KIF18A inhibitors and their uses

Abstract

Provided herein are compounds of formula (I) TIFF2025529821000230.tif2455, or a pharmaceutically acceptable salt thereof, which is useful for inhibiting KIF18A and treating various KIF18A-mediated conditions or diseases, such as cancer.

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 63 / 463,617, filed May 3, 2023, and U.S. Provisional Application No. 63 / 399,003, filed August 18, 2022. The entire contents of each of the foregoing applications are expressly incorporated herein by reference.

[0002] The present disclosure relates to inhibitors of kinesin family member 18A (KIF18A) and pharmaceutically acceptable salts thereof, compositions of these compounds, processes for their preparation, and their use in the treatment of disease. [Background technology]

[0003] Chromosomal abnormalities, such as aneuploidy, are common in various types of cancer. For example, whole-genome duplications have been found in over 30% of tumors and can serve as biomarkers for tumorigenesis (Prasad et al., Cancer Res. 2022 May 3;82(9):1736-1752; Bielski et al., Nat Genet. 2018 Aug;50(8):1189-1195). This genomic instability and duplication is thought to be the result of errors in cell division and proliferation, which cause or support the rapid cell division characteristic of cancer cells (Davoli, Annu Rev Cell Dev Biol. 2011;27:585-610). To target this rapid cell division and genetic instability, many conventional anticancer drugs, such as paclitaxel, target tubulin and block cell mitosis. However, these drugs are generally cytotoxic and often suffer from side effects and off-target toxicity. Therefore, research is focused on compounds that are more selective and have fewer side effects.

[0004] Kinesin family member 18A (KIF18A), as its name suggests, is a member of the kinesin protein family. The kinesin protein family is a group of motor proteins that utilize ATP hydrolysis to move along microtubule filaments and support mitosis and meiosis. KIF18A has been shown to be an important enzyme in the growth of cancers with chromosomal instability (Marquis et al., Nat Commun. 2021 Feb 22;12(1):1213). Furthermore, KIF18A knockout models demonstrate viability in non-cancer cells and mice, indicating that KIF18A is not essential for normal cell division, potentially enabling targeting with fewer side effects than essential targets (Tamayo et al., J Med Chem. 2022 Mar 24;65(6):4972-4990). The clinical utility of inhibitors of the kinesin motor protein class (e.g., KIF18A) has been limited by several properties of these compounds. These include high extracellular elimination, a long pharmacokinetic terminal half-life, and dose-limiting bone marrow suppression, particularly neutropenia and thrombocytopenia. These side effects have also been observed with inhibitors of the kinesin motor protein KIF11 (Eg-5), as discussed in detail in P. Navais, et al., Pharmaceutics 2021, 13, 1011.

[0005] Therefore, there is a need for KIF18A inhibitors that are potential therapeutic agents for the treatment of diseases or disorders that respond to KIF18A inhibition. In particular, there is a need for compounds that exhibit improved properties as described above (i.e., improved extracellular elimination, different pharmacokinetic terminal half-lives, and reduced bone marrow suppression, particularly reduced neutropenia and thrombocytopenia). Summary of the Invention

[0006] The present disclosure provides compounds that are KIF18A inhibitors. In a first aspect, the present disclosure provides a compound having formula I: [ka] or a pharmaceutically acceptable salt thereof, X 1 and X 2 However, each is independently CR 5 or N and X 3 is CR 4 or N, Ring A is phenyl, 6-membered heteroaryl, 6,5-bicyclic heteroaryl, or 4-10-membered monocyclic or bicyclic heterocyclyl; Z is *-NHC(O)- or *-C(O)NH-, where *- represents the bond to ring A; o is an integer from 0 to 3, R 1 But C 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, OR O1a , SO2R 1a , N.R. N1a SO2R 1a , N.R. N1a R N1b , -C(O)R 1a , halo, cyano, where C 1-6 Alkyl, C 3-6 Cycloalkyl and 3- to 6-membered monocyclic heterocyclyl each have one or more R 1b optionally substituted with R 1a But C 1-6 Alkyl, NR N1a R N1b , OR O1a , C 3-6 cycloalkyl, or 3- to 6-membered monocyclic heterocyclyl, where C 1-6 Alkyl, C 3-6 Cycloalkyl and 3- to 6-membered monocyclic heterocyclyl each have one or more R 1b optionally substituted with Each R 1b are independently halo, cyano, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, and C 1-6 haloalkoxy; or two R's 1b together with the atom(s) to which they are attached, form C 3-6 forming a cycloalkyl, R N1a and R N1b are each independently H and C 1-6 alkyl, wherein C 1-6 Alkyl is one or more R 1b optionally substituted with R O1a is H or C 1-6 alkyl, where C 1-6 Alkyl is one or more R 1b optionally replaced by R 2 But H, C 1-6 Alkyl, SO2R 2a , N.R. N2a SO2R 2a , OR O2a , S(O)(NR N2c )R 2a , halo, cyano, -C(O)R 2a , or NR N2a R N2b where C 1-6 Alkyl is one or more R 2b optionally replaced by R 2a But C 1-6 Alkyl, NR N2a R N2b , OR O2a , C 3-6 cycloalkyl, or 3- to 6-membered monocyclic heterocyclyl, where C 1-6 Alkyl, C 3-6 Cycloalkyl and heterocyclyl each have one or more R 2b optionally substituted with Each R 2b But independently, C 1-6 Alkyl, halo, hydroxy, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -N(R N2c )2, and -C(O)OC 1-6 alkyl, RN2a and R N2b are each independently H and C 1-6 alkyl, wherein C 1-6 Alkyl is one or more R 2b optionally substituted with Each R N2c However, independently, H, C 1-3 Alkyl, -C(O)(C 1-3 alkyl), R O2a is H or C 1-6 alkyl, where C 1-6 Alkyl is one or more of halo, hydroxy, C 1-6 Alkoxy or C 1-6 optionally substituted with haloalkoxy, R 3 But C 3-6 cycloalkyl, phenyl, or 3- to 6-membered monocyclic heterocyclyl, wherein the 3- to 6-membered monocyclic heterocyclyl is selected from one or more R 3a optionally substituted with Each R 3a But independently, Halo, C 1-6 Haloalkyl, or C 1-6 alkyl, or two R 3a together with the atom(s) to which they are attached form one or more R 3b C replaced with 3-6 forming a cycloalkyl, Each R 3b But independently, H, halo, C 1-6 Alkoxy and one or more halo, OH, or C 1-3 C optionally substituted with alkoxy 1-6 alkyl, R 4 But H, C 1-6 Alkyl, C 1-6 haloalkyl or halo, R 5 is H, halo, or C 1-6 is alkyl, Each R 6 But independently, C 1-6 Alkyl, C1-6 haloalkyl or halo, However, when ring A is phenyl or 6-membered heteroaryl, R 3 teeth, [ka] where j is 0 or 1. In some embodiments, R 2 But C 1-6 Alkyl, SO2R 2a , N.R. N2a SO2R 2a , OR O2a , halo, cyano, -C(O)R 2a , or NR N2a R N2b where C 1-6 Alkyl is one or more R 2b with the remaining variables as defined above.

[0007] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier.

[0008] In yet another aspect, the present disclosure provides a method for treating a disease or disorder responsive to the inhibition of KIF18A in a subject, comprising administering to the subject an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the method is for treating cancer.

[0009] Another aspect of the present disclosure relates to the use of at least one compound described herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease or disorder that responds to the inhibition of KIF18A.Also provided is a compound described herein or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder that responds to the inhibition of KIF18A.

[0010] In some embodiments, the compounds of the present disclosure exhibit reduced efflux, particularly compared to similar compounds known in the art. The advantages of compounds with reduced efflux include overcoming resistance in cells with increased expression of efflux pumps, broader disease applicability and targeting potential, and increased intracellular concentrations.

[0011] In some embodiments, the compounds of the present disclosure have reduced cytotoxicity to bone marrow cells, particularly compared to similar compounds known in the art. In some embodiments, these compounds have a fast terminal half-life and / or clearance, resulting in less systemic exposure and a reduced risk of toxicity to bone marrow cells. The benefits of compounds with reduced reactivity to bone marrow cells are well known, for example, patients treated with the compounds have a reduced risk of cytopenias, such as neutropenia and thrombocytopenia. DETAILED DESCRIPTION OF THE INVENTION

[0012] The present disclosure provides compounds and pharmaceutical compositions thereof that may be useful for treating diseases or disorders mediated by KIF18A function / activity. In some embodiments, the compounds of the present disclosure are KIF18A inhibitors. [Brief explanation of the drawings]

[0013] [Figure 1A] 1 shows the in vivo efficacy of the compound of Example 9 and Compound A in OVCAR-3 xenografts over 28 days. [Figure 1B] 1 shows the tolerability of the compound of Example 9 and Compound A in a 28-day in vivo efficacy study in OVCAR-3 xenografts. [Figure 2A] Figure 1 shows the in vivo efficacy of the compound of Example 1 and Compound A in OVCAR-3 xenografts over 28 days. Tumor volume over time. [Figure 2B] 1 shows the tolerability of the compound of Example 1 and Compound A in a 28-day in vivo efficacy study in OVCAR-3 xenografts. [Figure 3A]1 shows the in vivo efficacy of the compound of Example 29b and Compound A in OVCAR-3 xenografts over 28 days. [Figure 3B] Figure 1 shows the tolerability of the compound of Example 29b and Compound A in a 28-day in vivo efficacy study in OVCAR-3 xenografts.

[0014] Compounds and Compositions In a first embodiment, the present disclosure provides a compound of formula (I) [ka] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (I) are as defined below: X 1 and X 2 However, each is independently CR 5 or N and X 3 is CR 4 or N, Ring A is phenyl, 6-membered heteroaryl, 6,5-bicyclic heteroaryl, or 4-10-membered monocyclic or bicyclic heterocyclyl; Z is *-NHC(O)- or *-C(O)NH-, where *- represents the bond to ring A; o is an integer from 0 to 3, R 1 But C 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, OR O1a , SO2R 1a , N.R. N1a SO2R 1a , N.R. N1a R N1b , -C(O)R 1a , halo, cyano, where C 1-6 Alkyl, C 3-6 Cycloalkyl and 3- to 6-membered monocyclic heterocyclyl each have one or more R 1b optionally substituted with R 1a But C 1-6 Alkyl, NR N1a R N1b , ORO1a , C 3-6 cycloalkyl, or 3- to 6-membered monocyclic heterocyclyl, where C 1-6 Alkyl, C 3-6 Cycloalkyl and 3- to 6-membered monocyclic heterocyclyl each have one or more R 1b optionally substituted with Each R 1b independently halo, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkoxy; or two R's 1b together with the atoms to which they are bonded, C 3-6 forming a cycloalkyl, R N1a and R N1b are each independently H and C 1-6 alkyl, wherein C 1-6 Alkyl is one or more R 1b optionally substituted with R O1a is H or C 1-6 alkyl, where C 1-6 Alkyl is one or more R 1b optionally replaced by R 2 But H, C 1-6 Alkyl, SO2R 2a , N.R. N2a SO2R 2a , OR O2a , halo, cyano, -C(O)R 2a , or NR N2a R N2b where C 1-6 Alkyl is one or more R 2b optionally replaced by R 2a But C 1-6 Alkyl, NR N2a R N2b , OR O2a , C 3-6 cycloalkyl, or 3- to 6-membered monocyclic heterocyclyl, where C 1-6 Alkyl, C 3-6Cycloalkyl and heterocyclyl each have one or more R 2b optionally substituted with Each R 2b But independently, C 1-6 Alkyl, halo, hydroxy, C 1-6 Alkoxy, C 1-6 Haloalkoxy and -C(O)OC 1-6 alkyl, R N2a and R N2b are each independently H and C 1-6 alkyl, wherein C 1-6 Alkyl is one or more R 2b optionally substituted with R O2a is H or C 1-6 alkyl, where C 1-6 Alkyl is one or more of halo, hydroxy, C 1-6 Alkoxy or C 1-6 optionally substituted with haloalkoxy, R 3 But C 3-6 cycloalkyl, phenyl, or 3- to 6-membered monocyclic heterocyclyl, wherein the 3- to 6-membered monocyclic heterocyclyl is selected from one or more R 3a optionally substituted with Each R 3a may be independently halo or C 1-6 alkyl, or two R 3a together with the atoms to which they are bonded, C 3-6 forming a cycloalkyl, R 4 But H, C 1-6 Alkyl, C 1-6 haloalkyl or halo, R 5 But H or C 1-6 is alkyl, Each R 6 But independently, C 1-6 Alkyl, C 1-6 haloalkyl or halo, However, when ring A is phenyl or 6-membered heteroaryl, R3 teeth [ka] is.

[0015] In an alternative first embodiment, the present disclosure provides a compound of formula (I) [ka] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (I) are as defined below: X 1 and X 2 However, each is independently CR 5 or N and X 3 is CR 4 or N, Ring A is phenyl, 6-membered heteroaryl, 6,5-bicyclic heteroaryl, or 4-10-membered monocyclic or bicyclic heterocyclyl; Z is *-NHC(O)- or *-C(O)NH-, where *- represents the bond to ring A; o is an integer from 0 to 3, R 1 But C 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, OR O1a , SO2R 1a , N.R. N1a SO2R 1a , N.R. N1a R N1b , -C(O)R 1a , halo, cyano, where C 1-6 Alkyl, C 3-6 Cycloalkyl and 3- to 6-membered monocyclic heterocyclyl each have one or more R 1b optionally substituted with R 1a But C 1-6 Alkyl, NR N1a R N1b , OR O1a , C 3-6 cycloalkyl, or 3- to 6-membered monocyclic heterocyclyl, where C 1-6Alkyl, C 3-6 Cycloalkyl and 3- to 6-membered monocyclic heterocyclyl each have one or more R 1b optionally substituted with Each R 1b independently halo, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 haloalkoxy; or two R's 1b together with the atoms to which they are bonded, C 3-6 forming a cycloalkyl, R N1a and R N1b are each independently H and C 1-6 alkyl, wherein C 1-6 Alkyl is one or more R 1b optionally substituted with R O1a is H or C 1-6 alkyl, where C 1-6 Alkyl is one or more R 1b optionally replaced by R 2 But H, C 1-6 Alkyl, SO2R 2a , N.R. N2a SO2R 2a , OR O2a , halo, cyano, -C(O)R 2a , or NR N2a R N2b where C 1-6 Alkyl is one or more R 2b optionally replaced by R 2a But C 1-6 Alkyl, NR N2a R N2b , OR O2a , C 3-6 cycloalkyl, or 3- to 6-membered monocyclic heterocyclyl, where C 1-6 Alkyl, C 3-6 Cycloalkyl and heterocyclyl each have one or more R 2b optionally substituted with Each R2b But independently, C 1-6 Alkyl, halo, hydroxy, C 1-6 Alkoxy, C 1-6 Haloalkoxy and -C(O)OC 1-6 alkyl, R N2a and R N2b are each independently H and C 1-6 alkyl, wherein C 1-6 Alkyl is one or more R 2b optionally substituted with R O2a is H or C 1-6 alkyl, where C 1-6 Alkyl is one or more of halo, hydroxy, C 1-6 Alkoxy or C 1-6 optionally substituted with haloalkoxy, R 3 But C 3-6 cycloalkyl, phenyl, or 3- to 6-membered monocyclic heterocyclyl, wherein the 3- to 6-membered monocyclic heterocyclyl is selected from one or more R 3a optionally substituted with Each R 3a may be independently halo or C 1-6 alkyl, or two R 3a together with the atom(s) to which they are attached, form one or more R 3b C replaced with 3-6 forming a cycloalkyl, Each R 3b But independently, H, halo, C 1-6 Alkoxy and C optionally substituted with one or more halo or OH 1-6 alkyl, R 4 But H, C 1-6 Alkyl, C 1-6 haloalkyl or halo, R 5 But H or C 1-6 is alkyl, Each R 6 But independently, C 1-6 Alkyl, C1-6 haloalkyl or halo, However, when ring A is phenyl or 6-membered heteroaryl, R 3 teeth [ka] is.

[0016] In a second embodiment, for compounds of Formula (I) or pharmaceutically acceptable salts thereof, Z is *-C(O)NH-, where *- represents attachment to ring A, and the remainder of the variables are as described in the first embodiment, or first aspect, or any alternative embodiment described therein.

[0017] In a third embodiment, for the compounds of formula (I) or pharmaceutically acceptable salts thereof, ring A is phenyl, 6-membered heteroaryl, or 6,5-bicyclic heteroaryl, each of which is R 2 , R 3 , and 0 to 1 R 6 and the remaining variables are as described in the first or second embodiment, or the first aspect, or any alternative embodiments described therein. In an alternative third embodiment, for compounds of formula (I) or pharmaceutically acceptable salts thereof, ring A is phenyl, 6-membered heteroaryl, or 6,5-bicyclic heteroaryl, each of which is R 2 , R 3 , and 0 to 2 R 6 and the remaining variables are as described in the first or second embodiment, or first aspect, or any alternative embodiment described therein.

[0018] In a fourth embodiment, for the compounds of formula (I) or pharmaceutically acceptable salts thereof, ring A is phenyl, pyridinyl, or indazolyl, each of which is R 2 , R 3 , and 0 to 1 R 6and the remaining variables are as described in the first, second, or third embodiment, or the first aspect, or any alternative embodiments described therein. In an alternative fourth embodiment, for compounds of formula (I) or pharmaceutically acceptable salts thereof, ring A is phenyl, pyrazinyl, pyridinyl, or indazolyl, each of which is R 2 , R 3 , and 0 to 2 R 6 and the remaining variables are as described in the first, second, or third embodiment, or first aspect, or any alternative embodiment described therein.

[0019] In a fifth embodiment, for compounds of formula (I) or pharmaceutically acceptable salts thereof, ring A is [ka] and R 2 , R 3 , and 0 to 1 R 6 and the remaining variables are as described in the fourth embodiment, or the first aspect, or any alternative embodiments described therein. In an alternative fifth embodiment, for compounds of formula (I) or pharmaceutically acceptable salts thereof, ring A is substituted with the structural formula [ka] and R 2 , R 3 , and 0 to 2 R 6 and the remaining variables are as described in the fourth embodiment, or the first aspect, or any alternative embodiments described therein.

[0020] In a sixth embodiment, for compounds of formula (I) or pharmaceutically acceptable salts thereof, ring A is a group represented by the structural formula [ka] and the remaining variables are as described in the fourth embodiment, or the first aspect, or any alternative embodiment described therein. In an alternative sixth embodiment, for compounds of formula (I) or a pharmaceutically acceptable salt thereof, ring A is represented by the structural formula [ka] and the remaining variables are as described in the fourth embodiment, or the first aspect, or any alternative embodiment described therein. In another alternative sixth embodiment, for compounds of formula (I) or a pharmaceutically acceptable salt thereof, ring A is represented by the structural formula [ka] and the remaining variables are as described in the fourth embodiment, or the first aspect, or any alternative embodiment described therein.

[0021] In a seventh embodiment, for compounds of formula (I) or pharmaceutically acceptable salts thereof, ring A is R 2 and R 3 and the remainder of the variables are as described in the first, second, or third embodiment, or the first aspect, or any alternative embodiment described therein.

[0022] In an eighth embodiment, for compounds of formula (I) or pharmaceutically acceptable salts thereof, ring A is a group represented by the structural formula [ka] and the remaining variables are as described in the seventh embodiment, or the first aspect, or any alternative embodiment described therein.

[0023] In a ninth embodiment, the compound of the present disclosure has the formula (IA) [ka] a compound represented by or a pharmaceutically acceptable salt thereof, wherein the variable R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , and X 3 is as described in the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiment, or the first aspect, or any alternative embodiment therein.

[0024] In a tenth embodiment, for a compound of formula (I) or formula (IA), or a pharmaceutically acceptable salt thereof, X 1 and X 2 Both N and X 3 is CR 4 or X 1 and X 3 Both N and X 2 is CR 5 and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment, or the first aspect, or any alternative embodiment therein.

[0025] In an eleventh embodiment, for a compound of formula (I) or formula (IA), or a pharmaceutically acceptable salt thereof, X 3 is CR 4 and X 1 or X 2 One of them is N and the other is CR 5 and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment, or the first aspect, or any alternative embodiment therein.

[0026] In a twelfth embodiment, for a compound of formula (I) or formula (IA), or a pharmaceutically acceptable salt thereof, X 3 is CR 4 and X 1 and X 2 Both are CR 5and the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment, or any alternative embodiment therein.

[0027] In a thirteenth embodiment, for compounds of Formula (I) or Formula (IA), or pharmaceutically acceptable salts thereof, R 4 is H and R 5 is H or -CH3, and the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment, or the first aspect, or any alternative embodiment described therein. In an alternative thirteenth embodiment, for a compound of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt thereof, R 4 is H or -CH3, and R 5 is H or -CH3, and the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment, or the first aspect, or any alternative embodiment described therein. In another alternative thirteenth embodiment, for a compound of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt thereof, R 4 is H or -CH3, and R 5 is H, F, or -CH3, and the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment, or the first aspect, or any alternative embodiment therein.

[0028] In a fourteenth embodiment, for a compound of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt thereof, R 3 1 to 3 R 3aand the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment, or the first aspect, or any alternative embodiments described therein. In an alternative fourteenth embodiment, for a compound of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt thereof, R 3 1 to 3 R 3a and the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment, or the first aspect, or any alternative embodiment described therein.

[0029] In a fifteenth embodiment, for compounds of Formula (I) or Formula (IA), or pharmaceutically acceptable salts thereof, R 3 is piperidinyl or 1,4-azasirinanyl, each of which has 1 to 3 R 3a and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment, or the first aspect, or any alternative embodiment described therein. In an alternative fifteenth embodiment, for a compound of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt thereof, R 3 is piperidinyl, 1,3-azasilolidinyl, or 1,4-azasirinanyl, each of which is 1 to 3 R 3a and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment, or the first aspect, or any alternative embodiment therein.

[0030] In a sixteenth embodiment, for compounds of Formula (I) or Formula (IA), or pharmaceutically acceptable salts thereof, R 3 is the structural formula [ka] Each is represented by 1 to 3 R 3a and the remaining variables are as described in the fifteenth embodiment, or the first aspect, or any alternative embodiment described therein. In an alternative sixteenth embodiment, for a compound of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt thereof, R 3 is the structural formula [ka] where j is 0 or 1, and each j is 1 to 3 R 3a and the remaining variables are as described in the fifteenth embodiment, or the first aspect, or any alternative embodiment described therein.

[0031] In a seventeenth embodiment, for compounds of Formula (I) or Formula (IA), or pharmaceutically acceptable salts thereof, R 3 is the structural formula [ka] Each R 3a C 1-3 alkyl or two R 3a together with the atoms to which they are bonded to form C 3-6 and the remaining variables are as described in the sixteenth embodiment, or the first aspect, or any alternative embodiment described therein. In an alternative seventeenth embodiment, for a compound of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt thereof, R 3 is the structural formula [ka] Each R 3a C 1-3 alkyl or two R 3a together with the atom(s) to which they are attached, form 1 to 3 R 3bC is replaced by 3-6 and the remaining variables are as described in the sixteenth embodiment, or the first aspect, or any alternative embodiment described therein. In another alternative seventeenth embodiment, for compounds of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt thereof, R 3 is the structural formula [ka] Each R 3a C 1-3 alkyl or two R 3a together with the atom(s) to which they are attached, form 1 to 3 R 3b C is replaced by 3-6 cycloalkyl, and the remainder of the variables are as described in the sixteenth embodiment, or the first aspect, or any alternative embodiment described therein.

[0032] In an eighteenth embodiment, for a compound of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt thereof, each R 3a is -CH3 or two R 3a are taken together with the atom to which they are attached to form a cyclopropyl, and the remainder of the variables are as described in the seventeenth embodiment or the first aspect. In an alternative eighteenth embodiment, for compounds of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt thereof, each R 3a is -CH3 alkyl, or two R 3a together with the atom(s) to which they are attached, form 1 to 3 R 3b and forming a cyclopropyl group substituted with each R 3b is independently H, halo, -CH3, -CHF2, or -CH2OH, and the remaining variables are as described in the seventeenth embodiment, or the first aspect, or any alternative embodiment described therein. In another alternative eighteenth embodiment, for a compound of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt thereof, each R 3ais -CH3 or -CH2CH3, or two R 3a together with the atom(s) to which they are attached, form 1 to 3 R 3b and forming a cyclopropyl or cyclobutyl substituted with each R 3b is independently H, halo, —CH, —OCH, —CHF, —CHF, —CF, —CFCH, —CHOCH, or —CHOH, and the remainder of the variables are as described in the seventeenth embodiment, or the first aspect, or any alternative embodiment described therein.

[0033] In a nineteenth embodiment, for compounds of Formula (I) or Formula (IA), or pharmaceutically acceptable salts thereof, R 3 is the structural formula [ka] and the remaining variables are as described in the eighteenth embodiment, or the first aspect, or any alternative embodiment described therein. In an alternative nineteenth embodiment, for a compound of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt thereof, R 3 is the structural formula [ka] and the remaining variables are as described in the eighteenth embodiment, or the first aspect, or any alternative embodiment described therein. In another alternative nineteenth embodiment, for a compound of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt thereof, R 3 is the structural formula [ka] and the remaining variables are as described in the eighteenth embodiment, or the first aspect, or any alternative embodiment described therein.

[0034] In a twentieth embodiment, for a compound of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt thereof, each R3a is —CH 3 , and the remainder of the variables are as described in the eighteenth embodiment, or the first aspect, or any alternative embodiment described therein.

[0035] In a twenty-first embodiment, for a compound of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt thereof, R 1 But C 3-6 Cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, OR O1a , or SO2R 1a and C 3-6 Cycloalkyl and 3- to 6-membered monocyclic heterocyclyl each have 1 to 3 R 1b optionally substituted with R 1a -NHR N1b or C 3-6 is cycloalkyl, and R N1b But one or two R 1b C optionally substituted with 1-4 alkyl and R O1a However, 1 to 3 R 1b C optionally substituted with 1-3 alkyl, and each R 1b but independently, halo and C 1-3 alkyl, or two R 1b together with the atoms to which they are bonded, C 3-6 and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment, or the first aspect, or any alternative embodiment described therein. In an alternative twenty-first embodiment, for a compound of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt thereof, R 1 But C 3-6 Cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, OR O1a , or SO2R 1a and C 3-6 Cycloalkyl and 3- to 6-membered monocyclic heterocyclyl each have 1 to 3 R 1boptionally substituted with R 1a But, -NHR N1b , C 3-6 cycloalkyl, or 3- to 6-membered monocyclic heterocyclyl, wherein the 3- to 6-membered monocyclic heterocyclyl is optionally substituted with 1 to 3 halo; R N1b But one or two R 1b C optionally substituted with 1-4 alkyl and R O1a However, 1 to 3 R 1b C optionally substituted with 1-3 alkyl, and each R 1b but independently, halo and C 1-3 alkyl, or two R 1b together with the atoms to which they are bonded, C 3-6 and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment, or the first aspect, or any alternative embodiment therein. In another alternative twenty-first embodiment, for a compound of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt thereof, R 1 But C 3-6 Cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, OR O1a , or SO2R 1a and C 3-6 Cycloalkyl and 3- to 6-membered monocyclic heterocyclyl each have 1 to 3 R 1b optionally substituted with R 1a -NHR N1b , C 3-6 cycloalkyl, or 3- to 6-membered monocyclic heterocyclyl, wherein the 3- to 6-membered monocyclic heterocyclyl is optionally substituted with 1 to 3 halo; R N1b But one or two R 1b C optionally substituted with 1-4 alkyl and R O1a However, 1 to 3 R 1b C optionally substituted with 1-3alkyl, and each R 1b But independently, halo, cyano, C 1-3 Haloalkyl, and C 1-3 alkyl, or two R 1b together with the atom(s) to which they are attached, form C 3-6 and the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment, or the first aspect, or any alternative embodiment therein.

[0036] In a twenty-second embodiment, for compounds of Formula (I) or Formula (IA), or pharmaceutically acceptable salts thereof, R 1 is -S(O)2NHC(CH3)3, -SO2-cyclopentyl, -OCH2CH2CF3, cyclopropyl, cyclohexyl, morpholinyl, piperidinyl, azetidinyl, or pyrrolidinyl, and cyclopropyl, cyclohexyl, morpholinyl, piperidinyl, azetidinyl, and pyrrolidinyl each have 1 to 3 R 1b and each R 1b is -F or -CH3, or two R 1b are taken together with the atom to which they are attached to form cyclopropyl, and the remainder of the variables are as described in the twenty-first embodiment, or the first aspect, or any alternative embodiment described therein. In an alternative twenty-second embodiment, for compounds of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt thereof, R 1 is -S(O)2NHC(CH3)3, -SO2-cyclopentyl, -SO2-piperidinyl, -OCH2CH2CF3, cyclopropyl, cyclohexyl, morpholinyl, piperidinyl, azetidinyl, or pyrrolidinyl, and the piperidinyl, azetidinyl, and pyrrolidinyl of cyclopropyl, cyclohexyl, morpholinyl, piperidinyl, -SO2-piperidinyl each have 1 to 3 R 1b and each R1b is -F or -CH3, or two R 1b are taken together with the atom to which they are attached to form cyclopropyl, and the remainder of the variables are as described in the twenty-first embodiment, or the first aspect, or any alternative embodiment described therein. In another alternative twenty-second embodiment, for compounds of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt thereof, R 1 is -S(O)2NHC(CH3)3, -SO2-cyclopentyl, -SO2-piperidinyl, -OCH2CH2CF3, -OCH2CH(OH)CF3, cyclopropyl, cyclohexyl, morpholinyl, piperidinyl, azetidinyl, 3H-diazirinyl, or pyrrolidinyl, and the piperidinyl, azetidinyl, 3H-diazirinyl, and pyrrolidinyl of cyclopropyl, cyclohexyl, morpholinyl, piperidinyl, -SO2-piperidinyl each have 1 to 3 R 1b and each R 1b is -F, -CN, -CF3, or -CH3, or two R 1b are taken together with the atom to which they are attached to form cyclopropyl, and the remainder of the variables are as described in the twenty-first embodiment, or the first aspect, or any alternative embodiment described therein.

[0037] In a twenty-third embodiment, for a compound of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt thereof, R 1 But C 3-6 Cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, or SO2R 1a and C 3-6 Cycloalkyl and 3- to 6-membered monocyclic heterocyclyl each have 1 to 3 R 1b optionally substituted with R 1a But, -NHR N1b and R N1b But C 1-4 alkyl, and each R 1bis independently halo, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, or twenty-second embodiment, or the first aspect, or any alternative embodiment described therein.

[0038] In a twenty-fourth embodiment, for a compound of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt thereof, R 1 is —S(O)2NHC(CH3)3, cyclohexyl, morpholinyl, or piperidinyl, and cyclohexyl, morpholinyl, and piperidinyl each have 1 to 3 R 1b and each R 1b is -F, and the remainder of the variables are as described in the twenty-third embodiment, or the first aspect, or any alternative embodiment described therein.

[0039] In a twenty-fifth embodiment, for a compound of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt thereof, R 1 is -S(O)2NHC(CH3)3, or R 1 is the structural formula [ka] and the remaining variables are as described in the twenty-third embodiment, or the first aspect, or any alternative embodiment described therein.

[0040] In a 26th embodiment, for compounds of Formula (I) or Formula (IA), or pharmaceutically acceptable salts thereof, R 2 But H, C 1-3 Alkyl, SO2R 2a , or NHSO2R 2a and C 1-3 Alkyl is one to three R 2b optionally substituted with R 2a But C 1-4 Alkyl, -NHRN2b or 3- to 6-membered monocyclic heterocyclyl, C 1-3 Alkyl and 3- to 6-membered monocyclic heterocyclyl each have 1 to 3 R 2b optionally substituted with R N2b However, 1 to 3 R 2b C optionally substituted with 1-3 alkyl, and each R 2b independently hydroxy and C 1-3 alkyl, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, or twenty-fifth embodiment, or the first aspect, or any alternative embodiment described therein. In an alternative twenty-sixth embodiment, for a compound of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt thereof, R 2 But H, C 1-3 Alkyl, NR N2a R N2b , SO2R 2a , S(O)(NH)R 2a , or NHSO2R 2a and C 1-3 Alkyl is one to three R 2b optionally substituted with R 2a But C 1-4 Alkyl, -NHR N2b , C 3-4 cycloalkyl, or 3- to 6-membered monocyclic heterocyclyl, C 1-3 Alkyl and 3- to 6-membered monocyclic heterocyclyl each have 1 to 3 R 2b optionally substituted with R N2a and R N2b are each independently H or 1 to 3 R 2b C optionally substituted with 1-3 alkyl, and each R 2b are independently hydroxy, -N(R N2c )2, and C 1-3 alkyl, and each R N2c However, independently, H, C1-3 Alkyl, -C(O)(C 1-3 alkyl), and the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, or twenty-fifth embodiment, or the first aspect, or any alternative embodiment therein.

[0041] In a 27th embodiment, for compounds of Formula (I) or Formula (IA), or pharmaceutically acceptable salts thereof, R 2 is H, -NHS(O)2CH3, -NHS(O)2CH2CH2OH, -NHS(O)2C(CH3)3, -S(O)2NHCH2CH2OH, -CH2CH2OH, or R 2 is an expression [ka] and the remaining variables are as described in the twenty-sixth embodiment, or the first aspect, or any alternative embodiment described therein. In an alternative twenty-seventh embodiment, for a compound of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt thereof, R 2 is H, -NHS(O)2CH3, -NHS(O)2CH2CH2OH, -NHS(O)2C(CH3)3, -NHS(O)2NHCH2CH2OH, -S(O)2NHCH2CH2OH, -CH2CH2OH, or R 2 is an expression [ka] and the remaining variables are as described in the twenty-sixth embodiment, or the first aspect, or any alternative embodiment described therein. In another alternative twenty-seventh embodiment, for a compound of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt thereof, R 2is H, -NHS(O)2CH3, -NHS(O)2CH2CH2OH, -NHS(O)2CH2CH2NH2, -NHS(O)2CH2CH2NHCH3, -NHS(O)2CH2CH2NHC(O)C H3, -NHS(O)2C(CH3)3, -NHS(O)2NHCH3, -NHS(O)2NHCH2CH2OH, -NHS(O)2N(CH3)CH2CH2OH, -S(O)2NHCH2CH2OH, -NHC(CH3)2CH2OH, -S(O)(NH)-cyclopropyl, -S(O)2CH2CH2OH, -CH2CH2OH, -N(CH3)CH2CH2OH, or R 2 is the formula [ka] and the remaining variables are as described in the twenty-sixth embodiment, or the first aspect, or any alternative embodiment described therein.

[0042] In a 28th embodiment, for compounds of Formula (I) or Formula (IA), or pharmaceutically acceptable salts thereof, R 2 But NHSO2R 2a and R 2a However, 1 to 3 R 2b C optionally substituted with 1-4 alkyl, and each R 2b is hydroxy, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, or twenty-fifth embodiment, or the first aspect, or any alternative embodiment therein.

[0043] In a 29th embodiment, for compounds of Formula (I) or Formula (IA), or pharmaceutically acceptable salts thereof, R 2is —NHS(O)2CH2CH2OH, or —NHS(O)2C(CH3)3, and the remainder of the variables are as described in the twenty-eighth embodiment, or the first aspect, or any alternative embodiment described therein.

[0044] In a thirtieth embodiment, for the compounds of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt thereof, R4 is H, or C 1-3 is alkyl, and the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, or twenty-ninth embodiment, or the first aspect, or any alternative embodiment therein.

[0045] In a thirty-first embodiment, for compounds of Formula (I) or Formula (IA), or pharmaceutically acceptable salts thereof, R 4 is H, or —CH 3 , and the remaining variables are as described in the thirtieth embodiment, or the first aspect, or any alternative embodiment described therein.

[0046] In a thirty-second embodiment, for compounds of Formula (I) or Formula (IA), or pharmaceutically acceptable salts thereof, each R 6 is independently halo, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, or thirty-first embodiment, or the first aspect, or any alternative embodiment described therein.

[0047] In a thirty-third embodiment, for compounds of Formula (I) or Formula (IA), or pharmaceutically acceptable salts thereof, each R 6is -F, and the remainder of the variables are as described in the thirty-first embodiment, or the first aspect, or any alternative embodiment described therein.

[0048] In a thirty-fourth embodiment, for compounds of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt thereof, o is 0, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, or thirty-first embodiment, or the first aspect, or any alternative embodiment described therein.

[0049] In a thirty-fifth embodiment, the compound of the present disclosure has formula (II): [ka] or or a pharmaceutically acceptable salt thereof, X 1 and X 2 However, each is independently CR 5 or N and X 3 is CR 4 or N, R 1 But C 3-6 Cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, or SO2R 1a and C 3-6 Cycloalkyl and 3- to 6-membered monocyclic heterocyclyl each have 1 to 3 R 1b optionally substituted with R 1a But, -NHR N1b and R N1b But C 1-4 is alkyl, Each R 1b is independently a halo, R 2 But NHSO2R 2a and R 2a But one or two R 2b C optionally substituted with 1-4 is alkyl, Each R 2b is hydroxy, R 4 But H or C 1-3 is alkyl, R 5 is H or C 1-3 alkyl, and the remainder of the variables are as described in the first embodiment or first aspect. 3 is CR 4 In an alternative thirty-fifth embodiment, the compound of the present disclosure has formula (II) or (III): [ka] or or a pharmaceutically acceptable salt thereof, X 1 and X 2 However, each is independently CR 5 or N and X 3 is CR 4 or N, R 1 But C 3-6 Cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, or SO2R 1a and C 3-6 Cycloalkyl and 3- to 6-membered monocyclic heterocyclyl each have 1 to 3 R 1b optionally substituted with R 1a But, -NHR N1b and R N1b But C 1-4 is alkyl, Each R 1b is independently a halo, R 2 But NHSO2R 2a and R 2a But one or two R 2b C optionally substituted with 1-4is alkyl, Each R 2b is hydroxy, R 3b But H, C 1-3 Alkyl or C 1-3 is haloalkyl, R 4 But H or C 1-3 is alkyl, R 5 is H or C 1-3 alkyl, and the remainder of the variables are as described in the first embodiment or first aspect. 3 is CR 4 is. In another alternative thirty-fifth embodiment, the compound of the present disclosure has formula (II), (III), or (IV): [ka] or or a pharmaceutically acceptable salt thereof, X 1 and X 2 However, each is independently CR 5 or N and X 3 is CR 4 or N, R 1 But C 3-6 Cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, or SO2R 1a and C 3-6 Cycloalkyl and 3- to 6-membered monocyclic heterocyclyl each have 1 to 3 R 1b optionally substituted with R 1a But, -NHR N1b and R N1b But C 1-4 is alkyl, Each R 1b is independently a halo, R 2 But NHSO2R 2a and R 2a But one or two R 2bC optionally substituted with 1-4 is alkyl, Each R 2b is hydroxy, R 3b But, H, Halo, C 1-3 Alkyl or C 1-3 is haloalkyl, R 4 But H or C 1-3 is alkyl, R 5 is H or C 1-3 alkyl, and the remainder of the variables are as described in the first embodiment or first aspect. 3 is CR 4 is. In a thirty-sixth embodiment, the compound of the present disclosure has formula (IIA), (IIB), (IIC), (IID), or (IIE): [ka] or or a pharmaceutically acceptable salt thereof, wherein the variable R shown in formula (IIA), (IIB), (IIC), (IID), or (IIE) is 1 , R 2 , R 4 , and R 5 is as described in the thirty-fifth embodiment, or the first aspect, or any alternative embodiment described therein. In some embodiments, R 5 is H. In an alternative thirty-sixth embodiment, the compound of the present disclosure has formula (IIA), (IIB), (IIC), (IID), (IIE), or (IIIA) [ka] or or a pharmaceutically acceptable salt thereof, wherein the variable R shown in formula (IIA), (IIB), (IIC), (IID), (IIE), or (IIIA) is 1 , R 2 , R 3b , R 4 , and R 5is as described in the thirty-fifth embodiment, or the first aspect, or any alternative embodiment described therein. In some embodiments, R 5 is H. In another alternative thirty-sixth embodiment, the compound of the present disclosure has formula (IIA), (IIB), (IIC), (IID), (IIE), (IIIA), or (IVA) [ka] or or a pharmaceutically acceptable salt thereof, wherein the variable R shown in formula (IIA), (IIB), (IIC), (IID), (IIE), (IIIA), or (IVA) is 1 , R 2 , R 3b , R 4 , and R 5 is as described in the thirty-fifth embodiment, or the first aspect, or any alternative embodiment described therein. In yet another alternative thirty-sixth embodiment, the compound of the present disclosure has formula (IIIA): [ka] or or a pharmaceutically acceptable salt thereof, wherein the variable R shown in formula (IIIA) 1 , R 2 , R 3b , and R 4 is as described in the thirty-fifth embodiment, or the first aspect, or any alternative embodiment described therein. In yet another alternative thirty-sixth embodiment, the compound of the present disclosure has formula (IVA): [ka] or or a pharmaceutically acceptable salt thereof, wherein the variable R shown in formula (IVA) 1 , R 2 , R 3b , and R 4 as described in the thirty-fifth embodiment, or the first aspect, or any alternative embodiment thereof.

[0050] In a thirty-seventh embodiment, for compounds of Formula (II), (IIA), (IIB), (IIC), (IID), or (IIE), or a pharmaceutically acceptable salt thereof, R 1 is —S(O)2NHC(CH3)3, cyclohexyl, morpholinyl, or piperidinyl, and cyclohexyl, morpholinyl, and piperidinyl are each independently selected from one or two R 1b and each R 1b is -F, and the remainder of the variables are as described in the thirty-fifth embodiment, or the first aspect, or any alternative embodiment described therein. In an alternative thirty-seventh embodiment, for compounds of formula (II), (IIA), (IIB), (IIC), (IID), (IIE), (IIIA), or (IVA), or a pharmaceutically acceptable salt thereof, R 1 is —S(O)2NHC(CH3)3, cyclohexyl, morpholinyl, or piperidinyl, and cyclohexyl, morpholinyl, and piperidinyl are each independently selected from one or two R 1b and each R 1b is -F, and the remainder of the variables are as described in the thirty-fifth embodiment, or the first aspect, or any alternative embodiment described therein.

[0051] In a thirty-eighth embodiment, for compounds of Formula (II), (IIA), (IIB), (IIC), (IID), or (IIE), or a pharmaceutically acceptable salt thereof, R 1 is -S(O)2NHC(CH3)3, or R 1 is the structural formula [ka] and the remainder of the variables are as described in the thirty-seventh embodiment, or the first aspect, or any alternative embodiment described therein. In an alternative thirty-eighth embodiment, for a compound of formula (II), (IIA), (IIB), (IIC), (IID), (IIE), (IIIA), or (IVA), or a pharmaceutically acceptable salt thereof, R 1is -S(O)2NHC(CH3)3, or R 1 is the structural formula [ka] and the remaining variables are as described in the thirty-seventh embodiment, or the first aspect, or any alternative embodiment described therein.

[0052] In a thirty-ninth embodiment, for compounds of Formula (II), (IIA), (IIB), (IIC), (IID), or (IIE), or a pharmaceutically acceptable salt thereof, R 2 is -NHS(O)2CH2CH2OH, or -NHS(O)2C(CH3)3, and the remainder of the variables are as described in the thirty-fifth, thirty-sixth, thirty-seventh, or thirty-eighth embodiment, or the first aspect. In an alternative thirty-ninth embodiment, for a compound of formula (II), (IIA), (IIB), (IIC), (IID), (IIE), (IIIA), or (IVA), or a pharmaceutically acceptable salt thereof, R 2 is —NHS(O)2CH2CH2OH, or —NHS(O)2C(CH3)3, and the remainder of the variables are as described in the thirty-fifth, thirty-sixth, thirty-seventh, or thirty-eighth embodiment, or the first aspect, or any alternative embodiment therein.

[0053] In a fortieth embodiment, for a compound of Formula (II), (IIA), (IIB), (IIC), (IID), or (IIE), or a pharmaceutically acceptable salt thereof, R 4 and R 5 are each H or -CH3, and the remaining variables are as described in the thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, or thirty-ninth embodiment, or any alternative embodiment thereof, of the first aspect. In some embodiments, R 4 is H or -CH3, and R 5 is H. In an alternative embodiment, R 4 and R 5and are both H. In an alternative 40th embodiment, for compounds of formula (II), (IIA), (IIB), (IIC), (IID), (IIE), (IIIA), or (IVA), or a pharmaceutically acceptable salt thereof, R 4 and R 5 are each H or -CH3, and the remaining variables are as described in the thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, or thirty-ninth embodiment, or any alternative embodiment thereof, of the first aspect. In some embodiments, R 4 is H or -CH3, and R 5 is H. In an alternative embodiment, R 4 and R 5 Both are H.

[0054] In a forty-first embodiment, for compounds of Formula (IIIA) or Formula (IVA), or pharmaceutically acceptable salts thereof, R 3b is H, -CH3, or -CHF2, and the remainder of the variables are as described in the thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, or fortieth embodiment, or the first aspect. In an alternative forty-first embodiment, for compounds of Formula (IIIA) or Formula (IVA), or pharmaceutically acceptable salts thereof, R 3b is H, -F, -CH3, -CH2F, or -CHF2, and the remainder of the variables are as described in the thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, or fortieth embodiment, or the first aspect.

[0055] In a forty-second embodiment, the present disclosure provides a compound described herein (eg, a compound of any one of Examples 1-134), or a pharmaceutically acceptable salt thereof.

[0056] In an alternative forty-second embodiment, the present disclosure provides a compound selected from the group consisting of: N-(2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)-N-(5-methyl-6-morpholinopyridin-2-yl)benzamide, N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((1,1-dimethylethyl)sulfonamido)benzamide, 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)-N-(4-methyl-6-morpholinopyridin-2-yl)benzamide, N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)-N-(2-(3,3,3-trifluoropropoxy)pyrimidin-4-yl)benzamide, 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)-N-(2-(2-methylmorpholino)pyrimidin-4-yl)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)-1-(2-hydroxyethyl)-6-(6-azaspiro[2.5]octan-6-yl)-1,3-dihydro-212-indazole-5-carboxamide, N-(2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-5-fluoro-4-((2-hydroxyethyl)sulfonamido)benzamide, N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-5-fluoro-4-((2-hydroxyethyl)sulfonamido)benzamide, N-(2-cyclopropylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)-N-(6-(3,3,3-trifluoropropoxy)pyridin-2-yl)benzamide, (S)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)-N-(6-(2-methylmorpholino)pyridin-2-yl)benzamide, 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-(N-(2-hydroxyethyl)sulfamoyl)-N-(6-(2-methylmorpholino)pyridin-2-yl)benzamide, (R)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)-N-(6-(2-methylmorpholino)pyridin-2-yl)benzamide, N-(6-(3,3-difluoroazetidin-1-yl)-4-methylpyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-(methylsulfonamido)benzamide, 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)-N-(6-methyl-2-(5-azaspiro[2.4]heptan-5-yl)pyrimidin-4-yl)benzamide, N-(6-(cyclopentylsulfonyl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, 2-(4,4-difluoropiperidin-1-yl)-N-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)phenyl)pyrimidine-4-carboxamide, N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((3-methyloxetan-3-yl)sulfonyl)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)-1-(2-hydroxyethyl)-4-(6-azaspiro[2.5]octan-6-yl)-1H-indazole-5-carboxamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-3-(4,4-dimethyl-1,4-azasilinan-1-yl)-5-((2-hydroxyethyl)sulfonamido)picolinamide, N-(3-((4,4-difluoropiperidin-1-yl)sulfonyl)phenyl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)nicotinamide, 2-(7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, 2-((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-(hydroxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-4-((2-hydroxyethyl)sulfonamido)-6-((1R,6R)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-4-((2-hydroxyethyl)sulfonamido)-6-((1S,6S)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1R,6R)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)-4-(methylsulfonamido)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1S,6S)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)-4-(methylsulfonamido)benzamide, 2-(3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-((1S,6S)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-((1R,6R)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-((1R,6S)-6-(hydroxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-((1S,6R)-6-(hydroxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((N-(2-hydroxyethyl)sulfamoyl)amino)-2-((1R,6R)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((N-(2-hydroxyethyl)sulfamoyl)amino)-2-((1S,6S)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)benzamide, 2-(3-azabicyclo[4.1.0]heptan-3-yl)-N-(3-((4,4-difluoropiperidin-1-yl)sulfonyl)phenyl)nicotinamide, N-(3-((4,4-difluoropiperidin-1-yl)sulfonyl)phenyl)-2-(6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)nicotinamide, N-(3-((4,4-difluoropiperidin-1-yl)sulfonyl)phenyl)-2-((1S,6S)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)nicotinamide, N-(3-((4,4-difluoropiperidin-1-yl)sulfonyl)phenyl)-2-((1R,6R)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)nicotinamide, 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(N-(2-hydroxyethyl)sulfamoyl)-2-((1S,6S)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(N-(2-hydroxyethyl)sulfamoyl)-2-((1R,6R)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)benzamide, 2-((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(methylsulfonamido)benzamide, 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(methylsulfonamido)benzamide, 2-((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((N-(2-hydroxyethyl)sulfamoyl)amino)benzamide, 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((N-(2-hydroxyethyl)sulfamoyl)amino)benzamide, N-(2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-yl)-2-((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, N-(2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-yl)-2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, 2-((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, N-(2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-((1S,6S)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)benzamide, N-(2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-((1R,6R)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)benzamide, 2-((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, 2-((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, 2-((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-((2-hydroxyethyl)sulfonamido)-N-(6-methyl-2-((S)-3,3,3-trifluoro-2-hydroxypropoxy)pyrimidin-4-yl)benzamide, 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-((2-hydroxyethyl)sulfonamido)-N-(6-methyl-2-((S)-3,3,3-trifluoro-2-hydroxypropoxy)pyrimidin-4-yl)benzamide, 2-((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)-6-fluoro-4-((2-hydroxyethyl)sulfonamido)benzamide, 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)-6-fluoro-4-((2-hydroxyethyl)sulfonamido)benzamide, 2-((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-6-fluoro-4-((2-hydroxyethyl)sulfonamido)benzamide, 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-6-fluoro 4-((2-hydroxyethyl)sulfonamido)benzamide, 2-((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-((2-hydroxyethyl)sulfonamido)-N-(6-methyl-2-((R)-3,3,3-trifluoro-2-hydroxypropoxy)pyrimidin-4-yl)benzamide, 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-((2-hydroxyethyl)sulfonamido)-N-(6-methyl-2-((R)-3,3,3-trifluoro-2-hydroxypropoxy)pyrimidin-4-yl)benzamide, N-(2-(4,4-difluorocyclohexyl)pyrimidin-4-yl)-2-((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, N-(2-(4,4-difluorocyclohexyl)pyrimidin-4-yl)-2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, 2-((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(N-(2-hydroxyethyl)sulfamoyl)benzamide, 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(N-(2-hydroxyethyl)sulfamoyl)benzamide, 2-((1S,6R)-6-(1,1-difluoroethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, 2-((1R,6S)-6-(1,1-difluoroethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-((1R,6R)-6-methoxy-3-azabicyclo[4.1.0]heptan-3-yl)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-((1S,6S)-6-methoxy-3-azabicyclo[4.1.0]heptan-3-yl)benzamide, 2-((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-6-fluoro-4-((2-hydroxyethyl)sulfonamido)benzamide, 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-6-fluoro-4-((2-hydroxyethyl)sulfonamido)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-((1R,6S)-6-(trifluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-((1S,6R)-6-(trifluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)benzamide, 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)-N-(3-(3-(trifluoromethyl)-3H-diazirin-3-yl)phenyl)benzamide, N-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)phenyl)-2-(3,3,3-trifluoropropoxy)pyrimidine-4-carboxamide, N-(2-(cyclopentylsulfonyl)pyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, 2-(4,4-difluoropiperidin-1-yl)-N-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)-5-fluoro-4-((2-hydroxyethyl)sulfonamido)phenyl)pyrimidine-4-carboxamide, (S)—N-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)phenyl)-2-(2-methylmorpholino)pyrimidine-4-carboxamide, 2-(4,4-diethyl-1,4-azasilinan-1-yl)-N-(3-((4,4-difluoropiperidin-1-yl)sulfonyl)phenyl)nicotinamide, N-(3-((4,4-difluoropiperidin-1-yl)sulfonyl)phenyl)-2-(3,3-dimethyl-1,3-azasilolidin-1-yl)nicotinamide, N-(2-(3-cyanopiperidin-1-yl)pyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, 6-(4,4-difluoropiperidin-1-yl)-N-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)-5-fluoro-4-((2-hydroxyethyl)sulfonamido)phenyl)picolinamide, 6-(4,4-difluoropiperidin-1-yl)-N-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)phenyl)picolinamide, N-(3-(cyclopentylsulfonyl)phenyl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-6-((1-hydroxy-2-methylpropan-2-yl)amino)nicotinamide, N-(6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-(N-(2-hydroxyethyl)sulfamoyl)-N-(6-(3,3,3-trifluoropropoxy)pyridin-2-yl)benzamide, 4-((2-aminoethyl)sulfonamido)-N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)benzamide, N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-(methylamino)ethyl)sulfonamido)benzamide, 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)-N-(6-methyl-2-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyrimidin-4-yl)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-5-fluoro-4-((2-hydroxyethyl)sulfonamido)benzamide, 4-((2-acetamidoethyl)sulfonamido)-N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-3-(4,4-dimethyl-1,4-azasilinan-1-yl)-5-((2-hydroxyethyl)sulfonamido)pyrazine-2-carboxamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(4,4-dimethyl-1,4-azasilinan-1-yl)-6-((2-hydroxyethyl)sulfonamido)nicotinamide, N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-5-fluoro-4-((2-hydroxyethyl)sulfonamido)benzamide, N-(6-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-6-((2-hydroxyethyl)sulfonamido)nicotinamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-6-fluoro-4-((2-hydroxyethyl)sulfonamido)benzamide, (R)—N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxy-1-methylethyl)sulfonamido)benzamide, (S)—N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxy-1-methylethyl)sulfonamido)benzamide, 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxy-1-methylethyl)sulfonamido)-N-(6-(3,3,3-trifluoropropoxy)pyridin-2-yl)benzamide, N-(6-(3,3-difluoroazetidin-1-yl)-4-methylpyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxy-1-methylethyl)sulfonamido)benzamide, N-(2-(2,2-difluoromorpholino)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-3,6-difluoro-4-((2-hydroxyethyl)sulfonamido)benzamide, N-(2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((N-(2-hydroxyethyl)sulfamoyl)amino)benzamide, N-(2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((N-methylsulfamoyl)amino)benzamide, 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)-N-(6-(3,3,3-trifluoro-2-hydroxypropoxy)pyridin-2-yl)benzamide, 4-(cyclopropanesulfonimidoyl)-N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)benzamide, (R)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)-N-(6-(3,3,3-trifluoro-2-hydroxypropoxy)pyridin-2-yl)benzamide, (S)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)-N-(6-(3,3,3-trifluoro-2-hydroxypropoxy)pyridin-2-yl)benzamide, (R)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-6-fluoro-4-((2-hydroxyethyl)sulfonamido)-N-(6-(3,3,3-trifluoro-2-hydroxypropoxy)pyridin-2-yl)benzamide, (S)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-6-fluoro-4-((2-hydroxyethyl)sulfonamido)-N-(6-(3,3,3-trifluoro-2-hydroxypropoxy)pyridin-2-yl)benzamide, (R)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((N-(2-hydroxyethyl)sulfamoyl)amino)-N-(6-(3,3,3-trifluoro-2-hydroxypropoxy)pyridin-2-yl)benzamide, (S)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((N-(2-hydroxyethyl)sulfamoyl)amino)-N-(6-(3,3,3-trifluoro-2-hydroxypropoxy)pyridin-2-yl)benzamide, (R)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-(methylsulfonamido)-N-(6-(3,3,3-trifluoro-2-hydroxypropoxy)pyridin-2-yl)benzamide, (S)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-(methylsulfonamido)-N-(6-(3,3,3-trifluoro-2-hydroxypropoxy)pyridin-2-yl)benzamide, (R)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonyl)-N-(6-(3,3,3-trifluoro-2-hydroxypropoxy)pyridin-2-yl)benzamide, (S)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonyl)-N-(6-(3,3,3-trifluoro-2-hydroxypropoxy)pyridin-2-yl)benzamide, (R)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-(N-(2-hydroxyethyl)sulfamoyl)-N-(6-(3,3,3-trifluoro-2-hydroxypropoxy)pyridin-2-yl)benzamide, (S)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-(N-(2-hydroxyethyl)sulfamoyl)-N-(6-(3,3,3-trifluoro-2-hydroxypropoxy)pyridin-2-yl)benzamide, N-(6-(4,4-difluoropiperidin-1-yl)-5-fluoro-4-methylpyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, N-(2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((N-(2-hydroxyethyl)-N-methylsulfamoyl)amino)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-((1S,6R)-6-(methoxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-((1R,6S)-6-(methoxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1R,6R)-6-fluoro-3-azabicyclo[4.2.0]octan-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1S,6S)-6-fluoro-3-azabicyclo[4.2.0]octan-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1S,6R)-6-(fluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, and N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1R,6S)-6-(fluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide, or a pharmaceutically acceptable salt thereof.

[0057] The compounds and intermediates described herein may be isolated and used as compounds themselves. Alternatively, if moieties capable of forming salts are present, the compounds or intermediates may be isolated and used as their corresponding salts. As used herein, the term "salt" or "salts" refers to acid addition or base addition salts of the compounds described herein. "Salts" specifically includes "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds described herein and are typically not biologically or otherwise unsuitable. In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts due to the presence of amino and / or carboxyl groups, or groups similar thereto.

[0058] Pharmaceutically acceptable acid addition salts include those derived from inorganic or organic acids, such as acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, hydrogensulfate / sulfate, camphorsulfate, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, laurate ... The salts of hydroxybenzoates include methylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, stearate, succinate, sulfate, sulfosalicylate, tartrate, torusylate and trifluoroacetate.

[0059] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0060] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0061] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0062] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I-XII of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper, with particularly suitable salts including ammonium, potassium, sodium, calcium, and magnesium salts.

[0063] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc. Particular organic amines include isopropylamine, benzathine, cholate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0064] Salts can be synthesized from compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of an appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, or bicarbonate), or by reacting the free base form of these compounds with a stoichiometric amount of an appropriate acid. Such reactions are typically carried out in water or an organic solvent, or a mixture of the two. Generally, the use of non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where feasible. Additional lists of suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences," 20th Edition (Mack Publishing Company, Easton, Pa., 1985) and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0065] Isotopically labeled compounds of Formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the accompanying Examples and Preparations, substituting an appropriate isotopically labeled reagent for the previously used non-labeled reagent. In one embodiment, the present disclosure provides a deuterated compound described herein, or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable solvates in accordance with the present disclosure include those wherein the solvent of crystallization may be isotopically substituted, eg, D2O, d6-acetone, d6-DMSO.

[0066] It will be recognized by those skilled in the art that compounds of the present disclosure may contain chiral centers and therefore exist in different stereoisomeric forms. As used herein, the terms "optical isomer" or "stereoisomer" refer to any of the various stereoisomeric configurations that may exist in a given compound of the present disclosure. It is understood that a substituent may be attached to a chiral center of a carbon atom. Thus, the present disclosure includes enantiomers, diastereomers, or racemates of the compounds.

[0067] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The terms "racemic" or "rac" are used to indicate a racemic mixture when appropriate. When specifying the stereochemistry of compounds of the present disclosure, single stereoisomers with known relative and absolute configurations of two chiral centers are designated using the conventional RS system (e.g., (1S,2S)). "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is designated according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be designated by either R or S. Resolved compounds of unknown absolute configuration can be designated (+) or (-) depending on the direction (right-handed or left-handed) they rotate plane-polarized light at the wavelength of the sodium D line. Alternatively, resolved compounds can be defined by the retention times of each of the corresponding enantiomers / diastereomers via chiral HPLC.

[0068] Certain compounds described herein contain one or more asymmetric centers or axes and may therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined in terms of absolute stereochemistry as (R)- or (S)-.

[0069] Unless otherwise specified, the compounds of the present disclosure are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)-stereoisomers can be prepared using chiral synthesizers or chiral reagents or separated using conventional techniques (e.g., separation on chiral SFC or HPLC chromatography columns such as CHIRALPAK® and Chiralcel®, available from DAICEL Corp., using an appropriate solvent or solvent mixture to achieve good resolution). When a compound contains a double bond, the substituent may be in the E- or Z-configuration. When a compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.

[0070] The present disclosure also provides pharmaceutical compositions comprising a compound described herein (e.g., a compound described in any one of the preceding embodiments), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0071] How to use The compounds described herein have KIF18A inhibitory activity. As used herein, "KIF18A inhibitory activity" refers to the ability of a compound or composition to induce a detectable decrease in KIF18A activity in vivo or in vitro (e.g., at least a 10% decrease in KIF18A activity measured by a given assay, such as a bioassay described in the Examples and known in the art).

[0072] In certain embodiments, the present disclosure provides a method for treating a disease or disorder responsive to inhibition of KIF18A activity (referred to herein as a "KIF18A-mediated disease or disorder") in a subject in need thereof. The method comprises administering to the subject a compound described herein (e.g., a compound described in any one of the first to forty-second embodiments), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0073] In certain embodiments, the present disclosure provides use of a compound described herein (e.g., a compound described in any one of the first to forty-second embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a KIF18A-mediated disorder or disease in a subject in need of treatment.

[0074] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of the first to forty-second embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, for use in treating a KIF18A-mediated disorder or disease in a subject in need of treatment.

[0075] In certain embodiments, the KIF18A-mediated disease or disorder is cancer.

[0076] In some embodiments, the cancer is a cancer with chromosomal instability. In other embodiments, the cancer exhibits whole genome doubling. In other embodiments, the cancer has mutations in the TP53, BRCA1, BRCA2, RB1 genes, and / or amplifications of the CCNE1 gene.

[0077] In some embodiments, the cancer is small cell lung cancer, non-small cell lung cancer, pancreatic cancer, triple-negative breast cancer, colorectal cancer, hepatobiliary cancer, esophagogastric cancer, endometrial cancer, head and neck squamous cell carcinoma, ovarian cancer, platinum-resistant ovarian cancer, bladder cancer, soft tissue sarcoma, renal cell carcinoma, endometrial cancer, cervical cancer, or bone cancer.

[0078] In another embodiment, the KIF18A-mediated disease or disorder is (a) a solid or blood-borne tumor selected from bladder cancer, endometrial cancer, lung squamous cell carcinoma, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer; (b) leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, or leukemia. (c) hematopoietic tumors of the lymphoid system selected from acute myeloid leukemia and chronic myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia; (d) tumors of mesenchymal origin selected from fibrosarcoma and rhabdomyosarcoma; (e) tumors of the central and peripheral nervous system selected from astrocytoma, neuroblastoma, glioma, and Schwannoma; or (f) melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, or Kaposi's sarcoma.

[0079] The compounds described herein, or pharmaceutically acceptable salts thereof, may be used to decrease the expression or activity of KIF18A or otherwise affect the properties and / or behavior of KIF18A in cells.

[0080] One embodiment of the present disclosure includes a method for reducing the expression or activity of KIF18A in a subject or otherwise affecting the properties and / or behavior of KIF18A in a subject, comprising administering to the subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof.

[0081] In certain embodiments, the present disclosure relates to the aforementioned method, wherein the subject is a mammal.

[0082] In certain embodiments, the present disclosure relates to the aforementioned method, wherein the subject is a primate.

[0083] In certain embodiments, the present disclosure relates to the aforementioned method, wherein the subject is a human.

[0084] As used herein, the terms "effective amount" and "therapeutically effective amount" can be used interchangeably. This refers to an amount effective to treat or reduce the severity of one or more of the diseases, disorders, or conditions cited herein. In some embodiments, an effective dose can be between 10 μg and 500 mg.

[0085] The compounds and compositions according to the disclosed methods may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of the above-cited diseases, disorders, or conditions.

[0086] In certain embodiments, the present disclosure relates to the aforementioned method, wherein the compound is administered parenterally.

[0087] In certain embodiments, the present disclosure relates to the aforementioned method, wherein the compound is administered intramuscularly, intravenously, subcutaneously, orally, pulmonary, rectally, intrathecally, topically, or intranasally.

[0088] In certain embodiments, the present disclosure relates to the aforementioned method, wherein the compound is administered systemically.

[0089] The compounds of the present disclosure are typically used as pharmaceutical compositions (e.g., a compound of the present disclosure and at least one pharmaceutically acceptable carrier). As used herein, the term "pharmaceutically acceptable carrier" includes generally recognized as safe (GRAS) solvents, dispersion media, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonicity agents, salts, preservatives, drug stabilizers, buffers (e.g., maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, etc.), and the like, and combinations thereof, as known to those skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated. For purposes of this disclosure, solvates and hydrates are considered to be pharmaceutical compositions comprising a compound of the present disclosure and a solvent (ie, a solvate) or water (ie, a hydrate).

[0090] The formulations may be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., the compound of the present disclosure or a stabilized form of the compound (e.g., a complex with a cyclodextrin derivative or other known complexing agent)) is dissolved in a suitable solvent in the presence of one or more of the above-mentioned excipients. The compounds of the present disclosure are typically formulated into drug dosage forms to provide a controllable dose of the drug and provide patients with an elegant and easy-to-use product.

[0091] Pharmaceutical compositions (or formulations) for application can be packaged in a variety of ways depending on the method used to administer the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-evident assembly to prevent inadvertent access to the contents of the package. Additionally, the container has deposited thereon a label describing the contents of the container. The label also includes appropriate warnings.

[0092] Pharmaceutical compositions containing the compounds of the present disclosure will generally be formulated for parenteral or oral administration, or alternatively for use as suppositories.

[0093] For example, the pharmaceutical oral compositions of the present disclosure can be made up in a solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories), or in a liquid form (including, but not limited to, solutions, suspensions, or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization, and / or can contain conventional inert diluents, lubricants, or buffers, as well as adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, and buffers.

[0094] Typically, the pharmaceutical composition is a tablet or gelatin capsule containing the active ingredient together with: a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, such as silica, talcum, stearic acid, its magnesium or calcium salts, and / or polyethylene glycol, also in the case of tablets; c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, if desired; d) disintegrating agents, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures, and / or e) Absorbents, colorants, flavors and sweeteners. Tablets may be film coated or enteric coated according to methods known in the art.

[0095] Compositions suitable for oral administration include the compounds of the present disclosure in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions can contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically elegant and palatable preparation. Tablets may contain the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearin, or talc. Tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period of time. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate can be used. Formulations for oral use can be presented as hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules, in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0096] Parenteral compositions (e.g., intravenous (IV) formulations) are isotonic aqueous solutions or suspensions. Parenteral compositions may be sterilized and / or contain adjuvants such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating osmotic pressure and / or buffers. In addition, they may also contain other therapeutically useful substances. The compositions generally contain about 0.1 to 75%, or about 1 to 50%, of the active ingredient, prepared according to conventional mixing, granulating, or coating methods, respectively.

[0097] The compounds of the present disclosure or pharmaceutical compositions thereof for use in subjects (e.g., humans) are typically administered orally or parenterally in therapeutic doses. When administered intravenously via infusion, the dosage may depend on the infusion rate at which the IV preparation is administered. Generally, the therapeutically effective dosage of the compounds, pharmaceutical compositions, or combinations thereof depends on the subject's species, body weight, age, and individual condition, disorder, or disease, or its severity, being treated. A physician, pharmacist, clinician, or veterinarian skilled in the art can easily determine the effective amount of each active ingredient required to prevent, treat, or inhibit the progression of a disorder or disease.

[0098] The above dosage characteristics can be advantageously demonstrated in vitro and in vivo tests using mammals, such as mice, rats, dogs, monkeys, or their isolated organs, tissues, and preparations. The compounds of the present disclosure can be applied in vitro in the form of solutions, for example, aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, for example, as a suspension, or in aqueous solution. The dosage in vitro is about 10 -3 Molar concentration to 10 -9 Between molar concentrations.

[0099] definition As used herein, "patient," "subject," or "individual" are used interchangeably and refer to either a human or a non-human animal. This term includes mammals, such as humans. Typically, the animal is a mammal. A subject also refers to, for example, a primate (e.g., a human, male or female), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, etc. In certain embodiments, the subject is a primate. In some embodiments, the subject is a human.

[0100] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0101] As used herein, the terms "treat," "treating," or "treatment" of any disease, condition, or disorder refer to the management and care of a patient for the purpose of combating the disease, condition, or disorder, and include the administration of compounds of the present disclosure to achieve a desired pharmacological and / or physiological effect. The effect may be therapeutic, including partially or substantially achieving one or more of the following results: partially or completely reducing the severity of the disease, condition, or disorder; ameliorating or ameliorating clinical symptoms, complications, or indicators associated with the disease, condition, or disorder; or delaying, inhibiting, or reducing the likelihood of progression of the disease, condition, or disorder; or eliminating the disease, condition, or disorder. In certain embodiments, the effect may be preventing the onset of symptoms or complications of the disease, condition, or disorder.

[0102] As used herein, the term "cancer" has its meaning commonly accepted in the art. The term can refer broadly to abnormal cell growth.

[0103] As used herein, a subject is "in need" of a treatment (in some embodiments, a human) if such subject would benefit biologically, medically, or in quality of life from such treatment.

[0104] As used herein, the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." In general, the term "optionally substituted" refers to the replacement of a hydrogen radical in a given structure with the radical of a specified substituent. Specific substituents are described in the definitions and compound descriptions and examples thereof. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each position. In some embodiments, "one or more" substituents may be 1, 2, 3, 4, 5, 6, etc., substituents, each of which may be the same or different. In some embodiments, "one or more" substituents may be 1 to 6, 1 to 4, 1 to 3, or 1 to 2 substituents, each of which may be the same or different.

[0105] As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. 1-4 The term "alkyl" refers to an alkyl having 1 to 4 carbon atoms. 1-3 Alkyl" and "C 1-2 The term "alkyl" should be construed accordingly. 1-4 Representative examples of "alkyl" include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl. Similarly, the alkyl portion (i.e., alkyl moiety) of an alkoxy has the same definition as above. When indicated as "optionally substituted," the alkane radical or alkyl moiety can be unsubstituted or substituted with one or more substituents (generally 1 to 3 substituents, except in the case of halogen substituents such as perchloro or perfluoroalkyl).

[0106] As used herein, the term “alkoxy” refers to a fully saturated, branched or unbranched alkyl moiety attached through an oxygen bridge (i.e., C 1-4 alkyl is as defined herein, 1-4 "Alkoxy" refers to an alkyl group. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, and the like. In some embodiments, an alkoxy group has 1 to 6 carbons, 1 to 4 carbons, or 1 to 3 carbons, and in some embodiments, about 1 or 2 carbons. 1-2 The term "alkoxy" should be construed accordingly.

[0107] The number of carbon atoms in a group is indicated herein by the prefix "C x-xx ", where x and xx are integers. For example, "C 1-3 "Alkyl" is an alkyl group having 1 to 3 carbon atoms.

[0108] "Halogen" or "halo" can be fluorine, chlorine, bromine or iodine.

[0109] As used herein, the term "haloalkyl" refers to an alkyl group, as defined herein, in which at least one of the hydrogen atoms is replaced by a halo atom. 1-6 The term "haloalkyl" refers to a haloalkyl group having 1 to 6 carbon atoms. 1-4 Haloalkyl" and "C 1-3The term "haloalkyl" should be construed accordingly. Haloalkyl groups can be monohaloalkyl, dihaloalkyl, or polyhaloalkyl, including perhaloalkyl. Monohaloalkyls can have one iodo, bromo, chloro, or fluoro within the alkyl group. Dihaloalkyl and polyhaloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl. Typically, polyhaloalkyl groups contain up to 13, or 12, or 11, or 10, or 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2 halo groups. C 1-6 Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. A perhaloalkyl group refers to an alkyl group in which all hydrogen atoms have been replaced with halo atoms.

[0110] As used herein, the term "haloalkoxy" refers to an alkoxy group, as defined herein, in which at least one of the hydrogen atoms on the alkyl portion is replaced with a halo atom. 1-6 The term "haloalkoxy" refers to a haloalkoxy group having 1 to 6 carbon atoms. 1-4 -haloalkoxy" and "C 1-3The term "-haloalkoxy" should be construed accordingly. Haloalkoxy groups can be monohaloalkoxy, dihaloalkoxy, or polyhaloalkoxy, including perhaloalkyl. Monohaloalkoxy can have one iodo, bromo, chloro, or fluoro in the alkyl portion of the alkoxy group. Dihaloalkoxy and polyhaloalkoxy can have two or more of the same halo atoms or a combination of different halo groups in the alkyl portion of the alkoxy group. Typically, polyhaloalkoxy groups contain up to 13, or 12, or 11, or 10, or 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2 halo groups. C 1-6 Non-limiting examples of haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, pentafluoroethoxy, heptafluoropropoxy, difluorochloromethoxy, dichlorofluoromethoxy, difluoroethoxy, difluoropropoxy, dichloroethoxy, and dichloropropoxy.

[0111] The term "aryl" refers to an aromatic carbocyclic single ring or two fused ring systems containing from 6 to 10 carbon atoms. Examples include phenyl and naphthyl.

[0112] The term "heteroaryl" refers to a 5- to 12-membered aromatic radical containing 1 to 4 heteroatoms selected from N, O, and S. In some cases, the nitrogen atom in a heteroaryl may be quaternized. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic." Heteroaryl groups may be monocyclic or bicyclic. Monocyclic heteroaryls include, for example, pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithinyl, oxathianyl, triazinyl, tetrazinyl, and the like. Bicyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to an aryl or heteroaryl ring. Non-limiting examples include indolyl, indazolyl, benzofuranyl, benzimidazolyl, and imidazo[1,2-a]pyridine. A "6,5-bicyclic heteroaryl" refers to a bicyclic heteroaryl in which one ring is five-membered and the other is six-membered. For example, a "6,5-bicyclic heteroaryl" is a phenyl ring fused to a five-membered heteroaryl or a six-membered heteroaryl fused to a five-membered heteroaryl. In some embodiments, a "6,5-bicyclic heteroaryl" is bonded to group Z via the six-membered heteroaryl or phenyl ring. In other embodiments, a "6,5-bicyclic heteroaryl" is bonded to group Z via the five-membered heteroaryl.

[0113] The term "carbocyclic ring" or "carbocyclyl" refers to a 4- to 12-membered saturated or partially unsaturated hydrocarbon ring, which may exist as a monocyclic, bicyclic (including fused, spiro, or bridged) or spiro ring. Bicyclic carbocyclyl groups include unsaturated carbocyclic radicals fused to another unsaturated carbocyclic radical, a cycloalkyl, or an aryl, such as, for example, cyclohexyl, cyclohexenyl, 2,3-dihydroindenyl, indanyl, decahydronaphthalenyl, and 1,2,3,4-tetrahydronaphthalenyl. Unless otherwise specified, carbocyclic rings typically contain 4 to 10 ring members.

[0114] "C 3-6 The term "cycloalkyl" refers to a fully saturated carbocyclic ring (eg, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).

[0115] The term "heterocycle" or "heterocyclyl" refers to a 4- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. Heterocyclyl groups can be monocyclic or bicyclic (e.g., bridged, fused, or spiro bicyclic). Examples of monocyclic saturated or partially unsaturated heterocyclic radicals include, but are not limited to, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, and pyrrolidinyl. Bicyclic heterocyclyl groups include, for example, unsaturated heterocyclic radicals fused to another unsaturated heterocyclic radical, a cycloalkyl, aryl, or heteroaryl ring, such as indolinyl, 2,3-dihydro-1H-pyrrolopyridinyl, 6,7-dihydro-5H-pyrrolopyrazinyl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, 1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, 5,6-dihydro-4H-cyclopenta[b]thiophenyl, and 4,7-dihydro-5H-thieno[2,3-c]pyranyl. In some embodiments, the heterocyclyl group is a 4- to 6-membered monocyclic heterocyclyl group. In some embodiments, the heterocyclyl group is an 8-10 membered bicyclic heterocyclyl group.

[0116] As used herein, the term "spiro" ring refers to a two-ring system in which both rings share one common atom. Examples of spiro rings include 5-oxaspiro[2.3]hexane, oxaspiro[2.4]heptanyl, 5-oxaspiro[2.4]heptanyl, 4-oxaspiro[2.4]heptane, 4-oxaspiro[2.5]octanyl, 6-oxaspiro[2.5]octanyl, oxaspiro[2.5]octanyl, oxaspiro[3.4]octanyl, oxaspiro[bicyclo[2.1.1]hexane-2,3'-oxetan]-1-yl, oxaspiro[bicyclo[3.2.0]heptane-6,1'-cyclobutan]-7-yl, 2,6-diazaspiro[3.3]heptanyl, and -oxa-6-azaspiro[3.3]heptanyl. ]heptane, 2,2,6-diazaspiro[3.3]heptane, 3-azaspiro[5.5]undecanyl, 3,9-diazaspiro[5.5]undecanyl, 7-azaspiro[3.5]nonane, 2,6-diazaspiro[3.4]octane, 8-azaspiro[4.5]decane, 1,6-diazaspiro[3.3]heptane, 5-azaspiro[2.5]octane, 4,7-diazaspiro[2.5]octane, 5-oxa-2-azaspiro[3.4]octane, 6-oxa-1-azaspiro[3.3]heptane, 3-azaspiro[5.5]undecanyl, 3,9-diazaspiro[5.5]undecanyl, and the like.

[0117] The term "fused" ring refers to two ring systems that share two adjacent ring atoms. Fused heterocycles contain at least one ring atom that is a heteroatom selected from O, N, and S (e.g., 3-oxabicyclo[3.1.0]hexane).

[0118] As used herein, the term "bridged" refers to a 5- to 10-membered cyclic moiety joined by two non-adjacent ring atoms (e.g., bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptane, and bicyclo[3.2.1]octane).

[0119] The phrase "pharmaceutically acceptable" indicates that the substance, composition, or dosage form must be chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the mammal being treated therewith.

[0120] Unless otherwise specified, the term "compounds of the disclosure" refers to compounds of Formula (I) and all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, isotopically labeled compounds (including deuterium substitutions). Where moieties capable of forming salts are present, salts, particularly pharmaceutically acceptable salts, are also included.

[0121] As used herein, the terms "a," "an," "the," and similar terms used in the context of this disclosure (particularly in the context of the claims) should be construed to cover both the singular and the plural unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended merely to better clarify the disclosure and does not pose a limitation on the scope of the disclosure as otherwise claimed.

[0122] Intermediates and compounds of the present disclosure may exist in different tautomeric forms, and all such forms are encompassed within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is an imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0123] In one embodiment, the disclosure relates to a compound of formula (I) as defined herein in free form. In another embodiment, the disclosure relates to a compound of formula (I) as defined herein in the form of a salt. In another embodiment, the disclosure relates to a compound of formula (I) as defined herein in the form of an acid addition salt. In a further embodiment, the disclosure relates to a compound of formula (I) as defined herein in the form of a pharmaceutically acceptable salt. In yet another embodiment, the disclosure relates to a compound of formula (I) as defined herein in the form of a pharmaceutically acceptable acid addition salt. In yet a further embodiment, the disclosure relates to any one of the example compounds in free form. In yet a further embodiment, the disclosure relates to any one of the example compounds in the form of a salt. In yet another embodiment, the disclosure relates to any one of the example compounds in the form of an acid addition salt. In yet a further embodiment, the disclosure relates to any one of the example compounds in the form of a pharmaceutically acceptable salt. In yet another embodiment, the disclosure relates to any one of the example compounds in the form of a pharmaceutically acceptable salt.

[0124] The compounds of the present disclosure can be synthesized by synthetic routes that include processes similar to those well known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources such as Sigma-Aldrich, or are readily prepared using methods well known to those skilled in the art (e.g., Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York (1967-1999 ed.), or Beilstein's Handbuch der organischen Chemie, 4, Aufl. Springer-Verlag, Berlin (with supplements) (also available from the Beilstein online database)).

[0125] For illustrative purposes, the reaction schemes shown below provide potential routes for synthesizing the compounds of the present disclosure as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. While specific starting materials and reagents are shown in the schemes and described below, other starting materials and reagents can be readily substituted to provide a variety of derivatives and / or reaction conditions.

[0126] Example Abbreviation: BAST = bis(2-methoxyethyl)aminosulfur trifluoride BID = twice a day BINAP = (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) Bn = benzyl BnBr = benzyl bromide Boc = (tert-butoxycarbonyl) Boc2O = di-tert-butyl dicarbonate BSA = bovine serum albumin CFU-MK = human megakaryocyte clonogenic progenitor cells CH2I2 = diiodomethane Cs2CO3 = Cesium carbonate DCM = dichloromethane DMF = dimethylformamide DIPEA = DIEA = diisopropylethylamine DMEM = Dulbecco's Modified Eagle's Medium DMP = Dess-Martin periodinane DMSO = dimethyl sulfoxide EDTA = ethylenediaminetetraacetic acid ESI = electrospray ionization Et = ethyl Et2Zn = diethyl zinc Et3N = triethylamine EtOAc = EA = ethyl acetate EtOH = ethanol FA = formic acid FBS = fetal bovine serum H2 = Hydrogen H2O = Water HBSS = Hanks' Balanced Salt Solution HEPES = (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) HPLC = High Pressure Liquid Chromatography IMDM = Iscove's Modified Dulbecco's Medium K2CO3 = Potassium Carbonate K3PO4 = Potassium phosphate LCMS = Liquid Chromatography Mass Spectrometry LiBH4 = lithium borohydride LiHMDS = lithium bis(trimethylsilyl)amide MeOH = methanol MeCN = ACN = Acetonitrile N2 = nitrogen Na2SO3 = sodium sulfite Na2SO4 = sodium sulfate NaI = sodium iodide NaOH = Sodium hydroxide NH4Cl = ammonium chloride NH4OH = ammonium hydroxide NMP = N-methylpyrrolidone NMI = 1-methylimidazole Pd / C = palladium on carbon Pd(OH )2 = Palladium(II) hydroxide Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium(0) PE = petroleum ether QD = Once Daily QOD = every other day SFC = Supercritical Fluid Chromatography SOCl2 = thionyl chloride t-BuXPhos Pd G3 = [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate TBAI = tetra-n-butylammonium iodide TCFH = N'-tetramethylformamidinium hexafluorophosphate TFA = trifluoroacetic acid THF = tetrahydrofuran TMS = trimethylsilyl TMS-CHN2 = Trimethylsilyldiazomethane TMSCF3 = Trimethyl(trifluoromethyl)silane Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0127] General method 1. 1 The 1 H NMR spectrum was recorded at NMR10 Bruker AVANCE III HD 300MHz NMR16 Bruker AVANCE III HD 300MHz NMR19 Bruker AVANCE III HD 400MHz NMR24 Bruker AVANCE NEO 400MHz NMR30 Bruker AVANCE NEO 400MHz

[0128] 2. LCMS measurements were performed on a Shimadzu LCMS-2020 using the following conditions: Method A: Mobile phase: A: water (0.05% TFA), B: acetonitrile (0.05% TFA). Gradient: 5% B to 100% B in 2.0 min, 100% B in 0.7 min (total run time: 2.8 min). Flow rate: 1.5 mL / min. Column: HALO C18, 3.0 x 30 mm, 2.0 μm. Column temperature: 40 °C. Detectors: AD2 ELSD, PDA (220 nm and 254 nm), ESI. Method B: Mobile phase: A: water (0.1% FA), B: acetonitrile (0.1% FA). Gradient: 5% B to 100% B in 2.0 min, 100% B in 0.7 min (total run time: 2.8 min). Flow rate: 1.5 mL / min. Column: HALO C18, 3.0*30 mm, 2.0 μm. Column temperature: 40 °C. Detectors: AD2 ELSD, PDA (220 nm and 254 nm), ESI. Method C: Mobile phase: A: Water (5 mM NH4HCO3), B: Acetonitrile. Gradient: 10% B to 95% B in 2.0 min, 100% B in 0.6 min (total run time: 2.8 min). Flow rate: 1.5 mL / min. Column: Poroshell HPH-C18, 3.0*50 mm, 4.0 μm. Column temperature: 40 °C. Detectors: AD2 ELSD, PDA (220 nm and 254 nm), ESI.

[0129] For all compounds listed below, unless otherwise noted, the observed molecular ion is [M+H] + It is of the type.

[0130] Synthesis of common intermediate I: methyl 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-nitrobenzoate [ka] To a solution of methyl 2-fluoro-4-nitrobenzoate (20 g, 100 mmol) and 4,4-dimethyl-1,4-azasilinane hydrochloride (15 g, 90.5 mmol) in DMSO (150 mL) was added DIEA (30 mL, 171 mmol). The reaction mixture was stirred at 100° C. for 60 h. The reaction mixture was diluted with water (200 mL), acidified to pH 4 with HCl (2N in H2O), and extracted with EA (200 mL x 3). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated to give methyl 2-(4,4-dimethyl-1,4-azasilinane-1-yl)-4-nitrobenzoate (30 g) as a brown oil. LCMS:MS ESI (M+1) + =309.2. 1H NMR (400MHz, chloroform-d) δ=7.86(d,J=1.5Hz,1H),7.72-7.62(m,2H),3.94(s,3H),3.53-3.31(m,4H),1.03-0.81(m,4H),0.22-0.04(m,6H).

[0131] Preparation of Common Intermediate II N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-6-((1S,6S)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzamide, and Common Intermediate III N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-6-((1R,6R)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzamide [ka]

[0132] Step 1: Preparation of 2,6-difluoro-4-nitrobenzoyl chloride [ka] To a solution of 2,6-difluoro-4-nitrobenzoic acid (500 mg, 2.46 mmol) in DCM (10 mL) was added SOCl (1.56 g, 12.3 mmol) at 0 °C. The reaction mixture was then stirred at room temperature for 2 h. The mixture was concentrated in vacuo to give 2,6-difluoro-4-nitrobenzoyl chloride (500 mg, 2.25 mmol) as a colorless solid.

[0133] Step 2: Preparation of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2,6-difluoro-4-nitrobenzamide [ka] To a solution of 2,6-difluoro-4-nitrobenzoyl chloride (500 mg, 2.19 mmol) and EtN (912 μL, 6.57 mmol) in THF (1 mL) was added 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (507 mg, 2.29 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was then diluted with HO (10 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were concentrated in vacuo. The residue was dissolved in MeOH (10 mL), and KCO (500 mg) was added. The mixture was stirred at room temperature for 2 hours. The mixture was filtered and concentrated in vacuo to give N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2,6-difluoro-4-nitrobenzamide (500 mg, 0.84 mmol) as a brown solid.

[0134] Step 3: Preparation of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-6-((1S,6S)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzamide and N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-6-((1R,6R)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzamide [ka] To a solution of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2,6-difluoro-4-nitrobenzamide (460 mg, 1.11 mmol) in DMSO (5 mL) was added 6-methyl-3-azabicyclo[4.1.0]heptane (184 mg, 1.66 mmol) and DIEA (430 mg, 3.33 mmol), and the mixture was stirred at 40 °C overnight. The mixture was then diluted with HO (10 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with brine (3 × 30 mL) and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA gradient) to give racemic N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-6-(6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzamide (300 mg, 0.59 mmol) as a yellow solid. Chiral SFC separation of this racemate (CO2-EtOH (0.1% NH3H2O)) gave the first eluting peak arbitrarily assigned as N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-6-((1S,6S)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzamide (120 mg, 0.24 mmol) as a yellow solid, as determined by LCMS: MS ESI (M+1). + The first eluting peak gave 505.4 and a second eluting peak arbitrarily assigned as N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-6-((1R,6R)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzamide (110 mg, 0.22 mmol) as a yellow solid. LCMS:MS ESI (M+1) + 505.4. Second eluting peak LCMS:MS ESI (M+1) + 505.4.

[0135] Synthesis of common intermediates IV and V: methyl 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzoate and methyl 2-((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzoate [ka]

[0136] Step 1: Preparation of methyl 2-(6-(hydroxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzoate [ka] To a solution of methyl 2-fluoro-4-nitrobenzoate (40.0 g, 200 mmol) and (3-azabicyclo[4.1.0]heptan-6-yl)methanol (32.7 g, 200 mmol) in DMSO (450 mL) was added DIEA (77.5 g, 600 mmol), and the mixture was stirred at 80 °C for 12 h. The mixture was poured into saturated aqueous NH4Cl (1500 mL) and extracted with EtOAc (3 × 1500 mL). The combined organic extracts were washed with brine (1500 mL), dried over Na2SO4, filtered, and concentrated. The yellow residue was purified by silica gel column chromatography (PE:EA gradient) to give methyl 2-(6-(hydroxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzoate (45.0 g, 146 mmol) as a yellow oil. LCMS:MS ESI(M+1) + 307.0.

[0137] Step 2: Preparation of methyl 2-(6-formyl-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzoate [ka] To a solution of methyl 2-(6-(hydroxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzoate (45.0 g, 146 mmol) in DCM (450 mL) was added Dess-Martin periodinane (123 g, 292 mmol) at 0 °C, and the mixture was stirred at room temperature for 2 h. The mixture was poured into saturated aqueous NaSO (1500 mL) and extracted with EtOAc (3 × 800 mL). The combined organic extracts were washed with brine (1000 mL), dried over NaSO, filtered, and concentrated. The yellow residue was purified by silica gel column chromatography (PE:EA gradient) to give methyl 2-(6-formyl-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzoate (35.0 g, 115 mmol) as a yellow solid. LCMS:MS ESI(M+1) + 305.2.

[0138] Step 3: Preparation of methyl 2-(6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzoate [ka] To a solution of methyl 2-(6-formyl-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzoate (35.0 g, 115 mmol) in DCM (350 mL) was added bis(2-methoxyethyl)aminosulfur trifluoride (50.8 g, 230 mmol) dropwise at 0° C. The mixture was warmed to room temperature and stirred for 12 hours. Silica gel (70 g) was added to the mixture at 0° C., and the mixture was concentrated. The yellow residue was purified by silica gel column chromatography (PE:EA gradient) to give methyl 2-(6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzoate (30.0 g, 91.9 mmol) as a yellow solid. LCMS:MS ESI (M+1) + 327.1.

[0139] Step 4: Preparation of methyl 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzoate and methyl 2-((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzoate [ka] Methyl 2-(6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzoate (30.0 g, 91.9 mmol) was purified by chiral SFC (AD column (250 mm × 30 mm, 10 μm) CO-EtOH (0.1% NH3HO) to give a first eluting peak arbitrarily assigned as methyl 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzoate (7.20 g, 22.0 mmol) as a yellow solid, and a second eluting peak arbitrarily assigned as methyl 2-((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzoate (6.70 g, 20.5 mmol) as a yellow solid. First eluting peak 1 H NMR (400 MHz, chloroform-d) δ = 7.80 (s, 1H), 7.75 (s, 2H), 5.65-5.14 (m, 1H), 3.94 (s, 3H), 3.47 (br d, J = 11.6 Hz, 1H), 3.34 (dd, J = 4.2, 11.6 Hz, 1H), 3.10 (dtd, J = 2.0, 3.9, 10.8 Hz, 1H), 2.83 (ddd, J = 5.1, 10.9, 12.7 Hz, 1H), 2.24-2.13 (m, 1H), 2.12-2.00 (m, 1H), 1.46-1.35 (m, 1H), 0.99 (dd, J = 5.0, 9.2 Hz, 1H), 0.90 (q, J = 4.8 Hz, 1H). Second eluting peak 1H NMR(400MHz,chloroform-d)δ=7.81(s,1H),7.75(s,2H),5.63-5.20(m,1H),3.94(s,3H),3.48(br d,J=11.8Hz,1H),3.34(dd,J=4.2,11.6Hz,1H),3.10(td,J=4.2,8.0Hz,1H),2.83(ddd,J=5.0,11.0,12.6Hz,1H ),2.23-2.13(m,1H),2.12-2.00(m,1H),1.46-1.36(m,1H),1.00(dd,J=5.0,9.2Hz,1H),0.90(q,J=4.8Hz,1H).

[0140] Example 1: Synthesis of N-(2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide [ka]

[0141] Step 1: Preparation of 2-(4,4-difluorocyclohex-1-en-1-yl)-6-methylpyrimidin-4-amine [ka] To a solution of 2-chloro-6-methylpyrimidin-4-amine (300 mg, 2.08 mmol) and 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (507 mg, 2.08 mmol) in dioxane (6 mL) and HO (2 mL) was added potassium dihydrogen phosphate (1.32 g, 6.24 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (169 mg, 208 μmol) at 20 °C. The mixture was stirred at 100 °C for 16 h. The mixture was poured into HO (50 mL) and extracted with EA (2 × 30 mL). The combined organic extracts were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE:EA 10:1) to give 2-(4,4-difluorocyclohex-1-en-1-yl)-6-methylpyrimidin-4-amine (380 mg, 1.68 mmol) as a white solid. LCMS:MS ESI (M+1) + 226.1

[0142] Step 2: Preparation of 2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [ka] To a solution of 2-(4,4-difluorocyclohexyl-1-en-1-yl)-6-methylpyrimidin-4-amine (130 mg, 577 μmol) in EtOH (3 mL) was added Pd / C (60 mg, 10% w / w) at 25° C. The mixture was stirred under an H atmosphere (15 psi) at 25° C. for 16 hours. The mixture was filtered, and the filter cake was washed with DCM (40 mL). The filtrate was concentrated in vacuo to give 2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine (100 mg, 440 μmol) as a gray solid. LCMS:MS ESI (M+1) + 228.2.

[0143] Step 3: Preparation of N-(2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-nitrobenzamide [ka] To a solution of 2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine (100 mg, 440 μmol) and methyl 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-nitrobenzoate (135 mg, 440 μmol) in THF (4 mL) was added lithium bis(trimethylsilyl)amide (1.32 mL, 1.32 mmol, 1 M in THF) at 25° C. The mixture was stirred at 25° C. for 1 h. The mixture was poured into HO (20 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic extracts were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE:EA 10:1) to give N-(2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-nitrobenzamide (130 mg, 258 μmol) as a yellow solid. LCMS:MS ESI(M+1) + 504.2.

[0144] Step 4: Preparation of 4-amino-N-(2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)benzamide [ka] To a solution of N-(2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-nitrobenzamide (130 mg, 258 μmol) in THF (4 mL) was added Pd / C (100 mg, 10% w / w) at 25° C. The mixture was stirred under an H atmosphere (15 psi) at 25° C. for 4 hours. The mixture was filtered, and the filter cake was washed with MeOH (20 mL) and DCM (20 mL). The filtrate was concentrated in vacuo to give 4-amino-N-(2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)benzamide (110 mg, 232 μmol) as a white solid. LCMS:MS ESI(M+1) + 474.4.

[0145] Step 5: Preparation of ethyl 2-(N-(4-((2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-yl)carbamoyl)-3-(4,4-dimethyl-1,4-azasilinan-1-yl)phenyl)sulfamoyl)acetate [ka] To a solution of 4-amino-N-(2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)benzamide (110 mg, 232 μmol) and pyridine (91.7 mg, 1.16 mmol) in DCM (3 mL) was added ethyl 2-(chlorosulfonyl)acetate (129 mg, 696 μmol) at 0° C. The mixture was stirred at 25° C. for 4 h. The mixture was poured into HO (50 mL) and extracted with EA (2 × 30 mL). The combined organic extracts were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE:EA 10:1) to give ethyl 2-(N-(4-((2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-yl)carbamoyl)-3-(4,4-dimethyl-1,4-azasilinan-1-yl)phenyl)sulfamoyl)acetate (140 mg, 224 μmol) as a colorless oil. LCMS:MS ESI(M+1) + 624.6.

[0146] Step 6: Preparation of N-(2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide [ka] To a solution of ethyl 2-(N-(4-((2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-yl)carbamoyl)-3-(4,4-dimethyl-1,4-azasilinan-1-yl)phenyl)sulfamoyl)acetate (140 mg, 224 μmol) in THF (4 mL) was added lithium borohydride (0.168 mL, 336 μmol, 2 M in THF) at 0° C. The mixture was stirred at 0° C. for 0.5 h. The reaction was poured into saturated aqueous NH4Cl (20 mL). The mixture was extracted with EA (2 × 30 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA) to give N-(2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (57.25 mg, 98.4 μmol) as a white solid. LCMS:MS ESI(M+1) + 582.3. 1 H NMR(400MHz,DMSO-d6)δ=13.17(s,1H),10.06(s,1H),7.99-7.75(m,2H),7.10(d,J=2.0Hz,1H),6.96(dd,J=2.0,8.7Hz,1H),3.56(br s,2H),3.18(t,J=6.4Hz,2H),3.06-2.94(m,4H),2.78-2.63(m,1H),2.29(s,3H),1.95-1.56(m,8H),0.92-0.79(m,4H),0.00(s,6H).

[0147] Example 2: Synthesis of 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)-N-(5-methyl-6-morpholinopyridin-2-yl)benzamide [ka]

[0148] Step 1: Preparation of 5-methyl-6-morpholinopyridin-2-amine [ka] A solution of 6-bromo-5-methylpyridin-2-amine (2.00 g, 10.6 mmol) in morpholine (20 mL, 10.6 mmol) was stirred at 130° C. under a N atmosphere for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE:EA 10:1). 5-methyl-6-morpholinopyridin-2-amine (850 mg, 4.39 mmol) was obtained as a white solid. LCMS:MS ESI (M+1) + 194.2. 1 H NMR (400MHz, chloroform-d) δ=7.19(d,J= 8.0Hz,1H),6.12(d,J= 8.0Hz,1H),4.23-4.06(m,2H),3.87-3.77(m,4H),3.18-3.06(m,4H),2.15(s,3H).

[0149] Step 2: Preparation of 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-N-(5-methyl-6-morpholinopyridin-2-yl)-4-nitrobenzamide [ka] To a solution of 5-methyl-6-morpholinopyridin-2-amine (400 mg, 2.06 mmol) and methyl 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-nitrobenzoate (635 mg, 2.06 mmol) in THF (5 mL) was added LiHMDS (6.18 mL, 6.18 mmol, 1 M in THF) at 0 °C, and the mixture was stirred at 25 °C for 0.5 h. The reaction mixture was quenched with saturated aqueous NH Cl (30 mL) and then extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA 50:1) to give 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-N-(5-methyl-6-morpholinopyridin-2-yl)-4-nitrobenzamide (950 mg, 2.02 mmol) as a yellow solid. LCMS:MS ESI (M+1)+ 470.2. 1 H NMR(400MHz,chloroform-d)δ=12.16(s,1H),8.40(d,J= 8.8Hz,1H),8.15(d,J= 2.4Hz,1H),8.06(dd,J= 2.0,8.6Hz,1H),8.00(d,J= 8.0Hz,1H),7.50(d,J= 8.0Hz,1H),3.92-3.81(m,4H),3.41-3.28(m,4H),3.21-3.07(m,4H),2.28(s,3H),1.18-1.05(m,4H),0.20(s,6H).

[0150] Step 3: Preparation of 4-amino-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-N-(5-methyl-6-morpholinopyridin-2-yl)benzamide [ka] To a solution of 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-N-(5-methyl-6-morpholinopyridin-2-yl)-4-nitrobenzamide (100 mg, 212 μmol) in MeOH (3 mL) was added Pd / C (40 mg, 10% w / w), and the mixture was then stirred under H atmosphere (15 psi) at 25° C. for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give 4-amino-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-N-(5-methyl-6-morpholinopyridin-2-yl)benzamide (75 mg, 0.1705 mmol) as a white solid. LCMS:MS ESI (M+1) + 440.2.

[0151] Step 4: Preparation of ethyl 2-(N-(3-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((5-methyl-6-morpholinopyridin-2-yl)carbamoyl)phenyl)sulfamoyl)acetate [ka] To a solution of 4-amino-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-N-(5-methyl-6-morpholinopyridin-2-yl)benzamide (75 mg, 0.1705 mmol) and pyridine (40.4 mg, 0.5115 mmol) in DCM (1 mL) was added ethyl 2-(chlorosulfonyl)acetate (63.6 mg, 0.341 mmol) at 0° C., and the mixture was stirred at 25° C. for 1 h. The reaction mixture was extracted with DCM (3 × 20 mL) and HO (3 × 10 mL). The combined organic extracts were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. Ethyl 2-(N-(3-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((5-methyl-6-morpholinopyridin-2-yl)carbamoyl)phenyl)sulfamoyl)acetate (90 mg, 0.1525 mmol) was obtained as a yellow oil. LCMS:MS ESI(M+1) + 590.3.

[0152] Step 5: Preparation of 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)-N-(5-methyl-6-morpholinopyridin-2-yl)benzamide [ka] To a solution of ethyl 2-(N-(3-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((5-methyl-6-morpholinopyridin-2-yl)carbamoyl)phenyl)sulfamoyl)acetate (90 mg, 0.1525 mmol) in THF (1 mL) was added LiBH (228 μL, 0.4575 mmol, 2 M in THF) at 0° C., and the mixture was then stirred at 25° C. for 0.5 h. The reaction mixture was quenched with saturated aqueous NH Cl (30 mL) and then extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (TFA conditions). 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)-N-(5-methyl-6-morpholinopyridin-2-yl)benzamide (TFA salt, 38.52 mg, 0.07032 mmol) was obtained as a white solid. LCMS:MS ESI(M+1) + 548.3. 1 H NMR(400MHz,DMSO-d6)δ 12.45(s,1H),10.13(s,1H),8.05-7.99(m,1H),7.87(d,J= 8.0Hz,1H),7.55(d,J= 8.4Hz,1H),7.25(d,J= 2.0Hz,1H),7.09(dd,J= 2.0,8.6Hz,1H),3.75-3.71(m,6H),3.34(s,2H),3.19-3.15(m,4H),3.06-3.03(m,4H),2.22(s,3H),1.06-1.01(m,4H),0.18-0.16(m,6H).

[0153] Example 3: Synthesis of N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide [ka]

[0154] Step 1: Preparation of 2-(4,4-difluoropiperidin-1-yl)-6-nitropyridine [ka] To a solution of 2-chloro-6-nitropyridine (500 mg, 3.15 mmol) and 4,4-difluoropiperidine hydrochloride (595 mg, 3.78 mmol) in DMSO (5 mL) was added DIPEA (1.22 g, 9.45 mmol) at 25 °C. The mixture was stirred at 100 °C for 16 h. The mixture was poured into HO (50 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic extracts were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA 10:1) to give 2-(4,4-difluoropiperidin-1-yl)-6-nitropyridine (600 mg, 2.46 mmol) as a yellow oil. LCMS:MS ESI (M+1) + 244.0.

[0155] Step 2: Preparation of 6-(4,4-difluoropiperidin-1-yl)pyridin-2-amine [ka] To a solution of 2-(4,4-difluoropiperidin-1-yl)-6-nitropyridine (300 mg, 1.23 mmol) in EtOH (5 mL) and HO (1 mL) at 25 °C, ammonium chloride (328 mg, 6.15 mmol) and iron powder (686 mg, 12.3 mmol) were added. The mixture was stirred at 80 °C for 16 h. The mixture was filtered, and the filter cake was washed with ethyl acetate (50 mL). The filtrate was poured into HO (50 mL). The mixture was extracted with ethyl acetate (2 × 30 mL). The combined organic extracts were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give 6-(4,4-difluoropiperidin-1-yl)pyridin-2-amine (250 mg, 1.17 mmol) as a yellow oil. LCMS:MS ESI (M+1) + =214.1.

[0156] Step 3: Preparation of N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-nitrobenzamide [ka] To a solution of 6-(4,4-difluoropiperidin-1-yl)pyridin-2-amine (230 mg, 1.07 mmol) and methyl 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-nitrobenzoate (329 mg, 1.07 mmol) in THF (4 mL) was added LiHMDS (3.2 mL, 3.21 mmol, 1 M in THF) at 25 °C, and the mixture was stirred at 25 °C for 1 hour. The mixture was poured into HO (20 mL). The mixture was extracted with ethyl acetate (2 × 20 mL). The combined organic extracts were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA 10:1) to give N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-nitrobenzamide (260 mg, 531 μmol) as a yellow solid. MS ESI (M+1) + 490.3.

[0157] Step 4: Preparation of 4-amino-N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)benzamide [ka] To a solution of N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-nitrobenzamide (260 mg, 531 μmol) in THF (5 mL) was added Pd / C (130 mg, 531 μmol) at 25° C. The mixture was stirred under an H atmosphere (15 psi) at 25° C. for 16 hours. The mixture was filtered, and the filter cake was washed with DCM (20 mL). The filtrate was concentrated in vacuo to give 4-amino-N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)benzamide (220 mg, 478 μmol) as a white solid. LCMS:MS ESI(M+1) + =460.3.

[0158] Step 5: Preparation of ethyl 2-(N-(4-((6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)carbamoyl)-3-(4,4-dimethyl-1,4-azasilinan-1-yl)phenyl)sulfamoyl)acetate [ka] To a solution of 4-amino-N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)benzamide (100 mg, 217 μmol) and pyridine (51.4 mg, 651 μmol) in DCM (3 mL) was added ethyl 2-(chlorosulfonyl)acetate (60.6 mg, 325 μmol) at 0° C. The mixture was stirred at 25° C. for 3 h. The mixture was poured into HO (50 mL) and extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA 10:1) to give ethyl 2-(N-(4-((6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)carbamoyl)-3-(4,4-dimethyl-1,4-azasilinan-1-yl)phenyl)sulfamoyl)acetate (110 mg, 180 μmol) as a white solid. LCMS:MS ESI(M+1) + 610.4.

[0159] Step 6: Preparation of N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide [ka] To a solution of ethyl 2-(N-(4-((6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)carbamoyl)-3-(4,4-dimethyl-1,4-azasilinan-1-yl)phenyl)sulfamoyl)acetate (110 mg, 180 μmol) in THF (4 mL) was added lithium borohydride (180 μL, 360 μmol, 2 M in THF) at 0° C. The solution was then stirred at 25° C. for 1 h. The mixture was poured into saturated aqueous NH4Cl (50 mL) and extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA conditions) to give N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (35.66 mg, 62.8 μmol) as an off-white solid. LCMS:MS ESI (M+1) + 568.4. 1 H NMR(400MHz,DMSO-d6)δ=12.13(s,1H),9.99(s,1H),7.86(br d,J=8.6Hz,1H),7.58-7.40(m,2H),7.10(s,1H),6.95(br d,J=8.5Hz,1H),6.56(d,J=7.9Hz,1H),3.61(br t,J=6.4Hz,2H),3.54(br d,J=4.8Hz,4H),3.29-3.16(m,2H),3.09-2.93(m,4H),1.91-1.77(m,4H),0.87(br d,J=4.9Hz,4H),0.00(s,6H).

[0160] Example 4: Synthesis of N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((1,1-dimethylethyl)sulfonamido)benzamide [ka]

[0161] Step 1: Preparation of N-(tert-butyl)-3-nitrobenzenesulfonamide [ka] A solution of 3-nitrobenzenesulfonyl chloride (2.21 g, 0.01 mol) in DCM (15 mL) was treated with 2-methylpropan-2-amine (2.18 g, 0.030 mol) followed by DIPEA (3.86 g, 0.03 mol) at 0 °C. The resulting reaction mixture was stirred at 25 °C for 4 h. The reaction mixture was diluted with DCM (50 mL). The mixture was washed with saturated aqueous citric acid (2 × 20 mL) and brine (20 mL). The separated organic extract was dried over NaSO and concentrated under reduced pressure. N-(tert-butyl)-3-nitrobenzenesulfonamide (1.8 g, 6.96 mmol) was obtained as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=8.59(t,J=2.0Hz,1H),8.44(dd,J=1.6,8.0Hz,1H),8.25(d,J=8.0Hz,1H),7.97-7.82(m,2H),1.11(s,9H).

[0162] Step 2: Preparation of 3-amino-N-(tert-butyl)benzenesulfonamide [ka] To a solution of N-(tert-butyl)-3-nitrobenzenesulfonamide (1.8 g, 6.96 mmol) in EtOH (20 mL) and water (5 mL) was added Fe powder (3.1 g, 55.6 mmol) and NH4Cl (2.97 g, 55.6 mol). The mixture was stirred at 80 °C for 1.5 h. The suspension was then filtered through a pad of Celite, and the filter cake was washed with MeOH (20 mL). The combined filtrate was concentrated. The residue was partitioned between ethyl acetate (60 mL) and water (20 mL). The separated organic extract was washed with brine (2 × 20 mL), dried over Na2SO4, and concentrated to dryness. 3-amino-N-(tert-butyl)benzenesulfonamide (1.35 g, 5.91 mmol) was obtained as a colorless oil. LCMS:MS ESI (M+1)+ 229.2.

[0163] Step 3: Preparation of methyl 4-bromo-2-(4,4-dimethyl-1,4-azasilinan-1-yl)benzoate [ka] To a solution of methyl 4-bromo-2-fluorobenzoate (354 mg, 1.51 mmol) and 4,4-dimethyl-1,4-azasilinane hydrochloride (311 mg, 1.88 mmol) in DMSO (5 mL) was added K2CO3 (420 mg, 3.02 mmol) at 25 °C. The mixture was stirred at 100 °C for 15 h. The mixture was cooled to 25 °C, poured into water (25 mL), and extracted with ethyl acetate (3 × 35 mL). The combined organic extracts were washed with brine (3 × 25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA 50:1). Methyl 4-bromo-2-(4,4-dimethyl-1,4-azasilinane-1-yl)benzoate (460 mg, 1.34 mmol) was obtained as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ = 7.50 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 1.6 Hz, 1H), 7.02 (dd, J = 1.6, 8.4 Hz, 1H), 3.90 (s, 3H), 3.45-3.21 (m, 4H), 0.93-0.88 (m, 4H), 0.13 (s, 6H).

[0164] Step 4: Preparation of methyl 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((1,1-dimethylethyl)sulfonamido)benzoate [ka] To a solution of methyl 4-bromo-2-(4,4-dimethyl-1,4-azasilinan-1-yl)benzoate (450 mg, 1.31 mmol) in dioxane (5 mL) under a N atmosphere, 2-methylpropane-2-sulfonamide (268 mg, 1.96 mmol), cesium carbonate (426 mg, 1.31 mmol), and t-BuXPhos Pd G3 (0.104 g, 1.31 mmol) were added. The mixture was stirred at 90 °C for 15 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (3 × 25 mL). The combined organic extracts were washed with brine (2 × 15 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA 20:1) to give methyl 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((1,1-dimethylethyl)sulfonamido)benzoate (320 mg, 802 μmol) as a yellow solid.

[0165] Step 5: Preparation of 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((1,1-dimethylethyl)sulfonamido)benzoic acid [ka] To a solution of methyl 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((1,1-dimethylethyl)sulfonamido)benzoate (0.31 g, 0.777 mmol) in MeOH (5 mL), HO (5 mL), and THF (5 mL) was added LiOH · HO (97.7 mg, 2.33 mmol) was added. The mixture was stirred at 55 °C for 15 h. The mixture was cooled to 25 °C, adjusted to pH 3-4 with 1 N HCl, and extracted with ethyl acetate (2 × 30 mL). The combined organic extracts were washed with brine (2 × 15 mL), dried over NaSO, filtered, and concentrated to give 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((1,1-dimethylethyl)sulfonamido)benzoic acid (265 mg, 689 μmol) as a white solid. LCMS:MS ESI (M+1) + 385.1.

[0166] Step 6: Preparation of N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((1,1-dimethylethyl)sulfonamido)benzamide [ka] To a solution of 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((1,1-dimethylethyl)sulfonamido)benzoic acid (150 mg, 390 μmol) and 3-amino-N-(tert-butyl)benzenesulfonamide (115 mg, 507 μmol) in MeCN (3 mL) was added NMI (160 mg, 1.95 mmol) and TCFH (218 mg, 780 μmol). The mixture was stirred at 20 °C for 15 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (3 × 25 mL). The combined organic extracts were washed with brine (3 × 15 mL), dried over NaSO, filtered, and concentrated. The residue was purified by preparative HPLC (TFA conditions). N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((1,1-dimethylethyl)sulfonamido)benzamide (95.45 mg, 157 μmol) was obtained as a white solid. LCMS:MS ESI(M+1) + 595.4. 1 H NMR(400MHz,DMSO-d6)δ=11.95(s,1H),9.93(s,1H),8.33(s,1H),7.91-7.71(m,2 H),7.62-7.47(m,3H),7.29(d,J=1.6Hz,1H),7.08(dd,J=1.6,8.8Hz,1H),3.17(br t,J=5.6Hz,4H),1.31(s,9H),1.11(s,9H),0.89(br t,J=5.6Hz,4H),0.10(s,6H).

[0167] Example 5: Synthesis of 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)-N-(4-methyl-6-morpholinopyridin-2-yl)benzamide [ka]

[0168] Step 1: Preparation of tert-butyl (4-methyl-6-morpholinopyridin-2-yl)carbamate [ka] A solution of 4-(6-bromo-4-methylpyridin-2-yl)morpholine (300 mg, 1.16 mmol), tert-butyl carbamate (407 mg, 3.48 mmol), Pd(dba) (106 mg, 116 μmol), Xantphos (134 mg, 232 μmol), and CsCO (1.13 g, 3.48 mmol) in 2-methyl-2-butanol (6 mL) was stirred at 100 °C for 16 h. The mixture was poured into HO (50 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic extracts were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA 3:1) to give tert-butyl (4-methyl-6-morpholinopyridin-2-yl)carbamate (300 mg, 1.02 mmol) as a yellow oil.

[0169] Step 2: Preparation of 4-methyl-6-morpholinopyridin-2-amine [ka] To a solution of tert-butyl (4-methyl-6-morpholinopyridin-2-yl)carbamate (250 mg, 852 μmol) in dioxane (2 mL) was added HCl (2 mL, 4 M in dioxane). The resulting solution was stirred at 25° C. for 1 hour. The solution was concentrated to give 4-methyl-6-morpholinopyridin-2-amine (150 mg, 776 μmol) as a yellow oil. LCMS:MS ESI (M+1) + 194.1.

[0170] Step 3: Preparation of 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-N-(4-methyl-6-morpholinopyridin-2-yl)-4-nitrobenzamide [ka] To a solution of 4-methyl-6-morpholinopyridin-2-amine (150 mg, 776 μmol) and methyl 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-nitrobenzoate (215 mg, 698 μmol) in THF (4 mL) was added LiHMDS (3.10 mL, 3.10 mmol, 1 M in THF). The resulting solution was stirred at 25 °C for 1 h. The mixture was poured into saturated aqueous NH4Cl (50 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA 1:1). 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-N-(4-methyl-6-morpholinopyridin-2-yl)-4-nitrobenzamide (200 mg, 425 μmol) was obtained as a yellow oil. LCMS:MS ESI (M+1) + 470.3.

[0171] Step 4: Preparation of 4-amino-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-N-(4-methyl-6-morpholinopyridin-2-yl)benzamide [ka] To a solution of 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-N-(4-methyl-6-morpholinopyridin-2-yl)-4-nitrobenzamide (150 mg, 354 μmol) in THF (5 mL) was added Pd / C (50 mg, 10% w / w). The reaction was stirred under an H atmosphere (15 psi) at 25° C. for 3 hours. The solution was filtered and concentrated. 4-amino-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-N-(4-methyl-6-morpholinopyridin-2-yl)benzamide (180 mg, 409 μmol) was obtained as a yellow oil. LCMS:MS ESI (M+1) + 440.4.

[0172] Step 5: Preparation of ethyl 2-(N-(3-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((4-methyl-6-morpholinopyridin-2-yl)carbamoyl)phenyl)sulfamoyl)acetate [ka] To a solution of 4-amino-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-N-(4-methyl-6-morpholinopyridin-2-yl)benzamide (180 mg, 409 μmol) and pyridine (161 mg, 2.04 mmol) in DCM (4 mL) was added ethyl 2-(chlorosulfonyl)acetate (227 mg, 1.22 mmol) at 0° C. The reaction was stirred at 25° C. for 1 h. The mixture was poured into water (50 mL) and extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure. Ethyl 2-(N-(3-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((4-methyl-6-morpholinopyridin-2-yl)carbamoyl)phenyl)sulfamoyl)acetate (200 mg, 339 μmol) was obtained as a yellow oil. LCMS:MS ESI(M+1) + 590.2.

[0173] Step 6: Preparation of 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)-N-(4-methyl-6-morpholinopyridin-2-yl)benzamide [ka] To a solution of ethyl 2-(N-(3-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((4-methyl-6-morpholinopyridin-2-yl)carbamoyl)phenyl)sulfamoyl)acetate (180 mg, 186 μmol) in THF (4 mL) was added LiBH (457 μL, 915 μmol, 2 M in THF) at 0° C. The reaction was stirred at 25° C. for 1 h. The mixture was poured into saturated aqueous NH Cl (50 mL) and extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with brine (30 mL), dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA conditions). 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)-N-(4-methyl-6-morpholinopyridin-2-yl)benzamide (53.57 mg, 97.8 μmol) was obtained as a yellow gum. LCMS:MS ESI(M+1) + 548.3. 1 H NMR(400MHz,DMSO-d6)δ=12.19(s,1H),10.13(s,1H),7.99(d,J=8.6Hz,1H),7.53(s,1H),7.22(d,J=1.6Hz,1H),7.08(dd,J=1.9 ,8.6Hz,1H),6.43(s,1H),3.80-3.61(m,6H),3.47-3.28(m,6H),3.25-3.10(m,4H),2.26(s,3H),1.07-0.86(m,4H),0.12(s,6H).

[0174] Example 6: Synthesis of N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide [ka]

[0175] Step 1: Preparation of 4,4-difluoro-1-(3-nitrophenyl)piperidine [ka] To a solution of 1-bromo-3-nitrobenzene (500 mg, 2.47 mmol) and 4,4-difluoropiperidine hydrochloride (358 mg, 2.96 mmol) in toluene (5 mL) was added BINAP (153 mg, 247 μmol), sodium tert-butoxide (712 mg, 7.41 mmol), and Pd(dba) (112 mg, 123 μmol). The mixture was stirred at 100 °C for 12 h. The reaction mixture was poured into saturated aqueous NHCl (40 mL) and extracted with ethyl acetate (3 × 35 mL). The combined organic extracts were washed with brine (100 mL), dried over NaSO, filtered, and concentrated. The yellow residue was purified by silica gel column chromatography (PE:EA 50:1). 4,4-Difluoro-1-(3-nitrophenyl)piperidine (300 mg, 1.23 mmol) was obtained as a yellow solid. LCMS:MS ESI (M+1) + 243.1. 1 H NMR(400MHz,DMSO-d6)δ=7.75-7.71(m,1H),7.60(td,J=2.3,6.5Hz,1H),7.52-7.45(m,2H),3.52-3.44(m,4H),2.11-2.01(m,4H).

[0176] Step 2: Preparation of 3-(4,4-difluoropiperidin-1-yl)aniline [ka] To a solution of 4,4-difluoro-1-(3-nitrophenyl)piperidine (300 mg, 1.23 mmol) in MeOH (10 mL) was added Pd / C (130 mg, 10% w / w). The mixture was stirred under H atmosphere (15 psi) at 25° C. for 2 hours. The reaction mixture was filtered and concentrated in vacuo. 3-(4,4-difluoropiperidin-1-yl)aniline (250 mg, 1.17 mmol) was obtained as a yellow solid. LCMS:MS ESI (M+1) + 213.1.

[0177] Step 3: Preparation of N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-nitrobenzamide [ka] To a solution of 3-(4,4-difluoropiperidin-1-yl)aniline (100 mg, 471 μmol) and methyl 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-nitrobenzoate (145 mg, 471 μmol) in THF (3 mL) was added LiHMDS (1.17 mL, 1.17 mmol, 1 M in THF). The mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into saturated aqueous NH4Cl (40 mL) and extracted with ethyl acetate (3 × 35 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The yellow residue was purified by silica gel column chromatography (PE:EA 50:1). N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-nitrobenzamide (80 mg, 163 μmol) was obtained as a yellow solid. LCMS:MS ESI(M+1) + 489.3. 1H NMR(400MHz,DMSO-d6)δ=10.90(s,1H),7.93(d,J=2.3Hz,1H),7.90-7.85(m,1H),7.83-7.78(m,1H),7.45(d,J=1.9H) z,1H),7.26-7.16(m,2H),6.84-6.74(m,1H),3.38-3.32(m,8H),2.14-2.00(m,4H),0.87-0.82(m,4H),0.05(s,6H).

[0178] Step 4: Preparation of 4-amino-N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)benzamide [ka] To a solution of N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-nitrobenzamide (80 mg, 163 μmol) in MeOH (10 mL) was added Pd / C (17.3 mg, 10% w / w), and the mixture was stirred under a H atmosphere (15 psi) at 25° C. for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure. 4-amino-N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)benzamide (60 mg, 130 μmol) was obtained as a yellow solid.

[0179] Step 5: Preparation of ethyl 2-(N-(4-((3-(4,4-difluoropiperidin-1-yl)phenyl)carbamoyl)-3-(4,4-dimethyl-1,4-azasilinan-1-yl)phenyl)sulfamoyl)acetate [ka] To a solution of 4-amino-N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)benzamide (60 mg, 130 μmol) and pyridine (31.2 μL, 389 μmol) in DCM (2 mL) was added ethyl 2-(chlorosulfonyl)acetate (28.9 mg, 155 μmol) at 0° C. The mixture was stirred at 25° C. for 2 h. The reaction mixture was poured into saturated aqueous NH4Cl (40 mL) and extracted with ethyl acetate (3 × 35 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. Ethyl 2-(N-(4-((3-(4,4-difluoropiperidin-1-yl)phenyl)carbamoyl)-3-(4,4-dimethyl-1,4-azasilinan-1-yl)phenyl)sulfamoyl)acetate (72 mg, 120 μmol) was obtained as a yellow oil. LCMS:MS ESI(M+1) + 609.2.

[0180] Step 6: Preparation of N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide [ka] To a solution of ethyl 2-(N-(4-((3-(4,4-difluoropiperidin-1-yl)phenyl)carbamoyl)-3-(4,4-dimethyl-1,4-azasilinan-1-yl)phenyl)sulfamoyl)acetate (75 mg, 123 μmol) in THF (2 mL) was added LiBH (122 μL, 245 μmol, 2 M in THF) at 0° C. The mixture was stirred at 25° C. for 0.5 h. The reaction mixture was poured into saturated aqueous NH Cl (40 mL) and extracted with ethyl acetate (3 × 35 mL). The combined organic extracts were washed with brine (100 mL), dried over Na SO , filtered, and concentrated. The yellow residue was purified by preparative HPLC (FA conditions). N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (33.94 mg, 59.8 μmol) was obtained as an off-white solid. LCMS:MS ESI(M+1) + 567.2. 1 H NMR(400MHz,DMSO-d6)δ=11.75(s,1H),7.81(d,J=8.6Hz,1H),7.50(s,1H),7.25-7.17(m,1H),7.14- 7.08(m,2H),7.00(dd,J=2.0,8.6Hz,1H),6.74(dd,J=2.0,8.2Hz,1H),3.74(t,J=6.6Hz,2H),3.32(br d,J=1.8Hz,6H),3.17(br t,J=6.1Hz,4H),2.15-1.97(m,4H),0.92(br t,J=6.1Hz,4H),0.10(s,6H).

[0181] Example 7: Synthesis of N-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide [ka]

[0182] Step 1: Preparation of 2-(4,4-difluoropiperidin-1-yl)-4-nitropyridine [ka] To a solution of 2-chloro-4-nitropyridine (1.0 g, 6.30 mmol) and 4,4-difluoropiperidine hydrochloride (1.48 g, 9.45 mmol) in DMSO (10 mL) was added DIPEA (3.28 mL, 18.9 mmol), and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was poured into saturated aqueous NH4Cl (40 mL) and extracted with ethyl acetate (3×35 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The yellow residue was purified by silica gel column chromatography (PE:EA 50:1). 2-(4,4-difluoropiperidin-1-yl)-4-nitropyridine (300 mg, 1.23 mmol) was obtained as a yellow solid. LCMS:MS ESI (M+1) + 244.1. 1 H NMR(400MHz,DMSO-d6)δ=7.96(d,J=6.0Hz,1H),6.96(d,J=2.4Hz,1H),6.92(dd,J=2.4,6.1Hz,1H),3.61-3.50(m,4H),2.09-1.89(m,4H).

[0183] Step 2: Preparation of 2-(4,4-difluoropiperidin-1-yl)pyridin-4-amine [ka] To a solution of 2-(4,4-difluoropiperidin-1-yl)-4-nitropyridine (500 mg, 1.05 mmol) in MeOH (10 mL) was added Pd / C (111 mg, 105 μmol). The mixture was stirred under H (15 psi) at 25° C. for 2 hours. The reaction mixture was filtered and concentrated to give 2-(4,4-difluoropiperidin-1-yl)pyridin-4-amine (250 mg, 1.17 mmol) as a yellow solid.

[0184] Step 3: Preparation of N-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-nitrobenzamide [ka] To a solution of methyl 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-nitrobenzoate (150 mg, 703 μmol) and 2-(4,4-difluoropiperidin-1-yl)pyridin-4-amine (238 mg, 773 μmol) in THF (5 mL) was added LiHMDS (2.10 mL, 2.10 mmol, 1 M in THF). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was poured into saturated aqueous NH4Cl (40 mL) and extracted with ethyl acetate (3 × 35 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The yellow residue was purified by silica gel column chromatography (PE:EA 50:1) to give N-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-nitrobenzamide (220 mg, 449 μmol) as a yellow solid. LCMS:MS ESI(M+1) + 490.3.

[0185] Step 4: Preparation of 4-amino-N-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)benzamide [ka] To a solution of N-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-nitrobenzamide (100 mg, 204 μmol) in MeOH (5 mL) was added Pd / C (21.7 mg, 10% w / w). The mixture was stirred under H atmosphere (15 psi) at 25° C. for 2 hours. The reaction mixture was filtered and concentrated. 4-amino-N-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)benzamide (93 mg, 202 μmol) was obtained as a yellow solid. LCMS:MS ESI(M+1) + 460.4.

[0186] Step 5: Preparation of ethyl 2-(N-(4-((2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)carbamoyl)-3-(4,4-dimethyl-1,4-azasilinan-1-yl)phenyl)sulfamoyl)acetate [ka] To a solution of N-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-nitrobenzamide (93 mg, 202 μmol) and pyridine (48.7 μL, 606 μmol) in DCM (5 mL) was added ethyl 2-(chlorosulfonyl)acetate (48.8 mg, 262 μmol) at 0° C. The mixture was stirred at 25° C. for 1 h. The reaction mixture was poured into saturated aqueous NH4Cl (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine (30 mL), dried over NaSO, filtered, and concentrated to give ethyl 2-(N-(4-((2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)carbamoyl)-3-(4,4-dimethyl-1,4-azasilinan-1-yl)phenyl)sulfamoyl)acetate (120 mg, 196 μmol) as a yellow oil. LCMS:MS ESI(M+1) + 610.3.

[0187] Step 6: Preparation of N-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide [ka] To a solution of ethyl 2-(N-(4-((2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)carbamoyl)-3-(4,4-dimethyl-1,4-azasilinan-1-yl)phenyl)sulfamoyl)acetate (100 mg, 163 μmol) in THF (3 mL) was added lithium borohydride (163 μL, 326 μmol, 2 M in THF) at 0° C. The mixture was stirred at 25° C. for 0.5 h. The reaction mixture was poured into saturated aqueous NH4Cl (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The yellow residue was purified by preparative HPLC (TFA conditions) to give N-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)4-((2-hydroxyethyl)sulfonamido)benzamide (32.93 mg, 58.0 μmol) as a white solid. LCMS:MS ESI(M+1) + 568.4. 1 H NMR(400MHz,DMSO-d6)δ=11.92(s,1H),10.15(s,1H),8.08(d,J=6.5Hz,1H),7.79-7.68(m,2H),7.12(d,J=1.6Hz,1H),7.03-6.95(m,2H),3.75(br t,J=6.5Hz,6H),3.36-3.32(m,2H),3.19(br t,J=5.9Hz,4H),2.21-2.08(m,4H),0.88(br t,J=5.8Hz,4H),0.09(s,6H).

[0188] Example 8: Synthesis of N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide [ka]

[0189] Step 1: Preparation of 2-bromo-6-(4,4-difluoropiperidin-1-yl)-4-methylpyridine [ka] To a solution of 2-bromo-6-fluoro-4-methylpyridine (500 mg, 2.63 mmol) and 4,4-difluoropiperidine hydrochloride (620 mg, 3.94 mmol) in DMF (5 mL) was added DIPEA (1.36 mL, 7.89 mmol). The mixture was stirred at 100° C. for 12 hours. The reaction mixture was poured into saturated aqueous NH4Cl (40 mL) and extracted with ethyl acetate (3×35 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. 2-Bromo-6-(4,4-difluoropiperidin-1-yl)-4-methylpyridine (600 mg, 2.06 mmol) was obtained as a yellow oil. LCMS:MS ESI (M+1) + 290.9.

[0190] Step 2: Preparation of 6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-amine [ka] To a solution of 2-bromo-6-(4,4-difluoropiperidin-1-yl)-4-methylpyridine (350 mg, 1.20 mmol) and tert-butyl carbamate (420 mg, 3.59 mmol) in 2-methyl-2-butanol (5 mL) was added Pd2(dba)3 (109 mg, 120 μmol), Xantphos (138 mg, 240 μmol), and cesium carbonate (1.16 g, 3.59 mmol). The mixture was stirred at 100 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure. The yellow residue was purified by silica gel column chromatography (PE:EA 50:1) to give a yellow solid. The solid was dissolved in DCM (1 mL), and HCl (3 mL, 4 M in dioxane) was added to the mixture. The mixture was stirred at 25 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give 6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-amine (175 mg, 663 μmol) as a yellow solid.

[0191] Step 3: Preparation of N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-nitrobenzamide [ka] To a solution of 6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-amine (192 mg, 624 μmol) in THF (3 mL) was added LiHMDS (2.27 mL, 2.27 mmol, 1 M in THF). The mixture was stirred at 25° C. for 2 hours. The reaction mixture was poured into saturated aqueous NH4Cl (10 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA 50:1) to give N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-nitrobenzamide (200 mg, 397 μmol) as a yellow solid. LCMS:MS ESI(M+1) +504.2.

[0192] Step 4: Preparation of 4-amino-N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)benzamide [ka] To a solution of N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-nitrobenzamide (140 mg, 277 μmol) in MeOH (10 mL) was added Pd / C (111 mg, 10% w / w). The mixture was stirred under an H atmosphere (15 psi) at 25° C. for 2 hours. The reaction mixture was filtered and concentrated to give 4-amino-N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)benzamide (130 mg, 274 μmol) as a yellow solid. LCMS:MS ESI(M+1) + 474.3.

[0193] Step 5: Preparation of ethyl 2-(N-(4-((6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)carbamoyl)-3-(4,4-dimethyl-1,4-azasilinan-1-yl)phenyl)sulfamoyl)acetate [ka] To a solution of 4-amino-N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)benzamide (130 mg, 274 μmol) and pyridine (66.1 μL, 822 μmol) in DCM (3 mL) was added ethyl 2-(chlorosulfonyl)acetate (61.2 mg, 328 μmol) at 0° C. The mixture was stirred at 25° C. for 1 h. The reaction mixture was poured into saturated aqueous NH4Cl (10 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. Ethyl 2-(N-(4-((6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)carbamoyl)-3-(4,4-dimethyl-1,4-azasilinan-1-yl)phenyl)sulfamoyl)acetate (150 mg, 240 μmol) was obtained as a yellow oil. LCMS:MS ESI(M+1) + 624.2.

[0194] Step 6: Preparation of N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide [ka] To a solution of ethyl 2-(N-(4-((6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)carbamoyl)-3-(4,4-dimethyl-1,4-azasilinan-1-yl)phenyl)sulfamoyl)acetate (100 mg, 160 μmol) in THF (3 mL) was added lithium borohydride (0.160 mL, 320 μmol, 2 M in THF) at 0° C. The reaction was stirred at 25° C. for 0.5 h. The reaction mixture was poured into saturated aqueous NH4Cl (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (TFA conditions) to give N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (73.74 mg, 126 μmol) as an off-white solid. LCMS:MS ESI(M+1) + 582.3. 1 H NMR(400MHz,DMSO-d6)δ=12.18(s,1H),10.13(s,1H),7.98(d,J=8.6Hz,1H),7.53(s,1H),7.22(s,1H),7.08(br d,J=8.6Hz,1H),6.56(s,1H),3.74(t,J=6.5Hz,2H),3.66(br d,J=5.0Hz,4H),3.34(t,J=6.5Hz,2H),3.17(br t,J=5.7Hz,4H),2.26(s,3H),2.06-1.86(m,4H),0.99(br d,J=5.3Hz,4H),0.13(s,6H).

[0195] Example 9: Synthesis of N-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-(2-hydroxyethanesulfonamido)benzamide [ka]

[0196] Step 1: Preparation of benzyl 4-bromo-2-fluorobenzoate [ka] To a solution of 4-bromo-2-fluorobenzoic acid (800 mg, 3.65 mmol) in DMF (12.1 mL) was added sodium carbonate (464 mg, 4.38 mmol) and benzyl bromide (463 μL, 3.90 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 18 h. Water was added, and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0–10% EtOAc in heptane) to give benzyl 4-bromo-2-fluorobenzoate (947 mg, 3.06 mmol) as a pale yellow oil. 1 H NMR(400MHz,DMSO-d6)δ 7.85(t,J=8.2Hz,1H),7.74(dd,J=10.6,1.3Hz,1H),7.57(dd,J=8.4,1.6Hz,1H),7.49-7.44(m,2H),7.43-7.32(m,3H),5.35(s,2H). 19 F NMR(377MHz,DMSO-d6)δ -107.33(br.s.,1F).

[0197] Step 2: Preparation of benzyl 4-bromo-2-(4,4-dimethyl-1,4-azasilinan-1-yl)benzoate [ka] To a solution of benzyl 4-bromo-2-fluorobenzoate (330 mg, 1.06 mmol) in NMP (2.12 mL) was added 4,4-dimethyl-1,4-azasilinane hydrochloride (250 mg, 1.50 mmol) at room temperature. Potassium carbonate (439 mg, 3.18 mmol) was then added, and the reaction solution was stirred under nitrogen at 100 °C for 18 h. Water was added, and the product was extracted three times with EtOAc. The organic extracts were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-10% EtOAc in heptane) to give benzyl 4-bromo-2-(4,4-dimethyl-1,4-azasilinane-1-yl)benzoate (328 mg, 0.784 mmol). LCMS:MS ESI (M+1) + 418.0. 1 H NMR(400MHz,DMSO-d6)δ 7.49-7.31(m,6H),7.21(d,J=1.5Hz,1H),7.08(dd,J=8.1,1.5Hz,1H),5.30(s,2H),3.26-3.16(m,4H),0.79-0.67(m,4H),0.04(s,6H).

[0198] Step 3: Preparation of 4-bromo-2-(4,4-dimethyl-1,4-azasilinan-1-yl)benzoic acid [ka] To a solution of benzyl 4-bromo-2-(4,4-dimethyl-1,4-azasilinan-1-yl)benzoate (328 mg, 783 μmol) in 1,4-dioxane (522 μL) was added sodium hydroxide (1 mL, 2.00 mmol, 2 M in water), and the reaction mixture was stirred at 100 °C for 20 h. Volatiles were removed in vacuo. Water was added, and the mixture was acidified with aqueous hydrochloric acid (1 M) to pH 1. The resulting precipitate was collected by filtration. The solid was coevaporated with MeCN and dried to give 4-bromo-2-(4,4-dimethyl-1,4-azasilinan-1-yl)benzoic acid (220 mg, 0.67 mmol) as a white solid. LCMS:MS ESI (M+1) + 328.0. 1H NMR(400MHz,DMSO-d6)δ 8.05(d,J=1.2Hz,1H),7.89(d,J=8.6Hz,1H),7.58(dd,J=8.4,1.3Hz,1H),3.32(t,J=5.9Hz,4H),0.95(t,J=6.1Hz,4H),0.19(s,6H).

[0199] Step 4: Preparation of 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine [ka] A mixture of 2-chloro-6-methylpyrimidin-4-amine (500 mg, 3.48 mmol), 4,4-difluoropiperidine hydrochloride (822 mg, 5.22 mmol), and N,N-diisopropylethylamine (1.80 mL, 10.4 mmol) in NMP (5.04 mL) was stirred in a sealed tube at 180 °C for 24 h. The reaction mixture was cooled to room temperature, quenched with water, and extracted three times with ethyl acetate. The organic extracts were combined, washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by C column chromatography (H0:MeCN gradient) to give 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (745 mg, 3.26 mmol) as a pale yellow solid. LCMS:MS ESI (M+1) + 229.2. 1 H NMR(400MHz,DMSO-d6)δ 6.33(br.s.,2H),5.63(s,1H),3.84-3.72(m,4H),2.06(s,3H),1.97-1.79(m,4H).

[0200] Step 5: Preparation of 4-bromo-N-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-2-(4,4-dimethyl-1,4-azasilinan-1-yl)benzamide [ka] 4-Bromo-2-(4,4-dimethyl-1,4-azasilinan-1-yl)benzoic acid (150 mg, 456 μmol) was suspended in DCM (2 mL) under nitrogen. DMF (approximately 1 μL) was added, followed by the dropwise addition of thionyl chloride (69.2 μL, 957 μmol). After stirring at ambient temperature for 3 hours, the mixture was evaporated to dryness under reduced pressure. The residue was suspended in toluene and concentrated under reduced pressure twice. The residue was then suspended in DCM (2 mL) under nitrogen. Potassium phosphate tribasic (288 mg, 1.36 mmol) was added, followed by a solution of 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (108 mg, 474 μmol) and N,N-diisopropylethylamine (158 mg, 1.23 mmol) in DCM (1 mL). The mixture was stirred at room temperature for 21 hours. The mixture was evaporated to dryness under reduced pressure. The residue was suspended in dichloromethane and stirred for 10 minutes. The mixture was filtered, and the resulting filter cake was washed with additional dichloromethane. The filtrate was evaporated to dryness under reduced pressure. The residue was triturated with MeCN to give 4-bromo-N-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-2-(4,4-dimethyl-1,4-azasilinan-1-yl)benzamide (156 mg, 0.290 mmol) as a white solid. LCMS:MS ESI(M+1) + 538.0. 1 H NMR(400MHz,DMSO-d6)δ 12.64(br.s.,1H),7.92(d,J=8.1Hz,1H),7.72(br.s.,1H),7.61-7.35(m,2H),3.97-3.78( m,4H),3.28-3.15(m,4H),2.32(s,3H),2.06-1.88(m,4H),1.04-0.89(m,4H),0.14(s,6H). 19 F NMR(377MHz,DMSO-d6)δ -95.21(br.s.,2F).

[0201] Step 6: Preparation of N-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-(2-hydroxyethanesulfonamido)benzamide [ka] A mixture of 2-hydroxyethanesulfonamide (46.3 mg, 370 μmol), copper iodide (17.6 mg, 92.5 μmol), tripotassium phosphate (196 mg, 925 μmol), and sarcosine (16.4 mg, 185 μmol) in DMF (1.84 mL) was warmed to 50°C for 5 min. 4-Bromo-N-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-2-(4,4-dimethyl-1,4-azasilinan-1-yl)benzamide (100 mg, 185 μmol) was added, and the mixture was heated to 120°C for 20 h. The mixture was cooled to room temperature. EtOAc and water were added, and the resulting biphasic mixture was separated. The aqueous extract was washed twice with EtOAc. The combined organic extracts were washed with brine, aqueous NH4Cl / NH4OH (9:1), brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-100% EtOAc in heptane) to give N-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-(2-hydroxyethanesulfonamido)benzamide (46.7 mg, 80.1 μmol) as a white solid. LCMS:MS ESI (M+1) + 583.2. 1 H NMR(400MHz,DMSO-d6)δ 12.63(s,1H),10.18(br.s.,1H),7.98(d,J=8.6Hz,1H),7.46(s,1H),7.24(s,1H),7.10(d,J=8.6Hz,1H),5.01-4.85(m,1H),3.92-3.8 0(m,4H),3.79-3.69(m,2H),3.34(t,J=6.6Hz,2H),3.21-3.12(m,4H),2.31(s,3H),2.04-1.89(m,4H),1.06-0.95(m,4H),0.14(s,6H). 19 F NMR(377MHz,DMSO-d6)δ -95.19(br.s.,2F).

[0202] Examples 10 to 27 The following compounds were prepared in the same manner as in Examples 1 to 9 above. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0203] Example 28: Synthesis of 2-(7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide [ka]

[0204] Step 1: Preparation of tert-butyl 7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]heptane-3-carboxylate [ka] To a solution of tert-butyl 4-methyl-3,6-dihydropyridine-1(2H)-carboxylate (800 mg, 4.00 mmol) and NaI (302 mg, 2.02 mmol) in THF (16 mL) was added TMSCF 3(To the reaction mixture was added tert-butyl 7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]heptane-3-carboxylate (1.43 g, 10.1 mmol). The mixture was stirred overnight at 60° C. under a N atmosphere. The reaction mixture was diluted with water (5 mL) and extracted with EA (10 mL). The organic extract was concentrated and purified by silica gel column chromatography (PE:EA 4:1) to give tert-butyl 7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]heptane-3-carboxylate (400 mg, 1.61 mmol) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ = 4.17-3.07 (m, 4H), 2.06-1.86 (m, 1H), 1.61 (br s, 1H), 1.51-1.37 (m, 9H), 1.29-1.16 (m, 4H).

[0205] Step 2: Preparation of 7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]heptane hydrochloride [ka] A mixture of tert-butyl 7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]heptane-3-carboxylate (1.0 g, 4.04 mmol) and HCl (20 mL, 80 mmol, 4 M in dioxane) was stirred at room temperature overnight. The mixture was concentrated in vacuo to give 7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]heptane hydrochloride (500 mg, 2.72 mmol) as a yellow solid.

[0206] Step 3: Preparation of methyl 2-(7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)-4-iodobenzoate [ka] To a solution of 7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]heptane hydrochloride (300 mg, 1.63 mmol) and methyl 2-fluoro-4-iodobenzoate (456 mg, 1.63 mmol) in DMSO (2 mL) was added DIEA (632 mg, 4.89 mmol). The mixture was stirred at 100 °C overnight. The mixture was then diluted with water (10 mL) and extracted with EtOAc (10 mL). The organic extract was concentrated and purified by silica gel column chromatography (PE:EA 3:1) to give methyl 2-(7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)-4-iodobenzoate (400 mg, 982 μmol) as a yellow solid. LCMS:MS ESI (M+1) + 408.0.

[0207] Step 4: Preparation of 2-(7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodobenzamide [ka] To a solution of methyl 2-(7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)-4-iodobenzoate (400 mg, 982 μmol) and 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (335 mg, 1.47 mmol) in THF (8 mL) was added LiHMDS (2.9 mL, 2.9 mmol, 1 M in THF) at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (10 mL) and extracted with EtOAc (10 mL). The organic extract was concentrated and purified by silica gel column chromatography (PE:EA 3:1) to give 2-(7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodobenzamide (500 mg, 828 μmol) as a yellow solid. LCMS:MS ESI(M+1) + 604.2.

[0208] Step 5: Preparation of 2-(7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide [ka] To a solution of 2-(7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodobenzamide (41.2 mg, 330 μmol), copper(I) iodide (15.6 mg, 82.5 μmol), and 2-(methylamino)acetic acid (7.35 mg, 82.5 μmol) in DMF (2 mL) was added KPO (175 mg, 825 μmol), and the mixture was stirred at 60 °C for 10 min under a N atmosphere. Next, 2-hydroxyethane-1-sulfonamide (100 mg, 165 μmol) was added, and the mixture was stirred at 100 °C overnight. The mixture was filtered, and the filtrate was purified by preparative HPLC (neutral conditions) to give 2-(7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (33.1 mg, 55.2 μmol) as a yellow solid. LCMS:MS ESI(M+1) + 601.3. 1H NMR(400MHz,DMSO-d6)δ=11.16(s,1H),7.82(d,J=8.4Hz,1H),7.40(s,1H),7.20-6.92(m,2H),3.87(br t,J=5.2Hz,4H),3.75(t,J=6.4Hz,2H),3.49-3.37(m,1H),3.34(m,2H),3.05-2.85(m,2H),2.72-2.62(m,1H),2.31(m,4H),2.10(br d,J=13.4Hz,1H),2.03-1.89(m,4H),1.88-1.69(m,2H),1.23(s,3H).

[0209] Examples 29a and 29b: Synthesis of 2-((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (Example 29a) and 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (Example 29b) [ka]

[0210] Step 1: Preparation of methyl 2-(6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-iodobenzoate [ka] To a solution of 6-(difluoromethyl)-3-azabicyclo[4.1.0]heptane (100 mg, 679 μmol) in DMSO (2 mL) was added methyl 2-fluoro-4-iodobenzoate (190 mg, 679 μmol) and DIEA (87.7 mg, 679 μmol). The mixture was stirred at 100° C. overnight. The mixture was poured into water (3 mL) and extracted with EtOAc (3 × 5 mL). The combined organic extracts were washed with brine (2 × 2 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA 3:1) to give methyl 2-(6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-iodobenzoate (90.0 mg, 221 μmol) as a yellow gum. LCMS:MS ESI (M-100) + 408.0.

[0211] Step 2: Preparation of 2-((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodobenzamide and 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodobenzamide [ka] To a solution of methyl 2-(6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-iodobenzoate (80 mg, 196 μmol) and 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (89.4 mg, 392 μmol) in THF (10 mL) was added LiHMDS (0.59 mL, 0.59 mmol, 1 M in THF) at 0° C. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with brine (2 × 20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA 1:1) to give racemic 2-(6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodobenzamide. The racemic mixture was separated by chiral SFC (DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm) CO₂-EtOH (0.1% NH₃H₂O)) to give 2-((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodobenzamide (50 mg, 82.8 μmol). A first eluting peak arbitrarily assigned as 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodobenzamide (50 mg, 82.8 μmol) was obtained. First eluting peak LCMS:MS ESI (M-100) + 604.0. Second eluting peak LCMS:MS ESI (M-100) + 604.0.

[0212] Step 3A: Preparation of 2-((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide [ka] To a solution of 2-hydroxyethane-1-sulfonamide (25.9 mg, 207 μmol) in DMF (2 mL) was added 2-(methylamino)acetic acid (3.68 mg, 41.4 μmol), copper(I) iodide (15.6 mg, 82.8 μmol), and KPO (87.8 mg, 414 μmol). The mixture was stirred at 70° C. for 20 minutes. 2-((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodobenzamide (50 mg, 82.8 μmol) was added to the mixture, and the mixture was stirred at 100° C. overnight. The mixture was poured into water (5 mL) and extracted with EtOAc (3×3 mL). The combined organic extracts were washed with brine (2 × 2 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (TFA conditions) to give 2-((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (13.6 mg, 22.7 μmol) as a white solid. LCMS:MS ESI(M+1) + 601.4. 1H NMR(400MHz,DMSO-d6)δ=11.59(s,1H),10.22(s,1H),7.91(d,J=8.6Hz,1H),7.44(s,1H),7.19(s,1H),7.09(dd,J=1.4,8.4Hz,1H),5.66(br t,J=56.6Hz,1H),3.88(br d,J=5.0Hz,4H),3.76(t,J=6.4Hz,2H),3.35(t,J=6.4Hz,2H),3.28(br d,J=11.0Hz,1H),3.12(br dd,J=3.4,11.4Hz,1H),2.99-2.88(m,1H),2.60-2.51(m,1H),2.32(s,3H),2.21-2.06(m,2H),2.02-1.91(m,4H),1.49(br dd,J=4.2,8.6Hz,1H),1.37(br d,J=4.8Hz,1H),0.99(br dd,J=4.6,9.2Hz,1H).

[0213] Step 3B: Preparation of 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide [ka] To a solution of 2-hydroxyethane-1-sulfonamide (25.9 mg, 207 μmol) in DMF (2 mL) was added 2-(methylamino)acetic acid (3.68 mg, 41.4 μmol), copper(I) iodide (15.6 mg, 82.8 μmol), and KPO (87.8 mg, 414 μmol). The mixture was stirred at 70° C. for 20 minutes. 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)6-methylpyrimidin-4-yl)-4-iodobenzamide (50 mg, 82.8 μmol) was added to the mixture, and the mixture was stirred at 100° C. overnight. The mixture was poured into water (5 mL) and extracted with EtOAc (3×3 mL). The combined organic extracts were washed with brine (2 × 2 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (TFA conditions) to give 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)4-((2-hydroxyethyl)sulfonamido)benzamide (14.8 mg, 24.6 μmol) as a white solid. LCMS:MS ESI(M+1) + 601.2. 1 H NMR(400MHz,DMSO-d6)δ=11.60(s,1H),10.22(s,1H),7.91(br d,J=8.6Hz,1H),7.44(s,1H),7.19(br s,1H),7.09(br d,J=8.6Hz,1H),5.65(br s,1H),3.89(br s,4H),3.76(br t,J=6.2Hz,2H),3.35(br t,J=6.2Hz,2H),3.28(br d,J=11.2Hz,1H),3.12(br dd,J=3.2,10.8Hz,1H),2.94(br dd,J=1.6,7.0Hz,1H),2.54(br d,J=5.4Hz,1H),2.32(s,3H),2.20-2.08(m,2H),1.98(br s,4H),1.49(br s,1H),1.37(br d,J=4.4Hz,1H),1.04-0.94(m,1H).

[0214] Example 30: Synthesis of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-(hydroxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)benzamide [ka]

[0215] Step 1: Preparation of tert-butyl 4-((benzyloxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylate [ka] To a solution of tert-butyl 4-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylate (1.7 g, 7.97 mmol) in THF (10 mL) was added sodium hydride (349 mg, 8.76 mmol, 60% in mineral oil) at 0 °C. The mixture was warmed to room temperature and stirred at room temperature for 0.5 h. Next, benzyl bromide (1.58 g, 9.24 mmol) and TBAI (294 mg, 797 μmol) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (3 × 35 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA gradient) to give tert-butyl 4-((benzyloxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylate (1.90 g, 6.26 mmol) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ = 7.40–7.28 (m, 5H), 5.68 (br s, 1H), 4.49 (s, 2H), 3.94 (s, 4H), 3.52 (t, J = 5.6 Hz, 2H), 2.15 (br s, 2H), 1.48 (s, 9H).

[0216] Step 2: Preparation of tert-butyl 6-((benzyloxy)methyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate [ka] Under a N2 atmosphere, Et2Zn (8.3 mL, 8.3 mmol, 1.0 M in hexane) was added to DCM (12 mL) with ice cooling, followed by the dropwise addition of TFA (0.6 mL) in DCM (3 mL), and the mixture was stirred at 0 °C for 40 min. Next, a solution of diiodomethane (2.2 g, 8.2 mmol) in DCM (3 mL) was added dropwise. The mixture was then stirred at 0 °C for 40 min. A solution of tert-butyl 4-((benzyloxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylate (1.0 g, 3.20 mmol) in DCM (9 mL) was added dropwise. The reaction was allowed to warm to room temperature and stirred overnight. After cooling to 0 °C, the mixture was treated with Et3N to adjust the pH to 8. Boc2O (0.90 g, 4.1 mmol) was added, and the mixture was stirred at room temperature for 5 h. The mixture was treated with saturated aqueous NH4Cl (20 mL) and extracted with chloroform (3 × 30 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. The yellow residue was purified by silica gel column chromatography (PE:EA gradient) to give tert-butyl 6-((benzyloxy)methyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (800 mg, 2.52 mmol) as a yellow oil.

[0217] Step 3: Preparation of 6-((benzyloxy)methyl)-3-azabicyclo[4.1.0]heptane [ka] tert-Butyl 6-((benzyloxy)methyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (800 mg, 2.52 mmol) was added to hydrochloric acid (10 mL, 40 mmol, 4 M in dioxane). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo to give 6-((benzyloxy)methyl)-3-azabicyclo[4.1.0]heptane (520 mg, 2.39 mmol) as a yellow solid. LCMS:MS ESI(M+1) + 218.0.

[0218] Step 4: Preparation of methyl 2-(6-((benzyloxy)methyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-bromobenzoate [ka] To a solution of 6-((benzyloxy)methyl)-3-azabicyclo[4.1.0]heptane (520 mg, 2.39 mmol) and methyl 4-bromo-2-fluorobenzoate (556 mg, 2.39 mmol) in DMSO (5 mL) was added DIEA (926 mg, 7.17 mmol). The mixture was stirred at 100 °C overnight. The mixture was poured into saturated aqueous NH4Cl (30 mL) and extracted with EtOAc (3 × 35 mL). The combined organic extracts were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA gradient) to give methyl 2-(6-((benzyloxy)methyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-bromobenzoate (350 mg, 813 μmol) as a yellow oil. LCMS:MS ESI(M+1) + 430.1.

[0219] Step 5: Preparation of 2-(6-((benzyloxy)methyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)benzamide [ka] To a solution of methyl 2-(6-((benzyloxy)methyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-bromobenzoate (200 mg, 464 μmol) and 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (105 mg, 464 μmol) in THF (3 mL) was added LiHMDS (1.4 mL, 1.4 mmol, 1 M in THF) at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was poured into saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (3 × 15 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA gradient) to give 2-(6-((benzyloxy)methyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)benzamide (130 mg, 207 μmol) as a yellow oil. LCMS:MS ESI(M+1) + 626.2.

[0220] Step 6: Preparation of 2-(6-((benzyloxy)methyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide [ka] To a solution of 2-hydroxyethane-1-sulfonamide (51.8 mg, 414 μmol), 2-(methylamino)acetic acid (12.8 mg, 144 μmol), and copper(I) iodide (19.6 mg, 103 μmol) in DMF (1 mL) was added KPO (218 mg, 1.03 mmol). The mixture was stirred at 60° C. for 10 minutes. Next, 2-(6-((benzyloxy)methyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)benzamide (130 mg, 207 μmol) was added, and the mixture was stirred at 100° C. overnight. The mixture was poured into saturated aqueous NHCl (10 mL) and extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine (30 mL), dried over NaSO, filtered, and concentrated. The residue was purified by preparative HPLC (TFA conditions) to give 2-(6-((benzyloxy)methyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (100 mg, 149 μmol) as a yellow oil. LCMS:MS ESI(M+1) + 671.3.

[0221] Step 7: Preparation of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-(hydroxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)benzamide [ka] To a solution of 2-(6-((benzyloxy)methyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (40 mg, 59.6 μmol) in MeOH (5 mL) was added Pearlman's catalyst (10 mg, 20% Pd w / w), and the resulting suspension was stirred under an atmosphere of H (15 psi) at 45° C. overnight. The mixture was then filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (FA conditions) to give N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-(hydroxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)benzamide (8.39 mg, 14.4 μmol) as a white solid. LCMS:MS ESI(M+1) + 581.2. 1 H NMR(400MHz,DMSO-d6)δ=11.77(br s,1H),7.91(br d,J=8.4Hz,1H),7.43(s,1H),7.25-7.14(m,1H),7.05(br d,J=8.8Hz,1H),4.59(br s,1H),3.89(br s,4H),3.75(br t,J=6.4Hz,2H),3.27(br d,J=4.6Hz,2H),3.23-3.09(m,3H),2.89-2.77(m,1H),2.56(br dd,J=4.6,11.6Hz,2H),2.30(s,3H),2.18-2.07(m,1H),1.98(br s,5H),1.21-0.96(m,2H),0.68-0.50(m,1H).

[0222] Examples 31a and 31b: Synthesis of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-4-((2-hydroxyethyl)sulfonamido)-6-((1S,6S)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)benzamide (Example 31a) and N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-4-((2-hydroxyethyl)sulfonamido)-6-((1R,6R)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)benzamide (Example 31b) [ka]

[0223] Step 1A: Preparation of 4-amino-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-6-((1S,6S)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)benzamide [ka] To a solution of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-6-((1S,6S)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzamide (120 mg, 0.24 mmol) in MeOH (4 mL) was added Pd / C (50 mg, 10% w / w). The mixture was stirred at room temperature under an atmosphere of H (15 psi) for 1 h. The mixture was filtered and the filtrate was concentrated in vacuo to give 4-amino-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-6-((1S,6S)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)benzamide (100 mg, 0.211 mmol) as a colorless solid. LCMS:MS ESI(M+1) + 475.3.

[0224] Step 2A: Preparation of ethyl 2-(N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-3-fluoro-5-((1S,6S)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)phenyl)sulfamoyl)acetate [ka] To a solution of 4-amino-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-6-((1S,6S)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)benzamide (100 mg, 0.21 mmol) in DCM (2 mL) was added ethyl 2-(chlorosulfonyl)acetate (43.2 mg, 0.23 mmol) and pyridine (50.0 mg, 0.63 mmol). The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and purified by silica gel column chromatography (PE:EA gradient) to afford 2-(N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-3-fluoro-5-((1S,6S)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)phenyl)sulfamoyl)acetate (90.0 mg, 0.14 mmol) as a white solid. LCMS:MS ESI(M+1) + 625.3.

[0225] Step 3A: Preparation of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-4-((2-hydroxyethyl)sulfonamido)-6-((1S,6S)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)benzamide [ka] To a solution of ethyl 2-(N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-3-fluoro-5-((1S,6S)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)phenyl)sulfamoyl)acetate (70 mg, 0.11 mmol) in THF (1 mL) was added LiBH (0.17 mL, 0.34 mmol, 2 M in THF). The mixture was stirred at room temperature for 0.5 h. The mixture was then treated with HO (0.1 mL) and concentrated in vacuo. The residue was purified by preparative HPLC (FA conditions) to give N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-4-((2-hydroxyethyl)sulfonamido)-6-((1S,6S)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)benzamide (32.5 mg, 0.060 mmol) as a white solid. LCMS:MS ESI(M+1) + 583.4. 1 H NMR(400MHz,DMSO-d6)δ=10.59(br s,1H),8.25(s,1H),7.33(br s,1H),6.60(s,1H),6.56(br d,J=11.8Hz,1H),3.87(br s,4H),3.74(t,J=6.6Hz,2H),3.27(br t,J=6.6Hz,2H),3.22-3.12(m,2H),2.87-2.69(m,2H),2.30(br s,3H),1.96(br s,4H),1.75-1.59(m,2H),1.01(s,3H),0.90(br d,J=2.6Hz,1H),0.57(br s,1H),0.31(br dd, J = 3.8, 8.4 Hz, 1 H).

[0226] Step 1B: Preparation of 4-amino-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-6-((1R,6R)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)benzamide [ka] To a solution of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-6-((1R,6R)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzamide (110 mg, 0.22 mmol) in MeOH (3 mL) was added Pd / C (46.3 mg, 10% w / w). The mixture was stirred at room temperature under an atmosphere of H (15 psi) for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo to give 4-amino-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-6-((1R,6R)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)benzamide (100 mg, 0.22 mmol) as a colorless solid. LCMS:MS ESI(M+1) + 475.2.

[0227] Step 2B: Preparation of ethyl 2-(N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-3-fluoro-5-((1R,6R)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)phenyl)sulfamoyl)acetate [ka] To a solution of 4-amino-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-6-((1R,6R)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)benzamide (100 mg, 0.22 mmol) in DCM (2 mL) was added ethyl 2-(chlorosulfonyl)acetate (43.2 mg, 0.23 mmol) and pyridine (50.0 mg, 0.63 mmol). The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and purified by silica gel column chromatography (PE:EA gradient) to afford ethyl 2-(N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-3-fluoro-5-((1R,6R)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)phenyl)sulfamoyl)acetate (80.0 mg, 0.13 mmol) as a white solid. LCMS:MS ESI(M+1) + 625.4.

[0228] Step 3B: Preparation of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-4-((2-hydroxyethyl)sulfonamido)-6-((1R,6R)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)benzamide [ka] To a solution of ethyl 2-(N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-3-fluoro-5-((1R,6R)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)phenyl)sulfamoyl)acetate (80 mg, 0.13 mmol) in THF (1 mL) was added LiBH (0.19 mL, 0.38 mmol, 2 M in THF). The mixture was stirred at room temperature for 0.5 h. The mixture was then treated with HO (0.1 mL) and concentrated in vacuo. The residue was purified by preparative HPLC (FA conditions) to give N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-4-((2-hydroxyethyl)sulfonamido)-6-((1R,6R)-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl)benzamide (14.5 mg, 0.030 mmol) as a white solid. LCMS:MS ESI (M+1) + 583.4. 1 H NMR(400MHz,DMSO-d6)δ=10.59(br s,1H),7.32(br s,1H),6.61(s,1H),6.56(br d,J=11.4Hz,1H),3.87(br s,4H),3.75(t,J=6.6Hz,2H),3.30-3.27(m,2H),3.23-3.11(m,2H),2.88-2.70(m,2H),2.30(br s,3H),1.96(br s,4H),1.74-1.57(m,2H),1.01(s,3H),0.89(br s,1H),0.57(br s,1H),0.31(br dd,J=3.8,8.2Hz,1H).

[0229] Examples 32 to 47 The following compounds were prepared using procedures similar to those in Examples 28-31 above: [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] *The compound of Example 38 is the same as the compound of Example 31a, and the compound of Example 41 is the same as the compound of Example 29a except that the stereochemistry is not depicted in the compound structure of Example 41.

[0230] Example 48: 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide [ka]

[0231] Step 1: Preparation of 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-4-nitrobenzamide [ka] To a solution of methyl 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzoate (342 mg, 1.05 mmol) and 6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-amine (200 mg, 0.880 mmol) in THF (10 mL) was added LiHMDS (2.64 mL, 2.64 mmol, 1 M in THF) at 0° C. The mixture was stirred under a N atmosphere at 25° C. for 1 hour. The mixture was poured into water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (2×20 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA=3:1) to give 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-nitrobenzamide (200 mg, 383 μmol) as a yellow solid.

[0232] Step 2: Preparation of 4-amino-2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)benzamide [ka] To a solution of 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-4-nitrobenzamide (200 mg, 383 μmol) in MeOH (10 mL) was added Pd / C (60 mg, 10% w / w). The resulting mixture was stirred under H atmosphere (15 psi) at 25 °C for 1 h. The mixture was filtered and the filtrate was concentrated to give 4-amino-2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)benzamide (110 mg, 223 μmol) as a yellow solid. LCMS:MS ESI(M+1) + 492.3.

[0233] Step 3: Preparation of 2-(N-(3-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-((6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)carbamoyl)phenyl)sulfamoyl)acetate [ka] To a solution of 4-amino-2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)benzamide (110 mg, 223 μmol) in DCM (10 mL) were added pyridine (35.2 mg, 446 μmol) and ethyl 2-(chlorosulfonyl)acetate (41.6 mg, 223 μmol) at 0° C. The resulting mixture was stirred at 25° C. for 1 h and then poured into water (30 mL). The mixture was extracted with EtOAc (3 × 30 mL), and the combined organic extracts were washed with brine (2 × 20 mL), dried over NaSO, filtered, and concentrated. Ethyl 2-(N-(3-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-((6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)carbamoyl)phenyl)sulfamoylacetate (130 mg, 202 μmol) was obtained as a yellow gum. LCMS:MS ESI(M+1) + 642.2.

[0234] Step 4: Preparation of 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide [ka] To a solution of ethyl 2-(N-(3-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-((6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)carbamoyl)phenyl)sulfamoyl)acetate (130 mg, 202 μmol) in THF (5 mL) was added LiBH (0.606 mL, 0.606 mmol, 1 M in THF), and the mixture was stirred at 25 °C for 1 h. The mixture was poured into HO (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with brine (2 × 10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (TFA conditions) to give 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (17.1 mg, 28.5 μmol) as a white solid. LCMS:MS ESI(M+1) + 600.3. 1 H NMR(400MHz,DMSO-d6)δ=11.13(s,1H),10.17(s,1H),7.91(d,J=8.4Hz,1H), 7.51(s,1H),7.18(s,1H),7.08(dd,J=1.8,8.6Hz,1H),6.55(s,1H),5.65(br t,J=56.6Hz,1H),3.76(t,J=6.4Hz,2H),3.68(br d,J=5.0Hz,4H),3.35(t,J=6.4Hz,2H),3.30(br d,J=11.6Hz,1H),3.10(br dd,J=3.8,11.2Hz,1H),2.97(br d,J=11.2Hz,1H),2.54(br s,1H),2.26(s,3H),2.18-2.12(m,2H),2.02-1.92(m,4H),1.48(br d,J=4.6Hz,1H),1.37(br d,J=4.8Hz,1H),0.98(br dd,J=4.6,9.0Hz,1H).

[0235] Examples 49a and 49b: N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-((1S,6R)-6-(methoxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)benzamide (Example 49a), and N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-((1R,6S)-6-(methoxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)benzamide (Example 49b) [ka]

[0236] Step 1: Preparation of methyl 2-(6-(methoxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzoate [ka] To a solution of methyl 2-(6-(hydroxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzoate (1.00 g, 3.26 mmol) in DCM (30 mL) was added boron trifluoride diethyl etherate (46.2 mg, 326 μmol) followed by trimethylsilyldiazomethane (929 mg, 8.14 mmol) at 0° C. The mixture was stirred at 20° C. for 16 h. The mixture was concentrated, and the residue was purified by silica gel column chromatography (PE:EA gradient) to give methyl 2-(6-(methoxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzoate (500 mg, 1.56 mmol) as a yellow gum. LCMS:MS ESI (M+1) + 321.1.

[0237] Step 2: Preparation of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-(methoxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzamide [ka] To a solution of methyl 2-(6-(methoxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzoate (250 mg, 780 μmol) and 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (248 mg, 1.09 mmol) in THF (5 mL) was added LiHMDS (2.34 mL, 2.34 mmol, 1 M in THF) dropwise at 0° C. The mixture was stirred at 20° C. for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL). The organic extract was concentrated and purified by silica gel column chromatography (PE:EA gradient) to give N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-(methoxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzamide (200 mg, 387 μmol) as a yellow gum. LCMS:MS ESI (M+1) + 517.3.

[0238] Step 3: Preparation of 4-amino-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-(methoxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)benzamide [ka] To a solution of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-(methoxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzamide (250 mg, 483 μmol) in THF (2 mL) was added Pd / C (50 mg, 10% w / w), and the mixture was stirred under H atmosphere (15 psi) at 20° C. for 1 hour. The mixture was filtered, and the filtrate was concentrated to give 4-amino-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-(methoxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)benzamide (200 mg, 411 μmol) as a yellow gum. LCMS:MS ESI(M+1) + 487.3.

[0239] Step 4: Preparation of ethyl 2-(N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-3-(6-(methoxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)phenyl)sulfamoyl)acetate [ka] To a solution of 4-amino-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-(methoxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)benzamide (200 mg, 411 μmol) in DCM (4 mL) was added pyridine (97.2 mg, 1.23 mmol) and ethyl 2-(chlorosulfonyl)acetate (114 mg, 616 μmol) at 0° C. The mixture was stirred at 20° C. for 2 hours. The reaction mixture was purified by silica gel column chromatography (PE:EA gradient) to give ethyl 2-(N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-3-(6-(methoxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)phenyl)sulfamoyl)acetate (200 mg, 314 μmol) as a yellow gum. LCMS:MS ESI(M+1) +637.3.

[0240] Step 5: Preparation of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-((1S,6R)-6-(methoxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)benzamide and N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-((1R,6S)-6-(methoxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)benzamide [ka] To a solution of ethyl 2-(N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-3-(6-(methoxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)phenyl)sulfamoyl)acetate (150 mg, 235 μmol) in THF (3 mL) was added LiBH (0.705 mL, 0.705 mmol, 1 M in THF) at 0° C. The reaction mixture was stirred at 20° C. for 2 h and then quenched with water (2 drops). The mixture was first purified by preparative HPLC (FA conditions) to give racemic N-(N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-(methoxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)benzamide. The racemic compound was purified by chiral SFC (Chiralcel OX-3 (50 mm × 4.6 mm, 3 μm) CO₂-EtOH (0.05% diethylamine)) and arbitrarily assigned as N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-((1S,6R)-6-(methoxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)benzamide (72.7 mg, 122 μmol) as a white solid. A first eluting peak arbitrarily assigned as N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-((1R,6S)-6-(methoxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)benzamide (65.6 mg, 110 μmol) was obtained as a white solid. First eluting peak LCMS:MS ESI (M+1) + 595.3. Second eluting peak LCMS:MS ESI (M+1) + 595.3. First eluting peak 11H NMR (400 MHz, DMSO-d6) δ = 11.81 (s, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.43 (s, 1H), 7.07 (d, J = 1.4 Hz, 1H), 6.95 (dd, J = 1.8, 8.8 Hz, 1H), 3.89 (br t, J = 5.4 Hz, 4H), 3.73 (t, J = 6.5 Hz, 2H), 3.25 (s, 3H), 3.23 - 3.15 (m, 5H), 2.87 - 2.78 (m, 1H), 2.61 - 2.52 (m, 2H), 2.30 (s, 3H), 2.18 - 2.09 (m, 1H), 2.03 - 1.91 (m, 5H), 1.19 - 1.09 (m, 2H), 0.61 (br d, J = 4.9 Hz, 1H). Second elution peak 1 1H NMR (400 MHz, DMSO-d6) δ = 11.82 (s, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.44 (s, 1H), 7.06 (s, 1H), 6.94 (dd, J = 1.5, 8.6 Hz, 1H), 3.89 (br t, J = 5.4 Hz, 4H), 3.73 (t, J = 6.6 Hz, 2H), 3.25 (s, 3H), 3.23 - 3.15 (m, 5H), 2.90 - 2.76 (m, 1H), 2.61 - 2.51 (m, 2H), 2.30 (s, 3H), 2.21 - 2.10 (m, 1H), 2.03 - 1.90 (m, 5H), 1.20 - 1.07 (m, 2H), 0.61 (dd, J = 2.6, 7.4 Hz, 1H).

[0241] Examples 50a, 50b, 51a, and 51b: N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1R,6R)-6-fluoro-3-azabicyclo[4.2.0]octan-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (Example 50a), N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1S,6S)-6-fluoro-3-azabicyclo[4.2.0]octan-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (Example 50b), N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1S,6R)-6-(fluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (Example 51a), and N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1R,6S)-6-(fluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (Example 51b). [ka]

[0242] Step 1: Synthesis of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-4-nitrobenzamide [ka] To a solution of 2-fluoro-4-nitrobenzoic acid (25.0 g, 135 mmol) and 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (27.6 g, 121 mmol) in DCE (500 mL) was added 2-chloro-1-methylpyridin-1-ium iodide (103 g, 405 mmol) and triethylamine (40.9 g, 405 mmol), and the mixture was stirred at 80 °C for 12 h. The mixture was poured into saturated aqueous NH Cl (100 mL) and extracted with EtOAc (3 × 500 mL). The combined organic extracts were washed with brine (300 mL), dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA gradient) to give N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-4-nitrobenzamide (27.0 g, 68.2 mmol) as a yellow solid. LCMS:MS ESI (M+1) + 396.2. 1 H NMR(400MHz,DMSO-d6)δ=11.09(s,1H),8.27 - 8.20(m,1H),8.18 - 8.12(m,1H),7.97 - 7.86(m,1H),7.23(br s,1H),3.83(br s,4H),2.31(s,3H),1.95(br t,J=13.2Hz,4H).

[0243] Step 2: Preparation of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-(hydroxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzamide [ka] To a solution of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-4-nitrobenzamide (26.0 g, 65.7 mmol) and (3-azabicyclo[4.1.0]heptan-6-yl)methanol (10.7 g, 65.7 mmol) in DMSO (250 mL) was added DIPEA (25.4 g, 197 mmol), and the mixture was stirred at 100° C. for 12 h. The mixture was poured into saturated aqueous NH4Cl (400 mL) and extracted with EtOAc (3×450 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA gradient) to give N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-(hydroxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzamide (24.0 g, 47.7 mmol) as a yellow solid. LCMS:MS ESI (M+1) + 503.1.

[0244] Step 3: Preparation of a mixture containing N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-fluoro-3-azabicyclo[4.2.0]octan-3-yl)-4-nitrobenzamide and N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-(fluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzamide [ka] To a solution of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-(hydroxymethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzamide (24.0 g, 47.7 mmol) in DCM (240 mL) was added bis(2-methoxyethyl)aminosulfur trifluoride (21.1 g, 95.4 mmol) dropwise at 0° C., and the mixture was stirred at 25° C. for 12 hours. The reaction mixture was quenched by the slow addition of silica gel (15 g) at 0° C., and the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA gradient) to give a mixture (18.0 g, 35.6 mmol) of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-fluoro-3-azabicyclo[4.2.0]octan-3-yl)-4-nitrobenzamide and N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-(fluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-nitrobenzamide as a yellow solid.

[0245] Step 4: Preparation of a mixture containing 4-amino-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-fluoro-3-azabicyclo[4.2.0]octan-3-yl)benzamide and 4-amino-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-(fluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)benzamide [ka] To a solution of a mixture (18.0 g, 35.6 mmol) of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-fluoro-3-azabicyclo[4.2.0]octan-3-yl)-4-nitrobenzamide and N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-fluoro-3-azabicyclo[4.2.0]octan-3-yl)-4-nitrobenzamide in THF (180 mL), Pd / C (3.78 g, 10% w / w) was added, and the mixture was stirred under an atmosphere of H2 (15 psi) at 25 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a mixture of 4-amino-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-fluoro-3-azabicyclo[4.2.0]octan-3-yl)benzamide and 4-amino-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-(fluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)benzamide (16.8 g, 35.4 mmol) as a yellow oil. LCMS:MS ESI(M+1) + 475.3.

[0246] Step 5: Preparation of a mixture containing 2-(N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-3-(6-fluoro-3-azabicyclo[4.2.0]octan-3-yl)phenyl)sulfamoyl)methyl acetate and 2-(N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-3-(6-(fluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)phenyl)sulfamoyl)methyl acetate [ka] To a mixture of 4-amino-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-fluoro-3-azabicyclo[4.2.0]octan-3-yl)benzamide and 4-amino-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-(fluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)benzamide (16.8 g, 35.4 mmol) in DCM (15 mL) was added 2-(chlorosulfonyl)methyl acetate (9.16 g, 53.1 mmol) and pyridine (8.38 g, 106 mmol) at 0 ° C., and the mixture was stirred at 25 ° C. for 0.5 hours. The mixture was poured into saturated aqueous NH4Cl (200 mL) and extracted with EtOAc (3 x 150 mL). The combined organic extracts were washed with brine (150 mL), dried over NaSO, filtered, and concentrated to give a mixture containing methyl 2-(N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-3-(6-fluoro-3-azabicyclo[4.2.0]octan-3-yl)phenyl)sulfamoyl)acetate and methyl 2-(N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-3-(6-fluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)phenyl)sulfamoyl)acetate (21.0 g, 34.3 mmol) as a yellow oil. LCMS:MS ESI(M+1) + 611.2.

[0247] Step 6: Preparation of a mixture containing N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-fluoro-3-azabicyclo[4.2.0]octan-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide and N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-(fluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide [ka] To a mixture of methyl 2-(N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-3-(6-fluoro-3-azabicyclo[4.2.0]octan-3-yl)phenyl)sulfamoyl)acetate and methyl 2-(N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-3-(6-(fluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)phenyl)sulfamoyl)acetate (21.0 g, 34.3 mmol) in THF (200 mL) was added LiBH (68.6 mL, 68.6 mmol, 1 M in THF) at 0 °C, and the mixture was stirred at 25 °C for 0.5 h. The mixture was poured into saturated aqueous NH4Cl (200 mL) and extracted with EtOAc (3 x 150 mL). The combined organic extracts were washed with brine (250 mL), dried over Na2SO4, filtered, and concentrated to give a mixture (12.0 g, 20.5 mmol) containing N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-fluoro-3-azabicyclo[4.2.0]octan-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide and N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-(fluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide as a yellow oil.

[0248] Step 7: N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1R,6R)-6-fluoro-3-azabicyclo[4.2.0]octan-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide and N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1S,6S)-6-fluoro-3-azabicyclo[4.2.0]octan-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide. Preparation of 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1S,6R)-6-(fluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide and N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1R,6S)-6-(fluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide A mixture (10 g, 17.1 mmol) containing N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-fluoro-3-azabicyclo[4.2.0]octan-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide and N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-(fluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide was purified by silica gel column chromatography (PE: Purification by EA gradient) gave racemic N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-fluoro-3-azabicyclo[4.2.0]octan-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide as a colorless oil and racemic N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-(fluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide as a yellow oil.Racemic N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-fluoro-3-azabicyclo[4.2.0]octan-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide was purified using a chiral SFC (Daicel Chiralcel OJ-H (250 mm × 30 mm, 5 μm), mobile phase: CO2:MeOH 1:3 (0.1% Further purification with HCl (HCl) gave a first eluting peak arbitrarily assigned as N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1R,6R)-6-fluoro-3-azabicyclo[4.2.0]octan-3-yl)4-((2-hydroxyethyl)sulfonamido)benzamide (1100 mg, 1.37 mmol) as an off-white solid, and a second eluting peak arbitrarily assigned as N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1S,6S)-6-fluoro-3-azabicyclo[4.2.0]octan-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (1.15 g, 1.97 mmol) as an off-white solid. First eluting peak LCMS:MS ESI(M+1). + 583.4. Second eluting peak LCMS:MS ESI (M+1) + 583.2. First eluting peak 1 H NMR(400MHz,DMSO-d6)δ=11.79(s,1H),7.91(d,J=8.6Hz,1H),7.47(s,1H),7.20(d,J=1.8Hz,1H),7.08(dd,J =2.0,8.6Hz,1H),3.85(br t,J=5.4Hz,4H),3.75(t,J=6.4Hz,2H),3.35-3.33(m,2H),3.04-2.97(m,1H),2.93(d,J=3.0Hz,2H),2. 83-2.69(m,2H),2.31(s,3H),2.29-2.05(m,3H),2.01-1.89(m,6H),1.77(quin,J=8.9Hz,1H).Second elution peak 1H NMR(400MHz,DMSO-d6)δ=11.76(s,1H),10.60-9.87(m,1H),7.92(d,J=8.6Hz,1H),7.47 (s,1H),7.21(d,J=1.7Hz,1H),7.09(dd,J=1.8,8.6Hz,1H),5.29-4.66(m,1H),3.85(br t,J=5.1Hz,4H),3.75(t,J=6.4Hz,2H),3.35(t,J=6.4Hz,2H),3.05-2.98(m,1H),2.93(br d, J = 2.8 Hz, 2H), 2.82-2.66 (m, 2H), 2.31 (s, 3H), 2.29-2.08 (m, 3H), 2.02-1.89 (m, 6H), 1.77 (br t, J = 9.0 Hz, 1H). Racemic N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-(fluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide was purified three times consecutively by chiral SFC. First, a Daicel Chiralcel OJ-H (250 mm x 30 mm, 5 μm) was used with a mobile phase of CO2:MeOH 3:7 (0.1% NH3H2O), then a Daicel Chiralcel OX (250 mm x 30 mm, 10 μm) was used with a mobile phase of CO2:MeOH 2:3 (0.1% NH3H2O), and then a Daicel Chiralpak AD (250 mm x 30 mm, 10 μm) was used with a mobile phase of CO2:ACN / EtOH 1:3 (0.1% NH3H2O).A first eluting peak arbitrarily assigned as N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1S,6R)-6-(fluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (803.2 mg, 1.37 mmol) as an off-white solid, and a second eluting peak arbitrarily assigned as N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1R,6S)-6-(fluoromethyl)-3-azabicyclo[4.1.0]heptan-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (755.53 mg, 1.29 mmol) as an off-white solid were obtained. First eluting peak LCMS:MS ESI(M+1). + 583.3. Second eluting peak LCMS:MS ESI (M+1) + 583.3. First eluting peak 1 H NMR(400MHz,DMSO-d6)δ=11.70(s,1H),7.89(d,J=8.6Hz,1H),7.43(s,1H),7 .18(d,J=1.2Hz,1H),7.05(dd,J=1.6,8.6Hz,1H),4.42-4.07(m,2H),3.89(br s,4H),3.75(t,J=6.4Hz,2H),3.32(br s,2H),3.26-3.11(m,2H),2.91-2.82(m,1H),2.59(dt,J=4.5,11.6Hz,1H),2.30(s,3H),2.25-2.16(m,1H),2.07-1.91(m,5H),1.26(br s,2H),0.76(br d,J=4.8Hz,1H).Second elution peak 1H NMR(400MHz,DMSO-d6)δ=11.98(br s,1H),7.82(br d,J=8.6Hz,1H),7.45(s,1H),6.98(s,1H),6.88(br d,J=8.6Hz,1H),4.45-4.07(m,2H),3.89(br s,4H),3.72(br t,J=6.4Hz,2H),3.23-3.04(m,4H),2.83(br d,J=6.4Hz,1H),2.65-2.53(m,1H),2.35-2.18(m,4H),2.08-1.89(m,5H),1.37-1.21(m,2H),0.75(br d, J = 4.8 Hz, 1 H).

[0249] Examples 52 to 134 The following compounds were prepared in the same manner as in Examples 1-9, 28-31, or 48-51 above: [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12] [Table 3-13] [Table 3-14] [Table 3-15] [Table 3-16] [Table 3-17] [Table 3-18] [Table 3-19] [Table 3-20]

[0250] A comparative compound, "Compound A," whose structure is shown below, was also synthesized according to known methods and tested in the biological assays disclosed below. [ka] As can be seen from the data table below, many of the compounds of the present invention have better excretion rates than Compound A.

[0251] Assay 1. Caco-2 permeability assay: evaluation of bidirectional permeability of compounds. The samples were analyzed by LC / MS / MS to determine the apparent permeability coefficient (P app) was estimated. Caco-2 cells (American Type Culture Collection) were inoculated and seeded on HTS Transwell 96 permeable supports (Corning Corporation) and cultured for 14 days. The cell culture medium used was Dulbecco's Modified Eagle's Medium (DMEM) containing high glucose and L-glutamine, supplemented with 10% FBS, 1x penicillin-streptomycin mixture, and 1x non-essential amino acids (NEAA). The integrity of the cell monolayer was measured using an automated tissue resistance measurement system (World Precision Instruments). Stock solutions of compounds and control compounds in DMSO were diluted with HBSS (10 mM HEPES, pH 7.4) to a final concentration of 5 μM, with a final DMSO concentration of <0.1%. After a 30-minute preincubation, the HBSS was removed, and 75 μL of the test compound was added to the apical compartment of the transwell insert. The basolateral compartment was filled with 235 μL of HBSS (10 mM HEPES, pH 7.4) containing 2% BSA. Basolateral-to-apical drug transport rates were determined by adding 235 μL of test compound to the receiver plate well (basolateral compartment) and filling with 75 μL of HBSS (10 mM HEPES, pH 7.4) containing 2% BSA. Time 0 samples were prepared by transferring 25 μL of a 5 μM working solution to a well of a 96-deep-well plate containing 25 μL of HBSS (10 mM HEPES and 2% BSA, pH 7.4), followed by the addition of 200 μL of cold methanol containing the appropriate internal standards (100 nM alprazolam, 200 nM labetalol, 200 nM caffeine, and 200 nM diclofenac). After 2 hours of incubation at 37°C, 25 μL of sample from the donor side (apical compartment) was transferred to a 96-well plate containing 25 μL of HBSS (10 mM HEPES and 2% BSA, pH 7.4), and 25 μL of sample from the receiver side (basolateral compartment) was removed and transferred to a new plate containing 25 μL of HBSS (10 mM HEPES, pH 7.4).The reaction was terminated by adding 200 μL of cold methanol containing internal standards (100 nM alprazolam, 200 nM labetalol, 200 nM caffeine, and 200 nM diclofenac). The samples were vortexed for 5 minutes and then centrifuged at 3,220 g for 40 minutes. 100 μL of the supernatant was mixed with 100 μL of ultrapure water for LC-MS / MS analysis. All incubations were performed in duplicate. The solution was discarded from the transwell plate. 100 μL of Lucifer Yellow solution (100 μM in HBSS) was added to each well of the transwell insert, and 300 μL of HBSS was added to each well of the receiver. After 30 minutes of incubation at 37°C, 80 μL each from the apical and basolateral wells was dispensed into a black plate. The plate was then read on a Tecan Infinite™ M200 (excitation / emission wavelengths 485 nM / 530 nM).

[0252] All calculations were performed in Microsoft Excel. Peak areas were determined from extracted ion chromatograms. The amount of Lucifer Yellow leakage, in percent (%), can be calculated using the following formula:

number

[0253] LY leakage of less than 1% is an acceptable range indicating a properly formed Caco-2 monolayer. app ) is in units of centimeters per second and can be calculated for Caco-2 drug transport assays using the following formula:

number

[0254] where V A is the volume (mL) in the receiver well (0.235 mL for Ap → Bl flux, 0.075 mL for Bl → Ap flux), and Area is the surface area of ​​the membrane (0.143 cm for HTS Transwell 96 permeable support). 2), time is the total transport time (seconds). The emission rate can be calculated using the following formula:

number

[0255] where P app(B-A) is the apparent permeability coefficient from the basal to the apical side, P app(A-B) denotes the apparent permeability coefficient from the apical side to the basal side.

[0256] The recovery rate can be calculated using the following formula:

number

[0257] 2. KIF18A Biochemical Assay KIF18A ATPase assays were performed in a small-volume, non-binding, 384-well white plate with a final volume of 10 μL / well. Test compounds (10 mM solution in DMSO, 100 nL per well) were serially diluted in a 3-fold dilution series across a 10-step concentration range. KIF18A solution (0.4 nM, 5 μL / well, 1-367) was added to assay buffer (15 mM Tris-HCl [pH 7.5] (Boston Bioproducts Inc), 10 mM MgCl2 (Boston Bioproducts Inc), 0.01% Pluronic F-68 (Gibco Inc), 1 μM Taxol (Cytoskeleton Inc), 30 mg / ml preformed porcine microtubules (Cytoskeleton Inc)). The reaction was initiated by adding 5 μL of substrate solution (10 μM ultrapure ATP in assay buffer) to the well. Plates were incubated at room temperature for 45 minutes. After the indicated incubation time, 10 μL of ADP-Glo ​​reagent was added to the reaction, and the plate was incubated at room temperature for 40 minutes. 20 μL of kinase detection reagent was then added, and after a 40-minute incubation period, luminescence was recorded on an Envision plate reader (Perkin-Elmer, Billerica, MA).

[0258] 3. In vitro antiproliferative activity assay of KIF18A inhibitors in cancer cell line OVCAR-3 To evaluate the antiproliferative activity of KIF18A inhibitors against cancer cells in vitro, a 4-day or 7-day proliferation assay was performed on the ovarian cancer cell line OVCAR-3 using the Celitter-GLO 2.0 Luminescent Cell Viability Assay (CTG assay, Promega), which uses ATP as an indicator of cell viability. Briefly, OVCAR-3 cells were seeded at a density of 1,000 cells / mL in 40 μL of RPMI growth medium containing 10% FBS in black 384-well tissue culture plates. After 24 hours, the cells were treated with KIF18A inhibitors (10 concentrations ranging from 10.0 μM to 0.00051 μM, 3-fold dilutions). Assays were performed in duplicate. Four or seven days after treatment, 30 μL of CTG reagent was added to each well, and luminescence was detected using an Envision plate reader (Perkin Elmer). The percent inhibition was calculated based on the following formula:

number

[0259] 4. Evaluation of KIF18A Compounds in a Human Megakaryocyte Progenitor Cell Colony Formation Assay The clonogenic potential of human megakaryocytic progenitor cells (CFU-MK) was assessed in a collagen-based medium formulation containing 3% BSA, rhIL-3 (10 ng / mL), rhIL-6 (10 ng / mL), and rhTpo (50 ng / mL).

[0260] Human bone marrow mononuclear cells (Lot No. 0221006, ReachBio Research Labs, Seattle, WA) were stored at -152°C until required for the assay. On the day of the experiment, cells were rapidly thawed, and the contents were diluted with 10 mL of Iscove's Modified Dulbecco's Medium (IMDM) containing 10% fetal bovine serum (FBS) and washed by centrifugation (approximately 1500 rpm, 10 minutes, room temperature). The supernatant was discarded, and the cell pellet was resuspended in a known volume of IMDM + 10% FBS. Bone marrow samples were subjected to cell counts (3% glacial acetic acid) and viability assessment (trypan blue exclusion test).

[0261] Compounds were tested at final concentrations of 10, 3, 1, 0.3, 0.1, and 0.01 μM. DMSO was added as a vehicle control for the CFU-MK assay. 5-Fluorouracil (5-FU) was evaluated at 1.0 μg / mL, 0.1 μg / mL, and 0.01 μg / mL as a positive control for toxicity in all strains. Vehicle control cultures (containing no compound and 0.1% DMSO) and standard control cultures (containing neither compound nor DMSO) were also set up.

[0262] Cultures were incubated for 14 days. Human megakaryocyte cultures were then transferred from the 35 mm dishes to labeled slides, fixed with methanol / acetone fixative, and stained with anti-human CD41 antibody and alkaline phosphate detection according to the manufacturer's instructions. Colonies were evaluated microscopically, scored by trained staff, and divided into the following size categories: CFU-MK (3–20 cells), CFU-MK (21–49 cells), and CFU-MK (more than 50 cells).

[0263] For megakaryocytic progenitor cells, the mean ± 1 standard deviation of three replicate cultures was calculated. A two-tailed Student's t-test was performed to assess whether there was a difference in the number of colonies generated between vehicle control and treated cultures. Because colony counting can be subjective, a p value of <0.01 was considered significant. The concentration required to inhibit colony growth by 50% (IC 50 To calculate the concentration of 50% of colony growth inhibitory activity (IC), a dose-response curve was created using GraphPad Prism 9, plotting the logarithm of the compound concentration versus the control colony growth rate. 50 ) was calculated based on sigmoidal curve fitting using the equation for the one-site dose-response model.

[0264] y=A+[(BA) / (1+((C / x)^D))] where A = initial value (baseline response), B = maximum response, C = center (drug concentration that produces a response halfway between A and B), and D = slope of the curve at the midpoint.

[0265] Compound binding to components of the assay buffer system was also assessed. BSA and collagen were added to DMEM to the same final concentrations as in the buffer. Working solutions of test and control compounds were prepared in DMSO to a concentration of 5 mM, and then added to DMEM containing BSA and collagen. The final compound concentration was 25 μM. The final DMSO concentration was 0.5%. Ketoconazole was used as a positive control in the assay.

[0266] The dialysis membrane was soaked in ultrapure water for 60 minutes to separate the strips, then soaked in 20% ethanol for 20 minutes, and finally in dialysis buffer for 20 minutes. The dialysis set was assembled according to the manufacturer's instructions. Each cell was treated with 150 μL of sample and dialyzed against an equal volume of dialysis buffer (blank DMEM). The assay was performed in duplicate. The dialysis plate was sealed and incubated in an incubator at 37°C, 5% CO2, and 100 rpm for 6 hours. After the incubation period, 50 μL of both the buffer and the sample were transferred to wells of a 96-well plate.

[0267] To each buffer sample, 50 μL of blank DMEM containing BSA and collagen was added. The collected DMEM containing BSA and collagen was also supplemented with the same volume of blank DMEM. 400 μL of precipitation buffer acetonitrile containing internal standards (IS, 100 nM alprazolam, 200 nM labetalol, 200 nM imipramine, and 2 μM ketoprofen) was added to precipitate proteins and release compounds. The samples were vortexed for 2 minutes and centrifuged at 3,220 g for 30 minutes. 100 μL of the supernatant was diluted with 100 μL of ultrapure water, and this mixture was used for LC-MS / MS analysis.

[0268] All calculations were performed using Microsoft Excel. The concentrations of test compounds in the buffer chamber and the DMEM chamber containing BSA and collagen were determined from the peak area ratio. The percentage of bound compound was calculated as follows: % Release Rate = (peak area ratio of buffer chamber / peak area ratio of 2% BSA and collagen chamber) * 100 %Bound Rate = 100% - Free Rate Free fraction adjusted IC of test compound 50 is shown in Table 1 and was calculated using the following formula: Free fraction adjusted CFU-MK IC 50 (μM)=CFU-MK IC 50 (μM)*% release rate As can be seen, most of the tested compounds were significantly less potent on bone marrow mononuclear cells compared to the comparative compound A, indicating a significantly reduced risk of cytopenia or thrombocytopenia for these compounds.

[0269] [Table 5]

[0270] 5. In Vivo Pharmacokinetic Evaluation of KIF18A Compounds in Mice "The pharmacokinetics of the test compound was evaluated in female balb / c nude mice in a parallel study design by administering a single intravenous bolus (IV) dose of 3 mg / kg of solution and by oral administration (PO, solution / suspension) at a dose of 10 mg / kg. Blood samples from the IV group were collected at 0.083, 0.25, 0.5, 1, 2, 4, 7, 12, and 24 hours post-dose. Blood samples from the PO group were collected at 0.25, 0.5, 1, 2, 4, 7, 12, and 24 hours post-dose.

[0271] Working solutions of the desired serial concentrations were obtained by diluting the analyte stock solution with 50% aqueous acetonitrile. To prepare calibration standards ranging from 0.5 to 2000 ng / mL (0.5, 1, 2, 5, 10, 50, 100, 500, 1000, 2000 ng / mL), 5 μL of working solution (1, 2, 4, 10, 20, 100, 200, 1000, 4000 ng / mL) was added to 10 μL of blank female BALB / c nude mouse plasma for a total volume of 15 μL. Five quality control samples of plasma at concentrations of 1 ng / mL, 2 ng / mL, 5 ng / mL, 50 ng / mL, and 1600 ng / mL were prepared independently from those used for the calibration curve. These QC samples were prepared on the day of analysis using the same method as the calibration standards.

[0272] 15 μL of the standard sample, 15 μL of the QC sample, and 15 μL of the unknown sample (10 μL of plasma and 5 μL of blank solution) were each added to 200 μL of the IS mixture containing acetonitrile to precipitate proteins. The samples were then vortexed for 30 seconds. After centrifugation at 4000 rpm for 15 minutes at 4°C, the supernatant was diluted 3-fold with water. 10 μL of the diluted supernatant was injected into an LC / MS / MS system for quantitative analysis. PK parameters were estimated using a non-compartmental model with Phoenix (WinNonlin) pharmacokinetic software version 8.3.

[0273] Treatment with Examples 1, 9, 29b, and 50b at 3 mg / kg intravenous and 10 mg / kg oral doses was compared with Compound A at 10 mg / kg oral dose (Table 2). [Table 6]

[0274] 6. Demonstration of in vivo efficacy of KIF18A compounds Experiments were performed on female NOD SCID mice (GenPharmatech Co.). Animals were allowed to acclimate for 7 days before the study. The animals' general health was assessed by a veterinarian, and a complete health check was performed before the study. General procedures for animal care and husbandry followed the standards of the Commission on Life Sciences, National Research Council, Standard Operating Procedures (SOPs) of Pharmaron, Inc. Mice were kept in a laminar flow room at constant temperature and humidity with 3-5 mice in each cage. Animals were placed in a 300 x 180 x 150 mm 3Animals were housed in polycarbonate cages measuring 1.5 m² in size and in an environmentally monitored, well-ventilated room maintained at a temperature of 23 ± 3 °C and a relative humidity of 40% to 70%. Fluorescent lighting provided approximately 12 hours of light per day. Animals had free access to radiation-sterilized dry granular food throughout the study period, except for periods specified in the protocol, and sterile drinking water in bottles was available ad libitum during the quarantine and study periods.

[0275] The OVCAR-3 (ATCC) tumor cell line was maintained in vitro as a monolayer in RPMI 1640 medium supplemented with 20% heat-inactivated FBS at 37°C in an atmosphere of 5% CO2 in air. Tumor cells were subcultured for no more than 4–5 passages, and cells grown in the exponential growth phase were harvested and counted for tumor inoculation. Each mouse received 2 x 10 OVCAR-3 tumor cells in 0.2 mL of RPMI 1640 containing Matrigel (1:1) for model development. 7 ) was inoculated subcutaneously into the right flank.

[0276] The average tumor size is approximately 150-200 mm 3 Treatment was initiated when tumor size reached 100 mg / kg. Mice were randomly assigned to treatment groups to ensure comparable mean starting tumor sizes. Animals were then orally gavaged with vehicle or the indicated dose (10-100 mg / kg) of compound at a predetermined frequency (e.g., twice daily (BID), once daily (QD), 4 days on, 3 days off) with a final dose of 10 mL / kg.

[0277] All study animals were monitored not only for tumor growth, but also for behaviors such as locomotion, food and water consumption (cage-side checks only), body weight (BW), eye / hair gloss, and other abnormal effects. All animals were weighed and recorded twice weekly throughout the study. Weight change, expressed as a percentage, was calculated using the following formula: BW change rate (%) = (BWDay PG - DX / BWDay PG-D1 )×100, PG-D1 is on the first day of administration.

[0278] Tumor size measurements were performed using calipers and recorded twice weekly. Tumor volume (TV) (mm 3 ) was estimated using the following formula: TV = a × b 2 / 2, where "a" and "b" are the long and short diameters of the tumor, respectively.

[0279] TV was used to calculate tumor growth inhibition and tumor growth delay. For tumor growth inhibition (TGI), the following formula was used: %T / C=(Treatment group TV final -Treatment group TV initial ) / (Control group TV final -Control group TV initial ) x 100 %TGI=[1-(Treatment group TV final -Treatment group TV initial ) / (Control group TV final -Control group TV initial )] × 100 "TV final " and "TV initial " are the mean tumor volumes on the last and first days, respectively.

[0280] All statistical tests were performed in GraphPad, with a significance level of 5% or P<0.05. Group means and standard deviations were calculated for all measured parameters. Two-way RM ANOVA followed by Tukey's post hoc comparison of means was applied between groups.

[0281] On day 1, approximately 30-60 μL of whole blood was collected into tubes containing EDTA anticoagulant. These collections were performed 6 and 24 hours after the first dose in all treatment groups. Plasma was collected by centrifugation at 4,000 g for 5 minutes and stored at -80°C until analysis.

[0282] Working solutions of the desired serial concentrations were obtained by diluting the analyte stock solution with 50% aqueous acetonitrile. Five µL of working solution (1, 2, 4, 10, 20, 100, 200, 1000, and 2000 ng / mL) was added to 10 µL of blank NOD SCID mouse plasma in a total volume of 15 µL to obtain calibration curve standards ranging from 0.5 to 1000 ng / mL (0.5, 1, 2, 5, 10, 50, 100, 500, and 1000 ng / mL). Five quality control samples were prepared independently from those used for the calibration curve: 1 ng / mL, 2 ng / mL, 5 ng / mL, 50 ng / mL, and 800 ng / mL. These QC samples were prepared on the day of analysis using the same method as the calibration curve standards.

[0283] Fifteen microliters of standard, 15 μL of QC sample, and 15 μL of unknown sample (10 μL of plasma and 5 μL of blank) were added to 200 μL of IS mixture containing acetonitrile to precipitate proteins. The samples were then vortexed for 30 seconds and centrifuged at 4000 rpm for 15 minutes at 4°C. The supernatant was diluted 3-fold with water. 10 μL of the diluted supernatant was injected into an LC / MS / MS system for quantitative analysis. PK parameters were estimated using a non-compartmental model with Phoenix (WinNonlin) pharmacokinetic software version 8.3.

[0284] Tissues were collected from the animals on day 28. Approximately 30–60 μL of whole blood was collected into tubes containing EDTA anticoagulant, and plasma was collected by centrifugation at 4,000 g for 5 minutes and stored at -80°C until analysis. Plasma analysis followed the same protocol as for plasma analysis on day 1. Additionally, the femurs of the mice were cut and placed in pre-weighed tubes. Bone marrow was collected by centrifugation at 8,000 g for 15 minutes. The total weight of the bone marrow and tube was then recorded. The bone marrow was stored at -80°C until analysis.

[0285] The average tumor volume is approximately 150-200 mm 3At this point, treatment was initiated by oral administration of, for example, Example 9 and Compound A at 10 mg / kg and 100 mg / kg QD (once daily) (n=8 / group). The initial treatment period with Example 9 and Compound A was 28 days, after which overall efficacy and tolerability were evaluated based on tumor volume and body weight changes observed during the treatment period (Figures 1a and 1b). After compound treatment, the animals were observed for an additional 28 days without compound treatment.

[0286] On day 28, oral administration of Example 9 at 100 mg / kg BID once daily induced an antitumor response against OVCAR-3 xenografts in mice, with a %T / C value of -4% and a %TGI of 104%, p-values ​​of ≦0.0001 when compared with vehicle control using a one-way ordinary ANOVA test ( FIG. 1 a). Based on body weight, administration of all concentrations of Example 9 was well tolerated ( FIG. 1 b).

[0287] Treatment is performed on tumors with an average volume of approximately 150-200 mm 3 At this point, the following treatment was performed (n=8 / group): Example 1 was administered at 100 mg / kg QD (once daily), 100 mg / kg QOD (every other day), and 100 mg / kg once daily for 4 days followed by no administration for 3 days. Compound A was also orally administered at 100 mg / kg QD (once daily). The initial treatment period with Example 1 was 28 days, after which the overall efficacy and tolerability were evaluated based on the tumor volume and body weight changes observed during the treatment period (Figures 2a and 2b).

[0288] On day 28, oral administration of Example 1 at 100 mg / kg BID once daily for 4 days followed by 3 days without administration induced an antitumor response against OVCAR-3 xenografts in mice, with a %T / C value of -2% and a %TGI of 102%, p-value ≦0.0001 when compared with vehicle control using a one-way ordinary ANOVA test ( FIG. 2 a). Based on body weight, administration of all concentrations of Example 1 was well tolerated ( FIG. 2 b).

[0289] The average tumor volume is approximately 150-200 mm 3 At this time, treatment was initiated as follows (n=8 / group): Example 29b was orally administered at 10 mg / kg and 30 mg / kg QD (once daily), and Compound A was orally administered at 100 mg / kg QD (once daily). The initial treatment period with Example 1 was 28 days, after which overall efficacy and tolerability were assessed based on the tumor volume and body weight changes observed during the treatment period (Figures 3a and 3b).

[0290] On day 28, oral administration of Example 29 at 30 mg / kg BID once daily induced an antitumor response against OVCAR-3 xenografts in mice, with a %T / C value of -1% and a %TGI of 99%, with a p value of ≦0.0001 when compared with vehicle control using a one-way ordinary ANOVA test (FIG. 3a). Based on body weight, administration of all concentrations of Example 29b was well tolerated (FIG. 3b). As can be seen, despite its short half-life and rapid clearance, Example 29b showed a significant reduction in tumor growth in a dose-dependent manner.

[0291] Additionally, bone marrow was collected from mice treated with Example 29b orally at 10 mg / kg QD and 30 mg / kg QD, and from mice treated with Compound A orally at 30 mg / kg QD, and the total concentrations of compound observed in the bone marrow are shown in Table 3. Samples were collected from animals 6 hours after the last dose of compound and 24 hours after the last dose of compound. Table 3. Concentrations of Example 29b and Compound A in bone marrow 6 and 24 hours after the last dose for 28-day in vivo efficacy in OVCAR-3 xenografts. [Table 7]

Claims

1. Equation (I) 【Chemistry 1】 A compound represented by, or a pharmaceutically acceptable salt thereof (i) X １ and X ２ However, each is independent of CR ５ or N, X ３ CR ４ or N, Ring A is a phenyl, a 6-membered heteroaryl, a 6,5-bicyclic heteroaryl, or a 4- to 10-membered monocyclic or bicyclic heterocyclil. Z is *-NHC(O)- or *-C(O)NH-, where *- represents a bond to ring A. o is an integer between 0 and 3, R １ is C １－６ alkyl, C ３－６ cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, OR Ｏ１ａ , SO ２ R １ａ , NR Ｎ１ａ SO ２ R １ａ , NR Ｎ１ａ R Ｎ１ｂ , -C(O)R １ａ , halo, cyano, where C １－６ alkyl, C ３－６ cycloalkyl, and 3- to 6-membered monocyclic heterocyclyl are each optionally substituted with one or more R １ｂ s, R １ａ However, C １－６ Alkyl, NR Ｎ１ａ R Ｎ１ｂ , OR Ｏ１ａ , C ３－６ A cycloalkyl or a 3- to 6-membered monocyclic heterocycline, where C １－６ Alkyl, C ３－６ Cycloalkyls and 3- to 6-membered monocyclic heterocyclines each contain one or more R １ｂ It is optionally replaced by, Each R １ｂ These independently produce halo, cyano, hydroxy, and C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy and C １－６ Selected from haloalkoxys, or two R １ｂ However, together with the atoms (one or more) to which they are bonded, C ３－６ Forming a cycloalkyl group, R Ｎ１ａ and R Ｎ１ｂ However, H and C are independent of each other. １－６ Selected from alkyl, where C １－６ Alkyl is one or more R １ｂ It is optionally replaced by, R Ｏ１ａ is H or C １－６ It is alkyl, and here C １－６ Alkyl is one or more R １ｂ It is optionally replaced by, R ２ However, H, C １－６ Alkyl, SO ２ R ２ａ NR Ｎ２ａ SO ２ R ２ａ , OR Ｏ２ａ , S(O)(NR Ｎ２ｃ ) R ２ａ Halo, Cyano, -C(O)R ２ａ , or NR Ｎ２ａ R Ｎ２ｂ And here, C １－６ Alkyl is one or more R ２ｂ It is optionally replaced by, R ２ａ However, C １－６ Alkyl, NR Ｎ２ａ R Ｎ２ｂ , OR Ｏ２ａ , C ３－６ A cycloalkyl or a 3- to 6-membered monocyclic heterocycline, where C １－６ Alkyl, C ３－６ Cycloalkyls and heterocyclines each contain one or more R ２ｂ It is optionally replaced by, Each R ２ｂ However, independently, C １－６ Alkyl, halo, hydroxy, C １－６ Alkoxy, C １－６ Haloalkoxy, -N(R) Ｎ２ｃ ) ２ , and -C(O)OC １－６ Selected from alkyl groups, R Ｎ２ａ and R Ｎ２ｂ However, H and C are independent of each other. １－６ Selected from alkyl, where C １－６ Alkyl is one or more R ２ｂ It is optionally replaced by, Each R Ｎ２ｃ However, independently, H, C １－３ Alkyl, -C(O)(C １－３ It is alkyl, R Ｏ２ａ is H or C １－６ It is alkyl, and here C １－６ Alkyl is one or more halo, hydroxy, C １－６ Alkoxy, or C １－６ Optionally substituted with a haloalkoxy, R ３ is C ３－６ cycloalkyl, phenyl, or a 3- to 6-membered monocyclic heterocyclyl, where the 3- to 6-membered monocyclic heterocyclyl is optionally substituted with one or more R ３ａ and is optionally substituted with Each R ３ａ is independently selected from halo, C １－６ haloalkyl, or C １－６ alkyl, or two Rs ３ａ together with the atom(s) to which they are attached form one or more Rs ３ｂ substituted C ３－６ cycloalkyl, Each R ３ｂ However, they became independent: H, Halo, C １－６ Alkoxy, and one or more halos, OH groups, or C groups. １－３ C is optionally substituted with an alkoxy. １－６ Selected from alkyl groups, R ４ However, H, C １－６ Alkyl, C １－６ It is a haloalkyl or halo, R ５ is H, halo, or C １－６ It is alkyl, Each R ６ However, independently, C １－６ Alkyl, C １－６ It is a haloalkyl or halo, However, if ring A is phenyl or a 6-membered heteroaryl, R ３ teeth, 【Chemistry 2】 Here, j is either 0 or 1; (ii) X1 and X2 are each independently CR5 or N, and X3 is CR4 or N, Ring A is a phenyl, a 6-membered heteroaryl, a 6,5-bicyclic heteroaryl, or a 4- to 10-membered monocyclic or bicyclic heterocyclil. Z is *-NHC(O)- or *-C(O)NH-, where *- represents a bond to ring A. o is an integer between 0 and 3, R1 is a C1-6 alkyl, C3-6 cycloalkyl, 3- to 6-membered monocyclic heterocycline, OR O1a, SO2 R1a, NR N1a SO2 R1a, NR N1a R N1b, -C(O)R1a, halo, or cyano, where the C1-6 alkyl, C3-6 cycloalkyl, and 3- to 6-membered monocyclic heterocycline are each optionally substituted with one or more R1b. R1a is a C1-6 alkyl, NR N1a, R N1b, OR O1a, C3-6 cycloalkyl, or a 3- to 6-membered monocyclic heterocycline, where the C1-6 alkyl, C3-6 cycloalkyl, and 3- to 6-membered monocyclic heterocycline are each optionally substituted with one or more R1b. Each R1b is independently selected from halo, hydroxy, C1-6 alkyl, C1-6 alkoxy, and C1-6 haloalkoxy, Alternatively, two R1b atoms, together with the atom to which they are bonded, form a C3-6 cycloalkyl group. R N1a and R N1b are each independently selected from H and C 1-6 alkyl, where C 1-6 alkyl is optionally substituted with one or more R 1b. R O1a is H or C1-6 alkyl, where C1-6 alkyl is optionally substituted with one or more R1b. R2 is H, C1-6 alkyl, SO2R2a, NR N2a SO2R2a, OR O2a, halo, cyano, -C(O)R2a, or NR N2aR N2b, where C1-6 alkyl is optionally substituted with one or more R2b. R 2a is a C 1-6 alkyl, NR N2a NR N2b, OR O2a, C 3-6 cycloalkyl, or a 3- to 6-membered monocyclic heterocycline, where the C 1-6 alkyl, C 3-6 cycloalkyl, and heterocycline are each optionally substituted with one or more R 2b. Each R 2b is independently selected from C1-6 alkyl, halo, hydroxy, C1-6 alkoxy, C1-6 haloalkoxy, and -C(O)OC1-6 alkyl. R N2a and R N2b are each independently selected from H and C1-6 alkyl, where C1-6 alkyl is optionally substituted with one or more R2b. R O2a is H or C1-6 alkyl, where C1-6 alkyl is optionally substituted with one or more halo, hydroxy, C1-6 alkoxy, or C1-6 haloalkoxy. R3 is a C3-6 cycloalkyl, phenyl, or a 3- to 6-membered monocyclic heterocycline, where the 3- to 6-membered monocyclic heterocycline is optionally substituted with one or more R3a. Each R 3a is independently selected from a halo or a C 1-6 alkyl group, or two R 3a groups, together with the atom(s) to which they are bonded, form a C 3-6 cycloalkyl group substituted with one or more R 3b groups. Each R 3b is independently selected from H, halo, C1-6 alkoxy, and C1-6 alkyl groups optionally substituted with one or more halo or OH groups. R4 is H, C1-6 alkyl, C1-6 haloalkyl, or halo. R5 is H or C1-6 alkyl, Each R6 is independently a C1-6 alkyl, a C1-6 haloalkyl, or a halo. However, if ring A is phenyl or a 6-membered heteroaryl, R 3 is 【Transformation 3】 is; or, (iii) X1 and X2 are independently CR5 or N, and X3 is CR4 or N, Ring A is a phenyl, a 6-membered heteroaryl, a 6,5-bicyclic heteroaryl, or a 4- to 10-membered monocyclic or bicyclic heterocyclil. Z is *-NHC(O)- or *-C(O)NH-, where *- represents a bond to ring A. o is an integer between 0 and 3, R1 is a C1-6 alkyl, C3-6 cycloalkyl, 3- to 6-membered monocyclic heterocycline, OR O1a, SO2 R1a, NR N1a SO2 R1a, NR N1a R N1b, -C(O)R1a, halo, or cyano, where the C1-6 alkyl, C3-6 cycloalkyl, and 3- to 6-membered monocyclic heterocycline are each optionally substituted with one or more R1b. R1a is a C1-6 alkyl, NR N1a, R N1b, OR O1a, C3-6 cycloalkyl, or a 3- to 6-membered monocyclic heterocycline, where the C1-6 alkyl, C3-6 cycloalkyl, and 3- to 6-membered monocyclic heterocycline are each optionally substituted with one or more R1b. Each R1b is independently selected from halo, hydroxy, C1-6 alkyl, C1-6 alkoxy, and C1-6 haloalkoxy, Alternatively, two R1b atoms, together with the atom to which they are bonded, form a C3-6 cycloalkyl group. R N1a and R N1b are each independently selected from H and C 1-6 alkyl, where C 1-6 alkyl is optionally substituted with one or more R 1b. R O1a is H or C1-6 alkyl, where C1-6 alkyl is optionally substituted with one or more R1b. R2 is H, C1-6 alkyl, SO2R2a, NR N2a SO2R2a, OR O2a, halo, cyano, -C(O)R2a, or NR N2aR N2b, where C1-6 alkyl is optionally substituted with one or more R2b. R 2a is a C 1-6 alkyl, NR N2a NR N2b, OR O2a, C 3-6 cycloalkyl, or a 3- to 6-membered monocyclic heterocycline, where the C 1-6 alkyl, C 3-6 cycloalkyl, and heterocycline are each optionally substituted with one or more R 2b. Each R 2b is independently selected from C1-6 alkyl, halo, hydroxy, C1-6 alkoxy, C1-6 haloalkoxy, and -C(O)OC1-6 alkyl. R N2a and R N2b are each independently selected from H and C1-6 alkyl, where C1-6 alkyl is optionally substituted with one or more R2b. R O2a is H or C1-6 alkyl, where C1-6 alkyl is optionally substituted with one or more halo, hydroxy, C1-6 alkoxy, or C1-6 haloalkoxy. R3 is a C3-6 cycloalkyl, phenyl, or a 3- to 6-membered monocyclic heterocycline, where the 3- to 6-membered monocyclic heterocycline is optionally substituted with one or more R3a. Each R 3a is independently selected from a halo or a C1-6 alkyl group, or two R 3a groups together with the atom to which they are bonded form a C3-6 cycloalkyl group. R4 is H, C1-6 alkyl, C1-6 haloalkyl, or halo. R5 is H or C1-6 alkyl, Each R6 is independently a C1-6 alkyl, a C1-6 haloalkyl, or a halo. However, if ring A is phenyl or a 6-membered heteroaryl, R 3 is 【Chemistry 4】 That is, The aforementioned compound or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is *-C(O)NH-, where *- represents a bond to ring A.

3. (i) Ring A is phenyl, a 6-membered heteroaryl, or a 6,5-bicyclic heteroaryl, and each is R ２ , R ３ , and 0 to 2 R ６ It is replaced by; (ii) Ring A is phenyl, a 6-membered heteroaryl, or a 6,5-bicyclic heteroaryl, each substituted with R2, R3, and 0 to 1 R6; (iii) Ring A is phenyl, pyridinyl, pyrazinyl, or indazolyl, each of which is substituted with R2, R3, and 0 to 2 R6; (iv) Ring A is phenyl, pyridinyl, or indazolyl, each of which is substituted with R2, R3, and 0 to 1 R6; (v) Ring A is structural formula 【Transformation 5】 These are represented by R2, R3, and 0 to 2 R6, respectively; (vi) Ring A is structural formula 【Transformation 6】 These are represented by R2, R3, and 0 to 1 R6, respectively; (vii) Ring A is structural formula 【Transformation 7】 Represented by; (viiii) Ring A is structural formula 【Transformation 8】 Represented by; (ix) Ring A is structural formula 【Chemistry 9】 Represented by; (x) Ring A is a phenyl compound substituted with R2 and R3; or, (xi) Ring A is structural formula 【Chemistry 10】 Represented by, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. The aforementioned compound is of formula (IA). 【Chemistry 11】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, as represented by [formula].

5. X １ and X ２ Both are N, and X ３ CR ４ is or X １ and X ３ Both are N, and X ２ CR ５ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6. (i) X ３ CR ４ X １ or X ２ One of them is N, and the other is CR ５ is; or, (ii) X 3 is CR 4, and both X 1 and X 2 are CR 5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

7. (i) R ４ is H or -CH ３ And R ５ is H, and -F or -CH ３ It is; (ii) R4 is H or -CH3 and R5 is H or -CH3; or, (iii) R4 is H, and R5 is H or -CH3, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

8. (i) R ３ 1 to 3 R ３ａ It is a five- or six-membered monocyclic heterocycline that is optionally substituted with; (ii) A six-membered monocyclic heterocycline in which R3 is optionally replaced by 1 to 3 R3a; (iii) R3 is piperidinyl, 1,3-azacilloridinyl, or 1,4-azacillinanyl, each of which is optionally substituted with 1 to 3 R3a; or, (iv) R 3 is the structural formula 【Chemistry 12】 This is represented by where j is 0 or 1, each of which is arbitrarily substituted with 1 to 3 R 3a; (v) R 3 is the structural formula 【Chemistry 13】 This is represented by, where each is optionally substituted with 1 to 3 R 3a; (vi) R 3 is the structural formula 【Chemistry 14】 Represented by such that each R 3a is a C 1-3 alkyl group, or two R 3a groups, together with the atom(s) to which they are bonded, form a C 3-6 cycloalkyl group substituted with one to three R 3b groups; (vii) R 3 is the structural formula 【Chemistry 15】 Represented by such that each R 3a is a C 1-3 alkyl group, or two R 3a groups, together with the atom(s) to which they are bonded, form a C 3-6 cycloalkyl group substituted with one to three R 3b groups; (viiii) R 3 is the structural formula 【Chemistry 16】 Represented by such that each R 3a is a C 1-3 alkyl group, or two R 3a groups, together with the atom to which they are bonded, form a C 3-6 cycloalkyl group; (ix)R 3 is the structural formula 【Chemistry 17】 Represented by; (x)R 3 is the structural formula [Chemistry 18] Represented by; or (xi)R 3 is the structural formula 【Chemistry 19】 Represented by, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

9. (i) Each R ３ａ ga-CH ３ or -CH ２ CH ３ Either or two R ３ａ However, together with the atom (one or more) to which they are bonded, 1 to 3 R ３ｂ Forms cyclopropyl or cyclobutyl substituted with each R ３ｂ These are independently H, Halo, and -CH. ３ , -OCH ３ ien-CH ２ F, -CHF ２ , -CF ３ , -CF ２ CH ３ ien-CH ２ OCH ３ , or -CH ２ It is OH; (ii) Each R 3a is -CH 3, or two R 3a together with the atom(s) to which they are bonded to form a cyclopropyl substituted with 1 to 3 R 3b, each R 3b independently being H, halo, -CH 3, -CHF 2, or -CH 2 OH; (iii) Each R 3a is -CH 3, or two R 3a together with the atom to which they are bonded to form a cyclopropyl group; or, (iv) R 3a is -CH 3, The compound according to claim 8, or a pharmaceutically acceptable salt thereof.

10. (i) R １ However, C ３－６ Cycloalkyl, 3-membered to 6-membered monocyclic heterocyclyl, OR Ｏ１ａ , or SO ２ R １ａ C ３－６ Cycloalkyl and 3- to 6-membered monocyclic heterocyclines each have 1 to 3 R １ｂ It is optionally replaced by, R １ａ However, -NHR Ｎ１ｂ , C ３－６ The cycloalkyl or 3- to 6-membered monocyclic heterocycline is optionally substituted with 1 to 3 halos. R Ｎ１ｂ However, one or two R １ｂ C is optionally replaced by １－４ Alkyl R Ｏ１ａ However, 1 to 3 R １ｂ C is optionally replaced by １－３ It is alkyl, Each R １ｂ However, independently, Halo, Cyano, C １－３ Haloalkyl and C １－３ Selected from alkyl groups, or two R １ｂ However, together with the atoms (one or more) to which they are bonded, C ３－６ Forms a cycloalkyl group; (ii) R1 is a C3-6 cycloalkyl, a 3- to 6-membered monocyclic heterocycline, OR O1a, or SO2 R1a, and the C3-6 cycloalkyl and the 3- to 6-membered monocyclic heterocycline are each optionally substituted with 1 to 3 R1b. R1a is -NHR N1b, C3-6 cycloalkyl, or a 3- to 6-membered monocyclic heterocycline, where the 3- to 6-membered monocyclic heterocycline is optionally substituted with 1 to 3 halos. R N1b is a C1-4 alkyl group that is optionally substituted with one or two R1b groups. R O1a is a C1-3 alkyl group that is optionally substituted with 1 to 3 R1b groups. Each R1b is independently selected from halo and C1-3 alkyl groups, Alternatively, two R1b atoms, together with the atom to which they are bonded, form a C3-6 cycloalkyl group; (iii) R1 is a C3-6 cycloalkyl, a 3- to 6-membered monocyclic heterocycline, OR O1a, or SO2 R1a, and the C3-6 cycloalkyl and the 3- to 6-membered monocyclic heterocycline are each optionally substituted with 1 to 3 R1b. R1a is -NHR N1b or C3-6 cycloalkyl, R N1b is a C1-4 alkyl group that is optionally substituted with one or two R1b groups. R O1a is a C1-3 alkyl group that is optionally substituted with 1 to 3 R1b groups. Each R1b is independently selected from halo and C1-3 alkyl groups, Alternatively, two R1b atoms, together with the atom to which they are bonded, form a C3-6 cycloalkyl group; (iv) R1 is -S(O)2NHC(CH3)3, -SO2-cyclopentyl, -SO2-piperidinyl, -OCH2CH2CF3, -OCH2CH(OH)CF3, cyclopropyl, cyclohexyl, morpholinyl, piperidinyl, azetidinyl, 3H-diazilinyl, or pyrrolidinyl, and each of the piperidinyl, azetidinyl, 3H-diazilinyl, and pyrrolidinyl in cyclopropyl, cyclohexyl, morpholinyl, piperidinyl, -SO2-piperidinyl is optionally substituted with 1 to 3 R1b. Each R1b is either -F, -CN, -CF3, or -CH3. Alternatively, two R1b atoms, together with the atom to which they are bonded, form a cyclopropyl group; (v) R1 is -S(O)2NHC(CH3)3, -SO2-cyclopentyl, -SO2-piperidinyl, -OCH2CH2CF3, cyclopropyl, cyclohexyl, morpholinyl, piperidinyl, azetidinyl, or pyrrolidinyl, and the piperidinyl, azetidinyl, and pyrrolidinyl of cyclopropyl, cyclohexyl, morpholinyl, piperidinyl, and -SO2-piperidinyl are each optionally substituted with 1 to 3 R1b. Is each R1b -F or -CH3? Alternatively, two R1b atoms, together with the atom to which they are bonded, form a cyclopropyl group; (vi) R1 is -S(O)2NHC(CH3)3, -SO2-cyclopentyl, -OCH2CH2CF3, cyclopropyl, cyclohexyl, morpholinyl, piperidinyl, azetidinyl, or pyrrolidinyl, and each of cyclopropyl, cyclohexyl, morpholinyl, piperidinyl, azetidinyl, and pyrrolidinyl is optionally substituted with 1 to 3 R1b. Is each R1b -F or -CH3? Alternatively, two R1b atoms, together with the atom to which they are bonded, form a cyclopropyl group; (vii) R1 is a C3-6 cycloalkyl, a 3- to 6-membered monocyclic heterocycline, or SO2R1a, and the C3-6 cycloalkyl and the 3- to 6-membered monocyclic heterocycline are each optionally substituted with 1 to 3 R1b. R 1a is -NHR N1b, R N1b is a C1-4 alkyl group, Each R1b is an independent halo; (viiii) R1 is -S(O)2NHC(CH3)3, cyclohexyl, morpholinyl, or piperidinyl, and cyclohexyl, morpholinyl, and piperidinyl are each optionally substituted with 1 to 3 R1b. Each R1b is -F; or, (ix) R 1 is -S(O) 2 NHC(CH 3) 3, or R 1 is the structural formula 【Chemistry 20】 Represented by, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

11. (i) R ２ However, H, C １－３ Alkyl, NR Ｎ２ａ R Ｎ２ｂ SO ２ R ２ａ , S(O)(NH)R ２ａ , or NHSO ２ R ２ａ C １－３ Alkyl groups consist of 1 to 3 R groups. ２ｂ It is optionally replaced by, R ２ａ However, C １－４ Alkyl, -NHR Ｎ２ｂ , C ３－４ It is a cycloalkyl or a 3- to 6-membered monocyclic heterocycline, C １－３ Alkyl and 3- to 6-membered monocyclic heterocyclyls each have 1 to 3 R ２ｂ It is optionally replaced by, R Ｎ２ａ and R Ｎ２ｂ Each of these is independently H, or 1 to 3 R ２ｂ C is optionally replaced by １－３ It is alkyl, Each R ２ｂ However, independently, hydroxy, -N(R Ｎ２ｃ ) ２ , and C １－３ Selected from alkyl groups, Each R Ｎ２ｃ However, independently, H, C １－３ Alkyl, -C(O)(C １－３ It is alkyl; (ii) R2 is H, C1-3 alkyl, SO2R2a, or NHSO2R2a, and the C1-3 alkyl is optionally substituted with 1 to 3 R2b. R2a is a C1-4 alkyl, -NHRN2b, or a 3- to 6-membered monocyclic heterocycline, and the C1-3 alkyl and 3- to 6-membered monocyclic heterocyclines are each optionally substituted with 1 to 3 R2b groups. R N2b is a C1-3 alkyl group that is optionally substituted with 1 to 3 R2b groups. Each R2b is independently selected from hydroxyl and C1-3 alkyl groups; (iii) R 2 is H, -NHS(O) 2 CH 3 , -NHS(O) 2 CH 2 CH 2 OH, -NHS(O) 2 CH 2 CH 2 NH 2 , -NHS(O) 2 CH 2 CH 2 NHCH 3 , NHS(O) 2 CH 2 CH 2 NHC(O)CH 3 , -NHS(O) 2 C(CH 3 ) 3 , -NHS(O) 2 NHCH 3 , -NHS(O) 2 NHCH 2 CH 2 OH, -NHS(O) 2 N(CH 3 )CH 2 CH 2 OH, -S(O) 2 NHCH 2 CH 2 OH, -NHC(CH 3 ) 2 CH₂OH,-S(O)(NH)-cyclopropyl,-S(O)₂CH₂CH₂OH,-CH₂CH₂OH,-N(CH₃)CH₂CH₂OH, or R₂ is formula 【Chemistry 21】 Represented by; (iv) R2 is H, -NHS(O)2CH3, -NHS(O)2CH2CH2OH, -NHS(O)2C(CH3)3, -NHS(O)2NHCH2CH2OH, -S(O)2NHCH2CH2OH, -CH2CH2OH, or R2 is formula 【Chemistry 22】 Represented by; (v) R2 is H, -NHS(O)2CH3, -NHS(O)2CH2CH2OH, -NHS(O)2C(CH3)3, -S(O)2NHCH2CH2OH, -CH2CH2OH, or R2 is formula 【Chemistry 23】 Represented by; (vi) R 2 is NHSO 2 R 2a, R2a is a C1-4 alkyl group that is optionally substituted with 1 to 3 R2b groups. Each R 2b is hydroxyl; or (vii) R 2 is -NHS(O) 2 CH 2 CH 2 OH or -NHS(O) 2 C(CH 3) 3 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

12. (i) R ４ However, H, or C １－３ It is alkyl; or, (ii) R 4 is H or -CH 3, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

13. Each R ６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is a halo, and preferably R6 is -F.

14. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein o is 0.

15. (i) The compound is of formula (II), (III), or (IV) 【Chemistry 24】 It is represented by, or a pharmaceutically acceptable salt thereof X １ and X ２ However, each is independent of CR ５ or N, X ３ CR ４ or N, R １ However, C ３－６ Cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, or SO ２ R １ａ C ３－６ Cycloalkyl and 3- to 6-membered monocyclic heterocyclines each have 1 to 3 R １ｂ It is optionally replaced by, R １ａ However, -NHR Ｎ１ｂ And, R Ｎ１ｂ However, C １－４ It is alkyl, Each R １ｂ It is independent and is Haro, R ２ However, NHSO ２ R ２ａ And, R ２ａ However, one or two R ２ｂ C is optionally replaced by １－４ It is alkyl, Each R ２ｂ is hydroxyl, R ３ｂ However, H, Haro, C １－３ Alkyl, or C １－３ It is a haloalkyl, R ４ However, H, or C １－３ It is alkyl, R ５ However, H, or C １－３ It is alkyl; (ii) The compound is of formula (II) or (III) 【Chemistry 25】 It is represented by, or a pharmaceutically acceptable salt thereof X1 and X2 are independently CR5 or N, and X3 is CR4 or N, R1 is a C3-6 cycloalkyl group, a 3- to 6-membered monocyclic heterocycline, or SO2R1a, and the C3-6 cycloalkyl group and the 3- to 6-membered monocyclic heterocycline are each optionally substituted with 1 to 3 R1b groups. R 1a is -NHR N1b, R N1b is a C1-4 alkyl group, Each R1b is an independent halo, R 2 is NHSO 2 R 2a, R 2a is a C 1-4 alkyl group optionally substituted with one or two R 2b groups. Each R 2b is hydroxyl, R3b is H, C1-3 alkyl, or C1-3 haloalkyl, R4 is H or C1-3 alkyl, R5 is H or C1-3 alkyl; (iii) The compound is of formula (II) 【Chemistry 26】 It is represented by, or a pharmaceutically acceptable salt thereof X1 and X2 are independently CR5 or N, and X3 is CR4 or N, R1 is a C3-6 cycloalkyl group, a 3- to 6-membered monocyclic heterocycline, or SO2R1a, and the C3-6 cycloalkyl group and the 3- to 6-membered monocyclic heterocycline are each optionally substituted with 1 to 3 R1b groups. R 1a is -NHR N1b, R N1b is a C1-4 alkyl group, Each R1b is an independent halo, R 2 is NHSO 2 R 2a, R 2a is a C 1-4 alkyl group optionally substituted with one or two R 2b groups. Each R 2b is hydroxyl, R4 is H or C1-3 alkyl, R5 is H or C1-3 alkyl; (iv) The compound is of formula (IIA), (IIB), (IIC), (IID), (IIE), (IIIA), or (IVA) 【Chemistry 27】 It is represented by or a pharmaceutically acceptable salt thereof; (v) The compound is of formula (IIA), (IIB), (IIC), (IID), (IIE), or (IIIA) 【Chemistry 28】 It is represented by or a pharmaceutically acceptable salt thereof; (vi) The compound is of formula (IIA), (IIB), (IIC), (IID), or (IIE) 【Chemistry 29】 It is represented by or a pharmaceutically acceptable salt thereof; (vii) The compound is of formula (IIIA) 【Transformation 30】 It is represented by or a pharmaceutically acceptable salt thereof; or (viiii) The compound is of formula (IVA) 【Chemistry 31】 Represented by, or a pharmaceutically acceptable salt thereof, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

16. (a) (i) R １ However, -S(O) ２ NHC (CH ３ ) ３ , cyclohexyl, morpholinil, or piperidinil, and each of cyclohexyl, morpholinil, and piperidinil contains one or two R １ｂ It is optionally replaced by, Each R １ｂ is -F; or, (ii) R 1 is -S(O) 2 NHC(CH 3) 3, or R 1 is the structural formula 【Chemistry 32】 Represented by; (b) R 2 is -NHS(O) 2 CH 2 CH 2 OH or -NHS(O) 2 C(CH 3) 3; (c) R4 and R5 are H or -CH3, respectively; and / or (d) (i) R 3b is H, -F, -CH 3, -CH 2 F, or -CHF 2; or, (ii) R 3b is H, -CH 3, or -CHF 2, The compound according to claim 15, or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 1, wherein the compound is selected from any one of Examples 1 to 134, or from pharmaceutically acceptable salts thereof.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

19. The pharmaceutical composition according to claim 18 for use in treating a KIF18A-mediated disease or disorder in a subject.

20. The aforementioned disease or disorder (i) to have cancer; (ii) It is a cancer with chromosomal instability; (iii) A cancer that exhibits whole-genome doubling; (iv) Cancer having mutations in amplification of TP53, BRCA1, BRCA2, RB1, and / or CCNE1; (v) small cell lung cancer, non-small cell lung cancer, pancreatic cancer, triple-negative breast cancer, colorectal cancer, hepatobiliary cancer, esophageal and gastric cancer, endometrial cancer, head and neck squamous cell carcinoma, ovarian cancer, platinum-resistant ovarian cancer, bladder cancer, soft tissue sarcoma, renal cell carcinoma, endometrial cancer, cervical cancer, or bone cancer; and / or (vi) (a) solid or hematopoietic tumors selected from bladder cancer, endometrial cancer, lung squamous cell carcinoma, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, brain tumor, head and neck cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer; (b) leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, pilocytic cell lymphoma, and barkettley (c) Lymphoid hematopoietic malignancies selected from lymphomas; (d) Myeloid hematopoietic malignancies selected from acute myeloid leukemia and chronic myeloid leukemia, myelodysplastic syndromes, and promyelocytic leukemias; (e) Mesenchymal tumors selected from fibrosarcomas and rhabdomyosarcomas; (e) Central and peripheral nervous system tumors selected from astrocytomas, neuroblastomas, gliomas, and Schwann cell tumors; or (f) Melanoma, seminomas, teratomas, osteosarcomas, xeroderma pigmentosum, keratosarcomas, follicular thyroid carcinoma, or Kaposi's sarcoma. A pharmaceutical composition for use according to claim 19.

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