Claims for Patent: 11,944,627

Summary for Patent: 11,944,627

Title:	Methods for treating hematological malignancies and Ewing's sarcoma
Abstract:	The present disclosure provides methods for treating hematological malignancies and Ewings sarcoma using menin inhibitors. Compositions for use in these methods are also provided.
Inventor(s):	Francis Burrows, Linda V. KESSLER, Liansheng Li, Pingda Ren, Yi Wang, Tao Wu, Jingchuan Zhang
Assignee:	Wellspring Biosciences LLC , Kura Oncology Inc
Application Number:	US16/494,556
Patent Claims:	1. A method of treating acute myeloid leukemia or acute lymphoblastic leukemia in a subject, comprising administering a menin inhibitor to the subject, wherein the subject has elevated myeloid ecotropic viral integration site 1 (MEIS1) expression levels, and wherein the menin inhibitor is a compound of Formula (I-B-1): 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, —C(O)—, —C(O)O—, —C(O)N(R51)—, —C(O)N(R51)C(O)—, —C(O)N(R51)C(O)N(R51)—, —C(NR51)—, —C(NR51)N(R51)—, —S(O)2—, —S(O)O—, —S(O)—, S(O)2O—, —S(O)2N(R51)—, —S(O)N(R51)—, alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, wherein each alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene 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 and p are each independently an integer from 0 to 6; n is an integer from 0 to 5; 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, and —P(O)(R52)2, or two R50 groups attached to the same carbon are taken together to form ═O, ═S, or ═N(R52); C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is optionally substituted at each occurrence with one or more substituents independently 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 optionally substituted with one or more substituents independently 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; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted at each occurrence with one or more substituents independently 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 optionally substituted with one or more substituents independently 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; R56 is independently selected at each occurrence from: —NO2, —OR59, —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, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle and 3- to 12-membered heterocycle, or two R56 groups attached to the same carbon are taken together to form ═O, ═S, or ═N(R52), wherein each C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl in R56 is optionally substituted at each occurrence with one or more substituents independently 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 optionally substituted with one or more substituents independently 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 when R56 is —CH3, L3 is not further substituted with —OH, —NH2, or —CN. 2. The method of claim 1, wherein the administering reduces expression of a target gene. 3. The method of claim 2, wherein the target gene is Meis1. 4. The method of claim 1, wherein the subject has a nucleoporin 98 (NUP98) gene fusion, a mutation in the nucleophosmin (NPM1) gene, a mutation in the DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene, a mutation in the FMS-like tyrosine kinase-3 (FLT3) gene, a mutation in the isocitrate dehydrogenase 1 (IDH1) gene, a mutation in the isocitrate dehydrogenase 2 (IDH2) gene, or a mixed lineage leukemia (MLL) gene amplification. 5. The method of claim 1, wherein the subject has a mixed lineage leukemia (MLL) gene rearrangement or a partial tandem duplication of MLL. 6. The method of claim 1, wherein the subject has a mixed lineage luekemia (MLL) gene rearrangement. 7. The method of claim 1, wherein the subject has a partial tandem duplication of the mixed lineage leukemia (MLL) gene. 8. The method of claim 1, wherein the subject has a mutation in the nucleophosmin (NPM1) gene. 9. The method of claim 1, wherein the subject has a nucleoporin 98 (NUP98) gene fusion. 10. The method of claim 1, wherein the subject has a mutation in the isocitrate dehydrogenase 1 (IDH1) gene. 11. The method of claim 1, wherein the subject has a mutation in the isocitrate dehydrogenase 2 (IDH2) gene. 12. The method of claim 1, wherein the subject has a mutation in the DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene. 13. The method of claim 1, wherein the subject has a mutation in the FMS-like tyrosine kinase-3 (FLT3) gene. 14. The method of claim 1, wherein R2 is selected from halogen, —OR52, N(R52)2, —CN, C1-3 alkyl, —CH2OR52, —CH2N(R52)2, 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. 15. The method of claim 1, wherein R1 is C1-3 haloalkyl. 16. The method of claim 1, wherein m is 0 and n is an integer from 1 to 3. 17. The method of claim 1, wherein L2 is C1-4 alkylene, optionally substituted with one or more R50; and L3 is C1-4 alkylene, optionally substituted with one or more R50. 18. The method of claim 1, wherein the compound of Formula (I-B-1) or a pharmaceutically acceptable salt thereof is a compound of Formula (I-B-6) or Formula (I-B-8): or a pharmaceutically acceptable salt thereof. 19. The method of claim 1, wherein the compound of Formula (I-B-1) is: or a pharmaceutically acceptable salt thereof. 20. A method of treating acute myeloid leukemia or acute lymphoblastic leukemia in a subject comprising administering to the subject a compound that is: or a pharmaceutically acceptable salt thereof; wherein the subject has elevated MEIS1 expression levels.