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US-20260124309-A1 - STAT6 DEGRADERS AND USES THEREOF

US20260124309A1US 20260124309 A1US20260124309 A1US 20260124309A1US-20260124309-A1

Abstract

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

Inventors

  • Bin Yang
  • Thijs Beuming
  • Xue Fei
  • Philip Collier
  • Yi Zhang
  • Bruce C. Follows
  • Huijun Dong
  • Xiao Zhu
  • Matthew M. Weiss
  • Xiaozhang Zheng
  • Xin Huang
  • Lijing Su
  • Nello Mainolfi

Assignees

  • KYMERA THERAPEUTICS, INC.

Dates

Publication Date
20260507
Application Date
20240829

Claims (20)

  1. 1 . A compound of formula I-bb: or a pharmaceutically acceptable salt thereof, wherein Ring W is a 9-membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring X is a 6-membered saturated or partially unsaturated carbocyclylenyl or heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; G is hydrogen, halogen, or Ring Y is a 3- to 6-membered saturated or partially unsaturated carbocyclyl, or 4- to 6-membered monocyclic saturated or partially unsaturated heterocyclyl or heteroaryl ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R w , R x , and R y are independently selected from hydrogen, R A , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —SiR 3 , —S(O)R, —S(O) 2 R, —S(O)(NR)R, —S(O) 2 NR 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)NROR, —OC(O)R, —OC(O)NR 2 , —P(O)R 2 , —P(O)(OR) 2 , —OP(O)R 2 , —OP(O)(OR) 2 , —NRC(O)OR, —NRC(O)R, —NRC(O)N(R) 2 , and —NRS(O) 2 R; 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 5-10 membered monocyclic or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L X is a covalent bond or a C 1 s bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with —O—, —C(O)—, —C(S)—, —CR 2 —, —NR—, —S—, —S(O)—, or —S(O) 2 —; each of w, x, and y are independently 0, 1, 2, 3, or 4; L is a covalent bond, -Cy-(CH 2 ) 1-10 —, —(CH 2 ) 1-10 -Cy-(CH 2 ) 1-10 —, —(CH 2 ) 1-10 -Cy-(CH 2 CH 2 O) 1-10 CH 2 CH 2 —, -Cy-(CH 2 ) 1-10 -Cy-, -Cy-(CH 2 ) 1-10 -Cy-(CH 2 ) 1-10 —, -Cy-(CH 2 ) 1-10 -Cy-(CH 2 ) 1-10 -Cy-, —(CH 2 ) 1-10 -Cy-(CH 2 ) 1-10 -Cy-(CH 2 ) 1-10 —, -Cy-Cy-, -Cy-Cy-(CH 2 ) 1-10 —, -Cy-(CH 2 ) 1-10 -Cy-(CH 2 ) 1-10 —, -Cy-Cy-Cy-, -Cy-Cy-(CH 2 ) 1-10 -Cy-, or -Cy-Cy-(CH 2 ) 1-10 -Cy-(CH 2 ) 1-10 —; each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur: X 2 is N or CH; each R 1 is independently R A , halogen, —CN, —NO 2 , —OR, —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, —C(R) 2 N(R)C(O)R, —C(R) 2 N(R)C(O)NR 2 , —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, —NP(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; L 1 is a covalent bond, —C(O)—, —NR—, —O—, —S—, —S(O) 2 , —NRC(O)—, or —C(O)NR—; L 1 is a covalent bond, —C(O)—, —NR—, —O—, —S—, —S(O) 2 , —NRC(O)—, or —C(O)NR—; Ring A is phenylenyl or a 5 to 10-membered saturated or partially unsaturated monocyclic or bicyclic heterocyclylenyl or heteroarylenyl having 1-4 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 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 or adjacent atoms or R B and an R group are taken together with their intervening atoms to form an optionally substituted 3-11 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; m is 0, 1, 2, 3, 4, or 5.
  2. 2 . A compound of formula I-aa-1: or a pharmaceutically acceptable salt thereof, wherein: Ring W is a 9-membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring X is a 6-membered saturated or partially unsaturated carbocyclylenyl or heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; G is hydrogen, halogen, or Ring Y is a 3- to 6-membered saturated or partially unsaturated carbocyclyl, or 4- to 6-membered monocyclic saturated or partially unsaturated heterocyclyl or heteroaryl ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R x and R y are independently selected from hydrogen, R A , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —SiR 3 , —S(O)R, —S(O) 2 R, —S(O)(NR)R, —S(O) 2 NR 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)NROR, —OC(O)R, —OC(O)NR 2 , —P(O)R 2 , —P(O)(OR) 2 , —OP(O)R 2 , —OP(O)(OR) 2 , —NRC(O)OR, —NRC(O)R, —NRC(O)N(R) 2 , and —NRS(O) 2 R; each R w is independently selected from hydrogen, R A , R B′ halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —SiR 3 , —S(O)R, —S(O) 2 R, —S(O)(NR)R, —S(O) 2 NR 2 , —S(O)R, —C(O)R, —C(S)R, —C(NR)R, —C(O)OR, —C(O)NR 2 , —C(O)NROR, —OC(O)R, —OC(O)NR 2 , —P(O)R 2 , —P(O)(OR) 2 , —OP(O)R 2 , —OP(O)(OR) 2 , —NRC(O)OR, —NRC(O)R, —NRC(O)N(R) 2 , and —NRS(O) 2 R; each R A is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, naphthalenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered monocyclic or bicyclic aryl or heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 7-11 membered bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R B′ is independently -L B -Cy B1 -H or -L B -Cy B1 -Cy B2 ; each L B is independently a covalent bond or a C 1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with —O—, —C(O)—, —C(S)—, —C(NR)R—, —CR 2 —, —CF 2 —, —CRF—, —CR(OR)—, —NR—, —S—, —S(O)—, —S(O) 2 — —S(O)(NR)— or —CR═CR—; each Cy B1 is independently an optionally substituted ring selected from phenylenyl, a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclylenyl or heterocyclylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered monocyclic or bicyclic arylenyl or heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Cy B2 is independently an optionally ring selected from phenyl, a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered monocyclic or bicyclic aryl or heteroaryl with 1-4 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 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same atom or adjacent atoms are optionally taken together with their intervening atoms to form a 3-10 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic ring having 0-3 heteroatoms, in addition to the atom or adjacent atoms to which they are attached, independently selected from nitrogen, oxygen, and sulfur; L x is a covalent bond or an optionally substituted C 1-5 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with —O—, —C(O)—, —C(S)—, —CR 2 —, —NR—, —C(NR)—, —S—, —S(O)—, —S(O) 2 —, —S(O)(NR)—, or —CR═CR—; each of w, x, and y are independently 0, 1, 2, 3, or 4: L is a covalent bond or an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C 1-20 hydrocarbon chain, wherein 0-4 methylene units of L are independently replaced by -Cy-, —CHF—, —CF 2 —, —O—, —NR—, —SiR 2 —, —Si(OH)R—, —Si(OH) 2 —, —P(O)OR—, —P(O)R—, —P(O)NR 2 —, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O) 2 —, —NRS(O) 2 —, —S(O) 2 NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—, wherein: each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 3-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each r is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and X 1 and X 5 are independently a covalent bond, —CR 2 —, —SO 2 —, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)N(R) 2 —, —C(O)—, —C(S)—, or X 2 is N, C—R B , Si—R B , or P═O; X 3 and X 4 are independently a covalent bond, —CR 2 —, —CF 2 —, —O—, —S—, or X 3 —X 4 is —CR═CR—; each R 1 is independently —H, R A , halogen, —CN, —NO 2 , —OR, —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, —C(R) 2 N(R)C(O)R—C(R) 2 N(R)C(O)NR 2 , —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, —NP(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: two R 1 groups of Ring A are taken together with their intervening atoms to form an optionally substituted ring selected from a 3-10 membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; benzo: or a 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur: m is 0, 1, 2, 3, 4, or 5; each R B is independently, hydrogen, halogen, —CN, —OR, —SR, —S(O)R, —S(O) 2 R, —NR 2 , —P(O)(OR) 2 , —P(O)(NR 2 )OR, —P(O)(NR 2 ) 2 , —Si(OH) 2 R, —Si(OH)R 2 , —SiR 3 , or an optionally substituted Cia aliphatic; L 1 is a covalent bond or a C 1-3 bivalent hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with —C(O)—, —C(S)—, —CR 2 —, —CF 2 —, —NR—, —O—, —S—, or —S(O) 2 ; and Ring A is phenylenyl, naphthalenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-15 membered saturated or partially unsaturated tricyclic heterocyclylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-15 membered tricyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  3. 3 . The compound of claim 1 or 2 , wherein Ring W is: wherein: each of X and Y is independently N, NH, N—R W , —O—, —S—, C—H, C—R W , CH 2 , CH(R W ), or C(R W ) 2 , as allowed by valency.
  4. 4 . The compound of claim 3 , wherein: X is C—R w or CH, and Y is N—R w ; X is C—R w or CH, and Y is S; X is C—R w or CH, and Y is O; X is N—R w or NH, and Y is C—R w or CH; X is S, and Y is C—R w or CH; or X is O, and Y is C—R w or CH.
  5. 5 . The compound of any one of claims 1-4 , wherein Ring X is
  6. 6 . The compound of any one of claims 1-5 , wherein Ring Y is a 5 membered monocyclic heteroaryl ring with 1-4 heteroatoms independently selected form nitrogen, oxygen, and sulfur.
  7. 7 . The compound of any one of claims 1-6 , wherein Ring Y is pyrazolyl, imidazolyl, or triazolyl.
  8. 8 . The compound of any one of claims 1-7 , wherein Lx is a covalent bond or # -L XA -L XB -, wherein: # represents the point of attachment to Ring X: L XA is —C(O)—, —C(S)—, —CR 2 —, —S(O)—, or —S(O) 2 —; and L XD is a covalent bond or an optionally substituted C 1-4 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with —O—, —C(O)—, —C(S)—, —CR 2 —, —NR—, —S—, —S(O)—, or —S(O) 2 —.
  9. 9 . The compound of claim 8 , wherein L XA is —C(O)—.
  10. 10 . The compound of claim 8 or 9 , wherein L XB is an optionally substituted C 1-4 bivalent straight or branched saturated or unsaturated hydrocarbon chain.
  11. 11 . The compound of claims 1-10 , wherein an occurrence of R w is —C(S)R, —C(NR)R, —S(O)R, —S(O) 2 R, —S(O)(NR)R—S(O) 2 NR 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)NROR, —OC(O)R, —OC(O)NR 2 , —P(O)R 2 , —P(O)(OR) 2 , —OP(O)R 2 , —OP(O)(OR) 2 , —NRC(O)OR, —NRC(O)R, —NRC(O)N(R) 2 , or —NRS(O) 2 R.
  12. 12 . The compound of claims 1-11 , wherein an occurrence of R w is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  13. 13 . The compound of any one of claims 1-12 , wherein an occurrence of R w is halogen (e.g., fluoro).
  14. 14 . The compound of any one of claims 1-13 , wherein y is 0.
  15. 15 . The compound of any one of claims 1-14 , wherein: the compound is of formula I-bb-I, I-bb-IX, I-bb-A, I-bb-B, I-bb-C, I-bb-D, I-bb-E, or I-bb-F: or a pharmaceutically acceptable salt thereof; or the compound is of formula I-cc-1 I-cc-2, or I-cc-3: or a pharmaceutically acceptable salt thereof, wherein: R w′ is —S(O)R, —S(O) 2 R, —S(O)(NR)R, —S(O) 2 NR 2 , —C(O)R, —C(S)R, —C(NR)R, —C(O)OR, —C(O)NR 2 , —C(O)NROR, —OC(O)R, —OC(O)NR 2 , —P(O)R 2 , —P(O)(OR) 2 , —OP(O)R 2 , —OP(O)(OR) 2 , —NRC(O)OR, —NRC(O)R, —NRC(O)N(R) 2 , —NRS(O) 2 R, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, naphthalenyl, 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 5-10 membered monocyclic or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  16. 16 . The compound of claim 15 , wherein: R w′ is an optionally substituted 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R w′ is and Ring W 1 is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1 additional heteroatom selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R w′ is and Ring W 1 is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1 additional heteroatom selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R w′ is and Ring W 2 is an optionally substituted 3-7 membered partially unsaturated heterocyclic ring, or a 5-6 membered monocyclic heteroaryl ring having 1-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  17. 17 . The compound of claim 15 , wherein R w′ is —S(O)R, —S(O) 2 R, —S(O)(NR)R—S(O) 2 NR 2 —S(O)R, —C(S)R, —C(NR)R, —C(O)R, —C(O)OR, —C(O)NR 2 , or —C(O)NROR.
  18. 18 . The compound of any one of claims 1-17 , wherein: the compound is of formula I-cc-1A, I-cc-2A, or I-cc-3A: or a pharmaceutically acceptable salt thereof; or the compound is of formula I-cc-1B, I-cc-2B, I-cc-3B, I-cc-1C, I-cc-2C, or I-cc-3C: or a pharmaceutically acceptable salt thereof; or the compound is of formula I-cc-1D, I-cc-2D, I-cc-3D, I-cc-1E, I-cc-2E, or I-cc-3E: or a pharmaceutically acceptable salt thereof; or the compound is of formula I-cc-1F, I-cc-2F, I-cc-3F, I-cc-1G, I-cc-2G, or I-cc-3G: or a pharmaceutically acceptable salt thereof; or the compound is of formula I-cc-1H, I-cc-2H, 1-cc-3H, I-cc-J I-cc-2J, or I-cc-3J: or a pharmaceutically acceptable salt thereof.
  19. 19 . The compound of any one of claims 2-18 , wherein, L is: wherein: @ represents the point of attachment to Ring W; L 1′ is a covalent bond or an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C 1-6 hydrocarbon chain, wherein 1 methylene unit of L 1′ is optionally replaced by -Cy L1 -, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O) 2 —, —NRS(O) 2 —, —S(O) 2 NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, or —NRC(O)O—; L 2 is a covalent bond or an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C 1-6 hydrocarbon chain, wherein 1 methylene unit of L 2 is optionally replaced by -Cy L2 -, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O) 2 —, —NRS(O) 2 —, —S(O) 2 NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, or —NRC(O)O—; L 3 is a covalent bond or an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C 1-6 hydrocarbon chain, wherein 1 methylene unit of L 3 is optionally replaced by -Cy L3 -, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O) 2 —, —NRS(O) 2 —, —S(O) 2 NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, or —NRC(O)O—; L 4 is a covalent bond or an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C 1-6 hydrocarbon chain, wherein 1 methylene unit of L 4 is optionally replaced by -Cy L4 -, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O) 2 —, —NRS(O) 2 —, —S(O) 2 NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, or —NRC(O)O—; and each of -Cy L1 -Cy L2 -, -Cy L3 - and -Cy L4 - is independently -Cy-.
  20. 20 . The compound of claim 19 , wherein L is: wherein: L 1′ is -Cy L1 -; L 2 is -Cy L2 -; and L 3 is an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C 1-6 hydrocarbon chain.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority from U.S. Provisional Appl. No. 63/579,812, filed Aug. 30, 2023, U.S. Provisional Appl. No. 63/617,359, filed Jan. 3, 2024, U.S. Provisional Appl. No. 63/649,863, filed May 20, 2024, and U.S. Provisional Appl. No. 63/678,903, filed Aug. 2, 2024. TECHNICAL FIELD OF THE INVENTION The present invention relates to compounds and methods useful for the modulation of signal transducer and activator of transcription 6 (“STAT6”) 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). Signal transducer and activator of transcription 6 (STAT6 or Interleukin-4-Stat/IL4-STAT) is an undruggable transcription factor belonging to the structurally conserved Signal Transducer and Activator of Transcription (STAT) family of proteins (STAT1 through STAT6). Activation of STAT6, like other STAT proteins, is triggered upon binding of hormones, immunomodulatory cytokines or growth factors to specific receptors on the cell surface. Once activated, the phosphorylation of a C-terminal tyrosine residue occurs, leading to translocation and transmission of signals from the cytosol to the nucleus, resulting in activation of gene expression. STAT6 is implicated in driving Type 2 immunity, allergies. It may participate in IL-4/IL-13-mediated allergic reaction, and play a vital role in the differentiation of T-helper type 2 (Th2) cells (Hebenstreit et al. “Signaling mechanisms, interaction partners, and target genes of STAT6.” Cytokine & growth factor reviews 17.3 (2006): 173-188; Chapoval et al. “Regulation of the T helper cell type 2 (Th2)/T regulatory cell (Treg) balance by IL-4 and STAT6.” Journal of leukocyte biology 87.6 (2010): 1011-1018). STAT6 is a key node primarily activated in the Janus Kinase (JAK) pathway by inflammatory cytokines, interleukin-4 (IL4) and interleukin-13 (IL13) and their cognate receptors, which are produced by Th2 cells, mast cells and basophils. Human STAT6 mutations have been associated with severe allergies such as asthma and eczema (Goenka and Kaplan. “Transcriptional regulation by STAT6.” Immunologic research 50.1 (2011): 87-96.). There is a need to discover and develop STAT6 drugs, for example to treat allergic/inflammatory diseases and cancers (Glosson et al. “Wheezing and itching: The requirement for STAT proteins in allergic inflammation.” Jak-Stat 1.1 (2012): 3-15: Loh et al. “Signal transducer and activator of transcription (STATs) proteins in cancer and inflammation: functions and therapeutic implication.” Frontiers in oncology 9 (2019): 48). As such, small molecule compounds that leverage E3 ligase mediated protein degradation to target disease-associated proteins such as STAT6 hold promise as therapeutic agents. SUMMARY OF THE INVENTION The present application relates to novel bifunctional compounds, which function to recruit STAT6 protein to E3 ubiquitin ligase for degradation, and methods of preparation and uses thereof. In particular, the present disclosure provides bifunctional compounds, which find utility as modulators of targeted ubiquitination of STAT6 protein, which are then degraded and/or otherwise inhibited by the bifunctional compounds as described herein. Also provided are monovalent compounds, which find utility as inducers of targeted ubiquitination of STAT6 protein, which are then degraded and/