Claims for Patent: 10,781,218

Summary for Patent: 10,781,218

Title:	Substituted inhibitors of menin-MLL and methods of use
Abstract:	The present disclosure provides compounds of Formula (II-A), which inhibit the interaction of menin with one or more of MLL1, MLL2 and MLL-fusion oncoproteins. Also disclosed are methods 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):	Tao Wu, Liansheng Li, Yi Wang, Pingda Ren, Jolanta Grembecka, Tomasz Cierpicki, Szymon Klossowski, Jonathan Pollock, Dmitry Borkin
Assignee:	Wellspring Biosciences LLC , University of Michigan System , Kura Oncology Inc
Application Number:	US16/082,649
Patent Claims:	1. A compound of Formula (II-A): or a pharmaceutically acceptable salt thereof, wherein: C is selected from C3-12 carbocycle and 3- to 12-membered heterocycle; L2 is selected from bond, —O—, —S—, —N(R51)—, —N(R51)CH2—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R51)—, —C(O)N(R51)C(O)—, —C(O)N(R51)C(O)N(R51)—, —N(R51)C(O)—, —N(R51)C(O)N(R51)—, —N(R51)C(O)O—, —OC(O)N(R51)—, —C(NR51)—, —N(R51)C(NR51)—, —C(NR51)N(R51)—, —N(R51)C(NR51)N(R51)—, —S(O)2-, —OS(O)—, —S(O)O—, —S(O)—, —OS(O)2—, —S(O)2O—, —N(R51)S(O)2—, —S(O)2N(R51)—, —N(R51)S(O)—, —S(O)N(R51)—, —N(R51)S(O)2N(R51)—, —N(R51)S(O)N(R51)—, alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which is optionally substituted with one or more R50; L3 is selected from alkylene, alkenylene, and alkynylene, each of which is substituted with one or more R56 and optionally further substituted with one or more R50; R1 and R3 are each independently selected from hydrogen and R50; R2 is R50; RA, RB, and RC are each independently selected at each occurrence from R50, or two RA groups, two RB groups, or two RC groups attached to the same atom or different atoms can together optionally form a bridge or ring; m, n, and p are each independently an integer from 0 to 6; R50 is independently selected at each occurrence from: halogen, —NO2, —CN, —OR52, —SR52, —N(R52)2, —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(=O)2NR53R54, —NR52S(=O)2R52, —NR52S(=O)2N(R52)2, —NR52S(=O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)NR53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, ═O, ═S, and ═N(R52); C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO2, —CN, —OR52, —SR52, —N(R52)2, —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(=O)2NR53R54, —NR52S(=O)2R52, —NR52S(=O)2N(R52)2, —NR52S(=O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)NR53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, ═O, ═S, ═N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and C3-12 carbocycle and 3- to 12-membered heterocycle, wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R50 is independently optionally substituted with one or more substituents selected from halogen, —NO2, —CN, —OR52, —SR52, —N(R52)2, —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(=O)2NR53R54, —NR52S(=O)2R52, —NR52S(=O)2N(R52)2, —NR52S(=O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)NR53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, ═O, ═S, ═N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; R51 is independently selected at each occurrence from: hydrogen, —C(O)R52, —C(O)OR52, —C(O)N(R52)2,and —C(O)NR53R54; and 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, —NO2, —CN, —OR52, —SR52, —N(R52)2, —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(=O)2R52, —NR52S(=O)2N(R52)2, —NR52S(=O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)NR53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, ═O, ═S, ═N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; and C3-12 carbocycle and 3- to 12-membered heterocycle, wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R51 is independently optionally substituted with one or more substituents selected from halogen, —NO2, —CN, —OR52, —SR52, —N(R52)2, —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(=O)2R52, —NR52S(=O)2N(R52)2, —NR52S(=O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)NR53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, ═O, ═S, ═N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; R52 is independently selected at each occurrence from hydrogen; and C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, C1—6 heteroalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle; R53 and R54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R50; R56 is independently selected at each occurrence from: —NO2, —SR52, —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(=O)2R52, —NR52S(=O)2N(R52)2, —NR52S(=O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)NR53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, ═O, ═S, ═N(R52), C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein each C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl in R56 is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO2, —CN, —OR59, —SR52, —N(R52)2, —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(=O)2NR53R54, —NR52S(=O)2R52, —NR52S(=O)2N(R52)2, —NR52S(=O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)NR53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, ═O, ═S, ═N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R56 is independently optionally substituted with one or more substituents selected from halogen, —NO2, —CN, —OR52, —SR52, —N(R52)2, —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(=O)2NR53R54, —NR52S(=O)2R52, —NR52S(=O)2N(R52)2, —NR52S(=O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)NR53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, ═O, ═S, ═N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; and further wherein R56 optionally forms a bond to ring C; and R59 is independently selected at each occurrence from C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, C1—6 heteroalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle, wherein for a compound or salt of Formula (II-A), when R56 is —CH3, L3 is not further substituted with —OH, —NH2, or —CN. 2. The compound of claim 1, wherein Rc is selected from —C(O)R52, —S(=O)R52, —S(=O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(—O)2R52, =O, C1-3 alkyl, and C1-3 haloalkyl, or two RC groups attached to different atoms can together form a C1-3 bridge. 3. The compound of claim 1, wherein C is 5- to 12-membered saturated heterocycle, wherein the heterocycle comprises at least one nitrogen atom. 4. The compound of claim 1, wherein C is selected from: wherein R57 is selected from —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(=O)2R52, and C1-10 alkyl substituted with one or more substituents selected from —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, and —NR52S(=O)2R52. 5. The compound of claim 1, wherein: R2 is selected from hydrogen, halogen, —OH, —OR52, —NH2, —N(R52)2, —CN, C1-3 alkyl, C1-3 alkyl-N(R52)2, C1-3 haloalkyl, C2-3 alkenyl, and C2-3 alkynyl; and R3 is selected from hydrogen, halogen, —OH, —N(R52)2, —CN, —C(O)OR52, C1-3 alkyl, and C1-3 haloalkyl. 6. The compound of claim 1, wherein R1 is C1-3 haloalkyl. 7. The compound of claim 1, wherein m is 0. 8. The compound of claim 1, wherein n is an integer from 1 to 3. 9. The compound of claim 1, wherein L2 is C1-4 alkylene, optionally substituted with one or more R50. 10. The compound of claim 1, wherein L3 is substituted with =O, C1-6 alkyl, C1-6 haloalkyl, C1-3 alkyl(cyclopropyl), C1-3 alkyl(NR52C(O)R52) or —O(C1-6 alkyl). 11. The compound of claim 1, wherein L3 is selected from 12. The compound of claim 11, wherein R56 is methyl. 13. The compound of claim 1, wherein: L2 is selected from —O—, —S—, —NH—, and —CH2—; L3 is selected from C1-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene, each of which is substituted with one or more R56 and optionally further substituted with one or more R50; RA, RB, and RC are each independently selected at each occurrence from R50, or two RA groups, two RB groups, or two RC groups attached to the same atom or different atoms can together optionally form a bridge or ring; m is an integer from 0 to 3; n is an integer from 1 to 3; p is an integer from 0 to 6; R56 is independently selected at each occurrence from: —OR59, =O, C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl, wherein each C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl in R56 is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —NO2, —CN, —OR59, —SR52, —N(R52)2, —NR53R54, —S(=O)R52, —S(=O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(—O)2R52, —NR52S(=O)2N(R52)2, —NR52S(—O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)NR53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, ═O, ═S, ═N(R52), C3-12 carbocycle, and 3- to 12-membered heterocycle; wherein each C3-12 carbocycle and 3- to 12-membered heterocycle in R56 is independently optionally substituted with one or more substituents selected from halogen, —NO2, —CN, —OR52, —SR52, —N(R52)2, —NR53R54, —S(═O)R52, —S(═O)2R52, —S(═O)2N(R52)2, —S(═O)2NR53R54, —NR52S(=O)2R52, —NR52S(=O)2N(R52)2, —NR52S(=O)2NR53R54, —C(O)R52, —C(O)OR52, —OC(O)R52, —OC(O)OR52, —OC(O)N(R52)2, —OC(O)NR53R54, —NR52C(O)R52, —NR52C(O)OR52, —NR52C(O)N(R52)2, —NR52C(O)NR53R54, —C(O)N(R52)2, —C(O)NR53R54, —P(O)(OR52)2, —P(O)(R52)2, ═O, ═S, ═N(R52), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; and further wherein R56 optionally forms a bond to ring C; and R59 is independently selected at each occurrence from C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, C1—6 heteroalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, —CN, —NO2, —NH2, —NHCH3, —NHCH2CH3, ═O, —OH, —OCH3, —OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle. 14. The compound of claim 13, wherein p is 1 and RC is —S(═O)2R52, —S(═O)2N(R52)2, or —S(═O)2NR53R54. 15. The compound of claim 13, wherein the compound is a stereoisomer provided in at least 90% enantiomeric excess. 16. The compound of claim 1, wherein the compound has the structure of Formula (II-C): 17. The compound of claim 1, wherein the compound has the structure of Formula (II-F) or Formula (II-H): 18. The compound of claim 1, wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt thereof. 19. The compound of claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof. 20. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.