Tyk2 degraders and uses thereof

Patent metadata

Field	Value
Publication number	US-2025051338-A1
Application number	US-202218704633-A
Country	US
Kind code	A1
Filing date	Oct 24, 2022
Priority date	Oct 25, 2021
Publication date	Feb 13, 2025
Grant date	—

Abstract

The present invention provides compounds, compositions thereof, and methods of using the same. Compounds and compositions thereof that are useful, for example, for targeting, inhibiting, and/or degrading TYK2. In certain embodiments, provided are TYK2 inhibitors and/or degraders and methods of making same. More specifically, TYK2 degraders, compositions which comprise TYK2 degraders, and methods of treating TYK2-associated conditions are provided.

First claim

What is claimed is:

1 . A compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein
TBM is a TYK binding moiety capable of binding to TYK2 protein;
L is a bivalent moiety that connects TBM to ring A and wherein:
Ring AAA is selected from:

R 100 is C 1 -C 6 alkyl or H;
X 1 is a bivalent moiety selected from a covalent bond, —CH 2 —, —CHCF 3 —, —SO 2 —, —S(O)—, —P(O)R—, —

P(O)OR—, —P(O)NR 2 —, —C(O)—, —C(S)—, or

X 2 is a carbon atom, a nitrogen atom, or silicon atom;
X 3 is a bivalent moiety selected from a covalent bond, —CR 2 —, —NR—, —O—, —S—, or —Si(R) 2 —;

R 1 is absent, hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O) 2 R, —N(R) 2 , —P(O)(OR) 2 , —P(O)(NR 2 )OR, —P(O)(NR 2 ) 2 , —Si(OH) 2 R, —Si(OH)(R) 2 , —Si(R) 3 , or an optionally substituted C 1-4 aliphatic;
each R 2 is independently hydrogen, deuterium, —R 6 , halogen, —CN, —NO 2 , —OR, —SR, —N(R) 2 , —Si(R) 3 , —S(O) 2 R, —S(O) 2 N(R) 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(O)N(R)OR, —C(R) 2 N(R)C(O)R, —C(R) 2 N(R)C(O)N(R) 2 , —OC(O)R, —OC(O)N(R) 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)N(R) 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 , or —N(R)S(O) 2 R,
Ring A is selected from the group consisting of

6-membered aryl optionally substituted with one or more occurrences of halogen, and null,
Ring B is a fused ring selected from 6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to 7-membered saturated or partially unsaturated heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, or 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;
R 3 is selected from hydrogen, halogen, —OR, —N(R) 2 , or —SR;
each R 4 is independently hydrogen, —R 6 , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2NR2, —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;
R 5 is hydrogen, C 1 -C 4 aliphatic, or —CN;
each R 6 is independently an optionally substituted group selected from C1-6 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;
L 1 is a covalent bond or a C 1 -C 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(R) 2 —, —CH(R)—, —C(F) 2 —, —N(R)—, —S—, —S(O) 2 — or —(C)═CH—;
m is 0, 1, 2, 3 or 4; and
each R is independently hydrogen, or an optionally substituted group selected from C1-6 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 optionally 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.

2 . The compound of claim 1 , wherein ring AAA is:

3 . The compound of claim 1 or 2 , wherein ring A is:

4 . The compound of any one of claims 1-3 , wherein ring A is:

5 . The compound of claim 1 or 2 , wherein ring A is:

wherein R 200 is halogen.

6 . The compound of claim 1 , wherein TBM has a structure of Formula (IIAA′):

or a pharmaceutically acceptable salt thereof,
wherein Q is independently at each occurrence selected from —CH— and —N— when Q is attached to only single bonds, or Q is —C═ when Q is attached to a double bond;
R 1 is selected from a hydrogen, a C 1 -C 6 aliphatic, Ring 1, —C 1 -C 6 alkylene-Ring 1, and -Ring 1′-C 1 -C 6 aliphatic; wherein each of the C 1 -C 6 aliphatic, the Ring 1, the C 1 -C 6 alkylene-Ring 1, and the -Ring 1′-C 1 -C 6 aliphatic is independently optionally substituted with one or more of —F, —Cl, —Br, —I, and —OR C ;
R 2A is selected from a covalent bond, a C 1 -C 12 alkylene, which C 1 -C 12 alkylene optionally comprises 1-8 heteroatoms independently selected from O, N, and S, and Ring 2A, or R 2A is —C 1 -C 12 alkylene-Ring 2A-, -Ring 2A-Z 5 -, or -(Ring 2A)-Z 5 -(Ring 2A)-, wherein when R 2A is -(Ring 2A)-Z 5 -(Ring 2A)- two Ring 2A may be the same or different; wherein each of the C 1 -C 12 alkylene and the Ring 2A is independently optionally substituted with one or more of R K ;
R 3 is selected from a hydrogen and a C 1 -C 6 aliphatic, which C 1 -C 6 aliphatic optionally comprises 1-8 heteroatoms independently selected from O, N, and S, wherein the C 1 -C 6 aliphatic is optionally substituted with one or more of R K ;
Z 1 is selected from a covalent bond, —O—, —NR C —, —S—, —C(O)—, —C(S)—, —CR C 2 —, —OC(O)—, —C(O)O—, —S(O)—, —S(O) 2 —, —N(R C )S(O) 2 —, —S(O) 2 N(R C )—, —N(R C )C(O)—, —C(O)N(R C )—, —OC(O)N(R C )—, and —N(R C )C(O)O—;
Z 2 is selected from a covalent bond, —O—, —NR C —, —S—, —C(O)—, —C(S)—, —CR C 2 —, —OC(O)—, —C(O)O—, —S(O)—, —S(O) 2 —, —N(R C )S(O) 2 —, —S(O) 2 N(R C )—, —N(R C )C(O)—, —C(O)N(R C )—, —OC(O)N(R C )—, and —N(R C )C(O)O—;
Z 3 is selected from a covalent bond, —O—, —NR C —, —S—, —C(O)—, —C(S)—, —CR C 2 —, —OC(O)—, —C(O)O—, —S(O)—, —S(O) 2 —, —N(R C )S(O) 2 —, —S(O) 2 N(R C )—, —N(R C )C(O)—, —C(O)N(R C )—, —OC(O)N(R C )—, and —N(R C )C(O)O—;
Z 4 is selected from a covalent bond, —O—, —NR C —, —S—, —C(O)—, —C(S)—, —CR C 2 —, —OC(O)—, —C(O)O—, —S(O)—, —S(O) 2 —, —N(R C )S(O) 2 —, —S(O) 2 N(R C )—, —N(R C )C(O)—, —C(O)N(R C )—, —OC(O)N(R C )—, and —N(R C )C(O)O—;
Z 5 is selected from a covalent bond, —O—, —NR C —, —S—, —C(O)—, —C(S)—, —CR C 2 —, —OC(O)—, —C(O)O—, —S(O)—, —S(O) 2 —, —N(R C )S(O) 2 —, —S(O) 2 N(R C )—, —N(R C )C(O)—, —C(O)N(R C )—, —OC(O)N(R C )—, and —N(R C )C(O)O—;
Ring 1 is an optionally substituted ring selected from phenyl, a 3

Assignees

• Kymera Therapeutics Inc

Inventors

• Marx Isaac
• Yates Christopher M
• Zhu Xiao
• Pennington Lewis Dale
• Comer Eamon
• Ford Melissa

Classifications

• C07D401/14

  containing three or more hetero rings · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/5025

  ortho- or peri-condensed with heterocyclic ring systems · CPC title

• C07D487/10

  Spiro-condensed systems · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title