WO2021067215A1 - Composés de pipéridine utilisés en tant qu'inhibiteurs de ménine - Google Patents

Composés de pipéridine utilisés en tant qu'inhibiteurs de ménine Download PDF

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WO2021067215A1
WO2021067215A1 PCT/US2020/053186 US2020053186W WO2021067215A1 WO 2021067215 A1 WO2021067215 A1 WO 2021067215A1 US 2020053186 W US2020053186 W US 2020053186W WO 2021067215 A1 WO2021067215 A1 WO 2021067215A1
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compound
pharmaceutically acceptable
group
acceptable salt
cancer
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PCT/US2020/053186
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English (en)
Inventor
Shaomeng Wang
Angelo AGUILAR
Fuming XU
Meng Zhang
Liyue HUANG
Jeanne A. STUCKEY
Renqi XU
Haibin Zhou
Shilin Xu
Tao Liu
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Agios Pharmaceuticals, Inc.
The Regents Of The University Of Michigan
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Publication of WO2021067215A1 publication Critical patent/WO2021067215A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • the present disclosure provides compounds as menin inhibitors and therapeutic methods of treating conditions and diseases wherein inhibition of menin provides a benefit.
  • MLL Mixed-lineage leukemia
  • MLL is a proto-oncogene that was originally discovered at the site of chromosomal translocations in human leukemias. Due to chromosomal translocations, MLL is fused with more than 40 different partner proteins to yield a diverse collection of chimeric fusion proteins.
  • the MLL protein is a histone methyltransferase that covalently modifies chromatin and is mutated in certain subsets of acute leukemia.
  • Many of the fusion partners constitutively activate novel transcriptional effector properties of MLL that often correlate with its oncogenic potential in animal models of acute leukemia.
  • MLL normally associates with a group of highly conserved cofactors to form a macromolecular complex that includes menin, a product of the MEN1 tumor suppressor gene.
  • the MEN1 gene is mutated in heritable and sporadic endocrine tumors.
  • Menin is in involved in a diverse network of protein-protein interactions.
  • menin a component of a single-stranded DNA-binding protein involved in DNA repair and replication.
  • Menin also interacts with FANCD2, a nuclear protein that plays a critical role in maintaining genome stability with breast cancer 1 gene (Breal) product.
  • menin which does not have significant homology with other proteins, functions as a tumor suppressor
  • Menin plays a role in regulating cellular proliferation because Menl knockout mice show increased proliferation in neuroendocrine tissues, down-modulation of menin in epithelial cells increases proliferation, and Menl knockout fibroblasts proliferate more rapidly than wild-type cells as assayed by tritiated thymidine incorporation.
  • MEN1 cells also have increased sensitivity to DNA-damaging agents. Menin interacts with promoters of HOX genes.
  • MLL fusion proteins stably associate with menin through a high-affinity interaction that is required for the initiation of MLL-mediated leukemogenesis. Menin is essential for maintenance of MLL-associated but no other oncogene induced myeloid transformation. Acute genetic ablation of menin reverses HOX gene expression mediated by MLL-menin promoter-associated complexes, and specifically eliminates the differentiation arrest and oncogenic properties of MLL-transformed leukemic blasts.
  • MLL fusion proteins transform hematopoietic cells through two alternate mechanisms, by either constitutive transcriptional effector activity or inducing forced MLL dimerization and oligomerization. Both mechanisms result in the inappropriate expression of a subset of HOX genes, particularly HOXA9, whose consistent expression is a characteristic feature of human MLL leukemias.
  • HOXA9 Aberrant expression of HOX genes is also found in AML patients with mutations in NPM1.
  • NPM1 localizes predominantly in the nucleus and functions in diverse cellular processes, including ribosome assembly, nucleosome assembly and cell proliferation.
  • NPM1 Mutations in NPM1 lead to abnormal cytoplasmic localization and constitute one of the second most frequent mutations in AML accounting for nearly 30% of all AML patients. It has been recently demonstrated that menin contributes to modulation of HOX genes and cell proliferation in NPM1 mutant AML cells in vitro and in vivo, although the mechanism remains mostly unknown.
  • Menin interacts with transcription activators, e.g., sc-Myb, MLL1,
  • transcription repressors e.g., JunD, Sin3A, HDAC, EZH2, PRMT5, NFKB, Sirtl, CHES1, cell signaling proteins, e.g., AKT, SOS1/GEF, b-caten
  • the present disclosure provides piperidines, and related analogs, represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla- XIIc, below, and the pharmaceutically acceptable salts thereof, collectively referred to herein as "Compounds of the Disclosure.”
  • Compounds of the Disclosure are inhibitors of menin and are thus useful in treating diseases or conditions wherein inhibition of menin provides a therapeutic benefit to a patient.
  • the present disclosure provides a method of irreversibly inhibiting menin in a patient, comprising administering to the patient an effective amount of a Compound of the Disclosure.
  • the present disclosure provides methods of treating a condition or disease by administering a therapeutically effective amount of a Compound of the Disclosure to a patient, e.g., a human, in need thereof.
  • the disease or condition is treatable by inhibition of menin, for example, a cancer, e.g., leukemia, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.
  • methods of preventing the proliferation of unwanted proliferating cells, such as cancer, in a subject comprising administering a therapeutically effective amount of a Compound of the Disclosure to a subject at risk of developing a condition characterized by unwanted proliferating cells.
  • the Compounds of the Disclosure reduce the proliferation of unwanted cells by inducing apoptosis and/or differentiation in those cells.
  • the present disclosure provides a method of inhibiting menin in an individual, comprising administering to the individual an effective amount of at least one Compound of the Disclosure.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a Compound of the Disclosure and an excipient and/or pharmaceutically acceptable carrier.
  • the present disclosure provides a composition comprising a Compound of the Disclosure and an excipient and/or pharmaceutically acceptable carrier for use treating diseases or conditions wherein inhibition of menin provides a benefit, e.g., cancer.
  • a composition comprising: (a) a Compound of the Disclosure; (b) a second therapeutically active agent; and (c) optionally an excipient and/or pharmaceutically acceptable carrier.
  • the present disclosure provides a Compound of the Disclosure for use in treatment of a disease or condition of interest, e.g., cancer.
  • the present disclosure provides a use of a Compound of the Disclosure for the manufacture of a medicament for treating a disease or condition of interest, e.g., cancer.
  • the present disclosure provides a kit comprising a Compound of the Disclosure, and, optionally, a packaged composition comprising a second therapeutic agent useful in the treatment of a disease or condition of interest, and a package insert containing directions for use in the treatment of a disease or condition, e.g., cancer.
  • the present disclosure provides methods of preparing Compounds of the Disclosure.
  • Compounds of the Disclosure are menin inhibitors. In some embodiments, Compounds of the Disclosure covalently bind to and inhibit the function of menin.
  • Compounds of the Disclosure are compounds represented by Formula I:
  • R la , R lb , and R lc are each independently selected from the group consisting of hydrogen and halo;
  • R 2 is selected from the group consisting of:
  • R 3 is selected from the group consisting of:
  • R 10a is selected from the group consisting of hydrogen, halo, cyano, Ci-4 alkyl, Ci-4 alkoxy, and hydroxy;
  • X is selected from the group consisting of: [00035] wherein Y is attached to Z 2 ;
  • o and p are each independently 0, 1, 2, or 3;
  • R 8a and R 8b are independently selected from the group consisting of hydrogen and halo;
  • R 13a , R 13b , R 13c , and R 13d are each independently selected from the group consisting of hydrogen, methyl, and dimethylaminomethyl;
  • R a3 is selected from the group consisting of alkoxycarbonyl and alkylsulfonyl;
  • R a5 is selected from the group consisting of alkoxycarbonyl and alkylsulfonyl;
  • R 10a is hydrogen, F, OH, methyl or methoxy
  • Z 2 then R 13d is not hydrogen or methyl
  • R 10a is not hydrogen, F, OH, fluoromethyl, methyl or methoxy
  • R 10a is not hydrogen, F, or methyl
  • Compounds of the Disclosure are compounds represented by Formula la, or a pharmaceutically acceptable salt thereof, wherein
  • R la , R lb , and R lc are each independently selected from the group consisting of hydrogen and halo;
  • G is -SO2-X-Z 2 or -CH2-X-Z 2 ;
  • R 2 is selected from the group consisting of:
  • R 3 is selected from the group consisting of: , wherein the nitrogen atom of L is attached to the M; each R 10a is independently selected from the group consisting of hydrogen, halo, cyano, Ci-4 alkyl, C1-4 alkoxy, and hydroxy;
  • X is selected from the group consisting of:
  • o and p are each independently 0, 1, 2, or 3;
  • Z 2 is absent when X is X-l 0 or when X is X-45;
  • R 8a and R 8b are independently selected from the group consisting of hydrogen, -SO2-C1-C6 alkyl and halo;
  • R 13a , R 13b , R 13c , and R 13d are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, and di-Ci-C6 alkylaminoCi-C4 alkyl;
  • R a3 is selected from the group consisting of C1-C6 alkoxycarbonyl-, heterocyclyl-carbonyl-, halo-substituted heterocyclyl-carbonyl-, C1-C6 alkylamide and C1-C6 alkylsulfonyl;
  • R a5 is selected from the group consisting of C1-C6 alkoxycarbonyl-, heterocyclyl-carbonyl-, halo-substituted heterocyclyl-carbonyl-, C1-C6 alkylamide and Ci-Ce alkylsulfonyl;
  • Compounds of the Disclosure are compounds represented by Formula I or Formula la, and the pharmaceutically acceptable salts thereof, wherein: R 10a is hydrogen, fluoro, cyano, methyl, methoxy, ethoxy, or hydroxy.
  • Compounds of the Disclosure are compounds represented by Formula I or Formula la, and the pharmaceutically acceptable salts thereof, wherein:
  • X is X-l
  • R 8a and R 8b are independently selected from the group consisting of hydrogen and fluoro;
  • R 13a , R 13b , R 13c , and R 13d are each independently selected from the group consisting of hydrogen and dimethylaminomethyl.
  • Compounds of the Disclosure are compounds represented by any one or more of formulae Ib-Ie: lb,
  • Compounds of the Disclosure are compounds represented by any one or more of formulae Ig-Ij:
  • Compounds of the Disclosure are compounds represented by any one or more of formulae XI-XIc:
  • Compounds of the Disclosure are compounds represented by any one or more of formulae XII-XIIc:
  • R la , R lb , R lc , R 2 , R 3 , R 8a , R 8b , L, X, and Z 2 are as defined in connection with Formula I or Formula la.
  • Compounds of the Disclosure are compounds represented by Formula X:
  • compounds of the Disclosure are compounds represented by a compound having Formula X and the pharmaceutically acceptable salts thereof, wherein R la and R 8a are independently fluoro, and R 2 , L, X, and Z 2 are as defined in connection with Formula I or Formula la.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-X, and the pharmaceutically acceptable salts thereof.
  • compounds of the Disclosure are compounds represented by a compound having Formula XI’: and the pharmaceutically acceptable salts thereof, wherein R la , R lb , R lc , R 2 , R 3 , R 10a , R 8a , R 8b , X, and Z 2 are as defined in connection with Formula I or Formula XI.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R la is hydrogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R lb is hydrogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R lc is hydrogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R la is halogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R la is fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R lb is halogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R lb is fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R lc is halogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R lc is fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein at least one of R la , R lb and R lc is a halogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein at least one of R la , R lb and R lc is fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R a3 is alkoxy carbonyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R a3 is alkylsulfonyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R a3 is methoxy carbonyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R a3 is ethoxy carbonyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R a3 is methylsulfonyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R a3 is halo-substituted heterocyclyl- carbonyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein Z 2 is R a4 .
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R a5 is alkoxy carbonyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R a5 is methoxy carbonyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R a5 is ethoxy carbonyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R a5 is alkylsulfonyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R a5 is methylsulfonyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R a5 is heterocyclyl-carbonyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R a5 is halo-substituted heterocyclyl- carbonyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R a5 is fluoro-substituted heterocyclyl-carbonyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R 2 is [000135]
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R 2 is [000136]
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R 2 is .
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R 2 is [000138]
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R 2 is [000139]
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R 2 is [000142]
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R 2 is .
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R 3 is H
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R 3
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R 3 is H
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R 8a and R 8b are hydrogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein at least one of R 8a and R 8b is fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein both R 8a and R 8b are fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein: R 10a is hydrogen, fluoro, cyano, methyl, methoxy, ethoxy, or hydroxy.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R 10a is hydrogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R 10a is fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R 10a is cyano.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R 10a is methyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R 10a is methoxy.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R 10a is ethoxy.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R 10a is hydroxy.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein X is X-l.
  • o and p are 0.
  • X-l is selected from the group consisting of:
  • X-l is selected from the group consisting of:
  • X-l is selected from the group consisting of:
  • X-l is selected from the group consisting of:
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein X is X-9.
  • X-9 is selected from the group consisting of [000166]
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein X is X-10.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein X is X-12.
  • Compounds of the Disclosure are compounds those wherein X is X-21, X-22, X-23, X-24, X-25, X-26, X-27, X-28, X-29, X-30, X-
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein X is X-45.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein X is selected from the group consisting of X-21, X-22, X-23, X-24, X-25, X-26, X-27, X-28, X-29, X-30, X-31, X-
  • R 13a , R 13b , and R 13c are each hydrogen.
  • R 13a is dimethylaminomethyl
  • R 13b and R 13c are independently selected from the group consisting of hydrogen and methyl.
  • R 13a is hydrogen
  • R 13b and R 13c are independently selected from the group consisting of hydrogen, methyl and dimethylaminomethyl.
  • R 13a and R 13b are hydrogen, and R 13C is dimethylaminomethyl or methyl.
  • R 13a and R 13b are hydrogen, and R 13c is dimethylaminomethyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R 13a , R 13b , R 13c , and R 13d are each hydrogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R 13a , R 13b , R 13c , and R 13d are each independently selected from the group consisting of hydrogen and dimethylaminomethyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein R 13a , R 13b , R 13c , and R 13d are each independently selected from the group consisting of hydrogen and methyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein two of R 13a , R 13b , R 13c , and R 13d are each independently selected from the group consisting of methyl and dimethylaminomethyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein no more that one of R 13a , R 13b , R 13c , and R 13d is different from hydrogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein one or two of R 13a , R 13b , R 13c , and R 13d are not hydrogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XII, Ia-Ij, XIa-XIc, Xlla-XIIc, and the pharmaceutically acceptable salts thereof, wherein Z 2 is -CoCR 13d .
  • R 13d is hydrogen.
  • R 13d is methyl.
  • Compounds of the Disclosure are compounds represented by Formula I or la selected from any one or more of the compounds of Table 1 and Table 1A.
  • Tables 1 and 1A further provides the chemical names of the compounds of Tables 1 and 1A generated by Chemdraw ® Professional version 16.0. In the event of any ambiguity between their chemical structure and chemical name, Compounds of the Disclosure are defined by their chemical structure. [000180] Table 1
  • Compounds of the Disclosure inhibit menin and are useful in the treatment of a variety of diseases and conditions.
  • Compounds of the Disclosure are useful in methods of treating a disease or condition wherein inhibition of menin provides a benefit, for example, cancers and proliferative diseases.
  • Methods of the disclosure comprise administering a therapeutically effective amount of a Compound of the Disclosure to an individual in need thereof.
  • the present methods also encompass administering a second therapeutic agent to the individual in addition to the Compound of the Disclosure.
  • the second therapeutic agent is selected from drugs known as useful in treating the disease or condition afflicting the individual in need thereof, e.g., a chemotherapeutic agent and/or radiation known as useful in treating a particular cancer.
  • Salts of the Compounds of the Disclosure can also be used in the methods disclosed herein.
  • the present disclosure further includes all possible stereoisomers and geometric isomers of Compounds of the Disclosure to include both racemic compounds and optically active isomers.
  • a Compound of the Disclosure When a Compound of the Disclosure is desired as a single enantiomer, it can be obtained either by resolution of the final product or by stereospecific synthesis from either isomerically pure starting material or use of a chiral auxiliary reagent, for example, see Z. Ma et al, Tetrahedron: Asymmetry, 8(6), pages 883-888 (1997). Resolution of the final product, an intermediate, or a starting material can be achieved by any suitable method known in the art. Additionally, in situations where tautomers of the Compounds of the Disclosure are possible, the present disclosure is intended to include all tautomeric forms of the compounds.
  • Compounds of the Disclosure are enantiomerically enriched, e.g., the enantiomeric excess or "ee" of the compound is about 5% or more as measured by chiral HPLC.
  • the ee is about 10%.
  • the ee is about 20%.
  • the ee is about 30%.
  • the ee is about 40%.
  • the ee is about 50%.
  • the ee is about 60%.
  • the ee is about 70%.
  • the ee is about 80%.
  • the ee is about 85%.
  • the ee is about 90%.
  • the ee is about 91%. In another embodiment, the ee is about 92%. In another embodiment, the ee is about 93%. In another embodiment, the ee is about 94%. In another embodiment, the ee is about 95%. In another embodiment, the ee is about 96%. In another embodiment, the ee is about 97%. In another embodiment, the ee is about 98%. In another embodiment, the ee is about 99%.
  • the present disclosure encompasses the preparation and use of salts of Compounds of the Disclosure.
  • the pharmaceutical "pharmaceutically acceptable salt” refers to salts or zwitterionic forms of Compounds of the Disclosure. Salts of Compounds of the Disclosure can be prepared during the final isolation and purification of the compounds or separately by reacting the compound with an acid having a suitable cation.
  • the pharmaceutically acceptable salts of Compounds of the Disclosure can be acid addition salts formed with pharmaceutically acceptable acids.
  • acids which can be employed to form pharmaceutically acceptable salts include inorganic acids such as nitric, boric, hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric.
  • Nonlimiting examples of salts of compounds of the disclosure include, but are not limited to, the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethansulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerolphosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate
  • available amino groups present in the compounds of the disclosure can be quatemized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.
  • any reference Compounds of the Disclosure appearing herein is intended to include compounds of Compounds of the Disclosure as well as pharmaceutically acceptable salts thereof.
  • the present disclosure provides Compounds of the Disclosure as menin inhibitors for the treatment of diseases and conditions wherein inhibition of menin has a beneficial effect.
  • Compounds of the Disclosure typically have a binding affinity (IC50) to menin of less than 100 mM, e.g., less than 50 pM, less than 25 pM, and less than 5 pM, less than about 1 pM, less than about 0.5 pM, less than about 0.1 pM, less than about 0.05 pM, or less than about 0.01 pM.
  • the present disclosure relates to a method of treating an individual suffering from a disease or condition wherein inhibition of menin provides a benefit comprising administering a therapeutically effective amount of a Compound of the Disclosure to an individual in need thereof.
  • menin Diseases and conditions mediated by menin can be treated by administering Compounds of the Disclosure because these compounds are inhibitors of menin.
  • the present disclosure is thus directed generally to a method for treating a condition or disorder responsive to inhibition of menin, in an animal, e.g., a human, suffering from, or at risk of suffering from, the condition or disorder, the method comprising administering to the animal an effective amount of one or more Compounds of the Disclosure.
  • the present disclosure is further directed to a method of inhibiting menin in an animal in need thereof, said method comprising administering to the animal an effective amount of at least one Compound of the Disclosure.
  • the methods of the present disclosure can be accomplished by administering a Compound of the Disclosure as the neat compound or as a pharmaceutical composition.
  • Administration of a pharmaceutical composition, or neat compound of a Compound of the Disclosure can be performed during or after the onset of the disease or condition of interest.
  • the pharmaceutical compositions are sterile, and contain no toxic, carcinogenic, or mutagenic compounds that would cause an adverse reaction when administered.
  • kits comprising a Compound of the Disclosure and, optionally, a second therapeutic agent, packaged separately or together, and an insert having instructions for using these active agents.
  • a Compound of the Disclosure is administered in conjunction with a second therapeutic agent useful in the treatment of a disease or condition wherein inhibition of menin provides a benefit.
  • the second therapeutic agent is different from the Compound of the Disclosure.
  • a Compound of the Disclosure and the second therapeutic agent can be administered simultaneously or sequentially to achieve the desired effect.
  • the Compound of the Disclosure and second therapeutic agent can be administered from a single composition or two separate compositions.
  • the second therapeutic agent is administered in an amount to provide its desired therapeutic effect.
  • the effective dosage range for each second therapeutic agent is known in the art, and the second therapeutic agent is administered to an individual in need thereof within such established ranges.
  • a Compound of the Disclosure and the second therapeutic agent can be administered together as a single-unit dose or separately as multi-unit doses, wherein the Compound of the Disclosure is administered before the second therapeutic agent or vice versa.
  • One or more doses of the Compound of the Disclosure and/or one or more dose of the second therapeutic agent can be administered.
  • the Compound of the Disclosure therefore can be used in conjunction with one or more second therapeutic agents, for example, but not limited to, anticancer agents.
  • Diseases and conditions treatable by the methods of the present disclosure include, but are not limited to, cancer and other proliferative disorders, inflammatory diseases, sepsis, autoimmune disease, and viral infection.
  • a human patient is treated with a Compound of the Disclosure, or a pharmaceutical composition comprising a Compound of the Disclosure, wherein the compound is administered in an amount sufficient to inhibit menin activity in the patient.
  • the human patient is a human adult over 18 years old in need of treatment of a disease.
  • the human patient is a human child no more than 18 years old in need of treatment of a disease.
  • the present disclosure provides a method of treating cancer in a subject comprising administering a therapeutically effective amount of a Compound of the Disclosure. While not being limited to a specific mechanism, in some embodiments, Compounds of the Disclosure treat cancer by inhibiting menin.
  • treatable cancers include, but are not limited to, any one or more of the cancers of Table 2.
  • the cancer is a solid tumor.
  • the cancer is a hematological cancer.
  • Exemplary hematological cancers include, but are not limited to, the cancers listed in Table 3.
  • the hematological cancer is acute lymphocytic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia), or acute myeloid leukemia.
  • the hematological cancer is myelodysplastic syndrome. [000197] Table 3
  • the cancer is a leukemia, for example a leukemia selected from acute monocytic leukemia, acute lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia (MLL).
  • the leukemia is NPMlc mutant acute myelogenous leukemia.
  • the leukemia is MLL-r acute myelogenous leukemia.
  • the leukemia is MLL-r acute lymphocytic leukemia.
  • the cancer is NUT-midline carcinoma.
  • the cancer is multiple myeloma.
  • the cancer is a lung cancer such as small cell lung cancer (SCLC).
  • SCLC small cell lung cancer
  • the cancer is a neuroblastoma.
  • the cancer is Burkitt's lymphoma.
  • the cancer is cervical cancer.
  • the cancer is esophageal cancer.
  • the cancer is ovarian cancer.
  • the cancer is colorectal cancer.
  • the cancer is prostate cancer.
  • the cancer is breast cancer.
  • the cancer is Ewing’s sarcoma.
  • the present disclosure provides a method of treating a benign proliferative disorder, such as, but are not limited to, benign soft tissue tumors, bone tumors, brain and spinal tumors, eyelid and orbital tumors, granuloma, lipoma, meningioma, multiple endocrine neoplasia, nasal polyps, pituitary tumors, prolactinoma, pseudotumor cerebri, seborrheic keratoses, stomach polyps, thyroid nodules, cystic neoplasms of the pancreas, hemangiomas, vocal cord nodules, polyps, and cysts, Castleman disease, chronic pilonidal disease, dermatofibroma, pilar cyst, pyogenic granuloma, and juvenile polyposis syndrome.
  • a benign proliferative disorder such as, but are not limited to, benign soft tissue tumors, bone tumors, brain and spinal tumors, eyelid and orbital tumors, granul
  • Compounds of the Disclosure can also treat infectious and noninfectious inflammatory events and autoimmune and other inflammatory diseases by administration of an effective amount of a present compound to a mammal, in particular a human in need of such treatment.
  • autoimmune and inflammatory diseases, disorders, and syndromes treated using the compounds and methods described herein include inflammatory pelvic disease, urethritis, skin sunburn, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholocystitus, agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhin
  • the present disclosure provides a method of treating systemic inflammatory response syndromes, such as LPS-induced endotoxic shock and/or bacteria-induced sepsis by administration of an effective amount of a Compound of the Disclosure to a mammal, in particular a human in need of such treatment.
  • systemic inflammatory response syndromes such as LPS-induced endotoxic shock and/or bacteria-induced sepsis
  • the present disclosure provides a method for treating viral infections and diseases.
  • viral infections and diseases treated using the compounds and methods described herein include episome-based DNA viruses including, but not limited to, human papillomavirus, Herpesvirus, Epstein-Barr virus, human immunodeficiency virus, hepatis B virus, and hepatitis C virus.
  • the present disclosure provides therapeutic method of modulating protein methylation, gene expression, cell proliferation, cell differentiation and/or apoptosis in vivo in diseases mentioned above, in particular cancer, inflammatory disease, and/or viral disease is provided by administering a therapeutically effective amount of a Compound of the Disclosure to a subject in need of such therapy.
  • the present disclosure provides a method of regulating endogenous or heterologous promoter activity by contacting a cell with a Compound of the Disclosure.
  • a therapeutically effective amount of a Compound of the Disclosure is administered to a human being in need thereof. Whether such a treatment is indicated depends on the individual case and is subject to medical assessment (diagnosis) that takes into consideration signs, symptoms, and/or malfunctions that are present, the risks of developing particular signs, symptoms and/or malfunctions, and other factors.
  • a Compound of the Disclosure can be administered by any suitable route, for example by oral, buccal, inhalation, sublingual, rectal, vaginal, intracistemal or intrathecal through lumbar puncture, transurethral, nasal, percutaneous, i.e., transdermal, or parenteral (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intraarticular, intrathecal, retrobulbar, intrapulmonary injection and/or surgical implantation at a particular site) administration.
  • Parenteral administration can be accomplished using a needle and syringe or using a high pressure technique.
  • compositions include those wherein a Compound of the Disclosure is administered in an effective amount to achieve its intended purpose.
  • the exact formulation, route of administration, and dosage is determined by an individual physician in view of the diagnosed condition or disease. Dosage amount and interval can be adjusted individually to provide levels of a Compound of the Disclosure that is sufficient to maintain therapeutic effects.
  • Toxicity and therapeutic efficacy of the Compounds of the Disclosure can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the maximum tolerated dose (MTD) of a compound, which defines as the highest dose that causes no toxicity in animals.
  • MTD maximum tolerated dose
  • the dose ratio between the maximum tolerated dose and therapeutic effects (e.g. inhibiting of tumor growth) is the therapeutic index.
  • the dosage can vary within this range depending upon the dosage form employed, and the route of administration utilized. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • a therapeutically effective amount of a Compound of the Disclosure required for use in therapy varies with the nature of the condition being treated, the length of time that activity is desired, and the age and the condition of the patient, and ultimately is determined by the attendant physician. Dosage amounts and intervals can be adjusted individually to provide plasma levels of the menin inhibitor that are sufficient to maintain the desired therapeutic effects.
  • the desired dose conveniently can be administered in a single dose, or as multiple doses administered at appropriate intervals, for example as one, two, three, four or more subdoses per day.
  • a Compound of the Disclosure is administered once daily (QD).
  • a Compound of the Disclosure is administered twice daily (BID). Multiple doses often are desired, or required.
  • a Compound of the Disclosure can be administered at a frequency of: four doses delivered as one dose per day at four-day intervals (q4d x 4); four doses delivered as one dose per day at three- day intervals (q3d x 4); one dose delivered per day at five-day intervals (qd x 5); one dose per week for three weeks (qwk3); five daily doses, with two days rest, and another five daily doses (5/2/5); or, any dose regimen determined to be appropriate for the circumstance.
  • a Compound of the Disclosure used in a method of the present disclosure can be administered in an amount of about 0.005 to about 500 milligrams per dose, about 0.05 to about 250 milligrams per dose, or about 0.5 to about 100 milligrams per dose.
  • a Compound of the Disclosure can be administered, per dose, in an amount of about 0.005, about 0.05, about 0.5, about 5, about 10, about 20, about 30, about 40, about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500 milligrams, including all doses between 0.005 and 500 milligrams.
  • the dosage of a composition containing a Compound of the Disclosure can be from about 1 ng/kg to about 200 mg/kg, about 1 pg/kg to about 100 mg/kg, or about 1 mg/kg to about 50 mg/kg.
  • the dosage of a composition can be at any dosage including, but not limited to, about 1 pg/kg.
  • the dosage of a composition may be at any dosage including, but not limited to, about 1 pg/kg, about 10 pg/kg, about 25 pg/kg, about 50 pg/kg, about 75 pg/kg, about 100 pg/kg, about 125 pg/kg, about 150 pg/kg, about 175 pg/kg, about 200 pg/kg, about 225 pg/kg, about 250 pg/kg, about 275 pg/kg, about 300 pg/kg, about 325 pg/kg, about 350 pg/kg, about 375 pg/kg, about 400 pg/kg, about 425 pg/kg, about 450 pg/kg, about 475 pg/kg, about 500 pg/kg, about 525 pg/kg, about 550 pg/kg, about 575 pg/kg, about 600 pg/kg, about 625 pg/kg, about 650 pg/
  • the above dosages are exemplary of the average case, but there can be individual instances in which higher or lower dosages are merited, and such are within the scope of this disclosure.
  • the physician determines the actual dosing regimen that is most suitable for an individual patient, which can vary with the age, weight, and response of the particular patient.
  • a Compound of the Disclosure can be administered in combination with a second therapeutically active agent.
  • the second therapeutic agent is an epigenetic drug.
  • epigenetic drug refers to a therapeutic agent that targets an epigenetic regulator.
  • epigenetic regulators include the histone lysine methyltransferases, histone arginine methyl transferases, histone demethylases, histone deacetylases, histone acetylases, and DNA methyltransferases.
  • Histone deacetylase inhibitors include, but are not limited to, vorinostat.
  • chemotherapeutic agents or other anti proliferative agents can be combined with Compound of the Disclosure to treat proliferative diseases and cancer.
  • therapies and anticancer agents that can be used in combination with Compounds of the Disclosure include surgery, radiotherapy (e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes), endocrine therapy, a biologic response modifier (e.g., an interferon, an interleukin, tumor necrosis factor (TNF), hyperthermia and cryotherapy, an agent to attenuate any adverse effect (e.g., an anti emetic), and any other approved chemotherapeutic drug.
  • radiotherapy e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes
  • endocrine therapy e.g., a biologic response modifier (e.g
  • a Compound of the Disclosure and pharmaceutical compositions described herein can be used in combination with one or more substances selected from anti-angiogenesis agents, signal transduction inhibitors, antiproliferative agents, glycolysis inhibitors, autophagy inhibitors, demethylating agents, DOT1L inhibitors, IDH1 inhibitors, IDH2 inhibitors, IDH1/IDH2 dual inhibitors, LSD1 inhibitors, XPOl inhibitors, or dastinib.
  • the Compound of the Disclosure can be used in combination a second therapeutic agent selected from a demethylating agent, DOT1L inhibitor, IDH1 inhibitor, IDH2 inhibitor, IDH1/IDH2 dual inhibitor, an LSD1 inhibitor, an XPOl inhibitors, and dastinib.
  • a second therapeutic agent selected from a demethylating agent, DOT1L inhibitor, IDH1 inhibitor, IDH2 inhibitor, IDH1/IDH2 dual inhibitor, an LSD1 inhibitor, an XPOl inhibitors, and dastinib.
  • Demethylating agents include substances that inhibit or interfere with DNA methylation.
  • a demethylating agent is a DNA methyltransferase inhibitor.
  • Exemplary nonlimiting demethylating agents include 5- azacytidine, decitabine, methotrexate, edatrexate, 2’-deoxy-5-azacytidine, 6- thioguanine, 5-fluoro-2’-deoxycytidine, pseudoisocytidine, 5,6-dihydro-5-azacytidine, camrabine, zebularine, 2’-deoxy-5,6-dihydro-5-azacytidine, 4’-thio-2’-deoxycytidine, 5-aza-4’-thio-2’-deoxycytidine, RX-3117, SGI-110, NPEOC-DAC, CP-4200, and 2’3’5’triacetyl-5-azacytidine.
  • Exemplary nonlimiting examples of inhibitors of the histone methyltransferase DOT1L include EPZ-5676, SGC-0946, and EPZ004777.
  • Exemplary nonlimiting IDH1 inhibitors include tibsovo (ivosidnib), AG- 881, AG- 120, FT-2102 (olutasidenib), BAY 1436032, IDH-305, and ZX-06.
  • Exemplary nonlimiting examples of IDH2 inhibitors include idhifa (enasidenib; AG- 221), AG-881, AG1-6780, SH1573, and TQ05310.
  • Exemplary nonlimiting IDH1/IDH2 dual inhibitors include HMPL-306.
  • Exemplary nonlimiting examples of a LSD1 inhibitor include ORY- 1001, OG-L002, SP2509, 4SC-202, GSK2879552, T-3775440, and RN-1.
  • XPOl inhibitor examples include selinexor (KPT-330), KPT-8602, KPT25 1, and SL-801.
  • Anti-angiogenesis agents such as MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrixmetalloproteinase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors, can be used in conjunction with a Compound of the Disclosure and pharmaceutical compositions described herein.
  • Exemplary nonlimiting anti-angiogenesis agents include rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab.
  • Exemplary nonlimiting COX-II inhibitors include CELEBREXTM (alecoxib), valdecoxib, and rofecoxib.
  • Exemplary nonlimiting matrix metalloproteinase inhibitors include those described in WO 96/33172 (published October 24, 1996), WO 96/27583 (published March 7, 1996), European Patent Application No. 97304971.1 (filed July 8, 1997), European Patent Application No.
  • the MMP-2 and MMP-9 inhibitors selectively inhibit MMP-2 and/or AMP-9 relative to the other matrix- metalloproteinases (e g., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP- 7, MMP- 8, MMP-10, MMP-11, MMP-12, andMMP-13).
  • MMP inhibitors include AG-3340, RO 32-3555, and RS 13-0830.
  • Exemplary nonlimiting autophagy inhibitors include chloroquine, 3- methyladenine, hydroxychloroquine (PlaquenilTM), bafilomycin Al, 5-amino-4- imidazole carboxamide riboside (AICAR), okadaic acid, autophagy-suppressive algal toxins which inhibit protein phosphatases of type 2A or type 1, analogues of cAMP, and drugs which elevate cAMP levels such as adenosine, LY204002, N6- mercaptopurine riboside, and vinblastine.
  • antisense or siRNA that inhibits expression of proteins including but not limited to ATG5 (which are implicated in autophagy), may also be used.
  • antiproliferative compounds include, but are not limited to, an aromatase inhibitor; an anti-estrogen; an anti-androgen; a gonadorelin agonist; a topoisomerase I inhibitor; a topoisomerase II inhibitor; a microtubule active agent; an alkylating agent; a retinoid, a carontenoid, or a tocopherol; a cyclooxygenase inhibitor; an MMP inhibitor; an mTOR inhibitor; an antimetabolite; a platin compound; a methionine aminopeptidase inhibitor; a bisphosphonate; an antiproliferative antibody; a heparanase inhibitor; an inhibitor of Ras oncogenic isoforms; a telomerase inhibitor; a proteasome inhibitor; a compound used in the treatment of hematologic malignancies; a Flt-3 inhibitor; an Hsp90 inhibitor; a kinesin spindle protein inhibitor;
  • Nonlimiting exemplary aromatase inhibitors include, but are not limited to, steroids, such as atamestane, exemestane, and formestane, and non-steroids, such as aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole, and letrozole.
  • steroids such as atamestane, exemestane, and formestane
  • non-steroids such as aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole, and letrozole.
  • Nonlimiting anti-estrogens include, but are not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride.
  • Anti-androgens include, but are not limited to, bicalutamide.
  • Gonadorelin agonists include, but are not limited to, abarelix, goserelin, and goserelin acetate.
  • topoisomerase I inhibitors include, but are not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogues, 9-nitrocamptothecin, and the macromolecular camptothecin conjugate PNU-166148.
  • Topoisomerase II inhibitors include, but are not limited to, anthracyclines, such as doxorubicin, daunorubicin, epirubicin, idarubicin, and nemorubicin; anthraquinones, such as mitoxantrone and losoxantrone; and podophillotoxines, such as etoposide and teniposide.
  • Microtubule active agents include microtubule stabilizing, microtubule destabilizing compounds, and microtubulin polymerization inhibitors including, but not limited to, taxanes, such as pacbtaxel and docetaxel; vinca alkaloids, such as vinblastine, vinblastine sulfate, vincristine, and vincristine sulfate, and vinorelbine; discodermolides; cochi cine and epothilones and derivatives thereof.
  • taxanes such as pacbtaxel and docetaxel
  • vinca alkaloids such as vinblastine, vinblastine sulfate, vincristine, and vincristine sulfate, and vinorelbine
  • discodermolides cochi cine and epothilones and derivatives thereof.
  • Exemplary nonlimiting alkylating agents include cyclophosphamide, ifosfamide, melphalan, and nitrosoureas, such as carmustine and lomustine.
  • Exemplary nonlimiting cyclooxygenase inhibitors include Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib, rofecoxib, etoricoxib, valdecoxib, or a 5-alkyl-2-arylaminophenylacetic acid, such as lumiracoxib.
  • MMP inhibitors include collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, batimastat, marimastat, prinomastat, metastat, BMS-279251, BAY 12-9566, TAA211, MMI270B, and AAJ996.
  • Exemplary nonlimiting mTOR inhibitors include compounds that inhibit the mammalian target of rapamycin (mTOR) and possess antiproliferative activity such as sirolimus, everolimus, CCI-779, and ABT578.
  • Exemplary nonlimiting antimetabolites include 5-fluorouracil (5-FU), capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists, such as pemetrexed.
  • Exemplary nonlimiting platin compounds include carboplatin, cis-platin, cisplatinum, and oxaliplatin.
  • Exemplary nonlimiting methionine aminopeptidase inhibitors include bengamide or a derivative thereof and PPI-2458.
  • Exemplary nonlimiting bisphosphonates include etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid.
  • antiproliferative antibodies include trastuzumab, trastuzumab-DMl, cetuximab, bevacizumab, rituximab, PR064553, and 2C4.
  • antibody is meant to include intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity.
  • heparanase inhibitors include compounds that target, decrease, or inhibit heparin sulfate degradation, such as PI-88 and OGT2115.
  • an inhibitor of Ras oncogenic isoforms such as H-Ras, K- Ras, or N-Ras, as used herein refers to a compound which targets, decreases, or inhibits the oncogenic activity of Ras, for example, a famesyl transferase inhibitor, such as L-744832, DK8G557, tipifamib, and lonafamib.
  • telomere inhibitors include compounds that target, decrease, or inhibit the activity of telomerase, such as compounds that inhibit the telomerase receptor, such as telomestatin.
  • Exemplary nonlimiting proteasome inhibitors include compounds that target, decrease, or inhibit the activity of the proteasome including, but not limited to, bortezomid.
  • FMS-like tyrosine kinase inhibitors which are compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, I-b-D-arabinofuransylcytosine (ara-c), and bisulfan;
  • ALK inhibitors which are compounds that target, decrease, or inhibit anaplastic lymphoma kinase; and BH3 mimetics, which are compounds that target, decrease, or inhibit antiapoptotic proteins from the BCL-2 family.
  • Exemplary nonlimiting Flt-3 inhibitors include gilteritinib, PKC412, midostaurin, a staurosporine derivative, SU11248, and MLN518.
  • Exemplary nonlimiting HSP90 inhibitors include compounds targeting, decreasing, or inhibiting the intrinsic ATPase activity of HSP90; or degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway.
  • Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HD AC inhibitors.
  • Exemplary nonlimiting BH3 mimetics include venetoclax.
  • a compound targeting/decreasing a protein or lipid kinase activity; or a protein or lipid phosphatase activity; or any further anti-angiogenic compound includes a protein tyrosine kinase and/or serine and/or threonine kinase inhibitor or lipid kinase inhibitor, such as a) a compound targeting, decreasing, or inhibiting the activity of the platelet- derived growth factor-receptors (PDGFR), such as a compound that targets, decreases, or inhibits the activity of PDGFR, such as an N-phenyl-2-pyrimidine-amine derivatives, such as imatinib, SUIOI, SU6668, and GFB-111; b) a compound targeting, decreasing, or inhibiting the activity of the fibroblast growth factor-receptors (FGFR); c) a compound targeting, decreasing, or inhibiting the activity of the insulin-like growth factor receptor I
  • PDGFR platelet- derived growth
  • Bcr-Abl kinase and mutants, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib; PD180970; AG957; NSC 680410; PD173955; or dasatinib; j) a compound targeting, decreasing, or inhibiting the activity of members of the protein kinase C (PKC) and Raf family of serine/threonine kinases, members of the MEK, SRC, JAK, FAK, PDK1, PKB/Akt, and Ras/MAPK family members, and/or members of the cyclin-dependent kinase family (CDK), such as a staurosporine derivative disclosed in U.S.
  • PKC protein kinase C
  • Raf family of serine/threonine kinases members of the MEK, SRC, JAK, FAK, PDK1, PKB/Akt, and Ras/MAPK family members,
  • Patent No. 5,093,330 such as midostaurin
  • examples of further compounds include UCN-01, safmgol, BAY 43-9006, bryostatin 1, perifosine; ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196; a isochinoline compound; a famesyl transferase inhibitor; PD184352 or QAN697, or AT7519; k) a compound targeting, decreasing or inhibiting the activity of a protein- tyrosine kinase, such as imatinib mesylate or a tyrphostin, such as Tyrphostin A23/RG- 50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494;
  • Exemplary compounds that target, decrease, or inhibit the activity of a protein or lipid phosphatase include inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.
  • Further anti-angiogenic compounds include compounds having another mechanism for their activity unrelated to protein or lipid kinase inhibition, e.g., thalidomide and TNP-470.
  • Additional, nonlimiting, exemplary chemotherapeutic compounds include: daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatinum, PKC412, 6-mercaptopurine (6-MP), fludarabine phosphate, octreotide, SOM230, FTY720, 6-thioguanine, cladribine, 6-mercaptopurine, pentostatin, hydroxyurea, 2-hydroxy-lH-isoindole-l,3-dione derivatives, l-(4-chloroanilino)-4-(4- pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate, an
  • second therapeutic agents include, but are not limited to: a treatment for Alzheimer's Disease, such as donepezil and rivastigmine; a treatment for Parkinson's Disease, such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; an agent for treating multiple sclerosis (MS) such as beta interferon (e.g., AVONEX® and REBIF®), glatiramer acetate, and mitoxantrone; a treatment for asthma, such as albuterol and montelukast; an agent for treating schizophrenia, such as zyprexa, risperdal, seroquel, and haloperidol; an anti-inflammatory agent, such as a corticosteroid, a TNF blocker, IL-1
  • Compounds of the Disclosure typically are administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • Pharmaceutical compositions for use in accordance with the present disclosure are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of Compound of the Disclosure.
  • compositions can be manufactured, for example, by conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, entrapping, or lyophilizing processes. Proper formulation is dependent upon the route of administration chosen.
  • a therapeutically effective amount of the Compound of the Disclosure is administered orally, the composition typically is in the form of a tablet, capsule, powder, solution, or elixir.
  • the composition additionally can contain a solid carrier, such as a gelatin or an adjuvant.
  • the tablet, capsule, and powder contain about 0.01% to about 95%, and preferably from about 1% to about 50%, of a Compound of the Disclosure.
  • a liquid carrier such as water, petroleum, or oils of animal or plant origin
  • the liquid form of the composition can further contain physiological saline solution, dextrose or other saccharide solutions, or glycols.
  • the composition When administered in liquid form, the composition contains about 0.1% to about 90%, and preferably about 1% to about 50%, by weight, of a Compound of the Disclosure. [000252] When a therapeutically effective amount of a Compound of the
  • Disclosure is administered by intravenous, cutaneous, or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution.
  • the preparation of such parenterally acceptable solutions having due regard to pH, isotonicity, stability, and the like, is within the skill in the art.
  • a preferred composition for intravenous, cutaneous, or subcutaneous injection typically contains, an isotonic vehicle.
  • Compounds of the Disclosure can be readily combined with pharmaceutically acceptable carriers well-known in the art. Standard pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995. Such carriers enable the active agents to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained by adding the Compound of the Disclosure to a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations. If desired, disintegrating agents can be added.
  • Compound of the Disclosure can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection can be presented in unit dosage form, e.g., in ampules or in multidose containers, with an added preservative.
  • the compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and/or dispersing agents.
  • Pharmaceutical compositions for parenteral administration include aqueous solutions of the active agent in water-soluble form. Additionally, suspensions of a Compound of the Disclosure can be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters.
  • Aqueous injection suspensions can contain substances which increase the viscosity of the suspension.
  • the suspension also can contain suitable stabilizers or agents that increase the solubility of the compounds and allow for the preparation of highly concentrated solutions.
  • a present composition can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • Compounds of the Disclosure also can be formulated in rectal compositions, such as suppositories or retention enemas, e.g., containing conventional suppository bases.
  • the Compound of the Disclosure also can be formulated as a depot preparation.
  • Such long-acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
  • the Compound of the Disclosure can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins.
  • the Compounds of the Disclosure can be administered orally, buccally, or sublingually in the form of tablets containing excipients, such as starch or lactose, or in capsules or ovules, either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents.
  • excipients such as starch or lactose
  • capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents.
  • Such liquid preparations can be prepared with pharmaceutically acceptable additives, such as suspending agents.
  • Compound of the Disclosure also can be injected parenterally, for example, intravenously, intramuscularly, subcutaneously, or intracoronarily.
  • the Compound of the Disclosure are typically used in the form of a sterile aqueous solution which can contain other substances, for example, salts or monosaccharides, such as mannitol or glucose, to make the solution isotonic with blood.
  • a sterile aqueous solution which can contain other substances, for example, salts or monosaccharides, such as mannitol or glucose, to make the solution isotonic with blood.
  • the disclosure provides the following particular embodiments in connection with treating a disease in a subject.
  • Embodiment 1 A method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount a Compound of the Disclosure, wherein the subject has cancer.
  • Embodiment 2 The method of Embodiment 1 , wherein the cancer is any one or more of the cancers of Table 2.
  • Embodiment 3 The method of Embodiment 2, wherein the cancer is a hematological cancer.
  • Embodiment 4 The method of Embodiment 3, wherein the hematological cancer is any one or more of the cancers of Table 3.
  • Embodiment 5 The method of any one of Embodiments 1-4 further comprising administering a therapeutically effective amount of a second therapeutic agent useful in the treatment of cancer.
  • Embodiment 6 A pharmaceutical composition comprising a
  • Embodiment 7 The pharmaceutical composition of Embodiment 6, wherein the cancer is any one or more of the cancers of Table 2.
  • Embodiment 8 The pharmaceutical composition of Embodiment 7, wherein the cancer is a hematological cancer.
  • Embodiment 9 The pharmaceutical composition of Embodiment 8, wherein the hematological cancer is any one or more of the cancers of Table 3.
  • Embodiment 10 A Compound of the Disclosure for use in treatment of cancer.
  • Embodiment 11 The compound for use of Embodiment 10, wherein the cancer is any one or more of the cancers of Table 2.
  • Embodiment 12 The compound for use of Embodiment 11, wherein the cancer is a hematological cancer.
  • Embodiment 13 The compound for use of Embodiment 12, wherein the hematological cancer is any one or more of the cancers of Table 3.
  • Embodiment 14 Use of a Compound of the Disclosure for the manufacture of a medicament for treatment of cancer.
  • Embodiment 15 The use of Embodiment 14, wherein the cancer is any one or more of the cancers of Table 2.
  • Embodiment 16 The use of Embodiment 15, wherein the cancer is a hematological cancer.
  • Embodiment 17 The use of Embodiment 16, wherein the hematological cancer is any one or more of the cancers of Table 3.
  • kits which comprise a Compound of the Disclosure (or a composition comprising a Compound of the Disclosure) packaged in a manner that facilitates their use to practice methods of the present disclosure.
  • the kit includes a Compound of the Disclosure (or a composition comprising a Compound of the Disclosure) packaged in a container, such as a sealed bottle or vessel, with a label affixed to the container or included in the kit that describes use of the compound or composition to practice the method of the disclosure.
  • the compound or composition is packaged in a unit dosage form.
  • the kit further can include a device suitable for administering the composition according to the intended route of administration.
  • halo as used by itself or as part of another group refers to -Cl, -F, -Br, or -I.
  • nitro as used by itself or as part of another group refers to -NC .
  • cyano as used by itself or as part of another group refers to -CN.
  • hydroxy as used by itself or as part of another group refers to -OH.
  • alkyl refers to unsubstituted straight- or branched-chain aliphatic hydrocarbons containing from one to twelve carbon atoms, i.e., Ci-12 alkyl or C1-C12 alkyl, or the number of carbon atoms designated, e.g., a Ci alkyl such as methyl, a C2 alkyl such as ethyl, a C3 alkyl such as propyl or isopropyl, a C1-3 alkyl such as methyl, ethyl, propyl, or isopropyl, and so on.
  • the alkyl is a C 1-10 alkyl. In another embodiment, the alkyl is a Ci-6 alkyl. In another embodiment, the alkyl is a C1-4 alkyl. In another embodiment, the alkyl is a straight chain Ci-10 alkyl. In another embodiment, the alkyl is a branched chain C3-10 alkyl. In another embodiment, the alkyl is a straight chain Ci-6 alkyl. In another embodiment, the alkyl is a branched chain C3-6 alkyl. In another embodiment, the alkyl is a straight chain C1-4 alkyl. In another embodiment, the alkyl is a branched chain C3-4 alkyl.
  • the alkyl is a straight or branched chain C3-4 alkyl.
  • Non-limiting exemplary Ci-10 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl. tert- butyl, iso-butyl, 3- pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
  • Non-limiting exemplary C1-4 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert- butyl, and iso-butyl.
  • the term "optionally substituted alkyl" as used by itself or as part of another group refers to an alkyl that is either unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of nitro, haloalkoxy, aryloxy, aralkyloxy, alkylthio, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, and alkylcarbonyloxy.
  • the optionally substituted alkyl is substituted with two substituents.
  • the optionally substituted alkyl is substituted with one substituent. In another embodiment, the optionally substituted alkyl is unsubstituted.
  • cycloalkyl refers to unsubstituted saturated or partially unsaturated, e.g., containing one or two double bonds, cyclic aliphatic hydrocarbons containing one to three rings having from three to twelve carbon atoms, i.e., C3-12 cycloalkyl, or the number of carbons designated.
  • the cycloalkyl has two rings.
  • the cycloalkyl has one ring.
  • the cycloalkyl is saturated.
  • the cycloalkyl is unsaturated.
  • the cycloalkyl is a C3-8 cycloalkyl. In another embodiment, the cycloalkyl is a C3-6 cycloalkyl.
  • Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbomyl, decalin, adamantyl, cyclohexenyl, cyclopentenyl, and cyclopentanone.
  • the term "optionally substituted cycloalkyl” as used by itself or as part of another group refers to a cycloalkyl that is either unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, amino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl
  • optionally substituted cycloalkyl includes cycloalkyl groups having a fused optionally substituted aryl, e.g., phenyl, or fused optionally substituted heteroaryl, e.g., pyridyl.
  • An optionally substituted cycloalkyl having a fused optionally substituted aryl or fused optionally substituted heteroaryl group may be attached to the remainder of the molecule at any available carbon atom on the cycloalkyl ring.
  • the optionally substituted cycloalkyl is substituted with two substituents.
  • the optionally substituted cycloalkyl is substituted with one substituent.
  • the optionally substituted cycloalkyl is unsubstituted.
  • aryl refers to unsubstituted monocyclic or bicycbc aromatic ring systems having from six to fourteen carbon atoms, i.e., a C 4 aryl.
  • Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups.
  • the aryl group is phenyl or naphthyl.
  • the term "optionally substituted aryl" as used herein by itself or as part of another group refers to an aryl that is either unsubstituted or substituted with one to five substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, haloalkylsulfonyl cycloalkylsulfonyl, (cycloalkyl)alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl
  • the optionally substituted aryl is an optionally substituted phenyl. In another embodiment, the optionally substituted phenyl has four substituents. In another embodiment, the optionally substituted phenyl has three substituents. In another embodiment, the optionally substituted phenyl has two substituents. In another embodiment, the optionally substituted phenyl has one substituent. In another embodiment, the optionally substituted phenyl is unsubstituted.
  • Non-limiting exemplary substituted aryl groups include 2-methylphenyl,
  • optionally substituted aryl includes phenyl groups having a fused optionally substituted cycloalkyl or fused optionally substituted heterocyclo group.
  • An optionally substituted phenyl having a fused optionally substituted cycloalkyl or fused optionally substituted heterocyclo group may be atached to the remainder of the molecule at any available carbon atom on the phenyl ring.
  • Non-limiting examples include:
  • alkenyl refers to an alkyl containing one, two or three carbon-to-carbon double bonds. In one embodiment, the alkenyl has one carbon-to-carbon double bond. In another embodiment, the alkenyl is a C2-6 alkenyl. In another embodiment, the alkenyl is a C2-4 alkenyl.
  • Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, ve -butenyl. pentenyl, and hexenyl.
  • the term "optionally substituted alkenyl” as used herein by itself or as part of another group refers to an alkenyl that is either unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, heteroaryl, and optionally substituted heterocyclo.
  • alkynyl refers to an alkyl containing one to three carbon-to-carbon triple bonds. In one embodiment, the alkynyl has one carbon-to-carbon triple bond. In another embodiment, the alkynyl is a C2-6 alkynyl. In another embodiment, the alkynyl is a C2-4 alkynyl.
  • Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.
  • alkynyl refers to an alkynyl that is either unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, and heterocyclo.
  • haloalkyl refers to an alkyl substituted by one or more fluorine, chlorine, bromine and/or iodine atoms.
  • the alkyl group is substituted by one, two, or three fluorine and/or chlorine atoms.
  • the haloalkyl group is a Ci-4 haloalkyl group.
  • Non-limiting exemplary haloalkyl groups include fluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1- difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4- trifluorobutyl, and trichloromethyl groups.
  • hydroxyalkyl refers to an alkyl substituted with one, two, or three hydroxy groups.
  • the hydroxyalkyl is a monohydroxyalkyl, i.e., a hydroxyalkyl substituted with one hydroxy group.
  • the hydroxyalkyl is a dihydroxyalkyl, i.e., a hydroxyalkyl substituted with two hydroxy groups.
  • Non-limiting exemplary hydroxyalkyl groups include hydroxymethyl, hydroxy ethyl, hydroxypropyl and hydroxybutyl groups, such as 1 -hydroxy ethyl, 2- hydroxy ethyl, 1,2-dihydroxy ethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-l-methylpropyl, and l,3-dihydroxyprop-2-yl.
  • the term "(cycloalkyl)alkyl,” as used by itself or as part of another group refers to an alkyl substituted with an optionally substituted cycloalkyl.
  • the (cycloalkyl) alkyl is a "(C3-6 cycloalkyl)Ci-4 alkyl,” i.e., a Ci-4 alkyl substituted with an optionally substituted C3-6 cycloalkyl.
  • Non-limiting exemplary (cycloalkyl) alkyl groups include: [000296]
  • alkylsulfonyl as used by itself or as part of another group refers to a sulfonyl, i.e., -SO2-, substituted with an optionally substituted alkyl.
  • the alkyl is a Ci-6 alkyl.
  • the alkyl is a C1-4 alkyl.
  • a non-limiting exemplary alkylsulfonyl group is -SO2CH3.
  • haloalkylsulfonyl as used by itself or as part of another group refers to a sulfonyl, i.e., -SO2-, substituted with a haloalkyl.
  • a non-limiting exemplary alkylsulfonyl group is -SO2CF3.
  • cycloalkylsulfonyl as used by itself or as part of another group refers to a sulfonyl, i.e., -SO2-, substituted with an optionally substituted cycloalkyl.
  • Non-limiting exemplary alkylsulfonyl group include -SC -cyclopropyl and -SC -cyclopenyl.
  • (cycloalky l)alkylsulfonyl refers to a sulfonyl, i.e., -SO2-, substituted with a (cycloalkyl)alkyl.
  • Non-limiting exemplary (cycloalkyl)alkylsulfonyl groups include:
  • arylsulfonyl as used by itself or as part of another group refers to a sulfonyl, i.e., -SO2-, substituted with an optionally substituted aryl.
  • a non-limiting exemplary arylsulfonyl group is -SC Ph.
  • heteroarylsulfonyl refers to a sulfonyl, i.e., -SO2-, substituted with an optionally substituted heteroaryl group.
  • heteroarylsulfonyl groups include:
  • heterocyclosulfonyl refers to a sulfonyl, i.e., -SO2-, substituted with an optionally substituted heterocyclo group.
  • a non-limiting exemplary heterocyclosulfonyl group is:
  • sulfonamido refers to a radical of the formula -S02NR 21a R 21b , wherein R 21a and R 21b are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted aryl, or R 21a and R 21b taken together with the nitrogen to which they are attached from a 3- to 8-membered heterocyclo group.
  • Non-limiting exemplary sulfonamido groups include -SO2NH2, -S0 2 N(H)CH 3 , -S0 2 N(CH 3 )2, and -S0 2 N(H)Ph.
  • alkoxy refers to an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, or optionally substituted alkynyl attached to a terminal oxygen atom.
  • the alkoxy is an optionally substituted alkyl attached to a terminal oxygen atom.
  • the alkoxy group is a Ci-6 alkyl attached to a terminal oxygen atom.
  • the alkoxy group is a C1-4 alkyl attached to a terminal oxygen atom.
  • Non-limiting exemplary alkoxy groups include methoxy, ethoxy, tert-butoxy, and -OCfhSCteCfb.
  • alkylthio refers to an optionally substituted alkyl attached to a terminal sulfur atom.
  • the alkylthio group is a C1-4 alkylthio group.
  • Non-limiting exemplary alkylthio groups include -SCH 3 and -SCffeCfb.
  • alkoxyalkyl refers to an optionally alkyl substituted with an alkoxy group.
  • Non-limiting exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, iso-propoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl, tert- butoxymethyl, isobutoxymethyl, sec-butoxymethyl, and pentyloxymethyl.
  • haloalkoxy as used by itself or as part of another group refers to a haloalkyl attached to a terminal oxygen atom.
  • Non- limiting exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.
  • aryloxy as used by itself or as part of another group refers to an optionally substituted aryl attached to a terminal oxygen atom.
  • a non-limiting exemplary aryloxy group is PhO.
  • aralkyloxy refers to an aralkyl attached to a terminal oxygen atom.
  • Non- limiting exemplary aralkyloxy groups include PhCPkO- and PhCPkCPkO-.
  • heteroaryl refers to unsubstituted monocyclic and bicyclic aromatic ring systems having 5 to 14 ring atoms, i.e., a 5- to 14-membered heteroaryl, wherein at least one carbon atom of one of the rings is replaced with a heteroatom independently selected from the group consisting of oxygen, nitrogen and sulfur.
  • the heteroaryl contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur.
  • the heteroaryl has three heteroatoms.
  • the heteroaryl has two heteroatoms.
  • the heteroaryl has one heteroatom.
  • the heteroaryl is a 5- to 10-membered heteroaryl. In another embodiment, the heteroaryl is a 5- or 6-membered heteroaryl. In another embodiment, the heteroaryl has 5 ring atoms, e.g., thienyl, a 5-membered heteroaryl having four carbon atoms and one sulfur atom. In another embodiment, the heteroaryl has 6 ring atoms, e.g., pyridyl, a 6-membered heteroaryl having five carbon atoms and one nitrogen atom.
  • Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2//-pyrrolyl. pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3//-indolyl.
  • the heteroaryl is selected from the group consisting of thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3 -furyl), pyrrolyl (e.g., lH-pyrrol-2-yl and lH-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H- imidazol-4-yl), pyrazolyl (e.g., lH-pyrazol-3-yl, lH-pyrazol-4-yl, and lH-pyrazol-5- yl), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, and pyrimidin
  • the heteroaryl is a 5- or 6-membered heteroaryl.
  • the heteroaryl is a 5-membered heteroaryl, i.e., the heteroaryl is a monocyclic aromatic ring system having 5 ring atoms wherein at least one carbon atom of the ring is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • Non-limiting exemplary 5-membered heteroaryl groups include thienyl, furyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, and isoxazolyl.
  • the heteroaryl is a 6-membered heteroaryl, e.g., the heteroaryl is a monocyclic aromatic ring system having 6 ring atoms wherein at least one carbon atom of the ring is replaced with a nitrogen atom.
  • Non-limiting exemplary 6-membered heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl.
  • the term "optionally substituted heteroaryl” as used by itself or as part of another group refers to a heteroaryl that is either unsubstituted or substituted with one two, three, or four substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, haloalkylsulfonyl cycloalkylsulfonyl, (cycloalkyl)alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, carboxy, carboxyalkyl, optionally substituted al
  • the optionally substituted heteroaryl has one substituent. In another embodiment, the optionally substituted heteroaryl is unsubstituted. Any available carbon or nitrogen atom can be substituted.
  • the term optionally substituted heteroaryl includes heteroaryl groups having a fused optionally substituted cycloalkyl or fused optionally substituted heterocyclo group. An optionally substituted heteroaryl having a fused optionally substituted cycloalkyl or fused optionally substituted heterocyclo group may be attached to the remainder of the molecule at any available carbon atom on the heteroaryl ring.
  • heterocyclo refers to unsubstituted saturated and partially unsaturated, e.g., containing one or two double bonds, cyclic groups containing one, two, or three rings having from three to fourteen ring members, i.e., a 3- to 14-membered heterocyclo, wherein at least one carbon atom of one of the rings is replaced with a heteroatom.
  • Each heteroatom is independently selected from the group consisting of oxygen, sulfur, including sulfoxide and sulfone, and/or nitrogen atoms, which can be oxidized or quatemized.
  • cyclic ureido groups such as 2-imidazolidinone
  • cyclic amide groups such as b-lactam, g-lactam, d-lactam, e-lactam, and piperazin-2-one.
  • heterocyclo also includes groups having fused optionally substituted aryl groups, e.g., indolinyl or chroman-4-yl.
  • the heterocyclo group is a C4-6 heterocyclo, i.e., a 4-, 5- or 6-membered cyclic group, containing one ring and one or two oxygen and/or nitrogen atoms.
  • the heterocyclo group is a C4-6 heterocyclo containing one ring and one nitrogen atom.
  • the heterocyclo can be optionally linked to the rest of the molecule through any available carbon or nitrogen atom.
  • Non-limiting exemplary heterocyclo groups include azetidinyl, dioxanyl, tetrahydropyranyl, 2-oxopyrrolidin-3-yl, piperazin-2-one, piperazine-2, 6-dione, 2-imidazolidinone, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and indolinyl.
  • amino refers to a radical of the formula -NR 22a R 22b , wherein R 22a and R 22b are independently selected from the group consisting of hydrogen, alkyl, aralkyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, and optionally substituted heteroaryl, or R 22a and R 22b are taken together to form a 3- to 8-membered optionally substituted heterocyclo.
  • Non-limiting exemplary amino groups include -NH2, -N(H)(CH3),
  • the term "(amino)alkyl” as used by itself or as part of another group refers to a Ci-6 alkyl substituted with an amino.
  • the (amino)alkyl is -CH2NR 22a R 22b , wherein R 22a and R 22b are independently selected from the group consisting of hydrogen, alkyl, aralkyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, and optionally substituted heteroaryl, or R 22a and R 22b are taken together to form a 3- to 8-membered optionally substituted heterocyclo.
  • R 22a and R 22b are independently hydrogen or C1-4 alkyl.
  • Non-limiting exemplary (amino)alkyl groups include -CH2NH2, -CH2N(H)CH3, -CH2N(CH-
  • dialkylaminoalkyl refers to a C1-4 alkyl attached to a di-(Ci-6 alkyl) substituted amino.
  • Non-limiting exemplary dialkylaminoalkyl groups include -CH2N(CH- 3)2, -CH 2 CH 2 N(CH3)2, -CH2CH2CH 2 N(CH3)2, -CH2CH2CH2CH 2 N(CH3)2, and -CH 2 N(CH 2 CH3)2.
  • R 23a and R 23b are taken together to taken together with the nitrogen to which they are attached form a 3- to 8-membered optionally substituted heterocyclo group.
  • Non- limiting exemplary carboxamido groups include -CONH2, -CON(H)CH3, -CON(CH3)2, -CON(H)Ph,
  • R 24a is hydrogen and R 24b is Ci-6 alkyl.
  • R 24a is hydrogen and R 24b is Ci-4 alkyl.
  • R 24a and R 24b are each independently Ci-6 alkyl.
  • R 24a and R 24b are each independently Ci-4 alkyl.
  • Non-limiting exemplary alkylamide groups include -CON(H)CH 3 , -CON(CH 3 )2, -CON(H)CH 2 CH3, and -CON(CH 2 CH3)2.
  • a non-limiting exemplary arylcarbonyl group is -COPh.
  • the alkoxy is a Ci-4 alkoxy.
  • the alkoxy is a Ci-6 alkoxy.
  • (alkoxy carbonyl)alkyl refers to an alkyl substituted by an alkoxycarbonyl group.
  • carboxy alkyl as used by itself or as part of another group refers to an alkyl substituted with a -C0 2 H.
  • a non-limiting exemplary carboxyalkyl group is -CH 2 C0 2 H.
  • aralkyl refers to an alkyl substituted with one, two, or three optionally substituted aryl groups.
  • aralkyl is a Ci-4 alkyl substituted with one optionally substituted Cs or Ce aryl group.
  • the aralkyl is a Ci alkyl substituted with one optionally substituted aryl group.
  • the aralkyl is a C 2 alkyl substituted with one optionally substituted aryl group.
  • the aralkyl is a C3 alkyl substituted with one optionally substituted aryl group.
  • the aralkyl is a Ci or C 2 alkyl substituted with one optionally substituted phenyl group.
  • Non-limiting exemplary aralkyl groups include benzyl, phenethyl, -CHPh 2 , -CH(CH3)Ph, -CH 2 (4-F-Ph), -CH 2 (4-Me-Ph), -CH-
  • (heterocyclo)alkyl refers to an alkyl substituted with an optionally substituted heterocyclo group.
  • the (heterocyclo)alkyl is a Ci-4 alkyl substituted with one optionally substituted heterocyclo group.
  • Non-limiting exemplary (heterocyclo)alkyl groups include:
  • the term "(heteroaryl)alkyl” as used by itself or part of another group refers to an alkyl substituted with an optionally substituted heteroaryl group.
  • the (heteroaryl)alkyl is a Ci-4 alkyl substituted with one optionally substituted heteroaryl group.
  • the (heteroaryl)alkyl is a Ci alkyl substituted with one optionally substituted heteroaryl group
  • Non-limiting exemplary (heteroaryl)alkyl groups include:
  • the term "(carboxamido)alkyl” as used by itself or as part of another group refers to an alkyl substituted with one or two carboxamido groups.
  • the (carboxamido)alkyl is a Ci-4 alkyl substituted with one carboxamido group, i.e., a (carboxamido)Ci-4 alkyl.
  • the (carboxamido)alkyl is a Ci-4 alkyl substituted with two carboxamido groups.
  • Non-limiting exemplary (carboxamido)alkyl groups include -CH 2 CONH 2 , -C(H)CH 3 -CONH 2 , and -CH 2 CON(H)CH 3 .
  • the term "(aryloxy)alkyl” as used by itself or as part of another group refers to an alkyl substituted with an aryloxy group.
  • the "(aryloxy)alkyl” is a Ci-4 alkyl substituted with an aryloxy.
  • the "(aryloxy)alkyl” is a C 2 -4 alkyl substituted with an aryloxy.
  • Non-limiting exemplary (aryloxy)alkyl groups include -CH 2 CH 2 OPh and - CTkCTkCThOPh.
  • alkylcarbonyloxy refers to an oxy, e.g., -O-, substituted with an alkylcarbonyl group.
  • cycloalkylcarbonyloxy refers to an oxy, e.g., -O-, substituted with an cycloalkylcarbonyl group.
  • heterocyclylcarbonyl groups include:
  • the heterocyclo group is substituted with one halo group.
  • the heterocyclo group is substituted with two halo groups.
  • Non-limiting exemplary halo-substituted heterocyclylcarbonyl groups include:
  • menin inhibitor or “inhibitor of menin” as used herein refers to a compound that disrupts, e.g., inhibits, the menin-MLL fusion protein interaction.
  • a disease or condition wherein inhibition of menin provides a benefit pertains to a disease or condition in which menin and/or the interaction of menin with a menin-interacting protein is important or necessary, e.g., for the onset, progress, or expression of that disease or condition, or a disease or a condition which is known to be treated by a menin inhibitor.
  • Such conditions include, but are not limited to, a cancer, a chronic autoimmune disease, an inflammatory disease, a proliferative disease, sepsis, and a viral infection.
  • a cancer a chronic autoimmune disease
  • an inflammatory disease a proliferative disease
  • sepsis a viral infection.
  • One of ordinary skill in the art is readily able to determine whether a compound treats a disease or condition mediated by menin for any particular cell type, for example, by assays which conveniently can be used to assess the activity of particular compounds.
  • second therapeutic agent refers to a therapeutic agent different from a Compound of the Disclosure and that is known to treat the disease or condition of interest.
  • the second therapeutic agent can be a known chemotherapeutic drug, like taxol, or radiation, for example.
  • disease or “condition” denotes disturbances and/or anomalies that as a rule are regarded as being pathological conditions or functions, and that can manifest themselves in the form of particular signs, symptoms, and/or malfunctions.
  • Compounds of the Disclosure are menin inhibitors and can be used in treating diseases and conditions wherein menin inhibition provides a benefit.
  • the terms “treat,” “treating,” “treatment,” and the like refer to eliminating, reducing, or ameliorating a disease or condition, and/or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated.
  • the terms “treat,” “treating,” “treatment,” and the like may include “prophylactic treatment,” which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition.
  • treatment also includes relapse prophylaxis or phase prophylaxis, as well as the treatment of acute or chronic signs, symptoms and/or malfunctions.
  • the treatment can be orientated symptomatically, for example, to suppress symptoms. It can be effected over a short period, be oriented over a medium term, or can be a long-term treatment, for example within the context of a maintenance therapy.
  • terapéuticaally effective amount refers to an amount of the active ingredient(s) that is(are) sufficient, when administered by a method of the disclosure, to efficaciously deliver the active ingredient(s) for the treatment of condition or disease of interest to an individual in need thereof.
  • the therapeutically effective amount of the agent may reduce (i.e., retard to some extent and preferably stop) unwanted cellular proliferation; reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., retard to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., retard to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; reduce menin interactions in the target cells; and/or relieve, to some extent, one or more of the symptoms associated with the cancer.
  • the administered compound or composition prevents growth and/or kills existing cancer cells, it may be cytostatic and/or cytotoxic.
  • the term "container” means any receptacle and closure therefore suitable for storing, shipping, dispensing, and/or handling a pharmaceutical product.
  • the term “insert” means information accompanying a pharmaceutical product that provides a description of how to administer the product, along with the safety and efficacy data required to allow the physician, pharmacist, and patient to make an informed decision regarding use of the product.
  • the package insert generally is regarded as the "label" for a pharmaceutical product.
  • Constant administration means that two or more agents are administered concurrently to the subject being treated.
  • concurrently it is meant that each agent is administered either simultaneously or sequentially in any order at different points in time. However, if not administered simultaneously, it is meant that they are administered to an individual in a sequence and sufficiently close in time so as to provide the desired therapeutic effect and can act in concert.
  • a Compound of the Disclosure can be administered at the same time or sequentially in any order at different points in time as a second therapeutic agent.
  • a Compound of the Disclosure and the second therapeutic agent can be administered separately, in any appropriate form and by any suitable route.
  • a Compound of the Disclosure and the second therapeutic agent are not administered concurrently, it is understood that they can be administered in any order to a subject in need thereof.
  • a Compound of the Disclosure can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks,
  • a second therapeutic agent treatment modality e.g., radiotherapy
  • a Compound of the Disclosure and the second therapeutic agent are administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to
  • the components of the combination therapies are administered at about 1 minute to about 24 hours apart.
  • the term "stereoisomers” is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).
  • chiral center or "asymmetric carbon atom” refers to a carbon atom to which four different groups are attached.
  • enantiomer and “enantiomeric” refer to a molecule that cannot be superimposed on its mirror image and hence is optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction.
  • racemic refers to a mixture of equal parts of enantiomers and which mixture is optically inactive.
  • Compounds of the Disclosure are racemic.
  • absolute configuration refers to the spatial arrangement of the atoms of a chiral molecular entity (or group) and its stereochemical description, e.g., R or S.
  • enantiomeric excess refers to a measure for how much of one enantiomer is present compared to the other.
  • percent enantiomeric excess is defined as
  • *100, where R and S are the respective mole or weight fractions of enantiomers in a mixture such that R + S 1.
  • the percent enantiomeric excess is defined as ([a] Obs /[a]max)*100, where [a] 0bs is the optical rotation of the mixture of enantiomers and [a] max is the optical rotation of the pure enantiomer. Determination of enantiomeric excess is possible using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography or optical polarimetry.
  • R la , R lb , and R lc are each independently selected from the group consisting of hydrogen and halo;
  • R 2 is selected from the group consisting of:
  • R 10a is selected from the group consisting of hydrogen, halo, cyano, Ci-4 alkyl, Ci-4 alkoxy, and hydroxy;
  • X is selected from the group consisting of:
  • o and p are each independently 0, 1, 2, or 3;
  • R 8a and R 8b are independently selected from the group consisting of hydrogen and halo;
  • R 13a , R 13b , R 13c , and R 13d are each independently selected from the group consisting of hydrogen, methyl, and dimethylaminomethyl;
  • R a3 is selected from the group consisting of alkoxycarbonyl and alkylsulfonyl;
  • R a5 is selected from the group consisting of alkoxycarbonyl and alkylsulfonyl;
  • R 10a is not hydrogen, F, OH, fluoromethyl, methyl or methoxy
  • Aspect 2 The compound of Aspect 1 having Formula II:
  • Aspect 3 The compound of Aspect 1 having Formula XI
  • Aspect 4 The compound of any of Aspects 1 to 3, wherein:
  • R 2 is selected from the group consisting of: [000386] R 10a is selected from the group consisting of hydrogen, fluoro, cyano, methyl, methoxy, ethoxy, and hydroxy;
  • R 8a and R 8b are independently selected from the group consisting of hydrogen and fluoro;
  • R 13a , R 13b , R 13c , and R 13d are each independently selected from the group consisting of hydrogen, methyl, and dimethylaminomethyl.
  • Aspect 5 The compound of any one of Aspects 1-4, wherein R 2 is
  • Aspect 6 The compound of Aspects 1-4, or a pharmaceutically acceptable salt thereof, wherein R 2 is
  • Aspect 7 The compound of Aspect 4, or a pharmaceutically acceptable salt thereof, wherein R 2 is [000396]
  • Aspect 8 The compound of any one of Aspects 1-7, wherein R 8a and R 8b are hydrogen, or a pharmaceutically acceptable salt thereof.
  • Aspect 9 The compound of any one of Aspects 1-7, wherein R 8a is fluoro, or a pharmaceutically acceptable salt thereof.
  • Aspect 10 The compound of any one of Aspects 1-9, wherein at least one of R la , R lb and R lc is a fluoro, or a pharmaceutically acceptable salt thereof.
  • Aspect 11 The compound of any one of Aspects 1-10, wherein R 10a is hydrogen, or a pharmaceutically acceptable salt thereof.
  • Aspect 12 The compound of any one of Aspects 1-10, wherein R 10a is fluoro, or a pharmaceutically acceptable salt thereof.
  • Aspect 13 The compound of any one of Aspects 1-12, wherein X is
  • Aspect 14 The compound of any one of Aspects 1-13, wherein X is
  • Aspect 15 The compound of any one of Aspects 1-13, wherein X is
  • Aspect 16 The compound of any one of Aspects 1-12, wherein X is
  • Aspect 17 The compound of any one of Aspects 1-13, wherein X is
  • Aspect 18 The compound of any one of Aspects 1-17, wherein R 3
  • Aspect 20 The compound of any one of Aspects 1-19, wherein
  • Aspect 21 The compound of Aspect 20, wherein R 13a and R 13b are hydrogen and R 13c is dimethylaminomethyl, or a pharmaceutically acceptable salt thereof.
  • Aspect 22 The compound of Aspect 20, wherein R 13c is methyl and
  • R 13a and R 13b are hydrogen, or a pharmaceutically acceptable salt thereof.
  • Aspect 23 The compound of Aspect 20, wherein each of R 13a , R 13b , and R 13C is hydrogen, or a pharmaceutically acceptable salt thereof.
  • Aspect 25 The compound of any one of Aspects 1-12 and 18-24, wherein X is selected from the group consisting of:
  • Aspect 26 The compound of any one of Aspects 1-19, wherein Z 2 is selected from the group consisting of:
  • Aspect 27 The compound of Aspect 1 , wherein the compound is any one or more of the compounds of Table 1, or a pharmaceutically acceptable salt thereof.
  • Aspect 28 A pharmaceutical composition comprising the compound of any one of Aspects 1-27, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Aspect 29 A method of treating a patient, the method comprising administering to the patient a therapeutically effective amount of the compound of any one of Aspects 1-27, or a pharmaceutically acceptable salt thereof, wherein the patient has cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.
  • Aspect 30 The method of Aspect 29, wherein the patient has cancer.
  • Aspect 31 The method of Aspect 30, wherein the cancer is any one or more of the cancers of Table 2.
  • Aspect 32 The method of Aspect 31, wherein the cancer is selected from the group consisting of acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia mixed lineage leukemia, NUT-midline carcinoma, multiple myeloma, small cell lung cancer, neuroblastoma, Burkitfs lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colorectal cancer, prostate cancer, and breast cancer.
  • Aspect 33 The method of any one of Aspects 29-32 further comprising administering a therapeutically effective amount of a second therapeutic agent useful in the treatment of the disease or condition.
  • Aspect 34 The pharmaceutical composition of Aspect 28 for use in treating cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.
  • Aspect 35 The pharmaceutical composition of Aspect 34 for use in treating cancer.
  • Aspect 36 The pharmaceutical composition of Aspect 35, wherein the cancer is any one or more of the cancers of Table 2.
  • Aspect 37 The pharmaceutical composition of Aspect 36, wherein the cancer is selected from the group consisting of acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia mixed lineage leukemia, NUT-midline carcinoma, multiple myeloma, small cell lung cancer, neuroblastoma, Burkitfs lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colorectal cancer, prostate cancer, and breast cancer.
  • the cancer is selected from the group consisting of acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia mixed lineage leukemia, NUT-midline carcinoma, multiple myeloma, small cell lung cancer, neuroblastoma, Burkitfs lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colorectal cancer, prostate cancer, and breast cancer.
  • Aspect 38 A compound of any one of Aspects 1-27, or a pharmaceutically acceptable salt thereof, for use in treatment of cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.
  • Aspect 39 The compound of Aspect 38 for use in treating cancer.
  • Aspect 40 The compound of Aspect 39, wherein the cancer is any one or more of the cancers of Table 2.
  • Aspect 41 The compound of Aspect 40, wherein' the cancer is selected from the group consisting of acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia mixed lineage leukemia, NUT-midline carcinoma, multiple myeloma, small cell lung cancer, neuroblastoma, Burkitfs lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colorectal cancer, prostate cancer, and breast cancer.
  • the cancer is selected from the group consisting of acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia mixed lineage leukemia, NUT-midline carcinoma, multiple myeloma, small cell lung cancer, neuroblastoma, Burkitfs lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colorectal cancer, prostate cancer, and breast cancer.
  • Aspect 42 Use of a compound of any one of Aspects 1-27, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treatment of cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.
  • Aspect 43 The use of Aspect 42 for treatment of cancer.
  • Aspect 44 The use of Aspect 43, wherein the cancer is any one or more of the cancers of Table 2.
  • Aspect 45 The use of Aspect 44, wherein the cancer is selected from the group consisting of acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia mixed lineage leukemia, NUT-midline carcinoma, multiple myeloma, small cell lung cancer, neuroblastoma, Burkitfs lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colorectal cancer, prostate cancer, and breast cancer.
  • the cancer is selected from the group consisting of acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia mixed lineage leukemia, NUT-midline carcinoma, multiple myeloma, small cell lung cancer, neuroblastoma, Burkitfs lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colorectal cancer, prostate cancer, and breast cancer.
  • R la , R lb , and R lc are each independently selected from the group consisting of hydrogen and halo;
  • G is -SO2-X-Z 2 or -CH2-X-Z 2 ;
  • R 2 is selected from the group consisting of: [000444] R 3 is selected from the group consisting of:
  • L is , wherein the nitrogen atom of L is attached to the M;
  • each R 10a is independently selected from the group consisting of hydrogen, halo, cyano, Ci-4 alkyl, Ci-4 alkoxy, and hydroxy;
  • X is selected from the group consisting of:
  • 0 and p are each independently 0, 1, 2, or 3;
  • Z 2 is absent when X is X- 10 or when X is X-45;
  • R 8a and R 8b are independently selected from the group consisting of hydrogen, -SO2-C1-C6 alkyl and halo;
  • R 13a , R 13b , R 13c , and R 13d are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, and di-Ci-C6 alkylaminoCi-C4 alkyl;
  • R a3 is selected from the group consisting of C1-C6 alkoxycarbonyl-, heterocyclyl-carbonyl-, halo-substituted heterocyclyl-carbonyl-, C1-C6 alkylamide and C1-C6 alkylsulfonyl;
  • R a5 is selected from the group consisting of C1-C6 alkoxycarbonyl-, heterocyclyl-carbonyl-, halo-substituted heterocyclyl-carbonyl-, C1-C6 alkylamide and C1-C6 alkylsulfonyl;
  • R la is not hydrogen, F, OH, fluoromethyl, methyl or methoxy
  • R 10a is not hydrogen, F, or methyl
  • R 2 is -CN only when X is X-12; and [000465] the compound of formula (I) is not
  • Aspect 2 The compound of Aspect 1 having Formula II:
  • Aspect 3 The compound of Aspect 1 having Formula XI
  • Aspect 4 The compound of any of Aspects 1 to 3, wherein:
  • R 2 is selected from the group consisting of: [000472] R 10a is selected from the group consisting of hydrogen, fluoro, cyano, methyl, methoxy, ethoxy, and hydroxy;
  • R 8a and R 8b are independently selected from the group consisting of hydrogen and fluoro;
  • R 13a , R 13b , R 13c , and R 13d are each independently selected from the group consisting of hydrogen, methyl, and dimethylaminomethyl.
  • Aspect 5 The compound of any one of Aspects 1-4, wherein R 2 is
  • Aspect 6 The compound of Aspect 1-4, or a pharmaceutically acceptable salt thereof, wherein R 2 is
  • Aspect 7 The compound of Aspect 4, or a pharmaceutically acceptable salt thereof, wherein R 2 is [000482]
  • Aspect 8 The compound of any one of Aspects 1-7, wherein R 8a and R 8b are hydrogen, or a pharmaceutically acceptable salt thereof.
  • Aspect 9 The compound of any one of Aspects 1-7, wherein R 8a is fluoro, or a pharmaceutically acceptable salt thereof.
  • Aspect 10 The compound of any one of Aspects 1-9, wherein at least one of R la , R lb and R lc is a fluoro, or a pharmaceutically acceptable salt thereof.
  • Aspect 11 The compound of any one of Aspects 1-10, wherein R 10a is hydrogen, or a pharmaceutically acceptable salt thereof.
  • Aspect 12 The compound of any one of Aspects 1-10, wherein R 10a is fluoro, or a pharmaceutically acceptable salt thereof.
  • Aspect 13 The compound of any one of Aspects 1-12, wherein X is
  • Aspect 14 The compound of any one of Aspects 1-13, wherein X is
  • Aspect 15 The compound of any one of Aspects 1-13, wherein X is
  • Aspect 16 The compound of any one of Aspects 1-12, wherein X is
  • Aspect 17 The compound of any one of Aspects 1-13, wherein X is
  • Aspect 18 The compound of any one of Aspects 1-17, wherein R 3
  • Aspect 20 The compound of any one of Aspects 1-19, wherein
  • Aspect 21 The compound of Aspect 20, wherein R 13a and R 13b are hydrogen and R 13c is dimethylaminomethyl, or a pharmaceutically acceptable salt thereof.
  • Aspect 22 The compound of Aspect 20, wherein R 13c is methyl and
  • R 13a and R 13b are hydrogen, or a pharmaceutically acceptable salt thereof.
  • Aspect 23 The compound of Aspect 20, wherein each of R 13a , R 13b , and R 13C is hydrogen, or a pharmaceutically acceptable salt thereof.
  • Aspect 24 The compound of any one of Aspects 1-12 and 18-23, wherein X is selected from the group consisting of:
  • Aspect 25 The compound of any one of 1-19, wherein Z 2 is selected from the group consisting of:
  • Aspect 26 The compound of Aspect 1 , wherein the compound is any one or more of the compounds of Table 1, or a pharmaceutically acceptable salt thereof.
  • Aspect 27 A pharmaceutical composition comprising the compound of any one of Aspects 1-26, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Aspect 28 A method of treating a patient, the method comprising administering to the patient a therapeutically effective amount of the compound of any one of Aspects 1-26, or a pharmaceutically acceptable salt thereof, wherein the patient has cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.
  • Aspect 29 The method of Aspect 28, wherein the patient has cancer.
  • Aspect 30 The method of Aspect 29, wherein the cancer is any one or more of the cancers of Table 2.
  • Aspect 31 The method of Aspect 30, wherein the cancer is selected from the group consisting of acute monocytic leukemia, acute lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.
  • Aspect 32 The method of any one of Aspects 28-31 further comprising administering a therapeutically effective amount of a second therapeutic agent useful in the treatment of the disease or condition.
  • Aspect 33 The pharmaceutical composition of Aspect 27 for use in treating cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.
  • Aspect 34 The pharmaceutical composition of Aspect 33 for use in treating cancer.
  • Aspect 35 The pharmaceutical composition of Aspect 34, wherein the cancer is any one or more of the cancers of Table 2.
  • Aspect 36 The pharmaceutical composition of Aspect 34, wherein the cancer is selected from the group consisting of acute monocytic leukemia, acute lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.
  • Aspect 37 A compound of any one of Aspects 1-26, or a pharmaceutically acceptable salt thereof, for use in treatment of cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.
  • Aspect 38 The compound of Aspect 37 for use in treating cancer.
  • Aspect 39 The compound of Aspect 38, wherein the cancer is any one or more of the cancers of Table 2.
  • Aspect 40 The compound of Aspect 38, wherein the cancer is selected from the group consisting of acute monocytic leukemia, acute lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.
  • Aspect 41 Use of a compound of any one of Aspect 1-26, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treatment of cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.
  • Aspect 42 The use of Aspect 41 for treatment of cancer.
  • Aspect 43 The use of Aspect 42, wherein the cancer is any one or more of the cancers of Table 2.
  • Aspect 44 The use of Aspect 42, wherein the cancer is selected from the group consisting of acute monocytic leukemia, acute lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.
  • the residue was purified by column chromatograph to give the mixture of diastereomers in a ratio of 3:2 as a yellow solid (2.5 g, 73%). Then, the diastereomers were separated by reverse phase preparative HPLC to give the enantiopure title compounds S7 (1.2 g, 36%) and S8 (0.8 g, 24%) as salts of trifluoroacetic acid, respectively.
  • the enantiopure compound S7 is isolated by recrystallization in a solution of hexane and dichloromethane with a ratio of 4: 1.
  • Diisobutylaluminiumhydride (25% in toluene, 16.4 mL, 24.4 mmol, 4 eq) was injected into the reaction mixture with syringe slowly at 0 °C with stirring. Then the ice-bath was removed, the reaction was monitored using UPLC-Mass (about 4h). After the mass (492) of S7 disappeared, 20 ml of NaOH (1M) solution was added slowly into the reaction mixture at 0 °C to quench the reaction. After stirring for 5 min, the ice-bath was removed and additional 20 ml saturated brine was added. Then about 50 mL EA was added, the gel forms. The gel was filtered with celite, and was washed with EA, combine the solvent.
  • S13 may be converted to various intermediate compounds that are suitable for preparing some of the claimed compounds (e.g., compounds 27-29 and 35). Groups in other compounds corresponding to S13 can similarly be prepared by choosing appropriate S7 starting material. Following a variant of the procedure described below for converting S13 to S15, analogs of S15 may be prepared. For example, using appropriate S14a analogs (in which the group corresponding to R 10a is, for example, H, methyl, F, CN, etc.), analogs of S15 may be prepared.
  • S13 or its analogs may be converted to S18 or its analogs in accordance with the following scheme:
  • R 10a is H, F, cyano, etc.
  • A1 (3.63 g, 13.00 mmol) and A2 (1.58 g, 10.84 mmol) were dissolved in 50 mL of acetonitrile then K2CO3 (2.39g, 17.34 mmol) was added and the reaction was refluxed. After overnight, the reaction was cooled, water was added and the solution was extracted three times with ethyl acetate. After column purification, 3.26 g of A3 was obtained.
  • Triphenyl phosphine (1.83g, 6.967 mmol), and CBr4 (2.31g, 6.967 mmol) were added to a solution of A8 (l.Og, 4.645 mmol) in 16 mL of THF. After stirring overnight, the reaction was diluted with water, extracted with diethyl ether, concentrated and purified by column chromatography to yield 588 mg of A9.
  • Step A methyl 3-((6-chloro-5-fluoropyridin-3-yl)thio)propanoate
  • Step D tert-butyl (R)-3-((6-chloro-5-fluoropyridin-3- yl)sulfonyl)piperidine-l-carboxylate
  • Step E tert-butyl (R)-3-((6-(3-((4-((S)-2-(2-ethyl- lH-imidazol- 1-yl)- l-(3-fluorophenyl)- l-((lR,2S)-2-
  • Step F methyl ((lS,2R)-2-((S)-2-(2-ethyl-lH-imidazol-l-yl)-l-(l-((l- (3-fhioro-5-(((R)-piperidin-3-yl)sulfonyl)pyridin-2-yl)azetidin-3- yl)methyl)piperidin-4-yl)-l-(3-fluorophenyl)ethyl)cyclopentyl)carbamate [000382] A solution of tert-butyl (R)-3-((6-(3-((4-((S)-2-(2-ethyl-lH-imidazol-l- yl)-l-(3-fluorophenyl)-l-((lR,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl) piperi din-
  • Step G methyl ((lS,2R)-2-((S)-2-(2-ethyl-lH-imidazol-l-yl)-l-(l-((l-)
  • Step A tert-butyl 3-(4-bromobenzyl)azetidine-l-carboxylate
  • Step B tert-butyl 3-(4-(3-((4-((S)-2-(azetidin-l-yl)-l-(3- fluorophenyl)-l-((lR,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin- l-yl)methyl)azetidin-l-yl)benzyl)azetidine-l-carboxylate
  • Step C methyl ((lS,2R)-2-((S)-2-(azetidin-l-yl)-l-(l-((l-(4-(azetidin-
  • Step D tert-butyl (E)-(4-(dimethylamino)-4-oxobut-2-en-l- yl)carbamate
  • HATU 992 mg, 2.6 mmol, 1.5 eq.
  • dimethylamine 2.0 M in THF, 1.1 mL, 2.2 mmol, 1.27 eq.
  • TEA 0.5 mL, 3.479 mmol, 2.0 eq.
  • the mixture was stirred at 25°C for 16 h. Then the reaction mixture was dilute with FLO (10 mL) and extracted with EtOAc (10 mL x 3).
  • Step E (E)-4-amino-N,N-dimethylbut-2-enamide
  • Step F methyl ((lS,2R)-2-((S)-2-(azetidin-l-yl)-l-(l-((l-(4-((l-((E)-
  • a fluorescence polarization (FP) competitive binding assay was used to determine the binding affinities of representative menin inhibitors.
  • a FAM labeled fluorescent probe was designed and synthesized based on a MLL1 peptide (FAM-MM2).
  • Equilibrium dissociation constant (K t/ ) value of FAM-MM2 to menin protein was determined from protein saturation experiments by monitoring the total fluorescence polarization of mixtures composed with the fluorescent probe at a fixed concentration and the protein with increasing concentrations up to full saturation.
  • Serial dilutions of the protein were mixed with FAM-MM2 to a final volume of 200 m ⁇ in the assay buffer (PBS with 0.02% Bovine g-Globulin and 4% DMSO.
  • IC50 of representative Compounds of the Disclosure were determined in a competitive binding experiment. Mixtures of 5 m ⁇ of the tested compounds in DMSO and 195 m ⁇ of preincubated protein/probe complex solution in the assay buffer were added into assay plates which were incubated at room temperature for 30 minutes with gentle shaking. Final concentration of the menin protein was 4 nM, and final probe concentration is 2 nM. Negative controls containing protein/probe complex only (equivalent to 0% inhibition), and positive controls containing only free probes (equivalent to 100% inhibition), were included in each assay plate. FP values were measured as described above. IC50 values were determined by nonlinear regression fitting of the competition curves.
  • the cell viability reagent was added to each well at a final concentration of 10% (v/v), and then the plates were incubated at 37°C for 1-2 hours for color development.
  • the absorbance was measured at 450 nm using a SPECTRAmax PLUS plate reader (Molecular Devices, Sunnyvale, CA).
  • the readings were normalized to the DMSO-treated cells and the half maximal inhibitory concentration (IC50) was calculated by nonlinear regression (four parameters sigmoid fitted with variable slope, least squares fit, and no constraint) analysis using the GraphPad Prism 5 software (GraphPad Software, La Jolla, CA).
  • Cells were seeded in 96-well flat bottom (Coming COSTAR, Coming, NY, cat# 3903) at a density of 4,000-7,500 cells/well in 50 m ⁇ of culture medium. Compounds were serially diluted in the appropriate medium, and 50 m ⁇ of the diluted compounds were added to the appropriate wells of the cell plate. After the addition of compounds, the cells were incubated at 37°C in an atmosphere of 5% C02 for 4 or 7 days. Cell viability was determined using the CellTiter-Glo® Luminescent Cell Viability reagent according to the manufacturers’ instructions.

Abstract

La présente invention concerne des composés représentés par la formule (la) : et les sels pharmaceutiquement acceptables de ceux-ci, R1a, R1b, R1c, R2, R3 L, M et G étant tels que définis dans la description. La présente invention concerne également des composés de formule la destinés à être utilisés pour traiter une affection ou un trouble sensible à l'inhibition de ménine comme le cancer.
PCT/US2020/053186 2019-09-30 2020-09-29 Composés de pipéridine utilisés en tant qu'inhibiteurs de ménine WO2021067215A1 (fr)

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