TYK2 inhibitors and uses thereof
Described herein are compounds of Formula (I) that are useful in treating a TYK2-mediated disorder. In some embodiments, the TYK2-mediated disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation.
1 . A compound of Formula (Ia) or Formula (If), or a pharmaceutically acceptable salt, or stereoisomer thereof:
wherein:
L is a C 1 -C 4 alkylene; wherein one or two carbon atoms are optionally replaced by a heteroatom selected from oxygen, sulfur, and nitrogen; and wherein L is optionally substituted with one or more R L ;
R L is independently selected for each occurrence from the group consisting of deuterium, halogen, —CN, —OR b , —NO 2 , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
or two R L on the same carbon are taken together to form an oxo, a cycloalkyl, or a heterocycloalkyl;
Ring A is a bicyclic heteroaryl or phenyl;
Ring B is a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl;
R A is independently selected for each occurrence from the group consisting of deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, aryl, and heteroaryl; wherein each alkyl, aryl, and heteroaryl is independently optionally substituted with one or more R A1 ;
R A1 is independently selected for each occurrence from the group consisting of deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
n is 1 or 2;
each R B is independently selected for each occurrence from the group consisting of deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R B1 ;
or two R B on the same carbon are taken together to form an oxo;
R B1 is independently selected for each occurrence from the group consisting of deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
m is 0-4;
Y 3 is CR 3 ;
Y 6 is CR 6 ;
Y 8 is N;
Y 9 is N;
R 3 and R 6 are independently selected from the group consisting of hydrogen, deuterium, halogen, —CN, —OR b , —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl;
R 4 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R 4a ;
R 4a is independently selected for each occurrence from the group consisting of deuterium, halogen, —CN, —OR b , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
or two R 4a on the same carbon are taken together to form an oxo;
R 5 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 deuteroalkyl;
W is —O— or —NR 7 —;
R 7 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 deuteroalkyl;
R a is independently selected for each occurrence from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R b is independently selected for each occurrence from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and
R c and R d are independently selected for each occurrence from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
Ring A is selected from the group consisting of indolyl, indazolyl, benzimidazolyl, benzotriazolyl, benzothiophenyl, benzothiazolyl, benzofuranyl, and benzoxazolyl.
3 . The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R 6 is hydrogen.
4 . The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R 3 is hydrogen.
5 . The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R 4 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
6 . The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R 4 is C 1 -C 6 alkyl or C 1 -C 6 deuteroalkyl.
7 . The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R 5 is hydrogen.
8 . The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R 7 is hydrogen or C 1 -C 6 alkyl.
9 . The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
each R A is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
10 . The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
each R A is independently C 1 -C 6 deuteroalkyl.
11 . The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
L is a C 2 -C 4 alkylene; wherein one carbon atom is optionally replaced by a heteroatom selected from oxygen, sulfur, and nitrogen; and wherein L is optionally substituted with one or more R L .
12 . The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
L is a C 2 -C 3 alkylene; wherein one carbon atom is optionally replaced by a heteroatom selected from oxygen, sulfur, and nitrogen; and wherein L is optionally substituted with one or more R L .
13 . The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
L is a C 2 -alkylene; wherein one carbon atom is optionally replaced by a heteroatom selected from oxygen, sulfur, and nitrogen; and wherein L is optionally substituted with one or more R L .
14 . The compound of claim 11 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
the heteroatom is an oxygen or a sulfur.
15 . The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
L is —CH 2 —O— or —O—CH 2 —.
16 . A compound selected from the group consisting of:
or a pharmaceutically acceptable salt or stereoisomer thereof.
17 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient.