Dipeptidyl peptidase inhibitors
Compounds, pharmaceutical compositions, kits and methods are provided for use with DPP-IV and other S9 proteases that comprise a compound of the formula: wherein the substituents are as defined herein.
1. A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
V is CR 5 ;
W is CR 4 ;
X is NR 1 ;
Y is selected from the group consisting of CO and CR 7 ;
Z is NR 6 ;
R 1 is selected from the group consisting of hydrogen, a substituted or unsubstituted (C 1-10 )alkyl, and a substituted or unsubstituted aryl(C 1-10 )alkyl;
R 2 is a substituted or unsubstituted amino (C 1-6 )alkyl;
R 3 is selected from the group consisting of aryl and heteroaryl, each substituted or unsubstituted;
R 4 is selected from the group consisting of hydrogen, halo, cyano, and a substituted carbonyl group;
R 5 is hydrogen;
R 6 is selected from the group consisting of hydrogen and a substituted or unsubstituted (C 1-10 )alkyl; and
R 7 is selected from the group consisting of hydrogen, a substituted or unsubstituted (C 1-10 )alkyl and a substituted or unsubstituted aryl,
with the provisos that (a) at least one of X and Z forms part of a double bond; (b) R 1 is absent when X is NR 1 and forms part of a double bond; and (c) R 6 is absent when Z is NR 6 and forms part of a double bond.
2. The compound according to claim 1 , wherein X is NR 1 and Y is CO.
3. The compound according to claim 1 , wherein Y and Z form a double bond to each other.
4. The compound according to claim 1 , wherein X and Z each form a double bond with the carbon to which it is attached.
5. The compound according to claim 1 , wherein X and Y form a double bond to each other.
6. The compound according to claim 1 , of the formula:
wherein:
R 8 and R 9 are each independently selected from the group consisting of;
hydrogen,
thiol,
a substituted or unsubstituted perhalo(C 1-10 )alkyl, amino,(C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-l2 )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, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, and
a substituted imino group,
or R 8 and R 9 are taken together to form a ring; and
R 10 and R 10 ′ are each independently selected from the group consisting of:
hydrogen,
halogen,
cyano,
nitro,
a substituted or unsubstituted perhalo(C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, arylalkyl, heteroarylalkyl, 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, alkene, alkyne, aryl, heteroaryl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, or heteroarylsulfonyl, and
a substituted carbonyl group, imine group, sulfonyl group or sulfinyl group,
or where R 10 and R 10 ′ are taken together to form a substituted or unsubstituted ring.
7. The compound according to claim 1 , wherein R 3 is a substituted or unsubstituted aryl.
8. The compound according to claim 1 , wherein R 3 is a substituted or unsubstituted phenyl.
9. The compound according to claim 1 , wherein R 3 is a substituted or unsubstituted heteroaryl.
10. The compound according to claim 1 , wherein R 3 has a non-hydrogen substituent at a 2 or 3 position of the aryl or heteroaryl.
11. The compound according to claim 1 , wherein R 3 has a non-hydrogen substituent at a 2 or 3 position of the aryl or heteroaryl selected from the group consisting of:
cyano,
nitro,
halo,
a substituted or unsubstituted (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, or heteroaryloxy, and
a substituted carbonyl group, imino group, sulfonyl group or sulfinyl group.
12. The compound according to claim 1 , wherein R 3 is a substituted or unsubstituted halophenyl or dihalophenyl.
13. The compound according to claim 1 , wherein R 3 is a substituted or unsubstituted haloaryl, haloheteroaryl, dihaloaryl or dihaloheteroaryl.
14. The compound according to claim 1 , wherein R 3 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; (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.
15. The compound according to claim 1 , wherein R 3 is selected from the group consisting of
wherein
A is S, O or NR 12 ;
B is CR 13 or N;
R 12 is independently selected from the group consisting of:
hydrogen,
a substituted or unsubstituted 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 or heteroarylsulfonyl, and
a substituted imino group. carbonyl group or sulfinyl group; and
R 13 is independently selected from the group consisting of:
hydrogen,
halo,
thiol,
cyano,
CF 3 ,
nitro
a substituted or unsubstituted 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, or heteroarylsulfonyl, and
a substituted imino group, carbonyl group or sulfinyl group.
16. The compound according to claim 1 , wherein R 3 is selected from the group consisting of
wherein
t is 0,1,2,3,4 or 5; and each R 14 is independently selected from the group consisting of:
halo,
CF 3 ,
thiol,
cyano,
nitro,
a substituted or unsubstituted perhalo(C 1-10 )alkyl,(C 1-10 )alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, hydroxy, or alkoxy, and
a substituted carbonyl group, imino group, sulfonyl group or sulfinyl group.
17. The compound according to claim 1 , wherein R 3 is selected from the group consisting of
wherein
s is 0, 1, 2, or 3; and
each R 15 is independently selected from the group consisting of:
halo,
CF 3 ,
thiol,
cyano,
nitro,
a substituted or unsubstituted perhalo(C 1-10 )alkyl,(C 1-10 )alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, hydroxy, or alkoxy, and
a substituted carbonyl group, imino group, sulfonyl group and or sulfinyl group.
18. The compound according to claim 1 , wherein R 3 is an aryl substituted with one or more substituents selected from the group consisting of halo; hydroxy (C 1-6 )alkyl; amino (C 1-6 )alkyl; and (C 1-6 )alkoxy.
19. The compound according to claim 1 , of the formula:
wherein:
a is 0, 1, 2, 3, 4, or 5;
R 8 and R 9 are each independently selected from the group consisting of:
hydrogen,
thiol,
a substituted or unsubstituted 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 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, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, and
a substituted imino group,
or R 8 and R 9 are taken together to form a ring;
R 10 and R 10 ′ are each independently selected from the group consisting of:
hydrogen,
halogen,
cyano,
nitro,
a substituted or unsubstituted perhalo(C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, arylalkyl, heteroarylalkyl, 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, alkene, alkyne, aryl, heteroaryl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, or heteroarylsulfonyl, and
a substituted carbonyl group, imine group, sulfonyl group or sulfinyl group,
or where R 10 and R 10 ′ are taken together to form a substituted or unsubstituted ring; and
R 11 is selected from the group consisting of:
hydrogen,
halo,
nitro,
cyano,
thiol,
a substituted or unsubstituted perhalo(C 1-10 )alkyl, amino, sulfonamide, (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, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, and
a substituted carbonyl group, imino group, sulfonyl group or sulfinyl group.
20. The compound according to claim 19 , wherein R 8 and R 9 are taken together to form a ring.
21. The compound according to claim 20 , wherein the ring formed by taking R 8 and R 9 together is a substituted or unsubstituted 3, 4, 5 or 6 membered ring.
22. The compound according to claim 20 , wherein the ring formed by taking R 8 and R 9 together is a substituted or unsubstituted heterocycloalkyl, heterobicycloalkyl, heteroaryl, or hetero (C 8-12 )bicycloaryl.
23. The compound according to claim 1 , of the formula:
wherein:
a is 0, 1, 2, 3, 4, or 5; and
R 11 is selected from the group consisting of:
hydrogen,
halo,
nitro,
cyano,
thiol,
a substituted or unsubstituted perhalo(C 1-10 )alkyl, amino, sulfonamide, (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, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, and
a substituted carbonyl group, imino group, sulfonyl group or sulfinyl group.
24. The compound according to claim 1 , of the formula:
wherein:
X 2 is NR 1a ; and
R 1a is selected from the group consisting of hydrogen a substituted or unsubstituted (C 1-10 )alkyl and a substituted or unsubstituted aryl(C 1-10 )alkyl.
25. The compound according to claim 1 , of the formula:
wherein:
a is 0, 1, 2, 3, 4, or 5;
R 8 and R 9 are each independently selected from the group consisting of:
hydrogen,
thiol,
a substituted or unsubstituted 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 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, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, and
a substituted imino group, or R 8 and R 9 are taken together to form a ring;
R 10 and R 10 ′ are each independently selected from the group consisting of:
hydrogen,
halogen,
cyano,
nitro,
a substituted or unsubstituted perhalo(C 1-10 )alkyl, alkyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, arylalkyl, heteroarylalkyl, 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, alkene, alkyne, aryl, heteroaryl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, or heteroarylsulfonyl, and
a substituted carbonyl group, imine group, sulfonyl group or sulfinyl group, or where R 10 and R 10 ′ are taken together to form a substituted or unsubstituted ring; and
R 11 is selected from the group consisting of:
hydrogen,
halo,
nitro,
cyano,
thiol,
a substituted or unsubstituted perhalo(C 1-10 )alkyl, amino, sulfonamide,(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, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, and
a substituted carbonyl group, imino group, sulfonyl group or sulfinyl group.
26. The compound according to claim 25 , wherein R 8 and R 9 are taken together to form a ring.
27. The compound according to claim 26 , wherein the ring formed by taking R 8 and R 9 together is a substituted or unsubstituted 3, 4, 5 or 6 membered ring.
28. The compound according to claim 26 , wherein the ring formed by taking R 8 and R 9 together is a substituted or unsubstituted heterocycloalkyl, heterobicycloalkyl, heteroaryl, or hetero (C 8-12 )bicycloaryl.
29. The compound according to claim 1 , of the formula:
wherein:
a is 0, 1, 2, 3, 4, or 5; and
R 11 is selected from the group consisting of:
hydrogen,
halo,
nitro,
cyano,
thiol,
a substituted or unsubstituted perhalo(C 1-10 )alkyl, amino, sulfonamide, (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, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, and
a substituted carbonyl group, imino group, sulfonyl group or sulfinyl group.
30. The compound according to claim 1 , wherein R 4 is C(O)R 16 and R 16 is selected from the group consisting of:
hydrogen,
halo,
nitro,
cyano,
thiol,
a substituted or unsubstituted perhalo(C 1-10 )alkyl, amino, sulfonamide, (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, (C 1-10 )alkylamino, amino (C 1-10 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, and
a substituted carbonyl group, imino group, sulfonyl group or sulfinyl group.
31. A compound selected from the group consisting of:
C-(5-Phenyl-3H-benzoimidazol-4-yl)-methylamine;
C-(3-Methyl-5-phenyl-3H-benzoimidazol-4-yl)-methylamine;
C-(1-Methyl-5-phenyl-1 H-benzoimidazol-4-yl)-methylamine;
C-[5-(2,4-Dichloro-phenyl)-1 H-benzoimidazol-4-yl]-methylamine;
[2-(4-Aminomethyl-3-methyl-3H-benzoimidazol-5-yl)-phenyl]-methanol;
C-[5-(2,4-Dichloro-phenyl)-3-methyl-3H-benzoimidazol-4-yl]methylamine;
2-(4-Aminomethyl-3-methyl-3H-benzoimidazol-5-yl)-benzamide;
C-[5-(2-Chloro-phenyl)-3-methyl-3H-benzoimidazol-4-yl]-methylamine;
C-[5-(2-Methoxy-phenyl)-3-methyl-3H-benzoimidazol-4-yl]-methylamine;
C-[5-(2-Chloro-5-fluoro-phenyl)-3-methyl-3H-benzoimidazol-4-yl]-methylamine;
C-[5-(2,4-Dichloro-phenyl)-3-ethyl-3H-benzoimidazol-4-yl]-methylamine;
2-[7-Aminomethyl-6-(2-chloro-phenyl)-benzoimidazol- l-yl]-ethanol;
C-[5-(2-Chloro-phenyl)-2,3-dimethyl-3H-benzoimidazol-4-yl]-methylamine;
C-[5-(2,4-Difluoro-phenyl)-3-methyl-3H-4-benzoimidazol-4-yl]-methylamine;
2-(4-Aminomethyl-3-methyl-3H-benzoimidazol-5-yl)-phenol;
(6-(2-methoxyphenyl)-1 H-benzo [d]imidazol-7-yl)methanamine;
C-(3-Methyl-5-o-tolyl-3H-benzoimidazol-4-yl)-methylamine;
C-[5-(2-Chloro-phenyl)-2-methoxymethyl-3-methyl-3H-benzoimidazol-4-yl]-methylamine;
C-[3-Benzyl-5-(2-chloro-phenyl)-3H-benzoimidazol-4-yl]-methylamine;
7-Aminomethyl-6-(2-chloro-phenyl)-1-methyl-1,3-dihydro-benzoimidazol-2-one;
C-[6-Bromo-5-(2-chloro-phenyl)-3-methyl-3H-benzoimidazol-4yl]-methylamine;
7-Aminomethyl-6-(2-chloro-phenyl)-1-methyl-1H-benzoimidazol-5-carbonitrile;
7-Aminomethyl-6-(2-chloro-phenyl)-1-methyl-1H-benzoimidazol-5-carboxylic acid amide;
C-[5-(2-chloro-phenyl)-2-ethyl-3methyl-3H-benzoimidazol-4-yl]-methylamine;
C-[5-(2-chloro-phenyl)-3methyl-2-pyridin-3-yl-3H-benzoimidazol-4-yl]-methylamine; and
4-Aminomethyl-5-(2-methoxy-phenyl)-1,3-dihydro-benzoimidazol-2-one.
32. The compound according to claim 1 , wherein the compound is in the form of a pharmaceutically acceptable salt.
33. The compound according to claim 1 , wherein the compound is present in a mixture of stereoisomers.
34. The compound according to claim 1 , wherein the compound is present as a single stereoisomer.