Granted Patent B2

US 8,476,285 · App. 12/494,917 · Granted Jul 2, 2013

Abstract

Claims (65)

1. A pharmaceutical composition comprising: a pharmaceutically acceptable carrier and an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof,

wherein:

A is chosen from a substituted or unsubstituted aryl, heteroaryl, heterocyclic, or carbocyclic group;

B is chosen from a substituted or unsubstituted piperidine, homopiperidine, piperazine, pyrrolidine or azetidine group;

R1 is chosen from hydro, alkyl, aryl, heteroaryl, amino, or halo;

L 1 can be saturated, partially saturated, or unsaturated, and is chosen from —(CH 2 ) n —(CH 2 ) n —, —(CH 2 ) n C(═O)(CH 2 ) n —, —(CH 2 ) n C(═O)NH(CH 2 ) n —, —(CH 2 ) n NHC(═O)O(CH 2 ) n —, —(CH 2 ) n NHC(═S)S(CH 2 ) n —, —(CH 2 ) n OC(═O)S(CH 2 ) n —, —(CH 2 ) n NH(CH 2 ) n —, —(CH 2 ) n O(CH 2 ) n —, —(CH 2 ) n S(CH 2 ) n —, or —(CH 2 ) n NHC(═S)NH(CH 2 ) n —, where each n

is independently chosen from 0, 1, 2, 3, 4, 5, 6, 7 or 8, and wherein each carbon and/or nitrogen can be optionally substituted with one or more substituents independently chosen from hydroxyl, halo, alkoxy, C 1-3 alkyl, or C 3-6 cycloalkyl;

L 2 can be saturated, partially saturated, or unsaturated, and is chosen from —(CH 2 ) n —(CH 2 ) n —, —(CH 2 ) n C(═O)(CH 2 ) n —, —(CH 2 ) n C(═O)NH(CH 2 ) n —, —(CH 2 ) n NHC(═O)O(CH 2 ) n —, —(CH 2 ) n NHC(═O)NH(CH 2 ) n —, —(CH 2 ) n NHC(═S)S(CH 2 ) n —, —(CH 2 ) n OC(═O)S(CH 2 ) n —, —(CH 2 ) n NH(CH 2 ) n —, —(CH 2 ) n O(CH 2 ) n —, —(CH 2 ) n S(CH 2 ) n —, or —(CH 2 ) n NHC(═S)NH(CH 2 ) n —, where each n is

independently chosen from 0, 1, 2, 3, 4, 5, 6, 7 or 8, and wherein each carbon and/or nitrogen can be optionally substituted with one or more substituents independently chosen from hydroxyl, halo, alkoxy, C 1-3 alkyl, or C 3-6 cycloalkyl.

2. The pharmaceutical composition of claim 1 , wherein

B is a substituted or unsubstituted piperidine group.

3. The pharmaceutical composition of claim 2 , wherein

B is a piperidine group substituted with one or more substituents chosen from hydro, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, nitro, —CH 2 -aryl, —C(═O)alkyl, —C(═O)cycloalkyl, —C(═O)—NH-alkyl, cycloalkyl, hydroxyl, —COOH (and esters thereof), amino acid (chosen from natural and non-natural amino acids), peptide having 1-5 amino acid residues (chosen from natural and non-natural amino acids), —C(═O)alkyl where the alkyl is substituted with one or more substituents (chosen from alkyl, amino, alkoxy, haloalkyl, haloalkoxy, nitro, cyano, hydroxyl, —COOH (and esters thereof), sulfonyl, sulfonamide) and sulfonyl; or

wherein B is a piperidine group having one or more substituents chosen from hydro, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, nitro, —CH 2 -aryl, —C(═O)alkyl, —C(═O)—NH-alkyl, cycloalkyl, hydroxyl, —COOH (and esters thereof), and sulfonyl; or

wherein B is a piperidine group having one or more substituents chosen from —C(═O), —C(═O)CH 3 , —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —C( ═O)OCH 2 CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 CF 3 , —C(═O)OC(CH 3 ) 3 , —C(═O)OCH 2 -phenyl, —CH 2 -phenyl, —CH(CH 3 ) 2 , —C(═O)NHCH 2 CH 3 , —C(═O)NHCH(CH 3 ) 2 , —C(═O)NHC(CH 3 ) 3 , —C(═O)NHCH 2 C(═O)OCH 2 CH 3 , —C(═O)C(CH 3 ) 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —C(═O)CH 2 C(CH 3 ) 3 , and cyclopentyl.

4. The pharmaceutical composition of claim 1 , wherein

B is a piperazine group substituted with one or more substituents chosen from hydro, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, nitro, —CH 2 -aryl, —C(═O)alkyl, —C(═O)cycloalkyl, —C(═O)—NH-alkyl, cycloalkyl, hydroxyl, —COOH (and esters thereof), amino acid (chosen from natural and non-natural amino acids), peptide having 1-5 amino acid residues (chosen from natural and non-natural amino acids), —C(═O)alkyl where the alkyl is substituted with one or more substituents (chosen from alkyl, amino, alkoxy, haloalkyl, haloalkoxy, nitro, cyano, hydroxyl, —COOH (and esters thereof), sulfonyl, sulfonamide) and sulfonyl; or

wherein B is a piperazine group having one or more substituents chosen from hydro, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, nitro, —CH 2 -aryl, —C(═O)alkyl, —C(═O)—NH-alkyl, cycloalkyl, hydroxyl, —COOH (and esters thereof), and sulfonyl; or

wherein B is a piperazine group having one or more substituents chosen from —C(═O), —C(═O)CH 3 , —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —C(═OCH 2 CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 CF 3 , —C(═O)OC(CH 3 ) 3 , —C(═O)OCH 2 -phenyl, —CH 2 -phenyl, —CH(CH 3 ) 2 , —C(═O)NHCH 2 CH 3 , —C(═O)NHCH(CH 3 ) 2 , —C(═O)NHC(CH 3 ) 3 , —C(═O)NHCH 2 C(═O)OCH 2 CH 3 , —C(═O)C(CH 3 ) 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —C(═O)CH 2 C(CH 3 ) 3 , and cyclopentyl.

5. The pharmaceutical composition of claim 1 , wherein

B is a pyrrolidine group substituted with one or more substituents chosen from hydro, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, nitro, —CH 2 -aryl, —C(═O)alkyl, —C(═O)cycloalkyl, —C(═O)—NH-alkyl, cycloalkyl, hydroxyl, —COOH (and esters thereof), amino acid (chosen from natural and non-natural amino acids), peptide having 1-5 amino acid residues (chosen from natural and non-natural amino acids), —C(═O)alkyl where the alkyl is substituted with one or more substituents (chosen from alkyl, amino, alkoxy, haloalkyl, haloalkoxy, nitro, cyano, hydroxyl, —COOH (and esters thereof), sulfonyl, sulfonamide) and sulfonyl; or

wherein B is a pyrrolidine group having one or more substituents chosen from hydro, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, nitro, —CH 2 -aryl, —C(═O)alkyl, —C(═O)—NH-alkyl, cycloalkyl, hydroxyl, —COOH (and esters thereof), and sulfonyl; or

wherein B is a pyrrolidine group having one or more substituents chosen from —C(═O), —C( ═O)CH 3 , —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —C(═O)OCH 2 CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 CF 3 , —C(═O)OC(CH 3 ) 3 , —C(═O)OCH 2 phenyl, —CH 2 -phenyl, —CH(CH 3 ) 2 , —C(═O)NHCH 2 CH 3 , —C(═O)NHCH(CH 3 ) 2 , —C(═O)NHC(CH 3 ) 3 , —C(═O)NHCH 2 C(═O)OCH 2 CH 3 , —C(═O)C(CH 3 ) 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —C(═O)CH 2 C(CH 3 ) 3 , and cyclopentyl.

6. The pharmaceutical composition of claim 1 , wherein

B is an azetidine group substituted with one or more substituents chosen from hydro, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, nitro, —CH 2 -aryl, —C(═O)alkyl, —C(═O)cycloalkyl, —C(═O)—NH-alkyl, cycloalkyl, hydroxyl, —COOH (and esters thereof), amino acid (chosen from natural and non-natural amino acids), peptide having 1-5 amino acid residues (chosen from natural and non-natural amino acids), —C(═O)alkyl where the alkyl is substituted with one or more substituents (chosen from alkyl, amino, alkoxy, haloalkyl, haloalkoxy, nitro, cyano, hydroxyl, —COOH (and esters thereof), sulfonyl, sulfonamide) and sulfonyl; or

wherein B is an azetidine group having one or more substituents chosen from hydro, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, nitro, —CH 2 -aryl, —C(═O)alkyl, —C(═O)—NH-alkyl, cycloalkyl, hydroxyl, —COOH (and esters thereof), and sulfonyl; or

wherein B is an azetidine group having one or more substituents chosen from —C(═O), —C(═O)CH 3 , —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —C═O)OCH 2 CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 CF 3 , —C(═O)OC(CH 3 ) 3 , —C(═O)OCH 2 -phenyl, —CH 2 -phenyl, —CH(CH 3 ) 2 , —C(═O)NHCH 2 CH 3 , —C(═O)NHCH(CH 3 ) 2 , —C(═O)NHC(CH 3 ) 3 , —C(═O)NHCH 2 C(═O)OCH 2 CH 3 , —C(═O)C(CH 3 ) 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —C(═O)CH 2 C(CH 3 ) 3 , and cyclopentyl.

7. The pharmaceutical composition of claim 1 , wherein

B is a homopiperidine group substituted with one or more substituents chosen from hydro, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, nitro, —CH 2 -aryl, —C(═O)alkyl, —C(═O)cycloalkyl, —C(═O)—NH-alkyl, cycloalkyl, hydroxyl, —COOH (and esters thereof), amino acid (chosen from natural and non-natural amino acids), peptide having 1-5 amino acid residues (chosen from natural and non-natural amino acids), —C(═O)alkyl where the alkyl is substituted with one or more substituents (chosen from alkyl, amino, alkoxy, haloalkyl, haloalkoxy, nitro, cyano, hydroxyl, —COOH (and esters thereof), sulfonyl, sulfonamide) and sulfonyl; or

wherein B is a homopiperidine group having one or more substituents chosen from hydro, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, nitro, —CH 2 -aryl, —C(═O)alkyl, —C(═O)—NH-alkyl, cycloalkyl, hydroxyl, —COOH (and esters thereof), and sulfonyl; or

wherein B is a homopiperidine group having one or more substituents chosen from —C(═O), —C(═O)CH 3 , —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —C(═O)OCH 2 CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 CF 3 , —C(═O)OC(CH 3 ) 3 , —C(═O)OCH 2 -phenyl, —CH 2 -phenyl, —CH(CH 3 ) 2 , —C(═O)NHCH 2 CH 3 , —C(═O)NHCH(CH 3 ) 2 , —C(═O)NHC(CH 3 ) 3 , —C(═O)NHCH 2 C(═O)OCH 2 CH 3 , —C(═O)C(CH 3 ) 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —C(═O)CH 2 C(CH 3 ) 3 , and cyclopentyl.

8. The pharmaceutical composition of claim 1 , wherein L 1 is —S—.

9. The pharmaceutical composition of claim 1 , wherein

L 2 is —(CH 2 ) n —(CH 2 ) n —, and each n is independently chosen from 0, 1, 2, and 3 and wherein each carbon can be optionally substituted with one or more substituents independently chosen from hydroxyl, halo, alkoxy, alkyl, amino, —NR 2 R 3 , —NHSO 2 R 4 , —NHC(═O)NR 2 R 3 , heteroaryl, aryl, or a heterocycle;

R 2 and R 3 are independently chosen from —H, alkyl, or —C(═O)OR 4 ; and

R 4 is a C 1 -C 4 alkyl.

10. The pharmaceutical composition of claim 1 , wherein R1 is hydro.

11. A pharmaceutical composition according to claim 1 wherein said compound of Formula I is selected from

9-[2-(1-Acetylpiperidin-4-yl)ethyl]-8-[(6-bromo-1,3-benzodioxol-5-yl)thio]-9H-purin-6-amine,

4-(2-{6-Amino-8-[(6-bromo-1,3-benzodioxol-5-yl)thio]-9H-purin-9-yl}ethyl)piperidine-1-carbaldehyde,

4-(2-{6-Amino-8-[(7-bromo-2,3-dihydro-1,4-benzodioxin-6-yl)thio]-9H-purin-9-yl}ethyl)piperidine-1-carbaldehyde,

(2S)-1-[4-(2-{6-Amino-8-[(6-bromo-1,3-benzodioxol-5-yl)thio]-9H-purin-9-yl}ethyl)piperidin-1-yl]-1-oxopropan-2-ol,

4-(2-{6-Amino-8-[(1-oxo-2,3-dihydro-1H-inden-5-yl)thio]-9H-purin-9-yl}ethyl)piperidine-1-carbaldehyde,

2-[4-(2-{6-Amino-8-[(6-bromo-1,3-benzodioxol -5-yl)thio]-9H-purin-9-yl}ethyl)piperidin-1-yl]-2-oxoethanol, and

6-({9-[2-(1-Acetylpiperidin-4-yl)ethyl]-6-amino-9H-purin-8-yl}thio)-1,3-benzodioxole-5-carbonitrile,

or a pharmaceutically acceptable salt thereof.

12. The pharmaceutical composition of claim 11 , wherein the compound of Formula I is 9-[2-(1-acetylpiperidin-4-yl)ethyl]-8-[(6-bromo-1,3-benzodioxol-5-yl)thio]-9H-purin-6-amine.

13. The pharmaceutical composition of claim 11 , wherein the compound of Formula I is 4-(2-{6-amino-8-[(6-bromo-1,3-benzodioxol-5-yl)thio]-9H-purin-9-yl}ethyl)piperidine-1-carbaldehyde.

14. The pharmaceutical composition of claim 11 , wherein the compound of Formula I is (2S)-1-[4-(2-{6-amino-8-[(6-bromo-1,3-benzodioxol-5-yl)thio]-9H-purin-9-yl}ethyl)piperidin-1-yl]-1-oxopropan-2-ol.

15. The pharmaceutical composition of claim 11 , wherein the compound of Formula I is 2-[4-(2-{6-Amino-8-[(6-bromo-1,3-benzodioxol-5-yl)thio]-9H-purin-9-yl}ethyl)piperidin-1-yl]-2-oxoethanol.

16. The pharmaceutical composition of claim 11 , wherein the compound of Formula I is 6-({9-[2-(1-Acetylpiperidin-4-yl)ethyl]-6-amino-9H-purin-8-yl}thio)-1,3-benzodioxole-5-carbonitrile.

17. A pharmaceutical composition comprising, a pharmaceutically acceptable carrier and an effective amount of one or more compounds of Formula I, or a pharmaceutically acceptable salt thereof,

wherein:

A is chosen from a substituted or unsubstituted indanone or indone group;

B is chosen from a substituted or unsubstituted aryl, heteroaryl, heterocyclic, or carbocyclic group;

R1 is chosen from hydro, alkyl, aryl, heteroaryl, amino, or halo;

L 1 can be saturated, partially saturated, or unsaturated, and is chosen from —(CH 2 ) n —(CH 2 ) n —, —(CH 2 ) n C(═O)(CH 2 ) n —, —(CH 2 ) n C(═O)NH(CH 2 ) n —,—(CH 2 ) n NHC(═O)O(CH 2 ) n —, (CH 2 ) n NHC(═O)NH(CH 2 ) n —, —(CH 2 ) n NHC(═S)S(CH 2 ) n —, —(CH 2 ) n OC(═O)S(CH 2 ) n —, —(CH 2 ) n NH(CH 2 ) n —, —(CH 2 ) n O(CH 2 ) n —, —(CH 2 ) n S(CH 2 ) n —, or —(CH 2 ) n NHC(═S)NH(CH 2 ) n —, where each n is independently chosen from 0, 1, 2, 3, 4, 5, 6, 7, or 8, and wherein each carbon and/or nitrogen can be optionally substituted with one or more substituents independently chosen from hydroxyl, halo, alkoxy, alkyl, amino, —NR 2 R 3 , —NHSO 2 R 4 , —NHC(═O)NR 2 R 3 , heteroaryl, aryl, cycloalkyl, or a heterocycle;

R 2 and R 3 are independently chosen from —H, alkyl, or —C(═O)OR 4 ; and

R 4 is a C 1 -C 4 alkyl; and

L 2 can be saturated, partially saturated, or unsaturated, and is chosen from —(CH 2 ) n —(CH 2 ) n —, —(CH 2 ) n C(═O)(CH 2 ) n —, —(CH 2 ) n C(═O)NH(CH 2 ) n —, —(CH 2 ) n NHC(═O)O(CH 2 ) n —, —(CH 2 ) n NHC(═O)NH(CH 2 ) n —, —(CH 2 ) n NHC(═S)S(CH 2 ) n —, —(CH 2 ) n C(═O)S(CH 2 ) n —, —(CH 2 ) n NH(CH 2 ) n —, —(CH 2 ) n O(CH 2 ) n —, —(CH 2 ) n S(CH 2 ) n —, or —(CH 2 ) n NHC(═S)NH(CH 2 ) n —, where each n is independently chosen from 0, 1, 2, 3, 4, 5, 6, 7, or 8, and wherein each carbon and/or nitrogen can be optionally substituted with one or more substituents independently chosen from hydroxyl, halo, alkoxy, alkyl, amino, —NR 2 R 3 , —NHSO 2 R 4 ,

—NHC(═O)NR 2 R 3 , heteroaryl, aryl, cycloalkyl, and heterocyclic; wherein R 2 and R 3 are independently chosen from —H, alkyl, or —C(═O)0R 4 ; and wherein R 4 is a C 1 -C 4 alkyl.

18. The pharmaceutical composition of claim 17 , wherein

A is a substituted indanone group, having from 1-5 substituents independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkylthio, alkynyl, amino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, carbocycle, cyano, cyanato, halo, haloalkyl, halophenyl, hydroxyl, heteroaryl, heteroaryloxy, heterocycle, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamide, thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido.

19. The pharmaceutical composition of claim 17 , wherein

A is a substituted indane group, having from 1-5 substituents independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkylthio, alkynyl, amino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, carbocycle, cyano, cyanato, halo, haloalkyl, halophenyl, hydroxyl, heteroaryl, heteroaryloxy, heterocycle, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamide, thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido.

Assignments (11)