TYK2 inhibitors and uses thereof
The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of TYK2, and the treatment of TYK2-mediated disorders.
1. A compound of formula XVI-a:
or a pharmaceutically acceptable salt thereof, wherein:
X is N or C(R X );
one of Y 1 , Y 2 , Z 1 , and Z 2 is N, and the other three are C;
R 1 is an optionally substituted C 1-6 aliphatic group, R D , —NR 2 , —NRR D , —N(R D ) 2 , —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —N(R)C(O)NRR D , —N(R)C(NR)NRR D , —OR, or —OR D ;
R 2 is —N(R)C(O)Cy 2 ;
R 3 is H, halogen, or C 1-6 aliphatic;
each of Cy 1 and Cy 2 is independently phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 1 is substituted with n instances of R 5 ; and wherein Cy 2 is substituted with p instances of R 6 ;
each instance of R 5 , and R 6 is independently R A or R B , and is substituted by q instances of R C ;
each instance of R A is independently oxo, halogen, —CN, —NO 2 , —OR, —OR D , —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —S(O)NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R) C(O)R, —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —N(R)S(O) 2 NR 2 , or —N(R)S(O) 2 R;
each instance of R B is independently C 1-6 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring;
a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each instance of R C is independently oxo, halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —S(O)NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —N(R)S(O) 2 NR 2 , or —N(R)S(O) 2 R or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R D is a C 1-4 aliphatic group wherein one or more hydrogens are replaced by deuterium;
R X is H, halogen, or C 1-6 aliphatic;
each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and
each of n, p, and q is independently 0, 1, 2, 3, or 4.
2. The compound of claim 1 of formula XVIII-a or XVIII-b:
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 of formula XIX-a or XIX-b:
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 of formula XX-a or XX-b:
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 wherein Cy 1 (R 5 ) n taken together is one of the following:
6. The compound of claim 5 , wherein Cy 2 is selected from the following:
each of which is substituted by p instances of R 6 .
7. The compound of claim 6 , wherein R 2 is
8. The compound of claim 7 , wherein either of Y 2 or Z 2 is N.
9. A compound of formula XVI′:
or a pharmaceutically acceptable salt thereof, wherein:
Q is CH or N;
X is N or C(R X );
one of Y 1 , Y 2 , Z 1 , and Z 2 is N, and the other three are C;
R 1 is an optionally substituted C 1-6 aliphatic group, R D , —NR 2 , —NRR D , —N(R D ) 2 , —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —N(R)C(O)NRR D , —N(R)C(NR)NRR D , —OR, or —OR D ;
R 2 is —N(R)C(O)Cy 2 ;
R 3 is H, halogen, or C 1-6 aliphatic;
each of Cy 1 and Cy 2 is independently phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 1 is substituted with n instances of R 5 ; and wherein Cy 2 is substituted with p instances of R 6 ;
L 1 is a covalent bond;
each instance of R 5 , and R 6 is independently R A or R B , and is substituted by q instances of R C ;
each instance of R A is independently oxo, halogen, —CN, —NO 2 , —OR, —OR D , —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —S(O)NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R) C(O)R, —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —N(R)S(O) 2 NR 2 , or —N(R)S(O) 2 R;
each instance of R B is independently C 1-6 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each instance of R C is independently oxo, halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —S(O)NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R) C(O)R, —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —N(R)S(O) 2 NR 2 , or —N(R)S(O) 2 R or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R D is a C 1-4 aliphatic group wherein one or more hydrogens are replaced by deuterium;
R X is H, halogen, or C 1-6 aliphatic;
each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and
each of n, p, and q is independently 0, 1, 2, 3, or 4.
10. The compound of claim 9 wherein Q is CH.
11. The compound of claim 9 wherein Q is N.
12. A compound selected from
XVI-1
XVI-2
XVI-3
XVI-4
XVI-5
XVI-6
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 9 of formula XVI-a′:
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 9 of formula XVIII-a′ or XVIII-b′:
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 9 of formula XIX-a′ or XIX-b′:
or a pharmaceutically acceptable salt thereof.
16. The compound of claim 9 of formula XX-a′ or XX-b′:
or a pharmaceutically acceptable salt thereof.
17. The compound of claim 9 wherein Cy 1 (R 5 ) n taken together is one of the following:
18. The compound of claim 17 , wherein Cy 2 is selected from the following:
each of which is substituted by p instances of R 6 .
19. The compound of claim 18 , wherein R 2 is
20. A pharmaceutical composition comprising a compound according to claim 9 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.