WO2021207310A1 - Menin inhibitors and methods of use for treating cancer - Google Patents

Menin inhibitors and methods of use for treating cancer Download PDF

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Publication number
WO2021207310A1
WO2021207310A1 PCT/US2021/026111 US2021026111W WO2021207310A1 WO 2021207310 A1 WO2021207310 A1 WO 2021207310A1 US 2021026111 W US2021026111 W US 2021026111W WO 2021207310 A1 WO2021207310 A1 WO 2021207310A1
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pharmaceutically acceptable
compound
group
alkyl
methyl
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PCT/US2021/026111
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French (fr)
Inventor
Tao Liu
Shubao ZHOU
Shaomeng Wang
Meng Zhang
Fuming XU
Haibin Zhou
Angelo AGUILAR
Liyue HUANG
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Agios Pharmaceuticals, Inc.
The Regents Of The University Of Michigan
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Publication of WO2021207310A1 publication Critical patent/WO2021207310A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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

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. Cierpicki and Grembecka, Future Med. Chem. 6:447-462 (2014). Overexpression of menin leads to inhibition of Ras-transformed cells. Menin interacts with the transcription factors JunD and NF-KB and represses their activation of gene transcription. Studies on these interacting proteins suggest that menin exerts its effects predominantly through inhibitory effects on transcription. But an alternative possibility is that menin mediates its effects through transcriptional activation of target genes. Additionally, menin interacts with RPA2, 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 (Brcal) product.
  • RPA2 a component of a single-stranded DNA-binding protein involved in DNA repair and replication.
  • FANCD2 a nuclear protein that plays a critical role in maintaining genome stability with breast cancer 1 gene (Brcal) 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 MEN 1 knockout mice show increased proliferation in neuroendocrine tissues, down-modulation of menin in epithelial cells increases proliferation, and MEN1 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.
  • NPM1 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. 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, SMAD 1,3,5, Pern, Runx2, Hlbx9,ER, PPARy, vitamin D receptor, transcription repressors, e.g., JunD, Sin3A, HDAC, EZH2, PRMT5, NFKB, Sirtl, CHES1, cell signaling proteins, e.g., AKT, SOS1/GEF, b-catenin, SMAD 1,3,5, NFKB, ER, PPARy, vitamin D receptor, and other proteins, e.g., cell cycle: RPA2, ASK; DNA repair: FANCD2; cell structure: GFAP, vimenten, NMMHCIIA, IQGAP1; Others: HSP70, CHIP, ("menin-interacting proteins") involved in regulating gene transcription and cell signaling.
  • transcription activators e.g., sc-Myb, MLL1, SMAD 1,3,5, Pern, Run
  • the present disclosure provides Compounds of Formulae I-XXXIII, and the pharmaceutically acceptable salts thereof, collectively referred to herein as "Compounds of the Disclosure.”
  • Compounds of the Disclosure are menin inhibitors and thus are useful in treating diseases or conditions wherein inhibition of menin provides a therapeutic benefit to a patient.
  • 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 subject, 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 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.
  • the present disclosure provides a composition
  • 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.
  • Compounds of the Disclosure are menin inhibitors.
  • Compounds of the Disclosure are compounds represented by Formula I, and the pharmaceutically acceptable salts thereof, wherein: each R a is independently selected from the group consisting of hydrogen and C1-C4 alkyl; each R b is independently selected from the group consisting of hydrogen and C1-C4 alkyl;
  • R c is selected from the group consisting of hydrogen and halo; each R d is independently selected from the group consisting of halo; each n is independently 0, 1 or 2;
  • Q is -NHCO2-R
  • R is C1-C4 alkyl, C1-C4 haloalkyl, or CD3 ;
  • B is selected from the group consisting of:
  • R 2 is selected from the group consisting of hydrogen, halo, C1-C4 alkyl, hydroxy, Ci- C4 alkoxy, C1-C4 haloalkyl, and C1-C4 hydroxyalkyl;
  • E is selected from the group consisting of:
  • L 1 is -CH2- wherein E is E-l, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, E-10, E-13, and E- 14 and absent wherein E is E-l 1 or E-12; R 3a and R 3b are independently selected from the group consisting of hydrogen, halo, and
  • R 4 is hydrogen or C1-C4 alkyl; m is 1 or 2;
  • J is cyano, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocycloalkylsulfonyl, carboxamido, and -SO2X;
  • R 5 is hydrogen or alkenyl
  • R 6 is hydrogen or halo; n is 0 or 1;
  • R 7 is alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocycloalkylsulfonyl, or carboxamido;
  • L 2 is absent, -SO2-, or -CH2-
  • R 8a is selected from the group consisting of hydrogen, halo, alkoxy, and R al ;
  • R 8b is selected from the group consisting of alkoxy and R al ;
  • Z is alkylsulfonyl and cycloalkylsulfonyl
  • R al is (amino)alkyl, carboxamido, and (heterocyclo)alkyl;
  • X is selected from the group consisting of o and p are independently 0, 1, 2, or 3;
  • R 12 is selected from the group consisting of alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, and carboxamido;
  • R 13 is hydrogen or C1-C4 alkyl
  • R 14a , R 14b , R 14c , and R 14d are each independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, (amino)alkyl, and R a3 ;
  • R 19 is halo
  • R a3 is selected from the group consisting of alkoxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, and carboxamido;
  • R a4 is optionally substituted heterocyclo
  • R a5 is hydrogen or C1-C4 alkyl
  • R 15 is hydrogen or C1-C4 alkyl
  • R 16 is carboxamido
  • Compounds of the Disclosure are compounds represented by Formula I, and the pharmaceutically acceptable salts thereof, wherein B is B-l, B-2, B-3, B-4, B-5, or B-6.
  • Compounds of the Disclosure are compounds represented by Formula I, and the pharmaceutically acceptable salts thereof, wherein each R a and R b is hydrogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae II or III:
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae II-III, and the pharmaceutically acceptable salts thereof.
  • Compounds of the Disclosure are compounds represented by Formula II, and the pharmaceutically acceptable salts thereof, wherein E is E-l, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, or E-10.
  • Compounds of the Disclosure are compounds represented by Formula II, and the pharmaceutically acceptable salts thereof, wherein E is E-l.
  • Compounds of the Disclosure are compounds represented by Formula II, and the pharmaceutically acceptable salts thereof, wherein E is E-2.
  • Compounds of the Disclosure are compounds represented by Formula II, and the pharmaceutically acceptable salts thereof, wherein E is E-3, E-4, E-5, E-6, E-7, E-8, E-9, or E-10.
  • Compounds of the Disclosure are compounds represented by Formula III, and the pharmaceutically acceptable salts thereof, wherein E is E- 11 or E-12.
  • Compounds of the Disclosure are compounds represented by Formula II, and the pharmaceutically acceptable salts thereof, wherein E is E-13 or E-14.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae IV-XIII:
  • R a , R b , R c , R d , R 2 , R 3a , R 3b , n, Q, B, X, E and remaining variables are defined above in accordance with Formula I.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein at least one R a is hydrogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein each R a is hydrogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein at least one R b is hydrogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein each R b is hydrogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein each R a and R b are hydrogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein R c is hydrogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein R c is halo.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein R c is fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein n is 0.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein n is i.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein n is 2.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein n is 0 and R c is hydrogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein n is 1 and R c is hydrogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein n is 0 and R c is halo.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein n is 0 and R c is fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein n is 1 and R d is halo.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein n is 1 and R d is fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein n is 1 and R c and R d are each fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein R 2 is hydrogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein R 2 is halo.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein R 2 is fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein R 2 is methoxy.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein R 2 is hydroxy.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein R is -C1-C4 alkyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein R is methyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein R is -C1-C4 haloalkyl.
  • Compounds of the Disclosure are compounds represented by Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein B is B-l or B-2.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein B is B-l.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein B is B-2.
  • Compounds of the Disclosure are compounds represented by Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein B is B-3.
  • Compounds of the Disclosure are compounds represented by Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein B is B-4.
  • Compounds of the Disclosure are compounds represented by Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein B is B-5.
  • Compounds of the Disclosure are compounds represented by Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein B is B-6.
  • Compounds of the Disclosure are compounds represented by Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein B is B-6 wherein alkyl is methyl.
  • Compounds of the Disclosure are compounds represented by Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein B is B-7.
  • Compounds of the Disclosure are compounds represented by Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein B is B-7 wherein alkyl is methyl.
  • Compounds of the Disclosure are compounds represented by Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein B is B-8.
  • Compounds of the Disclosure are compounds represented by Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein B is B-9.
  • Compounds of the Disclosure are compounds represented by Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein B is B-10.
  • Compounds of the Disclosure are compounds represented by Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein B is B-l 1.
  • Compounds of the Disclosure are compounds represented by Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein B is B-12.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein at least one of R 3a and R 3b is hydrogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein both R 3a and R 3b are hydrogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein at least one of R 3a and R 3b is halo.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein both R 3a and R 3b are halo.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein at least one of R 3a and R 3b is fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein both R 3a and R 3b are fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein at least one of R 3a and R 3b is C1-C4 alkyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein both R 3a and R 3b are C1-C4 alkyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein at least one of R 3a and R 3b is Me.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein both R 3a and R 3b are Me.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein at least one of R 3a and R 3b is -CH2NMe2.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein at least one of R 3a and R 3b is -C(0)NMe2.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein at least one of R 3a and R 3b is
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-l, X-2, X-3, X-4, X-5, X-6, X-7, X-8, X-9, X-10, X-ll, X- 12, or X-13.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-l, X-2, X-3, X-4, X-6, X-7, X-8, X-9, X-10, X-ll, X-12, or X-13.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-l 4 or X-15.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-l.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-l.
  • o and p are 0.
  • X- 1 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-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-2.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-3.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-4.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-5.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-6.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-7.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-8.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-9.
  • o and p are 0.
  • X-9 is selected from the group consisting of:
  • X-9 is selected from the group consisting of:
  • X-9 is selected from the group consisting of:
  • X-9 is selected from the group consisting of:
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-10.
  • o and p are 0.
  • X-10 is selected from the group consisting of:
  • X-10 is selected from the group consisting of:
  • X-10 is selected from the group consisting of:
  • X-10 is selected from the group consisting of:
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-l 1.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-l 2.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-13.
  • o and p are 0.
  • X-13 is selected from the group consisting of:
  • X-13 is selected from the group consisting of:
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-14.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-14 and R 6 is halo.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-15.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein E is E-3.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein m is 1.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein m is 2.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein J is -CN.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein J is alkylsulfonyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein J is cycloalkylsulfonyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein J is heteroarylsulfonyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein J is arylsulfonyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein J is heterocycloalkylsulfonyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein J is carboxamido.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein J is -SO2X.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein J is -SO2X and X is X-l, X-2, X-5, or X-8.
  • the present invention provides a compound selected from any of Formulae XIV-XVIII:
  • R c , R 2 , R 3a , R 3b , X and remaining variables are defined above in accordance with Formula I.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein R c is hydrogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein R c is halo.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein R c is fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein R 2 is H.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein R 2 is fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein R 2 is methoxy.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein R 2 is hydroxy.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein R 3a and R 3b are H.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein at least one of R 3a and R 3b is halo.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein at least one of R 3a and R 3b is fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein R 3a and R 3b are fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein at least one of R 3a and R 3b is C1-C4 alkyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein at least one of R 3a and R 3b is Me.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein at least one of R 3a and R 3b is -CH2NMe2.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein at least one of R 3a and R 3b is -C(0)NMe2.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein at least one of R 3a and R 3b is
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein R 3a is -CFhNNto and R 3b is fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein R 3a is fluoro and R 3b is -CFhNNto.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein X is X-l, X-2, X-3, X-4, X-5, X-6, X-7, X-8, X-9, X-10, X-ll, X-12, orX-13.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein X is X-l, X-2, X-3, X-4, X-6, X-7, X-8, X-9, X- 10, X-ll, X-12, or X-13.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein X is X-l 4 or X-15.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein X is X-l.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein X is X-2.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein X is X-5.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein X is X-6.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, 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 XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein X is X-l 1.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein X is X-14.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein X is X-14 and R 6 is halo.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein X is X-l 5.
  • the present invention provides a compound selected from any of Formulae XIX-XXIV:
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-l, X-2, X-3, X-4, X-5, X-6, X-7, X-8, X-9, X-10, X-ll, X-12, orX-13.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-l, X-2, X-3, X-4, X-6, X-7, X-8, X-9, X- 10, X-ll, X-12, or X-13.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-14 or X-15.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-l, X-2, X-4, X-5, X-6, X-7, X-8, X-9, X- 10, X-l 1, X-12, or X-13.
  • Compounds of the Disclosure are compounds represented by Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-l.
  • Compounds of the Disclosure are compounds represented by Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-2.
  • Compounds of the Disclosure are compounds represented by Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-4.
  • Compounds of the Disclosure are compounds represented by Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-5.
  • Compounds of the Disclosure are compounds represented by Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-6.
  • Compounds of the Disclosure are compounds represented by Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-7.
  • Compounds of the Disclosure are compounds represented by Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-8.
  • Compounds of the Disclosure are compounds represented by Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-9.
  • Compounds of the Disclosure are compounds represented by Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-10.
  • Compounds of the Disclosure are compounds represented by Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-l 1.
  • Compounds of the Disclosure are compounds represented by Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-l 2.
  • Compounds of the Disclosure are compounds represented by Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-l 3.
  • the present invention provides a compound selected from any of Formulae XXV-XXVI: wherein R a , R 16 , and B are defined above in accordance with formula I.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXV-XXVI, and the pharmaceutically acceptable salts thereof.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXV-XXVI, and the pharmaceutically acceptable salts thereof, wherein R a is hydrogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXV-XXVI, and the pharmaceutically acceptable salts thereof, wherein R a is methyl.
  • the present invention provides a compound selected from any of Formulae XXVII-XXVIII:
  • the present invention provides a compound selected from any of Formulae XXIX-XXX: and the pharmaceutically acceptable salts thereof, wherein R c , B, Q, R 2 , R 4 , and X are defined above in accordance with Formula I.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein J is -CN.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein J is alkylsulfonyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein J is cycloalkylsulfonyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein J is heteroarylsulfonyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein J is arylsulfonyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein J is heterocycloalkylsulfonyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein J is carboxamido.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVII-XXX, and the pharmaceutically acceptable salts thereof, wherein R 4 is hydrogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVII-XXX, and the pharmaceutically acceptable salts thereof, wherein R 4 is methyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVII-XXX, and the pharmaceutically acceptable salts thereof, wherein Q is -NHCO2CH3.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVII-XXX, and the pharmaceutically acceptable salts thereof, wherein R c is halo.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVII-XXX, and the pharmaceutically acceptable salts thereof, wherein R c is fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVII-XXX, and the pharmaceutically acceptable salts thereof, wherein R 2 is hydrogen.
  • Compounds of the Disclosure are compounds represented by Formula XXXI: and the pharmaceutically acceptable salts thereof, wherein: each R a is independently selected from the group consisting of hydrogen and C1-C4 alkyl; each R b is independently selected from the group consisting of hydrogen and C1-C4 alkyl;
  • R c is selected from the group consisting of hydrogen and halo; each R d is independently selected from the group consisting of halo; each n is independently 0, 1 or 2;
  • K is selected from the group consisting of
  • R 20 is selected from the group consisting of (alkylsulfonamide)alkyl and
  • R 21 is selected from the group consisting of hydrogen and C1-C4 alkyl
  • R 22 is (alkyl)sulfonyl
  • R 23 is selected from the group consisting of hydrogen and C1-C4 alkyl; and R 24 is cyano.
  • Compounds of the Disclosure are compounds represented by Formula XXXI, and the pharmaceutically acceptable salts thereof,
  • Compounds of the Disclosure are compounds represented by Formula XXXI, and the pharmaceutically acceptable salts thereof, wherein each R a and R b are hydrogen.
  • Compounds of the Disclosure are compounds represented by Formula XXXI, and the pharmaceutically acceptable salts thereof, wherein R c is fluoro and each n is 0.
  • Compounds of the Disclosure are compounds represented by Formula XXXI, and the pharmaceutically acceptable salts thereof, wherein R is methyl.
  • Compounds of the Disclosure are compounds represented by Formula XXXII: and the pharmaceutically acceptable salts thereof, wherein:
  • R 25 is selected from the group consisting of (amino)alkyl and carboxamido.
  • Compounds of the Disclosure are compounds represented by Formula XXXII, and the pharmaceutically acceptable salts thereof, wherein B is B-l or B-2.
  • Compounds of the Disclosure are compounds represented by Formula XXXII, and the pharmaceutically acceptable salts thereof, wherein R is methyl.
  • Compounds of the Disclosure are compounds represented by Formula XXXIII: and the pharmaceutically acceptable salts thereof, wherein:
  • R 26a is selected from the group consisting of hydrogen and halo
  • R 26b is selected from the group consisting of (amino)alkyl, (heterocyclo)alkyl, and carboxamido;
  • R 27 is selected from the group consisting of cyano, -CF3, alkylsulfonyl, and cycloalkylsulfonyl.
  • Compounds of the Disclosure are compounds represented by Formula XXXIII, and the pharmaceutically acceptable salts thereof, wherein R 27 is methylsulfonyl.
  • Compounds of the Disclosure are compounds represented by Formula XXXIII, and the pharmaceutically acceptable salts thereof, wherein R 27 is cyclopropylsulfonyl.
  • Compounds of the Disclosure are any one or more of the compounds of Tables 1, 1A, IB, and 1C, and the pharmaceutically acceptable salts thereof.
  • Tables 1, 1A, IB, and 1C further provide the chemical names of the compounds of Tables 1, 1A, IB, and 1C generated by Chemdraw ® Professional version 16.0.
  • 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.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a Compound of the Disclosure and a pharmaceutically acceptable carrier.
  • 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 a suitable acid.
  • the pharmaceutically acceptable salts of Compounds of the Disclosure can be acid addition salts formed with pharmaceutically acceptable acids. Examples of 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.
  • Non-limiting 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, pival
  • 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.
  • 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 a subject in need thereof.
  • the present methods also encompass administering a second therapeutic agent to the subject 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 subject in need thereof, e.g., a chemotherapeutic agent and/or radiation known as useful in treating a particular cancer.
  • 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 mM, or less than about 0.01 mM.
  • IC50 binding affinity
  • 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.
  • Compounds of the Disclosure are inhibitors of menin protein, a number of diseases and conditions mediated by menin can be treated by employing these compounds.
  • the present disclosure is thus directed generally to a method for treating a condition or disorder responsive to menin inhibition 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 a subject 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. Examples of 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 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.
  • 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, hepatitis 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 1 gram per dose, about 0.005 to about 500 milligrams per dose, about 0.05 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, about 500, about 550, about 600, about 650, about 700, about 750, about 800, about 850, about 900, about 950 milligrams, or about 1 gram, including all doses between 0.005 milligrams and 1 gram.
  • 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 antiemetic), 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, phagocytosis inhibitors, demethylating agents, DOT1L inhibitors, IDH1 inhibitors, IDH2 inhibitors, IDH1/IDH2 dual inhibitors, LSD1 inhibitors, XPOl inhibitors, or dasatinib.
  • 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 dasatinib.
  • 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 dasatinib.
  • 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.
  • Non-limiting examples of inhibitors of the histone methyltransferase DOTIL include EPZ-5676, SGC-0946, and EPZ004777.
  • Exemplary nonlimiting IDH1 inhibitors include Tibsovo® (ivosidnib), AG- 881, AG-120, FT-2102 (olutasidenib), BAY1436032, IDH-305, and ZX-06.
  • Exemplary nonlimiting examples of IDH2 inhibitors include Idhifa® (enasidenib; AG- 221), AG-881, AG1-6780, SH1573, andTQ05310.
  • Exemplary nonbmitingIDHl/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.
  • an XPOl inhibitor examples include sebnexor (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.
  • Exemplary nonlimiting phagocytosis inhibitors include Hu5F9-G4 (Forty- Seven), CC-90002 (Celgene), TTI-621 (Trillium), ALX148 (Alexo Therapeutics), SRF231 (Surface Oncology), SHR-1603 (Hengrui), and IBI188 (Innovent Biologies).
  • 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.
  • Exemplary 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.
  • anthracyclines such as doxorubicin, daunorubicin, epirubicin, idarubicin, and nemorubicin
  • anthraquinones such as mitoxantrone and losoxantrone
  • podophillotoxines such as etoposide and teniposide.
  • Microtubule active agents include microtubule stabilizing, microtubule destabilizing compounds, and microtububn 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.
  • mTOR mammalian target of rapamycin
  • 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.
  • 5-fluorouracil 5-FU
  • capecitabine gemcitabine
  • DNA demethylating compounds such as 5-azacytidine and decitabine
  • methotrexate and edatrexate methotrexate and edatrexate
  • folic acid antagonists such as pemetrexed.
  • Exemplary nonlimiting platin compounds include carboplatin, cis-platin, cisplatinum, and oxabplatin.
  • 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.
  • Exemplary nonlimiting antiproliferative antibodies include trastuzumab, trastuzumab-DMl, cetuximab, bevacizumab, rituximab, PR064553, and 2C4.
  • the term “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.
  • Exemplary nonlimiting 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.
  • telomerase 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, SU101, 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), such as a compound that targets
  • 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 2 A, 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, pergobde, 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.
  • composition 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.
  • parenterally acceptable aqueous solution 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.
  • compositions for parenteral administration include aqueous solutions of the active agent in water-soluble form.
  • 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 subj ect 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 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 Compound of the Disclosure and a pharmaceutically acceptable carrier for use in treating cancer.
  • 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 -NO2.
  • 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 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 Ci-10 alkyl.
  • 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. In another embodiment, 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, /.vobutyl. 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
  • Non-limiting exemplary C1-4 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, .sec-butyl /e/7- butyl and /.vobutyl.
  • 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 atached 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.
  • Non-limiting exemplary substituted cycloalkyl groups include:
  • cycloalkylenyl refers to a divalent form of an optionally substituted cycloalkyl group.
  • the cycloalkylenyl is a 4-membered cycloalkylenyl.
  • the cycloalkylenyl is a 5-membered cycloalkylenyl.
  • the cycloalkylenyl is a 6-membered cycloalkylenyl.
  • Non-limiting exemplary cycloalkylenyl groups include:
  • aryl refers to unsubstituted monocyclic or bicyclic aromatic ring systems having from six to fourteen carbon atoms, i.e., a C6-14ryl.
  • 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, -CO2CH2Ph , alkylamino, dialkylamino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, haloalkylsulfonyl cycloalkylsulfonyl,
  • cycloalkyl alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocycloalkylsulfonyl, carboxy, carboxyalkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxycarbonyl, alkoxyalkyl, (amino)alkyl, (carboxamido)alkyl, (heterocyclo)alkyl, - defined in connection with optionally substituted cycloalkyl.
  • 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, 2-methoxyphenyl, 2- fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-methylphenyl, 3 -methoxy phenyl, 3- fluorophenyl, 3-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4- fluorophenyl, 4-chlorophenyl, 2,6-di-fluorophenyl, 2,6-di-chlorophenyl, 2-methyl, 3- methoxyphenyl, 2-ethyl, 3 -methoxy phenyl, 3,4-di-methoxyphenyl, 3,5-di- fluorophenyl 3,5-di-methylphenyl, 3,5-dimethoxy, 4-methylphenyl, 2-fluoro-3- chlorophenyl, 3-chloro-4-fluorophenyl, 4-(pyridin-4
  • An optionally substituted phenyl 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 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 C 2-6 alkenyl. In another embodiment, the alkenyl is a C 2- 4 alkenyl.
  • Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, se -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.
  • the term "optionally substituted alkynyl” as used herein by itself or as part 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 dihydroxy alkyl, i.e., a hydroxyalkyl substituted with two hydroxy groups.
  • Non-limiting exemplary hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxy butyl groups, such as 1 -hydroxyethyl, 2-hydroxy ethyl, 1,2- dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3 -hydroxy butyl, 4-hydroxybutyl, 2-hydroxy- 1-methylpropyl, and l,3-dihydroxyprop-2-yl.
  • heteroaralkyl refers to an alkyl substituted with one, two, or three optionally substituted heteroaryl groups.
  • the heteroaralkyl alkyl group is a Ci-4 alkyl substituted with one optionally substituted heteroaryl group.
  • Non-limiting exemplary heteroaralkyl groups include:
  • (cycloalkyl)alkyl refers to an alkyl substituted with an optionally substituted cycloalkyl.
  • the (cycloalkyl) alkyl is a
  • alkylsulfonyl as used by itself or as part of another group refers to a sulfonyl, i.e., -SO2-, substituted with an optionally substituted 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 refers to a sulfonyl, i.e., -SO2-, substituted with an optionally substituted cycloalkyl.
  • Non-limiting exemplary alkylsulfonyl group include -SO2- cyclopropyl and -SC -cyclopenyl.
  • (cycloalkyl)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 as used by itself or as part of another group 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 Ci-4 alkyl attached to a terminal oxygen atom.
  • Non-limiting exemplary alkoxy groups include methoxy, ethoxy, tert-butoxy, and -OCH2SO2CH3.
  • 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 -SCH3 and -SCH2CH3.
  • 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 PI1CH2CH2O-.
  • 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-5-
  • 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
  • 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.
  • heteroarylenyl refers to a divalent form of an optionally substituted heteroaryl group.
  • the heteroarylenyl is a 5-membered heteroarylenyl.
  • Non-limiting examples of a 5-membered heteroarylenyl include:
  • the heteroarylenyl is a 6-membered heteroarylenyl.
  • Non-limiting examples of a 6-membered heteroarylenyl include:
  • 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 ⁇ -lactam, ⁇ -lactam, ⁇ -lactam, ⁇ -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 C 4-6 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 C 4-6 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. Additional non-limiting examples of heterocyclo groups include oxetanyl and tetrahydrofuranyl.
  • Additional non-limiting exemplary substituted heterocyclo groups include:
  • amino as used by itself or as part of another together to form a 3- to 8-membered optionally substituted heterocyclo.
  • Non-limiting exemplary amino groups include
  • (amino)alkyl refers to an alkyl substituted with an amino.
  • R 23a and R 23b are each independently hydrogen or optionally substituted alkyl.
  • 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.
  • Additional non-limiting exemplary carboxamido groups include:
  • a non-limiting exemplary arylcarbonyl group is -COPh.
  • the alkoxy is a Ci-4 alkoxy.
  • (alkoxycarbonyl)alkyl refers to an alkyl substituted by an alkoxycarbonyl group.
  • carboxy as used by itself or as part of another group refers to a radical of the formula -C0 2 H.
  • carboxyalkyl 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 C 5 or C 6 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 C 3 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(CH 3 )Ph, -CH 2 (4-F-Ph), -CH 2 (4-Me-Ph), -CH 2 (4-CF 3 -Ph), and -CH(4-F-Ph) 2 .
  • the term "(heterocyclo)alkyl” as used by itself or part of another group refers to an alkyl substituted with an optionally substituted heterocyclo group.
  • the (heterocyclo)alkyl is a C1-4 alkyl substituted with one optionally substituted heterocyclo group.
  • Non-limiting exemplary (hetero)alkyl groups include:
  • heterocycloalkyl 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 C1-4 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:
  • (carboxamido)alkyl as used by itself or as part of another group refers to an alkyl substituted with one or two carboxamido groups.
  • 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 C1-4 alkyl substituted with an aryloxy.
  • the "(aryloxy)alkyl” is a C2-4 alkyl substituted with an aryloxy.
  • alkylcarbonyloxy as used by itself or as part of another group refers to an oxy, e.g., -0-, substituted with an alkylcarbonyl group.
  • alkylcarbonyloxy as used by itself or as part of another group refers to an oxy, e.g., -0-, substituted with an alkylcarbonyl group.
  • cycloalkylcarbonyloxy as used by itself or as part of another group refers to an oxy, e.g., -0-, substituted with an cycloalkylcarbonyl group.
  • 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.
  • examples of 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.
  • 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.
  • proliferative treatment 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.
  • the term “treat” and synonyms contemplate administering a therapeutically effective amount of a Compound of the Disclosure to an individual in need of such treatment.
  • 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.
  • Concurrent 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, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent 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, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapeutic agent treatment modality (e.g., radiotherapy), to an individual in need thereof.
  • 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 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 11 hours apart, 11 hours to 12 hours apart, no more than 24 hours apart or no more than 48 hours apart.
  • the components of the combination therapies are administered at about 1 minute to about 24 hours apart.
  • certain compounds have been designated as having a specific stereochemical configuration, which has not been confirmed by x-ray crystallography or by any other means.
  • the absolute configuration of any of the compounds disclosed herein could be confirmed by one of ordinary skill in the art using one or more well-known methods including x-ray crystallography or by other spectroscopic techniques such as NMR (using a chiral derivatizing agent, Mosher ester analysis, etc.).
  • 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 or "ee” refers to a measure for how much of one enantiomer is present compared to the other.
  • Compounds of Formula XXXI can, for example, be prepared by the general method shown in Scheme 3.
  • Aryl bromide 4-A is converted to aldehyde 4-C via a Suzuki coupling and subsequent acid hydrolysis.
  • a reductive animation reaction of piperidine 4-D and aldehyde 4-C affords the Compounds of Formula XXXI (4-E).
  • Aspect 1 A compound having Formula I, or a pharmaceutically acceptable salt thereof, wherein: each R a is independently selected from the group consisting of H and C1-C4 alkyl; each R b is independently selected from the group consisting of H and C1-C4 alkyl;
  • R c is selected from the group consisting of H and halogen; each R d is independently selected from the group consisting of halogen; each n is independently 0, 1 or 2;
  • R 2 is selected from the group consisting of hydrogen, halo, C1-C4 alkyl, hydroxy, Ci- C4 alkoxy, C1-C4 haloalkyl, and C1-C4 hydroxyalkyl;
  • E is selected from the group consisting of: J is cyano, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocycloalkylsulfonyl, carboxamido, and -SO2X;
  • R 5 is hydrogen or alkenyl
  • R 6 is hydrogen or halo; n is 0 or 1;
  • R 7 is alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocycloalkylsulfonyl, or carboxamido;
  • L 2 is absent, -SO2-, or -CH2-
  • R 8a and R 8b are independently selected from the group consisting of hydrogen, halo, and
  • Z is alkylsulfonyl and cycloalkylsulfonyl
  • R al is (amino)alkyl, carboxamido, and (heterocyclo)alkyl;
  • R 12 is selected from the group consisting of alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, and carboxamido;
  • R 13 is hydrogen or C1-C4 alkyl
  • R 14a , R 14b , R 14c , and R 14d are each independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, (amino)alkyl, and R a3 ;
  • R a3 is selected from the group consisting of alkoxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, and carboxamido;
  • R a4 is optionally substituted heterocyclo
  • R a5 is hydrogen or C1-C4 alkyl
  • R 15 is hydrogen or C1-C4 alkyl
  • R 16 is carboxamido
  • Aspect 2 The compound of Aspect 1 having Formula II:
  • E is E-l, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, or E-10.
  • Aspect 3 The compound of Aspect 1 having Formula III:
  • Aspect 4 The compound of Aspect 1 having Formula XII:
  • Aspect 5 The compound of Aspect 1 having Formula XIII:
  • Aspect 6 The compound of any of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein: [00407] Aspect 7. The compound of Aspect 6, or a pharmaceutically acceptable salt thereof, wherein B is B-l.
  • Aspect 8 The compound of Aspect 6, or a pharmaceutically acceptable salt thereof, wherein B is B-2.
  • Aspect 9 The compound of Aspect 6, or a pharmaceutically acceptable salt thereof, wherein R is methyl.
  • Aspect 10 The compound of any of Aspects 1 to 9, or a pharmaceutically acceptable salt thereof, wherein at least one of R 3a and R 3b is halogen.
  • Aspect 11 The compound of any of Aspects 1 to 9, or a pharmaceutically acceptable salt thereof, wherein at least one of R 3a and R 3b is fluoro.
  • Aspect 12 The compound of any of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.
  • Aspect 13 The compound of any of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 2 is fluoro.
  • Aspect 14 The compound of any of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 2 is methoxy.
  • Aspect 15 The compound of any of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydroxy.
  • Aspect 16 The compound of any of Aspects 1-2 and 6-10, or a pharmaceutically acceptable salt thereof, wherein E is E-l or E-2.
  • Aspect 17 The compound of any of Aspects 1-2 and 6-10, or a pharmaceutically acceptable salt thereof, wherein E is E-l.
  • Aspect 18 The compound of Aspect 17, or a pharmaceutically acceptable salt thereof, wherein X is X-l.
  • Aspect 19 The compound of Aspect 17, or a pharmaceutically acceptable salt thereof, wherein X is X-2.
  • Aspect 20 The compound of Aspect 17, or a pharmaceutically acceptable salt thereof, wherein X is X-l 1.
  • Aspect 21 The compound of any of Aspects 1-2 and 6-10, or a pharmaceutically acceptable salt thereof, wherein E is E-3.
  • Aspect 22 A compound, or a pharmaceutically acceptable salt, selected from one or more of the compounds of Table 1.
  • Aspect 23 A pharmaceutical composition comprising the compound of any one of Aspects 1-22, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Aspect 24 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 1-22, 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 25 The method of Aspect 24, wherein the patient has cancer.
  • Aspect 26 The method of Aspect 25, wherein the cancer is any one or more of the cancers of Table 2.
  • Aspect 27 The method of Aspect 25, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.
  • Aspect 28 The method of any one of Aspects 24-27 further comprising administering a therapeutically effective amount of a second therapeutic agent useful in the treatment of the disease or condition.
  • Aspect 29 The pharmaceutical composition of Aspect 23 for use in treating cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.
  • Aspect 30 The pharmaceutical composition of Aspect 29 for use in treating cancer.
  • Aspect 31 The pharmaceutical composition of Aspect 30, wherein the cancer is any one or more of the cancers of Table 2.
  • Aspect 32 The pharmaceutical composition of Aspect 30, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.
  • Aspect 33 A compound of any one of Aspects 1-22, 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 34 The compound of Aspect 33 for use in treating cancer.
  • Aspect 35 The compound of Aspect 34, wherein the cancer is any one or more of the cancers of Table 2.
  • Aspect 36 The compound of Aspect 34, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.
  • Aspect 37 Use of a compound of any one of Aspects 1-22, 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 38 The use of Aspect 37 for treatment of cancer.
  • Aspect 39 The use of Aspect 38, wherein the cancer is any one or more of the cancers of Table 2.
  • Aspect 40 The use of Aspect 38, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.
  • R c is selected from the group consisting of H and halogen; each R d is independently selected from the group consisting of halogen; each n is independently 0, 1 or 2;
  • Q is -NHCO2-R; R 3a and R 3b are independently selected from the group consisting of hydrogen, halo, and
  • R 4 is hydrogen or C1-C4 alkyl; m is 1 or 2;
  • J is cyano, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocycloalkylsulfonyl, carboxamido, and -SO2X;
  • R 5 is hydrogen or alkenyl
  • R 6 is hydrogen or halo; n is 0 or 1;
  • R 7 is alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocycloalkylsulfonyl, or carboxamido;
  • L 2 is absent, -SO2-, or -CH2-
  • R 8a is selected from the group consisting of hydrogen, halo, alkoxy, and R al ;
  • R 8b is selected from the group consisting of alkoxy and R al ;
  • Z is alkylsulfonyl and cycloalkylsulfonyl
  • R al is (amino)alkyl, carboxamido, and (heterocyclo)alkyl;
  • X is selected from the group consisting of o and p are independently 0, 1, 2, or 3;
  • R 12 is selected from the group consisting of alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, and carboxamido;
  • R 13 is hydrogen or C1-C4 alkyl
  • R 14a , R 14b , R 14c , and R 14d are each independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, (amino)alkyl, and R a3 ;
  • R 19 is halo
  • R a3 is selected from the group consisting of alkoxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, and carboxamido;
  • R a4 is optionally substituted heterocyclo
  • R a5 is hydrogen or C1-C4 alkyl
  • R 15 is hydrogen or C1-C4 alkyl
  • R 16 is carboxamido
  • Aspect 2 The compound of Aspect 1 having Formula II:
  • Aspect 6 The compound of any one of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein: each R a is independently selected from the group consisting of H and C1-C4 alkyl; each R b is independently selected from the group consisting of H and C1-C4 alkyl;
  • R c is fluoro
  • R is C1-C4 alkyl
  • B is B-l or B-2.
  • Aspect 7 The compound of Aspect 6, or a pharmaceutically acceptable salt thereof, wherein B is B-l.
  • Aspect 8 The compound of Aspect 6, or a pharmaceutically acceptable salt thereof, wherein B is B-2.
  • Aspect 9 The compound of Aspect 6, or a pharmaceutically acceptable salt thereof, wherein R is methyl.
  • Aspect 10 The compound of any one of Aspects 1 to 9, or a pharmaceutically acceptable salt thereof, wherein at least one of R 3a and R 3b is halogen.
  • Aspect 11 The compound of any one of Aspects 1 to 9, or a pharmaceutically acceptable salt thereof, wherein at least one of R 3a and R 3b is fluoro.
  • Aspect 12 The compound of any one of Aspects 1 to 9, or a pharmaceutically acceptable salt thereof, wherein at least one of R 3a and R 3b is (amino)alkyl or carboxamido.
  • Aspect 13 The compound of any one of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.
  • Aspect 14 The compound of any one of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 2 is fluoro.
  • Aspect 15 The compound of any one of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 2 is methoxy.
  • Aspect 16 The compound of any one of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydroxy.
  • Aspect 17 The compound of any one of Aspects 1-2 and 6-16, or a pharmaceutically acceptable salt thereof, wherein E is E-l or E-2.
  • Aspect 18 The compound of one any of Aspects 1-2 and 6-16, or a pharmaceutically acceptable salt thereof, wherein E is E-l.
  • Aspect 19 The compound of Aspect 18, or a pharmaceutically acceptable salt thereof, wherein X is X-l.
  • Aspect 20 The compound of Aspect 18, or a pharmaceutically acceptable salt thereof, wherein X is X-2.
  • Aspect 21 The compound of Aspect 18, or a pharmaceutically acceptable salt thereof, wherein X is X-l 1.
  • Aspect 22 The compound of any one of Aspects 1-2 and 6-16, or a pharmaceutically acceptable salt thereof, wherein E is E-3.
  • a compound having Formula XXXI: or a pharmaceutically acceptable salt thereof wherein: each R a is independently selected from the group consisting of hydrogen and C1-C4 alkyl; each R b is independently selected from the group consisting of hydrogen and C1-C4 alkyl;
  • R c is selected from the group consisting of hydrogen and halogen; each R d is independently selected from the group consisting of halogen; each n is independently 0, 1 or 2;
  • Aspect 29 A pharmaceutical composition comprising the compound of any one of Aspects 1-28, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Aspect 30 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 1-28, 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 31 The method of Aspect 30, wherein the patient has cancer.
  • Aspect 32 The method of Aspect 31, wherein the cancer is any one or more of the cancers of Table 2.
  • Aspect 33 The method of Aspect 32, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.
  • Aspect 34 The method of any one of Aspects 30-33 further comprising administering a therapeutically effective amount of a second therapeutic agent useful in the treatment of the disease or condition.
  • Aspect 35 The pharmaceutical composition of Aspect 29 for use in treating cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.
  • Aspect 36 The pharmaceutical composition of Aspect 35 for use in treating cancer.
  • Aspect 37 The pharmaceutical composition of Aspect 36, wherein the cancer is any one or more of the cancers of Table 2.
  • Aspect 38 The pharmaceutical composition of Aspect 37, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.
  • Aspect 39 A compound of any one of Aspects 1-28, 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 40 The compound of Aspect 39 for use in treating cancer.
  • Aspect 41 The compound of Aspect 40, wherein the cancer is any one or more of the cancers of Table 2.
  • Aspect 42 The compound of Aspect 41, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.
  • Aspect 43 Use of a compound of any one of Aspects 1-28, 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 44 The use of Aspect 43 for treatment of cancer.
  • Aspect 45 The use of Aspect 44, wherein the cancer is any one or more of the cancers of Table 2.
  • Aspect 46 The use of Aspect 45, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.
  • the flask was covered with a kimwipe and dried in a desiccator under vacuum for 1-2 days. After the drying step, the flask was removed from the desiccator and quickly capped with a septum. The system was vacuumed and protected under nitrogen atmosphere. The contents in the flask were then dissolved completely with 60 mL of freshly distilled THF. The solution was then briefly vacuumed and put under nitrogen atmosphere. (This purging was repeated two more times). The reaction was cooled to 0 °C, KHMDS (0.5M in toluene, 42.4 mL, 21.21 mmol) was added dropwise, and then the reaction was allowed to warm to room temperature and stirred overnight.
  • KHMDS 0.5M in toluene, 42.4 mL, 21.21 mmol
  • the enantiopure compound S7 can also be 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, and 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 EtOAc was added, and a gel formed.
  • dimethyl dicarbonate (410 mg, 3.05 mmol) was added to a solution of El and Et3N (1.13 mL, 8.16 mmol) in DCM (30 mL). After 2 hours, the reaction was concentrated and purified by column chromatography to produce E2 (770 mg).
  • Step A methyl ((lS,2R)-2-((S)-l-(l-benzylpiperidin-4-yl)-l-(3-fluorophenyl)- 2-(4H-l,2,4-triazol-4-yl)ethyl)cyclopentyl)carbamate (Tl)
  • Step B methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-l-(piperidin-4-yl)-2-(4H-
  • Step A methyl ((lS,2R)-2-((S)-l-(l-benzylpiperidin-4-yl)-l-(3-fluorophenyl)-
  • Step B methyl ((lS,2R)-2-((S)-l-(l-benzylpiperidin-4-yl)-l-(3-fluorophenyl)- 2-(prop-2-yn- 1 -y lamino)ethy l)cy clopentyl)carbamate (D2)
  • Step C l-((S)-2-(l-benzylpiperidin-4-yl)-2-(3-fluorophenyl)-2-((lR,2S)-2-
  • Step D methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-l-(piperidin-4-yl)-2-(lH- pyrazol-1 -yl)ethyl)cyclopentyl)carbamate (D4)
  • Step E tert-butyl 3-((4-((S)-l-(3-fluorophenyl)-l-((lR,2S)-2-
  • Step F methyl ((lS,2R)-2-((S)-l-(l-(azetidin-3-ylmethyl)piperidin-4-yl)-l-(3- fluorophenyl)-2-(lH-pyrazol-l-yl)ethyl)cyclopentyl)carbamate (D6)
  • Step A 2-bromo-4-((4-fluorophenyl)thio)pyridine
  • Step B 2-bromo-4-((4-fluorophenyl)sulfonyl)pyridine
  • Step A 4-chloro-6-((4-fluorophenyl)thio)pyrimidine
  • Step B 4-chloro-6-((4-fluorophenyl)sulfonyl)pyrimidine
  • Step C 4-((4-fluorophenyl)sulfonyl)-6-vinylpyrimidine
  • Step D methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-l-(l-((l-(2-(6-((4- fluorophenyl)sulfonyl)pyrimidin-4-yl)ethyl)azetidin-3-yl)methyl)piperidin-4-yl)-2- (lH-imidazol-l-yl)ethyl)cyclopentyl)carbamate (Cpd 88) and methyl ((lS,2R)-2-((S)- l-(3-fluorophenyl)-2-(lH-imidazol-l-yl)-l-(l-((l-(6-vinylpyrimidin-4-yl)azeti din-3- yl)methyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate (Cpd 26)
  • Step A benzyl 3-((3,4-difluorophenyl)thio)benzoate
  • Step B benzyl 3-((3,4-difluorophenyl)sulfonyl)benzoate
  • Step C 3-((3,4-difluorophenyl)sulfonyl)benzoic acid
  • Step D (E)-3-((3,4-difluorophenyl)sulfonyl)-N-(4-(dimethylamino)-4-oxobut-
  • Step E methyl ((lS,2R)-2-((S)-l-(l-((l-(4-((3-(((E)-4-(dimethylamino)-4- oxobut-2-en-l-yl)carbamoyl)phenyl)sulfonyl)-2-fluorophenyl)azetidin-3- yl)methyl)piperidin-4-yl)-l-(3-fluorophenyl)-2-(lH-imidazol-l- yl)ethyl)cyclopentyl)carbamate (Cpd 61)
  • Step B methyl 3-((3,4-difluorophenyl)sulfonyl)bicyclo[l.l.l]pentane-l- carboxylate
  • Step C methyl 3-((3-fluoro-4-(3-((4-((S)-l-(3-fluorophenyl)-2-(lH-imidazol-
  • Step D 3-((3-fluoro-4-(3-((4-((S)-l-(3-fluorophenyl)-2-(lH-imidazol-l-yl)-l-
  • Step E methyl ((lS,2R)-2-((S)-l-(l-((l-(2-fluoro-4-((3-(((E)-3-
  • Step A 6-bromo-2-(2,2-dimethoxyethyl)isoindolin-l-one
  • Step B 6-((3,4-difluorophenyl)thio)-2-(2,2-dimethoxyethyl)isoindolin-l-one
  • Step C 6-((3,4-difluorophenyl)sulfonyl)-2-(2,2-dimethoxyethyl)isoindolin-l- one
  • Step D 2-(6-((3,4-difluorophenyl)sulfonyl)-l-oxoisoindolin-2-yl)acetaldehyde
  • Step E (E)-6-((3,4-difluorophenyl)sulfonyl)-2-(3-
  • Step F methyl ((lS,2R)-2-((S)-l-(l-((l-(2-fluoro-4-((2-((E)-3-
  • Step A potassium 2-((dimethylamino)methyl)-3,4-difluorobenzenethiolate
  • Step B l-(2,3-difluoro-6-((l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4- yl)thio)phenyl)-N,N-dimethylmethanamine
  • Step C l-(2,3-difluoro-6-((l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4- yl)sulfonyl)phenyl)-N,N-dimethylmethanamine
  • Step D l-(6-((lH-pyrazol-4-yl)sulfonyl)-2,3-difluorophenyl)-N,N- dimethylmethanamine
  • Step E (E)-l-(2,3-difluoro-6-((l-(3-(methylsulfonyl)allyl)-lH-pyrazol-4- yl)sulfonyl)phenyl)-N,N-dimethylmethanamine
  • Step F methyl ((lS,2R)-2-((S)-l-(l-((l-(3-((dimethylamino)methyl)-2-fluoro- 4-((l-((E)-3-(methylsulfonyl)allyl)-lH-pyrazol-4-yl)sulfonyl)phenyl)azetidin-3- y l)methy l)piperidin-4-yl)- 1 -(3-fluorophenyl)-2-(2-methy 1- lH-imidazol- 1 - yl)ethyl)cyclopentyl)carbamate (Cpd 76)
  • Step A potassium 2-(tert-butoxycarbonyl)-7-fluoroisoindoline-4-thiolate
  • tert-butyl 4-fluoro-7-((3-methoxy-3- oxopropyl)thio)isoindoline-2-carboxylate 400 mg, 1.12 mmol, 1.0 eq.
  • dry THF 10 ml
  • t-BuOK 189 mg, 1.68 mmol, 1.5 eq.
  • Step B tert-butyl 4-fluoro-7-((l-methyl-lH-pyrazol-4-yl)thio)isoindoline-2- carboxylate
  • Step C tert-butyl 4-fluoro-7-((l-methyl-lH-pyrazol-4-yl)sulfonyl)isoindoline-
  • Step D tert-butyl 4-(3-((4-((S)-l-(3-fluorophenyl)-2-(lH-imidazol-l-yl)-l-
  • Step E methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(lH-imidazol-l-yl)-l-(l- ((1 -(7-((l -methyl- IH-py razol-4-yl)sulfonyl)isoindolin-4-yl)azeti din-3 - yl)methyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate (Cpd 92)
  • Step A 8-bromoisoquinolin-5-amine
  • Step B 8-bromoisoquinoline-5-carbonitrile
  • Step C methyl ((lS,2R)-2-((S)-cyano(l-((l-(5-cyanoisoquinolin-8-yl)azetidin-
  • Step D methyl ((lS,2R)-2-((S)-cyano(l-((l-(5-cyano-l,2,3,4- tetrahydroisoquinolin-8-yl)azetidin-3-yl)methyl)piperidin-4-yl)(3- fluorophenyl)methyl)cyclopentyl)carbamate (Cpd 97)
  • Step A l-bromo-2,3-bis(bromomethyl)-4-fluorobenzene
  • Step B 4-bromo-7-fluoro-2-(4-methoxybenzyl)isoindoline
  • Step D tert-butyl 4-bromo-7-fluoroisoindoline-2-carboxylate
  • TEA 4.2 ml, 30.55 mmol, 2.0 eq.
  • B0C2O 5.0 g, 22.91 mmol, 1.5 eq.
  • Step E tert-butyl 4-fluoro-7-((3-methoxy-3-oxopropyl)thio) isoindoline-2- carboxylate
  • Step F & G tert-butyl (R)-4-((l-((benzyloxy)carbonyl)piperidin-3-yl)thio)-7- fluoroisoindoline-2-carboxylate
  • Step H tert-butyl (R)-4-((l-((benzyloxy)carbonyl)piperidin-3-yl)sulfonyl)-7- fluoroisoindoline-2-carboxylate
  • Step I tert-butyl 4-(3-((4-((S)-2-(azetidin-l-yl)-l-(3-fluorophenyl)-l-((lR,2S)-
  • Step J tert-butyl 4-(3-((4-((S)-2-(azetidin-l-yl)-l-(3-fluorophenyl)-l-((lR,2S)-
  • Step K tert-butyl 4-(3-((4-((S)-2-(azetidin-l-yl)-l-(3-fluorophenyl)-l- ((1R, 2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)piperi din-1 - y l)methyl)azetidin- 1 -yl)-7-(((R)- 1 -(((E)-3-(methy lsulfonyl)allyl)carbamoy 1) piperidin- 3-yl)sulfonyl)isoindoline-2-carboxylate
  • Step L methyl ((lS,2R)-2-((S)-2-(azetidin-l-yl)-l-(3-fluorophenyl)-l-(l-((l-)
  • Step A methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol- l-yl)-l-(l-((l-(2-oxo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-lH- benzo[d]imidazol-5-yl)azetidin-3-yl)methyl)piperidin-4- yl)ethyl)cyclopentyl)carbamate
  • Step B methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol-
  • Step A 4-bromo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-l,3-dihydro-2H- benzo[d]imidazol-2-one
  • Step B methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol- l-yl)-l-(l-((l-(2-oxo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-lH- benzo[d]imidazol-4-yl)azetidin-3-yl)methyl)piperidin-4- yl)ethyl)cyclopentyl)carbamate
  • Step C methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol-
  • Step A 2-(4-(aminomethyl)phenyl)ethan-l-ol
  • Step C 4-(((tert-butoxycarbonyl)amino)methyl)phenethyl methanesulfonate
  • Step D methyl ((lS,2R)-2-((S)-l-(l-(4-(((tert- butoxycarbonyl)amino)methyl)phenethyl)piperidin-4-yl)-l-(3-fluorophenyl)-2-(2- methyl- lH-imidazol- 1 -yl)ethyl)cy clopentyl)carbamate
  • E5 To a solution of methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH- imidazol-l-yl)-l-(piperidin-4-yl)ethyl)cyclopentyl)carbamate (E5) (150 mg, 0.35 mmol) in MeCN (10 mL) was added 4-(((tert-butoxycarbonyl)amino)methyl)phenethyl methanesulfon
  • the reaction mixture was stirred at 80 °C for 10 hr.
  • the cooled mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 3).
  • the combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • Step E methyl ((lS,2R)-2-((S)-l-(l-(4-(aminomethyl)phenethyl)piperidin-4- yl)-l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol-l-yl)ethyl)cyclopentyl)carbamate
  • Step F methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol- 1 -yl)- 1 -( 1 -(4-(methylsulfonamidomethyl)phenethyl)piperidin-4- yl)ethyl)cyclopentyl)carbamate (Cpd 129)
  • Step A 5-allyl-l, 3-bis((2-(trimethylsilyl)ethoxy)methyl)-l,3-dihydro-2H- benzo[d]imidazol-2-one
  • Step B 2-(2-oxo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-lH- benzo[d]imidazol-5-yl)acetaldehyde
  • Step C methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol- l-yl)-l-(l-(2-(2-oxo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-lH- benzo[d]imidazol-5-yl)ethyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate
  • Step D methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol- l-yl)-l-(l-(2-(2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)ethyl)piperidin-4- yl)ethyl)cyclopentyl)carbamate (Cpd 132)
  • the reaction mixture was stirred at 25 ° C for 3 hr. The mixture was concentrated under reduced pressure.
  • Step A 5-bromo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-l,3-dihydro-2H- benzo[d]imidazol-2-one
  • Step B 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3-bis((2-
  • Step C 5-hydroxy-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazol-2(3H)-one
  • Step D methyl (lr,3r)-3-((2-oxo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3- dihydro-lH-benzo[d]imidazol-5-yl)oxy)cyclobutane-l-carboxylate & methyl (ls,3s)- 3-((2-oxo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-lH- benzo[d]imidazol-5-yl)oxy)cyclobutane-l-carboxylate
  • Step E 5-((lr,3r)-3-(hydroxymethyl)cyclobutoxy)-l,3-bis((2-
  • Step F ((lr,3r)-3-((2-oxo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3- dihydro-lH-benzo[d]imidazol-5-yl)oxy)cyclobutyl)methyl methanesulfonate [00682] To a solution of 5-((lr,3r)-3-(hydroxymethyl)cyclobutoxy)-l,3-bis((2-
  • Step G methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol-
  • Step H methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol- l-yl)-l-(l-(((lr,3S)-3-((2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5- yl)oxy)cyclobutyl)methyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate (Cpd 136)
  • Step A 5-((ls,3s)-3-(hydroxymethyl)cyclobutoxy)-l,3-bis((2-
  • Step B ((ls,3s)-3-((2-oxo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3- dihydro-lH-benzo[d]imidazol-5-yl)oxy)cyclobutyl)methyl methanesulfonate
  • Step C methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol-
  • Step A 5-bromo-2-(methylsulfonyl)isoindoline
  • Step B (E)-5-(2-ethoxyvinyl)-2-(methylsulfonyl)isoindoline
  • Step C 2-(2-(methylsulfonyl)isoindolin-5-yl)acetaldehyde
  • Step D methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol- l-yl)-l-(l-(2-(2-(methylsulfonyl)isoindolin-5-yl)ethyl)piperidin-4- yl)ethyl)cyclopentyl)carbamate (Cpd 134)
  • Step A 6-bromo-2-methylbenzo[d]isothiazol-3(2H)-one 1,1-dioxide
  • Steps B-D were completed following the procedures for Steps B-D described in Example 23 to afford methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-l-(l-(2-(2-methyl- l,l-dioxido-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yl)ethyl)piperidin-4-yl)-2-(2- methyl-lH-imidazol-l-yl)ethyl)cyclopentyl)carbamate (Cpd 128) as a white solid.
  • Step A N-(4-bromophenethyl)methanesulfonamide
  • Steps B-D were completed following the procedures for Steps B-D described in Example 23 to afford methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH- imidazol- 1 -yl)- 1 -( 1 -(4-(2-(methy lsulfonamido)ethy l)phenethy l)piperidin-4- yl)ethyl)cyclopentyl)carbamate (Cpd 130) as a white solid.
  • Step A 3-(4-bromophenyl)-l-(methylsulfonyl)azetidine
  • TEA 0.22 mL, 1.61 mmol
  • MsCI 0.08 mL, 0.97 mmol
  • the reaction mixture was stirred at room temperature for 2 hr. Then the mixture was diluted with TkO (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na 2 SO 4 and concentrated under reduced pressure.
  • Steps B-D were completed following the procedures for Steps B-D described in Example 23 to afford methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH- imidazol- 1 -yl)- 1 -(1 -(4-( 1 -(methy lsulfony l)azetidin-3-y l)phenethy l)piperidin-4- yl)ethyl)cyclopentyl)carbamate (Cpd 131) as a white solid.

Abstract

The present disclosure provides compounds represented by Formula (I): or a pharmaceutically acceptable salt thereof, wherein Ra, Rb, Rc, Rd, L1, R2 B, Q and E are as defined as set forth in the specification. The present disclosure also provides compounds of Formula (I) for use to treat cancer or any other disease, condition, or disorder that is responsive to inhibition of menin. :

Description

MENIN INHIBITORS AND METHODS OF USE FOR TREATING CANCER
CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of PCT Application No. PCT/CN2020/083753, filed April 8, 2020, and PCT application No. PCT/CN2020/118816, filed September 29, 2020, the disclosures of each of which are incorporated by reference in their entireties. U.S. GOVERNMENT LICENSE RIGHTS [0002] This invention was made with U.S. government support under Grant No. CA208267 awarded by the National Institutes of Health. The U.S. government has certain rights in the invention.
BACKGROUND OF THE INVENTION [0003] The present disclosure provides compounds as menin inhibitors and therapeutic methods of treating conditions and diseases wherein inhibition of menin provides a benefit.
[0004] 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.
[0005] Menin is in involved in a diverse network of protein-protein interactions. Cierpicki and Grembecka, Future Med. Chem. 6:447-462 (2014). Overexpression of menin leads to inhibition of Ras-transformed cells. Menin interacts with the transcription factors JunD and NF-KB and represses their activation of gene transcription. Studies on these interacting proteins suggest that menin exerts its effects predominantly through inhibitory effects on transcription. But an alternative possibility is that menin mediates its effects through transcriptional activation of target genes. Additionally, menin interacts with RPA2, 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 (Brcal) product.
[0006] The mechanisms by which menin, which does not have significant homology with other proteins, functions as a tumor suppressor are not completely understood. Menin plays a role in regulating cellular proliferation because MEN 1 knockout mice show increased proliferation in neuroendocrine tissues, down-modulation of menin in epithelial cells increases proliferation, and MEN1 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.
[0007] Certain oncogenic 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.
[0008] MLL fusion proteins, a consequence of acquired genetic aberrations, 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.
[0009] 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. 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. [0010] Menin interacts with transcription activators, e.g., sc-Myb, MLL1, SMAD 1,3,5, Pern, Runx2, Hlbx9,ER, PPARy, vitamin D receptor, transcription repressors, e.g., JunD, Sin3A, HDAC, EZH2, PRMT5, NFKB, Sirtl, CHES1, cell signaling proteins, e.g., AKT, SOS1/GEF, b-catenin, SMAD 1,3,5, NFKB, ER, PPARy, vitamin D receptor, and other proteins, e.g., cell cycle: RPA2, ASK; DNA repair: FANCD2; cell structure: GFAP, vimenten, NMMHCIIA, IQGAP1; Others: HSP70, CHIP, ("menin-interacting proteins") involved in regulating gene transcription and cell signaling. Matkar, Trends in Biochemical Sciences 38: 394-402 (2013). Targeting menin interactions, e.g., menin-MLL interaction, with small molecules represents an attractive strategy to develop new anticancer agents. See, e.g., Cierpicki and Grembecka, Future Med. Chem. 5:447-462 (2014); He et al., J. Med. Chem. 57:1543-1556 (2014); and Borkin etal, Cancer Cell 27: 589-602 (2015); Krivtsov et al. Cancer Cell 36: 660-673 (2019); Klossowski et al. J. Clin. Invest. 730:981-997 (2020); Uckelmann etal. Science 367: 586-590 (2020).
[0011] Small molecules that disrupt the interaction of MLL and menin are disclosed in U.S. Patent Nos. 9,212,180 and 9,216,993; U.S. Patent Application Publication Nos. 2011/0065690; 2014/0275070; 2016/0045504; and 2016/0046647; and
International Publication Nos. WO 2017/192543; WO 2018/183857; WO 2019/191526; WO 2020/072391, and PCT/US2020/053186. Peptides that disrupt the interaction of MLL and menin are disclosed in U.S. Patent Application Publication No. 2009/0298772.
[0012] There is an ongoing need for new small molecule drugs for treating cancer and other diseases responsive to menin inhibition.
BRIEF SUMMARY OF THE INVENTION
[0013] In one aspect, the present disclosure provides Compounds of Formulae I-XXXIII, and the pharmaceutically acceptable salts thereof, collectively referred to herein as "Compounds of the Disclosure." Compounds of the Disclosure are menin inhibitors and thus are useful in treating diseases or conditions wherein inhibition of menin provides a therapeutic benefit to a patient.
[0014] In another aspect, 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 subject, 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. Also provided are 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. In some embodiments, the Compounds of the Disclosure reduce the proliferation of unwanted cells by inducing apoptosis and/or differentiation in those cells.
[0015] In another aspect, 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.
[0016] In another aspect, the present disclosure provides a pharmaceutical composition comprising a Compound of the Disclosure and an excipient and/or pharmaceutically acceptable carrier.
[0017] In another aspect, 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.
[0018] In another aspect, the present disclosure provides 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.
[0019] In another aspect, the present disclosure provides a Compound of the Disclosure for use in treatment of a disease or condition of interest, e.g., cancer.
[0020] In another aspect, 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.
[0021] In another aspect, 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.
[0022] Additional embodiments and advantages of the disclosure will be set forth, in part, in the description that follows, and will flow from the description, or can be learned by practice of the disclosure. The embodiments and advantages of the disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.
[0023] It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only, and are not restrictive of the invention as claimed.
DETAILED DESCRIPTION OF THE INVENTION I. Compounds of the Disclosure [0024] Compounds of the Disclosure are menin inhibitors.
[0025] In one embodiment, Compounds of the Disclosure are compounds represented by Formula I,
Figure imgf000006_0001
and the pharmaceutically acceptable salts thereof, wherein: each Ra is independently selected from the group consisting of hydrogen and C1-C4 alkyl; each Rb is independently selected from the group consisting of hydrogen and C1-C4 alkyl;
Rc is selected from the group consisting of hydrogen and halo; each Rd is independently selected from the group consisting of halo; each n is independently 0, 1 or 2;
Q is -NHCO2-R;
R is C1-C4 alkyl, C1-C4 haloalkyl, or CD3 ;
B is selected from the group consisting of:
Figure imgf000007_0001
R2 is selected from the group consisting of hydrogen, halo, C1-C4 alkyl, hydroxy, Ci- C4 alkoxy, C1-C4 haloalkyl, and C1-C4 hydroxyalkyl;
E is selected from the group consisting of:
Figure imgf000007_0002
L1 is -CH2- wherein E is E-l, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, E-10, E-13, and E- 14 and absent wherein E is E-l 1 or E-12; R3aand R3b are independently selected from the group consisting of hydrogen, halo, and
Ral;
R4 is hydrogen or C1-C4 alkyl; m is 1 or 2;
J is cyano, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocycloalkylsulfonyl, carboxamido, and -SO2X;
R5 is hydrogen or alkenyl;
R6 is hydrogen or halo; n is 0 or 1;
R7 is alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocycloalkylsulfonyl, or carboxamido;
L2 is absent, -SO2-, or -CH2-
R8ais selected from the group consisting of hydrogen, halo, alkoxy, and Ral;
R8b is selected from the group consisting of alkoxy and Ral;
Z is alkylsulfonyl and cycloalkylsulfonyl;
Ral is (amino)alkyl, carboxamido, and (heterocyclo)alkyl;
X is selected from the group consisting of
Figure imgf000008_0001
o and p are independently 0, 1, 2, or 3;
Y is -C(=0)-;
Z2 is selected from the group consisting of -C(R14a)=C(R14b)(R14c), -CºCR14d, and Ra2 R9a and R9b are each independently selected from the group consisting of alkenyl; Ci- C4 alkyl, halo, (amino)alkyl, and -C(R14a)=C(R14b)(R14c);
Each U is independently selected from the group consisting of -CH2- and -C(=0)- R10 is selected from the group consisting of hydrogen, C1-C4 alkyl, and -CH2CH=CH-
Ra3;
R11 is -NHCOC(R14a)=C(R14b)(R14c) or -CH2CH=CH-Ra3;
R12 is selected from the group consisting of alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, and carboxamido;
R13 is hydrogen or C1-C4 alkyl;
R14a, R14b, R14c, and R14d are each independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, (amino)alkyl, and Ra3;
R18 is selected from the group consisting of cyano, -(C=0)NH2, and -(C=0)N(H)Ci- C4alkyl.
R19 is halo;
R32 is -N(R15)CH2CH=CH-Ra3 or -CH=CHCH2Ra4;
Ra3 is selected from the group consisting of alkoxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, and carboxamido;
Ra4 is optionally substituted heterocyclo;
Ra5 is hydrogen or C1-C4 alkyl R15 is hydrogen or C1-C4 alkyl;
R16 is carboxamido;
R17 is selected from the group consisting of hydrogen, C1-C4 alkyl, -OCH2CH=CH-Ra3, and -CH2CH=CH-Ra3 ; each W is independently selected from the group consisting of -CH- or -N-; wherein B is not B-10, B-ll, and B-12 when E is E-l or E-2; and provided that the compound is not methyl rac-((lS ,2R)-2-(2-(lH-imidazol-l-yl)-l-(l-((l-(4-(( 1- methyl- lH-pyrazol-4-yl)sulfonyl)phenyl)azetidin-3-yl)methyl)piperidin-4-yl)-l- phenylethyl)cyclopentyl)carbamate.
[0026] In another embodiment, Compounds of the Disclosure are compounds represented by Formula I, and the pharmaceutically acceptable salts thereof, wherein B is B-l, B-2, B-3, B-4, B-5, or B-6. [0027] In another embodiment, Compounds of the Disclosure are compounds represented by Formula I, and the pharmaceutically acceptable salts thereof, wherein each Ra and Rb is hydrogen.
[0028] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae II or III:
Figure imgf000010_0001
[0029] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae II-III, and the pharmaceutically acceptable salts thereof.
[0030] In another embodiment, Compounds of the Disclosure are compounds represented by Formula II, and the pharmaceutically acceptable salts thereof, wherein E is E-l, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, or E-10.
[0031] In another embodiment, Compounds of the Disclosure are compounds represented by Formula II, and the pharmaceutically acceptable salts thereof, wherein E is E-l.
[0032] In another embodiment, Compounds of the Disclosure are compounds represented by Formula II, and the pharmaceutically acceptable salts thereof, wherein E is E-2. [0033] In another embodiment, Compounds of the Disclosure are compounds represented by Formula II, and the pharmaceutically acceptable salts thereof, wherein E is E-3, E-4, E-5, E-6, E-7, E-8, E-9, or E-10.
[0034] In another embodiment, Compounds of the Disclosure are compounds represented by Formula III, and the pharmaceutically acceptable salts thereof, wherein E is E- 11 or E-12.
[0035] In another embodiment, Compounds of the Disclosure are compounds represented by Formula II, and the pharmaceutically acceptable salts thereof, wherein E is E-13 or E-14.
[0036] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae IV-XIII:
Figure imgf000011_0001
Figure imgf000012_0001
Figure imgf000013_0001
wherein Ra, Rb, Rc, Rd, R2, R3a, R3b, n, Q, B, X, E and remaining variables are defined above in accordance with Formula I.
[0037] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof.
[0038] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein at least one Ra is hydrogen.
[0039] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein each Ra is hydrogen.
[0040] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein at least one Rb is hydrogen.
[0041] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein each Rb is hydrogen. [0042] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein each Ra and Rb are hydrogen.
[0043] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein Rc is hydrogen.
[0044] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein Rc is halo.
[0045] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein Rc is fluoro.
[0046] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein n is 0.
[0047] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein n is i.
[0048] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein n is 2.
[0049] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein n is 0 and Rc is hydrogen.
[0050] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein n is 1 and Rc is hydrogen.
[0051] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein n is 0 and Rc is halo.
[0052] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein n is 0 and Rc is fluoro. [0053] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein n is 1 and Rd is halo.
[0054] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein n is 1 and Rd is fluoro.
[0055] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein n is 1 and Rc and Rd are each fluoro.
[0056] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein R2 is hydrogen.
[0057] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein R2 is halo.
[0058] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein R2 is fluoro.
[0059] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein R2 is methoxy.
[0060] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein R2 is hydroxy.
[0061] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein R is -C1-C4 alkyl.
[0062] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein R is methyl.
[0063] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein R is -C1-C4 haloalkyl. [0064] In another embodiment, Compounds of the Disclosure are compounds represented by Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein B is B-l or B-2.
[0065] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein B is B-l.
[0066] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein B is B-2.
[0067] In another embodiment, Compounds of the Disclosure are compounds represented by Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein B is B-3.
[0068] In another embodiment, Compounds of the Disclosure are compounds represented by Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein B is B-4.
[0069] In another embodiment, Compounds of the Disclosure are compounds represented by Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein B is B-5.
[0070] In another embodiment, Compounds of the Disclosure are compounds represented by Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein B is B-6.
[0071] In another embodiment, Compounds of the Disclosure are compounds represented by Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein B is B-6 wherein alkyl is methyl.
[0072] In another embodiment, Compounds of the Disclosure are compounds represented by Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein B is B-7.
[0073] In another embodiment, Compounds of the Disclosure are compounds represented by Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein B is B-7 wherein alkyl is methyl.
[0074] In another embodiment, Compounds of the Disclosure are compounds represented by Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein B is B-8. [0075] In another embodiment, Compounds of the Disclosure are compounds represented by Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein B is B-9.
[0076] In another embodiment, Compounds of the Disclosure are compounds represented by Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein B is B-10.
[0077] In another embodiment, Compounds of the Disclosure are compounds represented by Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein B is B-l 1.
[0078] In another embodiment, Compounds of the Disclosure are compounds represented by Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein B is B-12.
[0079] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein at least one of R3a and R3b is hydrogen.
[0080] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein both R3a and R3b are hydrogen.
[0081] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein at least one of R3a and R3b is halo.
[0082] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein both R3a and R3b are halo.
[0083] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein at least one of R3a and R3b is fluoro.
[0084] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein both R3a and R3b are fluoro.
[0085] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein at least one of R3a and R3b is C1-C4 alkyl. [0086] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I- XIII, and the pharmaceutically acceptable salts thereof, wherein both R3a and R3b are C1-C4 alkyl.
[0087] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein at least one of R3a and R3b is Me.
[0088] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein both R3a and R3b are Me.
[0089] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein at least one of R3a and R3b is -CH2NMe2.
[0090] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein at least one of R3a and R3b is -C(0)NMe2.
[0091] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein at least one of R3a and R3b is
Figure imgf000018_0001
[0092] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-l, X-2, X-3, X-4, X-5, X-6, X-7, X-8, X-9, X-10, X-ll, X- 12, or X-13.
[0093] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-l, X-2, X-3, X-4, X-6, X-7, X-8, X-9, X-10, X-ll, X-12, or X-13.
[0094] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-l 4 or X-15. [0095] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-l.
[0096] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-l. In another embodiment, o and p are 0. In another embodiment, X- 1 is selected from the group consisting of:
Figure imgf000019_0001
[0097] In another embodiment, X-l is selected from the group consisting of:
Figure imgf000019_0002
[0098] In another embodiment, X-l is selected from the group consisting of:
Figure imgf000019_0003
[0099] In another embodiment, X-l is selected from the group consisting of:
Figure imgf000019_0004
[00100] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-2.
[00101] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-3.
[00102] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-4. [00103] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-5.
[00104] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-5 and R10 is -CH2CH=CH-Ra3.
[00105] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-6.
[00106] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-7.
[00107] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-8.
[00108] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-9. In another embodiment, o and p are 0. In another embodiment, X-9 is selected from the group consisting of:
Figure imgf000020_0001
[00109] In another embodiment, X-9 is selected from the group consisting of:
Figure imgf000020_0002
[00110] In another embodiment, X-9 is selected from the group consisting of:
Figure imgf000020_0003
[00111] In another embodiment, X-9 is selected from the group consisting of:
Figure imgf000021_0001
[00112] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-10. In another embodiment, o and p are 0. In another embodiment, X-10 is selected from the group consisting of:
Figure imgf000021_0002
[00113] In another embodiment, X-10 is selected from the group consisting of:
Figure imgf000021_0003
[00114] In another embodiment, X-10 is selected from the group consisting of:
Figure imgf000021_0004
[00115] In another embodiment, X-10 is selected from the group consisting of:
Figure imgf000021_0005
[00116] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-l 1.
[00117] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-l 2.
[00118] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-13. In another embodiment, o and p are 0. In another embodiment, X-13 is selected from the group consisting of:
Figure imgf000022_0001
[00119] In another embodiment, X-13 is selected from the group consisting of:
Figure imgf000022_0002
[00120] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-14.
[00121] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-14 and R6 is halo.
[00122] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein X is X-15.
[00123] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein E is E-3.
[00124] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein m is 1.
[00125] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein m is 2.
[00126] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein J is -CN.
[00127] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein J is alkylsulfonyl. [00128] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein J is cycloalkylsulfonyl.
[00129] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein J is heteroarylsulfonyl.
[00130] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein J is arylsulfonyl.
[00131] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein J is heterocycloalkylsulfonyl.
[00132] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein J is carboxamido.
[00133] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein J is -SO2X.
[00134] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XIII, and the pharmaceutically acceptable salts thereof, wherein J is -SO2X and X is X-l, X-2, X-5, or X-8.
[00135] In some embodiments, the present invention provides a compound selected from any of Formulae XIV-XVIII:
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
wherein Rc, R2, R3a, R3b, X and remaining variables are defined above in accordance with Formula I.
[00136] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof.
[00137] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein Rc is hydrogen.
[00138] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein Rc is halo.
[00139] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein Rc is fluoro.
[00140] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein R2 is H.
[00141] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein R2 is fluoro.
[00142] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein R2 is methoxy.
[00143] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein R2 is hydroxy. [00144] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein R3a and R3b are H.
[00145] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein at least one of R3a and R3b is halo.
[00146] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein at least one of R3a and R3b is fluoro.
[00147] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein R3a and R3b are fluoro.
[00148] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein at least one of R3a and R3b is C1-C4 alkyl.
[00149] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein at least one of R3a and R3b is Me.
[00150] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein at least one of R3a and R3b is -CH2NMe2.
[00151] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein at least one of R3a and R3b is -C(0)NMe2.
[00152] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein at least one of R3a and R3b is
Figure imgf000026_0001
[00153] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein R3a is -CFhNNto and R3b is fluoro. [00154] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein R3a is fluoro and R3b is -CFhNNto.
[00155] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein X is X-l, X-2, X-3, X-4, X-5, X-6, X-7, X-8, X-9, X-10, X-ll, X-12, orX-13.
[00156] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein X is X-l, X-2, X-3, X-4, X-6, X-7, X-8, X-9, X- 10, X-ll, X-12, or X-13.
[00157] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein X is X-l 4 or X-15.
[00158] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein X is X-l.
[00159] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein X is X-2.
[00160] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein X is X-5.
[00161] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein X is X-5 and R10 is -CH2CH=CH-Ra3.
[00162] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein X is X-6.
[00163] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein X is X-10. [00164] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein X is X-l 1.
[00165] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein X is X-14.
[00166] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein X is X-14 and R6 is halo.
[00167] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIV-XVIII, and the pharmaceutically acceptable salts thereof, wherein X is X-l 5.
[00168] In some embodiments, the present invention provides a compound selected from any of Formulae XIX-XXIV:
Figure imgf000028_0001
Figure imgf000029_0001
wherein X and remaining variables are defined above in accordance with Formula I.
[00169] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof.
[00170] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-l, X-2, X-3, X-4, X-5, X-6, X-7, X-8, X-9, X-10, X-ll, X-12, orX-13.
[00171] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-l, X-2, X-3, X-4, X-6, X-7, X-8, X-9, X- 10, X-ll, X-12, or X-13. [00172] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-14 or X-15.
[00173] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-l, X-2, X-4, X-5, X-6, X-7, X-8, X-9, X- 10, X-l 1, X-12, or X-13.
[00174] In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-l.
[00175] In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-2.
[00176] In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-4.
[00177] In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-5.
[00178] In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-6.
[00179] In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-7.
[00180] In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-8.
[00181] In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-9.
[00182] In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-10. [00183] In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-l 1.
[00184] In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-l 2.
[00185] In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein X is X-l 3.
[00186] In some embodiments, the present invention provides a compound selected from any of Formulae XXV-XXVI:
Figure imgf000031_0001
wherein Ra, R16, and B are defined above in accordance with formula I.
[00187] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXV-XXVI, and the pharmaceutically acceptable salts thereof.
[00188] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXV-XXVI, and the pharmaceutically acceptable salts thereof, wherein Ra is hydrogen.
[00189] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXV-XXVI, and the pharmaceutically acceptable salts thereof, wherein Ra is methyl.
[00190] In some embodiments, the present invention provides a compound selected from any of Formulae XXVII-XXVIII:
Figure imgf000032_0001
And the pharmaceutically acceptable salts thereof, wherein Rc, Rd, n, B, Q, R2, R4, and J are defined above in accordance with Formula I.
[00191] In some embodiments, the present invention provides a compound selected from any of Formulae XXIX-XXX:
Figure imgf000032_0002
and the pharmaceutically acceptable salts thereof, wherein Rc, B, Q, R2, R4, and X are defined above in accordance with Formula I.
[00192] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein J is -CN.
[00193] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein J is alkylsulfonyl.
[00194] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein J is cycloalkylsulfonyl.
[00195] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein J is heteroarylsulfonyl.
[00196] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein J is arylsulfonyl. [00197] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein J is heterocycloalkylsulfonyl.
[00198] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein J is carboxamido.
[00199] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVII-XXX, and the pharmaceutically acceptable salts thereof, wherein R4 is hydrogen.
[00200] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVII-XXX, and the pharmaceutically acceptable salts thereof, wherein R4 is methyl.
[00201] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVII-XXX, and the pharmaceutically acceptable salts thereof, wherein Q is -NHCO2CH3.
[00202] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVII-XXX, and the pharmaceutically acceptable salts thereof, wherein Rc is halo.
[00203] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVII-XXX, and the pharmaceutically acceptable salts thereof, wherein Rc is fluoro.
[00204] In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVII-XXX, and the pharmaceutically acceptable salts thereof, wherein R2 is hydrogen.
[00205] In one embodiment, Compounds of the Disclosure are compounds represented by Formula XXXI:
Figure imgf000033_0001
and the pharmaceutically acceptable salts thereof, wherein: each Ra is independently selected from the group consisting of hydrogen and C1-C4 alkyl; each Rb is independently selected from the group consisting of hydrogen and C1-C4 alkyl;
Rc is selected from the group consisting of hydrogen and halo; each Rd is independently selected from the group consisting of halo; each n is independently 0, 1 or 2;
Figure imgf000034_0001
K is selected from the group consisting of
Figure imgf000035_0002
Figure imgf000035_0001
R20 is selected from the group consisting of (alkylsulfonamide)alkyl and
Figure imgf000035_0003
R21 is selected from the group consisting of hydrogen and C1-C4 alkyl;
R22 is (alkyl)sulfonyl;
R23 is selected from the group consisting of hydrogen and C1-C4 alkyl; and R24 is cyano.
[00206] In another embodiment, Compounds of the Disclosure are compounds represented by Formula XXXI, and the pharmaceutically acceptable salts thereof,
Figure imgf000035_0004
[00207] In another embodiment, Compounds of the Disclosure are compounds represented by Formula XXXI, and the pharmaceutically acceptable salts thereof, wherein each Ra and Rb are hydrogen. [00208] In another embodiment, Compounds of the Disclosure are compounds represented by Formula XXXI, and the pharmaceutically acceptable salts thereof, wherein Rc is fluoro and each n is 0.
[00209] In another embodiment, Compounds of the Disclosure are compounds represented by Formula XXXI, and the pharmaceutically acceptable salts thereof, wherein R is methyl.
[00210] In one embodiment, Compounds of the Disclosure are compounds represented by Formula XXXII: and the pharmaceutically acceptable salts
Figure imgf000036_0001
thereof, wherein:
Figure imgf000036_0002
R25 is selected from the group consisting of (amino)alkyl and carboxamido.
[00211] In another embodiment, Compounds of the Disclosure are compounds represented by Formula XXXII, and the pharmaceutically acceptable salts thereof, wherein B is B-l or B-2.
[00212] In another embodiment, Compounds of the Disclosure are compounds represented by Formula XXXII, and the pharmaceutically acceptable salts thereof, wherein R is methyl. [00213] In one embodiment, Compounds of the Disclosure are compounds represented by Formula XXXIII:
Figure imgf000037_0001
and the pharmaceutically acceptable salts thereof, wherein:
Figure imgf000037_0002
R26ais selected from the group consisting of hydrogen and halo;
R26b is selected from the group consisting of (amino)alkyl, (heterocyclo)alkyl, and carboxamido; and
R27 is selected from the group consisting of cyano, -CF3, alkylsulfonyl, and cycloalkylsulfonyl.
[00214] In another embodiment, Compounds of the Disclosure are compounds represented by Formula XXXIII, and the pharmaceutically acceptable salts thereof, wherein R27 is methylsulfonyl.
[00215] In another embodiment, Compounds of the Disclosure are compounds represented by Formula XXXIII, and the pharmaceutically acceptable salts thereof, wherein R27 is cyclopropylsulfonyl.
[00216] In another embodiment, Compounds of the Disclosure are any one or more of the compounds of Tables 1, 1A, IB, and 1C, and the pharmaceutically acceptable salts thereof. Tables 1, 1A, IB, and 1C further provide the chemical names of the compounds of Tables 1, 1A, IB, and 1C 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.
Figure imgf000037_0003
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Table 1A
Figure imgf000061_0002
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
_ _
Table IB
Figure imgf000065_0002
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Table 1C
Figure imgf000068_0002
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
[00217] In another embodiment, the disclosure provides a pharmaceutical composition comprising a Compound of the Disclosure and a pharmaceutically acceptable carrier.
[00218] In another embodiment, 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. In another embodiment, the ee is about 10%. In another embodiment, the ee is about 20%. In another embodiment, the ee is about 30%. In another embodiment, the ee is about 40%. In another embodiment, the ee is about 50%. In another embodiment, the ee is about 60%. In another embodiment, the ee is about 70%. In another embodiment, the ee is about 80%. In another embodiment, the ee is about 85%. In another embodiment, the ee is about 90%. In another embodiment, 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%.
[00219] The present disclosure encompasses the preparation and use of salts of Compounds of the Disclosure. As used herein, 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 a suitable acid. The pharmaceutically acceptable salts of Compounds of the Disclosure can be acid addition salts formed with pharmaceutically acceptable acids. Examples of 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. Non-limiting 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, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, paratoluenesulfonate, undecanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, ethanedisulfonate, benzene sulfonate, and p-toluenesulfonate salts. In addition, 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. In light of the foregoing, 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.
II. Therapeutic Methods of the Disclosure.
[00220] Compounds of the Disclosure inhibit menin and are useful in the treatment of a variety of diseases and conditions. In particular, 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 a subject in need thereof. The present methods also encompass administering a second therapeutic agent to the subject 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 subject in need thereof, e.g., a chemotherapeutic agent and/or radiation known as useful in treating a particular cancer.
[00221] 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 mM, or less than about 0.01 mM. In one embodiment, 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.
[00222] Since Compounds of the Disclosure are inhibitors of menin protein, a number of diseases and conditions mediated by menin can be treated by employing these compounds. The present disclosure is thus directed generally to a method for treating a condition or disorder responsive to menin inhibition 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.
[00223] The present disclosure is further directed to a method of inhibiting menin in a subject in need thereof, said method comprising administering to the animal an effective amount of at least one Compound of the Disclosure.
[00224] 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. Typically, the pharmaceutical compositions are sterile, and contain no toxic, carcinogenic, or mutagenic compounds that would cause an adverse reaction when administered. Further provided are 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.
[00225] In one embodiment, 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. In addition, the Compound of the Disclosure and second therapeutic agent can be administered from a single composition or two separate compositions.
[00226] 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.
[00227] 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.
[00228] 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. In one embodiment, 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. In another embodiment, the human patient is a human adult over 18 years old in need of treatment of a disease. In another embodiment, the human patient is a human child no more than 18 years old in need of treatment of a disease.
[00229] In another aspect, 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. Examples of treatable cancers include, but are not limited to, any one or more of the cancers of Table 2.
Table 2
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
[00230] In another embodiment, the cancer is a solid tumor. In another embodiment, the cancer a hematological cancer. Exemplary hematological cancers include, but are not limited to, the cancers listed in Table 3. In another embodiment, the hematological cancer is acute lymphocytic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia), or acute myeloid leukemia. In another embodiment, the hematological cancer is myelodysplastic syndrome.
Table 3
Figure imgf000078_0001
[00231] In another embodiment, 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). In another embodiment, the leukemia is NPMlc mutant acute myelogenous leukemia. In another embodiment, the leukemia is MLL-r acute myelogenous leukemia. In another embodiment, the leukemia is MLL- r acute lymphocytic leukemia. In another embodiment the cancer is NUT-midline carcinoma. In another embodiment the cancer is multiple myeloma. In another embodiment the cancer is a lung cancer such as small cell lung cancer (SCLC). In another embodiment the cancer is a neuroblastoma. In another embodiment the cancer is Burkitt's lymphoma. In another embodiment the cancer is cervical cancer. In another embodiment the cancer is esophageal cancer. In another embodiment the cancer is ovarian cancer. In another embodiment the cancer is colorectal cancer. In another embodiment, the cancer is prostate cancer. In another embodiment, the cancer is breast cancer. In another embodiment, the cancer is Ewing’s sarcoma.
[00232] In another embodiment, 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.
[00233] 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. Examples of 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 rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, Type I diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituatarism, Guillain-Barre syndrome, Behcet's disease, scleracierma, mycosis fungoides, acute inflammatory responses (such as acute respiratory distress syndrome and ischemia/reperfusion injury), and Graves' disease. [00234] In another embodiment, 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.
[00235] In another embodiment, the present disclosure provides a method for treating viral infections and diseases. Examples of 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, hepatitis B virus, and hepatitis C virus.
[00236] In another embodiment, 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.
[00237] In another embodiment, the present disclosure provides a method of regulating endogenous or heterologous promoter activity by contacting a cell with a Compound of the Disclosure.
[00238] In methods of the present disclosure, a therapeutically effective amount of a Compound of the Disclosure, typically formulated in accordance with pharmaceutical practice, 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.
[00239] 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. [00240] Pharmaceutical 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.
[00241] 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. 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.
[00242] 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. In one embodiment, a Compound of the Disclosure is administered once daily (QD). In another embodiment, a Compound of the Disclosure is administered twice daily (BID). Multiple doses often are desired, or required. For example, 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.
[00243] 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 1 gram per dose, about 0.005 to about 500 milligrams per dose, about 0.05 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. For example, 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, about 500, about 550, about 600, about 650, about 700, about 750, about 800, about 850, about 900, about 950 milligrams, or about 1 gram, including all doses between 0.005 milligrams and 1 gram.
[00244] The dosage of a composition containing a Compound of the Disclosure, or a composition containing the same, 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/kg, about 675 pg/kg, about 700 pg/kg, about 725 pg/kg, about 750 pg/kg, about 775 pg/kg, about 800 pg/kg, about 825 pg/kg, about 850 pg/kg, about 875 pg/kg, about 900 pg/kg, about 925 pg/kg, about 950 pg/kg, about 975 pg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 60 mg/kg, about 70 mg/kg, about 80 mg/kg, about 90 mg/kg, about 100 mg/kg, about 125 mg/kg, about 150 mg/kg, about 175 mg/kg, about 200 mg/kg, or more. 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. In practice, 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.
[00245] As stated above, a Compound of the Disclosure can be administered in combination with a second therapeutically active agent. In some embodiments, the second therapeutic agent is an epigenetic drug. As used herein, the term "epigenetic drug" refers to a therapeutic agent that targets an epigenetic regulator. Examples of 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.
[00246] In another embodiment, chemotherapeutic agents or other anti-proliferative agents can be combined with Compound of the Disclosure to treat proliferative diseases and cancer. Examples of 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 antiemetic), and any other approved chemotherapeutic drug.
[00247] In another embodiment, 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, phagocytosis inhibitors, demethylating agents, DOT1L inhibitors, IDH1 inhibitors, IDH2 inhibitors, IDH1/IDH2 dual inhibitors, LSD1 inhibitors, XPOl inhibitors, or dasatinib. In another embodiment, 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 dasatinib.
[00248] Demethylating agents include substances that inhibit or interfere with DNA methylation. In some examples, 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, fazarabine, 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.
[00249] Non-limiting examples of inhibitors of the histone methyltransferase DOTIL include EPZ-5676, SGC-0946, and EPZ004777.
[00250] Exemplary nonlimiting IDH1 inhibitors include Tibsovo® (ivosidnib), AG- 881, AG-120, FT-2102 (olutasidenib), BAY1436032, IDH-305, and ZX-06. Exemplary nonlimiting examples of IDH2 inhibitors include Idhifa® (enasidenib; AG- 221), AG-881, AG1-6780, SH1573, andTQ05310. Exemplary nonbmitingIDHl/IDH2 dual inhibitors include HMPL-306.
[00251] Exemplary nonlimiting examples of a LSD1 inhibitor include ORY-1001, OG- L002, SP2509, 4SC-202, GSK2879552, T-3775440, and RN-1.
[00252] Exemplary nonlimiting examples of an XPOl inhibitor include sebnexor (KPT- 330), KPT-8602, KPT25 1, and SL-801.
[00253] 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. 99308617.2 (filed October 29, 1999), WO 98/07697 (published February 26, 1998), WO 98/03516 (published Januaiy 29, 1998), WO 98/34918 (published August 13, 1998), WO 98/34915 (published August 13, 1998), WO 98/33768 (published August 6, 1998), WO 98/30566 (published July 16, 1998), European Patent Publication 606,046 (published July 13, 1994), European Patent Publication 931,788 (published July 28, 1999), WO 90/05719 (published May 31, 1990), WO 99/52910 (published October 21, 1999), WO 99/52889 (published October 21, 1999), WO 99/29667 (published June 17, 1999), PCT International Application No. PCT/IB98/01113 (filed July 21, 1998), European Patent Application No. 99302232.1 (filed March 25, 1999), Great Britain Patent Application No. 9912961.1 (filed June 3, 1999), United States Provisional Application No. 60/148,464 (filed August 12, 1999), United States Patent 5,863,949 (issued January 26, 1999), United States Patent 5,861,510 (issued January 19, 1999), and European Patent Publication 780,386 (published June 25, 1997), all of which are incorporated herein in their entireties by reference. In certain embodiments, the MMP-2 and MMP-9 inhibitors have litle or no activity inhibiting MMP-1. In certain embodiments, 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). Exemplary nonlimiting MMP inhibitors include AG-3340, RO 32-3555, and RS 13-0830.
[00254] Exemplary nonlimiting autophagy inhibitors include chloroquine, 3- methyladenine, hydroxychloroquine (Plaquenil™), 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. In addition, antisense or siRNA that inhibits expression of proteins including but not limited to ATG5 (which are implicated in autophagy), may also be used.
[00255] Exemplary nonlimiting phagocytosis inhibitors include Hu5F9-G4 (Forty- Seven), CC-90002 (Celgene), TTI-621 (Trillium), ALX148 (Alexo Therapeutics), SRF231 (Surface Oncology), SHR-1603 (Hengrui), and IBI188 (Innovent Biologies).
[00256] Examples of 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; a MEK inhibitor; an antitumor antibiotic; a nitrosourea; a mitotic inhibitor, a compound targeting/decreasing protein or lipid kinase activity, a compound targeting/decreasing protein or lipid phosphatase activity, or any further anti-angiogenic compound.
[00257] 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.
[00258] 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. [00259] Exemplary 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.
[00260] Microtubule active agents include microtubule stabilizing, microtubule destabilizing compounds, and microtububn 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.
[00261] Exemplary nonlimiting alkylating agents include cyclophosphamide, ifosfamide, melphalan, and nitrosoureas, such as carmustine and lomustine.
[00262] 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.
[00263] Exemplary nonlimiting matrix metalloproteinase inhibitors ("MMP inhibitors") include collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, batimastat, marimastat, prinomastat, metastat, BMS-279251, BAY 12-9566, TAA211, MMI270B, and AAJ996.
[00264] 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.
[00265] 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.
[00266] Exemplary nonlimiting platin compounds include carboplatin, cis-platin, cisplatinum, and oxabplatin.
[00267] Exemplary nonlimiting methionine aminopeptidase inhibitors include bengamide or a derivative thereof and PPI-2458.
[00268] Exemplary nonlimiting bisphosphonates include etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. [00269] Exemplary nonlimiting antiproliferative antibodies include trastuzumab, trastuzumab-DMl, cetuximab, bevacizumab, rituximab, PR064553, and 2C4. The term “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.
[00270] Exemplary nonlimiting heparanase inhibitors include compounds that target, decrease, or inhibit heparin sulfate degradation, such as PI-88 and OGT2115.
[00271] The term "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.
[00272] Exemplary nonlimiting telomerase inhibitors include compounds that target, decrease, or inhibit the activity of telomerase, such as compounds that inhibit the telomerase receptor, such as telomestatin.
[00273] Exemplary nonlimiting proteasome inhibitors include compounds that target, decrease, or inhibit the activity of the proteasome including, but not limited to, bortezomid.
[00274] The phrase "compounds used in the treatment of hematologic malignancies" as used herein includes 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.
[00275] Exemplary nonlimiting Flt-3 inhibitors include gilteritinib, PKC412, midostaurin, a staurosporine derivative, SU11248, and MLN518.
[00276] 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. [00277] Exemplary nonlimiting BH3 mimetics include venetoclax.
[00278] The phrase "a compound targeting/decreasing a protein or lipid kinase activity; or a protein or lipid phosphatase activity; or any further anti-angiogenic compound" as used herein 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, SU101, 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 (IGF-IR), such as a compound that targets, decreases, or inhibits the activity of IGF-IR; d) a compound targeting, decreasing, or inhibiting the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) a compound targeting, decreasing, or inhibiting the activity of the Axl receptor tyrosine kinase family; f) a compound targeting, decreasing, or inhibiting the activity of the Ret receptor tyrosine kinase; g) a compound targeting, decreasing, or inhibiting the activity of the Kit/SCFR receptor tyrosine kinase, such as imatinib; h) a compound targeting, decreasing, or inhibiting the activity of the c-Kit receptor tyrosine kinases, such as imatinib; i) a compound targeting, decreasing, or inhibiting the activity of members of the c-Abl family, their gene-fusion products (e.g. 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. 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; Tyrphostin AG 556, AG957 and adaphostin (4-{[(2,5- dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adaphostin); 1) a compound targeting, decreasing, or inhibiting the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such as CP 358774, ZD 1839, ZM 105180; trastuzumab, cetuximab, gefitinib, erlotinib, OSI-774, Cl-1033, EKB-569, GW-2016, antibodies El.l, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 and E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; and m) a compound targeting, decreasing, or inhibiting the activity of the c-Met receptor.
[00279] Exemplary compounds that target, decrease, or inhibit the activity of a protein or lipid phosphatase include inhibitors of phosphatase 1, phosphatase 2 A, or CDC25, such as okadaic acid or a derivative thereof.
[00280] 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.
[00281] Additional, nonlimiting, exemplary chemotherapeutic compounds, one or more of which may be used in combination with a Compound of the Disclosure, 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, angiostatin, endostatin, anthranilic acid amides, ZD4190, ZD6474, SU5416, SU6668, bevacizumab, rhuMAb, rhuFab, macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGl antibody, RPI 4610, bevacizumab, porfimer sodium, anecortave, triamcinolone, hydrocortisone, 11- a-epihydrocotisol, cortex olone, 17a-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone, dexamethasone, fluocinolone, a plant alkaloid, a hormonal compound and/or antagonist, a biological response modifier, such as a lymphokine or interferon, an antisense oligonucleotide or oligonucleotide derivative, shRNA, and siRNA.
[00282] Other examples of second therapeutic agents, one or more of which a Compound of the Disclosure also can be combined, 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, pergobde, 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 RA, azathioprine, cyclophosphamide, and sulfasalazine; an immunomodulatory agent, including immunosuppressive agents, such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, an interferon, a corticosteroid, cyclophosphamide, azathioprine, and sulfasalazine; a neurotrophic factor, such as an acetylcholinesterase inhibitor, an MAO inhibitor, an interferon, an anti-convulsant, an ion channel blocker, riluzole, or an anti-Parkinson's agent; an agent for treating cardiovascular disease, such as a beta-blocker, an ACE inhibitor, a diuretic, a nitrate, a calcium channel blocker, or a statin; an agent for treating liver disease, such as a corticosteroid, cholestyramine, an interferon, and an anti-viral agent; an agent for treating blood disorders, such as a corticosteroid, an anti-leukemic agent, or a growth factor; or an agent for treating immunodeficiency disorders, such as gamma globulin.
[00283] The above-mentioned second therapeutically active agents, one or more of which can be used in combination with a Compound of the Disclosure, are prepared and administered as described in the art.
[00284] 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.
[00285] These pharmaceutical 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. When 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. When administered in tablet form, 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. When administered in liquid form, a liquid carrier, such as water, petroleum, or oils of animal or plant origin, can be added. The liquid form of the composition can further contain physiological saline solution, dextrose or other saccharide solutions, or glycols. 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.
[00286] 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.
[00287] 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.
[00288] 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.
[00289] 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. Optionally, 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. Alternatively, a present composition can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
[00290] Compounds of the Disclosure also can be formulated in rectal compositions, such as suppositories or retention enemas, e.g., containing conventional suppository bases. In addition to the formulations described previously, 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. Thus, for example, 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.
[00291] In particular, 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. 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. For parenteral administration, 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.
[00292] The disclosure provides the following particular embodiments in connection with treating a disease in a subject.
[00293] Embodiment 1. A method of treating a subject in need thereof, the method comprising administering to the subj ect a therapeutically effective amount a Compound of the Disclosure, wherein the subject has cancer.
[00294] Embodiment 2. The method of Embodiment 1 , wherein the cancer is any one or more of the cancers of Table 2.
[00295] Embodiment 3. The method of Embodiment 2, wherein the cancer is a hematological cancer. [00296] Embodiment 4. The method of Embodiment 3, wherein the hematological cancer is any one or more of the cancers of Table 3.
[00297] 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.
[00298] Embodiment 6. A pharmaceutical composition comprising a Compound of the Disclosure and a pharmaceutically acceptable carrier for use in treating cancer.
[00299] Embodiment 7. The pharmaceutical composition of Embodiment 6, wherein the cancer is any one or more of the cancers of Table 2.
[00300] Embodiment 8. The pharmaceutical composition of Embodiment 7, wherein the cancer is a hematological cancer.
[00301] Embodiment 9. The pharmaceutical composition of Embodiment 8, wherein the hematological cancer is any one or more of the cancers of Table 3.
[00302] Embodiment 10. A Compound of the Disclosure for use in treatment of cancer.
[00303] Embodiment 11. The compound for use of Embodiment 10, wherein the cancer is any one or more of the cancers of Table 2.
[00304] Embodiment 12. The compound for use of Embodiment 11, wherein the cancer is a hematological cancer.
[00305] Embodiment 13. The compound for use of Embodiment 12, wherein the hematological cancer is any one or more of the cancers of Table 3.
[00306] Embodiment 14. Use of a Compound of the Disclosure for the manufacture of a medicament for treatment of cancer.
[00307] Embodiment 15. The use of Embodiment 14, wherein the cancer is any one or more of the cancers of Table 2.
[00308] Embodiment 16. The use of Embodiment 15, wherein the cancer is a hematological cancer.
[00309] Embodiment 17. The use of Embodiment 16, wherein the hematological cancer is any one or more of the cancers of Table 3.
III. Kits of the Disclosure
[00310] In another embodiment, the present disclosure provides 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. In one embodiment, 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. In one embodiment, 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.
IV. Definitions
[00311] In the present disclosure, the term "halo" as used by itself or as part of another group refers to -Cl, -F, -Br, or -I.
[00312] In the present disclosure, the term "nitro" as used by itself or as part of another group refers to -NO2.
[00313] In the present disclosure, the term "cyano" as used by itself or as part of another group refers to -CN.
[00314] In the present disclosure, the term "hydroxy" as used by itself or as part of another group refers to -OH.
[00315] In the present disclosure, the term "alkyl" as used by itself or as part of another group refers to unsubstituted straight- or branched-chain aliphatic hydrocarbons containing from one to twelve carbon atoms, i.e., Ci-12 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. In one embodiment, the alkyl is a Ci-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. In another embodiment, 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, /.vobutyl. 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl. Non-limiting exemplary C1-4 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, .sec-butyl /e/7- butyl and /.vobutyl.
[00316] In the present disclosure, 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. In one embodiment, the optionally substituted alkyl is substituted with two substituents. In another embodiment, the optionally substituted alkyl is substituted with one substituent. In another embodiment, the optionally substituted alkyl is unsubstituted. Non-limiting exemplary substituted alkyl groups include -CH2CH2NO2, -CH2SO2CH3, CH2CH2S02CH3,-CH2CH2C02H, - CH2SCH3, -CH2CH2SO2CH3, -CH2CH2COPh, and -CH20C(=0)CH3.
[00317] In the present disclosure, the term "cycloalkyl" as used by itself or as part of another group 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. In one embodiment, the cycloalkyl has two rings. In another embodiment, the cycloalkyl has one ring. In another embodiment, the cycloalkyl is saturated. In another embodiment, the cycloalkyl is unsaturated. In another embodiment, the cycloalkyl is a C3-8 cycloalkyl. In another embodiment, the cycloalkyl is a C3-6 cycloalkyl. The term "cycloalkyl" is meant to include groups wherein a ring -CH2- is replaced with a -C(=0)-. Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbomyl, decalin, adamantyl, cyclohexenyl, cyclopentenyl, and cyclopentanone.
[00318] In the present disclosure, 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 heterocyclo, alkoxyalkyl, (amino)alkyl, (carboxamido)alkyl, (heterocyclo)alkyl, -OC(=0)-amino, -N(R19a)C(=0)-R19b, and -N(R20a)SO2-R20b, wherein R19a is selected from the group consisting of hydrogen and alkyl, R19b is selected from the group consisting of amino, alkoxy, alkyl, e.g., C1-C6 alkyl, and optionally substituted aryl, R20a is selected from the group consisting of hydrogen and alkyl, and R20b is selected from the group consisting of amino, alkyl, and optionally substituted aryl. The term 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 atached to the remainder of the molecule at any available carbon atom on the cycloalkyl ring. In one embodiment, the optionally substituted cycloalkyl is substituted with two substituents. In another embodiment, the optionally substituted cycloalkyl is substituted with one substituent. In another embodiment, the optionally substituted cycloalkyl is unsubstituted. Non-limiting exemplary substituted cycloalkyl groups include:
Figure imgf000096_0001
[00319] In the present disclosure, the term "cycloalkylenyl" as used herein by itself or part of another group refers to a divalent form of an optionally substituted cycloalkyl group. In one embodiment, the cycloalkylenyl is a 4-membered cycloalkylenyl. In another embodiment, the cycloalkylenyl is a 5-membered cycloalkylenyl. In another embodiment, the cycloalkylenyl is a 6-membered cycloalkylenyl. Non-limiting exemplary cycloalkylenyl groups include:
Figure imgf000096_0002
[00320] In the present disclosure, the term "aryl" as used by itself or as part of another group refers to unsubstituted monocyclic or bicyclic aromatic ring systems having from six to fourteen carbon atoms, i.e., a C6-14ryl. Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. In one embodiment, the aryl group is phenyl or naphthyl.
[00321] In the present disclosure, 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, -CO2CH2Ph , alkylamino, dialkylamino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, haloalkylsulfonyl cycloalkylsulfonyl,
(cycloalkyl)alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocycloalkylsulfonyl, carboxy, carboxyalkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxycarbonyl, alkoxyalkyl, (amino)alkyl, (carboxamido)alkyl, (heterocyclo)alkyl, -
Figure imgf000097_0001
defined in connection with optionally substituted cycloalkyl.
[00322] In one embodiment, 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, 2-methoxyphenyl, 2- fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-methylphenyl, 3 -methoxy phenyl, 3- fluorophenyl, 3-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4- fluorophenyl, 4-chlorophenyl, 2,6-di-fluorophenyl, 2,6-di-chlorophenyl, 2-methyl, 3- methoxyphenyl, 2-ethyl, 3 -methoxy phenyl, 3,4-di-methoxyphenyl, 3,5-di- fluorophenyl 3,5-di-methylphenyl, 3,5-dimethoxy, 4-methylphenyl, 2-fluoro-3- chlorophenyl, 3-chloro-4-fluorophenyl, 4-(pyridin-4-ylsulfonyl)phenyl The term 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 attached to the remainder of the molecule at any available carbon atom on the phenyl ring. Non-limiting examples include:
Figure imgf000097_0002
[00323] Additional non-limiting examples of optionally substituted aryl include:
Figure imgf000097_0003
[00324] In the present disclosure, the term "alkenyl" as used by itself or as part of another group 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, se -butenyl. pentenyl, and hexenyl.
[00325] In the present disclosure, 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.
[00326] In the present disclosure, the term "alkynyl" as used by itself or as part of another group 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.
[00327] In the present disclosure, the term "optionally substituted alkynyl" as used herein by itself or as part 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.
[00328] In the present disclosure, the term "haloalkyl" as used by itself or as part of another group refers to an alkyl substituted by one or more fluorine, chlorine, bromine and/or iodine atoms. In one embodiment, the alkyl group is substituted by one, two, or three fluorine and/or chlorine atoms. In another embodiment, 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.
[00329] In the present disclosure, the term "hydroxyalkyl" as used by itself or as part of another group refers to an alkyl substituted with one, two, or three hydroxy groups. In one embodiment, the hydroxyalkyl is a monohydroxyalkyl, i.e., a hydroxyalkyl substituted with one hydroxy group. In another embodiment, the hydroxyalkyl is a dihydroxy alkyl, i.e., a hydroxyalkyl substituted with two hydroxy groups. Non-limiting exemplary hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxy butyl groups, such as 1 -hydroxyethyl, 2-hydroxy ethyl, 1,2- dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3 -hydroxy butyl, 4-hydroxybutyl, 2-hydroxy- 1-methylpropyl, and l,3-dihydroxyprop-2-yl.
[00330] In the present disclosure, the term "heteroaralkyl" as used by itself or as part of another group refers to an alkyl substituted with one, two, or three optionally substituted heteroaryl groups. In one embodiment, the heteroaralkyl alkyl group is a Ci-4 alkyl substituted with one optionally substituted heteroaryl group. Non-limiting exemplary heteroaralkyl groups include:
Figure imgf000099_0001
[00331] In the present disclosure, the term "(cycloalkyl)alkyl," as used by itself or as part of another group refers to an alkyl substituted with an optionally substituted cycloalkyl. In one embodiment, the (cycloalkyl) alkyl, is a
Figure imgf000099_0003
Figure imgf000099_0002
[00332] In the present disclosure, the term "alkylsulfonyl" as used by itself or as part of another group refers to a sulfonyl, i.e., -SO2-, substituted with an optionally substituted alkyl. A non-limiting exemplary alkylsulfonyl group is -SO2CH3.
[00333] In the present disclosure, the term "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.
[00334] In the present disclosure, the term "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 -SO2- cyclopropyl and -SC -cyclopenyl. [00335] In the present disclosure, the term "(cycloalkyl)alkylsulfonyl" as used by itself or as part of another group refers to a sulfonyl, i.e., -SO2-, substituted with a (cycloalkyl)alkyl. Non-limiting exemplary (cycloalkyl)alkylsulfonyl groups include:
Figure imgf000100_0001
[00336] In the present disclosure, the term "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.
[00337] In the present disclosure, the term "heteroarylsulfonyl" as used by itself or as part of another group refers to a sulfonyl, i.e., -SO2-, substituted with an optionally substituted heteroaryl group. Non-limiting exemplary heteroarylsulfonyl groups include:
Figure imgf000100_0002
[00338] In the present disclosure, the term "heterocyclosulfonyl" as used by itself or as part of another group refers to a sulfonyl, i.e., -SO2-, substituted with an optionally substituted heterocyclo group. A non-limiting exemplary heterocyclosulfonyl group is:
Figure imgf000100_0003
[00339] In the present disclosure, the term "sulfonamido" as used by itself or as part of another group refers to a radical of the formula -S02NR21aR21b, wherein R21a and R21b are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted aryl, or R21a and R21b 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, -S02N(H)CH3, -S02N(CH3)2, and -S02N(H)Ph.
[00340] In the present disclosure, the term "alkoxy" as used by itself or as part of another group refers to an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, or optionally substituted alkynyl attached to a terminal oxygen atom. In one embodiment, the alkoxy is an optionally substituted alkyl attached to a terminal oxygen atom. In one embodiment, the alkoxy group is a Ci-6 alkyl attached to a terminal oxygen atom. In another embodiment, the alkoxy group is a Ci-4 alkyl attached to a terminal oxygen atom. Non-limiting exemplary alkoxy groups include methoxy, ethoxy, tert-butoxy, and -OCH2SO2CH3.
[00341] In the present disclosure, the term "alkylthio" as used by itself or as part of another group refers to an optionally substituted alkyl attached to a terminal sulfur atom. In one embodiment, the alkylthio group is a C1-4 alkylthio group. Non-limiting exemplary alkylthio groups include -SCH3 and -SCH2CH3.
[00342] In the present disclosure, the term "alkoxyalkyl" as used by itself or as part of another group 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.
[00343] In the present disclosure, the term "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.
[00344] In the present disclosure, the term "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.
[00345] In the present disclosure, the term "aralkyloxy" as used by itself or as part of another group refers to an aralkyl attached to a terminal oxygen atom. Non-limiting exemplary aralkyloxy groups include PhCPkO- and PI1CH2CH2O-.
[00346] In the present disclosure, the term "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. In one embodiment, the heteroaryl contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur. In one embodiment, the heteroaryl has three heteroatoms. In another embodiment, the heteroaryl has two heteroatoms. In another embodiment, the heteroaryl has one heteroatom. In another embodiment, 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. indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4a//-carbazolyl. carbazolyl, b-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, and phenoxazinyl. In one embodiment, 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-5-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl), isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl), isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl), and indazolyl (e.g., lH-indazol- 3-yl). The term "heteroaryl" is also meant to include possible N-oxides. A non-limiting exemplary N-oxide is pyridyl N-oxide.
[00347] In one embodiment, the heteroaryl is a 5- or 6-membered heteroaryl. In one embodiment, 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. In another embodiment, 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. [00348] In the present disclosure, 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 alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl,
Figure imgf000103_0001
substituted cycloalkyl. In one embodiment, 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.
[00349] In the present disclosure, the term "heteroarylenyl" as used herein by itself or part of another group refers to a divalent form of an optionally substituted heteroaryl group. In one embodiment, the heteroarylenyl is a 5-membered heteroarylenyl. Non-limiting examples of a 5-membered heteroarylenyl include:
Figure imgf000103_0002
[00351] In another embodiment, the heteroarylenyl is a 6-membered heteroarylenyl. Non-limiting examples of a 6-membered heteroarylenyl include:
Figure imgf000104_0001
[00352] In the present disclosure, the term "heterocyclo" as used by itself or as part of another group 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. The term "heterocyclo" includes groups wherein a ring -CH2- is replaced with a -C(=O)-, for example, cyclic ureido groups such as 2-imidazolidinone and cyclic amide groups such as β-lactam, γ-lactam, δ-lactam, ε-lactam, and piperazin-2-one. The term "heterocyclo" also includes groups having fused optionally substituted aryl groups, e.g., indolinyl or chroman-4-yl. In one embodiment, 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. In one embodiment, 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. Additional non-limiting examples of heterocyclo groups include oxetanyl and tetrahydrofuranyl.
[00353] In the present disclosure, the term "optionally substituted heterocyclo" as used herein by itself or part of another group refers to a heterocyclo 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, cycloalkylcarbonyl, alkoxy carbonyl, CF3C(=O)-, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, (carboxamido)alkyl, (heterocyclo)alkyl,
Figure imgf000105_0003
Substitution may occur on any available carbon or nitrogen atom, or both. Non-limiting exemplary substituted heterocyclo groups include:
Figure imgf000105_0001
Additional non-limiting exemplary substituted heterocyclo groups include:
Figure imgf000105_0002
[00354] In the present disclosure, the term "amino" as used by itself or as part of another
Figure imgf000105_0004
together to form a 3- to 8-membered optionally substituted heterocyclo. Non-limiting exemplary amino groups include
Figure imgf000106_0001
[00355] In the present disclosure, the term "(amino)alkyl" as used by itself or as part of another group refers to an alkyl substituted with an amino. Non-limiting exemplary
Figure imgf000106_0002
[00356] In the present disclosure, the term "carboxamido" as used by itself or as part of
Figure imgf000106_0003
each independently selected from the group consisting of hydrogen, optionally substituted alkyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, and optionally substituted heteroaryl, or R23a and R23b taken together with the nitrogen to which they are attached form a 3- to 8-membered optionally substituted heterocyclo group. In one embodiment, R23a and R23b are each independently hydrogen or optionally substituted alkyl. In one embodiment, R23a and R23b 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
Figure imgf000106_0004
Figure imgf000106_0005
Additional non-limiting exemplary carboxamido groups include:
Figure imgf000106_0006
[00357] In the present disclosure, the term "alkylcarbonyl" as used by itself or as part of another group refers to a carbonyl group, i.e., -C(=0)-, substituted with an alkyl.
Figure imgf000106_0007
[00358] In the present disclosure, the term "hydroxyalkylcarbonyl" as used by itself or as part of another group refers to a carbonyl group, i.e., -C(=0)-, substituted with an hydroxyalkyl. Non-limiting exemplary alkylcarbonyl groups
Figure imgf000107_0001
[00359] In the present disclosure, the term " cycloalky lcarbonyl" as used by itself or as part of another group refers to a carbonyl group, i.e., -C(=0)-, substituted with a cycloalkyl. A non-limiting exemplary cycloalkylcarbonyl group is -C(=0)- cyclopropyl.
[00360] In the present disclosure, the term "arylcarbonyl" as used by itself or as part of another group refers to a carbonyl group, i.e., -C(=0)-, substituted with an optionally substituted aryl. A non-limiting exemplary arylcarbonyl group is -COPh.
[00361] In the present disclosure, the term "alkoxy carbonyl" as used by itself or as part of another group refers to a carbonyl group, i.e., -C(=0)-, substituted with an alkoxy. In one embodiment, the alkoxy is a Ci-4 alkoxy. Non-limiting exemplary
Figure imgf000107_0002
[00362] In the present disclosure, the term "(alkoxycarbonyl)alkyl" as used by itself or as part of another group refers to an alkyl substituted by an alkoxycarbonyl group. Non-limiting exemplary (alkoxycarbonyl)alkyl groups
Figure imgf000107_0003
[00363] In the present disclosure, the term "carboxy" as used by itself or as part of another group refers to a radical of the formula -C02H.
[00364] In the present disclosure, the term "carboxyalkyl" as used by itself or as part of another group refers to an alkyl substituted with a -C02H. A non-limiting exemplary carboxyalkyl group is -CH2C02H.
[00365] In the present disclosure, the term "aralkyl" as used by itself or as part of another group refers to an alkyl substituted with one, two, or three optionally substituted aryl groups. In one embodiment, aralkyl is a Ci-4 alkyl substituted with one optionally substituted C5 or C6 aryl group. In another embodiment, the aralkyl is a Ci alkyl substituted with one optionally substituted aryl group. In another embodiment, the aralkyl is a C2 alkyl substituted with one optionally substituted aryl group. In another embodiment, the aralkyl is a C3 alkyl substituted with one optionally substituted aryl group. In one embodiment, the aralkyl is a Ci or C2 alkyl substituted with one optionally substituted phenyl group. Non-limiting exemplary aralkyl groups include benzyl, phenethyl, -CHPh2, -CH(CH3)Ph, -CH2(4-F-Ph), -CH2(4-Me-Ph), -CH2(4-CF3-Ph), and -CH(4-F-Ph)2. [00366] In the present disclosure, the term "(heterocyclo)alkyl" as used by itself or part of another group refers to an alkyl substituted with an optionally substituted heterocyclo group. In one embodiment, the (heterocyclo)alkyl is a C1-4 alkyl substituted with one optionally substituted heterocyclo group. Non-limiting exemplary (heterocyclo)alkyl groups include:
Figure imgf000108_0001
Additional non-limiting exemplary (heterocyclo)alkyl groups include:
Figure imgf000108_0002
[00367] In the present disclosure, the term "(heteroaryl)alkyl" as used by itself or part of another group refers to an alkyl substituted with an optionally substituted heteroaryl group. In one embodiment, the (heteroaryl)alkyl is a C1-4 alkyl substituted with one optionally substituted heteroaryl group. In another embodiment, the (heteroaryl)alkyl is a Ci alkyl substituted with one optionally substituted heteroaryl group Non-limiting exemplary (heteroaryl)alkyl groups include:
Figure imgf000108_0003
[00368] In the present disclosure, 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.
Figure imgf000108_0004
[00369] In the present disclosure, the term "(aryloxy)alkyl" as used by itself or as part of another group refers to an alkyl substituted with an aryloxy group. In one embodiment, the "(aryloxy )alkyl" is a C1-4 alkyl substituted with an aryloxy. In one embodiment, the "(aryloxy)alkyl" is a C2-4 alkyl substituted with an aryloxy.
Figure imgf000109_0002
[00370] In the present disclosure, the term "alkylcarbonyloxy" as used by itself or as part of another group refers to an oxy, e.g., -0-, substituted with an alkylcarbonyl group. Non-limiting exemplary "alkylcarbonyloxy" groups
Figure imgf000109_0001
[00371] In the present disclosure, the term "cycloalkylcarbonyloxy" as used by itself or as part of another group refers to an oxy, e.g., -0-, substituted with an cycloalkylcarbonyl group. Non-limiting exemplary "cycloalkylcarbonyloxy" groups
Figure imgf000109_0003
[00372] The term "menin inhibitor" or "inhibitor of menin" as used herein refers to a compound that disrupts, e.g., inhibits, the menin-MLL fusion protein interaction.
[00373] The term "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. Examples of 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. 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.
[00374] The term "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. For example when a cancer is the disease or condition of interest, the second therapeutic agent can be a known chemotherapeutic drug, like taxol, or radiation, for example.
[00375] The term "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. As demonstrated below, Compounds of the Disclosure are menin inhibitors and can be used in treating diseases and conditions wherein menin inhibition provides a benefit. [00376] As used herein, 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. As used herein, 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. The term "treat" and synonyms contemplate administering a therapeutically effective amount of a Compound of the Disclosure to an individual in need of such treatment.
[00377] Within the meaning of the disclosure, "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.
[00378] The term "therapeutically effective amount" or "effective dose" as used herein 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. In the case of a cancer or other proliferation disorder, 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. To the extent the administered compound or composition prevents growth and/or kills existing cancer cells, it may be cytostatic and/or cytotoxic.
[00379] The term "container" means any receptacle and closure therefore suitable for storing, shipping, dispensing, and/or handling a pharmaceutical product.
[00380] 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.
[00381] "Concurrent administration," "administered in combination," "simultaneous administration," and similar phrases mean that two or more agents are administered concurrently to the subject being treated. By "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. For example, 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. When 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. For example, 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, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent 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, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapeutic agent treatment modality (e.g., radiotherapy), to an individual in need thereof. In various embodiments, 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 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 11 hours apart, 11 hours to 12 hours apart, no more than 24 hours apart or no more than 48 hours apart. In one embodiment, the components of the combination therapies are administered at about 1 minute to about 24 hours apart.
[00382] The use of the terms "a", "an", "the", and similar referents in the context of this disclosure (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated. Recitation of ranges of values herein are intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended to better illustrate the disclosure and is not a limitation on the scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure.
[00383] The term "about," as used herein, when used in combination with a numeric value or range of values means the value or range of values may deviate to an extent deemed reasonable to one of ordinary skill in the art.
[00384] Compounds of the Disclosure have asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present disclosure encompasses the use of all such possible forms, as well as their racemic and resolved forms and mixtures thereof. The individual enantiomers can be separated according to methods known in the art in view of the present disclosure. When the compounds described herein contain olefmic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that they include both E and Z geometric isomers. All tautomers are also encompassed by the present disclosure. For the purposes of this application, in some embodiments, certain compounds have been designated as having a specific stereochemical configuration, which has not been confirmed by x-ray crystallography or by any other means. The absolute configuration of any of the compounds disclosed herein could be confirmed by one of ordinary skill in the art using one or more well-known methods including x-ray crystallography or by other spectroscopic techniques such as NMR (using a chiral derivatizing agent, Mosher ester analysis, etc.).
[00385] As used herein, 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).
[00386] The term "chiral center" or "asymmetric carbon atom" refers to a carbon atom to which four different groups are attached. [00387] The terms "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.
[00388] The term "racemic" refers to a mixture of equal parts of enantiomers and which mixture is optically inactive. In one embodiment, Compounds of the Disclosure are racemic.
[00389] The term "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.
[00390] The stereochemical terms and conventions used in the specification are meant to be consistent with those described in Pure & Appl. Chem 68: 2193 (1996), unless otherwise indicated.
[00391] The term "enantiomeric excess" or "ee" refers to a measure for how much of one enantiomer is present compared to the other. For a mixture of R and S enantiomers,
Figure imgf000113_0001
V. Synthesis of Compounds of the Disclosure
[00392] Compounds of the Disclosure can be prepared by methods described in the Examples and by related methods known in the art.
[00393] For example, compounds of Formula I, wherein E is E-l, E-2, E-3, E-4, and E- 5 can be prepared by the general method shown in Scheme 1. A nucleophilic aromatic substitution reaction between azetidine 2-A and aryl fluoride 2-B in the presence of a base (e.g., K2CO3) affords the Compound of Formula I (2-C).
Scheme 1
Figure imgf000114_0001
[00394] Alternatively, compounds of Formula I, wherein E is E-6, E-7, and E-8, can be prepared by the general method shown in Scheme 2. A nucleophilic substitution reaction between azetidine 3-A and electrophile 3-B (LG = leaving group) in the presence of a base (e.g., K2CO3) affords the Compound of Formula I (3-C).
Figure imgf000114_0002
[00395] Compounds of Formula XXXI can, for example, be prepared by the general method shown in Scheme 3. Aryl bromide 4-A is converted to aldehyde 4-C via a Suzuki coupling and subsequent acid hydrolysis. A reductive animation reaction of piperidine 4-D and aldehyde 4-C affords the Compounds of Formula XXXI (4-E).
Scheme 3
Figure imgf000115_0001
[00396] Aspects I
[00397] Aspect 1. A compound having Formula I,
Figure imgf000115_0002
or a pharmaceutically acceptable salt thereof, wherein: each Ra is independently selected from the group consisting of H and C1-C4 alkyl; each Rb is independently selected from the group consisting of H and C1-C4 alkyl;
Rc is selected from the group consisting of H and halogen; each Rd is independently selected from the group consisting of halogen; each n is independently 0, 1 or 2;
Figure imgf000115_0003
Figure imgf000116_0001
R2 is selected from the group consisting of hydrogen, halo, C1-C4 alkyl, hydroxy, Ci- C4 alkoxy, C1-C4 haloalkyl, and C1-C4 hydroxyalkyl;
E is selected from the group consisting of:
Figure imgf000116_0002
Figure imgf000116_0003
J is cyano, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocycloalkylsulfonyl, carboxamido, and -SO2X;
R5 is hydrogen or alkenyl;
R6 is hydrogen or halo; n is 0 or 1;
R7 is alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocycloalkylsulfonyl, or carboxamido;
L2 is absent, -SO2-, or -CH2-
R8aand R8b are independently selected from the group consisting of hydrogen, halo, and
Ral;
Z is alkylsulfonyl and cycloalkylsulfonyl;
Ral is (amino)alkyl, carboxamido, and (heterocyclo)alkyl;
X is selected from the group consisting of
Figure imgf000117_0001
R9a and R9b are each independently selected from the group consisting of alkenyl; Ci- C4 alkyl, halo, (amino)alkyl, and -C(R14a)=C(R14b)(R14c);
Each U is independently selected from the group consisting of -CH2- and -C(=0)- R10 is selected from the group consisting of hydrogen, C1-C4 alkyl, and -CH2CH=CH-
Ra3;
R11 is -NHCOC(R14a)=C(R14b)(R14c) or -CH2CH=CH-Ra3;
R12 is selected from the group consisting of alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, and carboxamido;
R13 is hydrogen or C1-C4 alkyl;
R14a, R14b, R14c, and R14d are each independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, (amino)alkyl, and Ra3;
R32 is -N(R15)CH2CH=CH-Ra3 or -CH=CHCH2Ra4;
Ra3 is selected from the group consisting of alkoxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, and carboxamido;
Ra4 is optionally substituted heterocyclo;
Ra5 is hydrogen or C1-C4 alkyl R15 is hydrogen or C1-C4 alkyl;
R16 is carboxamido;
R17 is selected from the group consisting of hydrogen, C1-C4 alkyl, -OCH2CH=CH-Ra3, and -CH2CH=CH-Ra3; each W is independently selected from the group consisting of -CH- or -N-; and wherein B is not B-10, B-l 1, and B-12 when E is E-l or E-2.
[00398] Aspect 2. The compound of Aspect 1 having Formula II:
Figure imgf000118_0001
[00399] or a pharmaceutically acceptable salt thereof, wherein E is E-l, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, or E-10.
[00400] Aspect 3. The compound of Aspect 1 having Formula III:
Figure imgf000119_0001
[00401] or a pharmaceutically acceptable salt thereof, wherein E is E-l 1 or E-12. [00402] Aspect 4. The compound of Aspect 1 having Formula XII:
Figure imgf000119_0002
[00403] or a pharmaceutically acceptable salt thereof.
[00404] Aspect 5. The compound of Aspect 1 having Formula XIII:
Figure imgf000119_0003
[00405] or a pharmaceutically acceptable salt thereof.
[00406] Aspect 6. The compound of any of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein:
Figure imgf000119_0004
[00407] Aspect 7. The compound of Aspect 6, or a pharmaceutically acceptable salt thereof, wherein B is B-l.
[00408] Aspect 8. The compound of Aspect 6, or a pharmaceutically acceptable salt thereof, wherein B is B-2.
[00409] Aspect 9. The compound of Aspect 6, or a pharmaceutically acceptable salt thereof, wherein R is methyl.
[00410] Aspect 10. The compound of any of Aspects 1 to 9, or a pharmaceutically acceptable salt thereof, wherein at least one of R3a and R3b is halogen.
[00411] Aspect 11. The compound of any of Aspects 1 to 9, or a pharmaceutically acceptable salt thereof, wherein at least one of R3a and R3b is fluoro.
[00412] Aspect 12. The compound of any of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen.
[00413] Aspect 13. The compound of any of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R2 is fluoro.
[00414] Aspect 14. The compound of any of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R2 is methoxy.
[00415] Aspect 15. The compound of any of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R2 is hydroxy.
[00416] Aspect 16. The compound of any of Aspects 1-2 and 6-10, or a pharmaceutically acceptable salt thereof, wherein E is E-l or E-2.
[00417] Aspect 17. The compound of any of Aspects 1-2 and 6-10, or a pharmaceutically acceptable salt thereof, wherein E is E-l.
[00418] Aspect 18. The compound of Aspect 17, or a pharmaceutically acceptable salt thereof, wherein X is X-l.
[00419] Aspect 19. The compound of Aspect 17, or a pharmaceutically acceptable salt thereof, wherein X is X-2.
[00420] Aspect 20. The compound of Aspect 17, or a pharmaceutically acceptable salt thereof, wherein X is X-l 1.
[00421] Aspect 21. The compound of any of Aspects 1-2 and 6-10, or a pharmaceutically acceptable salt thereof, wherein E is E-3.
[00422] Aspect 22. A compound, or a pharmaceutically acceptable salt, selected from one or more of the compounds of Table 1. [00423] Aspect 23. A pharmaceutical composition comprising the compound of any one of Aspects 1-22, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
[00424] Aspect 24. 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 1-22, 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.
[00425] Aspect 25. The method of Aspect 24, wherein the patient has cancer.
[00426] Aspect 26. The method of Aspect 25, wherein the cancer is any one or more of the cancers of Table 2.
[00427] Aspect 27. The method of Aspect 25, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.
[00428] Aspect 28. The method of any one of Aspects 24-27 further comprising administering a therapeutically effective amount of a second therapeutic agent useful in the treatment of the disease or condition.
[00429] Aspect 29. The pharmaceutical composition of Aspect 23 for use in treating cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.
[00430] Aspect 30. The pharmaceutical composition of Aspect 29 for use in treating cancer.
[00431] Aspect 31. The pharmaceutical composition of Aspect 30, wherein the cancer is any one or more of the cancers of Table 2.
[00432] Aspect 32. The pharmaceutical composition of Aspect 30, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.
[00433] Aspect 33. A compound of any one of Aspects 1-22, 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.
[00434] Aspect 34. The compound of Aspect 33 for use in treating cancer. [00435] Aspect 35. The compound of Aspect 34, wherein the cancer is any one or more of the cancers of Table 2.
[00436] Aspect 36. The compound of Aspect 34, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.
[00437] Aspect 37. Use of a compound of any one of Aspects 1-22, 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.
[00438] Aspect 38. The use of Aspect 37 for treatment of cancer.
[00439] Aspect 39. The use of Aspect 38, wherein the cancer is any one or more of the cancers of Table 2.
[00440] Aspect 40. The use of Aspect 38, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.
[00441] Aspects II
[00442] Aspect 1. A compound having Formula I:
Figure imgf000122_0001
or a pharmaceutically acceptable salt thereof, wherein: each Ra is independently selected from the group consisting of H and C1-C4 alkyl; each Rb is independently selected from the group consisting of H and C1-C4 alkyl;
Rc is selected from the group consisting of H and halogen; each Rd is independently selected from the group consisting of halogen; each n is independently 0, 1 or 2;
Q is -NHCO2-R;
Figure imgf000123_0001
R3aand R3b are independently selected from the group consisting of hydrogen, halo, and
Ral;
R4 is hydrogen or C1-C4 alkyl; m is 1 or 2;
J is cyano, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocycloalkylsulfonyl, carboxamido, and -SO2X;
R5 is hydrogen or alkenyl;
R6 is hydrogen or halo; n is 0 or 1;
R7 is alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocycloalkylsulfonyl, or carboxamido;
L2 is absent, -SO2-, or -CH2-
R8ais selected from the group consisting of hydrogen, halo, alkoxy, and Ral;
R8b is selected from the group consisting of alkoxy and Ral;
Z is alkylsulfonyl and cycloalkylsulfonyl;
Ral is (amino)alkyl, carboxamido, and (heterocyclo)alkyl;
X is selected from the group consisting of
Figure imgf000124_0001
o and p are independently 0, 1, 2, or 3;
Y is -C(=0)-;
Z2 is selected from the group consisting of -C(R14a)=C(R14b)(R14c), -CºCR14d, and Ra2
R9a and R9b are each independently selected from the group consisting of alkenyl; Ci- C4 alkyl, halo, (amino)alkyl, and -C(R14a)=C(R14b)(R14c);
Each U is independently selected from the group consisting of -CH2- and -C(=0)-
R10 is selected from the group consisting of hydrogen, C1-C4 alkyl, and -CH2CH=CH- Ra3;
R11 is -NHCOC(R14a)=C(R14b)(R14c) or -CH2CH=CH-Ra3;
R12 is selected from the group consisting of alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, and carboxamido;
R13 is hydrogen or C1-C4 alkyl;
R14a, R14b, R14c, and R14d are each independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, (amino)alkyl, and Ra3;
R18 is selected from the group consisting of cyano, -(C=0)NH2, and -(C=0)N(H)Ci- C4alkyl.
R19 is halo;
R32 is -N(R15)CH2CH=CH-Ra3 or -CH=CHCH2Ra4;
Ra3 is selected from the group consisting of alkoxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, and carboxamido;
Ra4 is optionally substituted heterocyclo;
Ra5 is hydrogen or C1-C4 alkyl
R15 is hydrogen or C1-C4 alkyl;
R16 is carboxamido;
R17 is selected from the group consisting of hydrogen, C1-C4 alkyl, -OCH2CH=CH-Ra3, and -CH2CH=CH-Ra3; each W is independently selected from the group consisting of -CH- or -N-; wherein B is not B-10, B-l 1, and B-12 when E is E-l or E-2.
[00443] Aspect 2. The compound of Aspect 1 having Formula II:
Figure imgf000126_0001
Figure imgf000127_0001
or a pharmaceutically acceptable salt thereof.
[00447] Aspect 6. The compound of any one of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein: each Ra is independently selected from the group consisting of H and C1-C4 alkyl; each Rb is independently selected from the group consisting of H and C1-C4 alkyl;
Rc is fluoro;
R is C1-C4 alkyl;
B is B-l or B-2.
[00448] Aspect 7. The compound of Aspect 6, or a pharmaceutically acceptable salt thereof, wherein B is B-l.
[00449] Aspect 8. The compound of Aspect 6, or a pharmaceutically acceptable salt thereof, wherein B is B-2.
[00450] Aspect 9. The compound of Aspect 6, or a pharmaceutically acceptable salt thereof, wherein R is methyl.
[00451] Aspect 10. The compound of any one of Aspects 1 to 9, or a pharmaceutically acceptable salt thereof, wherein at least one of R3a and R3b is halogen.
[00452] Aspect 11. The compound of any one of Aspects 1 to 9, or a pharmaceutically acceptable salt thereof, wherein at least one of R3a and R3b is fluoro.
[00453] Aspect 12. The compound of any one of Aspects 1 to 9, or a pharmaceutically acceptable salt thereof, wherein at least one of R3a and R3b is (amino)alkyl or carboxamido.
[00454] Aspect 13. The compound of any one of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen.
[00455] Aspect 14. The compound of any one of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R2 is fluoro.
[00456] Aspect 15. The compound of any one of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R2 is methoxy. [00457] Aspect 16. The compound of any one of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R2 is hydroxy.
[00458] Aspect 17. The compound of any one of Aspects 1-2 and 6-16, or a pharmaceutically acceptable salt thereof, wherein E is E-l or E-2.
[00459] Aspect 18. The compound of one any of Aspects 1-2 and 6-16, or a pharmaceutically acceptable salt thereof, wherein E is E-l.
[00460] Aspect 19. The compound of Aspect 18, or a pharmaceutically acceptable salt thereof, wherein X is X-l.
[00461] Aspect 20. The compound of Aspect 18, or a pharmaceutically acceptable salt thereof, wherein X is X-2.
[00462] Aspect 21. The compound of Aspect 18, or a pharmaceutically acceptable salt thereof, wherein X is X-l 1.
[00463] Aspect 22. The compound of any one of Aspects 1-2 and 6-16, or a pharmaceutically acceptable salt thereof, wherein E is E-3.
[00464] Aspect 23. A compound having Formula XXXI:
Figure imgf000128_0001
or a pharmaceutically acceptable salt thereof, wherein: each Ra is independently selected from the group consisting of hydrogen and C1-C4 alkyl; each Rb is independently selected from the group consisting of hydrogen and C1-C4 alkyl;
Rc is selected from the group consisting of hydrogen and halogen; each Rd is independently selected from the group consisting of halogen; each n is independently 0, 1 or 2;
Figure imgf000128_0002
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
[00470] Aspect 28. A compound, or a pharmaceutically acceptable salt, selected from one or more of the compounds of Tables 1, 1A, IB, or 1C.
[00471] Aspect 29. A pharmaceutical composition comprising the compound of any one of Aspects 1-28, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
[00472] Aspect 30. 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 1-28, 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.
[00473] Aspect 31. The method of Aspect 30, wherein the patient has cancer.
[00474] Aspect 32. The method of Aspect 31, wherein the cancer is any one or more of the cancers of Table 2.
[00475] Aspect 33. The method of Aspect 32, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.
[00476] Aspect 34. The method of any one of Aspects 30-33 further comprising administering a therapeutically effective amount of a second therapeutic agent useful in the treatment of the disease or condition.
[00477] Aspect 35. The pharmaceutical composition of Aspect 29 for use in treating cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.
[00478] Aspect 36. The pharmaceutical composition of Aspect 35 for use in treating cancer.
[00479] Aspect 37. The pharmaceutical composition of Aspect 36, wherein the cancer is any one or more of the cancers of Table 2.
[00480] Aspect 38. The pharmaceutical composition of Aspect 37, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.
[00481] Aspect 39. A compound of any one of Aspects 1-28, 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.
[00482] Aspect 40. The compound of Aspect 39 for use in treating cancer.
[00483] Aspect 41. The compound of Aspect 40, wherein the cancer is any one or more of the cancers of Table 2.
[00484] Aspect 42. The compound of Aspect 41, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.
[00485] Aspect 43. Use of a compound of any one of Aspects 1-28, 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.
[00486] Aspect 44. The use of Aspect 43 for treatment of cancer.
[00487] Aspect 45. The use of Aspect 44, wherein the cancer is any one or more of the cancers of Table 2. [00488] Aspect 46. The use of Aspect 45, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.
EXAMPLES
EXAMPLE 1
[00489] Synthesis of Intermediate (S9)
Figure imgf000133_0001
mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature. After stirring overnight, the reaction mixture was washed with saturated brine and the water phase was extracted with dichloromethane twice. The combined organic solvent was dried over Na2SC>4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography to give the intermediate SI as oil (15.5 g, 96%). 'H NMR (400 MHz, CDCb) d 4.85 (s, 1H), 4.16 (s, 1H), 3.80 (s, 1H), 2.02-1.95 (m, 1H), 1.93-1.87 (m, 1H), 1.86-1.77 (m, 2H), 1.70-1.65 (m, 1H), 1.59-1.51 (m, 2H), 1.45 (s, 9H).
[00491] (3aS.6aR )-tetrahydrocyclopenta[d] [ 1.2.3 ]oxathiazole-3(3aH )-
Figure imgf000134_0001
carboxylate 2-oxide (S2): To a solution of thionyl chloride (7 mL, 96.3 mmol) in dry acetonitrile (150 mL) was added a solution of the intermediate SI (15.5g, 77.0 mmol) in acetonitrile (150mL) at -35°C. Then, pyridine (18.7 mL, 231 mmol) was added dropwise and the reaction mixture was allowed to slowly warm to room temperature. After stirring overnight, the reaction mixture was concentrated, and water and ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted three times with ethyl acetate. The combined organic solvent was dried over Na2SO 4, filtered and concentrated. The residue was purified by column chromatography to produce the intermediate S2 as oil (18.8 g, 98%). 1H NMR (400 MHz, CDCB) d 5.74 (t, J = 4.6 Hz, 1H), 4.46 (s, 1H), 2.14-2.09 (m, 1H), 1.90-1.68 (m, 5H), 1.52 (s, 9H).
[00492] (3ari'.6aR )-tetrahydrocyclopenta|6/|| 1.2.31 oxathiazole-3(3aH )-
Figure imgf000134_0002
carboxylate 2,2-dioxide (S3): To a solution of the intermediate S2 (18.8 g, 76 mmol) in acetonitrile (100 mL) and H2O (100 mL) was added NalCri (24.4 g, 114 mmol) in portions, followed by addition of RuCl33H20 (315 mg, 1.5 mmol) at 0 °C. The reaction was stirred at room temperature for 2 hours. Then, the aqueous layer was extracted with diethyl ether three time. The combined organic solvent was dried over Na2SC>4, filtered and concentrated. The residue was purified by column chromatography to produce the title compound S3 as a white solid (19 g, 95%). ¾ NMR (400 MHz, CDCl) d 5.18-5.15 (m, 1H), 4.56-4.53 (m, 1H), 2.23-2.18 (m, 1H), 2.06-1.95 (m, 3H), 1.87-1.77 (m, 2H), 1.55 (s, 9H). ESI-MS calculated for C10H17NO5S [M + Na]+ = 286.07, found: 286.10.
[00493] 2-(l-Benzylpiperidin-4-yl)-2-(3-fluorophenyl)acetonitrile (S5): Sodium methoxide (12 mL, 55.52 mmol of 25% wt in methanol) was added to a solution of 2- (3-fluorophenyl)acetonitrile (5g, 37.01 mmol) in MeOH (50 mL) and stirred briefly. To this solution was added l-benzylpiperidin-4-one (7.01 g, 37.01 mmol), and the reaction was refluxed. After overnight, the solvent was removed, water and EtOAc were added and separated. The aqueous layer was extracted two more times with EtOAc, dried over Na2S04, filtered and concentrated to give S4 that was used without further purification.
[00494] Crude S4 (37.01 mmol) was redissolved in MeOH (50 mL) and NaBEE (4.2 g, 111.03 mmol) was slowly added. After overnight, the reaction was checked by TLC (if the reaction is not complete more NaBEE was added). After complete conversion of S4 to S5, 8 mL of water was added, and the reaction was concentrated. Additional water and EtOAc were added, and the layers separated. The aqueous layer was extracted three times with EtOAc, dried over Na2S04, filtered, concentrated, and purified by column chromatography (DCM/EtOAc gradient) to produce S5 as an oil. ¾NMR (400 MHz, MeOD-ώ) d 7.44-7.38 (m, 1H), 7.32-7.28 (m, 4H), 7.27-7.22 (m, 1H), 7.18-7.16 (m, 1H), 7.13-7.05 (m, 2H), 3.98 (d, J= 7.1 Hz, 1H), 3.48 (s, 2H), 2.96- 2.87 (m, 2H), 2.00-1.92 (m, 2H), 1.87-1.80 (m, 1H), 1.79-1.72 (m, 1H), 1.59-1.52 (m, 1H), 1.50-1.39 (m, 2H); ESI-MS calculated for C20H21FN2 [M + H]+ = 309.17, found: 309.16.
[00495] tert-Butyl ((lS,2R)-2-((S)-(l-benzylpiperidin-4-yl)(cyano)(3- fluorophenyl)methyl) cyclopentyl)carbamate (S7) and tert-butyl ((lS,2R)-2-((R)-(l- benzylpiperidin-4-yl)(cyano)(3-fluorophenyl)methyl)cyclopentyl)carbamate (S8): Compound S5 (2.18 g, 7.07 mmol), 18-Crown-6 (5.61 g, 21.21 mmol), and compound S3 (5.58 g, 21.21 mmol) were added to a dry round-bottom flask. Then, the flask was covered with a kimwipe and dried in a desiccator under vacuum for 1-2 days. After the drying step, the flask was removed from the desiccator and quickly capped with a septum. The system was vacuumed and protected under nitrogen atmosphere. The contents in the flask were then dissolved completely with 60 mL of freshly distilled THF. The solution was then briefly vacuumed and put under nitrogen atmosphere. (This purging was repeated two more times). The reaction was cooled to 0 °C, KHMDS (0.5M in toluene, 42.4 mL, 21.21 mmol) was added dropwise, and then the reaction was allowed to warm to room temperature and stirred overnight. After overnight, a solution of concentrated H2SO4 (0.6 mL, 11.31 mmol) inH20 (10 mL) was added (Note: pH of solution should be < 7), and the solution was vigorously stirred overnight. Then, the reaction mixture was slowly quenched and basified with saturated NaHCCE and extracted with ethyl acetate three times. The combined organic solvent was dried over Na2SCE, filtered and concentrated. The residue was purified by column chromatography 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 can also be isolated by recrystallization in a solution of hexane and dichloromethane with a ratio of 4:1. Data for S7: ¾ NMR (400 MHz, MeOD-ώ) d 7.44-7.39 (m, 1H), 7.35 (d, J= 7.9 Hz, 1H), 7.31-7.22 (m, 6H), 7.11-7.06 (m, 1H), 3.82-3.77 (m, 1H), 3.46 (s, 2H), 2.91 (t, J= 12.5 Hz, 2H), 2.81-2.76 (m, 1H), 2.07-1.93 (m, 5H), 1.80-1.72 (m, 1H), 1.62- 1.46 (m, 5H), 1.33 (s, 9H), 1.27-1.17 (m, 2H); ESI-MS calculated for C30H38FN3O2 [M + H]+ = 492.29, found: 492.36. [a]D 20 = + 23.1, (c 1.17xl03 g/mL, MeOH); fe (UPLC) = 4.46 min. Data for S8: ¾ NMR (400 MHz, MeOD-ώ) d 7.50-7.43 (m, 6H), 7.27 (d, J= 7.3 Hz, 1H), 7.20 (d, J= 9.9 Hz, 1H), 7.14 (t, J= 8.3 Hz, 1H), 4.24 (s, 2H), 4.02- 3.98 (m, 1H), 3.54-3.45 (m, 2H), 3.08 (t, J= 11.4 Hz, 2H), 2.88-2.83 (m, 2H), 2.59 (t, J= 11.8 Hz, 1H), 2.25 (d,J= 14.0 Hz, 1H), 1.99-1.87 (m, 2H), 1.79-1.74 (m, 1H), 1.67- 1.57 (m, 3H), 1.46 (s, 9H), 1.43-1.37 (m, 2H), 1.33-1.18 (m, 1H); ESI-MS calculated for C30H38FN3O2 [M + H]+ = 492.29, found: 492.36. [a]ϋ20 = + 9.4, (c 1.07 xlO 3 g/mL, MeOH); /R (UPLC) = 4.63 min. The absolute stereochemistry of S7 and S8 was determined by single crystal x-ray analysis of S7. See S. Xu et al., “Design of the First- in-Class, Highly Potent Irreversible Inhibitor Targeting the Menin-MLL Protein- Protein Interaction,” 57 Angew. Chem. Int. Ed. 1601-05 (2018).
[00496] Synthesis of S9: S7 (3g, 6.1 mmol) was added to a dry RB-flask then covered with a kimwipe and put in a desiccator that was put under vacuum for 1-2 days. After the vacuuming step, the flask was removed from the desiccator and quickly capped with a septum and the system was vacuumed under N2 atmosphere. The anhydrous toluene (30 ml, Sigma catalog no. 244511) was added to the flask, and was cooled to 0 °C in the ice-bath. 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, and 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 EtOAc was added, and a gel formed. The gel was filtered with celite, washed with EtOAc, and the solvent combined. The solution was extracted with EtOAc and DCM twice respectively. The organic solvent was dried with Na2S04, filtered, and concentrated under rotatory vacuum. Then DCM (50 ml) was added and concentrated again (repeated twice to remove EtOAc completely).
[00497] Then the residue was redissolved in MeOH (100 mL), and NaBEE (461 mg, 12.2 mmol, 4 eq) was added slowly at 0 °C. The reaction mixture was stirred at room temperature, and the reaction was monitored using UPLC-Mass (about 2 days). NaBEE (1 eq) was added every 12 hours if there was still imine intermediate present (mass: 495). After the imine intermediate disappeared, the reaction mixture was concentrated, and diluted with water. The solution was extracted with EtOAc and DCM twice respectively. The organic solvent was dried withNa2S04, filter, and concentrated under
Figure imgf000137_0001
the reaction was complete, and the solvent was removed in vacuo to produce El that was used without purification. At 0°C, dimethyl dicarbonate (410 mg, 3.05 mmol) was added to a solution of El and Et3N (1.13 mL, 8.16 mmol) in DCM (30 mL). After 2 hours, the reaction was concentrated and purified by column chromatography to produce E2 (770 mg).
[00500] Methyl (( 1 S,2R)-2-((S)-2-amino- 1 -( 1 -benzylpiperidin-4-yl)- 1 -(3- fluorophenyl)ethyl)cyclopentyl)carbamate (E3): At 0°C, diisobutylaluminium hydride (3.90 mL, 6.86 mmol) was slowly added to a solution of E2 (770 mg, 1.715 mmol) in toluene (17 mL). After 1 hour at 0°C, the reaction was allowed to warm to room temperature for 15 minutes then the reaction was slowly quenched with 2M NaOH. The quenched reaction was diluted with ethyl acetate and brine and extracted 3 times. The combined organic layers were dried over sodium sulfate, filtered through celite, concentrated, and vacuumed to remove the residual solvent. This crude product was re-dissolved in methanol then treated with NaBEE (130 mg, 3.43 mmol). After overnight the reaction was quenched with 2M NaOH, diluted with ethyl acetate and brine, and then extracted 3 times. The combined organic layers were dried over sodium sulfate, filtered, concentrated, and vacuumed to remove the residual solvent to produce crude E3 (775 mg).
[00501] Methyl ((lS,2R)-2-((S)-l-(l-benzylpiperidin-4-yl)-l-(3-fluorophenyl)-2-(2- methyl-lH-imidazol-l-yl)ethyl)cyclopentyl)carbamate (E4): At 0°C, ammonium acetate (340 mg, 4.42 mmol), glyoxal (641 pL, 40% in water, 4.42 mmol), and acetaldehyde (495 pL, 8.83 mmol) were added to a solution of E3 (400 mg, 0.883 mmol) in methanol (25 mL). After stirring at 0°C for 30 minutes, the reaction was removed from the ice bath and allowed to stir at room temperature for 1 hour, and then heated to 60°C. After heating at 60°C overnight, the reaction was concentrated and purified by prep-HPLC to produce E4 (406 mg).
[00502] Methyl (( 1 S,2R)-2-((S)- 1 -(3 -fluorophenyl)-2-(2-methyl- 1 H-imidazol- 1 -yl)- 1 - (piperidin-4-yl)ethyl)cyclopentyl)carbamate (E5): Compound 5 (406 mg, 0.784 mmol) was dissolved with 10 mL of methanol, and the solution was purged twice by vacuuming briefly followed by adding nitrogen atmosphere. Pd/C (200 mg, 10% on carbon) was quickly added, and the reaction was vacuumed and put under ¾ atmosphere for 2 hours. After the Pd/C catalyst was filtered off through celite, the solvent was removed in vacuo to give E5 (318 mg) that was used without further purification. EXAMPLE 3
[00503] Preparation of intermediate methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-l- (piperidin-4-yl)-2-(4H-l,2,4-triazol-4-yl)ethyl)cyclopentyl)carbamate (T2)
Figure imgf000139_0001
[00504] Step A: methyl ((lS,2R)-2-((S)-l-(l-benzylpiperidin-4-yl)-l-(3-fluorophenyl)- 2-(4H-l,2,4-triazol-4-yl)ethyl)cyclopentyl)carbamate (Tl)
[00505] A solution of triethyl orthoformate (1.29 mL, 7.716 mmol, 1.8 eq.), formohydrazide (397 mg, 6.614 mmol, 1.5 eq.) in MeOH (10 mL) was refluxed at 70 °C. Then methyl ((lS,2R)-2-((S)-2-amino-l-(l-benzylpiperidin-4-yl)-l-(3- fluorophenyl)ethyl)cyclopentyl)carbamate (E3) (2 g, 4.409 mmol, 1.0 eq.) was added to the above solution. The mixture was further refluxed overnight. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give Tl (1.8 g, yield 81%) as a white solid. LC-MS: 506 (M+H)+.
[00506] Step B: methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-l-(piperidin-4-yl)-2-(4H-
1 ,2,4-triazol-4-yl)ethyl)cyclopentyl)carbamate (T2)
[00507] To a mixture of methyl ((lS,2R)-2-((S)-l-(l-benzylpiperidin-4-yl)-l-(3- fluorophenyl)-2-(4H-l,2,4-triazol-4-yl)ethyl)cyclopentyl)carbamate (Tl) (1.8 g, 3.56 mmol, 1.0 eq.) in CF3CH2OH (18 mL) was added 20% Pd(OH)2/C (0.36 g, 10% w/wt). The reaction was stirred at 25°C under H2 atmosphere (1 atm) for 16h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give T2 (1.4 g, yield 95%) which was used directly in next step. LC-MS: 416 (M+l)+.
EXAMPLE 4
[00508] Preparation of methyl ((lS,2R)-2-((S)-l-(l-(azetidin-3-ylmethyl)piperidin-4- yl)-l-(3-fluorophenyl)-2-(lH-pyrazol-l-yl)ethyl)cyclopentyl)carbamate (D6)
Figure imgf000140_0001
[00509] Step A: methyl ((lS,2R)-2-((S)-l-(l-benzylpiperidin-4-yl)-l-(3-fluorophenyl)-
2-((3-(trimethylsilyl)prop-2-yn-l-yl)amino)ethyl)cyclopentyl)carbamate (Dl)
[00510] A solution of methyl ((lS,2R)-2-((S)-2-amino-l-(l-benzylpiperidin-4-yl)-l-(3- fluorophenyl)ethyl)cyclopentyl)carbamate (E3) (2 g, 4.42 mmol, 1.0 eq.) and 3- (trimethylsilyl)propiolaldehyde (668 mg, 5.3 mmol, 1.2 eq.) in DCE (15 mL) was
Figure imgf000140_0002
added to the above solution, and the mixture was stirred at room temperature overnight.
Figure imgf000140_0003
[00511] Step B: methyl ((lS,2R)-2-((S)-l-(l-benzylpiperidin-4-yl)-l-(3-fluorophenyl)- 2-(prop-2-yn- 1 -y lamino)ethy l)cy clopentyl)carbamate (D2)
[00512] A mixture of methyl ((lS,2R)-2-((S)-l-(l-benzylpiperidin-4-yl)-l-(3- fluorophenyl)-2-((3-(trimethylsilyl)prop-2-yn-l- yl)amino)ethyl)cyclopentyl)carbamate (Dl) (2.3 g, 4.08 mmol, 1.0 eq.) and K2CO3 (1.69 g, 12.24 mmol, 3.0 eq.) in MeOH (15 mL) was stirred at room temperature for 4h. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give D2 (1 g, yield 95%) as a white solid. LC-MS: 492 (M+l)+.
[00513] Step C: l-((S)-2-(l-benzylpiperidin-4-yl)-2-(3-fluorophenyl)-2-((lR,2S)-2-
((methoxycarbonyl)amino)cyclopentyl)ethyl)-lH-pyrazole 2-oxide (D3)
[00514] A mixture of methyl ((lS,2R)-2-((S)-l-(l-benzylpiperidin-4-yl)-l-(3- fluorophenyl)-2-(prop-2-yn-l-ylamino)ethyl)cyclopentyl)carbamate (D2) (700 mg, 1.43 mmol, 1.0 eq.), NaNC (295 mg, 4.28 mmol, 3 eq.) and AgOTf (36 mg, 0.14 mmol, 0.1 eq.) in CHCh (10 mL) was stirred at 0°C, then acetic acid (2.5 mL) was added. The reaction mixture was stirred at room temperature for 16h. Then the reaction mixture was poured into water (10 mL) and diluted with saturated NaHCCb aq. (15 mL) and extracted with DCM (20 mL x 3). The organic layers were washed with brine (20 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give D3 (500 mg, yield 92%) as a white solid. LC-MS: 521 (M+l)+.
[00515] Step D: methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-l-(piperidin-4-yl)-2-(lH- pyrazol-1 -yl)ethyl)cyclopentyl)carbamate (D4)
[00516] A mixture of l-((S)-2-(l-benzylpiperidin-4-yl)-2-(3-fluorophenyl)-2-((lR,2S)-
2-((methoxycarbonyl)amino)cyclopentyl)ethyl)-lH-pyrazole2-oxide (D3) (500 mg, 0.96 mmol) and 20% Pd(OH)2/C (100 mg, 20% w/wt) in CF3CH2OH (15 ml) was stirred at room temperature under Lh atmosphere (1 atm) for 16h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give D4 (270 mg, yield 68%) as a white solid. LC-MS: 415 (M+l)+.
[00517] Step E: tert-butyl 3-((4-((S)-l-(3-fluorophenyl)-l-((lR,2S)-2-
((methoxycarbonyl)amino)cyclopentyl)-2-(lH-pyrazol-l-yl)ethyl)piperidin-l- yl)methyl)azetidine-l -carboxylate (D5)
[00518] A mixture of methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-l-(piperidin-4-yl)-2-
(lH-pyrazol-l-yl)ethyl)cyclopentyl)carbamate (D4) (270 mg, 0.651 mmol, 1.0 eq.), tert-butyl 3-(((methylsulfonyl)oxy)methyl)azetidine-l-carboxylate (173 mg, 0.651 mmol, 1.0 eq.), K2CO3 (180 mg, 1.303 mmol, 2.0 eq.) and KI (216.25 mg, 1.303 mmol, 2.0 eq.) in MeCN (10 mL) was stirred at 80°C under N2 atmosphere for 16h. Then the reaction was quenched with water (15 mL) and extracted with EtOAc (15 mL x 2). The organic layers were washed with brine (15 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford D5 (63 mg, yield 17%) as a yellow oil. LC-MS: 584 (M+l)+.
[00519] Step F: methyl ((lS,2R)-2-((S)-l-(l-(azetidin-3-ylmethyl)piperidin-4-yl)-l-(3- fluorophenyl)-2-(lH-pyrazol-l-yl)ethyl)cyclopentyl)carbamate (D6)
[00520] A solution of tert-butyl 3-((4-((S)-l-(3-fluorophenyl)-l-((lR,2S)-2-
((methoxycarbonyl)amino)cyclopentyl)-2-(lH-pyrazol-l-yl)ethyl)piperidin-l- y l)methyl)azeti dine- 1-carboxy late (D5) (62 mg, 0.106 mmol) in DCM (2 mL) and TFA (1 mL) was stirred at 25°C for 2h. Then the reaction mixture was concentrated under reduced pressure to give D6 (50 mg, TFA salt, crude) as a brown oil which was used directly in next step. LC-MS: 484 (M+l)+.
EXAMPLE 5
[00521] Preparation of methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(lH-imidazol-l- yl)-l-(l-((l-(4-((2-vinylpyridin-4-yl)sulfonyl)phenyl)azetidin-3-yl)methyl)piperidin- 4-yl)ethyl)cyclopentyl)carbamate (Cpd 15)
Figure imgf000143_0001
[00522] Step A: 2-bromo-4-((4-fluorophenyl)thio)pyridine
[00523] A mixture of 2-bromo-4-fluoropyridine (0.47 mL, 4.5 mmol, 1.0 eq.), 4- fluorobenzenethiol (0.6 g, 4.5 mmol, 1.0 eq.) and K2CO3 (1.3 g, 9 mmol, 2.0 eq.) in 1,4- dioxane (10 mL) was stirred at 80°C under N2 atmosphere overnight. Then the reaction
Figure imgf000143_0002
[00524] Step B: 2-bromo-4-((4-fluorophenyl)sulfonyl)pyridine
[00525] A mixture of 2-bromo-4-((4-fluorophenyl)thio)pyridine (653 mg, 2.3 mmol, 1.0 eq.), Oxone (4.2 g, 6.9 mmol, 3.0 eq.) in acetone (5 mL) and water (8 mL) was stirred at room temperature overnight. Then the reaction was quenched with water (15 mL) and extracted with EtOAc (15 mL x 2). The organic layers were washed with brine (15 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 2-bromo-4-((4- fluorophenyl)sulfonyl)pyridine (398 mg, yield 55%) as a white solid. LC-MS: 316 (M+l)+.
Figure imgf000144_0001
Figure imgf000145_0001
[00531] Step A: 4-chloro-6-((4-fluorophenyl)thio)pyrimidine
[00532] To a solution of 4,6-dichloropyrimidine (1.8 mL, 20.1 mmol, 1.2 eq.) and 4- fluorobenzenethiol (2.2 g, 16.7 mmol, 1.0 eq.) in acetone (75 mL) was added 1 NNaOH aq. (50.3 mL, 50.3 mmol, 3.0 eq.). The mixture was stirred at room temperature for 2h. Then the reaction was quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The organic layers were washed with brine (20 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 4-chloro-6-((4-fluorophenyl)thio)pyrimidine as a white solid. LC-MS: 241 (M+l)+.
[00533] Step B: 4-chloro-6-((4-fluorophenyl)sulfonyl)pyrimidine
[00534] To a solution of 4-chloro-6-((4-fluorophenyl)thio)pyrimidine (1.4 g, 5.8 mmol, 1.0 eq.) in water (20 mL) and acetone (20 mL) was added oxone (7.7 g, 17.5 mmol, 3.0 eq.) in portions. The mixture was stirred at room temperature overnight. Then the reaction was quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The organic layers were washed with brine (20 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 4-chloro-6-((4- fluorophenyl)sulfonyl)pyrimidine (1.2 g, yield 76%) as a white solid. LC-MS: 273 (M+H)+.
[00535] Step C: 4-((4-fluorophenyl)sulfonyl)-6-vinylpyrimidine
[00536] To a mixture of 4-chloro-6-((4-fluorophenyl)sulfonyl)pyrimidine (400 mg, 1.5 mmol, 1.0 eq.), tributyl(vinyl)stannane (0.6 mL, 2.2 mmol, 1.5 eq.) and Pd(PPh3)4 (169 mg, 0.15 mmol, 0.1 eq.) in toluene (10 mL) was stirred at 100°C under N2 atmosphere overnight. The reaction mixture was quenched with 1 M KF aq. (20 mL) and extracted with EtOAc (20 mL x 3). The organic layers were washed with brine (20 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 4-((4- fluorophenyl)sulfonyl)-6-vinylpyrimidine (200 mg, yield 52%) as a yellow oil. LC-MS: 265 (M+H)+.
[00537] Step D: methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-l-(l-((l-(2-(6-((4- fluorophenyl)sulfonyl)pyrimidin-4-yl)ethyl)azetidin-3-yl)methyl)piperidin-4-yl)-2- (lH-imidazol-l-yl)ethyl)cyclopentyl)carbamate (Cpd 88) and methyl ((lS,2R)-2-((S)- l-(3-fluorophenyl)-2-(lH-imidazol-l-yl)-l-(l-((l-(6-vinylpyrimidin-4-yl)azeti din-3- yl)methyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate (Cpd 26)
[00538] A mixture of methyl ((1 S,2R)-2-((S)-l-(l-(azetidin-3-ylmethyl)piperidin-4-yl)- l-(3-fluorophenyl)-2-(lH-imidazol-l-yl)ethyl)cyclopentyl)carbamate (242 mg, 0.5 mmol, 1.0 eq.), 4-ethenyl-6-(4-fluorobenzenesulfonyl)pyrimidine (164 mg, 0.6 mmol, 1.2 eq.), K2CO3 (428 mg, 3.1 mmol, 6.2 eq.) in MeCN (10 mL) was stirred at 80°C overnight. Then the reaction was quenched with water (10 mL), extracted with DCM (10 mL x 3). The organic layers were washed with brine (10 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel and RP-prep-HPLC to give Cpd 88 (13.5 mg, yield 4%) as a white solid, LC-MS: 748 (M+H)+, and Cpd 26 (10.1 mg, yield 3%) as a white solid, LC-MS: 588 (M+H)+. Cpd 88 ¾ NMR (400 MHz, MeOD-ri^) d 9.16 (s, 1H), 8.18 (s, 1H), 8.13 - 8.09 (m, 2H), 7.75 - 7.73 (m, 1H), 7.49 - 7.333 (m, 5H), 7.12 - 7.07 (m, 2H), 6.97 (s, 1H), 4.83 (d, 1H), 4.63 (d, 1H), 4.07 - 4.01 (m, 1H), 4.00 - 3.91 (m, 2H), 3.63 - 3.50 (m, 5H), 3.45 - 3.35 (m, 2H), 3.19 - 3.12 (m, 3H), 3.04 - 2.85 (m, 4H), 2.63 - 2.58 (m, 1H), 2.43 - 2.27 (m, 3H), 2.03 (d, 1H), 1.88 - 1.82 (m, 1H), 1.69 - 1.62 (m, 1H), 1.54 - 1.46 (m, 1H), 1.40 - 1.32 (m, 2H), 1.28 - 1.12 (m, 3H), 0.90 - 0.75 (m, 1H). Cpd 26 ¾ NMR (400 MHz, MeOD-L) d 8.35 (s, 1H), 7.76 (s, 1H), 7.49 - 7.39 (m, 3H), 7.13 - 7.11 (m, 2H), 6.99 (s, 1H), 6.62 (dd, 1H), 6.39 - 6.26 (m, 2H), 5.59 (d, 1H), 4.84 (d, 1H), 4.66 (d, 1H), 4.27 - 4.23 (m, 2H), 4.11 - 4.04 (m, 1H), 3.85 - 3.76 (m, 3H), 3.54 (s, 3H), 3.29 - 3.06 (m, 5H), 2.69 - 2.54 (m, 3H), 2.41 - 2.35 (m, 1H), 2.08 (d, 1H), 1.87 - 1.83 (m, 1H), 1.75 (d, 1H), 1.51 (d, 1H), 1.40 - 1.38 (m, 2H), 1.23 - 1.15 (m, 2H), 1.01 - 0.87 (m, 1H).
EXAMPLE 7
[00539] Preparation of methyl ((lS,2R)-2-((S)-l-(l-((l-(4-((3-(((E)-4-
(dimethylamino)-4-oxobut-2-en-l-yl)carbamoyl)phenyl)sulfonyl)-2- fluorophenyl)azetidin-3-yl)methyl)piperidin-4-yl)-l-(3-fluorophenyl)-2-(lH- imidazol-l-yl)ethyl)cyclopentyl)carbamate (Cpd 61)
Figure imgf000147_0001
[00540] Step A: benzyl 3-((3,4-difluorophenyl)thio)benzoate
[00541] A mixture of benzyl 3-iodobenzoate (4 g, 11.8 mmol, 1.0 eq.; Ref: Bioorganic and Medicinal Chemistry; vol. 20; nb. 16; (2012); p. 5027 - 5032), Xant-Phos (1.4 g, 2.4 mmol, 0.2 eq.), 3,4-difluorobenzenethiol (2.6 g, 17.7 mmol, 1.5 eq.), Pd2(dba)3 (1.1 g, 1.2 mmol, 0.1 eq.) and DIPEA (5.8 mL, 35mmol, 3.0 eq.) in dioxane (50 mL) was stirred at 100°C under N2 atmosphere overnight. Then the reaction was quenched with water (150 mL) and extracted with EtOAc (150 mL x 2). The organic layers were washed with brine (150 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford the product benzyl 3-((3,4-difluorophenyl)thio)benzoate (4 g, yield 95%) as a colourless oil.
[00542] Step B: benzyl 3-((3,4-difluorophenyl)sulfonyl)benzoate
[00543] To a solution of benzyl 3-((3,4-difluorophenyl)thio)benzoate (2 g, 5.6 mmol, 1.0 eq.) in DCM (30 mL) was added m-CPBA (4.5 g, 22.4 mmol, 4.0 eq.) at 0°C. The mixture was stirred at room temperature overnight. The mixture was quenched with 3 mL sat. Na2S2O3 aq., diluted with sat. NaHCO3 aq. (50 mL), and extracted with DCM (50 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO 4 and concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel to give benzyl 3-((3,4- difluorophenyl)sulfonyl)benzoate (2.1 g, yield 96%) as a white oil.
[00544] Step C: 3-((3,4-difluorophenyl)sulfonyl)benzoic acid
[00545] A mixture of benzyl 3-((3,4-difluorophenyl)sulfonyl)benzoate (1.53 g, 3.9 mmol) and 15% Pd-C (0.15 g, 10% w/wt) inTHF (lO mL) under H2 atmosphere (1 atm) for 2h. Then the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 3-((3,4- difluorophenyl)sulfonyl)benzoic acid (900 mg, yield 77%) as a white solid. LC-MS: 297 (M-H)-.
[00546] Step D: (E)-3-((3,4-difluorophenyl)sulfonyl)-N-(4-(dimethylamino)-4-oxobut-
2-en- 1 -yl)benzamide
[00547] A mixture of 3-((3,4-difluorophenyl)sulfonyl)benzoic acid (226 mg, 0.758 mmol, 1.0 eq.), DIPEA (0.5 mL, 3 mmol, 4.0 eq.), HATU (575 mg, 1.5 mmol, 2.0 eq.) and (E)-4-amino-N,N-dimethylbut-2-enamide (145 mg, 1.1 mmol, 1.5 eq.) in THF (15 mL) was stirred at room temperature for 2h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give (E)-3-((3,4-difluorophenyl)sulfonyl)-N-(4-(dimethylamino)-4-oxobut-2-en-l- yl)benzamide (252 mg, yield 81%) as a white solid. LC-MS: 409 (M+H)+. [00548] Step E: methyl ((lS,2R)-2-((S)-l-(l-((l-(4-((3-(((E)-4-(dimethylamino)-4- oxobut-2-en-l-yl)carbamoyl)phenyl)sulfonyl)-2-fluorophenyl)azetidin-3- yl)methyl)piperidin-4-yl)-l-(3-fluorophenyl)-2-(lH-imidazol-l- yl)ethyl)cyclopentyl)carbamate (Cpd 61)
[00549] A mixture of (E)-3-((3,4-difluorophenyl)sulfonyl)-N-(4-(dimethylamino)-4- oxobut-2-en-l-yl)benzamide (74 mg, 0.18 mmol, 1.1 eq.), methyl methyl ((lS,2R)-2- ((S)-l-(l -(azeti din-3 -y lmethy l)piperidin-4-y 1)- 1 -(3-fluorophenyl)-2-(l H-imidazol- 1 - yl)ethyl)cyclopentyl)carbamate (200 mg, 0.16 mmol, 1.0 eq.), K2CO3 (136 mg, 1.0 mmol, 6.0 eq.) in MeCN (10 mL) was stirred at 80°C overnight. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SC>4 and concentrated under reduced pressure. The residue was purified by Prep-TLC and RP-prep-HPLC to afford Cpd 61 (21.8 mg, yield 15%) as a white solid. LC MS: 872 (M+H)+. ¾ NMR (400 MHz, MeOD-i¾) d 8.35 (s, 1H), 8.06 (dd, 2H), 7.76 (s, 1H), 7.68 - 7.64 (m, 1H), 7.60 (dd, 1H), 7.54 (dd, 1H), 7.48 - 7.44 (m, 2H), 7.40 (d, 1H), 7.13 - 7.08 (m, 2H), 6.98 (s, 1H), 6.75 (dt, 1H), 6.58 - 6.53 (m, 2H), 4.84 (d, 1H), 4.65 (d, 1H), 4.29 - 4.21 (m, 2H), 4.18 (dd, 2H), 4.10 - 4.04 (m, 1H), 3.85 - 3.78 (m, 2H), 3.53 (s, 3H), 3.35 (d, 1H), 3.23 (d, 1H), 3.17 - 3.13 (m, 2H), 3.14 - 3.07 (m, 4H), 2.98 (s, 3H), 2.77 - 2.55 (m, 3H), 2.44 - 2.37 (m, 1H), 2.10 (d, 1H), 1.92 - 1.86 (m, 1H), 1.75 (d, 1H), 1.55 - 1.46 (m, 1H), 1.42 - 1.36 (m, 2H), 1.32 - 1.10 (m, 3H), 1.02 - 0.85 (m, 1H).
EXAMPLE 8
[00550] Preparation of methyl ((lS,2R)-2-((S)-l-(l-((l-(2-fluoro-4-((3-(((E)-3- (methylsulfonyl)allyl)carbamoyl)bicyclo[l.l.l]pentan-l-yl)sulfonyl)phenyl)azetidin- 3-yl)methyl)piperidin-4-yl)-l-(3-fluorophenyl)-2-(lH-imidazol-l- yl)ethyl)cyclopentyl)carbamate (Cpd 68)
Figure imgf000150_0001
[00553] Step B: methyl 3-((3,4-difluorophenyl)sulfonyl)bicyclo[l.l.l]pentane-l- carboxylate
[00554] A mixture of methyl 3-((3,4-difluorophenyl)thio)bicyclo[l.l.l]pentane-l- carboxylate (200 mg, 0.437 mmol, 1.0 eq.) and m-CPBA (225 mg, 1.3 mmol, 3.0 eq.) in 10 mL of DCM was stirred at room temperature for 16h. The reaction mixture was diluted with sat. NaHCCb aq. (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SC>4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give methyl 3-((3,4- difluorophenyl)sulfonyl)bicyclo[l.l.l]pentane-l-carboxylate (209 mg, yield 98%) as a white solid.
[00555] Step C: methyl 3-((3-fluoro-4-(3-((4-((S)-l-(3-fluorophenyl)-2-(lH-imidazol-
1 -yl)-l-((lR, 2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)piperi din-1 - y l)methyl)azetidin- 1 -yl)pheny l)sulfonyl)bicy clo[ 1.1.1 ] pentane- 1 -carboxy late
[00556] A mixture of methyl ((lS,2R)-2-((S)-l-(l-(azetidin-3-ylmethyl)piperidin-4- yl)-l-(3-fluorophenyl)-2-(lH-imidazol-l-yl)ethyl)cyclopentyl)carbamate (239 mg, 0.496 mmol, 1.0 eq.), K2CO3 (205 mg, 1.488 mmol, 3.0 eq.) and methyl 3-((3,4- difluorophenyl)sulfonyl)bicyclo[l.l.l]pentane-l-carboxylate (120 mg, 0.397 mmol, 0.9 eq.) in CLLCN (20 mL) was stirred at 80°C for 16h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SC>4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give methyl 3-((3-fluoro-4-(3-((4-((S)-l-(3-fluorophenyl)-2-(lH-imidazol-l-yl)- l-((lR,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin-l- y l)methyl)azetidin- 1 -yl)pheny l)sulfony l)bicy clo [ 1.1.1 ]pentane- 1 -carboxylate (101 mg, yield 27%) as a white solid. LC-MS: 766 (M+H)+.
[00557] Step D: 3-((3-fluoro-4-(3-((4-((S)-l-(3-fluorophenyl)-2-(lH-imidazol-l-yl)-l-
((1R, 2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)piperi din-1 - y l)methyl)azetidin- 1 -yl)pheny l)sulfony l)bicy clo [ 1.1.1 ]pentane- 1 -carboxylic acid
[00558] A mixture of methyl 3-((3-fluoro-4-(3-((4-((S)-l-(3-fluorophenyl)-2-(lH- imidazol- 1 -yl)- 1 -((1 R,2S)-2-((methoxy carbony l)amino)cy clopentyl)ethyl)piperidin- 1 - y l)methyl)azetidin- 1 -yl)pheny l)sulfony l)bicy clo [ 1.1.1 ]pentane- 1 -carboxylate (101 mg, 0.132 mmol, 1.0 eq.) and LiOH (4 mg, 0.198 mmol, 1.5 eq.) in THF/H2O (6 mL, 5/1) was stirred at room temperature for 3h. The reaction mixture was concentrated under reduced pressure to give 3-((3-fluoro-4-(3-((4-((S)-l-(3-fluorophenyl)-2-(lH- imidazol- 1 -yl)- 1 -((1 R,2S)-2-((methoxy carbony l)amino)cy clopentyl)ethyl)piperidin- 1 - y l)methyl)azetidin- 1 -yl)pheny l)sulfony l)bicy clo [ 1.1.1 ]pentane- 1 -carboxylic acid (99 mg, yield 100%) as a white solid and used directly to the next step. LC-MS: 752 (M+H)+.
[00559] Step E: methyl ((lS,2R)-2-((S)-l-(l-((l-(2-fluoro-4-((3-(((E)-3-
(methylsulfonyl)allyl)carbamoyl)bicyclo[l.l.l]pentan-l-yl)sulfonyl)phenyl)azetidin- 3-yl)methyl)piperidin-4-yl)-l-(3-fluorophenyl)-2-(lH-imidazol-l- yl)ethyl)cyclopentyl)carbamate (Cpd 68)
[00560] A mixture of 3-((3-fluoro-4-(3-((4-((S)-l-(3-fluorophenyl)-2-(lH-imidazol-l- yl)-l-((lR,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin-l- y l)methyl)azetidin- 1 -yl)pheny l)sulfony l)bicy clo [ 1.1.1 ]pentane- 1 -carboxylic acid (60 mg, 0.08 mmol, 1.0 eq.), (E)-3-(methylsulfonyl)prop-2-en-l -amine (24 mg, 0.16 mmol, 2.0 eq.), DIPEA (31 mg, 0.239 mmol, 3.0 eq.) and HATU (24 mg, 0.16 mmol, 2.0 eq.) in THF (10 mL) was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SC>4 and concentrated under reduced pressure. The residue was purified by Prep-TLC and RP-prep-HPLC to give Cpd 68 as a white solid. LC-MS: 869 (M+H)+. ¾ NMR (400 MHz, MeOD-L) d 7.68 (s, 1H), 7.46 - 7.44 (m, 3H), 7.40 - 7.31 (m, 2H), 7.10 - 7.05 (m, 2H), 6.94 (s, 1H), 6.89 - 6.70 (m, 1H), 6.65 - 6.53 (m, 2H), 4.83 (s, 1H), 4.64 (d, 1H), 4.30 - 4.20 (m, 3H), 4.16 (d, 1H), 4.05 (dd, 1H), 3.77 (t, 2H), 3.53 (s, 3H), 3.08 (s, 2H), 3.00 - 2.91 (m, 6H), 2.85 (d, 1H), 2.65 (d, 3H), 2.37 (s, 3H), 2.29 (s, 3H), 2.21 - 2.15 (m, 1H), 2.08 - 2.11 (m, 2H), 1.95 (d, 1H),1.88 - 1.80 (m, 1H), 1.63 - 1.56 (m, 1H), 1.53 - 1.47 (m, 1H), 1.37 - 1.34 (m, 4H), 1.20 - 1.10 (m, 1H), 0.85 - 0.72 (m, 1H).
EXAMPLE 9
[00561] Preparation of methyl ((lS,2R)-2-((S)-l-(l-((l-(2-fluoro-4-((2-((E)-3- (methylsulfonyl)allyl)-3-oxoisoindolin-5-yl)sulfonyl)phenyl)azeti din-3- yl)methyl)piperidin-4-yl)-l-(3-fluorophenyl)-2-(lH-imidazol-l- yl)ethyl)cyclopentyl)carbamate (Cpd 69)
Figure imgf000153_0001
[00562] Step A: 6-bromo-2-(2,2-dimethoxyethyl)isoindolin-l-one
[00563] A mixture of 6-bromoisoindolin-l-one (1.5 g, 7.1 mmol, 1.0 eq.), 2-chloro-l,l- dimethoxy ethane (1.3 mL, 10.6 mmol, 1.5 eq.) and CS2CO3 (4.6 g, 14.1 mmol, 2.0 eq.) in DMF (30 mL) was stirred at 100 °C overnight. The reaction mixture was diluted with H2O (100 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 6-bromo-2-(2,2-dimethoxyethyl)isoindolin-l-one (1.75 g, yield 82%) as a yellow solid. LC-MS: 300, 302 (M+H)+.
[00564] Step B: 6-((3,4-difluorophenyl)thio)-2-(2,2-dimethoxyethyl)isoindolin-l-one
[00565] A mixture of 6-bromo-2-(2,2-dimethoxyethyl)isoindolin-l-one (1.6 g, 5.3 mmol, 1.0 eq.), 3,4-difluorobenzene-l-thiol (0.9 mL, 8 mmol, 1.5 eq.), Pd2(dba)3 (0.49 g, 0.5 mmol, 0.1 eq.), XantPhos (0.62 g, 1.1 mmol, 0.2 eq.) and DIPEA (2.6 mL, 16 mmol, 3.0 eq.) in dioxane (30 mL) was stirred at 100°C under N2 atmosphere overnight. The reaction mixture was cooled to room temperature, diluted with H2O (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 6-((3,4- difluorophenyl)thio)-2-(2,2-dimethoxyethyl)isoindolin-l-one (1.8 g, yield 92%) as a yellow solid. LC-MS: 366 (M+H)+.
[00566] Step C: 6-((3,4-difluorophenyl)sulfonyl)-2-(2,2-dimethoxyethyl)isoindolin-l- one
[00567] To a solution of 6-((3,4-difluorophenyl)thio)-2-(2,2- dimethoxyethyl)isoindolin-l-one (1.75 g, 4.8 mmol, 1.0 eq.) in DCM (40 mL) was added m-CPBA (2.5 g, 14.4 mmol, 43 %, 3.0 eq.) at 0°C. The mixture was stirred at room temperature overnight. The reaction mixture was quenched with 3 mL sat. Na2SO 3 aq., diluted with sat. NaHCO3 aq. (40 mL), and extracted with DCM (40 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 6-((3,4-difluorophenyl)sulfonyl)-2-(2,2- dimethoxyethyl)isoindolin-l-one (825 mg, yield 43%) as a white solid. LC-MS: 398 (M+H)+.
[00568] Step D: 2-(6-((3,4-difluorophenyl)sulfonyl)-l-oxoisoindolin-2-yl)acetaldehyde
[00569] A mixture of 6-((3,4-difluorophenyl)sulfonyl)-2-(2,2- dimethoxyethyl)isoindolin-l-one (800 mg, 2 mmol) in DCM (10 mL) and TFA (3 mL) was stirred at room temperature for lh. Then the reaction mixture was diluted with H2O (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 2-(6-((3,4-difluorophenyl)sulfonyl)-l-oxoisoindolin-2-yl)acetaldehyde (350 mg, yield 49 %) as a white solid. LC-MS: 352 (M+H)+.
[00570] Step E: (E)-6-((3,4-difluorophenyl)sulfonyl)-2-(3-
(methy lsulfony l)allyl)isoindolin- 1 -one
[00571] A mixture of diethyl (methanesulfonylmethyl)phosphonate (98 mg, 0.4 mmol, 1.0 eq.) in THF (4 mL) was added NaH (60% in oil, 24 mg, 0.6 mmol, 1.5 eq.) at 0°C under N2 atmosphere. Then the mixture was stirred at room temperature for lh. A solution of 2-(6-((3,4-difluorophenyl)sulfonyl)-l-oxoisoindolin-2-yl)acetaldehyde (100 mg, 0.29 mmol, 0.7 eq.) in THF (1 mL) was added to above solution at 0°C. The mixture was stirred at room temperature for lh. The mixture was poured into 10 mL of sat. NH4CI aq. and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give (E)-6-((3,4-difluorophenyl)sulfonyl)-2-(3-(methylsulfonyl)allyl)isoindolin-l-one (40 mg, yield 33%) as a yellow oil. LC-MS: 428 (M+H)+.
[00572] Step F: methyl ((lS,2R)-2-((S)-l-(l-((l-(2-fluoro-4-((2-((E)-3-
(methylsulfonyl)allyl)-3-oxoisoindolin-5-yl)sulfonyl)phenyl)azeti din-3- yl)methyl)piperidin-4-yl)-l-(3-fluorophenyl)-2-(lH-imidazol-l- yl)ethyl)cyclopentyl)carbamate (Cpd 69)
[00573] A mixture of methyl ((1 S,2R)-2-((S)-l-(l-(azetidin-3-ylmethyl)piperidin-4-yl)- l-(3-fluorophenyl)-2-(lH-imidazol-l-yl)ethyl)cyclopentyl)carbamate (57 mg, 0.1 mmol, 1.0 eq.), (E)-6-((3,4-difluorophenyl)sulfonyl)-2-(3-
(methylsulfonyl)allyl)isoindolin-l-one (50 mg, 0.1 mmol, 1.0 eq.) and K2CO3 (97 mg, 0.7 mmol, 7.0 eq.) in DMSO (4 mL) was stirred at 80°C under N2 atmosphere for 2h. Then the mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO 4 and concentrated under reduced pressure. The residue was purified by RP-prep-HPLC to afford Cpd 69 (9.7 mg, yield 9%) as a white solid. LC-MS: 897 (M+H)+. 'H NMR (400 MHz, MeOD-L) d 8.26 (d, 1H), 8.17 (d, 1H), 7.79 (d, 1H), 7.70 (s, 1H), 7.60 (dd, 1H), 7.51 (dd, 1H), 7.47 - 7.36 (m, 5H), 7.12 - 7.04 (m, 2H), 6.94 (s, 1H), 6.55 - 6.50 (m, 1H), 5.49 - 5.04 (m, 1H), 4.82 - 4.77 (m, 3H), 4.62 (d, 1H), 4.25 - 4.18 (m, 2H), 4.05 (dd, 1H), 3.97 (d, 1H), 3.78 - 3.73 (m, 2H), 3.52 (s, 3H), 3.13 - 3.07 (m, 1H), 3.02 - 2.95 (m, 5H), 2.85 2.79 (m, 2H), 2.66 - 2.60 (m, 1H), 2.28 - 2.20 (m, 2H), 2.00 (d, 1H), 1.87 - 1.80 (m, 1H), 1.63 (d, 1H), 1.53 - 1.48 (m, 1H), 1.39 - 1.34 (m, 2H), 1.24 - 1.11 (m, 4H), 0.92 - 0.78 (m, 1H).
EXAMPLE 10
[00574] Preparation of methyl ((lS,2R)-2-((S)-l-(l-((l-(3-((dimethylamino)methyl)-2- fluoro-4-((l-((E)-3-(methylsulfonyl)allyl)-lH-pyrazol-4-yl)sulfonyl)phenyl)azetidin- 3-yl)methyl)piperidin-4-yl)-l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol-l- yl)ethyl)cyclopentyl)carbamate (Cpd 76)
Figure imgf000156_0001
[00575] Step A: potassium 2-((dimethylamino)methyl)-3,4-difluorobenzenethiolate
[00576] To a stirring solution of methyl 3-((2-((dimethylamino)methyl)-3,4- difluorophenyl)thio)propanoate (800 mg, 2.765 mmol, 1.0 eq.) in THF (5 mL) was added a solution of t-BuOK (465 mg, 4.15 mmol, 1.5 eq.) in 1 mL THF at - 60°C under N2 atmosphere. The reaction mixture was stirred at this temperature for lh. Then the reaction mixture was warmed to room temperature, used directly to the next step. LC- MS: 202 (M-l)-.
[00577] Step B: l-(2,3-difluoro-6-((l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4- yl)thio)phenyl)-N,N-dimethylmethanamine
[00578] To a solution of potassium 2-((dimethylamino)methyl)-3,4- difluorobenzenethiolate (600 mg, 2.952 mmol, 1.0 eq.) and 4-iodo-l-(tetrahydro-2H- pyran-2-yl)-lH-pyrazole (985.07 mg, 3.542 mmol, 1.1 eq.) in toluene (12 mL) was added CS2CO3 (2.8 g, 8.6 mmol, 3.0 eq.), 1,10-Phenanthroline hydrate (517.4 mg, 2.87 mmol, 1.0 eq.), followed by Cul (545.2 mg, 2.76 mmol, 1.0 eq.). Then the reaction mixture was stirred under N2 atmosphere at 100°C overnight. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give l-(2,3-difluoro-6-((l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4- yl)thio)phenyl)-N,N-dimethylmethanamine (950 mg, yield 91%) as a yellow oil. LC- MS: 354 (M+l)+
[00579] Step C: l-(2,3-difluoro-6-((l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4- yl)sulfonyl)phenyl)-N,N-dimethylmethanamine
[00580] To a stirring solution of l-(2,3-difluoro-6-((l-(tetrahydro-2H-pyran-2-yl)-lH- pyrazol-4-yl)thio)phenyl)-N,N-dimethylmethanamine (700 mg, 1.981 mmol, 1.0 eq.) in acetone/H2O (120 mL, 2:1) was added oxone (2.44 mg, 3.961 mmol, 2.0 eq.) at room temperature. Then the reaction solution was stirred at room temperature for 16h. The reaction solution was concentrated under reduced pressure and extracted with DCM (30 ml x3). The combined organic layers were washed with brine (30 mL), dried over Na2SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give l-(2,3-difluoro-6-((l-(tetrahydro-2H- pyran-2-yl)-lH-pyrazol-4-yl)sulfonyl)phenyl)-N,N-dimethylmethanamine (400 mg, yield 52%) as a yellow oil. LC-MS: 386 (M+l)+.
[00581] Step D: l-(6-((lH-pyrazol-4-yl)sulfonyl)-2,3-difluorophenyl)-N,N- dimethylmethanamine
[00582] To a solution of l-(2,3-difluoro-6-((l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-
4-yl)sulfonyl)phenyl)-N,N-dimethylmethanamine (400 mg, 1.038 mmol) in DCM (15 mL) was added TFA (3ml). The reaction mixture was stirred at 50°C overnight. The reaction solution was concentrated under reduced pressure to give l-(6-((lH-pyrazol- 4-yl)sulfonyl)-2,3-difluorophenyl)-N,N-dimethylmethanamine (280 mg, yield 90%) as a white oil without any further purification. LC-MS: 302 (M+l)+.
[00583] Step E: (E)-l-(2,3-difluoro-6-((l-(3-(methylsulfonyl)allyl)-lH-pyrazol-4- yl)sulfonyl)phenyl)-N,N-dimethylmethanamine
[00584] To a solution of l-(6-((lH-pyrazol-4-yl)sulfonyl)-2,3-difluorophenyl)-N,N- dimethylmethanamine (200 mg, 0.66 mmol, 1.0 eq.) and K2CO3 (183 mg, 1.3 mmol, 2.0 eq.) in MeCN (5 mL) was added (E)-3-bromo-l-(methylsulfonyl)prop-l-ene (159 mg, 0.8 mmol, 1.2 eq.). The mixture was stirred at room temperature for 2h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give (E)-l-(2,3-difluoro-6-((l-(3- (methylsulfonyl)allyl)-lH-pyrazol-4-yl)sulfonyl)phenyl)-N,N-dimethylmethanamine (30 mg, yield 11%) as a yellow solid. LC-MS: 420 (M+l)+.
[00585] Step F: methyl ((lS,2R)-2-((S)-l-(l-((l-(3-((dimethylamino)methyl)-2-fluoro- 4-((l-((E)-3-(methylsulfonyl)allyl)-lH-pyrazol-4-yl)sulfonyl)phenyl)azetidin-3- y l)methy l)piperidin-4-yl)- 1 -(3-fluorophenyl)-2-(2-methy 1- lH-imidazol- 1 - yl)ethyl)cyclopentyl)carbamate (Cpd 76)
[00586] To a solution of methyl ((lS,2R)-2-((S)-l-(l-(azetidin-3-ylmethyl)piperidin-4- yl)-l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol-l-yl)ethyl)cyclopentyl)carbamate (35 mg, 0.07 mmol, 1.0 eq.) and (E)-l-(2,3-difluoro-6-((l-(3-(methylsulfonyl)allyl)- lH-pyrazol-4-yl)sulfonyl)phenyl)-N,N-dimethylmethanamine (30 mg, 0.072 mmol, 1.0 eq.) in MeCN (15 mL) was added K2CO3 (58 mg, 0.422 mmol, 6.0 eq.). Then the reaction mixture was stirred under N2 atmosphere at 80°C for 16h. Two isomers (mixture with by-product) were detected by LCMS. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel and RP-prep-HPLC to give Cpd 76 (3.04 mg, yield 5%) as a white solid. LC-MS: 897 (M+l)+. ¾ NMR (400 MHz, MeOD-L) d 8.59 (s, 1H), 7.98 (s, 1H), 7.88 (d, 1H), 7.53 - 7.40 (m, 3H), 7.31 (d, 1H), 7.16 (t, 1H), 7.00 (s, 1H), 6.80 (s, 1H), 6.70 (t, 1H), 6.46
- 6.33 (m, 1H), 4.70 (d, 1H), 4.49 (s, 2H), 4.41 (d, 1H), 4.32 (s, 2H), 4.01 (d, 3H), 3.90
(s, 2H), 3.64 (s, 3H), 3.46 (d, 1H), 3.23 - 3.17 (m, 3H), 2.98 (s, 3H), 2.92 (s, 6H), 2.65 - 2.58 (m, 6H), 2.23 - 2.15 (m, 1H), 1.93 - 1.79 (m, 2H), 1.57 - 1.46 (m, 2H), 1.43 - 1.30 (m, 4H), 1.25 - 1.15 (m, 2H), 0.93 - 0.80 (m, 1H).
EXAMPLE 11
[00587] Preparation of methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH- imidazol- 1 -yl)- 1 -( 1 -((1 -(( 1 -(methy lsulfonyl)piperidin-4-yl)methy l)azetidin-3- yl)methyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate (Cpd 86)
Figure imgf000158_0001
[00588] To a solution of methyl ((lS,2R)-2-((S)-l-(l-(azetidin-3-ylmethyl)piperidin-4- yl)-l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol-l-yl)ethyl)cyclopentyl)carbamate (60 mg, 0.121 mmol, 1.0 eq.) in DMF (5 mL) was added (l-(methylsulfonyl)piperidin- 4-yl)methyl methanesulfonate (39 mg, 0.15 mmol, 1.2 eq.; Ref: Journal of Medicinal Chemistry; vol. 55; 5; (2012); p. 2416 - 2426), KI (40 mg, 0.241 mmol 2.0 eq.) and K2CO3 (100 mg, 0.723 mmol, 6.0 eq.). Then the reaction mixture was stirred at 80°C under N2 atmosphere for 24h. The reaction solution was cooled to room temperature, diluted with H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by Prep-TLC and RP-prep-HPLC to afford Cpd 86 (5 mg, yield 6%) as a white solid. LC-MS: 673 (M+H)+. ¾ NMR (400 MHz, MeOD-ώ) d 7.48 - 7.42 (m, 2H), 7.35 (d, 1H), 7.09 (t, 1H), 6.69 (d, 1H), 6.65 (s, 1H),
4.57 (d, 1H), 4.33 (d, 1H), 4.00 (dd, 1H), 3.68 (d, 2H), 3.61 (s, 3H), 3.60 - 3.58 (m, 2H),
2.98 - 2.87 (m, 3H), 2.79 (s, 3H), 2.76 (s, 1H), 2.72 - 2.64 (m, 3H), 2.60 (dd, 1H), 2.52 - 2.43 (m, 4H), 2.43 (s, 3H), 2.20 (t, 1H), 2.01 - 1.92 (m, 3H), 1.87 (s, 1H), 1.78 (d, 2H), 1.63 (d, 1H), 1.51 (s, 2H), 1.36 - 1.17 (m, 7H), 0.72 (dd, 1H).
EXAMPLE 12
[00589] Preparation of methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(lH-imidazol-l- yl)-l-(l-((l-(7-((l-methyl-lH-pyrazol-4-yl)sulfonyl)isoindolin-4-yl)azeti din-3- yl)methyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate (Cpd 92)
Figure imgf000159_0001
[00590] Step A: potassium 2-(tert-butoxycarbonyl)-7-fluoroisoindoline-4-thiolate [00591] To a mixture of tert-butyl 4-fluoro-7-((3-methoxy-3- oxopropyl)thio)isoindoline-2-carboxylate (400 mg, 1.12 mmol, 1.0 eq.) in dry THF (10 ml) was added t-BuOK (189 mg, 1.68 mmol, 1.5 eq.) at - 40°C. The mixture was stirred at this temperature for lh. Then the reaction mixture was used directly for next step.
[00592] Step B: tert-butyl 4-fluoro-7-((l-methyl-lH-pyrazol-4-yl)thio)isoindoline-2- carboxylate
[00593] A mixture of potassium 2-(tert-butoxycarbonyl)-7-fluoroisoindoline-4-thiolate
(500 mg, 1.85 mmol, 1.0 eq.), Pd2(dba)3 (169 mg, 0.185 mmol, 0.1 eq.), Xant-Phos (214 mg, 0.37 mmol, 0.2 eq.), DIPEA (0.93 mL, 5.6 mmol, 3.0 eq.) and 4-iodo-l-methyl- lH-pyrazole (386 mg, 1.85 mmol, 1.0 eq.) in THF (10 ml) was stirred at 80°C under N2 atmosphere overnight. Then the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give tert-butyl 4-fluoro- 7-((l -methyl- lH-pyrazol-4-yl)thio)isoindoline-2-carboxy late (50 mg, yield 7%) as a colorless oil. LC-MS: 372 (M+Na)+.
[00594] Step C: tert-butyl 4-fluoro-7-((l-methyl-lH-pyrazol-4-yl)sulfonyl)isoindoline-
2-carboxylate
[00595] To a mixture of tert-butyl 4-fluoro-7-((l-methyl-lH-pyrazol-4- yl)thio)isoindoline-2-carboxylate (50 mg, 0.14 mmol, 1.0 eq.) in acetone (3 ml) and H2O (3 ml) was added Oxone (175 mg, 0.28 mmol, 2.0 eq.) at 0°C. Then the mixture was stirred at room temperature overnight. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give tert-butyl 4-fluoro-7-((l-methyl-lH-pyrazol-4-yl)sulfonyl)isoindoline-2- carboxylate (35 mg, yield 64%) as a white solid. LC MS: 404 (M+Na)+.
[00596] Step D: tert-butyl 4-(3-((4-((S)-l-(3-fluorophenyl)-2-(lH-imidazol-l-yl)-l-
((lR,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin-l- yl)methyl)azeti din- l-yl)-7-((l -methyl- lH-pyrazol-4-y l)sulfony l)isoindoline-2- carboxylate
[00597] A mixture of tert-butyl 4-fluoro-7-((l-methyl-lH-pyrazol-4- yl)sulfonyl)isoindoline-2-carboxylate (35 mg, 0.092 mmol, 1.0 eq.), methyl ((1S,2R)- 2-((S)-l-(l-(azetidin-3-ylmethyl)piperidin-4-yl)-l-(3-fluorophenyl)-2-(lH-imidazol- l-yl)ethyl)cyclopentyl)carbamate (45 mg, 0.092 mmol, 1.0 eq.) and K2CO3 (76 mg, 0.551 mmol, 6.0 eq.) in MeCN (10 ml) was stirred at 80°C overnight. Then the mixture was stirred at room temperature overnight. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give tert-butyl 4-(3-((4-((S)-l-(3-fluorophenyl)-2-(lH-imidazol-l-yl)-l-((lR,2S)-2- ((methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin-l-yl)methyl)azetidin-l-yl)-7- ((l-methyl-lH-pyrazol-4-yl)sulfonyl)isoindoline-2-carboxylate (30 mg, yield 38%) as a white solid. LC-MS: 845 (M+H)+.
[00598] Step E: methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(lH-imidazol-l-yl)-l-(l- ((1 -(7-((l -methyl- IH-py razol-4-yl)sulfonyl)isoindolin-4-yl)azeti din-3 - yl)methyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate (Cpd 92)
[00599] To a mixture of tert-butyl 4-(3-((4-((S)-l-(3-fluorophenyl)-2-(lH-imidazol-l- yl)-l-((lR,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin-l- yl)methyl)azeti din- l-yl)-7-((l -methyl- lH-pyrazol-4-y l)sulfony l)isoindoline-2- carboxylate (30 mg, 0.036 mmol) in DCM (3 ml) was added TFA (1 ml) at 0°C. The mixture was stirred at room temperature for 3h. The reaction mixture was concentrated under reduced pressure and the residue was purified by RP-prep-HPLC to afford Cpd 92 (6 mg, yield 22%) as a white solid. LC-MS: 745 (M+H)+. ¾ NMR (400 MHz, MeOD-ώ) d 8.12 (s, 1H), 7.71 (s, 1H), 7.67 - 7.65 (m, 2H), 7.46 - 7.43 (m, 2H), 7.37 (d, 1H), 7.10 - 7.04 (m, 2H), 6.93 (s, 1H), 6.33 (d, 1H), 4.81 (d, 1H), 4.61 (d, 1H), 4.38 (s, 2H), 4.23 (s, 2H), 4.16 (t, 2H), 4.05 (dd, 1H), 3.88 (s, 3H), 3.73 - 3.67 (m, 2H), 3.52 (s, 3H), 2.96 - 2.80 (m, 3H), 2.67 - 2.56 (m, 3H), 2.20 - 2.12 (m, 1H), 2.05 - 1.93 (m, 3H), 1.86 - 1.79 (m, 1H), 1.59 - 1.53 (m, 1H), 1.52 - 1.47 (m, 1H), 1.43 - 1.33 (m, 3H), 1.22 - 1.10 (m, 2H), 0.85 - 0.73 (m, 1H).
EXAMPLE 13
[00600] Preparation of methyl ((lS,2R)-2-((S)-cyano(l-((l-(5-cyano-l,2,3,4- tetrahydroisoquinolin-8-yl)azetidin-3-yl)methyl)piperidin-4-yl)(3- fluorophenyl)methyl)cyclopentyl)carbamate (Cpd 97)
Figure imgf000162_0001
[00601] Step A: 8-bromoisoquinolin-5-amine
[00602] A mixture of 8-bromo-5-nitroisoquinoline (1 g, 3.9 mmol, 1.0 eq.), Fe (2.2 g, 39.5 mmol, 10.0 eq.) and NH4
Figure imgf000162_0002
Cl (1.06 g, 19.7 mmol, 5.0 eq.) in MeOH (10 mL) and
H2O (3 mL) was stirred at 50°C under N2 atmosphere for 2h. The reaction mixture was cooled to room temperature, filtered through a Celite pad and washed with DCM (40 mL). The combined organic layers were washed with brine (40 mL), dried over Na2S04 and concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel to give 8-bromoisoquinolin-5 -amine (700 mg, yield 79%) as a yellow solid. LC-MS: 223, 225 (M+H)+.
[00603] Step B: 8-bromoisoquinoline-5-carbonitrile
[00604] A mixture of CuCN (843 mg, 9.4 mmol, 1.0 eq.) in DMSO (10 mL) was stirred at 50°C under N2 atmosphere for 5 mins. Then isopentyl nitrite (1.2 mL, 9.4 mmol, 1.0 eq.) was added dropwise. After the mixture was stirred at 50°C for 10 mins, 8- bromoisoquinolin-5-amine (700 mg, 3.1 mmol, 0.3 eq.) in DMSO (3 mL) was added by drop. The mixture was stirred at 50°C for 30 mins. The reaction mixture was quenched with 50 mL 30% of NH3Ή2O aq. at 0°C and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 8-bromoisoquinoline-5-carbonitrile (200 mg, yield 27%) as a white solid. LC-MS: 233, 235 (M+H)+. [00605] Step C: methyl ((lS,2R)-2-((S)-cyano(l-((l-(5-cyanoisoquinolin-8-yl)azetidin-
3-yl)methyl)piperidin-4-yl)(3-fluorophenyl)methyl)cyclopentyl)carbamate [00606] A mixture of methyl ((lS,2R)-2-((S)-(l-(azetidin-3-ylmethyl)piperidin-4- yl)(cyano)(3-fluorophenyl)methyl)cyclopentyl)carbamate (150 mg, 0.35 mmol, 1.0 eq.), 8-bromoisoquinoline-5-carbonitrile (81.6 mg, 0.35 mmol, 1.0 eq.), X-Phos (33 mg, 0.07 mmol, 0.2 eq.), Pd2(dba)3 (32 mg, 0.04 mmol, 0.1 eq.) and CS2CO3 (358 mg, 1.1 mmol, 3.0 eq.) in toluene (5 mL) was stirred at 100°C under N2 atmosphere overnight. Then the mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give methyl ((lS,2R)-2-((S)-cyano(l-((l-(5- cyanoisoquinolin-8-yl)azetidin-3-yl)methyl)piperidin-4-yl)(3- fluorophenyl)methyl)cyclopentyl)carbamate (70 mg, yield 34%) as a yellow solid. LC- MS: 581 (M+H)+.
[00607] Step D: methyl ((lS,2R)-2-((S)-cyano(l-((l-(5-cyano-l,2,3,4- tetrahydroisoquinolin-8-yl)azetidin-3-yl)methyl)piperidin-4-yl)(3- fluorophenyl)methyl)cyclopentyl)carbamate (Cpd 97)
[00608] To a mixture of methyl ((lS,2R)-2-((S)-cyano(l-((l-(5-cyanoisoquinolin-8- yl)azetidin-3-yl)methyl)piperidin-4-yl)(3-fluorophenyl)methyl)cyclopentyl)carbamate (70 mg, 0.12 mmol, 1.0 eq.) in AcOH (3 mL) was added NaBH4 (9 mg, 0.24 mmol, 2.0 eq.). The mixture was stirred at room temperature for 20 mins. Then the mixture was diluted with sat. NaHCO3 aq. (15 mL) and extracted with DCM (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO 4 and concentrated under reduced pressure, the residue was purified by RP-prep-HPLC to give Cpd 97 (5 mg, yield 7%) as a white solid. LC-MS: 585 (M+H)+. ¾ NMR (400 MHz, MeOD-i¾) d 7.42 - 7.32 (m, 3H), 7.24 (d, 1H), 7.12 - 7.07 (m, 1H), 6.34 (d, 1H), 4.13 - 4.06 (m, 2H), 3.88 - 3.83 (m, 1H), 3.77 (s, 2H), 3.63 (t, 2H), 3.44 (s, 3H), 3.07 (t, 2H), 2.94 - 2.80 (m, 6H), 2.59 (d, 2H), 2.05 - 1.93 (m, 4H), 1.83 - 1.77 (m, 1H), 1.70 - 1.44 (m, 6H), 1.37 - 1.28 (m, 2H).
EXAMPLE 14
[00609] Preparation of methyl ((lS,2R)-2-((S)-2-(azetidin-l-yl)-l-(3-fluorophenyl)-l- (l-((l-(7-(((R)-l-(((E)-3-(methylsulfonyl)allyl)carbamoyl) piperidin-3- yl)sulfonyl)isoindolin-4-yl)azetidin-3-yl)methyl)piperidin-4- yl)ethyl)cyclopentyl)carbamate (Cpd 104)
Figure imgf000164_0001
Figure imgf000165_0001
[00610] Step A: l-bromo-2,3-bis(bromomethyl)-4-fluorobenzene
[00611] A mixture of l-bromo-4-fluoro-2,3-dimethylbenzene (10 g, 49.25 mmol, 1.0 eq.), BPO (1.19 g, 4.93 mmol, 0.1 eq.) andNBS (17.53 g, 98.49 mmol, 2.0 eq.) in CCU (300 ml) was stirred at 90°C for 16h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel to give l-bromo-2,3-bis(bromomethyl)-4-fluorobenzene (14 g, yield 78%) as a white solid.
[00612] Step B: 4-bromo-7-fluoro-2-(4-methoxybenzyl)isoindoline
[00613] A solution of l-bromo-2,3-bis(bromomethyl)-4-fluorobenzene (12 g, 33.25 mmol, 1.0 eq.), (4-methoxyphenyl)methanamine (5.47 g, 39.91 mmol, 1.2 eq.) and K2CO3 (18.38 g, 133.02 mmol, 4.0 eq.) in EtOH (800 ml) was stirred at 80°C for 2h. The reaction mixture was poured into sat. NaHCCb aq. (200 ml) and extracted with EtOAc (150 ml x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 4-bromo-7-fluoro-2-(4- methoxybenzyl)isoindoline (6 g, yield 54%). LC-MS: 336, 338 (M+H)+.
[00614] Step C: 4-bromo-7-fluoroisoindoline
[00615] To a solution of 4-bromo-7-fluoro-2-(4-methoxybenzyl)isoindoline (6 g, 17.85 mmol, 1.0 eq.) in chlorobenzene (60 ml) was added 1-chloroethyl carbonochloridate (7.65 g, 53.54 mmol, 3.0 eq.) at room temperature. Then the reaction was heated at 110°C for 3h. The reaction mixture was concentrated under reduced pressure and triturated with PE/EtOAc (20/1, 30 ml). The product was filtered to afford 4- bromo-7-fluoroisoindoline HC1 salt (3.3 g, yield 74%). LC-MS: 216, 218 (M+H)+.
[00616] Step D: tert-butyl 4-bromo-7-fluoroisoindoline-2-carboxylate [00617] To a solution of 4-bromo-7-fluoroisoindoline HC1 salt (3.3 g, 15.27 mmol, 1.0 eq.) in THF (20 ml) was added TEA (4.2 ml, 30.55 mmol, 2.0 eq.) and B0C2O (5.0 g, 22.91 mmol, 1.5 eq.) at 0°C. The reaction mixture was stirred at room temperature for lh. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give tert-butyl 4-bromo-7-fluoroisoindoline-2- carboxylate (4.2 g, yield 87%). LC-MS: 316, 318 (M+H)+.
[00618] Step E: tert-butyl 4-fluoro-7-((3-methoxy-3-oxopropyl)thio) isoindoline-2- carboxylate
[00619] A mixture of tert-butyl 4-bromo-7-fluoroisoindoline-2-carboxylate (4.2 g, 13.28 mmol, 1.0 eq.), methyl 3-mercaptopropanoate (2.39 g, 19.93 mmol, 1.5 eq.), Pd2(dba)3 (0.61 g, 0.66 mmol, 0.05 eq.), Xant-Phos (0.38 g, 0.66 mmol, 0.05 eq.),and DIPEA (5.2 g, 39.85 mmol, 2 eq.) in toluene (15 ml) was stirred at 100°C for 16h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel to afford tert-butyl 4- fluoro-7-((3-methoxy-3-oxopropyl)thio)isoindoline-2-carboxylate (3.7 g, yield 78%) as a yellow oil. LC-MS: 378 (M+Na)+.
[00620] Step F & G: tert-butyl (R)-4-((l-((benzyloxy)carbonyl)piperidin-3-yl)thio)-7- fluoroisoindoline-2-carboxylate
[00621] To a mixture of tert-butyl 4-fluoro-7-((3-methoxy-3- oxopropyl)thio)isoindoline-2-carboxylate (1.5 g, 4.22 mmol, 1.0 eq.) in THF (20 ml) was added t-BuOK (0.71 g, 6.33 mmol, 1.5 eq.) at - 40°C. Then the mixture was stirred at room temperature for lh. Then benzyl (S)-3-((methylsulfonyl)oxy)piperidine-l- carboxylate (1.16 g, 3.71 mmol, 0.88 eq.) and K2CO3 (1.03 g, 7.43 mmol, 1.76 eq.) was added to the above mixture. The reaction mixture was stirred at 80°C for 16h. The reaction mixture was concentrated under reduced pressure, and the crude was purified by flash column chromatography on silica gel to afford tert-butyl (R)-4-((l- ((benzyloxy)carbonyl)piperidin-3-yl)thio)-7-fluoroisoindoline-2-carboxylate (1.1 g, yield 61%) as a yellow oil. LC-MS: 509 (M+Na)+.
[00622] Step H: tert-butyl (R)-4-((l-((benzyloxy)carbonyl)piperidin-3-yl)sulfonyl)-7- fluoroisoindoline-2-carboxylate
[00623] To a mixture of tert-butyl (R)-4-((l-((benzyloxy)carbonyl)piperidin-3-yl)thio)- 7-fluoroisoindoline-2-carboxylate (1.1 g, 2.26 mmol, 1.0 eq.) in acetone (10 ml) and H2O (5 ml) was added oxone (4.16 g, 6.78 mmol, 3.0 eq.) at 0°C. The mixture was stirred at room temperature for 16h. The reaction mixture was stirred at room temperature for lh. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford tert-butyl (R)-4-((l- ((benzyloxy)carbonyl)piperidin-3-yl)sulfonyl)-7-fluoroisoindoline-2-carboxylate (900 mg, yield 76%) as a colorless oil. LC-MS: 541 (M+Na)+.
[00624] Step I: tert-butyl 4-(3-((4-((S)-2-(azetidin-l-yl)-l-(3-fluorophenyl)-l-((lR,2S)-
2-((methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin-l-yl)methyl) azeti din-1 -yl)- 7-(((R)-l-((benzyloxy)carbonyl)piperidin-3-yl)sulfonyl)isoindoline-2-carboxylate
[00625] A mixture of tert-butyl (R)-4-((l-((benzyloxy)carbonyl)piperidin-3- yl)sulfonyl)-7-fluoroisoindoline-2-carboxylate (500 mg, 0.96 mmol, 1.0 eq.), methyl (( 1 S,2R)-2-((S)-2-(azetidin- 1 -yl)- 1 -( 1 -(azeti din-3 -y lmethy l)piperidin-4-y 1)- 1 -(3- fluorophenyl)ethyl)cyclopentyl)carbamate (F3) (455 mg, 0.96 mmol, 1.0 eq.) and K2CO3 (266 mg, 1.92 mmol, 2.0 eq.) in DMSO (20 ml) was stirred at 80°C for 16h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford tert-butyl 4-(3-((4-((S)-2-(azetidin-l-yl)-l-(3- fluorophenyl)- 1 -(( 1 R,2S)-2-((methoxy carbonyl)amino)cy clopenty l)ethyl)piperidin- 1 - yl)methyl)azetidin-l-yl)-7-(((R)-l-((benzyloxy)carbonyl)piperidin-3-yl)sulfonyl) isoindoline-2-carboxylate (200 mg, yield 21%) as a white solid. LC-MS: 971 (M+H)+.
[00626] Step J: tert-butyl 4-(3-((4-((S)-2-(azetidin-l-yl)-l-(3-fluorophenyl)-l-((lR,2S)-
2-((methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin-l-yl)methyl) azeti din-1 -yl)- 7-(((R)-piperidin-3-yl)sulfonyl)isoindoline-2-carboxylate
[00627] A mixture of tert-butyl 4-(3-((4-((S)-2-(azetidin-l-yl)-l-(3-fluorophenyl)-l-
((1R, 2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)piperi din-1 - yl)methyl)azetidin-l-yl)-7-(((R)-l-((benzyloxy)carbonyl)piperidin-3-yl)sulfonyl) isoindoline-2-carboxylate (200 mg, 0.206 mmol) and 10% Pd/C (20 mg) in MeOH (10 ml) was stirred at room temperature for 16h under Lh atmosphere (1 atm). The reaction mixture was filtered and concentrated under reduced pressure to afford tert-butyl 4-(3- ((4-((S)-2-(azetidin- 1 -yl)- 1 -(3-fluoropheny 1)- 1 -(( 1 R,2S)-2-((methoxy carbony l)amino) cyclopentyl)ethyl)piperidin-l-yl)methyl)azetidin-l-yl)-7-(((R)-piperi din-3- yl)sulfonyl) isoindoline-2-carboxylate (160 mg, yield 92%) as a white solid. LC-MS: 837 (M+H)+.
[00628] Step K: tert-butyl 4-(3-((4-((S)-2-(azetidin-l-yl)-l-(3-fluorophenyl)-l- ((1R, 2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)piperi din-1 - y l)methyl)azetidin- 1 -yl)-7-(((R)- 1 -(((E)-3-(methy lsulfonyl)allyl)carbamoy 1) piperidin- 3-yl)sulfonyl)isoindoline-2-carboxylate
[00629] A mixture of (2E)-3-methanesulfonylprop-2-en-l -amine (38 mg, 0.28 mmol, 1.47 eq.; Ref: Journal of Medicinal Chemistry; 35; 6; (1992); p. 1067 - 1075), CDI (46 mg, 0.28 mmol, 1.47 eq.) and TEA (58 mg, 0.57 mmol, 3.94 eq.) in THF (3 ml) was stirred at room temperature for lh. Then tert-butyl 4-(3-((4-((S)-2-(azetidin-l-yl)-l-(3- fluorophenyl)-l-((lR,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl) piperidin-1- yl)methyl)azetidin-l-yl)-7-(((R)-piperidin-3-yl)sulfonyl)isoindoline-2-carboxylate (160 mg, 0.19 mmol, 1.0 eq.) in THF (2 ml) was added, and the mixture was stirred for 16h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel afford tert-butyl 4-(3-((4-((S)-2-(azetidin-l-yl)- l-(3-fluorophenyl)-l-((lR,2S)-2-((methoxycarbonyl)amino) cy clopentyl)ethyl)piperidin- 1 -yl)methyl)azetidin-l -yl)-7-(((R)- 1 -(((E)-3- (methylsulfonyl)allyl)carbamoyl)piperidin-3-yl)sulfonyl)isoindoline-2-carboxylate (70 mg, yield 36%) as a colorless oil. LC-MS: 998 (M+H)+.
[00630] Step L: methyl ((lS,2R)-2-((S)-2-(azetidin-l-yl)-l-(3-fluorophenyl)-l-(l-((l-
(7-(((R)- l-(((E)-3 -(methylsulfonyl)ally l)carbamoyl)piperi din-3 - yl)sulfonyl)isoindolin-4-yl)azetidin-3-yl)methyl)piperidin-4-yl)ethyl)cyclopentyl) carbamate
[00631] A mixture of tert-butyl 4-(3-((4-((S)-2-(azetidin-l-yl)-l-(3-fluorophenyl)-l-
((1R, 2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)piperi din-1 - y l)methyl)azetidin- 1 -yl)-7-(((R)- 1 -(((E)-3-(methy lsulfonyl)allyl)carbamoy l)piperidin- 3-yl)sulfonyl)isoindoline-2-carboxylate (70 mg, 0.07 mmol) in DCM (3 ml) and TFA (1 ml) was stirred at room temperature for 3h. The reaction mixture was concentrated under reduced pressure and the crude was purified by RP-prep-HPLC to afford methyl (( 1 S,2R)-2-((S)-2-(azetidin- 1 -yl)- 1 -(3-fluoropheny 1)- 1 -( 1 -(( 1 -(7-(((R)- 1 -(((E)-3- (methylsulfonyl)allyl)carbamoyl)piperidin-3-yl)sulfonyl)isoindolin-4-yl)azeti din-3- yl)methyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate (Cpd 104) (20 mg, yield 31%) as
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
[00637] Step A: methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol- l-yl)-l-(l-((l-(2-oxo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-lH- benzo[d]imidazol-5-yl)azetidin-3-yl)methyl)piperidin-4- yl)ethyl)cyclopentyl)carbamate
[00638] A mixture of methyl ((1 S,2R)-2-((S)-l-(l-(azetidin-3-ylmethyl)piperidin-4-yl)- l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol-l-yl)ethyl)cyclopentyl)carbamate (80 mg, 0.16 mmol), 5-bromo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-l,3-dihydro-2H- benzo[d]imidazol-2-one (83 mg, 0.18 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), X-Phos (8 mg, 0.016 mmol) and CS2CO3 (157 mg, 0.48 mmol) in toluene (5 mL) was stirred at 100°C under N2 atmosphere for 16 hr. Then the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were washed with brine (10 mL), dried over Na2SO 4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol-l-yl)-l-(l-((l-(2-oxo- l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-lH-benzo[d]imidazol-5- yl)azetidin-3-yl)methyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate (40 mg, yield 28%) as yellow solid. LC-MS: 890 (M+H)+.
[00639] Step B: methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol-
1 -yl)- 1 — ( 1 — (( 1 -(2-oxo-2,3 -dihy dro- 1 H-benzo [d] imidazol-5 -y l)azetidin-3- yl)methyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate
[00640] A solution of methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH- imidazol-l-yl)-l-(l-((l-(2-oxo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2, 3-dihydro- lH-benzo[d]imidazol-5-yl)azetidin-3-yl)methyl)piperidin-4- yl)ethyl)cyclopentyl)carbamate (40 mg, 0.045 mmol) in TFA (2 mL) was stirred at 0°C for 0.5 hr, then concentrated under reduced pressure. To the residue, MeOH (2 mL) and NH3.H2O (1 mL) were added. The mixture was stirred at room temperature for 2 hrs. Then the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by RP-prep- HPLC to give Cpd 103 (10 mg, yield 36%) as a white solid. LC-MS: 630 (M+H)+. ¾ NMR (400 MHz, MeOD-L) d 7.50 - 7.33 (m, 3H), 7.14 - 7.05 (m, 1H), 6.86 (d, 1H), 6.70 (d, 1H), 6.66 (d, 1H), 6.25 - 6.16 (m, 2H), 4.54 (d, 1H), 4.34 (d, 1H), 4.10 - 3.90 (m, 3H), 3.61 (s, 3H), 3.39 (t, 2H), 2.99 - 2.80 (m, 3H), 2.65 - 2.51 (m, 3H), 2.44 (s, 3H), 2.25 - 2.17 (m, 1H), 2.04 - 1.90 (m, 3H), 1.89 - 1.80 (m, 1H), 1.72 - 1.59 (m, 1H), 1.55 - 1.43 (m, 1H), 1.42 - 1.15 (m, 5H), 0.83 - 0.70 (m, 1H).
EXAMPLE 18
[00641] Preparation of methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH- imidazol- 1 -yl)- 1 -( 1 -(( 1 -(2-oxo-2,3-dihy dro- lH-benzo[d] imidazol-4-y l)azeti din-3 - yl)methyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate (Cpd 127)
Figure imgf000172_0001
[00642] Step A: 4-bromo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-l,3-dihydro-2H- benzo[d]imidazol-2-one
[00643] A mixture of 4-bromo-l,3-dihydro-2H-benzo[d]imidazol-2-one (300 mg, 1.4 mmol) and NaH (60% in oil, 112 mg, 2.8 mmol) in DMF (5 mL) was stirred at 0°C for 1 hr. Then SEMCI (705 mg, 4.2 mmol) was added and the mixture was stirred at room temperature for 2 hr. The mixture was poured into sat. NH4CI aq. (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 4-bromo-l,3-bis((2- (trimethylsilyl)ethoxy)methyl)-l,3-dihydro-2H-benzo[d]imidazol-2-one (500 mg, yield 75%) as a white solid. LC-MS: 473 (M+H)+.
[00644] Step B: methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol- l-yl)-l-(l-((l-(2-oxo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-lH- benzo[d]imidazol-4-yl)azetidin-3-yl)methyl)piperidin-4- yl)ethyl)cyclopentyl)carbamate
[00645] A mixture of methyl ((1 S,2R)-2-((S)-l-(l-(azetidin-3-ylmethyl)piperidin-4-yl)- l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol-l-yl)ethyl)cyclopentyl)carbamate (67 mg, 0.13 mmol), 4-bromo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-l,3-dihydro-2H- benzo[d]imidazol-2-one (76 mg, 0.16 mmol), Pd2(dba)3 (12 mg, 0.013 mmol), BINAP (8 mg, 0.013 mmol) and t-BuONa (39 mg, 0.40 mmol) in toluene (3 mL) was stirred at 110°C under N2 atmosphere for 16 hr. Then the reaction solution was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel to give methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH- imidazol-l-yl)-l-(l-((l-(2-oxo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2, 3-dihydro- lH-benzo[d]imidazol-4-yl)azetidin-3-yl)methyl)piperidin-4- yl)ethyl)cyclopentyl)carbamate (30 mg, yield 26%) as a white solid. LC-MS: 890 (M+H)+.
[00646] Step C: methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol-
1 -yl)- 1 — ( 1 — (( 1 -(2-oxo-2,3 -dihy dro- 1 H-benzo [d] imidazol-4-y l)azetidin-3- yl)methyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate (Cpd 127)
[00647] A solution of methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH- imidazol-l-yl)-l-(l-((l-(2-oxo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2, 3-dihydro- lH-benzo[d]imidazol-4-yl)azetidin-3-yl)methyl)piperidin-4- yl)ethyl)cyclopentyl)carbamate (10 mg, 0.011 mmol) in TFA (2 mL) was stirred at 0°C for 0.5 hr, then concentrated under reduced pressure. To the residue, MeOH (2 mL) and NH3.H2O (1 mL) were added. The mixture was stirred at room temperature for 2 hr. Then the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by RP-prep- HPLC to give Cpd 127 (2 mg, yield 28%) as a white solid. LC-MS: 630 (M+H)+. ¾ NMR (400 MHz, MeOD-ώ) d 7.50 - 7.33 (m, 3H), 7.14 - 7.05 (m, 1H), 6.90 (t, 1H), 6.74 (s, 1H), 6.69 (s, 1H), 6.55 (d, 1H), 6.21 (d, 1H), 4.54 (d, 1H), 4.37 (d, 1H), 4.05 - 3.90 (m, 1H), 3.61 (s, 3H), 3.60 - 3.56 (m, 2H), 3.12 - 3.04 (m, 1H), 2.98 - 2.88 (m, 2H), 2.79 - 2.67 (m, 2H), 2.65 - 2.57 (m, 1H), 2.46 (s, 3H), 2.32 - 2.25 (m, 1H), 2.08 - 1.97 (m, 3H), 1.92 - 1.81 (m, 1H), 1.75 - 1.65 (m, 1H), 1.64 - 1.45 (m, 3H), 1.43 - 1.10 (m, 5H), 0.83 - 0.70 (m, 1H).
EXAMPLE 19
[00648] Preparation of methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH- imidazol- 1 -yl)- 1 -(1 -(4-(methylsulfonamidomethy l)phenethy l)piperidin-4- yl)ethyl)cyclopentyl)carbamate (Cpd 129)
Figure imgf000174_0001
[00649] Step A: 2-(4-(aminomethyl)phenyl)ethan-l-ol
[00650] To a solution of 4-(2-hydroxyethyl)benzonitrile (850 mg, 5.7 mmol) in MeOH (10 mL) was added 10% Pd/C (200 mg, wet) and cone. HC1 (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 10 h under EE atmosphere. The mixture was filtered and concentrated under reduced pressure to give 2-(4-(aminomethyl)phenyl)ethan-l-ol (550 mg, yield 63%) as a white solid. LC-MS: 152 (M+H)+. [00651] Step B: tert-butyl (4-(2-hydroxyethyl)benzyl)carbamate
[00652] To asolution of 2-(4-(aminomethyl)phenyl)ethan-l-ol (300 mg, 1.98 mmol, 1.0 eq.) in DCM (10 mL) was added B0C2O (648 mg, 2.97 mmol) and TEA (0.55 mL, 3.96 mmol) at room temperature. The reaction mixture was stirred at this temperature for 2h. The mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO 4 and concentrated under reduced pressure. The residue was purified by flash chromatography to give tert-butyl (4-(2-hydroxyethyl)benzyl)carbamate (400 mg, yield 80%) as a yellow solid. LC-MS: 252 (M+H)+.
[00653] Step C: 4-(((tert-butoxycarbonyl)amino)methyl)phenethyl methanesulfonate
[00654] To a solution of tert-butyl 4-(2-hydroxyethyl)benzylcarbamate (350 mg, 1.39 mmol) in DCM (10 mL) was added TEA (0.38 mL, 2.78 mmol) followed by MsCl (0.11 mL, 1.39 mmol) at 0 °C. The mixture was stirred at room temperature for lhr. The mixture was poured into water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO 4 and concentrated under reduced pressure. The residue was purified by flash chromatography to give 4-(((tert-butoxycarbonyl)amino)methyl)phenethyl methanesulfonate (220 mg, yield 66%) as a white solid. LC-MS: 330 (M+H)+.
[00655] Step D: methyl ((lS,2R)-2-((S)-l-(l-(4-(((tert- butoxycarbonyl)amino)methyl)phenethyl)piperidin-4-yl)-l-(3-fluorophenyl)-2-(2- methyl- lH-imidazol- 1 -yl)ethyl)cy clopentyl)carbamate [00656] To a solution of methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH- imidazol-l-yl)-l-(piperidin-4-yl)ethyl)cyclopentyl)carbamate (E5) (150 mg, 0.35 mmol) in MeCN (10 mL) was added 4-(((tert-butoxycarbonyl)amino)methyl)phenethyl methanesulfonate (115 mg, 0.35 mmol), K2CO3 (96 mg, 0.70 mmol) and KI (58 mg, 0.35 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 10 hr. The cooled mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO 4 and concentrated under reduced pressure. The residue was purified by flash chromatography to give methyl ((lS,2R)-2-((S)-l-(l-(4-(((tert- butoxycarbonyl)amino)methyl)phenethyl)piperidin-4-yl)-l-(3-fluorophenyl)-2-(2- methyl-lH-imidazol-l-yl)ethyl)cyclopentyl)carbamate (140 mg, yield 60%) as a brown solid. LC-MS: 662 (M+H)+. [00657] Step E: methyl ((lS,2R)-2-((S)-l-(l-(4-(aminomethyl)phenethyl)piperidin-4- yl)-l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol-l-yl)ethyl)cyclopentyl)carbamate
[00658] To a solution of methyl ((lS,2R)-2-((S)-l-(l-(4-(((tert- butoxycarbonyl)amino)methyl)phenethyl)piperidin-4-yl)-l-(3-fluorophenyl)-2-(2- methyl-lH-imidazol-l-yl)ethyl)cyclopentyl)carbamate (140 mg, 0.21 mmol) in DCM (6 mL) was added TFA (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hr. The mixture was concentrated under reduced pressure. Then the residue was diluted with sat. NaHCO3 aq. (30 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO 4 and concentrated under reduced pressure to give methyl ((lS,2R)-2-((S)-l-(l- (4-(aminomethyl)phenethyl)piperidin-4-yl)-l-(3-fluorophenyl)-2-(2-methyl-lH- imidazol-l-yl)ethyl)cyclopentyl)carbamate (110 mg, yield 93%) as a brown oil. LC- MS: 562 (M+H)+.
[00659] Step F: methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol- 1 -yl)- 1 -( 1 -(4-(methylsulfonamidomethyl)phenethyl)piperidin-4- yl)ethyl)cyclopentyl)carbamate (Cpd 129)
[00660] To a solution of methyl ((lS,2R)-2-((S)-l-(l-(4- (aminomethyl)phenethyl)piperidin-4-yl)-l-(3-fluorophenyl)-2-(2-methyl-lH- imidazol-l-yl)ethyl)cyclopentyl)carbamate (56 mg, 0.1 mmol) in DCM (5 mL) was added TEA (27 uL, 0.2 mmol), followed by MsCl (8 uL, 0.1 mmol) at 0 °C, and the mixture was stirred at this temperature for 1 hr. The mixture was poured into water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO 4 and concentrated under reduced pressure. The residue was purified by prep-TLC and RP-prep-HPLC to give Cpd 129 (8 mg, yield 12%) as a white solid. LC-MS: 640 (M+H)+. ¾ NMR (400 MHz, DMSO- de) d 7.49 - 7.36 (m, 4H), 7.25 - 7.19 (m, 2H), 7.18 - 7.10 (m, 3H), 6.64 (s, 1H), 6.54 (s, 1H), 4.46 (d, 1H), 4.25 (d, 1H), 4.09 (s, 2H), 3.85 - 3.75 (m, 1H), 3.49 (s, 3H), 3.46 - 3.43 (m, 1H), 2.94 - 2.83 (m, 1H), 2.82 (s, 3H), 2.81 - 2.73 (m, 1H), 2.68 - 2.56 (m, 3H), 2.42 - 2.28 (m, 2H), 2.34 (s, 3H), 2.20 - 1.95 (m, 1H), 1.90 - 1.83 (m, 1H), 1.75 (t, 3H), 1.50 - 1.35 (m, 2H), 1.30 - 0.95 (m, 4H), 1.18 - 1.07 (m, 1H), 0.60 - 0.42 (m, 1H).
EXAMPLE 20
[00661] Preparation of methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH- imidazol-l-yl)-l-(l-(2-(2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)ethyl)piperidin- 4-yl)ethyl)cyclopentyl)carbamate (Cpd 132)
Figure imgf000177_0001
[00662] Step A: 5-allyl-l, 3-bis((2-(trimethylsilyl)ethoxy)methyl)-l,3-dihydro-2H- benzo[d]imidazol-2-one
[00663] A mixture of 5-bromo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-l,3-dihydro-
2H-benzo[d]imidazol-2-one (300 mg, 0.63 mmol, 1.0 eq.), 2-allyl-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (160 mg, 0.95 mmol), Pd(dppl)Cl2 (46 mg, 0.063 mmol), K3PO4 (400 mg, 1.89 mmol), and H2O (1 mL) in 1,4-dioxane (5 mL) was stirred at 80 °C under N2 atmosphere for 16 h. Then the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried overNa2SO 4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to give 5-allyl-l ,3-bis((2- (trimethylsilyl)ethoxy)methyl)-l,3-dihydro-2H-benzo[d]imidazol-2-one (255 mg, yield 93%) as a white solid. LC-MS: 435 (M+H)+.
[00664] Step B: 2-(2-oxo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-lH- benzo[d]imidazol-5-yl)acetaldehyde
[00665] To a solution of 5-allyl-l, 3-bis((2-(trimethylsilyl)ethoxy)methyl)-l,3-dihydro-
2H-benzo[d]imidazol-2-one (250 mg, 0.58 mmol), K2OsO4 (10 mg, cat.), and H2O (1 mL) in THF (5 mL) was added NalCri (370 mg, 1.73 mmol) at 0 °C, and the mixture was stirred at this temperature for 30 min. Then the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO 4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to give 2-(2- oxo-1, 3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-lH-benzo[d]imidazol-5- yl)acetaldehyde (140 mg, yield 55%) as a white solid. LC-MS: 437 (M+H)+.
[00666] Step C: methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol- l-yl)-l-(l-(2-(2-oxo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-lH- benzo[d]imidazol-5-yl)ethyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate
[00667] A mixture of 2-(2-oxo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro- lH-benzo[d]imidazol-5-yl)acetaldehyde (60 mg, 0.141 mmol), methyl ((lS,2R)-2-((S)- l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol-l-yl)-l-(piperidin-4- yl)ethyl)cyclopentyl)carbamate (E5) (73 mg, 0.168 mmol) and AcOH (8 mg, 0.141 mmol) in DCM (10 mL) was stirred at room temperature for 1 hr. Then NaBH(OAc)3 (59 mg, 0.282 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with H2O (10 mL), adjusted to pH ~ 7 with sat. NaHCO3 aq. and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO 4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to give methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol-l-yl)-l-(l- (2-(2-oxo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-lH- benzo[d]imidazol-5-yl)ethyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate (40 mg, yield 33%) as a yellow solid. LC-MS: 849 (M+H)+.
[00668] Step D: methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol- l-yl)-l-(l-(2-(2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)ethyl)piperidin-4- yl)ethyl)cyclopentyl)carbamate (Cpd 132)
[00669] To a solution of methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH- imidazol-l-yl)-l-(l-(2-(2-oxo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2, 3-dihydro- lH-benzo[d]imidazol-5-yl)ethyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate (40 mg, 0.047 mmol) in DCM (6 mL) was added TFA (2 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 3 hr. The mixture was concentrated under reduced pressure. The
Figure imgf000178_0001
6.68 (d, 1H), 4.56 (d, 1H), 4.36 (d, 1H), 4.05 - 3.95 (m, 1H), 3.60 (s, 3H), 3.20 - 3.11 (m, 1H), 3.10 - 3.02 (m, 1H), 2.85 - 2.72 (m, 2H), 2.70 - 2.55 (m, 3H), 2.45 (s, 3H), 2.35 - 1.99 (m, 4H), 1.93 - 1.82 (m, 1H), 1.78 - 1.67 (m, 1H), 1.57 - 1.45 (m, 1H), 1.42 - 1.10 (m, 5H), 0.87 - 0.72 (m, 1H).
EXAMPLE 21
[00670] Preparation of methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH- imidazol-l-yl)-l-(l-(((lr,3S)-3-((2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5- yl)oxy)cyclobutyl)methyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate (Cpd 136)
Figure imgf000179_0001
[00671] Step A: 5-bromo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-l,3-dihydro-2H- benzo[d]imidazol-2-one [00672] To a solution of 5-bromo-l,3-dihydro-2H-benzo[d]imidazol-2-one (4 g, 18.8 mmol) in DMF (40 mL) was added NaH (1.9 g, 46.9 mmol, 60% wt/wt in oil) at 0 C and the mixture was stirred at this temperature for 10 min. A solution of (2- (chloromethoxy)ethyl)trimethylsilane (7.2 g, 43.2 mmol) in THF (10 mL) was added to the reaction at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The mixture was poured into sat. NFLCl aq. (50 mL) and extracted with EtOAc (80 mL x 2). The combined organic layers were washed with water, brine (50 mL), dried over Na2SO 4 and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography to give 5-bromo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)- l,3-dihydro-2H-benzo[d]imidazol-2-one (5.3 g, yield 59%) as a white solid. LC-MS: 473, 475 (M+H)+.
[00673] Step B : 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3-bis((2-
(trimethylsilyl)ethoxy)methyl)-l,3-dihydro-2H-benzo[d]imidazol-2-one
[00674] To a solution of 5-bromo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-l,3- dihydro-2H-benzo[d]imidazol-2-one (2 g, 4.2 mmol) and 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane) (1.6 g, 6.3 mmol) in 1,4-dioxane (25 mL) was added Pd(dppl)Cl2 (310 mg, 0.42 mmol) and AcOK (1.2 g, 12.7 mmol) at room temperature. The mixture was stirred at 100 °C under N2 atmosphere for 18 hr. The mixture was filtered and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography to give 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3- bis((2-(trimethylsilyl)ethoxy)methyl)-l,3-dihydro-2H-benzo[d]imidazol-2-one (2 g, yield 91%) as a yellow oil. LC-MS: 521 (M+H)+.
[00675] Step C: 5-hydroxy-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazol-2(3H)-one
[00676] To a solution of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3-bis((2-
(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-2(3H)-one (1 g, 1.9 mmol, 1.0 eq.) and NaOH (1 M in FLO, 1.9 mL, 1.9 mmol, 1.0 eq.) in THF (15 mL) was added H2O2 (330 mg, 2.9 mmol, 30% wt/wt in H2O) at 0 °C. The reaction mixture was stirred at room temperature for 30 min. The mixture was adjusted to pH ~ 7 with 1 N HC1 aq. and extracted with EtOAc (60 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2S04 and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography to give 5-hydroxy-l,3-bis((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-2(3H)-one (680 mg, yield 86%) as a white solid. LC-MS: 411 (M+H)+.
[00677] Step D: methyl (lr,3r)-3-((2-oxo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3- dihydro-lH-benzo[d]imidazol-5-yl)oxy)cyclobutane-l-carboxylate & methyl (ls,3s)- 3-((2-oxo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-lH- benzo[d]imidazol-5-yl)oxy)cyclobutane-l-carboxylate
[00678] A 25 mL microwave vial was charged with a magnetic stirrer bar, 5-hydroxy-
1.3-bis((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-2(3H)-one (800 mg, 1.9 mmol), methyl (ls,3s)-3-((methylsulfonyl)oxy)cyclobutane-l-carboxylate (527 mg, 2.5 mmol; Ref: WO2018/69863, 2018, Al), CS2CO3 (1.9 g, 5.8 mmol), KI (323 mg, 1.9 mmol) and DMSO (15 mL). Then the reaction was irradiated at 100 °C for 50 min. The mixture was poured into water (30 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2S04 and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography to give methyl (lr,3r)-methyl 3-(2-oxo-l,3-bis((2- (trimethylsilyl)ethoxy)methyl)-2,3-dihydro-lH-benzo[d]imidazol-5- yloxy)cyclobutanecarboxylate (130 mg, yield 13%) as a yellow oil, LC-MS: 523(M+H)+; and (ls,3s)-methyl 3-(2-oxo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-
2.3-dihydro-lH-benzo[d]imidazol-5-yloxy)cyclobutanecarboxylate (125 mg, yield 13%) as a yellow oil, LC-MS: 523(M+H)+.
[00679] Step E: 5-((lr,3r)-3-(hydroxymethyl)cyclobutoxy)-l,3-bis((2-
(trimethylsilyl)ethoxy)methyl)-l,3-dihydro-2H-benzo[d]imidazol-2-one
[00680] To a solution of methyl (lr,3r)-3-((2-oxo-l,3-bis((2- (trimethylsilyl)ethoxy)methyl)-2,3-dihydro-lH-benzo[d]imidazol-5- yl)oxy)cyclobutane-l-carboxylate (120 mg, 0.23 mmol) in THF (5 mL) was added L1AIH4 (1 M in THF, 0.34 mL, 0.34 mmol) at - 40 °C. The mixture was stirred at this temperature for 30 min and quenched withNa2SO4.10H2O (1 g). Then EtOAc (50 mL) was added to the mixture and filtered. The filtrate was dried over Na2S04 and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography to give 5-((lr,3r)-3-(hydroxymethyl)cyclobutoxy)-l,3-bis((2- (trimethylsilyl)ethoxy)methyl)-l,3-dihydro-2H-benzo[d]imidazol-2-one (100 mg, yield 88%) as a yellow oil. LC-MS: 495(M+H)+.
[00681] Step F: ((lr,3r)-3-((2-oxo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3- dihydro-lH-benzo[d]imidazol-5-yl)oxy)cyclobutyl)methyl methanesulfonate [00682] To a solution of 5-((lr,3r)-3-(hydroxymethyl)cyclobutoxy)-l,3-bis((2-
(trimethylsilyl)ethoxy)methyl)-l,3-dihydro-2H-benzo[d]imidazol-2-one (100 mg, 0.20 mmol) and TEA (0.04 mL, 0.30 mmol) in DCM (3 mL) was added MsCl (0.02 mL, 0.22 mmol) at 0 °C. The mixture was stirred at room temperature for 1.5 hr. The mixture was poured into the water (20 mL) and extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO 4 and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography to give ((lr,3r)-3-((2-oxo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-lH- benzo[d]imidazol-5-yl)oxy)cyclobutyl)methyl methanesulfonate (90 mg, yield 65%) as a yellow oil. LC-MS: 573(M+H)+.
[00683] Step G: methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol-
1-yl)-l-(l-(((lr,3S)-3-((2-oxo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2, 3-dihydro- lH-benzo[d]imidazol-5-yl)oxy)cyclobutyl)methyl)piperidin-4- yl)ethyl)cyclopentyl)carbamate
[00684] To a solution of methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH- imidazol-l-yl)-l-(piperidin-4-yl)ethyl)cyclopentyl)carbamate (E5) (70 mg, 0.18 mmol) and ((lr,3r)-3-((2-oxo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-lH- benzo[d]imidazol-5-yl)oxy)cyclobutyl)methyl methanesulfonate (90 mg, 0.18 mmol) in MeCN (5 mL) was added K2CO3 (52 mg, 0.37 mmol) and KI (62 mg, 0.37 mmol) at room temperature. The mixture was stirred at 80 °C for 18 h. The mixture was cooled and filtered. The filtrate was concentrated under reduced pressure to dryness. The residue was purified by prep-TLC to give methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-
2-(2-methyl-lH-imidazol-l-yl)-l-(l-(((lr,3S)-3-((2-oxo-l,3-bis((2- (trimethylsilyl)ethoxy)methyl)-2,3-dihydro-lH-benzo[d]imidazol-5- yl)oxy)cyclobutyl)methyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate (40 mg, yield 24%) as a yellow solid. LC-MS: 905 (M+H)+.
[00685] Step H: methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol- l-yl)-l-(l-(((lr,3S)-3-((2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5- yl)oxy)cyclobutyl)methyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate (Cpd 136)
[00686] To a solution of methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH- imidazol-l-yl)-l-(l-(((lr,3S)-3-((2-oxo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3- dihydro-lH-benzo[d]imidazol-5-yl)oxy)cyclobutyl)methyl)piperidin-4- yl)ethyl)cyclopentyl)carbamate (40 mg, 0.044 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The mixture was stirred at this temperature for 1.5 hr and concentrated under reduced pressure to dryness. The residue was dissolved in MeOH (2 mL) and added NH4OH (28% in H2O, 2 mL) at room temperature. The mixture was stirred at this temperature for 1.5h. The mixture was concentrated under reduced pressure to dryness. The residue was purified by RP-prep-HPLC to give Cpd 136 (4.3 mg, yield 15%) as a white solid. LC-MS: 645 (M+H)+. ¾ NMR (400 MHz, MeOD- d4) d 7.49 - 7.40 (m, 2H), 7.39 - 7.31 (m, 1H), 7.13 - 7.05 (m, 1H), 6.88 (dd, 1H), 6.70 (d, 1H), 6.65 (d, 1H), 6.54 - 6.47 (m, 2H), 4.71 - 4.65 (m, 1H), 4.53 (d, 1H), 4.33 (d, 1H), 4.05 - 3.96 (m, 1H), 3.60 (s, 3H), 3.02 - 2.93 (m, 1H), 2.90 - 2.81 (m, 1H), 2.65 - 2.55 (m, 2H), 2.53 - 2.47 (m, 2H), 2.43 (s, 3H), 2.30 - 2.13 (m, 4H), 2.05 - 1.94 (m, 4H), 1.91 - 1.81 (m, 1H), 1.71 - 1.60 (m, 1H), 1.55 - 1.42 (m, 1H), 1.40 - 1.10 (m, 5H), 0.85 - 0.70 (m, 1H).
EXAMPLE 22
[00687] Preparation of methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH- imidazol- 1 -yl)- 1 -(1 -((( 1 s,3R)-3 -((2-oxo-2, 3 -dihydro- 1 H-benzo [d] imidazol-5 - yl)oxy)cyclobutyl)methyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate (Cpd 137)
Figure imgf000183_0001
[00688] Step A: 5-((ls,3s)-3-(hydroxymethyl)cyclobutoxy)-l,3-bis((2-
(trimethylsilyl)ethoxy)methyl)-l,3-dihydro-2H-benzo[d]imidazol-2-one [00689] To a solution of methyl (ls,3s)-3-((2-oxo-l,3-bis((2- (trimethylsilyl)ethoxy)methyl)-2,3-dihydro-lH-benzo[d]imidazol-5- yl)oxy)cyclobutane-l-carboxylate (120 mg, 0.23 mmol) prepared as set forth in Example 21 in THF (5 mL) was added LiAlFL (1 M in THF, 0.34 mL, 0.34 mmol) at - 40 °C. The mixture was stirred at this temperature for 30 min and quenched with Na2SO4.10H2O (1 g). Then EtOAc (50 mL) was added to the mixture and filtered. The filtrate was dried over Na2SO 4 and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography to give 5-((ls,3s)-3- (hydroxymethyl)cyclobutoxy)-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-l, 3-dihydro- 2H-benzo[d]imidazol-2-one (105 mg, yield 88%) as ayellow oil. LC-MS: 495(M+H)+.
[00690] Step B: ((ls,3s)-3-((2-oxo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3- dihydro-lH-benzo[d]imidazol-5-yl)oxy)cyclobutyl)methyl methanesulfonate
[00691] To a solution of 5-((ls,3s)-3-(hydroxymethyl)cyclobutoxy)-l,3-bis((2-
(trimethylsilyl)ethoxy)methyl)-l,3-dihydro-2H-benzo[d]imidazol-2-one (100 mg, 0.20 mmol) and TEA (0.04 mL, 0.30 mmol) in DCM (3 mL) was added MsCl (0.02 mL, 0.22 mmol) at 0 °C. The mixture was stirred at room temperature for 1.5 hr. The mixture was poured into the water (20 mL) and extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2S04 and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography to give ((ls,3s)-3-((2-oxo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-lH- benzo[d]imidazol-5-yl)oxy)cyclobutyl)methyl methanesulfonate (93 mg, yield 65%) as ayellow oil. LC-MS: 573(M+H)+.
[00692] Step C: methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol-
1-yl)-l-(l-(((ls,3R)-3-((2-oxo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2, 3-dihydro- lH-benzo[d]imidazol-5-yl)oxy)cyclobutyl)methyl)piperidin-4- yl)ethyl)cyclopentyl)carbamate
[00693] To a mixture of methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH- imidazol-l-yl)-l-(piperidin-4-yl)ethyl)cyclopentyl)carbamate (E5) (70 mg, 0.18 mmol) and ((ls,3s)-3-((2-oxo-l,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-lH- benzo[d]imidazol-5-yl)oxy)cyclobutyl)methyl methanesulfonate (93 mg, 0.18 mmol) in MeCN (5 mL) and K2CO3 (52 mg, 0.37 mmol) was added KI (62 mg, 0.37 mmol) at room temperature. The mixture was stirred at 80 °C for 18 hr. The mixture was cooled and filtered. The filtrate was concentrated under reduced pressure to dryness. The residue was purified by prep-TLC to give methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-
2-(2-methyl-lH-imidazol-l-yl)-l-(l-(((ls,3R)-3-((2-oxo-l,3-bis((2- (trimethylsilyl)ethoxy)methyl)-2,3-dihydro-lH-benzo[d]imidazol-5-
Figure imgf000185_0001
Figure imgf000186_0001
[00697] Step A: 5-bromo-2-(methylsulfonyl)isoindoline
[00698] To a mixture of 5-bromoisoindoline hydrochloride (500 mg, 2.13 mmol) in DCM (10 mL) was added TEA (1.18 mL, 8.52 mmol) and MsCl (0.18 mL, 2.35 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 hr. Then the mixture was diluted with H2O (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 5-bromo-2-(methylsulfonyl)isoindoline (560 mg, yield 95%) as a white solid. LC-MS: 276, 278 (M+H)+.
[00699] Step B: (E)-5-(2-ethoxyvinyl)-2-(methylsulfonyl)isoindoline
[00700] A mixture of 5-bromo-2-(methylsulfonyl)isoindoline (300 mg, 1.08 mmol), (E)- 2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (258 mg, 1.31 mmol), Pd(dppf)Cl2 (79 mg, 0.11 mmol) andNa2CC>3 (345 mg, 3.25 mmol) in dioxane (10 mL) and H2O (1 mL) was stirred at 90 °C under N2 atmosphere for 3 hr. Then the mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give (E)-5 -(2-ethoxy vinyl)-2-(methylsulfonyl)isoindoline (240 mg, yield 82%) as a white solid. LC-MS: 268 (M+H)+.
[00701] Step C: 2-(2-(methylsulfonyl)isoindolin-5-yl)acetaldehyde
[00702] A mixture of (E)-5 -(2-ethoxy vinyl)-2-(methylsulfonyl)isoindoline (200 mg, 0.74 mmol) and IN HC1 aq. (2 mL) in THF (2 mL) was stirred at 60 °C for 1 hr. Then the reaction mixture was adjusted to pH ~ 7 with sat. NaHCCh aq. and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO 4 and concentrated under reduced pressure to give 2-(2- (methylsulfonyl)isoindolin-5-yl)acetaldehyde (100 mg, crude) as a yellow solid. LC- MS: 240 (M+H)+.
[00703] Step D: methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol- l-yl)-l-(l-(2-(2-(methylsulfonyl)isoindolin-5-yl)ethyl)piperidin-4- yl)ethyl)cyclopentyl)carbamate (Cpd 134)
[00704] A mixture of methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH- imidazol-l-yl)-l-(piperidin-4-yl)ethyl)cyclopentyl)carbamate (70 mg, 0.16 mmol), 2- (2-(methylsulfonyl)isoindolin-5-yl)acetaldehyde (97 mg, 0.32 mmol) and AcOH (20 mg, 0.32 mmol) in DCM (10 mL) was stirred at room temperature for 1 hr. Then NaBH(OAc)3 (69 mg, 0.32 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hr. The mixture was diluted with LhO (10 mL), adjusted to pH ~ 7 with sat. NaHCCh aq. and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO 4 and concentrated under reduced pressure. The residue was purified by prep-TLC and RP-prep-HPLC to give Cpd 134 (7 mg, yield 6%) as a white solid. LC-MS: 652 (M+H)+. ¾ NMR (400 MHz, MeOD-ώ) d 7.49 - 7.43 (m, 2H), 7.39 - 7.32 (m, 1H), 7.20 (d, 1H), 7.14 - 7.06 (m, 3H), 6.70 (d, 1H), 6.66 (d, 1H), 4.63 (s, 4H), 4.54 (d, 1H), 4.35 (d, 1H), 4.07 - 3.96 (m, 1H), 3.60 (s, 3H), 3.09 - 3.01 (m, 1H), 2.99 - 2.93 (m, 1H), 2.90 (s, 3H), 2.78 - 2.68 (m, 2H), 2.66 - 2.56 (m, 1H), 2.54 - 2.43 (m, 2H), 2.44 (s, 3H), 2.27 - 2.16 (m, 1H), 2.09 - 1.98 (m, 3H), 1.93 - 1.82 (m, 1H), 1.75 - 1.63 (m, 1H), 1.56 - 1.43 (m, 1H), 1.42 - 1.10 (m, 5H), 0.85 - 0.70 (m, 1H).
EXAMPLE 24
[00705] Preparation of methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-l-(l-(2-(2-methyl- l,l-dioxido-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yl)ethyl)piperidin-4-yl)-2-(2- methyl-lH-imidazol-l-yl)ethyl)cyclopentyl)carbamate (Cpd 128)
Figure imgf000188_0001
[00706] Step A: 6-bromo-2-methylbenzo[d]isothiazol-3(2H)-one 1,1-dioxide
[00707] A mixture of 6-bromobenzo[d]isothiazol-3(2H)-one 1,1-dioxide (500 mg, 1.91 mmol) and K2CO3 (132 mg, 0.96 mmol) in 10 mL of H2O was stirred at room temperature for 15 min, and then concentrated under reduced pressure. To the residue in DMF (10 mL) was added CH3I (0.12 mL, 1.91 mmol) at room temperature, and then the mixture was stirred at 90 °C for 16 hr. Then the mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 6-bromo-2- methylbenzo[d]isothiazol-3(2H)-one 1,1-dioxide (380 mg, yield 72%) as a white solid. LC-MS: 276, 278 (M+H)+.
[00708] Steps B-D were completed following the procedures for Steps B-D described in Example 23 to afford methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-l-(l-(2-(2-methyl- l,l-dioxido-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yl)ethyl)piperidin-4-yl)-2-(2- methyl-lH-imidazol-l-yl)ethyl)cyclopentyl)carbamate (Cpd 128) as a white solid. LC- MS: 652 (M+H)+. ¾ NMR (400 MHz, MeOD-ώ) d 8.01 - 7.95 (m, 2H), 7.76 (d, 1H), 7.50 - 7.36 (m, 3H), 7.14 - 7.05 (m, 1H), 6.79 (s, 1H), 6.72 (s, 1H), 4.59 (d, 1H), 4.38 (d, 1H), 4.08 - 3.98 (m, 1H), 3.61 (s, 3H), 3.19 (s, 3H), 3.15 - 3.00 (m, 4H), 2.85 - 2.71 (m, 2H), 2.68 - 2.56 (m, 1H), 2.48 (s, 3H), 2.39 - 2.18 (m, 3H), 2.15 - 2.03 (m, 1H), 1.94 - 1.83 (m, 1H), 1.80 - 1.70 (m, 1H), 1.57 - 1.45 (m, 1H), 1.40 - 1.15 (m, 5H), 0.85 - 0.72 (m, 1H).
EXAMPLE 25
[00709] Preparation of methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH- imidazol- 1 -yl)- 1 -( 1 -(4-(2-(methylsulfonamido)ethyl)phenethyl)piperidin-4- yl)ethyl)cyclopentyl)carbamate (Cpd 130)
Figure imgf000189_0001
[00710] Step A: N-(4-bromophenethyl)methanesulfonamide
[00711] To a mixture of 2-(4-bromophenyl)ethan-l -amine hydrochloride (822 mg, 3.5 mmol) in DCM (8 mL) was added TEA (1.9 mL, 14.0 mmol) and MsCI (0.3 mL, 3.85 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1.5 hr. Then the mixture was diluted with H2O (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give N-(4-bromophenethyl)methanesulfonamide (570 mg, yield 59%) as a yellow solid. LC-MS: 278, 280 (M+H)+. [00712] Steps B-D were completed following the procedures for Steps B-D described in Example 23 to afford methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH- imidazol- 1 -yl)- 1 -( 1 -(4-(2-(methy lsulfonamido)ethy l)phenethy l)piperidin-4- yl)ethyl)cyclopentyl)carbamate (Cpd 130) as a white solid. LC-MS: 654 (M+H)+. 'H NMR (400 MHz, MeOD-ώ) d 7.49 - 7.37 (m, 3H), 7.20 - 7.12 (m, 5H), 6.73 (d, 1H), 6.69 (d, 1H), 4.57 (d, 1H), 4.38 (d, 1H), 4.08 - 3.98 (m, 1H), 3.61 (s, 3H), 3.27 (t, 2H), 3.18 - 3.10 (m, 1H), 3.07 - 2.98 (m, 1H), 2.84 - 2.78 (m, 5H), 2.77 - 2.71 (m, 2H), 2.69 - 2.61 (m, 1H), 2.60 - 2.51 (m, 2H), 2.47 (s, 3H), 2.33 - 2.23 (m, 1H), 2.17 - 2.00 (m, 3H), 1.95 - 1.85 (m, 1H), 1.77 - 1.65 (m, 1H), 1.56 - 1.47 (m, 1H), 1.45 - 1.15 (m, 5H), 0.87 - 0.72 (m, 1H).
EXAMPLE 26
[00713] Preparation of methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH- imidazol- 1 -yl)- 1 -(1 -(4-( 1 -(methy lsulfony l)azetidin-3-y l)phenethy l)piperidin-4- yl)ethyl)cyclopentyl)carbamate (Cpd 131)
Figure imgf000190_0001
[00714] Step A: 3-(4-bromophenyl)-l-(methylsulfonyl)azetidine [00715] To a mixture of 3-(4-bromophenyl)azetidine (170 mg, 0.81 mmol) in DCM (5 mL) was added TEA (0.22 mL, 1.61 mmol) and MsCI (0.08 mL, 0.97 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 hr. Then the mixture was diluted with TkO (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 3-(4-bromophenyl)-l-(methylsulfonyl)azetidine (200 mg, yield 86%) as a yellow oil. LC-MS: 290, 292 (M+H)+.
[00716] Steps B-D were completed following the procedures for Steps B-D described in Example 23 to afford methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-2-(2-methyl-lH- imidazol- 1 -yl)- 1 -(1 -(4-( 1 -(methy lsulfony l)azetidin-3-y l)phenethy l)piperidin-4- yl)ethyl)cyclopentyl)carbamate (Cpd 131) as a white solid. LC-MS: 666 (M+H)+. ¾ NMR (400 MHz, MeOD-ώ) d 7.40 - 7.31 (m, 2H), 7.30 - 7.25 (m, 1H), 7.20 (d, 2H), 7.09 (d, 2H), 7.04 - 6.95 (m, 1H), 6.62 (d, 1H), 6.58 (d, 1H), 4.45 (d, 1H), 4.26 (d, 1H), 4.15 (t, 2H), 3.98 - 3.88 (m, 1H), 3.86 (t, 2H), 3.79 - 3.67 (m, 1H), 3.50 (s, 3H), 3.08 - 3.00 (m, 2H), 2.99 - 2.90 (m, 1H), 2.88 (s, 3H), 2.70 - 2.62 (m, 2H), 2.59 - 2.43 (m, 3H), 2.35 (s, 3H), 2.22 - 2.12 (m, 1H), 2.10 - 1.92 (m, 3H), 1.85 - 1.74 (m, 1H), 1.66 - 1.57 (m, 1H), 1.45 - 1.33 (m, 1H), 1.31 - 1.00 (m, 4H), 0.78 - 0.67 (m, 1H).
EXAMPLE 27
[00717] Preparation of methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-l-(l-(2-(2-methyl- l,l-dioxido-3-oxo-2,3-dihydrobenzo[d]isothiazol-5-yl)ethyl)piperidin-4-yl)-2-(2- methyl-lH-imidazol-l-yl)ethyl)cyclopentyl)carbamate (Cpd 133)
Figure imgf000192_0001
[00718] Step A: 5-bromo-2-methylbenzo[d]isothiazol-3(2H)-one 1,1-dioxide
[00719] A mixture of 5-bromobenzo[d]isothiazol-3(2H)-one 1,1-dioxide (1.38 g, 5.27 mmol) andK2C03 (0.36 g, 2.64 mmol) in lOmLofH2O was stirred at room temperature for 15 min, and then concentrated under reduced pressure. To the residue in DMF (15 mL) was added CH3l (0.33 mL, 5.27 mmol) at room temperature, and then the mixture was stirred at 90 °C for 16 hr. Then the mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 5-bromo-2- methylbenzo[d]isothiazol-3(2H)-one 1,1-dioxide (1.1 g, yield 76%) as a white solid. LC-MS: 276, 278 (M+H)+.
[00720] Steps B-D were completed following the procedures for Steps B-D described in Example 23 to afford methyl ((lS,2R)-2-((S)-l-(3-fluorophenyl)-l-(l-(2-(2-methyl- l,l-dioxido-3-oxo-2,3-dihydrobenzo[d]isothiazol-5-yl)ethyl)piperidin-4-yl)-2-(2- methyl-lH-imidazol-l-yl)ethyl)cyclopentyl)carbamate (Cpd 133) as a white solid. LC- MS: 652 (M+H)+. ¾ NMR (400 MHz, MeOD-d4) d 7.96 (d, 1H), 7.91 (d, 1H), 7.79 (dd, 1H), 7.48 - 7.33 (m, 3H), 7.11 - 7.06 (m, 1H), 6.71 (d, 1H), 6.68 (d, 1H), 4.54 (d, 1H), 4.36 (d, 1H), 4.07 - 3.96 (m, 1H), 3.60 (s, 3H), 3.30 (s, 3H), 3.12 - 3.02 (m, 1H), 3.01 - 2.91 (m, 3H), 2.68 - 2.57 (m, 3H), 2.43 (s, 3H), 2.30 - 2.18 (m, 1H), 2.15 - 1.94 (m, 3H), 1.93 - 1.82 (m, 1H), 1.75 - 1.63 (m, 1H), 1.56 - 1.43 (m, 1H), 1.42 - 1.10 (m, 5H), 0.85 - 0.70 (m, 1H).
EXAMPLE 28
[00721] Preparation of methyl ((lS,2R)-2-((S)-l-(l-(2-(2-cyano-l,4-dimethyl-lH- indol-5-yl)ethyl)piperidin-4-yl)-l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol-l- yl)ethyl)cyclopentyl)carbamate (Cpd 135)
Figure imgf000193_0001
[00722] Step A: 5-bromo-l,4-dimethyl-lH-indole-2-carbonitrile [00723] Amixture of 5-bromo-4-methyl-lH-indole-2-carbonitrile (250 mg, 1.07 mmol), CS2CO3 (1.04 g, 3.2 mmol) and Mel (0.13 mL, 2.14 mmol) in 10 mL of DMF was stirred at room temperature for 2 hr. Then the mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 5-bromo- l,4-dimethyl-lH-indole-2-carbonitrile (260 mg, yield 98%) as a white solid. LC-MS: 249, 251 (M+H)+.
[00724] Step B: (E)-5-(2-ethoxy vinyl)- 1, 4-dimethyl- lH-indole-2-carbonitrile
[00725] (E)-5-(2-ethoxyvinyl)-l,4-dimethyl-lH-indole-2-carbonitrile was synthesized from 5-bromo-l,4-dimethyl-lH-indole-2-carbonitrile according to the procedure set forth in Step B in Example 23 to afford a white solid (210 mg, yield 84 %). LC-MS: 241 (M+H)+.
[00726] Step C: l,4-dimethyl-5-(2-oxoethyl)-lH-indole-2-carbonitrile [00727] A mixture of (E)-5-(2-ethoxyvinyl)-l,4-dimethyl-lH-indole-2-carbonitrile (210 mg, 0.87 mmol) and TFA (3 mL) in DCM (9 mL) was stirred at room temperature for 2 h. Then the mixture was diluted with H2O (20 mL), adjusted to pH ~ 7 with sat. NaHCCh aq. and extracted with DCM (15 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give l,4-dimethyl-5-(2-oxoethyl)-lH-indole-2-carbonitrile (80 mg, yield 43%) as a light yellow solid. LC-MS: 213 (M+H)+.
[00728] Step D was completed in accordance to the procedure for Step D described in Example 23 to afford methyl ((lS,2R)-2-((S)-l-(l-(2-(2-cyano-l,4-dimethyl-lH-indol- 5-yl)ethyl)piperidin-4-yl)-l-(3-fluorophenyl)-2-(2-methyl-lH-imidazol-l- yl)ethyl)cyclopentyl)carbamate (Cpd 135) as a white solid. LC-MS: 625 (M+H)+. ¾ NMR (400 MHz, MeOD-L) d 7.50 - 7.35 (m, 3H), 7.25 (s, 1H), 7.24 (d, 1H), 7.18 (d, 1H), 7.14 - 7.06 (m, 1H), 6.70 (d, 1H), 6.66 (d, 1H), 4.56 (d, 1H), 4.35 (d, 1H), 4.04 - 3.96 (m, 1H), 3.86 (s, 3H), 3.60 (s, 3H), 3.17 - 3.06 (m, 1H), 3.05 - 2.96 (m, 1H), 2.90 - 2.80 (m, 2H), 2.68 - 2.57 (m, 1H), 2.50 - 2.39 (m, 2H), 2.46 (s, 6H), 2.25 - 2.10 (m, 1H), 2.00 - 1.95 (m, 3H), 1.93 - 1.81 (m, 1H), 1.75 - 1.63 (m, 1H), 1.56 - 1.43 (m, 1H), 1.42 - 1.10 (m, 5H), 0.85 - 0.70 (m, 1H).
EXAMPLE 29
Synthesis and Characterization of Compounds of the Disclosure
[00729] Other Compounds of the Disclosure can be prepared using methods described in preceding Schemes and in the preceding EXAMPLES and related methods, see, e.g.. WO 2017/192543, WO 2018/183857, WO 2019/191526, WO 2020/072391, and PCT/US2020/053186. The LCMS (ESI) data for representative Compounds of the Disclosure prepared by these methods are provided in Tables 1, 1A, IB, and 1C.
[00730] 'H NMR data for additional Compounds of the Disclosure is provided in Table 4.
Table 4
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
EXAMPLE 30
Menin Binding Affinity
[00731] Binding Assay 1
[00732] A fluorescence polarization (FP) competitive binding assay was used to determine the binding affinities of representative Compounds of the Disclosure. A FAM labeled fluorescent probe was designed and synthesized based on a MLL1 peptide (FAM-MM2). Equilibrium dissociation constant (Kt/) 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 mΐ in the assay buffer (PBS with 0.02% Bovine g-Globulin and 4% DMSO. 0.01% Triton X-100 was added right before assays). Final FAM-MM2 concentration was 2 nM. Plates were incubated at room temperature for 30 minutes with gentle shaking to assure equilibrium. FP values in millipolarization units (mP) were measured using the Infinite M-1000 plate reader (Tecan U.S., Research Triangle Park, NC) in Microfluor 1 96-well, black, v-bottom plates (Thermo Scientific, Waltham, MA) at an excitation wavelength of 485 nm and an emission wavelength of 530 nm. Kt/ value of FAM-MM2, which was calculated by fihing the sigmoidal dose-dependent FP increases as a function of protein concentrations using Graphpad Prism 6.0 software (Graphpad Software, San Diego, CA), was determined as 1.4 nM.
[00733] The IC50 of representative Compounds of the Disclosure were determined in a competitive binding experiment. See Table 5. Mixtures of 5 mΐ of the tested compounds in DMSO and 195 mΐ 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.
[00734] Binding Assays 2 and 3
[00735] Compound binding potency was also measured by fluorescence-based polarization ligand displacement assay using one of two probes, 36 or 37, against recombinant menin protein, as described in Zhou (2013) with the following adaptations. See Zhou, et al., Structure-Based Design of High- Affinity Macrocyclic Peptidomimetics to Block the Menin-Mixed Lineage Leukemia 1 (MLL1) Protein- Protein Interaction. J. Med. Chem., 2013; 56(3): 1113-23. All compounds were prepared as 10 mM stock solutions in DMSO.
[00736] For assay of compounds using probe 36 (Binding Assay 2), binding studies were conducted in buffer containing 100 mM potassium phosphate, pH 7.5; 100 ug/ml bovine gamma globulin, 0.02% sodium azide, 0.005% Triton X-100, and 2% DMSO. A 10-point dose response curve of compound was first added to the wells, followed by buffer solution containing 90 nM recombinant menin protein and 6 nM probe 36. The system was allowed to equilibrate for 60 minutes in the dark at room temperature, and then the FP signal was read at Ex480/Em530. The FP signal data was fit to four- parameter dose equation to allow the extraction of IC50 data.
[00737] For assay of compounds using probe 37 (Binding Assay 3), the assay buffer was 100 mM potassium phosphate 7.5, 100 ug/ml bovine gamma globulin, 0.01% triton X- 100, 5% DMSO. A 10-point dose response curve of compound was first added to the wells, followed by assay buffer containing 4 nM recombinant menin protein and 4 nM probe 37. The system was allowed to equilibrate for one hour at room temperature in the dark, and then FP signal was read at Ex480/Em530. The FP signal data was fit to four-parameter dose response equation to allow the extraction of IC50 data.
[00738] Specific compounds disclosed herein were tested in the foregoing binding assays and they were determined have an IC50 according to the following scores: (A) less than 50 nM, (B) between 50 nM and 100 nM, (C) greater than 100 nM, and (NT) not tested, as shown in Table 5 below.
Table 5
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
EXAMPLE 31 Cell Growth Inhibition [00739] Procedure 1
[00740] The effect of representative Compounds of the Disclosure on cell viability was determined in a 4-day or 7-day proliferation assay. Cells were maintained in the appropriate culture medium with 10% FBS at 37°C and an atmosphere of 5% CC .
[00741] Cells were seeded in 96-well flat bottom (Coming COSTAR, Coming, NY, cat# 3595) at a density of 2,000-3,000 cells/well in 100 pi of culture medium. Compounds were serially diluted in the appropriate medium, and 100 mΐ 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% CCh for 4 or 7 days. In the 7- day assays, cell viability was determined using the WST (2-(2-methoxy-4-nitrophenyl)- 3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt) Cell Counting-8 Kit (Dojindo Molecular Technologies, Inc., Rockville, MD) according to the manufacturers’ instructions. In the 4-day assays, cell viability was determined using the CellTiter-Glo® Luminescent Cell Viability reagent according to the manufacturers’ instructions.
[00742] 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).
[00743] Specific compounds disclosed herein were tested in the foregoing assay and they were determined to inhibit cellular proliferation with an IC50 according to the following scores: (A) less than 100 nM, (B) between 100 nM and 500 nM, (C) between 500 nM and 1 mM, (D) greater than 1 mM, (E) no fit, and (NT) not tested, as shown in Table 6 below.
[00744] Procedure 2
[00745] The effect of representative Compounds of the Disclosure on cell viability was determined in a 4-day or 7-day proliferation assay. Cells were maintained in the appropriate culture medium with 10% FBS at 37°C and an atmosphere of 5% C02.
[00746] 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 mΐ of culture medium. Compounds were serially diluted in the appropriate medium, and 50 pi 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.
[00747] CellTiter-Glo® Luminescent Cell Viability reagent was added to each well and incubated for 10 minutes on an orbital shaker at room temperature. The luminescence signal was measured using EnSpire® plate reader (PerkinElmer, Waltham, MA) 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).
[00748] Specific compounds disclosed herein were tested in the foregoing assay and they were determined to inhibit cellular proliferation with an IC50 according to the following scores: (A) less than 100 nM, (B) between 100 nM and 500 nM, (C) between 501 nM and 1 mM, (D) greater than 1 mM, (E) no fit, and (NT) not tested, as shown in Table 6 below.
Table 6
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
[00749] Having now fully described the methods, compounds, and compositions of matter provided herein, it will be understood by those of skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations, and other parameters without affecting the scope of the methods, compounds, and compositions provided herein or any embodiment thereof.
[00750] All patents, patent applications and publications cited herein are fully incorporated by reference herein in their entirety.

Claims

What is Claimed Is:
1. A compound having Formula I:
Figure imgf000224_0001
or a pharmaceutically acceptable salt thereof, wherein: each Ra is independently selected from the group consisting of hydrogen and C1-C4 alkyl; each Rb is independently selected from the group consisting of hydrogen and C1-C4 alkyl;
Rc is selected from the group consisting of hydrogen and halo; each Rd is independently selected from the group consisting of halo; each n is independently 0, 1 or 2;
Q is -NHCO2-R;
R is C1-C4 alkyl, C1-C4 haloalkyl, or CD3 ;
B is selected from the group consisting of:
Figure imgf000224_0002
R2 is selected from the group consisting of hydrogen, halo, C1-C4 alkyl, hydroxy, Ci- C4 alkoxy, C1-C4 haloalkyl, and C1-C4 hydroxyalkyl; E is selected from the group consisting of:
Figure imgf000225_0001
L1 is -CH2- wherein E is E-l, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, E-10, E-13, and E- 14 and absent wherein E is E-l 1 or E-12;
R3aand R3b are independently selected from the group consisting of hydrogen, halo, and Ral;
R4 is hydrogen or C1-C4 alkyl; m is 1 or 2;
J is cyano, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocycloalkylsulfonyl, carboxamido, and -SO2X;
R5 is hydrogen or alkenyl;
R6 is hydrogen or halo; n is 0 or 1;
R7 is alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocycloalkylsulfonyl, or carboxamido;
L2 is absent, -SO2-, or -CH2- R8ais selected from the group consisting of hydrogen, halo, alkoxy, and Ral; R8b is selected from the group consisting of alkoxy and Ral;
Z is alkylsulfonyl and cycloalkylsulfonyl;
Ral is (amino)alkyl, carboxamido, and (heterocyclo)alkyl;
X is selected from the group consisting of
Figure imgf000226_0001
o and p are independently 0, 1, 2, or 3;
Y is -C(=0)-;
Z2 is selected from the group consisting of -C(R14a)=C(R14b)(R14c), -CºCR14d, and Ra2 R9a and R9b are each independently selected from the group consisting of alkenyl; Ci- C4 alkyl, halo, (amino)alkyl, and -C(R14a)=C(R14b)(R14c);
Each U is independently selected from the group consisting of -CH2- and -C(=0)- R10 is selected from the group consisting of hydrogen, C1-C4 alkyl, and -CH2CH=CH- Ra3;
R11 is -NHCOC(R14a)=C(R14b)(R14c) or -CH2CH=CH-Ra3;
R12 is selected from the group consisting of alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, and carboxamido;
R13 is hydrogen or C1-C4 alkyl; Rl4a. R14b, R14c, and R14d are each independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, (amino)alkyl, and Ra3;
R18 is selected from the group consisting of cyano, -(C=0)NH2, and -(C=0)N(H)Ci- C4alkyl.
R19 is halo;
R32 is -N(R15)CH2CH=CH-Ra3 or -CH=CHCH2Ra4;
Ra3 is selected from the group consisting of alkoxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, and carboxamido;
Ra4 is optionally substituted heterocyclo;
Ra5 is hydrogen or C1-C4 alkyl
R15 is hydrogen or C1-C4 alkyl;
R16 is carboxamido;
R17 is selected from the group consisting of hydrogen, C1-C4 alkyl, -OCH2CH=CH-Ra3, and -CH2CH=CH-Ra3; each W is independently selected from the group consisting of -CH- or -N-; wherein B is not B-10, B-l 1, and B-12 when E is E-l or E-2; and provided that the compound is not methyl rac-((lS ,2R)-2-(2-(lH-imidazol-l-yl)-l-(l-((l-(4-(( 1-methyl- 1H- pyrazol-4-y l)sulfonyl)pheny l)azeti din-3 -yl)methyl)piperidin-4-yl)-l- phenylethyl)cyclopentyl)carbamate.
2. The compound of claim 1 having Formula II:
Figure imgf000227_0001
or a pharmaceutically acceptable salt thereof, wherein E is E-l, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, E-10, E-13, or E-14.
3. The compound of claim 1 having Formula III:
Figure imgf000228_0001
or a pharmaceutically acceptable salt thereof, wherein E is E-l 1 or E-12.
4. The compound of claim 1 having Formula XII:
Figure imgf000228_0002
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 having Formula XIII:
Figure imgf000228_0003
or a pharmaceutically acceptable salt thereof.
6. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein: each Ra is independently selected from the group consisting of hydrogen and C1-C4 alkyl; each Rb is independently selected from the group consisting of hydrogen and C1-C4 alkyl; Rc is fluoro;
R is C1-C4 alkyl;
B is B-l or B-2.
7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein B is B-l.
8. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein B is B-2.
9. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R is methyl.
10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein at least one of R3a and R3b is halo.
11. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein at least one of R3a and R3b is fluoro.
12. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein at least one of R3a and R3b is (amino)alkyl or carboxamido.
13. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen.
14. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R2 is fluoro.
15. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R2 is methoxy.
16. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R2 is hydroxy.
17. The compound of any one of claims 1-2 and 6-16, or a pharmaceutically acceptable salt thereof, wherein E is E-l or E-2.
18. The compound of one any of claims 1-2 and 6-16, or a pharmaceutically acceptable salt thereof, wherein E is E-l.
19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein X is
X-l.
20. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein X is X-2.
21. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein X is X-ll.
22. The compound of any one of claims 1-2 and 6-16, or a pharmaceutically acceptable salt thereof, wherein E is E-3.
23. A compound having Formula XXXI:
Figure imgf000230_0001
or a pharmaceutically acceptable salt thereof, wherein: each Ra is independently selected from the group consisting of hydrogen and C1-C4 alkyl; each Rb is independently selected from the group consisting of hydrogen and C1-C4 alkyl;
Rc is selected from the group consisting of hydrogen and halo; each Rd is independently selected from the group consisting of halo; each n is independently 0, 1 or 2;
Q is -NHCO2-R;
R is C1-C4 alkyl, C1-C4 haloalkyl, or CD3;
Figure imgf000231_0001
24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein:
Figure imgf000232_0001
25. A compound having Formula XXXII:
Figure imgf000232_0002
26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein:
Figure imgf000233_0001
27. A compound having Formula XXXIII:
Figure imgf000233_0002
28. A compound, or a pharmaceutically acceptable salt, selected from one or more of the compounds of Tables 1, 1A, IB, or 1C.
29. A pharmaceutical composition comprising the compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
30. A method of treating a patient, the method comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1-28, 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.
31. The method of claim 30, wherein the patient has cancer.
32. The method of claim 31, wherein the cancer is any one or more of the cancers of Table 2
33. The method of claim 32, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.
34. The method of any one of claims 30-33 further comprising administering a therapeutically effective amount of a second therapeutic agent useful in the treatment of the disease or condition.
35. The pharmaceutical composition of claim 29 for use in treating cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.
36. The pharmaceutical composition of claim 35 for use in treating cancer.
37. The pharmaceutical composition of claim 36, wherein the cancer is any one or more of the cancers of Table 2.
38. The pharmaceutical composition of claim 37, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.
39. A compound of any one of claims 1-28, 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.
40. The compound of claim 39 for use in treating cancer.
41. The compound of claim 40, wherein the cancer is any one or more of the cancers of Table 2.
42. The compound of claim 41, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.
43. Use of a compound of any one of claims 1-28, 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.
44. The use of claim 43 for treatment of cancer.
45. The use of claim 44, wherein the cancer is any one or more of the cancers of Table 2.
46. The use of claim 45, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.
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