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US-12616682-B2 - 1-H-pyrrolo[2,3-c]pyridine compounds

US12616682B2US 12616682 B2US12616682 B2US 12616682B2US-12616682-B2

Abstract

Compounds having the structure of Formula (I): and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4 , and A are as defined in the specification; pharmaceutical compositions comprising such compounds and salts; use of such compounds and salts to treat or prevent Menin-mediated conditions; kits comprising such compounds and salts; and methods for manufacturing such compounds and salts.

Inventors

  • Stephen Atkinson
  • Gerjan DE BRUIN
  • Flavia Izzo
  • Chimed JANSEN
  • Olaf Kinzel
  • Martin Packer
  • Saskia Verkaik
  • Robin VOETS

Assignees

  • ACERTA PHARMA B.V.

Dates

Publication Date
20260505
Application Date
20250127

Claims (19)

  1. 1 . A compound that is(S)-2-(3-(1-(5,5-dimethylpyrrolidine-2-carbonyl) piperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N,N-diisopropylbenzamide having the structure: or a pharmaceutically acceptable salt thereof.
  2. 2 . A compound that is (S)-2-(3-(1-(5,5-dimethylpyrrolidine-2-carbonyl) piperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N,N-diisopropylbenzamide having the structure: or a pharmaceutically acceptable salt thereof.
  3. 3 . The compound of claim 2 that is (S)-2-(3-(1-(5,5-dimethylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N,N-diisopropylbenzamide having the structure:
  4. 4 . The salt of claim 2 that is the pharmaceutically acceptable salt of the compound that is (S)-2-(3-(1-(5,5-dimethylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N,N-diisopropylbenzamide having the structure:
  5. 5 . A pharmaceutical composition comprising a compound that is (S)-2-(3-(1-(5,5-dimethylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N,N-diisopropylbenzamide having the structure: or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipients.
  6. 6 . The pharmaceutical composition of claim 5 comprising the compound that is (S)-2-(3-(1-(5,5-dimethylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N,N-diisopropylbenzamide having the structure: and one or more pharmaceutically acceptable excipients.
  7. 7 . The pharmaceutical composition of claim 5 comprising the pharmaceutically acceptable salt of the compound that is (S)-2-(3-(1-(5,5-dimethylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N,N-diisopropylbenzamide having the structure: and one or more pharmaceutically acceptable excipients.
  8. 8 . A method of treating leukemia in a subject suffering from or susceptible to the leukemia, wherein the method comprises administering to the subject a therapeutically effective amount of a compound that is (S)-2-(3-(1-(5,5-dimethylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N,N-diisopropylbenzamide having the structure: or a pharmaceutically acceptable salt thereof.
  9. 9 . The method of claim 8 , wherein the method comprises administering to the subject a therapeutically effective amount of a compound that is ((S)-2-(3-(1-(5,5-dimethylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N,N-diisopropylbenzamide having the structure:
  10. 10 . The method of claim 8 , wherein the method comprises administering to the subject a therapeutically effective amount of the pharmaceutically acceptable salt of the compound that is(S)-2-(3-(1-(5,5-dimethylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N,N-diisopropylbenzamide having the structure:
  11. 11 . The method of claim 8 , wherein the leukemia is selected from the group consisting of acute myeloid leukemia and acute lymphoid leukemia.
  12. 12 . The method of claim 8 , wherein the leukemia is acute myeloid leukemia.
  13. 13 . The method of claim 8 , wherein the leukemia is selected from the group consisting of mixed-lineage leukemia (MLL)-rearranged leukemia and NPM1-mutant acute myeloid leukemia.
  14. 14 . The method of claim 9 , wherein the leukemia is selected from the group consisting of acute myeloid leukemia and acute lymphoid leukemia.
  15. 15 . The method of claim 9 , wherein the leukemia is acute myeloid leukemia.
  16. 16 . The method of claim 9 , wherein the leukemia is selected from the group consisting of mixed-lineage leukemia (MLL)-rearranged leukemia and NPM1-mutant acute myeloid leukemia.
  17. 17 . The method of claim 10 , wherein the leukemia is selected from the group consisting of acute myeloid leukemia and acute lymphoid leukemia.
  18. 18 . The method of claim 10 , wherein the leukemia is acute myeloid leukemia.
  19. 19 . The method of claim 10 , wherein the leukemia is selected from the group consisting of mixed-lineage leukemia (MLL)-rearranged leukemia and NPM1-mutant acute myeloid leukemia.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 18/613,180 filed on Mar. 22, 2024, which claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63/491,978, filed on Mar. 24, 2023. The above-listed applications are incorporated by reference in their entirety for all purposes. FIELD The present disclosure relates generally to 1-H-pyrrolo[2,3-c]pyridines and pharmaceutically acceptable salts thereof. The specification further relates to pharmaceutical compositions comprising such compounds and salts; use of such compounds and salts to treat or prevent Menin-mediated conditions; kits comprising such compounds and salts; and methods for manufacturing such compounds and salts. BACKGROUND MLL1 is a histone methyltransferase encoded by the mixed-lineage leukemia 1 (MLL1) gene (also known as the KMT2A gene) on chromosome 11q23. MLL1 is a transcriptional coactivator that plays an essential role in regulating gene expression during early development and hematopoiesis. Multiple chromosomal translocations involving the MLL1 gene are the cause of certain acute myeloid leukemias (AML) and acute lymphoid leukemias (ALL). These chromosomal translocations have the downstream effect of upregulating HOXA9 and MEIS1 gene expression critical to leukemogenesis. HOXA9 and MEIS1 then contribute to enhanced proliferation and blockage of hematopoietic differentiation ultimately leading to acute leukemias. MLL1-rearranged (MLL1-r) leukemias are associated with resistance to standard therapies and higher rates of relapse. Patients with MLL1-r leukemias generally have an unfavorable prognosis and respond poorly to available treatments relative to patients with non-MLL1-r leukemias. MLL1 normally associates with a cohort of highly conserved cofactors to form a macromolecular complex. One of these cofactors is Menin, a product of the MEN1 tumor suppressor gene. Menin is an essential cofactor necessary for binding of the MLL1 complex to promoters of target genes. The Menin binding site on MLL1 is located on the N-terminus and preserved throughout MLL1 fusion proteins resulting from the chromosomal rearrangements. Current treatments for MLL1-r leukemias are conventional chemotherapeutics that non-selectively kill all rapidly proliferating cells including normal stem/progenitor cells in the bone marrow and other organs including the intestines. Such treatments can cause severe toxicities, side effects, and even secondary cancers. Targeted pharmacologic inhibition of Menin-MLL1 binding is a presently unexploited therapeutic approach for treating leukemias and other diseases associated with Menin activity. No approved pharmacological agents that inhibit Menin activity generally, or that inhibit Menin activity specifically, are currently available. Accordingly, there is a need for Menin inhibitors, particularly Menin inhibitors having pharmacologically appropriate properties including selectivity and bioavailability, that are suitable for administration to a subject in need of such treatment. The present disclosure addresses this large unmet need by providing such compounds together with corresponding pharmaceutical compositions and methods for the treatment or prevention of cancers, particularly MLL1-r leukemias, and other Menin-mediated conditions. SUMMARY In one aspect, the present disclosure provides compounds having the structure of Formula (I): and pharmaceutically acceptable salts thereof, wherein: R1 is selected from the group consisting of hydrogen and methyl;R2 is hydrogen or fluoro;R3 is hydrogen or fluoro;R4 is selected from the group consisting of:(a) —C(O)NR5R6;(b) phenyl optionally substituted with one to three substituents independently selected from the group consisting of fluoro, cyano, C1-4-alkyl, halo-C1-4-alkyl, C3-4-cycloalkyl, and halo-C3-4-cycloalkyl; and(c) 5- or 6-membered ring heteroaryl having one, two, or three ring atoms independently selected from nitrogen, oxygen, and sulfur with the remaining ring atoms being carbon, wherein the heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of fluoro, cyano, C1-4-alkyl, halo-C1-4-alkyl, C3-4-cycloalkyl, and halo-C3-4-cycloalkyl;R5 and R6 are independently selected from C1-4-alkyl and halo-C1-4-alkyl; or R5 and R6, together with the nitrogen atom to which they are attached, form a 5- to 7-membered ring heterocyclyl, wherein the heterocyclyl: (i) is a saturated monocyclic ring, (ii) has one or two ring atoms independently selected from nitrogen and oxygen with the remaining ring atoms being carbon, and (iii) is optionally substituted with one to three substituents independently selected from the group consisting of C1-4-alkyl and halo-C1-4-alkyl;X is —C(R9)— or —N—;R9 is selected from the group consisting of hydrogen, fluorine, and methyl;A is selected from the group consisting of: each RA substituent is optionally and independentl