 6 h before concentration in vacuo, to yield the title compound (0.29 g, 90.51%) as an off white solid. LCMS (ES+) 262.2 [M+H].sup.+, RT 1.04 minutes (method 1).

Intermediate 13

4-Chloro-1-methylpyrazolo[3,4-d]pyrimidin-6-amine

(22) To a suspension of 2-amino-4,6-dichloropyrimidine-5-carbaldehyde (5.35 g, 26.75 mmol) in THF (60 mL) was added triethylamine (11.5 mL, 82.5 mmol) and the mixture was cooled to 5 C. (ice bath). Methylhydrazine (1.4 mL, 27 mmol) was added, and the mixture was stirred at 5 C. for 1 h, before warming to r.t. The bright yellow mixture was stirred at r.t. for a further 30 minutes before filtering under reduced pressure. The resulting solid was washed with diethyl ether followed by water, then dried, to yield the title compound (4.06 g, 82.6%) as a yellow solid. .sub.H (DMSO-d.sub.6) 7.97 (s, 1H), 7.29 (s, 2H), 3.79 (s, 3H).

Intermediate 14

tert-Butyl (3R)-4-(6-amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-3-(hydroxymethyl)-piperazine-1-carboxylate

(23) To Intermediate 13 (3.99 g, 21.7 mmol) was added tert-butyl (3R)-3-(hydroxymethyl)piperazine-1-carboxylate (5.21 g, 24 mmol), and the mixture was suspended in 1,4-dioxane (100 mL). To this was added DIPEA (4.6 mL, 26 mmol) and the mixture was heated at 80 C. for 1 h. Further DIPEA (9 mL) was added and the mixture was heated at 100 C. for 48 h. The reaction mixture was cooled to r.t. and concentrated in vacuo, to yield an orange solid which was triturated with water/ether/dichloromethane and filtered. The solid was discarded, and the filtrate was concentrated in vacuo. The resulting orange oil was purified by flash column chromatography on silica [Biotage SNAP 200 g, Isolera, gradient elution (80% EtOAc/isohexanes to 100% EtOAc; followed by 100% DCM to 20% MeOH/DCM)], to yield the title compound (4.51 g, 57.1%) as a yellow oil. LCMS (ES+) 364.8 [M+H].sup.+, RT 1.20 minutes (method 3).

Intermediate 15

[(2R)-1-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)piperazin-2-yl]methanol hydrochloride

(24) Intermediate 14 (0.5 g, 1.38 mmol) was stirred for 3 days with 4N HCl in 1,4-dioxane (10 mL). The reaction mixture was concentrated in vacuo and slurried in diethyl ether. Further concentration in vacuo gave the title compound (0.41 g, 99.0%) as a pale yellow powder. LCMS (ES+) 264.8 [M+H].sup.+, RT 0.65 minutes (method 1).

Intermediate 16

tert-Butyl (3S)-4-[2-amino-6-chloro-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrimidin-4-yl]-3-methylpiperazine-1-carboxylate

(25) To Intermediate 5 (1.51 g, 4.25 mmol) were added CsF (0.067 g, 0.44 mmol) and THF (40 mL). The mixture was stirred at r.t. under nitrogen for 2 minutes prior to the dropwise addition of (trifluoromethyl)trimethylsilane (3.8 mL, 25 mmol). The mixture was stirred at r.t. for 4 h, then the reaction was quenched with 0.5M hydrochloric acid (30 mL) and the mixture was stirred for 10 minutes. The mixture was partitioned between water (50 mL) and EtOAc (50 mL). The organic phase washed with water (50 mL) and brine (50 mL), then dried over sodium sulfate. The solvent was removed in vacuo. The resulting orange oil was purified by flash column chromatography on silica [Biotage SNAP 50 g, Isolera, gradient elution (10% EtOAc/isohexane to 40% EtOAc/isohexane)], to yield the title compound (0.75 g, 49.4%) as a yellow foam. LCMS (ES+) 426.2 [M+H].sup.+, RT 1.32 minutes (method 1).

Intermediate 17

tert-Butyl (3S)-4-[2-amino-6-chloro-5-(2,2,2-trifluoroacetyl)pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate

(26) To Intermediate 16 (0.47 g, 1.13 mmol) were added manganese dioxide (1.03 g, 11.9 mmol) and DCM (25 mL) and the mixture was stirred under nitrogen at r.t. overnight. Further manganese dioxide (1.57 g, 18 mmol) was added and the mixture was heated at 40 C. for 3 h before cooling to r.t. the mixture was filtered through Celite, washing with further DCM. The solvent was removed in vacuo, to yield the title compound (0.39 g, 82.3%). LCMS (ES+) 424.2 [M+H].sup.+, RT 2.95 minutes (method 1).

Intermediate 18

tert-Butyl (3S)-4-[6-amino-1-methyl-3-(trifluoromethyl)pyrazolo[3,4-d]pyrimidin-4-yl]-3-methylpiperazine-1-carboxylate

(27) To Intermediate 17 (0.39 g, 0.93 mmol) dissolved in THF (15 mL) were added methylhydrazine (0.06 mL, 1 mmol) and triethylamine (0.26 mL, 1.9 mmol). The mixture was heated at 68 C. under nitrogen for 48 h. The mixture was cooled to r.t. and concentrated in vacuo. The resulting yellow solid was purified by flash column chromatography on silica [Biotage SNAP 25 g, Isolera, gradient elution (20% EtOAc/isohexane to 100% EtOAc)], to yield the title compound (0.15 g, 38.8%) as an off-white solid. LCMS (ES+) 416.2 [M+H].sup.+, RT 2.60 minutes (method 1).

Intermediate 19

1-Methyl-4-[(2S)-2-methylpiperazin-1-yl]-3-(trifluoromethyl)pyrazolo[3,4-d]pyrimidin-6-amine hydrochloride

(28) To Intermediate 18 (0.15 g, 0.36 mmol) dissolved in DCM (10 mL) was added 4N HCl in 1,4-dioxane (10 mL) and the reaction mixture was stirred at r.t. for 1 h. A cloudy white precipitate formed and the mixture was diluted with methanol. The solvent was removed in vacuo to yield the title compound (0.15 g, 99.31%) as an off-white gum.

(29) LCMS (ES+) 316.2 [M+H].sup.+, RT 1.77 minutes (method 1).

Intermediate 20

tert-Butyl (3R)-4-(2-amino-6-chloro-5-formylpyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

(30) 2-Amino-4,6-dichloropyrimidine-5-carboxaldehyde (17.1 mmol), tert-butyl (3R)-3-methylpiperazine-1-carboxylate (3.43 g, 17.1 mmol) and DIPEA (2.66 g, 20.6 mmol) were heated in 1,4-dioxane (200 mL) at 60 C. After 4 h, the reaction mixture was cooled and stirred at r.t. overnight. The reaction mixture was re-heated for a further 4 h at 80 C., then stirred at r.t. overnight. The reaction mixture was then concentrated in vacuo, and partitioned between diethyl ether and water. A fine orange solid was filtered off and discarded. The ether washings were dried over sodium sulfate and concentrated in vacuo, to give the title compound (4 g, 65.6%) as a yellow foam. LCMS (ES+) 356.2 [M+H].sup.+, RT 2.26 minutes (method 1).

Intermediate 21

tert-Butyl (3R)-4-(6-amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

(31) Intermediate 20 (4 g, 11.24 mmol) in THF (100 mL) was treated with triethylamine (2.28 g, 22.48 mmol) and methylhydrazine (12.37 mmol). The reaction mixture was stirred at 60 C. for 1 h, then cooled and left overnight. The reaction mixture was concentrated in vacuo, and the residue was partitioned between DCM and water. The organic phases were separated and concentrated in vacuo, to give the title compound (3.9 g, 100%) as a yellow foam. LCMS (ES+) 348.2 [M+H].sup.+, RT 1.36 minutes (method 1).

Intermediate 22

1-Methyl-4-[(2R)-2-methylpiperazin-1-yl]pyrazolo[3,4-d]pyrimidin-6-amine hydrochloride

(32) Intermediate 21 (4.5 g, 13 mmol) was dissolved in 4N HCl in 1,4-dioxane (20 mL) and stirred for 1 h. MeOH (5 mL) was added to aid solubility. The reaction mixture was stirred for 1 h, then concentrated in vacuo. The residue was triturated from diethyl ether to give the title compound (3.5 g, 95%) as a pale yellow powder. LCMS (ES+) 248.3 [M+H].sup.+, RT 0.45 minutes (method 1).

Intermediate 23

Phenyl N-[6-(3,3-difluoroazetidin-1-yl)-2-methylpyridin-3-yl]carbamate

(33) To a solution of 6-(3,3-difluoroazetidin-1-yl)-2-methylpyridin-3-amine (WO 2010/139747; 7.2 g, 36 mmol) in THF (100 mL) at 0 C. (ice bath) were added pyridine (3.6 g, 45 mmol) then phenyl chloroformate (38 mmol) dropwise. The reaction mixture was stirred for 3 h, then left at r.t. overnight. Another aliquot of phenyl chloroformate (1 mL) and pyridine (1 mL) was added, and the reaction mixture was stirred at r.t. for 4 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between EtOAc and 2% HCl solution. The organic layers were dried over sodium sulfate and concentrated in vacuo, to yield an off-white waxy solid. The aqueous acidic layer was neutralised with saturated aqueous sodium bicarbonate solution, and a solid was collected by filtration. The batches of recovered material were combined to give the title compound (9.92 g, 86.0%). LCMS (ES+) 320.2 [M+H].sup.+, RT 1.34 minutes.

Intermediate 24

Phenyl N-(6-methoxy-2-methylpyridin-3-yl)carbamate

(34) To a solution of 6-methoxy-2-methylpyridin-3-amine (2.02 g, 13.9 mmol) in DCM (50 mL) were added triethylamine (2.3 mL, 17 mmol) and phenyl chloroformate (1.9 mL, 15 mmol) and the mixture was stirred under nitrogen at r.t. overnight. The mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was separated, and concentrated in vacuo. To the resulting brown oil was added diethyl ether. Following the addition of isohexane, a solid precipitated out of solution, to yield the title compound (2.79 g, 56.0%) as an off-white/pale pink solid. LCMS (ES+) 259.8 [M+H].sup.+, RT 1.77 minutes.

Intermediate 25

Phenyl N-(4-methoxy-2-methylphenyl)carbamate

(35) To a solution of 4-methoxy-2-methylaniline (5 g, 36.45 mmol) in THF (100 mL) at 0 C. (ice bath) were added pyridine (45.56 mmol) then phenyl chloroformate (38.27 mmol). The reaction mixture was allowed to warm to r.t. and stirred overnight. The reaction mixture was then partitioned between 5% HCl solution and EtOAc. The organic layers were washed further with 5% HCl solution, then saturated aqueous sodium bicarbonate solution. The organic layers were dried over sodium sulfate and concentrated in vacuo, to yield the title compound (7.61 g, 81.1%) as a pale purple powder. .sub.H (DMSO-d.sub.6) 9.30 (s, 1H), 7.40 (t, J 7.7 Hz, 2H), 7.30-7.09 (m, 3H), 6.90-6.62 (m, 3H), 3.72 (s, 3H), 2.25 (s, 3H).

Intermediate 26

2-(3,3-Difluoroazetidin-1-yl)-4-methyl-5-nitropyridine

(36) To a solution of 2-chloro-4-methyl-5-nitropyridine (1 g, 5.7 mmol) in DMF (10 mL) were added Cs.sub.2CO.sub.3 (3.7 g, 11.4 mmol) followed by 3,3-difluoroazetidine (1.4 g, 11.4 mmol), and the reaction mixture was heated for 3 h at 80 C. The reaction mixture was then diluted with EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate solution, then dried over sodium sulfate and concentrated in vacuo. The resulting crude material was purified by flash column chromatography on silica (100-200 mesh, 2-3% MeOH/DCM), to afford the title compound (1.1 g, 83.0%) as a light brown solid. .sub.H (DMSO-d.sub.6) 8.85 (s, 1H), 6.58 (s, 1H), 4.59 (t, 4H), 2.53 (s, 3H).

Intermediate 27

6-(3,3-Difluoroazetidin-1-yl)-4-methylpyridin-3-amine

(37) To a stirred solution of Intermediate 26 (0.28 mmol) in MeOH (10 mL) was added Pd/C (50 mg). The reaction mixture was stirred under a hydrogen atmosphere for 4 h at r.t. The reaction mixture was then filtered through Celite. The organic layer was concentrated, to afford the title compound (0.26 g, 59.0%) as an off-white solid. .sub.H (DMSO-d.sub.6) 7.60 (s, 1H), 6.30 (s, 1H), 4.30 (br s, 2H), 4.20 (t, 4H), 2.05 (s, 3H).

Intermediate 28

tert-Butyl N-(2-chloro-4-methylpyrimidin-5-yl)carbamate

(38) To a solution of 2-chloro-4-methylpyrimidin-5-amine (WO 2009/112524; 0.8 g, 5.59 mmol) and triethylamine (2.6 mL, 19.58 mmol) in DCM (10 mL) was added di-tert-butyl dicarbonate (22.0 mmol). The reaction mixture was stirred for 18 h at r.t. The reaction mixture was then diluted with DCM. The organic layer was washed with saturated aqueous sodium bicarbonate solution, then dried over sodium sulfate and concentrated in vacuo. The resulting crude material was purified by flash column chromatography on silica (100-200 mesh, 40% EtOAc/isohexanes), to afford the title compound (0.7 g, 51.0%) as a semi-solid. LCMS (ES+) 244.05 [M+H].sup.+, RT 2.15 minutes (method 5).

Intermediate 29

N2,N2,4-Trimethylpyrimidine-2,5-diamine hydrochloride

(39) To a solution of Intermediate 28 (0.2 g, 0.8 mmol) in MeOH (2 mL) was added dimethylamine in water (0.5 mL). The reaction mixture was heated at 60 C. for 3 h. The reaction mixture was diluted with EtOAc, then the organic layer was washed with water and brine, dried over sodium sulphate, and concentrated in vacuo. The resulting crude material was purified by flash column chromatography on silica (100-200 mesh, 2-5% MeOH/DCM). The resulting white solid was taken up in 1,4-dioxane (1 mL), treated with 4N HCl in 1,4-dioxane (2 mL) and stirred at r.t. for 3 h. The reaction mixture was concentrated, then the resulting crude material was triturated with diethyl ether, to afford the title compound (0.1 g, 83.0%). LCMS (ES+) 153.00 [M+H].sup.+, RT 0.95 minutes (method 5).

Intermediate 30

2-(3,3-Difluoroazetidin-1-yl)-4-methylpyrimidin-5-amine hydrochloride

(40) To a solution of Intermediate 28 (0.3 g, 1.23 mmol) in DMF (5 mL) were added Cs.sub.2CO.sub.3 (0.8 g, 2.4 mmol) and 3,3-difluoroazetidine (0.3 g, 2.4 mmol) and the reaction mixture was heated at 80 C. for 3 h. The reaction mixture was diluted with EtOAc, then the organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo. The resulting crude material was purified by flash column chromatography on silica (100-200 mesh, 30% EtOAc/isohexanes). The resulting off-white solid was taken up in 1,4-dioxane (1 mL), treated with 4N HCl in 1,4-dioxane (2 mL) and stirred at r.t. for 3 h. The reaction mixture was concentrated, then the resulting crude material was triturated with diethyl ether, to afford the title compound (0.12 g, 82.0%). LCMS (ES+) 201.05 [M+H].sup.+, RT 0.96-1.21 minutes (method 5).

Intermediate 31

1-Methyl-6-sulfanyl-5H-pyrazolo[3,4-d]pyrimidin-4-one

(41) To a solution of ethyl 5-amino-1-methyl-1H-pyrazole-4-carboxylate (2.0 g, 11.8 mmol) in acetone (30 mL) at r.t. was added benzoyl isothiocyanate (1.7 mL, 12.6 mmol). The reaction mixture was continuously stirred for 8 h, then concentrated in vacuo. The residue was dissolved in acetone (120 mL), MeOH (120 mL) and water (15 mL), and potassium carbonate (3.27 g, 23.6 mmol) was added. The mixture was heated under reflux with stirring for 4 h. The solution was allowed to cool down to r.t. and glacial acetic acid was added until all potassium carbonate was dissolved. The solution was cooled to 0 C. and the precipitate was collected, to yield the title compound (1.68 g) as a white solid. .sup.13C NMR (DMSO-d.sub.6, 75 MHz) 175.0, 156.2, 144.1, 135.5, 102.0, 35.9. MS (m/z) 183 [M+H].sup.+.

Intermediate 32

1-Methyl-6-(methylsulfanyl)-5H-pyrazolo[3,4-d]pyrimidin-4-one

(42) To a solution of Intermediate 31 (1.779 g, 9.76 mmol) in THF (90 mL) were added triethylamine (1.630 mL, 11.7 mmol) and iodomethane (0.638 mL, 10.2 mmol). The reaction mixture was continuously stirred for 1 h, then partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and evaporated in vacuo, affording the title compound (1.79 g) as a white solid. .sup.13C NMR (DMSO-d.sub.6, 75 MHz) 160.6, 157.9, 151.9, 134.2, 102.8, 33.9, 13.0. MS (m/z) 197 [M+H].sup.+.

Intermediate 33

tert-Butyl (3S)-3-methyl-4-[1-methyl-6-(methylsulfanyl)pyrazolo[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

(43) To Intermediate 32 (1.449 g, 7.4 mmol) were added POCl.sub.3 (15 mL) and N,N-dimethylaniline (0.5 mL) at r.t. The suspension was continuously stirred for 2 h at 105 C., by which time the suspension had become a solution. The reaction mixture was evaporated, then the residue was extracted using EtOAc and brine. The organic solvent was dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in 1,4-dioxane (70 mL), then DIPEA (2.634 mL, 15.9 mmol) and (S)-tert-butyl 3-methylpiperazine-1-carboxylate (1.595 g, 7.9 mmol) were added. The reaction mixture was continuously stirred for 4 h at 105 C. The solution was evaporated in vacuo, then the residue was purified by silica gel chromatography (10% EtOAc/cyclohexane), to provide the title compound (1.733 g) as a yellow solid. .sup.13C NMR (DMSO-d.sub.6, 75 MHz) 167.5, 155.5, 154.6, 133.1, 128.6, 111.1, 79.2 (3C), 48.6, 47.6, 42.9, 42.4, 33.5, 15.1, 13.7. MS (m/z) 379 [M+H].sup.+.

Intermediate 34

1-Methyl-4-[(2S)-2-methylpiperazin-1-yl]-6-(methylsulfanyl)pyrazolo[3, 4-d]pyrimidine trifluoroacetate

(44) Prepared via Method A by treating Intermediate 33 (50 mg, 0.13 mmol) with DCM (1 mL) and TFA (1 mL). The title compound was obtained as a crude product that was utilised in subsequent reactions without further purification. MS (m/z) 279 [M+H].sup.+.

Intermediate 35

tert-Butyl (3S)-4-(2-amino-6-chloro-5-formylpyrimidin-4-yl)-3-ethylpiperazine-1-carboxylate

(45) To a solution of tert-butyl (3S)-3-ethylpiperazine-1-carboxylate (0.5 g, 2.3 mmol) and 2-amino-4,6-dichloropyrimidine-5-carbaldehyde (0.45 g) in 1,4-dioxane (8.0 mL) was added DIPEA (1.2 mL, 7.0 mmol). The reaction mixture was heated at 120 C. overnight in a sealed Wheaton vial, then cooled and stirred at room temperature over the weekend. The solvent was removed in vacuo, and the residue was partitioned between water and DCM. The organic layers were phase separated and concentrated in vacuo to give the title compound (0.85 g, 99%) as a yellow glass. LCMS (ES+) [M+H].sup.+ 370, RT 1.81 minutes (method 2).

Intermediate 36

tert-Butyl (3S)-4-(6-amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-3-ethylpiperazine-1-carboxylate

(46) To a solution of Intermediate 35 (1.0 g) in THF (10 mL) were added triethylamine (0.55 g, 0.75 mL) and methylhydrazine (0.14 g, 0.16 mL). The reaction mixture was stirred for 5 h at room temperature, then concentrated in vacuo and partitioned between DCM and water. The organic layers were phase separated and concentrated in vacuo to yield the title compound (0.9 g, 90%) as a pale cream foam. LCMS (ES+) [M+H].sup.+ 362.4, RT 1.50 minutes (method 2).

Intermediate 37

4-[(2S)-2-Ethylpiperazin-1-yl]-1-methylpyrazolo[3,4-d]pyrimidin-6-amine dihydrochloride

(47) Intermediate 36 (0.9 g, 2 mmol) was stirred in HCl (4N in 1,4-dioxane, 10 mL) for 2 h, then concentrated in vacuo, to give the title compound (0.8 g, quantitative) as a white powder. LCMS (ES+) [M+H].sup.+ 262, RT 0.57 minutes (method 2).

INTERMEDIATES 38 TO 66

(48) To a cooled (ice bath) solution of the specified amine (1 mmol) in THF (50 mL) was added pyridine (1.1 equiv.), followed by phenyl chloroformate (1 equiv.) dropwise. The reaction mixture was allowed to warm to room temperature. When LCMS confirmed complete conversion of the amine to the desired carbamate, the reaction mixture was quenched with water. The desired carbamate was then either collected by filtration, or extracted into DCM, phase separated and concentrated in vacuo, then used without further purification. The indicated carbamates were prepared.

(49) TABLE-US-00008 LCMS Data Int. Amine Carbamate Method RT [M + H].sup.+ 38 2-Methyl-4-(trifluoro- Phenyl N-[2-methyl-4-(trifluoro- 2 2.26 312.2 methoxy)aniline methoxy)phenyl]carbamate 39 2-Fluoro-4-(trifluoro- Phenyl N-[2-fluoro-4-(trifluoro- 1 1.56 316 methoxy)aniline methoxy)phenyl]carbamate 40 2-Chloro-4-(trifluoro- Phenyl N-[2-chloro-4-(trifluoro- 1 1.59 332 methoxy)aniline methoxy)phenyl]carbamate 41 3-Methoxy-5-(trifluoro- Phenyl N-[3-methoxy-5-(trifluoro- 2 2.64 312.2 methyl)aniline methyl)phenyl]carbamate 42 1-Ethylindazol-3-amine Phenyl N-(1-ethylindazol-3-yl)- 1 1.39 282.0 carbamate 43 6-(Difluoromethoxy)-2- Phenyl N-[6-(difluoromethoxy)-2- 1 0.98 295.2 methylpyridin-3-amine methylpyridin-3-yl]carbamate 44 6-Ethoxy-5-fluoro- Phenyl N-(6-ethoxy-5-fluoropyridin- 1 1.41 277 pyridin-3-amine 3-yl)carbamate 45 2-Chloro-4-fluoro-5- Phenyl N-(2-chloro-4-fluoro-5- 2 2.36 280 methylaniline methylphenyl)carbamate 46 5-Fluoro-6-methoxy- Phenyl N-(5-fluoro-6-methoxy- 1 1.39 263 pyridin-3-amine pyridin-3-yl)carbamate 47 6-Ethoxy-2-methyl- Phenyl N-(6-ethoxy-2-methylpyridin- 1 1.45 273 pyridin-3-amine 3-yl)carbamate 48 1-Methyl-5-(trifluoro- Phenyl N-[1-methyl-5-(trifluoro- 1 1.50 336 methyl)indazol-3-amine methyl)indazol-3-yl]carbamate 49 3-Amino-6-fluoro-1- Phenyl N-(6-fluoro-1-methylindazol- 1 1.36 286 methylindazole 3-yl)carbamate 50 5-Fluoro-1-methyl- Phenyl N-(5-fluoro-1-methylindazol- 1 1.38 286 indazol-3-amine 3-yl)carbamate 51 Imidazo[1,2-a]pyridin-8- Phenyl N-(imidazo[1,2-a]pyridin-8- 1 254.1 amine yl)carbamate 52 5-Methylisoxazol-3- Phenyl N-(5-methylisoxazol-3-yl)- 1 219.1 amine carbamate 53 1,2-Benzoxazol-3-amine Phenyl N-(1,2-benzoxazol-3-yl)- 1 1.35 255 carbamate 54 1-Methylindazol-3-amine Phenyl N-(1-methylindazol-3-yl)- 1 1.34 268 carbamate 55 5-Amino-6-methyl- Phenyl N-(6-cyano-2-methylpyridin- 1 253.2 pyridine-2-carbonitrile 3-yl)carbamate 56 2-Methyl-4-(methyl- Phenyl N-[2-methyl-4-(methyl- 1 1.28 306 sulfonyl)aniline sulfonyl)phenyl]carbamate 57 6-(Difluoromethoxy)-4- Phenyl N-[6-(difluoromethoxy)-4- 1 1.42 295 methylpyridin-3-amine methylpyridin-3-yl]carbamate 58 6-Methoxy-5-methyl- Phenyl N-(6-methoxy-5-methyl- 1 1.38 259 pyridin-3-amine pyridin-3-yl)carbamate 59 6-Methoxy-4-methyl- Phenyl N-(6-methoxy-4-methyl- 1 1.30 259 pyridin-3-amine pyridin-3-yl)carbamate 60 5-Methoxy-2-methyl- Phenyl N-(5-methoxy-2-methyl- 1 258.1 aniline phenyl)carbamate 61 3-Chloro-4-methylaniline Phenyl N-(3-chloro-4-methylphenyl)- 1 262 carbamate 62 2,5-Dichloroaniline Phenyl N-(2,5-dichlorophenyl)- 1 283 carbamate 63 4-Amino-3-methyl- Phenyl N-(4-cyano-2-methylphenyl)- 1 1.57 253 benzonitrile carbamate 64 2,6-Dimethoxypyridin-3- Phenyl N-(2,6-dimethoxypyridin-3- 1 1.44 275 amine yl)carbamate 65 4-Methoxy-3-methyl- Phenyl N-(4-methoxy-3-methyl- 1 1.47 258 aniline phenyl)carbamate 66 4-(Difluoromethoxy)-2- Phenyl N-[4-(difluoromethoxy)-2- 1 1.45 294 methylaniline methylphenyl]carbamate

Intermediate 67

tert-Butyl N-(5-bromo-3-methylpyrazin-2-yl)carbamate

(50) To a solution of 2-amino-5-bromo-3-methylpyrazine (46.5 g, 247.3 mmol) in acetonitrile (450 mL) and THF (750 mL) was added DMAP (3 g, 24.7 mmol). The reaction mixture was stirred for 15 minutes before the addition of di-tert-butyl dicarbonate (242 g, 1112.8 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated in vacuo, then diluted with EtOAc (750 mL) and washed with water (500 mL). The organic layers were dried over magnesium sulphate and concentrated in vacuo. The black tar was purified via flash chromatography, using a 10-15% EtOAc in heptane gradient. The resultant solid was triturated with IPA. The resulting white solid (the bis-tert-butoxycarbonyl derivative) was dissolved in methanol (3000 mL), then K.sub.2CO.sub.3 (61.25 g, 443 mmol) was added. The reaction mixture was stirred overnight at room temperature, then at 60 C. for 1 h, then allowed to cool and concentrated in vacuo. The residue was dissolved in DCM (1000 mL), then washed with water (21000 mL) and brine (500 mL). The organic layers were dried over magnesium sulphate, then concentrated in vacuo, to give the title compound (38 g, 80% pure by LCMS). LCMS (ES+) [M+H].sup.+ 288.1 and 289.1, RT 1.42 minutes (method 1).

Intermediate 68

tert-Butyl N-[5-(dimethylamino)-3-methylpyrazin-2-yl]carbamate

(51) To Intermediate 67 was added dimethylamine in ethanol (5.6M, 400 mL). The solution was heated at 55 C. overnight in an auotoclave. The crude reaction mixture was concentrated in vacuo and purified by flash chromatography, using a gradient of 20-100% EtOAc in heptane, to yield the title compound (14 g) as a solid. LCMS (ES+) [M+H].sup.+196 (fragment minus tert-butyl), RT 1.56 minutes (method 1).

Intermediate 69

N5,N5,3-Trimethylpyrazine-2,5-diamine

(52) Intermediate 68 (7 g, 27.7 mmol) was taken up in HCl (3.34M in 1,4-dioxane, 70 mL) and stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The resulting yellow solid was stirred in triethylamine (28 g) for 4 h, then concentrated in vacuo. The resulting black paste was purified by flash chromatography, eluting with a gradient of 50% EtOAc in heptane to 10% MeOH in EtOAc, to give the title compound (2.1 g, 50%). .sub.H (CDCl.sub.3) 7.40 (s, 1H), 3.80 (br s, 2H), 3.00 (s, 6H), 2.30 (s, 3H).

Intermediate 70

Phenyl N-[5-(dimethylamino)-3-methylpyrazin-2-yl]carbamate

(53) To a cooled (ice bath) solution of Intermediate 69 (2.1 g, 13.79 mmol) in dry acetonitrile (20 mL) was added pyridine (1.3 g, 16.54 mmol), followed by phenyl chloroformate (2.16 g, 13.79 mmol) dropwise. The reaction mixture was slowly allowed to warm to room temperature over 1 h. The reaction mixture was concentrated in vacuo onto silica, then purified by flash chromatography, eluting with a gradient of 20-60% EtOAc in heptane, to yield the title compound (3.1 g, 82%) as a solid. .sub.H (CDCl.sub.3) 7.65 (s, 1H), 7.35 (m, 1H), 7.15 (m, 3H), 6.80 (br s, 1H), 3.05 (s, 6H), 2.42 (s, 3H).

Intermediate 71

2-Ethyl-6-methoxy-3-nitropyridine

(54) To a degassed solution of 2-chloro-6-methoxy-3-nitropyridine (3 g, 15.95 mmol), ethylboronic acid (3 g, 47.80 mmol) and K.sub.2CO.sub.3 (6 g, 47.80 mmol) in 1,4-dioxane (60 mL) was added Pd(dppf)Cl.sub.2 (1 g, 1.59 mmol). The reaction mixture was stirred at 100 C. for 12 h, then filtered through Celite. The filtrate was concentrated in vacuo and the crude material was purified using column chromatography (silica 100-200 mesh; 10% EtOAc in hexane) to yield the title compound (1.4 g, 48%). .sub.H (CDCl.sub.3) 8.20 (d, J 8.1 Hz, 1H), 6.82 (d, J 7.9 Hz, 1H), 4.05 (s, 3H), 3.19 (q, 2H), 1.28 (t, 3H). LCMS: [M+1]183.20 (95.43% LCMS purity).

Intermediate 72

2-Ethyl-6-methoxypyridin-3-amine

(55) To a solution of Intermediate 71 (1.4 g, 7.6 mmol) in MeOH (25 mL) was added Pd/C (150 mg). The reaction mixture was stirred at room temperature for 12 h under an atmosphere of hydrogen (balloon), then filtered through Celite. The filtrate concentrated in vacuo. The crude material was purified using column chromatography (Silica 100-200 mesh, 20% EtOAc in hexane) to yield the title compound (0.9 g, 77%). .sub.H (DMSO-d.sub.6) 6.99 (d, J 8.2 Hz, 1H), 6.38 (d, J 8.2 Hz, 1H), 4.28 (s, 2H), 3.70 (s, 3H), 4.55 (s, 2H), 3.70 (s, 3H), 2.25 (q, 2H), 1.18 (t, 3H). LCMS: [M+1]153.1 (99.86% LCMS purity).

Intermediate 73

2-[1-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)piperazin-2-yl]ethanol dihydrochloride

(56) Intermediate 13 (2.00 g, 10.9 mmol) and tert-butyl 3-(2-hydroxyethyl)piperazine-1-carboxylate (10.9 mmol, 2.51 g) in n-butanol (51 mL) and DIPEA (13.1 mmol, 1.71 g, 2.42 mL) was heated at 100 C. for 4 h. The reaction mixture was cooled, partitioned between DCM and water and filtered, then the organic phases were separated and concentrated in vacuo. The residual oil was purified by flash column chromatography on silica (Biotage SNAP 50 g, Isolera, gradient elution: 100% DCM to 35% MeOH/DCM). The resulting clear oil was taken up in DCM (40 mL) and HCl (4N in 1,4-dioxane, 8 mL). The solution was stirred overnight, then concentrated to dryness and washed with diethyl ether. The resulting sticky solid was dried under vacuum to yield the title compound (1.5 g, 39%) as an off-white foam. LCMS (ES+) [M+H].sup.+ 278, RT 2.13 minutes (method 2).

Intermediate 74

2-Amino-4-[(2S,6S)-4-benzyl-2,6-dimethylpiperazin-1-yl]-6-chloropyrimidine-5-carbaldehyde

(57) To a solution of (3S,5S)-1-benzyl-3,5-dimethylpiperazine (3 g, 15 mmol) and 2-amino-4,6-dichloropyrimidine-5-carbaldehyde (2.84 g, 14.8 mmol) in n-butanol (30 mL) was added DIPEA (31 mmol). The reaction mixture was heated at 110 C. for 2 h, then cooled and partitioned between water and EtOAc. The aqueous layer was further extracted with EtOAc. The combined organic layers were dried over magnesium sulphate, then concentrated in vacuo. The orange oil was purified by flash column chromatography (4:1 heptane:EtOAc) to give the title compound (4.68 g, 89%) as a yellow oil. LCMS (ES+) [M+H].sup.+ 360, RT 1.69 minutes (method 1).

Intermediate 75

4-[(2S,6S)-4-Benzyl-2,6-dimethylpiperazin-1-yl]-1-methylpyrazolo[3,4-d]pyrimidin-6-amine

(58) To a solution of Intermediate 74 (4.6 g, 13 mmol) in THF (43 mL) were added triethylamine (3.96 g, 5.4 mL, 39 mmol) and methylhydrazine (0.6 g, 0.68 mL, 13 mmol). The reaction mixture was stirred for 2 h at room temperature, then partitioned between water and EtOAc. The aqueous layer was further extracted with EtOAc, and the combined organic extracts were concentrated in vacuo. The resulting orange oil was purified by flash column chromatography (EtOAc) to yield the title compound (3.37 g, 74%) as a cream foam. LCMS (ES+) [M+H].sup.+ 352.3, RT 1.53 minutes (method 1).

Intermediate 76

4-[(2S,6S)-2,6-Dimethylpiperazin-1-yl]-1-methylpyrazolo[3,4-d]pyrimidin-6-amine

(59) Intermediate 75 (3.3 g, 9.59 mmol) was dissolved in IMS (190 mL). Pd/C (5%, 2.3 g) and ammonium formate (10 equiv.) were added and the mixture was heated at 80 C. overnight. The reaction mixture was allowed to cool, then filtered through a pad of Celite, washing with MeOH. The combined filtrate and washings were concentrated in vacuo to give the title compound (2.43 g, 93%) as a yellow solid. LCMS (ES+) [M+H].sup.+ 262, RT 0.99 minutes (method 1).

Intermediate 77

4-[4-Benzyl-2-(2,2,2-trifluoroethyl)piperazin-1-yl]-1-methylpyrazolo[3,4-d]pyrimidin-6-amine

(60) Intermediate 13 (2.13 g, 11.62 mmol) and 1-benzyl-3-(2,2,2-trifluoroethyl)-piperazine (3 g, 11.62 mmol) in n-butanol (30 mL) and DIPEA (4.5 g, 34.8 mmol) were heated at 100 C. for 72 h. The reaction mixture was cooled, then concentrated in vacuo. The residue was diluted with DCM and washed with sodium bicarbonate, then water, then brine. The organic layers were dried over magnesium sulphate and concentrated in vacuo. The residual oil was purified by flash column chromatography on silica, using a gradient of 40-100% EtOAc in heptane, to yield the title compound (3.2 g, 68%) as a yellow solid. LCMS (ES+) [M+H].sup.+ 406.3, RT 1.61 minutes (method 1).

Intermediate 78

1-Methyl-4-[2-(2,2,2-trifluoroethyl)piperazin-1-yl]pyrazolo[3,4-d]pyrimidin-6-amine dihydrochloride

(61) Intermediate 77 (3.2 g, 7.89 mmol) was dissolved in IMS (70 mL). Pd/C (5%, 0.83 g) and ammonium formate (4.97 g) were added and the mixture was heated at 85 C. overnight. The reaction mixture was allowed to cool, then filtered through a pad of Celite, washing with MeOH. The combined filtrate and washings were concentrated in vacuo. The residue was purified by flash chromatography, using a gradient from 100% EtOAc to 10% MeOH with NH.sub.3 in EtOAc. The resultant solid was taken up in HCl (4N in 1,4-dioxane, 10 mL) and stirred for 4 h. The precipitate was collected by filtration, then washed with ether and dried, to give the title compound (1.86 g, 66%) as a white solid. LCMS (ES+) [M+H].sup.+ 316.2, RT 1.06 minutes (method 1).

Intermediate 79

tert-Butyl 4-(2-amino-6-chloro-5-formylpyrimidin-4-yl)-3-(trifluoromethyl)piperazine-1-carboxylate

(62) To a solution of 3-(trifluoromethyl)piperazine-1-carboxylic acid tert-butyl ester (0.79 g) and 2-amino-4,6-dichloropyrimidine-5-carbaldehyde (0.58 g) in 1,4-dioxane (5.0 mL) was added DIPEA (1.6 mL, 9.0 mmol). The reaction mixture was heated at 120 C. overnight in a sealed Wheaton vial, then allowed to cool and concentrated in vacuo. The residue was partitioned between DCM and water. The organic phases were separated and concentrated in vacuo to give the title compound (1 g, 81%) as a semi-solid. LCMS (ES+) [M+H]+ 410, RT 1.82 minutes (method 2).

Intermediate 80

1-Methyl-4-[2-(trifluoromethyl)piperazin-1-yl]pyrazolo[3,4-d]pyrimidin-6-amine dihydrochloride

(63) Intermediate 79 (1 g, 2.44 mmol) in THF (20 mL) was treated with triethylamine (0.68 mL, 4.88 mmol) and methylhydrazine (0.12 g, 0.14 mL). The reaction mixture was stirred at room temperature overnight, then concentrated in vacuo and partitioned between DCM and water. The organic layers were phase separated, then concentrated in vacuo. The material was purified by flash column chromatography on silica (Biotage SNAP 25 g, Isolera, gradient elution: 100% EtOAc to 20% MeOH/EtOAc). The resulting pale yellow foam was dissolved in 4N HCl in 1,4-dioxane (5 mL) and stirred for 2 h. The reaction mixture was concentrated in vacuo to yield the title compound (0.35 g, 87%) as a pale yellow solid. LCMS (ES+) [M+H].sup.+ 302.2, RT 0.7 minutes (method 2).

Intermediate 81

4-[(2S)-2-Isopropylpiperazin-1-yl]-1-methylpyrazolo[3,4-d]pyrimidin-6-amine dihydrochloride

(64) 2-Amino-4,6-dichloropyrimidine-5-carbaldehyde (2.4 g, 13 mmol) and tert-butyl (3S)-3-isopropylpiperazine-1-carboxylate (2.9 g, 13 mmol) in 1,4-dioxane (50 mL) were treated with DIPEA (3.3 g, 5 mL, 25 mmol) and heated at 90 C. for 6 h. The reaction mixture was cooled and concentrated in vacuo, then partitioned between DCM and water. The organic layers were phase separated and concentrated. The resulting golden foam was taken up in THF (100 mL) with triethylamine (2.7 g, 4 mL, 27 mmol) and methylhydrazine (0.64 g, 0.73 mL, 14 mmol), then stirred for 72 h at room temperature. The reaction mixture was concentrated in vacuo and partitioned between DCM and water, then phase separated. The organic layers were further concentrated in vacuo. The residual foam was taken up in DCM (100 mL), then 4N HCl in 1,4-dioxane (20 mL) was added and the mixture was stirred overnight. The resultant solution was concentrated in vacuo and triturated with diethyl ether to give the title compound (3.8 g, 95%) as a sticky foam that was >95% pure by LCMS. LCMS (ES+) [M+H]+ 276.2, RT 0.72 minutes (method 2).

Intermediate 82

4-[(2S)-2-Isobutylpiperazin-1-yl]-1-methylpyrazolo[3,4-d]pyrimidin-6-amine dihydrochloride

(65) 2-Amino-4,6-dichloropyrimidine-5-carbaldehyde (2.3 g, 12 mmol) and tert-butyl (3S)-3-isobutylpiperazine-1-carboxylate (12 mmol, 2.9 g) in 1,4-dioxane (50 mL) were treated with DIPEA (3.3 g, 5 mL, 25 mmol) and heated at 90 C. for 6 h. The reaction mixture was cooled and concentrated in vacuo, then partitioned between DCM and water. The organic layers were phase separated and concentrated. The resulting golden foam was taken up in THF (100 mL) with triethylamine (2.5 g, 4 mL, 25 mmol) and methylhydrazine (0.61 g, 0.70 mL, 13 mmol), then stirred for 72 h at room temperature. The reaction mixture was concentrated in vacuo and partitioned between DCM and water, then phase separated. The organic layers were further concentrated in vacuo. The residual foam was taken up in DCM (100 mL), then 4N HCl in 1,4-dioxane (20 mL) was added and the mixture was stirred overnight. The resultant solution was concentrated in vacuo and triturated with diethyl ether to give the title compound (3.6 g, 92%) as a sticky foam that was >90% pure by LCMS. LCMS (ES+) [M+H]+ 290.2, RT 0.92 minutes (method 2).

Intermediate 83

3-Bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine

(66) To a suspension of Intermediate 1 (923 mg, 5.44 mmol) and sodium acetate (4.13 g, 50.4 mmol) in a mixture of acetic acid (50 mL) and water (10 mL) at 0 C. was added bromine (2.2 mL, 43.54 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and continuously stirred for 5.5 h. The reaction mixture was concentrated in vacuo. The residue was precipitated into water. The precipitate was collected by filtration and dried in vacuo to provide the title compound (0.99 g, 73%). .sup.13C NMR (DMSO-d.sub.6, 75 MHz) 161.6 (C-2), 157.9 (C-4), 153.0 (C-7a), 119.5 (C-5), 103.9 (C-4a). MS (m/z) 247, 249 [M+H].sup.+.

Intermediate 84

tert-Butyl (3S)-4-(6-amino-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

(67) A mixture of Intermediate 83 (1 g, 4.02 mmol), tert-butyl (3S)-3-methyl-piperazine-1-carboxylate (806 mg, 4.02 mmol) and DIPEA (1.4 mL, 8.04 mmol) in DMF (25 mL) was heated at 105 C. for 39 h. The reaction mixture was evaporated in vacuo and purified by silica gel chromatography (DCM/MeOH, 40:1) to provide the title compound (849 mg, 51%). .sup.13C NMR (CDCl.sub.3+CD.sub.3OD, 75 MHz) 161.6 (C-4), 160.2 (C-2), 159.5 (CO), 156.1 (C-7a), 120.4 (C-5), 97.6 (C-4a), 80.9 [OC(CH.sub.3).sub.3], 52.1 (NCH.sub.2), 43.2 (NCH.sub.2), 28.5 (CH.sub.3), 14.9 [(S)CH.sub.3]. MS (m/z) 412, 414 [M+H].sup.+.

Intermediate 85

tert-Butyl (3S)-4-(6-amino-3-bromo-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-3-methyl-piperazine-1-carboxylate

(68) To a solution of Intermediate 84 (849 mg, 2.06 mmol) in DMF (10 mL) was added NaH (60%, 99 mg, 2.47 mmol) at 0 C. under N.sub.2. The reaction mixture was warmed to room temperature over 10 minutes, then cooled to 0 C. Iodomethane (154 L, 2.47 mmol) was added and the reaction mixture was continuously stirred for 3.5 h. The reaction mixture was quenched with cold aqueous NH.sub.4Cl solution, then extracted with DCM twice. The organic phase was washed with water and brine, then dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with DCM/MeOH (80:1) then DCM/MeOH (40:1), to provide the title compound (625 mg, 71%). .sup.13C NMR (CDCl.sub.3, 75 MHz) 160.9 (C-4), 159.8 (C-2), 158.2 (CO), 155.4 (C-7a), 118.5 (C-5), 98.0 (C-4a), 80.1 [OC(CH.sub.3).sub.3], 51.8 (NCH.sub.2), 43.0 (NCH.sub.2), 33.8 (NCH.sub.3), 28.5 (CH.sub.3), 14.9 [(S)CH.sub.3]. MS (m/z) 426, 428 [M+H].sup.+.

Intermediate 86

tert-Butyl (3S)-4-[6-amino-3-(4-fluorophenyl)-1-methylpyrazolo[3,4-d]pyrimidin-4-yl]-3-methylpiperazine-1-carboxylate

(69) To a suspension of Intermediate 85 (105 mg, 0.246 mmol) in a mixture of 1,4-dioxane (1.6 mL) and water (0.4 mL) were added 4-fluorophenylboronic acid (31 mg, 0.246 mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.012 mmol) and K.sub.2CO.sub.3 (102 mg, 0.739 mmol). The reaction mixture was degassed and heated at 110 C. under microwave irradiation (150 W) for 1 h under N.sub.2. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography, eluting with DCM/MeOH (40:1) then DCM/MeOH (30:1), to provide the title compound (83 mg, 79%). MS (m/z) 442 [M+H].sup.+.

Intermediate 87

tert-Butyl (3S)-4-[6-amino-1-methyl-3-(pyridin-3-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-3-methylpiperazine-1-carboxylate

(70) To a suspension of Intermediate 85 (105 mg, 0.246 mmol) in a mixture of 1,4-dioxane (1.6 mL) and water (0.4 mL) were added pyridin-3-ylboronic acid (35 mg, 0.246 mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.012 mmol) and K.sub.2CO.sub.3 (102 mg, 0.739 mmol). The reaction mixture was degassed and heated at 110 C. under microwave irradiation (150 W) for 1 h under N.sub.2. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography, eluting with DCM/MeOH (60:1) then DCM/MeOH (40:1), to provide the title compound (97 mg, 89%). .sup.13C NMR (CDCl.sub.3, 75 MHz) 161.3 (C-4), 160.8 (C-2), 158.5 (C-7a), 155.1 (CO), 149.6 (py), 149.5 (py), 141.1 (py), 135.2 (py), 130.7 (C-5), 123.5 (py), 95.8 (C-4a), 80.0 [OC(CH.sub.3).sub.3], 50.8 (NCH.sub.2), 48.0 (NCH.sub.2), 43.3 (NCH.sub.2), 42.6 (NCH.sub.2), 33.7 (NMe), 28.4 (Me), 14.3 (Me). MS (m/z) 425 [M+H].sup.+.

Intermediate 88

3-(4-Fluorophenyl)-1-methyl-4-[(2S)-2-methylpiperazin-1-yl]pyrazolo[3,4-d]pyrimidin-6-amine

(71) A mixture of Intermediate 86 (97 mg, 0.22 mmol) in TFA (4 mL) and DCM (4 mL) was stirred for 40 minutes. The reaction mixture was evaporated in vacuo, then co-evaporated with NH.sub.3-MeOH solution (7N) to dryness, to provide the crude title compound, which was used directly for the next stage without further purification. MS (m/z) 342 [M+H].sup.+.

Intermediate 89

1-Methyl-4-[(2S)-2-methylpiperazin-1-yl]-3-(pyridin-3-yl)pyrazolo[3,4-d]pyrimidin-6-amine

(72) A mixture of Intermediate 87 (83 mg, 0.195 mmol) in TFA (4 mL) and DCM (4 mL) was stirred for 30 minutes. The reaction mixture was evaporated in vacuo, then co-evaporated with NH.sub.3-MeOH solution (7N) to dryness, to provide the crude title compound, which was used directly for the next stage without further purification. MS (m/z) 325 [M+H].sup.+.

Example 1 (Method B)

6-Amino-4-{4-[(4-methoxy-2-methylphenyl)carbamyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine

(73) To a suspension of Intermediate 2 (66 mg, 0.3 mmol) in DMF (2 mL) at r.t. was added 4-methoxy-2-methylphenyl isocyanate (40 L, 0.3 mmol). The reaction mixture was stirred overnight, then concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM:MeOH 20:1; then DCM:MeOH:NH.sub.3-MeOH (7N) 10:1:1%) to provide the title compound (52 mg, 45%) as a white solid. .sup.13C NMR (DMSO-d.sub.6, 75 MHz) 161.4 (C-2), 158.6 (C-4), 157.1 (C-7a), 156.6 (CO), 155.9 (phenyl), 135.3 (phenyl), 133.7 (C-5), 130.6 (phenyl), 127.9 (phenyl), 115.1 (phenyl), 110.9 (phenyl), 94.5 (C-4a), 55.1 (OMe), 44.2 (NCH.sub.2), 43.2 (NCH.sub.2), 18.1 (Me). MS (m/z) 383 [M+H].sup.+.

Example 2

6-Amino-4-{4-[(4-methoxyphenyl)carbamyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]-pyrimdine

(74) Prepared via Method B using Intermediate 2 (66 mg, 0.3 mmol) and 4-methoxyphenyl isocyanate (40 L, 0.3 mmol). The title compound (51 mg, 46%) was obtained as a white solid. .sup.13C NMR (DMSO-d.sub.6, 75 MHz) 161.4 (C-2), 158.6 (C-4), 157.1 (C-7a), 155.3 (CO), 154.5 (phenyl), 133.7 (C-5), 133.3 (phenyl), 121.7 (phenyl), 113.5 (phenyl), 94.5 (C-4a), 55.1 (OMe), 44.2 (NCH.sub.2), 43.1 (NCH.sub.2). MS (m/z) 369 [M+H].sup.+.

Example 3

6-Amino-4-{4-[(4-methoxy-2-methylphenyl)carbamyl]-2-(S)-methylpiperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine

(75) Prepared via Method B using Intermediate 4 (0.29 mmol) and 4-methoxy-2-methylphenyl isocyanate (39 L, 0.29 mmol). The title compound (47 mg, 41%) was obtained as a white solid. MS (m/z) 397 [M+H].sup.+.

Example 4

6-Amino-4-{4-[(4-methoxyphenyl)carbamyl]-2-(S)-methylpiperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine

(76) Prepared via Method B using Intermediate 4 (0.29 mmol) and 4-methoxyphenyl isocyanate (37 L, 0.29 mmol). The title compound (23 mg, 21%) was obtained as a white solid. .sub.H (DMSO-d.sub.6, 300 MHz) 1.23 (s, 3H), 3.11-3.16 (m, 1H), 3.43 (m, 2H), 3.71 (s, 3H), 3.96-4.06 (m, 2H), 4.39-4.77 (m, 2H), 6.04 (br, 2H), 6.82 (d, J 7.5 Hz, 2H), 7.33 (d, J 7.5 Hz, 2H), 7.93 (s, 1H), 8.42 (s, 1H), 12.61 (s, 1H). MS (m/z) 383 [M+H].sup.+.

Example 5

6-Amino-4-{4-[(4-methoxy-2-methylphenyl)carbamyl]-2-(S)-methylpiperazin-1-yl}-1-methylpyrazolo[3,4-d]pyrimidine

(77) Prepared via Method B using Intermediate 7 (0.25 mmol) and 4-methoxy-2-methylphenyl isocyanate (34 L, 0.25 mmol). The title compound (100 mg, 97%) was obtained as a white solid. .sup.13C NMR (DMSO-d.sub.6, 150 MHz) 161.5 (C-2), 157.0 (C-4), 156.9 (C-7a), 156.7 (CO), 156.2 (phenyl), 135.6 (phenyl), 132.8 (C-5), 130.7 (phenyl), 128.1 (phenyl), 115.2 (phenyl), 111.1 (phenyl), 94.7 (C-4a), 55.2 (OMe), 47.2 (NCH.sub.2), 43.2 (NCH.sub.2), 33.1 (NMe), 18.1 (Me), 15.3 (Me). MS (m/z) 411 [M+H].sup.+.

Example 6

6-Amino-4-{4-[(4-methoxyphenyl)carbamyl]-2-(S)-methylpiperazin-1-yl}-1-methylpyrazolo[3,4-d]pyrimidine

(78) Prepared via Method B using Intermediate 7 (0.31 mmol) and 4-methoxyphenyl isocyanate (40 L, 0.31 mmol). The title compound (131 mg, quantitative) was obtained as a white solid. .sup.13C NMR (DMSO-d.sub.6, 75 MHz) 161.0 (C-2), 157.3 (C-4), 156.4 (C-7a), 156.2 (CO), 156.1 (phenyl), 132.6 (phenyl), 131.9 (C-5), 123.1 (phenyl), 114.1 (phenyl), 95.8 (C-4a), 55.5 (OMe), 49.3 (NCH), 47.0 (NCH), 43.3 (NCH), 39.5 (NCH), 33.6 (NMe), 16.2 (Me). MS (m/z) 397 [M+H].sup.+.

Example 7

6-Amino-4-[4-(indan-5-ylcarbamyl)-2-(S)-methylpiperazin-1-yl]-methylpyrazolo[3,4-d]pyrimidine

(79) Prepared via Method B using Intermediate 7 (0.31 mmol) and 5-indanyl isocyanate (45 L, 0.31 mmol). The title compound (130 mg, quantitative) was obtained as a white solid. .sup.13C NMR (DMSO-d.sub.6, 75 MHz) 161.1 (C-2), 157.4 (C-4), 156.5 (C-7a), 155.9 (CO), 145.0 (phenyl), 139.5 (phenyl), 136.9 (phenyl), 132.6 (C-5), 124.3 (phenyl), 119.0 (phenyl), 117.4 (phenyl), 95.9 (C-4a), 49.3 (NCH), 47.1 (NCH), 43.4 (NCH), 39.6 (NCH), 33.6 (NMe), 33.0 (CH.sub.2), 32.2 (CH.sub.2), 25.6 (CH.sub.2), 16.2 (Me). MS (m/z) 407 [M+H].sup.+.

Example 8

6-Amino-4-(4-{[4-(dimethylamino)phenyl]carbamyl}-2-(S)-methylpiperazin-1-yl)-1-methylpyrazolo[3,4-d]pyrimidine

(80) Prepared via Method B using Intermediate 7 (0.2 mmol) and 4-(dimethylamino)-phenyl isocyanate (33 L, 0.2 mmol). The title compound (82 mg, 100%) was obtained as a white solid. .sup.13C NMR (CDCl.sub.3+MeOD, 75 MHz) 160.9, 157.4, 156.3, 132.8, 123.3, 113.3, 95.9, 49.4, 47.1, 43.4, 41.3, 39.7, 33.7, 16.3. MS (m/z) 410 [M+H].sup.+.

Example 9 (Method C)

(3S)-4-(6-Amino-1,3-dimethylpyrazolo[3,4-d]pyrimidin-4-yl)-N-[6-(3,3-difluoroazetidin-1-yl)-2-methylpyridin-3-yl]-3-methylpiperazine-1-carboxamide

(81) To Intermediate 12 (0.1 g, 0.27 mmol) and Intermediate 23 (0.1 g, 0.32 mmol) were added acetonitile (5 mL) and DIPEA (0.21 mL, 1.2 mmol). The mixture was stirred at 50 C. under nitrogen for 2.5 h, then concentrated in vacuo to yield a brown oil. The crude material was purified by preparative HPLC to give the title compound (0.073 g, 54.0%) as a white freeze-dried solid. .sub.H (DMSO-d.sub.6) 7.99 (s, 1H), 7.28 (d, J 8.6 Hz, 1H), 6.32 (d, J 8.6 Hz, 1H), 6.17 (s, 2H), 4.53-4.42 (m, 1H), 4.26 (t, J 12.7 Hz, 4H), 4.04 (d, J 12.4 Hz, 1H), 3.93-3.82 (m, 1H), 3.57 (s, 3H), 3.36-3.22 (m, 2H), 3.14 (dd, J 13.2, 3.5 Hz, 1H), 3.04-2.92 (m, 1H), 2.35 (s, 3H), 2.18 (s, 3H), 1.17 (d, J 6.6 Hz, 3H). LCMS (ES) 485 [MH].sup., RT 1.57 minutes (method 2).

Example 10

(3S)-4-(6-Amino-1,3-dimethylpyrazolo[3,4-d]pyrimidin-4-yl)-N-(4-methoxy-2-methylphenyl)-3-methylpiperazine-1-carboxamide

(82) Prepared via Method C using Intermediate 12 (0.26 mmol) and Intermediate 25 (0.37 mmol) to yield the title compound (0.072 g, 63.9%) as a white freeze-dried solid. .sub.H (DMSO-d.sub.6) 7.90 (s, 1H), 6.96 (d, J 8.8 Hz, 1H), 6.71 (d, J 3.0 Hz, 1H), 6.63 (dd, J 8.6, 3.0 Hz, 1H), 6.17 (s, 2H), 4.54-4.41 (m, 1H), 4.04 (d, J 12.9 Hz, 1H), 3.94-3.80 (m, 1H), 3.65 (s, 3H), 3.57 (s, 3H), 3.36-3.19 (m, 1H), 3.13 (dd, J 13.0, 3.2 Hz, 1H), 3.03-2.90 (m, 1H), 2.35 (s, 3H), 2.08 (s, 3H), 1.17 (d, J 6.6 Hz, 3H). LCMS (ES+) 425.8 [M+H].sup.+, RT 1.36 minutes (method 4).

Example 11

(3S)-4-(6-Amino-1,3-dimethylpyrazolo[3,4-d]pyrimidin-4-yl)-N-(6-methoxy-2-methyl-pyridin-3-yl)-3-methylpiperazine-1-carboxamide

(83) Prepared via Method C using Intermediate 12 (0.24 mmol) and Intermediate 24 (0.34 mmol) to yield the title compound (0.064 g, 63.6%) as a white freeze-dried solid. .sub.H (DMSO-d.sub.6) 8.05 (s, 1H), 7.36 (d, J 8.6 Hz, 1H), 6.53 (d, J 8.6 Hz, 1H), 6.18 (s, 2H), 4.53-4.42 (m, 1H), 4.05 (br d, J 13.0 Hz, 1H), 3.94-3.82 (m, 2H), 3.74 (s, 3H), 3.57 (s, 3H), 3.38-3.29 (m, 1H), 3.15 (dd, J 13.2, 3.4 Hz, 1H), 3.06-2.93 (m, 1H), 2.36 (s, 3H), 2.22 (s, 3H), 1.17 (d, J 6.6 Hz, 3H). LCMS (ES) 424.0 [MH].sup., RT 1.35 minutes (method 2).

Example 12

(3R)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-N-[6-(3,3-difluoroazetidin-1-yl)-2-methylpyridin-3-yl]-3-(hydroxymethyl)piperazine-1-carboxamide

(84) Prepared via Method C using Intermediate 15 (0.54 mmol) and Intermediate 23 (0.54 mmol) to yield the title compound (0.021 g, 8%) as a white solid. .sub.H (DMSO-d.sub.6) 8.02 (s, 1H), 7.91 (s, 1H), 7.37 (d, J 8.5 Hz, 1H), 6.39 (d, J 8.5 Hz, 1H), 6.17 (s, 2H), 5.01 (br s, 1H), 4.70-4.35 (br s, 2H), 4.32 (t, J 12.7 Hz, 4H), 4.17 (d, J 13.2 Hz, 1H), 4.01-3.80 (m, 1H), 3.70 (s, 3H), 3.69-3.51 (m, 2H), 3.39-3.02 (m, 3H), 2.21 (s, 3H). LCMS (ES) 487 [MH].sup., RT 1.29 minutes (method 2).

Example 13

(3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-N-[6-(3,3-difluoroazetidin-1-yl)-2-methylpyridin-3-yl]-3-methylpiperazine-1-carboxamide

(85) Prepared via Method C using Intermediate 7 (0.29 mmol) and Intermediate 23 (0.34 mmol) to yield the title compound (0.084 g, 61.5%) as a white freeze-dried solid. .sub.H (DMSO-d.sub.6) 8.01 (s, 1H), 7.86 (s, 1H), 7.29 (d, J 8.4 Hz, 1H), 6.33 (d, J 8.4 Hz, 1H), 6.12 (s, 2H), 4.86-4.56 (s, 1H), 4.26 (t, J 12.7 Hz, 4H), 4.50-4.20 (br s, 1H), 4.02 (d, J 2.1 Hz, 1H), 3.90 (d, J 13.4 Hz, 1H), 3.64 (s, 3H), 3.42-3.15 (m, 2H), 3.11-2.98 (m, 1H), 2.18 (s, 3H), 1.17 (d, J 6.5 Hz, 3H). LCMS (ES) 471 [MH].sup., RT 1.42 minutes (method 2).

Example 14

(3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-N-(6-methoxy-2-methyl-pyridin-3-yl)-3-methylpiperazine-1-carboxamide

(86) Prepared via Method C using Intermediate 7 (0.28 mmol) and Intermediate 24 (0.36 mmol) to yield the title compound (0.072 g, 60.7%) as a white freeze-dried solid. .sub.H (DMSO-d.sub.6) 8.08 (s, 1H), 7.86 (s, 1H), 7.36 (d, J 8.6 Hz, 1H), 6.54 (d, J 8.6 Hz, 1H), 6.12 (s, 2H), 4.94-4.52 (s, 1H), 4.52-4.17 (s, 1H), 4.03 (d, J 12.5 Hz, 1H), 3.91 (d, J 13.2 Hz, 1H), 3.75 (s, 3H), 3.64 (s, 3H), 3.46-3.15 (m, 2H), 3.12-2.99 (m, 1H), 2.22 (s, 3H), 1.17 (d, J 6.6 Hz, 3H). LCMS (ES) 410 [MH].sup., RT 1.23 minutes (method 2).

Example 15 (Method D)

(3R)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-N-(4-methoxy-2-methyl-phenyl)-3-methylpiperazine-1-carboxamide

(87) Intermediate 22 (3.5 g, 12 mmol) and DIPEA (25 mmol) were stirred in DCM (150 mL) at 0 C. (ice bath) for 30 minutes with 4-methoxy-2-methylphenyl isocyanate (12 mmol). After 30 minutes, water was added and the mixture was acidified with 10% aqueous HCl solution. The aqueous layer was further extracted with DCM, then neutralised with saturated aqueous sodium bicarbonate solution. The neutralised aqueous layer was extracted with DCM, then the organic phase was separated and concentrated in vacuo. The recovered crude solid was triturated with ether, to yield the title compound (1.68 g, 33%) as a fine powder. .sub.H (DMSO-d.sub.6) 8.01 (s, 1H), 7.92 (s, 1H), 7.03 (d, J 8.6 Hz, 1H), 6.77 (d, J 2.9 Hz, 1H), 6.70 (dd, J 8.6, 2.9 Hz, 1H), 6.21 (s, 1H), 4.80-4.20 (m, 2H), 4.09 (d, J 12.6 Hz, 1H), 3.97 (d, J 13.1 Hz, 1H), 3.71 (s, 3H), 3.70 (s, 3H), 3.41-3.01 (m, 3H), 2.13 (s, 3H), 1.23 (d, J 6.5 Hz, 3H). LCMS (ES+) 411 [M+H].sup.+, RT 1.45 minutes (method 2).

Example 16 (Method E)

(3S)-4-[6-Amino-1-methyl-3-(trifluoromethyl)pyrazolo[3,4-d]pyrimidin-4-yl]-N-[6-(3,3-difluoroazetidin-1-yl)-2-methylpyridin-3-yl]-3-methylpiperazine-1-carboxamide

(88) To Intermediate 19 (0.05 g, 0.12 mmol) and Intermediate 23 (0.05 g, 0.160 mmol) were added acetonitrile (5 mL) and DIPEA (0.1 mL, 0.6 mmol) and the mixture was stirred at r.t. under nitrogen overnight. The solvent was removed in vacuo to yield a brown oil that was purified by preparative HPLC, to yield the title compound (0.033 g, 49.4%) as a freeze-dried white solid. .sub.H (DMSO-d.sub.6) 8.06 (s, 1H), 7.35 (d, J 8.5 Hz, 1H), 6.72 (s, 2H), 6.39 (d, J 8.6 Hz, 1H), 4.51-4.40 (m, 1H), 4.33 (t, J 12.5 Hz, 4H), 4.14-4.04 (m, 1H), 3.99-3.90 (m, 1H), 3.80 (s, 3H), 3.72-3.64 (m, 1H), 3.47-3.35 (m, 1H), 3.27-3.19 (m, 1H), 3.07-2.96 (m, 1H), 2.24 (s, 3H), 1.20 (d, J 6.5 Hz, 3H). LCMS (ES+) 541.8 [M+H].sup.+, RT 1.61 minutes (method 4).

Example 17

(3S)-4-[6-Amino-1-methyl-3-(trifluoromethyl)pyrazolo[3,4-d]pyrimidin-4-yl]-N-(6-methoxy-2-methylpyridin-3-yl)-3-methylpiperazine-1-carboxamide

(89) Prepared via Method E using Intermediate 19 (0.12 mmol) and Intermediate 24 (0.17 mmol) to yield the title compound (0.023 g, 39.4%) as an off-white freeze-dried solid. .sub.H (DMSO-d.sub.6) 8.12 (s, 1H), 7.42 (d, J 8.4 Hz, 1H), 6.73 (s, 2H), 6.60 (d, J 8.6 Hz, 1H), 4.52-4.40 (m, 1H), 4.15-4.03 (m, 1H), 4.00-3.90 (m, 1H), 3.82 (s, 6H), 3.73-3.64 (m, 1H), 3.49-3.35 (m, 1H), 3.31 (s, 3H), 3.24 (dd, J 13.0, 3.2 Hz, 1H), 3.09-2.97 (m, 1H), 2.28 (s, 3H), 1.21 (d, J 6.6 Hz, 3H). LCMS (ES+) 480.8 [M+H].sup.+, RT 1.76 minutes (method 4).

Example 18

(3S)-4-[6-Amino-1-methyl-3-(trifluoromethyl)pyrazolo[3,4-d]pyrimidin-4-yl]-N-(4-methoxy-2-methylphenyl)-3-methylpiperazine-1-carboxamide

(90) Prepared via Method E using Intermediate 19 (0.12 mmol) and Intermediate 25 (0.17 mmol) to yield the title compound (0.021 g, 37.5%) as an off-white freeze-dried solid. .sub.H (DMSO-d.sub.6) 7.97 (s, 1H), 7.02 (d, J 8.6 Hz, 1H), 6.79-6.67 (m, 4H), 4.51-4.39 (m, 1H), 4.14-4.04 (m, 1H), 3.99-3.91 (m, 1H), 3.81 (s, 3H), 3.72 (s, 3H), 3.71-3.63 (m, 1H), 3.47-3.34 (m, 1H), 3.26-3.17 (m, 1H), 3.06-2.93 (m, 1H), 2.14 (s, 3H), 1.20 (d, J 6.7 Hz, 3H). LCMS (ES+) 479.8 [M+H].sup.+, RT 2.06 minutes (method 4).

Examples 19 to 30 (Method F)

(91) To a solution of the appropriate amine (0.29 mmol) in DMF (2 mL) were added DIPEA (0.30 mmol) and 1,1-carbonyldiimidazole (0.41 mmol). The mixture was stirred at r.t. for 30 minutes. A solution of Intermediate 7 (0.28 mmol) and DIPEA (0.30 mmol) in DMF (lmL) was added. The mixture was stirred at r.t. for up to 16 h. The progress of the reaction was monitored by LCMS. Upon completion, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, then water, and dried over sodium sulfate. The organic layer was concentrated in vacuo and the resulting crude material was purified either by column chromatography (silica gel 100-200 mesh, 10% MeOH/DCM), or reverse-phase preparative HPLC, to afford the title compound.

(92) TABLE-US-00009 LCMS Data Ex. Name Method RT [M + H].sup.+ 19 (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-N- 2 1.56 407.8 (2,1,3-benzothiadiazol-4-yl)-3-methylpiperazine-1- carboxamide 20 (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-N- 2 1.33 407.8 (1H-indazol-7-yl)-3-methylpiperazine-1-carboxamide 21 (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-N- 2 1.53 425.8 (2,1,3-benzothiadiazol-5-yl)-3-methylpiperazine-1- carboxamide 22 (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-N- 2 1.55 406.8 (1H-indol-7-yl)-3-methylpiperazine-1-carboxamide 23 (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-N- 2 1.29 406.8 (1H-indol-4-yl)-3-methylpiperazine-1-carboxamide 24 (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-3- 2 1.25 421.8 methyl-N-(2-methyl-1H-benzimidazol-4-yl)piperazine-1- carboxamide 25 (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-3- 2 1.26 421.8 methyl-N-(1-methylindazol-7-yl)piperazine-1-carboxamide 26 (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-3- 2 1.49 421.8 methyl-N-(4-methyl-1H-indazol-7-yl)piperazine-1- carboxamide 27 (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-N- 2 0.85 398.8 (6-hydroxy-2-methylpyridin-3-yl)-3-methylpiperazine-1- carboxamide 28 (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-3- 2 1.86 480.8 methyl-N-[2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl]- piperazine-1-carboxamide 29 (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-N- 2 0.95 412.8 (1,2-dimethyl-6-oxopyridin-3-yl)-3-methylpiperazine-1- carboxamide 30 (3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-3- 2 1.14 411.8 methyl-N-[2-methyl-6-(methylamino)pyridin-3-yl]- piperazine-1-carboxamide

Examples 31 to 37 (Method G)

(93) To a solution of the indicated amine (0.57 mmol) in THF (10 mL) at 0 C. was added pyridine (0.75 mmol), followed by phenyl chloroformate (0.69 mmol). The reaction mixture was stirred at 0 C. for 2 h. The reaction mixture was diluted with EtOAc, then washed with saturated aqueous sodium bicarbonate solution, water and brine. The organic layer was concentrated in vacuo. To a solution of the resulting material (0.53 mmol) and Intermediate 7 (0.35 mmol) in DMSO (2 mL) was added DIPEA (1.0 mmol). The reaction mixture was heated at 60 C. for 3 h. After this time, the reaction mixture was diluted with EtOAc, then the organic layer was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The resulting crude material was purified by flash column chromatography on silica (100-200 mesh, 5% MeOH/DCM), to afford the title compound as an off-white solid.

(94) TABLE-US-00010 LCMS Data Ex. Amine Name Method RT [M + H].sup.+ 31 Intermediate 30 (3S)-4-(6-Amino-1-methylpyrazolo- 5 1.57 473.3 [3,4-d]pyrimidin-4-yl)-N-[2-(3,3- difluoroazetidin-1-yl)-4-methyl- pyrimidin-5-yl]-3-methylpiperazine-1- carboxamide 32 4-(Difluoro- (3S)-4-(6-Amino-1-methylpyrazolo- 5 1.89 447.3 methoxy)-2- [3,4-d]pyrimidin-4-yl)-N-[4-(difluoro- methylaniline methoxy)-2-methylphenyl]-3-methyl- piperazine-1-carboxamide 33 Intermediate 29 (3S)-4-(6-Amino-1-methylpyrazolo- 5 1.54 426.3 [3,4-d]pyrimidin-4-yl)-N-[2-(dimethyl- amino)-4-methylpyrimidin-5-yl]-3- methylpiperazine-1-carboxamide 34 6-(Azetidin-1-yl)- (3S)-4-(6-Amino-1-methylpyrazolo- 5 1.37 436.5 2-methylpyridin-3- [3,4-d]pyrimidin-4-yl)-N-[6-(azetidin- amine 1-yl)-2-methylpyridin-3-yl]-3-methyl- (WO 2010/139747) piperazine-1-carboxamide 35 Intermediate 27 (3S)-4-(6-Amino-1-methylpyrazolo- 5 1.57 473.3 [3,4-d]pyrimidin-4-yl)-N-[6-(3,3- difluoroazetidin-1-yl)-4-methylpyridin- 3-yl]-3-methylpiperazine-1- carboxamide 36 N.sup.2,N.sup.2,6-Trimethyl- (3S)-4-(6-Amino-1-methylpyrazolo- 5 1.45 425.3 pyridine-2,5- [3,4-d]pyrimidin-4-yl)-N-[6-(dimethyl- diamine amino)-2-methylpyridin-3-yl]-3- (WO 2010/139747) methylpiperazine-1-carboxamide 37 N.sup.2,N.sup.2,4-Trimethyl- (3S)-4-(6-Amino-1-methylpyrazolo- 5 1.43 425.3 pyridine-2,5- [3,4-d]pyrimidin-4-yl)-N-[6-(dimethyl- diamine amino)-4-methylpyridin-3-yl]-3- (WO 2009/093747) methylpiperazine-1-carboxamide

Examples 38 to 40

(95) The following compounds were prepared via Method G, using Intermediate 12.

(96) TABLE-US-00011 LCMS Data Ex. Amine Name Method RT [M + H].sup.+ 38 6-(Azetidin-1-yl)- (3S)-4-(6-Amino-1,3-dimethyl- 5 1.47 451.3 2-methylpyridin-3- pyrazolo[3,4-d]pyrimidin-4-yl)-N-[6- amine (azetidin-1-yl)-2-methylpyridin-3-yl]- (WO 2010/139747) 3-methylpiperazine-1-carboxamide 39 N.sup.2,N.sup.2,4-Trimethyl- (3S)-4-(6-Amino-1,3-dimethyl- 5 1.53 439.4 pyridine-2,5- pyrazolo[3,4-d]pyrimidin-4-yl)-N-[6- diamine (dimethylamino)-4-methylpyridin-3- (WO 2009/093747) yl]-3-methylpiperazine-1-carboxamide 40 N.sup.2,N.sup.2,6-Trimethyl- (3S)-4-(6-Amino-1,3-dimethyl- 5 1.55 439.4 pyridine-2,5- pyrazolo[3,4-d]pyrimidin-4-yl)-N-[6- diamine (dimethylamino)-2-methylpyridin-3- (WO 2010/139747) yl]-3-methylpiperazine-1-carboxamide

Example 41 (Method H)

(3S)-4-(6-Amino-1,3-dimethylpyrazolo[3,4-d]pyrimidin-4-yl)-N-(4-methoxyphenyl)-3-methylpiperazine-1-carboxamide

(97) To a stirred solution of Intermediate 12 (50 mg, 0.18 mmol) in DMF (2 mL), maintained at 0 C., was added DIPEA (1.14 mmol), followed by 4-methoxyphenyl isocyanate (0.38 mmol). The reaction mixture was stirred at r.t. for 15 minutes. The reaction mixture was then diluted with water and extracted with EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The resulting crude material was purified by flash column chromatography on silica (100-200 mesh, 10% MeOH/DCM), to yield the title compound (0.07 g, 94%) as a white solid. LCMS (ES+) 411.3 [M+H].sup.+, RT 1.60 minutes (method 5).

Examples 42 to 44 (Method I)

(98) To Intermediate 7 (0.05 g, 0.14 mmol) were added HATU (0.11 g, 0.28 mmol) and the appropriate carboxylic acid (0.18 mmol). The mixture was dissolved in DMF (5 mL) and DIPEA (0.11 mL, 0.64 mmol) was added. The mixture was stirred under nitrogen at r.t. for 72 h. The residue was concentrated in vacuo and purified by preparative HPLC, to yield the title compound as an off-white solid.

(99) TABLE-US-00012 LCMS Data Ex. Acid Name Method RT [M + H].sup.+ 42 2,3-Dihydro-1- [(3S)-4-(6-Amino-1-methylpyrazolo- 2 2.03 394.8 benzofuran-2- [3,4-d]pyrimidin-4-yl)-3-methyl- carboxylic acid piperazin-1-yl](2,3-dihydrobenzo- furan-2-yl)methanone 43 2-Oxo-2-phenyl- 1-[(3S)-4-(6-Amino-1-methylpyrazolo- 2 1.57 380.8 acetic acid [3,4-d]pyrimidin-4-yl)-3-methyl- piperazin-1-yl]-2-phenylethane-1,2- dione 44 5-Methoxybenzo- [(3S)-4-(6-Amino-1-methylpyrazolo- 2 1.78 422.8 furan-2-carboxylic [3,4-d]pyrimidin-4-yl)-3-methyl- acid piperazin-1-yl](5-methoxybenzofuran- 2-yl)methanone

Example 45

(3S)N-(4-Methoxy-2-methylphenyl)-3-methyl-4-[1-methyl-6-(methylsulfanyl)-pyrazolo[3,4-d]pyrimidin-4-yl]piperazine-1-carboxamide

(100) To a solution of Intermediate 34 in DCM (3 mL) at r.t. were added DIPEA (218 L, 1.3 mmol) and 4-methoxy-2-methylphenyl isocyanate (19 L, 0.14 mmol). The reaction mixture was stirred overnight, then concentrated in vacuo. The residue was purified by silica gel chromatography (gradient 70% EtOAc/cyclohexane to 90% EtOAc/cyclohexane), to provide the title compound (51 mg, 87%) as a white solid. MS (m/z) 442 [M+H].sup.+.

Example 46

(3S)N-(Indan-5-yl)-3-methyl-4-[1-methyl-6-(methylsulfonyl)pyrazolo[3,4-d]pyrimidin-4-yl]piperazine-1-carboxamide

(101) Intermediate 34 was dissolved in DCM (15 mL), then DIPEA (873 L, 5.3 mmol) and 5-isocyanato-2,3-dihydro-1H-indene (80 L, 0.55 mmol) were added. The reaction mixture was stirred overnight, then concentrated in vacuo. The residue was dissolved in DCM (3 mL), then MCPBA (70%; 267 mg, 1.1 mmol) was added at 0 C. The reaction mixture was continuously stirred for 2 h at r.t. To the solution was added a saturated aqueous solution of Na.sub.2SO.sub.3 (4 mL). The reaction mixture was partitioned between DCM and 2N aqueous NaOH solution. The organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (gradient 70% EtOAc/cyclohexane to 90% EtOAc/cyclohexane), to provide the title compound (201 mg, 81%) as a white solid. MS (m/z) 470 [M+H].sup.+.

Example 47

(3S)N-(Indan-5-yl)-4-(6-methoxy-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-3-methyl-piperazine-1-carboxamide

(102) To a solution of Example 46 (50 mg, 0.11 mmol) in MeOH (2 mL) was added sodium methoxide (30 wt %; 18 L, 1.2 mmol). The reaction mixture was stirred for 1 h at 60 C., then concentrated in vacuo. The residue was purified by silica gel chromatography (gradient 60% EtOAc/cyclohexane to 80% EtOAc/cyclohexane), to provide the title compound (25 mg, 56%) as a white solid. MS (m/z) 422 [M+H].sup.+.

Example 48

(3S)-4-(6-Cyano-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-N-(indan-5-yl)-3-methyl-piperazine-1-carboxamide

(103) To a solution of Example 46 (50 mg, 0.11 mmol) in DMF (2 mL) was added sodium cyanide (5 mg, 1.2 mmol). The reaction mixture was stirred overnight at 60 C., then concentrated in vacuo. The residue was purified by silica gel chromatography (gradient 70% EtOAc/cyclohexane to 90% EtOAc/cyclohexane), to provide the title compound (17 mg, 38%) as a white solid. MS (m/z) 417 [M+H].sup.+.

Example 49

(3S)-4-[6-(2-Hydroxyethylamino)-1-methylpyrazolo[3,4-d]pyrimidin-4-yl]-N-(4-methoxy-2-methylphenyl)-3-methylpiperazine-1-carboxamide

(104) To a solution of Intermediate 33 (100 mg, 0.26 mmol) in DCM (4 mL) at 0 C. was added MCPBA (70%; 133 mg, 0.54 mmol). The reaction mixture was continuously stirred for 2 h at r.t., then a saturated aqueous solution of Na.sub.2SO.sub.3 (4 mL) was added. The reaction mixture was partitioned between DCM and 2N aqueous NaOH solution. The organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in 1,4-dioxane (2 mL) and H.sub.2O (2 mL), then 2-aminoethanol (79 L, 1.3 mmol) was added. The reaction mixture was continuously stirred in a sealed vessel for 24 h at 100 C. The mixture was concentrated in vacuo. The residue was dissolved in DCM (2 mL) and TFA (2 mL). After 1 h at r.t., the reaction mixture was concentrated in vacuo. The resulting crude material was dissolved in DCM (4 mL) and DIPEA (437 L, 2.6 mmol), then 4-methoxy-2-methylphenyl isocyanate (37 L, 0.28 mmol) was added. The reaction mixture was stirred overnight at r.t., then concentrated in vacuo. The residue was purified by silica gel chromatography (gradient 4% 7N NH.sub.3 in MeOH/EtOAc to 6% 7N NH.sub.3 in MeOH/EtOAc) to provide the title compound (29 mg, 24%) as a white solid. MS (m/z) 455 [M+H].sup.+.

Example 50 (Method J)

(3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-3-methyl-N-[2-methyl-4-(trifluoromethoxy)phenyl]piperazine-1-carboxamide

(105) Intermediate 7 (2.38 g, 7.43 mmol) and Intermediate 38 (2.31 g, 7.42 mmol) were taken up in acetonitrile (150 mL) and DIPEA (2.91 g, 4.0 mL, 22.3 mmol) was added. The reaction mixture was stirred overnight, then concentrated in vacuo and partitioned between DCM and water. The organic layers were phase separated and concentrated in vacuo. The residue was purified by flash column chromatography on silica (Biotage SNAP 100 g, Isolera, gradient elution: 100% EtOAc to 20% MeOH/EtOAc) to yield the title compound (2.35 g, 68.2%) as a white solid. .sub.H (DMSO-d.sub.6) 8.20 (s, 1H), 7.93 (s, 1H), 7.30 (m, 1H), 7.18 (m, 2H), 6.19 (s, 2H), 4.60 (m, 2H), 4.04 (m, 2H), 3.71 (s, 3H), 3.39 (m, 2H), 3.16 (m, 1H), 2.21 (s, 3H), 1.28 (d, J 6.6 Hz, 3H). LCMS (ES+) [M+H].sup.+ 465.8, RT 1.96 minutes (method 2).

Examples 51 to 75

(106) The following compounds were prepared via Method J utilising Intermediate 7 and the indicated carbamate intermediate.

(107) TABLE-US-00013 LCMS Data Ex. Int. Name Method RT [M + H].sup.+ 51 39 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 4 1.67 469 pyrimidin-4-yl)-N-[2-fluoro-4-(trifluoromethoxy)- phenyl]-3-methylpiperazine-1-carboxamide 52 40 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 4 1.79 485.6 pyrimidin-4-yl)-N-[2-chloro-4-(trifluoromethoxy)- phenyl]-3-methylpiperazine-1-carboxamide 53 41 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 4 1.73 465.8 pyrimidin-4-yl)-N-[3-methoxy-5-(trifluoromethyl)- phenyl]-3-methylpiperazine-1-carboxamide 54 42 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 2 1.51 435.8 pyrimidin-4-yl)-N-(1-ethyl-1H-indazol-3-yl)-3-methyl- piperazine-1-carboxamide 55 43 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 2 1.60 448 pyrimidin-4-yl)-N-[6-(difluoromethoxy)-2-methyl- pyridin-3-yl]-3-methylpiperazine-1-carboxamide 56 44 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 2 1.57 430.8 pyrimidin-4-yl)-N-(6-ethoxy-5-fluoropyridin-3-yl)-3- methylpiperazine-1-carboxamide 57 45 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 2 1.75 433.9 pyrimidin-4-yl)-N-(2-chloro-4-fluoro-5-methylphenyl)- 3-methylpiperazine-1-carboxamide 58 46 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 2 1.42 416.8 pyrimidin-4-yl)-N-(5-fluoro-6-methoxypyridin-3-yl)-3- methylpiperazine-1-carboxamide 59 47 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 2 1.39 426.8 pyrimidin-4-yl)-N-(6-ethoxy-2-methylpyridin-3-yl)-3- methylpiperazine-1-carboxamide 60 48 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 2 1.80 449.7 pyrimidin-4-yl)-3-methyl-N-[1-methyl-5-(trifluoro- methyl)-1H-indazol-3-yl]piperazine-1-carboxamide 61 49 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 2 1.49 439.8 pyrimidin-4-yl)-N-(6-fluoro-1-methyl-1H-indazol-3-yl)- 3-methylpiperazine-1-carboxamide 62 50 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 2 1.47 439.8 pyrimidin-4-yl)-N-(5-fluoro-1-methyl-1H-indazol-3-yl)- 3-methylpiperazine-1-carboxamide 63 51 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 2 1.13 407.44 pyrimidin-4-yl)-N-(imidazo[1,2-a]pyridin-8-yl)-3- methylpiperazine-1-carboxamide 64 52 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 2 1.10 372.4 pyrimidin-4-yl)-3-methyl-N-(5-methyl-1,2-oxazol-3-yl)- piperazine-1-carboxamide 65 53 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 2 1.20 408.43 pyrimidin-4-yl)-N-(1,2-benzoxazol-3-yl)-3-methyl- piperazine-1-carboxamide 66 54 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 2 1.16 421.47 pyrimidin-4-yl)-3-methyl-N-(1-methyl-1H-indazol-3- yl)piperazine-1-carboxamide 67 55 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 2 1.13 407.44 pyrimidin-4-yl)-N-(6-cyano-2-methylpyridin-3-yl)-3- methylpiperazine-1-carboxamide 68 56 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 2 1.11 459.84 pyrimidin-4-yl)-3-methyl-N-[2-methyl-4-(methyl- sulfonyl)phenyl]piperazine-1-carboxamide 69 57 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 2 1.24 448.44 pyrimidin-4-yl)-N-[6-(difluoromethoxy)-4-methyl- pyridin-3-yl]-3-methylpiperazine-1-carboxamide 70 58 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 2 1.18 412.46 pyrimidin-4-yl)-N-(6-methoxy-5-methylpyridin-3-yl)-3- methylpiperazine-1-carboxamide 71 59 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 2 1.11 412.46 pyrimidin-4-yl)-N-(6-methoxy-4-methylpyridin-3-yl)-3- methylpiperazine-1-carboxamide 72 60 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 2 1.21 411.47 pyrimidin-4-yl)-N-(5-methoxy-2-methylphenyl)-3- methylpiperazine-1-carboxamide 73 61 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 2 1.35 415.89 pyrimidin-4-yl)-N-(3-chloro-4-methylphenyl)-3-methyl- piperazine-1-carboxamide 74 62 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 2 1.36 436.31 pyrimidin-4-yl)-N-(2,5-dichlorophenyl)-3-methyl- piperazine-1-carboxamide 75 63 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 2 1.19 406.46 pyrimidin-4-yl)-N-(4-cyano-2-methylphenyl)-3-methyl- piperazine-1-carboxamide

Example 76

(3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-3-ethyl-N-(6-methoxy-2-methylpyridin-3-yl)piperazine-1-carboxamide

(108) Intermediate 37 (0.4 g, 1 mmol) in acetonitrile (10 mL) and DIPEA (0.5 g, 0.7 mL, 4 mmol) were treated with Intermediate 24 (0.3 g, 1 mmol). The reaction mixture was stirred at room temperature overnight, then concentrated in vacuo. The residue was partitioned between water and DCM. The organic layers were phase separated, and the residual solid was triturated with diethyl ether, to yield the title compound (0.408 g, 80%) as a white powder. .sub.H (DMSO-d.sub.6) 8.15 (s, 1H), 7.92 (s, 1H), 7.42 (d, J 8.6 Hz, 1H), 6.60 (d, J 8.5 Hz, 1H), 6.18 (s, 2H), 4.65 (m, 2H), 4.10 (m, 2H), 3.72 (s, 3H), 3.65 (s, 3H), 3.15 (m, 3H), 2.28 (s, 3H), 1.69 (m, 2H), 1.66 (t, J 7.3 Hz, 3H). LCMS (ES+) [M+H]+ 426, RT 1.38 minutes (method 2).

Example 77

(3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-N-(6-ethoxy-2-methylpyridin-3-yl)-3-ethylpiperazine-1-carboxamide

(109) Intermediate 37 (0.043 g, 0.16 mmol) was dissolved in acetonitrile (5 mL) and Intermediate 47 (45 mg, 0.16 mmol) was added, followed by DIPEA (0.042 g, 0.33 mmol). The reaction mixture was stirred at 70 C. for 1 h, then concentrated. The residue was purified by HPLC at basic pH to yield the title compound (0.035 g, 48.6%) as a freeze-dried white solid. .sub.H (DMSO-d.sub.6) 8.14 (s, 1H), 7.93 (s, 1H), 7.41 (d, J 8.5 Hz, 1H), 6.58 (d, J 8.5 Hz, 1H), 6.18 (s, 2H), 4.52 (m, 2H), 4.28 (q, J 7.0 Hz, 2H), 4.12 (m, 2H), 3.71 (s, 3H), 3.15 (m, 3H), 2.27 (s, 3H), 1.69 (m, 2H), 1.31 (m, 3H), 0.90 (m, 3H). LCMS (ES+) [M+H].sup.+ 440.5, RT 1.52 minutes (method 2).

Example 78

(3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-N-(2,6-dimethoxypyridin-3-yl)-3-ethylpiperazine-1-carboxamide

(110) Intermediate 37 (0.20 g, 0.60 mmol) and Intermediate 64 (0.16 g, 0.58 mmol) in acetonitrile (20 mL) were treated with DIPEA (0.2 g, 0.3 mL, 2 mmol). The reaction mixture was stirred over the weekend at room temperature, then concentrated in vacuo and partitioned between DCM and water. The organic layers were phase separated and concentrated in vacuo. The residue was purified by flash column chromatography on silica (Biotage SNAP 50 g, Isolera, gradient elution: 100% EtOAc to 30% MeOH/EtOAc) to yield the title compound (0.099 g, 37%) as a white solid. .sub.H (DMSO-d.sub.6) 7.91 (s, 1H), 7.79 (s, 1H), 7.63 (d, J 8.3 Hz, 1H), 6.34 (d, J 8.2 Hz, 1H), 6.17 (s, 2H), 4.61 (m, 2H), 4.05 (m, 2H), 3.86 (d, J 11.9 Hz, 6H), 3.70 (s, 3H), 3.10 (m, 3H), 1.68 (m, 2H), 0.88 (t, J 7.4 Hz, 3H). LCMS (ES+) [M+H].sup.+ 442.5, RT 1.63 minutes (method 2).

Example 79

(3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-3-ethyl-N-(4-methoxy-2-methylphenyl)piperazine-1-carboxamide

(111) Intermediate 37 (0.20 g, 0.60 mmol) and Intermediate 25 (0.15 g, 0.58 mmol) in acetonitrile (8 mL) with DIPEA (0.23 g, 1.8 mmol) were heated at 40 C. for 2 h. The reaction mixture was cooled, then stirred at room temperature overnight. A slurry had formed, to which was added water. The solid was collected by filtration, and washed further with water, then with diethyl ether, to yield the title compound (0.119 g, 47%) as a white powder. .sub.H (DMSO-d.sub.6) 8.00 (s, 1H), 7.92 (s, 1H), 7.02 (d, J 8.6 Hz, 1H), 6.77 (m, 1H), 6.70 (dd, J 8.5, 2.9 Hz, 1H), 6.17 (s, 2H), 4.65 (m, 2H), 4.11 (m, 2H), 3.71 (m, 6H), 3.12 (m, 3H), 2.14 (s, 3H), 1.68 (m, 2H), 0.89 (t, J 7.4 Hz, 3H). LCMS (ES+) [M+H].sup.+ 425.8, RT 1.55 minutes (method 2).

Example 80

(3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-N-[6-(3,3-difluoroazetidin-1-yl)-2-methylpyridin-3-yl]-3-ethylpiperazine-1-carboxamide

(112) Intermediate 37 (0.20 g, 0.60 mmol) and Intermediate 23 (0.19 g, 0.60 mmol) in acetonitrile (8 mL) were treated with DIPEA (0.23 g, 1.8 mmol) and stirred at 40 C. for 2 h. The reaction mixture was cooled and stirred at room temperature overnight, then concentrated in vacuo, and partitioned between DCM and water. The organic layers were phase separated and concentrated in vacuo. The residue was purified by flash column chromatography on silica (Biotage SNAP 50 g, Isolera, gradient elution: 100% EtOAc to 40% MeOH/EtOAc) to yield the title compound (0.15 g, 52%) as a white solid. .sub.H (DMSO-d.sub.6) 8.08 (s, 1H), 7.91 (s, 1H), 7.34 (d, J 8.5 Hz, 1H), 6.38 (d, J 8.5 Hz, 1H), 6.17 (s, 2H), 4.50 (br s, 2H), 4.32 (t, J 12.5 Hz, 4H), 4.03 (m, 2H), 3.70 (s, 3H), 3.20 (m, 3H), 2.23 (s, 3H), 1.70 (m, 2H), 0.82 (t, J 7.4 Hz, 3H). LCMS (ES+) [M+H].sup.+ 487.8, RT 1.61 minutes (method 2).

Example 81

(3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-3-ethyl-N-[2-methyl-4-(trifluoromethoxy)phenyl]piperazine-1-carboxamide

(113) Intermediate 37 (0.15 g, 0.45 mmol) and Intermediate 38 (0.14 g, 0.45 mmol) in acetonitrile (20 mL) with DIPEA (0.18 g, 0.25 mL, 1.4 mmol) were stirred overnight. The reaction mixture was concentrated in vacuo and partitioned between DCM and water. The organic layers were phase separated and concentrated in vacuo. The residue was purified by flash column chromatography on silica (Biotage SNAP 50 g, Isolera, gradient elution: 100% EtOAc to 20% MeOH/EtOAc) to yield the title compound (0.038 g, 18%) as a white solid. .sub.H (DMSO-d.sub.6) 8.20 (s, 1H), 7.93 (s, 1H), 7.30 (m, 1H), 7.22 (dd, J 2.1, 1.0 Hz, 1H), 7.14 (m, 1H), 6.19 (s, 2H), 4.64 (m, 2H), 4.10 (m, 1H), 3.98 (m, 1H), 3.71 (s, 3H), 3.35 (m, 2H), 3.16 (m, 1H), 2.21 (s, 3H), 1.61 (m, 2H), 0.91 (t, J 7.0 Hz, 3H). LCMS (ES+) [M+H].sup.+ 479.8, RT 2.07 minutes (method 2).

Example 82

(3S)-4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-3-ethyl-N-(4-methoxy-3-methylphenyl)piperazine-1-carboxamide

(114) Intermediate 37 (0.05 g, 0.1679 mmol) was dissolved in acetonitrile (5 mL) and Intermediate 65 (0.047 g, 0.1847 mmol) was added, followed by DIPEA (0.065 g, 0.50 mmol). The reaction mixture was stirred at 70 C. for 1 h, then concentrated in vacuo. The residue was purified by flash column chromatography on silica (Biotage SNAP 50 g, Isolera, gradient elution: 100% DCM to 7% MeOH/DCM) to yield the title compound (0.071 g, quantitative) as a white solid. .sub.H (DMSO-d.sub.6) 8.34 (s, 1H), 7.93 (s, 1H), 7.22 (m, 2H), 6.82 (m, 1H), 6.18 (s, 2H), 4.56 (m, 2H), 4.12 (m, 2H), 3.73 (m, 6H), 3.11 (m, 3H), 2.12 (s, 3H), 1.65 (m, 2H), 0.87 (t, J 7.4 Hz, 3H). LCMS (ES+) [M+H].sup.+ 425.8, RT 1.48 minutes (method 4).

Examples 83 to 100

(115) The following compounds were prepared via Method J utilising Intermediate 37 and the indicated carbamate intermediate.

(116) TABLE-US-00014 LCMS Data Ex. Int. Name Method RT [M + H].sup.+ 83 53 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.26 422.4 pyrimidin-4-yl)-N-(l,2-benzoxazol-3-yl)-3-ethyl- piperazine-1-carboxamide 84 54 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.22 435.5 pyrimidin-4-yl)-3-ethyl-N-(1-methyl-1H-indazol-3-yl)- piperazine-1-carboxamide 85 57 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.29 462.4 pyrimidin-4-yl)-N-[6-(difluoromethoxy)-4-methyl- pyridin-3-yl]-3-ethylpiperazine-1-carboxamide 86 58 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.23 426.47 pyrimidin-4-yl)-3-ethyl-N-(6-methoxy-5-methyl- pyridin-3-yl)piperazine-1-carboxamide 87 56 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.15 473.5 pyrimidin-4-yl)-3-ethyl-N-[2-methyl-4-(methyl- sulfonyl)phenyl]piperazine-1-carboxamide 88 59 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.15 426.5 pyrimidin-4-yl)-3-ethyl-N-(6-methoxy-4-methyl- pyridin-3-yl)piperazine-1-carboxamide 89 48 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.35 503.5 pyrimidin-4-yl)-3-ethyl-N-[1-methyl-5-(trifluoro- methyl)-1H-indazol-3-yl]piperazine-1-carboxamide 90 49 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.23 453.5 pyrimidin-4-yl)-3-ethyl-N-(6-fluoro-1-methyl-1H- indazol-3-yl)piperazine-1-carboxamide 91 50 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.23 453.5 pyrimidin-4-yl)-3-ethyl-N-(5-fluoro-1-methyl-1H- indazol-3-yl)piperazine-1-carboxamide 92 43 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.29 462.5 pyrimidin-4-yl)-N-[6-(difluoromethoxy)-2-methyl- pyridin-3-yl]-3-ethylpiperazine-1-carboxamide 93 51 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.18 421.5 pyrimidin-4-yl)-3-ethyl-N-(imidazo[1,2-a]pyridin-8- yl)piperazine-1-carboxamide 94 44 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.29 444.4 pyrimidin-4-yl)-N-(6-ethoxy-5-fluoropyridin-3-yl)-3- ethylpiperazine-1-carboxamide 95 45 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.39 447.9 pyrimidin-4-yl)-N-(2-chloro-4-fluoro-5-methyl- phenyl)-3-ethylpiperazine-1-carboxamide 96 46 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.25 430.4 pyrimidin-4-yl)-3-ethyl-N-(5-fluoro-6-methoxy- pyridin-3-yl)piperazine-1-carboxamide 97 55 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.19 421.5 pyrimidin-4-yl)-N-(6-cyano-2-methylpyridin-3-yl)-3- ethylpiperazine-1-carboxamide 98 63 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.24 420.5 pyrimidin-4-yl)-N-(4-cyano-2-methylphenyl)-3-ethyl- piperazine-1-carboxamide 99 66 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.31 461.5 pyrimidin-4-yl)-N-[4-(difluoromethoxy)-2-methyl- phenyl]-3-ethylpiperazine-1-carboxamide 100 71 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.17 440.5 pyrimidin-4-yl)-N-[5-(dimethylamino)-3-methyl- pyrazin-2-yl]-3-ethylpiperazine-1-carboxamide

Examples 101 to 106

(117) The following compounds were prepared via Method F utilising Intermediate 7 and the appropriate amine.

(118) TABLE-US-00015 LCMS Data Ex. Name Method RT [M + H].sup.+ 101 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)- 4 1.25 421.8 3-methyl-N-(1-methyl-1H-indazol-4-yl)-piperazine-1- carboxamide 102 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)- 2 1.57 412.5 N-(2-methoxy-6-methylpyridin-3-yl)-3-methylpiperazine-1- carboxamide 103 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)- 2 1.53 420.8 3-methyl-N-(1-methyl-1H-indol-4-yl)piperazine-1- carboxamide 104 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)- 2 1.35 422.8 3-methyl-N-(1-methyl-1H-benzotriazol-4-yl)piperazine-1- carboxamide 105 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)- 2 1.02 407.44 N-(imidazo[1,2-a]pyridin-5-yl)-3-methylpiperazine-1- carboxamide 106 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)- 2 1.03 407.44 N-(imidazo[1,2-a]pyridin-3-yl)-3-methylpiperazine-1- carboxamide

Examples 107 to 119

(119) The following compounds were prepared via Method G utilising the stated piperazine intermediate and the appropriate amine.

(120) The amine utilised for Examples 112 and 118 was Intermediate 72. The amine utilised for Example 113 was Intermediate 69.

(121) TABLE-US-00016 LCMS Data Ex. Int. Name Method RT [M + H].sup.+ 107 7 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.10 422.4 pyrimidin-4-yl)-3-methyl-N-(1-methyl-1H-pyrazolo- [4,3-c]pyridin-4-yl)piperazine-1-carboxamide 108 7 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.11 432.8 pyrimidin-4-yl)-N-(3-chloro-5-methoxypyridin-2-yl)- 3-methylpiperazine-1-carboxamide 109 7 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.20 431.8 pyrimidin-4-yl)-N-(2-chloro-4-methoxyphenyl)-3- methylpiperazine-1-carboxamide 110 7 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.25 466.4 pyrimidin-4-yl)-N-[6-methoxy-2-(trifluoromethyl)- pyridin-3-yl]-3-methylpiperazine-1-carboxamide 111 7 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.19 439.4 pyrimidin-4-yl)-N-(6-fluoro-1-methyl-1H-indazol-4- yl)-3-methylpiperazine-1-carboxamide 112 7 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.18 426.5 pyrimidin-4-yl)-N-(2-ethyl-6-methoxypyridin-3-yl)-3- methylpiperazine-1-carboxamide 113 7 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.10 426.5 pyrimidin-4-yl)-N-[5-(dimethylamino)-3-methyl- pyrazin-2-yl]-3-methylpiperazine-1-carboxamide 114 37 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.53 460.4 pyrimidin-4-yl)-3-ethyl-N-(1-methyl-1H-pyrazolo[4,3- c]pyridin-4-yl)piperazine-1-carboxamide 115 37 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.25 445.9 pyrimidin-4-yl)-N-(2-chloro-4-methoxyphenyl)-3- ethylpiperazine-1-carboxamide 116 37 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.24 453.5 pyrimidin-4-yl)-3-ethyl-N-(6-fluoro-1-methyl-1H- indazol-4-yl)piperazine-1-carboxamide 117 37 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.3 480.5 pyrimidin-4-yl)-3-ethyl-N-[6-methoxy-2-(trifluoro- methyl)pyridin-3-yl]piperazine-1-carboxamide 118 37 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.23 440.5 pyrimidin-4-yl)-3-ethyl-N-(2-ethyl-6-methoxypyridin- 3-yl)piperazine-1-carboxamide 119 12 (3S)-4-(6-Amino-1,3-dimethyl-1H-pyrazolo[3,4-d]- 6 1.13 440.5 pyrimidin-4-yl)-N-[2-(dimethylamino)-4-methyl- pyrimidin-5-yl]-3-methylpiperazine-1-carboxamide

Example 120

4-(6-Amino-1-methylpyrazolo[3,4-d]pyrimidin-4-yl)-3-(2-hydroxyethyl)-N-[2-methyl-4-(trifluoromethoxy)phenyl]piperazine-1-carboxamide

(122) Intermediate 73 (0.17 g, 0.49 mmol) and Intermediate 38 (0.15 g, 0.48 mmol) in acetonitrile (10 mL) and DIPEA (0.19 g, 0.26 mL, 1.5 mmol) were stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, then partitioned between DCM and water. The organic layers were phase separated and concentrated in vacuo. The residue was purified by flash column chromatography on silica (Biotage SNAP 50 g, Isolera, gradient elution: 100% EtOAc to 20% MeOH/EtOAc) to yield the title compound (0.12 g, 50%) as a white solid. .sub.H (DMSO-d.sub.6) 8.23 (s, 1H), 8.06 (m, 1H), 7.31 (m, 1H), 7.21 (m, 1H), 7.13 (m, 1H), 6.19 (d, J 0.2 Hz, 2H), 4.75 (m, 3H), 4.09 (m, 2H), 3.70 (s, 3H), 3.54 (m, 2H), 3.15 (m, 3H), 2.20 (s, 3H), 1.81 (m, 2H). LCMS (ES+) [M+H].sup.+ 495.8, RT 1.76 minutes (method 4).

Example 121

(3R)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-(hydroxymethyl)-N-[2-methyl-4-(trifluoromethoxy)phenyl]piperazine-1-carboxamide

(123) Intermediate 15 (0.20 g, 0.59 mmol) and Intermediate 38 (0.19 g, 0.61 mmol) in acetonitrile (10 mL) and DIPEA (0.23 g, 0.32 mL, 1.8 mmol) were stirred at room temperature for 6 h. The reaction mixture was concentrated in vacuo, then partitioned between DCM and water. The organic layers were phase separated and concentrated in vacuo. The residue was purified by flash column chromatography on silica (Biotage SNAP 50 g, Isolera, gradient elution: 100% EtOAc to 30% MeOH/EtOAc) to yield the title compound (0.09 g, 33%) as a white solid. .sub.H (DMSO-d.sub.6) 8.12 (s, 1H), 7.91 (s, 1H), 7.36 (d, J 8.7 Hz, 1H), 7.19 (m, 1H), 7.15 (m, 1H), 6.18 (s, 2H), 5.07 (br s, 1H), 4.49 (br s, 2H), 4.15 (m, 1H), 3.95 (m, 1H), 3.70 (s, 3H), 3.61 (m, 3H), 3.31 (m, 1H), 3.12 (m, 1H), 2.21 (s, 3H). LCMS (ES+) [MH].sup. 479.0, RT 1.55 minutes (method 4).

Examples 122 to 138

(124) The following examples were prepared via Method J utilising the indicated carbamate and piperazine intermediates.

(125) TABLE-US-00017 LCMS Data Ex. Int. Name Method RT [M + H].sup.+ 122 24 & 81 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.21 440.5 pyrimidin-4-yl)-N-(6-methoxy-2-methylpyridin-3- yl)-3-(propan-2-yl)piperazine-1-carboxamide 123 24 & 82 (3S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.28 454.5 pyrimidin-4-yl)-N-(6-methoxy-2-methylpyridin-3- yl)-3-(2-methylpropyl)piperazine-1-carboxamide 124 24 & 78 4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.21 480.5 pyrimidin-4-yl)-N-(6-methoxy-2-methylpyridin-3- yl)-3-(2,2,2-trifluoroethyl)piperazine-1- carboxamide 125 51 & 78 4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.23 575.4 pyrimidin-4-yl)-N-(imidazo[1,2-a]pyridin-8-yl)-3- (2,2,2-trifluoroethyl)piperazine-1-carboxamide 126 42 & 76 (3S,5S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.25 449.5 pyrimidin-4-yl)-N-(1-ethyl-1H-indazol-3-yl)-3,5- dimethylpiperazine-1-carboxamide 127 54 & 76 (3S,5S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.2 435.5 pyrimidin-4-yl)-3,5-dimethyl-N-(1-methyl-1H- indazol-3-yl)piperazine-1-carboxamide 128 70 & 76 (3S,5S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.14 440.5 pyrimidin-4-yl)-N-[5-(dimethylamino)-3-methyl- pyrazin-2-yl]-3,5-dimethylpiperazine-1- carboxamide 129 51 & 76 (3S,5S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.17 421.5 pyrimidin-4-yl)-N-(imidazo[1,2-a]pyridin-8-yl)- 3,5-dimethylpiperazine-1-carboxamide 130 38 & 76 (3S,5S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.39 479.5 pyrimidin-4-yl)-3,5-dimethyl-N-[2-methyl-4- (trifluoromethoxy)phenyl]piperazine-1- carboxamide 131 24 & 76 (3S,5S)-4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.13 426.5 pyrimidin-4-yl)-N-(6-methoxy-2-methylpyridin-3- yl)-3,5-dimethylpiperazine-1-carboxamide 132 24 & 80 4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.18 466.4 pyrimidin-4-yl)-N-(6-methoxy-2-methylpyridin-3- yl)-3-(trifluoromethyl)piperazine-1-carboxamide 133 25 & 80 4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]- 6 1.25 465.4 pyrimidin-4-yl)-N-(4-methoxy-2-methylphenyl)-3- (trifluoromethyl)piperazine-1-carboxamide 134 49 & 12 (3S)-4-(6-Amino-1,3-dimethyl-1H-pyrazolo[3,4-d]- 6 1.22 453.5 pyrimidin-4-yl)-N-(6-fluoro-1-methyl-1H-indazol- 3-yl)-3-methylpiperazine-1-carboxamide 135 50 & 12 (3S)-4-(6-Amino-1,3-dimethyl-1H-pyrazolo[3,4-d]- 6 1.22 453.5 pyrimidin-4-yl)-N-(5-fluoro-1-methyl-1H-indazol- 3-yl)-3-methylpiperazine-1-carboxamide 136 43 & 12 (3S)-4-(6-Amino-1,3-dimethyl-1H-pyrazolo[3,4-d]- 6 1.28 462.4 pyrimidin-4-yl)-N-[6-(difluoromethoxy)-2-methyl- pyridin-3-yl]-3-methylpiperazine-1-carboxamide 137 70 & 12 (3S)-4-(6-Amino-1,3-dimethyl-1H-pyrazolo[3,4-d]- 6 1.14 439.5 pyrimidin-4-yl)-N-[5-(dimethylamino)-3-methyl- pyrazin-2-yl]-3-methylpiperazine-1-carboxamide 138 66 & 12 (3S)-4-(6-Amino-1,3-dimethyl-1H-pyrazolo[3,4-d]- 6 1.28 460.5 pyrimidin-4-yl)-N-[4-(difluoromethoxy)-2-methyl- phenyl]-3-methylpiperazine-1-carboxamide

Example 139

(3S)-4-[6-Amino-3-(4-fluorophenyl)-1-methylpyrazolo[3,4-d]pyrimidin-4-yl]-N-(4-methoxy-2-methylphenyl)-3-methylpiperazine-1-carboxamide

(126) Prepared via Method B using Intermediate 88 (0.22 mmol) and 2-methyl-4-methoxyphenyl isocyanate (36 L, 0.26 mmol). The title compound (107 mg, 96%) was obtained as a white solid. .sup.13C NMR (CDCl.sub.3, 75 MHz) 161.2 (d, J.sub.F,C 246.7 Hz, phenyl), 161.1 (C-4), 160.7 (C-2), 158.3 (C-7a), 157.1 (CO), 156.3 (phenyl), 143.4 (phenyl), 133.9 (phenyl), 130.8 (C-5), 130.1 (d, J.sub.F,C 8.0 Hz, phenyl), 129.6 (phenyl), 126.7 (phenyl), 115.8 (d, J.sub.F,C 6.9 Hz, phenyl), 115.6 (phenyl), 111.6 (phenyl), 95.6 (C-4a), 55.4 (OCH.sub.3), 50.3 (NCH.sub.2), 47.8 (NCH.sub.2), 43.6 (NCH.sub.2), 43.4 (NCH.sub.2), 33.6 (NCH.sub.3), 18.2 (Me), 14.7 (Me). MS (m/z) 505 [M+H].sup.+.

Example 140

(3S)-4-[6-Amino-1-methyl-3-(pyridin-3-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-N-(4-methoxy-2-methylphenyl)-3-methylpiperazine-1-carboxamide

(127) Prepared via Method B using Intermediate 89 (0.195 mmol) and 2-methyl-4-methoxyphenyl isocyanate (36 L, 0.26 mmol). The title compound (78 mg, 82%) was obtained as a white solid. .sup.13C NMR (CDCl.sub.3, 75 MHz) 161.1 (C-4), 160.9 (C-2), 158.5 (C-7a), 157.1 (CO), 156.3 (phenyl), 149.5 (py), 149.4 (py), 141.0 (py), 135.2 (py), 133.9 (phenyl), 130.7 (C-5), 129.6 (phenyl), 126.7 (phenyl), 123.6 (py), 115.8 (phenyl), 111.6 (phenyl), 95.8 (C-4a), 55.4 (OMe), 50.6 (NCH.sub.2), 47.7 (NCH.sub.2), 43.5 (NCH.sub.2), 33.7 (NCH.sub.3), 18.2 (Me), 14.7 (Me). MS (m/z) 488 [M+H].sup.+.