Inhibitors of menin-MLL interaction

Inventors: Thomas Butler (Redwood City, CA); Jim Palmer (Warrandyte, AU); Ravi Upasani (San Jose, CA); Matthew Welsch (New Haven, CT); Sridhar Vempati (Edison, NJ); Brendan Kelly (Castlecomer, IE); Edward Painter (Chappaqua, NY)

Assignee: BIOMEA FUSION, INC.

C07D487/04 A61K9/0014 A61K9/0019 A61K9/0031 A61K9/0048 A61K9/0053 A61K9/006 A61K9/0078 A61K9/06 A61P3/10 A61P35/02 C07D471/04 C07D473/00

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Quick Facts

Patent No.: US 12,275,739
App. No.: 18/387,420
Granted: Apr 15, 2025
Kind: B2

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Abstract

Disclosed herein are heterocyclic compounds that inhibit the binding of menin and MLL or MLL fusion proteins. Also described are specific inhibitors of menin-MLL interaction. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the menin-MLL inhibitors are disclosed, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, leukemia and other diseases or conditions dependent on menin-MLL interaction.

Claims (59)

1. A method for treating diabetes, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt thereof or pharmaceutical composition thereof, wherein:

A is O, or N (R 6a );

Cy is:

wherein R 7 is an optionally substituted group selected from a 4-7 membered heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, an 8-10 membered bicyclic aryl ring, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

one of X and Y is —NR 3a —; and the other is —C(R 3b ) 2 —, —NR 3b —, or —O—;

R 1 is an optionally substituted group selected from C 1-6 alkyl, C 3-7 cycloalkyl, phenyl, an 8-10 membered bicyclic aryl ring, a 4-7 membered heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 2 is H, C 1-6 alkyl, C 1-6 haloalkyl, halo, or CN;

each R 3a , and R 3b is independently H or C 1-6 alkyl;

each R 4 is independently H, halo, CN, OR, —N(R) 2 , —C(O)N(R) 2 , —NRC(O)R, —SO 2 R, —C(O)R, —CO 2 R, or an optionally substituted group selected from C 1-6 alkyl, C 3-7 cycloalkyl, a 4-7 membered heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, an 8-10 membered bicyclic aryl ring, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R is independently H, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, an 8-10 membered bicyclic aryl ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or 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, or sulfur;

R 6a is H or and C 1-6 alkyl; and

n is 1, 2, 3, or 4,

wherein the treating consists of alleviating, abating, ameliorating, inhibiting, arresting the development of, relieving, causing regression of, or stopping the symptoms of the diabetes.

2. The method according to claim 1 , wherein the compound is according to formula (IVa), (IVb), (IVc), (IVd), (Va), (Vb), (Vc), or (Vd):

or a pharmaceutically acceptable salt thereof,

wherein:

R 7 is an optionally substituted group selected from a 4-7 membered heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

3. The method according to claim 1 , wherein the compound is according to formula (VIa′), (VIb′), (VIc′), (VId′), (VIIa′), (VIIb′), (VIIc′), or (VIId′):

or a pharmaceutically acceptable salt thereof;

wherein:

4. The method according to claim 1 , wherein R 1 is phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, thiadiazolyl, pyridyl, pyrimidinyl, or pyrazinyl, wherein each is unsubstituted, or substituted with Me, Et, i-Pr, OMe, CF 3 , F, Cl, and CN.

5. The method according to claim 1 , wherein R 7 is a 4-7 membered heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with Me, Et, or i-Pr.

6. The method according to claim 1 , wherein R 7 is substituted or unsubstituted pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, triazolyl, thiazolyl, oxadiazolyl, or thiadiazolyl.

7. The method according to claim 1 , wherein R 7 is morpholinyl.

8. The method according to claim 1 , wherein the compound is according to formula (VIIIa), (VIIIb), (VIIIc), (VIIId), (IXa), (IXb), (IXc), or (IXd):