TYK2 inhibitors
This disclosure relates to compounds of formula (I′), or pharmaceutically acceptable salts thereof, in which all of the variables are as defined in the application. The compounds of the present disclosure are capable of inhibiting the activity of tyrosine kinase 2 (TYK2). The disclosure further provides methods of preparing the compounds of the disclosure, and methods for their therapeutic use.
1 . A compound of formula (I′) below:
or a pharmaceutically acceptable salt thereof, wherein:
is a single bond or double bond, provided the ring containing X 1 , X 2 , X 3 , X 4 , X 5 , X 6 and X 7 is a bicyclic heteroaryl ring;
X 1 is N, NH, or CR 1 ;
X 2 is N or CR 2 ;
X 3 is N or CR 3 ;
X 4 is N or CR 4 ;
X 5 is NR 5 or CR 5 ;
X 6 and X 7 are both C, or one of X 6 and X 7 is N and the other is C;
Y is C(O) or S(O) 2 ;
R 1 , R 2 , R 3 and R 4 , when present, are each independently selected from H, halo, —CN, —NR 1a R 1b , —OR 1c , C 1-4 alkyl and C 1-4 haloalkyl;
R 5 is C 3-8 cycloalkyl, 4 to 10 membered heterocycloalkyl, 5 to 7 membered partially saturated heterocyclyl, a 5 or 6 membered monocyclic heteroaryl or a 8 to 10 membered bicyclic heteroaryl; wherein the C 3-8 cycloalkyl, 4 to 10 membered heterocycloalkyl, 5 to 7 membered partially saturated heterocyclyl, 5 or 6 membered monocyclic heteroaryl and the 8 to 10 membered bicyclic heteroaryl are each optionally substituted with 1, 2 or 3 R 7 ;
R 6 is H, C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 4 to 10 membered heterocycloalkyl or 5 to 10 membered heteroaryl, wherein the C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 4 to 10 membered heterocycloalkyl and 5 to 10 membered heteroaryl represented by R 6 are each optionally substituted with one or more R 8 ;
R 7 , for each occurrence, is independently halo, —CN, oxo(═O), —NR 1a R 1b , —OR 1c , —C(O)OR 1c , C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, or 4 to 6 membered monocyclic heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O; wherein the C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl and 4 to 6 membered monocyclic heterocycloalkyl are each optionally substituted with 1, 2 or 3 substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, —NR 1a R 1b , —OR 1c and 4 to 6 membered monocyclic heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O;
R 8 , for each occurrence, is independently selected form halo, —NR 1a R 1b , —OR 1c , —CN, C 1-6 alkyl, C 1-3 hydroxyalkyl, —C(═O)OR 1c , and C 1-6 haloalkyl;
R 1a and R 1b are each independently H or C 1-4 alkyl;
R 1c is H, C 1-4 alkyl or C 1-4 haloalkyl; and
m is 0 or an integer from 1 to 6.
2 . The compound of claim 1 , wherein the compound is represented by formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X 1 is N and X 2 is CR 2 , or X 2 is N and X 1 is CR 1 .
3 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein X 1 is CR 1 and X 2 is N.
4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 and R 4 , when present, are each independently H, halo, —NH 2 , —OH, C 1-4 alkyl, or C 1-4 haloalkyl.
5 . The compound of claim 1 , wherein the compound is represented by the following formula:
or a pharmaceutically acceptable salt thereof.
6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is
C(O).
7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 , when present, is H, halo, C 1-4 alkyl or C 1-4 haloalkyl.
8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 5 is a 5 or 6 membered monocyclic heteroaryl or a 8 to 10 membered bicyclic heteroaryl; wherein the 5 or 6 membered monocyclic heteroaryl and the 8 to 10 membered bicyclic heteroaryl are each optionally substituted with 1, 2 or 3 R 7 ;
R 7 , for each occurrence, is independently halo, —CN, —NR 1a R 1b , —OR 1c , —C(O)OR 1c , C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, or 4 to 6 membered monocyclic heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O; wherein the C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl and 4 to 6 membered monocyclic heterocycloalkyl are each optionally substituted with 1, 2 or 3 substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, —NR 1a R 1b , —OR 1c and 4 to 6 membered monocyclic heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O.
9 . The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein:
R 5 is a 5 membered monocyclic heteroaryl that is pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole or pyrrole, each of which is optionally substituted with 1, 2 or 3 R 7 .
10 . The compound of claim 1 , wherein the compound is represented by the following formula:
or a pharmaceutically acceptable salt thereof, wherein:
R 9a is C 1-4 alkyl, C 3-6 cycloalkyl, or 4 to 6 membered monocyclic heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O; wherein the C 1-4 alkyl, C 3-6 cycloalkyl, and 4 to 6 membered monocyclic heterocycloalkyl are each optionally substituted with 1, 2 or 3 substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, —NR 1a R 1b , —OR 1c and 4 to 6 membered monocyclic heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O; and
R 9b and R 9c are each independently H, C 1-4 alkyl or C 1-4 haloalkyl.
11 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 9a is —CH 3 , —CH 2 CH 3 ,
—CHF 2 , —CH 2 F, —CF 3 ,
and one of R 9b and R 9c is H, and the other is H, —CH 3 , —CHF 2 , or —CF 3 .
12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is
C 1-4 alkyl, C 3-6 monocyclic cycloalkyl, C 5-8 bicyclic cycloalkyl, a 4 to 6 membered monocyclic heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O, or a 5 to 8 membered bicyclic heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O, wherein the C 1-4 alkyl, the C 3-6 monocyclic cycloalkyl, the C 5-8 bicyclic cycloalkyl, the 4 to 6 membered monocyclic heterocycloalkyl, and the 5 to 8 membered bicyclic heterocycloalkyl are each optionally substituted with 1 to 3 substituent independently selected from halo, —CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-3 hydroxyalkyl, —C(═O)OR 1c , and C 1-4 alkoxy, where R 1c is H or C 1-3 alkyl.
13 . The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein:
R 6 is a C 3-6 monocyclic cycloalkyl optionally substituted with 1, 2 or 3 substituents independently selected from halo, —CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-3 hydroxyalkyl, —C(═O)OR 1c , and C 1-4 alkoxy, where R 1c is H or C 1-3 alkyl.
14 . The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein:
R 6 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is optionally substituted with 1, 2 or 3 substituent independently selected from halo, —CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-3 hydroxyalkyl, —C(═O)OR 1c , and C 1-4 alkoxy, where R 1c is H or C 1-3 alkyl.
15 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1.
16 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein —(CH 2 ) m —R 6 is CH 3 , —CH 2 CH 3 ,
—CF 3 , —CF 2 CH 3 , —CH 2 CF 3 ,
17 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula:
or a pharmaceutically acceptable salt thereof, wherein:
R 6 is C 3-6 monocyclic cycloalkyl optionally substituted with 1 or 2 substituents independently selected from halo, —CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-3 hydroxyalkyl, —C(═O)OR 1c , and C 1-4 alkoxy, where R 1c is H or C 1-3 alkyl; and
R 9a is C 1-4 alkyl.
18 . The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein:
R 6 is C 3-6 monocyclic cycloalkyl optionally substituted with 1 or 2 substituents independently selected from halo, C 1-4 alkyl and C 1-4 haloalkyl; and
R 9a is C 1-3 alkyl.
19 . The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein:
R 6 is a cyclopropyl optionally substituted with 1 or 2 substituents independently selected from halo, C 1-4 alkyl and C 1-4 haloalkyl.
20 . A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.