Claims for Patent: 10,174,041

Summary for Patent: 10,174,041

Title:	Methods and compositions for inhibiting the interaction of menin with MLL proteins
Abstract:	The present disclosure provides compositions and methods of use to inhibit the interaction of menin with MLL1, MLL2 and MLL-fusion oncoproteins. The compositions and methods of use are useful for the treatment of leukemia, solid cancers, diabetes and other diseases dependent on activity of MLL1, MLL2, MLL fusion proteins, and/or menin.
Inventor(s):	Jolanta Grembecka, Tomasz Cierpicki, Dmitry Borkin, Jonathan Pollock, Liansheng Li, Tao Wu, Jun Feng, Pingda Ren, Yi Liu, Szymon Klossowski
Assignee:	Wellspring Biosciences LLC , University of Michigan System , Kura Oncology Inc
Application Number:	US16/014,996
Patent Claims:	1. A method of treating a menin-mediated disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula II-A: or a pharmaceutically acceptable salt thereof, wherein: X2 is CR2 or N; X5 is S; X6 is CR3 or N; L3 is a carbonyl, O, S, —NR5—, —NR6CH2—, —NR6C(═O)—, —NR6SO2—, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl, or heteroalkylenecarbonyl; L2 is a bond, carbonyl, O, S, —NR5—, —NR6CH2—, —NR6C(═O)—, —NR6SO2—, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl, or heteroalkylenecarbonyl; m is an integer from 0 to 12; B is selected from B-I, B-II, B-III, and B-IV; wherein B is connected at any ring atom to L2; B-I is B-II is B-III is B-IV is each of Z1, Z2, Z3, and Z4 is independently CR7, N, or NR9; Z5 is C or N; each of Z6, Z7, and Z8 is independently CR8, N, NR9, O, or S; each of Z9, Z10, and Z11 is independently CR10, CR11R12, NR13, O, or S; n is an integer from 0 to 6; each of R1, R2, R3, R5, R6, R7, R8, R9, R10, R11, R12, and R13 is, at each occurrence, independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclyl alkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino; each of RA and RB is, at each occurrence, independently selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino, wherein two RA groups or two RB groups attached to the same atom or different atoms can together optionally form a bridge or ring; and R14 is halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, or heteroarylalkylamino, wherein the disease or condition comprises a leukemia, a lymphoma, a hematologic malignancy, a solid tumor cancer, prostate cancer, pancreatic cancer, lung cancer, skin cancer, breast cancer, liver cancer, a brain tumor, or diabetes. 2. The method of claim 1, wherein R14 is halo, hydroxyl, alkoxy, alkylamino, amino, cyano, amido, alkyl, heteroalkyl, or haloalkyl. 3. The method of claim 2, wherein R14 is hydroxyl, alkylamino, or amino. 4. The method of claim 1, wherein X6 is CR3 and R3 in X6 is selected from H, halo, amino, carboxyl, and alkyl. 5. The method of claim 1, wherein L3 is carbonyl, O, S, or —NR5—. 6. The method of claim 1, wherein L2 is C1-C4 alkylene. 7. The method of claim 1, wherein X2 is N. 8. The method of claim 1, wherein R1 is haloalkyl. 9. The method of claim 1, wherein m is 0 and n is 1 or 2. 10. The method of claim 1, wherein R5 is H or alkyl. 11. The method of claim 1, wherein B is B-II. 12. The method of claim 11, wherein B-II is 13. The method of claim 1, comprising B-II, wherein: Z1 and Z2 are CR7; Z5 is C; Z6 is NRB; and Z7 and Z8 are CR8. 14. The method of claim 1, comprising B-II, wherein: Z1 is CCH3; Z2 and Z8 are CH; Z5 is C; Z6 is NRB; and Z7 is CCN. 15. The method of claim 1, comprising an RB selected from: wherein: G is selected from a bond, alkylene, heteroalkylene, C3-12 carbocycle, 3- to 12-membered heterocycle, and combinations thereof, wherein G is optionally substituted with one or more R32 groups; V is absent or selected from a C3-12 carbocycle, and 3- to 12-membered heterocycle; wherein V is optionally substituted with one or more R32 groups; each of R21 and R32 is, at each occurrence, independently selected from: H, halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, ═O, ═S, ═N(R20), —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, and —CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, ═O, ═S, ═N(R20), —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, —CN, C3-10 carbocycle, and 3- to 10-membered heterocycle; and C3-10 carbocycle and 3- to 10-membered heterocycle; wherein two R32 on the same carbon atom can come together to form a C3-10 carbocycle or 3- to 10-membered heterocycle; wherein each C3-10 carbocycle and 3- to 10-membered heterocycle of R32 is independently optionally substituted with one or more substituents selected from halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, ═O, ═S, ═N(R20), —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, —CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl; R20 is, at each occurrence, independently selected from: hydrogen; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —OR30, —SR30, —N(R30)2, —N(R30)C(O)R30, —C(O)R30, —C(O)OR30, —C(O)N(R30)2, —OC(O)R30, —S(O)2R30, —S(O)2N(R30)2, —N(R30)S(O)2R30, —NO2, —P(O)(OR30)2, —P(O)(R30)2, —OP(O)(OR30)2, and —CN; and 3- to 10-membered heterocycle and C3-10 carbocycle; and R30 is, at each occurrence, independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. 16. The method of claim 15, wherein V is selected from: any one of which is optionally substituted with one or more R32 groups. 17. The method of claim 15, wherein G is alkylene optionally substituted with one or more R32 groups. 18. The method of claim 15, wherein: X5 is S; X6 is CR3, wherein R3 in X6 is selected from H, halo, amino, carboxyl, and alkyl; L2 is C1-C4 alkylene; L3 is carbonyl, O, S, or —NR5—; B is Z1 and Z2 are CR7; Z5 is C; Z6 is NRB; Z7 and Z8 are CR8; R1 is haloalkyl; R14 is halo, hydroxyl, alkoxy, alkylamino, amino, cyano, amido, alkyl, heteroalkyl, or haloalkyl; and V is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which optionally substituted with one or more R32 groups. 19. The method of claim 18, wherein R14 is hydroxyl, alkylamino, or amino. 20. The method of claim 1, further comprising administering a second therapeutic agent to the subject. 21. The method of claim 1, wherein the disease or disorder is selected from acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, small lymphocytic lymphoma, chronic myelogenous leukemia, acute monocytic leukemia, hairy cell leukemia, Hodgkins lymphoma, non-Hodgkins lymphoma, mixed lineage leukemia, T-cell prolymphocyte leukemia, T-cell lymphoma, and Burkitt lymphoma. 22. The method of claim 1, wherein the disease or disorder is selected from AML, ALL, mixed lineage leukemia, and leukemia having a Partial Tandem Duplication of MLL. 23. A method of inhibiting the interaction of menin and one or more of MLL1, MLL2, an MLL fusion protein, and an MLL Partial Tandem Duplication, comprising contacting menin with an effective amount of a compound of Formula II-A: or a pharmaceutically acceptable salt thereof, wherein: X2 is CR2 or N; X5 is S; X6 is CR3 or N; L3 is a carbonyl, O, S, —NR5—, —NR6CH2—, —NR6C(═O)—, —NR6SO2—, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl, or heteroalkylenecarbonyl; L2 is a bond, carbonyl, O, S, —NR5—, —NR6CH2—, —NR6C(═O)—, —NR6SO2—, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl, or heteroalkylenecarbonyl; m is an integer from 0 to 12; B is selected from B-I, B-II, B-III, and B-IV; wherein B is connected at any ring atom to L2; B-I is B-II is B-III is B-IV is each of Z1, Z2, Z3, and Z4 is independently CR7, N, or NR9; Z5 is C or N; each of Z6, Z7, and Z8 is independently CR8, N, NR9, O, or S; each of Z9, Z10, and Z11 is independently CR10, CR11R12, NR13, O, or S; n is an integer from 0 to 6; each of R1, R2, R3, R5, R6, R7, R8, R9, R10, R11, R12, and R13 is, at each occurrence, independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino; each of RA and RB is, at each occurrence, independently selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino, wherein two RA groups or two RB groups attached to the same atom or different atoms can together optionally form a bridge or ring; and R14 is halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, or heteroarylalkylamino. 24. The method of claim 23, wherein: X5 is S; X6 is CR3, wherein R3 in X6 is selected from H, halo, amino, carboxyl, and alkyl; L2 is C1-C4 alkylene; L3 is carbonyl, O, S, or —NR5—; B is Z1 and Z2 are CR7; Z5 is C; Z6 is NRB; Z7 and Z8 are CR8; R1 is haloalkyl; and R14 is halo, hydroxyl, alkoxy, alkylamino, amino, cyano, amido, alkyl, heteroalkyl, or haloalkyl.