Claims for Patent: 10,077,271

Summary for Patent: 10,077,271

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:	US15/829,604
Patent Claims:	1. 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, cycloalkyl alkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclyl alkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclyl amino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkyl amino, 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, cycloalkyl amino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, or heteroarylalkylamino. 2. The compound of claim 1, wherein R14 is halo, hydroxyl, alkoxy, alkylamino, amino, cyano, amido, alkyl, heteroalkyl, or haloalkyl. 3. The compound of claim 1, wherein X6 is CR3 and R3 in X6 is selected from H, halo, amino, carboxyl, and alkyl. 4. The compound of claim 1, wherein L3 is carbonyl, O, S, or —NR5—. 5. The compound of claim 1, wherein L2 is C1-C4 alkylene. 6. The compound of claim 1, wherein X2 is N. 7. The compound of claim 1, wherein R1 is a haloalkyl. 8. The compound of claim 1, wherein m is 0 and n is 1 or 2. 9. The compound of claim 1, wherein R5 is H or alkyl. 10. The compound of claim 1, wherein B is B-II. 11. The compound of claim 10, wherein B-II is 12. The compound of claim 1, comprising B-II, wherein: Z1 and Z2 are CR7; Z5 is C; Z6 is NRB; and Z7 and Z8 are CR8. 13. The compound 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. 14. The compound 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. 15. The compound of claim 14, wherein V is selected from: any one of which is optionally substituted with one or more R32 groups. 16. The compound of claim 14, wherein G is alkylene optionally substituted with one or more R32 groups. 17. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. 18. The compound of claim 14, 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 a 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.