Inhibitors of menin-MLL interaction
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; or a pharmaceutically acceptable salt thereof.
1. A compound according to formula (I):
or a pharmaceutically acceptable salt 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 5a is H, C 1-6 alkyl, C 1-6 haloalkyl, halo, or CN;
R 6a is H or and C 1-6 alkyl; and
n is 1, 2, 3, or 4.
2. The compound according to claim 1 , wherein the compound is according to formula (IIa′), or (IIb′):
or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 1 , wherein the compound is according to formula (IIIa′), or (IIIb′):
or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 3 , wherein the compound is according to formula (IVa), (IV), (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.
5. The compound according to claim 3 , wherein the compound is according to formula (VIa′), (VIb′), (VIc′), (VId′), (VIIa′), (VIIb′), (VIIc′) or (VIId′):
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;
or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 3 , wherein R 1 is substituted or unsubstituted phenyl, substituted or unsubstituted 8-10 membered bicyclic aryl, or substituted or unsubstituted 5-6 membered heteroaryl.
7. The compound according to claim 3 , wherein R 1 is phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, thiadiazolyl, pyridyl, pyrimidinyl, or pyrazinyl, wherein each is substituted or unsubstituted.
8. The compound according to claim 7 , wherein the substitution is selected from C 1-6 alkyl, C 1-6 haloalkyl, alkoxy, halo, and CN.
9. The compound according to claim 7 , wherein the substitution on phenyl, 8-10 membered bicyclic aryl or heteroaryl is selected from Me, Et, i-Pr, OMe, CF 3 , F, Cl, and CN.
10. The compound according to claim 3 , 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.
11. The compound according to claim 3 , wherein R 7 is substituted or unsubstituted pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, triazolyl, thiazolyl, oxadiazolyl, or thiadiazolyl.
12. The compound according to claim 3 , wherein R 7 is morpholinyl.
13. The compound according to claim 3 , wherein R 7 is imidazoyl substituted with Me, Et, i-Pr, Cl, F, CF 3 , or CN.
14. The compound according to claim 1 , wherein the compound is according to formula (VIIIa), (VIIIb), (VIIIc), (VIIId), (IXa), (IXb), (IXc) or (IXd):
or a pharmaceutically acceptable salt thereof.
15. The compound according to claim 1 , wherein the compound is according to formula (Xa), (Xb), (Xc), (Xd), (Xe), (Xf), (Xg), (Xh), (XIa), (XIb), (XIc), (XId), (XIe), (XIf), (XIg) or (XIh):
or a pharmaceutically acceptable salt thereof.
16. The compound according to claim 1 , wherein the compound is according to formula (XIIa), (XIIb), (XIIc), (XIId), (XIIIa), (XIIIb), (XIIIc) or (XIIId):
or a pharmaceutically acceptable salt thereof.
17. The compound according to claim 1 , wherein the compound is according to formula (XIVa), (XIVb), (XIVc), (XIVd), (XIVe), (XIVf), (XIVg) or (XIVh), (XVa), (XVb), (XVc), (XVd)), (XVe), (XVf), (XVg) or (XVh):
or a pharmaceutically acceptable salt thereof.
18. The compound according to claim 1 , wherein the compound is according to formula (XVIa), (XVIb), (XVIc), (XVId), (XVIIa), (XVIIb), (XVIIc) or (XVIId):
or a pharmaceutically acceptable salt thereof.
19. The compound according to claim 1 , wherein the compound is according to formula (XVIIIa), (XVIIIb), (XVIIIc), (XVIIId), (XVIIIe), (XVIIIf), (XVIIIg), (XVIIIh) (XIXa), (XIXb), (XIXc), (XIXd), (XIXe), (XIXf), (XIXg) or (XIXh):
or a pharmaceutically acceptable salt thereof.
20. The compound according to claim 1 , wherein the compound is according to formula (XXa), (XXb), (XXc), (XXd), (XXIa), (XXIb), (XXIc) or (XXId):
or a pharmaceutically acceptable salt thereof.
21. The compound according to claim 1 , wherein the compound is according to formula (XXIIa), (XXIIb), (XXIIc), (XXIId), (XXIIe), (XXIIf), (XXIIg), (XXIIh), (XXIIIa), (XXIIIb) (XXIIIc), (XXIIId), (XXIIIe), (XXIIIf), (XXIIIg) or (XXIIIh):
or a pharmaceutically acceptable salt thereof.
22. The compound according to claim 1 , wherein the compound is according to formula (VIIb), (XIVb), or (XIVf):
or a pharmaceutically acceptable salt thereof.
23. A compound selected from any one of the following compounds, or a pharmaceutically acceptable salt thereof:
24. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 ; or a pharmaceutically acceptable salt, or solvate, thereof; and a pharmaceutically acceptable excipient.
25. The pharmaceutical composition of claim 24 that is formulated for a route of administration selected from oral administration, parenteral administration, buccal administration, nasal administration, topical administration, and rectal administration.