IP Library › Patent Application 18273411

Patent Application

App. No. 18/273,411

COMBINATION OF A 3-(IMIDAZOL-4-YL)-4-(AMINO)-BENZENESULFONAMIDE TEAD INHIBITOR WITH AN EGFR INHIBITOR AND/OR MEK INHIBITOR FOR USE IN THE TREATMENT OF LUNG CANCER

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Patent No.: US None
App. No.: 18/273,411

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Abstract

The present invention provides TEAD inhibitors, and methods of use thereof.

Claims (119)

1 . A method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a TEAD inhibitor and an EGFR inhibitor.

2 . The method of claim 1 , wherein the TEAD inhibitor is a compound of Formula A:

or a pharmaceutically acceptable salt thereof, wherein

L1 is C 1 -6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with —O—, —CH(OR)—, —CH(SR)—, —CH(N(R) 2 )—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)—, —C(O)N(R)—, —(R)NC(O)—, —OC(O)N(R)—, —(R)NC(O)O—, —N(R)C(O)N(R)—, —S—, —SO—, —SO 2 —, —SO 2 N(R)—, —(R)NSO 2 —, —C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—, —(R)NC(S)—, or —(R)NC(S)N(R)—;

Ring A is an optionally substituted ring selected from phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8-10 membered bicyclic aromatic ring, or a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

Ring B is an optionally substituted ring selected from phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8-10 membered bicyclic aromatic ring, a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R w is an optionally substituted 4-, 5-, or 6-membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

each R is independently —H or optionally substituted −C 1-6 aliphatic.

3 . The method of claim 1 , wherein the TEAD inhibitor is a compound of Formula B:

or a pharmaceutically acceptable salt thereof, wherein

L1 is a covalent bond, or a C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with —O—, —CH(OR)—, —CH(SR)—, —CH(N(R) 2 )—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)—, —C(O)N(R)—, —(R)NC(O)—, —OC(O)N(R)—, —(R)NC(O)O—, —N(R)C(O)N(R)—, —S—, —SO—, —SO 2 —, —SO 2 N(R)—, —(R)NSO 2 —, —C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—, —(R)NC(S)—, or —(R)NC(S)N(R)—;

R w is a warhead group; wherein when R w is a saturated or partially unsaturated monocyclic carbocyclic or heterocyclic ring, it optionally forms a spiro bicyclic ring with Ring B; and

each R is independently —H or optionally substituted —C 1-6 aliphatic.

4 . The method of claim 1 , wherein the TEAD inhibitor is a compound of Formula C:

or a pharmaceutically acceptable salt thereof, wherein

L1 is a covalent bound, or a C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with —N(R)—, —O—, or —C(O)—;

Ring A is selected from

each of which is optionally substituted;

Ring B is selected from

each R 2 is independently selected from —OR, —C(O)NR 2 , optionally substituted —C 1-6 aliphatic,

each Y is independently N or CR 5 ;

R 3 is H, —C(O)R, or optionally substituted —C 1-6 aliphatic;

each R 4 is independently —S(O) 2 NR 2 , —S(O) 2 R, —C(O)NR 2 , —C(O)R, or optionally substituted —C 1-6 aliphatic;

each R 5 is independently R, —CN, —C(O)R, —C(O)NR 2 , or optionally substituted 5-6 membered heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each m is independently 0, 1, or 2; and

each R is independently H, optionally substituted —C 1-6 aliphatic, optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl, or optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

5 . The method of claim 1 , wherein the TEAD inhibitor is a compound of Formula D:

or a pharmaceutically acceptable salt thereof, wherein

Ring A is selected from

each of which is optionally substituted;

Ring B is

each R 2 is independently selected from —OR, —C(O)NR 2 , optionally substituted —C 1-6 aliphatic,

each Y is independently N or CR 5 ;

each R 4 is independently —S(O) 2 NR 2 , —S(O) 2 R, —C(O)NR 2 , —C(O)R, or optionally substituted —C 1-6 aliphatic;

each R 5 is independently R, —CN, —C(O)R, —C(O)NR 2 , or optionally substituted 5-6 membered heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each m is independently 0, 1, or 2; and

6 . The method of claim 1 , wherein the TEAD inhibitor is a compound of Formula E:

or a pharmaceutically acceptable salt thereof, wherein

Ring A is selected from

each of which is optionally substituted;

Ring B is selected from

each R w is independently selected from

each R 2 is independently selected from —OR, —C(O)NR 2 , optionally substituted —C 1-6 aliphatic,

each Y is independently N or CR 5 ;

each R 3 is independently H or optionally substituted —C 1-6 aliphatic;

each R 4 is independently —S(O) 2 NR 2 , —S(O) 2 R, —C(O)NR 2 , —C(O)R, or optionally substituted —C 1-6 aliphatic;

each R 5 is independently R, —CN, —C(O)R, —C(O)NR 2 , or optionally substituted 5-6 membered heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each m is independently 0, 1, or 2;

p is 0, 1, or 2, and

7 . The method of claim 1 , wherein the EGFR inhibitor is selected from cetuximab, necitumumab, panitumumab, zalutumumab, nimotuzumab, and matuzumab.

8 . The method of claim 1 , wherein the EGFR inhibitor is selected from osimertinib, gefitinib, erlotinib, lapatinib, neratinib, vandetanib, afatinib, brigatinib, dacomitinib, and icotinib.

9 . The method of claim 1 , further comprising administering an MEK inhibitor.

10 . The method of claim 9 , wherein the MEK inhibitor is selected from refametinib, selumetinib, trametinib, and cobimetinib.

11 . The method of claim 1 , wherein the cancer is an EGFR mutant resistant cancer.

12 . The method of claim 11 , wherein the cancer is an EGFR mutant resistant lung cancer, or an EGFR mutant resistant NSCLC.

13 . A method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a TEAD inhibitor and a MEK inhibitor.

14 . The method of claim 13 , wherein the TEAD inhibitor is a compound of Formula A:

or a pharmaceutically acceptable salt thereof, wherein

R w is an optionally substituted 4-, 5-, or 6-membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

each R is independently —H or optionally substituted —C 1-6 aliphatic.

15 . The method of claim 13 , wherein the TEAD inhibitor is a compound of Formula B:

or a pharmaceutically acceptable salt thereof, wherein

L 1 is a covalent bond, or a C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with —O—, —CH(OR)—, —CH(SR)—, —CH(N(R) 2 )—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)—, —C(O)N(R)—, —(R)NC(O)—, —OC(O)N(R)—, —(R)NC(O)O—, —N(R)C(O)N(R)—, —S—, —SO—, —SO 2 —, —SO 2 N(R)—, —(R)NSO 2 —, —C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—, —(R)NC(S)—, or —(R)NC(S)N(R)—;

R w is a warhead group; wherein when R w is a saturated or partially unsaturated monocyclic carbocyclic or heterocyclic ring, it optionally forms a spiro bicyclic ring with Ring B; and

each R is independently —H or optionally substituted —C 1-6 aliphatic.

16 . The method of claim 13 , wherein the TEAD inhibitor is a compound of Formula C:

or a pharmaceutically acceptable salt thereof, wherein

L 1 is a covalent bound, or a C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with —N(R)—, —O—, or —C(O)—;

Ring A is selected from

each of which is optionally substituted;

Ring B is selected from

each R 2 is independently selected from —OR, —C(O)NR 2 , optionally substituted —C 1-6 aliphatic,

each Y is independently N or CR 5 ;

R 3 is H, —C(O)R, or optionally substituted —C 1-6 aliphatic;

each R 4 is independently —S(O) 2 NR 2 , —S(O) 2 R, —C(O)NR 2 , —C(O)R, or optionally substituted —C 1-6 aliphatic;

each R 5 is independently R, —CN, —C(O)R, —C(O)NR 2 , or optionally substituted 5-6 membered heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each m is independently 0, 1, or 2; and

17 . The method of claim 13 , wherein the TEAD inhibitor is a compound of Formula D:

or a pharmaceutically acceptable salt thereof, wherein

Ring A is selected from

each of which is optionally substituted;

Ring B is

each R 2 is independently selected from —OR, —C(O)NR 2 , optionally substituted —C 1-6 aliphatic,

each Y is independently N or CR 5 ;

each R 4 is independently —S(O) 2 NR 2 , —S(O) 2 R, —C(O)NR 2 , —C(O)R, or optionally substituted —C 1-6 aliphatic;

each R 5 is independently R, —CN, —C(O)R, —C(O)NR 2 , or optionally substituted 5-6 membered heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each m is independently 0, 1, or 2; and

18 . The method of claim 13 , wherein the TEAD inhibitor is a compound of Formula E:

or a pharmaceutically acceptable salt thereof, wherein

Ring A is selected from

each of which is optionally substituted;

Ring B is selected from

each R w is independently selected from

each R 2 is independently selected from —OR, —C(O)NR 2 , optionally substituted —C 1-6 aliphatic,

each Y is independently N or CR 5 ;

each R 3 is independently H or optionally substituted —C 1-6 aliphatic;

each R 4 is independently —S(O) 2 NR 2 , —S(O) 2 R, —C(O)NR 2 , —C(O)R, or optionally substituted —C 1-6 aliphatic;

each R 5 is independently R, —CN, —C(O)R, —C(O)NR 2 , or optionally substituted 5-6 membered heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each m is independently 0, 1, or 2;

p is 0, 1, or 2, and

19 . The method of claim 13 , wherein the MEK inhibitor is selected from refametinib, selumetinib, trametinib, cobimetinib, binimetinib, mirdametinib, and pimasertib.

20 . The method of claim 13 , wherein the cancer is a KRAS mutant cancer that harbors one or more KRAS mutations selected from a KRAS G12C, a KRAS G12D mutation, a KRAS G12V mutation, and a KRAS G13 mutation.

21 . (canceled)

Assignments (3)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 11, 2026

From: IMAGENEBIO, INC.

To: THE EHE FOUNDATION

Reel/Frame 073758/0595 →

CHANGE OF NAME Recorded Dec 23, 2025

From: IKENA ONCOLOGY, INC.

To: IMAGENEBIO, INC.

Reel/Frame 073522/0031 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 12, 2024

From: CASTRO, ALFREDO C.; BURKE, MICHAEL; AMIDON, BENJAMIN; FROSCH, HYEJIN

To: IKENA ONCOLOGY, INC.

Reel/Frame 066438/0684 →