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US-20260125387-A1 - (R)-N-ETHYL-5-FLUORO-N-ISOPROPYL-2-((5-(2-(6-((2-METHOXYETHYL)(METHYL)AMINO)-2-METHYLHEXAN-3-YL)-2,6-DIAZASPIRO[3.4]OCTAN-6-YL)-1,2,4-TRIAZIN-6-YL)OXY)BENZAMIDE BESYLATE SALT

US20260125387A1US 20260125387 A1US20260125387 A1US 20260125387A1US-20260125387-A1

Abstract

The present invention relates to (R)—N-ethyl-5-fluoro-N-isopropyl-2-(5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide besylate salt and solvates thereof. This compound may be useful for therapy and/or prophylaxis in a mammal, pharmaceutical composition comprising such compound, and use as menin/MLL protein/protein interaction inhibitor, useful for treating diseases such as cancer, including but not limited to leukemia, myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN); and diabetes.

Inventors

  • Wei Cai
  • Vineet Pande
  • Edward Cleator
  • Cyril BEN HAIM
  • Simon Jan C. SMOLDERS
  • Xuedong Dai
  • Olivier Alexis Georges Querolle
  • Johannes Wilhelmus J. Thuring
  • Alicia Tee Fuay Ng
  • Nicolas Freddy Jacques BRUNO
  • Robert Michael Geertman
  • Dipali AHUJA
  • Yingtao LIU

Assignees

  • JANSSEN PHARMACEUTICA NV

Dates

Publication Date
20260507
Application Date
20220616
Priority Date
20210617

Claims (20)

  1. 1 . (R)—N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide besylate salt or a solvate thereof.
  2. 2 . The compound according to claim 1 wherein the solvate is a hydrate.
  3. 3 . The compound according to claim 1 wherein the compound is a crystalline form A of (R)—N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide bis-besylate salt hydrate, wherein the crystalline form produces an X-ray powder diffraction pattern comprising peaks at 5.4, 7.2, 11.1, 11.9, and 21.7 degrees two theta±0.2 degrees two theta.
  4. 4 . The crystalline form of claim 3 , wherein the X-ray powder diffraction pattern may further comprise at least one peak selected from 13.7, 14.5, 14.7, 15.0, 16.5, 17.8, 19.0, 19.4, and 20.1 degrees two theta±0.2 degrees two theta.
  5. 5 . The crystalline form of claim 3 , further characterized by an X-ray powder diffraction pattern substantially as depicted in FIG. 1 .
  6. 6 . A pharmaceutical composition comprising a compound of claim 1 and at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and a pharmaceutically acceptable diluent.
  7. 7 . A process for preparing a pharmaceutical composition as defined in claim 6 comprising mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of a compound according to claim 1 .
  8. 8 . A compound as claimed in claim 1 use as a medicament.
  9. 9 . A compound as claimed in claim 1 for use in the prevention or treatment of cancer.
  10. 10 . The compound as claimed in claim 9 where the cancer is leukemia, myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN).
  11. 11 . The compound for use according to claim 10 in the prevention or treatment of leukemia wherein the leukemia is (NPM1)-mutated leukemia.
  12. 12 . The compound for use according to claim 9 , wherein cancer is selected from leukemias, lymphomas, myelomas or solid tumor cancers such as prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma and glioblastoma.
  13. 13 . The compound for use according to claim 10 , wherein the leukemia is selected from acute leukemias, chronic leukemias, myeloid leukemias, myelogenous leukemias, lymphoblastic leukemias, lymphocytic leukemias, Acute myelogenous leukemias (AML), Chronic myelogenous leukemias (CML), Acute lymphoblastic leukemias (ALL), Chronic lymphocytic leukemias (CLL), T cell prolymphocytic leukemias (T-PLL), Large granular lymphocytic leukemia, Hairy cell leukemia (HCL), MLL-rearranged leukemias, MLL-PTD leukemias, MLL amplified leukemias, MLL-positive leukemias, and leukemias exhibiting HOX/MEIS1 gene expression signatures.
  14. 14 . A method of treating or preventing cancer, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound as claimed in claim 1 .
  15. 15 . A process for preparing the crystalline form of claim 3 , comprising the step of recrystallising (R)—N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl) (methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy) benzamide (Compound A) wherein the recrystallisation comprises the steps of: a) adding Compound A, or a hydrate or solvate thereof, to a mixture of suitable solvents, in the presence of benzenesulfonic acid, and adjusting to a temperature in the range of from about 20° C. to solvent reflux temperature; b) seeding with crystalline form A; c) yielding a precipitate of the crystalline form of claim 3 .
  16. 16 . The process of claim 15 , wherein the mixture of suitable solvents is a mixture of acetone, water and IPAc.
  17. 17 . The process of claim 15 , wherein the mixture of suitable solvents is a mixture of isopropanol, water and IPAc.
  18. 18 . The process of claim 15 wherein the temperature is about 25° C.
  19. 19 . A crystalline form of Bn citric acid salt, wherein the crystalline form produces an X-ray powder diffraction pattern comprising peaks at 5.82, 10.09 and 18.42 degrees two theta±0.2 degrees two theta.
  20. 20 . A method to provide N-ethyl-5-fluoro-2-hydroxy-N-isopropylbenzamide via a one step reaction by reacting 5-fluoro-2-hydroxy-benzoic acid in the presence of the coupling agent CDI, in a suitable solvent:

Description

SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Aug. 20, 2025 is named JAB7103USPCT3 SL.txt and is 6,392 bytes in size. FIELD OF THE INVENTION The present invention relates to (R)—N-ethyl-5-fluoro-N-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide besylate salt and solvates thereof. This compound may be useful for therapy and/or prophylaxis in a mammal, pharmaceutical composition comprising such compound, and use as menin/MLL protein/protein interaction inhibitor, useful for treating diseases such as cancer, including but not limited to leukemia, myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN); and diabetes. BACKGROUND OF THE INVENTION Chromosomal rearrangements affecting the mixed lineage leukemia gene (MLL; MLL1; KMT2A) result in aggressive acute leukemias across all age groups and still represent mostly incurable diseases emphasizing the urgent need for novel therapeutic approaches. Acute leukemias harboring these chromosomal translocations of MLL represent as lymphoid, myeloid or biphenotypic disease and constitute 5 to 10% of acute leukemias in adults and approximately 70% in infants (Marschalek, Br J Haematol 2011. 152(2), 141-54; Tomizawa et al., Pediatr Blood Cancer 2007. 49(2), 127-32). MLL is a histone methyltransferase that methylates histone H3 on lysine 4 (H3K4) and functions in multiprotein complexes. Use of inducible loss-of-function alleles of Mill demonstrated that Mll1 plays an essential role in sustaining hematopoietic stem cells (HSCs) and developing B cells although its histone methyltransferase activity is dispensable for hematopoiesis (Mishra et al., Cell Rep 2014. 7(4), 1239-47). Fusion of MLL with more than 60 different partners has been reported to date and has been associated with leukemia formation/progression (Meyer et al., Leukemia 2013. 27, 2165-2176). Interestingly, the SET (Su(var)3-9, enhancer of zeste, and trithorax) domain of MLL is not retained in chimeric proteins but is replaced by the fusion partner (Thiel et al., Bioessays 2012. 34, 771-80). Recruitment of chromatin modifying enzymes like Dot1L and/or the pTEFb complex by the fusion partner leads to enhanced transcription and transcriptional elongation of MLL target genes including HOXA genes (e.g. HOXA9) and the HOX cofactor MEIS1 as the most prominent ones. Aberrant expression of these genes in turn blocks hematopoietic differentiation and enhances proliferation. Menin which is encoded by the Multiple Endocrine Neoplasia type 1 (MEN1) gene is expressed ubiquitously and is predominantly localized in the nucleus. It has been shown to interact with numerous proteins and is, therefore, involved in a variety of cellular processes. The best understood function of menin is its role as an oncogenic cofactor of MLL fusion proteins. Menin interacts with two motifs within the N-terminal fragment of MLL that is retained in all fusion proteins, MBM1 (menin-binding motif 1) and MBM2 (Thiel et al., Bioessays 2012. 34, 771-80). Menin/MLL interaction leads to the formation of a new interaction surface for lens epithelium-derived growth factor (LEDGF). Although MLL directly binds to LEDGF, menin is obligatory for the stable interaction between MLL and LEDGF and the gene specific chromatin recruitment of the MLL complex via the PWWP domain of LEDGF (Cermakova et al., Cancer Res 2014. 15, 5139-51; Yokoyama & Cleary, Cancer Cell 2008. 8, 36-46). Furthermore, numerous genetic studies have shown that menin is strictly required for oncogenic transformation by MLL fusion proteins suggesting the menin/MLL interaction as an attractive therapeutic target. For example, conditional deletion of Men1 prevents leukemogenesis in bone marrow progenitor cells ectopically expressing MLL fusions (Chen et al., Proc Natl Acad Sci 2006. 103, 1018-23). Similarly, genetic disruption of menin/MLL fusion interaction by loss-of-function mutations abrogates the oncogenic properties of the MLL fusion proteins, blocks the development of leukemia in vivo and releases the differentiation block of MLL-transformed leukemic blasts. These studies also showed that menin is required for the maintenance of HOX gene expression by MLL fusion proteins (Yokoyama et al., Cell 2005. 123, 207-18). In addition, small molecule inhibitors of menin/MLL interaction have been developed suggesting druggability of this protein/protein interaction and have also demonstrated efficacy in preclinical models of AML (Borkin et al., Cancer Cell 2015. 27, 589-602; Cierpicki and Grembecka, Future Med Chem 2014. 6, 447-462). Together with the observation that menin is not a requisite cofactor of MLL1 during normal hematopoiesis (Li et al., Blood 2013. 122, 2039-2046), these data validate the disruption of menin/MLL interaction