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 VIII:
or a pharmaceutically acceptable salt thereof, wherein:
X is C(R 3 );
Y is C(R 1 );
R 1 is H, D, or halogen;
R 2 is —N(R)C(O)Cy 2 , —N(R)S(O) 2 Cy 2 , or —N(R)Cy 2 ;
R 3 is H or halogen;
Cy 1 is phenyl or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy 1 is substituted with n instances of R 5 ;
Cy 2 is phenyl; a 5-6 membered monocyclic 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; wherein Cy 2 is substituted with p instances of R 6 ;
Cy 3 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy 3 is substituted with r instances of R 8 ;
L 1 is —N(R)—;
each instance of R 4 , R 5 , R 6 , R 7 and R 8 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;
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 m, n, p, q, and r is independently 0, 1, 2, 3, or 4.
2. The compound of claim 1 of formula XI-b:
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 of formula XII-b:
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , wherein R 1 is H.
5. The compound of claim 4 , wherein R 3 is H.
6. The compound of claim 5 , wherein Cy 3 is a 5-membered ring.
7. The compound of claim 6 , wherein Cy 1 (R 5 ) n taken together is one of the following:
8. The compound of claim 7 , wherein R 2 is —N(H)Cy 2 or —N(H)C(O)Cy 2 .
9. The compound of claim 8 , wherein Cy 2 is selected from the following:
each of which is substituted by p instances of R 6 .
10. The compound of claim 9 , wherein R 2 is
11. A compound selected from
Compound
Structure
VIII-1
VIII-2
VIII-3
VIII-4
VIII-5
VIII-6
VIII-7
VIII-8
VIII-9
VIII-10
VIII-11
VIII-12
VIII-13
VIII-14
VIII-15
VIII-16
VIII-17
or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.