IP Library › Granted Patent US 7,790,734

Granted Patent B2

US 7,790,734 · App. 10/934,326 · Granted Sep 7, 2010

Dipeptidyl peptidase inhibitors

Assignee: Takeda Pharmaceutical Company Limited

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Quick Facts

Patent No.: US 7,790,734
App. No.: 10/934,326
Granted: Sep 7, 2010
Kind: B2

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Abstract

Compounds, pharmaceuticals, kits and methods are provided for use with DPP-IV inhibitors comprising Formula I: wherein the substituents are as described herein.

Claims (160)

1. A compound comprising Formula I:

or a pharmaceutically acceptable salt thereof, wherein

Q is CO;

Z is a substituted or unsubstituted 3-amino-piperidin-1-yl;

R 2 is selected from the group consisting of hydrogen, (C 1-10 )alkyl, (C 3-12 )cycloalkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, hetero(C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl(C 1-5 )alkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl, (C 9-12 )bicycloaryl(C 1-5 )alkyl, hetero(C 4-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl(C 1-5 )alkyl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, and heteroaryloxy, each substituted or unsubstituted;

R 3 is selected from the group consisting of hydrogen, halo, perhalo(C 1-10 )alkyl, amino, cyano, nitro, thio, (C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, and alkynyl, each substituted or unsubstituted;

L is a linker providing 0-6 atom separation between X and the ring to which L is attached selected from the group consisting of —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —C(O)—, —CH 2 C(O)—, —C(O)CH 2 —, —CH 2 —C(O)CH 2 —, —C(O)CH 2 CH 2 —, —CH 2 CH 2 C(O)—, —O—, —OCH 2 —, —CH 2 O—, —CH 2 OCH 2 —, —OCH 2 CH 2 —, —CH 2 CH 2 O—, —N(CH 3 )—, —NHCH 2 —, —CH 2 NH—, —CH 2 NHCH 2 —, —NHCH 2 CH 2 —, —CH 2 CH 2 NH—, —NH—C(O)—, —NCH 3 —C(O)—, —C(O)NH—, —C(O)NCH 3 —, —NHC(O)CH 2 —, —C(O)NHCH 2 —, —C(O)CH 2 NH—, —CH 2 NHC(O)—, —CH 2 C(O)NH—, —NHCH 2 C(O)—, —S—, —SCH 2 —, —CH 2 S—, —SCH 2 CH 2 —, —CH 2 SCH 2 —, —CH 2 CH 2 S—, —C(O)S—, —C(O)SCH 2 —, —CH 2 C(O)S—, —C(O)CH 2 S—, —CH 2 SC(O)—, CHR 12 —, —C(R 12 )(R 12′ )—, —C(S)—, —C(NH)—, —C(NR 12 )—, —N(H)— and —N(R 12 )—, where R 12 and R 12′ are each independently selected from the group consisting of hydrogen, perhalo(C 1-10 )alkyl, amino, halo, cyano, (C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, and alkynyl, each substituted or unsubstituted; and

X is selected from the group consisting of (C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 4-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, and cyano, each substituted or unsubstituted.

2. A compound according to claim 1 , wherein L is —O—.

3. A compound according to claim 1 , wherein L is —N(R 12 )—.

4. A compound according to claim 1 , wherein L is —C(O)—.

5. A compound according to claim 1 , wherein L is selected from the group consisting of —CH 2 —, —CHR 12 —, —C(R 12 )(R 12′ )—, —C(O)—, —C(S)—, —C(NH)—, —C(NR 12 )—, —O—, —N(H)—, —N(R 12 )—, and —S— where R 12 and R 12′ are each independently selected from the group consisting of hydrogen, perhalo(C 1-10 )alkyl, amino, halo, cyano, (C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, and alkynyl, each substituted or unsubstituted or where or R 12 and R 12′ are taken together to form a 5, 6, or 7 membered ring, each substituted or unsubstituted.

6. A compound according to claim 1 , wherein L is selected from the group consisting of —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —C(O)—, —CH 2 C(O)—, —C(O)CH 2 —, —CH 2 —C(O)CH 2 —, —C(O)CH 2 CH 2 —, —CH 2 CH 2 C(O)—, —O—, —OCH 2 —, —CH 2 O—, —CH 2 OCH 2 —, —OCH 2 CH 2 —, —CH 2 CH 2 O—, —N(CH 3 )—, —NHCH 2 —, —CH 2 NH—, —CH 2 NHCH 2 —, —NHCH 2 CH 2 —, —CH 2 CH 2 NH—, —NH—C(O)—, —NCH 3 —C(O)—, —C(O)NH—, —C(O)NCH 3 —, —NHC(O)CH 2 —, —C(O)NHCH 2 —, —C(O)CH 2 NH—, —CH 2 NHC(O)—, —CH 2 C(O)NH—, —NHCH 2 C(O)—, —S—, —SCH 2 , —CH 2 S—, —SCH 2 CH 2 —, —CH 2 SCH 2 —, —CH 2 CH 2 S—, —C(O)S—, —C(O)SCH 2 —, —CH 2 C(O)S—, —C(O)CH 2 S—, and —CH 2 SC(O)—.

7. A compound according to claim 1 , wherein L is selected from the group consisting of —CH 2 —, —C(O)—, —CH 2 C(O)—, —C(O)CH 2 —, —CH 2 —C(O)CH 2 —, —C(O)CH 2 CH 2 —, and —CH 2 CH 2 C(O)—.

8. A compound according to claim 1 , wherein X is selected from the group consisting of (C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 4-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, and cyano, each substituted or unsubstituted.

9. A compound according to claim 1 , wherein X is selected from the group consisting of cycloalkyl, aryl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted.

10. A compound according to claim 1 , wherein X is a substituted or unsubstituted cycloalkyl or heterocycloalkyl.

11. A compound according to claim 1 , wherein X is a substituted or unsubstituted (C 3-7 )cycloalkyl.

12. A compound according to claim 1 , wherein X is a substituted or unsubstituted (C 3-7 )heterocycloalkyl.

13. A compound according to claim 1 , wherein X is a substituted or unsubstituted aryl or heteroaryl.

14. A compound according to claim 1 , wherein X is a substituted or unsubstituted phenyl.

15. A compound according to claim 1 , wherein X is a substituted or unsubstituted heteroaryl.

16. A compound according to claim 1 , wherein X is a ring having a non-hydrogen substituent at a 2 or 3 position of the ring.

17. A compound according to claim 1 , wherein X has a non-hydrogen substituent at a 2 or 3 position of the ring wherein the non-hydrogen substituent is selected from the group consisting of (C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, and cyano, nitro, halo, each substituted or unsubstituted.

18. A compound according to claim 1 , wherein X is selected from the group consisting of (2-cyano)phenyl; (3-cyano)phenyl; (2-hydroxy)phenyl; (3-hydroxy)phenyl; (2-alkenyl)phenyl; (3-alkenyl)phenyl; (2-alkynyl)phenyl; (3-alkynyl)phenyl; (2-methoxy)phenyl; (3-methoxy)phenyl; (2-nitro)phenyl; (3-nitro)phenyl; (2-carboxy)phenyl; (3-carboxy)phenyl; —(CH 2 )-(2-carboxamido)phenyl; (3-carboxamido)phenyl; (2-sulfonamido)phenyl; (3-sulfonamido)phenyl; (2-tetrazolyl)phenyl; (3-tetrazolyl)phenyl; (2-aminomethyl)phenyl; (3-aminomethyl)phenyl; (2-hydroxymethyl)phenyl; (3-hydroxymethyl)phenyl; (2-phenyl)phenyl; (3-phenyl)phenyl; (2-halo)phenyl; (3-halo)phenyl; (2-CONH 2 )phenyl; (3-CONH 2 )phenyl; (2-CONH(C 1-7 )alkyl)phenyl; (3-CONH(C 1-7 )alkyl)phenyl; (2-CO 2 (C 1-7 )alkyl)phenyl; (3-CO 2 (C 1-7 )alkyl)phenyl; (2-NH 2 )phenyl; (3-NH 2 )phenyl; (2-(C 3-7 )alkyl)phenyl; (3-(C 3-7 )alkyl)phenyl; (2-(C 3-7 )cycloalkyl)phenyl; (3-(C 3-7 )cycloalkyl)phenyl; (2-aryl)phenyl; (3-aryl)phenyl; (2-heteroaryl)phenyl; (3-heteroaryl)phenyl; 2-bromo-5-fluoro phenyl; 2-chloro-5-fluoro phenyl; 2-cyano-5-fluoro phenyl; 2,5-dichloro phenyl; 2,5-difluoro phenyl; 2,5-dibromo phenyl; 2-bromo-3,5-difluoro phenyl; 2-chloro-3,5-difluoro phenyl; 2,3,5-trifluoro phenyl; 2,3,5,6-tetrafluorophenyl; 2-bromo-3,5,6-trifluoro phenyl; 2-chloro-3,5,6-trifluoro phenyl; 2-cyano-3,5-difluoro phenyl; 2-cyano-3,5,6-trifluoro phenyl; (2-heterocycloalkyl)phenyl; and (3-heterocycloalkyl)phenyl, each substituted or unsubstituted.

19. A compound according to claim 1 , wherein X is selected from the group consisting of:

wherein

A is S, O, or NR 21 ;

B is CR 20 or N;

R 20 is independently selected from the group consisting of hydrogen, halo, perhalo(C 1-10 )alkyl, amino, thio, cyano, CF 3 , nitro, (C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, aminosulfonyl, alkylsulfonyl, arylsulfonyl, and heteroarylsulfonyl; and

R 21 is independently selected from the group consisting of hydrogen, perhalo(C 1-10 )alkyl, amino, (C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, aminosulfonyl, alkylsulfonyl, arylsulfonyl, and heteroarylsulfonyl.

20. A compound according to claim 1 , wherein X is selected from the group consisting of

wherein

t is 0, 1, 2, or 3; and

each R 7 is independently selected from the group consisting of halo, perhalo(C 1-10 )alkyl, CF 3 , (C 1-10 )alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, and alkoxy, each substituted or unsubstituted.

21. A compound according to claim 1 , wherein X is selected from the group consisting of:

wherein

t is 0, 1, 2, or 3; and

each R 7 is independently selected from the group consisting of halo, perhalo(C 1-10 )alkyl, CF 3 , alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, and alkoxy, each substituted or unsubstituted.

22. A compound according to claim 21 , wherein R 7 is independently selected from the group consisting of -cyano, -methoxy, -nitro, -carboxy, -sulfonamido, -tetrazolyl, -aminomethyl, -hydroxymethyl, -phenyl, -halo, —CONH 2 , —CONH(C 1-7 )alkyl, —CO 2 (C 1-7 )alkyl, —NH 2 , —OH, —(C 1-5 )alkyl, -alkenyl, -alkynyl, —CCH, (C 1-5 )cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, each substituted or unsubstituted.

23. A compound according to claim 1 , wherein -LX is —OR 11 , where R 11 is selected from the group consisting of substituted or unsubstituted alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl.

24. A compound according to claim 1 , wherein -L-X taken together is selected from the group consisting of —(CH 2 )-(2-cyano)phenyl; —(CH 2 )-(3-cyano)phenyl; —(CH 2 )-(2-hydroxy)phenyl; —(CH 2 )-(3-hydroxy)phenyl; —(CH 2 )-(2-alkenyl)phenyl; —(CH 2 )-(3-alkenyl)phenyl; —(CH 2 )-(2-alkynyl)phenyl; —(CH 2 )-(3-alkynyl)phenyl; —(CH 2 )-(2-methoxy)phenyl; —(CH 2 )-(3-methoxy)phenyl; —(CH 2 )-(2-nitro)phenyl; —(CH 2 )-(3-nitro)phenyl; —(CH 2 )-(2-carboxy)phenyl; —(C 1-12 )-(3-carboxy)phenyl; —(CH 2 )-(2-carboxamido)phenyl; —(CH 2 )-(3-carboxamido)phenyl; —(CH 2 )-(2-sulfonamido)phenyl; —(CH 2 )-(3-sulfonamido)phenyl; —(CH 2 )-(2-tetrazolyl)phenyl; —(CH 2 )-(3-tetrazolyl)phenyl; —(CH 2 )-(2-aminomethyl)phenyl; —(CH 2 )-(3-aminomethyl)phenyl; —(CH 2 )-(2-hydroxymethyl)phenyl; —(CH 2 )-(3-hydroxymethyl)phenyl; —(CH 2 )-(2-phenyl)phenyl; —(CH 2 )-(3-phenyl)phenyl; —(CH 2 )-(2-halo)phenyl; —(CH 2 )-(3-halo)phenyl; —(CH 2 )-(2-CONH 2 )phenyl; —(CH 2 )-(3-CONH 2 )phenyl; —(CH 2 )-(2-CONH(C 1-7 )alkyl)phenyl; —(CH 2 )-(3-CONH(C 1-7 )alkyl)phenyl; —(CH 2 )-(2-CO 2 (C 1-7 )alkyl)phenyl; —(CH 2 )-(3-CO 2 (C 1-7 )alkyl)phenyl; —(CH 2 )-(2-NH 2 )phenyl; —(CH 2 )-(3-NH 2 )phenyl; —(CH 2 )-(2-(C 3-7 )alkyl)phenyl; —(CH 2 )-(3-(C 3-7 )alkyl)phenyl; —(CH 2 )-(2-(C 3-7 )cycloalkyl)phenyl; —(CH 2 )-(3-(C 3-7 )cycloalkyl)phenyl; —(CH 2 )-(2-aryl)phenyl; —(CH 2 )-(3-aryl)phenyl; —(CH 2 )-(2-heteroaryl)phenyl; —(CH 2 )-(3-heteroaryl)phenyl; —(CH 2 )-2-bromo-5-fluoro phenyl; —(CH 2 )-2-chloro-5-fluoro phenyl; —(CH 2 )-2-cyano-5-fluoro phenyl; —(CH 2 )-2,5-dichloro phenyl; —(CH 2 )-2,5-difluoro phenyl; —(CH 2 )-2,5-dibromo phenyl; —(CH 2 )-2-bromo-3,5-difluoro phenyl; —(CH 2 )-2-chloro-3,5-difluoro phenyl; —(CH 2 )-2,3,5-trifluoro phenyl; —(CH 2 )-2,3,5,6-tetrafluorophenyl; —(CH 2 )-2-bromo-3,5,6-trifluoro phenyl; —(CH 2 )-2-chloro-3,5,6-trifluoro phenyl; —(CH 2 )-2-cyano-3,5-difluoro phenyl; —(CH 2 )-2-cyano-3,5,6-trifluoro phenyl; —(CH 2 )-(2-heterocycloalkyl)phenyl; and —(CH 2 )-(3-heterocycloalkyl)phenyl, each substituted or unsubstituted.

25. A compound comprising Formula I:

or a pharmaceutically acceptable salt thereof, wherein

Q is CO;

Z is a substituted or unsubstituted 3-amino-piperidin-1-yl;

-LX is selected from the group consisting of —(C 1 )alkyl-aryl, —(C 1 )alkyl-bicycloaryl, -aminoaryl, -aminoheteroaryl, -aminobicycloaryl, -aminoheterobicycloaryl, —O-aryl, —O-heteroaryl, —O-bicycloaryl, —O-heterobicycloaryl, —(S)-aryl, —(S)-heteroaryl, —(S)-bicycloaryl, —S-heterobicycloaryl, —C(O)-aryl, —C(O)-heteroaryl, —C(O)-bicycloaryl, —C(O)-heterobicycloaryl, —C(S)-aryl, —C(S)-heteroaryl, —C(S)-bicycloaryl, —C(S)-heterobicycloaryl, —S(O)-aryl, —S(O)-heteroaryl, —S(O)-bicycloaryl, —SO 2 -heterobicycloaryl, —SO 2 -aryl, —SO 2 -heteroaryl, —SO 2 -bicycloaryl, —SO 2 -heterobicycloaryl, —C(NR 13 )-aryl, —C(NR 13 )-heteroaryl, —C(NR 13 )-bicycloaryl, —C(NR 13 )-heterobicycloaryl, each substituted or unsubstituted where R 13 is selected from the group consisting of hydrogen, perhalo(C 1-10 )alkyl, amino, cyano, (C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, and alkynyl, each substituted or unsubstituted.

26. A compound according to claim 1 , wherein at least one of R 2 and R 3 is hydrogen.

27. A compound according to claim 1 , wherein at least one of R 2 and R 3 is selected from the group consisting of —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHC 1-3 -alkyl, and —N(C 1-3 -alkyl) 2 , each substituted or unsubstituted.

28. A compound according to claim 1 , wherein at least one of R 2 and R 3 is selected from the group consisting of a (C 2-10 )alkenyl; an amino, (C 1-10 )alkyl, or alkoxy carbonyl (C 1-3 )alkenyl; an amino, (C 1-10 )alkyl, or alkoxy thiocarbonyl (C 1-3 )alkenyl; an amino, (C 1-10 )alkyl, or alkoxy sulfonyl (C 1-3 )alkenyl; an amino, (C 1-10 )alkyl, or alkoxy sulfinyl (C 1-3 )alkenyl; an amino, (C 1-10 )alkyl, or alkoxy imino (C 1-3 )alkenyl; an aryl (C 1-5 )alkenyl; and a heteroaryl (C 1-5 ) alkenyl, each substituted or unsubstituted.

29. A compound according to claim 1 , wherein at least one of R 2 and R 3 is selected from the group consisting of a (C 2-10 )alkynyl; an amino, (C 1-10 )alkyl, or alkoxy carbonyl (C 1-3 )alkynyl; an amino, (C 1-10 )alkyl, or alkoxy thiocarbonyl (C 1-3 )alkynyl; an amino, (C 1-10 )alkyl, or alkoxy sulfonyl (C 1-3 )alkynyl; an amino, (C 1-10 )alkyl, or alkoxy sulfinyl (C 1-3 )alkynyl; an amino, (C 1-10 )alkyl, or alkoxy imino (C 1-3 )alkynyl; an aryl (C 1-5 ) alkynyl; and heteroaryl (C 1-5 )alkynyl, each substituted or unsubstituted.

30. A compound according to claim 1 , wherein at least one of R 2 and R 3 is substituted or unsubstituted (C 3-7 )cycloalkyl.

31. A compound according to claim 1 , wherein at least one of R 2 and R 3 is substituted or unsubstituted (C 3-7 )heterocycloalkyl.

32. A compound according to claim 1 , wherein at least one of R 2 and R 3 is substituted or unsubstituted aryl.

33. A compound according to claim 1 , wherein at least one of R 2 and R 3 is substituted or unsubstituted phenyl.

34. A compound according to claim 1 , wherein at least one of R 2 and R 3 is selected from the group consisting of 2-fluorophenyl, 4-fluorostyryl, 2-methoxyphenyl, pyrrolidin-1-yl, imidazolyl, and 3-furanyl, each substituted or unsubstituted.

35. A compound according to claim 1 , wherein at least one of R 2 and R 3 is substituted or unsubstituted heteroaryl.

36. A compound according to claim 1 , wherein at least one of R 2 and R 3 is selected from the group consisting of hydrogen, cyano, —CF 3 , and hydroxy.

37. A compound according to claim 1 , wherein R 2 is selected from the group consisting of hydrogen and hydroxy.

38. A compound according to claim 1 , wherein R 3 is selected from the group consisting of I, Br, Cl, and F.

39. A compound according to claim 1 , wherein at least one of R 2 and R 3 is —OR 13 where R 13 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted.

40. A compound according to claim 1 , wherein R 3 is selected from the group consisting of —SH, —SCH 3 , and —S(C 1-3 )alkyl, each substituted or unsubstituted.

41. A compound according to claim 1 , wherein at least one of R 2 and R 3 is —NR 14 R 15 where R 14 is selected from the group consisting of (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 6-12 )aryl, hetero(C 5-12 )aryl, (C 9-12 )bicycloaryl and hetero(C 8-12 )bicycloaryl, each substituted or unsubstituted, and R 15 is selected from the group consisting of hydrogen and a substituted or unsubstituted (C 1-8 )alkyl, and where R 14 and R 15 together are —(CH 2 ) 4-5 — optionally interrupted by one O, S, NH, or —N(C 1-3 )alkyl group, unsubstituted or substituted.

42. A compound according to claim 1 , wherein at least one of R 2 and R 3 is selected from the group consisting of a (C 1-3 )alkyl; an amino carbonyl (C 1-3 )alkyl, a (C 1-10 )alkyl carbonyl (C 1-3 )alkyl, or an alkoxy carbonyl (C 1-3 )alkyl; an amino thiocarbonyl (C 1-3 )alkyl, a (C 1-10 )alkyl thiocarbonyl (C 1-3 )alkyl, or an alkoxy thiocarbonyl (C 1-3 )alkyl; an amino sulfonyl (C 1-3 )alkyl, a (C 1-10 )alkyl sulfonyl (C 1-3 )alkyl, or an alkoxy sulfonyl (C 1-3 )alkyl; an amino sulfinyl (C 1-3 )alkyl, a (C 1-10 )alkyl sulfinyl (C 1-3 )alkyl, or an alkoxy sulfinyl (C 1-3 )alkyl; an amino imino (C 1-3 )alkyl, a (C 1-10 )alkyl imino (C 1-3 )alkyl, or an alkoxy imino (C 1-3 )alkyl; an aryl (C 1-5 )alkyl; and a heteroaryl (C 1-5 )alkyl, each unsubstituted or substituted.

43. A compound according to claim 1 , wherein at least one of R 2 and R 3 is selected from the group consisting of 1,2-dihydro-2-oxo-pyridinyl-, 1,4-dihydro-4-oxo-pyridinyl-, 2,3-dihydro-3-oxo-pyridazinyl-, 1,2,3,6-tetrahydro-3,6-dioxo-pyridazinyl-, 1,2-dihydro-2-oxo-pyrimidinyl-, 3,4-dihydro-4-oxo-pyrimidinyl-, 1,2,3,4-tetrahydro-2,4-dioxo-pyrimidinyl-, 1,2-dihydro-2-oxo-pyrazinyl, 1,2,3,4-tetrahydro-2,3-dioxo-pyrazinyl-, 2,3-dihydro-2-oxo-indolyl-, 2,3-dihydrobenzofuranyl-, 2,3-dihydro-2-oxo-1H-benzimidazolyl-, 2,3-dihydro-2-oxo-benzoxazolyl-, 1,2-dihydro-2-oxo-quinolinyl-, 1,4-dihydro-4-oxo-quinolinyl-, 1,2-dihydro-1-oxo-iso-quinolinyl-, 1,4-dihydro-4-oxo-cinnolinyl-, 1,2-dihydro-2-oxo-quinazolinyl-, 1,4-dihydro-4-oxo-quinazolinyl-, 1,2,3,4-tetrahydro-2,4-dioxo-quinazolinyl-, 1,2-dihydro-2-oxo-quinoxalinyl-, 1,2,3,4-tetrahydro-2,3-dioxo-quinoxalinyl-, 1,2-dihydro-1-oxo-phthalazinyl-, 1,2,3,4-tetrahydro-1,4-dioxo-phthalazinyl-, chromanyl-, cumarinyl-, 2,3-dihydro-benzo[1,4]dioxinyl-, and 3,4-dihydro-3-oxo-2H-benzo[1,4]oxazinyl-, each unsubstituted or substituted.

44. A compound according to claim 1 , wherein at least one of R 2 and R 3 is not hydrogen.

45. A compound according to claim 1 , wherein R 2 and R 3 are not hydrogen.

46. A compound according to claim 1 , wherein R 2 is selected from the group consisting of 2-fluorophenyl, styryl, 4-fluorostyryl, 2-methoxyphenyl, pyrrolidin-1-yl, imidazolyl, and 3-furanyl each unsubstituted or substituted, and R 3 is selected from the group consisting of hydrogen, (C 1-10 )alkyl, and aryl, each unsubstituted or substituted.

47. A compound according to claim 1 , wherein R 2 is selected from the group consisting of hydrogen, carboxyl, cyano, —CH 3 and hydroxy, and R 3 is selected from the group consisting of hydrogen, (C 1-10 )alkyl, and aryl, each unsubstituted or substituted.

48. A compound according to claim 1 , wherein R 2 is selected from the group consisting of hydrogen, carboxyl, cyano, —CH 3 and hydroxy, and R 3 is selected from the group consisting of hydrogen, (C 3-7 )cycloalkyl and aryl, each unsubstituted or substituted.

49. A compound selected from the group consisting of:

2-[4-(3-Amino-piperidin-1-yl)-6-oxo-1,6-dihydro-pyrimidin-5-ylmethyl]benzonitrile;

2-[4-(3-Amino-piperidin-1-yl)-1-methyl-6-oxo-1,6-dihydro-pyrimidin-5-ylmethyl]-benzonitrile;

2-[4-(3-Amino-piperidin-1-yl)-1-methyl-6-oxo-2-phenyl-1,6-dihydro-pyrimidin-5-yloxy]-benzonitrile;

2-{[4-(3-Amino-piperidin-1-yl)-1-methyl-6-oxo-2-phenyl-1,6-dihydro-pyrimidin-5-ylmethyl]-amino}-benzonitrile;

2-[4-(3-Amino-piperidin-1-yl)-6-oxo-2-phenyl-1,6-dihydro-pyrimidin-5-ylmethyl]-benzonitrile;

2-[4-(3-Amino-piperidin-1-yl)-1-methyl-6-oxo-2-phenyl-1,6-dihydro-pyrimidin-5-ylmethyl]-benzonitrile;

2-[4-(3-Amino-piperidin-1-yl)-1-methyl-6-oxo-2-phenyl-1,6-dihydro-pyrimidin-5-yloxymethyl]-benzonitrile; and

2-{[4-(3-Amino-piperidin-1-yl)-1-methyl-6-oxo-1,6-dihydro-pyrimidin-5-ylmethyl]-amino}-benzonitrile.

50. A compound according to claim 1 , wherein the compound is in the form of a pharmaceutically acceptable salt.

51. A compound comprising Formula II:

wherein

n is 0, 1, 2, or 3;

Q is CO;

Z is a substituted or unsubstituted 3-amino-piperidin-1-yl;

R 2 is selected from the group consisting of hydrogen, (C 1-10 )alkyl, (C 3-12 )cycloalkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl , hetero(C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl(C 1-5 )alkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl, (C 9-12 )bicycloaryl(C 1-5 )alkyl, hetero(C 4-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl(C 1-5 )alkyl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, and heteroaryloxy, each substituted or unsubstituted;

R 5 and R 6 are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted (C 1-10 )alkyl, a substituted or unsubstituted (C 1-10 )alkoxy, cyano, and halo, or where R 5 and R 6 are taken together to form a ring; and

52. A compound according to claim 51 , wherein R 5 and R 6 are taken together to form a ring.

53. A compound according to claim 51 , wherein at least one of R 5 and R 6 is a substituted or unsubstituted —(C 1-8 )alkyleneR 17 , wherein R 17 is selected from the group consisting of (C 3-12 )cycloalkyl, hetero(C 4-12 )cycloalkyl, (C 6-12 )aryl, hetero(C 5-12 )aryl, (C 9-12 )bicycloalkyl, hetero(C 9-12 )bicycloalkyl, (C 9-12 )bicycloaryl and hetero(C 8-12 )bicycloaryl, each substituted or unsubstituted.

54. A compound according to claim 51 , wherein at least one of R 5 and R 6 is optionally substituted by one to three radicals selected from the group consisting of (C 1-6 )alkyl, cyano, halo, nitro, halo-substituted(C 1-6 )alkyl, —NR 18 R 18 , —NR 18 C(O)OR 18 , —NR 18 C(O)NR 18 R 18 , —NR 18 C(NR 18 )NR 18 R 18 , —OR 18 , —SR 18 , —C(O)OR 18 , —C(O)NR 18 R 18 , —S(O) 2 NR 18 R 18 , —P(O)OR 18 )OR 18 , —OP(O)(OR 18 )OR 18 , —NR 18 C(O)R 18 , —S(O)R 18 , —S(O) 2 R 18 , —(C 1-8 )alkyleneC(O)R 8 , —(C 1-8 )alkyleneNR 18 R 18 , —(C 1-8 )alkyleneNR 18 C(O)OR 18 , —(C 1-8 )alkyleneNR 18 C(O)NR 18 R 18 , —(C 1-8 )alkyleneNR 18 C(NR 18 )NR 18 R 18 , —(C 1-8 )alkyleneOR 18 , —(C 1-8 )alkyleneSR 18 , —(C 1-8 )alkyleneC(O)OR 18 , —(C 1-8 )alkyleneC(O)NR 18 R 18 , —(C 1-8 )alkyleneS(O) 2 NR 18 R 18 , —(C 1-8 )alkyleneP(O)(OR 18 )OR 18 , —(C 1-8 )alkyleneOP(O)(OR 18 )OR 18 , —(C 1-8 )alkyleneNR 18 C(O)R 18 , —(C 1-8 )alkyleneS(O)R 18 , —(C 1-8 )alkyleneS(O) 2 R 18 and —(C 1-8 )alkyleneC(O)R 18 where each R 18 substituent is independently selected from the group consisting of hydrogen and a substituted or unsubstituted (C 1-8 )alkyl.

55. A compound according to claim 51 , wherein at least one of R 5 and R 6 is optionally substituted by one to three radicals selected from the group consisting of —NH 2 , —NHC(NH)NH 2 , —OH, —SH, —C(O)OH and —C(O)NH 2 .

56. A compound according to claim 51 , wherein R 5 and R 6 are hydrogen.

57. A compound according to claim 56 , wherein n is 1 or 2.

58. A compound comprising Formula III:

wherein

m is 0, 1, 2, 3, 4, or 5;

n is 0, 1, 2, or 3;

Q is CO;

Z is a substituted or unsubstituted 3-amino-piperidin-1-yl;

59. A compound according to claim 58 , wherein R 5 and R 6 are taken together to form a ring.

60. A compound according to claim 58 , wherein at least one of R 5 and R 6 is a substituted or unsubstituted —(C 1-8 )alkyleneR 17 , wherein R 17 is selected from the group consisting of (C 3-12 )cycloalkyl, hetero(C 4-12 )cycloalkyl, (C 6-12 )aryl, hetero(C 5-12 )aryl, (C 9-12 )bicycloalkyl, hetero(C 9-12 )bicycloalkyl, (C 9-12 )bicycloaryl and hetero(C 8-12 )bicycloaryl, each substituted or unsubstituted.

61. A compound according to claim 28 , wherein at least one of R 5 and R 6 is optionally substituted by one to three radicals selected from the group consisting of (C 1-6 )alkyl, cyano, halo, nitro, halo-substituted(C 1-6 )alkyl, —NR 18 R 18 , —NR 18 C(O)OR 18 , —NR 18 C(O)NR 18 R 18 , —NR 18 C(NR 18 )NR 18 R 18 , —OR 18 , —SR 18 , —C(O)OR 18 , —C(O)NR 18 R 18 , —S(O) 2 NR 18 R 18 , —P(O)(OR 18 )OR 18 , —OP(O)(OR 18 )OR 18 , —NR 18 C(O)R 18 , —S(O)R 18 , —S(O) 2 R 18 , —(C 1-8 )alkyleneC(O)R 18 , —(C 1-8 )alkyleneNR 18 R 18 , —(C 1-8 )alkyleneNR 18 C(O)OR 18 , —(C 1-8 )alkyleneNR 18 C(O)NR 18 R 18 , —(C 1-8 )alkyleneNR 18 C(NR 18 )NR 18 R 18 , —(C 1-8 )alkyleneOR 18 , —(C 1-8 )alkyleneSR 18 , —(C 1-8 )alkyleneC(O)OR 18 , —(C 1-8 )alkyleneC(O)NR 18 R 18 , —(C 1-8 )alkyleneS(O) 2 NR 18 R 18 , —(C 1-8 )alkyleneP(O)(OR 18 )OR 18 , —(C 1-8 )alkyleneOP(O)(OR 18 )OR 18 , —(C 1-8 )alkyleneNR 18 C(O)R 18 , —(C 1-8 )alkyleneS(O)R 18 , —(C 1-8 )alkyleneS(O) 2 R 18 and —(C 1-8 )alkyleneC(O)R 18 where each R 18 substituent is independently selected from the group consisting of hydrogen and a substituted or unsubstituted (C 1-8 )alkyl.

62. A compound according to claim 58 , wherein at least one of R 5 and R 6 is optionally substituted by one to three radicals selected from the group consisting of —NH 2 , —NHC(NH)NH 2 , —OH, —SH, —C(O)OH and —C(O)NH 2 .

63. A compound according to claim 58 , wherein R 5 and R 6 are hydrogen.

64. A compound according to claim 63 , wherein n is 1 or 2.

65. A compound according to claim 58 , wherein R 5 and R 6 are hydrogen and each R 7 is independently selected from the group consisting of halo, perhalo(C 1-10 )alkyl, CF 3 , (C 1-10 )alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, and alkoxy, each substituted or unsubstituted.

66. A compound according to claim 58 , wherein R 5 and R 6 are hydrogen and two R 7 are taken together to form a substituted or unsubstituted fused or bridged ring.

67. A compound according to claim 58 , wherein R 5 and R 6 are hydrogen, n is 1, and R 7 is 2-cyano.

68. A compound according to claim 58 , wherein:

n is 1, 2, or 3;

R 5 and R 6 are hydrogen; and

each R 7 is independently selected from the group consisting of halo, perhalo(C 1-10 )alkyl, CF 3 , heteroaryl, aryloxy, heteroaryloxy, cyano, nitro, hydroxy, and alkoxy, each substituted or unsubstituted.

69. A compound according to claim 58 , wherein R 5 and R 6 are hydrogen and R 7 is 2-cyano.

70. A compound according to claim 58 , wherein two R 7 are taken together to form a substituted or unsubstituted fused ring.

71. A compound according to claim 58 , wherein two R 7 are taken together to form a substituted or unsubstituted bridged ring.

72. A compound comprising one of Formulae IVa, IVb, and IVc:

wherein

n is 0, 1, 2, or 3;

Q is CO;

each of T, U, V, W and Y is independently nitrogen or CR 16 , provided that no more than two of T, U, V, W and Y are nitrogen;

Z is a substituted or unsubstituted 3-amino-piperidin-1-yl;

each R 16 is independently selected from the group consisting of halo, perhalo(C 1-10 )alkyl, CF 3 , (C 1-10 )alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, and alkoxy, each substituted or unsubstituted.

73. A compound according to claim 72 , wherein R 5 and R 6 are taken together to form a ring.

74. A compound according to claim 72 , wherein at least one of R 5 and R 6 is a substituted or unsubstituted —(C 1-8 )alkyleneR 17 , wherein R 17 is selected from the group consisting of (C 3-12 )cycloalkyl, hetero(C 4-12 )cycloalkyl, (C 6-12 )aryl, hetero(C 5-12 )aryl, (C 9-12 )bicycloalkyl, hetero(C 9-12 )bicycloalkyl, (C 9-12 )bicycloaryl and hetero(C 8-12 )bicycloaryl, each substituted or unsubstituted.

75. A compound according to claim 72 , wherein at least one of R 5 and R 6 is optionally substituted by one to three radicals selected from the group consisting of (C 1-6 )alkyl, cyano, halo, nitro, halo-substituted(C 1-6 )alkyl, —NR 18 R 18 , —NR 18 C(O)OR 18 , —NR 18 C(O)NR 18 R 18 , —NR 18 C(NR 18 )NR 18 R 18 , —OR 18 , —SR 18 , —C(O)OR 18 , —C(O)NR 18 R 18 , —S(O) 2 NR 18 R 18 , —P(O)(OR 18 )OR 18 , —OP(O)(OR 18 )OR 18 , —NR 18 C(O)R 18 , —S(O)R 18 , —S(O) 2 R 18 , —(C 1-8 )alkyleneC(O)R 18 , —(C 1-8 )alkyleneNR 18 R 18 , —(C 1-8 )alkyleneNR 18 C(O)OR 18 , —(C 1-8 )alkyleneNR 18 C(O)NR 18 R 18 , —(C 1-8 )alkyleneNR 18 C(NR 18 )NR 18 R 18 , —(C 1-8 )alkyleneOR 18 , —(C 1-8 )alkyleneSR 18 , —(C 1-8 )alkyleneC(O)OR 18 , —(C 1-8 )alkyleneC(O)NR 18 R 18 , —(C 1-8 )alkyleneS(O) 2 NR 18 R 18 , —(C 1-8 )alkyleneP(O)(OR 18 )OR 18 , —(C 1-8 )alkyleneOP(O)(OR 18 )OR 18 , —(C 1-8 )alkyleneNR 18 C(O)R 18 , —(C 1-8 )alkyleneS(O)R 18 , —(C 1-8 )alkyleneS(O) 2 R 18 and —(C 1-8 )alkyleneC(O)R 18 where each R 18 substituent is independently selected from the group consisting of hydrogen and a substituted or unsubstituted (C 1-8 )alkyl.

76. A compound according to claim 72 , wherein at least one of R 5 and R 6 is optionally substituted by one to three radicals selected from the group consisting of —NH 2 , —NHC(NH)NH 2 , —OH, —SH, —C(O)OH and —C(O)NH 2 .

77. A compound according to claim 72 , wherein R 5 and R 6 are hydrogen.

78. A compound according to claim 77 , wherein n is 1 or 2.

79. A compound according to claim 1 , wherein the compound is present in a mixture of stereoisomers.

80. A compound according to claim 1 , wherein the compound comprises a single stereoisomer.

81. A pharmaceutical composition comprising, as an active ingredient, a compound according to claim 1 .

82. A pharmaceutical composition according to claim 81 , wherein the composition is a solid formulation adapted for oral administration.

83. A pharmaceutical composition according to claim 81 , wherein the composition is a tablet.

84. A pharmaceutical composition according to claim 81 , wherein the composition is a liquid formulation adapted for oral administration.

85. A pharmaceutical composition according to claim 81 , wherein the composition is a liquid formulation adapted for parenteral administration.

86. A pharmaceutical composition comprising a compound according to claim 1 , wherein the composition is adapted for administration by a route selected from the group consisting of orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery, subcutaneously, intraadiposally, intraarticularly, and intrathecally.

87. A kit comprising:

a compound according to claim 1 ; and

instructions which comprise one or more forms of information selected from the group consisting of indicating a disease state for which the compound is to be administered, storage information for the compound, dosing information and instructions regarding how to administer the compound.

88. A kit according to claim 83 , wherein the kit comprises the compound in a multiple dose form.

89. An article of manufacture comprising:

a compound according to claim 1 ; and

packaging materials.

90. An article of manufacture according to claim 89 , wherein the packaging material comprises a container for housing the compound.

91. An article of manufacture according to claim 90 , wherein the container comprises a label indicating one or more members of the group consisting of a disease state for which the compound is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition.

92. An article of manufacture according to claim 89 , wherein the article of manufacture comprises the compound in a multiple dose form.

93. A method of treating type II diabetes in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound according to claim 1 .

94. A method of treating type I diabetes in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound according to claim 1 .

95. A method of treating colorectal, prostate, breast, thyroid, skin, and lung cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound according to claim 1 .

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 12, 2006

From: TAKEDA SAN DIEGO, INC.

To: TAKEDA PHARMACEUTICAL COMPANY LIMITED

Reel/Frame 017182/0214 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 3, 2004

From: CAO, SHELDON X.; FENG, JUN; GWALTNEY, STEPHEN L.; KALDOR, STEPHEN W.; STAFFORD, JEFFREY A.; WALLACE, MICHAEL B.; XIAO, XIAO-YI; ZHANG, ZHIYUAN

To: SYRRX, INC.

Reel/Frame 016046/0346 →

Continuity (2)

Provisional Application 6050145800 · Sep 8, 2003

Related Publication 20050065145A1 · Mar 24, 2005