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 - 3 . (canceled)
4 . A compound of formula IV:
or a pharmaceutically acceptable salt thereof, wherein:
each of X and Y is independently ═C(R 6 )—, ═N—, or ═N + (→O − )—, provided that X and Y are not simultaneously ═C(R 6 )—;
Ring A is phenyl; a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 4-6 membered saturated or partially unsaturated carbocyclic ring; wherein Ring A is substituted with m instances of R 7 ;
each R 2 is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 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 3 is a group selected from C 1-6 alkyl, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, 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; wherein R 3 is substituted with n instances of R 8 ;
R 4 is hydrogen or optionally substituted C 1-6 aliphatic; or
R 4 and one instance of R 7 are taken together with their intervening atoms to form a 5-6 membered partially unsaturated or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;
R 5 is a group selected from halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —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)S(O) 2 R, phenyl, a 3-14 membered saturated or partially unsaturated heterocyclic ring having 1-4 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; wherein R 5 is substituted with p instances of R 9 ;
R 6 is hydrogen, —R 2 , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —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 , or —N(R)S(O) 2 R;
each instance of R 7 , R 8 , R 10 , and R 11 is independently oxo, —R 2 , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2J —S(O)R, —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 , or —N(R)S(O) 2 R;
each instance of R 9 is independently oxo, C 1-6 hydroxyaliphatic, —R 2 , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2J —S(O)R, —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 , or —N(R)S(O) 2 R;
L 1 is a covalent bond or a C 1-6 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —C(R 10 ) 2 —, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O) 2 —, —S(O) 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O) 2 —; or
L 1 and one instance of R 7 are taken together with their intervening atoms to form a 5-10 membered partially unsaturated or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, sulfur, and boron; wherein said ring is substituted by q instances of R 11 ; and R 5 is attached to any position of the ring formed by L 1 and R 7 ;
m is 0-4;
n is 0-4;
p is 0-6;
q is 0-4; and
each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 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.
5 . The compound of claim 4 , wherein Ring A is phenyl, pyridin-2-yl, pyridine-3-yl, or pyrazol-4-yl.
6 . The compound of claim 5 , wherein Ring A is pyridin-2-yl.
7 . The compound of claim 4 , wherein X is ═C(R 6 )—; and Y is ═N—.
8 . The compound of claim 7 , wherein R 6 is hydrogen.
9 . The compound of claim 4 , wherein L 1 is —CH 2 C(O)—, —C(O)—, or a covalent bond.
10 . The compound of claim 9 , wherein L 1 is —C(O)—.
11 . The compound of claim 9 , wherein L 1 is a covalent bond.
12 . The compound of claim 4 , wherein R 3 is phenyl, pyrrolidinyl, or piperidinyl.
13 . The compound of claim 12 , wherein R 3 is phenyl.
14 . The compound of claim 4 , wherein wherein n is 2, and at least one R 8 is fluoro.
15 . (canceled)
16 . A pharmaceutical composition comprising a compound of claim 4 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
17 - 36 . (canceled)
37 . The compound of claim 5 , wherein Ring A is phenyl.
38 . The compound of claim 5 , wherein Ring A is pyridine-3-yl.
39 . The compound of claim 5 , wherein Ring A is pyrazol-4-yl.
40 . The compound of claim 4 , wherein X is ═N— and Y is ═N—.
41 . The compound of claim 4 , wherein X is ═N— and Y is ═C(R 6 )—.
42 . The compound of claim 9 , wherein L 1 is —CH 2 C(O)—.
43 . The compound of claim 12 , wherein R 3 is pyrrolidinyl.
44 . The compound of claim 12 , wherein R 3 is piperidinyl.