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US-20260125400-A1 - TYK2 DEGRADERS AND USES THEREOF

US20260125400A1US 20260125400 A1US20260125400 A1US 20260125400A1US-20260125400-A1

Abstract

The present invention provides compounds, compositions thereof, and methods of using the same.

Inventors

  • Isaac Marx
  • Nan Ji
  • Eamon Comer
  • Melissa FORD
  • Xiao Zhu
  • Christopher M. Yates
  • Bin Yang
  • Xiaozhang Zheng
  • Michael D. Sintchak
  • Yi Zhang
  • Matthew M. Weiss
  • Lewis Dale Pennington

Assignees

  • KYMERA THERAPEUTICS, INC.

Dates

Publication Date
20260507
Application Date
20240419

Claims (20)

  1. 1 . A compound of formula I-a′: or a pharmaceutically acceptable salt thereof, wherein: X is a bivalent moiety selected from —CH 2 — or —C(O)—; X 1 is a covalent bond, or an optionally substituted ring selected from 4-6 membered saturated carbocyclylenyl or heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenylenyl, 5-6 membered heteroarylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-8 membered saturated bridged bicyclic heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; X 2 is a covalent bond, —O—, or —NR—; Y is N or CH; Y 1 is a covalent bond, —O—, —S—, —NR—, or —C(O)NR—; Z 1 and Z 2 are independently N or C, where one of Z and Z 2 is N and the other of Z 1 and Z 2 is C; each is independently a single or double bond; Ring A is a ring selected from phenylenyl, pyridinylenyl, Ring B is a fused ring selected from benzo, a 5-6 membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is phenylenyl, pyridylenyl, a 9-10 membered saturated or partially unsaturated bicyclic heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8-10 membered bicyclic heteroarylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 12-15 membered saturated or partially unsaturated tricyclic spirocyclic heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen; R a is hydrogen, halogen, —CN, —OR, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or: two R a on the same carbon atom or adjacent carbon atoms connect to form a 3-6 membered saturated carbocyclic or heterocyclic ring having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur; a is 0, 1, or 2; R b is hydrogen, or: R b connects with the nitrogen where R 1 is attached to form an optionally substituted 5-6 membered partially unsaturated or aromatic heterocyclic ring having 0-2 heteroatoms in addition to the nitrogen atom where R 1 is attached selected from nitrogen, oxygen, and sulfur; R 1 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl; each R 2 and R 5 is independently hydrogen, halogen, —CN, —NO 2 , —OR, oxo, —SR, —NR 2 , —SiR 3 , —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 , —OP(O)R 2 , —OP(O)(OR) 2 , —OP(O)(OR)NR 2 , —OP(O)(NR 2 ) 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —N(R)P(O)R 2 , —N(R)P(O)(OR) 2 , —N(R)P(O)(OR)NR 2 , —N(R)P(O)(NR 2 ) 2 , —N(R)S(O) 2 R, or R A ; m and n are independently 0, 1, 2, 3, or 4; R 3 is hydrogen, or a C 1-6 alkyl or 3-9 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with 1-2 substituents selected from halogen, —CN, C 1-6 alkyl, C 1-6 haloalkyl, —OR, —CH 2 OR, or a 5-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: R 3 and R 5 are joined by a bivalent, saturated or partially unsaturated, straight or branched C 3-6 hydrocarbon chain, wherein 0-2 methylene units of the chain are independently replaced by —CR 2 —, —CRF—, —CF 2 —, —O—, —NR—, —C(O)—; R 4 is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, —OC 1-6 alkyl, or —OC 1-6 haloalkyl; L is a covalent bond, —CR 2 —, —CRF—, —CF 2 —, —O—, —NR—, —C(O)—, or a bivalent, saturated or partially unsaturated, straight or branched C 1-10 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, —CR 2 —, —CRF—, —CF 2 —, —CR(OR)—, —O—, —NR—, —C(O)—; each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, 8-10 membered bicyclic arylenyl, 4-7 membered saturated or partially unsaturated carbocyclylenyl, 6-11 membered saturated or partially unsaturated spirocyclic or bridged bicyclic carbocyclylenyl, 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-11 membered saturated or partially unsaturated spirocyclic or bridged bicyclic heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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 carbocyclic or 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, or: two R groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 0-3 heteroatoms, in addition to the carbon or nitrogen from which the two R groups are attached, independently selected from nitrogen, oxygen, and sulfur; and each R A is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or 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.
  2. 2 . A compound of formula I-a: or a pharmaceutically acceptable salt thereof, wherein: X is a bivalent moiety selected from —CH 2 — or —C(O)—; X 1 is a covalent bond, or an optionally substituted ring selected from 4-6 membered saturated carbocyclylenyl or heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenylenyl, 5-6 membered heteroarylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-8 membered saturated bridged bicyclic heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; X 2 is a covalent bond, —O—, or —NR—; Y is N or CH; Y 1 is a covalent bond, —O—, —S—, —NR—, or —C(O)NR—; Z 1 and Z 2 are independently N or C, where one of Z and Z 2 is N and the other of Z 1 and Z 2 is C; Ring A is a ring selected from phenylenyl, pyridinylenyl, Ring B is a fused ring selected from benzo, a 5-6 membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is phenylenyl, pyridylenyl, a 9-10 membered saturated or partially unsaturated bicyclic heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8-10 membered bicyclic heteroarylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 12-15 membered saturated or partially unsaturated tricyclic spirocyclic heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen; R a is hydrogen, halogen, —CN, —OR, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or: two R a on the same carbon atom or adjacent carbon atoms connect to form a 3-6 membered saturated carbocyclic or heterocyclic ring having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur; a is 0, 1, or 2; R b is hydrogen, or: R b connects with the nitrogen where R 1 is attached to form an optionally substituted 5-6 membered partially unsaturated or aromatic heterocyclic ring having 0-2 heteroatoms in addition to the nitrogen atom where R 1 is attached selected from nitrogen, oxygen, and sulfur; R 1 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl; each R 2 and R 5 is independently hydrogen, halogen, —CN, —NO 2 , —OR, oxo, —SR, —NR 2 , —SiR 3 , —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 , —OP(O)R 2 , —OP(O)(OR) 2 , —OP(O)(OR)NR 2 , —OP(O)(NR 2 ) 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —N(R)P(O)R 2 , —N(R)P(O)(OR) 2 , —N(R)P(O)(OR)NR 2 , —N(R)P(O)(NR 2 ) 2 , —N(R)S(O) 2 R, or R A ; m and n are independently 0, 1, 2, 3, or 4; R 3 is hydrogen, or a C 1-6 alkyl or C 3-6 cycloalkyl optionally substituted with 1-2 substituents selected from halogen, —CN, C 1-6 alkyl, C 1-6 haloalkyl, and —OR, or: R 3 and R 5 are joined by a bivalent, saturated or partially unsaturated, straight or branched C3.6 hydrocarbon chain, wherein 0-2 methylene units of the chain are independently replaced by —CR 2 —, —CRF—, —CF 2 —, —O—, —NR—, —C(O)—; R 4 is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, —OC 1-6 alkyl, or —OC 1-6 haloalkyl; L is a covalent bond, —CR 2 —, —CRF—, —CF 2 —, —O—, —NR—, —C(O)—, or a bivalent, saturated or partially unsaturated, straight or branched C 1-10 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, —CR 2 —, —CRF—, —CF 2 —, —CR(OR)—, —O—, —NR—, —C(O)—; each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, 8-10 membered bicyclic arylenyl, 4-7 membered saturated or partially unsaturated carbocyclylenyl, 6-11 membered saturated or partially unsaturated spirocyclic or bridged bicyclic carbocyclylenyl, 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-11 membered saturated or partially unsaturated spirocyclic or bridged bicyclic heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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 carbocyclic or 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, or: two R groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms, in addition to the carbon or nitrogen from which the two R groups are attached, independently selected from nitrogen, oxygen, and sulfur; and each R A is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or 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.
  3. 3 . The compound of claim 1 or claim 2 , wherein X 2 is a covalent bond.
  4. 4 . The compound of any one of claims 1-3 , wherein Ring C is phenylenyl, pyridylenyl, a 9-membered partially unsaturated bicyclic heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9-membered bicyclic heteroarylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 14-membered partially unsaturated tricyclic spirocyclic heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen
  5. 5 . The compound of any one of claims 1-4 , wherein Ring C is
  6. 6 . The compound of any one of claims 1-5 wherein X 1 is a covalent bond, or an optionally substituted ring selected from 4-6 membered saturated carbocyclylenyl or heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenylenyl, 6-membered heteroarylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 8-membered saturated bridged bicyclic heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  7. 7 . The compound of any one of claims 1-6 , wherein X 1 is a covalent bond,
  8. 8 . The compound of any one of claims 1-7 , wherein the compound is of any one of the following formulae: or a pharmaceutically acceptable salt thereof
  9. 9 . The compound of any one of claims 1-8 , wherein R 1 is hydrogen or C 1-6 alkyl.
  10. 10 . The compound of any one of claims 1-9 , wherein R 3 is hydrogen, methyl, ethyl, isopropyl,
  11. 11 . A compound of formula I-b or a pharmaceutically acceptable salt thereof, wherein: X is a bivalent moiety selected from —CH 2 — or —C(O)—; X 2 and X 3 are independently a covalent bond, —O—, or —NR—; Y is N or CH; Y 1 is a covalent bond, —O—, —S—, —NR—, or —C(O)NR—; Ring A is a ring selected from phenylenyl, pyridinylenyl, Ring B is a fused ring selected from benzo, a 5-6 membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring D is a bivalent ring selected from phenylenyl, 4-7 membered saturated or partially unsaturated carbocyclylenyl or heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring E is a bivalent ring selected from phenylenyl, naphthylenyl, 4-7 membered saturated or partially unsaturated carbocyclylenyl or heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered heteroarylenyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 9-10 membered saturated or partially unsaturated bicyclic heterocyclylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-10 membered bicyclic heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring F is phenyl, 4-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl 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 a is hydrogen, halogen, —CN, —OR, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or: two R a on the same carbon atom or adjacent carbon atoms connect to form a 3-6 membered saturated carbocyclic or heterocyclic ring having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur; a is 0, 1, or 2; each R 2 , R 5 , R 6 , and R 7 are independently hydrogen, halogen, —CN, —NO 2 , —OR, oxo, —SR, —NR 2 , —SiR 3 , —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 , —OP(O)R 2 , —OP(O)(OR) 2 , —OP(O)(OR)NR 2 , —OP(O)(NR 2 ) 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —N(R)P(O)R 2 , —N(R)P(O)(OR) 2 , —N(R)P(O)(OR)NR 2 , —N(R)P(O)(NR 2 ) 2 , —N(R)S(O) 2 R, or R A ; each of m, n, o, and p are independently 0, 1, 2, 3, or 4; R 4 is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, —OC 1-6 alkyl, or —OC 1-6 haloalkyl; L is a covalent bond, —CR 2 —, —CRF—, —CF 2 —, —O—, —NR—, —C(O)—, or a bivalent, saturated or partially unsaturated, straight or branched C 1-10 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, —CR 2 —, —CRF—, —CF 2 —, —CR(OR)—, —O—, —NR—, —C(O)—; each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, 8-10 membered bicyclic arylenyl, 4-7 membered saturated or partially unsaturated carbocyclylenyl, 6-11 membered saturated or partially unsaturated spirocyclic or bridged bicyclic carbocyclylenyl, 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-11 membered saturated or partially unsaturated spirocyclic or bridged bicyclic heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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 carbocyclic or 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, or: two R groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms, in addition to the carbon or nitrogen from which the two R groups are attached, independently selected from nitrogen, oxygen, and sulfur; and each R A is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or 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.
  12. 12 . The compound of claim 11 , wherein the compound is of any one of the following formulae: or a pharmaceutically acceptable salt thereof.
  13. 13 . The compound of claim 11 or claim 12 , wherein Ring F is phenyl or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  14. 14 . A compound of formula I-c: or a pharmaceutically acceptable salt thereof, wherein: X is a bivalent moiety selected from —CH 2 — or —C(O)—; X 1 is a covalent bond, an optionally substituted ring selected from 4-6 membered saturated carbocyclylenyl or heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenylenyl, 5-6 membered heteroarylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-8 membered saturated bridged bicyclic heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Y is N or CH; Y 1 is a covalent bond, —O—, —S—, —NR—, or —C(O)NR—; Z 1 and Z 2 are independently N or C, where one of Z 1 and Z 2 is N and the other of Z 1 and Z 2 is C; each is independently a single or double bond; Ring A is a ring selected from phenylenyl, pyridinylenyl, Ring B is a fused ring selected from benzo, a 5-6 membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring F is phenyl, 4-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl 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 a is hydrogen, halogen, —CN, —OR, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or: two R a on the same carbon atom or adjacent carbon atoms connect to form a 3-6 membered saturated carbocyclic or heterocyclic ring having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur; a is 0, 1, or 2; each R 2 , R 5 , and R 6 are independently hydrogen, halogen, —CN, —NO 2 , —OR, oxo, —SR, —NR 2 , —SiR 3 , —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 , —OP(O)R 2 , —OP(O)(OR) 2 , —OP(O)(OR)NR 2 , —OP(O)(NR 2 ) 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —N(R)P(O)R 2 , —N(R)P(O)(OR) 2 , —N(R)P(O)(OR)NR 2 , —N(R)P(O)(NR 2 ) 2 , —N(R)S(O) 2 R, or R A , or: two R 6 on adjacent atoms connect to form a fused optionally substituted 5-6 membered partially saturated or aromatic heterocyclic ring having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur; each of m, n, and o are independently 0, 1, 2, 3, or 4; R 4 is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, —OC 1-6 alkyl, or —OC 1-6 haloalkyl; L is a covalent bond, —CR 2 —, —CRF—, —CF 2 —, —O—, —NR—, —C(O)—, or a bivalent, saturated or partially unsaturated, straight or branched C 1-10 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, —CR 2 —, —CRF—, —CF 2 —, —CR(OR)—, —O—, —NR—, —C(O)—; each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, 8-10 membered bicyclic arylenyl, 4-7 membered saturated or partially unsaturated carbocyclylenyl, 6-11 membered saturated or partially unsaturated spirocyclic or bridged bicyclic carbocyclylenyl, 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-11 membered saturated or partially unsaturated spirocyclic or bridged bicyclic heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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 carbocyclic or 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, or: two R groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms, in addition to the carbon or nitrogen from which the two R groups are attached, independently selected from nitrogen, oxygen, and sulfur; and each R A is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or 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.
  15. 15 . The compound of claim 14 , wherein said compound is a compound of any of the following formulae: or pharmaceutically acceptable salt thereof.
  16. 16 . The compound of any one of claims 1-15 , wherein
  17. 17 . The compound of any one of claims 1-16 , wherein is
  18. 18 . The compound of any one of claims 1-17 , wherein R 2 is hydrogen, fluoro, chloro, methyl, ethyl, cyclopropyl, —CHF 2 , —CF 3 , oxo, —OMe, or -OEt.
  19. 19 . The compound of any one of claims 1-18 , wherein L is a bivalent, saturated or partially unsaturated, straight or branched C 1-5 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, —CR 2 —, —CRF—, —CF 2 —, —CR(OR)—, —O—, —NR—, —C(O)—.
  20. 20 . The compound of any one of claims 1-19 , wherein L is a bivalent, saturated or partially unsaturated, straight or branched C 5 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, —CR 2 —, —CRF—, —CF 2 —, —CR(OR)—, —O—, —NR—, —C(O)—.

Description

CROSS REFERENCE TO RELATED APPLICATION The application claims the benefit of priority of U.S. Provisional Appl. No. 63/497,504, filed Apr. 21, 2023, U.S. Provisional Appl. No. 63/587,879, filed Oct. 4, 2023, U.S. Provisional Appl. No. 63/596,205, filed Nov. 3, 2023, and U.S. Provisional Appl. No. 63/617,188, filed Jan. 3, 2024, the content of each of which in herein incorporated by reference. TECHNICAL FIELD OF THE INVENTION The present invention relates to compounds and methods useful for the modulation of tyrosine kinase 2 (“TYK2”) protein via ubiquitination and/or degradation by compounds according to the present invention. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders. BACKGROUND OF THE INVENTION Ubiquitin-Proteasome Pathway (UPP) or Ubiquitin-Proteasome System (UPS) is a critical pathway that regulates key regulator proteins and degrades misfolded or abnormal proteins. UPP is central to multiple cellular processes, and if defective or imbalanced, it leads to pathogenesis of a variety of diseases. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases. The UPP is used to induce selective protein degradation, including use of fusion proteins to artificially ubiquitinate target proteins and synthetic small-molecule probes to induce proteasome-dependent degradation. Bifunctional compounds composed of a target protein-binding ligand and an E3 ubiquitin ligase ligand, induced proteasome-mediated degradation of selected proteins via their recruitment to E3 ubiquitin ligase and subsequent ubiquitination. These drug-like molecules offer the possibility of temporal control over protein expression. Such compounds are capable of inducing the inactivation of a protein of interest upon addition to cells or administration to an animal or human, and could be useful as biochemical reagents and lead to a new paradigm for the treatment of diseases by removing pathogenic or oncogenic proteins (Crews C, Chemistry & Biology, 2010, 17(6):551-555; Schnnekloth J S Jr., Chembiochem, 2005, 6(1):40-46). TYK2 is an enzyme encoded by the TYK2 gene in humans and a member of the Janus Kinase (JAKs) family of proteins. TYK2 is involved IL-12, IL-23 and type I-interferon (IFN) signaling (Morris R, et al., Protein Science, Volume: 27, Issue: 12, Pages: 1984-2009, 2018). Human genetic studies suggest that TYK2 inhibition can be broadly beneficial for treating autoimmune and inflammatory diseases (Dendrou C, et al., Science Translational Medicine, Vol 8, Issue 363, p. 363ra149 2016). An ongoing need exists in the art for effective treatments for diseases, especially autoimmune and inflammatory diseases and disorders mediated by pro-inflammatory molecules such as IFN-α/β, IL-12, and IL-23 without JAK 1/2 inhibition which may cause on-target adverse events. As such, small molecule therapeutic agents that leverage E3 ligase mediated protein degradation to pro-inflammatory associated proteins such as tyrosine kinase 2 (TYK2) while potentially sparing molecules involved in wound healing and protection against microbes such as IL-10 and IL-22 hold promise as therapeutic agents for the treatment of conditions such as Crohn's disease and ulcerative colitis. Accordingly, there remains a need to find compounds that are TYK2 degraders useful as therapeutic agents. SUMMARY OF THE INVENTION It has now been found that the heterobifunctional compounds of this invention, and pharmaceutically acceptable compositions thereof, are effective degraders of TYK2. In certain embodiments, the invention provides for compounds of the formulae presented herein. Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with modulating TYK2. Such diseases, disorders, or conditions include those described herein. Compounds provided by this invention are also useful for the study of TYK2 kinase in biological and pathological phenomena; the study of intracellular signal transduction pathways occurring in bodily tissues; and the comparative evaluation of new TYK2 inhibitors or other regulators of kinases, signaling pathways, and cytokine levels in vitro or in vivo. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description of Certain Embodiments of the Invention In certain embodiments, the present invention provides a compound of any one of the following formulae: or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein, both singly and in combination. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula I-a, I-c, or I-c and a pharmaceutically acceptable carrier, adjuvant, or diluent. In some embodiments, the present invention provides