WO2021204159A1

WO2021204159A1 - Menin inhibitors and methods of use for treating cancer

Info

Publication number: WO2021204159A1
Application number: PCT/CN2021/085824
Authority: WO
Inventors: Shubao ZHOU; Tao Liu; Jingjing Ji; Shaomeng Wang; Meng Zhang; Fuming XU; Haibin Zhou; Angelo AGUILAR; Renqi XU; Liyue HUANG; Jeanne STUCKEY
Original assignee: Agios Pharmaceuticals, Inc.; The Regents Of The University Of Michigan
Priority date: 2020-04-08
Filing date: 2021-04-07
Publication date: 2021-10-14
Also published as: TW202204333A

Abstract

The present disclosure provides compounds represented by Formula (I), or a pharmaceutically acceptable salt thereof, wherein R^a, R^b, R^c, R^d, V, Q, T, 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

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of PCT Application No. PCT/CN2020/083752, filed April 8, 2020, the disclosure of which is incorporated by reference in their entireties.

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 in NPM1. NPM1 localizes predominantly in the nucleus and functions in diverse cellular processes, including ribosome assembly, nucleosome assembly and cell proliferation. Mutations in NPM1 lead to abnormal cytoplasmic localization and constitute one of the second most frequent mutations in AML accounting for nearly 30%of all AML patients. It has been recently demonstrated that menin contributes to modulation of HOX genes and cell proliferation in NPM1 mutant AML cells in vitro and in vivo, although the mechanism remains mostly unknown.

Menin interacts with transcription activators, e.g., sc-Myb, MLL1, SMAD 1, 3, 5, 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-XLV, 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,

or a pharmaceutically acceptable salt thereof, wherein:

each R ^a is independently selected from the group consisting of hydrogen and C ₁-C ₄ alkyl;

each R ^b is independently selected from the group consisting of hydrogen and C ₁-C ₄ alkyl;

R ^c is selected from the group consisting of hydrogen and halo;

each R ^d is independently selected from the group consisting of halo;

p, q, r and s are independently 1 or 2;

each n is independently 0, 1 or 2;

Q is selected from the group consisting of -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,

V is selected from the group consisting of -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,

each R ^f is independently selected from the group consisting of hydrogen, C ₁-C ₄ alkyl, hydroxy, C ₁-C ₄ alkoxy, and halo;

each R ^g is independently selected from the group consisting of hydrogen, C ₁-C ₄ alkyl, and 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;

T is selected from the group consisting of -C ₁-C ₄ alkyl, C ₁-C ₄ alkylsulfonyl, cycloalkylsulfonyl, -C ₁-C ₄ alkylcarbonyl, arylcarbonyl,

wherein

R ⁴ is hydrogen, C ₁-C ₄ alkyl, C ₁-C ₄ alkylcarbonyl, heterocyclo, and haloalkyl;

each m is independently 1 or 2;

J is hydrogen, cyano, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, heterocycloalkylsulfonyl, and carboxamido;

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 selected from the group consisting of 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 selected from the group consisting of 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, and R ^a1;

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, and cycloalkylsulfonyl;

R ^a1 is cyano, alkoxyalkyl, aralkyloxy, alkylsulfonyl, (amino) alkyl, carboxamido, 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, and (heterocyclo) alkyl;

X is selected from the group consisting of -C ₁-C ₄ alkyl, -C ₂-C ₄ alkenyl, -NH ₂, -NHC ₁-C ₄alkyl, -N (C ₁-C ₄alkyl) ₂, (amino) alkyl, and -CH ₂CH ₂NR ¹Y-Z ²;

wherein

t and u are independently 0, 1, 2, or 3;

Y is absent or is -C (=O) -, -SO ₂-, -C (=O) NH-, -C (=O) N (Me) -;

Z ² is selected from the group consisting of -C (R ^14a) =C (R ^14b) (R ^14c) , -C≡CR ^14d, alkyl, alkoxy, haloalkyl, and R ^a2

R ^9a and R ^9b are each independently selected from the group consisting of alkenyl, alkynyl, cyano, -C ₁-C ₄ alkyl, halo, (amino) alkyl, and -C (R ^14a) =C (R ^14b) (R ^14c) ;

each Q ¹ is independently selected from the group consisting of -CH ₂-and -C (=O) -

R ¹⁰ is selected from the group consisting of 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, -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 selected from the group consisting of alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, and carboxamido;

R ¹³ is hydrogen or C ₁-C ₄ alkyl;

R ^14a, R ^14b, R ^14c, and R ^14d are each independently selected from the group consisting of hydrogen, halo, C ₁-C ₄ alkyl, (amino) alkyl, and R ^a3;

R ^a2 is -N (R ¹⁵) CH ₂CH=CH-R ^a3 or -CH=CHCH ₂R ^a4;

R ^a3 is selected from the group consisting of alkoxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, and carboxamido;

R ^a4 is optionally subsubstituted heterocyclo;

R ^a5 is selected from the group consisting of cyano and (amino) alkyl;

R ^a6 is hydrogen or carboxamido;

R ¹⁵ is hydrogen or C ₁-C ₄ alkyl; and

each W is independently selected from the group consisting of -CH-or -N-.

In another embodiment, Compounds of the Disclosure are compounds represented by Formula I, and the pharmaceutically acceptable salts thereof, wherein each R ^a and R ^b is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds represented by Formula I, and the pharmaceutically acceptable salts thereof, wherein p, q, r and s are each 1.

In another embodiment, Compounds of the Disclosure are compounds represented by Formula I, and the pharmaceutically acceptable salts thereof, wherein R ^c is fluorine.

In another embodiment, Compounds of the Disclosure are compounds represented by Formula I, and the pharmaceutically acceptable salts thereof, wherein Q is -NHCO ₂Me.

In another embodiment, Compounds of the Disclosure are compounds represented by Formula I, and the pharmaceutically acceptable salts thereof, wherein V is -CH ₂OMe;

In another embodiment, Compounds of the Disclosure are compounds represented by Formula I, and the pharmaceutically acceptable salts thereof, wherein T is

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae II-XVI:

wherein Q, V, X, T, R ^a, R ^b, R ^c, R ^d, R ^8a, R ^8b, R ^8c, R ^8d, 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-XVI, and the pharmaceutically acceptable salts thereof.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-X, 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-X, 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-X, 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-X, 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-XVI, 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-XVI, 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-XVI, 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-X or XII-XVI, and the pharmaceutically acceptable salts thereof, wherein at each n is independently 0 or 1.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-X or XII-XVI, 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-X or XII-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one R ^d is halo.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-X or XII-XVI, and the pharmaceutically acceptable salts thereof, wherein each R ^d is halo.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-X or XII-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one R ^d is fluoro.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-X or XII-XVI, and the pharmaceutically acceptable salts thereof, wherein each R ^d is fluoro.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-X or XII-XVI, 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-X or XII-XVI, 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-X or XII-XVI, 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-XVI, 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-XVI, 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-XVI, and the pharmaceutically acceptable salts thereof, wherein Q is

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-X, 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-X, 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-X, 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-X, 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-X, 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-X, 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-X, 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 I-XVI, and the pharmaceutically acceptable salts thereof, wherein V is selected from the group consisting of -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 ¹CON (R ¹) 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,

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein V is -CH ₂NR ¹CON (R ¹) ₂ or -CH ₂NHCONHCH ₂CF ₃.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein V is -CH ₂NHCONH ₂, -CH ₂NHCONHiPr, -CH ₂NHCONHMe, or -CH ₂NHCONHEt.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein V is -CH ₂NR ¹CO ₂Me, -CH ₂NR ¹CO ₂CD ₃, -CH ₂NR ¹CO ₂Et, or -CH ₂NR ¹CO ₂iPr.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein V is -CONH ₂, -CONHMe, -CONMe ₂, -CONHEt, -CONEt ₂, -CON (Me) (Et) , -CON (CD ₃) ₂, -CON (Me) (CD ₃) , -CON (Et) (CD ₃) , or -CON (i-Pr) (CD ₃) .

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, 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-XVI, 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-XVI, 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-XVI, 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-XVI, 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-XVI, 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-XVI, 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-XVI, and the pharmaceutically acceptable salts thereof, wherein V is

wherein each R ^f is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, and hydroxy.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one R ^f is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein each R ^f is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one R ^f is methyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein each R ^f is methyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one R ^f is ethyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein each R ^f is ethyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein one R ^f is methyl and the other R ^f is hydroxy.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-I-XVI, and the pharmaceutically acceptable salts thereof, wherein V is

wherein each R ^g is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, and -NH ₂.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one R ^g is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein each R ^g is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one R ^g is methyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one R ^g is ethyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one R ^g is isopropyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one R ^g is -NH ₂.

wherein R ^g is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, and -NH ₂.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein R ^g is methyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein R ^g is ethyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein R ^g is isopropyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein R ^g is -NH ₂.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein T is T-1, T-2, T-3, T-4, T-5, T-14, T-15, T-16, T-17, T-18, T-19, T-20, T-21, T-22, T-24, T-25, T-26, T-29, T-31, T-32, or T-36.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein T is T-6, T-7, T-8, T-9, T-10, T-11, T-12, T-30, T-33, T-34, or T-35.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein T is T-27 or T-28.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein T is C ₁-C ₄ alkyl, C ₁-C ₄ alkylsulfonyl, cycloalkylsulfonyl, -C ₁-C ₄ alkylcarbonyl, arylcarbonyl, or T-5.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein T is T-1, T-2, T-3, T-29, or T-32.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein T is T-14, T-15, T-16, T-17, T-18, T-19, T-24, T-25, T-26, T-31, or T-36.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein T is T-1, T-2, or T-3.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein T is T-1 or T-2.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein T is

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein 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-XVI, and the pharmaceutically acceptable salts thereof, wherein at least two 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-XVI, and the pharmaceutically acceptable salts thereof, wherein at least three 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-XVI, and the pharmaceutically acceptable salts thereof, wherein 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-XVI, and the pharmaceutically acceptable salts thereof, wherein 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-XVI, and the pharmaceutically acceptable salts thereof, wherein at least two 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-XVI, and the pharmaceutically acceptable salts thereof, wherein at least three 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-XVI, and the pharmaceutically acceptable salts thereof, wherein 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-XVI, and the pharmaceutically acceptable salts thereof, wherein at least two 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-XVI, and the pharmaceutically acceptable salts thereof, wherein at least three 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-XVI, and the pharmaceutically acceptable salts thereof, wherein 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-XVI, and the pharmaceutically acceptable salts thereof, wherein at least two 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-XVI, and the pharmaceutically acceptable salts thereof, wherein at least three 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-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8a, R ^8b, R ^8c, and R ^8d is methyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least two of R ^8a, R ^8b, R ^8c, and R ^8d is methyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least three of R ^8a, R ^8b, R ^8c, and R ^8d is methyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8a, R ^8b, R ^8c, and R ^8d is -CH ₂NMe ₂.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8a, R ^8b, R ^8c, and R ^8d is -C (O) NMe ₂.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8a, R ^8b, R ^8c, and R ^8d is -C ₁-C ₄ alkoxy or -CH ₂OC ₁-C ₄ alkyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8a, R ^8b, R ^8c, and R ^8d is

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein X is X-1, X-2, X-3, X-5, X-6, X-11, X-12, X-13, X-14, X-16, X-18, X-19, X-20, X-21, X-22, or X-23.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein X is X-1, X-10, X-16, X-17, X-18, X-19, or X-20.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein X is X-1.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein X is X-2 or X-3.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein X is X-5 or X-21.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein X is X-5.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein X is X-21.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein X is X-6.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein X is X-11 or X-12.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein X is X-11.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein X is X-12.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein X is X-13.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein X is X-14.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein X is X-16.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein X is X-18.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein X is X-19.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein X is X-20.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein X is X-22.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein X is X-23.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8a, 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-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8a, 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-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8a, R ^8b, and R ^8c is chloro.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8a, 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-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8a, 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-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8a, R ^8b, and R ^8c is -CH ₂NMe ₂.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8a, R ^8b, and R ^8c is -C (O) NMe ₂.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8a, R ^8b, and R ^8c is -C ₁-C ₄ alkoxy or -CH ₂OC ₁-C ₄ alkyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8a, R ^8b, and R ^8c is

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8a, R ^8b, and R ^8d is halo.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8a, R ^8b, and R ^8d is fluoro.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8a, R ^8b, and R ^8d is chloro.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8a, R ^8b, 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-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8a, R ^8b, and R ^8d is methyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8a, R ^8b, and R ^8d is -CH ₂NMe ₂.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8a, R ^8b, and R ^8d is -C (O) NMe ₂.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8a, R ^8b, and R ^8d is -C ₁-C ₄ alkoxy or -CH ₂OC ₁-C ₄ alkyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein 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-XVI, and the pharmaceutically acceptable salts thereof, wherein 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-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8a and R ^8b is chloro.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein 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-XVI, and the pharmaceutically acceptable salts thereof, wherein 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-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8a and R ^8b is -CH ₂NMe ₂.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8a and R ^8b is -C (O) NMe ₂.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8a and R ^8b is -C ₁-C ₄ alkoxy or -CH ₂OC ₁-C ₄ alkyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8a and R ^8b is

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein 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-XVI, and the pharmaceutically acceptable salts thereof, wherein 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-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8b and R ^8c is chloro.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein 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-XVI, and the pharmaceutically acceptable salts thereof, wherein 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-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8b and R ^8c is -CH ₂NMe ₂.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8b and R ^8c is -C (O) NMe ₂.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8b and R ^8c is -C ₁-C ₄ alkoxy or -CH ₂OC ₁-C ₄ alkyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8b and R ^8c is

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein Z is cyano, haloalkyl, alkylsulfonyl, or cycloalkylsulfonyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein Z is cyano, alkylsulfonyl, or cycloalkylsulfonyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein Z is cyano, -CF ₃, methylsulfonyl, or cyclopropylsulfonyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein Z is cyano.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein Z is -CF ₃.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein Z is -NO ₂.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein Z is fluoro.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein Z is chloro.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein Z is alkylsulfonyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein Z is methylsulfonyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein Z is cycloalkylsulfonyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein Z is cyclopropylsulfonyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one W is N.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein each W is N.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein at least one W is -CH-.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein each W is -CH-.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein one W is -CH-and one W is -N-.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein t is 1 and u is 1.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein t is 0 and u is 0.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein t is 0 and u is 1.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein t is 1 and u is 0.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein R ⁷ is cyano.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein R ⁷ is C ₁-C ₄alkyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein R ⁷ is alkylsulfonyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein R ⁷ is carboxamido.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein R ¹⁰ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein R ¹⁰ is C ₁-C ₄ alkyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein R ¹⁰ is -NHCOMe.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein R ¹⁰ is -NHSO ₂Me.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae I-XVI, and the pharmaceutically acceptable salts thereof, wherein Y is -C (=O) -.

In some embodiments, the present invention provides a compound selected from any of Formulae XVI-XXI:

wherein X, R ^c, R ^d, R ^g, R ^8a, R ^8b, 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-XXI, and the pharmaceutically acceptable salts thereof.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XVI-XXI, 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 XVI-XXI, 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 XVI-XXI, and the pharmaceutically acceptable salts thereof, wherein R ^c is halo and R ^d is halo.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XVI-XXI, and the pharmaceutically acceptable salts thereof, wherein R ^c is fluoro and R ^d is fluoro.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XVI-XXI, and the pharmaceutically acceptable salts thereof, wherein R ^d is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XVI-XXI, and the pharmaceutically acceptable salts thereof, wherein R ^g is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XVI-XXI, and the pharmaceutically acceptable salts thereof, wherein R ^g is methyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XVI-XXI, and the pharmaceutically acceptable salts thereof, wherein R ^g is ethyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XVI-XXI, and the pharmaceutically acceptable salts thereof, wherein R ^g is isopropyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XVI-XXI, and the pharmaceutically acceptable salts thereof, wherein R ^8a and R ^8b are hydrogen.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XVI-XXI, and the pharmaceutically acceptable salts thereof, wherein 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 XVI-XXI, and the pharmaceutically acceptable salts thereof, wherein 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 XVI-XXI, and the pharmaceutically acceptable salts thereof, wherein R ^8a and R ^8b are fluoro.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XVI-XXI, and the pharmaceutically acceptable salts thereof, wherein 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 XVI-XXI, and the pharmaceutically acceptable salts thereof, wherein 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 XVI-XXI, and the pharmaceutically acceptable salts thereof, wherein R ^8a and R ^8b are methyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XVI-XXI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8a and R ^8b is -CH ₂NMe ₂.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XVI-XXI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8a and R ^8b is -C (O) NMe ₂.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XVI-XXI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8a and R ^8b is -C ₁-C ₄ alkoxy or -CH ₂OC ₁-C ₄ alkyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XVI-XXI, and the pharmaceutically acceptable salts thereof, wherein at least one of R ^8a and R ^8b is

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XVI-XXI, and the pharmaceutically acceptable salts thereof, wherein X is -CH ₃.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XVI-XXI, and the pharmaceutically acceptable salts thereof, wherein X is -NH ₂.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XVI-XXI, and the pharmaceutically acceptable salts thereof, wherein X is X-1, X-2, X-3, X-5, X-6, X-11, X-12, X-13, X-14, X-16, X-18, X-19, X-20, X-21, X-22, or X-23.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XVI-XXI, and the pharmaceutically acceptable salts thereof, wherein X is X-1, X-10, X-16, X-17, X-18, X-19, or X-20.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XVI-XXI, and the pharmaceutically acceptable salts thereof, wherein X is X-1.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XVI-XXI, and the pharmaceutically acceptable salts thereof, wherein X is X-11.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XVI-XXI, and the pharmaceutically acceptable salts thereof, wherein X is X-12.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XVI-XXI, and the pharmaceutically acceptable salts thereof, wherein Y is -C (=O) -.

In some embodiments, the present invention provides a compound selected from any of Formulae XXII-XXVII:

wherein V, X, R ^8b 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 XXII-XXVII, and the pharmaceutically acceptable salts thereof.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVII, and the pharmaceutically acceptable salts thereof, wherein V is

wherein R ^g is hydrogen.

wherein R ^g is methyl.

wherein R ^g is ethyl.

wherein R ^g is isopropyl.

In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XXII-XXVII, and the pharmaceutically acceptable salts thereof, wherein X is -CH ₃, -NH ₂, X-1, X-2, X-3, X-5, X-16, or X-18.

In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XXII-XXVII, and the pharmaceutically acceptable salts thereof, wherein X is -CH ₃.

In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XXII-XXVII, and the pharmaceutically acceptable salts thereof, wherein X is -NH ₂.

In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XXII-XXVII, and the pharmaceutically acceptable salts thereof, wherein X is X-1.

In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XXII-XXVII, and the pharmaceutically acceptable salts thereof, wherein X is X-2 or X-3.

In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XXII-XXVII, and the pharmaceutically acceptable salts thereof, wherein X is X-5.

In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XXII-XXVII, and the pharmaceutically acceptable salts thereof, wherein X is X-11.

In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XXII-XXVII, and the pharmaceutically acceptable salts thereof, wherein X is X-12.

In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XXII-XXVII, and the pharmaceutically acceptable salts thereof, wherein X is X-16.

In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XXII-XXVII, and the pharmaceutically acceptable salts thereof, wherein X is X-18.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVII, and the pharmaceutically acceptable salts thereof, wherein Y is -C (=O) -.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVII, and the pharmaceutically acceptable salts thereof, wherein R ^8b is hydrogen, -CH ₂NMe ₂, -C (O) NMe ₂, -C ₁-C ₄ alkoxy, -CH ₂OC ₁-C ₄ alkyl,

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVII, and the pharmaceutically acceptable salts thereof, wherein R ^8b is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVII, and the pharmaceutically acceptable salts thereof, wherein R ^8b is -CH ₂NMe ₂.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVII, and the pharmaceutically acceptable salts thereof, wherein R ^8b is -C (O) NMe ₂.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVII, and the pharmaceutically acceptable salts thereof, wherein R ^8b is -C ₁-C ₄ alkoxy or -CH ₂OC ₁-C ₄ alkyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXII-XXVII, and the pharmaceutically acceptable salts thereof, wherein R ^8b is

In some embodiments, the present invention provides a compound selected from any of Formulae XXVIII-XXXIII:

wherein V, R ^8b, Z 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 XXVIII-XXXIII, and the pharmaceutically acceptable salts thereof.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVIII-XXXIII, and the pharmaceutically acceptable salts thereof, wherein V is

wherein R ^g is hydrogen.

wherein R ^g is methyl.

wherein R ^g is ethyl.

wherein R ^g is isopropyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVIII-XXXIII, and the pharmaceutically acceptable salts thereof, wherein Z is cyano, haloalkyl, alkylsulfonyl, or cycloalkylsulfonyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVIII-XXXIII, and the pharmaceutically acceptable salts thereof, wherein Z is cyano, alkylsulfonyl, or cycloalkylsulfonyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVIII-XXXIII, and the pharmaceutically acceptable salts thereof, wherein Z is cyano, -CF ₃, methylsulfonyl, or cyclopropylsulfonyl.

In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XXVIII-XXXIII, and the pharmaceutically acceptable salts thereof, wherein Z is cyano.

In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XXVIII-XXXIII, and the pharmaceutically acceptable salts thereof, wherein Z is methylsulfonyl.

In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XXVIII-XXXIII, and the pharmaceutically acceptable salts thereof, wherein Z is -CF ₃.

In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XXVIII-XXXIII, and the pharmaceutically acceptable salts thereof, wherein Z is cyclopropylsulfonyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVIII-XXXIII, and the pharmaceutically acceptable salts thereof, wherein R ^8b is hydrogen, -CH ₂NMe ₂, -C (O) NMe ₂, -C ₁-C ₄ alkoxy, -CH ₂OC ₁-C ₄ alkyl,

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVIII-XXXIII, and the pharmaceutically acceptable salts thereof, wherein R ^8b is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVIII-XXXIII, and the pharmaceutically acceptable salts thereof, wherein R ^8b is -CH ₂NMe ₂.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVIII-XXXIII, and the pharmaceutically acceptable salts thereof, wherein R ^8b is -C (O) NMe ₂.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVIII-XXXIII, and the pharmaceutically acceptable salts thereof, wherein R ^8b is -C ₁-C ₄ alkoxy or -CH ₂OC ₁-C ₄ alkyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVIII-XXXIII, and the pharmaceutically acceptable salts thereof, wherein R ^8b is

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXVIII-XXXIII, and the pharmaceutically acceptable salts thereof, wherein R ^8b is (heterocyclo) alkyl.

In some embodiments, the present invention provides a compound selected from any of Formulae XXXIV-XXXIX:

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXXIV-XXXIX, and the pharmaceutically acceptable salts thereof.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXXIV-XXXIX, and the pharmaceutically acceptable salts thereof, wherein V is

wherein R ^g is hydrogen.

wherein R ^g is methyl.

wherein R ^g is ethyl.

wherein R ^g is isopropyl.

In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XXXIV-XXXIX, and the pharmaceutically acceptable salts thereof, wherein X is -CH ₃.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXXIV-XXXIX, and the pharmaceutically acceptable salts thereof, wherein X is X-1, X-2, X-3, X-5, X-6, X-11, X-12, X-13, X-14, X-16, X-18, X-19, X-20, X-21, X-22, or X-23.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXXIV-XXXIX, and the pharmaceutically acceptable salts thereof, wherein X is X-1, X-10, X-16, X-17, X-18, X-19, or X-20.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXXIV-XXXIX, and the pharmaceutically acceptable salts thereof, wherein X is X-1.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXXIV-XXXIX, and the pharmaceutically acceptable salts thereof, wherein X is X-2 or X-3.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXXIV-XXXIX, and the pharmaceutically acceptable salts thereof, wherein X is X-5 or X-21.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXXIV-XXXIX, and the pharmaceutically acceptable salts thereof, wherein X is X-5.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXXIV-XXXIX, and the pharmaceutically acceptable salts thereof, wherein X is X-21.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXXIV-XXXIX, and the pharmaceutically acceptable salts thereof, wherein X is X-6.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXXIV-XXXIX, and the pharmaceutically acceptable salts thereof, wherein X is X-11 or X-12.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXXIV-XXXIX, and the pharmaceutically acceptable salts thereof, wherein X is X-11.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXXIV-XXXIX, and the pharmaceutically acceptable salts thereof, wherein X is X-12.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXXIV-XXXIX, and the pharmaceutically acceptable salts thereof, wherein X is X-13.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXXIV-XXXIX, and the pharmaceutically acceptable salts thereof, wherein X is X-14.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXXIV-XXXIX, and the pharmaceutically acceptable salts thereof, wherein X is X-16.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXXIV-XXXIX, and the pharmaceutically acceptable salts thereof, wherein X is X-18.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXXIV-XXXIX, and the pharmaceutically acceptable salts thereof, wherein X is X-19.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXXIV-XXXIX, and the pharmaceutically acceptable salts thereof, wherein X is X-20.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXXIV-XXXIX, and the pharmaceutically acceptable salts thereof, wherein X is X-22.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXXIV-XXXIX, and the pharmaceutically acceptable salts thereof, wherein X is X-23.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXXIV-XXXIX, and the pharmaceutically acceptable salts thereof, wherein Y is -C (=O) -.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXXIV-XXXIX, and the pharmaceutically acceptable salts thereof, wherein R ^8b is -CH ₂NMe ₂, -C (O) NMe ₂, -C ₁-C ₄ alkoxy, -CH ₂OC ₁-C ₄ alkyl,

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXXIV-XXXIX, and the pharmaceutically acceptable salts thereof, wherein R ^8b is -CH ₂NMe ₂.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXXIV-XXXIX, and the pharmaceutically acceptable salts thereof, wherein R ^8b is -C (O) NMe ₂.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXXIV-XXXIX, and the pharmaceutically acceptable salts thereof, wherein R ^8b is -C ₁-C ₄ alkoxy or -CH ₂OC ₁-C ₄ alkyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XXXIV-XXXIX, and the pharmaceutically acceptable salts thereof, wherein R ^8b is

In some embodiments, the present invention provides a compound selected from any of Formulae XL-XLV:

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XL-XLV, and the pharmaceutically acceptable salts thereof.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XL-XLV, and the pharmaceutically acceptable salts thereof, wherein V is

wherein R ^g is hydrogen.

wherein R ^g is methyl.

wherein R ^g is ethyl.

wherein R ^g is isopropyl.

In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XL-XLV, and the pharmaceutically acceptable salts thereof, wherein Z is cyano, haloalkyl, alkylsulfonyl, or cycloalkylsulfonyl

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XL-XLV, and the pharmaceutically acceptable salts thereof, wherein Z is cyano, alkylsulfonyl, or cycloalkylsulfonyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XL-XLV, and the pharmaceutically acceptable salts thereof, wherein Z is cyano, -CF ₃, methylsulfonyl, or cyclopropylsulfonyl.

In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XL-XLV, and the pharmaceutically acceptable salts thereof, wherein Z is cyano.

In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XL-XLV, and the pharmaceutically acceptable salts thereof, wherein Z is -CF ₃.

In another embodiment, Compounds of the Disclosure are compounds represented by Formulae XL-XLV, and the pharmaceutically acceptable salts thereof, wherein Z is methylsulfonyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XL-XLV, and the pharmaceutically acceptable salts thereof, wherein Z is cyclopropylsulfonyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XL-XLV, and the pharmaceutically acceptable salts thereof, wherein Z is fluoro.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XL-XLV, and the pharmaceutically acceptable salts thereof, wherein Z is chloro.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XL-XLV, and the pharmaceutically acceptable salts thereof, wherein R ^8b is -CH ₂NMe ₂, -C (O) NMe ₂, -C ₁-C ₄ alkoxy, -CH ₂OC ₁-C ₄ alkyl,

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XL-XLV, and the pharmaceutically acceptable salts thereof, wherein R ^8b is -CH ₂NMe ₂.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XL-XLV, and the pharmaceutically acceptable salts thereof, wherein R ^8b is -C (O) NMe ₂.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XL-XLV, and the pharmaceutically acceptable salts thereof, wherein R ^8b is -C ₁-C ₄ alkoxy or -CH ₂OC ₁-C ₄ alkyl.

In another embodiment, Compounds of the Disclosure are compounds represented by any one or more of Formulae XL-XLV, and the pharmaceutically acceptable salts thereof, wherein R ^8b is

In another embodiment, Compounds of the Disclosure are any one or more of the compounds of Table 1, and the pharmaceutically acceptable salts thereof. Table 1 further provides the chemical names of the compounds of Table 1 generated by

Professional version 16.0. In the event of any ambiguity between their chemical structure and chemical name, Compounds of the Disclosure are defined by their chemical structure.

Table 1

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

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

(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.

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.,

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, 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" 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 ^19a) C (=O) -R ^19b, and -N (R ^20a) SO ₂-R ^20b, wherein R ^19a is selected from the group consisting of hydrogen and alkyl, R ^19b is selected from the group consisting of amino, alkoxy, alkyl, e.g., C ₁-C ₆ alkyl, and optionally substituted aryl, R ^20a is selected from the group consisting of hydrogen and alkyl, and R ^20b 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:

(including

) and

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:

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 ^19a) C (=O) -R ^19b, and -N (R ^20a) SO ₂-R ^20b, wherein R ^19a, R ^19b, R ^20a, and R ^20b 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, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 2, 6-di-fluorophenyl, 2, 6-di-chlorophenyl, 2-methyl, 3-methoxyphenyl, 2-ethyl, 3-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, 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:

Additional non-limiting examples of optionally substituted aryl include:

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, 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:

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:

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. A non-limiting exemplary alkylsulfonyl group is -SO 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 alkylsulfonyl 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 alkylsulfonyl group 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:

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:

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:

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:

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 ^21aR ^21b, wherein R ^21a and R ^21b are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted aryl, or R ^21a and R ^21b taken together with the nitrogen to which they are attached from a 3-to 8-membered heterocyclo group. Non-limiting exemplary sulfonamido groups include -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 heterocyclosulfonyl groups include:

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 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 ^19a) C (=O) -R ^19b, and -N (R ^20a) SO ₂-R ^20b, wherein R ^19a, R ^19b, R ^20a, and R ^20b 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.

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:

Additional non-limiting examples of a 5-membered heteroarylenyl include:

In another embodiment, the heteroarylenyl is a 6-membered heteroarylenyl. Non-limiting examples of a 6-membered heteroarylenyl include:

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, piperazin-2-one, piperazine-2, 6-dione, 2-imidazolidinone, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and indolinyl. Additional non-limiting examples of heterocyclo groups include oxetanyl and tetrahydrofuranyl.

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 ^19a) C (=O) -R ^19b, and -N (R ^20a) SO ₂-R ^20b, wherein R ^19a, R ^19b, R ^20a, and R ^20b 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:

Additional non-limiting exemplary substituted heterocyclo groups include:

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 ^22aR ^22b, wherein R ^22a and R ^22b are each independently selected from the group consisting of hydrogen, alkyl, alkenylcarbonyl, alkyoxy, aralkyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted heteroaryl, (heterocyclo) alkyl and (heteroaryl) alkyl, or R ^22a and R ^22b are taken together to form a 3-to 8-membered optionally substituted heterocyclo. Non-limiting exemplary amino groups include -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 ^23aR ^23b, wherein R ^23a and R ^23b are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, and optionally substituted heteroaryl, or R ^23a and R ^23b taken together with the nitrogen to which they are attached form a 3-to 8-membered optionally substituted heterocyclo group. In one embodiment, R ^23a and R ^23b are each independently hydrogen or optionally substituted alkyl. In one embodiment, R ^23a and R ^23b are taken together to taken together with the nitrogen to which they are attached form a 3-to 8-membered optionally substituted heterocyclo group. Non-limiting exemplary carboxamido groups include -CONH ₂, -CON (H) CH ₃, -CON (CH ₃) ₂, -CON (H) Ph,

Additional non-limiting exemplary carboxamido groups include:

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 alkylcarbonyl 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, 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 alkyoxy 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 ^23aR ^23b, wherein R ^23a and R ^23b are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, and optionally substituted heteroaryl, or R ^23a and R ^23b taken together with the nitrogen to which they are attached form a 3-to 8-membered optionally substituted heterocyclo group. In one embodiment, R ^23a and R ^23b are each independently hydrogen or optionally substituted alkyl. In one embodiment, R ^23a and R ^23b are taken together to taken together with the nitrogen to which they are attached form a 3-to 8-membered optionally substituted heterocyclo group. Non-limiting exemplary carboxamido groups include -C (=S) NH ₂, -C (=S) N (H) CH ₃, -C (=S) N (CH ₃) ₂, -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:

Additional non-limiting exemplary (heterocyclo) alkyl groups include:

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:

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 ₃-CONH ₂, and -CH ₂CON (H) CH ₃.

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 ₂CH ₃, -OC (=O) CH ₃, i.e., acetoxy, -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 “aminocarbonyloxy” as used by itself or as part of another group refers an oxy, i.e., -O-, substituted with an aminocarbonyl group. Non-limiting exemplary carboxamidooxy groups include:

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 in Pure & 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 of R and S enantiomers, the percent enantiomeric excess is defined as │R -S│*100, where R and S 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

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, -

Scheme 2

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 substituent wherein V is -CH ₂NR ¹CO ₂Me, -CH ₂NR ¹CO ₂CD ₃, -CH ₂NR ¹CO ₂Et, -CH ₂NR ¹CO ₂iPr, -CH ₂NR ¹CONH ₂, -CH ₂NHCONHCH ₂CF ₃, -CH ₂NHCONHiPr, -CH ₂NHCONHMe, -CH ₂NHCONHEt,

Scheme 3

As an example of a coupling reaction, Compounds of Formula I, wherein T is T-1, T-2, T-3, T-4, T-6, T-7, T-8, T-9, T-10, T-12, T-27, T-28, T-29, T-32, T-33, T-34, and T-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

Alternatively, Compounds of Formula I, wherein T is T-1, T-2, T-4, T-6, T-7, T-8, T-9, T-10, T-11, T-12, T-29, T-30, T-32, T-33, T-34, and T-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

Alternatively, Compounds of Formula I, wherein T is C ₁-C ₄ alkylsulfonyl, cycloalkylsulfonyl, -C ₁-C ₄ alkylcarbonyl, arylcarbonyl, T-5, T-14, T-15, T-16, T-17, T-18, T-19, T-20, T-21, T-22, T-23, T-24, T-25, T-26, and T-31 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

EXAMPLES

EXAMPLE 1

Synthesis of Intermediate S7

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 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 of S4 to S5, 8 mL of water was added, and the reaction was concentrated. Additional 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

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 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, basified with saturated NaHCO ₃, and 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%) . Then, the diastereomers were separated by reverse phase preparative HPLC to give the enantiopure title compounds S7 (1.2 g, 36%) and S8 (0.8 g, 24%) as salts of trifluoroacetic acid, respectively.

The enantiopure compound S7 is isolated by recrystallization in a solution of hexane and dichloromethane with a ratio of 4: 1. Data for S7: 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 (E5)

Methyl ( (1S, 2R) -2- ( (S) - (1-benzylpiperidin-4-yl) (cyano) (3-fluorophenyl) methyl) cyclopentyl) carbamate (E3) : 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 E1 that was used without purification. At 0℃, dimethyl dicarbonate (410 mg, 3.05 mmol) was added to a solution of E1 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 E2 (770 mg) .

Methyl ( (1S, 2R) -2- ( (S) -2-amino-1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) ethyl) cyclopentyl) carbamate (E3) : At 0℃, diisobutylaluminium hydride (3.90 mL, 6.86 mmol) was slowly added to a solution of E2 (770 mg, 1.715 mmol) in toluene (17 mL) . After 1 hour at 0℃, 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 E3 (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 (E4) : 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 E3 (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 E4 (406 mg) .

Methyl ( (1S, 2R) -2- ( (S) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) -1- (piperidin-4-yl) ethyl) cyclopentyl) carbamate (E5) : E4 (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 E5 (318 mg) that was used without further purification.

EXAMPLE 3

Preparation of intermediate methyl ( (1S, 2R) -2- ( (S) -1- (3-fluorophenyl) -1- (piperidin-4-yl) -2- (4H-1, 2, 4-triazol-4-yl) ethyl) cyclopentyl) carbamate (E7)

Step A: methyl ( (1S, 2R) -2- ( (S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2- (4H-1, 2, 4-triazol-4-yl) ethyl) cyclopentyl) carbamate (E6)

A solution of triethyl orthoformate (1.29 mL, 7.716 mmol, 1.8 eq. ) , formohydrazide (397 mg, 6.614 mmol, 1.5 eq. ) in MeOH (10 mL) was refluxed at 70 ℃. Then methyl ( (1S, 2R) -2- ( (S) -2-amino-1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) ethyl) cyclopentyl) carbamate (E3) (2 g, 4.409 mmol, 1.0 eq. ) was added to the above solution. The mixture was further refluxed overnight. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give E6 (1.8 g, yield 81%) as a white solid. LC-MS: 506 (M+H) ⁺.

Step B: methyl ( (1S, 2R) -2- ( (S) -1- (3-fluorophenyl) -1- (piperidin-4-yl) -2- (4H-1, 2, 4-triazol-4-yl) ethyl) cyclopentyl) carbamate (E7)

To a mixture of methyl ( (1S, 2R) -2- ( (S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2- (4H-1, 2, 4-triazol-4-yl) ethyl) cyclopentyl) carbamate (E6) (1.8 g, 3.56 mmol, 1.0 eq. ) in CF ₃CH ₂OH (18 mL) was added 20%Pd (OH) ₂/C (0.36 g, 10%w/wt) . The reaction was stirred at 25℃ under H ₂ atmosphere (1 atm) for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give E7 (1.4 g, yield 95%) which was used directly in next step. LC-MS: 416 (M+1) ⁺.

EXAMPLE 4

Preparation of intermediate methyl ( (1S, 2R) -2- ( (S) -1- (3-fluorophenyl) -1- (piperidin-4-yl) -2- (1H-pyrazol-1-yl) ethyl) cyclopentyl) carbamate (E11)

Step A: methyl ( (1S, 2R) -2- ( (S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2- ( (3- (trimethylsilyl) prop-2-yn-1-yl) amino) ethyl) cyclopentyl) carbamate (E8)

A solution of methyl ( (1S, 2R) -2- ( (S) -2-amino-1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) ethyl) cyclopentyl) carbamate (E3) (2 g, 4.42 mmol, 1.0 eq. ) and 3- (trimethylsilyl) propiolaldehyde (668 mg, 5.3 mmol, 1.2 eq. ) in DCE (15 mL) was stirred at room temperature for 3 hours. Then NaBH ₃CN (1.388 g, 22.1 mmol, 5 eq. ) was added to above solution, and the mixture was stirred at room temperature overnight. Then the reaction was quenched with water (15 mL) and extracted with EtOAc (15 mL x 2) . The organic layers were washed with brine (15 mL) , dried over Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give E8 (2.3 g, yield 93%) as a white solid. LC-MS: 564 (M+1) ⁺.

Step B: methyl ( (1S, 2R) -2- ( (S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2- (prop-2-yn-1-ylamino) ethyl) cyclopentyl) carbamate (E9)

A mixture of methyl ( (1S, 2R) -2- ( (S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2- ( (3- (trimethylsilyl) prop-2-yn-1-yl) amino) ethyl) cyclopentyl) carbamate (E8) (2.3 g, 4.08 mmol, 1.0 eq. ) and K ₂CO ₃ (1.69 g, 12.24 mmol, 3.0 eq. ) in MeOH (15 mL) was stirred at room temperature for 4 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give E9 (1 g, yield 95%) as a white solid. LC-MS: 492 (M+1) ⁺.

Step C: 1- ( (S) -2- (1-benzylpiperidin-4-yl) -2- (3-fluorophenyl) -2- ( (1R, 2S) -2- ( (methoxycarbonyl) amino) cyclopentyl) ethyl) -1H-pyrazole 2-oxide (E10)

A mixture of methyl ( (1S, 2R) -2- ( (S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2- (prop-2-yn-1-ylamino) ethyl) cyclopentyl) carbamate (E9) (700 mg, 1.43 mmol, 1.0 eq. ) , NaNO ₂ (295 mg, 4.28 mmol, 3 eq. ) and AgOTf (36 mg, 0.14 mmol, 0.1 eq. ) in CHCl ₃ (10 mL) was stirred at 0℃, and then acetic acid (2.5 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. Then the reaction mixture was poured into water (10 mL) and diluted with saturated NaHCO ₃ aq. (15 mL) and extracted with DCM (20 mL x 3) . The organic layers were washed with brine (20 mL) , dried over Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give E10 (500 mg, yield 92%) as a white solid. LC-MS: 521 (M+1) ⁺.

Step D: methyl ( (1S, 2R) -2- ( (S) -1- (3-fluorophenyl) -1- (piperidin-4-yl) -2- (1H-pyrazol-1-yl) ethyl) cyclopentyl) carbamate (E11)

A mixture of 1- ( (S) -2- (1-benzylpiperidin-4-yl) -2- (3-fluorophenyl) -2- ( (1R, 2S) -2- ( (methoxycarbonyl) amino) cyclopentyl) ethyl) -1H-pyrazole2-oxide (E10) (500 mg, 0.96 mmol) and 20%Pd (OH) ₂/C (100 mg, 20%w/wt) in CF ₃CH ₂OH (15 ml) was stirred at room temperature under H ₂ atmosphere (1 atm) for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give E11 (270 mg, yield 68%) as a white solid. LC-MS: 415 (M+1) ⁺.

EXAMPLE 5

Synthesis of Intermediate A14

Sythesis of cyclopropyl (4-fluorophenyl) sulfane (A13) : To a stirred solution of A12 (2.0 mL, 18.7 mmol) in DMSO (50 mL) under an N ₂ atmosphere were added cyclopropyl bromide (1.6 mL, 20.6 mmol) and t-BuONa (4.49 g, 46.8 mmol) . Then the reaction mixture was heated at 80° C for 24 hours. After cooling to room temperature, the mixture was poured into H ₂O (250 mL) and extracted with Et ₂O three times. The combined organic phases were washed with brine, dried over Na ₂SO ₄ and concentrated in vacuum. The residue was purified column chromatography (silica gel, hexane/EtOAc 100: 1 to 15: 1) to give A13 (1.32 g, 42%) .

Synthesis of 1- (cyclopropylsulfonyl) -4-fluorobenzene (A14) : m-CPBA (4.28 g, 17.4 mmol, 70%) at 0 ℃ was added to a stirred solution of A13 (1.46 g, 8.68 mmol) in DCM (80 mL) . After 2 hours, the reaction mixture was quenched with 1M NaOH (aq. ) and extracted with DCM three times. The combined organic phases were washed with brine, dried over Na ₂SO ₄ and concentrated in vacuum. The residue was purified column chromatography (silica gel, hexane/EtOAc 10: 1 to 1: 1) to give A14 (1.58 g, 91%) . ¹H NMR (400 MHz, CDCl ₃) δ 7.97 –7.91 (m, 2H) , 7.28 –7.22 (m, 2H) , 2.47 (tt, 1H) , 1.40 –1.34 (m, 2H) , 1.11 –1.03 (m, 2H) .

EXAMPLE 6

Preparation of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (4-cyano-3- (dimethylcarbamoyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (3-hydroxy-3-methylazetidin-1-yl) ethyl) cyclopentyl) carbamate (Cpd 6)

Step A: methyl ( (1S, 2R) -2- ( (S) - (1-benzylpiperidin-4-yl) (cyano) (3-fluorophenyl) methyl) cyclopentyl) carbamate (J-1)

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 by rotary evaporation to produce a residue that was used without purification. At 0℃, dimethyl dicarbonate (410 mg, 3.05 mmol) was added to a solution of crude S7-deprotected 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 J-1 (770 mg) . ESI-MS calculated for C ₂₇H ₃₃FN ₃O ₂ [M+H] ⁺ = 450.25, found: 450.45.

Step B: methyl ( (1S, 2R) -2- ( (S) -2-amino-1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) ethyl) cyclopentyl) carbamate (J-2)

At 0℃, diisobutylaluminium hydride (3.90 mL, 6.86 mmol) was added to a solution of J-1 (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 and brine, and extracted 3 times. The combined organic layers were dried over sodium sulfate, filtered through celite, concentrated, and vacuumed to remove the residual solvent. This crude product was re-dissolved in methanol and treated with NaBH ₄ (130 mg, 3.43 mmol) . After stirring overnight, the reaction was quenched with 2M NaOH, diluted with ethyl acetate, and brine, 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 J-2 (775 mg) . ESI-MS calculated for C ₂₇H ₃₇FN ₃O ₂ [M+H] ⁺ = 454.28, found: 454.41.

Step C: methyl ( (1S, 2R) -2- ( (S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2- (3-hydroxy-3-methylazetidin-1-yl) ethyl) cyclopentyl) carbamate (J-4)

In a microwave reaction tube, compound J-2 (300 mg, 0.662 mmol) and epoxide J-3 (70 mg, 0.662 mmol) were dissolved in n-butanol (6 mL) , and the reaction was microwaved at 140℃ for 20 hours. After cooling, the reaction was diluted with MeOH/H2O (1: 1) , acidified with trifluoroacetic acid and purified by prep-HPLC to produce J-4 (140 mg) . ESI-MS calculated for C ₃₁H ₄₃FN ₃O ₃ [M+H] ⁺ = 524.69, found: 524.22.

Step D: methyl ( (1S, 2R) -2- ( (S) -1- (3-fluorophenyl) -2- (3-hydroxy-3-methylazetidin-1-yl) -1- (piperidin-4-yl) ethyl) cyclopentyl) carbamate (J-5)

Compound J-4 (140 mg, 0.267 mmol) was dissolved with 4 mL of methanol, and the solution was purged twice by vacuuming briefly followed by adding nitrogen atmosphere. Pd/C (50 mg, 10%wt) was quickly added, then the reaction was vacuumed and put under H2 atmosphere for 2 hours. After the Pd/C catalyst was filtered off through celite, the solvent was removed by rotary evaporation to give the product J-5 (113 mg) , which was used without further purification. ESI-MS calculated for C ₂₄H ₃₇FN ₃O ₃ [M+H] ⁺ = 434.57, found: 434.23.

Step E: methyl ( (1S, 2R) -2- ( (S) -1- (1- (2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (3-hydroxy-3-methylazetidin-1-yl) ethyl) cyclopentyl) carbamate (J-7)

Triethylamine (0.096 mL, 0.692 mmol) was added to a solution of J-5 (100 mg, 0.231 mmol) in 1, 2-dichloroethane (2.5 mL) and the reaction stirred for 10 minutes. Compound J-6 (73 mg, 0.347 mmol) was added to the reaction and stirred for 1 hour. Next, sodium triacetoxyborohydride (195 mg, 0.924 mmol) was added, and the reaction stirred. After 2 hours the reaction was complete, as detected by UPLC, so it was diluted with methanol, concentrated, and then purified by prep-HPLC. The solvent was removed by rotoevaporation, and the residue was treated with CF ₃CO ₂H (1mL) to remove the Boc protection on the amine. After 10 minutes the trifluoracetic acid was removed, and the remaining product was dissolved in acetonitrile, water, and lyophilized to give J-7 (94 mg) . ESI-MS calculated for C ₃₀H ₄₆FN ₄O ₃ [M+H] ⁺ = 529.71, found: 529.53.

Step F: methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (4-cyano-3- (dimethylcarbamoyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (3-hydroxy-3-methylazetidin-1-yl) ethyl) cyclopentyl) carbamate (Cpd 6)

Potassium carbonate (20 mg, 0.144 mmol) was added to a solution of J-7 (19 mg, 0.0360 mmol) and J-8 (10.4 mg, 0.0540 mmol) in DMSO (0.5 mL) , and the reaction was heated to 90℃. After 1 hour the reaction was complete, so it was cooled to room temperature and water, methanol, and trifluoroacetic acid were added. The solution was purified by prep-HPLC to produce Cpd 6 (14 mg) as white powder. ¹H NMR (400 MHz, Methanol-d ₄) δ 7.52 (d, 1H) , 7.45 (q, 1H) , 7.19 –7.08 (m, 2H) , 7.06 –6.97 (m, 1H) , 6.48 (dd, 1H) , 6.36 (d, 1H) , 4.72 –4.61 (m, 1H) , 4.55 –4.39 (m, 2H) , 4.32 –4.19 (m, 2H) , 4.04 (s, 2H) , 3.91 (s, 2H) , 3.86 (s, 1H) , 3.60 –3.51 (m, 1H) , 3.46 –3.41 (m, 1H) , 3.22 (s, 3H) , 3.11 (s, 3H) , 2.92 (s, 3H) , 2.87 –2.67 (m, 4H) , 2.66 –2.57 (m, 2H) , 2.44 –2.33 (m, 2H) , 2.16 –2.04 (m, 2H) , 2.04 –1.94 (m, 2H) , 1.84 –1.59 (m, 6H) , 1.53 (s, 2H) , 1.45 –1.29 (m, 2H) , 0.94 –0.80 (m, 1H) . ESI-MS calculated for C ₄₀H ₅₄FN ₆O ₄ [M+H] ⁺ = 701.90, found: 701.62.

EXAMPLE 7

Preparation of methyl ( (1S, 2R) -2- (1- (1- (2- (4- (cyclopropylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -2- (dimethylamino) -1- (3-fluorophenyl) -2-oxoethyl) cyclopentyl) carbamate (Cpd 45)

Synthesis of A1

To a solution of S7 (15 g, 30.5 mmol) in methanol/THF (150/75 mL) was added acetic acid (3.5 mL, 61.1 mmol) and Pd/C (1.5 g, 10%wt) under N ₂ atomsphere. Then the mixture was stirred at room temperature under hydrogen atmosphere (normal pressure) . After 4 hours, the Pd/C catalyst was filtered off, and the solvent was removed by rotary evaporation to give A1, which was used without further purification.

Synthesis of A2

A1 obtained in last step was dissolved in DCM (250 mL) . Triethylamine (10.6 mL, 76.3 mmol) and N- (Benzyloxycarbonyloxy) succinimide (7.6 g, 30.5 mmol) were added subsequently. Then the mixture was stirred for 1 h at room temperature. Solvent was removed by rotary evaporation after stirring under room temperature for 1 h. The mixture was purified by Flash Column Chromatography (hexane/EtOAc as eluent) to give A2 as white foam.

Synthesis of Pt Catalyst

[PtH (PMe ₂OH) (PMe ₂O) ₂H] was made according to procedure set forth in Tetrahedron Letter, 1995, 36, 8657. The reaction time was prolonged to 5 hours.

Synthesis of A3 (see J. Org. Chem. 2004, 69, 2327)

To a solution of A2 (3.93 g, 6.83 mmol) in ethanol/H ₂O (30/10 mL) was added [PtH (PMe ₂OH) (PMe ₂O) ₂H] (146 mg, 0.341 mmol) . The mixture was heated in a sealed tube under 120 ℃ for 4 days. Solvent was removed by rotary evaporation, and the mixture was purified by Flash Column Chromatography (hexane/EtOAC as eluent) to give A3 as white foam (1.33 g, 34%, 62%b.r.s.m) .

Synthesis of A4

A3 (1.33 g, 2.40 mmol) was dissolved in dichloromethane (7 mL) and trifluoroacetic acid (3.5 mL) was added . After stirring for 1 hour at room temperature, the reaction mixture was concentrated under vacuum to give A4, which was used without further purification.

Synthesis of A5

A4 obtained in last step was dissolved in acetonitrile/H ₂O (12/6 mL) . K ₂CO ₃ (2.0 g, 14.4 mmol) and allyl bromide (0.83 mL, 9.60 mmol) were added subsequently. The mixture was stirred overnight at room temperature. Water was then added, and the mixture was extracted three times with EtOAC, concentrated and purified by Flash Column Chromatography (DCM/MeOH as eluent) to give A5 (1.27 g, 99%) as white solid.

Synthesis of A6

A5 (250 mg, 0.47 mmol) was dissolved in THF (5 mL) . NaH (68 mg, 2.82 mmol) was added under 0 ℃, and the mixture was stirred for 30 minutes. MeI (116 μL, 1.88 mmol) was then added, and the mixture was stirred overnight. Water was then added, and the mixture was extracted three times with EtOAC, concentrated and purified by Flash Column Chromatography (DCM/MeOH as eluent) to give A6 (150 mg, 58%) .

Synthesis of A7

A6 (150 mg, 0.274 mmol) was dissolved in DMF (2 mL) . NaH (44 mg, 1.10 mmol) was added under 0 ℃, and the mixture was stirred for 30 minutes. MeI (101 μL, 1.64 mmol) was then added and the mixture was stirred overnight. Water was then added, and the mixture was extracted three times with EtOAC, concentrated and purified by Flash Column Chromatography (DCM/MeOH as eluent) to give A7 (103 mg, 67%) .

Synthesis of A8

Under an argon atmosphere, Pd (PPh ₃) ₄ (51 mg, 0.44 mmol) and Barbituric acid (400 mg, 2.64 mmol) were added to a solution of A7 (245 mg, 0.44 mmol) in DCM (6 mL) . The mixture was heated under 35 ℃ for 5 hours before cooled down to room temperature. DIPEA (768 μL, 4.4 mmol) and dimethyl dicarbonate (118 mg, 0.88 mmol) were added. After stirring at room temperature for 2 hours, water was added, and the mixture was extracted three times with DCM, concentrated and purified by Flash Column Chromatography (DCM/MeOH as eluent) to give A8 (145 mg, 61%) .

Synthesis of A9

To a solution of A8 (145 mg, 0.268 mmol) in methanol (4 mL) was added acetic acid (31 μL, 0.536 mmol) and Pd/C (40 mg, 10%wt) under N ₂ atomsphere. The mixture was stirred at room temperature under hydrogen atmosphere (normal pressure) . After 4 hours, the Pd/C catalyst was filtered off, and the solvent was removed by rotary evaporation to give amide A9, which was used without further purification.

Synthesis of A11

To a solution of A9 (110 mg, 0.272 mmol) in DCE (3 mL) was added Et ₃N (94 μL, 0.679 mmol) , AcOH (47 μL, 0.816 mmol) and A10 (86 mg, 0.408 mmol) subsequently. After 3 hours, NaBH (OAc) ₃ (173 mg, 0.816 mmol) was added. The mixture was stirred overnight, quenched with water, and concentrated under vacuum. The residue was purified by reverse phase preparative HPLC to give the title compound A11 (132 mg, 81%yield) as a salt of trifluoroacetic acid.

Synthesis of methyl ( (1S, 2R) -2- (1- (1- (2- (4- (cyclopropylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -2- (dimethylamino) -1- (3-fluorophenyl) -2-oxoethyl) cyclopentyl) carbamate (Cpd 45)

Compound A11 (60 mg, 0.100mmol) was dissolved in DCM (2 mL) , then trifluoroacetic acid (0.2 mL) was added. After stirring for 2 hours at room temperature, the reaction mixture was evaporated to give the crude title product without further purification.

The crude deprotection product and K ₂CO ₃ (55 mg, 0.400 mmol) were added to a solution of the intermediate A14 (30 mg, 0.150 mmol) in DMSO (1.5 mL) . The mixture was stirred at 80 ℃ overnight. The mixture was quenched with water and purified by reverse phase preparative HPLC to give the trifluoroacetate salt of Cpd 45 (42mg, 61%yield) . ¹H NMR (400 MHz, Acetonitrile-d ₃) δ 11.18 (s, 1H) , 7.71 –7.59 (m, 2H) , 7.53 –7.32 (m, 1H) , 7.19 (s, 1H) , 7.14 –6.92 (m, 2H) , 6.54 –6.44 (m, 2H) , 5.74 (s, 1H) , 4.03 (s, 2H) , 3.92 (d, 2H) , 3.78 (s, 1H) , 3.64 (s, 3H) , 3.52 (d, 3H) , 3.13 (s, 2H) , 2.92 (s, 3H) , 2.68 –2.58 (m, 5H) , 2.52 –2.45 (m, 3H) , 2.19 (s, 2H) , 2.08 (d, 1H) , 1.89 (d, 1H) , 1.51 (d, 3H) , 1.37 (s, 2H) , 1.30 (s, 2H) , 1.16 –1.08 (m, 2H) , 1.01 –0.91 (m, 2H) . ESI-MS calculated for C ₃₇H ₅₀FN ₄O ₅S [M + H] ⁺ = 681.35, found: 681.19.

EXAMPLE 8

Preparation of methyl ( (1S, 2R) -2- (1- (1- (2- (4-cyanophenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2-methoxyethyl) cyclopentyl) carbamate (Cpd 24)

Synthesis of tert-butyl ( (1S, 2R) -2- ( (S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2-iminoethyl) cyclopentyl) carbamate (S9)

S7 (2g, 4.1 mmol) an anhydrous toluene (40 ml) was added to the flask and cooled to 0 ℃ in an ice-bath. Diisobutylaluminiumhydride (25%in toluene, 10.8 mL, 16.3 mmol) was injected into the reaction mixture with syringe slowly at 0 ℃ with stirring. The ice-bath was removed, and the reaction was monitored using UPLC-Mass (about 4 hours) . After the mass (492) of S7 disappeared, 20 ml of NaOH (1M) solution was added slowly into the reaction mixture at 0 ℃ to quench the reaction. After stirring for 5 minutes, the ice-bath was removed, and 20 ml saturated brine was added. After addition of about 50 mL EtOAc, a gel formed. The gel was filtered through celite, washed with EtOAc, and the solvent combined. The solution was extracted with EtOAc and DCM twice. The organic solvent was dried with Na ₂SO ₄, filtered, and concentrated under rotatory vacuum to give crude product S9 without further purification.

Synthesis of tert-butyl ( (1S, 2R) -2- ( (S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2-oxoethyl) cyclopentyl) carbamate (B1)

S9 (obtained last step) was dissolved in 1, 4-dioxane (30 mL) . H ₂O and acetic acid (5 mL) were added, and the mixture was heated under reflux overnight. Saturated NaHCO ₃ solution was than added to the mixture carefully, and the solution was extracted with three times. The organic solvent was dried with Na ₂SO ₄, filter, and concentrated under rotatory vacuum to give crude product B1 (1.86 g) without further purification. ESI-MS calculated for C ₃₀H ₄₀FN ₂O ₃ [M + H] ⁺ = 495.30, found: 495.51.

Synthesis of C3

C3 was prepared from B1 according to the procedure described for the preparation of A5.

Synthesis of C4

To a solution of C3 (400 mg, 0.77 mmol) in MeOH/THF (9/3mL) , NaBH ₄ (114 mg, 3.08 mmol, 4 eq) was added slowly at 0 ℃, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and diluted with water. The solution was extracted with EtOAC. The organic solvent was dried with Na ₂SO ₄, filtered, and concentrated under rotatory vacuum. The mixture was purified by Flash Column Chromatography (DCM/MeOH as eluent) to give C4 as white foam.

Synthesis of C5

C4 (278 mg, 0.535 mmol) was dissolved in THF (3 mL) . NaH (43 mg, 1.07 mmol) was added under 0 ℃, and the mixture was stirred for 30 minutes. MeI (100 μL, 1.61 mmol) was then added, and the mixture was stirred overnight. Water was then added, and the mixture was extracted three times with EtOAc, concentrated and purified by Flash Column Chromatography (DCM/MeOH as eluent) to give C5.

Synthesis of C7

C7 was prepared according to the procedure described for the preparation of A9.

Synthesis of methyl ( (1S, 2R) -2- (1- (1- (2- (4-cyanophenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2-methoxyethyl) cyclopentyl) carbamate (Cpd 24)

Cpd 24 was prepared from C7 according to the procedure described for the preparation of Cpd 45. ESI-MS calculated for C ₃₄H ₄₄FN ₄O ₃ [M + H] ⁺ = 575.34, found: 575.20.

EXAMPLE 9

Synthesis of methyl ( (1S, 2R) -2- (1- (1- (2- (4- (cyclopropylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2-hydroxyethyl) cyclopentyl) carbamate (Cpd 23)

Synthesis of D1

Starting with B1, D1 was prepared according to the procedure described for the preparation of C4.

Synthesis of D4

Starting with D1, D4 was prepared according to the procedure described for the preparation of B5.

Cpd 23 was prepared from D4 according to the procedure described for the preparation of Cpd 45. ESI-MS calculated for C ₃₅H ₄₇FN ₃O ₅S [M + H] ⁺ = 640.32, found: 640.25.

EXAMPLE 10

Synthesis of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (4- (cyclopropylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3, 5-difluorophenyl) -2- (1H-imidazol-1-yl) ethyl) cyclopentyl) carbamate (Cpd 220)

Intermediate F3 was prepared according to the procedures described for the preparation of S7 (the corresponding mono-F analog of F3) .

Compound F3 (1.2 g, 2.4 mmol) was dissolved in dichloromethane (15 mL) , and trifluoroacetic acid (5 mL) was added slowly at 0 ℃. After stirring for 2 hours at room temperature, the reaction mixture was concentrated under vacuum, and redissolved in 50 mL of DCM.

A21 (2g) (resin, Sigma catalog no. 216410) was added and stirred for 30 min to neutralize the TFA. Then, the resin was filtered, and the organic solvent was concentrated to give the crude product F5 without further purification. ESI-MS: 424.7.

F5 (402 mg, 0.95 mmol) was dissolved in dry dichloromethane (10 mL) . DIPEA (0.66 mL, 3.8 mmol) and dimethyl dicarbonate (152 mg, 1.1 mmol, ) were added at 0 ℃. After stirring for 2 hours at room temperature, the reaction mixture was concentrated under vacuum. The residue was purified by reverse phase preparative HPLC to give F6. ESI-MS: 482.5.

F6 (294 mg, 0.61 mmol) was added to a dry RB-flask which was vacuumed under N ₂ atmosphere. Anhydrous toluene (5 ml, Sigma catalog no. 244511) was added to the flask, and the flask was cooled to 0 ℃ in the ice-bath. Diisobutylaluminiumhydride (25%in toluene, 1.6 mL) was injected into the reaction mixture with a syringe slowly at 0 ℃ with stirring. Then the ice-bath was removed, and the reaction was monitored using UPLC-Mass (about 4 hours) . 2 ml of NaOH (1M) solution was added slowly into the reaction mixture at 0 ℃ to quench the reaction. After stirring for 5 minutes, the ice-bath was removed, and 2 ml saturated brine was added. After about 10 mL EtOAc was added, a gel formed. The gel was filtered through celite, washed with EtOAc, and the solvent combined. The solution was extracted with EtOAc and DCM twice respectively. The organic solvent was dried with Na ₂SO ₄, filtered, and concentrated under rotatory vacuum. Then DCM (5 ml) was added and concentrated again. Then the residue was redissolved in MeOH (10 mL) , and NaBH ₄ (46 mg, 1.2 mmol) was added slowly at 0 ℃. The reaction mixture was stirred at room temperature, and the reaction was monitored using UPLC-Mass. The reaction mixture was concentrated and diluted with water. The solution was extracted with EtOAc and DCM twice respectively. The organic solvent was dried with Na ₂SO ₄, filter, and concentrated under rotatory vacuum to give crude product F7. ESI-MS: 382.9.

To a solution of the intermediate F7 (200 mg g, 0.52 mmol) in methanol (10 mL) was added Glyoxal (40%aqueous solutionsolution, 0.24 mL, 2.6 mmol) , ammonium acetate (200 mg, 2.6 mmol) and formaldehyde (37%aqueous solutionsolution, 0.43 mL, 5.2 mmol) at room temperature. The mixture was stirred at 60 ℃ for 1～2 days. Then, the mixture was concentrated and was purified by reverse phase preparative HPLC to give F8. ESI-MS: 433.8.

Cpd 220 was prepared from F8 according to the procedure described for the preparation of Cpd 45. 1H NMR (400 MHz, Methanol-d ₄) δ 8.98 (s, 1H) , 7.71 –7.62 (m, 2H) , 7.61 –7.51 (m, 2H) , 7.39 –7.24 (m, 2H) , 7.07 (tt, 1H) , 6.63 –6.42 (m, 2H) , 5.05 (q, 2H) , 4.05 (s, 2H) , 3.92 (s, 2H) , 3.58-3.50 (m, 4H) , 3.46-3.43 (m, 1H) , 2.92 –2.79 (m, 1H) , 2.77 –2.38 (m, 8H) , 2.30 –2.17 (m, 1H) , 2.10 –1.88 (m, 2H) , 1.65-1.56 (m, 1H) , 1.51 –1.28 (m, 7H) , 1.20-1.14 (m, 3H) , 1.03-1.00 (m, 2H) .

EXAMPLE 11

Preparation of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (4-cyanophenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- ( (methoxycarbonyl) amino) ethyl) cyclopentyl) carbamate (Cpd 36)

G1 was prepared from S7 according to the procedure described for the preparation of F7.

G1 (908 mg, 2 mmol) was dissolved in dry dichloromethane (20 mL) . Then, DIPEA (1.4 mL, 8 mmol) and dimethyl dicarbonate (321 mg, 2.4 mmol, ) were added at 0 ℃. After stirring for 2 hours at room temperature, the reaction mixture was concentrated under vacuum. The residue was purified by reverse phase preparative HPLC to give G2. ESI-MS: 512.9.

To a solution of G2 (500 mg, 0.98 mmol) in methanol (15 mL) was added acetic acid (31 μL, 0.536 mmol) and Pd/C (150 mg, 10%wt) under N ₂ atomsphere. The mixture was stirred at room temperature under hydrogen atmosphere (normal pressure) . After 4 hours, the Pd/C catalyst was filtered off, and the solvent was removed by rotary evaporation to give G3, which was used without further purification. ESI-MS: 422.7.

Cpd 36 was prepared from G3 according to the procedure described for the preparation of Cpd 45. 1H NMR (400 MHz, Methanol-d ₄) δ 7.48 –7.40 (m, 2H) , 7.40 –7.34 (m, 1H) , 7.27 –7.14 (m, 2H) , 7.06 –6.95 (m, 1H) , 6.52 –6.32 (m, 2H) , 4.17 –3.95 (m, 3H) , 3.90 –3.77 (m, 4H) , 3.65 (s, 3H) , 3.61 –3.42 (m, 6H) , 2.76-2.73 (m, 1H) , 2.68 –2.54 (m, 3H) , 2.50-2.48 (m, 1H) , 2.42 –2.32 (m, 2H) , 2.27-2.20 (m, 2H) , 1.99 –1.80 (m, 2H) , 1.70 –1.17 (m, 7H) . ESI-MS: 618.91.

EXAMPLE 12

Preparation of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (4-cyano-3- ( ( (E) -3- (methylsulfonyl) allyl) oxy) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) carbamate (Cpd 187)

Step A: (E) -3-bromo-1- (methylsulfonyl) prop-1-ene

A mixture of 1, 2-dibromo-3- (methylsulfonyl) propane (22 g, 78.58 mmol, 1.0 eq.; Ref: Journal of Organic Chemistry; 48; 23; (1983) ; p. 4393 -4394) and Na ₂CO ₃ (16.66 g, 157.15 mmol, 2.0 eq. ) in acetone (250 mL) was stirred and refluxed at 60℃ for 2 hours. The mixture was filtered and concentrated under reduced pressure. Then the mixture was diluted with H ₂O (30 mL) and extracted with DCM (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 (E) -3-bromo-1- (methylsulfonyl) prop-1-ene (13 g, yield 83%) as a yellow solid. LC-MS: 199 (M+H) ⁺.

Step B: (E) -4-fluoro-2- ( (3- (methylsulfonyl) allyl) oxy) benzonitrile

To the solution of 4-fluoro-2-hydroxybenzonitrile (1 g, 7.29 mmol, 1.0 eq. ) and (E) -3-bromo-1- (methylsulfonyl) prop-1-ene (1.45 g, 7.29 mmol, 1.0 eq. ) in DMF (15 mL) was added K ₂CO ₃ (3.02 g, 21.88 mmol, 3.0 eq. ) at room temperature. The mixture was stirred at room temperature for 3 hours. The 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 (E) -4-fluoro-2- ( (3- (methylsulfonyl) allyl) oxy) benzonitrile (60 mg, yield 3%) as a yellow solid. LC-MS: 256 (M+H) ⁺.

Step C: methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (4-cyano-3- ( ( (E) -3- (methylsulfonyl) allyl) oxy) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) carbamate (Cpd 187)

To a solution 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 (60 mg, 0.115 mmol, 1.0 eq. ) and (E) -4-fluoro-2- ( (3- (methylsulfonyl) allyl) oxy) benzonitrile (32 mg, 0.126 mmol, 1.1 eq. ) in CH ₃CN (10 mL) was added K ₂CO ₃ (95 mg, 0.687 mmol, 6.0 eq. ) . The mixture was stirred at 80℃ overnight under N ₂ atmosphere. The 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 to give Cpd 187 (20 mg, yield 23%) as a white solid. LC-MS: 759 (M+H) ⁺. ¹H NMR (400 MHz, Methanol-d ₄) δ 7.49 -7.42 (m, 2H) , 7.38 (d, 2H) , 7.11 (t, 1H) , 7.02 (d, 1H) , 6.74 (d, 2H) , 6.16 (dd, 1H) , 6.11 (d, 1H) , 5.16 (td, 1H) , 4.59 (d, 1H) , 4.38 (d, 1H) , 4.03 -3.96 (m, 6H) , 3.92 -3.79 (m, 3H) , 3.64 (s, 3H) , 3.09 -3.02 (m, 1H) , 2.99 (s, 3H) , 2.96 -2.89 (m, 1H) , 2.87 -2.76 (m, 1H) , 2.67 -2.58 (m, 1H) , 2.51 (s, 3H) , 2.44 -2.35 (m, 2H) , 2.34 -2.23 (m, 1H) , 2.17 -2.06 (m, 3H) , 2.00 -1.85 (m, 3H) , 1.77 -1.69 (m, 1H) , 1.53 -1.45 (m, 1H) , 1.37 -1.31 (m, 2H) , 1.22 -1.16 (m, 1H) , 0.84 -0.66 (m, 1H)

EXAMPLE 13

Preparation of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (5-cyano-4- (dimethylcarbamoyl) pyrimidin-2-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 195)

Step A: 5-bromo-N, N-dimethyl-2- (methylthio) pyrimidine-4-carboxamide

To a mixture of 5-bromo-2- (methylthio) pyrimidine-4-carboxylic acid (3 g, 12 mmol) , HATU (6.87 g, 18 mmol) and DIPEA (6 mL, 36 mmol) in THF (20 ml) was added dimethylamine (2 M in THF, 12 ml, 24 mmol) at room temperature. The mixture was stirred overnight. The reaction was concentrated, and the residue was purified by flash column chromatography on silica gel to give 5-bromo-N, N-dimethyl-2- (methylthio) pyrimidine-4-carboxamide (2.8 g, yield 84%) as a white solid. LC-MS: 276/278 (M+H) ⁺.

Step B: 5-cyano-N, N-dimethyl-2- (methylthio) pyrimidine-4-carboxamide

A mixture of 5-bromo-N, N-dimethyl-2- (methylthio) pyrimidine-4-carboxamide (1.1 g, 4 mmol) , Zn (CN) ₂ (940 mg, 8 mmol) , Pd (t-Bu ₃P) ₂ (204 mg, 0.4 mmol) and dppf (221 mg, 0.4 mmol) in DMAc (10 ml) was stirred at 100℃ overnight under N ₂ atmosphere. 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 5-cyano-N, N-dimethyl-2- (methylthio) pyrimidine-4-carboxamide (800 mg, yield 90%) as a white solid. LC-MS: 223 (M+H) ⁺.

Step C: 5-cyano-N, N-dimethyl-2- (methylsulfonyl) pyrimidine-4-carboxamide

To a mixture of 5-cyano-N, N-dimethyl-2- (methylthio) pyrimidine-4-carboxamide (440 mg, 1.98 mmol) in DCM (10 ml) was added m-CPBA (1 g, 5.94 mmol) in portions at 0℃. After addition, the mixture was stirred at room temperature overnight. The mixture was diluted with water (10 mL) and extracted with DCM (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 flash column chromatography on silica gel to give 5-cyano-N, N-dimethyl-2- (methylsulfonyl) pyrimidine-4-carboxamide (100 mg, yield 20%) as a white solid. LC-MS: 255 (M+H) ⁺.

Step D: methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (5-cyano-4- (dimethylcarbamoyl) pyrimidin-2-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 195)

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 (50 mg, 0.095 mmol) , 5-cyano-N, N-dimethyl-2- (methylsulfonyl) pyrimidine-4-carboxamide (29 mg, 0.115 mmol) and K ₂CO ₃ (39 mg, 0.286 mmol) in MeCN (10 ml) was stirred at 80℃ overnight. The reaction mixture was concentrated, and the residue was purified by Prep-TLC and RP-prep-HPLC to give Cpd 195 (20 mg, yield 30%) as a white solid. LC-MS: 698 (M+H) ⁺. 1H NMR (400 MHz, Methanol-d ₄) δ 8.63 (s, 1H) , 7.49 –7.41 (m, 2H) , 7.36 (d, 1H) , 7.10 (t, 1H) , 6.71 (d, 1H) , 6.66 (d, 1H) , 4.56 (d, 1H) , 4.36 (d, 1H) , 4.22 (d, 2H) , 4.09 (d, 2H) , 4.03 -3.93 (m, 1H) , 3.60 (s, 3H) , 3.10 (s, 3H) , 3.03 –2.79 (m, 6H) , 2.75 –2.68 (m, 1H) , 2.65 –2.60 (m, 1H) , 2.45 (s, 3H) , 2.41 –2.35 (m, 2H) , 2.26 –2.20 (m, 1H) , 2.12 –1.99 (m, 3H) , 1.90 –1.77 (m, 3H) , 1.70 (d, 1H) , 1.54 –1.44 (m, 1H) , 1.39 –1.18 (m, 2H) , 1.24 –1.13 (m, 2H) , 0.78 –0.66 (m, 1H) .

EXAMPLE 14

Preparation of 1- ( (1S, 2R) -2- ( (S) -1- (1- (2- (3- ( (dimethylamino) methyl) -4- (methylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) -3-methylimidazolidin-2-one (Cpd 201)

Step A: tert-butyl ( (1S, 2R) -2- ( (S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) carbamate

A mixture of tert-butyl ( (1S, 2R) -2- ( (S) -2-amino-1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) ethyl) cyclopentyl) carbamate (18 g, 39.683 mmol, 1 eq. ) , oxaldehyde (10 mL, 87.302 mmol, 2 eq. ) , acetaldehyde (23.4 mL, 416.667 mmol, 10 eq. ) , and NH ₄OAC (6.73 g, 87.302 mmol, 2 eq. ) in MeOH (135 mL) was stirred at 50℃ in a sealed-tube for 36 hours. The reaction mixture was cooled to 25℃, poured into 300 ml of water, and extracted with EtOAC (400ml x 2) . The combined organic phrases were washed by sat. NaHCO ₃. aq. (400 ml) , 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 ( (1S, 2R) -2- ( (S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) carbamate (5.6 g, yield 41%) as a yellow oil. LC-MS: 561 (M+H) ⁺.

Step B: tert-butyl ( (1S, 2R) -2- ( (S) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) -1- (piperidin-4-yl) ethyl) cyclopentyl) carbamate

To a mixture of tert-butyl ( (1S, 2R) -2- ( (S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) carbamate (5.6 g, 9.986 mmol) in CF ₃CH ₂OH (200 mL) was added 20%Pd (OH) ₂/C (1.8 g, 20%w/wt) . The reaction was stirred at 25 ℃ under H ₂ atmosphere (1 atm) for 72 hours. The solution was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl ( (1S, 2R) -2- ( (S) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) -1- (piperidin-4-yl) ethyl) cyclopentyl) carbamate (4.5 g, yield 95%) as a white solid. LC-MS: 471 (M+H) ⁺.

Step C: benzyl 6- (4- ( (S) -1- ( (1R, 2S) -2- ( (tert-butoxycarbonyl) amino) cyclopentyl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) piperidin-1-yl) -2-azaspiro [3.3] heptane-2-carboxylate

A solution of tert-butyl ( (1S, 2R) -2- ( (S) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) -1- (piperidin-4-yl) ethyl) cyclopentyl) carbamate (4.8 g, 10.199 mmol, 1 eq. ) , AcOH (1.753 mL, 30.597 mmol, 3 eq. ) and benzyl 6-oxo-2-azaspiro [3.3] heptane-2-carboxylate (1.08 g, 11.219 mmol, 1.1 eq. ) in DCM (40 mL) was stirred for 2 hours at room temperature. NaBH (OAc) ₃ (1.03 g, 30.597 mmol, 3 eq. ) was added, and the solution was stirred at room temperature overnight. The reaction was washed with NaHCO ₃ (40 mL) and brine (40 mL) . The organic layer concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel to give benzyl 6- (4- ( (S) -1- ( (1R, 2S) -2- ( (tert-butoxycarbonyl) amino) cyclopentyl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) piperidin-1-yl) -2-azaspiro [3.3] heptane-2-carboxylate (3.2 g, yield 57%) as a yellow solid. LC-MS: 700 (M+H) ⁺.

Step D: tert-butyl ( (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

To a solution of benzyl 6- (4- ( (S) -1- ( (1R, 2S) -2- ( (tert-butoxycarbonyl) amino) cyclopentyl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) piperidin-1-yl) -2-azaspiro [3.3] heptane-2-carboxylate (3.2 g, 5.81 mmol) and 20%Pd (OH) ₂-C (0.64 g, 20%w/wt) in 2, 2, 2-trifluoroethan-1-ol (30 mL) was stirred under H ₂ atmosphere (1 atm) for 16 hours. The reaction mixture was filtered, and concentrated under reduced pressure to give tert-butyl ( (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 (3 g, yield 92%) as a yellow solid. LC-MS: 566 (M+H) ⁺.

Step E: 1- (5-fluoro-2- (methylsulfonyl) phenyl) -N, N-dimethylmethanamine

To a solution of 1- (2-bromo-5-fluorophenyl) -N, N-dimethylmethanamine (400 mg, 1.73 mmol, 1.0 eq., Ref: Journal of the American Chemical Society, 2017, vol. 139, # 28, p. 9519 -9522) in NMP (5 mL) was added sodium methanesulfinate (194 mg, 1.89 mmol, 1.09 eq. ) , CuCl (85 mg, 0.86 mmol, 0.5 eq. ) and quinoline (111 mg, 0.86 mmol, 0.5 eq. ) . The mixture was stirred at 110℃ for 3 hours under N ₂ atmosphere. The reaction was quenched with water (15 mL) and extracted with EtOAc (15 mL x 2) . The organic layers were washed with brine (15 mL) , dried over Na ₂SO ₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 1- (5-fluoro-2- (methylsulfonyl) phenyl) -N, N-dimethylmethanamine (80 mg, yield 20%) as a white solid. LC-MS: 232 (M+H) ⁺.

Step F: tert-butyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (3- ( (dimethylamino) methyl) -4- (methylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) carbamate

To a solution of tert-butyl ( (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 (3 g, 5.302 mmol, 1eq. ) and 1- (5-fluoro-2- (methylsulfonyl) phenyl) -N, N-dimethylmethanamine (1.47 g, 6.363 mmol, 1.2 eq. ) in DMF (30 mL) was added K ₂CO ₃ (1.47 g, 10.605 mmol, 2 eq. ) . The reaction mixture was stirred under N ₂ atmosphere at 80℃ overnight. Then the mixture was diluted with H ₂O (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 tert-butyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (3- ( (dimethylamino) methyl) -4- (methylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4- yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) carbamate (2.3 g, yield 56%) as a yellow oil. LC-MS: 777 (M+H) ⁺.

Step G: (1S, 2R) -2- ( (S) -1- (1- (2- (3- ( (dimethylamino) methyl) -4- (methylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentan-1-amine

To a solution of tert-butyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (3- ( (dimethylamino) methyl) -4- (methylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) carbamate (2.3 g, 2.960 mmol) in DCM (9 mL) was added TFA (3 mL) . Then the reaction solution was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to give (1S, 2R) -2- ( (S) -1- (1- (2- (3- ( (dimethylamino) methyl) -4- (methylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentan-1-amine (1.9 g, yield 95%) as a yellow oil. LC-MS: 677 (M+H) ⁺.

Step H: tert-butyl (2- ( ( (1S, 2R) -2- ( (S) -1- (1- (2- (3- ( (dimethylamino) methyl) -4- (methylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) amino) ethyl) (methyl) carbamate

A solution of (1S, 2R) -2- ( (S) -1- (1- (2- (3- ( (dimethylamino) methyl) -4- (methylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentan-1-amine (250 mg, 0.603 mmol, 1.0 eq. ) and tert-butyl methyl (2-oxoethyl) carbamate (140 mg, 0.663 mmol, 1.1 eq. ) in DCM (5 mL) and MeOH (1 mL) was stirred at room temperature for 2 hours. NaBH (OAc) ₃ (30 mg, 0.886 mmol, 1.5 eq. ) was added to the above solution at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with H ₂O (10 mL) and extracted with DCM (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 tert-butyl (2- ( ( (1S, 2R) -2- ( (S) -1- (1- (2- (3- ( (dimethylamino) methyl) -4- (methylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) amino) ethyl) (methyl) carbamate (200 mg, yield 81%) as a yellow oil. LC-MS: 834 (M+H) ⁺.

Step I: N1- ( (1S, 2R) -2- ( (S) -1- (1- (2- (3- ( (dimethylamino) methyl) -4- (methylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) -N2-methylethane-1, 2-diamine

To the solution of tert-butyl (2- ( ( (1S, 2R) -2- ( (S) -1- (1- (2- (3- ( (dimethylamino) methyl) -4- (methylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) amino) ethyl) (methyl) carbamate (200 mg, 0.24 mmol, 1.0 eq. ) in DCM (5 mL) was added TFA (1 mL) at room temperature. The solution was stirred at room temperature for 1 hour. The resulting reaction was concentrated under reduced pressure to afford N1- ( (1S, 2R) -2- ( (S) -1- (1- (2- (3- ( (dimethylamino) methyl) -4- (methylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) -N2-methylethane-1, 2-diamine (500 mg, yield 93%) as a dark yellow oil which was used directly in the next step. LC-MS: 734 (M+H) ⁺.

Step J: 1- ( (1S, 2R) -2- ( (S) -1- (1- (2- (3- ( (dimethylamino) methyl) -4- (methylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) -3-methylimidazolidin-2-one (Cpd 201)

To a solution of N1- ( (1S, 2R) -2- ( (S) -1- (1- (2- (3- ( (dimethylamino) methyl) -4- (methylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) -N2-methylethane-1, 2-diamine (170 mg, 0.2 mmol, 1.0 eq. ) in THF (10 mL) was added 1- (1H-imidazole-1-carbonyl) -1H-imidazole (0.027 mL, 0.221 mmol, 1.1 eq. ) and TEA (0.139 mL, 1.002 mmol, 5.0 eq. ) at room temperature. The mixture was stirred at 30℃ under N ₂ atmosphere overnight. The 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 and RP-prep-HPLC to give Cpd 201 (25 mg, yield 16%) as a white solid. LC-MS: 760 (M+H) ⁺. ¹H NMR (400 MHz, Methanol-d ₄) δ 7.86 (d, 1H) , 7.59 -7.47 (m, 3H) , 7.33 -7.27 (m, 1H) , 7.25 -7.18 (m, 1H) , 6.99 -6.91 (m, 1H) , 6.63 -6.54 (m, 2H) , 4.58 (d, 1H) , 4.47 (s, 2H) , 4.44 -4.38 (m, 1H) , 4.13 -4.07 (m, 2H) , 3.96 (s, 2H) , 3.62 -3.56 (m, 2H) , 3.50 -3.38 (m, 4H) , 3.13 (s, 3H) , 2.88 (s, 6H) , 2.82 -2.70 (m, 9H) , 2.66 -2.59 (m, 2H) , 2.57 -2.45 (m, 3H) , 2.22 -2.14 (m, 1H) , 2.00 -1.90 (m, 2H) , 1.65 -1.38 (m, 4H) , 1.37 -1.27 (m, 2H) , 1.19 -1.10 (m, 2H) , 0.91 -0.80 (m, 1H) .

EXAMPLE 15

Preparation of 1- ( (1S, 2R) -2- ( (S) -1- (1- (2- (3- ( (dimethylamino) methyl) -4- (methylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) -3-methyl-1, 3-dihydro-2H-imidazol-2-one (Cpd 205)

Step A: 1- (2, 2-dimethoxyethyl) -3- ( (1S, 2R) -2- ( (S) -1- (1- (2- (3- ( (dimethylamino) methyl) -4- (methylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) -1-methylurea

To a solution of (1S, 2R) -2- ( (S) -1- (1- (2- (3- ( (dimethylamino) methyl) -4- (methylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentan-1-amine (100 mg, 0.148 mmol, 1.0 eq. ) and TEA (0.11 mL, 0.791 mmol, 5.3 eq. ) in THF (25 mL) was added a solution of 4-nitrophenyl carbonochloridate (80 mg, 0.397 mmol, 2.6 eq. ) in THF (25 mL) at 0℃. After 1 hour, 2, 2-dimethoxy-N-methylethan-1-amine (0.05 mL, 0.420 mmol, 2.8 eq. ) was added to the above solution at 0℃. The reaction solution was stirred at room temperature for 3 hours. The 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 1- ( (1S, 2R) -2- ( (S) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) -1- (1- (2- (3- ( (methylamino) methyl) -4- (methylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) ethyl) cyclopentyl) -3-methyl-1H-imidazol-2 (3H) -one (48 mg, yield 40%) as a yellow oil. LC-MS: 822 (M+H) ⁺.

Step B: 1- ( (1S, 2R) -2- ( (S) -1- (1- (2- (3- ( (dimethylamino) methyl) -4- (methylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) -3-methyl-1, 3-dihydro-2H-imidazol-2-one (Cpd 205)

A solution of 1- ( (1S, 2R) -2- ( (S) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) -1- (1- (2- (3- ( (methylamino) methyl) -4- (methylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) ethyl) cyclopentyl) -3-methyl-1H-imidazol-2 (3H) -one (40 mg, 0.049 mmol) in sulfuric acid (2 mL) was stirred at 0℃ for 10 minutes. Then the mixture was stirred at 50℃ for 1 hour. The mixture was quenched with sat. NaHCO ₃ aq. (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 RP-prep-HPLC to afford Cpd 205 (10 mg, yield 28%) as a white solid. LC-MS: 758 (M+H) ⁺. ¹H NMR (400 MHz, MeOD-d ₄) δ 7.67 (d, 1H) , 7.44 -7.29 (m, 3H) , 7.04 -7.97 (m, 1H) , 6.63 -6.54 (m, 3H) , 6.39 (d, 1H) , 6.34 -6.28 (m, 2H) , 4.55 (d, 1H) , 4.44 -4.38 (m, 1H) , 4.28 (d, 1H) , 3.88 (s, 2H) , 3.75 -3.68 (m, 4H) , 3.16 -3.11 (m, 6H) , 2.84 -1.97 (m, 1H) , 2.70 -2.60 (m, 2H) , 2.57 -2.48 (m, 1H) , 2.40 (s, 3H) , 2.28 -2.16 (m, 8H) , 2.14 -2.08 (m, 1H) , 1.96 -1.87 (m, 3H) , 1.73 -1.65 (m, 1H) , 1.59 -1.50 (m, 2H) , 1.49 -1.40 (m, 2H) , 1.37 -1.18 (m, 3H) , 1.08 -0.97 (m, 2H) , 0.55 -0.45 (m, 1H)

EXAMPLE 16

Synthesis of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (4- ( ( (S) -1-acryloylpiperidin-3-yl) sulfonyl) -2-fluorophenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (1H-imidazol-1-yl) ethyl) cyclopentyl) carbamate (Cpd 241) and methyl ( (1S, 2R) -2- ( (1S) -1- (1- (2- (4- ( ( (S) -1-acryloylpiperidin-3-yl) sulfonyl) -2-fluorophenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (7-oxo-6, 7-dihydro-5H-imidazo [2, 1-b] [1, 3] oxazin-1 (8aH) -yl) ethyl) cyclopentyl) carbamate (Cpd 244)

Acrylic anhydride (14 mg) was added to a solution of I (50 mg) and DIEA (0.06 mL) in DCM (4 mL) . The mixture was stirred for 2 hours, and the solvent was evaporated. The residue was purified and both Cpd 241 (ESI-MS: 805.7) and Cpd 244 (ESI-MS: 877.8) were achieved.

EXAMPLE 17

Synthesis of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (7- (cyclopropylsulfonyl) -1-oxoisoindolin-4-yl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (1H-imidazol-1-yl) ethyl) cyclopentyl) carbamate (Cpd 255)

Cyclopropanethiol (250 mg) and Cs ₂CO ₃ (1.4 g) were added to a solution of J-10 (580 mg) in DMF (5 mL) . The mixture was stirred at 80 ℃ overnight. The mixture was quenched with water and purified by Flash Column Chromatography to give J-11.

mCPBA (492 mg) was added slowly in the solution of J-11 (254 mg) in DCM (10 mL) at 0 ℃. The mixture was allowed to warm to room temperature and stirred overnight at room temperature. The reaction mixture was washed with saturated sodium sulfite solution (aq. ) and brine. The organic solvent was dried over Na ₂SO ₄, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography to give J-12.

Cpd 255 was prepared from J-12 according to the procedure described for the preparation of Cpd 45. ESI-MS: 745.6.

EXAMPLE 18

Synthesis of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (7- (cyclopropylsulfonyl) -2-methyl-1, 3-dioxoisoindolin-4-yl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (1H-imidazol-1-yl) ethyl) cyclopentyl) carbamate (Cpd 256)

NaH (7 mg) was added to a solution of J-13 (33 mg) in THF (3 mL) , and the mixture was stirred for 0.5 hour at 0℃. Then MeI (22 mg) was added, and the resultant mixture was heated to 50 ℃ for 5 hours. Water was added, and the mixture was extracted three times with EtOAC, concentrated and purified by Flash Column Chromatography give J-14.

Cpd 256 was prepared from J-14 according to the procedure described for the preparation of Cpd 45. ESI-MS: 745.6.

EXAMPLE 19

Preparation of methyl ( (1S, 2R) -2- ( (S) -2- (2-amino-1H-imidazol-1-yl) -1- (1- (2- (3- ( (dimethylamino) methyl) -4- (methylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) ethyl) cyclopentyl) carbamate (Cpd 300)

Step A: tert-butyl N- [ (2S) -2- (1-benzylpiperidin-4-yl) -2- (3-fluorophenyl) -2- [ (1R, 2S) -2- [ (methoxycarbonyl) amino] cyclopentyl] ethyl] carbamate

A mixture of methyl ( (1S, 2R) -2- ( (S) -2-amino-1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) ethyl) cyclopentyl) carbamate (E3) (3 g, 6.6 mmol, 1.0 eq. ) , Boc ₂O (2.16 g, 9.9 mmol 1.5 eq. ) and TEA (1.8 mL, 13 mmol, 2 eq. ) in DCM (25 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with H ₂O (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 N- [ (2S) -2- (1-benzylpiperidin-4-yl) -2- (3-fluorophenyl) -2- [ (1R, 2S) -2- [ (methoxycarbonyl) amino] cyclopentyl] ethyl] carbamate (3 g, yield 82%) as a white solid. LC-MS: 554 (M+H) ⁺.

Step B: tert-butyl N- [ (2S) -2- (3-fluorophenyl) -2- [ (1R, 2S) -2- [ (methoxycarbonyl) amino] cyclopentyl] -2- (piperidin-4-yl) ethyl] carbamate

To a solution of tert-butyl N- [ (2S) -2- (1-benzylpiperidin-4-yl) -2- (3-fluorophenyl) -2- [ (1R, 2S) -2- [ (methoxycarbonyl) amino] cyclopentyl] ethyl] carbamate (3 g, 5.4 mmol) in CF ₃CH ₂OH (60 mL) was added 20%Pd (OH) ₂/C (0.7 g, 20%w/wt) . The reaction was stirred at 25 ℃ under H ₂ atmosphere (1 atm) for 16 hours. The solution was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl N- [ (2S) -2- (3-fluorophenyl) -2- [ (1R, 2S) -2- [ (methoxycarbonyl) amino] cyclopentyl] -2- (piperidin-4-yl) ethyl] carbamate (2.5 g, yield 99%) as a white solid without any further purification. LC-MS: 464 (M+H) ⁺.

Step C: benzyl 6- (4- ( (S) -2- ( (tert-butoxycarbonyl) amino) -1- (3-fluorophenyl) -1- ( (1R, 2S) -2- ( (methoxycarbonyl) amino) cyclopentyl) ethyl) piperidin-1-yl) -2-azaspiro [3.3] heptane-2-carboxylate

A solution of tert-butyl N- [ (2S) -2- (3-fluorophenyl) -2- [ (1R, 2S) -2- [ (methoxycarbonyl) amino] cyclopentyl] -2- (piperidin-4-yl) ethyl] carbamate (2.2 g, 4.7 mmol, 1.0 eq. ) , AcOH (0.28 g, 4.7 mmol, 1.0 eq. ) and benzyl 6-oxo-2-azaspiro [3.3] heptane-2-carboxylate (1.16 g, 4.746 mmol, 1.1 eq. ) in DCM (30 mL) was stirred at room temperature for 2 hours. Then NaBH (OAc) ₃ (2 g, 9.4 mmol, 2.0 eq. ) was added to the above solution. The mixture was stirred at room temperature overnight. The mixture was quenched with sat. NaHCO ₃ aq. (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 afford benzyl 6- (4- ( (S) -2- ( (tert-butoxycarbonyl) amino) -1- (3-fluorophenyl) -1- ( (1R, 2S) -2- ( (methoxycarbonyl) amino) cyclopentyl) ethyl) piperidin-1-yl) -2-azaspiro [3.3] heptane-2-carboxylate (2.7 g, yield 82%) as a white solid. LC-MS: 693 (M+H) ⁺.

Step D: ( (S) -2- (1- (2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -2- (3-fluorophenyl) -2- ( (1R, 2S) -2- ( (methoxycarbonyl) amino) cyclopentyl) ethyl) carbamate

To a solution of benzyl 6- (4- ( (S) -2- ( (tert-butoxycarbonyl) amino) -1- (3-fluorophenyl) -1- ( (1R, 2S) -2- ( (methoxycarbonyl) amino) cyclopentyl) ethyl) piperidin-1-yl) -2-azaspiro [3.3] heptane-2-carboxylate (2.7g, 3.8 mmol, ) ) in CF ₃CH ₂OH (40 mL) was added 20%Pd (OH) ₂/C (0.6 g, 20%w/wt) . The reaction was stirred at 25℃ under H ₂ atmosphere (1 atm) for 16 hours. The solution was filtered and the filtrate was concentrated under reduced pressure to give ( (S) -2- (1- (2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -2- (3-fluorophenyl) -2- ( (1R, 2S) -2- ( (methoxycarbonyl) amino) cyclopentyl) ethyl) carbamate (2 g, yield 91%) as a white solid without any further purification. LC-MS: 559 (M+H) ⁺.

Step E: tert-butyl ( (S) -2- (1- (2- (3- ( (dimethylamino) methyl) -4- (methylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -2- (3-fluorophenyl) -2- ( (1R, 2S) -2- ( (methoxycarbonyl) amino) cyclopentyl) ethyl) carbamate

A mixture of ( (S) -2- (1- (2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -2- (3-fluorophenyl) -2- ( (1R, 2S) -2- ( (methoxycarbonyl) amino) cyclopentyl) ethyl) carbamate (2.3 g, 4.1 mmol, 1.0 eq. ) , K ₂CO ₃ (1.7 g, 12.3 mmol, 3.0 eq. ) and 1- (5-fluoro-2- (methylsulfonyl) phenyl) -N, N-dimethylmethanamine (1.0 g, 4.5 mmol, 1.1 eq. ) in DMSO (35 mL) was stirred at 80℃ overnight. The reaction mixture was diluted with H ₂O (100 mL) and extracted with EtOAc (100 mL x 3) . The combined organic layers were washed with brine (100 mL) , 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 ( (S) -2- (1- (2- (3- ( (dimethylamino) methyl) -4- (methylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -2- (3-fluorophenyl) -2- ( (1R, 2S) -2- ( (methoxycarbonyl) amino) cyclopentyl) ethyl) carbamate (1.5 g, yield 47%) as a white solid. LC-MS: 770 (M+H) ⁺.

Step F: methyl ( (1S, 2R) -2- ( (S) -2-amino-1- (1- (2- (3- ( (dimethylamino) methyl) -4- (methyl sulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) ethyl) cyclopentyl) carbamate

A solution of tert-butyl ( (S) -2- (1- (2- (3- ( (dimethylamino) methyl) -4- (methylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -2- (3-fluorophenyl) -2- ( (1R, 2S) -2- ( (methoxycarbonyl) amino) cyclopentyl) ethyl) carbamate (1.5 g, 1.9 mmol) in DCM (7 mL) and TFA (2 mL) was stirred at room temperature for 2 hours. The resulting reaction was concentrated under reduced pressure and diluted with sat. NaHCO ₃ aq. (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 to give methyl ( (1S, 2R) -2- ( (S) -2-amino-1- (1- (2- (3- ( (dimethylamino) methyl) -4- (methylsulfonyl) phenyl) -2- azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) ethyl) cyclopentyl) carbamate (1.2 g, yield 92%) as a white solid. LC-MS: 670 (M+H) ⁺.

Step G: methyl ( (1S, 2R) -2- ( (S) -2- ( (2, 2-dimethoxyethyl) amino) -1- (1- (2- (3- ( (dimethylamino) methyl) -4- (methylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) ethyl) cyclopentyl) carbamate

A solution of methyl ( (1S, 2R) -2- ( (S) -2-amino-1- (1- (2- (3- ( (dimethylamino) methyl) -4- (methylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) ethyl) cyclopentyl) carbamate (400 mg, 0.597 mmol, 1.0 eq. ) , 2, 2-dimethoxyacetaldehyde (0.065 mL, 0.717 mmol, 1.2 eq. ) and AcOH (0.103 mL, 1.791 mmol, 3.0 eq. ) in DCM (10 mL) was stirred at room temperature for 1 hour. Then NaBH (OAc) ₃ (253.17 mg, 1.194 mmol, 2.0 eq. ) was added to the mixture. The reaction was stirred at room temperature for 3 hours, diluted with water (20 mL) , adjusted to pH ～8 with sat. NaHCO ₃ aq. and extracted with DCM (20 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 methyl ( (1S, 2R) -2- ( (S) -2- ( (2, 2-dimethoxyethyl) amino) -1- (1- (2- (3- ( (dimethylamino) methyl) -4- (methylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) ethyl) cyclopentyl) carbamate (300 mg, yield 66%) as a white solid. LC-MS: 758 (M+H) ⁺.

Step H: tert-butyl ( (Z) -N'- (tert-butoxycarbonyl) -N- (2, 2-dimethoxyethyl) -N- ( (S) -2- (1- (2- (3- ( (dimethylamino) methyl) -4- (methylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -2- (3-fluorophenyl) -2- ( (1R, 2S) -2- ( (methoxycarbonyl) amino) cyclopentyl) ethyl) carbamimidoyl) -l2-azanecarboxylate

To a solution of methyl ( (1S, 2R) -2- ( (S) -2- ( (2, 2-dimethoxyethyl) amino) -1- (1- (2- (3- ( (dimethylamino) methyl) -4- (methylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) ethyl) cyclopentyl) carbamate (300 mg, 0.396 mmol, 1.0 eq. ) , TEA (0.28 mL, 1.979 mmol, 5.0 eq. ) and tert-butyl (E) - ( ( (tert-butoxycarbonyl) imino) (methylthio) methyl) -l2-azanecarboxylate (253 mg, 0.871 mmol, 2.2 eq. ) in DMF (5 mL) was added HgCl ₂ (440 mg, 1.624 mmol, 4.0 eq. ) at 0℃. The mixture was stirred at room temperature for 2 hours under N ₂ atmosphere. The mixture was filtered through a Celite pad, and the filtrate was diluted with H ₂O (20 mL) and extracted with EtOAc (20 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 afford tert-butyl ( (Z) -N'- (tert-butoxycarbonyl) -N- (2, 2-dimethoxyethyl) -N- ( (S) -2- (1- (2- (3- ( (dimethylamino) methyl) -4- (methylsulfonyl) phenyl) -2- azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -2- (3-fluorophenyl) -2- ( (1R, 2S) -2- ( (methoxycarbonyl) amino) cyclopentyl) ethyl) carbamimidoyl) -l2-azanecarboxylate (320 mg, yield 81%) as a white solid. LC-MS: 1000 (M+H) ⁺.

Step I: methyl ( (1S, 2R) -2- ( (S) -2- (2-amino-1H-imidazol-1-yl) -1- (1- (2- (3- ( (dimethylamino) methyl) -4- (methylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) ethyl) cyclopentyl) carbamate (Cpd 300)

A solution of tert-butyl ( (Z) -N'- (tert-butoxycarbonyl) -N- (2, 2-dimethoxyethyl) -N- ( (S) -2- (1- (2- (3- ( (dimethylamino) methyl) -4- (methylsulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -2- (3-fluorophenyl) -2- ( (1R, 2S) -2- ( (methoxycarbonyl) amino) cyclopentyl) ethyl) carbamimidoyl) -l2-azanecarboxylate (300 mg, 0.3 mmol) in DCM (6 mL) and TFA (2 mL) was stirred at room temperature for 2 hours. Then the reaction was concentrated under reduced pressure. The residue was dissolved into toluene (10 mL) , and the solution was stirred at 70℃ overnight. The reaction was concentrated under reduced pressure and purified by purified by Prep-TLC and RP-prep-HPLC to afford Cpd 300 (30 mg, yield 14%) as a white solid. LC-MS: 736 (M+H) ⁺. ¹H NMR (400 MHz, Methanol-d ₄) δ 7.77 (d, 1H) , 7.43 -7.38 (m, 2H) , 7.33 (d, 1H) , 7.08 -7.02 (m, 1H) , 6.44 -6.34 (m, 4H) , 4.39 (dd, 2H) , 4.05 (dd, 1H) , 3.97 (s, 2H) , 3.83 (s, 2H) , 3.71 (d, 2H) , 3.49 (s, 3H) , 3.25 (s, 3H) , 2.91 (d, 1H) , 2.84 (d, 1H) , 2.72 -2.60 (m, 2H) , 2.38 -2.28 (m, 2H) , 2.25 -2.23 (m, 6H) , 2.18 -2.10 (m, 1H) , 2.07 -2.05 (m, 1H) , 2.03 -2.00 (m, 1H) , 1.95 (d, 1H) , 1.84 -1.74 (d, 3H) , 1.73 -1.66 (m, 1H) , 1.52 -1.44 (m, 1H) , 1.39 -1.29 (m, 3H) , 1.27 -1.18 (m, 2H) , 1.04 -0.94 (m, 1H) .

EXAMPLE 20

Preparation of Cpd 337

2-Chloroethyl chloroformate (189 mg, 1.3 mmol) was added to a solution of E3 (500 mg, 1.1 mmol) and trimethylamine (0.48 mL, 3.3 mmol) in dichloromethane (5 mL) . The resultant mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated under reduced pressure to remove the dichloromethane and the residue was purified by Flash Column Chromatography (DCM/MeOH as eluent) to give H2. ESI-MS: 560.6.

H2 (320 mg, 0.57 mmol) was dissolved in THF (3 mL) . NaH (92 mg, 2.28 mmol) was added, and the mixture was heated to 60 ℃ for 5 hours. Water was then added, and the mixture was extracted three times with EtOAC, concentrated and purified by Flash Column Chromatography (DCM/MeOH as eluent) to give H3. ESI-MS: 524.4.

To a solution of H3 (180 mg, 0.34 mmol) in methanol (5 mL) was added acetic acid (31 μL, 0.536 mmol) and Pd/C (50 mg, 10%wt) under N ₂ atomsphere. Then the mixture was stirred at room temperature under hydrogen atmosphere (normal pressure) . After 4 hours, the Pd/C catalyst was filtered off, the solvent was removed by rotary evaporation to give H4, which was used without further purification. ESI-MS: 434.7.

Cpd 337was prepared from H4 according to the procedure described for the preparation of Cpd 45. ESI-MS: 630.84.

EXAMPLE 21

Preparation of Cpd 338

Cpd 338 was prepared starting from E3 and 4-chlorobutanoyl chloride employing similar procedures described for the preparation of Cpd 337. ESI-MS: 628.91.

EXAMPLE 23

Preparation of methyl ( (1S, 2R) -2- ( (S) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) -1- (1- (2- (2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-5-yl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) ethyl) cyclopentyl) carbamate (Cpd 340)

Step A: 5-bromo-1, 3-bis ( (2- (trimethylsilyl) ethoxy) methyl) -1, 3-dihydro-2H-benzo [d] imidazol-2-one

To a solution of 5-bromo-1, 3-dihydro-2H-benzo [d] imidazol-2-one (4 g, 18.8 mmol) in DMF (40 mL) was added NaH (60%in mineral oil, 1.9 g, 46.9 mmol) at 0℃, and the mixture was stirred at this temperature for 10 minutes. A solution of (2- (chloromethoxy) ethyl) trimethylsilane (7.2 g, 43.2 mmol) in THF (10 mL) was added to the reaction at 0℃. The mixture was stirred at room temperature for 2 hours. The mixture was then poured into sat. NH ₄Cl aq. (50 mL) and extracted with EtOAc (80 mL x 2) . The combined organic layers were washed with water, brine (50 mL) , dried over Na ₂SO ₄ and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography to give 5-bromo-1, 3-bis ( (2- (trimethylsilyl) ethoxy) methyl) -1, 3-dihydro-2H-benzo [d] imidazol-2-one (5.3 g, yield 59%) as a white solid. LC-MS: 473, 475 (M+H) ⁺.

Step B: methyl ( (1S, 2R) -2- ( (S) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) -1- (1- (2- (2-oxo-1, 3-bis ( (2- (trimethylsilyl) ethoxy) methyl) -2, 3-dihydro-1H-benzo [d] imidazol-5-yl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) 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- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) carbamate (84 mg, 0.16 mmol) , 5-bromo-1, 3-bis ( (2- (trimethylsilyl) ethoxy) methyl) -1, 3-dihydro-2H-benzo [d] imidazol-2-one (33 mg, 0.18 mmol) , X-Phos (8 mg, 0.016 mmol) , Pd ₂ (dba) ₃ (13 mg, 0.016 mmol) and Cs ₂CO ₃ (157 mg, 0.48 mmol) in toluene (5 mL) was stirred at 100℃ 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 column chromatography on silica gel to give methyl ( (1S, 2R) -2- ( (S) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) -1- (1- (2- (2-oxo-1, 3-bis ( (2- (trimethylsilyl) ethoxy) methyl) -2, 3-dihydro-1H-benzo [d] imidazol-5-yl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) ethyl) cyclopentyl) carbamate (40 mg, yield 33%) as yellow liquid. LC-MS: 916 (M+H) ⁺.

Step C: methyl ( (1S, 2R) -2- ( (S) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) -1- (1- (2- (2-oxo-2, 3-dihydro-1H-benzo [d] imidazol-5-yl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) ethyl) cyclopentyl) carbamate (Cpd 340)

A mixture of methyl ( (1S, 2R) -2- ( (S) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) -1- (1- (2- (2-oxo-1, 3-bis ( (2- (trimethylsilyl) ethoxy) methyl) -2, 3-dihydro-1H-benzo [d] imidazol-5-yl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4- yl) ethyl) cyclopentyl) carbamate (40 mg, 0.044 mmol) and TFA (1 mL) in DCM (3 mL) was stirred at room temperature for 1 hour and concentrated under reduced pressure. Then the residue was dissolved in MeOH (3 mL) and NH ₃H ₂O (1 mL) was added. The mixture was stirred at room temperature for another 0.5 hour. Then the reaction was concentrated under reduced pressure. The residue was purified by RP-prep-HPLC to give Cpd 340 (10 mg, yield 37%) as yellow solid. LC-MS: 656 (M+H) ⁺. ¹H NMR (400 MHz, Methanol-d ₄) δ 7.51 –7.30 (m, 3H) , 7.15 –7.03 (m, 1H) , 6.85 (d, 1H) , 6.67 (d, 2H) , 6.26 -6.19 (m, 2H) , 4.59 –4.50 (m, 1H) , 4.40 –4.33 (m, 1H) , 4.08 –3.95 (m, 1H) , 3.78 (s, 2H) , 3.65 (s, 2H) , 3.60 (s, 3H) , 2.97 –2.87 (m, 1H) , 2.85 –2.76 (m, 1H) , 2.70 –2.57 (m, 2H) , 2.48 (s, 3H) , 2.35 –2.25 (m, 2H) , 2.23 –2.16 (m, 1H) , 2.07 –1.97 (m, 3H) , 1.91 –1.81 (m, 1H) , 1.80 –1.61 (m, 3H) , 1.53 –1.45 (m, 1H) , 1.47 –1.18 (m, 5H) , 0.80 –0.67 (m, 1H) .

EXAMPLE 24

Preparation of methyl ( (1S, 2R) -2- ( (S) -cyano ( (2R, 6R) -1- (2- (4-cyanophenyl) -2-azaspiro [3.3] heptan-6-yl) -2, 6-dimethylpiperidin-4-yl) (3-fluorophenyl) methyl) cyclopentyl) carbamate (Cpd 375)

Step A: 2- ( (2R, 6R) -1-benzyl-2, 6-dimethylpiperidin-4-ylidene) -2- (3-fluorophenyl) acetonitrile (trans configuration, not absolute configuration)

To a solution of (2R, 6R) -1-benzyl-2, 6-dimethylpiperidin-4-one (5 g, 23 mmol; Ref: PCT Int. Appl., 2020119819, 18 Jun 2020) and 2- (3-fluorophenyl) acetonitrile (3.2 mL, 27.6 mmol) in THF (50 mL) was added NaHMDS (2 M in THF, 13.8 mL, 27.6 mmol) at room temperature under N ₂ atmosphere. The mixture was stirred at 60℃ overnight. Then the reaction was quenched with sat. NH ₄Cl aq. (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 2- ( (2R, 6R) -1-benzyl-2, 6-dimethylpiperidin-4-ylidene) -2- (3-fluorophenyl) acetonitrile (7.1 g, yield 92%) as a yellow oil. LC-MS: 335 (M+H) ⁺.

Step B: 2- ( (2R, 6R) -1-benzyl-2, 6-dimethylpiperidin-4-yl) -2- (3-fluorophenyl) acetonitrile

To a mixture of 2- ( (2R, 6R) -1-benzyl-2, 6-dimethylpiperidin-4-ylidene) -2- (3-fluorophenyl) acetonitrile (7.1 g, 21.2 mmol) and Mg (5.2 g, 212 mmol) in MeOH (100 mL) was added I ₂ (9.4 g, 21.2 mmol) . The mixture was stirred at room temperature for 2 hours. Then the reaction was quenched with water (200 mL) and extracted with DCM (200 mL x 2) . The combined organic layers were washed with brine (200 mL) , dried over Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether (PE) : EtOAc = 0 ～ 50%) to give a mixture, then separated by supercritical fluid chromatography (SFC) to afford 2- ( (2R, 6R) -1-benzyl-2, 6-dimethylpiperidin-4-yl) -2- (3-fluorophenyl) acetonitrile (3 g, yield 42%) as a yellow solid. LC-MS: 337 (M+H) ⁺.

Step C: methyl ( (1S, 2R) -2- ( (S) - ( (2R, 6R) -1-benzyl-2, 6-dimethylpiperidin-4-yl) (cyano) (3-fluorophenyl) methyl) cyclopentyl) carbamate

To a solution of 2- ( (2R, 6R) -1-benzyl-2, 4, 6-trimethylpiperidin-4-yl) -2- (3-fluorophenyl) acetonitrile (200 mg, 0.6 mmol) , methyl (3aS, 6aR) -tetrahydrocyclopenta [d] [1, 2, 3] oxathiazole-3 (3aH) -carboxylate 2, 2-dioxide (197 mg, 0.9 mmol) and DMPU (0.2 mL) in THF (2 mL) was added LiHMDS (1 M in THF; 0.7 mL, 0.7 mmol) drop-wisely at -5℃ under N ₂ atmosphere. The mixture was stirred at room temperature overnight. Then 2 N HCl (0.5 mL) was added to above solution, and the mixture was stirred at room temperature for 1 hour. The mixture was adjusted to pH 8 with sat. NaHCO ₃ aq. 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 (PE: EtOAc = 0 ～ 50%) to afford a mixture (200 mg) , then separated by SFC (2 peaks) to afford methyl ( (1S, 2R) -2- ( (S) - ( (2R, 6R) -1-benzyl-2, 6-dimethylpiperidin-4-yl) (cyano) (3-fluorophenyl) methyl) cyclopentyl) carbamate (136 mg, yield 48%) as a white solid (main peak) . LC-MS: 478 (M+H) ⁺.

Step D: methyl ( (1S, 2R) -2- ( (S) -cyano ( (2R, 6R) -2, 6-dimethylpiperidin-4-yl) (3-fluorophenyl) methyl) cyclopentyl) carbamate

To a solution of methyl ( (1S, 2R) -2- ( (S) - ( (2R, 6R) -1-benzyl-2, 6-dimethylpiperidin-4-yl) (cyano) (3-fluorophenyl) methyl) cyclopentyl) carbamate (136 mg, 0.3 mmol) in 2, 2, 2-trifluoroethan-1-ol (5 mL) was added 10%Pd (OH) ₂/C (40 mg, 30%wt/wt) . The mixture was stirred at room temperature under H ₂ atmosphere (1 atm) for 12 hours. The reaction mixture was filtered through a Celite pad and washed with MeOH. The filtrate was concentrated under reduced pressure to give methyl ( (1S, 2R) -2- ( (S) -cyano ( (2R, 6R) -2, 6-dimethylpiperidin-4-yl) (3-fluorophenyl) methyl) cyclopentyl) carbamate (100 mg, crude) as a yellow oil. LC-MS: 388 (M+H) ⁺.

Step E: methyl ( (1S, 2R) -2- ( (S) -cyano ( (2R, 6R) -1- (2- (4-cyanophenyl) -2-azaspiro [3.3] heptan-6-yl) -2, 6-dimethylpiperidin-4-yl) (3-fluorophenyl) methyl) cyclopentyl) carbamate (Cpd 375)

A mixture of methyl ( (1S, 2R) -2- ( (S) -cyano ( (2R, 6R) -2, 6-dimethylpiperidin-4-yl) (3-fluorophenyl) methyl) cyclopentyl) carbamate (50 mg, 0.13 mmol) and 4- (6-oxo-2-azaspiro [3.3] heptan-2-yl) benzonitrile (33 mg, 0.16 mmol) in DCM (3 mL) was stirred at room temperature for 2 hours. Then NaBH (OAc) ₃ (54 mg, 0.26 mmol) was added, and the mixture was stirred at 50℃ for 48 hours. The reaction mixture was quenched with water (10 mL) and extracted with DCM (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 RP-prep-HPLC to give Cpd 375 (7.8 mg, yield 10%) as a white solid. LC-MS: 584 (M+H) ⁺. ¹H NMR (400 MHz, Methanol-d ₄) δ 7.39 –7.32 (m, 3H) , 7.30 –7.25 (m, 1H) , 7.21 (d, 1H) , 7.06 –7.00 (m, 1H) , 6.33 (d, 2H) , 3.89 (s, 2H) , 3.82 (q, 1H) , 3.74 (s, 2H) , 3.42 –3.30 (m, 4H) , 2.97 –2.78 (m, 1H) , 2.69 (q, 1H) , 2.53 –2.35 (m, 3H) , 2.32 –2.21 (m, 1H) , 2.18 –2.10 (m, 1H) , 2.05 –1.87 (m, 2H) , 1.73 –1.61 (m, 1H) , 1.55 –1.37 (m, 5H) , 1.33 –1.18 (m, 3H) , 1.04 (d, 3H) , 0.95 (d, 3H) .

EXAMPLE 25

Preparation of methyl ( (1S, 2R) -2- ( (S) -cyano ( (2S, 4s, 6R) -1- (2- (4-cyanophenyl) -2-azaspiro [3.3] heptan-6-yl) -2, 6-dimethylpiperidin-4-yl) (3-fluorophenyl) methyl) cyclopentyl) carbamate (Cpd 378)

Step A: diethyl 2, 6-dimethyl-4-oxopiperidine-3, 5-dicarboxylate

To a solution of diethyl 3-oxopentanedioate (9 mL, 49 mmol) and 98%acetaldehyde (5.6 mL, 98.9 mmol) in EtOH (100 mL) was added 28%NH ₃H ₂O (6.7 mL, 49 mmol) drop-wisely at 0℃. The mixture was stirred at room temperature for 48 hours. The reaction mixture was quenched with water (200 mL) and extracted with EtOAc (200 mL x 2) . The combined organic layers were washed with brine (200 mL) , dried over Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give diethyl 2, 6-dimethyl-4-oxopiperidine-3, 5-dicarboxylate (11 g, yield 82%) as a yellow oil. LC-MS: 272 (M+H) ⁺.

Step B: 2, 6-dimethylpiperidin-4-one

A mixture of diethyl 2, 6-dimethyl-4-oxopiperidine-3, 5-dicarboxylate (11 g, 40.5 mmol) in conc. HCl (50 mL) was stirred at 70℃ overnight. Then the reaction mixture was concentrated under reduced pressure to give 2, 6-dimethylpiperidin-4-one (5 g, crude) , which was used to the next step without further purification. LC-MS: 128 (M+H) ⁺.

Step C: (2S, 6R) -1-benzyl-2, 6-dimethylpiperidin-4-one

A mixture of 2, 6-dimethylpiperidin-4-one (5 g, 39.3 mmol) , K ₂CO ₃ (10.9 g, 78.6 mmol) and BnBr (6.95 mL, 59 mmol) in MeCN (60 mL) was stirred at 60℃ under N ₂ atmosphere overnight. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL x 2) . The combined organic layers were washed with brine (100 mL) , dried over Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give (2S, 6R) -1-benzyl-2, 6-dimethylpiperidin-4-one (4 g, yield 47%; cis configuration, not absolute configuration) as a yellow solid and (2S, 6S) -1-benzyl-2, 6-dimethylpiperidin-4-one (0.5 g, yield 6%; trans configuration, not absolute configuration) as a yellow oil. LC-MS: 218 (M+H) ⁺. ¹H NMR (400 MHz, CDCl ₃) δ 7.33 (d, 2H) , 7.24 (dd, 2H) , 7.19 –7.11 (m, 1H) , 3.77 (s, 2H) , 3.12 –2.92 (m, 2H) , 2.26 (dd, 4H) , 1.07 (d, 6H) (cis configuration) .

Step D: (E) -2- ( (2R, 6S) -1-benzyl-2, 6-dimethylpiperidin-4-ylidene) -2- (3-fluorophenyl) acetonitrile

To a solution of (2S, 6R) -1-benzyl-2, 6-dimethylpiperidin-4-one (4 g, 18.4 mmol) and 2- (3-fluorophenyl) acetonitrile (2.6 mL, 22 mmol) in THF (50 mL) was added NaHMDS (2 M in THF, 11 mL, 22 mmol) at room temperature under N ₂ atmosphere. The mixture was stirred at 60℃ overnight. The reaction mixture was quenched with sat. NH ₄Cl aq. (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 (E) -2- ( (2R, 6S) -1-benzyl-2, 6-dimethylpiperidin-4-ylidene) -2- (3-fluorophenyl) acetonitrile (5 g, yield 81%) as a yellow oil. LC-MS (ESI) : m/z 335 (M+H) ⁺.

Step E: 2- ( (2R, 4s, 6S) -1-benzyl-2, 6-dimethylpiperidin-4-yl) -2- (3-fluorophenyl) acetonitrile & 2- ( (2R, 4r, 6S) -1-benzyl-2, 6-dimethylpiperidin-4-yl) -2- (3-fluorophenyl) acetonitrile

To a mixture of (E) -2- ( (2R, 6S) -1-benzyl-2, 6-dimethylpiperidin-4-ylidene) -2- (3-fluorophenyl) acetonitrile (5 g, 15 mmol) and Mg (3.6 g, 149.5 mmol) in MeOH (100 mL) was added I ₂ (0.7 g, 1.5 mmol) . The mixture was stirred at 50℃ for 2 hours. The reaction mixture was quenched with water (200 mL) and extracted with DCM (200 mL x 2) . The combined organic layers were washed with brine (200 mL) , dried over Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE: EtOAc = 0-50%) to afford 2- ( (2R, 4s, 6S) -1-benzyl-2, 6-dimethylpiperidin-4-yl) -2- (3-fluorophenyl) acetonitrile (2.2 g, yield 44%) as a yellow solid and 2- ( (2S, 4r, 6R) -1-benzyl-2, 6-dimethylpiperidin-4-yl) -2- (3-fluorophenyl) acetonitrile (1.85 g, yield 37%) as a yellow solid. LC-MS: 337 (M+H) ⁺.

2- ( (2R, 4s, 6S) -1-benzyl-2, 6-dimethylpiperidin-4-yl) -2- (3-fluorophenyl) acetonitrile: ¹H NMR (400 MHz, CDCl ₃) δ 7.30 –7.19 (m, 5H) , 7.17 –7.11 (m, 1H) , 7.02 –6.91 (m, 3H) , 3.72 –3.64 (m, 3H) , 2.94 –2.85 (m, 1H) , 2.85 –2.76 (m, 1H) , 2.22 –2.12 (m, 1H) , 1.82 –1.72 (m, 1H) , 1.69 –1.60 (m, 1H) , 1.34 (t, 2H) , 0.99 (d, 3H) , 0.90 (d, 3H) .

2- ( (2S, 4r, 6R) -1-benzyl-2, 6-dimethylpiperidin-4-yl) -2- (3-fluorophenyl) acetonitrile: ¹H NMR (400 MHz, CDCl ₃) δ 7.31 –7.24 (m, 3H) , 7.23 –7.17 (m, 2H) , 7.11 (t, 1H) , 7.02 –6.90 (m, 3H) , 3.71 (s, 2H) , 3.50 (d, 1H) , 2.52 –2.33 (m, 2H) , 1.85 –1.73 (m, 1H) , 1.71 –1.63 (m, 1H) , 1.45 –1.37 (m, 1H) , 1.24 –1.11 (m, 2H) , 1.00 (dd, 6H) .

Step F: methyl ( (1S, 2R) -2- ( (S) - ( (2S, 4s, 6R) -1-benzyl-2, 6-dimethylpiperidin-4-yl) (cyano) (3-fluorophenyl) methyl) cyclopentyl) carbamate

To a solution of 2- ( (2R, 4s, 6S) -1-benzyl-2, 6-dimethylpiperidin-4-yl) -2- (3-fluorophenyl) acetonitrile (200 mg, 0.6 mmol) , methyl (3aS, 6aR) -tetrahydrocyclopenta [d] [1, 2, 3] oxathiazole-3 (3aH) -carboxylate 2, 2-dioxide (197 mg, 0.9 mmol) and DMPU (0.2 mL) and THF (2 mL) was added LiHMDS (1 M in THF; 0.6 mL, 0.6 mmol) drop-wisely at -5℃ under N ₂ atmosphere.

The mixture was stirred at room temperature overnight. Then 2 N HCl (0.5 mL) was added to above solution, and the mixture was stirred at room temperature for 1 hour. The mixture was adjusted to pH 8 with sat. NaHCO ₃ aq. 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 (PE: EtOAc = 0 ～ 50%) to afford a mixture (200 mg) , then separated by SFC (2 peaks) to afford methyl ( (1S, 2R) -2- ( (S) - ( (2S, 4s, 6R) -1-benzyl-2, 6-dimethylpiperidin-4-yl) (cyano) (3-fluorophenyl) methyl) cyclopentyl) carbamate (120 mg, yield 42%) as a white solid (main peak) . LC-MS: 478 (M+H) ⁺.

Step G: methyl ( (1S, 2R) -2- ( (S) -cyano ( (2S, 4s, 6R) -2, 6-dimethylpiperidin-4-yl) (3-fluorophenyl) methyl) cyclopentyl) carbamate

To a solution of methyl ( (1S, 2R) -2- ( (S) - ( (2S, 4s, 6R) -1-benzyl-2, 6-dimethylpiperidin-4-yl) (cyano) (3-fluorophenyl) methyl) cyclopentyl) carbamate (120 mg, 0.25 mmol) in 2, 2, 2-trifluoroethan-1-ol (5 mL) was added 10%Pd (OH) ₂/C (35 mg, 30%wt/wt) . The mixture was stirred at room temperature under H ₂ atmosphere (1 atm) for 12 hours. The reaction mixture was filtered through a Celite pad and washed with MeOH. The filtrated was concentrated under reduced pressure to give methyl ( (1S, 2R) -2- ( (S) -cyano ( (2S, 4s, 6R) -2, 6-dimethylpiperidin-4-yl) (3-fluorophenyl) methyl) cyclopentyl) carbamate (90 mg, crude) as a yellow oil. LC-MS: 388 (M+H) ⁺.

Step H: methyl ( (1S, 2R) -2- ( (S) -cyano ( (2S, 4s, 6R) -1- (2- (4-cyanophenyl) -2-azaspiro [3.3] heptan-6-yl) -2, 6-dimethylpiperidin-4-yl) (3-fluorophenyl) methyl) cyclopentyl) carbamate (Cpd 378)

A mixture of methyl ( (1S, 2R) -2- ( (S) -cyano ( (2S, 4s, 6R) -2, 6-dimethylpiperidin-4-yl) (3-fluorophenyl) methyl) cyclopentyl) carbamate (90 mg, 0.2 mmol) and 4- (6-oxo-2-azaspiro [3.3] heptan-2-yl) benzonitrile (59 mg, 0.3 mmol) in DCM (5 mL) was stirred at room temperature for 2 hour. Then NaBH (OAc) ₃ (99 mg, 0.5 mmol) was added, and the mixture was stirred at 50℃ for 48 hours. The reaction mixture was quenched with water and extracted with DCM. The reaction mixture was quenched with water (10 mL) and extracted with DCM (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 to give Cpd 378 (13.3 mg , 10%) as a white solid. LC-MS: 584 (M+H) ⁺. ¹H NMR (400 MHz, Methanol-d ₄) δ 7.37 –7.22 (m, 4H) , 7.18 (d, 1H) , 7.05 –6.98 (m, 1H) , 6.32 (d, 2H) , 3.94 –3.79 (m, 3H) , 3.71 (s, 2H) , 3.39 –3.26 (m, 4H) , 3.08 –2.97 (m, 2H) , 2.75 (q, 1H) , 2.55 –2.39 (m, 1H) , 2.30 –2.15 (m, 2H) , 2.05 –1.95 (m, 1H) , 1.89 –1.76 (m, 3H) , 1.73 –1.65 (m, 1H) , 1.58 –1.47 (m, 2H) , 1.45 –1.33 (m, 3H) , 1.30 –1.18 (m, 2H) , 1.04 –0.93 (m, 6H) .

EXAMPLE 26

Preparation of methyl ( (1S, 2R) -2- ( (S) -cyano ( (2R, 4r, 6S) -1- (2- (4-cyanophenyl) -2-azaspiro [3.3] heptan-6-yl) -2, 6-dimethylpiperidin-4-yl) (3-fluorophenyl) methyl) cyclopentyl) carbamate (Cpd 379)

Cpd 379 was synthesized from 2- ( (2S, 4r, 6R) -1-benzyl-2, 6-dimethylpiperidin-4-yl) -2- (3-fluorophenyl) acetonitrile via procedure for Cpd 378 (Step F -H) as a white solid. LC-MS: 584 (M+H) ⁺. ¹H NMR (400 MHz, Methanol-d ₄) δ 7.50 –7.42 (m, 3H) , 7.38 (d, 1H) , 7.30 (d, 1H) , 7.18 –7.12 (m, 1H) , 6.44 (d, 2H) , 4.00 –3.87 (m, 3H) , 3.84 (s, 2H) , 3.52 –3.36 (m, 4H) , 2.87 –2.63 (m, 3H) , 2.48 –2.31 (m, 5H) , 2.10 –2.00 (m, 1H) , 1.95 –1.84 (m 1H) , 1.82 –1.71 (m, 1H) , 1.69 –1.44 (m, 5H) , 1.35 –1.26 (m, 2H) , 1.23 (d, 3H) , 1.17 (d, 3H) .

EXAMPLE 27

Preparation of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (6- ( (dimethylamino) methyl) -5- (methylsulfonyl) pyridin-2-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 452)

Step A: 1- (3, 6-bis (methylthio) pyridin-2-yl) -N, N-dimethylmethanamine

To a solution of 1- (3-bromo-6-fluoropyridin-2-yl) -N, N-dimethylmethanamine (220 mg, 0.79 mmol) in DMF (3 ml) was added MeSNa (516 mg, 3.14 mmol) . The mixture was stirred at 80℃ overnight. Then the reaction was quenched with 20 mL of water and extracted with EtOAc (20 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 1- (3, 6-bis (methylthio) pyridin-2-yl) -N, N-dimethylmethanamine (120 mg, yield 67%) as colorless oil. LC-MS: 229 (M+H) ⁺.

Step B: 1- (3, 6-bis (methylsulfonyl) pyridin-2-yl) -N, N-dimethylmethanamine

A mixture of 1- (3, 6-bis (methylthio) pyridin-2-yl) -N, N-dimethylmethanamine (220 mg, 0.97 mmol) and Oxone (13 g, 2.12 mmol) in acetone (3 mL) and water (3 mL) was stirred at room temperature overnight. Then the reaction was diluted with 10 mL of water and extracted with EtOAc (10 mL x 2) . The combined organic layers were washed with sat Na ₂S ₂O ₃ aq. (20 mL) and 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 1- (3, 6-bis (methylsulfonyl) pyridin-2-yl) -N, N-dimethylmethanamine (120 mg, yield 42%) as white solid. LC-MS: 293 (M+H) ⁺.

Step C: methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (6- ( (dimethylamino) methyl) -5- (methylsulfonyl) pyridin-2-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 452)

A solution 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 (60 mg, 0.12 mmol) , 1- (3, 6-bis (methylthio) pyridin-2-yl) -N, N-dimethylmethanamine (50 mg, 0.17 mmol) and DIPEA (0.1 mL, 0.6 mmol) in MeCN (5 mL) was stirred at 50℃ overnight. Then the mixture was diluted with 10 mL of water 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 RP-prep-HPLC to give Cpd 452 (15 mg, yield 18%) as white solid. LC-MS: 736 (M+H) ⁺. ¹H NMR (400 MHz, Methanol-d ₄) δ 7.93 (d, 1H) , 7.50 –7.40 (m, 2H) , 7.39 –7.31 (m, 1H) , 7.13 –7.05 (m, 1H) , 6.71 –6.61 (m, 2H) , 6.29 (d, 1H) , 4.59 –4.50 (m, 1H) , 4.42 –4.31 (m, 1H) , 4.11 (s, 2H) , 4.04 –3.98 (m, 1H) , 3.97 (s, 2H) , 3.79 (s, 2H) , 3.60 (s, 3H) , 3.26 (s, 3H) , 2.95 –2.88 (m, 1H) , 2.85 –2.78 (m, 1H) , 2.66 –2.58 (m, 2H) , 2.45 (s, 3H) , 2.36 –2.30 (m, 2H) , 2.27 (s, 6H) , 2.23 –2.14 (m, 1H) , 2.10 –1.98 (m, 3H) , 1.92 –1.82 (m, 1H) , 1.80 –1.64 (m, 3H) , 1.54 –1.44 (m, 1H) , 1.42 –1.26 (m, 3H) , 1.25 –1.14 (m, 2H) , 0.80 –0.63 (m, 1H) .

EXAMPLE 28

Preparation of methyl ( (1S, 2R) -2- (1- (1- (2- (4-cyano-3-isopropoxyphenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (3-methyl-2-oxoimidazolidin-1-yl) ethyl) cyclopentyl) carbamate (Cpd 485)

Step-1: tert-butyl (2- ( (2- (1-benzylpiperidin-4-yl) -2- (3-fluorophenyl) -2- ( (1R, 2S) -2- ( (methoxycarbonyl) amino) cyclopentyl) ethyl) amino) ethyl) (methyl) carbamate (H8)

To a solution of E3 (200 mg, 0.441 mmol) in DCE (4 mL) were added tert-butyl methyl (2-oxoethyl) carbamate (76 mg, 0.441 mmol) and AcOH (50 μL, 0.882 mmol) . The mixture was stirred at room temperature for 2 hours before NaBH (OAc) ₃ was added. The mixture was stirred overnight, quenched with water and and purified by reverse phase preparative HPLC to give H8 (248 mg, 92%) . ESI-MS calculated for C ₃₅H ₅₂FN ₄O ₄ [M + H] + = 611.40, found: 611.48.

Step-2: methyl ( (1S, 2R) -2- (1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2- (3-methyl-2-oxoimidazolidin-1-yl) ethyl) cyclopentyl) carbamate (H9)

Compound H8 (248 mg, 0.406 mmol) was dissolved in DCM (6 mL) , and then trifluoroacetic acid (0.6 mL, 8.12 mmol) was added. After stirring for 2 hours at room temperature, the reaction mixture was evaporated to give the product without further purification. The resulting residue was then dissolved in THF (4 mL) . DIPEA (212 μL, 1.21 mmol) and CDI (99 mg, 0.609 mmol) were added subsequently. The mixture was stirred overnight, quenched with water and and purified by reverse phase preparative HPLC to give H9 (114 mg, 52%) . ESI-MS calculated for C ₃₁H ₄₂FN ₄O ₃ [M + H] + = 537.32, found: 537.35.

Synthesis of Cpd 485: Cpd 485 was synthesized according to the same procedure employed for Cpd 6 with compound H9 and 4-fluoro-2-isopropoxybenzonitrile.

EXAMPLE 29

Preparation of methyl ( (1S, 2R) -2- ( (R) -1- (1- (2- (4-cyanophenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (1-methyl-1H-pyrazol-3-yl) ethyl) cyclopentyl) carbamate (Cpd 489)

Step A: methyl ( (1S, 2R) -2- ( (S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2-iminoethyl) cyclopentyl) carbamate

To a solution of methyl ( (1S, 2R) -2- ( (S) - (1-benzylpiperidin-4-yl) (cyano) (3-fluorophenyl) methyl) cyclopentyl) carbamate (1 g, 2.2 mmol) in toluene (15 mL) was added DIBAL-H (1.5 M in toluene, 8.9 mL, 13.3 mmol) drop-wisely at 0℃ under N ₂ atmosphere. Then the mixture was stirred at room temperature for 2 hours and quenched with Rochelle salt (2 M in water, 20 mL) at 0℃. The suspension was filtered, and the filtrate was 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 to give methyl ( (1S, 2R) -2- ( (S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2-iminoethyl) cyclopentyl) carbamate (1 g, crude) as a white solid. The residue was used directly in next step. LC-MS: 452 (M+H) ⁺.

Step B: methyl ( (1S, 2R) -2- ( (S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2-oxoethyl) cyclopentyl) carbamate

To a solution of methyl ( (1S, 2R) -2- ( (S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2-iminoethyl) cyclopentyl) carbamate (2 g, 4.4 mmol) in THF (20 mL) was added H ₂SO ₄ (5%in water, 4 mL) . The solution was stirred at room temperature for 2 hours. Then the mixture was adjusted to pH 7～8 with sat. NaHCO ₃ aq. 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 methyl ( (1S, 2R) -2- ( (S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2-oxoethyl) cyclopentyl) carbamate (1.4 g, yield 70%) as a white solid. LC-MS: 453 (M+H) ⁺.

Step C: methyl ( (1S, 2R) -2- ( (S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2-oxoethyl) cyclopentyl) (4-methoxybenzyl) carbamate

To a solution of methyl ( (1S, 2R) -2- ( (S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2-oxoethyl) cyclopentyl) carbamate (300 mg, 0.66 mmol) in DMF (5 mL) was added NaH (60%in mineral oil., 40 mg, 0.99 mmol) at 0℃ under N ₂ atmosphere. After 0.5 hour, 1- (chloromethyl) -4-methoxybenzene (0.1 mL, 0.8 mmol) was added to the above mixture and the reaction was stirred at room temperature for 2 hours. The reaction was quenched with 20 mL of sat. NH ₄Cl aq. 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 methyl ( (1S, 2R) -2- ( (S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2-oxoethyl) cyclopentyl) (4-methoxybenzyl) carbamate (270 mg, yield 71%) as a white solid. LC-MS: 573 (M+H) ⁺.

Step D: methyl ( (1S, 2R) -2- ( (1S, 2S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2-hydroxy-2- (1-methyl-1H-pyrazol-3-yl) ethyl) cyclopentyl) (4-methoxybenzyl) carbamate

To a solution of 3-bromo-1-methyl-1H-pyrazole (1.1 g, 6.9 mmol) and methyl ( (1S, 2R) -2- ( (S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2-oxoethyl) cyclopentyl) (4-methoxybenzyl) carbamate (1 g, 1.7 mmol) in dry THF (20 mL) was added n-BuLi (2.5 M in hexane, 2.8 mL, 7 mmol) drop-wisely at -65℃ under N ₂ atmosphere. Then the reaction was stirred at this temperature for 1 hour. The reaction was quenched with sat. NH ₄Cl aq. (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 methyl ( (1S, 2R) -2- ( (1S, 2S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2-hydroxy-2- (1-methyl-1H-pyrazol-3-yl) ethyl) cyclopentyl) (4-methoxybenzyl) carbamate (500 mg, yield 44%) as a yellow solid. LC-MS: 655 (M+H) ⁺.

Step E: methyl ( (1S, 2R) -2- ( (1S, 2S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2- (1-methyl-1H-pyrazol-3-yl) -2- ( ( (methylthio) carbonothioyl) oxy) ethyl) cyclopentyl) (4-methoxybenzyl) carbamate

A mixture of methyl ( (1S, 2R) -2- ( (1S, 2S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2-hydroxy-2- (1-methyl-1H-pyrazol-3-yl) ethyl) cyclopentyl) (4-methoxybenzyl) carbamate (650 mg, 0.99 mmol) and NaH (60%in mineral oil, 99 mg, 2.48 mmol) in dry THF (10 mL) was stirred at 0℃ under N ₂ atmosphere for 1 hour. Then carbon disulfide (0.2 mL, 3.47 mmol) was added. After stirring for 30 minutes at 0℃, MeI (211 mg, 1.49 mmol) was added. The reaction was warmed to room temperature and stirred overnight. After then, the reaction was cooled to -10℃, and quenched with sat. NaHCO ₃ aq. (15 mL) . The organic layer was separated, and the aqueous layer was extracted with EtOAc (15 mL x 3) . The combined organic layers were washed with brine (20 mL) , dried over Na ₂SO ₄ and concentrated under reduced pressure to give methyl ( (1S, 2R) -2- ( (1S, 2S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2- (1-methyl-1H-pyrazol-3-yl) -2- ( ( (methylthio) carbonothioyl) oxy) ethyl) cyclopentyl) (4-methoxybenzyl) carbamate (450 mg, crude) as a yellow oil. The residue was used directly in next step. LC-MS: 745 (M+H) ⁺.

Step F: methyl ( (1S, 2R) -2- ( (R) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2- (1-methyl-1H-pyrazol-3-yl) ethyl) cyclopentyl) (4-methoxybenzyl) carbamate

A mixture of methyl ( (1S, 2R) -2- ( (1S, 2S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2- (1-methyl-1H-pyrazol-3-yl) -2- ( ( (methylthio) carbonothioyl) oxy) ethyl) cyclopentyl) (4-methoxybenzyl) carbamate (450 mg, 0.6 mmol) , AIBN (10 mg, 0.06 mmol) and tributylstannane (0.26 mL, 1 mmol) in 10 mL of dry toulene was stirred at 100℃ overnight. Then the reaction was concentrated under reduced pressure. And the residue was purified by flash column chromatography on silica gel to give methyl ( (1S, 2R) -2- ( (R) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2- (1-methyl-1H-pyrazol-3-yl) ethyl) cyclopentyl) (4-methoxybenzyl) carbamate (250 mg, yield 65%) as a yellow solid. LC-MS: 639 (M+H) ⁺.

Step G: methyl ( (1S, 2R) -2- ( (R) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2- (1-methyl-1H-pyrazol-3-yl) ethyl) cyclopentyl) carbamate

A solution of methyl ( (1S, 2R) -2- ( (R) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2- (1-methyl-1H-pyrazol-3-yl) ethyl) cyclopentyl) (4-methoxybenzyl) carbamate (250 mg, 0.39 mmol) in TFA (5 mL) was stirred at 50℃ for 3h. Then the reaction was concentrated under reduced pressure. And the residue was diluted with water (10 mL) , and the solution was adjusted to pH 7 ～ 8 with sat. NaHCO ₃ aq. The mixture was 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 to give methyl ( (1S, 2R) -2- ( (R) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2- (1-methyl-1H-pyrazol-3-yl) ethyl) cyclopentyl) carbamate (200 mg, crude) as a yellow solid. The residue was used directly in next step. LC-MS: 519 (M+H) ⁺.

Step H: methyl ( (1S, 2R) -2- ( (R) -1- (3-fluorophenyl) -2- (1-methyl-1H-pyrazol-3-yl) -1- (piperidin-4-yl) ethyl) cyclopentyl) carbamate

A mixture of methyl ( (1S, 2R) -2- ( (R) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2- (1-methyl-1H-pyrazol-3-yl) ethyl) cyclopentyl) carbamate (200 mg, 0.39 mmol) , and 10%Pd (OH) ₂/C (20 mg, 10%w/t) in CF ₃CH ₂OH (7 mL) was stirred at room temperature overnight under hydrogen atmosphere (1 atm) . The mixture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure to give methyl ( (1S, 2R) -2- ( (R) -1- (3-fluorophenyl) -2- (1-methyl-1H-pyrazol-3-yl) -1- (piperidin-4-yl) ethyl) cyclopentyl) carbamate (100 mg, crude) as a white solid. The residue was used directly in next step. LC-MS: 429 (M+H) ⁺.

Step I: methyl ( (1S, 2R) -2- ( (R) -1- (1- (2- (4-cyanophenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (1-methyl-1H-pyrazol-3-yl) ethyl) cyclopentyl) carbamate (Cpd 489)

A mixture of methyl ( (1S, 2R) -2- ( (R) -1- (3-fluorophenyl) -2- (1-methyl-1H-pyrazol-3-yl) -1- (piperidin-4-yl) ethyl) cyclopentyl) carbamate (50 mg, 0.12 mmol) , 4- (6-oxo-2-azaspiro [3.3] heptan-2-yl) benzonitrile (30 mg, 0.14 mmol) and AcOH (2 drops) in DCM (5 mL) was stirred at room temperature for 1.5 hours. Then NaBH (OAc) 3 (74 mg, 0.35 mmol) was added, and the mixture was stirred at room temperature for another 2 hours. The resulting solution was diluted with water (10 mL) and extracted with DCM (10 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by Prep-TLC and RP-prep-HPLC to give Cpd 489 (3.2 mg, yield 4%) as a white solid. LC-MS: 625 (M+H) +. 1H NMR (400 MHz, Methanol-d ₄) δ 7.38 –7.19 (m, 6H) , 6.93 –6.84 (m, 1H) , 6.32 (d, 2H) , 5.82 (d, 1H) , 4.07 –3.91 (m, 1H) , 3.86 (s, 2H) , 3.74 (s, 3H) , 3.72 (s, 2H) , 3.40 (s, 3H) , 3.32 –3.23 (m, 1H) , 3.21 –3.13 (m, 2H) , 2.88 –2.70 (m, 2H) , 2.68 –2.49 (m, 2H) , 2.31 –2.19 (m, 2H) , 2.01 –1.95 (m, 2H) , 1.84 –1.78 (m, 1H) , 1.77 –1.61 (m, 3H) , 1.53 –1.45 (m, 1H) , 1.42 –1.30 (m, 2H) , 1.26 –1.22 (m, 1H) , 1.16 –1.04 (m, 3H) , 1.04 –0.94 (m, 1H) .

EXAMPLE 30

Preparation of methyl ( (1S, 2R) -2- ( (1S, 2S) -1- (1- (2- (4-cyanophenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2-hydroxy-2- (1-methyl-1H-pyrazol-3-yl) ethyl) cyclopentyl) carbamate (Cpd 488)

Step A: methyl ( (1S, 2R) -2- ( (1S, 2S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2-hydroxy-2- (1-methyl-1H-pyrazol-3-yl) ethyl) cyclopentyl) carbamate

A solution of methyl ( (1S, 2R) -2- ( (1S, 2S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2-hydroxy-2- (1-methyl-1H-pyrazol-3-yl) ethyl) cyclopentyl) (4-methoxybenzyl) carbamate (200 mg, 0.31 mmol) in TFA (6 mL) was stirred at room temperature for 5 hours. Then the reaction was concentrated under reduced pressure. The residue was diluted with water (10 mL) , and the solution was adjusted to pH 7 ～ 8 with saturated aqueous NaHCO ₃. The mixture was 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 to give methyl ( (1S, 2R) -2- ( (1S, 2S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2-hydroxy-2- (1-methyl-1H-pyrazol-3-yl) ethyl) cyclopentyl) carbamate (190 mg, crude) as a white solid. The residue was used directly in next step. LC-MS: 535 (M+H) ⁺.

Step B: methyl ( (1S, 2R) -2- ( (1S, 2S) -1- (3-fluorophenyl) -2-hydroxy-2- (1-methyl-1H-pyrazol-3-yl) -1- (piperidin-4-yl) ethyl) cyclopentyl) carbamate

A mixture of methyl ( (1S, 2R) -2- ( (1S, 2S) -1- (1-benzylpiperidin-4-yl) -1- (3-fluorophenyl) -2-hydroxy-2- (1-methyl-1H-pyrazol-3-yl) ethyl) cyclopentyl) carbamate (190 mg, 0.36 mmol) , and 10%Pd (OH) ₂/C (95 mg, 50%w/t) in CF ₃CH ₂OH (10 mL) was stirred at room temperature for 4 days under hydrogen atmosphere (1 atm) . The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to give methyl ( (1S, 2R) -2- ( (1S, 2S) -1- (3-fluorophenyl) -2-hydroxy-2- (1-methyl-1H-pyrazol-3-yl) -1- (piperidin-4-yl) ethyl) cyclopentyl) carbamate (120 mg, crude) as a white solid. The residue was used directly in next step. LC-MS: 445 (M+H) ⁺.

Step C: methyl ( (1S, 2R) -2- ( (1S, 2S) -1- (1- (2- (4-cyanophenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2-hydroxy-2- (1-methyl-1H-pyrazol-3-yl) ethyl) cyclopentyl) carbamate (Cpd 488)

A mixture of methyl ( (1S, 2R) -2- ( (1S, 2S) -1- (3-fluorophenyl) -2-hydroxy-2- (1-methyl-1H-pyrazol-3-yl) -1- (piperidin-4-yl) ethyl) cyclopentyl) carbamate (120 mg, 0.27 mmol) , 4- (6-oxo-2-azaspiro [3.3] heptan-2-yl) benzonitrile (63 mg, 0.3 mmol) and AcOH (2 drops) in DCM (5 mL) was stirred at room temperature for 1.5 hour. Then NaBH (OAc) ₃ (114 mg, 0.54 mmol) was added, and the mixture was stirred at room temperature for another 2 hours. The resulting solution was diluted with water (10 mL) and extracted with DCM (10 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by Prep-TLC and RP-prep-HPLC to give Cpd 488 (5 mg, yield 3%) as a white solid. LC-MS: 641 (M+H) ⁺. ¹H NMR (400 MHz, Methanol-d ₄) δ 7.44 –7.14 (m, 7H) , 6.92 –6.81 (m, 1H) , 6.33 (d, 2H) , 4.20 –4.05 (m, 1H) , 3.87 (s, 2H) , 3.82 –3.71 (m, 5H) , 3.55 –3.35 (m, 4H) , 3.05 –2.61 (m, 5H) , 2.33 –2.24 (m, 2H) , 2.08 –1.95 (m, 3H) , 1.80 –1.63 (m, 3H) , 1.48 –1.32 (m, 3H) , 1.24 –1.10 (m, 4H) , 0.91 –0.67 (m, 1H) .

EXAMPLE 31

Preparation of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (4-cyanophenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -2- (5, 5-dimethyl-2-oxooxazolidin-3-yl) -1- (3-fluorophenyl) ethyl) cyclopentyl) carbamate (Cpd 496)

Triphosgene (150 mg) in DCM (5 mL) was added to a solution of 1-chloro-2-methylpropan-2-ol (120 500 mg) in DCM (5 mL) . The resultant mixture was stirred for 10 minutes and then pyridine (0.1 mL) was added and stirred for 1 hour at room temperature. A solution of E3 (500 mg) and trimethylamine (0.48 mL) in dichloromethane (5 mL) was then added to the reaction mixture. The resultant mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated under reduced pressure to remove the dichloromethane and the residue was purified by Flash Column Chromatography (DCM/MeOH as eluent) to give H10. ESI-MS: 588.5.

H10 (336 mg, 0.57 mmol) was dissolved in THF (3 mL) . NaH (92 mg, 2.28 mmol) was added, and the mixture was heated to 60 ℃ for 5 hours. Water was then added, and the mixture was extracted three times with EtOAc, concentrated and purified by Flash Column Chromatography (DCM/MeOH as eluent) to give H11. ESI-MS: 552.4.

To a solution of H11 (195 mg) in methanol (5 mL) was added acetic acid (31 μL, 0.536 mmol) and Pd/C (50 mg, 10%wt) under N ₂ atomsphere. Then the mixture was stirred at room temperature under hydrogen atmosphere (normal pressure) . After 4 hours, the Pd/C catalyst was filtered off, and the solvent was removed by rotary evaporation to give H12, which was used without further purification. ESI-MS: 462.7.

Cpd 496 was prepared from H12 according to the procedure described for the preparation of Cpd 45. ESI-MS: 658.7.

EXAMPLE 32

Preparation of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (4-cyano-3- (dimethylcarbamoyl) -2, 6-difluorophenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) carbamate (Cpd 507)

Step A: 6-bromo-2, 3, 4-trifluorobenzaldehyde

To a stirred mixture of 5-bromo-1, 2, 3-trifluorobenzene (2 g, 9.48 mmol) in THF (20 mL) was added LDA (2 M in THF, 5.7 mL, 11.37 mmol) at –65℃ for 30 minutes. Then DMF (1.1 mL, 14.22 mmol) was added to above solution. The reaction mixture was stirred at this temperature for 3 hours. Then the mixture was quenched with sat. NH ₄Cl aq. (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 6-bromo-2, 3, 4-trifluorobenzaldehyde (1.4 g, yield 62%) as a yellow solid. LC-MS: 239, 241 (M+H) ⁺.

Step B: 6-bromo-2, 3, 4-trifluorobenzoic acid

A mixture of 6-bromo-2, 3, 4-trifluorobenzaldehyde (750 mg, 3.14 mmol) , 2-methyl-2-butene (2.6 mL, 31.38 mmol) , NaClO ₂ (1.4 g, 15.61 mmol) and NaH ₂PO ₄ (1.3 mL, 15.69 mmol) in t-BuOH (20 mL) and THF (10 mL) was stirred at room temperature for 30 minutes. The mixture was adjusted to pH ～ 3 with 1 N HCl aq. 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 to give 6-bromo-2, 3, 4-trifluorobenzoic acid (1 g, crude) as a white solid. LC-MS: 255, 257 (M+H) ⁺.

Step C: 6-bromo-2, 3, 4-trifluoro-N, N-dimethylbenzamide

A mixture of 6-bromo-2, 3, 4-trifluorobenzoic acid (500 mg, 1.96 mmol) , dimethylamine hydrochloride (190 mg, 2.35 mmol) , DIPEA (1.3 mL, 7.84 mmol) and HATU (1.49 g, 3.92 mmol) in DCM (20 mL) was stirred at room temperature for 3 h. 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 6-bromo-2, 3, 4-trifluoro-N, N-dimethylbenzamide (260 mg, yield 47%) as a white solid. LC-MS: 282, 284 (M+H) ⁺.

Step D: 6-cyano-2, 3, 4-trifluoro-N, N-dimethylbenzamide

A mixture of 6-bromo-2, 3, 4-trifluoro-N, N-dimethylbenzamide (140 mg, 0.49 mmol) , dppf (55 mg, 0.09 mmol) , Pd (t-Bu ₃P) ₂ (50 mg, 0.09 mmol) and Zn (CN) ₂ (87 mg, 0.74 mmol) in DMAc (5 mL) was stirred at 100 ℃ under N ₂ atmosphere for 2 hours. The cooled mixture was filtered through a Celite pad, and the filtrate 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 6-cyano-2, 3, 4-trifluoro-N, N-dimethylbenzamide (100 mg, yield 88%) as a white solid. LC-MS: 229 (M+H) ⁺.

Step E: methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (4-cyano-3- (dimethylcarbamoyl) -2, 6-difluorophenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) carbamate (Cpd 507)

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 (50 mg, 0.095 mmol) , 6-cyano-2, 3, 4-trifluoro-N, N-dimethylbenzamide (26 mg, 0.11 mmol) and K ₂CO ₃ (40 mg, 0.29 mmol) in DMSO (5 mL) was stirred at 80℃ overnight. The cooled 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 Prep-TLC and RP-prep-HPLC to give Cpd 507 (7 mg, yield 10%) as a white solid. LC-MS: 732 (M+H) ⁺. ¹H NMR (400 MHz, Methanol-d ₄) δ 7.50 –7.24 (m, 4H) , 7.13 –7.04 (m, 1H) , 6.74 –6.59 (m, 2H) , 4.54 (d, 1H) , 4.42 –4.29 (m, 3H) , 4.23 (s, 2H) , 4.03 –3.93 (m, 1H) , 3.60 (s, 3H) , 3.35 –3.31 (m, 1H) , 3.12 (s, 3H) , 2.98 –2.88 (m, 4H) , 2.84 –2.76 (m, 1H) , 2.66 –2.53 (m, 2H) , 2.44 (s, 3H) , 2.38 –2.30 (m, 2H) , 2.23 –2.15 (m, 1H) , 2.06 –1.96 (m, 3H) , 1.79 –1.64 (m, 3H) , 1.53 –1.42 (m, 1H) , 1.30 –1.06 (m, 5H) , 0.79 –0.64 (m, 1H) .

EXAMPLE 33

Preparation of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (4-cyano-3- (N, N-dimethylsulfamoyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) carbamate (Cpd 510)

Step A: 2- (benzylthio) -4-fluorobenzonitrile

A mixture of 2-bromo-4-fluorobenzonitrile (500 mg, 2.5 mmol) , Pd ₂ (dba) ₃ (115 mg, 0.13 mmol) , Xant-Phos (72 mg, 0.13 mmol) , DIEA (1.2 mL, 7.5 mmol) , and BnSH (0.3 mL, 2.75 mmol) in toluene (10 mL) was stirred at 100℃ under N ₂ temperature overnight. The mixture was washed with water (10 mL) and extracted with EtOAc (10 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 2- (benzylthio) -4-fluorobenzonitrile (469 mg, yield 77%) as a brown solid. LC-MS: 244 (M+H) ⁺.

Step B: 2-cyano-5-fluorobenzenesulfonyl chloride

To a solution of 2- (benzylthio) -4-fluorobenzonitrile (469 mg, 1.93 mmol) in MeCN (8 mL) was added 1, 3-dichloro-5, 5-dimethylimidazolidine-2, 4-dione (570 mg, 2.89 mmol) , 1 N HCl aq. (0.2 mL) and water (0.4 mL) at -15℃. The mixture was stirred at 0 ℃for 2 hours. Then the mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3) . The combined organic layers were washed with brine (30 mL) , dried over Na ₂SO ₄ and concentrated under reduced pressure to give 2-cyano-5-fluorobenzenesulfonyl chloride (400 mg, crude) as a brown solid. LC-MS: 220 (M+H) ⁺.

Step C: 2-cyano-5-fluoro-N, N-dimethylbenzenesulfonamide

A mixture of 2-cyano-5-fluorobenzenesulfonyl chloride (400 mg, 0.91 mmol) , TEA (0.383 mL, 2.73 mmol) and dimethylamine (2 M in THF, 1.8 mL, 3.64 mmol) in DCM (10 mL) was stirred at 0℃ for 2 hours. The mixture was washed with water (10 mL) and extracted with DCM (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 flash column chromatography on silica gel to give 2-cyano-5-fluoro-N, N-dimethylbenzene-1-sulfonamide (103 mg, yield 50%) as a brown solid. LC-MS: 229 (M+H) ⁺.

Methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (4-cyano-3- (N, N-dimethylsulfamoyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) carbamate (Cpd 510) was synthesized from 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 & 2-cyano-5-fluoro-N, N-dimethylbenzene-1-sulfonamide following the procedure for Cpd 6 as a white solid. LC–MS: 732 (M+H) ⁺. ¹H NMR (400 MHz, Methanol-d ₄) δ 7.64 (d, 1H) , 7.47 –7.41 (m, 2H) , 7.36 (m, 1H) , 7.09 (t, 1H) , 6.79 (d, 1H) , 6.69 (d, 1H) , 6.65 (s, 1H) , 6.60 (dd, 1H) , 4.55 (d, 1H) , 4.35 (d, 1H) , 4.05 (s, 2H) , 4.02 –3.96 (m, 1H) , 3.91 (s, 2H) , 3.60 (s, 3H) , 2.93 (d, 1H) , 2.86 –2.74 (m, 8H) , 2.68 –2.58 (m, 2H) , 2.45 (s, 3H) , 2.40 –2.32 (m, 2H) , 2.25 –2.16 (m, 1H) , 2.12 –1.98 (m, 3H) , 1.91 –1.83 (m, 1H) , 1.80 –1.64 (m, 3H) , 1.52 –1.43 (m, 1H) , 1.34 –1.18 (m, 4H) , 0.79 –0.66 (m, 1H) .

EXAMPLE 34

Preparation of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (2-chloro-4- ( (1, 3-dimethyl-1H-pyrazol-4-yl) sulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) carbamate (Cpd 518)

Step A: 4- ( (3-chloro-4-fluorophenyl) thio) -1, 3-dimethyl-1H-pyrazole

A mixture of 3-chloro-4-fluorobenzenethiol (162 mg, 1 mmol) , 4-iodo-1, 3-dimethyl-1H-pyrazole (266 mg, 1.2 mmol) , CuI (190 mg, 1 mmol) , 1, 10-phenanthroline (180 mg, 1 mmol) and C _S2CO ₃ (977 mg, 3 mmol) in toluene (6 mL) was stirred at 100℃ under N ₂ temperature overnight. 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 reduce pressure. The residue was purified by flash column chromatography on silica gel to give 4- ( (3-chloro-4-fluorophenyl) thio) -1, 3-dimethyl-1H-pyrazole (93 mg, yield 36%) as a yellow solid. LC–MS: 257 (M+H) ⁺.

Step B: 4- ( (3-chloro-4-fluorophenyl) sulfonyl) -1, 3-dimethyl-1H-pyrazole

A mixture of 4- ( (3-chloro-4-fluorophenyl) thio) -1, 3-dimethyl-1H-pyrazole (90 mg, 0.35 mmol) and Oxone (432 mg, 0.7 mmol) in acetone (4 mL) and water (4 mL) was stirred at room temperature overnight. Then the reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3) . The combined organic layers were washed with Na ₂S ₂O ₃ aq. (20 mL) and 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 give 4- ( (3-chloro-4-fluorophenyl) sulfonyl) -1, 3-dimethyl-1H-pyrazole (90 mg, yield 89%) as a white solid. LC-MS: 289 (M+H) ⁺.

Then methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (2-chloro-4- ( (1, 3-dimethyl-1H-pyrazol-4-yl) sulfonyl) phenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (2- methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) carbamate (Cpd 518) was synthesized from 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 & 4- ( (3-chloro-4-fluorophenyl) sulfonyl) -1, 3-dimethyl-1H-pyrazole following the procedure for Cpd 45 as a white solid. LC–MS: 792 (M+H) ⁺. ¹H NMR (400 MHz, Methanol-d ₄) δ 7.73 (s, 1H) , 7.62 (d, 1H) , 7.58 (dd, 1H) , 7.47 –7.41 (m, 2H) , 7.35 (d, 1H) , 7.12 –7.06 (m, 1H) , 6.71 –6.62 (m, 2H) , 6.53 (d, 1H) , 4.54 (d, 1H) , 4.37 (d, 1H) , 4.18 (s, 2H) , 4.04 (s, 2H) , 4.01 –3.94 (m, 1H) , 3.76 (s, 3H) , 3.60 (s, 3H) , 2.94 –2.89 (m, 1H) , 2.83 –2.77 (m, 1H) , 2.65 –2.57 (m, 2H) , 2.44 (s, 3H) , 2.41 (s, 3H) , 2.34 –2.28 (m, 2H) , 2.22 –2.15 (m, 1H) , 2.05 –1.97 (m, 3H) , 1.88 –1.82 (m, 1H) , 1.77 –1.64 (m, 3H) , 1.51 –1.45 (m, 1H) , 1.35 –1.29 (m, 3H) , 1.25 –1.17 (m, 2H) , 0.77 –0.65 (m, 1H) .

EXAMPLE 35

Preparation of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (4-cyano-3- (dimethylcarbamoyl) -5-fluoro-2-methylphenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) carbamate (Cpd 519)

Step A: 3-fluoro-2-iodo-6-methylbenzoic acid

A mixture of 5-fluoro-2-methylbenzoic acid (5 g, 32.4 mmol) , NIS (8 g, 35.7 mmol) , and Pd (OAc) ₂ (0.4 g, 1.62 mmol) in DMF (20 ml) was stirred at 100℃ under N ₂ temperature for 16 hours. Then the reaction was quenched with sat. Na ₂SO ₃ aq. (2 mL) . The resulting solution 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 to give 3-fluoro-2-iodo-6-methylbenzoic acid (7 g, crude) as a white solide. The residue was used directly in next step. LC-MS: 279 (M-H) ⁺.

Step B: 3-bromo-5-fluoro-6-iodo-2-methylbenzoic acid

To a solution of 3-fluoro-2-iodo-6-methylbenzoic acid (3 g, 10.7 mmol) in conc. H ₂SO ₄ (30 ml) was added NBS (1.91 g, 10.7 mmol) in portions at 0℃. The reaction was stirred at room temperature for 16 hours. Then the mixture was pooled into ice water (100 mL) slowly and extracted with EtOAc (100 mL x 3) . The combined organic layers were washed with brine (100 mL) , dried over Na ₂SO ₄ and concentrated under reduced pressure to give 3-bromo-5-fluoro-6-iodo-2-methylbenzoic acid (3 g, crude) as a white solid. The residue was used directly in next step. LC-MS: 357, 359 (M-H) ⁺.

Step C: 3-bromo-5-fluoro-6-iodo-N, N, 2-trimethylbenzamide

A solution of 3-bromo-5-fluoro-6-iodo-2-methylbenzoic acid (720 mg, 2 mmol) , HATU (1.1 g, 3 mmol) , DIPEA (0.65 mL, 4 mmol) and dimethylamine (2 M in THF, 2 mL, 4 mmol) in DCM (15 ml) was stirred at room temperature for 2 hours. The resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 2) . The combined organic layers were washed with brine (40 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-5-fluoro-6-iodo-N, N, 2-trimethylbenzamide (500 mg, yield 64%) as a white solid. LC-MS: 386 (M+H) ⁺.

Step D: 3-bromo-6-cyano-5-fluoro-N, N, 2-trimethylbenzamide

A mixture of 3-bromo-5-fluoro-6-iodo-N, N, 2-trimethylbenzamide (300 mg, 0.78 mmol) , Zn (CN) ₂ (110 mg, 0.94 mmol) , dppf (40 mg, 0.08 mmol) and Pd (t-Bu ₃P) ₂ (43 mg, 0.08 mmol) and in DMAc (3 mL) was stirred at 100 ℃ under N ₂ atmosphere for 2 hours. The cooled mixture was filtered through a Celite pad, and the filtrate 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 flash column chromatography on silica gel to give 3-bromo-6-cyano-5-fluoro-N, N, 2-trimethylbenzamide (30 mg, yield 14%) as a white solid. LC-MS: 285 (M+H) ⁺.

Step E: methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (4-cyano-3- (dimethylcarbamoyl) -5-fluoro-2-methylphenyl) -2-azaspiro [3.3] heptan-6-yl) piperidin-4-yl) -1- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) ethyl) cyclopentyl) carbamate (Cpd 519)

A mixture of 3-bromo-6-cyano-5-fluoro-N, N, 2-trimethylbenzamide (20 mg, 0.07 mmol) , 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 (37 mg, 0.07 mmol) , Pd ₂ (dba) ₃ (6 mg, 0.007 mmol) , Ru-Phos (6 mg, 0.014 mmol) and C _S2CO ₃ (46 mg, 0.14 mmol) in toluene (1 ml) was stirred at 100℃ 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 RP-prep-HPLC to give Cpd 519 (2 mg, yield 4%) as a white solid. LC–MS: 728 (M+H) ⁺. ¹H NMR (400 MHz, Methanol-d ₄) δ 7.52 –7.40 (m, 2H) , 7.36 (d, 1H) , 7.09 (t, 1H) , 6.69 (d, 1H) , 6.65 (s, 1H) , 6.23 (d, 1H) , 4.55 (d, 1H) , 4.35 (d, 1H) , 4.17 (s, 2H) , 4.04 (s, 2H) , 4.02 –3.95 (m, 1H) , 3.60 (s, 3H) , 3.12 (s, 3H) , 3.01 –2.86 (m, 4H) , 2.86 –2.76 (m, 1H) , 2.69 –2.54 (m, 2H) , 2.45 (s, 3H) , 2.37 –2.27 (m, 2H) , 2.25 –2.14 (m, 1H) , 2.07 (s, 3H) , 2.03 –1.97 (m, 2H) , 1.92 –1.81 (m, 1H) , 1.80 –1.63 (m, 3H) , 1.54 –1.43 (m, 1H) , 1.40 –1.28 (m, 3H) , 1.28 –1.10 (m, 3H) , 0.80 –0.62 (m, 1H) .

EXAMPLE 36

Preparation of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (8-cyano-2-methyl-1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-5-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 544)

Step A: 2- (5-bromo-2-fluorophenyl) ethan-1-amine

To a solution of 2- (5-bromo-2-fluorophenyl) acetonitrile (13 g, 60.7 mmol) in THF (100 mL) was added BH ₃-THF (2 M in THF, 121.4 mL, 242.8 mmol) at room temperature. Then the mixture was stirred at 80℃ for 18 hours. The cooled mixture was quenched with MeOH (100 mL) and concentrated under reduce pressure. The residue was purified by flash column chromatography on silica gel to give 2- (5-bromo-2-fluorophenyl) ethan-1-amine (6.3 g, yield 47%) as a yellow oil. LC-MS: 218, 220 (M+H) ⁺.

Step B: methyl (5-bromo-2-fluorophenethyl) carbamate

To a solution of 2- (5-bromo-2-fluorophenyl) ethan-1-amine (4 g, 18.3 mmol) and DIPEA (6.7 mL, 36.7 mmol) in DCM (40 mL) was added methyl carbonochloridate (1.7 mL, 22 mmol) at 0℃. Then the mixture was stirred at room temperature for 1.5 hours. The reaction was poured into ice water (40 mL) and extracted with DCM (40 mL x 2) . The combined organic layers were washed with brine (40 mL) , dried over Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give methyl (5-bromo-2-fluorophenethyl) carbamate (4 g, yield 79%) as a yellow oil. LC-MS: 276, 278 (M+H) ⁺.

Step C: 8-bromo-5-fluoro-3, 4-dihydroisoquinolin-1 (2H) -one

A solution of methyl (5-bromo-2-fluorophenethyl) carbamate (5.3 g, 19.2 mmol) in TfOH (25 mL) was stirred at 100℃ for 4 hours. The mixture was poured into the ice water (100 mL) and extracted with EtOAc (100 mL x 2) . The organic phase was washed with sat. NaHCO ₃ aq. (100 mL) and brine (100 mL) , dried over Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 8-bromo-5-fluoro-3, 4-dihydroisoquinolin-1 (2H) -one (500 mg, yield 10%) as a white solid. LC-MS: 244, 246 (M+H) ⁺.

Step D: 8-bromo-5-fluoro-2-methyl-3, 4-dihydroisoquinolin-1 (2H) -one

To a solution of 8-bromo-5-fluoro-3, 4-dihydroisoquinolin-1 (2H) -one (430 mg, 1.8 mmol) in DMF (5 mL) was added NaH (60%in mineral oil, 106 mg, 2.6 mmol) at 0 ℃. The mixture was stirred at 0℃ 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 8-bromo-5-fluoro-2-methyl-3, 4-dihydroisoquinolin-1 (2H) -one (420 mg, yield 92%) as a white solid. LC-MS: 258, 260 (M+H) ⁺.

Step E: 5-fluoro-2-methyl-1-oxo-1, 2, 3, 4-tetrahydroisoquinoline-8-carbonitrile

A mixture of 8-bromo-5-fluoro-2-methyl-3, 4-dihydroisoquinolin-1 (2H) -one (120 mg, 0.46 mmol) , Zn (CN) ₂ (82 mg, 0.7 mmol) , Pd (t-Bu ₃P) ₂ (48 mg, 0.09 mmol) and dppf (52 mg, 0.09 mmol) in DMAc (1 mL) was stirred at 100℃ under Microwave for 1 hour. Then 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 5-fluoro-2-methyl-1-oxo-1, 2, 3, 4-tetrahydroisoquinoline-8-carbonitrile (68 mg, yield 72%) as a white solid. LC-MS: 205 (M+H) ⁺.

Methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (8-cyano-2-methyl-1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-5-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 544) was synthesized from 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 & 5-fluoro-2-methyl-1-oxo-1, 2, 3, 4-tetrahydroisoquinoline-8-carbonitrile following the procedure of Cpd 6 as a white solid. LC–MS: 708 (M+H) ⁺. ¹H NMR (400 MHz, Methanol-d ₄) δ 7.54 –7.36 (m, 4H) , 7.14 (t, 1H) , 6.88 (s, 1H) , 6.75 (s, 1H) , 6.64 (d, 1H) , 4.66 (d, 1H) , 4.42 (d, 1H) , 4.10 (s, 2H) , 4.00 –3.96 (m, 3H) , 3.62 (s, 3H) , 3.53 –3.48 (m, 2H) , 3.25 –3.14 (m, 2H) , 3.12 (s, 3H) , 2.91 – 2.85 (m, 2H) , 2.66 –2.61 (m, 1H) , 2.57 (s, 3H) , 2.53 –2.45 (m, 3H) , 2.40 –2.30 (m, 3H) , 2.23 –2.12 (m, 2H) , 1.90 –1.80 (m, 2H) , 1.65 –1.50 (m, 2H) , 1.35 –1.28 (m, 4H) , 1.27 –1.18 (m, 1H) , 0.80 –0.70 (m, 1H) .

EXAMPLE 37

Preparation of methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (8-cyano-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-5-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 552)

Step A: N- (5-bromo-2-fluorophenethyl) -2, 2, 2-trifluoroacetamide

A mixture of 2- (5-bromo-2-fluorophenyl) ethan-1-amine (4.5 g, 21 mol) and Py (5 mL, 63 mol) in DCM (80 mL) was added (CF ₃CO) ₂O (5.76 mL, 42 mol) at 0 ℃. The mixture was stirred at room temperature for 3 hours. Then the reaction mixture was diluted with ice water (100 mL) and extracted with DCM (80 mL x 3) . The combined organic layers were washed with brine (100 mL) , dried over Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give N- (5-bromo-2-fluorophenethyl) -2, 2, 2-trifluoroacetamide (5.3 g, yield 82%) as a white solid. LC-MS: 314, 316 (M+H) ⁺.

Step B: 1- (8-bromo-5-fluoro-3, 4-dihydroisoquinolin-2 (1H) -yl) -2, 2, 2-trifluoroethan-1-one

To a mixture of N- (5-bromo-2-fluorophenethyl) -2, 2, 2-trifluoroacetamide (5.3 g, 17 mol) in AcOH/H ₂SO ₄ (60 mL/15 mL) was added HCHO (37%in water, 6.8 mL, 84 mol) at 0℃. The mixture was stirred at 50℃ for 16 hours. Then the reaction mixture was diluted with ice water (100 mL) and extracted with EtOAc (80 mL x 3) . The combined organic layers were washed with brine (100 mL) , dried over Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 1- (8-bromo-5-fluoro-3, 4-dihydroisoquinolin-2 (1H) -yl) -2, 2, 2-trifluoroethan-1-one (1.35 g, yield 24%) as a white solid. LC-MS: 326, 328 (M+H) ⁺.

Step C: 8-bromo-5-fluoro-1, 2, 3, 4-tetrahydroisoquinoline

A mixture of 1- (8-bromo-5-fluoro-3, 4-dihydroisoquinolin-2 (1H) -yl) -2, 2, 2-trifluoroethan-1-one (1.35 g, 4.15 mmol) and K ₂CO ₃ (1.7 g, 12.46 mmol) in EtOH/H ₂O (15 mL/15 mL) was stirred at 80℃ for 3 hours. Then the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3) . The combined organic layers were washed with brine (100 mL) , dried over Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 8-bromo-5-fluoro-1, 2, 3, 4-tetrahydroisoquinoline (910 mg, yield 95%) as a white solid. LC-MS: 230, 232 (M+H) ⁺.

Step D: 8-bromo-5-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline

A mixture of 8-bromo-5-fluoro-1, 2, 3, 4-tetrahydroisoquinoline (910 mg, 3.74 mmol) , HCHO (37%in water, 561 mg, 18.7 mmol) and AcOH (2 drops) in MeOH (15 mL) was stirred at room temperature for 30 minutes. After then, NaBH ₃CN (706 mg, 11.2 mmol) was added. The reaction was stirred at this temperature for another 16 hours. Then 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 8-bromo-5-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline (860 mg, yield 82%) as a yellow solid. LC-MS: 244, 246 (M+H) ⁺.

Step E: 5-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-8-carbonitrile

A mixture of 8-bromo-5-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline (500 mg, 2.05 mmol) , Zn (CN) ₂ (288 mg, 2.46 mmol) , dppf (115 mg, 0.2 mmol) and Pd (t-Bu ₃P) ₂ (116 mg, 0.2 mmol) in DMAc (3 ml) was stirred at 110℃ under Microwave for 1 hour. Then the reaction 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 5-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-8-carbonitrile (310 mg, yield 79%) as a yellow solid. LC-MS: 191 (M+H) ⁺.

Then methyl ( (1S, 2R) -2- ( (S) -1- (1- (2- (8-cyano-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-5-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 552) was synthesized from 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 & 5-fluoro-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-8-carbonitrile following the procedure of Cpd 6 as a white solid. LC–MS: 694 (M+H) ⁺. ¹H NMR (400 MHz, Methanol-d ₄) δ 7.50 –7.46 (m, 2H) , 7.37 (d, 2H) , 7.13 –7.10 (m, 1H) , 6.72 (d, 2H) , 6.35 (d, 1H) , 4.57 –4.55 (d, 1H) , 4.39 –4.37 (d, 1H) , 4.07 (s, 2H) , 4.01 –3.97 (m, 1H) , 3.96 (s, 2H) , 3.68 (s, 2H) , 3.61 (s, 3H) , 3.11 –3.04 (m, 1H) , 3.00 –2.77 (m, 2H) , 2.75 –2.70 (m, 4H) , 2.67 –2.60 (m, 1H) , 2.50 (s, 3H) , 2.48 (s, 3H) , 2.41 –2.37 (m, 2H) , 2.35 –2.28 (m, 1H) , 2.20 –2.02 (m, 4H) , 1.98 –1.80 (m, 3H) , 1.77 –1.70 (m, 1H) , 1.54 –1.48 (m, 1H) , 1.39 –1.28 (m, 2H) , 1.24 –1.18 (m, 2H) , 0.79 –0.68 (m, 1H) .

EXAMPLE 38

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, and PCT/US2020/053186. The LCMS (ESI) data for representative Compounds of the Disclosure prepared by these methods are provided in Table 1.

¹H NMR for additional Compounds of the Disclosure is provided in Table 4.

Table 4

EXAMPLE 39

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 Assays 2 and 3

Compound binding potency was also measured by fluorescence-based polarization ligand displacement assay using one of two probes, 36 or 37, against recombinant menin protein, as described in Zhou (2013) with the following adaptations. See Zhou, et al., Structure-Based Design of High-Affinity Macrocyclic Peptidomimetics to Block the Menin-Mixed Lineage Leukemia 1 (MLL1) Protein–Protein Interaction. J. Med. Chem., 2013; 56 (3) : 1113-23. All compounds were prepared as 10 mM stock solutions in DMSO.

For assay of compounds using probe 36 (Binding Assay 2) , binding studies were conducted in buffer containing 100 mM potassium phosphate, pH 7.5; 100 ug/ml bovine gamma globulin, 0.02%sodium azide, 0.005%Triton X-100, and 2%DMSO. A 10-point dose response curve of compound was first added to the wells, followed by buffer solution containing 90 nM recombinant menin protein and 6 nM probe 36. The system was allowed to equilibrate for 60 minutes in the dark at room temperature, and then the FP signal was read at Ex480/Em530. The FP signal data was fit to four-parameter dose equation to allow the extraction of IC50 data.

For assay of compounds using probe 37 (Binding Assay 3) , the assay buffer was 100 mM potassium phosphate 7.5, 100 ug/ml bovine gamma globulin, 0.01%triton X-100, 5%DMSO. A 10-point dose response curve of compound was first added to the wells, followed by assay buffer containing 4 nM recombinant menin protein and 4 nM probe 37. The system was allowed to equilibrate for one hour at room temperature in the dark, and then FP signal was read at Ex480/Em530. The FP signal data was fit to four-parameter dose response equation to allow the extraction of IC50 data.

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

EXAMPLE 40

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

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

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

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

ASPECTS

Aspect 1. A compound having Formula I,

or a pharmaceutically acceptable salt thereof, wherein:

each R ^a is independently selected from the group consisting of H and C ₁-C ₄ alkyl;

each R ^b is independently selected from the group consisting of H and C ₁-C ₄ alkyl;

R ^c is selected from the group consisting of H and halo;

each R ^d is independently selected from the group consisting of halo;

p, q, r and s are independently 1 or 2;

each n is independently 0, 1 or 2;

V is selected from the group consisting of -CH ₂OH, -CH ₂OMe, -CH ₂OEt, -CH ₂NH ₂, -CH ₂NHMe, -CH ₂NMe ₂, -CN, -CO ₂Me, -CO ₂Et, -CH ₂NHCO ₂Me, -CH ₂NHCO ₂Et, -CH ₂NHCO ₂iPr, -CH ₂N (H) CONH 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,

each R ^f is independently selected from the group consisting of H, C ₁-C ₄ alkyl, OH, C ₁-C ₄ alkoxy, and F;

each R ^g is independently selected from the group consisting of H, C ₁-C ₄ alkyl, and NH ₂;

each R is independently C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, or CD ₃;

T is selected from the group consisting of -C ₁-C ₄alkyl, -SO ₂C ₁-C ₄alkyl, -SO ₂-cycloalkyl, -C (O) C ₁-C ₄alkyl, -C (O) aryl,

wherein

R ⁴ is hydrogen or C ₁-C ₄ alkyl;

m is 1 or 2;

J is cyano, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, heterocycloalkylsulfonyl, and carboxamido;

v is 0 or 1;

R ⁶ is halo, haloalkyl, -C ₁-C ₄alkyl, -C (O) C ₁-C ₄alkyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, heterocycloalkylsulfonyl, carboxamido, mesylate, or tert-butoxycarbonyl;

each R ⁷ is independently selected from the group consisting of cyano, halo, haloalkyl, -C ₁-C ₄alkyl, -C (O) C ₁-C ₄alkyl, -OH, sulfonamido, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, heterocycloalkylsulfonyl, or carboxamido;

R ^8a and R ^8b are independently selected from the group consisting of hydrogen, halo, -C ₁-C ₄ alkyl, -C ₁-C ₄ alkoxy, -CH ₂OC ₁-C ₄ alkyl, -CH ₂SO ₂C ₁-C ₄ alkyl and R ^a1;

Z is hydrogen, C ₁-C ₄ alkyl, -C (O) C ₁-C ₄ alkyl, -OH, -CN, -CF ₃, -NO ₂, halo, -NHSO ₂Me, -NHCOMe, -CONH ₂, -CONH (C ₁-C ₄ alkyl) , amino, sulfonamido, alkylsulfonyl and cycloalkylsulfonyl;

R ^a1 is -CN, alkoxyalkyl, alkylsulfonyl, (amino) alkyl, carboxamido, optionally substituted heteroaryl, (heteroaryl) alkyl, -NR ₄C (O) C ₁-C ₄ alkyl, -OCH ₂CH=CH-alkylsulfonyl and (heterocyclo) alkyl;

X is selected from the group consisting of -C ₁-C ₄ alkyl, -C ₁-C ₄ alkenyl, -NH ₂, -NHC ₁-C ₄alkyl, -NH (C ₁-C ₄alkyl) ₂, (amino) alkyl, and -CH ₂CH ₂NR ₄Y-Z ²;

wherein

t and u are independently 0, 1, 2, or 3;

Y is absent or is -C (=O) -, -SO ₂-, -C (=O) NH-, -C (=O) N (Me) -;

Z ² is selected from the group consisting of -C (R ^14a) =C (R ^14b) (R ^14c) , -C≡CR ^14d, haloalkyl, and R ^a2

R ^9a and R ^9b are each independently selected from the group consisting of alkenyl, alkynyl, -CN, -C ₁-C ₄ alkyl, halo, (amino) alkyl, and -C (R ^14a) =C (R ^14b) (R ^14c) ;

each Q ¹ is independently selected from the group consisting of -CH ₂-and -C (=O) -R ¹⁰ is selected from the group consisting of hydrogen, -C ₁-C ₄ alkyl, -NHCOMe, -NHSO ₂Me, -CN, halo, -OCH ₂CH=CH-R ^a3, -CH ₂CH ₂CH=CH-R ^a3;

R ¹¹ is -NHCOC (R ^14a) =C (R ^14b) (R ^14c) , carboxamido, -C (O) NHCH ₂Ra ⁵, -C (O) NHCH ₂C≡CR ^a6, or -CH ₂CH ₂CH=CH-R ^a3;

R ¹³ is hydrogen or C ₁-C ₄ alkyl;

R ^a2 is -N (R ¹⁵) CH ₂CH=CH-R ^a3 or -CH=CHCH ₂R ^a4;

R ^a4 is optionally subsubstituted heterocyclo;

R ^a5 is selected from the group consisting of cyano and (amino) alkyl;

R ^a6 is hydrogen or carboxamido;

R ¹⁵ is hydrogen or C ₁-C ₄ alkyl; and

each W is independently selected from the group consisting of -CH-or -N-.

Aspect 2. The compound of Aspect 1 having Formula X’:

or a pharmaceutically acceptable salt thereof.

Aspect 3. The compound of Aspect 1 having Formula XI’:

or a pharmaceutically acceptable salt thereof.

Aspect 4. The compound of any of Aspects 1 to 3, or a pharmaceutically acceptable salt thereof, wherein:

R ^c is selected from the group consisting of H and halo;

Q is selected from the group consisting of -NHCO ₂Me, -NHCONHMe, -CHCOEt, -NHCOEt, -NHCOMe,

V is selected from the group consisting of

wherein each R ^f is independently selected from the group consisting of H, Me, Et, iPr, OH, and

wherein each R ^g is independently selected from the group consisting of H, Me, Et, iPr and NH ₂.

Aspect 5. The compound of any of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein:

Q is selected from the group consisting of -NHCO ₂Me,

V is

wherein each R ^f is independently selected from the group consisting of H, Me, Et, iPr, and OH.

Aspect 6. The compound of any of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein:

Q is selected from the group consisting of -NHCO ₂Me,

V is

Aspect 7. The compound of any of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Q is -NHCO ₂Me.

Aspect 8. The compound of any of Aspects 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R ^c is halo.

Aspect 9. The compound of any of Aspects 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R ^c is fluoro.

Aspect 10. The compound of any of Aspects 1 to 7, or a pharmaceutically acceptable salt thereof, wherein at least one of R ^8a and R ^8b is halo.

Aspect 11. The compound of any of Aspects 1 to 7, or a pharmaceutically acceptable salt thereof, wherein at least one of R ^8a and R ^8b is fluoro.

Aspect 12. The compound of any of Aspects 1-2, or a pharmaceutically acceptable salt thereof, wherein p, q, r and s are 1.

Aspect 13. The compound of any of Aspects 1 to 7, or a pharmaceutically acceptable salt thereof, wherein one R ^g is C ₁-C ₄ alkyl.

Aspect 14. The compound of any of Aspects 1 to 7, or a pharmaceutically acceptable salt thereof, wherein one R ^g is methyl.

Aspect 15. The compound of any of Aspects 1 to 7, or a pharmaceutically acceptable salt thereof, wherein each R ^g is hydrogen.

Aspect 16. The compound of any of Aspects 1 to 7, or a pharmaceutically acceptable salt thereof, wherein T is T-1, T-2 or T-31.

Aspect 17. The compound of any of Aspects 1 to 7, or a pharmaceutically acceptable salt thereof, wherein T is T-1.

Aspect 18. The compound of any of Aspects 1 to 7, or a pharmaceutically acceptable salt thereof, wherein T is T-2.

Aspect 19. The compound of any of Aspects 1 to 7, or a pharmaceutically acceptable salt thereof, wherein T is T-31.

Aspect 20. The compound of Aspect 17, or a pharmaceutically acceptable salt thereof, wherein X is -CH ₃, X-1, X-11 or X-12.

Aspect 21. The compound of Aspect 17, wherein X is -CH ₃.

Aspect 22. The compound of Aspect 17, wherein X is X-1.

Aspect 23. The compound of Aspect 17, wherein X is X-11.

Aspect 24. The compound of Aspect 17, wherein X is X-12.

Aspect 25. The compound of Aspect 1, wherein the compound is any one or more of the compounds of Table 1, or a pharmaceutically acceptable salt thereof.

Aspect 26. A pharmaceutical composition comprising the compound of any one of Aspects 1-25, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Aspect 27. A method of treating a patient, the method comprising administering to the patient a therapeutically effective amount of the compound of any one of Aspects 1-25, or a pharmaceutically acceptable salt thereof, wherein the patient has cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.

Aspect 28. The method of Aspect 27, wherein the patient has cancer.

Aspect 29. The method of Aspect 28, wherein the cancer is any one or more of the cancers of Table 2.

Aspect 30. The method of Aspect 28, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.

Aspect 31. The method of any one of Aspects 27-30 further comprising administering a therapeutically effective amount of a second therapeutic agent useful in the treatment of the disease or condition.

Aspect 32. The pharmaceutical composition of Aspect 26 for use in treating cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.

Aspect 33. The pharmaceutical composition of Aspect 32 for use in treating cancer.

Aspect 34. The pharmaceutical composition of Aspect 33, wherein the cancer is any one or more of the cancers of Table 2.

Aspect 35. The pharmaceutical composition of Aspect 33, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.

Aspect 36. A compound of any one of Aspects 1-25, or a pharmaceutically acceptable salt thereof, for use in treatment of cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.

Aspect 37. The compound of Aspect 36 for use in treating cancer.

Aspect 38. The compound of Aspect 37, wherein the cancer is any one or more of the cancers of Table 2.

Aspect 39. The compound of Aspect 37, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.

Aspect 40. Use of a compound of any one of Aspects 1-25, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treatment of cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.

Aspect 41. The use of Aspect 40 for treatment of cancer.

Aspect 42. The use of Aspect 41, wherein the cancer is any one or more of the cancers of Table 2.

Aspect 43. The use of Aspect 41, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.

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

A compound having Formula I,

or a pharmaceutically acceptable salt thereof, wherein:

each R ^a is independently selected from the group consisting of hydrogen and C ₁-C ₄ alkyl;

each R ^b is independently selected from the group consisting of hydrogen and C ₁-C ₄ alkyl;

R ^c is selected from the group consisting of hydrogen and halo;

each R ^d is independently selected from the group consisting of halo;

p, q, r and s are independently 1 or 2;

each n is independently 0, 1 or 2;

Q is selected from the group consisting of -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,

V is selected from the group consisting of -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,

each R ^f is independently selected from the group consisting of hydrogen, C ₁-C ₄ alkyl, hydroxy, C ₁-C ₄ alkoxy, and halo;

each R ^g is independently selected from the group consisting of hydrogen, C ₁-C ₄ alkyl, and 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;

T is selected from the group consisting of -C ₁-C ₄ alkyl, C ₁-C ₄ alkylsulfonyl, cycloalkylsulfonyl, -C ₁-C ₄ alkylcarbonyl, arylcarbonyl,

wherein

R ⁴ is hydrogen, C ₁-C ₄ alkyl, C ₁-C ₄ alkylcarbonyl, heterocyclo, and haloalkyl;

each m is independently 1 or 2;

J is hydrogen, cyano, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, heterocycloalkylsulfonyl, and carboxamido;

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 selected from the group consisting of 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 selected from the group consisting of 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, and R ^a1;

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, and cycloalkylsulfonyl;

R ^a1 is cyano, alkoxyalkyl, aralkyloxy, alkylsulfonyl, (amino) alkyl, carboxamido, 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, and (heterocyclo) alkyl;

X is selected from the group consisting of -C ₁-C ₄ alkyl, -C ₂-C ₄ alkenyl, -NH ₂, -NHC ₁-C ₄alkyl, -N (C ₁-C ₄alkyl) ₂, (amino) alkyl, and -CH ₂CH ₂NR ¹Y-Z ²;

wherein

t and u are independently 0, 1, 2, or 3;

Y is absent or is -C (=O) -, -SO ₂-, -C (=O) NH-, -C (=O) N (Me) -;

Z ² is selected from the group consisting of -C (R ^14a) =C (R ^14b) (R ^14c) , -C≡CR ^14d, alkyl, alkoxy, haloalkyl, and R ^a2

R ^9a and R ^9b are each independently selected from the group consisting of alkenyl, alkynyl, cyano, -C ₁-C ₄ alkyl, halo, (amino) alkyl, and -C (R ^14a) =C (R ^14b) (R ^14c) ;

each Q ¹ is independently selected from the group consisting of -CH ₂-and -C (=O) -R ¹⁰ is selected from the group consisting of 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, -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 selected from the group consisting of alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, and carboxamido;

R ¹³ is hydrogen or C ₁-C ₄ alkyl;

R ^14a, R ^14b, R ^14c, and R ^14d are each independently selected from the group consisting of hydrogen, halo, C ₁-C ₄ alkyl, (amino) alkyl, and R ^a3;

R ^a2 is -N (R ¹⁵) CH ₂CH=CH-R ^a3 or -CH=CHCH ₂R ^a4;

R ^a3 is selected from the group consisting of alkoxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, and carboxamido;

R ^a4 is optionally subsubstituted heterocyclo;

R ^a5 is selected from the group consisting of cyano and (amino) alkyl;

R ^a6 is hydrogen or carboxamido;

R ¹⁵ is hydrogen or C ₁-C ₄ alkyl; and

each W is independently selected from the group consisting of -CH-or -N-.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

each R ^a is hydrogen;

each R ^b is hydrogen;

R ^c is selected from the group consisting of hydrogen and halo;

Q is selected from the group consisting of -NHCO ₂Me, -NHCONHMe, -CHCOEt, -NHCOEt, -NHCOMe,

V is selected from the group consisting of
wherein each R ^f is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, hydroxy, and
wherein each R ^g is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl and NH ₂.
The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein p, q, r and s are 1.
A compound of claim 1, having Formula XII, XIII, XIV, XV, or XVI:

or a pharmaceutically acceptable salt thereof.
The compound of any of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein T is T-1, T-2, T-3, T-29, or T-32.
The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein T is T-1 or T-2.
The compound of any of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein T is T-14, T-15, T-16, T-17, T-18, T-19, T-24, T-25, T-26, T-31, or T-36.
The compound of any of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Z is cyano, haloalkyl, alkylsulfonyl, or cycloalkylsulfonyl.
The compound of claim 1, having Formula XI:

or a pharmaceutically acceptable salt thereof.
The compound of any of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein:

Q is selected from the group consisting of -NHCO ₂Me,

V is
wherein each R ^f is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, and hydroxy.
The compound of any of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein:

Q is selected from the group consisting of -NHCO ₂Me,

V is
wherein each R ^g is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, and NH ₂.
The compound of any of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein Q is -NHCO ₂Me.
The compound of claim 1, having Formula XVIII:

or a pharmaceutically acceptable salt thereof.
The compound of any of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R ^c is halo.
The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R ^c is fluoro.
The compound of any of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein at least one of R ^8a and R ^8b is halo.
The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein at least one of R ^8a and R ^8b is fluoro.
The compound of any of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein X is X-1, X-10, X-16, X-17, X-18, X-19, or X-20.
The compound of any of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein, wherein X is X-2 or X-3.
The compound of any of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein, wherein X is X-5 or X-21.
The compound of any of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein, wherein X is X-11 or X-12.
The compound of any of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein one R ^g is C ₁-C ₄ alkyl.
The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein one R ^g is methyl.
The compound of claim 1, having Formula XXIV or XXX:

or a pharmaceutically acceptable salt thereof.
The compound according to claim 24, or a pharmaceutically acceptable salt thereof, wherein X is -CH ₃, -NH ₂, X-1, X-2, X-3, X-5, X-16, or X-18;

Z is cyano, haloalkyl, alkylsulfonyl, or cycloalkylsulfonyl; and

R ^8b is hydrogen, -CH ₂NMe ₂, -C (O) NMe ₂, -C ₁-C ₄ alkoxy, -CH ₂OC ₁-C ₄ alkyl,
The compound of claim 1, having Formula XXVI or XLII:

or a pharmaceutically acceptable salt thereof.
The compound according to claim 26, or a pharmaceutically acceptable salt thereof, wherein R ^8b is -CH ₂NMe ₂, -C (O) NMe ₂, -C ₁-C ₄ alkoxy, -CH ₂OC ₁-C ₄ alkyl,

X is X-1, X-2, X-3, X-5, X-6, X-11, X-12, X-13, X-14, X-16, X-18, X-19, X-20, X-21, X-22, or X-23; and

Z is cyano, haloalkyl, alkylsulfonyl, or cycloalkylsulfonyl.
The compound according to any one of claims 1-8 and 24-27, or a pharmaceutically acceptable salt thereof, wherein Z is cyano, -CF ₃, methylsulfonyl, or cyclopropylsulfonyl.
The compound of claim 1, wherein the compound is any one or more of the compounds of Table 1, or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising the compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
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 1-29, 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.
The method of claim 31, wherein the patient has cancer.
The method of claim 32, wherein the cancer is any one or more of the cancers of Table 2.
The method of claim 32, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.
The method of any one of claims 31-34 further comprising administering a therapeutically effective amount of a second therapeutic agent useful in the treatment of the disease or condition.
The pharmaceutical composition of claim 30 for use in treating cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.
The pharmaceutical composition of claim 36 for use in treating cancer.
The pharmaceutical composition of claim 37, wherein the cancer is any one or more of the cancers of Table 2.
The pharmaceutical composition of claim 37, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.
A compound of any one of claims 1-29, 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.
The compound of claim 40 for use in treating cancer.
The compound of claim 41, wherein the cancer is any one or more of the cancers of Table 2.
The compound of claim 41, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.
Use of a compound of any one of claims 1-29, 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.
The use of claim 44 for treatment of cancer.
The use of claim 45, wherein the cancer is any one or more of the cancers of Table 2.
The use of claim 45, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia.