WO2023056589A1 - 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
WO2023056589A1
WO2023056589A1 PCT/CN2021/122588 CN2021122588W WO2023056589A1 WO 2023056589 A1 WO2023056589 A1 WO 2023056589A1 CN 2021122588 W CN2021122588 W CN 2021122588W WO 2023056589 A1 WO2023056589 A1 WO 2023056589A1
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Prior art keywords
alkyl
pharmaceutically acceptable
compound
optionally substituted
hydrogen
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PCT/CN2021/122588
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French (fr)
Inventor
Tao Liu
Zhihua Sui
Shubao ZHOU
Jingjing Ji
Shaomeng Wang
Meng Zhang
Angelo AGUILAR
Haibin Zhou
Fuming XU
Liyue HUANG
Jeanne STUCKEY
Paul Kirchhoff
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Servier Pharmaceuticals Llc
The Regents Of The University Of Michigan
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Priority to PCT/CN2021/122588 priority Critical patent/WO2023056589A1/en
Publication of WO2023056589A1 publication Critical patent/WO2023056589A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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- ⁇ B 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 (Brca1) 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 MEN1 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 inNPM1.
  • 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, Pem, Runx2, Hlbx9, ER, PPAR ⁇ , vitamin D receptor, transcription repressors, e.g., JunD, Sin3A, HDAC, EZH2, PRMT5, NF ⁇ B, Sirt1, CHES1, cell signaling proteins, e.g., AKT, SOS1/GEF, ⁇ -catenin, SMAD 1, 3, 5, NF ⁇ B, ER, PPAR ⁇ , 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,
  • the present disclosure provides compounds represented by Formulae I-XXXI, 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,
  • each R a is independently hydrogen or C 1 -C 4 alkyl
  • each R b is independently hydrogen or C 1 -C 4 alkyl
  • R c is hydrogen or halo
  • each R d is independently halo
  • p, q, r and s are independently 1 or 2;
  • n 0, 1 or 2;
  • each R is independently C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or CD 3 ;
  • each R 1 is independently hydrogen or C 1 -C 4 alkyl
  • each R 2 is independently C 1 -C 4 alkyl
  • each k is independently 0, 1, 2, 3, or 4;
  • L is absent or is optionally substituted C 1 -C 6 alkyl or C 1 -C 6 haloalkyl
  • J 2 is C 1 -C 4 alkyl, C 1 -C 6 haloalkyl, cyano, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, or optionally substituted heterocyclo;
  • R 4 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkylcarbonyl, heterocyclo, or haloalkyl;
  • W is -NH-, -O-, or -S-;
  • R 5 is hydrogen, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or halo;
  • each m is independently 1 or 2;
  • v 0 or 1
  • R 6 is hydrogen, haloalkyl, C 1 -C 4 alkyl, C 1 -C 4 alkylcarbonyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, heterocycloalkylsulfonyl, carboxamido, mesylate, or tert-butoxycarbonyl;
  • each R 7 is independently hydrogen, cyano, halo, haloalkyl, C 1 -C 4 alkyl, C 1 -C 4 alkylcarbonyl, hydroxy, sulfonamido, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, heterocycloalkylsulfonyl, or carboxamido;
  • each W 1 is independently -CH-or -N-;
  • t and u are independently 0, 1, 2, or 3;
  • X is C 2 -C 4 alkenyl, (amino) alkyl, -CH 2 CH 2 NR 1 Y 1 -Z 2 ,
  • R 12 is alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, or carboxamido;
  • R 13 is hydrogen or C 1 -C 4 alkyl
  • R 14a , R 14b , R 14c , and R 14d are each independently hydrogen, halo, C 1 -C 4 alkyl, (amino) alkyl, or R a3 ;
  • R a3 is alkoxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, or carboxamido;
  • R a4 is optionally subsubstituted heterocyclo
  • R a5 is cyano or (amino) alkyl
  • R a6 is hydrogen or carboxamido
  • R 15 is hydrogen or C 1 -C 4 alkyl
  • R 16 is hydrogen or C 1 -C 4 alkyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae II-IX:
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-IX, and the pharmaceutically acceptable salts thereof.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-IX, 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-IX, 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-IX, 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-IX, 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-IX, 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 I-IX, and the pharmaceutically acceptable salts thereof, wherein p, q r and s are 1.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-IX, and the pharmaceutically acceptable salts thereof, wherein p, q and r are 1 and s is 2.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-IX, and the pharmaceutically acceptable salts thereof, wherein p, r and s are 1 and q is 2.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-IX, and the pharmaceutically acceptable salts thereof, wherein q, r and s are 1 and p is 2.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-IX, and the pharmaceutically acceptable salts thereof, wherein p, q and s are 1 and r is 2.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-IX, and the pharmaceutically acceptable salts thereof, wherein p and q are 1 and r and s are 2.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-IX, and the pharmaceutically acceptable salts thereof, wherein p and q are 2 and r and s are 1.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae X-XV:
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae X-XV, and the pharmaceutically acceptable salts thereof.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, 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-XV, 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-XV, 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-XV, and the pharmaceutically acceptable salts thereof, wherein n is 0 or 1.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, 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-XV, and the pharmaceutically acceptable salts thereof, wherein R c is halo and n is 0.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein R c is fluoro and n is 0.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein R d is fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein n is 1.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, 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-XV, 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-XV, and the pharmaceutically acceptable salts thereof, wherein Q is -NHCO 2 CH 3 or -NHCO 2 CH 2 CH 3 .
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein Q is -NHCO 2 CH 3 .
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, E-10, E-11, E-12, E-13, E-14, E-15, and E-16.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-2, and E-3.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, and E-18.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-4 and E-5.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-6 and E-7.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-13, E-14 and E-15.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least one of R 8a , R 8b , R 8c , and R 8d is hydrogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least two of R 8a , R 8b , R 8c , and R 8d are hydrogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least three of R 8a , R 8b , R 8c , and R 8d are hydrogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein wherein E is E-1, E-17, or E-18 and each of R 8a , R 8b , R 8c , and R 8d are hydrogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least one of R 8a , R 8b , R 8c , and R 8d is halo.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least two of R 8a , R 8b , R 8c , and R 8d are halo.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least one of R 8a , R 8b , R 8c , and R 8d is fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least two of R 8a , R 8b , R 8c , and R 8d are fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least one of R 8a , R 8b , R 8c , and R 8d is C 1 -C 4 alkyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least two of R 8a , R 8b , R 8c , and R 8d are C 1 -C 4 alkyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least one of R 8a , R 8b , R 8c , and R 8d are methyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least two of R 8a , R 8b , R 8c , and R 8d are methyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least one of R 8a , R 8b , R 8c , and R 8d is C 1-4 alkyl, halo, optionally substituted heteroaryl, carboxamido, thioamide, (carboxamido) alkyl, heterocyclooxy, carboxamidooxy, alkoxy, haloalkyl, aralkyloxy, or (amino) alkyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least one of R 8a , R 8b , R 8c , and R 8d is carboxamido.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least one of R 8a , R 8b , R 8c , and R 8d is
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least one of R 8a , R 8b , R 8c , and R 8d is
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least one of R 8a , R 8b , R 8c , and R 8d is optionally substituted heteroaryl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least one of R 8a , R 8b , R 8c , and R 8d is optionally substituted heteroaryl, wherein the optionally substituted heteroaryl is pyrazolyl, oxazolyl, thiazolyl, pyrazolyl, or pyridinyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least one of R 8a , R 8b , R 8c , and R 8d is optionally substituted heteroaryl, wherein the optionally substituted heteroaryl is pyrazol-3-yl, oxazol-2-yl, thiazol-2-yl, pyrazol-4-yl, or pyridin-2-yl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is and at least one of R 8a and R 8b is halo.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is and at least one of R 8a and R 8b is fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is and at least one of R 8a and R 8b is C 1 -C 4 alkyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is and at least one of R 8a and R 8b is methyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is R 8a is C 1 -C 4 alkyl or halo; and R 8b is hydrogen or carboxamido.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is and at least one of R 8b and R 8c is halo.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is and at least one of R 8b and R 8c is fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is and at least one of R 8b and R 8c is C 1 -C 4 alkyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is and at least one of R 8b and R 8c is methyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is R 8b is optionally substituted heteroaryl, carboxamido, or thioamide; and R 8c is hydrogen or halo.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is R 8b is carboxamido, and R 8c is hydrogen or fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is R 8b is and R 8c is hydrogen or fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is R 8b is and R 8c is hydrogen or fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is and at least one of R 8b , R 8c , and R 8d is carboxamido or (amino) alkyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-2, and at least one of R 8b , R 8c , and R 8d is –CH 2 N (CH 3 ) 2 .
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-2, and at least one of R 8b , R 8c , and R 8d is
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-2 and at least one of R 8b , R 8c , and R 8d is
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is R 4 is C 1 -C 4 alkyl, C 1 -C 4 alkylcarbonyl, heterocyclo, or C 1 -C 4 haloalkyl; and J is cyano, optionally substituted heteroaryl, or heteroarylsulfonyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-4 or E-5; R 4 is methyl, ethyl, isopropyl, acetyl, oxetanyl, tetrahydropyranyl, -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F or -CH (CH 2 F) 2 ; and J is cyano, optionally substituted heteroaryl, or heteroarylsulfonyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is R 4 is C 1 -C 4 alkyl; and J is cyano or optionally substituted heteroaryl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is and J is cyano or optionally substituted heteroaryl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is R 5 is amino; and J is cyano or optionally substituted heteroaryl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is and L is absent or is -CH 2 -, -C (CH 3 ) 2 -, or -CF 2 -.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is wherein R 8a , R 8b , R 8c , and R 8d , Z, R 1 , R 6 , R 7 , 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-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-16, and J 2 is optionally substituted heterocyclo, wherein the optionally substituted hetercyclo is and R 6 , t and u are defined above in accordance with Formula I.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-16, and J 2 is optionally substituted cycloalkyl, wherein the optionally substituted cycloalkyl is and R 7 , t, and u are defined above in accordance with Formula I.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is and X is X-5 or X-21.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XVI-XVIII:
  • V 1 , R 8b , R 8c , J 2 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 XVI-XVIII, and the pharmaceutically acceptable salts thereof.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is cyano or alkylsulfonyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is cyano.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is -CF 3 .
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is methylsulfonyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is -SO 2 CF 3 .
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is optionally substituted heterocyclo and the optionally substituted heterocyclo is
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is haloalkoxy, alkoxy, carboxamidooxy, heteroaryloxy, or aralkyloxy.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is optionally substituted heteroaryl and the optionally substituted heteroaryl is pyrazolyl, oxazolyl, isoxazolyl, pyrimidinyl, thiazolyl, triazolyl, triazinyl, oxadiazolyl, pyridinyl, quinazolinyl, pyrazolo [3, 4-d] pyrimidinyl, benzo [d] oxazolyl, thiadiazolyl, benzo [d] thiazolyl, pyrazolo [4, 3-d] pyrimidinyl, pyrrolo [2, 3-d] pyrimidinyl, thiazolo [5, 4-d] pyrimidinyl, purinyl, pyrazinyl, pyridazinyl, or tetrazolyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is optionally substituted heteroaryl and the optionally substituted heteroaryl is oxazol-2-yl, isoxazole-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, 1, 2, 4-oxadiazol-5-yl, thiazol-2-yl, pyrazol-4-yl, pyrazol-3-yl, quinazolin-2-yl, pyrazolo [3, 4-d] pyrimidin-6-yl, benzo [d] thiazol-2-yl, benzo [d] oxazol-2-yl, 1, 3, 5-triazol-2-yl, 1, 2, 4-triazol-3-yl, 1, 3, 4-oxadiazol-2-yl, 1, 2, 4-oxadiazol-3-yl, pyrazin-2-yl, pyridazin-3-
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is optionally substituted heteroaryl and the optionally substituted heteroaryl is substituted with one or more of:
  • C 1 -C 4 alkyl such as methyl, ethyl, propyl, isopropyl, or butyl;
  • halo such as Br, Cl, or F
  • C 1 -C 4 haloalkyl such as CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CH (CH 2 F) 2 C (CH 3 ) 2 F, or C (CH 3 ) F 2 ;
  • amino such as NH 2 , or N (CH 2 ) 3 ;
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is R 17 and R 18 are, independently, hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, cyano, halo, or amino; and R 19 is hydrogen or C 1-4 alkyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is and R 17 is hydrogen, C 1-4 alkyl such as methyl or ethyl, or amino, or preferably hydrogen or methyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is and R 17 and R 18 are, independently, hydrogen or C 1-4 alkyl such as methyl or ethyl, or preferably hydrogen or methyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is R 17 and R 18 are, independently, hydrogen, C 1-4 alkyl such as methyl or ethyl, or halo such as chloro or fluoro, or preferably hydrogen, methyl, or fluoro; and R 19 is hydrogen or C 1-4 alkyl such as methyl or ethyl, or preferably hydrogen or methyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is and R 17 is hydrogen, C 1-4 alkyl such as methyl, ethyl, or isopropyl, C 1-4 haloalkyl such as CF 3 , cyano, or halo such as chloro or fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is and R 17 and R 18 are, independently, hydrogen or C 1-4 alkyl such as methyl or ethyl, or preferably hydrogen or methyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is R 17 is hydrogen, C 1-4 alkyl such as methyl or ethyl, or halo such as chloro or fluoro, or preferably hydrogen, methyl, or fluoro; and R 19 is hydrogen or C 1-4 alkyl such as methyl or ethyl, or preferably hydrogen or methyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XVI-XVIII, and the pharmaceutically acceptable salts thereof, wherein R 8b is
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XVI-XVIII, and the pharmaceutically acceptable salts thereof, wherein R 8b is
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIX-XXIV:
  • V 1 , Y, L, J 2 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 XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein the optionally substituted aryl is substituted with one or more of:
  • C 1 -C 4 alkyl such as methyl, ethyl, propyl, isopropyl, or butyl;
  • halo such as Br, Cl, or F
  • C 1 -C 4 haloalkyl such as CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CH (CH 2 F) 2 C (CH 3 ) 2 F, or C (CH 3 ) F 2 ; and
  • haloalkoxy such as OCF 3 .
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein J 2 is and R 20 is halogen such as chloro or fluoro, cyano, carboxamido, C 1-4 haloalkoxy such as OCF 3 , or C 1-4 haloalkyl such as CF 3 .
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein J 2 is and R 20 and R 21 are, independently, halogen such as fluoro, cyano, carboxamido, C 1-4 haloalkoxy such as OCF 3 , or C 1-4 haloalkyl such as CF 3 .
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein:
  • J 2 is optionally substituted cycloalkyl, wherein the optionally substituted cycloalkyl is:
  • t and u are, independently, 0, 1, 2, or 3;
  • R 22 and R 23 are independently hydrogen, cyano, halo, haloalkyl, C 1 -C 4 alkyl, C 1 -C 4 alkylcarbonyl, hydroxy, alkoxy, amino, sulfonamido, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, heterocycloalkylsulfonyl, carboxamido, optionally substituted aryl, or optionally substituted heteroaryl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XIX-XXIV, and the pharmaceutically acceptable salts thereof, wherein the optionally substituted heteroaryl is substituted with one or more of:
  • C 1 -C 4 alkyl such as methyl, ethyl, propyl, isopropyl, or butyl;
  • halo such as Br, Cl, or F
  • C 1 -C 4 haloalkyl such as CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CH (CH 2 F) 2 C (CH 3 ) 2 F, or C (CH 3 ) F 2 ; and
  • haloalkoxy such as OCF 3 .
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XXIV, and the pharmaceutically acceptable salts thereof, wherein V 1 is -N (CH 3 ) SO 2 CH 3 .
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XXIV, and the pharmaceutically acceptable salts thereof, wherein R 2 is C 1 -C 4 alkyl and k is 0, 1, or 2.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XXIV, and the pharmaceutically acceptable salts thereof, wherein k is 0.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XXIV, and the pharmaceutically acceptable salts thereof, wherein R 2 is C 1 -C 4 alkyl and k is 1.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XXIV, and the pharmaceutically acceptable salts thereof, wherein R 2 is C 1 -C 4 alkyl and k is 2.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XXIV, and the pharmaceutically acceptable salts thereof, wherein R 2 is methyl and k is 0, 1, or 2.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XXIV, and the pharmaceutically acceptable salts thereof, wherein R 2 is methyl and k is 1.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XXIV, and the pharmaceutically acceptable salts thereof, wherein R 2 is methyl and k is 2.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XXIV, and the pharmaceutically acceptable salts thereof, wherein V 1 is
  • Compounds of the Disclosure are compounds represented by Formula XXII:
  • each R a is independently hydrogen or C 1 -C 4 alkyl
  • each R b is independently hydrogen or C 1 -C 4 alkyl
  • R c is hydrogen or halo
  • each R d is independently halo
  • p, q, r and s are independently 1 or 2;
  • n is independently 0, 1 or 2;
  • each R f is independently hydrogen, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, or halo;
  • each R g is independently hydrogen, C 1 -C 4 alkyl, or NH 2 ;
  • each R is independently C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or CD 3 ;
  • each R 1 is independently hydrogen or C 1 -C 4 alkyl
  • each R 2 is independently C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl
  • each k is independently 0, 1, 2, 3, or 4;
  • R 4 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkylcarbonyl, heterocyclo, and haloalkyl;
  • W is -NH-, -O-, or -S-;
  • each m is independently 1 or 2;
  • R 5 is hydrogen, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or halo;
  • R 13 is hydrogen or C 1 -C 4 alkyl
  • R 16 is hydrogen or C 1 -C 4 alkyl
  • R a3 is alkoxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, or carboxamido;
  • L is absent or is optionally substituted C 1 -C 6 alkyl or C 1 -C 6 haloalkyl
  • J 5 is C 1 -C 4 alkyl, C 1 -C 6 haloalkyl, cyano, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, or optionally substituted heterocyclo.
  • Compounds of the Disclosure are compounds represented by Formulae XXII, and the pharmaceutically acceptable salts thereof.
  • Compounds of the Disclosure are compounds represented by Formulae XXII, and the pharmaceutically acceptable salts thereof, wherein at least one R a is hydrogen.
  • Compounds of the Disclosure are compounds represented by Formulae XXII, and the pharmaceutically acceptable salts thereof, wherein each R a is hydrogen.
  • Compounds of the Disclosure are compounds represented by Formulae XXII, and the pharmaceutically acceptable salts thereof, wherein at least one R b is hydrogen.
  • Compounds of the Disclosure are compounds represented by Formulae XXII, and the pharmaceutically acceptable salts thereof, wherein each R b is hydrogen.
  • Compounds of the Disclosure are compounds represented by Formulae XXII, and the pharmaceutically acceptable salts thereof, wherein each R a and R b is hydrogen.
  • Compounds of the Disclosure are compounds represented by Formulae XXII, and the pharmaceutically acceptable salts thereof, wherein p, q r and s are 1.
  • Compounds of the Disclosure are compounds represented by Formulae XXII, and the pharmaceutically acceptable salts thereof, wherein p, q and r are 1 and s is 2.
  • Compounds of the Disclosure are compounds represented by Formulae XXII, and the pharmaceutically acceptable salts thereof, wherein p, r and s are 1 and q is 2.
  • Compounds of the Disclosure are compounds represented by XXII, and the pharmaceutically acceptable salts thereof, wherein q, r and s are 1 and p is 2.
  • Compounds of the Disclosure are compounds represented by Formulae XXII, and the pharmaceutically acceptable salts thereof, wherein p, q and s are 1 and r is 2.
  • Compounds of the Disclosure are compounds represented by Formulae XXII, and the pharmaceutically acceptable salts thereof, wherein p and q are 1 and r and s are 2.
  • Compounds of the Disclosure are compounds represented by Formulae XXII, and the pharmaceutically acceptable salts thereof, wherein p and q are 2 and r and s are 1.
  • Compounds of the Disclosure are compounds represented by any one or more of Formula XXIII-XXVIII:
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, 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 XXII-XXVIII, 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 XXII-XXVIII, 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 XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein n is 0 or 1.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein n is 0.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein R c is halo and n is 0.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein R c is fluoro and n is 0.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein R d is fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein n is 1.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein n is 2.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, 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 XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein Q is -NHCO 2 CH 3 or -NHCO 2 CH 2 CH 3 .
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein Q is -NHCO 2 CH 3 .
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein V is -CH 2 NR 1 CO 2 Me, -CH 2 NR 1 CO 2 Et, -CH 2 NR 1 CO 2 iPr, -CH 2 NR 1 CONH 2 , -CONH 2 , -CONHMe, -CONMe 2 , -CONHEt, -CONEt 2 , -CON (Me) (Et) , wherein each R g is independently hydrogen, methyl, ethyl, and isopropyl and each R 2 is independently methyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein E is E-10, E-12, E-13, E-36, or E-37.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein E is E-36 or E-37.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein E is E-37 or E-38.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein E is E-36 and at least one of R 8a , R 8b , R 8c , and R 8d is hydrogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein E is E-36 and at least two of R 8a , R 8b , R 8c , and R 8d are hydrogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein E is E-36 and at least three of R 8a , R 8b , R 8c , and R 8d are hydrogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein wherein E is E-36 and each of R 8a , R 8b , R 8c , and R 8d are hydrogen.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein E is E-36 and at least one of R 8a , R 8b , R 8c , and R 8d is halo.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein E is E is E-36 and at least two of R 8a , R 8b , R 8c , and R 8d are halo.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein E is E-36 and at least one of R 8a , R 8b , R 8c , and R 8d is fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein E is E-36 and at least two of R 8a , R 8b , R 8c , and R 8d are fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein E is E-36 and at least one of R 8a , R 8b , R 8c , and R 8d is halo or carboxamido.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein E is E-36 and at least one of R 8a , R 8b , R 8c , and R 8d is carboxamido.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein E-36 and at least one of R 8a , R 8b , R 8c , and R 8d is
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein E is E-36 and at least one of R 8a , R 8b , R 8c , and R 8d is
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein E is R 5 is amino; and J is cyano or optionally substituted heteroaryl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formula XXIX-XXXI:
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXXI, and the pharmaceutically acceptable salts thereof.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXXI, and the pharmaceutically acceptable salts thereof, wherein J 3 is optionally substituted heteroaryl and the optionally substituted heteroaryl is pyrazolyl, oxazolyl, pyrimidinyl, oxadiazolyl, or pyridinyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXXI, and the pharmaceutically acceptable salts thereof, wherein J 3 is optionally substituted heteroaryl and the optionally substituted heteroaryl is oxazol-2-yl, oxazol-5-yl, pyrimidin-2-yl, pyrazol-3-yl, 1, 3, 4-oxadiazol-2-yl, 1, 2, 4-oxadiazol-3-yl, or pyridin-2-yl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXXI, and the pharmaceutically acceptable salts thereof, wherein J 3 is optionally substituted heteroaryl and the optionally substituted heteroaryl is substituted with one or more of:
  • C 1-6 alkyl such as methyl, ethyl, propyl, isopropyl, or butyl;
  • halo such as Br, Cl, or F
  • C 1-6 haloalkyl such as CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CH (CH 2 F) 2 C (CH 3 ) 2 F, or C (CH 3 ) F 2 ;
  • amino such NH 2 , or N (CH 2 ) 3 ;
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXXI, and the pharmaceutically acceptable salts thereof, wherein J 3 is R 17 and R 18 are, independently, hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, cyano, halo, or amino; and R 19 is hydrogen or C 1-4 alkyl.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXIX-XXXI, and the pharmaceutically acceptable salts thereof, wherein R 8b is carboxamido such as and preferably and R 8c is hydrogen or halo, such as fluoro or chloro, or preferably hydrogen or fluoro.
  • Compounds of the Disclosure are compounds represented by any one or more of Formulae XXIX-XXXI, and the pharmaceutically acceptable salts thereof, wherein V is -CH 2 NR 1 CO 2 Me, -CON (Me) (Et) ,
  • Compounds of the Disclosure are any one or more of the compounds of Tables 1A and 1B, and the pharmaceutically acceptable salts thereof.
  • Tables 1A and 1B further provide the chemical names of the compounds of Tables 1A and 1B generated by 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%.
  • 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, glycerolphsphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate,
  • available amino groups present in the compounds of the disclosure can be quaternized 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 (IC 50 ) to menin of less than 100 ⁇ M, e.g., less than 50 ⁇ M, less than 25 ⁇ M, and less than 5 ⁇ M, less than about 1 ⁇ M, less than about 0.5 ⁇ M, less than about 0.1 ⁇ M, less than about 0.05 ⁇ M, or less than about 0.01 ⁇ M.
  • 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.
  • 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 is a hematological cancer.
  • Exemplary hematological cancers include, but are not limited to, the cancers listed in Table 3.
  • the hematological cancer is acute lymphocytic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia) , or acute myeloid leukemia.
  • the hematological cancer is myelodysplastic syndrome.
  • ALL acute lymphocytic leukemia
  • AML acute eosinophilic leukemia acute myeloid leukemia
  • CLL acute erythroid leukemia chronic lymphocytic leukemia
  • SLL acute lymphoblastic leukemia small lymphocytic lymphoma
  • MM acute megakaryoblastic leukemia multiple myeloma
  • HL acute monocytic leukemia
  • HL acute promyelocytic leukemia
  • non-Hodgkin's lymphoma (NHL) acute myelogeous leukemia mantle cell lymphoma (MCL) B-cell prolymphocytic leukemia marginal zone B-cell lymphoma B-cell lymphoma splenic marginal zone lymphoma MALT lymphoma follicular lymphoma (FL) precursor T-lymphoblastic lymphoma Waldenstrom's macroglobulinemia (WM) T-cell lymphoma diffuse large B-cell lymphoma (DLBCL) mast cell leukemia marginal zone lymphoma (MZL) adult T cell leukemia/lymphoma hairy cell leukemia (HCL) aggressive NK-cell leukemia Burkitt's lymphoma (BL) angioimmunoblastic T-cell lymphoma Richter's transformation myelodysplastic syndromes
  • 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 NPM1c 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 rhinitis,
  • 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, intracisternal 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. 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, or a composition containing the same can be from about 1 ng/kg to about 200 mg/kg, about 1 ⁇ g/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 ⁇ g/kg.
  • the dosage of a composition may be at any dosage including, but not limited to, about 1 ⁇ g/kg, about 10 ⁇ g/kg, about 25 ⁇ g/kg, about 50 ⁇ g/kg, about 75 ⁇ g/kg, about 100 ⁇ g/kg, about 125 ⁇ g/kg, about 150 ⁇ g/kg, about 175 ⁇ g/kg, about 200 ⁇ g/kg, about 225 ⁇ g/kg, about 250 ⁇ g/kg, about 275 ⁇ g/kg, about 300 ⁇ g/kg, about 325 ⁇ g/kg, about 350 ⁇ g/kg, about 375 ⁇ g/kg, about 400 ⁇ g/kg, about 425 ⁇ g/kg, about 450 ⁇ g/kg, about 475 ⁇ g/kg, about 500 ⁇ g/kg, about 525 ⁇ g/kg, about 550 ⁇ g/kg, about 575 ⁇ g/kg, about 600 ⁇ g/kg, about 625 ⁇ g/kg, about 650 ⁇ g/
  • 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
  • a Compound of the Disclosure and pharmaceutical compositions described herein can be used in combination with one or more substances selected from anti-angiogenenesis 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, XPO1 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 XPO1 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 XPO1 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 DOTlL include EPZ-5676, SGC-0946, and EPZ004777.
  • Exemplary nonlimiting IDHl inhibitors include (ivosidnib) , AG-881, AG-120, FT-2102 (olutasidenib) , BAY1436032, IDH-305, and ZX-06.
  • Exemplary nonlimiting examples of IDH2 inhitors include (enasidenib; AG-221) , AG-881, AGl-6780, SH1573, and TQ05310.
  • Exemplary nonlimiting IDH1/IDH2 dual inhitors 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 XPO1 inhibtor includes selinexor (KPT-330) , KPT-8602, KPT25 l, 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-ll, 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 (Plaquenil TM ) , bafilomycin A1, 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 Biologics) .
  • 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
  • Nonlimiting exemplary aromatase inhibitors include, but are not limited to, steroids, such as atamestane, exemestane, and formestane, and non-steroids, such as aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole, and letrozole.
  • steroids such as atamestane, exemestane, and formestane
  • non-steroids such as aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole, and letrozole.
  • Nonlimiting anti-estrogens include, but are not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride.
  • Anti-androgens include, but are not limited to, bicalutamide.
  • Gonadorelin agonists include, but are not limited to, abarelix, goserelin, and goserelin acetate.
  • topoisomerase I inhibitors include, but are not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogues, 9-nitrocamptothecin, and the macromolecular camptothecin conjugate PNU-166148.
  • Topoisomerase II inhibitors include, but are not limited to, anthracyclines, such as doxorubicin, daunorubicin, epirubicin, idarubicin, and nemorubicin; anthraquinones, such as mitoxantrone and losoxantrone; and podophillotoxines, such as etoposide and teniposide.
  • Microtubule active agents include microtubule stabilizing, microtubule destabilizing compounds, and microtubulin polymerization inhibitors including, but not limited to, taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine, vinblastine sulfate, vincristine, and vincristine sulfate, and vinorelbine; discodermolides; cochicine and epothilones and derivatives thereof.
  • taxanes such as paclitaxel and docetaxel
  • vinca alkaloids such as vinblastine, vinblastine sulfate, vincristine, and vincristine sulfate, and vinorelbine
  • discodermolides such as cochicine 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
  • 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 oxaliplatin.
  • Exemplary nonlimiting methionine aminopeptidase inhibitors include bengamide or a derivative thereof and PPI-2458.
  • Exemplary nonlimiting bisphosphonates include etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid.
  • antiproliferative antibodies include trastuzumab, trastuzumab-DMl, cetuximab, bevacizumab, rituximab, PR064553, and 2C4.
  • antibody is meant to include intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity.
  • 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 farnesyl transferase inhibitor, such as L-744832, DK8G557, tipifarnib, and lonafarnib.
  • 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, ⁇ - ⁇ -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.
  • FMS-like tyrosine kinase inhibitors which are compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R) ; interferon, ⁇ - ⁇ -D-arabinofuransylcytosine (ara-c) , and bisulfan
  • ALK inhibitors which are compounds that target, decrease, or inhibit anaplastic lymphom
  • 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 HDAC 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, SUlOl, 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) ,
  • 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, safingol, BAY 43-9006, bryostatin 1, perifosine; ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521 ; LY333531/LY379196; a isochinoline compound; a farnesyl 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; Tyr
  • Exemplary compounds that target, decrease, or inhibit the activity of a protein or lipid phosphatase include inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.
  • anti-angiogenic compounds include compounds having another mechanism for their activity unrelated to protein or lipid kinase inhibition, e.g., thalidomide and TNP-470.
  • 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, 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine succinate, angiostatin, endostat
  • second therapeutic agents include, but are not limited to: a treatment for Alzheimer's Disease, such as donepezil and rivastigmine; a treatment for Parkinson's Disease, such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; an agent for treating multiple sclerosis (MS) such as beta interferon (e.g., and ) , 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, cycl
  • 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 subject a therapeutically effective amount a Compound of the Disclosure, wherein the subject has cancer.
  • Embodiment 2 The method of Embodiment 1, wherein the cancer is any one or more of the cancers of Table 2.
  • Embodiment 3 The method of Embodiment 2, wherein the cancer is a hematological cancer.
  • Embodiment 4 The method of Embodiment 3, wherein the hematological cancer is any one or more of the cancers of Table 3.
  • Embodiment 5 The method of any one of Embodiments 1-4 further comprising administering a therapeutically effective amount of a second therapeutic agent useful in the treatment of cancer.
  • Embodiment 6 A pharmaceutical composition comprising a 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 or “halogen” 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 -NO 2 .
  • 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., C 1-12 alkyl, or the number of carbon atoms designated, e.g., a C 1 alkyl such as methyl, a C 2 alkyl such as ethyl, a C 3 alkyl such as propyl or isopropyl, a C 1-3 alkyl such as methyl, ethyl, propyl, or isopropyl, and so on.
  • the alkyl is a C 1-10 alkyl.
  • the alkyl is a C 1-6 alkyl. In another embodiment, the alkyl is a C 1-4 alkyl. In another embodiment, the alkyl is a straight chain C 1-10 alkyl. In another embodiment, the alkyl is a branched chain C 3-10 alkyl. In another embodiment, the alkyl is a straight chain C 1-6 alkyl. In another embodiment, the alkyl is a branched chain C 3-6 alkyl. In another embodiment, the alkyl is a straight chain C 1-4 alkyl. In another embodiment, the alkyl is a branched chain C 3-4 alkyl. In another embodiment, the alkyl is a straight or branched chain C 3-4 alkyl.
  • Non-limiting exemplary C 1-10 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
  • Non-limiting exemplary C 1-4 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and iso-butyl.
  • the term "optionally substituted alkyl" as used by itself or as part of another group refers to an alkyl that is either unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of nitro, haloalkoxy, aryloxy, aralkyloxy, alkylthio, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, and alkylcarbonyloxy.
  • the optionally substituted alkyl is substituted with two substituents.
  • the optionally substituted alkyl is substituted with one substituent. In another embodiment, the optionally substituted alkyl is unsubstituted.
  • cycloalkyl refers to unsubstituted saturated or partially unsaturated, e.g., containing one or two double bonds, cyclic aliphatic hydrocarbons containing one to three rings having from three to twelve carbon atoms, i.e., C 3-12 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 C 3-8 cycloalkyl.
  • the cycloalkyl is a C 3-6 cycloalkyl.
  • Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, 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
  • optionally substituted cycloalkyl includes cycloalkyl groups having a fused optionally substituted aryl, e.g., phenyl, or fused optionally substituted heteroaryl, e.g., pyridyl.
  • An optionally substituted cycloalkyl having a fused optionally substituted aryl or fused optionally substituted heteroaryl group may be attached to the remainder of the molecule at any available carbon atom on the cycloalkyl ring.
  • the optionally substituted cycloalkyl is substituted with two substituents.
  • the optionally substituted cycloalkyl is substituted with one substituent.
  • the optionally substituted cycloalkyl is unsubstituted.
  • 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 C 6-14 aryl.
  • Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph” ) , naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups.
  • the aryl group is phenyl or naphthyl.
  • the term "optionally substituted aryl" as used herein by itself or as part of another group refers to an aryl that is either unsubstituted or substituted with one to five substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, -CO 2 CH 2 Ph, alkylamino, dialkylamino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, haloalkylsulfonyl cycloalkylsulfonyl, (cycloalkyl) alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulf
  • 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-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-cyanophenyl, 3-trifluoromethoxyphenyl, 3-trifluoromethylphenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 2, 6-di-fluorophenyl, 2, 6-di-chlorophenyl, 2-methyl, 3- methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3, 4-di-methoxyphenyl, 3, 5-di-fluorophenyl 3, 5-di-methylphen
  • 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:
  • optionally substituted aryl 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.
  • 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 C 2-6 alkynyl. In another embodiment, the alkynyl is a C 2-4 alkynyl.
  • Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.
  • alkynyl refers to an alkynyl that is either unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, and heterocyclo.
  • haloalkyl refers to an alkyl substituted by one or more fluorine, chlorine, bromine and/or iodine atoms.
  • the alkyl group is substituted by one, two, or three fluorine and/or chlorine atoms.
  • the haloalkyl group is a C 1-4 haloalkyl group.
  • Non-limiting exemplary haloalkyl groups include fluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1, 1-difluoroethyl, 2, 2-difluoroethyl, 2, 2, 2-trifluoroethyl, 1, 3-difluoropropan-2-yl, 3, 3, 3-trifluoropropyl, 4, 4, 4-trifluorobutyl, and trichloromethyl groups.
  • hydroxyalkyl refers to an alkyl substituted with one, two, or three hydroxy groups.
  • the hydroxyalkyl is a monohydroxyalkyl, i.e., a hydroxyalkyl substituted with one hydroxy group.
  • the hydroxyalkyl is a dihydroxyalkyl, i.e., a hydroxyalkyl substituted with two hydroxy groups.
  • Non-limiting exemplary hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups, such as 1-hydroxyethyl, 2-hydroxyethyl, 1, 2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl, and 1, 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 C 1-4 alkyl substituted with one optionally substituted heteroaryl group.
  • Non-limiting exemplary heteroaralkyl groups include:
  • the term " (cycloalkyl) alkyl, " as used by itself or as part of another group refers to an alkyl substituted with an optionally substituted cycloalkyl.
  • the (cycloalkyl) alkyl is a " (C 3-6 cycloalkyl) C 1-4 alkyl, " i.e., a C 1-4 alkyl substituted with an optionally substituted C 3-6 cycloalkyl.
  • Non-limiting exemplary (cycloalkyl) alkyl groups include:
  • alkylsulfonyl refers to a sulfonyl, i.e., -SO 2 -, substituted with an optionally substituted alkyl.
  • the alkyl sulfonyl group is a C 1-4 alkylsulfonyl group.
  • Non-limiting exemplary alkylsulfonyl groups include -SO 2 CH 3 and -SO 2 CH 2 CH 3 .
  • haloalkylsulfonyl as used by itself or as part of another group refers to a sulfonyl, i.e., -SO 2 -, substituted with a haloalkyl.
  • a non-limiting exemplary haloalkylsulfonyl group is -SO 2 CF 3 .
  • cycloalkylsulfonyl as used by itself or as part of another group refers to a sulfonyl, i.e., -SO 2 -, substituted with an optionally substituted cycloalkyl.
  • Non-limiting exemplary cycloalkylsulfonyl groups include -SO 2 -cyclopropyl and -SO 2 -cyclopenyl.
  • (cycloalkyl) alkylsulfonyl refers to a sulfonyl, i.e., -SO 2 -, 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., -SO 2 -, substituted with an optionally substituted aryl.
  • a non-limiting exemplary arylsulfonyl group is -SO 2 Ph.
  • heteroarylsulfonyl refers to a sulfonyl, i.e., -SO 2 -, substituted with an optionally substituted heteroaryl group.
  • heteroarylsulfonyl groups include:
  • heterocyclosulfonyl refers to a sulfonyl, i.e., -SO 2 -, substituted with an optionally substituted heterocyclo group.
  • heterocyclosulfonyl groups include:
  • (heterocyclo) alkylsulfonyl refers to a sulfonyl, i.e., -SO 2 -, substituted with a (heterocyclo) alkyl.
  • Non-limiting exemplary (heterocyclo) alkylsulfonyl groups include:
  • sulfonamido refers to a radical of the formula -SO 2 NR 31a R 31b , wherein R 31a and R 31b are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted aryl, or R 31a and R 31b taken together with the nitrogen to which they are attached from a 3-to 8-membered heterocyclo group.
  • Non-limiting exemplary sulfonamido groups include -SO 2 NH 2 , -SO 2 N (H) CH 3 , -SO 2 N (CH 3 ) 2 , and -SO 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 C 1-6 alkyl attached to a terminal oxygen atom.
  • the alkoxy group is a C 1-4 alkyl attached to a terminal oxygen atom.
  • Non-limiting exemplary alkoxy groups include methoxy, ethoxy, tert-butoxy, and isopropoxy.
  • heterocyclooxy as used by itself or as part of another group refers an oxy, i.e., -O-, substituted with an optionally substituted heterocyclo group.
  • Non-limiting exemplary heterocyclooxy groups include:
  • alkylthio refers to an optionally substituted alkyl attached to a terminal sulfur atom.
  • the alkylthio group is a C 1-4 alkylthio group.
  • Non-limiting exemplary alkylthio groups include -SCH 3 and -SCH 2 CH 3 .
  • 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 PhCH 2 O-and PhCH 2 CH 2 O-.
  • 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.
  • the heteroaryl is a 5-or 6-membered heteroaryl.
  • the heteroaryl has 5 ring atoms, e.g., thienyl, a 5-membered heteroaryl having four carbon atoms and one sulfur atom.
  • 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, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, ⁇ -carbolin
  • 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., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl) , imidazolyl (e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl) , pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-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
  • 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 heteroaryl is a bicyclic aromatic ring system having 9 ring atoms wherein at least one carbon atom of the ring system is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • Non-limiting exemplary bicyclic aromatic ring system having 9 ring atoms include imidazo [1, 5-a] pyridyl, [1, 2, 4] triazolo [4, 3-a] pyridyl, imidazo [1, 2-a] pyridyl, imidazo [1, 2-c] pyrimidinyl, pyrazolo [1, 5-a] pyridyl, imidazo [1, 2-a] pyrazinyl, imidazo [1, 2-a] pyrimidinyl,
  • 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, optional
  • 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.
  • Non-limiting exemplary substituted heteroaryls include:
  • 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:
  • Additional non-limiting examples of a 5-membered heteroarylenyl include:
  • the heteroarylenyl is a 6-membered heteroarylenyl.
  • 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 quaternized.
  • 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, 2-oxopyrrolidin-1-yl, 2-oxooxazolidin-3-yl, piperazin-2-one, piperazine-2, 6-dione, 2-imidazolidinone, piperidinyl, 2-oxopiperidin-1-yl, morpholinyl, piperazinyl, pyrrolidinyl, indolinyl, and isoxazolidin-2-yl.
  • Additional non-limiting examples of heterocyclo groups include oxetanyl, tetrahydrofuranyl, tetrahydropuranyl,
  • Additional non-limiting exemplary substituted heterocyclo groups include:
  • amino refers to a radical of the formula -NR 32a R 32b , wherein R 32a and R 32b are each independently selected from the group consisting of hydrogen, alkyl, alkenylcarbonyl, alkoxy, aralkyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted heteroaryl, (heterocyclo) alkyl and (heteroaryl) alkyl, or R 32a and R 32b are taken together to form a 3-to 8-membered optionally substituted heterocyclo.
  • Non-limiting exemplary amino groups include -NH 2 , -N (H) (CH 3 ) , -N (CH 3 ) 2 .
  • (amino) alkyl refers to an alkyl substituted with an amino.
  • Non-limiting exemplary (amino) alkyl groups include -CH 2 CH 2 NH 2 , and -CH 2 CH 2 N (H) CH 3 , -CH 2 CH 2 N (CH 3 ) 2 , and -CH 2 N (H) -cyclopropyl.
  • Additional non-limiting exemplary (amino) alkyl groups include -CH 2 N (CH 3 ) 2 and -CH 2 NH (CH 3 ) .
  • R 33a and R 33b are taken together to taken together with the nitrogen to which they are attached form a 3-to 8-membered optionally substituted heterocyclo group.
  • Non-limiting exemplary carboxamido groups include -CONH 2 , -CON (H) CH 3 , -CON (CH 3 ) 2 , -CON (H) Ph,
  • Additional non-limiting exemplary carboxamido groups include:
  • the alkylcarbonyl group is a C 1-4 alkyl attached to the carbonyl group.
  • the alkoxy group is a C 1-4 alkyl attached to a terminal oxygen atom.
  • a non-limiting exemplary arylcarbonyl group is -COPh.
  • the alkoxy is a C 1-4 alkoxy.
  • (alkoxycarbonyl) alkyl refers to an alkyl substituted by an alkoxycarbonyl group.
  • the alkoxy is a C 1-4 alkoxy.
  • the alkenyl group is a C 2-6 alkenyl.
  • the alkenyl is a C 2-4 alkenyl.
  • carboxy as used by itself or as part of another group refers to a radical of the formula -CO 2 H.
  • carboxyalkyl as used by itself or as part of another group refers to an alkyl substituted with a -CO 2 H.
  • a non-limiting exemplary carboxyalkyl group is -CH 2 CO 2 H.
  • R 33a and R 33b are each independently hydrogen or optionally substituted alkyl.
  • R 33a and R 33b are taken together to taken together with the nitrogen to which they are attached form a 3-to 8-membered optionally substituted heterocyclo group.
  • aralkyl refers to an alkyl substituted with one, two, or three optionally substituted aryl groups.
  • aralkyl is a C 1-4 alkyl substituted with one optionally substituted C 5 or C 6 aryl group.
  • the aralkyl is a C 1 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 C 1 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 C 1-4 alkyl substituted with one optionally substituted heterocyclo group.
  • Non-limiting exemplary (heterocyclo) alkyl groups include:
  • heterocyclo alkyl groups include:
  • the term " (heteroaryl) alkyl” as used by itself or part of another group refers to an alkyl substituted with an optionally substituted heteroaryl group.
  • the (heteroaryl) alkyl is a C 1-4 alkyl substituted with one optionally substituted heteroaryl group.
  • the (heteroaryl) alkyl is a C 1 alkyl substituted with one optionally substituted heteroaryl group
  • Non-limiting exemplary (heteroaryl) alkyl groups include:
  • the term " (carboxamido) alkyl” as used by itself or as part of another group refers to an alkyl substituted with one or two carboxamido groups.
  • the (carboxamido) alkyl is a C 1-4 alkyl substituted with one carboxamido group, i.e., a (carboxamido) C 1-4 alkyl.
  • the (carboxamido) alkyl is a C 1- 4 alkyl substituted with two carboxamido groups.
  • Non-limiting exemplary (carboxamido) alkyl groups include -CH 2 CONH 2 , -C (H) CH 3 CONH 2 , -CH 2 CON (H) CH 3 , and -CH 2 CON (CH 3 ) 2 .
  • 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 C 1-4 alkyl substituted with an aryloxy.
  • the (aryloxy) alkyl is a C 2-4 alkyl substituted with an aryloxy.
  • Non-limiting exemplary (aryloxy) alkyl groups include -CH 2 CH 2 OPh and -CH 2 CH 2 CH 2 OPh.
  • alkylcarbonyloxy refers to an oxy, e.g., -O-, substituted with an alkylcarbonyl group.
  • cycloalkylcarbonyloxy refers to an oxy, e.g., -O-, substituted with a cycloalkylcarbonyl group.
  • carboxamidooxy as used by itself or as part of another group refers an oxy, i.e., -O-, substituted with a carboxamido group.
  • Non-limiting exemplary carboxamidooxy groups include:
  • heteroaryloxy as used by itself or as part of another group refers an oxy, i.e., -O-, substituted with an optionally substituted heteroaryl group.
  • Non-limiting exemplary heteroaryloxy groups include:
  • menin inhibitor or “inhibitor of menin” as used herein refers to a compound that disrupts, e.g., inhibits, the menin-MLL fusion protein interaction.
  • a disease or condition wherein inhibition of menin provides a benefit pertains to a disease or condition in which menin and/or the interaction of menin with a menin-interacting protein is important or necessary, e.g., for the onset, progress, or expression of that disease or condition, or a disease or a condition which is known to be treated by a menin inhibitor.
  • 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.
  • 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 affected 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.
  • tainer means any receptacle and closure therefore suitable for storing, shipping, dispensing, and/or handling a pharmaceutical product.
  • insert means information accompanying a pharmaceutical product that provides a description of how to administer the product, along with the safety and efficacy data required to allow the physician, pharmacist, and patient to make an informed decision regarding use of the product.
  • the package insert generally is regarded as the "label" for a pharmaceutical product.
  • Constant administration means that two or more agents are administered concurrently to the subject being treated.
  • each agent is administered either simultaneously or sequentially in any order at different points in time.
  • 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 refers to a measure for how much of one enantiomer is present compared to the other.
  • the percent enantiomeric excess is defined as ( [ ⁇ ] obs / [ ⁇ ] max ) *100, where [ ⁇ ] obs is the optical rotation of the mixture of enantiomers and [ ⁇ ] max is the optical rotation of the pure enantiomer. Determination of enantiomeric excess is possible using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography or optical polarimetry. In one embodiment, ee is determined by chiral HPLC.
  • Compounds of Formula I can be prepared by the general method shown in Scheme 1.
  • PG Protecting Group
  • Any suitable amine protecting group known in the art for example, a carboxybenzyl (Cbz) group may be used.
  • Azaspiro ketone 1-B can be prepared from the commercially available amines (for example, 2-Azaspiro [3.3] heptan-6-one, 2-Azaspiro [3.5] nonan-7-one, 2-Azaspiro [3.4] octan-6-one, 6-Azaspiro [3.4] octan-2-one, 7-Azaspiro [3.5] nonan-2-one, and 3-Azaspiro [5.5] undecan-9-one) , followed by addition of a suitable amine protecting group by methods known in the art.
  • Intermediate 1-D can then be used in the coupling reactions described in general Schemes 4-6 to yield compounds of Formula I.
  • Compounds of Formula I can be prepared by the general method shown in Scheme 2.
  • a reductive animation reaction between amine 2-A and ketone 1-B affords intermediate 2-B, which upon deprotection of the protecting group PG 2 on the azaspiro 2-C yields intermediate 2-C.
  • Any suitable amine protecting group known in the art may be used although when there are multiple amine protecting groups, those protecting groups should be different (for example, PG 1 can be t-butyloxycarbonyl (BOC) and PG 2 can be Cbz) .
  • Compounds of Formula I can be prepared by the general method shown in Scheme 3.
  • a reductive animation reaction between amine 3-A and ketone 1-B affords intermediate 3-B, which upon deprotection of the protecting group PG 2 on the azaspiro 3-B yields intermediate 3-C.
  • Any suitable amine protecting group known in the art may be used although when there are multiple amine protecting groups, those protecting groups should be different (for example, PG can be t-butyloxycarbonyl (BOC) and PG 2 can be Cbz) .
  • Intermediate 3-C can then be used in the coupling reactions described in Schemes 4-6, followed by deprotection of the remaining protecting group and the formation of the V 1 substituent.
  • a nucleophilic aromatic substitution reaction between azaspiro 1-D and aryl fluoride 1-E or azaspiro 1-D and aryl sulfonylmethyl 1-F in the presence of a base affords the Compound of Formula I.
  • Compounds of Formula I wherein E is E-1, E-4, E-5, E-6, E-7, E-8, E-9, E-10, E-11, E-12, E-13, E-14, E-15, E-17, E-18, E-19, E-20, E-21, E-22, E-23, E-24, E-25, and E-35 can be prepared by the general method shown in Scheme 5.
  • a Buchwald-Hartwig amination reaction between azaspiro 1-D and aryl bromide 1-F affords the Compound of Formula I.
  • Compounds of Formula I wherein E is E-16, E-26, E-27, E-28, E-29, E-30, E-33, and E-34 can be prepared by the general method shown in Scheme 6 or by other methods known in the art for preparing sulfonamides and carbamates.
  • the enantiopure compound S7 is isolated by recrystallization in a solution of hexane and dichloromethane with a ratio of 4: 1.
  • the quenched reaction was diluted with ethyl acetate, 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 NaBH 4 (130 mg, 3.43 mmol) . After overnight the reaction was quenched with 2M NaOH, diluted with ethyl acetate, 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 S11 (775 mg) .
  • Step A methyl ( (1S, 2R) -2- ( (S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2- (methylamino) ethyl) cyclopentyl) carbamate (S14)
  • Step B methyl ( (1S, 2R) -2- ( (S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate (S15)
  • Step C methyl ( (1S, 2R) -2- ( (S) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) -1- (piperidin-4-yl) ethyl) cyclopentyl) carbamate (S16)
  • Step D tert-butyl 6- (4- ( (S) -1- (3-fluorophenyl) -1- ( (1R, 2S) -2- ( (methoxycarbonyl) amino) cyclopentyl) -2- (N-methylmethylsulfonamido) ethyl) piperidin-1-yl) -2-azaspiro [3.3] heptane-2-carboxylate (S17)
  • Step E methyl ( (1S, 2R) -2- ( (S) -1- (1- (2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate (S18)
  • Step A methyl ( (1S, 2R) -2- ( (S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylacetamido) ethyl) cyclopentyl) carbamate (S19)
  • Step A 5-bromo-N, N-dimethyl-2- (pyrimidin-2-yl) benzamide
  • Step B methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (3- (dimethylcarbamoyl) -4- (pyrimidin-2-yl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate (Cpd 75)
  • Cpd 96 was made in the same manner with 1-Methyl-1H-pyrazole-4-boronic acid pinacol ester.
  • Step A 2- (benzo [d] thiazol-2-yl) -5-bromo-N, N-dimethylbenzamide
  • Step B methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (4- (benzo [d] thiazol-2-yl) -3- (dimethylcarbamoyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate (Cpd 104)
  • Step B 5-bromo-4-fluoro-N, N-dimethyl-2- (1-methyl-1H-pyrazol-3-yl) benzamide
  • Step C methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (5- (dimethylcarbamoyl) -2-fluoro-4- (1-methyl-1H-pyrazol-3-yl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate (Cpd 110)
  • Cpd 121 was made in the same manner with 4, 5-dimethyl-2- (tributylstannyl) thiazole.
  • Step A 4, 5-dimethyl-2- (tributylstannyl) oxazole
  • Step B 5-bromo-2- (4, 5-dimethyloxazol-2-yl) -N, N-dimethylbenzamide
  • Step C methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (3- (dimethylcarbamoyl) -4- (4, 5-dimethyloxazol-2-yl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate (Cpd 124)
  • Step A (4-bromo-2- (dimethylcarbamoyl) -5-fluorophenyl) boronic acid
  • Step D 5-bromo-4-fluoro-2- (4-fluoro-1-methyl-1H-pyrazol-3-yl) -N, N-dimethylbenzamide
  • Step E methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (5- (dimethylcarbamoyl) -2-fluoro-4- (4-fluoro-1-methyl-1H-pyrazol-3-yl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate (Cpd 155)
  • Step A 5-bromo-4-fluoro-N, N-dimethyl-2- (pyridazin-3-yl) benzamide
  • Step B methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (5- (dimethylcarbamoyl) -2-fluoro-4- (pyridazin-3-yl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate
  • Step B 6-fluoro-N, N-dimethyl-3- (oxazol-2-yl) picolinamide
  • Step C methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (6- (dimethylcarbamoyl) -5- (oxazol-2-yl) pyridin-2-yl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylacetamido) ethyl) cyclopentyl) carbamate (Cpd 162)
  • Step A (4-bromo-2- (dimethylcarbamoyl) -5-fluorophenyl) boronic acid

Abstract

The present disclosure provides compounds represented by Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ra, Rb, Rc, Rd, V1, Q, E, n, p, q, r and s 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
U.S. GOVERNMENT LICENSE RIGHTS
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 Field of the Invention
The present disclosure provides compounds as menin inhibitors and therapeutic methods of treating conditions and diseases wherein inhibition of menin provides a benefit.
Background
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-κB 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 (Brca1) product.
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 MEN1 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.
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.
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.
Aberrant expression of HOX genes is also found in AML patients with mutations inNPM1. 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, Pem, Runx2, Hlbx9, ER, PPARγ, vitamin D receptor, transcription repressors, e.g., JunD, Sin3A, HDAC, EZH2, PRMT5, NFκB, Sirt1, CHES1, cell signaling proteins, e.g., AKT, SOS1/GEF, β-catenin, SMAD 1, 3, 5, NFκB, ER, PPARγ, 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. 6: 447-462 (2014) ; He et al., J. Med. Chem. 57: 1543-1556 (2014) ; and Borkin et al., Cancer Cell 27: 589–602 (2015) ; Krivtsov et al. Cancer Cell 36: 660-673 (2019) ; Klossowski et al. J. Clin. Invest. 130: 981-997 (2020) ; Uckelmann et al. Science 367: 586-590 (2020) .
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.
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
In one aspect, the present disclosure provides compounds represented by Formulae I-XXXI, 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.
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.
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.
In another aspect, the present disclosure provides a pharmaceutical composition comprising a Compound of the Disclosure and an excipient and/or pharmaceutically acceptable carrier.
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.
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.
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.
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.
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.
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.
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
Compounds of the Disclosure are menin inhibitors.
In one embodiment, Compounds of the Disclosure are compounds represented by Formula I,
Figure PCTCN2021122588-appb-000001
or a pharmaceutically acceptable salt thereof, wherein:
each R a is independently hydrogen or C 1-C 4 alkyl;
each R b is independently hydrogen or C 1-C 4 alkyl;
R c is hydrogen or halo;
each R d is independently halo;
p, q, r and s are independently 1 or 2;
n is 0, 1 or 2;
V 1 is -NR 1SO 2 (C 1-C 4 alkyl) , -NR 1SO 2 (C 1-C 4 haloalkyl) , -NR 1 (C=O) (C 1-C 4 alkyl) , -NR 1 (C=O) (C 1-C 4 haloalkyl) , -NR 1 (C=O) H, 
Figure PCTCN2021122588-appb-000002
Figure PCTCN2021122588-appb-000003
Q is -N (H) C (=O) OR, -N (R) C (=O) OR, -N (H) C (=O) R, -N (H) C (O) NHR, -N (H) C (O) NR 2, -OC (=O) NR 2, 
Figure PCTCN2021122588-appb-000004
each R is independently C 1-C 4 alkyl, C 1-C 4 haloalkyl, or CD 3;
each R 1 is independently hydrogen or C 1-C 4 alkyl;
each R 2 is independently C 1-C 4 alkyl;
each k is independently 0, 1, 2, 3, or 4;
E is
Figure PCTCN2021122588-appb-000005
Figure PCTCN2021122588-appb-000006
Figure PCTCN2021122588-appb-000007
J is optionally substituted heteroaryl, optionally substituted heterocyclo, optionally substituted aryl, carboxamido, haloalkoxy, alkoxy, alkylcarbonyloxy, carboxamidooxy, (carboxamido) alkyl, aralkyloxy, aryloxy, heterocyclooxy, heteroaryloxy, alkoxycarbonyl, hydrogen, C 1-C 4 alkyl, C 1-C 4 alkylcarbonyl, hydroxy, cyano, haloalkyl, -NO 2, halo, -NR 1SO 2 (C 1-C 4 alkyl) , -NR 1SO 2 (C 2-C 6 alkenyl) , -NR 1CO (C 1-C 4 alkyl) , -S (=O) (=NR 1) CF 3, S (=O) (=NR 1) (C 1-C 4 alkyl) , amino, sulfonamido, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, heterocycloalkylsulfonyl, or C 1-C 4 phosphine oxide;
Y is -C (=O) -, -SO 2-, -C (=O) NH-, or -C (=O) N (C 1-C 4alkyl) -;
L is absent or is optionally substituted C 1-C 6 alkyl or C 1-C 6 haloalkyl;
J 2 is C 1-C 4 alkyl, C 1-C 6 haloalkyl, cyano, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, or optionally substituted heterocyclo;
R 4 is hydrogen, C 1-C 4 alkyl, C 1-C 4alkylcarbonyl, heterocyclo, or haloalkyl;
W is -NH-, -O-, or -S-;
R 5 is hydrogen, amino, C 1-C 6 alkyl, C 1-C 6 alkoxy, or halo;
each m is independently 1 or 2;
Y 1 is absent or is -C (=O) -, -SO 2-, -C (=O) NH-, or -C (=O) N (Me) -;
v is 0 or 1;
R 6 is hydrogen, haloalkyl, C 1-C 4 alkyl, C 1-C 4 alkylcarbonyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, heterocycloalkylsulfonyl, carboxamido, mesylate, or tert-butoxycarbonyl;
each R 7 is independently hydrogen, cyano, halo, haloalkyl, C 1-C 4 alkyl, C 1-C 4 alkylcarbonyl, hydroxy, sulfonamido, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, heterocycloalkylsulfonyl, or carboxamido;
R 8a, R 8b, R 8c, and R 8d are independently hydrogen, halo, carboxy, hydroxy, C 1-C 4 alkoxycarbonyl, C 1-C 4 alkyl, C 1-C 4 alkoxy, haloalkyl, haloalkoxy, -CH 2SO 2C 1-C 4 alkyl, sulfonamido, cyano, alkoxyalkyl, aralkyloxy, alkylsulfonyl, (amino) alkyl, carboxamido, (carboxamido) alkyl, thioamide, optionally substituted heteroaryl, (heteroaryl) alkyl, -NR 13C (O) C 1-C 4 alkyl, -OCH 2CH=CH-alkylsulfonyl, -O (C 1-C 4 alkyl) O (C 1-C 4 alkyl) , C 2-C 6 alkenyl, heterocyclooxy, aminocarbonyloxy, or (heterocyclo) alkyl;
Z is hydrogen, C 1-C 4 alkyl, C 1-C 4 alkylcarbonyl, hydroxy, cyano, haloalkyl, -NO 2, halo, -NR 1SO 2 (C 1-C 4 alkyl) , -NR 1SO 2 (C 2-C 6 alkenyl) , -NR 1CO (C 1-C 4 alkyl) , -CONH 2, -CONH (C 1-C 4 alkyl) , -CON (C 1-C 4 alkyl)  2, -S (=O) (=NR 1) CF 3, S (=O) (=NR 1) (C 1-C 4 alkyl) , amino, sulfonamido, alkylsulfonyl, haloalkylsulfonyl, or cycloalkylsulfonyl;
each W 1 is independently -CH-or -N-;
t and u are independently 0, 1, 2, or 3;
X is C 2-C 4 alkenyl, (amino) alkyl, -CH 2CH 2NR 1Y 1-Z 2,
Figure PCTCN2021122588-appb-000008
Figure PCTCN2021122588-appb-000009
Figure PCTCN2021122588-appb-000010
wherein
Z 2is -C (R 14a) =C (R 14b) (R 14c) , -C≡CR 14d, alkyl, alkoxy, haloalkyl, or R a2;
R 9a and R 9b are each independently alkenyl, alkynyl, cyano, C 1-C 4 alkyl, halo, (amino) alkyl, or -C (R 14a) =C (R 14b) (R 14c) ;
each Q 1 is independently -CH 2-or -C (=O) -;
R 10 is hydrogen, C 1-C 4 alkyl, -NR 13CO (C 1-C 4 alkyl) , -NR 13SO 2 (C 1-C 4 alkyl) , cyano, halo, -OCH 2CH=CH-R a3, or -CH 2CH 2CH=CH-R a3;
R 11 is halo, -NR 13COC (R 14a) =C (R 14b) (R 14c) , carboxamido, -C (O) NR 13CH 2R a5, -C (O) NR 13CH 2CH=CH-R a3, -C (O) NR 13CH 2C≡CR a6, or -CH 2CH 2CH=CH-R a3;
R 12 is alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, or carboxamido;
R 13 is hydrogen or C 1-C 4 alkyl;
R 14a, R 14b, R 14c, and R 14d are each independently hydrogen, halo, C 1-C 4 alkyl, (amino) alkyl, or R a3;
R a2 is -N (R 15) CH 2CH=CH-R a3 or -CH=CHCH 2R a4;
R a3 is alkoxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, or carboxamido;
R a4 is optionally subsubstituted heterocyclo;
R a5 is cyano or (amino) alkyl;
R a6 is hydrogen or carboxamido;
R 15 is hydrogen or C 1-C 4 alkyl; and
R 16 is hydrogen or C 1-C 4 alkyl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae II-IX:
Figure PCTCN2021122588-appb-000011
Figure PCTCN2021122588-appb-000012
wherein Q, V 1, E, R a, R b, R c, R d, n, p, q, r, s, and remaining variables are defined above in accordance with Formula I.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-IX, and the pharmaceutically acceptable salts thereof.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-IX, and the pharmaceutically acceptable salts thereof, wherein at least one R a is hydrogen.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-IX, and the pharmaceutically acceptable salts thereof, wherein each R a is hydrogen.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-IX, and the pharmaceutically acceptable salts thereof, wherein at least one R b is hydrogen.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-IX, and the pharmaceutically acceptable salts thereof, wherein each R b is hydrogen.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-IX, and the pharmaceutically acceptable salts thereof, wherein each R aand R b is hydrogen.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-IX, and the pharmaceutically acceptable salts thereof, wherein p, q r and s are 1.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-IX, and the pharmaceutically acceptable salts thereof, wherein p, q and r are 1 and s is 2.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-IX, and the pharmaceutically acceptable salts thereof, wherein p, r and s are 1 and q is 2.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-IX, and the pharmaceutically acceptable salts thereof, wherein q, r and s are 1 and p is 2.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-IX, and the pharmaceutically acceptable salts thereof, wherein p, q and s are 1 and r is 2.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-IX, and the pharmaceutically acceptable salts thereof, wherein p and q are 1 and r and s are 2.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-IX, and the pharmaceutically acceptable salts thereof, wherein p and q are 2 and r and s are 1.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae X-XV:
Figure PCTCN2021122588-appb-000013
Figure PCTCN2021122588-appb-000014
wherein Q, V 1, E, R c, R d, n, and remaining variables are defined above in accordance with Formula I.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae X-XV, and the pharmaceutically acceptable salts thereof.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein R c is hydrogen.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein R c is halo.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein R c is fluoro.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein n is 0 or 1.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein n is 0.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein R c is halo and n is 0.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein R c is fluoro and n is 0.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein R d is fluoro.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein n is 1.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein n is 2.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein n is 1 and R d is fluoro.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein Q is -N (H) C (=O) OR.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein Q is -N (H) C (=O) OR and R is C 1-C 4 alkyl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein Q is -NHCO 2CH 3 or -NHCO 2CH 2CH 3.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein Q is -NHCO 2CH 3.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, E-10, E-11, E-12, E-13, E-14, E-15, and E-16.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-2, and E-3.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, and E-18.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-4 and E-5.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-6 and E-7.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-13, E-14 and E-15.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is
Figure PCTCN2021122588-appb-000015
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least one of R 8a, R 8b, R 8c, and R 8d is hydrogen.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least two of R 8a, R 8b, R 8c, and R 8d are hydrogen.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least three of R 8a, R 8b, R 8c, and R 8d are hydrogen.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein wherein E is E-1, E-17, or E-18 and each of R 8a, R 8b, R 8c, and R 8d are hydrogen.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least one of R 8a, R 8b, R 8c, and R 8d is halo.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least two of R 8a, R 8b, R 8c, and R 8d are halo.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least one of R 8a, R 8b, R 8c, and R 8d is fluoro.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least two of R 8a, R 8b, R 8c, and R 8d are fluoro.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least one of R 8a, R 8b, R 8c, and R 8d is C 1-C 4 alkyl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least two of R 8a, R 8b, R 8c, and R 8d are C 1-C 4 alkyl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least one of R 8a, R 8b, R 8c, and R 8d are methyl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least two of R 8a, R 8b, R 8c, and R 8d are methyl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least one of R 8a, R 8b, R 8c, and R 8d is C 1-4 alkyl, halo, optionally substituted heteroaryl, carboxamido, thioamide, (carboxamido) alkyl, heterocyclooxy, carboxamidooxy, alkoxy, haloalkyl, aralkyloxy, or (amino) alkyl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least one of R 8a, R 8b, R 8c, and R 8d is carboxamido.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least one of R 8a, R 8b, R 8c, and R 8d is
Figure PCTCN2021122588-appb-000016
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least one of R 8a, R 8b, R 8c, and R 8d is
Figure PCTCN2021122588-appb-000017
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least one of R 8a, R 8b, R 8c, and R 8d is optionally substituted heteroaryl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least one of R 8a, R 8b, R 8c, and R 8d is optionally substituted heteroaryl, wherein the optionally substituted heteroaryl is pyrazolyl, oxazolyl, thiazolyl, pyrazolyl, or pyridinyl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-1, E-17, or E-18 and at least one of R 8a, R 8b, R 8c, and R 8d is optionally substituted heteroaryl, wherein the optionally substituted heteroaryl is pyrazol-3-yl, oxazol-2-yl, thiazol-2-yl, pyrazol-4-yl, or pyridin-2-yl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is
Figure PCTCN2021122588-appb-000018
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is
Figure PCTCN2021122588-appb-000019
and at least one of R 8a and R 8b is halo.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is
Figure PCTCN2021122588-appb-000020
and at least one of R 8a and R 8b is fluoro.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is
Figure PCTCN2021122588-appb-000021
and at least one of R 8a and R 8b is C 1-C 4 alkyl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is
Figure PCTCN2021122588-appb-000022
and at least one of R 8a and R 8b is methyl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is
Figure PCTCN2021122588-appb-000023
R 8a is C 1-C 4 alkyl or halo; and R 8b is hydrogen or carboxamido.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is
Figure PCTCN2021122588-appb-000024
and at least one of R 8b and R 8c is halo.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is
Figure PCTCN2021122588-appb-000025
and at least one of R 8b and R 8c is fluoro.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is
Figure PCTCN2021122588-appb-000026
and at least one of R 8b and R 8c is C 1-C 4 alkyl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is
Figure PCTCN2021122588-appb-000027
and at least one of R 8b and R 8c is methyl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is
Figure PCTCN2021122588-appb-000028
R 8b is optionally substituted heteroaryl, carboxamido, or thioamide; and R 8c is hydrogen or halo.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is
Figure PCTCN2021122588-appb-000029
R 8b is carboxamido, and R 8c is hydrogen or fluoro.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable  salts thereof, wherein E is
Figure PCTCN2021122588-appb-000030
R 8b is
Figure PCTCN2021122588-appb-000031
Figure PCTCN2021122588-appb-000032
Figure PCTCN2021122588-appb-000033
and R 8c is hydrogen or fluoro.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is
Figure PCTCN2021122588-appb-000034
R 8b is
Figure PCTCN2021122588-appb-000035
and R 8c is hydrogen or fluoro.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is
Figure PCTCN2021122588-appb-000036
and at least one of R 8b, R 8c, and R 8d is carboxamido or (amino) alkyl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-2, and at least one of R 8b, R 8c, and R 8d is –CH 2N (CH 3)  2.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable  salts thereof, wherein E is E-2, and at least one of R 8b, R 8c, and R 8d is
Figure PCTCN2021122588-appb-000037
Figure PCTCN2021122588-appb-000038
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-2 and at least one of R 8b, R 8c, and R 8d is
Figure PCTCN2021122588-appb-000039
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is
Figure PCTCN2021122588-appb-000040
R 4 is C 1-C 4 alkyl, C 1-C 4 alkylcarbonyl, heterocyclo, or C 1-C 4 haloalkyl; and J is cyano, optionally substituted heteroaryl, or heteroarylsulfonyl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-4 or E-5; R 4 is methyl, ethyl, isopropyl, acetyl, oxetanyl, tetrahydropyranyl, -CH 2CF 3, -CH 2CHF 2, -CH 2CH 2F or -CH (CH 2F)  2; and J is cyano, optionally substituted heteroaryl, or heteroarylsulfonyl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable  salts thereof, wherein E is
Figure PCTCN2021122588-appb-000041
R 4 is C 1-C 4 alkyl; and J is cyano or optionally substituted heteroaryl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is
Figure PCTCN2021122588-appb-000042
and J is cyano or optionally substituted heteroaryl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is
Figure PCTCN2021122588-appb-000043
R 5 is amino; and J is cyano or optionally substituted heteroaryl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is
Figure PCTCN2021122588-appb-000044
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is
Figure PCTCN2021122588-appb-000045
and L is absent or is -CH 2-, -C (CH 3)  2-, or -CF 2-.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts  thereof, wherein E is
Figure PCTCN2021122588-appb-000046
Figure PCTCN2021122588-appb-000047
wherein R 8a, R 8b, R 8c, and R 8d, Z, R 1, R 6, R 7, and remaining variables are defined above in accordance with Formula I.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-16, and J 2 is optionally substituted heterocyclo, wherein the optionally substituted hetercyclo is
Figure PCTCN2021122588-appb-000048
and R 6, t and u are defined above in accordance with Formula I.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is E-16, and J 2 is optionally substituted cycloalkyl, wherein the optionally substituted cycloalkyl is
Figure PCTCN2021122588-appb-000049
and R 7, t, and u are defined above in accordance with Formula I.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XV, and the pharmaceutically acceptable salts thereof, wherein E is
Figure PCTCN2021122588-appb-000050
and X is X-5 or X-21.
In some embodiments, Compounds of the Disclosure are compounds represented by any one or more of Formulae XVI-XVIII:
Figure PCTCN2021122588-appb-000051
wherein V 1, R 8b, R 8c, J 2 and remaining variables are defined above in accordance with Formula I.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XVI-XVIII, and the pharmaceutically acceptable salts thereof.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is cyano, alkylsulfonyl, haloalkyl, haloalkylsulfonyl, halo, optionally substituted heteroaryl, heteroarylsulfonyl, carboxamido, haloalkoxy, alkoxy, carboxamidooxy, (carboxamido) alkyl, heteroaryloxy, aralkyloxy, -NR 1SO 2 (C 1-C 4alkyl) , -NR 1CO (C 1-C 4alkyl) , -S (=O) (=NR 1) CF 3, or -S (=O) (=NR 1) (C 1-C 4alkyl) .
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is cyano or alkylsulfonyl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is cyano.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is -CF 3.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is methylsulfonyl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is -SO 2CF 3.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is fluoro.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is optionally substituted heterocyclo and the optionally substituted heterocyclo is
Figure PCTCN2021122588-appb-000052
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is haloalkoxy, alkoxy, carboxamidooxy, heteroaryloxy, or aralkyloxy.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is
Figure PCTCN2021122588-appb-000053
Figure PCTCN2021122588-appb-000054
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is optionally substituted heteroaryl and the optionally substituted heteroaryl is pyrazolyl, oxazolyl, isoxazolyl, pyrimidinyl, thiazolyl, triazolyl, triazinyl, oxadiazolyl, pyridinyl, quinazolinyl, pyrazolo [3, 4-d] pyrimidinyl, benzo [d] oxazolyl, thiadiazolyl, benzo [d] thiazolyl, pyrazolo [4, 3-d] pyrimidinyl, pyrrolo [2, 3-d] pyrimidinyl, thiazolo [5, 4-d] pyrimidinyl, purinyl, pyrazinyl, pyridazinyl, or tetrazolyl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is optionally substituted heteroaryl and the optionally substituted heteroaryl is oxazol-2-yl, isoxazole-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, 1, 2, 4-oxadiazol-5-yl, thiazol-2-yl, pyrazol-4-yl, pyrazol-3-yl, quinazolin-2-yl, pyrazolo [3, 4-d] pyrimidin-6-yl, benzo [d] thiazol-2-yl, benzo [d] oxazol-2-yl, 1, 3, 5-triazol-2-yl, 1, 2, 4-triazol-3-yl, 1, 3, 4-oxadiazol-2-yl, 1, 2, 4-oxadiazol-3-yl, pyrazin-2-yl, pyridazin-3-yl, 1, 3, 4-thiadiazol-2-yl, pyrazolo [4, 3-d] pyrimidin-5-yl, pyrrolo [2, 3-d] pyrimidin-2-yl, thiazolo [5, 4-d] pyrimidin-5-yl, purin-2-yl, 1, 2, 4-triazin-3-yl, tetrazol-5-yl, or pyridin-2-yl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is optionally substituted heteroaryl and the optionally substituted heteroaryl is substituted with one or more of:
C 1-C 4alkyl, such as methyl, ethyl, propyl, isopropyl, or butyl;
halo such as Br, Cl, or F;
cyano;
C 1-C 4haloalkyl, such as CF 3, CH 2F, CHF 2, CH 2CF 3, CH 2CHF 2, CH 2CH 2F, CH (CH 2F)  2 C (CH 3)  2F, or C (CH 3) F 2;
amino, such as NH 2, or N (CH 2)  3; and
carboxamido, such as – (C=O) N (CH 3)  2.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is
Figure PCTCN2021122588-appb-000055
Figure PCTCN2021122588-appb-000056
Figure PCTCN2021122588-appb-000057
R 17 and R 18 are, independently, hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, cyano, halo, or amino; and R 19 is hydrogen or C 1-4 alkyl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable  salts thereof, wherein J is
Figure PCTCN2021122588-appb-000058
Figure PCTCN2021122588-appb-000059
and R 17 is hydrogen, C 1-4 alkyl such as methyl or ethyl, or amino, or preferably hydrogen or methyl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is
Figure PCTCN2021122588-appb-000060
and R 17 and R 18 are, independently, hydrogen or C 1-4 alkyl such as methyl or ethyl, or preferably hydrogen or methyl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is
Figure PCTCN2021122588-appb-000061
R 17 and R 18 are, independently, hydrogen, C 1-4 alkyl such as methyl or ethyl, or halo such as chloro or fluoro, or preferably hydrogen, methyl, or fluoro; and R 19 is hydrogen or C 1-4 alkyl such as methyl or ethyl, or preferably hydrogen or methyl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is
Figure PCTCN2021122588-appb-000062
and R 17 is hydrogen, C 1-4 alkyl such as methyl, ethyl, or isopropyl, C 1-4 haloalkyl such as CF 3, cyano, or halo such as chloro or fluoro.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable  salts thereof, wherein J is
Figure PCTCN2021122588-appb-000063
and R 17 and R 18 are, independently, hydrogen or C 1-4 alkyl such as methyl or ethyl, or preferably hydrogen or methyl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVIII, and the pharmaceutically acceptable salts thereof, wherein J is
Figure PCTCN2021122588-appb-000064
Figure PCTCN2021122588-appb-000065
R 17 is hydrogen, C 1-4 alkyl such as methyl or ethyl, or halo such as chloro or fluoro, or preferably hydrogen, methyl, or fluoro; and R 19 is hydrogen or C 1-4 alkyl such as methyl or ethyl, or preferably hydrogen or methyl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XVI-XVIII, and the pharmaceutically acceptable salts thereof, wherein R 8b is
Figure PCTCN2021122588-appb-000066
Figure PCTCN2021122588-appb-000067
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XVI-XVIII, and the pharmaceutically acceptable salts thereof, wherein R 8b is
Figure PCTCN2021122588-appb-000068
In some embodiments, Compounds of the Disclosure are compounds represented by any one or more of Formulae XIX-XXIV:
Figure PCTCN2021122588-appb-000069
Figure PCTCN2021122588-appb-000070
wherein V 1, Y, L, J 2 and remaining variables are defined above in accordance with Formula I.
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 Y is -C (=O) -, -C (=O) NH-, or -C (=O) N (C 1-C 4 alkyl) -; L is absent or is -CH 2-or -C (CH 3)  2-; and J 2 is C 1-C 6 haloalkyl or cyano.
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 Y is -C (=O) -or -C (=O) NH-; L is absent or is haloalkyl; and J 2 is optionally substituted aryl.
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 the optionally substituted aryl is substituted with one or more of:
C 1-C 4alkyl, such as methyl, ethyl, propyl, isopropyl, or butyl;
halo such as Br, Cl, or F;
cyano;
carboxamido such as
Figure PCTCN2021122588-appb-000071
C 1-C 4haloalkyl, such as CF 3, CH 2F, CHF 2, CH 2CF 3, CH 2CHF 2, CH 2CH 2F, CH (CH 2F)  2 C (CH 3)  2F, or C (CH 3) F 2; and
haloalkoxy, such as OCF 3.
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 J 2 is
Figure PCTCN2021122588-appb-000072
and R 20 is halogen such as chloro or fluoro, cyano, carboxamido, C 1-4 haloalkoxy such as OCF 3, or C 1-4 haloalkyl such as CF 3.
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 J 2 is
Figure PCTCN2021122588-appb-000073
Figure PCTCN2021122588-appb-000074
and R 20 and R 21 are, independently, halogen such as fluoro, cyano, carboxamido, C 1-4 haloalkoxy such as OCF 3, or C 1-4 haloalkyl such as CF 3.
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:
Y is -C (=O) -;
J 2 is optionally substituted cycloalkyl, wherein the optionally substituted cycloalkyl is:
Figure PCTCN2021122588-appb-000075
t and u are, independently, 0, 1, 2, or 3; and
R 22 and R 23 are independently hydrogen, cyano, halo, haloalkyl, C 1-C 4 alkyl, C 1-C 4 alkylcarbonyl, hydroxy, alkoxy, amino, sulfonamido, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, heterocycloalkylsulfonyl, carboxamido, optionally substituted aryl, or optionally substituted heteroaryl.
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 Y is -C (=O) -; L is absent; J 2 is
Figure PCTCN2021122588-appb-000076
R 22 is cyano or C 1-C 4 haloalkyl; and R 23 is hydrogen.
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 Y is -C (=O) -; L is absent; J 2 is
Figure PCTCN2021122588-appb-000077
and R 22 is cyano or C 1-C 4 haloalkyl.
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 Y is -C (=O) -; J 2 is optionally substituted heterocyclo, wherein the optionally substituted heterocyclo is
Figure PCTCN2021122588-appb-000078
t and u are, independently, 0, 1, 2, or 3; and R 22 and R 23 are independently hydrogen, cyano, halo, haloalkyl, C 1-C 4 alkyl, C 1-C 4 alkylcarbonyl, hydroxy, alkoxy, amino, sulfonamido, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, heterocycloalkylsulfonyl, carboxamido, or optionally substituted aryl, or optionally substituted heteroaryl.
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 Y is -C (=O) -; L is absent; J 2is
Figure PCTCN2021122588-appb-000079
Figure PCTCN2021122588-appb-000080
R 22 is hydrogen, cyano, halo such as fluoro or chloro, C 1- 4 haloalkyl such as CF 3, C 1-C 4 alkyl such as methyl, ethyl, propyl, isopropyl, or butyl, hydroxy, amino, carboxamido, or alkylsulfonyl such as methylsulfonyl or ethylsulfonyl, or preferably cyano, fluoro, methyl, or methylsulfonyl ; and R 23 is hydrogen, halo such as fluoro or chloro, or C 1-C 4 alkyl such as methyl, ethyl, propyl, isopropyl, or butyl, or preferably hydrogen, fluoro, or methyl.
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 Y is -C (=O) -; J 2 is
Figure PCTCN2021122588-appb-000081
t and u are, independently, 0, 1, 2, or 3; and R 24 is hydrogen, haloalkyl, C 1-C 4 alkyl, C 1-C 4 alkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, heterocycloalkylsulfonyl, carboxamido, mesylate, or tert-butoxycarbonyl.
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 Y is -C (=O) -; L is absent; J 2 is
Figure PCTCN2021122588-appb-000082
R 24 is haloalkyl such as -CH 2CH 2F, -CH 2CHF 2, or -CH 2CF 3, C 1-C 4 alkylcarbonyl such as – (C=O) Me, - (C=O) Et, - (C=O) Pr, or – (C=O) iPr, alkenylcarbonyl such as -C (=O) CH=CH 2, -C (=O) CH 2CH=CH 2, or -C (=O) CH 2CH 2CH=CH 2, or alkoxycarbonyl such as -C (=O) OMe, -C (=O) OEt, -C (=O) OPr, -C (=O) OiPr, or -C (=O) OtBu, or preferably -CH 2CHF 2, -CH 2CF 3, – (C=O) Me, -C (=O) CH=CH 2, -C (=O) OMe, -C (=O) OEt, or -C (=O) OiPr.
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 Y is -C (=O) -, -SO 2-, -C (=O) NH-or -C (=O) N (CH 3) -; L is absent or haloalkyl such as -CF 2-, or optionally substituted alkyl such as -CH 2-, -CH (CH 3) -, and -C (CH 3)  2-; and J 2 is optionally substituted heteroaryl.
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 the optionally substituted heteroaryl is substituted with one or more of:
C 1-C 4 alkyl, such as methyl, ethyl, propyl, isopropyl, or butyl;
halo such as Br, Cl, or F;
cyano;
optionally substituted cycloalkyl;
carboxamido;
C 1-C 4 haloalkyl, such as CF 3, CH 2F, CHF 2, CH 2CF 3, CH 2CHF 2, CH 2CH 2F, CH (CH 2F)  2 C (CH 3)  2F, or C (CH 3) F 2; and
haloalkoxy, such as OCF 3.
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 Y is -C (=O) -, -SO 2-, -C (=O) NH-; L is absent or haloalkyl such as -CF 2-, or optionally substituted alkyl such as -CH 2-, -CH (CH 3) -, and -C (CH 3)  2-; and J 2 is optionally substituted heteroaryl, wherein the optionally substituted heteroaryl is pyridinyl, pyrazolyl, pyrazolo [1, 5-a] pyridinyl, indazolyl, imidazo [1, 5-a] pyridinyl, 1, 2, 4-triazolo [4, 3-a] pyridinyl, imidazo [1, 2-a] pyridinyl, imidazo [1, 2-c] pyrimidinyl, imidazo [1, 2-a] pyrazinyl, or imidazo [1, 2-a] pyrimidinyl.
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 wherein Y is -C (=O) -or -SO 2-; L is absent, or haloalkyl such as -CF 2-, or optionally substituted alkyl such as -CH 2-, -CH (CH 3) -, and -C (CH 3)  2-; and J 2 is
Figure PCTCN2021122588-appb-000083
Figure PCTCN2021122588-appb-000084
wherein R 25 and R 26 are, independently, hydrogen, C 1-C 4 alkyl such as methyl, ethyl, or isopropyl, or halo such as fluoro or chloro, or preferably hydrogen, methyl, or fluoro; and R 27 is hydrogen, C 1-4 alkyl such as methyl, ethyl, isopropyl, or t-butyl, C 1-C 4 haloalkyl such as CF 3, or cycloalkyl.
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 Y is -C (=O) -or -SO 2-; L is absent, haloalkyl such as -CF 2-, -NH-, or optionally substituted alkyl such as -CH 2-, -CH (CH 3) -, and -C (CH 3)  2-; J 2 is
Figure PCTCN2021122588-appb-000085
Figure PCTCN2021122588-appb-000086
Figure PCTCN2021122588-appb-000087
wherein R 27 is hydrogen or C 1-C 4 alkyl such as methyl, ethyl, or isopropyl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XXIV, and the pharmaceutically acceptable salts thereof, wherein V 1 is -NR 1SO 2 (C 1-C 4 alkyl) or -NR 1 (C=O) (C 1-C 4 alkyl) .
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XXIV, and the pharmaceutically acceptable salts thereof, wherein V 1 is -NR 1SO 2CH 3 or -NR 1 (C=O) (CH 3) .
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XXIV, and the pharmaceutically acceptable salts thereof, wherein V 1 is -NHSO 2 (C 1-C 4 alkyl) , -NHSO 2 (C 1-C 4 haloalkyl) , -NH (C=O) (C 1-C 4 alkyl) , or -NH (C=O) (C 1-C 4 haloalkyl) .
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XXIV, and the pharmaceutically acceptable salts thereof, wherein V 1 is -N (CH 3) SO 2 (C 1-C 4 alkyl) , -N (CH 3) SO 2 (C 1-C 4 haloalkyl) , -N (CH 3) (C=O) (C 1-C 4 alkyl) , or -N (CH 3) (C=O) (C 1-C 4 haloalkyl) .
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XXIV, and the pharmaceutically acceptable salts thereof, wherein V 1 is -N (CH 3) SO 2CH 3 or -N (CH 3) (C=O) (CH 3) .
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XXIV, and the pharmaceutically acceptable salts thereof, wherein V 1 is -N (CH 3) SO 2CH 3.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XXIV, and the pharmaceutically acceptable salts thereof, wherein V 1 is -N (CH 3) (C=O) (CH 3) .
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XXIV, and the pharmaceutically acceptable salts thereof, wherein R 2 is C 1-C 4 alkyl and k is 0, 1, or 2.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XXIV, and the pharmaceutically acceptable salts thereof, wherein k is 0.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XXIV, and the pharmaceutically acceptable salts thereof, wherein R 2 is C 1-C 4 alkyl and k is 1.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XXIV, and the pharmaceutically acceptable salts thereof, wherein R 2 is C 1-C 4 alkyl and k is 2.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XXIV, and the pharmaceutically acceptable salts thereof, wherein R 2 is methyl and k is 0, 1, or 2.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XXIV, and the pharmaceutically acceptable salts thereof, wherein R 2 is methyl and k is 1.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XXIV, and the pharmaceutically acceptable salts thereof, wherein R 2 is methyl and k is 2.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XXIV, and the pharmaceutically acceptable salts thereof, wherein V 1 is
Figure PCTCN2021122588-appb-000088
Figure PCTCN2021122588-appb-000089
In one embodiment, Compounds of the Disclosure are compounds represented by Formula XXII:
Figure PCTCN2021122588-appb-000090
or a pharmaceutically acceptable salt thereof, wherein:
each R a is independently hydrogen or C 1-C 4 alkyl;
each R b is independently hydrogen or C 1-C 4 alkyl;
R c is hydrogen or halo;
each R d is independently halo;
p, q, r and s are independently 1 or 2;
n is independently 0, 1 or 2;
Q is -N (H) C (=O) OR, -N (R) C (=O) OR, -N (H) C (=O) R, -N (H) C (O) NHR, -N (H) C (O) NR 2, -OC (=O) NR 2, 
Figure PCTCN2021122588-appb-000091
V is -CH 2OH, -CH 2OMe, -CH 2OEt, -CH 2NH 2, -CH 2NHMe, -CH 2NMe 2, cyano, - (C=O) H, -CO 2Me, -CO 2Et, -CH 2NR 1CO 2Me, -CH 2NR 1CO 2CD 3, -CH 2NR 1CO 2Et, -CH 2NR 1CO 2iPr, -CH 2NR 1CONH 2, -CO 2H, -CONH 2, -CONHMe, -CONMe 2, -CONHEt, -CONEt 2, -CON(Me) (Et) , -CON (CD 3)  2, -CON (Me) (CD 3) , -CON (Et) (CD 3) , -CON (i-Pr) (CD 3) , -CH 2NHCONHCH 2CF 3, -CH 2NHCONHiPr, -CH 2NHCONHMe, -CH 2NHCONHEt, 
Figure PCTCN2021122588-appb-000092
Figure PCTCN2021122588-appb-000093
each R f is independently hydrogen, C 1-C 4 alkyl, hydroxy, C 1-C 4 alkoxy, or halo;
each R g is independently hydrogen, C 1-C 4 alkyl, or NH 2;
each R is independently C 1-C 4 alkyl, C 1-C 4 haloalkyl, or CD 3;
each R 1 is independently hydrogen or C 1-C 4 alkyl;
each R 2 is independently C 1-C 4 alkyl or C 3-C 6 cycloalkyl;
each k is independently 0, 1, 2, 3, or 4;
E is
Figure PCTCN2021122588-appb-000094
Figure PCTCN2021122588-appb-000095
Figure PCTCN2021122588-appb-000096
Figure PCTCN2021122588-appb-000097
wherein
R 4 is hydrogen, C 1-C 4 alkyl, C 1-C 4alkylcarbonyl, heterocyclo, and haloalkyl;
W is -NH-, -O-, or -S-;
each m is independently 1 or 2;
J is optionally substituted heteroaryl, optionally substituted heterocyclo, optionally substituted aryl, carboxamido, haloalkoxy, alkoxy, alkylcarbonyloxy, carboxamidooxy, (carboxamido) alkyl, aralkyloxy, aryloxy, heterocyclooxy, heteroaryloxy, alkoxycarbonyl, hydrogen, C 1-C 4 alkyl, C 1-C 4 alkylcarbonyl, hydroxy, cyano, haloalkyl, -NO 2, halo, -NR 1SO 2 (C 1-C 4 alkyl) , -NR 1SO 2 (C 2-C 6 alkenyl) , -NR 1CO (C 1-C 4 alkyl) , -S (=O) (=NR 1) CF 3, S (=O) (=NR 1) (C 1-C 4 alkyl) , amino, sulfonamido, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, heterocycloalkylsulfonyl, or C 1-C 4 phosphine oxide;
J 3 is optionally substituted heteroaryl, optionally substituted heterocyclo, optionally substituted aryl, haloalkoxy, alkoxy, alkylcarbonyloxy, carboxamidooxy, (carboxamido) alkyl, aralkyloxy, aryloxy, heterocyclooxy, heteroaryloxy, alkoxycarbonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, heterocycloalkylsulfonyl, C 1-C 4 phosphine oxide, or carboxamido, provided that J 3 is not -C (=O) NH 2, -C (=O) NH (CH 3) , or -C (=O) N (CH 3)  2;
J 4 is optionally substituted heteroaryl, optionally substituted heterocyclo, optionally substituted aryl, haloalkoxy, alkoxy, alkylcarbonyloxy, carboxamidooxy, (carboxamido) alkyl, aralkyloxy,  aryloxy, heterocyclooxy, heteroaryloxy, alkoxycarbonyl, C 1-C 4 alkyl, C 1-C 4 alkylcarbonyl, hydroxy, haloalkyl, -NO 2, halo, -NR 1SO 2 (C 1-C 4alkyl) , -NR 1SO 2 (C 2-C 6alkenyl) , -NR 1CO (C 1-C 4 alkyl) , -S (=O) (=NR 1) CF 3, S (=O) (=NR 1) (C 1-C 4 alkyl) , amino, sulfonamido, or C 1-C 4 phosphine oxide;
R 8a, R 8b, R 8c, and R 8d are independently hydrogen, halo, carboxy, hydroxy, C 1-C 4 alkoxycarbonyl, C 1-C 4 alkyl, C 1-C 4 alkoxy, haloalkyl, haloalkoxy, -CH 2SO 2C 1-C 4 alkyl, sulfonamido, cyano, alkoxyalkyl, aralkyloxy, alkylsulfonyl, (amino) alkyl, carboxamido, (carboxamido) alkyl, thioamide, optionally substituted heteroaryl, (heteroaryl) alkyl, -NR 13C (O) C 1-C 4 alkyl, -OCH 2CH=CH-alkylsulfonyl, -O (C 1-C 4 alkyl) O (C 1-C 4 alkyl) , C 2-C 6 alkenyl, heterocyclooxy, aminocarbonyloxy, or (heterocyclo) alkyl;
R 5 is hydrogen, amino, C 1-C 6 alkyl, C 1-C 6 alkoxy, or halo;
R 10 is hydrogen, C 1-C 4 alkyl, -NR 13CO (C 1-C 4 alkyl) , -NR 13SO 2 (C 1-C 4 alkyl) , cyano, halo, -OCH 2CH=CH-R a3, or -CH 2CH 2CH=CH-R a3;
R 13 is hydrogen or C 1-C 4 alkyl;
R 16 is hydrogen or C 1-C 4 alkyl;
R a3 is alkoxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, or carboxamido;
Y is -C (=O) -, -SO 2-, -C (=O) NH-, or -C (=O) N (C 1-C 4alkyl) -;
L is absent or is optionally substituted C 1-C 6 alkyl or C 1-C 6 haloalkyl; and
J 5 is C 1-C 4 alkyl, C 1-C 6 haloalkyl, cyano, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, or optionally substituted heterocyclo.
In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XXII, and the pharmaceutically acceptable salts thereof.
In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XXII, and the pharmaceutically acceptable salts thereof, wherein at least one R a is hydrogen.
In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XXII, and the pharmaceutically acceptable salts thereof, wherein each R a is hydrogen.
In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XXII, and the pharmaceutically acceptable salts thereof, wherein at least one R b is hydrogen.
In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XXII, and the pharmaceutically acceptable salts thereof, wherein each R b is hydrogen.
In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XXII, and the pharmaceutically acceptable salts thereof, wherein each R aand R b is hydrogen.
In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XXII, and the pharmaceutically acceptable salts thereof, wherein p, q r and s are 1.
In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XXII, and the pharmaceutically acceptable salts thereof, wherein p, q and r are 1 and s is 2.
In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XXII, and the pharmaceutically acceptable salts thereof, wherein p, r and s are 1 and q is 2.
In another embodiment, Compounds of the Disclosure are compounds represented by XXII, and the pharmaceutically acceptable salts thereof, wherein q, r and s are 1 and p is 2.
In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XXII, and the pharmaceutically acceptable salts thereof, wherein p, q and s are 1 and r is 2.
In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XXII, and the pharmaceutically acceptable salts thereof, wherein p and q are 1 and r and s are 2.
In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XXII, and the pharmaceutically acceptable salts thereof, wherein p and q are 2 and r and s are 1.
In one embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formula XXIII-XXVIII:
Figure PCTCN2021122588-appb-000098
Figure PCTCN2021122588-appb-000099
wherein Q, V, E, R c, R d, n, and remaining variables are defined above in accordance with Formula XXII.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein R c is hydrogen.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein R c is halo.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein R c is fluoro.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein n is 0 or 1.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein n is 0.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein R c is halo and n is 0.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein R c is fluoro and n is 0.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein R d is fluoro.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein n is 1.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein n is 2.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein n is 1 and R d is fluoro.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein Q is -N (H) C (=O) OR.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein Q is -N (H) C (=O) OR and R is C 1-4 alkyl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein Q is -NHCO 2CH 3 or -NHCO 2CH 2CH 3.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein Q is -NHCO 2CH 3.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein V is -CH 2NR 1CO 2Me, -CH 2NR 1CO 2Et, -CH 2NR 1CO 2iPr, -CH 2NR 1CONH 2, -CONH 2, -CONHMe, -CONMe 2, -CONHEt, -CONEt 2, -CON (Me) (Et) , 
Figure PCTCN2021122588-appb-000100
Figure PCTCN2021122588-appb-000101
wherein each R g is independently hydrogen, methyl, ethyl, and isopropyl and each R 2is independently methyl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein E is E-10, E-12, E-13, E-36, or E-37.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein E is E-36 or E-37.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein E is E-37 or E-38.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein E is E-36 and at least one of R 8a, R 8b, R 8c, and R 8d is hydrogen.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein E is E-36 and at least two of R 8a, R 8b, R 8c, and R 8d are hydrogen.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein E is E-36 and at least three of R 8a, R 8b, R 8c, and R 8d are hydrogen.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein wherein E is E-36 and each of R 8a, R 8b, R 8c, and R 8d are hydrogen.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein E is E-36 and at least one of R 8a, R 8b, R 8c, and R 8d is halo.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein E is E is E-36 and at least two of R 8a, R 8b, R 8c, and R 8d are halo.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein E is E-36 and at least one of R 8a, R 8b, R 8c, and R 8d is fluoro.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein E is E-36 and at least two of R 8a, R 8b, R 8c, and R 8d are fluoro.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein E is E-36 and at least one of R 8a, R 8b, R 8c, and R 8d is halo or carboxamido.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein E is E-36 and at least one of R 8a, R 8b, R 8c, and R 8d is carboxamido.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein E-36 and at least one of R 8a, R 8b, R 8c, and R 8d is
Figure PCTCN2021122588-appb-000102
Figure PCTCN2021122588-appb-000103
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein E is E-36 and at least one of R 8a, R 8b, R 8c, and R 8d is
Figure PCTCN2021122588-appb-000104
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVIII, and the pharmaceutically acceptable salts thereof, wherein E is
Figure PCTCN2021122588-appb-000105
R 5 is amino; and J is cyano or optionally substituted heteroaryl.
In one embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formula XXIX-XXXI:
Figure PCTCN2021122588-appb-000106
wherein V, R 8b, R 8c, J 3, and remaining variables are defined above in accordance with Formula XXII.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXXI, and the pharmaceutically acceptable salts thereof.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXXI, and the pharmaceutically acceptable salts thereof, wherein J 3 is optionally substituted heteroaryl and the optionally substituted heteroaryl is pyrazolyl, oxazolyl, pyrimidinyl, oxadiazolyl, or pyridinyl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXXI, and the pharmaceutically acceptable salts thereof, wherein J 3 is optionally substituted heteroaryl and the optionally substituted heteroaryl is oxazol-2-yl, oxazol-5-yl, pyrimidin-2-yl, pyrazol-3-yl, 1, 3, 4-oxadiazol-2-yl, 1, 2, 4-oxadiazol-3-yl, or pyridin-2-yl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXXI, and the pharmaceutically acceptable salts thereof, wherein J 3 is optionally substituted heteroaryl and the optionally substituted heteroaryl is substituted with one or more of:
C 1-6alkyl, such as methyl, ethyl, propyl, isopropyl, or butyl;
halo such as Br, Cl, or F;
cyano;
C 1-6haloalkyl, such as CF 3, CH 2F, CHF 2, CH 2CF 3, CH 2CHF 2, CH 2CH 2F, CH (CH 2F)  2 C (CH 3)  2F, or C (CH 3) F 2;
amino, such NH 2, or N (CH 2)  3; and
carboxamido, such as – (C=O) N (CH 3)  2.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXXI, and the pharmaceutically acceptable salts thereof, wherein J 3 is
Figure PCTCN2021122588-appb-000107
Figure PCTCN2021122588-appb-000108
Figure PCTCN2021122588-appb-000109
Figure PCTCN2021122588-appb-000110
R 17 and R 18 are, independently, hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, cyano, halo, or amino; and R 19 is hydrogen or C 1-4 alkyl.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXIX-XXXI, and the pharmaceutically acceptable salts thereof, wherein R 8b is carboxamido such as
Figure PCTCN2021122588-appb-000111
Figure PCTCN2021122588-appb-000112
Figure PCTCN2021122588-appb-000113
and preferably
Figure PCTCN2021122588-appb-000114
and R 8c is hydrogen or halo, such as fluoro or chloro, or preferably hydrogen or fluoro.
In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXIX-XXXI, and the pharmaceutically  acceptable salts thereof, wherein V is -CH 2NR 1CO 2Me, -CON (Me) (Et) , 
Figure PCTCN2021122588-appb-000115
Figure PCTCN2021122588-appb-000116
In another embodiment, Compounds of the Disclosure are any one or more of the compounds of Tables 1A and 1B, and the pharmaceutically acceptable salts thereof. Tables 1A and 1B further provide the chemical names of the compounds of Tables 1A and 1B generated by
Figure PCTCN2021122588-appb-000117
In the event of any ambiguity between their chemical structure and chemical name, Compounds of the Disclosure are defined by their chemical structure.
Table 1A
Figure PCTCN2021122588-appb-000118
Figure PCTCN2021122588-appb-000119
Figure PCTCN2021122588-appb-000120
Figure PCTCN2021122588-appb-000121
Figure PCTCN2021122588-appb-000122
Figure PCTCN2021122588-appb-000123
Figure PCTCN2021122588-appb-000124
Figure PCTCN2021122588-appb-000125
Figure PCTCN2021122588-appb-000126
Figure PCTCN2021122588-appb-000127
Figure PCTCN2021122588-appb-000128
Figure PCTCN2021122588-appb-000129
Figure PCTCN2021122588-appb-000130
Figure PCTCN2021122588-appb-000131
Figure PCTCN2021122588-appb-000132
Figure PCTCN2021122588-appb-000133
Figure PCTCN2021122588-appb-000134
Figure PCTCN2021122588-appb-000135
Figure PCTCN2021122588-appb-000136
Figure PCTCN2021122588-appb-000137
Figure PCTCN2021122588-appb-000138
Figure PCTCN2021122588-appb-000139
Figure PCTCN2021122588-appb-000140
Figure PCTCN2021122588-appb-000141
Figure PCTCN2021122588-appb-000142
Figure PCTCN2021122588-appb-000143
Figure PCTCN2021122588-appb-000144
Figure PCTCN2021122588-appb-000145
Figure PCTCN2021122588-appb-000146
Figure PCTCN2021122588-appb-000147
Figure PCTCN2021122588-appb-000148
Figure PCTCN2021122588-appb-000149
Figure PCTCN2021122588-appb-000150
Figure PCTCN2021122588-appb-000151
Figure PCTCN2021122588-appb-000152
Figure PCTCN2021122588-appb-000153
Figure PCTCN2021122588-appb-000154
Figure PCTCN2021122588-appb-000155
Figure PCTCN2021122588-appb-000156
Figure PCTCN2021122588-appb-000157
Figure PCTCN2021122588-appb-000158
Figure PCTCN2021122588-appb-000159
Figure PCTCN2021122588-appb-000160
Figure PCTCN2021122588-appb-000161
Figure PCTCN2021122588-appb-000162
Figure PCTCN2021122588-appb-000163
Figure PCTCN2021122588-appb-000164
Figure PCTCN2021122588-appb-000165
Figure PCTCN2021122588-appb-000166
Figure PCTCN2021122588-appb-000167
Figure PCTCN2021122588-appb-000168
Figure PCTCN2021122588-appb-000169
Figure PCTCN2021122588-appb-000170
Figure PCTCN2021122588-appb-000171
Figure PCTCN2021122588-appb-000172
Figure PCTCN2021122588-appb-000173
Figure PCTCN2021122588-appb-000174
Figure PCTCN2021122588-appb-000175
Figure PCTCN2021122588-appb-000176
Figure PCTCN2021122588-appb-000177
Figure PCTCN2021122588-appb-000178
Figure PCTCN2021122588-appb-000179
Figure PCTCN2021122588-appb-000180
Figure PCTCN2021122588-appb-000181
Figure PCTCN2021122588-appb-000182
Figure PCTCN2021122588-appb-000183
Figure PCTCN2021122588-appb-000184
Figure PCTCN2021122588-appb-000185
Figure PCTCN2021122588-appb-000186
Figure PCTCN2021122588-appb-000187
Figure PCTCN2021122588-appb-000188
Figure PCTCN2021122588-appb-000189
Figure PCTCN2021122588-appb-000190
Figure PCTCN2021122588-appb-000191
Figure PCTCN2021122588-appb-000192
Figure PCTCN2021122588-appb-000193
Figure PCTCN2021122588-appb-000194
Figure PCTCN2021122588-appb-000195
Figure PCTCN2021122588-appb-000196
Figure PCTCN2021122588-appb-000197
Figure PCTCN2021122588-appb-000198
Figure PCTCN2021122588-appb-000199
Figure PCTCN2021122588-appb-000200
Figure PCTCN2021122588-appb-000201
Figure PCTCN2021122588-appb-000202
Figure PCTCN2021122588-appb-000203
Figure PCTCN2021122588-appb-000204
Figure PCTCN2021122588-appb-000205
Figure PCTCN2021122588-appb-000206
Figure PCTCN2021122588-appb-000207
Figure PCTCN2021122588-appb-000208
Figure PCTCN2021122588-appb-000209
Figure PCTCN2021122588-appb-000210
Table 1B
Figure PCTCN2021122588-appb-000211
Figure PCTCN2021122588-appb-000212
Figure PCTCN2021122588-appb-000213
Figure PCTCN2021122588-appb-000214
Figure PCTCN2021122588-appb-000215
Figure PCTCN2021122588-appb-000216
Figure PCTCN2021122588-appb-000217
Figure PCTCN2021122588-appb-000218
In another embodiment, the disclosure provides a pharmaceutical composition comprising a Compound of the Disclosure and a pharmaceutically acceptable carrier.
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%.
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, glycerolphsphate, 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 quaternized 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.
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.
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 (IC 50) to menin of less than 100 μM, e.g., less than 50 μM, less than 25 μM, and less than 5 μM, less than about 1 μM, less than about 0.5 μM, less than about 0.1 μM, less than about 0.05 μM, or less than about 0.01 μM. 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.
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.
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. 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.
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.
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. 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.
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 PCTCN2021122588-appb-000219
Figure PCTCN2021122588-appb-000220
Figure PCTCN2021122588-appb-000221
In another embodiment, the cancer is a solid tumor. In another embodiment, the cancer is 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
acute lymphocytic leukemia (ALL) acute eosinophilic leukemia
acute myeloid leukemia (AML) acute erythroid leukemia
chronic lymphocytic leukemia (CLL) acute lymphoblastic leukemia
small lymphocytic lymphoma (SLL) acute megakaryoblastic leukemia
multiple myeloma (MM) acute monocytic leukemia
Hodgkins lymphoma (HL) acute promyelocytic leukemia
non-Hodgkin's lymphoma (NHL) acute myelogeous leukemia
mantle cell lymphoma (MCL) B-cell prolymphocytic leukemia
marginal zone B-cell lymphoma B-cell lymphoma
splenic marginal zone lymphoma MALT lymphoma
follicular lymphoma (FL) precursor T-lymphoblastic lymphoma
Waldenstrom's macroglobulinemia (WM) T-cell lymphoma
diffuse large B-cell lymphoma (DLBCL) mast cell leukemia
marginal zone lymphoma (MZL) adult T cell leukemia/lymphoma
hairy cell leukemia (HCL) aggressive NK-cell leukemia
Burkitt's lymphoma (BL) angioimmunoblastic T-cell lymphoma
Richter's transformation myelodysplastic syndromes
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 NPM1c 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.
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.
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.
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.
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.
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.
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.
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.
A Compound of the Disclosure can be administered by any suitable route, for example by oral, buccal, inhalation, sublingual, rectal, vaginal, intracisternal 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.
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.
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.
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. 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.
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.
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 μg/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 μg/kg. The dosage of a composition may be at any dosage including, but not limited to, about 1 μg/kg, about 10 μg/kg, about 25 μg/kg, about 50 μg/kg, about 75 μg/kg, about 100 μg/kg, about 125 μg/kg, about 150 μg/kg, about 175 μg/kg, about 200 μg/kg, about 225 μg/kg, about 250 μg/kg, about 275 μg/kg, about 300 μg/kg, about 325 μg/kg, about 350 μg/kg, about 375 μg/kg, about 400 μg/kg, about 425 μg/kg, about 450 μg/kg, about 475 μg/kg, about 500 μg/kg, about 525 μg/kg, about 550 μg/kg, about 575 μg/kg, about 600 μg/kg, about 625 μg/kg, about 650 μg/kg, about 675 μg/kg, about 700 μg/kg, about 725 μg/kg, about 750 μg/kg, about 775 μg/kg, about 800 μg/kg, about 825 μg/kg, about 850 μg/kg, about 875 μg/kg, about 900 μg/kg, about 925 μg/kg, about 950 μg/kg, about 975 μg/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.
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.
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.
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-angiogenenesis 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, XPO1 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 XPO1 inhibitors, and dasatinib.
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.
Non-limiting examples of inhibitors of the histone methyltransferase DOTlL include EPZ-5676, SGC-0946, and EPZ004777.
Exemplary nonlimiting IDHl inhibitors include
Figure PCTCN2021122588-appb-000222
 (ivosidnib) , AG-881, AG-120, FT-2102 (olutasidenib) , BAY1436032, IDH-305, and ZX-06. Exemplary nonlimiting examples of IDH2 inhitors include
Figure PCTCN2021122588-appb-000223
 (enasidenib; AG-221) , AG-881, AGl-6780, SH1573, and TQ05310. Exemplary nonlimiting IDH1/IDH2 dual inhitors include HMPL-306.
Exemplary nonlimiting examples of a LSD1 inhibitor include ORY-1001, OG-L002, SP2509, 4SC-202, GSK2879552, T-3775440, and RN-1.
Examplary nonlimiting examples of an XPO1 inhibtor include selinexor (KPT-330) , KPT-8602, KPT25 l, 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. 99308617.2 (filed October 29, 1999) , WO 98/07697 (published February 26, 1998) , WO 98/03516 (published January 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 little 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-ll, MMP-12, andMMP-13) . Exemplary nonlimiting MMP inhibitors include AG-3340, RO 32-3555, and RS 13-0830.
Exemplary nonlimiting autophagy inhibitors include chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil TM) , bafilomycin A1, 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.
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 Biologics) .
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.
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.
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.
Microtubule active agents include microtubule stabilizing, microtubule destabilizing compounds, and microtubulin polymerization inhibitors including, but not limited to, taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine, vinblastine sulfate, vincristine, and vincristine sulfate, and vinorelbine; discodermolides; cochicine 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.
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.
Exemplary nonlimiting mTOR inhibitors include compounds that inhibit the mammalian target of rapamycin (mTOR) and possess antiproliferative activity such as sirolimus, everolimus, CCI-779, and ABT578.
Exemplary nonlimiting antimetabolites include 5-fluorouracil (5-FU) , capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists, such as pemetrexed.
Exemplary nonlimiting platin compounds include carboplatin, cis-platin, cisplatinum, and oxaliplatin.
Exemplary nonlimiting methionine aminopeptidase inhibitors include bengamide or a derivative thereof and PPI-2458.
Exemplary nonlimiting bisphosphonates include etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid.
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.
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 farnesyl transferase inhibitor, such as L-744832, DK8G557, tipifarnib, and lonafarnib.
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.
Exemplary nonlimiting proteasome inhibitors include compounds that target, decrease, or inhibit the activity of the proteasome including, but not limited to, bortezomid.
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, Ι-β-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 HDAC inhibitors.
Exemplary nonlimiting BH3 mimetics include venetoclax.
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, SUlOl, 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, safingol, BAY 43-9006, bryostatin 1, perifosine; ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521 ; LY333531/LY379196; a isochinoline compound; a farnesyl 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.
Exemplary compounds that target, decrease, or inhibit the activity of a protein or lipid phosphatase include inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.
Further anti-angiogenic compounds include compounds having another mechanism for their activity unrelated to protein or lipid kinase inhibition, e.g., thalidomide and TNP-470.
Additional, nonlimiting, exemplary chemotherapeutic compounds, 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, 1- (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 IgGI 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.
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, pergolide, trihexephendyl, and amantadine; an agent for treating multiple sclerosis (MS) such as beta interferon (e.g., 
Figure PCTCN2021122588-appb-000224
and
Figure PCTCN2021122588-appb-000225
) , 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.
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.
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.
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.
When a therapeutically effective amount of a Compound of the Disclosure is administered by intravenous, cutaneous, or subcutaneous injection, the composition is in the  form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable solutions, having due regard to pH, isotonicity, stability, and the like, is within the skill in the art. A preferred composition for intravenous, cutaneous, or subcutaneous injection typically contains, an isotonic vehicle.
Compounds of the Disclosure can be readily combined with pharmaceutically acceptable carriers well-known in the art. Standard pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995. Such carriers enable the active agents to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by adding the Compound of the Disclosure to a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations. If desired, disintegrating agents can be added.
Compound of the Disclosure can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, e.g., in ampules or in multidose containers, with an added preservative. The compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and/or dispersing agents.
Pharmaceutical compositions for parenteral administration include aqueous solutions of the active agent in water-soluble form. Additionally, suspensions of a Compound of the Disclosure can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension. 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.
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.
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.
The disclosure provides the following particular embodiments in connection with treating a disease in a subject.
Embodiment 1. A method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount a Compound of the Disclosure, wherein the subject has cancer.
Embodiment 2. The method of Embodiment 1, wherein the cancer is any one or more of the cancers of Table 2.
Embodiment 3. The method of Embodiment 2, wherein the cancer is a hematological cancer.
Embodiment 4. The method of Embodiment 3, wherein the hematological cancer is any one or more of the cancers of Table 3.
Embodiment 5. The method of any one of Embodiments 1-4 further comprising administering a therapeutically effective amount of a second therapeutic agent useful in the treatment of cancer.
Embodiment 6. A pharmaceutical composition comprising a 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.
III. Kits of the Disclosure
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
In the present disclosure, the term "halo" or “halogen” as used by itself or as part of another group refers to -Cl, -F, -Br, or -I.
In the present disclosure, the term "nitro" as used by itself or as part of another group refers to -NO 2.
In the present disclosure, the term "cyano" as used by itself or as part of another group refers to -CN.
In the present disclosure, the term "hydroxy" as used by itself or as part of another group refers to -OH.
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., C 1-12 alkyl, or the number of carbon atoms designated, e.g., a C 1 alkyl such as methyl, a C 2 alkyl such as ethyl, a C 3 alkyl such as propyl or isopropyl, a C 1-3 alkyl such as methyl, ethyl, propyl, or isopropyl, and so on. In one embodiment, the alkyl is a C 1-10 alkyl. In another embodiment, the alkyl is a C 1-6 alkyl. In another embodiment, the alkyl is a C 1-4 alkyl. In another embodiment, the alkyl is a straight chain C 1-10 alkyl. In another embodiment, the alkyl is a branched chain C 3-10 alkyl. In another embodiment, the alkyl is a straight chain C 1-6 alkyl. In another embodiment, the alkyl is a branched chain C 3-6 alkyl. In another embodiment, the alkyl is a straight chain C 1-4 alkyl. In another embodiment, the alkyl is a branched chain C 3-4 alkyl. In another embodiment, the alkyl is a straight or branched chain C 3-4 alkyl. Non-limiting exemplary C 1-10 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl. Non-limiting exemplary C 1-4 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and iso-butyl.
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 -CH 2CH 2NO 2, -CH 2SO 2CH 3, CH 2CH 2SO 2CH 3, -CH 2CH 2CO 2H, -CH 2SCH 3, -CH 2CH 2SO 2CH 3, -CH 2CH 2COPh, and -CH 2OC (=O) CH 3.
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., C 3-12 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 C 3-8 cycloalkyl. In  another embodiment, the cycloalkyl is a C 3-6 cycloalkyl. The term "cycloalkyl" is meant to include groups wherein a ring -CH 2-is replaced with a -C (=O) -. Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, cyclopentenyl, and cyclopentanone.
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 (=O) -amino, -N (R 29a) C (=O) -R 29b, and -N (R 30a) SO 2-R 30b, wherein R 29a is selected from the group consisting of hydrogen and alkyl, R 29b is selected from the group consisting of amino, alkoxy, alkyl, e.g., C 1-C 6 alkyl, alkenyl, and optionally substituted aryl, R 30a is selected from the group consisting of hydrogen and alkyl, and R 30b 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 attached 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 PCTCN2021122588-appb-000226
 (including
Figure PCTCN2021122588-appb-000227
) , 
Figure PCTCN2021122588-appb-000228
 (including
Figure PCTCN2021122588-appb-000229
) , 
Figure PCTCN2021122588-appb-000230
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 PCTCN2021122588-appb-000231
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 C 6-14 aryl. 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.
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, -CO 2CH 2Ph, alkylamino, dialkylamino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, haloalkylsulfonyl cycloalkylsulfonyl, (cycloalkyl) alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, carboxy, carboxyalkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxycarbonyl, alkoxyalkyl, (amino) alkyl, (carboxamido) alkyl, (heterocyclo) alkyl, -N (R 29a) C (=O) -R 29b, and -N (R 30a) SO 2-R 30b, wherein R 29a, R 29b, R 30a, and R 30b are as defined in connection with optionally substituted cycloalkyl.
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-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-cyanophenyl, 3-trifluoromethoxyphenyl, 3-trifluoromethylphenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 2, 6-di-fluorophenyl, 2, 6-di-chlorophenyl, 2-methyl, 3- methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 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, and 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 PCTCN2021122588-appb-000232
Additional non-limiting examples of optionally substituted aryl include:
Figure PCTCN2021122588-appb-000233
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 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, sec-butenyl, pentenyl, hexenyl, and -CH=C (CH 3)  2.
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.
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 C 2-6 alkynyl. In another embodiment, the alkynyl is a C 2-4 alkynyl. Non-limiting  exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.
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.
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 C 1-4 haloalkyl group. Non-limiting exemplary haloalkyl groups include fluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1, 1-difluoroethyl, 2, 2-difluoroethyl, 2, 2, 2-trifluoroethyl, 1, 3-difluoropropan-2-yl, 3, 3, 3-trifluoropropyl, 4, 4, 4-trifluorobutyl, and trichloromethyl groups.
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 dihydroxyalkyl, i.e., a hydroxyalkyl substituted with two hydroxy groups. Non-limiting exemplary hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups, such as 1-hydroxyethyl, 2-hydroxyethyl, 1, 2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl, and 1, 3-dihydroxyprop-2-yl.
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 C 1-4 alkyl substituted with one optionally substituted heteroaryl group. Non-limiting exemplary heteroaralkyl groups include:
Figure PCTCN2021122588-appb-000234
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 " (C 3-6 cycloalkyl) C 1-4 alkyl, " i.e., a C 1-4 alkyl substituted with an optionally substituted C 3-6 cycloalkyl. Non-limiting exemplary (cycloalkyl) alkyl groups include:
Figure PCTCN2021122588-appb-000235
In the present disclosure, the term "alkylsulfonyl" as used by itself or as part of another group refers to a sulfonyl, i.e., -SO 2-, substituted with an optionally substituted alkyl. In one embodiment, the alkyl sulfonyl group is a C 1-4 alkylsulfonyl group. Non-limiting exemplary alkylsulfonyl groups include -SO 2CH 3 and -SO 2CH 2CH 3.
In the present disclosure, the term "haloalkylsulfonyl" as used by itself or as part of another group refers to a sulfonyl, i.e., -SO 2-, substituted with a haloalkyl. A non-limiting exemplary haloalkylsulfonyl group is -SO 2CF 3.
In the present disclosure, the term "cycloalkylsulfonyl" as used by itself or as part of another group refers to a sulfonyl, i.e., -SO 2-, substituted with an optionally substituted cycloalkyl. Non-limiting exemplary cycloalkylsulfonyl groups include -SO 2-cyclopropyl and -SO 2-cyclopenyl.
In the present disclosure, the term " (cycloalkyl) alkylsulfonyl" as used by itself or as part of another group refers to a sulfonyl, i.e., -SO 2-, substituted with a (cycloalkyl) alkyl. Non-limiting exemplary (cycloalkyl) alkylsulfonyl groups include:
Figure PCTCN2021122588-appb-000236
In the present disclosure, the term "arylsulfonyl" as used by itself or as part of another group refers to a sulfonyl, i.e., -SO 2-, substituted with an optionally substituted aryl. A non-limiting exemplary arylsulfonyl group is -SO 2Ph.
In the present disclosure, the term "heteroarylsulfonyl" as used by itself or as part of another group refers to a sulfonyl, i.e., -SO 2-, substituted with an optionally substituted heteroaryl group. Non-limiting exemplary heteroarylsulfonyl groups include:
Figure PCTCN2021122588-appb-000237
In the present disclosure, the term "heterocyclosulfonyl" as used by itself or as part of another group refers to a sulfonyl, i.e., -SO 2-, substituted with an optionally substituted heterocyclo group. Non-limiting exemplary heterocyclosulfonyl groups include:
Figure PCTCN2021122588-appb-000238
In the present disclosure, the term “ (heterocyclo) alkylsulfonyl” as used by itself or as part of another group refers to a sulfonyl, i.e., -SO 2-, substituted with a (heterocyclo) alkyl. Non-limiting exemplary (heterocyclo) alkylsulfonyl groups include:
Figure PCTCN2021122588-appb-000239
In the present disclosure, the term "sulfonamido" as used by itself or as part of another group refers to a radical of the formula -SO 2NR 31aR 31b, wherein R 31a and R 31b are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted aryl, or R 31a and R 31b taken together with the nitrogen to which they are attached from a 3-to 8-membered heterocyclo group. Non-limiting exemplary sulfonamido groups include -SO 2NH 2, -SO 2N (H) CH 3, -SO 2N (CH 3)  2, and -SO 2N (H) Ph.
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 C 1-6 alkyl attached to a terminal oxygen atom. In another embodiment, the alkoxy group is a C 1-4 alkyl attached to a terminal oxygen atom. Non-limiting exemplary alkoxy groups include methoxy, ethoxy, tert-butoxy, and isopropoxy.
In the present disclosure, the term “heterocyclooxy” as used by itself or as part of another group refers an oxy, i.e., -O-, substituted with an optionally substituted heterocyclo group. Non-limiting exemplary heterocyclooxy groups include:
Figure PCTCN2021122588-appb-000240
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 C 1-4 alkylthio group. Non-limiting exemplary alkylthio groups include -SCH 3 and -SCH 2CH 3.
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.
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.
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-.
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 PhCH 2O-and PhCH 2CH 2O-.
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, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-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., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl) , imidazolyl (e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl) , pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-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., 1H-indazol-3-yl) . The term "heteroaryl" is also meant to include possible N-oxides. A non-limiting exemplary N-oxide is pyridyl N-oxide.
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. In another embodiment, the heteroaryl is a bicyclic aromatic ring system having 9 ring atoms wherein at least one carbon atom of the ring system is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur. Non-limiting exemplary bicyclic aromatic ring system having 9 ring atoms include imidazo [1, 5-a] pyridyl, [1, 2, 4] triazolo [4, 3-a] pyridyl, imidazo [1, 2-a] pyridyl, imidazo [1, 2-c] pyrimidinyl, pyrazolo [1, 5-a] pyridyl, imidazo [1, 2-a] pyrazinyl, imidazo [1, 2-a] pyrimidinyl,
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, (carboxamido) alkyl, (heterocyclo) alkyl, -N (R 29a) C (=O) -R 29b, and -N (R 30a) SO 2-R 30b, wherein R 29a, R 29b, R 30a, and R 30b are as defined in connection with optionally 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. Non-limiting exemplary substituted heteroaryls include:
Figure PCTCN2021122588-appb-000241
Figure PCTCN2021122588-appb-000242
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 PCTCN2021122588-appb-000243
Additional non-limiting examples of a 5-membered heteroarylenyl include:
Figure PCTCN2021122588-appb-000244
In another embodiment, the heteroarylenyl is a 6-membered heteroarylenyl. Non-limiting examples of a 6-membered heteroarylenyl include:
Figure PCTCN2021122588-appb-000245
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 quaternized. The term "heterocyclo" includes groups wherein a ring -CH 2-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 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. In one embodiment, 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, 2-oxopyrrolidin-1-yl, 2-oxooxazolidin-3-yl, piperazin-2-one, piperazine-2, 6-dione, 2-imidazolidinone, piperidinyl, 2-oxopiperidin-1-yl, morpholinyl, piperazinyl, pyrrolidinyl, indolinyl, and isoxazolidin-2-yl. Additional non-limiting examples of heterocyclo groups include oxetanyl, tetrahydrofuranyl, tetrahydropuranyl, 
Figure PCTCN2021122588-appb-000246
Figure PCTCN2021122588-appb-000247
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, alkoxycarbonyl, CF 3C (=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, hydroxyalkylcarbonyl, and -N (R 29a) C (=O) -R 29b, and -N (R 30a) SO 2-R 30b, wherein R 29a, R 29b, R 30a, and R 30b are as defined in connection with optionally substituted cycloalkyl. Substitution may occur on any available carbon or nitrogen atom, or both. Non-limiting exemplary substituted heterocyclo groups include:
Figure PCTCN2021122588-appb-000248
Additional non-limiting exemplary substituted heterocyclo groups include:
Figure PCTCN2021122588-appb-000249
Figure PCTCN2021122588-appb-000250
In the present disclosure, the term "amino" as used by itself or as part of another group refers to a radical of the formula -NR 32aR 32b, wherein R 32a and R 32b are each independently selected from the group consisting of hydrogen, alkyl, alkenylcarbonyl, alkoxy, aralkyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted heteroaryl, (heterocyclo) alkyl and (heteroaryl) alkyl, or R 32a and R 32b are taken together to form a 3-to 8-membered optionally substituted heterocyclo. Non-limiting exemplary amino groups include -NH 2, -N (H) (CH 3) , -N (CH 3)  2.
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 (amino) alkyl groups include -CH 2CH 2NH 2, and -CH 2CH 2N (H) CH 3, -CH 2CH 2N (CH 3)  2, and -CH 2N (H) -cyclopropyl. Additional non-limiting exemplary (amino) alkyl groups include -CH 2N (CH 3)  2 and -CH 2NH (CH 3) . An additional non-limiting exemplary (amino) alkyl group includes -CH 2N (CH 3) (COCH=CH 2) .
In the present disclosure, the term "carboxamido" as used by itself or as part of another group refers to a radical of formula -C (=O) NR 33aR 33b, whereinR 33a and R 33b are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, hydroxyalkyl, alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, and optionally substituted heteroaryl, or R 33a and R 33b taken together with the nitrogen to which they are attached form a 3-to 8-membered optionally substituted heterocyclo group. In one embodiment, R 33a and R 33b are each independently hydrogen or optionally substituted alkyl. In one embodiment, R 33a and R 33b are taken together to taken together with the nitrogen to which they are attached form a 3-to 8-membered optionally substituted heterocyclo group. Non-limiting exemplary carboxamido groups include -CONH 2, -CON (H) CH 3, -CON (CH 3)  2, -CON (H) Ph,
Figure PCTCN2021122588-appb-000251
Additional non-limiting exemplary carboxamido groups include:
Figure PCTCN2021122588-appb-000252
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 (=O) -, substituted with an alkyl. In one embodiment, the alkylcarbonyl group is a C 1-4 alkyl attached to the carbonyl group. In another embodiment, the alkoxy group is a C 1-4 alkyl attached to a terminal oxygen atom. Non-limiting exemplary alkylcarbonyl groups include -C (=O) CH 3, -C (=O) CH 2CH 3, -C (=O) CH 2CH 2CH 3, and -C (=O) CH 2CH 2CH 2CH 3.
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 (=O) -, substituted with an hydroxyalkyl. Non-limiting exemplary hydroxyalkylcarbonyl groups include -C (=O) C (CH 3)  2OH and -C (=O) CH 2CH 2CH 2OH.
In the present disclosure, the term "cycloalkylcarbonyl" as used by itself or as part of another group refers to a carbonyl group, i.e., -C (=O) -, substituted with a cycloalkyl. A non-limiting exemplary cycloalkylcarbonyl group is -C (=O) -cyclopropyl.
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 (=O) -, substituted with an optionally substituted aryl. A non-limiting exemplary arylcarbonyl group is -COPh.
In the present disclosure, the term "alkoxycarbonyl" as used by itself or as part of another group refers to a carbonyl group, i.e., -C (=O) -, substituted with an alkoxy. In one embodiment, the alkoxy is a C 1-4 alkoxy. Non-limiting exemplary alkoxycarbonyl groups include -C (=O) OMe, -C (=O) OEt, -C (=O) OPr, -C (=O) OiPr, and -C (=O) OtBu.
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. In one  embodiment, the alkoxy is a C 1-4 alkoxy. Non-limiting exemplary (alkoxycarbonyl) alkyl groups include -CH 2C (=O) OMe, -CH 2C (=O) OEt, and -CH 2C (=O) OtBu.
In the present disclosure, the term "alkenylcarbonyl" as used by itself or as part of another group refers to a carbonyl group, i.e., -C (=O) -, substituted by an alkenyl group. In one embodiment, the alkenyl group is a C 2-6 alkenyl. In another embodiment, the alkenyl is a C 2-4 alkenyl. Non-limiting exemplary alkenylcarbonyl groups include -C (=O) CH=CH 2, -C (=O) CH 2CH=CH 2, and -C (=O) CH 2CH 2CH=CH 2.
In the present disclosure, the term "carboxy" as used by itself or as part of another group refers to a radical of the formula -CO 2H.
In the present disclosure, the term "carboxyalkyl" as used by itself or as part of another group refers to an alkyl substituted with a -CO 2H. A non-limiting exemplary carboxyalkyl group is -CH 2CO 2H.
In the present disclosure, the term "thioamide" as used by itself or as part of another group refers to a radical of formula -C (=S) NR 33aR 33b, whereinR 33a and R 33b are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, hydroxyalkyl, alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, and optionally substituted heteroaryl, or R 33a and R 33b taken together with the nitrogen to which they are attached form a 3-to 8-membered optionally substituted heterocyclo group. In one embodiment, R 33a and R 33b are each independently hydrogen or optionally substituted alkyl. In one embodiment, R 33a and R 33b 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 thioamide groups include -C (=S) NH 2, -C (=S) N (H) CH 3, -C (=S) N (CH 3)  2, and -C (=S) N (H) Ph.
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 C 1-4 alkyl substituted with one optionally substituted C 5 or C 6 aryl group. In another embodiment, the aralkyl is a C 1 alkyl substituted with one optionally substituted aryl group. In another embodiment, the aralkyl is a C 2 alkyl substituted with one optionally substituted aryl group. In another embodiment, the aralkyl is a C 3 alkyl substituted with one optionally substituted aryl group. In one embodiment, the aralkyl is a C 1 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.
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 C 1-4 alkyl substituted with one optionally substituted heterocyclo group. Non-limiting exemplary (heterocyclo) alkyl groups include:
Figure PCTCN2021122588-appb-000253
Additional non-limiting exemplary (heterocyclo) alkyl groups include:
Figure PCTCN2021122588-appb-000254
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 C 1-4 alkyl substituted with one optionally substituted heteroaryl group. In another embodiment, the (heteroaryl) alkyl is a C 1 alkyl substituted with one optionally substituted heteroaryl group Non-limiting exemplary (heteroaryl) alkyl groups include:
Figure PCTCN2021122588-appb-000255
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. In one embodiment, the (carboxamido) alkyl is a C 1-4 alkyl substituted with one carboxamido group, i.e., a (carboxamido) C 1-4 alkyl. In another embodiment, the (carboxamido) alkyl is a C 1- 4 alkyl substituted with two carboxamido groups. Non-limiting exemplary (carboxamido) alkyl groups include -CH 2CONH 2, -C (H) CH 3CONH 2, -CH 2CON (H) CH 3, and -CH 2CON (CH 3)  2.
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 C 1-4 alkyl substituted with an aryloxy. In one embodiment, the  (aryloxy) alkyl is a C 2-4 alkyl substituted with an aryloxy. Non-limiting exemplary (aryloxy) alkyl groups include -CH 2CH 2OPh and -CH 2CH 2CH 2OPh.
In the present disclosure, the term "alkylcarbonyloxy" as used by itself or as part of another group refers to an oxy, e.g., -O-, substituted with an alkylcarbonyl group. Non-limiting exemplary alkylcarbonyloxy groups include -OC (=O) CH 3, i.e., acetoxy, -OC (=O) CH 2CH 3, -OC (=O) CH 2CH 2CH 3, and -OC (=O) CH (CH 3)  2.
In the present disclosure, the term "cycloalkylcarbonyloxy" as used by itself or as part of another group refers to an oxy, e.g., -O-, substituted with a cycloalkylcarbonyl group. Non-limiting exemplary cycloalkylcarbonyloxy groups include -OC (=O) -cyclopropyl and -OC (=O) -cyclopenyl.
In the present disclosure, the term “carboxamidooxy” as used by itself or as part of another group refers an oxy, i.e., -O-, substituted with a carboxamido group. Non-limiting exemplary carboxamidooxy groups include:
Figure PCTCN2021122588-appb-000256
In the present disclosure, the term “heteroaryloxy” as used by itself or as part of another group refers an oxy, i.e., -O-, substituted with an optionally substituted heteroaryl group. Non-limiting exemplary heteroaryloxy groups include:
Figure PCTCN2021122588-appb-000257
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.
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.
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.
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.
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.
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 affected 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.
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.
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, " "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.
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.
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.
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 olefinic 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. ) .
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) .
The term "chiral center" or "asymmetric carbon atom" refers to a carbon atom to which four different groups are attached.
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.
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.
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.
The stereochemical terms and conventions used in the specification are meant to be consistent with those described inPure &Appl. Chem 68: 2193 (1996) , unless otherwise indicated.
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 ofR and S enantiomers, the percent enantiomeric excess is defined as │R -S│*100, whereR andS are the respective mole or weight fractions of enantiomers in a mixture such that R +S = 1. With knowledge of the optical rotation of a chiral substance, the percent enantiomeric excess is defined as ( [α]  obs/ [α]  max) *100, where [α]  obs is the optical rotation of the mixture of enantiomers and [α]  max is the optical rotation of the pure enantiomer. Determination of enantiomeric excess is possible using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography or optical polarimetry. In one embodiment, ee is determined by chiral HPLC.
V. Synthesis of Compounds of the Disclosure
Compounds of the Disclosure can be prepared by methods described in the Examples and by related methods known in the art.
For example, Compounds of Formula I can be prepared by the general method shown in Scheme 1. A reductive animation reaction between amine 1-A and ketone 1-B affords azaspiro 1-C, which upon deprotection of the protecting group (PG = Protecting Group) yields intermediate 1-D Any suitable amine protecting group known in the art (for example, a carboxybenzyl (Cbz) group) may be used. Azaspiro ketone 1-B can be prepared from the  commercially available amines (for example, 2-Azaspiro [3.3] heptan-6-one, 2-Azaspiro [3.5] nonan-7-one, 2-Azaspiro [3.4] octan-6-one, 6-Azaspiro [3.4] octan-2-one, 7-Azaspiro [3.5] nonan-2-one, and 3-Azaspiro [5.5] undecan-9-one) , followed by addition of a suitable amine protecting group by methods known in the art. Intermediate 1-D can then be used in the coupling reactions described in general Schemes 4-6 to yield compounds of Formula I.
Scheme 1
Figure PCTCN2021122588-appb-000258
Alternatively, Compounds of Formula I can be prepared by the general method shown in Scheme 2. A reductive animation reaction between amine 2-A and ketone 1-B affords intermediate 2-B, which upon deprotection of the protecting group PG 2 on the azaspiro 2-C yields intermediate 2-C. Any suitable amine protecting group known in the art may be used although when there are multiple amine protecting groups, those protecting groups should be different (for example, PG 1 can be t-butyloxycarbonyl (BOC) and PG 2 can be Cbz) . Intermediate 2-C can then be used in the coupling reactions described in Schemes 4-6, followed by deprotection of the remaining protecting group PG 1 and the formation of the Q substituent wherein Q is -N (H) C (=O) OR, -N (R) C (=O) OR, -N (H) C (=O) R, -N (H) C (O) NHR, -N (H) C (O) NR 2, -
Figure PCTCN2021122588-appb-000259
Scheme 2
Figure PCTCN2021122588-appb-000260
Alternatively, Compounds of Formula I can be prepared by the general method shown in Scheme 3. A reductive animation reaction between amine 3-A and ketone 1-B affords intermediate 3-B, which upon deprotection of the protecting group PG 2 on the azaspiro 3-B yields intermediate 3-C. Any suitable amine protecting group known in the art may be used although when there are multiple amine protecting groups, those protecting groups should be different (for example, PG can be t-butyloxycarbonyl (BOC) and PG 2 can be Cbz) . Intermediate 3-C can then be used in the coupling reactions described in Schemes 4-6, followed by deprotection of the remaining protecting group and the formation of the V 1 substituent.
Scheme 3
Figure PCTCN2021122588-appb-000261
As an example of a coupling reaction, Compounds of Formula I, wherein E is E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, E-10, E-11, E-12, E-13, E-14, E-15, E-17, E-18, E-19, E-20, E-21, E-22, E-23, E-24, E-25, E-31, E-32, and E-35 can be prepared by the general method shown in Scheme 4. A nucleophilic aromatic substitution reaction between azaspiro 1-D and aryl fluoride 1-E or azaspiro 1-D and aryl sulfonylmethyl 1-F in the presence of a base (e.g., K 2CO 3 or DIPEA) affords the Compound of Formula I.
Scheme 4
Figure PCTCN2021122588-appb-000262
Alternatively, Compounds of Formula I, wherein E is E-1, E-4, E-5, E-6, E-7, E-8, E-9, E-10, E-11, E-12, E-13, E-14, E-15, E-17, E-18, E-19, E-20, E-21, E-22, E-23, E-24, E-25, and E-35 can be prepared by the general method shown in Scheme 5. A Buchwald-Hartwig amination reaction between azaspiro 1-D and aryl bromide 1-F affords the Compound of Formula I.
Scheme 5
Figure PCTCN2021122588-appb-000263
Alternatively, Compounds of Formula I, wherein E is E-16, E-26, E-27, E-28, E-29, E-30, E-33, and E-34 can be prepared by the general method shown in Scheme 6 or by other methods known in the art for preparing sulfonamides and carbamates. A nucleophilic substitution reaction between azaspiro 1-D and electrophile 1-G (LG = leaving group) in the presence of a base (e.g., K 2CO 3) affords the Compound of Formula I.
Scheme 6
Figure PCTCN2021122588-appb-000264
Compounds of Formula XXII can be prepared, for example, using the methods described in the preceding Schemes and EXAMPLES herein and in the Schemes, EXAMPLES, and related methods described in PCT/CN2021/085824.
EXAMPLES
Abbreviations list:
General
anhy.     anhydrous
aq.       aqueous
atm       atmosphere
min       minute (s)
hrs       hours
mL        milliliter
mmol      millimole (s)
mol       mole (s)
MS        mass spectrometry
LC-MS     Liquid chromatography–mass spectrometry
NMR       nuclear magnetic resonance
TLC       thin layer chromatography
HPLC      high-perfomrnnce liquid chromatography
satd.     saturated
℃        degrees Celsius
wt        weight
Spectrum
Hz        hertz
δ        chemical shift
s         singlet
d         doublet
t         triplet
q         quartet
m         multiplet
CDCl 3     chloroform-d
J         coupling constant
Solvents and Reagents
CHCl 3           chloroform
DCM             dichloromethane
DCE             1, 2-dichloroethane
DMF             dimethylformamide
EtOH            ethyl alcohol
EtOAc           ethyl acetate
MeOH            methyl alcohol
MeCN or CH 3CN   acetonitrile
PE              petroleum ether
THF             tetrahydrofuran
DMSO            dimethyl sulfoxide
DMAc            dimethylacetamide
AcOH            acetic acid
HCl             hydrochloric acid
H 2SO 4           sulfuric acid
NH 4C1           ammonium chloride
NaOH            sodium hydroxide
LiOH            lithium hydroxide
K 2CO 3           potassium carbonate
Na 2CO 3          sodium carbonate
Cs 2CO 3          cesium carbonate
TFA or CF 3CO 2H  trifluoroacetic acid
HCO 2H           formic acid
Na 2SO 4          sodium sulfate
NaBH 4           sodium borohydride
Na 2CO 3          sodium carbonate
NaHCO 3          sodium bicarbonate
KHMDS           potassium hexamethyldisilazide
NaH             sodium hydride
NaBH 4           sodium borohydride
NaBH (OAc)  3    sodium triacetoxyborohydride
NaBH 3CN         sodium cyanoborohydride
NH 4OH           ammonium hydroxide
Et 3N or TEA     triethylamine
NHMe 2           dimethylamine
DIPEA           N, N-diisopropylethylamine
KF              potassium fluoride
n-BuLi          n-butyllithium
dppf            1, 1'-bis (diphenylphosphino) ferrocene
HATU            1- [Bis (dimethylamino) methylene] -1H-1, 2, 3-triazolo [4, 5-b] pyridinium
                3-oxid hexafluorophosphate
BINAP           2, 2'-bis (diphenylphosphino) -1, 1'-binaphthyl
Boc 2O           di-tert-butyl dicarbonate
MsCl            mesyl chloride
H 2O             water
NaIO 4           sodium periodate
RuCl 3. 3H 2O     ruthenium (III) chloride trihydrate
Pd/C            palladium on carbon
Pd (OH)  2/C     palladium hydroxide
Pd (PPh 3)  4     Tetrakis (triphenylphosphine) palladium (0)
Pd (PPh 3)  2Cl 2  bis (triphenylphosphine) palladium (II) dichloride
Pd 2 (dba)  3        tris (dibenzylideneacetone) dipalladium (0)
Pd (dppf) Cl 2      [1, 1′-Bis (diphenylphosphino) ferrocene] dichloropalladium (II)
Pd (t-Bu 3P)  2      Bis (tri-tert-butylphosphine) palladium (0)
Pd (OAc)  2         palladium (II) acetate
CF 3CH 2OH           trifluoroethyl alcohol
CuI                copper iodine
LiCl               lithium chloride
t-BuONa            sodium tert-butoxide
t-BuOK             potassium tert-butoxide
DMP                Dess–Martin periodinane
SOCl 2              thionyl chloride
i-PrMgBr           iso-propyl magnesium bromide
MeI                methyl iodide
K 3PO 4              potassium triphosphate
Zn (CN)  2          zinc cyanide
EXAMPLE 1
Synthesis of Intermediate S7
Figure PCTCN2021122588-appb-000265
Synthesis of S1
To a solution of (1R, 2S) -2-aminocyclopentanol hydrochloride S0 (11 g, 79.9 mmol) and Boc 2O (20.9 g, 95.9 mmol) in dichloromethane (200 mL) was added dropwise Et 3N (20.9 mL, 119.9 mmol) at 0 ℃. 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 Na 2SO 4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography to give the intermediate S1 as oil (15.5 g, 96%) .  1H NMR (400 MHz, CDCl 3)  δ 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) .
Synthesis of S2
To a solution of thionyl chloride (7 mL, 96.3 mmol) in dry acetonitrile (150 mL) was added a solution of the intermediate S1 (15.5g, 77.0 mmol) in acetonitrile (150mL) at -35℃. 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 Na 2SO 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, CDCl 3) δ 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) .
Synthesis of S3
To a solution of the intermediate S2 (18.8 g, 76 mmol) in acetonitrile (100 mL) and H 2O (100 mL) was added NaIO 4 (24.4 g, 114 mmol) in portions, followed by addition of RuCl 3. 3H 2O (315 mg, 1.5 mmol) at 0 ℃. The reaction was stirred at room temperature for 2 hours. Then, the aqueous layer was extracted with diethyl ether three times. The combined organic solvent was dried over Na 2SO 4, filtered and concentrated. The residue was purified by column chromatography to produce the title compound S3 as a white solid (19 g, 95%) .  1H NMR (400 MHz, CDCl 3) δ 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 C 10H 17NO 5S [M + Na]  + = 286.07, found: 286.10.
Synthesis of 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 1-benzylpiperidin-4-one (7.01 g, 37.01 mmol) and reaction was refluxed. After overnight, the solvent was removed, water and EtOAc were added, and the layers separated. The aqueous layer was extracted two more times with EtOAc, dried over Na 2SO 4, filtered and concentrated to give S4 that was used without further purification.
Crude S4 (37.01 mmol) was redissolved in MeOH (50 mL) and NaBH 4 (4.2 g, 111.03 mmol) was slowly added. After overnight, the reaction was checked by TLC (if the reaction is not complete more NaBH 4 was added) . After complete conversion ofS4 to S5, 8 mL of water was added, and the reaction was concentrated. Then more H 2O and EtOAc were  added, and the layers separated. The aqueous layer was extracted three times with EtOAc, dried over Na 2SO 4, filtered, concentrated, and purified by column chromatography (DCM/EtOAc gradient) to produce S5 as an oil.  1H NMR (400 MHz, Methanol-d 4) δ 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 C 20H 21FN 2 [M + H]  + = 309.17, found: 309.16.
Synthesis of S7 and S8
Figure PCTCN2021122588-appb-000266
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 then put under a nitrogen atmosphere. (This purging was repeated two more times) . The reaction was cooled to 0 ℃, KHMDS (0.5M in toluene, 42.4 mL, 21.21 mmol) was added dropwise, and the reaction was allowed to warm to room temperature and stirred overnight. After overnight, a solution of concentrated H 2SO 4 (0.6 mL, 11.31 mmol) in H 2O (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 NaHCO 3, extracted with ethyl acetate three times. The combined organic solvent was dried over Na 2SO 4, 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%) . The diastereomers were separated by reverse phase preparative HPLC to give the enantiopure title compounds S7 (1.2 g, 36%) and S8 (0.8 g, 24%) as salts of trifluoroacetic acid, respectively.
The enantiopure compound S7 is isolated by recrystallization in a solution of hexane and dichloromethane with a ratio of 4: 1.  Data forS7:  1H NMR (400 MHz, Methanol-d 4) δ 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 C 30H 38FN 3O 2 [M + H]  + = 492.29, found: 492.36. [α]  D 20 = + 23.1, (c 1.17×10 -3 g/mL, MeOH) ; t R (UPLC) = 4.46 min.  Data for S8:  1H NMR (400 MHz, Methanol-d 4) δ 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 C 30H 38FN 3O 2 [M + H]  + = 492.29, found: 492.36. [α]  D 20 = + 9.4, (c 1.07 ×10 -3 g/mL, MeOH) ; t 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) .
EXAMPLE 2
Synthesis of intermediate methyl ( (1S, 2R) -2- ( (S) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) -1- (piperidin-4-yl) ethyl) cyclopentyl) carbamate (S13)
Figure PCTCN2021122588-appb-000267
Methyl ( (1S, 2R) -2- ( (S) - (1-benzylpiperidin-4-yl) (cyano) (3-fluorophenyl) methyl) cyclopentyl) carbamate (S10) : Compound S7 (1.0 g, 2.04 mmol) was dissolved in DCM (2 mL) , and then CF 3CO 2H (6 mL) was added. After 15 minutes, the reaction was complete, and the solvent was removed in vacuo to produce S9 that was used  without purification. At 0℃, dimethyl dicarbonate (410 mg, 3.05 mmol) was added to a solution ofS9 and Et 3N (1.13 mL, 8.16 mmol) in DCM (30 mL) . After 2 hours, the reaction was concentrated and purified by column chromatography to produce S10 (770 mg) .
Methyl ( (1S, 2R) -2- ( (S) -2-amino-1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) ethyl) cyclopentyl) carbamate (S11) : At 0℃, diisobutylaluminium hydride (3.90 mL, 6.86 mmol) was slowly added to a solution ofS10 (770 mg, 1.715 mmol) in toluene (17 mL) . After 1 hour at 0℃, the reaction was allowed to warm to room temperature for 15 minutes, and then the reaction was slowly quenched with 2M NaOH. The quenched reaction was diluted with ethyl acetate, 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 NaBH 4 (130 mg, 3.43 mmol) . After overnight the reaction was quenched with 2M NaOH, diluted with ethyl acetate, 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 S11 (775 mg) .
Methyl ( (1S, 2R) -2- ( (S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) carbamate (S12) : At 0℃, ammonium acetate (340 mg, 4.42 mmol) , glyoxal (641 μL, 40%in water, 4.42 mmol) , and acetaldehyde (495 μL, 8.83 mmol) were added to a solution of S11 (400 mg, 0.883 mmol) in methanol (25 mL) . After stirring at 0℃ for 30 minutes, the reaction was removed from the ice bath and allowed to stir at room temperature for 1 hour then it was heated to 60℃. After heating at 60℃ overnight, the reaction was concentrated and purified by prep-HPLC to produce S12 (406 mg) .
Methyl ( (1S, 2R) -2- ( (S) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) -1- (piperidin-4-yl) ethyl) cyclopentyl) carbamate (S13) : S12 (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 then the reaction was vacuumed and put under H 2 atmosphere for 2 hours. After the Pd/C catalyst was filtered off through celite, the solvent was removed in vacuo to give S13 (318 mg) that was used without further purification.
EXAMPLE 3
Preparation of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate (S18)
Figure PCTCN2021122588-appb-000268
Step A: methyl ( (1S, 2R) -2- ( (S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2- (methylamino) ethyl) cyclopentyl) carbamate (S14)
A solution of methyl ( (1S, 2R) -2- ( (S) -2-amino-1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) ethyl) cyclopentyl) carbamate S11 (4.5 g, 10 mmol; Ref: WO2020/72391, 2020, A1) in MeOH (100 mL) was added formaldehyde (35%in H 2O, 0.83 mL, 12 mmol) at room temperature followed by Na 2SO 4 (5.0 g, 40 mmol) . The mixture was stirred at room temperature for 1 hour. Then NaBH 4 (675 mg, 20 mmol) was added in one portion to the mixture. After stirring for 30 minutes, the reaction mixture was poured into ice water (100 ml) and extracted with EtOAc (100 mL x 3) . The combined organic layers were washed with brine (100 mL x 2) , dried over Na 2SO 4, and concentrated under reduced pressure to give S14 (4.5 g, yield 87%) as a white solid. LC-MS: 468 (M+H)  +.
Step B: methyl ( (1S, 2R) -2- ( (S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate (S15)
To a solution ofS14 (4 g, 8.6 mmol ) in DCM (100 mL) was added TEA (3.6 mL, 25.7 mmol) , followed by MsCl (0.8 mL, 10.3 mmol) at 0℃. The reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into ice water (100 ml) and extracted with DCM (100 mL x 2) . The combined organic layers were washed with brine (100  mL x 2) , dried over Na 2SO 4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give S15 (3.5 g, yield 67%) as a white solid. LC-MS: 546 (M+H)  +.
Step C: methyl ( (1S, 2R) -2- ( (S) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) -1- (piperidin-4-yl) ethyl) cyclopentyl) carbamate (S16)
To a solution ofS15 (2.8 g, 5.1 mmol) in CF 3CH 2OH (100 mL) was added 10%Pd (OH)  2/C (280 mg) . The mixture was stirred at 25℃ under H 2 atmosphere (1 atm) for 16 hours. Then the mixture was filtered and concentrated under reduced pressure to give S16 (2.2 g, yield 89%) as a white solid. LC-MS: 456 (M+H)  +.
Step D: tert-butyl 6- (4- ( (S) -1- (3-fluorophenyl) -1- ( (1R, 2S) -2- ( (methoxycarbonyl) amino) cyclopentyl) -2- (N-methylmethylsulfonamido) ethyl) piperidin-1-yl) -2-azaspiro [3.3] heptane-2-carboxylate (S17)
To a solution ofS16 (2.2 g, 4.8 mmol) in DCM (100 mL) was added tert-butyl 6-oxo-2-azaspiro [3.3] heptane-2-carboxylate (1.2 g, 5.8 mmol) and two drops of AcOH at room temperature. The reaction mixture was stirred at room temperature for 1 hour. Then sodium triacetoxyborohydride (2 g, 9.6 mmol) was added in one portion to the mixture, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water (100 ml) and extracted with DCM (100 mL x 2) . The combined organic layers were washed with brine (100 mL x 2) , dried over Na 2SO 4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give S17 (2.4 g, yield 77%) as a white solid. LC-MS: 651 (M+H)  +.
Step E: methyl ( (1S, 2R) -2- ( (S) -1- (1- (2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate (S18)
To a solution of S17 (2.4 g, 3.7 mmol) in DCM (40 mL) was added TFA (10 mL) under N 2 atmosphere. The reaction mixture was stirred at 25℃ for 2 hours. Then the mixture was concentrated under reduced pressure. The residue was adjusted to pH 8 ～ 9 with sat. NaHCO 3 aq. and purified by reverse phase flash column chromatography (C18 Reversed-Phase Silica Gel, H 2O/MeOH) to give S18 (1.5 g, yield 75%) as a yellow solid. LC-MS: 551 (M+H)  +.
EXAMPLE 4
Preparation of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylacetamido) ethyl) cyclopentyl) carbamate (S20)
Figure PCTCN2021122588-appb-000269
Step A. methyl ( (1S, 2R) -2- ( (S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylacetamido) ethyl) cyclopentyl) carbamate (S19)
To a solution of methyl ( (1S, 2R) -2- ( (S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2- (methylamino) ethyl) cyclopentyl) carbamate (3 g, 5.89 mmol, 1.0 eq. ) and TEA (2.5 mL, 17.66 mmol, 3.0 eq. ) in DCM (30 mL) was added Ac 2O (0.7 mL, 7.06 mmol, 1.2 eq. ) at 0℃. The mixture was stirred at room temperature for 2 h. The reaction solution was poured into the water (50 mL) and extracted with DCM (30 mL x 3) . The combined organic layer was washed with brine (50 mL) , dried and concentrated under reduced pressure. The residue was purified by flash chromatography (eluent, 0 ～ 10%MeOH in DCM) to afford methyl ( (1S, 2R) -2- ( (S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylacetamido) ethyl) cyclopentyl) carbamate (2.5 g, yield 77%) as a white solid. LC-MS: m/z 510 (M+H)  +.
Step B through Step D: methyl ( (1S, 2R) -2- ( (S) -1- (1- (2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylacetamido) ethyl) cyclopentyl) carbamate (S20)
S20 was synthesized as in Steps C through E for Example 3.
LC-MS: m/z 515 (M+H)  +.
EXAMPLE 5
Preparation of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (3- (dimethylcarbamoyl) -4- (pyrimidin-2-yl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate (Cpd 75)
Figure PCTCN2021122588-appb-000270
Step A: 5-bromo-N, N-dimethyl-2- (pyrimidin-2-yl) benzamide
A mixture of 5-bromo-2-iodo-N, N-dimethylbenzamide (300 mg, 0.85 mmol) , 2- (tributylstannyl) pyrimidine (375 mg, 1.02 mmol) , Pd (PPh 3)  4 (98 mg, 0.09 mmol) , CuI (16 mg, 0.09 mmol) and LiCl (36 mg, 0.85 mmol) in toluene (5 mL) was stirred at 90 ℃ under N 2 atmosphere overnight. Then the reaction mixture was filtered, diluted with water (20 mL) , and extracted with EtOAc (20 mL x 3) . The combined organic layers were washed with brine (20 mL) , dried over Na 2SO 4, and concentrated under reduce pressure. The residue was purified by flash column chromatography on silica gel to afford 5-bromo-N, N-dimethyl-2- (pyrimidin-2-yl) benzamide (137 mg, yield 53%) as a white solid. LC-MS: 306, 308 (M+H)  +.
Step B: methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (3- (dimethylcarbamoyl) -4- (pyrimidin-2-yl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate (Cpd 75)
A mixture of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate S18 (80 mg, 0.15 mmol) , 5-bromo-N, N-dimethyl-2- (pyrimidin-2-yl) benzamide (58 mg, 0.19 mmol) , Pd 2 (dba)  3 (13 mg, 0.015 mmol) , BINAP (18 mg, 0.03 mmol ) and t-BuONa (21 mg, 0.22 mmol) in toluene (2 mL) was stirred at 90℃ under N 2 atmosphere overnight. Then the reaction mixture was filtered, diluted with water (10 mL) , and extracted with EtOAc (10 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over Na 2SO 4, and concentrated under reduce pressure. The residue was purified by Prep-TLC and reverse-phase-prep-HPLC to give Cpd 75 (50 mg, yield  44%) as a white solid. LC-MS: 776.7 (M+H)  +.  1H NMR (400 MHz, Methanol-d 4) δ 8.69 (d, 2H) , 8.20 (d, 1H) , 7.47 -7.34 (m, 3H) , 7.19 (t, 1H) , 7.02 (t, 1H) , 6.55 (dd, 1H) , 6.27 (d, 1H) , 4.03 -3.97 (m, 3H) , 3.87 –3.74 (m, 4H) , 3.59 (s, 3H) , 3.24 –3.04 (m, 6H) , 2.92 (s, 3H) , 2.75 (s, 3H) , 2.70 –2.58 (m, 4H) , 2.52 -2.41 (m, 2H) , 2.34 -2.03 (m, 5H) , 2.02 -1.95 (m, 1H) , 1.94 -1.73 (m, 3H) , 1.72 -1.42 (m, 4H) , 1.39 -1.27 (m, 2H) .
EXAMPLE 6
Synthesis of methyl ( (1S, 2R) -2- (1- (1- (2- (3- (dimethylcarbamoyl) -4- (1-methyl-1H-pyrazol-3-yl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate (Cpd 97)
Figure PCTCN2021122588-appb-000271
Synthesis of compound A3
2-azaspiro [3.3] heptan-6-ol hydrochloride 2 (800 mg, 5.35 mmol) and K 2CO 3 (2.96 g, 21.4 mmol) were added to a solution of 2-bromo-5-fluorobenzonitrile A1 (1.07 g, 5.35 mmol) in DMSO (18 mL) . The mixture was stirred at 100 ℃ overnight. The mixture was quenched with water, extracted three times with EtOAc, washed with brine and concentrated. The residue was purified by flash column chromatography (silica gel, hexane/EtOAc) to give A3 as white solid (1.20 g, 77%) .
Synthesis of compound A5
Compound A3 (1.09 g, 3.70 mmol) was added to a 10%NaOH solution (20 mL) . The mixture was stirred under reflux overnight. After cooling to room temperature, HCl (aq) was added to adjust the pH to 1. The mixture was extracted three times with EtOAc,  washed with brine and concentrated to give crude A4, which was used without further purification.
To a DMF (20 mL) solution of crude compound A4 was added NHMe 2 (2M in THF, 7.4 mmol) , DIPEA (2.6 mL, 14.8 mmol) and HATU (2.11 g, 5.56 mmol) subsequently. The mixture was stirred under room temperature for 15 minutes, quenched with water and purified by reverse phase flash column chromatography (C18 Reversed-Phase Silica Gel, H 2O/CH 3CN) to give compound A5 (1.2 g, 99%) .
Synthesis of compound A6
To a solution of compound A5 (1.2 g, 3.7 mmol) in DCM (40 mL) was added pyridine (0.9 mL, 11.1 mmol) and DMP (2.35 g, 5.55 mmol) under 0 ℃. After 1 hour, the mixture was quenched with water and purified by reverse phase flash column chromatography (C18 Reversed-Phase Silica Gel, H 2O/CH 3CN) to give compound A6 (0.46 g, 37%) .
Synthesis of compound A7
Under a nitrogen atmosphere, 1-methyl-1H-pyrazole-3-boronic acid pinacol ester (92.6 mg, 0.445 mmol) , Pd (dppf) Cl 2·DCM (24.3 mg, 0.0297 mmol) , and K 2CO 3 (123 mg, 0.891 mmol) was added to a solution of compound A6 (100 mg, 0.297 mmol) in dioxane/H 2O (2.8/0.7 mL) . The mixture was stirred at 100 ℃ overnight, quenched with water and purified by reverse phase flash column chromatography (C18 Reversed-Phase Silica Gel, H 2O/CH 3CN) to give compound A7 (49 mg, 49%) .
Synthesis of methyl ( (1S, 2R) -2- (1- (1- (2- (3- (dimethylcarbamoyl) -4- (1-methyl-1H-pyrazol-3-yl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate (Cpd 97)
To a solution ofS16 (14.6 mg, 0.032 mmol) in DCE (1 mL) was added A7 (13 mg, 0.0384 mmol) , Et 3N (9μL, 0.064 mmol) and AcOH (6μL, 0.096 mmol) subsequently. After 3 hours, NaBH (OAc)  3 (20.3 mg, 0.096 mmol) was added. The mixture was stirred overnight, quenched with water and and purified by reverse phase preparative HPLC to Cpd 97.  1H NMR (400 MHz, Methanol-d4) δ 7.61 –7.48 (m, 2H) , 7.48 –7.34 (m, 3H) , 7.14 –6.99 (m, 1H) , 6.89 –6.68 (m, 0.5 H) , 6.62 –6.50 (m, 1H) , 6.37 –6.31 (m, 0.5 H) , 6.31 –6.23 (m, 1H) , 4.07 –3.95 (m, 2H) , 3.93 –3.75 (m, 6H) , 3.71 –3.54 (m, 6H) , 3.54 –3.43 (m, 1H) , 3.28 –3.19 (m, 1H) , 3.05 –2.96 (m, 4H) , 2.96 –2.89 (m, 2H) , 2.87 –2.73 (m, 2H) , 2.72 –2.60 (m, 7H) , 2.60 –2.40 (m, 3H) , 2.38 –1.98 (m, 6H) , 1.91 –1.78 (m, 1H) , 1.61 –1.44 (m, 2H) , 1.41 –1.24 (m, 3H) . ESI-MS calculated for C 41H 57FN 7O 5S [M + H]  + = 778.41, found: 778.26.
Cpd 96 was made in the same manner with 1-Methyl-1H-pyrazole-4-boronic acid pinacol ester.
EXAMPLE 7
Preparation of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (4- (benzo [d] thiazol-2-yl) -3- (dimethylcarbamoyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate (Cpd 104)
Figure PCTCN2021122588-appb-000272
Step A: 2- (benzo [d] thiazol-2-yl) -5-bromo-N, N-dimethylbenzamide
A mixture of 5-bromo-2-iodo-N, N-dimethylbenzamide (500 mg, 1.41 mmol;  Ref: PCT Int. Appl., 2008124850) , 2- (tributylstannyl) benzo [d] thiazole (722 mg, 1.69 mmol) , Pd (dppf) Cl 2 (103 mg, 0.14 mmol) and LiCl (59 mg, 1.41 mmol) in toluene (10 mL) was stirred at 90 ℃ under N 2 atmosphere for 16 hours. Then the reaction mixture was diluted with H 2O (10 mL) and extracted with EtOAc (10 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over Na 2SO 4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 2- (benzo [d] thiazol-2-yl) -5-bromo-N, N-dimethylbenzamide (160 mg, yield 31%) as a white solid. LC-MS: 361, 363 (M+H)  +.
Step B: methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (4- (benzo [d] thiazol-2-yl) -3- (dimethylcarbamoyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate (Cpd 104)
A mixture of 2- (benzo [d] thiazol-2-yl) -5-bromo-N, N-dimethylbenzamide (50 mg, 0.14 mmol) , methyl ( (1S, 2R) -2- ( (S) -1- (1- (2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1-  (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate S18 (80 mg, 0.14 mmol) , Pd 2 (dba)  3 (13 mg, 0.013 mmol) , Ru-Phos (6 mg, 0.013 mmol) , and Cs 2CO 3 (136 mg, 0.42 mmol) in toluene (10 mL) was stirred at 90 ℃ under N 2atmosphere for 16 hours. The reaction mixture was diluted with H 2O (10 mL) and extracted with EtOAc (10 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over Na 2SO 4, and concentrated under reduced pressure. The residue was purified by Prep-TLC and RP-prep-HPLC to give Cpd 104 (12 mg, yield 10%) as a white solid. LC-MS: 831.4 (M+H)  +.  1H NMR (400 MHz, Methanol-d 4) δ 7.92 (d, 1H) , 7.87 (d, 1H) , 7.81 (d, 1H) , 7.47 -7.33 (m, 5H) , 7.02 (t, 1H) , 6.56 (dd, 1H) , 6.33 (d, 1H) , 4.04 -3.97 (m, 3H) , 3.89 (s, 2H) , 3.83 (s, 2H) , 3.59 (s, 3H) , 3.22 -3.06 (m, 6H) , 2.92 (s, 3H) , 2.78 (s, 3H) , 2.70 -2.60 (m, 4H) , 2.51 -2.41 (m, 2H) , 2.32 –2.09 (m, 4H) , 2.02 –1.91 (m, 2H) , 1.89 –1.74 (m, 3H) , 1.70 –1.42 (m, 4H) , 1.39 –1.25 (m, 2H) .
EXAMPLE 8
Preparation of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (5- (dimethylcarbamoyl) -2-fluoro-4- (1-methyl-1H-pyrazol-3-yl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate (Cpd 110)
Figure PCTCN2021122588-appb-000273
Step A: 5-bromo-4-fluoro-2-iodo-N, N-dimethylbenzamide
A solution of 5-bromo-4-fluoro-2-iodobenzoic acid (6 g, 17.4 mmol;  Ref:  Journal of the American Chemical Society, 142 (5) , 2549-2561; 2020) in SOCl 2 (50 mL) was stirred at 80℃ for 2 hours. The reaction mixture was then concentrated under reduced pressure. To the residue was added dimethylamine (1 M in THF; 34.7 mL, 34.8 mmol) and stirred at room temperature for 30 minutes. The mixture was filtered, and the filtrate was concentrated  under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 5-bromo-4-fluoro-2-iodo-N, N-dimethylbenzamide (5 g, yield 77%) as a white solid. LC-MS: 372, 374 (M+H)  +.
Step B: 5-bromo-4-fluoro-N, N-dimethyl-2- (1-methyl-1H-pyrazol-3-yl) benzamide
A mixture of 5-bromo-4-fluoro-2-iodo-N, N-dimethylbenzamide (3.49 g, 9.37 mmol) , 1-methyl-3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (1.5 g, 7.21 mmol) , Pd (PPh 3)  2Cl 2 (0.51 g, 0.72 mmol) and Na 2CO 3 (2.29 g, 21.6 mmol) in dioxane (27 mL) and H 2O (1 mL) was stirred at 90 ℃ under N 2 atmosphere for 16 hours. The reaction was cooled to room temperature, and the cooled mixture was passed through a Celite pad. The filtrate was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3) . The combined organic layers were washed with brine (50 mL) , dried over Na 2SO 4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 5-bromo-4-fluoro-N, N-dimethyl-2- (1-methyl-1H-pyrazol-3-yl) benzamide (800 mg, yield 34%) as a yellow solid. LC-MS: 326, 328 (M+H)  +.
Step C: methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (5- (dimethylcarbamoyl) -2-fluoro-4- (1-methyl-1H-pyrazol-3-yl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate (Cpd 110)
A mixture of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate S18 (100 mg, 0.18 mmol) , 5-bromo-4-fluoro-N, N-dimethyl-2- (1-methyl-1H-pyrazol-3-yl) benzamide (88 mg, 0.27 mmol) , RuphosPdG2 (13 mg, 0.018 mmol) , BINAP (23 mg, 0.36 mmol) and t-BuONa (35 mg, 0.36 mmol) in toluene (1 mL) was stirred under N 2 atmosphere at 90℃ for 16 hours. The reaction mixture was filtered, diluted with water (10 mL) , and extracted with EtOAc (10 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over Na 2SO 4, and concentrated under reduced pressure. The residue was purified by Prep-TLC and reverse phase-prep-HPLC to give Cpd 110 (55 mg , yield 38%) as a white solid. LC-MS: 796 (M+H) +.  1H NMR (400 MHz, Methanol-d 4) δ 7.53 (d, 1H) , 7.46 -7.36 (m, 3H) , 7.33 (d, 1H) , 7.08 -6.92 (m, 1H) , 6.37 (d, 1H) , 6.28 (d, 1H) , 4.01 (s, 3H) , 3.90 -3.80 (m, 7H) , 3.59 (s, 3H) , 3.18 -3.07 (m, 2H) , 2.99 (s, 3H) , 2.91 (s, 3H) , 2.71 -2.62 (m, 4H) , 2.62 (s, 3H) , 2.50 -2.41 (m, 2H) , 2.32 -2.05 (m, 5H) , 2.01 -1.95 (m, 1H) , 1.94 -1.75 (m, 3H) , 1.73 -1.57 (m, 2H) , 1.56 -1.44 (m, 2H) , 1.36 -1.27 (m, 3H) .
EXAMPLE 9
Preparation of methyl ( (1S, 2R) -2- (1- (1- (2- (5- (dimethylcarbamoyl) -2-fluoro-4- (4-methylthiazol-2-yl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate (Cpd 120)
Figure PCTCN2021122588-appb-000274
Synthesis of compound B3
Under a nitrogen atmosphere, methyl 5-bromo-4-fluoro-2-iodobenzoate B1 (400 mg, 1.11 mmol) , 4-methyl-2- (tributylstannyl) thiazole B2 (433 mg, 1.11 mmol) , Pd (PPh 3)  4 (24.3 mg, 0.0297 mmol) and 6 mL of toluene were added to a microwave vial. The mixture was stirred at 150 ℃ under microwave for 3 hours. The mixture was quenched with KF (aq. ) and purified by flash column chromatography (hexane/EtOAc) to give compound B3 (282 mg, 77%) .
Synthesis of compound B5
Under a nitrogen atmosphere, B3 (282 mg, 0.854 mmol) , 2-azaspiro [3.3] heptan-6-ol hydrochloride B4 (148 mg, 0.939 mmol) , Pd (OAc)  2 (38 mg, 0.171 mmol) , XantPhos (198 mg, 0.342 mmol) and 8 mL of dioxane were added to a schlenk flask. The mixture was stirred  at 95 ℃ overnight. The mixture was concentrated, and the residue was purified by flash column chromatography (hexane/EtOAc) to give compound B5 (188 mg, 54%) .
Synthesis of compound B6
Amberlyst 15 (20 mg) was added to a solution ofB5 (28 mg, 0.0689 mmol) in acetone/H 2O (1/0.1 mL) . After 2 hours at room temperature, the mixture was filtered, and the filtrate was concentrated to give crude B6, which was used without further purification.
Synthesis of compound B8
To a solution ofB6 (0.0689 mmol) in DCE (30 mL) was added Et 3N (19μL, 0.138 mmol) , AcOH (16μL, 0.276 mmol) and S16 (31 mg, 0.0689 mmol) subsequently. After stirring for 3 hours, NaBH (OAc)  3 (44 mg, 0.207 mmol) was added. The mixture was stirred overnight and concentrated under vacuum. The residue was dissolved in MeOH/H 2O. LiOH·H2O was added, and the mixture was stirred at 55 ℃ overnight. The mixture was then concentrated under vacuum, purified by reverse phase preparative HPLC to give B7 (41.9 mg, 77%) .
Synthesis of methyl ( (1S, 2R) -2- (1- (1- (2- (5- (dimethylcarbamoyl) -2-fluoro-4- (4-methylthiazol-2-yl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate (Cpd 120) 
To a DMF (1 mL) solution of compound B7 (42 mg, 0.0533 mmol) was added NHMe 2 (53μL, 2M in THF) , DIPEA (37μL, 0.213 mmol) , and HATU (30 mg, 0.0800 mmol) subsequently. The mixture was stirred at room temperature for 15 minutes, quenched with water, and purified by reverse phase preparative HPLC to give Cpd 120.  1H NMR (400 MHz, Methanol-d4) δ 7.53 (d, J = 13.4 Hz, 1H) , 7.50 –7.39 (m, 3H) , 7.15 –7.05 (m, 2H) , 6.42 (d, J = 8.9 Hz, 1H) , 4.21 –4.13 (m, 2H) , 4.05 (s, 3H) , 3.84 (q, J = 14.3 Hz, 2H) , 3.74 –3.57 (m, 5H) , 3.56 –3.42 (m, 2H) , 3.07 (s, 3H) , 2.96 (s, 3H) , 2.90 –2.77 (m, 2H) , 2.75 (s, 3H) , 2.74 –2.66 (m, 4H) , 2.65 –2.51 (m, 3H) , 2.52 –2.46 (m, 2H) , 2.44 (s, 3H) , 2.30 –2.19 (m, 1H) , 2.16 –2.01 (m, 2H) , 1.95 –1.83 (m, 1H) , 1.67 –1.45 (m, 2H) , 1.44 –1.30 (m, 3H) . ESI-MS calculated for C 41H 55F 2N 6O 5S 2 [M + H]  + = 813.36, found: 813.22.
Cpd 121 was made in the same manner with 4, 5-dimethyl-2- (tributylstannyl) thiazole.
EXAMPLE 10
Preparation of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (3- (dimethylcarbamoyl) -4- (4, 5-dimethyloxazol-2-yl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate (Cpd 124)
Figure PCTCN2021122588-appb-000275
Step A: 4, 5-dimethyl-2- (tributylstannyl) oxazole
To a solution of 4, 5-dimethyloxazole (2 mL, 20.59 mmol) in THF (30 mL) was added n-BuLi (1.6 M in hexane; 15.4 mL, 24.71 mmol) at -65℃. After 30 minutes, tributylchlorostannane (4.5 mL, 16.47 mmol) in THF (5 mL) was added. The reaction was stirred at -65℃ for 30 minutes. The mixture was then warmed to room temperature and stirred for 30 minutes. The reaction mixture was concentrated directly under reduced pressure at room temperature and dissolved with hexane (30 mL) . After filtering, the filtrate was concentrated under reduce pressure at room temperature to afford 4, 5-dimethyl-2- (tributylstannyl) oxazole (6.6 g, crude) as a colorless oil.
Step B: 5-bromo-2- (4, 5-dimethyloxazol-2-yl) -N, N-dimethylbenzamide
A mixture of 4, 5-dimethyl-2- (tributylstannyl) oxazole (2 g, 5.09 mmol) , 5-bromo-2-iodo-N, N-dimethylbenzamide (1.5 g, 4.24 mmol) , Pd (dppf) Cl 2 (307 mg, 0.42 mmol) , LiCl (178 mg, 4.24 mmol) and CuI (80 mg, 0.42 mmol) in toluene (30 mL) was stirred at 90℃ under N 2 atmosphere overnight. Then the reaction mixture was filtered, diluted with water (20 mL) and extracted with EtOAc (20 mL x 3) . The combined organic layers were washed with brine (20 mL) , dried over Na 2SO 4, and concentrated under reduce pressure. The residue was purified by flash column chromatography on silica gel to afford 5-bromo-2- (4, 5- dimethyloxazol-2-yl) -N, N-dimethylbenzamide (360 mg, yield 26%) as a yellow solid. LC-MS: m/z 323 (M+H)  +.
Step C: methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (3- (dimethylcarbamoyl) -4- (4, 5-dimethyloxazol-2-yl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate (Cpd 124) 
A mixture of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate S18 (300 mg, 0.55 mmol) , 5-bromo-2- (4, 5-dimethyloxazol-2-yl) -N, N-dimethylbenzamide (184 mg, 0.57 mmol) , RuPhosPdG2 (42.3 mg, 0.05 mmol) , Ru-Phos (50.9 mg, 0.11 mmol) , and Cs 2CO 3 (530 mg, 1.63 mmol) in toluene (20 mL) was stirred at 90℃ under N 2 atmosphere overnight. Then the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3) . The combined organic layers were washed with brine (20 mL) , dried over Na 2SO 4, and concentrated under reduced pressure. The residue was purified by Prep-TLC and reverse-phase-prep-HPLC to afford Cpd 124 (105 mg, yield 23%) as a white solid. LC-MS: m/z 793.5 (M+H)  +.  1H NMR (400 MHz, Methanol-d 4) δ 7.85 -7.72 (m, 1H) , 7.48 -7.36 (m, 3H) , 7.03 (t, 1H) , 6.53 (dd, 1H) , 6.28 (d, 1H) , 4.06 -3.95 (m, 3H) , 3.87 (s, 2H) , 3.82 (s, 2H) , 3.60 (s, 3H) , 3.28 -3.16 (m, 2H) , 3.08 (s, 3H) , 2.92 (s, 3H) , 2.76 (s, 3H) , 2.67 (s, 3H) , 2.61 -2.47 (m, 3H) , 2.38 -2.18 (m, 7H) , 2.13 -1.97 (m, 5H) , 1.96 -1.77 (m, 3H) , 1.65 -1.43 (m, 3H) , 1.41 -1.14 (m, 4H) .
EXAMPLE 11
Preparation of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (5- (dimethylcarbamoyl) -2-fluoro-4- (4-fluoro-1-methyl-1H-pyrazol-3-yl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate (Cpd 155)
Figure PCTCN2021122588-appb-000276
Step A: (4-bromo-2- (dimethylcarbamoyl) -5-fluorophenyl) boronic acid
To a solution of 5-bromo-4-fluoro-2-iodo-N, N-dimethylbenzamide (3 g, 8.1 mmol) in THF (20 mL) was added i-PrMgBr (1 M in THF; 20 mL) at -15℃. The mixture was stirred at this temperature for 1 hour. Then trimethyl borate (2.2 mL, 20 mmol) was added at -20℃, and the reaction was stirred for 1 hour at 0℃. The reaction was quenched with 10 ml of water and extracted with EtOAc (50 mL x 3) . The combined organic layers were washed with brine (50 mL) , dried over Na 2SO 4, and concentrated under reduced pressure. The residue was washed with PE and filtered to give (4-bromo-2- (dimethylcarbamoyl) -5-fluorophenyl) boronic acid (1.5 g, yield 64%) as a white solid. LC-MS: 288 (M-1)  +.
Step B: 4-fluoro-3-iodo-1H-pyrazole
A mixture of 4-fluoro-1H-pyrazole (500 mg, 5.81 mmol) and NIS (1.4 g, 6.39 mmol) in CHCl 3 (5 mL) was stirred at 65℃ for 16 hrs. The reaction was poured into ice water (20 mL) and extracted with DCM (20 mL x 2) . The combined organic layers were washed with brine (20 mL) , dried over Na 2SO 4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 4-fluoro-3-iodo-1H-pyrazole (270 mg, yield 22%) as a white solid. LC-MS: 213 (M+1)  +.
Step C: 4-fluoro-3-iodo-1-methyl-1H-pyrazole
To a solution of 4-fluoro-3-iodo-1H-pyrazole (300 mg, 1.42 mmol) in DMF (5 mL) was added NaH (60%in mineral oil, 106 mg, 2.6 mmol) at 0℃. The mixture was stirred at this temperature for 20 minutes. Then MeI (0.17 mL, 2.6 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was quenched with sat. NH 4Cl aq. (30 mL) and extracted with EtOAc (30 mL x 2) . The organic phase was washed with brine (30 mL) , dried over Na 2SO 4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 4-fluoro-3-iodo-1-methyl-1H-pyrazole (120 mg, yield 37%) as a white solid. LC-MS: 226 (M+H)  +.
Step D: 5-bromo-4-fluoro-2- (4-fluoro-1-methyl-1H-pyrazol-3-yl) -N, N-dimethylbenzamide
A mixture of 4-fluoro-3-iodo-1-methyl-1H-pyrazole (300 mg, 1.33 mmol) , (4-bromo-2- (dimethylcarbamoyl) -5-fluorophenyl) boronic acid (325 mg, 1.33 mmol) , Pd (dppf) Cl 2 (97 mg, 0.13 mmol) and K 3PO 4 (704 mg, 3.32 mmol) in THF (5 mL) and H 2O (1 mL) was stirred at 85℃ under N 2 temperature for 2 hours. Then the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over Na 2SO 4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 5-bromo-4-fluoro-2- (4-fluoro-1-methyl-1H-pyrazol-3-yl) -N, N-dimethylbenzamide (90 mg, yield 20%) as a white solid. LC-MS: 344, 346 (M+1)  +.
Step E: methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (5- (dimethylcarbamoyl) -2-fluoro-4- (4-fluoro-1-methyl-1H-pyrazol-3-yl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate (Cpd 155)
A mixture of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate S18 (60 mg, 0.11 mmol) , 5-bromo-4-fluoro-2- (4-fluoro-1-methyl-1H-pyrazol-3-yl) -N, N-dimethylbenzamide (45 mg, 0.13 mmol) , Pd 2 (dba)  3 (10 mg, 0.011 mmol) , Ru-Phos (10 mg, 0.02 mmol) and Cs 2CO 3 (107 mg, 0.33 mmol) in toluene (5 mL) was stirred at 90℃ under N 2 atmosphere overnight. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2) . The combined organic layers were washed with brine (10 mL) , dried over Na 2SO 4, and concentrated under reduced pressure. The residue was purified by Prep-TLC and reverse-phase-prep-HPLC to give Cpd 155 (25 mg, yield 28%) as a white solid. LC-MS: 814.4 (M+1)  +.  1HNMR (400 MHz, Methanol-d 4) δ 7.58 (d, 1H) , 7.46 -7.38 (m, 3H) , 7.25 (d, 1H) , 7.08 –6.98 (m, 1H) , 6.42 (d, 1H) , 4.04 (s, 2H) , 4.02 -3.96 (m, 1H) , 3.93 (s, 2H) , 3.82 (s, 2H) , 3.79 (s, 3H) , 3.61 (s, 3H) , 3.25 -3.18 (m, 1H) , 2.99  (s, 3H) , 2.92 (s, 3H) , 2.72 (s, 3H) , 2.68 (s, 3H) , 2.62 -2.45 (m, 4H) , 2.36 –2.31 (m, 1H) , 2.30 –2.21 (m, 3H) , 2.10 –2.04 (m, 2H) , 1.94 -1.79 (m, 3H) , 1.59 -1.42 (m, 3H) , 1.39 -1.31 (m, 3H) , 1.30 (s, 1H) .
EXAMPLE 12
Preparation of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (5- (dimethylcarbamoyl) -2-fluoro-4- (pyridazin-3-yl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate (Cpd 157)
Figure PCTCN2021122588-appb-000277
Step A: 5-bromo-4-fluoro-N, N-dimethyl-2- (pyridazin-3-yl) benzamide
A mixture of (4-bromo-2- (dimethylcarbamoyl) -5-fluorophenyl) boronic acid (300 mg, 1.04 mmol) , 3-bromopyridazine (181 mg, 1.14 mmol) , Pd (dppf) Cl 2 (76 mg, 0.1 mmol) , K 3PO 4 (659 mg, 3.11 mmol) in THF (10 mL) and water (2 mL) was stirred at 65℃ under N 2 atmosphere for 2 hours. The mixture was cooled to room temperature, diluted with water (20 mL) , and extracted with EtOAc (20 mL x 3) . The combined organic layers were washed with brine (20 mL) , dried over Na 2SO 4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 5-bromo-4-fluoro-N, N-dimethyl-2- (pyridazin-3-yl) benzamide (160 mg, yield 48%) as a white solid. LC-MS: 324, 326 (M+H)  +.
Step B: methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (5- (dimethylcarbamoyl) -2-fluoro-4- (pyridazin-3-yl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate
A mixture of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate S18 (70 mg, 0.13 mmol) , 5-bromo-4-fluoro-N, N-dimethyl-2- (pyridazin-3-yl) benzamide (62 mg, 0.19 mmol) , Pd 2 (dba)  3 (12 mg, 0.013 mmol) , Ru-Phos (6 mg, 0.013 mmol) , and C S2CO 3 (125 mg, 0.38 mmol) in toluene (2 ml) was stirred at 90℃ under N 2 atmosphere for 16 hours. The cooled mixture was filtered through a Celite pad, and the filtrate was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3) . The combined organic layers were washed with brine (20 mL) , dried over Na 2SO 4, and concentrated under reduced pressure. The residue was purified by Prep-TLC and reverse-phase-prep-HPLC to give Cpd 157 (10 mg, yield 10%) as a white solid. LC-MS: 794 (M+H)  +.  1H NMR (400 MHz, Methanol-d 4) δ 9.06 (dd, 1H) , 7.87 (dd, 1H) , 7.72 (dd, 1H) , 7.54 -7.36 (m, 4H) , 7.03 (t, 1H) , 6.49 (d, 1H) , 4.12 (s, 2H) , 4.00 (s, 3H) , 3.83 (s, 2H) , 3.60 (s, 3H) , 3.29 -3.16 (m, 2H) , 2.99 (s, 3H) , 2.94 (s, 3H) , 2.78 (s, 3H) , 2.68 (s, 3H) , 2.65 -2.61 (m, 1H) , 2.58 -2.47 (m, 3H) , 2.43 -2.22 (m, 4H) , 2.11 -1.75 (m, 5H) , 1.65 -1.44 (m, 3H) , 1.41 -1.28 (m, 3H) .
EXAMPLE 13
Preparation of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (6- (dimethylcarbamoyl) -5- (oxazol-2-yl) pyridin-2-yl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylacetamido) ethyl) cyclopentyl) carbamate (Cpd 162)
Figure PCTCN2021122588-appb-000278
Step A: 3-bromo-6-fluoro-N, N-dimethylpicolinamide
A mixture of 3-bromo-6-fluoropicolinic acid (1.1 g, 5 mmol) , HATU (3.8 g, 10 mmol) , DIPEA (3.33 mL, 20 mmol) , and Me 2NH HCl salt (0.61 g, 7.5 mmol) in DCM (20 mL) was stirred at room temperature for 3 hours. 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 Na 2SO 4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 3-bromo-6-fluoro-N, N-dimethylpicolinamide (1.2 g, yield 97 %) as a white solid. LC-MS: 247, 249 (M+H)  +.
Step B: 6-fluoro-N, N-dimethyl-3- (oxazol-2-yl) picolinamide
A mixture of 3-bromo-6-fluoro-N, N-dimethylpicolinamide (300 mg, 1.21 mmol) , 2- (tributylstannyl) oxazole (868 mg, 2.42 mmol) , and Pd (PPh 3)  4 (140 mg, 0.12 mmol) in dioxane (24 mL) was stirred at 80℃ under N 2 atmosphere for 4 hours. The reaction was quenched with sat. KF aq. (10 mL) . And the mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3) . The combined organic layers were washed with brine (50 mL) , dried over Na 2SO 4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 6-fluoro-N, N-dimethyl-3- (oxazol-2-yl) picolinamide (100 mg, yield 25 %) as a white solid. LC-MS: 236 (M+H)  +.
Step C: methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (6- (dimethylcarbamoyl) -5- (oxazol-2-yl) pyridin-2-yl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylacetamido) ethyl) cyclopentyl) carbamate (Cpd 162)
A mixture of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylacetamido) ethyl) cyclopentyl) carbamate S20 (80 mg, 0.16 mmol) , 6-fluoro-N, N-dimethyl-3- (oxazol-2-yl) picolinamide (37 mg, 0.16  mmol) , and K 2CO 3 (40 mg, 0.29 mmol) in DMSO (5 mL) was stirred at 80℃ overnight. The mixture was cooled to room temperature, diluted with water (30 mL) , and extracted with EtOAc (30 mL x 3) . The combined organic layers were washed with brine (30 mL) , dried over Na 2SO 4, and concentrated under reduced pressure. The residue was purified by Prep-TLC and reverse-phase-prep-HPLC to give Cpd 162 (80 mg, yield 71%) as a white solid. LC-MS: 730 (M+H)  +.  1H NMR (400 MHz, Methanol-d 4) δ 8.09 (d, 1H) , 7.88 (d, 1H) , 7.46 -7.34 (m, 3H) , 7.20 (d, 1H) , 7.05 -6.97 (m, 1H) , 6.48 (d, 1H) , 4.22 (d, 1H) , 4.13 (s, 2H) , 4.07 -3.95 (m, 4H) , 3.60 (s, 3H) , 3.11 (s, 3H) , 3.09 -2.98 (m, 2H) , 2.88 (s, 3H) , 2.83 (s, 3H) , 2.68 –2.58 (m, 1H) , 2.49 -2.39 (m, 2H) , 2.25 -2.08 (m, 6H) , 2.08 -1.67 (m, 6H) , 1.55 -1.50 (m, 1H) , 1.48 -1.37 (m, 3H) , 1.36 (s, 2H) , 1.23 –1.10 (m, 1H) .
EXAMPLE 14
Synthesis of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (5- (dimethylcarbamoyl) -2-fluoro-4- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylacetamido) ethyl) cyclopentyl) carbamate (Cpd 199)
Figure PCTCN2021122588-appb-000279
Step A. (4-bromo-2- (dimethylcarbamoyl) -5-fluorophenyl) boronic acid
To a solution of 5-bromo-4-fluoro-2-iodo-N, N-dimethylbenzamide (2 g, 5.41 mmol, 1.0 eq. ) in THF (10 mL) was added Isopropyl magnesium bromide solution (13.5 mL, 13.53 mmol, 2.5 eq.; 1 M in THF) at -25℃. The mixture was stirred for 1 h at this temperature.  Then trimethyl borate (1.8 mL, 16.23 mmol, 3.0 eq. ) was added to the above solution and the mixture was stirred at 0℃ for 1h. The reaction was quenched with aq. NH 4Cl (20 mL) , then the mixture was extracted with EtOAc (40 mL x 3) and washed with brine (40 mL) . The combined organic layer was dried and concentrated under reduced pressure to afford (4-bromo-2- (dimethylcarbamoyl) -5-fluorophenyl) boronic acid (1 g, yield 64 %) as a yellow solid. LC-MS: m/z 270, 272 (M+H)  +.
Step B. 5-bromo-4-fluoro-N, N-dimethyl-2- (1-methyl-1H-1, 2, 4-triazol-3-yl) benzamide
To a solution of (4-bromo-2- (dimethylcarbamoyl) -5-fluorophenyl) boronic acid (400 mg, 1.38 mmol, 1.0 eq. ) and 3-iodo-1-methyl-1H-1, 2, 4-triazole (350 mg, 1.66 mmol, 1.2 eq. ) in toluene/MeOH/H 2O (12 mL, 1 : 1 : 1) was added Pd (PPh 3)  4 (80 mg, 0.07 mmol, 0.05 eq. ) and Cs 2CO 3 (1.4 g, 4.14 mmol, 3.0 eq. ) at room temperature. The mixture was stirred at 65℃ under N 2 atmosphere for 16h. The mixture was filtered and diluted with H 2O (20 mL) . Then the mixture was extracted with EtOAc (20 mL x 3) , and the combined organic layer was washed with brine (30 mL) , dried and concentrated under reduced pressure. The residue was purified by flash chromatography (eluent, 0 ～ 100%EtOAc in PE) to afford 5-bromo-4-fluoro-N, N-dimethyl-2- (1-methyl-1H-1, 2, 4-triazol-3-yl) benzamide (60 mg, yield 10 %) as a yellow solid. LC-MS: m/z 327, 329 (M+H)  +.
Step C. methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (5- (dimethylcarbamoyl) -2-fluoro-4- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylacetamido) ethyl) cyclopentyl) carbamate
To a mixture of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylacetamido) ethyl) cyclopentyl) carbamate (60 mg, 0.12 mmol, 1.0 eq. ) and 5-bromo-4-fluoro-N, N-dimethyl-2- (1-methyl-1H-1, 2, 4-triazol-3-yl) benzamide (46 mg, 0.14 mmol, 1.2 eq. ) in Toluene (5 mL) was added Ruphos G2 Pd (9 mg, 0.01 mmol, 0.1 eq. ) , BINAP (15 mg, 0.02 mmol, 0.2 eq. ) and t-BuONa (22 mg, 0.23 mmol, 2.0 eq. ) at room temperature. The mixture was stirred at 90℃ under N 2 atmosphere for 16h. The mixture was filtered and extracted with EtOAc (20 mL x 2) . The combined organic layer was washed with brine (20 mL) , dried and concentrated under reduced pressure. The residue was purified by prep-HPLC (0.1%FA in H 2O-MeOH, 5%to 50%) and RP-prep-TLC (DCM/MeOH = 12 : 1) to afford methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (5- (dimethylcarbamoyl) -2-fluoro-4- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylacetamido) ethyl) cyclopentyl) carbamate (31 mg, yield 35 %) as a white solid.
LC-MS: m/z 761 (M+H)  +.  1H NMR (400 MHz, MeOD) δ 8.31 (s, 1H) , 7.60 (d, 1H) , 7.46 –7.35 (m, 3H) , 7.06 –6.98 (m, 1H) , 6.38 (d, 1H) , 4.17 –4.12 (m, 1H) , 4.12 –3.99 (m, 4H) , 3.98 –3.94 (m, 2H) , 3.90 (s, 3H) , 3.58 (s, 3H) , 3.24 –3.17 (m, 2H) , 3.05 (s, 3H) , 2.92 (s, 3H) , 2.73 (s, 3H) , 2.66 –2.59 (m, 1H) , 2.57 –2.49 (m, 2H) , 2.44 –2.32 (m, 1H) , 2.30 –2.19 (m, 4H) , 2.13 (s, 3H) , 2.10 –2.05 (m, 1H) , 1.90 –1.79 (m, 2H) , 1.54 –1.31 (m, 7H) , 1.20 –1.09 (m, 1H) .
EXAMPLE 15
Synthesis of methyl ( (1S, 2R) -2- ( (S) -1- (3-fluorophenyl) -1- (1- (2- (2-methyl-8- (pyrimidin-2-yl) -1, 2, 3, 4-tetrahydroisoquinolin-5-yl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate (Cpd 221)
Figure PCTCN2021122588-appb-000280
Step A: 5-bromo-8-iodoisoquinoline
To a mixture of CuI (5.55 g, 29.1 mmol, 1.3 eq. ) in DMSO (50 mL) was added isoamyl nitrite (9.1 mL, 67.2 mmol, 3.0 eq. ) and 5-bromoisoquinolin-8-amine (5 g, 22.4 mmol, 1.0 eq. ) at 60℃. Then the mixture was stirred at this temperature for 2 hours under N 2 atmosphere. The reaction mixture was diluted with NH 4OH (28%in H 2O, 20 mL) and H 2O (50 mL) and extracted with EtOAc (100 mL x 3) . The combined organic layers were washed with brine (100 mL x 2) , dried over Na 2SO 4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 5-bromo-8-iodoisoquinoline (3.7 g, yield 49 %) as a yellow solid. LC-MS: 334, 336 (M+H)  +.
Step B: 5-bromo-8-iodo-1, 2, 3, 4-tetrahydroisoquinoline
To a solution of 5-bromo-8-iodoisoquinoline (3.7 g, 11.1 mmol, 1.0 eq. ) in AcOH (30 mL) was added NaBH 4 (930 mg, 24.4 mmol, 2.2 eq. ) at room temperature slowly. The mixture was stirred for 20 minutes under N 2. Then the reaction mixture was poured into ice water (100 ml) , adjusted to pH 7 ～ 8 with sat. NaHCO 3 aq., and extracted with EtOAc (100 mL x 3) . The combined organic layers were washed with brine (100 mL x 2) , dried over Na 2SO 4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 5-bromo-8-iodo-1, 2, 3, 4-tetrahydroisoquinoline (4 g, yield 95%) as a pale yellow solid. LC-MS: 338, 340 (M+H)  +.
Step C: tert-butyl 5-bromo-8-iodo-3, 4-dihydroisoquinoline-2 (1H) -carboxylate
To a solution of 5-bromo-8-iodo-1, 2, 3, 4-tetrahydroisoquinoline (3.2 g, 9.5 mmol, 1.0 eq. ) and TEA (2.6 mL, 18.9 mmol, 2.0 eq. ) in DCM (30 mL) was added di-tert-butyl dicarbonate (2.4 mL, 11.4 mmol, 1.2 eq. ) at 0℃. Then the solution was stirred at room temperature for 1 hour. The resulting solution was diluted with H 2O (20 ml) and extracted with DCM (20 mL x 3) . The combined organic layers were washed with brine (20 mL x 2) , dried over Na 2SO 4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give tert-butyl 5-bromo-8-iodo-1, 2, 3, 4-tetrahydroisoquinoline-2-carboxylate (3.8 g, yield 92%) as a yellow solid. LC-MS: 438, 440 (M+H)  +.  1HNMR (400 MHz, CDCl 3) δ 7.57 (d, 1H) , 7.17 (d, 1H) , 4.43 (s, 2H) , 3.63 (t, 2H) , 2.82 (t, 2H) , 1.50 (s, 9H) .
Step D: tert-butyl 5-bromo-8- (pyrimidin-2-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate
A mixture of tert-butyl 5-bromo-8-iodo-1, 2, 3, 4-tetrahydroisoquinoline-2-carboxylate (1.2 g, 2.7 mmol, 1.0 eq. ) , 2- (tributylstannyl) pyrimidine (1.1 g, 2.97 mmol, 1.1 eq. ) , Pd (PPh 3)  2Cl 2 (0.11 g, 0.14 mmol, 0.1 eq. ) , CuI (0.05 g, 0.27 mmol, 0.1 eq. ) , and LiCl (0.14 g, 3.29 mmol, 1.2 eq. ) in toluene (20 mL) was stirred at 90℃ for 16 hours under N 2  atmosphere. Then 20 ml of sat. KF aq. was added to the reaction mixture at room temperature. After stirring for 30 minutes, the mixture was extracted with EtOAc (20 mL x 3) . The combined organic layers were washed with brine (20 mL x 2) , dried over Na 2SO 4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give tert-butyl 5-bromo-8- (pyrimidin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline-2-carboxylate (700 mg, yield 66%) as a yellow solid. LC-MS: 390, 392 (M+H)  +.
Step E: 5-bromo-8- (pyrimidin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline
To a solution of tert-butyl 5-bromo-8- (pyrimidin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline-2-carboxylate (700 mg, 1.79 mmol, 1.0 eq. ) in DCM (6 mL) was added TFA (2 mL) at 0℃. The solution was stirred at room temperature for 2 hours. The reaction was diluted with water (10 mL) , then adjusted to pH 8 ～ 9 with sat. NaHCO 3 aq., and extracted with DCM (10 mL x 3) . The combined organic layers were washed with brine (10 mL x 2) , dried over Na 2SO 4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 5-bromo-8- (pyrimidin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline (500 mg, yield 96%) as a yellow solid. LC-MS: 290, 292 (M+H)  +.
Step F: 5-bromo-2-methyl-8- (pyrimidin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline
A mixture of 5-bromo-8- (pyrimidin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline (500 mg, 1.7 mmol, 1.0 eq. ) , (CH 2O)  n (310 mg, 3.4 mmol, 2.0 eq. ) , and AcOH (0.1 mL, 1.7 mmol, 1.0 eq. ) in MeOH (10 mL) was stirred at room temperature for 30 minutes. Then NaBH 3CN (217 mg, 3.4 mmol, 2.0 eq. ) was added to above mixture. The reaction mixture was stirred at 60℃ overnight under N 2 atmosphere. The reaction was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3) . The combined organic layers were washed with brine (20 mL x 2) , dried over Na 2SO 4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 5-bromo-2-methyl-8- (pyrimidin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline (500 mg, yield 95%) as a white solid. LC-MS: 304, 306 (M+H)  +.
Step G: methyl ( (1S, 2R) -2- ( (S) -1- (3-fluorophenyl) -1- (1- (2- (2-methyl-8- (pyrimidin-2-yl) -1, 2, 3, 4-tetrahydroisoquinolin-5-yl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate (Cpd 221) 
A mixture of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate (100 mg, 0.18 mmol, 1.0 eq. ) , 5-bromo-2-methyl-8- (pyrimidin-2-yl) -1, 2, 3, 4-tetrahydroisoquinoline (61 mg, 0.2 mmol, 1.1 eq. ) , Pd 2 (dba)  3 (17 mg, 0.018 mmol, 0.1 eq. ) , BINAP (23 mg, 0.04 mmol, 0.2 eq. ) , and t-BuONa (35 mg, 0.36 mmol, 2.0 eq. ) in toluene (5 mL) was stirred at 90℃ overnight under N 2 atmosphere.  The resulting solution was diluted with H 2O (10 mL) and extracted with EtOAc (10 mL x 3) . The combined organic layers were washed with brine (10 mL x 2) , dried over Na 2SO 4, and concentrated under reduced pressure, the residue was purified by reverse phase flash column chromatography (C18 Reversed-Phase Silica GelRP-flash (C18, 0.1%HCO 2H aq. /MeOH, 5%-50%) and Prep-TLC (DCM/MeOH = 13/1) to afford Cpd 221 (45 mg, yield 32%) as a yellow solid. LC-MS: 774 (M+H)  +.  1H NMR (400 MHz, Methanol-d 4) δ 8.80 (d, 2H) , 7.66 (d, 1H) , 7.46 -7.34 (m, 3H) , 7.31 (t, 1H) , 7.07-6.98 (m, 1H) , 6.54 (d, 1H) , 4.08 (s, 2H) , 4.01 (s, 3H) , 3.89 (s, 2H) , 3.82 (s, 2H) , 3.59 (s, 3H) , 3.21 -2.98 (m, 3H) , 2.91 (s, 3H) , 2.88 -2.78 (m, 4H) , 2.70 -2.60 (m, 4H) , 2.52 (s, 3H) , 2.48 -2.39 (m, 2H) , 2.23 -2.09 (m, 4H) , 2.01 -1.95 (m, 1H) , 1.93 -1.76 (m, 3H) , 1.71 -1.48 (m, 4H) , 1.40 -1.32 (m, 2H) , 0.97 -0.79 (m, 1H) .
EXAMPLE 16
Preparation of 2- (dimethylcarbamoyl) -5-fluoro-4- (6- (4- ( (S) -1- (3-fluorophenyl) -1- ( (1R, 2S) -2- ( (methoxycarbonyl) amino) cyclopentyl) -2- (N-methylmethylsulfonamido) ethyl) piperidin-1-yl) -2-azaspiro [3.3] heptan-2-yl) phenyl dimethylcarbamate (Cpd 324)
Figure PCTCN2021122588-appb-000281
Step A: 5-bromo-4-fluoro-2-hydroxy-N, N-dimethylbenzamide
To a mixture of (4-bromo-2- (dimethylcarbamoyl) -5-fluorophenyl) boronic acid (500 mg, 1.73 mmol) and NaOH (207 mg, 5.17 mmol) in THF (10 mL) was added 27%hydrogen peroxide aq. (1 mL) at 0℃. The reaction was stirred at room temperature for 2 hours. Then the mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3) . The combined organic layers were washed with brine (30 mL) , dried over Na 2SO 4, and concentrated  under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 5-bromo-4-fluoro-2-hydroxy-N, N-dimethylbenzamide (200 mg, yield 44%) as a white solid. LC-MS: 262, 264 (M+H)  +.
Step B: 4-bromo-2- (dimethylcarbamoyl) -5-fluorophenyl dimethylcarbamate
A mixture of 5-bromo-4-fluoro-2-hydroxy-N, N-dimethylbenzamide (100 mg, 0.38 mmol) and dimethylcarbamic chloride (62 mg, 0.57 mmol) in pyridine (2 mL) was stirred at room temperature for 2 hours. Then the mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over Na 2SO 4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 4-bromo-2- (dimethylcarbamoyl) -5-fluorophenyl dimethylcarbamate (100 mg, yield 79%) . LC-MS: 333, 335 (M+H)  +.
Step C: 2- (dimethylcarbamoyl) -5-fluoro-4- (6- (4- ( (S) -1- (3-fluorophenyl) -1- ( (1R, 2S) -2- ( (methoxycarbonyl) amino) cyclopentyl) -2- (N-methylmethylsulfonamido) ethyl) piperidin-1-yl) -2-azaspiro [3.3] heptan-2-yl) phenyl dimethylcarbamate (Cpd 324)
A mixture of 4-bromo-2- (dimethylcarbamoyl) -5-fluorophenyl dimethylcarbamate (91 mg, 0.27 mmol) , methyl ( (1S, 2R) -2- ( (S) -1- (1- (2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (N-methylmethylsulfonamido) ethyl) cyclopentyl) carbamate S18 (100 mg, 0.18 mmol) , Pd 2 (dba)  3 (17 mg, 0.018 mmol) , Ru-Phos (9 mg, 0.018 mmol) , and C S2CO 3 (177 mg, 0.55 mmol) in toluene (2 ml) was stirred at 90℃ under N 2 atmosphere for 2 hours. The mixture was cooled to room temperature and filtered through a Celite pad. The filtrate was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over Na 2SO 4, and concentrated under reduced pressure. The residue was purified by Prep-TLC and reverse-phase-prep-HPLC to give Cpd 324 (21 mg, yield 14%) as a white solid. LC–MS: 803.4 (M+H)  +.  1H NMR (400 MHz, Methanol-d 4) δ7.47 –7.34 (m, 3H) , 7.05 –6.98 (m, 1H) , 6.93 (d, 1H) , 6.42 (d, 1H) , 4.04 –3.92 (m, 3H) , 3.87 –3.76 (m, 4H) , 3.59 (s, 3H) , 3.18 –3.07 (m, 2H) , 3.03 (d, 6H) , 2.94 (s, 3H) , 2.89 (d, 6H) , 2.70 –2.57 (m, 4H) , 2.48 –2.38 (m, 2H) , 2.24 –2.07 (m, 4H) , 2.00 –1.94 (m, 1H) , 1.91 –1.72 (m, 3H) , 1.70 –1.45 (m, 4H) , 1.43 –1.07 (m, 4H) .
EXAMPLE 17
Preparation of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (4-cyano-3- (dimethylamino) benzo [d] isoxazol-7-yl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) carbamate (Cpd 372)
Figure PCTCN2021122588-appb-000282
Step A: 6-bromo-2, 3-difluorobenzonitrile
A mixture of 6-bromo-2, 3-difluorobenzaldehyde (1.5 g, 6.79 mmol) and hydroxylamine hydrochloride (0.51 g, 7.45 mmol) in HCO 2H (15 mL) was stirred at 90℃ under N 2 atmosphere overnight. Then the mixture was poured into ice water (100 mL) slowly. The precipitate was filtered and washed with water (5 mL) to afford 6-bromo-2, 3-difluorobenzonitrile (1.1 g, yield 74%) as a white solid.
Step B: 6-bromo-3-fluoro-2- ( (propan-2-ylideneamino) oxy) benzonitrile
A mixture of 6-bromo-2, 3-difluorobenzonitrile (1 g, 4.59 mmol) , propan-2-one oxime (0.67 g, 9.17 mmol) , and t-BuOK (1.03 g, 9.17 mmol) in THF (10 mL) was stirred at 50℃ under N 2 atmosphere for 2 hours. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 2) . The combined organic layers were washed with brine (30 mL) , dried over Na 2SO 4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 6-bromo-3-fluoro-2- ( (propan-2-ylideneamino) oxy) benzonitrile (1 g, yield 80 %) as a white solid.
Step C: 4-bromo-7-fluorobenzo [d] isoxazol-3-amine
A mixture of 6-bromo-3-fluoro-2- ( (propan-2-ylideneamino) oxy) benzonitrile (1 g, 3.69 mmol) and 1 N HCl aq. (8 mL) in EtOH (20 mL) was stirred at 50℃ for 2 hours. The resulting solution was diluted with water (50 mL) and extracted with EtOAc (50 mL x 2) . The combined organic layers were washed with brine (50 mL) , dried over Na 2SO 4 and concentrated under reduced pressure to give 4-bromo-7-fluorobenzo [d] isoxazol-3-amine (800 mg, crude) as a gray solid. LC-MS: 231, 233 (M+H)  +.
Step D: 4-bromo-7-fluoro-N, N-dimethylbenzo [d] isoxazol-3-amine
To a solution of 4-bromo-7-fluorobenzo [d] isoxazol-3-amine (800 mg, 3.5 mmol) in DMF (10 mL) was added NaH (60%in mineral oil, 560 mg, 14 mmol) at 0℃. The mixture was stirred at 0℃ for 20 minutes. Then MeI (0.69 mL, 10.5 mmol) was added and the mixture was stirred at room temperature for 1 hour. The mixture was quenched with sat. NH 4Cl aq. (30 mL) and extracted with EtOAc (30 mL x 2) . The organic phase was washed with brine (30 mL) , dried over Na 2SO 4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 4-bromo-7-fluoro-N, N-dimethylbenzo [d] isoxazol-3-amine (700 mg, yield 80 %) as a white solid. LC-MS: 259, 261 (M+H)  +.
Step E: 3- (dimethylamino) -7-fluorobenzo [d] isoxazole-4-carbonitrile
A mixture of 4-bromo-7-fluoro-N, N-dimethylbenzo [d] isoxazol-3-amine (200 mg, 0.77 mmol) , Zn (CN)  2 (181 mg, 1.54 mmol) , Pd (t-Bu 3P)  2 (43 mg, 0.08 mmol) and dppf (40 mg, 0.08 mmol) in DMAc (3 mL) was stirred at 80℃ under N 2 atmosphere for 16 hours. The reaction mixture was filtered, and the filtrate was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over Na 2SO 4, and concentrated under reduce pressure. The residue was purified by flash chromatography to give 3- (dimethylamino) -7-fluorobenzo [d] isoxazole-4-carbonitrile (100 mg, yield 63%) as a white solid. LC-MS: 206 (M+H)  +.
Step F: methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (4-cyano-3- (dimethylamino) benzo [d] isoxazol-7-yl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) carbamate (Cpd 372)
A mixture of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) carbamate (63 mg, 0.12 mmol) , 3- (dimethylamino) -7-fluorobenzo [d] isoxazole-4-carbonitrile (30 mg, 0.15 mmol) and K 2CO 3 (34 mg, 0.24 mmol) in MeCN (3 ml) was stirred at 80℃ overnight. Then the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC and  reverse-phase-prep-HPLC to give Cpd 372 (2 mg, yield 2%) as a white solid. LC-MS: 709 (M+H)  +.  1H NMR (400 MHz, Methanol-d 4) δ 7.50 (d, 1H) , 7.49 -740 (m, 2H) , 7.36 (d, 1H) , 7.13 –7.07 (m, 1H) , 6.71 -6.62 (m, 2H) , 6.40 (d, 1H) , 4.55 (d, 1H) , 4.36 (d, 1H) , 4.29 (s, 2H) , 4.14 (s, 2H) , 4.03 -3.97 (m, 1H) , 3.61 (s, 3H) , 3.03 (s, 6H) , 2.93 (d, 1H) , 2.82 (d, 1H) , 2.67 -2.59 (m, 2H) , 2.45 (s, 3H) , 2.40 -2.34 (m, 2H) , 2.25 -2.17 (m, 1H) , 2.12 -1.99 (m, 3H) , 1.91 –1.83 (m, 1H) , 1.80 -1.65 (m, 3H) , 1.52 –1.48 (m, 1H) , 1.33 -1.18 (m, 5H) , 0.75 –0.68 (m, 1H) .
EXAMPLE 18
Synthesis and Characterization of Compounds of the Disclosure
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, PCT/US2020/053186, PCT/US2021/026111, and PCT/CN2021/085824. The LCMS (ESI) data for representative Compounds of the Disclosure prepared by these methods are provided in Tables 1A and 1B.
1H NMR for additional Compounds of the Disclosure is provided in Table 4.
Table 4
Figure PCTCN2021122588-appb-000283
Figure PCTCN2021122588-appb-000284
Figure PCTCN2021122588-appb-000285
Figure PCTCN2021122588-appb-000286
Figure PCTCN2021122588-appb-000287
Figure PCTCN2021122588-appb-000288
Figure PCTCN2021122588-appb-000289
Figure PCTCN2021122588-appb-000290
Figure PCTCN2021122588-appb-000291
Figure PCTCN2021122588-appb-000292
Figure PCTCN2021122588-appb-000293
Figure PCTCN2021122588-appb-000294
Figure PCTCN2021122588-appb-000295
Figure PCTCN2021122588-appb-000296
Figure PCTCN2021122588-appb-000297
Figure PCTCN2021122588-appb-000298
Figure PCTCN2021122588-appb-000299
Figure PCTCN2021122588-appb-000300
Figure PCTCN2021122588-appb-000301
Figure PCTCN2021122588-appb-000302
Figure PCTCN2021122588-appb-000303
Figure PCTCN2021122588-appb-000304
Figure PCTCN2021122588-appb-000305
Figure PCTCN2021122588-appb-000306
Figure PCTCN2021122588-appb-000307
Figure PCTCN2021122588-appb-000308
Figure PCTCN2021122588-appb-000309
EXAMPLE 19
Menin Binding Affinity
Binding Assay 1
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 (K d) 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 μl in the assay buffer (PBS with 0.02%Bovine γ-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. K d value of FAM-MM2, which was calculated by fitting 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.
The IC 50 of representative Compounds of the Disclosure were determined in a competitive binding experiment. See Table 5. Mixtures of 5 μl of the tested compounds in DMSO and 195 μl 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. IC 50 values were determined by nonlinear regression fitting of the competition curves.
Binding Assay 2
Compound binding potency was also measured by fluorescence-based polarization ligand displacement assay using probe 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.
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.
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
Cpd No. Binding Assay 1 Binding Assay 2
1 A NT
2 A NT
3 A NT
4 A NT
5 A NT
6 NT A
7 NT A
8 NT A
9 A NT
10 NT A
11 NT A
12 NT A
13 NT A
14 A NT
15 A NT
16 A NT
Cpd No. Binding Assay 1 Binding Assay 2
17 A NT
18 A NT
19 A NT
20 A NT
21 A A
22 A NT
23 A NT
24 A NT
25 A NT
26 A NT
27 A NT
28 NT A
29 NT A
30 A NT
31 A NT
32 NT A
33 NT A
34 A NT
35 A NT
36 NT A
37 NT A
38 A NT
39 A NT
40 A NT
41 A NT
42 A NT
43 A NT
44 A NT
45 A NT
46 A NT
47 A NT
48 A NT
49 NT A
50 A NT
51 A NT
52 A NT
53 NT A
54 NT A
55 NT A
56 NT A
57 NT A
58 NT A
59 NT A
60 NT A
61 NT A
Cpd No. Binding Assay 1 Binding Assay 2
62 A NT
63 C NT
64 A NT
65 A NT
66 A NT
67 A NT
68 A NT
69 NT A
70 A NT
71 A NT
72 A NT
73 NT A
74 NT A
75 NT A
76 NT A
77 NT A
78 NT A
79 NT A
80 NT A
81 NT A
82 NT A
83 NT A
84 NT A
85 NT A
86 NT A
87 NT A
88 NT A
89 NT A
90 NT A
91 A A
92 A A
93 A A
94 A A
95 A A
96 A NT
97 A A
98 A A
99 NT A
100 NT A
101 NT A
102 NT A
103 NT A
104 NT A
105 NT A
106 NT A
Cpd No. Binding Assay 1 Binding Assay 2
107 A NT
108 A NT
109 NT A
110 NT A
111 NT C
112 NT C
113 A NT
114 A NT
115 A NT
116 A NT
117 NT A
118 NT A
119 NT A
120 A NT
121 A NT
122 NT A
123 NT A
124 NT A
125 NT A
126 NT A
127 C NT
128 A NT
129 A NT
130 NT A
131 NT A
132 NT A
133 NT A
134 NT A
135 NT A
136 NT A
137 NT A
138 NT A
139 NT A
140 NT A
141 NT A
142 NT A
143 A A
144 A A
145 A NT
146 NT A
147 NT A
148 A NT
149 A NT
150 A NT
151 A NT
Cpd No. Binding Assay 1 Binding Assay 2
152 A NT
153 A NT
154 NT A
155 NT A
156 NT A
157 NT A
158 NT A
159 A NT
160 NT A
161 NT A
162 NT A
163 NT A
164 NT A
165 NT A
166 A NT
167 A NT
168 A NT
169 A NT
170 A NT
171 A NT
173 A A
174 A NT
175 A NT
176 A NT
177 A NT
178 A NT
179 A NT
180 A NT
181 NT A
182 A NT
183 A NT
184 A NT
185 A NT
186 A NT
187 A NT
188 NT A
189 NT A
190 NT A
191 A NT
192 A NT
193 A NT
194 A NT
195 A NT
196 A A
197 A A
Cpd No. Binding Assay 1 Binding Assay 2
198 A NT
199 NT A
200 NT A
201 NT A
202 NT A
203 NT A
204 NT A
205 NT A
206 NT A
207 NT A
208 NT A
209 NT A
210 NT A
211 NT A
212 NT A
213 NT A
214 NT A
215 NT A
216 NT A
217 A NT
218 A NT
219 A A
220 A A
221 NT A
222 NT A
223 A NT
224 A NT
225 A NT
226 A NT
227 A NT
228 NT A
229 NT A
230 NT A
231 NT A
232 NT A
233 NT A
234 NT B
235 NT A
236 NT A
237 NT B
238 NT A
239 NT A
240 NT A
241 NT A
242 NT A
Cpd No. Binding Assay 1 Binding Assay 2
243 NT A
244 NT A
245 NT A
246 NT A
247 NT A
248 NT A
249 A NT
250 NT A
251 NT A
252 NT A
253 NT A
254 NT A
255 NT A
256 NT A
257 NT A
258 NT A
259 NT A
260 NT A
261 NT A
262 NT A
263 A NT
264 A NT
265 A NT
266 A NT
267 A NT
268 A NT
269 A NT
270 A NT
271 A NT
272 A NT
273 A NT
274 A NT
275 A NT
276 A NT
277 A NT
278 A NT
279 A NT
280 A NT
281 B NT
282 A NT
283 A NT
284 A NT
285 A NT
286 A NT
287 A NT
Cpd No. Binding Assay 1 Binding Assay 2
288 A NT
289 B NT
290 A NT
291 A NT
292 A NT
293 A NT
294 A NT
295 A NT
296 A NT
297 A NT
298 A NT
300 A NT
301 A NT
302 A NT
303 A NT
304 A NT
305 A NT
306 A NT
307 A NT
308 A NT
309 A NT
310 A NT
311 A NT
312 A NT
313 A NT
314 A NT
315 A NT
316 A NT
317 A NT
318 A NT
319 A NT
320 A NT
321 A NT
322 A NT
323 NT A
324 NT A
325 NT A
326 NT A
327 NT A
328 NT A
329 NT A
330 NT A
331 NT A
332 NT A
333 NT A
Cpd No. Binding Assay 1 Binding Assay 2
334 NT A
335 NT A
336 NT A
337 NT A
338 NT A
339 A NT
340 A NT
341 A NT
342 A NT
343 A NT
344 A NT
345 A NT
346 A NT
347 A NT
348 A NT
349 NT A
350 A NT
351 A NT
352 A NT
353 A NT
354 NT A
355 NT A
356 NT A
357 NT A
358 NT A
359 NT A
360 NT A
361 NT A
362 NT A
363 NT A
364 NT A
365 NT A
366 A NT
367 A NT
368 A NT
369 NT A
370 A NT
371 A NT
372 NT A
373 NT A
374 NT A
375 NT A
376 NT A
EXAMPLE 20
Cell Growth Inhibition
Procedure 1
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℃ and an atmosphere of 5%CO 2.
Cells were seeded in 96-well flat bottom (Corning COSTAR, Corning, NY, cat#3595) at a density of 2,000-3,000 cells/well in 100 μl of culture medium. Compounds were serially diluted in the appropriate medium, and 100 μl 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℃ in an atmosphere of 5%CO 2 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
Figure PCTCN2021122588-appb-000310
Luminescent Cell Viability reagent according to the manufacturers’ instructions.
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℃ 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 (IC 50) 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) .
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 μM, (D) greater than 1 μM, (E) no fit, and (NT) not tested, as shown in Table 6 below.
Procedure 2
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℃ and an atmosphere of 5%CO2.
Cells were seeded in 96-well flat bottom (Corning COSTAR, Corning, NY, cat#3903) at a density of 4,000-7,500 cells/well in 50 μl of culture medium. Compounds were serially diluted in the appropriate medium, and 50 μl 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℃ in an atmosphere of 5%CO2 for 4 or 7 days. Cell viability was determined using the
Figure PCTCN2021122588-appb-000311
Luminescent Cell Viability reagent according to the manufacturers’ instructions.
Figure PCTCN2021122588-appb-000312
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
Figure PCTCN2021122588-appb-000313
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) .
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 μM, (D) greater than 1 μM, (E) no fit, and (NT) not tested, as shown in Table 6 below.
Table 6
Figure PCTCN2021122588-appb-000314
Figure PCTCN2021122588-appb-000315
Figure PCTCN2021122588-appb-000316
Figure PCTCN2021122588-appb-000317
Figure PCTCN2021122588-appb-000318
Figure PCTCN2021122588-appb-000319
Figure PCTCN2021122588-appb-000320
Figure PCTCN2021122588-appb-000321
Figure PCTCN2021122588-appb-000322
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.
All patents, patent applications and publications cited herein are fully incorporated by reference herein in their entirety.

Claims (73)

  1. A compound having Formula I,
    Figure PCTCN2021122588-appb-100001
    or a pharmaceutically acceptable salt thereof, wherein:
    each R a is independently hydrogen or C 1-C 4 alkyl;
    each R b is independently hydrogen or C 1-C 4 alkyl;
    R c is hydrogen or halo;
    each R d is independently halo;
    p, q, r and s are independently 1 or 2;
    n is 0, 1 or 2;
    V 1 is -NR 1SO 2 (C 1-C 4 alkyl) , -NR 1SO 2 (C 1-C 4 haloalkyl) , -NR 1 (C=O) (C 1-C 4 alkyl) , -NR 1 (C=O) (C 1-C 4 haloalkyl) , -NR 1 (C=O) H, 
    Figure PCTCN2021122588-appb-100002
    Figure PCTCN2021122588-appb-100003
    Q is -N (H) C (=O) OR, -N (R) C (=O) OR, -N (H) C (=O) R, -N (H) C (O) NHR, -N (H) C (O) NR 2, -OC (=O) NR 2, 
    Figure PCTCN2021122588-appb-100004
    each R is independently C 1-C 4 alkyl, C 1-C 4 haloalkyl, or CD 3;
    each R 1 is independently hydrogen or C 1-C 4 alkyl;
    each R 2 is independently C 1-C 4 alkyl;
    each k is independently 0, 1, 2, 3, or 4;
    E is
    Figure PCTCN2021122588-appb-100005
    Figure PCTCN2021122588-appb-100006
    Figure PCTCN2021122588-appb-100007
    J is optionally substituted heteroaryl, optionally substituted heterocyclo, optionally substituted aryl, carboxamido, haloalkoxy, alkoxy, alkylcarbonyloxy, carboxamidooxy, (carboxamido) alkyl, aralkyloxy, aryloxy, heterocyclooxy, heteroaryloxy, alkoxycarbonyl, hydrogen, C 1-C 4 alkyl, C 1-C 4 alkylcarbonyl, hydroxy, cyano, haloalkyl, -NO 2, halo, -NR 1SO 2 (C 1-C 4 alkyl) , -NR 1SO 2 (C 2-C 6 alkenyl) , -NR 1CO (C 1-C 4 alkyl) , -S (=O) (=NR 1) CF 3, S (=O) (=NR 1) (C 1-C 4 alkyl) , amino, sulfonamido, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, heterocycloalkylsulfonyl, or C 1-C 4 phosphine oxide;
    Y is -C (=O) -, -SO 2-, -C (=O) NH-, or -C (=O) N (C 1-C 4alkyl) -;
    L is absent or is optionally substituted C 1-C 6 alkyl, or C 1-C 6 haloalkyl;
    J 2 is C 1-C 4 alkyl, C 1-C 6 haloalkyl, cyano, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, or optionally substituted heterocyclo;
    R 4 is hydrogen, C 1-C 4 alkyl, C 1-C 4alkylcarbonyl, heterocyclo, or haloalkyl;
    W is -NH-, -O-, or -S-;
    R 5 is hydrogen, amino, C 1-C 6 alkyl, C 1-C 6 alkoxy, or halo;
    each m is independently 1 or 2;
    Y 1 is absent or is -C (=O) -, -SO 2-, -C (=O) NH-, or -C (=O) N (Me) -;
    v is 0 or 1;
    R 6 is hydrogen, haloalkyl, C 1-C 4 alkyl, C 1-C 4 alkylcarbonyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, heterocycloalkylsulfonyl, carboxamido, mesylate, or tert-butoxycarbonyl;
    each R 7 is independently hydrogen, cyano, halo, haloalkyl, C 1-C 4 alkyl, C 1-C 4 alkylcarbonyl, hydroxy, sulfonamido, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, heterocycloalkylsulfonyl, or carboxamido;
    R 8a, R 8b, R 8c, and R 8d are independently hydrogen, halo, carboxy, hydroxy, C 1-C 4 alkoxycarbonyl, C 1-C 4 alkyl, C 1-C 4 alkoxy, haloalkyl, haloalkoxy, -CH 2SO 2C 1-C 4 alkyl, sulfonamido, cyano, alkoxyalkyl, aralkyloxy, alkylsulfonyl, (amino) alkyl, carboxamido, (carboxamido) alkyl, thioamide, optionally substituted heteroaryl, (heteroaryl) alkyl, -NR 13C (O) C 1-C 4 alkyl, -OCH 2CH=CH-alkylsulfonyl, -O (C 1-C 4 alkyl) O (C 1-C 4 alkyl) , C 2-C 6 alkenyl, heterocyclooxy, aminocarbonyloxy, or (heterocyclo) alkyl;
    Z is hydrogen, C 1-C 4 alkyl, C 1-C 4 alkylcarbonyl, hydroxy, cyano, haloalkyl, -NO 2, halo, -NR 1SO 2 (C 1-C 4 alkyl) , -NR 1SO 2 (C 2-C 6 alkenyl) , -NR 1CO (C 1-C 4 alkyl) , -CONH 2, -CONH (C 1-C 4 alkyl) , -CON (C 1-C 4 alkyl)  2, -S (=O) (=NR 1) CF 3, S (=O) (=NR 1) (C 1-C 4 alkyl) , amino, sulfonamido, alkylsulfonyl, haloalkylsulfonyl, or cycloalkylsulfonyl;
    each W 1 is independently -CH-or -N-;
    t and u are independently 0, 1, 2, or 3;
    X is C 2-C 4 alkenyl, (amino) alkyl, -CH 2CH 2NR 1Y 1-Z 2,
    Figure PCTCN2021122588-appb-100008
    Figure PCTCN2021122588-appb-100009
    Figure PCTCN2021122588-appb-100010
    wherein
    Z 2is -C (R 14a) =C (R 14b) (R 14c) , -C≡CR 14d, alkyl, alkoxy, haloalkyl, or R a2;
    R 9a and R 9b are each independently alkenyl, alkynyl, cyano, C 1-C 4 alkyl, halo, (amino) alkyl, or -C (R 14a) =C (R 14b) (R 14c) ;
    each Q 1 is independently -CH 2-or -C (=O) -;
    R 10 is hydrogen, C 1-C 4 alkyl, -NR 13CO (C 1-C 4 alkyl) , -NR 13SO 2 (C 1-C 4 alkyl) , cyano, halo, -OCH 2CH=CH-R a3, or -CH 2CH 2CH=CH-R a3;
    R 11 is halo, -NR 13COC (R 14a) =C (R 14b) (R 14c) , carboxamido, -C (O) NR 13CH 2R a5, -C (O) NR 13CH 2CH=CH-R a3, -C (O) NR 13CH 2C≡CR a6, or -CH 2CH 2CH=CH-R a3;
    R 12 is alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, or carboxamido;
    R 13 is hydrogen or C 1-C 4 alkyl;
    R 14a, R 14b, R 14c, and R 14d are each independently hydrogen, halo, C 1-C 4 alkyl, (amino) alkyl, or R a3;
    R a2 is -N (R 15) CH 2CH=CH-R a3 or -CH=CHCH 2R a4;
    R a3 is alkoxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, or carboxamido;
    R a4 is optionally subsubstituted heterocyclo;
    R a5 is cyano or (amino) alkyl;
    R a6 is hydrogen or carboxamido;
    R 15 is hydrogen or C 1-C 4 alkyl; and
    R 16 is hydrogen or C 1-C 4 alkyl.
  2. The compound of claim 1, having Formula X, XI, XII, XIII, XIV, or XV:
    Figure PCTCN2021122588-appb-100011
    Figure PCTCN2021122588-appb-100012
    or a pharmaceutically acceptable salt thereof.
  3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula X.
  4. The compound of any one of claim 1-3, or a pharmaceutically acceptable salt thereof, wherein:
    n is 0;
    R c is fluoro;
    Q is -NHCO 2R;
    R is C 1-C 4 alkyl; and
    E is
    Figure PCTCN2021122588-appb-100013
    Figure PCTCN2021122588-appb-100014
  5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein E is:
    Figure PCTCN2021122588-appb-100015
    and
    R 8b is carboxamido, optionally substituted heteroaryl, (carboxamido) alkyl, heterocyclooxy, carboxamidooxy, alkoxy, haloalkyl, aralkyloxy, or (amino) alkyl.
  6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein E is :
    Figure PCTCN2021122588-appb-100016
    R 8a is C 1-C 4 alkyl or halo; and
    R 8b is hydrogen or carboxamido.
  7. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein E is:
    Figure PCTCN2021122588-appb-100017
    R 8b is optionally substituted heteroaryl, carboxamido, or thioamide; and
    R 8c is hydrogen or halo.
  8. The compound of claim 1, having Formula XVI:
    Figure PCTCN2021122588-appb-100018
    or a pharmaceutically acceptable salt thereof.
  9. The compound of claim 8, having Formula XVII:
    Figure PCTCN2021122588-appb-100019
    or a pharmaceutically acceptable salt thereof.
  10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein J is cyano, alkylsulfonyl, haloalkyl, haloalkylsulfonyl, halo, optionally substituted heteroaryl, heteroarylsulfonyl, carboxamido, haloalkoxy, alkoxy, carboxamidooxy, (carboxamido) alkyl, heteroaryloxy, aralkyloxy, -NR 1SO 2 (C 1-C 4alkyl) , -NR 1CO (C 1-C 4alkyl) , -S (=O) (=NR 1) CF 3, or -S (=O) (=NR 1) (C 1-C 4alkyl) .
  11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein J is optionally substituted heteroaryl and the optionally substituted heteroaryl is pyrazolyl, oxazolyl, isoxazolyl, pyrimidinyl, thiazolyl, triazolyl, triazinyl, oxadiazolyl, pyridinyl, quinazolinyl, pyrazolo [3, 4-d] pyrimidinyl, benzo [d] oxazolyl, thiadiazolyl, benzo [d] thiazolyl, pyrazolo [4, 3-d] pyrimidinyl, pyrrolo [2, 3-d] pyrimidinyl, thiazolo [5, 4-d] pyrimidinyl, purinyl, pyrazinyl, pyridazinyl, or tetrazolyl.
  12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted heteroaryl is oxazol-2-yl, isoxazole-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, 1, 2, 4-oxadiazol-5-yl, thiazol-2-yl, pyrazol-4-yl, pyrazol-3-yl, quinazolin-2-yl, pyrazolo [3, 4-d] pyrimidin-6-yl, benzo [d] thiazol-2-yl, benzo [d] oxazol-2-yl, 1, 3, 5-triazol-2-yl, 1, 2, 4-triazol-3-yl, 1, 3, 4-oxadiazol-2-yl, 1, 2, 4-oxadiazol-3-yl, pyrazin-2-yl, pyridazin-3-yl, 1, 3, 4-thiadiazol-2-yl, pyrazolo [4, 3-d] pyrimidin-5-yl, pyrrolo [2, 3-d] pyrimidin-2-yl, thiazolo [5, 4-d] pyrimidin-5-yl, purin-2-yl, 1, 2, 4-triazin-3-yl, tetrazol-5-yl, or pyridin-2-yl.
  13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted heteroaryl is substituted with one or more of:
    C 1-4alkyl, such as methyl, ethyl, propyl, isopropyl, or butyl;
    halo such as Br, Cl, or F;
    cyano;
    C 1-4 haloalkyl, such as CF 3, CH 2F, CHF 2, CH 2CF 3, CH 2CHF 2, CH 2CH 2F, CH (CH 2F)  2 C (CH 3)  2F, or C (CH 3) F 2;
    amino, such as NH 2, or N (CH 2)  3; and
    carboxamido, such as – (C=O) N (CH 3)  2.
  14. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein J is:
    Figure PCTCN2021122588-appb-100020
    wherein:
    R 17 and R 18 are, independently, hydrogen, C 1-4alkyl, C 1-4haloalkyl, cyano, halo, or amino; and
    R 19 is hydrogen or C 1-4alkyl.
  15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein J is:
    Figure PCTCN2021122588-appb-100021
    wherein:
    R 17 is hydrogen, C 1-4alkyl such as methyl or ethyl, or amino, or preferably hydrogen or methyl.
  16. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein J is:
    Figure PCTCN2021122588-appb-100022
    wherein:
    R 17 and R 18 are, independently, hydrogen or C 1-4alkyl such as methyl or ethyl, or preferably hydrogen or methyl.
  17. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein J is:
    Figure PCTCN2021122588-appb-100023
    wherein:
    R 17 and R 18 are, independently, hydrogen, C 1-4alkyl such as methyl or ethyl, or halo such as chloro or fluoro, or preferably hydrogen, methyl, or fluoro; and
    R 19 is hydrogen or C 1-4alkyl such as methyl or ethyl, or preferably hydrogen or methyl.
  18. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein J is:
    Figure PCTCN2021122588-appb-100024
    wherein:
    R 17 is hydrogen, C 1-4alkyl such as methyl, ethyl, or isopropyl, C 1-4haloalkyl such as CF 3, cyano, or halo such as chloro or fluoro.
  19. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein J is:
    Figure PCTCN2021122588-appb-100025
    wherein:
    R 17 and R 18 are, independently, hydrogen or C 1-4alkyl such as methyl or ethyl, or preferably hydrogen or methyl.
  20. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein J is:
    Figure PCTCN2021122588-appb-100026
    wherein:
    R 17 is hydrogen, C 1-4alkyl such as methyl or ethyl, or halo such as chloro or fluoro, or preferably hydrogen, methyl, or fluoro; and
    R 19 is hydrogen or C 1-4alkyl such as methyl or ethyl, or preferably hydrogen or methyl.
  21. The compound of any one of claims 1-4 or 7-20, or a pharmaceutically acceptable salt thereof, wherein:
    R 8b is carboxamido such as
    Figure PCTCN2021122588-appb-100027
    Figure PCTCN2021122588-appb-100028
    or preferably
    Figure PCTCN2021122588-appb-100029
    and
    R 8c is hydrogen or halo, such as fluoro or chloro, or preferably hydrogen or fluoro.
  22. The compound of claim 1, having Formula XIX or XX:
    Figure PCTCN2021122588-appb-100030
    or a pharmaceutically acceptable salt thereof.
  23. The compound of claim 22, having Formula XXI or XXII:
    Figure PCTCN2021122588-appb-100031
    or a pharmaceutically acceptable salt thereof.
  24. The compound of any one of claims 1-4, 22, or 23, or a pharmaceutically acceptable salt thereof, wherein
    Y is -C (=O) -or -C (=O) NH-;
    L is absent or is haloalkyl; and
    J 2 is optionally substituted aryl.
  25. The compound of any one of claims 1-4, or 22-24, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted aryl is substituted with one or more of:
    C 1-C 4alkyl, such as methyl, ethyl, propyl, isopropyl, or butyl;
    halo such as Br, Cl, or F;
    cyano;
    carboxamido, such as
    Figure PCTCN2021122588-appb-100032
    C 1-C 4haloalkyl, such as CF 3, CH 2F, CHF 2, CH 2CF 3, CH 2CHF 2, CH 2CH 2F, CH (CH 2F)  2 C (CH 3)  2F, or C (CH 3) F 2; and
    haloalkoxy, such as OCF 3.
  26. The compound of any one of claims 1-4, or 22-24, or a pharmaceutically acceptable salt thereof, wherein
    J 2 is
    Figure PCTCN2021122588-appb-100033
    R 20 is halogen such as chloro or fluoro, cyano, carboxamido such as
    Figure PCTCN2021122588-appb-100034
    C 1-C 4 haloalkoxy such as OCF 3, or C 1-C 4haloalkyl such as CF 3.
  27. The compound of any one of claims 1-4, or 22-24, or a pharmaceutically acceptable salt thereof, wherein
    J 2 is
    Figure PCTCN2021122588-appb-100035
    wherein R 20 and R 21 are, independently, halogen such as fluoro, cyano, C 1-C 4haloalkoxy such as OCF 3, or C 1-C 4haloalkyl such as CF 3.
  28. The compound of any one of claims 1-4, 22, or 23, or a pharmaceutically acceptable salt thereof, wherein:
    Y is -C (=O) -;
    J 2 is optionally substituted cycloalkyl, wherein the optionally substituted cycloalkyl is:
    Figure PCTCN2021122588-appb-100036
    t and u are, independently, 0, 1, 2, or 3; and
    R 22 and R 23 are independently hydrogen, cyano, halo, haloalkyl, C 1-C 4 alkyl, C 1-C 4 alkylcarbonyl, hydroxy, alkoxy, amino, sulfonamido, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, heterocycloalkylsulfonyl, carboxamido, optionally substituted aryl, or optionally substituted heteroaryl.
  29. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein J 2 is
    Figure PCTCN2021122588-appb-100037
  30. The compound of claim 28 or 29, or a pharmaceutically acceptable salt thereof, wherein L is absent;
    R 22 is cyano or C 1-C 4haloalkyl; and
    R 23 is hydrogen.
  31. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein:
    J 2 is
    Figure PCTCN2021122588-appb-100038
    L is absent; and
    R 22 is cyano or C 1-C 4haloalkyl.
  32. The compound of any one of claims 1-4, 22, or 23, or a pharmaceutically acceptable salt thereof, wherein:
    Y is -C (=O) -;
    J 2 is optionally substituted heterocyclo, wherein the optionally substituted heterocyclo is
    Figure PCTCN2021122588-appb-100039
    t and u are, independently, 0, 1, 2, or 3; and
    R 22 and R 23 are independently hydrogen, cyano, halo, haloalkyl, C 1-C 4alkyl, C 1-C 4 alkylcarbonyl, hydroxy, alkoxy, amino, sulfonamido, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, heterocycloalkylsulfonyl, carboxamido, optionally substituted aryl, or optionally substituted heteroaryl.
  33. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein:
    L is absent;
    J 2 is
    Figure PCTCN2021122588-appb-100040
    R 22 is hydrogen, cyano, halo such as fluoro or chloro, C 1-C 4 haloalkyl such as CF 3, C 1-C 4 alkyl such as methyl, ethyl, propyl, isopropyl, or butyl, hydroxy, amino, carboxamido, or alkylsulfonyl such as methylsulfonyl or ethylsulfonyl, or preferably cyano, fluoro, methyl, or methylsulfonyl; and
    R 23 is hydrogen, halo such as fluoro or chloro, or C 1-C 4 alkyl such as methyl, ethyl, propyl, isopropyl, or butyl, or preferably hydrogen, fluoro, or methyl.
  34. The compound of any one of claims 1-4, 22, or 23, or a pharmaceutically acceptable salt thereof, wherein:
    Y is -C (=O) -;
    J 2 is optionally substituted heterocyclo, wherein the optionally substituted heterocyclo is
    Figure PCTCN2021122588-appb-100041
    t and u are, independently, 0, 1, 2, or 3; and
    R 24 is hydrogen, haloalkyl, C 1-C 4alkyl, C 1-C 4alkylcarbonyl, alkenylcarbonyl,
    alkoxycarbonyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl,  heteroarylsulfonyl, heterocyclosulfonyl, heterocycloalkylsulfonyl, carboxamido, mesylate, or tert-butoxycarbonyl.
  35. The compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein
    L is absent;
    J 2 is
    Figure PCTCN2021122588-appb-100042
    R 24 is haloalkyl such as -CH 2CH 2F, -CH 2CHF 2, or -CH 2CF 3, C 1-C 4alkylcarbonyl such as – (C=O) Me, - (C=O) Et, - (C=O) Pr, or – (C=O) iPr, alkenylcarbonyl such as -C (=O) CH=CH 2, -C (=O) CH 2CH=CH 2, or -C (=O) CH 2CH 2CH=CH 2, or alkoxycarbonyl such as -C (=O) OMe, -C (=O) OEt, -C (=O) OPr, -C (=O) OiPr, or -C (=O) OtBu, or preferably -CH 2CHF 2, -CH 2CF 3, – (C=O) Me, -C (=O) CH=CH 2, -C (=O) OMe, -C (=O) OEt, or -C (=O) OiPr.
  36. The compound of any one of claims 1-4, 22, or 23, or a pharmaceutically acceptable salt thereof, wherein:
    Y is -C (=O) -, -SO 2-, -C (=O) NH-or -C (=O) N (CH 3) -;
    L is absent or haloalkyl such as -CF 2-, or optionally substituted alkyl such as -CH 2-, -CH (CH 3) -, and -C (CH 3)  2-; and
    J 2 is optionally substituted heteroaryl.
  37. The compound of claim 36, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted heteroaryl is pyridinyl, pyrazolyl, pyrazolo [1, 5-a] pyridinyl, indazolyl, imidazo [1, 5-a] pyridinyl, 1, 2, 4-triazolo [4, 3-a] pyridinyl, imidazo [1, 2-a] pyridinyl, imidazo [1, 2-c]pyrimidinyl, imidazo [1, 2-a] pyrazinyl, or imidazo [1, 2-a] pyrimidinyl.
  38. The compound of claim 36, or a pharmaceutically acceptable salt thereof, wherein:
    Y is -C (=O) -or -SO 2-;
    J 2 is:
    Figure PCTCN2021122588-appb-100043
    Figure PCTCN2021122588-appb-100044
    wherein:
    R 25 and R 26 are, independently, hydrogen, C 1-C 4 alkyl such as methyl, ethyl, or isopropyl, or halo such as fluoro or chloro, or preferably hydrogen, methyl, or fluoro; and
    R 27 is hydrogen, C 1-4alkyl such as methyl, ethyl, isopropyl, or t-butyl, C 1-C 4haloalkyl such as CF 3, or cycloalkyl.
  39. The compound of claim 36, or a pharmaceutically acceptable salt thereof, wherein:
    Y is -C (=O) -or -SO 2-;
    J 2 is:
    Figure PCTCN2021122588-appb-100045
    Figure PCTCN2021122588-appb-100046
    wherein R 27 is hydrogen or C 1-C 4alkyl such as methyl, ethyl, or isopropyl.
  40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, wherein V 1 is -NR 1SO 2 (C 1-C 4 alkyl) or -NR 1 (C=O) (C 1-C 4 alkyl) , or preferably -N (CH 3) SO 2 (CH 3) or -N (CH 3) (C=O) (CH 3) .
  41. The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein V 1 is -N (CH 3) SO 2 (CH 3) .
  42. The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein V 1 is -N (CH 3) (C=O) (CH 3) .
  43. A compound having Formula XXII:
    Figure PCTCN2021122588-appb-100047
    or a pharmaceutically acceptable salt thereof, wherein:
    each R a is independently hydrogen or C 1-C 4 alkyl;
    each R b is independently hydrogen or C 1-C 4 alkyl;
    R c is hydrogen or halo;
    each R d is independently halo;
    p, q, r and s are independently 1 or 2;
    n is 0, 1 or 2;
    Q is -N (H) C (=O) OR, -N (R) C (=O) OR, -N (H) C (=O) R, -N (H) C (O) NHR, -N (H) C (O) NR 2, -OC (=O) NR 2, 
    Figure PCTCN2021122588-appb-100048
    V is -CH 2OH, -CH 2OMe, -CH 2OEt, -CH 2NH 2, -CH 2NHMe, -CH 2NMe 2, cyano, - (C=O) H, -CO 2Me, -CO 2Et, -CH 2NR 1CO 2Me, -CH 2NR 1CO 2CD 3, -CH 2NR 1CO 2Et, -CH 2NR 1CO 2iPr, -CH 2NR 1CONH 2, -CO 2H, -CONH 2, -CONHMe, -CONMe 2, -CONHEt, -CONEt 2, -CON (Me) (Et) , -CON (CD 3)  2, -CON (Me) (CD 3) , -CON (Et) (CD 3) , -CON (i-Pr) (CD 3) , -CH 2NHCONHCH 2CF 3, -CH 2NHCONHiPr, -CH 2NHCONHMe, -CH 2NHCONHEt, 
    Figure PCTCN2021122588-appb-100049
    each R f is independently hydrogen, C 1-C 4 alkyl, hydroxy, C 1-C 4 alkoxy, or halo;
    each R g is independently hydrogen, C 1-C 4 alkyl, or NH 2;
    each R is independently C 1-C 4 alkyl, C 1-C 4 haloalkyl, or CD 3;
    each R 1 is independently hydrogen or C 1-C 4 alkyl;
    each R 2 is independently C 1-C 4 alkyl or C 3-C 6 cycloalkyl;
    each k is independently 0, 1, 2, 3, or 4;
    E is
    Figure PCTCN2021122588-appb-100050
    Figure PCTCN2021122588-appb-100051
    Figure PCTCN2021122588-appb-100052
    wherein
    R 4 is hydrogen, C 1-C 4 alkyl, C 1-C 4alkylcarbonyl, heterocyclo, and haloalkyl;
    each m is independently 1 or 2;
    W is -NH-, -O-, or -S-;
    J is optionally substituted heteroaryl, optionally substituted heterocyclo, optionally substituted aryl, carboxamido, haloalkoxy, alkoxy, alkylcarbonyloxy, carboxamidooxy, (carboxamido) alkyl, aralkyloxy, aryloxy, heterocyclooxy, heteroaryloxy, alkoxycarbonyl, hydrogen, C 1-C 4 alkyl, C 1-C 4 alkylcarbonyl, hydroxy, cyano, haloalkyl, -NO 2, halo, -NR 1SO 2 (C 1-C 4 alkyl) , -NR 1SO 2 (C 2-C 6 alkenyl) , -NR 1CO (C 1-C 4 alkyl) , -S (=O) (=NR 1) CF 3, S (=O) (=NR 1) (C 1-C 4 alkyl) , amino, sulfonamido, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, heterocycloalkylsulfonyl, or C 1-C 4 phosphine oxide;
    J 3 is optionally substituted heteroaryl, optionally substituted heterocyclo, optionally substituted aryl, haloalkoxy, alkoxy, alkylcarbonyloxy, carboxamidooxy, (carboxamido) alkyl, aralkyloxy, aryloxy, heterocyclooxy, heteroaryloxy, alkoxycarbonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, heterocycloalkylsulfonyl, C 1-C 4 phosphine oxide, or carboxamido, provided that J 3 is not -C (=O) NH 2, -C (=O) NH (CH 3) , or -C (=O) N (CH 3)  2;
    J 4 is optionally substituted heteroaryl, optionally substituted heterocyclo, optionally substituted aryl, haloalkoxy, alkoxy, alkylcarbonyloxy, carboxamidooxy, (carboxamido) alkyl, aralkyloxy, aryloxy, heterocyclooxy, heteroaryloxy, alkoxycarbonyl, C 1-C 4 alkyl, C 1-C 4 alkylcarbonyl, hydroxy, haloalkyl, -NO 2, halo, -NR 1SO 2 (C 1-C 4alkyl) , -NR 1SO 2 (C 2-C 6alkenyl) , -NR 1CO (C 1-C 4 alkyl) , -S (=O) (=NR 1) CF 3, S (=O) (=NR 1) (C 1-C 4 alkyl) , amino, sulfonamido, or C 1-C 4 phosphine oxide;
    R 8a, R 8b, R 8c, and R 8d are independently hydrogen, halo, carboxy, hydroxy, C 1-C 4 alkoxycarbonyl, C 1-C 4 alkyl, C 1-C 4 alkoxy, haloalkyl, haloalkoxy, -CH 2SO 2C 1-C 4 alkyl, sulfonamido, cyano, alkoxyalkyl, aralkyloxy, alkylsulfonyl, (amino) alkyl, carboxamido, (carboxamido) alkyl, thioamide, optionally substituted heteroaryl, (heteroaryl) alkyl, -NR 13C (O) C 1-C 4 alkyl, -OCH 2CH=CH-alkylsulfonyl, -O (C 1-C 4 alkyl) O (C 1-C 4 alkyl) , C 2-C 6 alkenyl, heterocyclooxy, aminocarbonyloxy, or (heterocyclo) alkyl;
    R 5 is hydrogen, amino, C 1-C 6 alkyl, C 1-C 6 alkoxy, or halo;
    R 10 is hydrogen, C 1-C 4 alkyl, -NR 13CO (C 1-C 4 alkyl) , -NR 13SO 2 (C 1-C 4 alkyl) , cyano, halo, -OCH 2CH=CH-R a3, or -CH 2CH 2CH=CH-R a3;
    R 13 is hydrogen or C 1-C 4 alkyl;
    R 16 is hydrogen or C 1-C 4 alkyl;
    R a3 is alkoxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, or carboxamido;
    Y is -C (=O) -, -SO 2-, -C (=O) NH-, or -C (=O) N (C 1-C 4alkyl) -;
    L is absent or is optionally substituted C 1-C 6 alkyl or C 1-C 6 haloalkyl; and
    J 5 is C 1-C 4 alkyl, C 1-C 6 haloalkyl, cyano, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, or optionally substituted heterocyclo, provided that E is not C 1-C 4 alkylsulfonyl, cycloalkylsulfonyl, -C 1-C 4 alkylcarbonyl, arylcarbonyl,
    Figure PCTCN2021122588-appb-100053
    wherein R 1, R 6, R 7, R 8a, R 8b, R 8c, R 8d, R 10, t, u, v, W 1, Y 1 and Z are as defined before.
  44. The compound of claim 43, having Formula XXIII, XXIV, XXV, XXVI, XXVII, or XXVIII:
    Figure PCTCN2021122588-appb-100054
    Figure PCTCN2021122588-appb-100055
    Figure PCTCN2021122588-appb-100056
    or a pharmaceutically acceptable salt thereof.
  45. The compound of claim 44, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula XXIII.
  46. The compound of any one of claims 43-45, or a pharmaceutically acceptable salt thereof, wherein:
    R c is hydrogen and halo;
    n is 0;
    Q is -NHCO 2R;
    R is C 1-C 4 alkyl;
    V is -CH 2NR 1CO 2Me, -CH 2NR 1CO 2Et, -CH 2NR 1CO 2iPr, -CH 2NR 1CONH 2, -CONH 2, -CONHMe, -CONMe 2, -CONHEt, -CONEt 2, -CON (Me) (Et) , 
    Figure PCTCN2021122588-appb-100057
    Figure PCTCN2021122588-appb-100058
    Figure PCTCN2021122588-appb-100059
    wherein each R g is independently hydrogen, methyl, ethyl, and isopropyl and each R 2is independently methyl; and
    E is E-10, E-12, E-13, E-36, or E-37.
  47. The compound of claim 43, having Formula XXIX:
    Figure PCTCN2021122588-appb-100060
    or a pharmaceutically acceptable salt thereof.
  48. The compound of claim 47, having Formula XXX:
    Figure PCTCN2021122588-appb-100061
    or a pharmaceutically acceptable salt thereof.
  49. The compound of any one of claims 43-48, wherein J 3 is optionally substituted heteroaryl and the optionally substituted heteroaryl is pyrazolyl, oxazolyl, pyrimidinyl, oxadiazolyl, or pyridinyl.
  50. The compound of claim 49, wherein the optionally substituted heteroaryl is oxazol-2-yl, oxazol-5-yl, pyrimidin-2-yl, pyrazol-3-yl, 1, 3, 4-oxadiazol-2-yl, 1, 2, 4-oxadiazol-3-yl, or pyridin-2-yl.
  51. The compound of any one of claims 43-50, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted heteroaryl is substituted with one or more of:
    C 1-C 6alkyl, such as methyl, ethyl, propyl, isopropyl, or butyl;
    halo such as Br, Cl, or F;
    cyano;
    C 1-C 6haloalkyl, such as CF 3, CH 2F, CHF 2, CH 2CF 3, CH 2CHF 2, CH 2CH 2F, CH (CH 2F)  2C (CH 3)  2F, or C (CH 3) F 2;
    amino, such NH 2, or N (CH 2)  3; and
    carboxamido, such as – (C=O) N (CH 3)  2.
  52. The compound of any one of claims 43-48, or a pharmaceutically acceptable salt thereof, wherein J 3 is:
    Figure PCTCN2021122588-appb-100062
    Figure PCTCN2021122588-appb-100063
    wherein:
    R 17 and R 18 are, independently, hydrogen, C 1-C 4alkyl, C 1-C 4haloalkyl, cyano, halo, or amino; and
    R 19 is hydrogen or C 1-C 4alkyl.
  53. The compound of any one of claims 43-52, or a pharmaceutically acceptable salt thereof, wherein:
    R 8b is carboxamido such as
    Figure PCTCN2021122588-appb-100064
    Figure PCTCN2021122588-appb-100065
    Figure PCTCN2021122588-appb-100066
    and preferably
    Figure PCTCN2021122588-appb-100067
    and
    R 8c is hydrogen or halo, such as fluoro or chloro, or preferably hydrogen or fluoro.
  54. The compound of claim 1, wherein the compound is any one or more of the compounds of Table 1A, or a pharmaceutically acceptable salt thereof.
  55. The compound of claim 43, wherein the compound is any one or more of the compounds of Table 1B, or a pharmaceutically acceptable salt thereof.
  56. A pharmaceutical composition comprising the compound of any one of claims 1-55, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  57. 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 1-55, 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.
  58. The method of claim 57, wherein the patient has cancer.
  59. The method of claim 58, wherein the cancer is any one or more of the cancers of Table 2.
  60. The method of claim 58, 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.
  61. The method of any one of claims 57-60, further comprising administering a therapeutically effective amount of a second therapeutic agent useful in the treatment of the disease or condition.
  62. The pharmaceutical composition of claim 56 for use in treating cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.
  63. The pharmaceutical composition of claim 62 for use in treating cancer.
  64. The pharmaceutical composition of claim 63, wherein the cancer is any one or more of the cancers of Table 2.
  65. The pharmaceutical composition of claim 63, 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.
  66. A compound of any one of claims 1-55, 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.
  67. The compound of claim 66 for use in treating cancer.
  68. The compound of claim 67, wherein the cancer is any one or more of the cancers of Table 2.
  69. The compound of claim 67, 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.
  70. Use of a compound of any one of claims 1-55, 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.
  71. The use of claim 70 for treatment of cancer.
  72. The use of claim 71, wherein the cancer is any one or more of the cancers of Table 2.
  73. The use of claim 71, 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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