Inhibitors of HPK1 and methods of use thereof
Disclosed herein are compounds that are Hematopoietic Progenitor Kinase 1 (HPK1) inhibitors having a structure according to Formula I, and compositions containing those compounds. Methods of preparing the compounds, and methods of using the compounds for the treatment of diseases, disorders, or conditions are also described.
1 . A compound having a structure of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is-NH—C(O)-phenyl, —NH—(C 1 -C 3 -alkylene)-phenyl, —O—(C 1 -C 3 -alkylene)-phenyl, —O-(5- to 10-membered heteroaryl), phenyl, 5- to 10-membered heteroaryl, or 5- to 8-membered heterocycloalkyl; wherein said 5- to 10-membered heteroaryl and 5- to 8-membered heterocycloalkyl have from 1-3 ring heteroatoms independently selected from N, O, and S; and wherein said —NH—C(O)-phenyl, phenyl, —O—(C 1 -C 3 -alkylene)-phenyl, 5- to 10-membered heteroaryl and 5- to 8-membered heterocycloalkyl are substituted with 0-3 R 1a ;
each R 1a , when present, is independently selected from:
a) halo, oxo, —CN, —OH, —C 1 -C 6 -alkyl, —O—C 1 -C 6 -alkyl, —O—C 1 -C 6 -haloalkyl, —O—(C 1 -C 3 -alkylene)-(C 3 -C 6 -cycloalkyl), —S(O) 2 —R 1b , —S(O) 2 NR a R b , —NR a S(O) 2 —(C 1 -C 6 -alkyl), —NR a R b , —C(O)NR a R b , and phenyl;
b) —C 1 -C 6 -alkyl substituted with 1-4 substituents independently selected from —OH, halo, —CN, —O—C 1 -C 3 -alkyl, —C 3 -C 6 -cycloalkyl, —O—(C 3 -C 6 -cycloalkyl), —S(O) 2-(C 1 -C 3 -alkyl), —C(O)NR a R b , phenyl, and -5- to 6-membered heterocycloalkyl; wherein said 5- to 6-membered heterocycloalkyl has 1-3 ring heteroatoms independently selected from N, O, and S; wherein said 5- to 6-membered heterocycloalkyl is substituted with 0-1 oxo; and wherein said C 3 -C 6 -cycloalkyl is substituted with 0-2 substituents independently selected from halo;
c) —C 3 -C 7 -cycloalkyl substituted with 0-3 substituents independently selected from the group consisting of halo, —OH, —C 1 -C 6 -alkoxy, and —C(O)NR a R b ;
d) 4- to 8-membered heterocycloalkyl and —O-(4- to 8-membered heterocycloalkyl); wherein said 4- to 8-membered heterocycloalkyl has 1-3 ring heteroatoms independently selected from N, O, and S; and said 4- to 8-membered heterocycloalkyl is substituted with 0-3 substituents independently selected from the group consisting of oxo, —OH, halo, —C 1 -C 6 alkyl, —C 1 -C 3 -alkoxy, —C(O)(C 1 -C 3 -alkyl), and —S(O) 2 (C 1 -C 3 -alkyl);
e) 5- to 6-membered heteroaryl, —O-(5- to 6-membered heteroaryl), and —C≡C-(5- to 6-membered heteroaryl), wherein said 5- to 6-membered heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S; and wherein said 5- to 6-membered heteroaryl is substituted with 0-2 substituents independently selected from —OH, halo, and —C 1 -C 6 -alkyl; and
f) two adjacent R 1a are taken together with the atoms to which they are attached to form a 5- to 7-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl; wherein said 5- to 7-membered heterocycloalkyl and 5- to 6-membered heteroaryl each have 1-2 ring heteroatoms independently selected from N, O, and S; and wherein said 5- to 7-membered heterocycloalkyl is substituted with 0-3 substituents independently selected from oxo, —C 1 -C 6 -alkyl, —C(O)(C 1 -C 3 -alkyl), and —S(O) 2 (C 1 -C 3 -alkyl);
R 1b is —C 1 -C 6 -alkyl, —C 3 -C 6 -cycloalkyl, or —(C 1 -C 3 -alkylene)-(C 3 -C 6 -cycloalkyl);
each R a and R b , when present, are independently selected from —H; —C 1 -C 6 -alkyl; —C 3 -C 7 -cycloalkyl; —C 1 -C 6 -hydroxyalkyl; —C(O)(C 1 -C 3 -alkyl); —C(O)(C 3 -C 6 -cycloalkyl); phenyl; 5- to 10-membered heterocycloalkyl; and C 1 -C 3 -alkyl substituted with —C 3 -C 6 -cycloalkyl, —O—C 1 -C 3 -alkyl, phenyl, or 5- to 6-membered heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, O, and S; wherein each 5- to 10-membered heterocycloalkyl has 1-3 ring heteroatoms independently selected from N, O, and S; and said 5- to 10-membered heterocycloalkyl is substituted with 0-1 substituents selected from —S(O) 2 (C 1 -C 3 alkyl), and —C(O)(C 1 -C 3 -alkyl); or
R a and R b are taken together with the N atom to which they are attached to form a 5- to 10-membered heterocycloalkyl having 0-2 additional ring heteroatoms independently selected from N, O, and S; and said 5- to 10-membered heterocycloalkyl is substituted with 0-2 substituents independently selected from the group consisting of halo, —OH, —C 1 -C 3 -alkyl, —C 1 -C 3 -alkoxy, and —C 1 -C 3 -alkylene-O—(C 1 -C 3 -alkyl);
A 1 is N, or CR A1 ;
A 2 is N, or CR A2 ;
A 3 is N, or CR A3 ;
A 4 is N, or CH;
R 2 is —X 1 —NR 2a R 2b , or —X 1 -(5- to 10-membered heterocycloalkyl) having 1-4 ring heteroatom or heteroatom groups independently selected from N, O, S(O), and S(O) 2 ; wherein said 5- to 10-membered heterocycloalkyl is substituted with 0-3 substituents independently selected from the group consisting of halo, —OH, —CN, —NH 2 , —C 1 -C 6 -alkyl, —C 1 -C 6 -haloalkyl, —C 1 -C 6 -hydroxyalkyl, —Y 1 —NR 2c R 2d , —Y 1 —O—(C 1 -C 3 -alkyl), —Y 1 —C(O)NR 2c R 2d , —Y 1 —O—(C 1 -C 3 -hydroxyalkyl), —Y 1 —(C 3 -C 6 -cycloalkyl), —Y 1 -phenyl, —Y 1 -(5- to 6-membered heteroaryl), 5- to 6-membered heterocycloalkyl, and —Y 1 -(5- to 6-membered heterocycloalkyl); wherein said 5- to 6-membered heteroaryl, and 5- to 6-membered heterocycloalkyl each have 1-3 ring heteroatoms independently selected from N, O, and S; said 5- to 6-membered heteroaryl is unsubstituted or substituted with —C 1 -C 3 -alkyl; and said 5- to 6-membered heterocycloalkyl is unsubstituted or substituted with —S(O) 2 (C 1 -C 3 alkyl), or —C(O)(C 1 -C 3 alkyl); wherein:
X 1 is —O—, —(CR o R o ) n —, or —O—C 1 -C 6 -alkylene-;
n is 0, 1 or 2;
each R o is independently —H or —C 1 -C 6 -alkyl; or
two R o attached to the same C atom taken together form —C 3 -C 5 -cycloalkyl;
R 2a and R 2b are independently selected from the group consisting of —H, —C 1 -C 6 -alkyl, —S(O) 2 (C 1 -C 6 -alkyl), —C 1 -C 2 -alkylene-(5- to 6-membered heteroaryl), and 5- to 6-membered heterocycloalkyl; wherein said 5- to 6-membered heteroaryl and 5- to 6-membered heterocycloalkyl have 1-2 ring heteroatoms independently selected from N, O, and S; and wherein said 5- to 6-membered heteroaryl is optionally substituted with one-C 1 -C 3 -alkyl;
Y 1 is —C 1 -C 3 -alkylene; and
R 2c and R 2d are independently —H, —C 1 -C 3 -alkyl, —C(O)(C 1 -C 3 -alkyl), or —S(O) 2 (C 1 -C 3 -alkyl);
R A1 is selected from —H, -halo, —C 1 -C 6 -alkyl, —O—C 1 -C 6 -alkyl, and 5- to 6-membered heterocycloalkyl having 1-2 ring heteroatoms independently selected from N and O;
R A2 is selected from —H, -halo, —C 1 -C 6 -alkyl, —C 1 -C 6 -haloalkyl, —C 1 -C 6 -hydroxyalkyl, —O—C 1 -C 6 -alkyl, —C 3 -C 6 -cycloalkyl, 5- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; wherein said 5- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl have 1-2 ring heteroatoms independently selected from N and O; and wherein said —C 3 -C 6 -cycloalkyl, 5- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each substituted with 0-2 substituents independently selected from halo, —CN, and —OH; and
R A3 is —H, -halo, —C 1 -C 6 -alkyl, —C 1 -C 6 -haloalkyl, —C 3 -C 6 -cycloalkyl, or 5- to 6-membered heterocycloalkyl having 1-2 ring heteroatoms independently selected from N, O, and S; wherein said 5- to 6-membered heterocycloalkyl is optionally substituted with 1-2 substituents independently selected from -halo and —OH; or
R 2 and R A3 taken together with the atoms to which they are attached to form phenyl, —C 5 -C 7 -cycloalkyl, or 5- to 8-membered heterocycloalkyl having 1-3 ring heteroatoms selected from N, O, and S; wherein said phenyl, —C 5 -C 7 -cycloalkyl and 5- to 8-membered heterocycloalkyl are substituted with 0-3 substituents independently selected from —C 1 -C 3 -alkyl, —NH 2 , —C 1 -C 3 -alkylene-NH 2 , and 5- to 8-membered heterocycloalkyl having 1-2 ring heteroatoms independently selected from N and O.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 is —X 1 -(5- to 10-membered heterocycloalkyl) having 1-4 ring heteroatoms independently selected from N, O and S, wherein said 5- to 10-membered heterocycloalkyl is substituted with 0-3 substituents independently selected from the group consisting of halo, —OH, —CN, —NH 2 , —C 1 -C 6 -alkyl, —C 1 -C 6 -haloalkyl, —C 1 -C 6 -hydroxyalkyl, —Y 1 —NR 2c R 2d , —Y 1 —O—(C 1 -C 3 -alkyl), —Y 1 —C(O)NR 2c R 2d , —Y 1 —O—(C 1 -C 3 -hydroxyalkyl), —Y 1 —(C 3 -C 6 -cycloalkyl), —Y 1 -phenyl, —Y 1 -(5- to 6-membered heteroaryl), 5- to 6-membered heterocycloalkyl, and —Y 1 -(5- to 6-membered heterocycloalkyl); wherein said 5- to 6-membered heteroaryl, and 5- to 6-membered heterocycloalkyl each have 1-3 ring heteroatoms independently selected from N, O, and S; said 5- to 6-membered heteroaryl is unsubstituted or substituted with —C 1 -C 3 -alkyl; and said 5- to 6-membered heterocycloalkyl is unsubstituted or substituted with —S(O) 2 (C 1 -C 3 alkyl), or —C(O)(C 1 -C 3 alkyl);
X 1 is —(CR o R o ) n —;
n is 0; and
Y 1 is —C 1 -C 3 -alkylene.
3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of
each of which is substituted with 0-3 substituents independently selected from the group consisting of halo, —OH, —CN, —NH 2 , —C 1 -C 6 -alkyl, —C 1 -C 6 -haloalkyl, —C 1 -C 6 -hydroxyalkyl, —Y 1 —NR 2c R 2d , —Y 1 —O—(C 1 -C 3 -alkyl), —Y 1 —C(O)NR 2c R 2d , —Y 1 —O—(C 1 -C 3 -hydroxyalkyl), —Y 1 —(C 3 -C 6 -cycloalkyl), —Y 1 -phenyl, —Y 1 -(5- to 6-membered heteroaryl), 5- to 6-membered heterocycloalkyl, and —Y 1 -(5- to 6-membered heterocycloalkyl); wherein said 5- to 6-membered heteroaryl, and 5- to 6-membered heterocycloalkyl each have 1-3 ring heteroatoms independently selected from N, O, and S; said 5- to 6-membered heteroaryl is unsubstituted or substituted with —C 1 -C 3 -alkyl; and said 5- to 6-membered heterocycloalkyl is unsubstituted or substituted with —S(O) 2 (C 1 -C 3 alkyl), or —C(O)(C 1 -C 3 alkyl).
4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is
which is substituted with 0-3 substituents independently selected from the group consisting of halo, —OH, —CN, —NH 2 , —C 1 -C 6 -alkyl, —C 1 -C 6 -haloalkyl, —C 1 -C 6 -hydroxyalkyl, —Y 1 —NR 2c R 2d , —Y 1 —O—(C 1 -C 3 -alkyl), —Y 1 —C(O)NR 2c R 2d , —Y 1 —O—(C 1 -C 3 -hydroxyalkyl), —Y 1 —(C 3 -C 6 -cycloalkyl), —Y 1 -phenyl, —Y 1 -(5- to 6-membered heteroaryl), 5- to 6-membered heterocycloalkyl, and —Y 1 -(5- to 6-membered heterocycloalkyl); wherein said 5- to 6-membered heteroaryl, and 5- to 6-membered heterocycloalkyl each have 1-3 ring heteroatoms independently selected from N, O, and S; said 5- to 6-membered heteroaryl is unsubstituted or substituted with —C 1 -C 3 -alkyl; and said 5- to 6-membered heterocycloalkyl is unsubstituted or substituted with —S(O) 2 (C 1 -C 3 alkyl), or —C(O)(C 1 -C 3 alkyl).
5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is substituted with 0-2 substituents independently selected from the group consisting of —F, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —OH, —NH 2 , —CH 2 OH, —CH 2 NH 2 , —(CH 2 ) 2 —OH, —(CH 2 ) 2 —O—CH 3 , —(CH 2 ) 2 —O—CH 2 CH 3 , —(CH 2 ) 2 —O—(CH 2 ) 2 —OH, —(CH 2 ) 2 —O—CH(CH 3 ) 2 , —(CH 2 ) 2 —NH 2 ,
6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 and R A3 taken together with the atoms to which they are attached form phenyl, —C 5 -C 7 -cycloalkyl, or 5- to 8-membered heterocycloalkyl having 1-3 ring heteroatoms selected from N, O, and S; wherein said phenyl, —C 5 -C 7 -cycloalkyl and 5- to 8-membered heterocycloalkyl are substituted with 0-3 substituents independently selected from —C 1 -C 3 -alkyl, —NH 2 , —C 1 -C 3 -alkylene-NH 2 , and 5- to 8-membered heterocycloalkyl having 1-2 ring heteroatoms independently selected from N and O.
7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is pyridyl, pyridinonyl, phenyl, pyrazolyl, imidazolyl, oxazolyl, 1,2,4-triazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, piperidinyl, morpholinyl, pyrrolidinyl, pyrrolidonyl, tetrahydropyranyl, tetrahydrofuranyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyrazinyl, pyrazolo[1,5-a]pyridinyl, —NH—C(O)-phenyl, —NH—CH(CH 3 )-phenyl, —O—CH(CH 3 )-phenyl, or —O-pyridyl, each of which is substituted with 0-3 R 1a .
8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein, when present, at least one R 1a is selected from halo, oxo, —CN, —OH, —C 1 -C 6 -alkyl, —O—C 1 -C 6 -alkyl, —O—C 1 -C 6 -haloalkyl, —O—(C 1 -C 3 -alkylene)-(C 3 -C 6 -cycloalkyl), —S(O) 2 —R 1b , —S(O) 2 NR a R b , —NR a S(O) 2 —(C 1 -C 6 -alkyl), —NR a R b , —C(O)NR a R b , and phenyl.
9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein, when present, at least one R 1a is-C 1 -C 6 -alkyl substituted with 1-4 substituents independently selected from —OH, halo, —CN, —O—C 1 -C 3 -alkyl, —C 3 -C 6 -cycloalkyl, —O—(C 3 -C 6 -cycloalkyl), —S(O) 2 —(C 1 -C 3 -alkyl), —C(O)NR a R b , phenyl, and -5- to 6-membered heterocycloalkyl; wherein said 5- to 6-membered heterocycloalkyl has 1-3 ring heteroatoms independently selected from N, O, and S; wherein said 5- to 6-membered heterocycloalkyl is substituted with 0-1 oxo; and wherein said —C 3 -C 6 -cycloalkyl is substituted with 0-2 substituents independently selected from halo.
10 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein, when present, at least one R 1a is —C 3 -C 7 -cycloalkyl substituted with 0-3 substituents independently selected from the group consisting of halo, —OH, —C 1 -C 6 -alkoxy, and —C(O)NR a R b .
11 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein at least one R 1a is
each of which is unsubstituted or substituted with a substituent selected from —OH and —C(O)NR a R b .
12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein, when present, at least one R 1a is 4- to 8-membered heterocycloalkyl or —O-(4- to 8-membered heterocycloalkyl); wherein said 4- to 8-membered heterocycloalkyl has 1-3 ring heteroatoms independently selected from N, O, and S; and said 4- to 8-membered heterocycloalkyl is substituted with 0-3 substituents independently selected from the group consisting of oxo, —OH, halo, —C 1 -C 6 alkyl, —C 1 -C 3 -alkoxy, —C(O)(C 1 -C 3 -alkyl), and —S(O) 2 (C 1 -C 3 -alkyl).
13 . The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein at least one R 1a is
each of which is substituted with 0-2 substituents independently selected from oxo, —OH, halo, —C 1 -C 3 alkyl, —C 1 -C 3 -alkoxy, —C(O)CH 3 , and —S(O) 2 CH 3 .
14 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein, when present, at least one R 1a is 5- to 6-membered heteroaryl, —O-(5- to 6-membered heteroaryl), or —C≡C-(5- to 6-membered heteroaryl), wherein said 5- to 6-membered heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S; and wherein said 5- to 6-membered heteroaryl is substituted with 0-2 substituents independently selected from —OH, halo, and —C 1 -C 6 -alkyl.
15 . The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein at least one R 1a is
each of which is substituted with 0-2 substituents independently selected from halo and C 1 -C 3 -alkyl.
16 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein, two adjacent R 1a are taken together with the atoms to which they are attached to form a 5- to 7-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl; wherein said 5- to 7-membered heterocycloalkyl and 5- to 6-membered heteroaryl each have 1-2 ring heteroatoms independently selected from N, O, and S; and wherein said 5- to 7-membered heterocycloalkyl is substituted with 0-3 substituents independently selected from oxo, —C 1 -C 6 -alkyl, —C(O)(C 1 -C 3 -alkyl), and —S(O) 2 (C 1 -C 3 -alkyl).
17 . The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein R 1 is:
each of which is substituted with 0-3 substituents independently selected from oxo, —C 1 -C 6 -alkyl, —C(O)(C 1 -C 3 -alkyl), and —S(O) 2 (C 1 -C 3 -alkyl); or
18 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 is —X 1 -(5- to 6-membered heterocycloalkyl) having 1-3 ring heteroatoms or heteroatom groups selected from N, O, and S(O) 2 , wherein said 5- to 6-membered heterocycloalkyl is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, —OH, —CN, —NH 2 , —C 1 -C 6 -alkyl, —C 1 -C 6 -hydroxyalkyl, —C 1 -C 2 -alkylene-NH 2 , and 5- to 6-membered heterocycloalkyl having 1-2 ring heteroatoms selected from N and O;
X 1 is —(CR o R o ) n —;
each R o is —H; and
n is 1 or 2.
19 . The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of:
each 5- to 6-membered heterocycloalkyl of which is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, —OH, —CN, —NH 2 , —C 1 -C 6 -alkyl, —C 1 -C 6 -hydroxyalkyl, —C 1 -C 2 -alkylene-NH 2 , and 5- to 6-membered heterocycloalkyl having 1-2 ring heteroatoms selected from N and O.
20 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 is —X 1 —NR 2a R 2b ,
X 1 is —(CR o R o ) n —,
n is 0 or 1;
each R o is independently H or —C 1 -C 6 -alkyl; or
two R o attached to the same C atom taken together form —C 3 -C 5 -cycloalkyl; and
R 2a and R 2b are independently selected from the group consisting of —H, C 1 -C 6 -alkyl, —S(O) 2 (C 1 -C 6 -alkyl), —C 1 -C 2 -alkylene-(5- to 6-membered heteroaryl), and 5- to 6-membered heterocycloalkyl, wherein said 5- to 6-membered heteroaryl and 5- to 6-membered heterocycloalkyl have from 1-2 ring heteroatoms selected from N and O, and wherein said 5- to 6-membered heteroaryl is optionally substituted with one C 1 -C 3 -alkyl.
21 . The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 2 is
22 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 is —X 1 -(5- to 6-membered heterocycloalkyl) having one ring N heteroatom, wherein said 5- to 6-membered heterocycloalkyl is optionally substituted with 1-2 substituents independently selected from halo, and C 1 -C 3 -alkyl; and
X 1 is —O—.
23 . The compound of claim 22 , or a pharmaceutically acceptable salt thereof, wherein R 2 is —O-piperidine, or —O-pyrrolidine, each of which is optionally substituted with 1-2 halo.
24 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R A1 , when present, is —H, halo, C 1 -C 6 -alkyl, —O—C 1 -C 6 -alkyl, or 5- to 6-membered heterocycloalkyl having 1-2 ring heteroatoms independently selected from N and O;
R A2 , when present, is —H, halo, C 1 -C 6 -alkyl, or 5- to 6-membered heterocycloalkyl having 1-2 ring heteroatoms independently selected from N and O; and
R A3 , when present, is —H, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 6 -cycloalkyl, or 5- to 6-membered heterocycloalkyl having 1-2 ring heteroatoms independently selected from N and O, wherein said 5- to 6-membered heterocycloalkyl is optionally substituted with 1-2 substituents independently selected from halo and —OH.
25 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R A1 , when present, is —H, —F, —CH 3 , —OCH 3 , or morpholinyl;
R A2 , when present, is H, —F, —CH 3 , tetrahydropyranyl, or morpholiny; and
R A3 , when present, is H, -halo, —C 1 -C 3 -alkyl, —C 1 -haloalkyl, cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyrrolidinyl, or piperidinyl, wherein said tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyrrolidinyl, and piperidinyl are optionally substituted with 1-2 substituents independently selected from —F and —OH.
26 . The compound of claim 25 , or a pharmaceutically acceptable salt thereof, wherein R A3 , when present, is —H, —Cl, —F, —CH 3 , CF 3 , —NH 2 ,
27 . A compound selected from the compounds in Table 1 and Table 2, or a pharmaceutically acceptable salt thereof.
28 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.