Substituted pyrazolo[3,4-b]pyridines as ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) modulators
Provided herein are small molecule modulators of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), compositions comprising the compounds of Formula (XI), and methods of using the compounds and compositions comprising the compounds
1 . A compound of Formula (XI):
or a pharmaceutically acceptable salt thereof,
wherein:
R 30 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, phenyl, or monocyclic heteroaryl, wherein the C 1 -C 6 alkyl, phenyl, or monocyclic heteroaryl is optionally substituted with one, two, or three independently selected R 37 substituents;
each R 37 is independently halogen, CN, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, NR 1A R 1A , OR 1B , or SR 1B ;
R 31 is H, halogen, C 1 -C 6 alkyl, C 1 -C 4 fluoroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or phenyl, wherein the phenyl is optionally substituted with one, two, or three independently selected R 38 substituents;
each R 38 is independently halogen, CN, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, NR 1A R 1A , OR 1B , or SR 1B ;
R 32 is H, halogen, CN, C 1 -C 6 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 6 alkyl-OH, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, NR 1A R 1A , OR 1B , OC 1 -C 4 fluoroalkyl, SR 1B , monocyclic C 2 -C 6 heterocycloalkyl, phenyl, or monocyclic 5- or 6-membered heteroaryl, wherein the C 1 -C 6 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, or monocyclic 5- or 6-membered heteroaryl is optionally substituted with one, two, or three independently selected R 39 substituents;
each R 39 is independently halogen, CN, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, NR 1A R 1A , OR 1B , or SR 1B ;
Y a is CH;
R 34 is S(O) 2 NR 1A R 1A ;
w is 0, 1, 2, or 3;
each R 35 is independently halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 4 alkynyl, OR 1B , or cycloalkyl;
each R 1A is independently H, C 1 -C 6 alkyl, CH 2 -phenyl, cycloalkyl, or aryl; and
each R 1B is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 32 is H, halogen, CN, C 1 -C 6 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 6 alkyl-OH, NR 1A R 1A , or OR 1B .
3 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 32 is CH 3 , CH 2 CH 3 , NH 2 , NHCH 3 , NHCH 2 CH 3 , N(CH 3 ) 2 , or OCH 3 .
4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 34 is S(O) 2 NH 2 , S(O) 2 NHC 1 -C 3 alkyl, or S(O) 2 N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl).
5 . The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 34 is S(O) 2 NH 2 .
6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein w is 0.
7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 35 is independently halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or OR 1B .
8 . The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein each R 35 is independently F, Cl, Br, CH 3 , or CF 3 .
9 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
10 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
11 . A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
12 . The pharmaceutical composition of claim 11 , wherein the pharmaceutical composition is formulated for administration to a mammal by dermal administration, inhalation, intravenous administration, ophthalmic administration, nasal administration, oral administration, or subcutaneous administration.
13 . The pharmaceutical composition of claim 11 , wherein the pharmaceutical composition is formulated as a capsule, a dispersion, an emulsion, a gel, a liquid, a lotion, an ointment, a pill, a solution, a suspension, or a tablet.
14 . A method for treating arthritis in a mammal, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
15 . The method of claim 14 , wherein the arthritis is false gout or pseudogout.
16 . A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.