CD38 inhibitors
One embodiment of the invention is a compound represented by Formula I: or a pharmaceutically acceptable salt thereof. The variables in Formula I are defined herein. Compounds of Formula I are CD38 inhibitors, which can be used to treat a disease or condition in a subject that benefits from an increase in NAD+ or to treat a mitochondrial disorder in a subject.
1 . A compound represented by the structural formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X 1 and X 2 are independently CH or N, provided that X 1 and X 2 are not both CH;
Cy is C 3-7 cycloalkyl optionally substituted with an oxo group or with one or two R x groups, wherein R x is halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, —NHSO 2 C 1 -C 4 alkyl, or —SO 2 C 1 -C 4 alkyl;
R 1 is —H, —NR a R b , halo, —CN, —C(—O)NH 2 , —COOH, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 hydroxyalkyl, C 2 -C 4 alkenyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxyalkyl, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfone, C 1 -C 4 alkoxyalkylthio, C 1 -C 4 haloalkylthio, C 1 -C 4 haloalkoxy, C 3 -C 4 cycloalkyl, or a 5-membered heteroaryl, wherein the 5-membered heteroaryl is optionally substituted with one, two or three C 1-4 alkyl groups;
R 2 is a 5-membered heteroaryl optionally substituted with one, two or three deuterium or C 1-4 alkyl groups;
R d is C 1-4 haloalkyl, C 1-4 hydroxyalkyl, or C 1-4 alkyl optionally substituted with C 1-4 alkoxy;
R a and R b independently are —H or C 1 -C 4 alkyl; and
n is 1.
2 . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
X 1 and X 2 are independently CH or N, provided that X 1 and X 2 are not both CH;
Cy is C 3-7 cycloalkyl optionally substituted with an oxo group or with one or two R x groups, wherein R x is halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl or SO 2 Me;
R 1 is —H, —NR a R b , halo, —CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxyalkyl, C 1 -C 4 alkylthio, C 1 -C 4 alkoxyalkylthio, C 1 -C 4 haloalkylthio, C 1 -C 4 haloalkoxy or a 5-membered heteroaryl, wherein the 5-membered heteroaryl is optionally substituted with one, two or three C 1-4 alkyl groups;
R 2 is a 5-membered heteroaryl optionally substituted with one, two or three C 1-4 alkyl groups;
R d is C 1-4 alkyl optionally substituted with C 1-4 alkoxy;
R a and R b independently are —H or C 1 -C 4 alkyl; and
n is 1.
3 . The compound of claim 2 , wherein the compound is represented by the structural formula (IIa), (IIb), (IIc), (IIIa), (IIIb), (IIIc), (IVa), (IVb), or (IVc):
or a pharmaceutically acceptable salt thereof.
4 . The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R d is C 1-4 alkyl optionally substituted with C 1-4 alkoxy.
5 . The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R d is —CH 2 CH 2 OCH 3 .
6 . The compound or pharmaceutically acceptable salt thereof of claim 2 , wherein R d is —CH 3 or —CH 2 CH 2 OCH 3 .
7 . The compound or pharmaceutically acceptable salt thereof of claim 6 , wherein R 1 is a 5-membered heteroaryl optionally substituted with one, two or three C 1-4 alkyl groups.
8 . The compound or pharmaceutically acceptable salt thereof of claim 6 , wherein R 1 is selected from the group consisting of
9 . The compound or pharmaceutically acceptable salt thereof of claim 4 , wherein R 1 is —H, —NR a R b , halo, —CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxyalkyl, C 1 -C 4 alkylthio, C 1 -C 4 alkoxyalkylthio or C 1 -C 4 haloalkylthio.
10 . The compound or pharmaceutically acceptable salt thereof of claim 5 , wherein R 1 is —H, —CH 3 , —CF 3 , —OCH 3 , —SCH 3 , —F, —Cl, —Br or —NH 2 .
11 . The compound or pharmaceutically acceptable salt thereof of claim 9 , wherein R 2 is imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole, isoxazole, thiadiazole or oxadiazole, optionally substituted with one, two or three C 1-4 alkyl groups.
12 . The compound or pharmaceutically acceptable salt thereof of claim 10 , wherein R 2 is selected from the group consisting of
13 . The compound or pharmaceutically acceptable salt thereof of claim 1 wherein
R 1 is —C(═O)NH 2 , —COOH, C 1 -C 4 haloalkyl, C 1 -C 4 hydroxyalkyl, C 2 -C 4 alkenyl, —CN, C 1 -C 4 alkylsulfone, or C 3 -C 4 cycloalkyl; and/or
R 2 is a 5-membered heteroaryl substituted with one, two, or three deuterium; and/or
R d is C 1-4 haloalkyl or C 1-4 hydroxyalkyl; and/or
Cy is cyclohexyl substituted with —NHSO 2 (C 1 -C 4 alkyl).
14 . The compound or pharmaceutically acceptable salt thereof of claim 13 , wherein
R 1 is —C(═O)NH 2 , —COOH, —CHF 2 , —CH 2 F, —CH(OH)CH 3 , —C(OH)(CH 3 ) 2 , —CH 2 OH, —CH═CH 2 , —SO 2 Me, or cyclopropyl; and/or
R 2 is imidazole substituted with one, two, or three deuterium; and/or
R d is —CHF 2 or —CH 2 CH 2 OH; and/or
Cy is cyclohexyl substituted with NHSO 2 Et.
15 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
16 . A method of inhibiting an enzymatic activity of CD38 in a cell, comprising administering to the cell an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
17 . The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
18 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and the compound of claim 17 , or a pharmaceutically acceptable salt thereof.