KIF18A inhibitor and application thereof

Abstract

The present invention provides compounds of Formula (I), # imgabs0 #, or a pharmaceutically acceptable salt thereof, which are useful for the inhibition of KIF18A and the treatment of a variety of KIF18A-mediated conditions or diseases, such as cancer.

Description

[0001] Related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 463,617, filed on May 3, 2023, and U.S. Provisional Application No. 63 / 399,003, filed on August 18, 2022. The entire contents of the foregoing applications are hereby expressly incorporated herein by reference. Technical Field

[0003] The present disclosure relates to inhibitors of kinesin family member 18A (KIF18A), pharmaceutically acceptable salts thereof, compositions of these compounds, methods for their preparation, and their use in the treatment of diseases. Background Art

[0004] Chromosomal abnormalities, such as aneuploidy, are common in a variety of different cancer types. For example, whole-genome duplication has been found in more than 30% of tumors, and it can serve as a biomarker for tumorigenesis. (Prasad et al., Cancer Res. May 3, 2022; 82(9):1736-1752; Bielski et al., Nat Genet. August 2018; 50(8):1189-1195). It is believed that this genomic instability and replication are caused by errors in cell division and proliferation, which occur and / or support the rapid cell division that is characteristic of cancer cells. (Davoli, Annu Rev Cell Dev Biol 127:585-610). To target this rapid cell division and genetic instability, many traditional cancer drugs, such as Paclitaxel, target tubulin and prevent mitosis of cells. However, these drugs are generally cytotoxic and often have side effects and off-target toxicity problems. Therefore, research has focused on compounds with higher selectivity and fewer side effects.

[0005] Kinesin family member 18A (KIF18A), as its name indicates, is a member of the kinesin family, which is a group of motor proteins that utilize ATP hydrolysis to move along microtubule filaments and support mitosis and meiosis. KIF18A has been found to be a key enzyme in the proliferation of chromosomally unstable cancers (Marquis et al., Nat Commun. February 22, 2021; 12(1):1213). In addition, in non-cancer cells and mice, the KIF18A knockout model shows viability, indicating that KIF18A is not essential for normal cell division and may therefore be able to have fewer side effects compared to essential targets as a target. (Tamayo et al., J Med Chem. March 24, 2022; 65(6):4972-4990). The clinical utility of previous inhibitors of kinesin motor protein target classes, such as KIF18A, has been limited by several properties of these compounds, such as high cellular efflux, long pharmacokinetic terminal half-life, and dose-limiting myelosuppression, especially neutropenia and thrombocytopenia, as previously seen in, for example, kinesin motor protein KIF11 (Eg-5) inhibitors, as discussed by P. Navais et al., Pharmaceutics 2021, 13, 1011.

[0006] Accordingly, there is a need in the art for KIF18A inhibitors as potential therapeutic agents for treating diseases or disorders responsive to KIF18A inhibition, and in particular for compounds that exhibit improved properties as described above (i.e., better cellular efflux, different pharmacokinetic terminal half-life, and reduced myelosuppression, especially neutropenia and thrombocytopenia). SUMMARY OF THE INVENTION

[0007] The present disclosure provides compounds that are KIF18A inhibitors. In a first aspect, the present disclosure relates to compounds having Formula I:

[0008]

[0009] or a pharmaceutically acceptable salt thereof, wherein:

[0010] X 1 and X 2 are each independently CR 5 or N, and X 3 is CR 4 or N;

[0011] Ring A is phenyl, 6-membered heteroaryl, 6,5-bicyclic heteroaryl, or a 4- to 10-membered monocyclic or bicyclic heterocyclic group;

[0012] Z is *-NHC(O)- or *-C(O)NH-, where *- represents the connection to Ring A;

[0013] o is an integer from 0 to 3;

[0014] R 1 is C 1-6 alkyl, C 3-6 cycloalkyl, a 3- to 6-membered monocyclic heterocyclic group, OR O1a , SO2R 1a , NR N1a SO2R 1a , NR N1a R N1b , -C(O)R 1a , a halogen group, a cyano group, wherein the C 1-6 alkyl, the C 3-6 cycloalkyl and the 3- to 6-membered monocyclic heterocyclic group are each optionally substituted by one or more R 1b substituents;

[0015] R 1a is C 1-6 alkyl, NR N1a R N1b , OR O1a , C 3-6 cycloalkyl or a 3- to 6-membered monocyclic heterocyclic group, wherein the C 1-6 alkyl, the C 3-6 cycloalkyl and the 3- to 6-membered monocyclic heterocyclic group are each optionally substituted by one or more R 1b substituents;

[0016] Each R 1b is independently selected from a halogen group, a cyano group, a hydroxyl group, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy;

[0017] Or two R 1b together with one or more atoms to which it is attached form C 3-6 cycloalkyl;

[0018] R N1a and R N1b are each independently selected from H and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted by one or more R 1b substituents;

[0019] R O1a is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted by one or more R 1b substituents;

[0020] R2 is H, C 1-6 alkyl, SO2R 2a , NR N2a SO2R 2a , OR O2a , S(O)(NR N2c )R 2a , halo, cyano, -C(O)R 2a or NR N2a R N2b , wherein said C 1-6 alkyl is optionally substituted with one or more R 2b ;

[0021] R 2a is C 1-6 alkyl, NR N2a R N2b , OR O2a , C 3-6 cycloalkyl or a 3- to 6-membered monocyclic heterocyclic group, wherein said C 1-6 alkyl, said C 3-6 cycloalkyl and said heterocyclic group are each optionally substituted with one or more R 2b ;

[0022] Each R 2b is independently selected from 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;

[0023] R N2a and R N2b are each independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more R 2b ;

[0024] Each R N2c is independently H, C 1-3 alkyl, -C(O)(C 1-3 alkyl);

[0025] R O2a is H or C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more halo, hydroxy, C 1-6 alkoxy or C 1-6 haloalkoxy;

[0026] R 3 is C 3-6A cycloalkyl group, a phenyl group or a 3- to 6-membered monocyclic heterocyclic group, wherein the 3- to 6-membered monocyclic heterocyclic group is optionally substituted with one or more R 3a substituents;

[0027] Each R 3a is independently selected from a halogen group, C 1-6 haloalkyl or C 1-6 alkyl; or two Rs 3a together with one or more atoms to which they are attached form a C 3b cycloalkyl group substituted with one or more R 3-6 substituents;

[0028] Each R 3b is independently selected from H, a halogen group, C 1-6 alkoxy and optionally C 1-3 alkyl substituted with one or more halogen groups, OH or C 1-6 alkoxy;

[0029] R 4 is H, C 1-6 alkyl, C 1-6 haloalkyl or a halogen group;

[0030] R 5 is H, a halogen group or C 1-6 alkyl;

[0031] Each R 6 is independently C 1-6 alkyl, C 1-6 haloalkyl or a halogen group;

[0032] Provided that if ring A is a phenyl group or a 6-membered heteroaryl group, then R 3 is where j is 0 or 1. In some embodiments, R 2 is C 1-6 alkyl, SO2R 2a NR N2a SO2R 2a OR O2a a halogen group, a cyano group, -C(O)R 2a or NR N2a R N2b wherein the C 1-6 alkyl is optionally substituted with one or more R 2b substituents; and the remaining variables are as described above.

[0033] 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.

[0034] In another aspect, the present disclosure provides a method of treating a disease or disorder in a subject responsive to inhibition of KIF18A, 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.

[0035] Another aspect of the present disclosure relates to the use of at least one compound described herein or a pharmaceutically acceptable salt thereof for manufacturing a medicament for treating a disease or disorder responsive to inhibition of KIF18A. Also provided are the compounds described herein or pharmaceutically acceptable salts thereof for treating a disease or disorder responsive to inhibition of KIF18A.

[0036] In some aspects, the compounds of the present disclosure have low efflux, especially compared to similar compounds known in the art. The benefits of compounds with low efflux are well known, such as overcoming the resistance of cells with increased prevalence of efflux pumps, a wider range of diseases and greater targeting ability, and higher cell concentrations.

[0037] In some aspects, the compounds of the present disclosure are less cytotoxic to myeloid cells, especially compared to similar compounds known in the art. In some aspects, the compounds have a more rapid terminal half-life and / or clearance rate, which allows for less systemic exposure and a reduced likelihood of toxicity to myeloid cells. The benefits of compounds with low reactivity to myeloid cells are well known, such as a low risk of cytopenia (such as neutropenia or thrombocytopenia) for patients treated with the compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1a Shows the 28-day in vivo efficacy of the compound of Example 9 and Compound A in an OVCAR-3 xenograft.

[0039] Figure 1b Shows the tolerance of the compound of Example 9 and Compound A in a 28-day in vivo efficacy study in an OVCAR-3 xenograft.

[0040] Figure 2a Shows the 28-day in vivo efficacy of the compound of Example 1 and Compound A in an OVCAR-3 xenograft: change in tumor volume over time;

[0041] Figure 2b Shows the tolerance of the compound of Example 1 and Compound A in a 28-day in vivo efficacy study in an OVCAR-3 xenograft.

[0042] Figure 3a Shows the 28-day in vivo efficacy of the compound of Example 29b and Compound A in an OVCAR-3 xenograft.

[0043] Figure 3b Show the tolerability of Compound 29b and Compound A in a 28-day in vivo efficacy study in OVCAR-3 xenografts. Detailed Description

[0044] The present disclosure provides compounds and their pharmaceutical compositions, which can be used to treat diseases or disorders by modulating KIF18A function / activity. In some embodiments, the compounds of the present disclosure are KIF18A inhibitors.

[0045] Compounds and Compositions

[0046] In a first embodiment, the present disclosure provides a compound of formula (I):

[0047]

[0048] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (I) are defined as follows:

[0049] X 1 and X 2 are each independently CR 5 or N, and X 3 is CR 4 or N;

[0050] Ring A is phenyl, 6-membered heteroaryl, 6,5-bicyclic heteroaryl or a 4- to 10-membered monocyclic or bicyclic heterocyclic group;

[0051] Z is *-NHC(O)- or *-C(O)NH-, where *- represents the connection to Ring A;

[0052] o is an integer from 0 to 3;

[0053] R 1 is C 1-6 alkyl, C 3-6 cycloalkyl, a 3- to 6-membered monocyclic heterocyclic group, OR O1a , SO2R 1a , NR N1a SO2R 1a , NR N1a R N1b , -C(O)R 1a , halo, cyano, wherein the C 1-6 alkyl, the C 3-6 cycloalkyl and the 3- to 6-membered monocyclic heterocyclic group are each optionally substituted with one or more R 1b ;

[0054] R 1a is C 1-6 alkyl, NR N1a RN1b 、 OR O1a 、 C 3-6 cycloalkyl or a 3- to 6-membered monocyclic heterocyclic group, wherein said C 1-6 alkyl, said C 3-6 cycloalkyl and said 3- to 6-membered monocyclic heterocyclic group are each optionally substituted with one or more R 1b substituents;

[0055] Each R 1b is independently selected from halo, hydroxy, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 haloalkoxy;

[0056] Or two R 1b together with the atom to which they are attached form a C 3-6 cycloalkyl;

[0057] R N1a and R N1b are each independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more R 1b substituents;

[0058] R O1a is H or C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more R 1b substituents;

[0059] R 2 is H, C 1-6 alkyl, SO2R 2a , NR N2a SO2R 2a , OR O2a , halo, cyano, -C(O)R 2a or NR N2a R N2b wherein said C 1-6 alkyl is optionally substituted with one or more R 2b substituents;

[0060] R 2a is C 1-6 alkyl, NR N2a R N2b , OR O2a , C 3-6 cycloalkyl or a 3- to 6-membered monocyclic heterocyclic group, wherein said C 1-6 alkyl, said C 3-6 cycloalkyl and said heterocyclic group are each optionally substituted with one or more R 2b substituents;

[0061] Each R 2b is independently selected from C 1-6 alkyl, halo, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy and -C(O)OC 1-6 alkyl;

[0062] R N2a and R N2b are each independently selected from H and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more R 2b groups;

[0063] R O2a is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1 or more halo, hydroxy, C 1-6 alkoxy or C 1-6 haloalkoxy groups;

[0064] R 3 is C 3-6 cycloalkyl, phenyl or a 3- to 6-membered monocyclic heterocyclic group, wherein the 3- to 6-membered monocyclic heterocyclic group is optionally substituted with one or more R 3a groups;

[0065] Each R 3a is independently selected from halo or C 1-6 alkyl; or two R 3a groups together with the atom to which they are attached form a C 3-6 cycloalkyl;

[0066] R 4 is H, C 1-6 alkyl, C 1-6 haloalkyl or halo;

[0067] R 5 is H or C 1-6 alkyl;

[0068] Each R 6 is independently C 1-6 alkyl, C 1-6 haloalkyl or halo;

[0069] Provided that if ring A is phenyl or a 6-membered heteroaryl, then R 3 is

[0070] In an alternative first embodiment, the present disclosure provides a compound of formula (I):

[0071]

[0072] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (I) are defined as follows:

[0073] X 1 and X 2 are each independently CR 5 or N, and X 3 is CR 4 or N;

[0074] Ring A is phenyl, 6-membered heteroaryl, 6,5-bicyclic heteroaryl or a 4- to 10-membered monocyclic or bicyclic heterocyclic group;

[0075] Z is *-NHC(O)- or *-C(O)NH-, where *- represents the connection to Ring A;

[0076] o is an integer from 0 to 3;

[0077] R 1 is C 1-6 alkyl, C 3-6 cycloalkyl, a 3- to 6-membered monocyclic heterocyclic group, OR O1a , SO2R 1a , NR N1a SO2R 1a , NR N1a R N1b , -C(O)R 1a , halo, cyano, wherein the C 1-6 alkyl, the C 3-6 cycloalkyl and the 3- to 6-membered monocyclic heterocyclic group are each optionally substituted with one or more R 1b substituents;

[0078] R 1a is C 1-6 alkyl, NR N1a R N1b , OR O1a , C 3-6 cycloalkyl or a 3- to 6-membered monocyclic heterocyclic group, wherein the C 1-6 alkyl, the C 3-6 cycloalkyl and the 3- to 6-membered monocyclic heterocyclic group are each optionally substituted with one or more R 1b substituents;

[0079] Each R 1b is independently selected from halo, hydroxy, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 haloalkoxy;

[0080] Or two R 1b together with the atom to which they are attached form a C 3-6 cycloalkyl;

[0081] R N1a and R N1b are each independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more R 1b substituents;

[0082] R O1a is H or C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more R 1b substituents;

[0083] R 2 is H, C 1-6 alkyl, SO2R 2a , NR N2a SO2R 2a , OR O2a , halo, cyano, -C(O)R 2a or NR N2a R N2b , wherein said C 1-6 alkyl is optionally substituted with one or more R 2b substituents;

[0084] R 2a is C 1-6 alkyl, NR N2a R N2b , OR O2a , C 3-6 cycloalkyl or a 3- to 6-membered monocyclic heterocyclic group, wherein said C 1-6 alkyl, said C 3-6 cycloalkyl and said heterocyclic group are each optionally substituted with one or more R 2b substituents;

[0085] Each R 2b is independently selected from C 1-6 alkyl, halo, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy and -C(O)OC 1-6 alkyl;

[0086] R N2a and R N2b are each independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more R 2b substituents;

[0087] R O2a is H or C 1-6 alkyl, wherein said C 1-6The alkyl group is optionally substituted with 1 or more halogen groups, hydroxyl groups, C 1-6 alkoxy groups or C 1-6 haloalkoxy groups;

[0088] R 3 is C 3-6 cycloalkyl, phenyl or a 3- to 6-membered monocyclic heterocyclic group, wherein the 3- to 6-membered monocyclic heterocyclic group is optionally substituted with one or more R 3a substituents;

[0089] Each R 3a is independently selected from a halogen group or C 1-6 alkyl; or two R 3a together with one or more atoms to which they are attached form a C 3b cycloalkyl substituted with 1 or more R 3-6 substituents;

[0090] Each R 3b is independently selected from H, a halogen group, C 1-6 alkoxy and C 1-6 alkyl optionally substituted with one or more halogen groups or OH;

[0091] R 4 is H, C 1-6 alkyl, C 1-6 haloalkyl or a halogen group;

[0092] R 5 is H or C 1-6 alkyl;

[0093] Each R 6 is independently C 1-6 alkyl, C 1-6 haloalkyl or a halogen group;

[0094] Provided that if ring A is phenyl or a 6-membered heteroaryl, then R 3 is

[0095] In a second embodiment, for a compound of formula (I) or a pharmaceutically acceptable salt thereof, Z is *-C(O)NH-, where *- represents the connection to ring A; and the remaining variables are as described in the first embodiment or the first aspect or any alternative embodiment described herein.

[0096] In a third embodiment, for a compound of formula (I) or a pharmaceutically acceptable salt thereof, ring A is phenyl, a 6-membered heteroaryl or a 6,5-bicyclic heteroaryl, each of which is substituted with R 2 、R 3 and 0 to 1 R 6Substituted; and the remaining variables are as described in the first or second embodiment or the first aspect or any alternative embodiment described herein. In an alternative third embodiment, for a compound of formula (I) or a pharmaceutically acceptable salt thereof, ring A is phenyl, 6-membered heteroaryl or 6,5-bicyclic heteroaryl, each of which is substituted by R 2 、R 3 and 0 to 2 R 6 substituents; and the remaining variables are as described in the first or second embodiment or the first aspect or any alternative embodiment described herein.

[0097] In a fourth embodiment, for a compound of formula (I) or a pharmaceutically acceptable salt thereof, ring A is phenyl, pyridyl or indazolyl, each of which is substituted by R 2 、R 3 and 0 to 1 R 6 substituents; and the remaining variables are as described in the first, second or third embodiment or the first aspect or any alternative embodiment described herein. In an alternative fourth embodiment, for a compound of formula (I) or a pharmaceutically acceptable salt thereof, ring A is phenyl, pyrazinyl, pyridyl or indazolyl, each of which is substituted by R 2 、R 3 and 0 to 2 R 6 substituents; and the remaining variables are as described in the first, second or third embodiment or the first aspect or any alternative embodiment described herein.

[0098] In a fifth embodiment, for a compound of formula (I) or a pharmaceutically acceptable salt thereof, ring A is represented by the following structural formula: each of which is substituted by R 2 、R 3 and 0 to 1 R 6 substituents; and the remaining variables are as described in the fourth embodiment or the first aspect or any alternative embodiment described herein. In an alternative fifth embodiment, for a compound of formula (I) or a pharmaceutically acceptable salt thereof, ring A is represented by the following structural formula: each of which is substituted by R 2 、R 3 and 0 to 2 R 6 substituents; and the remaining variables are as described in the fourth embodiment or the first aspect or any alternative embodiment described herein.

[0099] In a sixth embodiment, for a compound of formula (I) or a pharmaceutically acceptable salt thereof, ring A is represented by the following structural formula: and the remaining variables are as described in the fourth embodiment or the first aspect or any alternative embodiment described herein. In an alternative sixth embodiment, for a compound of formula (I) or a pharmaceutically acceptable salt thereof, ring A is represented by the following structural formula: and the remaining variables are as described in the fourth embodiment or the first aspect or any alternative embodiment described herein. In another alternative sixth embodiment, for a compound of formula (I) or a pharmaceutically acceptable salt thereof, ring A is represented by the following structural formula: and the remaining variables are as described in the fourth embodiment or the first aspect or any alternative embodiment described herein.

[0100] In a seventh embodiment, for a compound of formula (I) or a pharmaceutically acceptable salt thereof, ring A is a phenyl substituted with R 2 and R 3 ; and the remaining variables are as described in the first, second or third embodiment or the first aspect or any alternative embodiment described herein.

[0101] In an eighth embodiment, for a compound of formula (I) or a pharmaceutically acceptable salt thereof, ring A is represented by the following structural formula: and the remaining variables are as described in the seventh embodiment or the first aspect or any alternative embodiment described herein.

[0102] In a ninth embodiment, a compound of the present disclosure is represented by formula (IA):

[0103]

[0104] or a pharmaceutically acceptable salt thereof; wherein the variables R 1 , R 2 , R 3 , R 4 , X 1 , X 2 and X 3 are as described in the first, second, third, fourth, fifth, sixth, seventh or eighth embodiment or the first aspect or any alternative embodiment described herein.

[0105] In a tenth embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, both X 1 and X 2 are N and X 3 is CR 4 ; or both X 1 and X 3 are 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 described herein.

[0106] In the eleventh embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, X 3 is CR 4 , 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 described herein.

[0107] In the twelfth embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, X 3 is CR 4 , and both X 1 and X 2 are CR 5 ; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth or ninth embodiment or any alternative embodiment described herein.

[0108] In the thirteenth embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, R 4 is H and R 5 is H or -CH3; and the remaining 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 herein. 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 remaining 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 herein. 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 remaining 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 herein.

[0109] In the fourteenth embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, R 3 is optionally substituted with 1 to 3 R 3aa substituted 6-membered monocyclic heterocyclic group; and 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 embodiment described herein. In an alternative fourteenth embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, R 3 is an optionally 1-3 R 3a substituted 5- or 6-membered monocyclic heterocyclic group; and 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 embodiment described herein.

[0110] In a fifteenth embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, R 3 is a piperidinyl or 1,4-azasilahexanyl group, each optionally substituted with 1-3 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 herein. In an alternative fifteenth embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, R 3 is a piperidinyl, 1,3-azasilolidinyl or 1,4-azasilahexanyl group, each optionally substituted with 1-3 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 herein.

[0111] In a sixteenth embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, R 3 is represented by the following structural formula: each optionally substituted with 1-3 R 3a ; and the remaining variables are as described in the fifteenth embodiment or the first aspect or any alternative embodiment described herein. In an alternative sixteenth embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, R 3 is represented by the following structural formula: wherein j is 0 or 1, each optionally substituted with 1-3 R 3a ; and the remaining variables are as described in the fifteenth embodiment or the first aspect or any alternative embodiment described herein.

[0112] In the seventeenth embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, R 3 is represented by the following structural formula: and each R 3a is C 1-3 alkyl, or two Rs 3a together with the atom to which they are attached form C 3-6 cycloalkyl; and the remaining variables are as described in the sixteenth embodiment or the first aspect or any alternative embodiment described herein. In an alternative seventeenth embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, R 3 is represented by the following structural formula: and each R 3a is C 1-3 alkyl, or two Rs 3a together with one or more atoms to which they are attached form a C 3b cycloalkyl substituted with 1 to 3 Rs 3-6 ; and the remaining variables are as described in the sixteenth embodiment or the first aspect or any alternative embodiment described herein. In another alternative seventeenth embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, R 3 is represented by the following structural formula: and each R 3a is C 1-3 alkyl, or two Rs 3a together with one or more atoms to which they are attached form a C 3b cycloalkyl substituted with 1 to 3 Rs 3-6 ; and the remaining variables are as described in the sixteenth embodiment or the first aspect or any alternative embodiment described herein.

[0113] In the eighteenth embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, each R 3a is -CH3, or two Rs 3a together with the atom to which they are attached form cyclopropyl; and the remaining variables are as described in the seventeenth embodiment or the first aspect. In an alternative eighteenth embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, each R 3a is -CH3, or two Rs 3a together with one or more atoms to which they are attached form a cyclopropyl substituted with 1 to 3 Rs 3b , and each R 3bindependently is H, a halogen group, -CH3, -CHF2 or -CH2OH; and the remaining variables are as described in the seventeenth embodiment or the first aspect or any alternative embodiment described herein. In another alternative eighteenth embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, each R 3a is -CH3 or -CH2CH3, or two Rs 3a together with one or more atoms to which it is attached form a cyclopropyl or cyclobutyl group substituted with 1 to 3 Rs 3b and each R 3b independently is H, a halogen group, -CH3, -OCH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2OCH3 or -CH2OH; and the remaining variables are as described in the seventeenth embodiment or the first aspect or any alternative embodiment described herein.

[0114] In a nineteenth embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, R 3 is represented by the following structural formula: and the remaining variables are as described in the eighteenth embodiment or the first aspect or any alternative embodiment described herein. In an alternative nineteenth embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, R 3 is represented by the following structural formula: and the remaining variables are as described in the eighteenth embodiment or the first aspect or any alternative embodiment described herein. In another alternative nineteenth embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, R 3 is represented by the following structural formula: and the remaining variables are as described in the eighteenth embodiment or the first aspect or any alternative embodiment described herein.

[0115] In a twentieth embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, each R 3a is -CH3; and the remaining variables are as described in the eighteenth embodiment or the first aspect or any alternative embodiment described herein.

[0116] In a twenty - first embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, R 1 is C 3-6 cycloalkyl, a 3 - to 6 - membered monocyclic heterocyclic group, OR O1a or SO2R 1a , wherein the C 3-6The cycloalkyl group and the 3- to 6-membered monocyclic heterocyclic group are each optionally substituted with 1 to 3 R 1b ; R 1a is -NHR N1b or C 3-6 cycloalkyl; R N1b is C 1b alkyl optionally substituted with 1 or 2 R 1-4 ; R O1a is C 1b alkyl optionally substituted with 1 to 3 R 1-3 ; each R 1b is independently selected from a halogen group and C 1-3 alkyl; or two R 1b together with the atom to which they are attached form C 3-6 cycloalkyl; 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 herein. In an alternative twenty-first embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, R 1 is C 3-6 cycloalkyl, a 3- to 6-membered monocyclic heterocyclic group, OR O1a or SO2R 1a , wherein the C 3-6 cycloalkyl group and the 3- to 6-membered monocyclic heterocyclic group are each optionally substituted with 1 to 3 R 1b ; R 1a is -NHR N1b , C 3-6 cycloalkyl or a 3- to 6-membered monocyclic heterocyclic group, wherein the 3- to 6-membered monocyclic heterocyclic group is optionally substituted with 1 to 3 halogen groups; R N1b is C 1b alkyl optionally substituted with 1 or 2 R 1-4 ; R O1a is C 1b alkyl optionally substituted with 1 to 3 R 1-3 ; each R 1b is independently selected from a halogen group and C 1-3 alkyl; or two R 1b together with the atom to which they are attached form C 3-6is cycloalkyl; 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 herein. In another alternative twenty-first embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, R 1 is C 3-6 cycloalkyl, a 3- to 6-membered monocyclic heterocyclic group, OR O1a or SO2R 1a , wherein said C 3-6 cycloalkyl and said 3- to 6-membered monocyclic heterocyclic group are each optionally substituted with 1 to 3 R 1b ; R 1a is -NHR N1b , C 3-6 cycloalkyl or a 3- to 6-membered monocyclic heterocyclic group, wherein said 3- to 6-membered monocyclic heterocyclic group is optionally substituted with 1 to 3 halo groups; R N1b is C 1b alkyl optionally substituted with 1 or 2 R 1-4 ; R O1a is C 1b alkyl optionally substituted with 1 to 3 R 1-3 ; each R 1b is independently selected from halo, cyano, C 1-3 haloalkyl and C 1-3 alkyl; or two R 1b together with one or more atoms to which they are attached form C 3-6 cycloalkyl; 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 herein.

[0117] In a twenty-second embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, R 1 is -S(O)2NHC(CH3)3, -SO2-cyclopentyl, -OCH2CH2CF3, cyclopropyl, cyclohexyl, morpholinyl, piperidinyl, azetidinyl or pyrrolidinyl, wherein said cyclopropyl, said cyclohexyl, said morpholinyl, said piperidinyl, said azetidinyl and said pyrrolidinyl are each optionally substituted with 1 to 3 R 1b ; and each R 1b is -F or -CH3; or two R 1bforms a cyclopropyl together with the atom to which it is attached; and the remaining variables are as described in the twenty - first embodiment or the first aspect or any alternative embodiment described herein. In an alternative twenty - second embodiment, for a compound 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, wherein the cyclopropyl, the cyclohexyl, the morpholinyl, the piperidinyl, the piperidinyl of the - SO2 - piperidinyl, the azetidinyl and the pyrrolidinyl are each optionally substituted with 1 to 3 R 1b ; and each R 1b is - F or - CH3; or two R 1b form a cyclopropyl together with the atom to which they are attached; and the remaining variables are as described in the twenty - first embodiment or the first aspect or any alternative embodiment described herein. In another alternative twenty - second embodiment, for a compound 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, wherein the cyclopropyl, the cyclohexyl, the morpholinyl, the piperidinyl, the piperidinyl of the - SO2 - piperidinyl, the azetidinyl, the 3H - diazirinyl and the pyrrolidinyl are each optionally substituted with 1 to 3 R 1b ; and each R 1b is - F, - CN, - CF3 or - CH3; or two R 1b form a cyclopropyl together with the atom to which they are attached; and the remaining variables are as described in the twenty - first embodiment or the first aspect or any alternative embodiment described herein.

[0118] In a twenty - third embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, R 1 is C 3-6 cycloalkyl, a 3 - to 6 - membered monocyclic heterocyclic group or SO2R 1a , wherein the C 3-6 cycloalkyl and the 3 - to 6 - membered monocyclic heterocyclic group are each optionally substituted with 1 to 3 R 1b ; R 1a is - NHR N1b ; R N1b is C 1-4 alkyl; each R 1bindependently a halogen group; 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 herein.

[0119] 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, wherein the cyclohexyl, the morpholinyl and the piperidinyl are each optionally substituted with 1 to 3 R 1b ; and each R 1b is -F; and the remaining variables are as described in the twenty-third embodiment or the first aspect or any alternative embodiment described herein.

[0120] 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 represented by the following structural formula: and the remaining variables are as described in the twenty-third embodiment or the first aspect or any alternative embodiment described herein.

[0121] In a twenty-sixth embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, R 2 is H, C 1-3 alkyl, SO2R 2a or NHSO2R 2a , wherein the C 1-3 alkyl is optionally substituted with 1 to 3 R 2b ; R 2a is C 1-4 alkyl, -NHR N2b or a 3- to 6-membered monocyclic heterocyclic group, wherein the C 1-3 alkyl and the 3- to 6-membered monocyclic heterocyclic group are each optionally substituted with 1 to 3 R 2b ; R N2b is C 2b alkyl optionally substituted with 1 to 3 R 1-3 ; each R 2b is independently selected from hydroxy and C 1-3alkyl; 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 herein. In an alternative twenty - sixth embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, R 2 is H, C 1-3 alkyl, NR N2a R N2b , SO2R 2a , S(O)(NH)R 2a or NHSO2R 2a , wherein the C 1-3 alkyl is optionally substituted with 1 to 3 R 2b ; R 2a is C 1-4 alkyl, -NHR N2b , C 3-4 cycloalkyl or a 3 - to 6 - membered monocyclic heterocyclic group, wherein the C 1-3 alkyl and the 3 - to 6 - membered monocyclic heterocyclic group are each optionally substituted with 1 to 3 R 2b ; R N2a and R N2b are each independently H or C 2b alkyl optionally substituted with 1 to 3 R 1-3 ; each R 2b is independently selected from hydroxy, -N(R N2c )2 and C 1-3 alkyl; each R N2c is independently H, C 1-3 alkyl, -C(O)(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 herein.

[0122] In a 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, -S(O)2NHCH2CH2OH, -CH2CH2OH, or R 2 is represented by the formula: and the remaining variables are as described in the twenty-sixth embodiment or the first aspect or any alternative embodiment described herein. 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 represented by the formula: and the remaining variables are as described in the twenty-sixth embodiment or the first aspect or any alternative embodiment described herein. In another 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)2CH2CH2NH2, -NHS(O)2CH2CH2NHCH3, -NHS(O)2CH2CH2NHC(O)CH3, -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 represented by the formula: and the remaining variables are as described in the twenty-sixth embodiment or the first aspect or any alternative embodiment described herein.

[0123] In the twenty-eighth embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, R 2 is NHSO2R 2a ; R 2a is C 2b alkyl optionally substituted with 1 to 3 R 1-4 ; 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 described herein.

[0124] In the twenty-ninth embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, R 2 is -NHS(O)2CH2CH2OH or -NHS(O)2C(CH3)3; and the remaining variables are as described in the twenty-eighth embodiment or the first aspect or any alternative embodiment described herein.

[0125] In the thirtieth embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, R4 is H or 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, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth or twenty-ninth embodiment or the first aspect or any alternative embodiment described herein.

[0126] In the thirty-first embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, R 4 is H or -CH3; and the remaining variables are as described in the thirtieth embodiment or the first aspect or any alternative embodiment described herein.

[0127] In the thirty-second embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, each R 6 is independently a halogen group; 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 herein.

[0128] In the thirty-third embodiment, for a compound of formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof, each R 6 is -F; and the remaining variables are as described in the thirty-first embodiment or the first aspect or any alternative embodiment described herein.

[0129] In the thirty-fourth embodiment, for a compound 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 herein.

[0130] In the thirty-fifth embodiment, the compounds of the present disclosure are represented by formula (II):

[0131]

[0132] or a pharmaceutically acceptable salt thereof; wherein:

[0133] X 1 and X 2 are each independently CR 5 or N, and X 3 is CR 4 or N;

[0134] R 1 is C 3-6 cycloalkyl, a 3- to 6-membered monocyclic heterocyclic group or SO2R 1a , wherein the C 3-6 cycloalkyl and the 3- to 6-membered monocyclic heterocyclic group are each optionally substituted with 1 to 3 R 1b substituents;

[0135] R 1a is -NHR N1b ;

[0136] R N1b is C 1-4 alkyl;

[0137] Each R 1b is independently a halogen;

[0138] R 2 is NHSO2R 2a ;

[0139] R 2a is C 2b alkyl optionally substituted with 1 or 2 R 1-4 substituents;

[0140] Each R 2b is a hydroxyl group;

[0141] R 4 is H or C 1-3alkyl;

[0142] R 5 is H or C 1-3 alkyl; and the remaining variables are as described in the first embodiment or the first aspect. In some embodiments, X 3 is CR 4 . In an alternative thirty-fifth embodiment, the compounds of the present disclosure are represented by formula (II) or (III):

[0143]

[0144] or a pharmaceutically acceptable salt thereof; wherein:

[0145] X 1 and X 2 are each independently CR 5 or N, and X 3 is CR 4 or N;

[0146] R 1 is C 3-6 cycloalkyl, a 3- to 6-membered monocyclic heterocyclic group or SO2R 1a , wherein the C 3-6 cycloalkyl and the 3- to 6-membered monocyclic heterocyclic group are each optionally substituted with 1 to 3 R 1b substituents;

[0147] R 1a is -NHR N1b ;

[0148] R N1b is C 1-4 alkyl;

[0149] Each R 1b is independently a halogen;

[0150] R 2 is NHSO2R 2a ;

[0151] R 2a is optionally substituted with 1 or 2 R 2b substituents and is C 1-4 alkyl;

[0152] Each R 2b is a hydroxyl group;

[0153] R 3b is H, C 1-3 alkyl or C 1-3 haloalkyl;

[0154] R 4 is H or C 1-3 alkyl;

[0155] R 5 is H or C 1-3 is alkyl; and the remaining variables are as described in the first embodiment or the first aspect. In some embodiments, X 3 is CR 4 .

[0156] In another alternative thirty-fifth embodiment, the compounds of the present disclosure are represented by formula (II), formula (III) or formula (IV):

[0157]

[0158] or a pharmaceutically acceptable salt thereof; wherein:

[0159] X 1 and X 2 are each independently CR 5 or N, and X 3 is CR 4 or N;

[0160] R 1 is C 3-6 cycloalkyl, a 3- to 6-membered monocyclic heterocyclic group or SO2R 1a , wherein the C 3-6 cycloalkyl and the 3- to 6-membered monocyclic heterocyclic group are each optionally substituted with 1 to 3 R 1b ;

[0161] R 1a is -NHR N1b ;

[0162] R N1b is C 1-4 alkyl;

[0163] Each R 1b is independently a halogen;

[0164] R 2 is NHSO2R 2a ;

[0165] R 2a is C 2b alkyl optionally substituted with 1 or 2 R 1-4 ;

[0166] Each R 2b is a hydroxyl group;

[0167] R 3b is H, a halogen, C 1-3 alkyl or C 1-3 haloalkyl;

[0168] R 4 is H or C1-3 alkyl;

[0169] R 5 is H or C 1-3 alkyl; and the remaining variables are as described in the first embodiment or the first aspect. In some embodiments, X 3 is CR 4 .

[0170] In the thirty-sixth embodiment, the compounds of the present disclosure are represented by formula (IIA), formula (IIB), formula (IIC), formula (IID), or formula (IIE):

[0171]

[0172] or a pharmaceutically acceptable salt thereof; wherein the variables R 1 , R 2 , R 4 , and R 5 depicted in formula (IIA), formula (IIB), formula (IIC), formula (IID), or formula (IIE) are as described in the thirty-fifth embodiment or the first aspect or any alternative embodiments described herein. In some embodiments, R 5 is H. In an alternative thirty-sixth embodiment, the compounds of the present disclosure are represented by formula (IIA), formula (IIB), formula (IIC), formula (IID), formula (IIE), or formula (IIIA):

[0173]

[0174] or a pharmaceutically acceptable salt thereof; wherein the variables R 1 , R 2 , R 3b , R 4 , and R 5 depicted in formula (IIA), formula (IIB), formula (IIC), formula (IID), formula (IIE), or formula (IIIA) are as described in the thirty-fifth embodiment or the first aspect or any alternative embodiments described herein. In some embodiments, R 5 is H. In another alternative thirty-sixth embodiment, the compounds of the present disclosure are represented by formula (IIA), formula (IIB), formula (IIC), formula (IID), formula (IIE), formula (IIIA), or formula (IVA):

[0175]

[0176]

[0177] or a pharmaceutically acceptable salt thereof; wherein the variables R depicted in Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (IIE), Formula (IIIA) or Formula (IVA) 1 、R 2 、R 3b 、R 4 and R 5 are as described in the thirty-fifth embodiment or the first aspect or any alternative embodiment described herein. In another alternative thirty-sixth embodiment, the compound of the present disclosure is represented by Formula (IIIA):

[0178]

[0179] or a pharmaceutically acceptable salt thereof; wherein the variables R depicted in Formula (IIIA) 1 、R 2 、R 3b and R 4 are as described in the thirty-fifth embodiment or the first aspect or any alternative embodiment described herein. In another alternative thirty-sixth embodiment, the compound of the present disclosure is represented by Formula (IVA):

[0180]

[0181] or a pharmaceutically acceptable salt thereof; wherein the variables R depicted in Formula (IVA) 1 、R 2 、R 3b and R 4 are as described in the thirty-fifth embodiment or the first aspect or any alternative embodiment described herein.

[0182] In the thirty-seventh embodiment, for a compound of Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID) or Formula (IIE) or a pharmaceutically acceptable salt thereof, R 1 is -S(O)2NHC(CH3)3, cyclohexyl, morpholinyl or piperidinyl, wherein the cyclohexyl, the morpholinyl and the piperidinyl are each optionally substituted with 1 to 2 R 1b ; and each R 1b is -F; and the remaining variables are as described in the thirty-fifth or thirty-sixth embodiment or the first aspect or any alternative embodiment described herein. In an alternative thirty-seventh embodiment, for a compound of Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (IIE), Formula (IIIA) or Formula (IVA) or a pharmaceutically acceptable salt thereof, R 1is -S(O)2NHC(CH3)3, cyclohexyl, morpholinyl or piperidinyl, wherein the cyclohexyl, the morpholinyl and the piperidinyl are each optionally substituted with 1 to 2 R 1b substituents; and each R 1b is -F; and the remaining variables are as described in the thirty-fifth or thirty-sixth embodiment or the first aspect or any alternative embodiment described herein.

[0183] In the thirty-eighth embodiment, for a compound of formula (II), formula (IIA), formula (IIB), formula (IIC), formula (IID) or formula (IIE) or a pharmaceutically acceptable salt thereof, R 1 is -S(O)2NHC(CH3)3, or R 1 is represented by the following structural formula: and the remaining variables are as described in the thirty-seventh embodiment or the first aspect or any alternative embodiment described herein. In an alternative thirty-eighth embodiment, for a compound of formula (II), formula (IIA), formula (IIB), formula (IIC), formula (IID), formula (IIE), formula (IIIA) or formula (IVA) or a pharmaceutically acceptable salt thereof, R 1 is -S(O)2NHC(CH3)3, or R 1 is represented by the following structural formula: and the remaining variables are as described in the thirty-seventh embodiment or the first aspect or any alternative embodiment described herein.

[0184] In the thirty-ninth embodiment, for a compound of formula (II), formula (IIA), formula (IIB), formula (IIC), formula (IID) or formula (IIE) or a pharmaceutically acceptable salt thereof, R 2 is -NHS(O)2CH2CH2OH or -NHS(O)2C(CH3)3; and the remaining 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), formula (IIA), formula (IIB), formula (IIC), formula (IID), formula (IIE), formula (IIIA) or formula (IVA) or a pharmaceutically acceptable salt thereof, R 2 is -NHS(O)2CH2CH2OH or -NHS(O)2C(CH3)3; and the remaining variables are as described in the thirty-fifth, thirty-sixth, thirty-seventh or thirty-eighth embodiment or the first aspect or any alternative embodiment described herein.

[0185] In the fortieth embodiment, for a compound of formula (II), formula (IIA), formula (IIB), formula (IIC), formula (IID), or formula (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 the first aspect or any alternative embodiment described herein. In some embodiments, R 4 is H or -CH3 and R 5 is H. In other embodiments, both R 4 and R 5 are H. In an alternative fortieth embodiment, for a compound of formula (II), formula (IIA), formula (IIB), formula (IIC), formula (IID), formula (IIE), formula (IIIA), or formula (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 the first aspect or any alternative embodiment described herein. In some embodiments, R 4 is H or -CH3 and R 5 is H. In other embodiments, both R 4 and R 5 are H.

[0186] In the forty-first embodiment, for a compound of formula (IIIA) or formula (IVA) or a pharmaceutically acceptable salt thereof, R 3b is H, -CH3, or -CHF2; and the remaining 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 a compound of formula (IIIA) or formula (IVA) or a pharmaceutically acceptable salt thereof, R 3b is H, -F, -CH3, -CH2F, or -CHF2; and the remaining variables are as described in the thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, or fortieth embodiment or the first aspect.

[0187] In the forty-second embodiment, the present disclosure provides a compound described herein (e.g., a compound of any one of Examples 1 to 134) or a pharmaceutically acceptable salt thereof.

[0188] In an alternative forty-second embodiment, the present disclosure provides a compound selected from the group consisting of:

[0189] N-(2-(4,4-Difluorocyclohexyl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinane-1-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0190] 2-(4,4-Dimethyl-1,4-azasilinane-1-yl)-4-((2-hydroxyethyl)sulfonylamino)-N-(5-methyl-6-morpholinopyridin-2-yl)benzamide;

[0191] N-(6-(4,4-Difluoropiperidin-1-yl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinane-1-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0192] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-2-(4,4-dimethyl-1,4-azasilinane-1-yl)-4-((1,1-dimethylethyl)sulfonylamino)benzamide;

[0193] 2-(4,4-Dimethyl-1,4-azasilinane-1-yl)-4-((2-hydroxyethyl)sulfonylamino)-N-(4-methyl-6-morpholinopyridin-2-yl)benzamide;

[0194] N-(3-(4,4-Difluoropiperidin-1-yl)phenyl)-2-(4,4-dimethyl-1,4-azasilinane-1-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0195] N-(2-(4,4-Difluoropiperidin-1-yl)pyridin-4-yl)-2-(4,4-dimethyl-1,4-azasilinane-1-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0196] N-(6-(4,4-Difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinane-1-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0197] N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinane-1-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0198] 2-(4,4-Dimethyl-1,4-azasilinane-1-yl)-4-((2-hydroxyethyl)sulfonylamino)-N-(2-(3,3,3-trifluoropropoxy)pyrimidin-4-yl)benzamide;

[0199] 2-(4,4-Dimethyl-1,4-azasila-cyclohexan-1-yl)-4-((2-hydroxyethyl)sulfonylamino)-N-(2-(2-methylmorpholinyl)pyrimidin-4-yl)benzamide;

[0200] N-(2-(4,4-Difluoropiperidin-1-yl)pyrimidin-4-yl)-1-(2-hydroxyethyl)-6-(6-azaspiro[2.5]oct-6-yl)-1,3-dihydro-2H-indazole-5-carboxamide;

[0201] N-(2-(4,4-Difluoropiperidin-1-yl)pyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasila-cyclohexan-1-yl)-5-fluoro-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0202] N-(6-(4,4-Difluoropiperidin-1-yl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasila-cyclohexan-1-yl)-5-fluoro-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0203] N-(2-Cyclopropylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasila-cyclohexan-1-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0204] 2-(4,4-Dimethyl-1,4-azasila-cyclohexan-1-yl)-4-((2-hydroxyethyl)sulfonylamino)-N-(6-(3,3,3-trifluoropropoxy)pyridin-2-yl)benzamide;

[0205] (S)-2-(4,4-Dimethyl-1,4-azasila-cyclohexan-1-yl)-4-((2-hydroxyethyl)sulfonylamino)-N-(6-(2-methylmorpholinyl)pyridin-2-yl)benzamide;

[0206] 2-(4,4-Dimethyl-1,4-azasila-cyclohexan-1-yl)-4-(N-(2-hydroxyethyl)sulfamoyl)-N-(6-(2-methylmorpholinyl)pyridin-2-yl)benzamide;

[0207] (R)-2-(4,4-Dimethyl-1,4-azasila-cyclohexan-1-yl)-4-((2-hydroxyethyl)sulfonylamino)-N-(6-(2-methylmorpholinyl)pyridin-2-yl)benzamide;

[0208] N-(6-(3,3-Difluoroazetidin-1-yl)-4-methylpyridin-2-yl)-2-(4,4-dimethyl-1,4-azasila-cyclohexan-1-yl)-4-(methylsulfonylamino)benzamide;

[0209] 2-(4,4-Dimethyl-1,4-azasilahexan-1-yl)-4-((2-hydroxyethyl)sulfonylamino)-N-(6-methyl-2-(5-azaspiro[2.4]hept-5-yl)pyrimidin-4-yl)benzamide;

[0210] N-(6-(Cyclopentylsulfonyl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilahexan-1-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0211] 2-(4,4-Difluoropiperidin-1-yl)-N-(2-(4,4-dimethyl-1,4-azasilahexan-1-yl)-4-((2-hydroxyethyl)sulfonylamino)phenyl)pyrimidine-4-carboxamide;

[0212] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-2-(4,4-dimethyl-1,4-azasilahexan-1-yl)-4-((3-methyloxetan-3-yl)sulfonyl)benzamide;

[0213] N-(2-(4,4-Difluoropiperidin-1-yl)pyrimidin-4-yl)-1-(2-hydroxyethyl)-4-(6-azaspiro[2.5]oct-6-yl)-1H-indazole-5-carboxamide;

[0214] N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-3-(4,4-dimethyl-1,4-azasilahexan-1-yl)-5-((2-hydroxyethyl)sulfonylamino)picolinamide;

[0215] N-(3-((4,4-Difluoropiperidin-1-yl)sulfonyl)phenyl)-2-(4,4-dimethyl-1,4-azasilahexan-1-yl)nicotinamide;

[0216] 2-(7,7-Difluoro-6-methyl-3-azabicyclo[4.1.0]hept-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0217] 2-((1S,6R)-6-(Difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0218] 2-((1R,6S)-6-(Difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0219] N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonylamino)-2-(6-(hydroxymethyl)-3-azabicyclo[4.1.0]hept-3-yl)benzamide;

[0220] N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-4-((2-hydroxyethyl)sulfonylamino)-6-((1R,6R)-6-methyl-3-azabicyclo[4.1.0]hept-3-yl)benzamide;

[0221] N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-4-((2-hydroxyethyl)sulfonylamino)-6-((1S,6S)-6-methyl-3-azabicyclo[4.1.0]hept-3-yl)benzamide;

[0222] N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1R,6R)-6-methyl-3-azabicyclo[4.1.0]hept-3-yl)-4-(methylsulfonylamino)benzamide;

[0223] N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1S,6S)-6-methyl-3-azabicyclo[4.1.0]hept-3-yl)-4-(methylsulfonylamino)benzamide;

[0224] 2-(3-Azabicyclo[4.1.0]hept-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0225] N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonylamino)-2-((1S,6S)-6-methyl-3-azabicyclo[4.1.0]hept-3-yl)benzamide;

[0226] N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonylamino)-2-((1R,6R)-6-methyl-3-azabicyclo[4.1.0]hept-3-yl)benzamide;

[0227] N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonylamino)-2-(6-methyl-3-azabicyclo[4.1.0]hept-3-yl)benzamide;

[0228] N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonylamino)-2-((1R,6S)-6-(hydroxymethyl)-3-azabicyclo[4.1.0]hept-3-yl)benzamide;

[0229] N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonylamino)-2-((1S,6R)-6-(hydroxymethyl)-3-azabicyclo[4.1.0]hept-3-yl)benzamide;

[0230] 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]hept-3-yl)benzamide;

[0231] 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]hept-3-yl)benzamide;

[0232] 2-(3-Azabicyclo[4.1.0]hept-3-yl)-N-(3-((4,4-difluoropiperidin-1-yl)sulfonyl)phenyl)nicotinamide;

[0233] N-(3-((4,4-Difluoropiperidin-1-yl)sulfonyl)phenyl)-2-(6-methyl-3-azabicyclo[4.1.0]hept-3-yl)nicotinamide;

[0234] N-(3-((4,4-Difluoropiperidin-1-yl)sulfonyl)phenyl)-2-((1S,6S)-6-methyl-3-azabicyclo[4.1.0]hept-3-yl)nicotinamide;

[0235] N-(3-((4,4-Difluoropiperidin-1-yl)sulfonyl)phenyl)-2-((1R,6R)-6-methyl-3-azabicyclo[4.1.0]hept-3-yl)nicotinamide;

[0236] 2-((1R,6S)-6-(Difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide;

[0237] 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]hept-3-yl)benzamide;

[0238] 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]hept-3-yl)benzamide;

[0239] 2-((1S,6R)-6-(Difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(methylsulfonamido)benzamide;

[0240] 2-((1R,6S)-6-(Difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(methylsulfonamido)benzamide;

[0241] 2-((1S,6R)-6-(Difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((N-(2-hydroxyethyl)sulfamoyl)amino)benzamide;

[0242] 2-((1R,6S)-6-(Difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((N-(2-hydroxyethyl)sulfamoyl)amino)benzamide;

[0243] N-(2-(4,4-Difluorocyclohexyl)-6-methylpyrimidin-4-yl)-2-((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide;

[0244] N-(2-(4,4-Difluorocyclohexyl)-6-methylpyrimidin-4-yl)-2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0245] 2-((1S,6R)-6-(Difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0246] 2-((1R,6S)-6-(Difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0247] N-(2-(4,4-Difluorocyclohexyl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonylamino)-2-((1S,6S)-6-methyl-3-azabicyclo[4.1.0]hept-3-yl)benzamide;

[0248] N-(2-(4,4-Difluorocyclohexyl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonylamino)-2-((1R,6R)-6-methyl-3-azabicyclo[4.1.0]hept-3-yl)benzamide;

[0249] 2-((1S,6R)-6-(Difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0250] 2-((1S,6R)-6-(Difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0251] 2-((1R,6S)-6-(Difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0252] 2-((1S,6R)-6-(Difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-((2-hydroxyethyl)sulfonylamino)-N-(6-methyl-2-((S)-3,3,3-trifluoro-2-hydroxypropoxy)pyrimidin-4-yl)benzamide;

[0253] 2-((1R,6S)-6-(Difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-((2-hydroxyethyl)sulfonylamino)-N-(6-methyl-2-((S)-3,3,3-trifluoro-2-hydroxypropoxy)pyrimidin-4-yl)benzamide;

[0254] 2-((1S,6R)-6-(Difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)-6-fluoro-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0255] 2-((1R,6S)-6-(Difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)-6-fluoro-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0256] 2-((1S,6R)-6-(Difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-6-fluoro-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0257] 2-((1R,6S)-6-(Difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-6-fluoro-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0258] 2-((1S,6R)-6-(Difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-((2-hydroxyethyl)sulfonylamino)-N-(6-methyl-2-((R)-3,3,3-trifluoro-2-hydroxypropoxy)pyrimidin-4-yl)benzamide;

[0259] 2-((1R,6S)-6-(Difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-((2-hydroxyethyl)sulfonylamino)-N-(6-methyl-2-((R)-3,3,3-trifluoro-2-hydroxypropoxy)pyrimidin-4-yl)benzamide;

[0260] N-(2-(4,4-Difluorocyclohexyl)pyrimidin-4-yl)-2-((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0261] N-(2-(4,4-Difluorocyclohexyl)pyrimidin-4-yl)-2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0262] 2-((1S,6R)-6-(Difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(N-(2-hydroxyethyl)sulfamoyl)benzamide;

[0263] 2-((1R,6S)-6-(Difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(N-(2-hydroxyethyl)sulfamoyl)benzamide;

[0264] 2-((1S,6R)-6-(1,1-Difluoroethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0265] 2-((1R,6S)-6-(1,1-Difluoroethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0266] N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonylamino)-2-((1R,6R)-6-methoxy-3-azabicyclo[4.1.0]hept-3-yl)benzamide;

[0267] N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonylamino)-2-((1S,6S)-6-methoxy-3-azabicyclo[4.1.0]hept-3-yl)benzamide;

[0268] 2-((1S,6R)-6-(Difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-6-fluoro-4-((2-hydroxyethyl)sulfonamido)benzamide;

[0269] 2-((1R,6S)-6-(Difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-6-fluoro-4-((2-hydroxyethyl)sulfonamido)benzamide;

[0270] 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]hept-3-yl)benzamide;

[0271] 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]hept-3-yl)benzamide;

[0272] 2-(4,4-Dimethyl-1,4-azasilinane-1-yl)-4-((2-hydroxyethyl)sulfonamido)-N-(3-(3-(trifluoromethyl)-3H-diazirin-3-yl)phenyl)benzamide;

[0273] N-(2-(4,4-Dimethyl-1,4-azasilinane-1-yl)-4-((2-hydroxyethyl)sulfonamido)phenyl)-2-(3,3,3-trifluoropropoxy)pyrimidine-4-carboxamide;

[0274] N-(2-(Cyclopentanesulfonyl)pyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinane-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide;

[0275] 2-(4,4-Difluoropiperidin-1-yl)-N-(2-(4,4-dimethyl-1,4-azasilinane-1-yl)-5-fluoro-4-((2-hydroxyethyl)sulfonamido)phenyl)pyrimidine-4-carboxamide;

[0276] (S)-N-(2-(4,4-Dimethyl-1,4-azasilinane-1-yl)-4-((2-hydroxyethyl)sulfonamido)phenyl)-2-(2-methylmorpholino)pyrimidine-4-carboxamide;

[0277] 2-(4,4-Diethyl-1,4-azasilahexan-1-yl)-N-(3-((4,4-difluoropiperidin-1-yl)sulfonyl)phenyl)nicotinamide;

[0278] N-(3-((4,4-Difluoropiperidin-1-yl)sulfonyl)phenyl)-2-(3,3-dimethyl-1,3-azasilacyclopentan-1-yl)nicotinamide;

[0279] N-(2-(3-Cyanopiperidin-1-yl)pyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilahexan-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide;

[0280] 6-(4,4-Difluoropiperidin-1-yl)-N-(2-(4,4-dimethyl-1,4-azasilahexan-1-yl)-5-fluoro-4-((2-hydroxyethyl)sulfonamido)phenyl)pyridinecarboxamide;

[0281] 6-(4,4-Difluoropiperidin-1-yl)-N-(2-(4,4-dimethyl-1,4-azasilahexan-1-yl)-4-((2-hydroxyethyl)sulfonamido)phenyl)pyridinecarboxamide;

[0282] N-(3-(Cyclopentylsulfonyl)phenyl)-2-(4,4-dimethyl-1,4-azasilahexan-1-yl)-6-((1-hydroxy-2-methylpropan-2-yl)amino)nicotinamide;

[0283] N-(6-(N-(tert-Butyl)sulfamoyl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilahexan-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide;

[0284] 2-(4,4-Dimethyl-1,4-azasilahexan-1-yl)-4-(N-(2-hydroxyethyl)sulfonamido)-N-(6-(3,3,3-trifluoropropoxy)pyridin-2-yl)benzamide;

[0285] 4-((2-Aminoethyl)sulfonamido)-N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilahexan-1-yl)benzamide;

[0286] N-(6-(4,4-Difluoropiperidin-1-yl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilahexan-1-yl)-4-((2-(methylamino)ethyl)sulfonamido)benzamide;

[0287] 2-(4,4-dimethyl-1,4-azasila-cyclohexan-1-yl)-4-((2-hydroxyethyl)sulfonylamino)-N-(6-methyl-2-(4-oxa-7-azaspiro[2.5]oct-7-yl)pyrimidin-4-yl)benzamide;

[0288] N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasila-cyclohexan-1-yl)-5-fluoro-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0289] 4-((2-acetamidoethyl)sulfonylamino)-N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasila-cyclohexan-1-yl)benzamide;

[0290] N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-3-(4,4-dimethyl-1,4-azasila-cyclohexan-1-yl)-5-((2-hydroxyethyl)sulfonylamino)pyrazine-2-carboxamide;

[0291] N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(4,4-dimethyl-1,4-azasila-cyclohexan-1-yl)-6-((2-hydroxyethyl)sulfonylamino)nicotinamide;

[0292] N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-2-(4,4-dimethyl-1,4-azasila-cyclohexan-1-yl)-5-fluoro-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0293] N-(6-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)-2-(4,4-dimethyl-1,4-azasila-cyclohexan-1-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0294] N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasila-cyclohexan-1-yl)-6-((2-hydroxyethyl)sulfonylamino)nicotinamide;

[0295] N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasila-cyclohexan-1-yl)-6-fluoro-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0296] (R)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasila-cyclohexan-1-yl)-4-((2-hydroxy-1-methylethyl)sulfonylamino)benzamide;

[0297] (S)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasila-cyclohexan-1-yl)-4-((2-hydroxy-1-methylethyl)sulfonylamino)benzamide;

[0298] 2-(4,4-Dimethyl-1,4-azasila-cyclohexan-1-yl)-4-((2-hydroxy-1-methylethyl)sulfonylamino)-N-(6-(3,3,3-trifluoropropoxy)pyridin-2-yl)benzamide;

[0299] N-(6-(3,3-Difluoroazetidin-1-yl)-4-methylpyridin-2-yl)-2-(4,4-dimethyl-1,4-azasila-cyclohexan-1-yl)-4-((2-hydroxy-1-methylethyl)sulfonylamino)benzamide;

[0300] N-(2-(2,2-Difluoromorpholinyl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasila-cyclohexan-1-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0301] N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasila-cyclohexan-1-yl)-3,6-difluoro-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0302] N-(2-(4,4-Difluorocyclohexyl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasila-cyclohexan-1-yl)-4-((N-(2-hydroxyethyl)sulfamoyl)amino)benzamide;

[0303] N-(2-(4,4-Difluorocyclohexyl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasila-cyclohexan-1-yl)-4-((N-methylsulfamoyl)amino)benzamide;

[0304] 2-(4,4-Dimethyl-1,4-azasila-cyclohexan-1-yl)-4-((2-hydroxyethyl)sulfonylamino)-N-(6-(3,3,3-trifluoro-2-hydroxypropoxy)pyridin-2-yl)benzamide;

[0305] 4-(Cyclopropanesulfonylimino)-N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasila-cyclohexan-1-yl)benzamide;

[0306] (R)-2-(4,4-Dimethyl-1,4-azasila-cyclohexan-1-yl)-4-((2-hydroxyethyl)sulfonylamino)-N-(6-(3,3,3-trifluoro-2-hydroxypropoxy)pyridin-2-yl)benzamide;

[0307] (S)-2-(4,4-Dimethyl-1,4-azasila-cyclohexan-1-yl)-4-((2-hydroxyethyl)sulfonylamino)-N-(6-(3,3,3-trifluoro-2-hydroxypropoxy)pyridin-2-yl)benzamide;

[0308] (R)-2-(4,4-Dimethyl-1,4-azasila-cyclohexan-1-yl)-6-fluoro-4-((2-hydroxyethyl)sulfonylamino)-N-(6-(3,3,3-trifluoro-2-hydroxypropoxy)pyridin-2-yl)benzamide;

[0309] (S)-2-(4,4-Dimethyl-1,4-azasila-cyclohexan-1-yl)-6-fluoro-4-((2-hydroxyethyl)sulfonylamino)-N-(6-(3,3,3-trifluoro-2-hydroxypropoxy)pyridin-2-yl)benzamide;

[0310] (R)-2-(4,4-Dimethyl-1,4-azasila-cyclohexan-1-yl)-4-((N-(2-hydroxyethyl)sulfamoyl)amino)-N-(6-(3,3,3-trifluoro-2-hydroxypropoxy)pyridin-2-yl)benzamide;

[0311] (S)-2-(4,4-Dimethyl-1,4-azasila-cyclohexan-1-yl)-4-((N-(2-hydroxyethyl)sulfamoyl)amino)-N-(6-(3,3,3-trifluoro-2-hydroxypropoxy)pyridin-2-yl)benzamide;

[0312] (R)-2-(4,4-Dimethyl-1,4-azasila-cyclohexan-1-yl)-4-(methylsulfonylamino)-N-(6-(3,3,3-trifluoro-2-hydroxypropoxy)pyridin-2-yl)benzamide;

[0313] (S)-2-(4,4-Dimethyl-1,4-azasila-cyclohexan-1-yl)-4-(methylsulfonylamino)-N-(6-(3,3,3-trifluoro-2-hydroxypropoxy)pyridin-2-yl)benzamide;

[0314] (R)-2-(4,4-Dimethyl-1,4-azasilahexan-1-yl)-4-((2-hydroxyethyl)sulfonyl)-N-(6-(3,3,3-trifluoro-2-hydroxypropoxy)pyridin-2-yl)benzamide;

[0315] (S)-2-(4,4-Dimethyl-1,4-azasilahexan-1-yl)-4-((2-hydroxyethyl)sulfonyl)-N-(6-(3,3,3-trifluoro-2-hydroxypropoxy)pyridin-2-yl)benzamide;

[0316] (R)-2-(4,4-Dimethyl-1,4-azasilahexan-1-yl)-4-(N-(2-hydroxyethyl)sulfamoyl)-N-(6-(3,3,3-trifluoro-2-hydroxypropoxy)pyridin-2-yl)benzamide;

[0317] (S)-2-(4,4-Dimethyl-1,4-azasilahexan-1-yl)-4-(N-(2-hydroxyethyl)sulfamoyl)-N-(6-(3,3,3-trifluoro-2-hydroxypropoxy)pyridin-2-yl)benzamide;

[0318] N-(6-(4,4-Difluoropiperidin-1-yl)-5-fluoro-4-methylpyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilahexan-1-yl)-4-((2-hydroxyethyl)sulfamoyl)benzamide;

[0319] N-(2-(4,4-Difluorocyclohexyl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilahexan-1-yl)-4-((N-(2-hydroxyethyl)-N-methylsulfamoyl)amino)benzamide;

[0320] N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfamoyl)-2-((1S,6R)-6-(methoxymethyl)-3-azabicyclo[4.1.0]hept-3-yl)benzamide;

[0321] N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfamoyl)-2-((1R,6S)-6-(methoxymethyl)-3-azabicyclo[4.1.0]hept-3-yl)benzamide;

[0322] N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1R,6R)-6-fluoro-3-azabicyclo[4.2.0]oct-3-yl)-4-((2-hydroxyethyl)sulfamoyl)benzamide;

[0323] N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1S,6S)-6-fluoro-3-azabicyclo[4.2.0]oct-3-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0324] N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1S,6R)-6-(fluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide; and

[0325] N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1R,6S)-6-(fluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide;

[0326] or a pharmaceutically acceptable salt thereof.

[0327] The compounds and intermediates described herein can be isolated and used as the compounds themselves. Alternatively, when there are moieties capable of forming salts, the compounds or intermediates can be isolated and used as their corresponding salts. As used herein, the term "salt(s)" refers to acid addition salts or base addition salts of the compounds described herein. "Salt" particularly includes "pharmaceutically acceptable salt". The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the compounds described herein and are generally not biologically or otherwise undesirable. In many cases, the compounds of the present disclosure are capable of forming acid salts and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0328] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids or organic acids, such as acetates, aspartates, benzoates, benzenesulfonates, bromides / hydrobromides, bicarbonates / carbonates, bisulfates / sulfates, camphorsulfonates, chlorides / hydrochlorides, choline salts, citrates, edisylates, fumarates, glucoheptonates, gluconates, glucuronates, hippurates, hydroiodides / iodides, isethionates, lactates, lactobionates, lauryl sulfates, malates, maleates, malonates, mandelates, mesylates, methyl sulfates, naphthoates, naphthalenesulfonates, nicotinates, nitrates, octadecanoates, oleates, oxalates, palmitates, pamoates, phosphates / monohydrogen phosphates / dihydrogen phosphates, polygalacturonates, propionates, stearates, succinates, sulfates, sulfosalicyclates, tartrates, toluenesulfonates, and trifluoroacetates.

[0329] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0330] 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.

[0331] Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases.

[0332] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I through XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0333] Organic bases from which salts can be derived include, for example, primary amines, secondary amines, and tertiary amines; substituted amines, including naturally occurring substituted amines; cyclic amines; basic ion exchange resins; and the like. Certain organic amines include isopropylamine, benzathine, cholates, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0334] Salts can be synthesized from compounds containing basic or acidic moieties 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 hydroxides, carbonates, bicarbonates of Na, Ca, Mg, or K, or the like), or by reacting the free base form of these compounds with a stoichiometric amount of an appropriate acid. Such reactions are generally carried out in water or in an organic solvent or in a mixture of the two. Generally, if feasible, it is desirable to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. Lists of other suitable salts can be found, for example, in “Remington's Pharmaceutical Sciences”, 20th edition, Mack Publishing Company, Easton, Pa., (1985); and Stahl and Wermuth, “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (Wiley-VCH, Weinheim, Germany, 2002).

[0335] Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by a process similar to the processes described in the accompanying examples and preparations, using appropriate isotopically labeled reagents in place of the unlabeled reagents previously employed. In one embodiment, the present disclosure provides the deuterated compounds described herein or pharmaceutically acceptable salts thereof.

[0336] Pharmaceutically acceptable solvates according to the present disclosure include solvates in which the crystallization solvent may be isotopically substituted, such as D2O, d6-acetone, d6-DMSO.

[0337] Those skilled in the art will recognize that the compounds of the present disclosure may contain chiral centers and may thus exist in different stereoisomeric forms. As used herein, the terms "optical isomers" or "stereoisomers" refer to any of the various stereoisomeric configurations that may exist in a given compound of the present disclosure. It is understood that substituents may be attached to the chiral centers of carbon atoms. Accordingly, the present disclosure encompasses enantiomers, diastereomers or racemates of the compounds.

[0338] "Enantiomers" are pairs of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of enantiomer pairs is a "racemic" mixture. In appropriate cases, the term "racemic (racemic or rac)" is used to name a racemic mixture. When naming the stereochemistry of the compounds of the present disclosure, the conventional RS system is used to name a single stereoisomer for which the relative and absolute configurations of two chiral centers are known (e.g., (1S,2S)). "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is assigned according to the Cahn-Ingold-Prelog R-S system. When the compound is a pure enantiomer, the stereochemistry of each chiral carbon can be designated as R or S. A resolved compound of unknown absolute configuration can be designated as (+) or (-) depending on the direction (right or left) in which it rotates plane-polarized light at the sodium D line wavelength. Alternatively, a resolved compound can be defined by the respective retention times of the corresponding enantiomers / diastereomers via chiral HPLC.

[0339] Certain compounds described herein contain one or more asymmetric centers or axes and can thus give rise to enantiomers, diastereomers and other stereoisomeric forms that can be defined as (R)- or (S)- in terms of absolute stereochemistry.

[0340] Unless otherwise specified, the compounds of the present disclosure are intended to include all such possible stereoisomers, including racemic mixtures, optically pure forms, and mixtures of intermediates. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., achieving good separation using a suitable solvent or solvent mixture, separating on a chiral SFC or HPLC column, such as CHIRALPAK RTM and CHIRALCEL RTM ). If a compound contains a double bond, the substituents can be in the E or Z configuration. If a compound contains a disubstituted cycloalkyl, the cycloalkyl substituents can have cis or trans configurations. All tautomeric forms are also expected to be included.

[0341] The present disclosure also provides pharmaceutical compositions that include a compound described herein (e.g., a compound according to any one of the foregoing embodiments) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0342] Methods of Use

[0343] 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., a decrease in KIF18A activity of at least 10% as measured by a given assay, such as a bioassay described in the examples and known in the art).

[0344] In certain embodiments, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof that responds to inhibition of KIF18A activity (referred to herein as a "KIF18A-mediated disease or disorder"). The method includes 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.

[0345] In certain embodiments, the present disclosure provides the 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 treating a KIF18A-mediated disorder or disease in a subject in need thereof.

[0346] 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 treating a KIF18A-mediated disorder or disease in a subject in need thereof.

[0347] In certain embodiments, the KIF18A-mediated disease or disorder is cancer.

[0348] 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 TP53, BRCA1, BRCA2, RB1 gene mutations and / or CCNE1 gene amplification.

[0349] 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, uterine cancer, cervical cancer or bone cancer.

[0350] In other embodiments, the KIF18A-mediated disease or disorder is (a) a solid or hematogenous tumor selected from bladder cancer, endometrial cancer, squamous cell lung cancer, 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) a hematopoietic tumor of lymphoid lineage selected from leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B cell lymphoma, T cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma, (c) a hematopoietic tumor of myeloid lineage selected from acute and chronic myeloid leukemia, myelodysplastic syndrome and promyelocytic leukemia, (d) a tumor of mesenchymal origin selected from fibrosarcoma and rhabdomyosarcoma, (e) a tumor 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 cancer or Kaposi's sarcoma.

[0351] The compounds described herein or pharmaceutically acceptable salts thereof can be used to reduce the expression or activity of KIF18A, or otherwise affect the properties and / or behavior of KIF18A in cells.

[0352] One embodiment of the present disclosure includes a method of reducing the expression or activity of KIF18A or otherwise affecting the properties and / or behavior of KIF18A in a subject, which includes administering to the subject an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof.

[0353] In certain embodiments, the present disclosure relates to the method mentioned above, wherein the subject is a mammal.

[0354] In certain embodiments, the present disclosure relates to the method mentioned above, wherein the subject is a primate.

[0355] In certain embodiments, the present disclosure relates to the method mentioned above, wherein the subject is a human.

[0356] As used herein, "effective amount" and "therapeutically effective amount" are used interchangeably. It means an amount effective for treating or alleviating the severity of one or more diseases, disorders or conditions listed herein. In some embodiments, the effective dose can be between 10 μg and 500 mg.

[0357] According to the method of the present disclosure, the compounds and compositions can be administered using any amount and any route of administration effective for treating or alleviating the severity of one or more diseases, disorders or conditions listed above.

[0358] In certain embodiments, the present disclosure relates to the method mentioned above, wherein the compound is administered parenterally.

[0359] In certain embodiments, the present disclosure relates to the method mentioned above, wherein the compound is administered intramuscularly, intravenously, subcutaneously, orally, by inhalation, rectally, intrathecally, topically or intranasally.

[0360] In certain embodiments, the present disclosure relates to the method mentioned above, wherein the compound is administered systemically.

[0361] The compounds of the present disclosure are generally used as pharmaceutical compositions (e.g., the compounds 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), isotonic agents, salts, preservatives, pharmaceutical stabilizers, buffers (e.g., maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate and the like) and the like and combinations thereof (see, e.g., Remington's Pharmaceutical Sciences, 18th Edition, Mack Printing Company, 1990, pp. 1289-1329). Unless any conventional carrier is incompatible with the active ingredient, it is contemplated for use in therapeutic or pharmaceutical compositions. For the purposes of the present disclosure, solvates and hydrates are considered to include pharmaceutical compositions of the compounds of the present disclosure and the solvent (i.e., solvate) or water (i.e., hydrate).

[0362] Formulations can be prepared using conventional dissolution and mixing procedures. For example, the bulk active ingredient (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 excipients described above. The compounds of the present disclosure are generally formulated into pharmaceutical dosage forms to provide a readily controllable drug dose and to give the patient an aesthetically pleasing and readily disposable product.

[0363] The pharmaceutical composition (or formulation) for administration can be packaged in a variety of ways depending on the method of administration of the drug. Generally, the dispensing article includes a container having disposed therein a pharmaceutical formulation in a suitable 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 tamper-resistant fittings to prevent inadvertent contact with the contents of the package. Additionally, a label describing the contents of the container is placed on the container. The label may also include appropriate warnings.

[0364] Pharmaceutical compositions comprising the compounds of the present disclosure are generally formulated for parenteral or oral administration or alternatively as suppositories.

[0365] For example, the oral pharmaceutical compositions of the present disclosure can be prepared in solid form (including but not limited to capsules, tablets, pills, granules, powders or suppositories) or in 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, emulsifying agents and buffers, etc.).

[0366] Typically, the pharmaceutical composition is a tablet or a gelatin capsule, which comprises an active ingredient and

[0367] a) a diluent, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[0368] b) a lubricant, such as silica, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; for tablets, it also includes

[0369] c) a binder, such as aluminum magnesium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if desired, it includes

[0370] d) a disintegrant, such as starch, agar, alginic acid or its sodium salt or an effervescent mixture; and / or

[0371] e) absorbents, colorants, flavoring agents and sweetening agents.

[0372] Tablets can be film-coated or enteric-coated by methods known in the art.

[0373] Suitable compositions for oral administration comprise 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 are prepared by any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preservatives in order to provide a pharmaceutically elegant and palatable preparation. Tablets may contain a mixture of the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients are, 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 gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a longer period of sustained action. For example, delayed-release materials such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may 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 a water or oil medium such as peanut oil, liquid paraffin or olive oil.

[0374] The parenteral composition (e.g., intravenous (IV) formulation) is an aqueous isotonic solution or suspension. The parenteral composition may be sterilized and / or contain adjuvants such as preservatives, stabilizers, wetting agents or emulsifying agents, solubilizing agents, salts and / or buffers that regulate osmotic pressure. Additionally, it may also contain other therapeutically valuable substances. The compositions are generally prepared respectively according to conventional mixing, granulating or coating methods and contain from about 0.1% to 75% or contain from about 1% to 50% of the active ingredient.

[0375] The disclosed compounds or their pharmaceutical compositions for a subject (e.g., a human) are generally administered orally or parenterally in a therapeutic dose. When administered intravenously via infusion, the dose may depend on the infusion rate of the IV formulation. Generally, the therapeutically effective dose of the compound, pharmaceutical composition or their combination depends on the species, body weight, age and condition of the subject, the disorder or disease being treated or its severity. A physician, pharmacist, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient required to prevent, treat or inhibit the progression of a disorder or disease.

[0376] The dose properties listed above can be advantageously confirmed in in vitro and in vivo tests using mammals (e.g., mice, rats, dogs, monkeys or their isolated organs, tissues and preparations). The disclosed compounds can be applied in vitro in the form of a solution (e.g., an aqueous solution), and in vivo in an enteral, parenteral, advantageously intravenous manner, for example as a suspension or an aqueous solution. The in vitro dose can be in the range between about 10 -3 moles and 10 -9 molar concentration.

[0377] Definitions

[0378] As used herein, "patient", "subject" or "individual" are used interchangeably and refer to a human or non-human animal. The term includes mammals such as humans. Generally, the animal is a mammal. The subject also refers to, for example, a primate (e.g., a human, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In some embodiments, the subject is a human.

[0379] As used herein, the terms "inhibit", "inhibition" or "inhibiting" mean to reduce or suppress a given condition, symptom or disorder or disease, or to significantly reduce the baseline activity of a biological activity or process.

[0380] As used herein, the terms "treat", "treating", or "treatment" with respect to any disease, disorder, or condition refer to the management and care of a patient for the purpose of combating the disease, disorder, or condition, and includes the administration of a compound of the disclosure to obtain the desired pharmacological and / or physiological effect. The effect can be therapeutic, which includes partially or substantially achieving one or more of the following results: partially or completely reducing the severity of the disease, disorder, or condition; improving or ameliorating the clinical symptoms, complications, or markers associated with the disease, disorder, or condition; or delaying, inhibiting the progression of, or reducing the likelihood of progression of the disease, disorder, or condition; or eliminating the disease, disorder, or condition. In certain embodiments, the effect can be preventing the onset of symptoms or complications of the disease, disorder, or condition.

[0381] As used herein, the term "cancer" has its generally accepted meaning in the art. The term can broadly refer to abnormal cell growth.

[0382] As used herein, a subject "needs" treatment if the subject would benefit, in terms of biology, medicine, or quality of life (in some embodiments a human), from the treatment.

[0383] As used herein, the phrase "optionally substituted" can be used interchangeably with the phrase "substituted or unsubstituted". In general, the term "optionally substituted" means replacement of a hydrogen group in a given structure with a specified substituent group. Specific substituents are described in the definitions and in the description of the compounds and examples thereof. Unless otherwise indicated, an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from the specified groups, the substituents at each position can be the same or different. In some embodiments, the "one or more" substituents can be 1, 2, 3, 4, 5, 6... substituents, each of which can be the same or different. In some embodiments, the "one or more" substituents can be 1 to 6, 1 to 4, 1 to 3, or 1 to 2 substituents, each of which can be the same or different.

[0384] As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. The term "C 1-4 alkyl" refers to an alkyl having 1 to 4 carbon atoms. The terms "C 1-3 alkyl" and "C 1-2 alkyl" should be interpreted accordingly. "C 1-4Representative examples of “alkyl” include (but are not limited to) methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. Similarly, the alkyl moiety of an alkoxy group (i.e., the alkyl portion) has the same definition as above. When indicated as “optionally substituted”, the alkane group or alkyl moiety may be unsubstituted or substituted with one or more substituents (generally, one to three substituents, except in the case of halogen substituents such as perchloro or perfluoroalkyl).

[0385] As used herein, the term “alkoxy” refers to a fully saturated branched or unbranched alkyl moiety linked via an oxygen bridge (i.e., --O--C 1-4 alkyl, where C 1-4 alkyl is as defined herein). Representative examples of alkoxy groups include (but are not limited to) methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, and the like. In some embodiments, the alkoxy group has 1 to 6 carbons, 1 to 4 carbons, or 1 to 3 carbons, and in some embodiments has about 1 to 2 carbons. The term “C 1-2 alkoxy” shall be interpreted accordingly.

[0386] The number of carbon atoms in a group is designated 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.

[0387] “Halogen” or “halo” may be fluorine, chlorine, bromine, or iodine.

[0388] As used herein, the term “haloalkyl” refers to an alkyl group as defined herein, wherein at least one hydrogen atom is replaced by a halogen atom. The term “C 1-6 haloalkyl” refers to a haloalkyl group having 1 to 6 carbon atoms. The terms “C 1-4 haloalkyl” and “C 1-3 haloalkyl” shall be interpreted accordingly. The haloalkyl group may be a monohaloalkyl, dihaloalkyl, or polyhaloalkyl, including perhaloalkyl. The monohaloalkyl may have one iodine, bromine, chlorine, or fluorine within the alkyl group. The dihaloalkyl and polyhaloalkyl may have two or more identical halogen atoms or a combination of different halogen atoms within the alkyl group. Generally, the polyhaloalkyl contains 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 halogen atoms. Non-limiting examples of C 1-6 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 are replaced by halogen atoms.

[0389] As used herein, the term "haloalkoxy" means an alkoxy as defined herein, wherein at least one hydrogen atom on the alkyl portion is replaced by a halogen atom. The term "C 1-6 haloalkoxy" means a haloalkoxy having 1 to 6 carbon atoms. The terms "C 1-4 haloalkoxy" and "C 1-3 haloalkoxy" shall be interpreted accordingly. A haloalkoxy can be a mono-haloalkoxy, di-haloalkoxy or poly-haloalkoxy, including a perhaloalkyl group. A mono-haloalkoxy can have one iodine, bromine, chlorine or fluorine within the alkyl portion of the alkoxy. A di-haloalkoxy and poly-haloalkoxy can have two or more of the same halogen atoms or a combination of different halogens within the alkyl portion of the alkoxy. Generally, a poly-haloalkoxy contains 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 halogen atoms. Non-limiting examples of C 1-6 haloalkoxys include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, pentafluoroethoxy, heptafluoropropoxy, difluorochloromethoxy, dichlorofluoromethoxy, difluoroethoxy, difluoropropoxy, dichloroethoxy and dichloropropoxy.

[0390] The term "aryl" means an aromatic carbocyclic monocyclic or two fused ring systems containing 6 to 10 carbon atoms. Examples include phenyl and naphthyl.

[0391] The term "heteroaryl" refers to a 5- to 12-membered aromatic group containing 1 to 4 heteroatoms selected from N, O, and S. In some cases, the nitrogen atom in the heteroaryl may be quaternized. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic". The heteroaryl may be monocyclic or bicyclic. Monocyclic heteroaryls include, for example, pyrrolyl, furyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxolenyl, dithiinyl, oxathiolanyl, 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. The term "6,5-bicyclic heteroaryl" refers to a bicyclic heteroaryl in which one ring is a 5-membered ring and the other ring is a 6-membered ring. For example, "6,5-bicyclic heteroaryl" is a benzene ring fused to a 5-membered heteroaryl or a 6-membered heteroaryl fused to a 5-membered heteroaryl. In some embodiments, the "6,5-bicyclic heteroaryl" is attached to group Z via the 6-membered heteroaryl or benzene ring. In other embodiments, the "6,5-bicyclic heteroaryl" is attached to group Z via the 5-membered heteroaryl.

[0392] The term "carbocyclic" or "carbocyclic group" refers to a 4- to 12-membered saturated or partially unsaturated hydrocarbon ring, and may exist as a monocyclic, bicyclic (including fused, spiro, or bridged carbocycles), or spiro ring. Bicyclic carbocyclic groups include, for example, unsaturated carbocyclic groups fused to another unsaturated carbocyclic group, cycloalkyl, or aryl (such as cyclohexyl, cyclohexenyl, 2,3-dihydroindenyl, indanyl, decahydronaphthyl, and 1,2,3,4-tetrahydronaphthyl). Unless otherwise specified, carbocycles generally contain 4 to 10 ring members.

[0393] The term "C 3-6 cycloalkyl" refers to a fully saturated carbocyclic ring (such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).

[0394] The term "heterocycle" or "heterocyclic group" refers to a 4- to 12-membered saturated or partially unsaturated heterocycle containing 1 to 4 heteroatoms independently selected from N, O, and S. The heterocyclic group can be monocyclic or bicyclic (e.g., bridged, fused, or spiro bicyclic). Examples of monocyclic saturated or partially unsaturated heterocyclic groups include, but are not limited to, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, and pyrrolidinyl. Bicyclic heterocyclic groups include, for example, unsaturated heterocyclic groups fused to another unsaturated heterocyclic group, cycloalkyl, aryl, or heteroaryl ring (such as indolinyl, 2,3-dihydro-1H-pyrrolo[3,2-b]pyridinyl, 6,7-dihydro-5H-pyrrolo[2,3-c]pyrazinyl, 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]thienyl, and 4,7-dihydro-5H-thieno[2,3-c]pyranyl). In some embodiments, the heterocyclic group is a 4- to 6-membered monocyclic heterocyclic group. In some embodiments, the heterocyclic group is an 8- to 10-membered bicyclic heterocyclic group.

[0395] As used herein, the term "spiro" ring means a bicyclic system in which two rings share a common atom. Examples of spiro rings include 5-oxaspiro[2.3]hexane, oxaspiro[2.4]heptyl, 5-oxaspiro[2.4]heptyl, 4-oxaspiro[2.4]heptane, 4-oxaspiro[2.5]octyl, 6-oxaspiro[2.5]octyl, oxaspiro[2.5]octyl, oxaspiro[3.4]octyl, oxaspiro[bicyclo[2.1.1]hexane-2,3'-oxetane]-1-yl, oxaspiro[bicyclo[3.2.0]heptane-6,1'-cyclobutane]-7-yl, 2,6-diazaspiro[3.3]heptyl, -oxa-6-azaspiro[3.3]heptane, 2,2,6-diazaspiro[3.3]heptane, 3-azaspiro[5.5]undecyl, 3,9-diazaspiro[5.5]undecyl, 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]undecyl, 3,9-diazaspiro[5.5]undecyl, and the like.

[0396] The term "fused" ring means a bicyclic system that shares two adjacent ring atoms. At least one ring system of the fused heterocycle contains ring atoms selected from O, N, and S heteroatoms (such as 3-oxabicyclo[3.1.0]hexane).

[0397] As used herein, the term "bridged" refers to a 5- to 10-membered cyclic moiety (such as bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptane, and bicyclo[3.2.1]octane) that is connected at two non-adjacent ring atoms.

[0398] The phrase "pharmaceutically acceptable" indicates that a substance, composition, or dosage form must be chemically and / or toxicologically compatible with the other ingredients that make up the formulation and / or the mammal being treated therewith.

[0399] Unless otherwise specified, the term "compounds of the present disclosure" refers to compounds of formula (I), as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, isotopically labeled compounds (including deuterium substitutions). When moieties capable of forming salts are present, salts, particularly pharmaceutically acceptable salts, are also included.

[0400] Unless otherwise indicated herein or the context clearly dictates otherwise, as used herein, the terms "a", "an", "the", and similar terms in the context of the present disclosure (especially in the context of the claims) are to be construed to cover both the singular and the plural. The use of any and all examples or exemplary language (such as "such as") provided herein is merely intended to better illustrate the present disclosure and is not to be construed as limiting the scope of the present disclosure otherwise claimed.

[0401] The intermediates and compounds of the present disclosure may also exist in different tautomeric forms, and all such forms are embraced 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, prototropic tautomers (also known as protonotropic tautomers) involve interconversion via proton migration, such as keto-enol and imine-enamine isomerization. Specific examples of prototropic tautomers are imidazole moieties, where the proton can migrate between two ring nitrogens. Valence tautomers involve interconversion due to the reorganization of some bonding electrons.

[0402] In one embodiment, the present disclosure relates to a compound of formula (I) in free form as defined herein. In another embodiment, the present disclosure relates to a compound of formula (I) in salt form as defined herein. In another embodiment, the present disclosure relates to a compound of formula (I) in acid addition salt form as defined herein. In another embodiment, the present disclosure relates to a compound of formula (I) in pharmaceutically acceptable salt form as defined herein. In another embodiment, the present disclosure relates to a compound of formula (I) in pharmaceutically acceptable acid addition salt form as defined herein. In another embodiment, the present disclosure relates to any one of the exemplified compounds in free form. In another embodiment, the present disclosure relates to any one of the exemplified compounds in salt form. In another embodiment, the present disclosure relates to any one of the exemplified compounds in acid addition salt form. In another embodiment, the present disclosure relates to any one of the exemplified compounds in pharmaceutically acceptable salt form. In another embodiment, the present disclosure relates to any one of the exemplified compounds in pharmaceutically acceptable acid addition salt form.

[0403] The compounds of the present disclosure can be synthesized by synthetic routes that include processes similar to those well-known in chemical art, particularly in accordance with the instructions contained herein. Starting materials are generally commercially available, such as from Sigma-Aldrich, or can be readily prepared using methods well-known to those skilled in the art (e.g., prepared by the methods outlined in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, 1st - 19th Edition, Wiley, New York (1967 - 1999), or Beilsteins Handbuch der organischen Chemie, 4th Aufl., edited by Springer-Verlag, Berlin, including supplementary materials (also available via the Beilstein online database)).

[0404] For illustrative purposes, the reaction schemes shown below provide potential routes for synthesizing the compounds of the present disclosure and key intermediates. For a more detailed description of individual reaction steps, see the Examples section below. Although specific starting materials and reagents are shown in the schemes and discussed below, other starting materials and reagents can be readily substituted to provide various derivatives and / or reaction conditions.

[0405] Illustrative

[0406] Abbreviations:

[0407] BAST = bis(2-methoxyethyl)aminosulfur trifluoride

[0408] BID = twice a day

[0409] BINAP = (2,2'-Bis(diphenylphosphino)-1,1'-binaphthalene)

[0410] Bn = Benzyl

[0411] BnBr = Benzyl bromide

[0412] Boc = tert-Butyloxycarbonyl

[0413] Boc2O = Di-tert-butyl dicarbonate

[0414] BSA = Bovine serum albumin

[0415] CFU-MK = Colony-forming unit-megakaryocyte

[0416] CH2I2 = Diiodomethane

[0417] Cs2CO3 = Cesium carbonate

[0418] DCM = Dichloromethane

[0419] DMF = N,N-Dimethylformamide

[0420] DIPEA = DIEA = Diisopropylethylamine

[0421] DMEM = Dulbecco's Modified Eagle Medium

[0422] DMP = Dess-Martin periodinane

[0423] DMSO = Dimethyl sulfoxide

[0424] EDTA = Ethylenediaminetetraacetic acid

[0425] ESI = Electrospray ionization

[0426] Et = Ethyl

[0427] Et2Zn = Diethylzinc

[0428] Et3N = Triethylamine

[0429] EtOAc = EA = Ethyl acetate

[0430] EtOH = Ethanol

[0431] FA = Formic acid

[0432] FBS = Fetal bovine serum

[0433] H2 = Hydrogen

[0434] H2O = water

[0435] HBSS = Hanks' Balanced Salt Solution

[0436] HEPES = (4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid)

[0437] HPLC = High Performance Liquid Chromatography

[0438] IMDM = Iscove's Modified Dulbecco's Medium

[0439] K2CO3 = Potassium carbonate

[0440] K3PO4 = Potassium phosphate

[0441] LCMS = Liquid Chromatography Mass Spectrometry

[0442] LiBH4 = Lithium borohydride

[0443] LiHMDS = Lithium bis(trimethylsilyl)amide

[0444] MeOH = Methanol

[0445] MeCN = ACN = Acetonitrile

[0446] N2 = Nitrogen

[0447] Na2SO3 = Sodium sulfite

[0448] Na2SO4 = Sodium sulfate

[0449] NaI = Sodium iodide

[0450] NaOH = Sodium hydroxide

[0451] NH4Cl = Ammonium chloride

[0452] NH4OH = Ammonium hydroxide

[0453] NMP = N-Methylpyrrolidone

[0454] NMI = 1-Methylimidazole

[0455] Pd / C = Palladium on carbon

[0456] Pd(OH)2 = Palladium(II) hydroxide

[0457] Pd2(dba)3 = Tris(dibenzylideneacetone)dipalladium(0)

[0458] PE = Petroleum ether

[0459] QD = Once a day

[0460] QOD = Every other day

[0461] SFC = Supercritical fluid chromatography

[0462] SOCl2 = Thionyl chloride

[0463] t-BuXPhos Pd G3 = Palladium(II) [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)] methanesulfonate

[0464] TBAI = Tetra-n-butylammonium iodide

[0465] TCFH = N'-Tetramethylformamidinium hexafluorophosphate

[0466] TFA = Trifluoroacetic acid

[0467] THF = Tetrahydrofuran

[0468] TMS = Trimethylsilyl

[0469] TMS-CHN2 = Trimethylsilyldiazomethane

[0470] TMSCF3 = Trimethyl(trifluoromethyl)silane

[0471] Xantphos = 4,5-Bis(diphenylphosphino)-9,9-dimethyldibenzopyran

[0472] General method

[0473] 1. 1 1H NMR spectra were recorded on:

[0474] NMR10 Bruker AVANCEⅢHD 300 MHz

[0475] NMR16 Bruker AVANCEⅢHD 300 MHz

[0476] NMR19 Bruker AVANCEⅢHD 400 MHz

[0477] NMR24 Bruker AVANCE NEO 400 MHz

[0478] NMR30 Bruker AVANCE NEO 400 MHz

[0479] 2. LCMS measurements were run on a SHIMADZU LCMS-2020 under the following conditions:

[0480] Method A: Mobile phase: A: water (0.05% TFA), B: acetonitrile (0.05% TFA); Gradient phase: 5% B to 100% B in 2.0 min, 100% B for 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. Detector: AD2 ELSD, PDA (220 nm and 254 nm), ESI.

[0481] Method B: Mobile phase: A: water (0.1% FA), B: acetonitrile (0.1% FA); Gradient phase: 5% B to 100% B in 2.0 min, 100% B for 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. Detector: AD2 ELSD, PDA (220 nm and 254 nm), ESI.

[0482] Method C: Mobile phase: A: water (5 mM NH4HCO3), B: acetonitrile; Gradient phase: 10% B to 95% B in 2.0 min, 100% B for 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. Detector: AD2 ELSD, PDA (220 nm and 254 nm), ESI.

[0483] Unless otherwise indicated, the observed molecular ions for all compounds listed below relate to [M + H]. + 。

[0484] Synthesis of common intermediate I: Methyl 2-(4,4-dimethyl-1,4-azasilinane-1-yl)-4-nitrobenzoate

[0485]

[0486] 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 (2 N in H2O), and then extracted with EA (200 mL × 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: MSESI (M+1) + = 309.2. 1 H NMR (400 MHz, chloroform-d) δ = 7.86 (d, J = 1.5 Hz, 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).

[0487] Common Intermediate II: 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]hept-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]hept-3-yl)-4-nitrobenzamide

[0488]

[0489] Step 1: Preparation of 2,6-difluoro-4-nitrobenzoyl chloride

[0490]

[0491] To a solution of 2,6-difluoro-4-nitrobenzoic acid (500 mg, 2.46 mmol) in DCM (10 mL) at 0 °C was added SOCl2 (1.56 g, 12.3 mmol). The reaction mixture was then stirred at room temperature for 2 h. The mixture was then concentrated in vacuo to give 2,6-difluoro-4-nitrobenzoyl chloride (500 mg, 2.25 mmol) as a colorless solid.

[0492] Step 2: Preparation of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2,6-difluoro-4-nitrobenzamide

[0493]

[0494] To a solution of 2,6-difluoro-4-nitrobenzoyl chloride (500 mg, 2.19 mmol) and Et3N (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 h. The mixture was then diluted with H2O (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 K2CO3 (500 mg) was added. The mixture was stirred at room temperature for 2 h. The mixture was then 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.

[0495] 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]hept-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]hept-3-yl)-4-nitrobenzamide

[0496]

[0497] 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 H2O (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]hept-3-yl)-4-nitrobenzamide (300 mg, 0.59 mmol) as a yellow solid. Chiral SFC separation of the racemate (CO2-EtOH (0.1% NH3H2O) gave the first elution peak (120 mg, 0.24 mmol) assigned arbitrarily as N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-6-((1S,6S)-6-methyl-3-azabicyclo[4.1.0]hept-3-yl)-4-nitrobenzamide, LCMS:MS ESI(M+1) + 505.4, and the second elution peak (110 mg, 0.22 mmol) assigned arbitrarily as N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-6-((1R,6R)-6-methyl-3-azabicyclo[4.1.0]hept-3-yl)-4-nitrobenzamide as a yellow solid. First elution peak LCMS:MS ESI(M+1) + 505.4. Second elution peak LCMS:MS ESI(M+1) + 505.4.

[0498] Common intermediates IV and V: Synthesis of methyl 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-nitrobenzoate and methyl 2-((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-nitrobenzoate

[0499]

[0500] Step 1: Preparation of methyl 2-(6-(hydroxymethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-nitrobenzoate

[0501]

[0502] To a solution of methyl 2-fluoro-4-nitrobenzoate (40.0 g, 200 mmol) and (3-azabicyclo[4.1.0]hept-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]hept-3-yl)-4-nitrobenzoate (45.0 g, 146 mmol) as a yellow oil. LCMS: MS ESI (M+1) + 307.0。

[0503] Step 2: Preparation of methyl 2-(6-formyl-3-azabicyclo[4.1.0]hept-3-yl)-4-nitrobenzoate

[0504]

[0505] To a solution of methyl 2-(6-(hydroxymethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-nitrobenzoate (45.0 g, 146 mmol) in DCM (450 mL) at 0 °C was added Dess-Martin periodinane (123 g, 292 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was poured into saturated aqueous Na2SO3 (1500 mL), and extracted with EtOAc (3 × 800 mL). The combined organic extracts were washed with brine (1000 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-formyl-3-azabicyclo[4.1.0]hept-3-yl)-4-nitrobenzoate (35.0 g, 115 mmol) as a yellow solid. LCMS: MS ESI (M+1) + 305.2。

[0506] Step 3: Preparation of methyl 2-(6-(difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-nitrobenzoate

[0507]

[0508] To a solution of methyl 2-(6-formyl-3-azabicyclo[4.1.0]hept-3-yl)-4-nitrobenzoate (35.0 g, 115 mmol) in DCM (350 mL) at 0 °C was added dropwise bis(2-methoxyethyl)aminosulfur trifluoride (50.8 g, 230 mmol). The mixture was warmed to room temperature and stirred for 12 h. 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]hept-3-yl)-4-nitrobenzoate (30.0 g, 91.9 mmol) as a yellow solid. LCMS: MSESI (M+1) + 327.1。

[0509] Step 4: Preparation of methyl 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-nitrobenzoate and methyl 2-((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-nitrobenzoate

[0510]

[0511] Methyl 2-(6-(difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-nitrobenzoate (30.0 g, 91.9 mmol) was separated by chiral SFC (AD column, (250 mm × 30 mm, 10 μm) CO2-EtOH (0.1% NH3H2O)) to give the first elution peak (7.20 g, 22.0 mmol) arbitrarily designated as methyl 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-nitrobenzoate and the second elution peak (6.70 g, 20.5 mmol) arbitrarily designated as methyl 2-((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-nitrobenzoate, both as yellow solids. The first elution peak 11H 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 elution peak 1 1H NMR (400 MHz, 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 = 11.8 Hz, 1H), 3.34 (dd, J = 4.2, 11.6 Hz, 1H), 3.10 (td, J = 4.2, 8.0 Hz, 1H), 2.83 (ddd, J = 5.0, 11.0, 12.6 Hz, 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, 9.2 Hz, 1H), 0.90 (q, J = 4.8 Hz, 1H).

[0512] Example 1: Synthesis of N-(2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinane-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide

[0513]

[0514] Step 1: Preparation of 2-(4,4-difluorocyclohex-1-en-1-yl)-6-methylpyrimidin-4-amine

[0515]

[0516] 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 H2O (2 mL) at 20 °C was added potassium dihydrogen phosphate (1.32 g, 6.24 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (169 mg, 208 μmol). The mixture was stirred at 100 °C for 16 h. Then the mixture was poured into H2O (50 mL), and 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 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。

[0517] Step 2: Preparation of 2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine

[0518]

[0519] To a solution of 2-(4,4-difluorocyclohex-1-en-1-yl)-6-methylpyrimidin-4-amine (130 mg, 577 μmol) in EtOH (3 mL) at 25 °C was added Pd / C (60 mg, 10% w / w). The mixture was stirred at 25 °C for 16 h under H2 atmosphere (15 psi). 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 grey solid. LCMS: MS ESI (M+1) + 228.2。

[0520] Step 3: Preparation of N-(2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinane-1-yl)-4-nitrobenzamide

[0521]

[0522] At 25 °C, to a solution of 2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine (100 mg, 440 μmol) and methyl 2-(4,4-dimethyl-1,4-azasilinane-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). The mixture was stirred at 25 °C for 1 h. The mixture was poured into H2O (20 mL), followed by extraction 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 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-azasilinane-1-yl)-4-nitrobenzamide as a yellow solid (130 mg, 258 μmol). LCMS: MSESI (M+1) + 504.2

[0523] Step 4: Preparation of 4-amino-N-(2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinane-1-yl)benzamide

[0524]

[0525] At 25 °C, to a solution of N-(2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilinane-1-yl)-4-nitrobenzamide (130 mg, 258 μmol) in THF (4 mL) was added Pd / C (100 mg, 10% w / w). The mixture was stirred at 25 °C under H2 atmosphere (15 psi) for 4 h. 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-azasilinane-1-yl)benzamide as a white solid (110 mg, 232 μmol). LCMS: MS ESI (M+1) + 474.4

[0526] Step 5: Preparation of ethyl 2-(N-(4-((2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-yl)carbamoyl)-3-(4,4-dimethyl-1,4-azasilinane-1-yl)phenyl)sulfamoyl)acetate

[0527]

[0528] At 0 °C, ethyl 2-(chlorosulfonyl)acetate (129 mg, 696 μmol) was added 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). The mixture was stirred at 25 °C for 4 h. The mixture was poured into H2O (50 mL) and 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 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。

[0529] 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)sulfamoyl)benzamide

[0530]

[0531] At 0 °C, lithium borohydride (0.168 mL, 336 μmol, 2 M in THF) was added to a solution of ethyl 2-(N-(4-((2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-yl)carbamoyl)-3-(4,4-dimethyl-1,4-azasilinane-1-yl)phenyl)sulfamoyl)acetate (140 mg, 224 μmol) in THF (4 mL). The mixture was stirred at 0 °C for 0.5 h. The reaction mixture was poured into saturated aqueous NH4Cl solution (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-azasilinane-1-yl)-4-((2-hydroxyethyl)sulfamoylamino)benzamide (57.25 mg, 98.4 μmol) as a white solid. LCMS: MS ESI (M+1) + 582.3 1 H NMR (400 MHz, DMSO-d6) δ = 13.17 (s, 1H), 10.06 (s, 1H), 7.99 - 7.75 (m, 2H), 7.10 (d, J = 2.0 Hz, 1H), 6.96 (dd, J = 2.0, 8.7 Hz, 1H), 3.56 (br s, 2H), 3.18 (t, J = 6.4 Hz, 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).

[0532] Example 2: Synthesis of 2-(4,4-dimethyl-1,4-azasilinane-1-yl)-4-((2-hydroxyethyl)sulfamoylamino)-N-(5-methyl-6-morpholinopyridin-2-yl)benzamide

[0533]

[0534] Step 1: Preparation of 5-methyl-6-morpholinopyridin-2-amine

[0535]

[0536] 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 for 16 h under a N2 atmosphere. 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 (400 MHz, chloroform-d) δ = 7.19 (d, J = 8.0 Hz, 1H), 6.12 (d, J = 8.0 Hz, 1H), 4.23 - 4.06 (m, 2H), 3.87 - 3.77 (m, 4H), 3.18 - 3.06 (m, 4H), 2.15 (s, 3H).

[0537] Step 2: Preparation of 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-N-(5-methyl-6-morpholinopyridin-2-yl)-4-nitrobenzamide

[0538]

[0539] 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) at 0 °C was added LiHMDS (6.18 mL, 6.18 mmol, 1 M in THF), and the mixture was stirred at 25 °C for 0.5 h. The reaction mixture was quenched with saturated aqueous NH4Cl (30 mL) and then extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were dried over Na2SO4, 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 11H NMR (400 MHz, chloroform-d) δ = 12.16 (s, 1H), 8.40 (d, J = 8.8 Hz, 1H), 8.15 (d, J = 2.4 Hz, 1H), 8.06 (dd, J = 2.0, 8.6 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 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).

[0540] Step 3: Preparation of 4-Amino-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-N-(5-methyl-6-morpholinopyridin-2-yl)benzamide

[0541]

[0542] 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 then the mixture was stirred at 25 °C for 2 h under a H2 atmosphere (15 psi). 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.

[0543] 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

[0544]

[0545] At 0 °C, ethyl 2-(chlorosulfonyl)acetate (63.6 mg, 0.341 mmol) was added 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), and the mixture was stirred at 25 °C for 1 h. The reaction mixture was extracted with DCM (3 × 20 mL) and H2O (3 × 10 mL). The combined organic extracts were dried over Na2SO4, 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。

[0546] Step 5: Preparation of 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfamoyl)-N-(5-methyl-6-morpholinopyridin-2-yl)benzamide

[0547]

[0548] At 0 °C, LiBH4 (228 μL, 0.4575 mmol, 2 M in THF) was added 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), and then the mixture was stirred at 25 °C for 0.5 h. The reaction mixture was quenched with saturated aqueous NH4Cl (30 mL), and then extracted with ethyl acetate (2 × 20 mL). The combined organic extracts were dried over Na2SO4, 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)sulfamoyl)-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。 11H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 10.13 (s, 1H), 8.05 - 7.99 (m, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.09 (dd, J = 2.0, 8.6 Hz, 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).

[0549] Example 3: Synthesis of N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasila-cyclohexan-1-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide

[0550]

[0551] Step 1: Preparation of 2-(4,4-difluoropiperidin-1-yl)-6-nitropyridine

[0552]

[0553] At 25 °C, DIPEA (1.22 g, 9.45 mmol) was added 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). The mixture was stirred at 100 °C for 16 h. The mixture was poured into H2O (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 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.

[0554] Step 2: Preparation of 6-(4,4-difluoropiperidin-1-yl)pyridin-2-amine

[0555]

[0556] At 25 °C, ammonium chloride (328 mg, 6.15 mmol) and iron powder (686 mg, 12.3 mmol) were added to a solution of 2-(4,4-difluoropiperidin-1-yl)-6-nitropyridine (300 mg, 1.23 mmol) in EtOH (5 mL) and H2O (1 mL). 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 H2O (50 mL). The mixture was 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 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.

[0557] Step 3: Preparation of N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinane-1-yl)-4-nitrobenzamide

[0558]

[0559] At 25 °C, LiHMDS (3.2 mL, 3.21 mmol, 1 M in THF) was added 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-azasilinane-1-yl)-4-nitrobenzoate (329 mg, 1.07 mmol) in THF (4 mL). The mixture was stirred at 25 °C for 1 h. The mixture was poured into H2O (20 mL). The mixture was extracted with ethyl acetate (2 × 20 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 10:1) to give N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinane-1-yl)-4-nitrobenzamide (260 mg, 531 μmol) as a yellow solid. MS ESI (M+1) + 490.3.

[0560] Step 4: Preparation of 4-amino-N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinane-1-yl)benzamide

[0561]

[0562] To a solution of N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinane-1-yl)-4-nitrobenzamide (260 mg, 531 μmol) in THF (5 mL) at 25 °C was added Pd / C (130 mg, 531 μmol). The mixture was stirred at 25 °C for 16 h under a H2 atmosphere (15 psi). The mixture was filtered and the 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-azasilinane-1-yl)benzamide (220 mg, 478 μmol) as a white solid. LCMS: MS ESI (M+1) + = 460.3

[0563] Step 5: Preparation of ethyl 2-(N-(4-((6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)carbamoyl)-3-(4,4-dimethyl-1,4-azasilinane-1-yl)phenyl)sulfamoyl)acetate

[0564]

[0565] To a solution of 4-amino-N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinane-1-yl)benzamide (100 mg, 217 μmol) and pyridine (51.4 mg, 651 μmol) in DCM (3 mL) at 0 °C was added ethyl 2-(chlorosulfonyl)acetate (60.6 mg, 325 μmol). The mixture was stirred at 25 °C for 3 h. The mixture was poured into H2O (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 10:1) to give ethyl 2-(N-(4-((6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)carbamoyl)-3-(4,4-dimethyl-1,4-azasilinane-1-yl)phenyl)sulfamoyl)acetate (110 mg, 180 μmol) as a white solid. LCMS: MS ESI (M+1) + 610.4

[0566] Step 6: Preparation of N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinane-1-yl)-4-((2-hydroxyethyl)sulfamoyl)benzamide

[0567]

[0568] To a solution of ethyl 2-(N-(4-((6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)carbamoyl)-3-(4,4-dimethyl-1,4-azasila-cyclohexan-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-azasila-cyclohexan-1-yl)-4-((2-hydroxyethyl)sulfamoylamino)benzamide (35.66 mg, 62.8 μmol) as an off-white solid. LCMS: MS ESI (M+1) + 568.4。 1 H NMR (400 MHz, DMSO-d6) δ = 12.13 (s, 1H), 9.99 (s, 1H), 7.86 (brd, J = 8.6 Hz, 1H), 7.58 - 7.40 (m, 2H), 7.10 (s, 1H), 6.95 (br d, J = 8.5 Hz, 1H), 6.56 (d, J = 7.9 Hz, 1H), 3.61 (br t, J = 6.4 Hz, 2H), 3.54 (br d, J = 4.8 Hz, 4H), 3.29 - 3.16 (m, 2H), 3.09 - 2.93 (m, 4H), 1.91 - 1.77 (m, 4H), 0.87 (br d, J = 4.9 Hz, 4H), 0.00 (s, 6H).

[0569] Example 4: Synthesis of N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-2-(4,4-dimethyl-1,4-azasila-cyclohexan-1-yl)-4-((1,1-dimethylethyl)sulfamoylamino)benzamide

[0570]

[0571] Step 1: Preparation of N-(tert-butyl)-3-nitrobenzenesulfonamide

[0572]

[0573] 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), and then treated with 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 Na2SO4 and concentrated under reduced pressure. N-(tert-Butyl)-3-nitrobenzenesulfonamide (1.8 g, 6.96 mmol) was obtained as a pale yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ = 8.59 (t, J = 2.0 Hz, 1H), 8.44 (dd, J = 1.6, 8.0 Hz, 1H), 8.25 (d, J = 8.0 Hz, 1H), 7.97 - 7.82 (m, 2H), 1.11 (s, 9H).

[0574] Step 2: Preparation of 3-amino-N-(tert-butyl)benzenesulfonamide

[0575]

[0576] 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 filtered through a Celite pad, and the filter cake was washed with MeOH (20 mL). The combined filtrates were 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.

[0577] Step 3: Preparation of methyl 4-bromo-2-(4,4-dimethyl-1,4-azasilinan-1-yl)benzoate

[0578]

[0579] 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 1H 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).

[0580] Step 4: Preparation of methyl 2-(4,4-dimethyl-1,4-azasilinane-1-yl)-4-((1,1-dimethylethyl)sulfonylamino)benzoate

[0581]

[0582] To a solution of methyl 4-bromo-2-(4,4-dimethyl-1,4-azasilinane-1-yl)benzoate (450 mg, 1.31 mmol) in dioxane (5 mL) under N2 atmosphere was added 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). 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 Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA 20:1) to obtain methyl 2-(4,4-dimethyl-1,4-azasilinane-1-yl)-4-((1,1-dimethylethyl)sulfonylamino)benzoate (320 mg, 802 μmol) as a yellow solid.

[0583] Step 5: Preparation of 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((1,1-dimethylethyl)sulfonylamino)benzoic acid

[0584]

[0585] To a solution of methyl 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((1,1-dimethylethyl)sulfonylamino)benzoate (0.31 g, 0.777 mmol) in MeOH (5 mL), H2O (5 mL) and THF (5 mL) was added LiOH·H2O (97.7 mg, 2.33 mmol). The mixture was stirred at 55 °C for 15 h. The mixture was cooled to 25 °C, adjusted to pH 3 - 4 with 1N HCl, and extracted with ethyl acetate (2 × 30 mL). The combined organic extracts were washed with brine (2 × 15 mL), dried over Na2SO4, filtered and concentrated to give 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((1,1-dimethylethyl)sulfonylamino)benzoic acid (265 mg, 689 μmol) as a white solid. LCMS: MS ESI (M+1) + 385.1。

[0586] Step 6: Preparation of N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((1,1-dimethylethyl)sulfonylamino)benzamide

[0587]

[0588] To a solution of 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((1,1-dimethylethyl)sulfonylamino)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 Na2SO4, 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)sulfonylamino)benzamide (95.45 mg, 157 μmol) was obtained as a white solid. LCMS: MS ESI (M+1) + 595.4 1 H NMR (400 MHz, DMSO-d6) δ = 11.95 (s, 1H), 9.93 (s, 1H), 8.33 (s, 1H), 7.91 - 7.71 (m, 2H), 7.62 - 7.47 (m, 3H), 7.29 (d, J = 1.6 Hz, 1H), 7.08 (dd, J = 1.6, 8.8 Hz, 1H), 3.17 (br t, J = 5.6 Hz, 4H), 1.31 (s, 9H), 1.11 (s, 9H), 0.89 (br t, J = 5.6 Hz, 4H), 0.10 (s, 6H).

[0589] Example 5: Synthesis of 2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-((2-hydroxyethyl)sulfonylamino)-N-(4-methyl-6-morpholinopyridin-2-yl)benzamide

[0590]

[0591] Step 1: Preparation of tert-butyl (4-methyl-6-morpholinopyridin-2-yl)carbamate

[0592]

[0593] A solution of 4-(6-bromo-4-methylpyridin-2-yl)morpholine (300 mg, 1.16 mmol), tert-butyl carbamate (407 mg, 3.48 mmol), Pd2(dba)3 (106 mg, 116 μmol), Xantphos (134 mg, 232 μmol), and Cs2CO3 (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 H2O (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 3:1). tert-Butyl (4-methyl-6-morpholinopyridin-2-yl)carbamate (300 mg, 1.02 mmol) was obtained as a yellow oil.

[0594] Step 2: Preparation of 4-methyl-6-morpholinopyridin-2-amine

[0595]

[0596] HCl (2 mL, 4 M in dioxane) was added to a solution of tert-butyl (4-methyl-6-morpholinopyridin-2-yl)carbamate (250 mg, 852 μmol) in dioxane (2 mL). The solution was stirred at 25 °C for 1 h. 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.

[0597] Step 3: Preparation of 2-(4,4-dimethyl-1,4-azasilinane-1-yl)-N-(4-methyl-6-morpholinopyridin-2-yl)-4-nitrobenzamide

[0598]

[0599] 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 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

[0600] Step 4: Preparation of 4-amino-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-N-(4-methyl-6-morpholinopyridin-2-yl)benzamide

[0601]

[0602] 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 mixture was stirred at 25 °C under H2 atmosphere (15 psi) for 3 h. 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

[0603] 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

[0604]

[0605] At 0 °C, ethyl 2-(chlorosulfonyl)acetate (227 mg, 1.22 mmol) was added to a solution of 4-amino-2-(4,4-dimethyl-1,4-disilazanylcyclohexan-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). The reaction mixture 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 Na2SO4, filtered and concentrated under reduced pressure. Ethyl 2-(N-(3-(4,4-dimethyl-1,4-disilazanylcyclohexan-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

[0606] Step 6: Preparation of 2-(4,4-dimethyl-1,4-disilazanylcyclohexan-1-yl)-4-((2-hydroxyethyl)sulfamoyl)-N-(4-methyl-6-morpholinopyridin-2-yl)benzamide

[0607]

[0608] At 0 °C, LiBH4 (457 μL, 915 μmol, 2 M in THF) was added to a solution of ethyl 2-(N-(3-(4,4-dimethyl-1,4-disilazanylcyclohexan-1-yl)-4-((4-methyl-6-morpholinopyridin-2-yl)carbamoyl)phenyl)sulfamoyl)acetate (180 mg, 186 μmol) in THF (4 mL). The reaction mixture was stirred at 25 °C for 1 h. The mixture was poured into saturated aqueous NH4Cl solution (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). 2-(4,4-dimethyl-1,4-disilazanylcyclohexan-1-yl)-4-((2-hydroxyethyl)sulfamoyl)-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 11H NMR (400 MHz, DMSO-d6) δ = 12.19 (s, 1H), 10.13 (s, 1H), 7.99 (d, J = 8.6 Hz, 1H), 7.53 (s, 1H), 7.22 (d, J = 1.6 Hz, 1H), 7.08 (dd, J = 1.9, 8.6 Hz, 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).

[0609] Example 6: Synthesis of N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4,4-dimethyl-1,4-azasila-cyclohexan-1-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide

[0610]

[0611] Step 1: Preparation of 4,4-difluoro-1-(3-nitrophenyl)piperidine

[0612]

[0613] 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 Pd2(dba)3 (112 mg, 123 μmol). The mixture was stirred at 100 °C for 12 h. The reaction mixture was poured into saturated aqueous NH4Cl solution (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). 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 1H NMR (400 MHz, DMSO-d6) δ = 7.75 - 7.71 (m, 1H), 7.60 (td, J = 2.3, 6.5 Hz, 1H), 7.52 - 7.45 (m, 2H), 3.52 - 3.44 (m, 4H), 2.11 - 2.01 (m, 4H).

[0614] Step 2: Preparation of 3-(4,4-difluoropiperidin-1-yl)aniline

[0615]

[0616] 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 at 25 °C for 2 h under a H2 atmosphere (15 psi). 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。

[0617] Step 3: Preparation of N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4,4-dimethyl-1,4-azasilinane-1-yl)-4-nitrobenzamide

[0618]

[0619] To a solution of 3-(4,4-difluoropiperidin-1-yl)aniline (100 mg, 471 μmol) and methyl 2-(4,4-dimethyl-1,4-azasilinane-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-azasilinane-1-yl)-4-nitrobenzamide (80 mg, 163 μmol) was obtained as a yellow solid. LCMS: MS ESI (M+1) + 489.3。 1 H NMR (400 MHz, DMSO-d6) δ = 10.90 (s, 1H), 7.93 (d, J = 2.3 Hz, 1H), 7.90 - 7.85 (m, 1H), 7.83 - 7.78 (m, 1H), 7.45 (d, J = 1.9 Hz, 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).

[0620] Step 4: Preparation of 4-amino-N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4,4-dimethyl-1,4-azasila-cyclohexan-1-yl)benzamide

[0621]

[0622] To a solution of N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4,4-dimethyl-1,4-azasila-cyclohexan-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 at 25 °C for 2 h under a H2 atmosphere (15 psi). 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-azasila-cyclohexan-1-yl)benzamide (60 mg, 130 μmol) was obtained as a yellow solid.

[0623] Step 5: Preparation of ethyl 2-(N-(4-((3-(4,4-difluoropiperidin-1-yl)phenyl)carbamoyl)-3-(4,4-dimethyl-1,4-azasila-cyclohexan-1-yl)phenyl)sulfamoyl)acetate

[0624]

[0625] To a solution of 4-amino-N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4,4-dimethyl-1,4-azasila-cyclohexan-1-yl)benzamide (60 mg, 130 μmol) and pyridine (31.2 μL, 389 μmol) in DCM (2 mL) at 0 °C was added ethyl 2-(chlorosulfonyl)acetate (28.9 mg, 155 μmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into saturated aqueous NH4Cl solution (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-azasila-cyclohexan-1-yl)phenyl)sulfamoyl)acetate (72 mg, 120 μmol) was obtained as a yellow oil. LCMS: MS ESI (M+1) + 609.2.

[0626] Step 6: Preparation of N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4,4-dimethyl-1,4-azasila-cyclohexan-1-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide

[0627]

[0628] To a solution of ethyl 2-(N-(4-((3-(4,4-difluoropiperidin-1-yl)phenyl)carbamoyl)-3-(4,4-dimethyl-1,4-azasila-cyclohexan-1-yl)phenyl)sulfamoyl)acetate (75 mg, 123 μmol) in THF (2 mL) at 0 °C was added LiBH4 (122 μL, 245 μmol, 2 M in THF). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was poured into saturated aqueous NH4Cl solution (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 preparative HPLC (FA conditions). N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4,4-dimethyl-1,4-azasila-cyclohexan-1-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide (33.94 mg, 59.8 μmol) was obtained as an off-white solid. LCMS: MS ESI (M+1) + 567.2 1 1H NMR (400 MHz, DMSO-d6) δ = 11.75 (s, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.50 (s, 1H), 7.25 - 7.17 (m, 1H), 7.14 - 7.08 (m, 2H), 7.00 (dd, J = 2.0, 8.6 Hz, 1H), 6.74 (dd, J = 2.0, 8.2 Hz, 1H), 3.74 (t, J = 6.6 Hz, 2H), 3.32 (br d, J = 1.8 Hz, 6H), 3.17 (br t, J = 6.1 Hz, 4H), 2.15 - 1.97 (m, 4H), 0.92 (br t, J = 6.1 Hz, 4H), 0.10 (s, 6H).

[0629] Example 7: Synthesis of N-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-2-(4,4-dimethyl-1,4-azasila-cyclohexan-1-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide

[0630]

[0631] Step 1: Preparation of 2-(4,4-difluoropiperidin-1-yl)-4-nitropyridine

[0632]

[0633] 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 h. The reaction mixture was poured into saturated aqueous NH4Cl solution (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 (400 MHz, DMSO-d6) δ = 7.96 (d, J = 6.0 Hz, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.92 (dd, J = 2.4, 6.1 Hz, 1H), 3.61 - 3.50 (m, 4H), 2.09 - 1.89 (m, 4H).

[0634] Step 2: Preparation of 2-(4,4-difluoropiperidin-1-yl)pyridin-4-amine

[0635]

[0636] 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 at 25 °C under H2 (15 psi) for 2 h. 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.

[0637] Step 3: Preparation of N-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-2-(4,4-dimethyl-1,4-azasilinane-1-yl)-4-nitrobenzamide

[0638]

[0639] 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 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) to give N-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-2-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-nitrobenzamide as a yellow solid (220 mg, 449 μmol). LCMS: MS ESI (M+1) + 490.3

[0640] 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

[0641]

[0642] 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 at 25 °C under H2 atmosphere (15 psi) for 2 h. 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 was obtained as a yellow solid (93 mg, 202 μmol). LCMS: MS ESI (M+1) + 460.4

[0643] 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

[0644]

[0645] 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) at 0 °C was added ethyl 2-(chlorosulfonyl)acetate (48.8 mg, 262 μmol). 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 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

[0646] 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)sulfamoyl)benzamide

[0647]

[0648] 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) at 0 °C was added lithium borohydride (163 μL, 326 μmol, 2 M in THF). 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)sulfamoyl)benzamide (32.93 mg, 58.0 μmol) as a white solid. LCMS: MS ESI (M+1) + 568.4 11H NMR (400 MHz, DMSO-d6) δ = 11.92 (s, 1H), 10.15 (s, 1H), 8.08 (d, J = 6.5 Hz, 1H), 7.79 - 7.68 (m, 2H), 7.12 (d, J = 1.6 Hz, 1H), 7.03 - 6.95 (m, 2H), 3.75 (br t, J = 6.5 Hz, 6H), 3.36 - 3.32 (m, 2H), 3.19 (br t, J = 5.9 Hz, 4H), 2.21 - 2.08 (m, 4H), 0.88 (br t, J = 5.8 Hz, 4H), 0.09 (s, 6H).

[0649] Example 8: Synthesis of N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-2-(4,4-dimethyl-1,4-azasilinane-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide

[0650]

[0651] Step 1: Preparation of 2-bromo-6-(4,4-difluoropiperidin-1-yl)-4-methylpyridine

[0652]

[0653] 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 DMSO (5 mL) was added DIPEA (1.36 mL, 7.89 mmol). The mixture was stirred at 100 °C for 12 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. 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.

[0654] Step 2: Preparation of 6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-amine

[0655]

[0656] 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.

[0657] 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

[0658]

[0659] 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 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 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.

[0660] 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

[0661]

[0662] 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 at 25 °C for 2 h under a H2 atmosphere (15 psi). 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

[0663] 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

[0664]

[0665] 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) at 0 °C was added ethyl 2-(chlorosulfonyl)acetate (61.2 mg, 328 μmol). 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

[0666] 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)sulfamoyl)benzamide

[0667]

[0668] 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 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 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)sulfamoylamino)benzamide (73.74 mg, 126 μmol) as an off-white solid. LCMS: MS ESI (M+1) + 582.3。 1 H NMR (400 MHz, DMSO-d6) δ = 12.18 (s, 1H), 10.13 (s, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.53 (s, 1H), 7.22 (s, 1H), 7.08 (br d, J = 8.6 Hz, 1H), 6.56 (s, 1H), 3.74 (t, J = 6.5 Hz, 2H), 3.66 (br d, J = 5.0 Hz, 4H), 3.34 (t, J = 6.5 Hz, 2H), 3.17 (br t, J = 5.7 Hz, 4H), 2.26 (s, 3H), 2.06 - 1.86 (m, 4H), 0.99 (br d, J = 5.3 Hz, 4H), 0.13 (s, 6H).

[0669] 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

[0670]

[0671] Step 1: Preparation of benzyl 4-bromo-2-fluorobenzoate

[0672]

[0673] To a solution of 4-bromo-2-fluorobenzoic acid (800 mg, 3.65 mmol) in DMF (12.1 mL) at 0 °C was added sodium carbonate (464 mg, 4.38 mmol) and benzyl bromide (463 μL, 3.90 mmol). 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 Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 10% EtOAc in heptane) to give benzyl 4-bromo-2-fluorobenzoate (947 mg, 3.06 mmol) as a pale yellow oil. 1 1H NMR (400 MHz, DMSO-d6) δ 7.85 (t, J = 8.2 Hz, 1H), 7.74 (dd, J = 10.6, 1.3 Hz, 1H), 7.57 (dd, J = 8.4, 1.6 Hz, 1H), 7.49 - 7.44 (m, 2H), 7.43 - 7.32 (m, 3H), 5.35 (s, 2H). 19 19F NMR (377 MHz, DMSO-d6) δ -107.33 (br.s., 1F).

[0674] Step 2: Preparation of benzyl 4-bromo-2-(4,4-dimethyl-1,4-azasilinan-1-yl)benzoate

[0675]

[0676] To a solution of benzyl 4-bromo-2-fluorobenzoate (330 mg, 1.06 mmol) in NMP (2.12 mL) at room temperature was added 4,4-dimethyl-1,4-azasilinan hydrochloride (250 mg, 1.50 mmol). Then, potassium carbonate (439 mg, 3.18 mmol) was 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 to 10% EtOAc in heptane) to give benzyl 4-bromo-2-(4,4-dimethyl-1,4-azasilinan-1-yl)benzoate (328 mg, 0.784 mmol). LCMS: MS ESI (M+1) + 418.0. 11H NMR (400 MHz, DMSO-d6) δ 7.49 - 7.31 (m, 6H), 7.21 (d, J = 1.5 Hz, 1H), 7.08 (dd, J = 8.1, 1.5 Hz, 1H), 5.30 (s, 2H), 3.26 - 3.16 (m, 4H), 0.79 - 0.67 (m, 4H), 0.04 (s, 6H).

[0677] Step 3: Preparation of 4-bromo-2-(4,4-dimethyl-1,4-azasilinane-1-yl)benzoic acid

[0678]

[0679] To a solution of benzyl 4-bromo-2-(4,4-dimethyl-1,4-azasilinane-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 HCl (1 M) until the mixture reached pH 1. The resulting precipitate was recovered by filtration. The solid was dried by co-evaporation with MeCN to give 4-bromo-2-(4,4-dimethyl-1,4-azasilinane-1-yl)benzoic acid (220 mg, 0.67 mmol) as a white solid. LCMS: MS ESI (M+1) + 328.0. 1 1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 1.2 Hz, 1H), 7.89 (d, J = 8.6 Hz, 1H), 7.58 (dd, J = 8.4, 1.3 Hz, 1H), 3.32 (t, J = 5.9 Hz, 4H), 0.95 (t, J = 6.1 Hz, 4H), 0.19 (s, 6H).

[0680] Step 4: Preparation of 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine

[0681]

[0682] In a sealed tube, 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 at 180 °C for 24 h. The reaction mixture was cooled to room temperature, quenched with water, and extracted twice with ethyl acetate. The organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (H2O: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 (400 MHz, 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).

[0683] 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

[0684]

[0685] 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 (ca. 1 μL) was added, followed by dropwise addition of thionyl chloride (69.2 μL, 957 μmol). After stirring for 3 h at ambient temperature, the mixture was evaporated to dryness under reduced pressure. After suspending the residue in toluene and concentrating twice under reduced pressure, the residue was suspended in DCM (2 mL) under nitrogen. Potassium phosphate (288 mg, 1.36 mmol) was added, followed by addition of 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 yellow mixture was stirred at room temperature for 21 h. The mixture was evaporated to dryness under reduced pressure. The residue was suspended in dichloromethane and stirred for 10 min. The mixture was filtered, and the resulting cake was washed with additional dichloromethane. The filtrate was evaporated to dryness under reduced pressure. The residue was triturated in MeCN to afford 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 (400 MHz, DMSO-d6) δ 12.64 (br.s., 1H), 7.92 (d, J = 8.1 Hz, 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 (377 MHz, DMSO-d6) δ -95.21 (br.s., 2F).

[0686] 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

[0687]

[0688] A mixture of 2-hydroxyethanesulfonamide (46.3 mg, 370 μmol), copper(I) iodide (17.6 mg, 92.5 μmol), potassium phosphate (196 mg, 925 μmol), and sarcosine (16.4 mg, 185 μmol) in DMF (1.84 mL) was heated 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-azasilinane-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, an aqueous solution of NH4Cl / NH4OH (9:1), brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 100% EtOAc in heptane) to give N-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-2-(4,4-dimethyl-1,4-azasilinane-1-yl)-4-(2-hydroxyethanesulfonamido)benzamide (46.7 mg, 80.1 μmol) as a white solid. LCMS: MS ESI (M+1) + 583.2 1 1H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 10.18 (br.s., 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.46 (s, 1H), 7.24 (s, 1H), 7.10 (d, J = 8.6 Hz, 1H), 5.01 - 4.85 (m, 1H), 3.92 - 3.80 (m, 4H), 3.79 - 3.69 (m, 2H), 3.34 (t, J = 6.6 Hz, 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 19F NMR (377 MHz, DMSO-d6) δ -95.19 (br.s., 2F).

[0689] Examples 10 to 27

[0690] The following compounds were prepared using procedures similar to those of Examples 1 to 9 above:

[0691]

[0692]

[0693]

[0694]

[0695]

[0696] Example 28: Synthesis of 2-(7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]hept-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide

[0697]

[0698] Step 1: Preparation of tert-butyl 7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]heptane-3-carboxylate

[0699]

[0700] 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 TMSCF3 (1.43 g, 10.1 mmol). The mixture was stirred overnight at 60 °C under a N2 atmosphere. The reaction mixture was diluted with water (5 mL) and extracted with EA (10 mL). The organic extract was concentrated and then 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 1H 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).

[0701] Step 2: Preparation of 7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]heptane hydrochloride

[0702]

[0703] 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 overnight at room temperature. The mixture was concentrated in vacuo to give 7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]heptane hydrochloride as a yellow solid (500 mg, 2.72 mmol).

[0704] Step 3: Preparation of methyl 2-(7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]hept-3-yl)-4-iodobenzoate

[0705]

[0706] 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 overnight at 100 °C. Then the mixture was 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]hept-3-yl)-4-iodobenzoate as a yellow solid (400 mg, 982 μmol). LCMS: MS ESI (M+1) + 408.0.

[0707] Step 4: Preparation of 2-(7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]hept-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodobenzamide

[0708]

[0709] To a solution of methyl 2-(7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]hept-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). The mixture was stirred at room temperature for 1 h. Then 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]hept-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodobenzamide (500 mg, 828 μmol) as a yellow solid. LCMS: MSESI (M+1) + 604.2

[0710] Step 5: Preparation of 2-(7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]hept-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide

[0711]

[0712] To a solution of 2-(7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]hept-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 K3PO4 (175 mg, 825 μmol), and the mixture was stirred at 60 °C under N2 atmosphere for 10 min. Then, 2-hydroxyethane-1-sulfonamide (100 mg, 165 μmol) was added, and the mixture was stirred at 100 °C overnight. Then 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]hept-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide (33.1 mg, 55.2 μmol) as a yellow solid. LCMS: MS ESI (M+1) + 601.3 11H NMR (400 MHz, DMSO-d6) δ = 11.16 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H), 7.20 - 6.92 (m, 2H), 3.87 (br t, J = 5.2 Hz, 4H), 3.75 (t, J = 6.4 Hz, 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 = 13.4 Hz, 1H), 2.03 - 1.89 (m, 4H), 1.88 - 1.69 (m, 2H), 1.23 (s, 3H).

[0713] Examples 29a and 29b: Synthesis of 2 - ((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]hept-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]hept-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (Example 29b)

[0714]

[0715] Step 1: Preparation of methyl 2-(6-(difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-iodobenzoate

[0716]

[0717] 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 overnight at 100 °C. Then 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 Na2SO4, 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]hept-3-yl)-4-iodobenzoate (90.0 mg, 221 μmol) as a yellow gum. LCMS: MS ESI (M - 100) + 408.0.

[0718] Step 2: Preparation of 2-((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]hept-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]hept-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodobenzamide

[0719]

[0720] At 0 °C, LiHMDS (0.59 mL, 0.59 mmol, 1 M in THF) was added to a solution of methyl 2-(6-(difluoromethyl)-3-azabicyclo[4.1.0]hept-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). The mixture was stirred at room temperature for 1 h. 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]hept-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodobenzamide. The racemate was separated by chiral SFC (DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm) CO2-EtOH (0.1% NH3H2O)) to give the first elution peak (50 mg, 82.8 μmol) arbitrarily designated as 2-((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodobenzamide and the second elution peak (50 mg, 82.8 μmol) arbitrarily designated as 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodobenzamide. First elution peak LCMS: MS ESI (M - 100) + 604.0. Second elution peak LCMS: MS ESI (M - 100) + 604.0.

[0721] Step 3A: Preparation of 2-((1S,6R)-6-(difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide

[0722]

[0723] 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 K3PO4 (87.8 mg, 414 μmol). The mixture was stirred at 70 °C for 20 min. 2-((1S,6R)-6-(Difluoromethyl)-3-azabicyclo[4.1.0]hept-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 then 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 Na2SO4, 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]hept-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。 11H NMR (400 MHz, DMSO-d6) δ = 11.59 (s, 1H), 10.22 (s, 1H), 7.91 (d, J = 8.6 Hz, 1H), 7.44 (s, 1H), 7.19 (s, 1H), 7.09 (dd, J = 1.4, 8.4 Hz, 1H), 5.66 (br t, J = 56.6 Hz, 1H), 3.88 (br d, J = 5.0 Hz, 4H), 3.76 (t, J = 6.4 Hz, 2H), 3.35 (t, J = 6.4 Hz, 2H), 3.28 (br d, J = 11.0 Hz, 1H), 3.12 (br dd, J = 3.4, 11.4 Hz, 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, 8.6 Hz, 1H), 1.37 (br d, J = 4.8 Hz, 1H), 0.99 (br dd, J = 4.6, 9.2 Hz, 1H).

[0724] Step 3B: Preparation of 2 - ((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide

[0725]

[0726] 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 K3PO4 (87.8 mg, 414 μmol). The mixture was stirred at 70 °C for 20 min. 2-((1R,6S)-6-(Difluoromethyl)-3-azabicyclo[4.1.0]hept-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 then 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 Na2SO4, 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]hept-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 (400 MHz, DMSO-d6) δ = 11.60 (s, 1H), 10.22 (s, 1H), 7.91 (br d, J = 8.6 Hz, 1H), 7.44 (s, 1H), 7.19 (br s, 1H), 7.09 (br d, J = 8.6 Hz, 1H), 5.65 (br s, 1H), 3.89 (br s, 4H), 3.76 (br t, J = 6.2 Hz, 2H), 3.35 (br t, J = 6.2 Hz, 2H), 3.28 (br d, J = 11.2 Hz, 1H), 3.12 (br dd, J = 3.2, 10.8 Hz, 1H), 2.94 (br dd, J = 1.6, 7.0 Hz, 1H), 2.54 (br d, J = 5.4 Hz, 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 = 4.4 Hz, 1H), 1.04 - 0.94 (m, 1H).

[0727] 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]hept-3-yl)benzamide

[0728]

[0729] Step 1: Preparation of tert-butyl 4-((benzyloxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0730]

[0731] To a solution of tert-butyl 4-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylate (1.7 g, 7.97 mmol) in THF (10 mL) at 0 °C was added sodium hydride (349 mg, 8.76 mmol, 60% in mineral oil). The mixture was warmed to room temperature and stirred at room temperature for 0.5 h. Then 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 1H 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).

[0732] Step 2: Preparation of tert-butyl 6-((benzyloxy)methyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate

[0733]

[0734] Under N2 atmosphere, after adding Et2Zn (8.3 mL, 8.3 mmol, 1.0 M in hexane) to DCM (12 mL) under ice-cooling, a solution of TFA (0.6 mL) in DCM (3 mL) was added dropwise, and the mixture was stirred at 0 °C for 40 min. Then a solution of diiodomethane (2.2 g, 8.2 mmol) in DCM (3 mL) was added dropwise. Then the mixture was 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 reactants were warmed to room temperature and stirred overnight. After cooling to 0 °C, the mixture was treated with Et3N to adjust to pH 8. Then Boc2O (0.90 g, 4.1 mmol) was added, and the mixture was stirred at room temperature for 5 h. Then 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.

[0735] Step 3: Preparation of 6-((benzyloxy)methyl)-3-azabicyclo[4.1.0]heptane

[0736]

[0737] To HCl (10 mL, 40 mmol, 4 M in dioxane) was added tert-butyl 6-((benzyloxy)methyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (800 mg, 2.52 mmol). The mixture was stirred at room temperature for 1 h. Then the mixture was concentrated under vacuum 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.

[0738] Step 4: Preparation of methyl 2-(6-((benzyloxy)methyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-bromobenzoate

[0739]

[0740] 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. Then 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]hept-3-yl)-4-bromobenzoate (350 mg, 813 μmol) as a yellow oil. LCMS: MS ESI (M+1) + 430.1。

[0741] Step 5: Preparation of 2-(6-((benzyloxy)methyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)benzamide

[0742]

[0743] To a solution of methyl 2-(6-((benzyloxy)methyl)-3-azabicyclo[4.1.0]hept-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) at room temperature was added LiHMDS (1.4 mL, 1.4 mmol, 1 M in THF). The mixture was stirred at room temperature for 1 h. Then 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]hept-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。

[0744] Step 6: Preparation of 2-(6-((Benzyloxy)methyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide

[0745]

[0746] 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 K3PO4 (218 mg, 1.03 mmol). The mixture was stirred at 60 °C for 10 min. Then, 2-(6-((benzyloxy)methyl)-3-azabicyclo[4.1.0]hept-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 then 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 preparative HPLC (TFA conditions) to give 2-(6-((benzyloxy)methyl)-3-azabicyclo[4.1.0]hept-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。

[0747] 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]hept-3-yl)benzamide

[0748]

[0749] To a solution of 2-(6-((benzyloxy)methyl)-3-azabicyclo[4.1.0]hept-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 overnight at 45 °C under a H2 atmosphere (15 psi). The mixture was then filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (FA conditions) to afford N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-(hydroxymethyl)-3-azabicyclo[4.1.0]hept-3-yl)benzamide (8.39 mg, 14.4 μmol) as a white solid. LCMS: MS ESI (M+1) + 581.2。 1 H NMR (400 MHz, DMSO-d6) δ = 11.77 (br s, 1H), 7.91 (br d, J = 8.4 Hz, 1H), 7.43 (s, 1H), 7.25 - 7.14 (m, 1H), 7.05 (br d, J = 8.8 Hz, 1H), 4.59 (br s, 1H), 3.89 (br s, 4H), 3.75 (br t, J = 6.4 Hz, 2H), 3.27 (brd, J = 4.6 Hz, 2H), 3.23 - 3.09 (m, 3H), 2.89 - 2.77 (m, 1H), 2.56 (br dd, J = 4.6, 11.6 Hz, 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).

[0750] 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]hept-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]hept-3-yl)benzamide (Example 31b)

[0751]

[0752] 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]hept-3-yl)benzamide

[0753]

[0754] 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]hept-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 for 1 h under a H2 atmosphere (15 psi). The mixture was then 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]hept-3-yl)benzamide (100 mg, 0.211 mmol) as a colorless solid. LCMS: MS ESI (M+1) + 475.3。

[0755] 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]hept-3-yl)phenyl)sulfamoyl)acetate

[0756]

[0757] 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]hept-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 overnight at room temperature. The mixture was then concentrated in vacuo and 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-fluoro-5-((1S,6S)-6-methyl-3-azabicyclo[4.1.0]hept-3-yl)phenyl)sulfamoyl)acetate (90.0 mg, 0.14 mmol) as a white solid. LCMS: MS ESI (M+1) + 625.3

[0758] Step 3A: Preparation of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-4-((2-hydroxyethyl)sulfamoyl)-6-((1S,6S)-6-methyl-3-azabicyclo[4.1.0]hept-3-yl)benzamide

[0759]

[0760] 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]hept-3-yl)phenyl)sulfamoyl)acetate (70 mg, 0.11 mmol) in THF (1 mL) was added LiBH4 (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 H2O (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)sulfamoyl)-6-((1S,6S)-6-methyl-3-azabicyclo[4.1.0]hept-3-yl)benzamide (32.5 mg, 0.060 mmol) as a white solid. LCMS: MS ESI (M+1) + 583.4 11H NMR (400 MHz, 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 = 11.8 Hz, 1H), 3.87 (br s, 4H), 3.74 (t, J = 6.6 Hz, 2H), 3.27 (br t, J = 6.6 Hz, 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 = 2.6 Hz, 1H), 0.57 (br s, 1H), 0.31 (br dd, J = 3.8, 8.4 Hz, 1H).

[0761] 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]hept-3-yl)benzamide

[0762]

[0763] 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]hept-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 for 1 h under a H2 atmosphere (15 psi). The mixture was then 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]hept-3-yl)benzamide (100 mg, 0.22 mmol) as a colorless solid. LCMS: MS ESI (M+1) + 475.2.

[0764] 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]hept-3-yl)phenyl)sulfamoyl)acetate

[0765]

[0766] 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]hept-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 overnight at room temperature. Then the mixture was concentrated in vacuo and 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-fluoro-5-((1R,6R)-6-methyl-3-azabicyclo[4.1.0]hept-3-yl)phenyl)sulfamoyl)acetate (80.0 mg, 0.13 mmol) as a white solid. LCMS: MS ESI (M+1) + 625.4。

[0767] Step 3B: Preparation of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-4-((2-hydroxyethyl)sulfamoyl)-6-((1R,6R)-6-methyl-3-azabicyclo[4.1.0]hept-3-yl)benzamide

[0768]

[0769] 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]hept-3-yl)phenyl)sulfamoyl)acetate (80 mg, 0.13 mmol) in THF (1 mL) was added LiBH4 (0.19 mL, 0.38 mmol, 2 M in THF). The mixture was stirred at room temperature for 0.5 h. Then the mixture was treated with H2O (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)sulfamoyl)-6-((1R,6R)-6-methyl-3-azabicyclo[4.1.0]hept-3-yl)benzamide (14.5 mg, 0.030 mmol) as a white solid. LCMS: MS ESI (M+1) + 583.4。 11H NMR (400 MHz, DMSO-d6) δ = 10.59 (br s, 1H), 7.32 (br s, 1H), 6.61 (s, 1H), 6.56 (br d, J = 11.4 Hz, 1H), 3.87 (br s, 4H), 3.75 (t, J = 6.6 Hz, 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, 8.2 Hz, 1H).

[0770] Examples 32 to 47

[0771] The following compounds were prepared using a procedure similar to that of Examples 28 to 31 above:

[0772]

[0773]

[0774]

[0775]

[0776]

[0777] *The compound of Example 38 is the same as the compound of Example 31a; Compound 41 is the same as the compound of Example 29a, except that the stereochemistry is not shown in the structure of the compound of Example 41.

[0778] Example 48: 2 - ((1R,6S)-6-(Difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide

[0779]

[0780] Step 1: Preparation of 2 - ((1R,6S)-6-(Difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-4-nitrobenzamide

[0781]

[0782] To a solution of methyl 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]hept-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 at 25 °C for 1 h under N2 atmosphere. 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 Na2SO4, 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]hept-3-yl)-N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-4-nitrobenzamide (200 mg, 383 μmol) as a yellow solid.

[0783] Step 2: Preparation of 4-amino-2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)benzamide

[0784]

[0785] To a solution of 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]hept-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 at 25 °C for 1 h under H2 atmosphere (15 psi). The mixture was filtered and the filtrate was concentrated to give 4-amino-2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]hept-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.

[0786] Step 3: Preparation of Ethyl 2-(N-(3-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-((6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)carbamoyl)phenyl)sulfamoyl)acetate

[0787]

[0788] At 0 °C, pyridine (35.2 mg, 446 μmol) and ethyl 2-(chlorosulfonyl)acetate (41.6 mg, 223 μmol) were added to a solution of 4-amino-2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)benzamide (110 mg, 223 μmol) in DCM (10 mL). 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 Na2SO4, filtered, and concentrated to give ethyl 2-(N-(3-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-((6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)carbamoyl)phenyl)sulfamoyl)acetate (130 mg, 202 μmol) as a yellow gum. LCMS: MSESI (M+1) + 642.2。

[0789] Step 4: Preparation of 2-((1R,6S)-6-(Difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfamoyl)benzamide

[0790]

[0791] To a solution of ethyl 2-(N-(3-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]hept-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 LiBH4 (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 H2O (10 mL), and extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with brine (2 × 10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase HPLC (TFA conditions) to give 2-((1R,6S)-6-(difluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfamoyl)benzamide (17.1 mg, 28.5 μmol) as a white solid. LCMS: MS ESI (M+1) + 600.3。 1 H NMR (400 MHz, DMSO-d6) δ = 11.13 (s, 1H), 10.17 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.51 (s, 1H), 7.18 (s, 1H), 7.08 (dd, J = 1.8, 8.6 Hz, 1H), 6.55 (s, 1H), 5.65 (br t, J = 56.6 Hz, 1H), 3.76 (t, J = 6.4 Hz, 2H), 3.68 (br d, J = 5.0 Hz, 4H), 3.35 (t, J = 6.4 Hz, 2H), 3.30 (br d, J = 11.6 Hz, 1H), 3.10 (br dd, J = 3.8, 11.2 Hz, 1H), 2.97 (brd, J = 11.2 Hz, 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 = 4.6 Hz, 1H), 1.37 (br d, J = 4.8 Hz, 1H), 0.98 (br dd, J = 4.6, 9.0 Hz, 1H).

[0792] Examples 49a and 49b: N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonylamino)-2-((1S,6R)-6-(methoxymethyl)-3-azabicyclo[4.1.0]hept-3-yl)benzamide (Example 49a) and N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonylamino)-2-((1R,6S)-6-(methoxymethyl)-3-azabicyclo[4.1.0]hept-3-yl)benzamide (Example 49b)

[0793]

[0794] Step 1: Preparation of methyl 2-(6-(methoxymethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-nitrobenzoate

[0795]

[0796] To a solution of methyl 2-(6-(hydroxymethyl)-3-azabicyclo[4.1.0]hept-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 addition of 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]hept-3-yl)-4-nitrobenzoate (500 mg, 1.56 mmol) as a yellow gum. LCMS: MS ESI (M+1) + 321.1.

[0797] Step 2: Preparation of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-(methoxymethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-nitrobenzamide

[0798]

[0799] To a solution of methyl 2-(6-(methoxymethyl)-3-azabicyclo[4.1.0]hept-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) at 0 °C was added dropwise LiHMDS (2.34 mL, 2.34 mmol, 1 M in THF). The mixture was stirred at 20 °C for 2 h. 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]hept-3-yl)-4-nitrobenzamide (200 mg, 387 μmol) as a yellow gum. LCMS: MS ESI (M+1) + 517.3

[0800] 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]hept-3-yl)benzamide

[0801]

[0802] To a solution of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-(methoxymethyl)-3-azabicyclo[4.1.0]hept-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 at 20 °C under H2 atmosphere (15 psi) for 1 h. 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]hept-3-yl)benzamide (200 mg, 411 μmol) as a yellow gum. LCMS: MS ESI (M+1) + 487.3

[0803] 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]hept-3-yl)phenyl)sulfamoyl)acetate

[0804]

[0805] At 0 °C, pyridine (97.2 mg, 1.23 mmol) and ethyl 2-(chlorosulfonyl)acetate (114 mg, 616 μmol) were added 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]hept-3-yl)benzamide (200 mg, 411 μmol) in DCM (4 mL). The mixture was stirred at 20 °C for 2 h. 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]hept-3-yl)phenyl)sulfamoyl)acetate (200 mg, 314 μmol) as a yellow gum. LCMS: MS ESI (M+1) + 637.3

[0806] Step 5: Preparation of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfamoyl)-2-((1S,6R)-6-(methoxymethyl)-3-azabicyclo[4.1.0]hept-3-yl)benzamide and N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfamoyl)-2-((1R,6S)-6-(methoxymethyl)-3-azabicyclo[4.1.0]hept-3-yl)benzamide

[0807]

[0808] 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]hept-3-yl)phenyl)sulfamoyl)acetate (150 mg, 235 μmol) in THF (3 mL) was added LiBH4 (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-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfamoylamino)-2-(6-(methoxymethyl)-3-azabicyclo[4.1.0]hept-3-yl)benzamide. The racemic compound was separated by chiral SFC (Chiralcel OX-3 (50 mm × 4.6 mm, 3 μm) CO2-EtOH (0.05% diethylamine)) to give the first elution peak (72.7 mg, 122 μmol) arbitrarily designated as N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfamoylamino)-2-((1S,6R)-6-(methoxymethyl)-3-azabicyclo[4.1.0]hept-3-yl)benzamide as a white solid, and the second elution peak (65.6 mg, 110 μmol) arbitrarily designated as N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfamoylamino)-2-((1R,6S)-6-(methoxymethyl)-3-azabicyclo[4.1.0]hept-3-yl)benzamide as a white solid. First elution peak LCMS: MS ESI (M+1) + 595.3. Second elution peak LCMS: MS ESI (M+1) + 595.3. First elution 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).

[0809] 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]oct-3-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide (Example 50a), N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1S,6S)-6-fluoro-3-azabicyclo[4.2.0]oct-3-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide (Example 50b), N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1S,6R)-6-(fluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-((2-hydroxyethyl)sulfonylamino)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]hept-3-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide (Example 51b)

[0810]

[0811] Step 1: Synthesis of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-4-nitrobenzamide

[0812]

[0813] 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 NH4Cl (100 mL), and extracted with EtOAc (3 × 500 mL). The combined organic extracts were washed with brine (300 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-fluoro-4-nitrobenzamide (27.0 g, 68.2 mmol) as a yellow solid. LCMS: MS ESI (M+1) + 396.2。 11H NMR (400 MHz, 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 = 13.2 Hz, 4H).

[0814] Step 2: Preparation of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-(hydroxymethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-nitrobenzamide

[0815]

[0816] 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]hept-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]hept-3-yl)-4-nitrobenzamide (24.0 g, 47.7 mmol) as a yellow solid. LCMS: MS ESI (M+1) + 503.1.

[0817] 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]oct-3-yl)-4-nitrobenzamide and N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-(fluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-nitrobenzamide

[0818]

[0819] To a solution of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-(hydroxymethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-nitrobenzamide (24.0 g, 47.7 mmol) in DCM (240 mL) at 0 °C was added dropwise bis(2-methoxyethyl)aminosulfur trifluoride (21.1 g, 95.4 mmol), and the mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by slowly adding 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]oct-3-yl)-4-nitrobenzamide and N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-(fluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-nitrobenzamide as a yellow solid.

[0820] Step 4: Preparation of a mixture of 4-amino-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-fluoro-3-azabicyclo[4.2.0]oct-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]hept-3-yl)benzamide

[0821]

[0822] To a solution of a mixture of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-fluoro-3-azabicyclo[4.2.0]oct-3-yl)-4-nitrobenzamide and N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-(fluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-nitrobenzamide (18.0 g, 35.6 mmol) in THF (180 mL) was added Pd / C (3.78 g, 10% w / w), and the mixture was stirred at 25 °C for 2 h under a H2 atmosphere (15 psi). 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]oct-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]hept-3-yl)benzamide as a yellow oil (16.8 g, 35.4 mmol). LCMS: MS ESI (M+1) + 475.3。

[0823] Step 5: Preparation of 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]oct-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]hept-3-yl)phenyl)sulfamoyl)acetate

[0824]

[0825] At 0 °C, methyl 2-(chlorosulfonyl)acetate (9.16 g, 53.1 mmol) and pyridine (8.38 g, 106 mmol) were added to a solution of a mixture of 4-amino-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-fluoro-3-azabicyclo[4.2.0]oct-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]hept-3-yl)benzamide (16.8 g, 35.4 mmol) in DCM (15 mL), 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 × 150 mL). The combined organic extracts were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated to give a mixture (21.0 g, 34.3 mmol) of methyl 2-(N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-3-(6-fluoro-3-azabicyclo[4.2.0]oct-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]hept-3-yl)phenyl)sulfamoyl)acetate as a yellow oil. LCMS: MSESI (M+1) + 611.2。

[0826] Step 6: Preparation of a mixture of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-fluoro-3-azabicyclo[4.2.0]oct-3-yl)-4-((2-hydroxyethyl)sulfamoyl)benzamide and N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-(fluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-((2-hydroxyethyl)sulfamoyl)benzamide

[0827]

[0828] To a solution of 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]oct-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]hept-3-yl)phenyl)sulfamoyl)acetate (21.0 g, 34.3 mmol) in THF (200 mL) was added LiBH4 (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 × 150 mL). The combined organic extracts were washed with brine (250 mL), dried over Na2SO4, filtered and concentrated to give a mixture of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-fluoro-3-azabicyclo[4.2.0]oct-3-yl)-4-((2-hydroxyethyl)sulfamoyl)benzamide and N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-(fluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-((2-hydroxyethyl)sulfamoyl)benzamide (12.0 g, 20.5 mmol) as a yellow oil.

[0829] Step 7: Preparation of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1R,6R)-6-fluoro-3-azabicyclo[4.2.0]oct-3-yl)-4-((2-hydroxyethyl)sulfamoyl)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1S,6S)-6-fluoro-3-azabicyclo[4.2.0]oct-3-yl)-4-((2-hydroxyethyl)sulfamoyl)benzamide, N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1S,6R)-6-(fluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-((2-hydroxyethyl)sulfamoyl)benzamide and N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1R,6S)-6-(fluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-((2-hydroxyethyl)sulfamoyl)benzamide

[0830] Purify 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]oct-3-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide and N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-(fluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide by silica gel column chromatography (PE:EA gradient) to obtain racemic N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-fluoro-3-azabicyclo[4.2.0]oct-3-yl)-4-((2-hydroxyethyl)sulfonylamino)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]hept-3-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide as a yellow oil. Further purify racemic N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-fluoro-3-azabicyclo[4.2.0]oct-3-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide by chiral SFC (Daicel Chiralcel OJ-H (250 mm × 30 mm, 5 μm); mobile phase: CO2:MeOH 1:3 (0.1% NH3H2O)) to obtain a first elution peak (1100 mg, 1.37 mmol) arbitrarily designated as N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1R,6R)-6-fluoro-3-azabicyclo[4.2.0]oct-3-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide as an off-white solid, and a second elution peak (1.15 g, 1.97 mmol) arbitrarily designated as N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1S,6S)-6-fluoro-3-azabicyclo[4.2.0]oct-3-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide as an off-white solid. First elution peak LCMS: MS ESI(M+1) + 583.4. Second elution peak LCMS: MS ESI(M+1) + 583.2. First elution peak 11H NMR (400 MHz, DMSO-d6) δ = 11.79 (s, 1H), 7.91 (d, J = 8.6 Hz, 1H), 7.47 (s, 1H), 7.20 (d, J = 1.8 Hz, 1H), 7.08 (dd, J = 2.0, 8.6 Hz, 1H), 3.85 (br t, J = 5.4 Hz, 4H), 3.75 (t, J = 6.4 Hz, 2H), 3.35 - 3.33 (m, 2H), 3.04 - 2.97 (m, 1H), 2.93 (d, J = 3.0 Hz, 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 = 8.9 Hz, 1H). The second elution peak 11H NMR (400 MHz, DMSO-d6) δ = 11.76 (s, 1H), 10.60 - 9.87 (m, 1H), 7.92 (d, J = 8.6 Hz, 1H), 7.47 (s, 1H), 7.21 (d, J = 1.7 Hz, 1H), 7.09 (dd, J = 1.8, 8.6 Hz, 1H), 5.29 - 4.66 (m, 1H), 3.85 (br t, J = 5.1 Hz, 4H), 3.75 (t, J = 6.4 Hz, 2H), 3.35 (t, J = 6.4 Hz, 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). The racemic N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-(fluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide was further purified by consecutive 3 rounds of chiral SFC (Daicel Chiralcel OJ-H (250 mm × 30 mm, 5 μm); mobile phase: CO2:MeOH 3:7 (0.1% NH3H2O)), then (Daicel Chiralcel OX (250 mm × 30 mm, 10 μm); mobile phase: CO2:MeOH 2:3 (0.1% NH3H2O)), then (Daicel Chiralpak AD (250 mm × 30 mm, 10 μm); mobile phase: CO2:ACN / EtOH 1:3 (0.1% NH3H2O)) to obtain the first elution peak (803.2 mg, 1.37 mmol) arbitrarily designated as N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1S,6R)-6-(fluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide as an off-white solid, and the second elution peak (755.53 mg, 1.29 mmol) arbitrarily designated as N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-((1R,6S)-6-(fluoromethyl)-3-azabicyclo[4.1.0]hept-3-yl)-4-((2-hydroxyethyl)sulfonylamino)benzamide as an off-white solid. First elution peak LCMS: MS ESI (M+1) + 583.3. Second elution peak LCMS: MS ESI (M+1) + 583.3. First elution peak 1HNMR (400 MHz, DMSO-d6) δ = 11.70 (s, 1H), 7.89 (d, J = 8.6 Hz, 1H), 7.43 (s, 1H), 7.18 (d, J = 1.2 Hz, 1H), 7.05 (dd, J = 1.6, 8.6 Hz, 1H), 4.42 - 4.07 (m, 2H), 3.89 (br s, 4H), 3.75 (t, J = 6.4 Hz, 2H), 3.32 (br s, 2H), 3.26 - 3.11 (m, 2H), 2.91 - 2.82 (m, 1H), 2.59 (dt, J = 4.5, 11.6 Hz, 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 = 4.8 Hz, 1H). Second elution peak 1 HNMR (400 MHz, DMSO-d6) δ = 11.98 (br s, 1H), 7.82 (br d, J = 8.6 Hz, 1H), 7.45 (s, 1H), 6.98 (s, 1H), 6.88 (br d, J = 8.6 Hz, 1H), 4.45 - 4.07 (m, 2H), 3.89 (br s, 4H), 3.72 (br t, J = 6.4 Hz, 2H), 3.23 - 3.04 (m, 4H), 2.83 (br d, J = 6.4 Hz, 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, 1H).

[0831] Examples 52 to 134

[0832] The following compounds were prepared using procedures similar to those of Examples 1 to 9, 28 to 31, or 48 to 51 above:

[0833]

[0834]

[0835]

[0836]

[0837]

[0838]

[0839]

[0840]

[0841]

[0842]

[0843]

[0844]

[0845]

[0846]

[0847]

[0848]

[0849]

[0850]

[0851]

[0852] The structure of the comparator "Compound A" is shown below, and it was also synthesized according to known methods and tested in the biological assays disclosed below.

[0853]

[0854] As can be seen in the data table below, many compounds of the present invention have an efflux ratio superior to that of Compound A.

[0855] Analysis

[0856] 1. Caco-2 permeability assay: To evaluate the bidirectional permeability of the compounds.

[0857] Samples were analyzed by LC / MS / MS to estimate the apparent permeability coefficient (P of the compounds across the Caco-2 cell monolayer app) Caco-2 cells (American Type Culture Collection) were cultured and seeded onto HTS Transwell-96 well permeable supports (Corning Corporation) with cell culture medium for 14 days. The cell culture medium consisted of Dulbecco's Modified Eagle Medium (DMEM) with high glucose and L-glutamine supplemented with 10% FBS, 1× penicillin-streptomycin mixture, and 1× 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 the compound and control compound in DMSO were diluted with HBSS (10 mM HEPES, pH 7.4) to achieve a final concentration of 5 μM and a final DMSO concentration < 0.1%. Then, after a 30-minute pre-incubation, 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. The drug transport rate in the basolateral-to-apical direction was obtained by adding 235 μL of the test compound to the receiving plate wells (basolateral compartment) and filling 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 each 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 appropriate internal standards (100 nM alprazolam, 200 nM labetalol, 200 nM caffeine, and 200 nM diclofenac). After incubation at 37 °C for 2 h, 25 μL of the 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). 25 μL of the sample was taken from the receiving side (basolateral compartment) and transferred to a new plate containing 25 μL of HBSS (10 mM HEPES, pH 7.4). 200 μL of cold methanol containing internal standards (100 nM alprazolam, 200 nM labetalol, 200 nM caffeine, and 200 nM diclofenac) was added to terminate the reaction. The samples were vortexed for 5 minutes and then centrifuged at 3,220 g for 40 minutes. 100 μL of the supernatant aliquot was mixed with 100 μL of ultrapure water for LC-MS / MS analysis. All incubations were performed in duplicate. The solutions were discarded from the transwell plates.Add 100 μL of lucifer yellow solution (100 μM in HBSS) to each well of the transwell insert and 300 μL of HBSS to each well of the receiver. After incubation at 37 °C for 30 minutes, take 80 μL aliquots from each well on the apical and basolateral sides to a pure black plate. Then use Tecan Infinite. TM M200 (excitation / emission wavelength 485 nm / 530 nm) to read the plate.

[0858] All calculations were performed using Microsoft Excel. The peak area was determined from the extracted ion chromatogram. The lucifer yellow leakage in percentage (%) can be calculated using the following equation:

[0859]

[0860] LY leakage < 1% is acceptable, indicating good Caco-2 monolayer performance. The apparent permeability coefficient (P app ) for Caco-2 drug transport analysis, in units of cm / s, can be calculated using the following equation:

[0861]

[0862] where V A is the volume (mL) in the receiver well (0.235 mL for Ap→Bl flow and 0.075 mL for Bl→Ap flow), the area is the membrane surface area (0.143 cm 2 ) for the HTS Transwell-96 well permeable support, and the time is the total transport time in seconds.

[0863] The efflux ratio can be determined using the following equation:

[0864]

[0865] where P app(B-A) indicates the apparent permeability coefficient in the basolateral to apical direction, and P app(A-B) indicates the apparent permeability coefficient in the apical to basolateral direction.

[0866] The recovery can be determined using the following equation:

[0867]

[0868] where V A is the volume (mL) in the receptor well (0.235 mL for Ap→Bl flow and 0.075 mL for Bl→Ap), V Dis the volume (mL) in the donor well (0.075 mL for Ap→Bl flow and 0.235 mL for Bl→Ap).

[0869] 2. KIF18A Biochemical Analysis

[0870] The KIF18A ATPase assay was performed in a low-volume non-binding 384-well white plate with a final volume of 10 μL / well. Test compounds (10 mM solution in DMSO; 100 nL / well) were serially diluted 3-fold across a 10-point concentration range. KIF18A (0.4 nM, 5 μL / well; 1-367) was in a solution of 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 paclitaxel (Cytoskeleton Inc), 30 mg / ml preformed porcine microtubules (Cytoskeleton Inc)). The reaction was initiated by adding 5 μL of substrate solution (10 μM ultra-pure ATP in assay buffer) to each well. The plate was 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 min. Then, 20 μL of kinase detection reagent was added, and after a 40-min incubation time, luminescence was recorded on an Envision plate reader (PerkinElmer, Billerica, MA).

[0871] 3. In Vitro Anti-Proliferative Activity Analysis of KIF18A Inhibitors in Cancer Cell Line OVCAR-3

[0872] To evaluate the anti-proliferative activity of KIF18A inhibitors in cancer cells in vitro, a 4-day or 7-day growth assay was performed in the ovarian cancer cell line OVCAR-3 using the CelITiter-GLO 2.0 luminescent cell viability assay (CTG assay, Promega), which uses ATP as a marker 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 a black 384-well tissue culture plate. After 24 hours, the cells were treated with KIF18A inhibitors (10-point concentration range 10.0 μM to 0.00051 μM, 3-fold dilution). The assay was performed in duplicate. After 4 or 7 days of treatment, 30 μL of CTG reagent was added to each well and luminescence was detected using an Envision plate reader (PerkinElmer). The inhibition % was calculated based on the following formula:

[0873]

[0874] Where HC = high control and LC = low control. The high control was obtained from DMSO-treated cells and the low control was obtained from cells treated with 10 uM staurosporin.

[0875] Analyze the data from 1 to 3

[0876]

[0877]

[0878]

[0879]

[0880] “++++” means <0.1 μM; “+++” means 0.1 - 0.5 μM; “++” means >0.5 - 1 μM; “+” means >1 μM;

[0881] “**” means efflux ratio <10; “*” means efflux ratio >=10;

[0882] NT means not tested;

[0883] a Indicates a 4-day analysis;

[0884] b Indicates a 7-day analysis.

[0885] 4. Evaluate the KIF18A compound in the human megakaryocyte progenitor colony formation assay

[0886] Evaluate the clonogenic progenitors (CFU-MK) of human megakaryocytes in a collagen-based media formulation containing 3% BSA, rhIL-3 (10 ng / mL), rhIL-6 (10 ng / mL), and rhTpo (50 ng / mL).

[0887] Human bone marrow monocytes (Lot No. 0221006, ReachBio Research Labs, Seattle, WA) were stored at -152 °C until analysis was required. On the day of the experiment, the cells were rapidly thawed, the contents were diluted in 10 mL of Iscove's Modified Dulbecco's Medium (IMDM + 10% FBS) containing 10% fetal bovine serum, and washed by centrifugation (approximately 1500 r.p.m., 10 minutes, room temperature). The supernatant was discarded, and the cell pellet was resuspended in a known volume of IMDM + 10% FBS. Cell counting (3% glacial acetic acid) and viability assessment (trypan blue exclusion test) were performed on the bone marrow samples.

[0888] The compounds were tested at final concentrations of 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM, and 0.01 μM. DMSO was added as a solvent 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 all-lineage toxicity. Solvent control cultures (without compounds but containing 0.1% DMSO) and standard controls (without compounds or DMSO) were also initiated.

[0889] The cultures were incubated for 14 days. Subsequently, the human megakaryocyte cultures were transferred from 35 mm culture dishes to labeled glass slides, fixed with methanol / acetone fixative, and then stained with anti-human CD41 antibody and alkaline phosphatase detection system according to the manufacturer's instructions. The colonies were evaluated under a microscope and scored by trained personnel and classified into the following categories based on size: CFU-MK (3 - 20), CFU-MK (21 - 49), and CFU-MK (≥50).

[0890] The mean ± 1 standard deviation of triplicate cultures of megakaryocyte progenitors was calculated. A two-tailed student's t-test was performed to evaluate whether there was a difference in the number of colonies generated between the solvent control and the treated cultures. Due to the potential subjectivity of colony counting, a p-value less than 0.01 was considered significant. To calculate the 50% inhibitory concentration (IC 50 ) of colony growth, a dose-response curve of the logarithm of the compound concentration versus the percentage of control colony growth was generated using GraphPad Prism 9. The 50% inhibitory concentration (IC 50 ) of colony growth was calculated using the dose-response single-point model formula based on sigmoidal curve fitting:

[0891] y = A + [(B - A) / (1 + ((C / x)^D))],

[0892] Where A = initial value (baseline response), B = maximum response, C = central value (drug concentration that elicits a response midway between A and B), and D = slope at the midpoint of the curve.

[0893] The binding of the compounds to the components of the assay buffer system was also evaluated. BSA and collagen were added to DMEM to obtain final concentrations similar to those of the above buffer. Working solutions of the test compound and the control compound were prepared at a concentration of 5 mM in DMSO and then spiked into DMEM containing BSA and collagen. The final concentration of the compound was 25 μM. The final concentration of DMSO was 0.5%. Ketoconazole was used as a positive control in the assay.

[0894] The dialysis membrane was soaked in ultrapure water for 60 minutes to separate the strips, then in 20% ethanol for 20 minutes, and finally in dialysis buffer for 20 minutes. The dialysis setup was assembled according to the manufacturer's instructions. Each unit was treated with 150 μL of sample and dialyzed with 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 and 5% CO2 at 100 rpm for 6 h. At the end of the incubation, 50 μL of sample from both the buffer and the sample was transferred to the wells of a 96-well plate.

[0895] 50 μL of blank DMEM containing BSA and collagen was added to each buffer sample, and an equal volume of blank DMEM was added to the collected DMEM containing BSA and collagen samples. 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 the protein and release the compound. The samples were vortexed for 2 minutes and centrifuged at 3,220 g for 30 minutes. 100 μL of the supernatant aliquot was diluted with 100 μL of ultrapure H2O, and the mixture was used for LC-MS / MS analysis.

[0896] All calculations were performed using Microsoft Excel. The concentrations of the test compound in the buffer chamber and the DMEM chamber containing BSA and collagen were determined based on the peak area ratio. The percentage of bound compound was calculated as follows:

[0897] Free % = (peak area ratio buffer chamber / peak area ratio 2% BSA and collagen chamber) * 100%

[0898] Bound % = 100% - Free %

[0899] The IC of the test compound adjusted for the free fraction 50See Table 1 for details and it is calculated using the following formula:

[0900] CFU-MK IC adjusted for the free fraction 50 (μM) = CFU-MK IC 50 (μM) * free percentage

[0901] As can be seen, compared to the reference compound A, the potency of most of the test compounds against bone marrow monocytes is significantly lower, indicating a significantly reduced risk of these compounds causing cytopenia or thrombocytopenia.

[0902] Table 1. CFU-MK IC adjusted for the free fraction of several examples 50 Values

[0903] Instance number <![CDATA[CFU-MK IC adjusted by the free portion 50 (μM)]]> 1 0.017 14 0.061 29b 0.11 36 0.082 107 0.047 Compound A 0.048

[0904] 5. In vivo pharmacokinetic (PK) evaluation of KIF18A compounds in mice

[0905] Using a parallel study design, the pharmacokinetics of the test compounds were evaluated in female balb / c nude mice after a single intravenous bolus (IV) injection of the solution at a dose of 3 mg / kg and oral administration (PO) of the solution / suspension at a dose of 10 mg / kg. Blood samples were collected from the IV dose group at 0.083, 0.25, 0.5, 1, 2, 4, 7, 12, and 24 hours after dosing. Blood samples were collected from the PO dose group at 0.25, 0.5, 1, 2, 4, 7, 12, and 24 hours after dosing.

[0906] Working solutions with desired series of concentrations were obtained by diluting the stock solution of the analyte with 50% aqueous acetonitrile. 5 μL of the working solution (1, 2, 4, 10, 20, 100, 200, 1000, 2000, 4000 ng / mL) was added to 10 μL of blank female balb / c nude mouse plasma to obtain calibration standards at 0.5 - 2000 ng / mL (0.5, 1, 2, 5, 10, 50, 100, 500, 1000, 2000 ng / mL) in a total volume of 15 μL. Five plasma quality control samples at 1 ng / mL, 2 ng / mL, 5 ng / mL, 50 ng / mL, and 1600 ng / mL were prepared independently of those used for the calibration curve. These QC samples were prepared on the day of analysis in the same manner as the calibration standards.

[0907] 15 μL of the standard, 15 μL of the QC sample, and 15 μL of the unknown sample (10 μL of plasma containing 5 μL of blank solution) were each added to 200 μL of acetonitrile containing the IS mixture for protein precipitation. The samples were then vortexed for 30 s. After centrifugation at 4000 rpm for 15 min at 4 °C, the supernatant was diluted 3 times with water. 10 μL of the diluted supernatant was injected into the LC / MS / MS system for quantitative analysis. The non-compartmental model was used, and the PK parameters were estimated using Phoenix (WinNonlin) pharmacokinetic software version 8.3.

[0908] The treatments of Examples 1, 9, 29b, and 50b at 3 mg / kg IV and 10 mg / kg PO were compared with the treatment of Compound A at 10 mg / kg PO (Table 2).

[0909] Table 2. PK parameters of Examples 1, 9, 29b, 50b, and Compound A dosed at 3 mg / kg IV and 10 mg / kg PO in mice

[0910]

[0911] 6. In vivo efficacy demonstration of KIF18A compounds

[0912] The experiments were conducted in female NOD SCID mice (GenPharmatech Co.). Before the study, the animals were acclimated for 7 days. The general health status of the animals was evaluated by a veterinarian, and a comprehensive health examination was performed before the study. The general procedures for animal care and housing complied with the standard operating procedures (SOP) of the Commission on Life Sciences, National Research Council, and Pharmaron, Inc. The mice were placed in a laminar flow room with constant temperature and humidity, with 3 - 5 mice per cage. The animals were housed in polycarbonate cages measuring 300 × 180 × 150 mm 3 and were in a well-ventilated room with environmental monitoring, with the temperature maintained at 23 ± 3 °C and the relative humidity at 40% - 70%. Fluorescent lights provided approximately 12 hours of illumination per day. Throughout the study, the animals had free access to irradiated and sterilized dry pellet food, except during the periods specified by the protocol, and bottled sterile drinking water was freely available at all times during quarantine and the study.

[0913] The OVCAR-3 (ATCC) tumor cell line was maintained in vitro as a monolayer at 37 °C in an atmosphere of air containing 5% CO2 in RPMI 1640 medium supplemented with 20% heat-inactivated FBS. The tumor cells were passaged no more than 4 - 5 times, and cells growing in the exponential growth phase were harvested and counted for tumor inoculation. Each mouse was inoculated subcutaneously in the right flank with OVCAR-3 tumor cells (2 × 10 7 ) in 0.2 mL of RPMI-1640 (1:1) containing Matrigel for model development.

[0914] Treatment was initiated when the average tumor size reached approximately 150 - 200 mm 3 , at which time the mice were randomly assigned to treatment groups such that the average starting tumor size of each treatment group was similar. The animals were then treated with vehicle or the compound at the indicated mg / kg (10 - 100) by oral gavage at a final dosing volume of 10 mL / kg at a defined frequency (e.g., BID, QD, treat for 4 days then stop treatment for 3 days).

[0915] Not only was tumor growth monitored in all study animals, but also behavior such as locomotor activity, food and water consumption (by cage-side inspection only), body weight (BW), eye / hair pad, and any other abnormal effects. Body weight of all animals was measured and recorded twice weekly throughout the study. The change in body weight (expressed as a percentage) was calculated using the following formula:

[0916] Change in body weight (%) = (body weight on day PG-DX / body weight on day PG-D1 ) × 100; PG-D1 was the first day of dosing.

[0917] Tumor size was measured using calipers and recorded twice weekly. Tumor volume (TV) (mm 2 ) was estimated using the formula TV = a × b 3 / 2, where "a" and "b" were the long and short diameters of the tumor, respectively.

[0918] TV was used to calculate tumor growth inhibition and tumor growth delay. For tumor growth inhibition (TGI), values were calculated using the following formula:

[0919] T / C% = (treatment TV 最终 - treatment TV 初始 ) / (vehicle TV 最终 - vehicle TV 初始 ) × 100

[0920] TGI% = [1 - (treatment TV 最终 - treatment VT 初始 ) / (vehicle TV 最终 - vehicle TV初始 )]×100

[0921] “TV 最终 ” and “TV 初始 ” are the average tumor volumes on the last day and the first day, respectively.

[0922] All statistical tests were performed on GraphPad, and the significance level was set at 5% or P < 0.05. The group mean and standard deviation of all measured triplicates were calculated. Two-factor RM ANOVA was applied between groups, followed by Tukey post hoc mean comparison.

[0923] On day 1, approximately 30 - 60 μL of whole blood was collected into tubes containing EDTA anticoagulant. For all treatment groups, these collections were performed 6 hours and 24 hours after the first dosing. Plasma was harvested by centrifugation at 4,000g × 5 min and stored at -80 °C until analysis.

[0924] Working solutions of desired series concentrations were obtained by diluting the analyte stock solution with 50% aqueous acetonitrile. 5 μL of the working solutions (1, 2, 4, 10, 20, 100, 200, 1000, 2000 ng / mL) were added to 10 μL of blank NOD SCID mouse plasma to obtain calibration standards at 0.5 - 1000 ng / mL (0.5, 1, 2, 5, 10, 50, 100, 500, 1000 ng / mL) in a total volume of 15 μL. Five quality control samples at 1 ng / mL, 2 ng / mL, 5 ng / mL, 50 ng / mL, and 800 ng / mL were prepared independently of the samples used for the calibration curve. These QC samples were prepared on the day of analysis in the same manner as the calibration standards.

[0925] 15 μL of the standards, 15 μL of the QC samples, and 15 μL of the unknown samples (10 μL of plasma containing 5 μL of blank solution) were added separately to 200 μL of acetonitrile containing the IS mixture for protein precipitation. The samples were then vortexed for 30 s and centrifuged at 4000 rpm for 15 min at 4 °C. The supernatant was diluted 3 times with water. 10 μL of the diluted supernatant was injected into the LC / MS / MS system for quantitative analysis. Non-compartmental models were used, and PK triplicates were estimated using Phoenix (WinNonlin) pharmacokinetic software version 8.3.

[0926] On day 28, tissues were collected from the animals. Approximately 30 - 60 μL of whole blood was collected into a tube containing EDTA anticoagulant, and plasma was harvested by centrifugation at 4,000 g × 5 min and stored at -80 °C until analysis. Plasma analysis followed the same protocol as the plasma analysis on day 1. Additionally, the femurs of the mice were excised and placed into pre-weighed tubes. Bone marrow was harvested by centrifugation at 8,000 g × 15 min. Then, the total weight of both the bone marrow and the tube was recorded. The bone marrow was stored at -80 °C until analysis.

[0927] When the tumor volume was on average approximately 150 - 200 mm 3 (n = 8 animals / group), treatment was initiated using QD (once a day) oral administration with Example 9 and Compound A at 10 mg / kg and 100 mg / kg, respectively. The initial treatment period for Example 9 and Compound A was 28 days, after which the overall efficacy and tolerance were evaluated based on the changes in tumor volume and body weight observed during the treatment period ( Figure 1a and Figure 1b ). Additionally, after compound treatment, the animals were observed for an additional 28 days without compound treatment.

[0928] On day 28, when compared to the vehicle control using a one-way ordinary ANOVA test, Example 9 administered orally at 100 mg / kg once a day induced an anti-tumor response against OVCAR-3 xenografts in mice, where the T / C% value was -4% and the TGI% was 104%, p-value = <0.0001( Figure 1a ). Based on body weight, administration of all concentrations of Example 9 was well tolerated( Figure 1b ).

[0929] When the tumor volume was on average approximately 150 - 200 mm 3 (n = 8 animals / group), treatment was initiated using Example 1 at 100 mg / kg with QD (once a day), 100 mg / kg QOD (every other day), 100 mg / kg administered once a day for 4 days followed by 3 days without administration, and Compound A at 100 mg / kg with QD (once a day) oral administration. The initial treatment period for Example 1 was 28 days, after which the overall efficacy and tolerance were evaluated based on the changes in tumor volume and body weight observed during the treatment period ( Figure 2a and Figure 2b ).

[0930] On day 28, when compared to the vehicle control using a one-way ordinary ANOVA test, Example 1 administered orally at 100 mg / kg for 4 days followed by 3 days without administration induced an anti-tumor response against OVCAR-3 xenografts in mice, where the T / C% value was -2% and the TGI% was 102%, p-value = <0.0001(Figure 2a )。Based on body weight, administration of all concentrations in Example 1 was well tolerated ( Figure 2b ).

[0931] When the tumor volume was on average approximately 150 - 200 mm 3 (n = 8 animals / group), treatment was initiated by oral administration using, for example, Example 29b at 10 mg / kg and 30 mg / kg QD and Compound A at 100 mg / kg QD. The initial treatment period for Example 1 was 28 days, after which overall efficacy and tolerance were evaluated based on changes in tumor volume and body weight observed during the treatment period ( Figure 3a and Figure 3b ).

[0932] On day 28, when compared to the vehicle control using a one - way ordinary ANOVA test, oral administration of Example 29b at 30 mg / kg once daily induced an anti - tumor response against OVCAR - 3 xenografts in mice, where the T / C% value was 1% and the TGI% was 99%, p - value = <0.0001( Figure 3a ). Based on body weight, administration of all concentrations of Example 29b was well tolerated ( Figure 3b ). As can be seen, despite having a shorter half - life and faster clearance rate, Example 29b showed a significant reduction in tumor growth in a dose - dependent manner.

[0933] In addition, bone marrow was collected from orally treated mice dosed with Example 29b at 10 mg / kg QD and 30 mg / kg QD and Compound A at 30 mg / kg QD, and the total compound concentrations observed in the bone marrow are shown in Table 3. Samples were collected from the animals 6 h after the last compound administration and 24 h after the last compound administration.

[0934] Table 3. Concentrations of Example 29b and Compound A in bone marrow 6 h and 24 h after the last administration for 28 - day in vivo efficacy in OVCAR - 3 xenografts

[0935]

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein: X 1 and X 2 are each 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- to 10-membered monocyclic or bicyclic heterocyclic group; Z is *-NHC(O)- or *-C(O)NH-, where *- represents the connection to Ring A; o is an integer from 0 to 3; R 1 is C 1-6 alkyl, C 3-6 cycloalkyl, a 3- to 6-membered monocyclic heterocyclic group, OR O1a , SO2R 1a , NR N1a SO2R 1a , NR N1a R N1b , -C(O)R 1a , a halogen group, a cyano group, wherein the C 1-6 alkyl, the C 3-6 cycloalkyl and the 3- to 6-membered monocyclic heterocyclic group are each optionally substituted by one or more R 1b substituents; R 1a is C 1-6 alkyl, NR N1a R N1b , OR O1a , C 3-6 cycloalkyl or a 3- to 6-membered monocyclic heterocyclic group, wherein said C 1-6 alkyl, said C 3-6 cycloalkyl and said 3- to 6-membered monocyclic heterocyclic group are each optionally substituted with one or more R 1b substituents; Each R 1b is independently selected from a halogen group, a cyano group, a hydroxyl group, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group, and a C 1-6 haloalkoxy group; or two Rs 1b which together with one or more atoms to which it is attached forms a C 3-6 cycloalkyl; R N1a and R N1b each independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more R 1b substituents; R O1a is H or C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more R 1b substituents; R 2 is H, C 1-6 alkyl, SO2R 2a , NR N2a SO2R 2a , OR O2a , S(O)(NR N2c )R 2a , halogen, cyano, -C(O)R 2a or NR N2a R N2b , wherein said C 1-6 alkyl is optionally substituted by 1 or more R 2b ; R 2a is C 1-6 alkyl, NR N2a R N2b , OR O2a , C 3-6 cycloalkyl or a 3- to 6-membered monocyclic heterocyclic group, wherein said C 1-6 alkyl, said C 3-6 cycloalkyl and said heterocyclic group are each optionally substituted with 1 or more R 2b substituents; Each R 2b is independently selected from C 1-6 alkyl, halogen, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, -N(R N2c )2 and -C(O)OC 1-6 alkyl; R N2a and R N2b each independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more R 2b substituents; Each R N2c is independently H, C 1-3 alkyl, -C(O)(C 1-3 alkyl); R O2a is H or C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted by 1 or more halogen groups, hydroxyl groups, C 1-6 alkoxy groups or C 1-6 haloalkoxy groups; R 3 is C 3-6 a cycloalkyl group, a phenyl group or a 3- to 6-membered monocyclic heterocyclic group, wherein the 3- to 6-membered monocyclic heterocyclic group is optionally substituted with one or more R 3a substituents; Each R 3a is independently selected from a halogen group, C 1-6 haloalkyl, or C 1-6 alkyl; or two Rs 3a together with one or more atoms to which they are attached form a C 3b cycloalkyl substituted with 1 or more Rs 3-6 ; Each R 3b is independently selected from H, a halogen group, C 1-6 alkoxy and optionally C substituted with one or more halogen groups, OH or C 1-3 alkoxy; 1-6 alkyl; R 4 is H, C 1-6 alkyl, C 1-6 haloalkyl or halo group; R 5 is H, a halogen group or C 1-6 alkyl; Each R 6 is independently C 1-6 alkyl, C 1-6 haloalkyl or halo; Provided that when ring A is phenyl or 6-membered heteroaryl, then R 3 is where j is 0 or 1.

2. The compound according to claim 1, wherein the compound is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein: X 1 and X 2 are each 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- to 10-membered monocyclic or bicyclic heterocyclic group; Z is *-NHC(O)- or *-C(O)NH-, where *- represents the connection to Ring A; o is an integer from 0 to 3; R 1 is C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered monocyclic heterocyclic group, OR O1a , SO2R 1a , NR N1a SO2R 1a , NR N1a R N1b , -C(O)R 1a , halogen, cyano, wherein said C 1-6 alkyl, said C 3-6 cycloalkyl and said 3- to 6-membered monocyclic heterocyclic group are each optionally substituted with one or more R 1b substituents; R 1a is C 1-6 alkyl, NR N1a R N1b , OR O1a , C 3-6 cycloalkyl or a 3- to 6-membered monocyclic heterocyclic group, wherein said C 1-6 alkyl, said C 3-6 cycloalkyl and said 3- to 6-membered monocyclic heterocyclic group are each optionally substituted with one or more R 1b substituents; Each R 1b is independently selected from a halogen group, a hydroxyl group, a C 1-6 alkyl group, a C 1-6 alkoxy group, and a C 1-6 haloalkoxy group; or two Rs 1b which together with the atom to which it is attached forms a C 3-6 cycloalkyl group; R N1a and R N1b each independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more R 1b substituents; R O1a is H or C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted by one or more R 1b substituents; R 2 is H, C 1-6 alkyl, SO2R 2a , NR N2a SO2R 2a , OR O2a , halo, cyano, -C(O)R 2a or NR N2a R N2b , wherein said C 1-6 alkyl is optionally substituted with 1 or more R 2b ; R 2a is C 1-6 alkyl, NR N2a R N2b , OR O2a , C 3-6 cycloalkyl or a 3- to 6-membered monocyclic heterocyclic group, wherein said C 1-6 alkyl, said C 3-6 cycloalkyl and said heterocyclic group are each optionally substituted by 1 or more R 2b substituents; Each R 2b is independently selected from 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 each independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more R 2b substituents; R O2a is H or C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1 or more halo groups, hydroxy groups, C 1-6 alkoxy groups or C 1-6 haloalkoxy groups; R 3 is C 3-6 a cycloalkyl, phenyl or 3- to 6-membered monocyclic heterocyclic group, wherein said 3- to 6-membered monocyclic heterocyclic group is optionally substituted with 1 or more R 3a substituents; Each R 3a is independently selected from a halogen group or a C 1-6 alkyl group; or two Rs 3a together with one or more atoms to which they are attached form a C 3b cycloalkyl group substituted with 1 or more Rs 3-6 ; Each R 3b is independently selected from H, a halogen group, C 1-6 alkoxy and optionally C substituted with one or more halogen groups or OH 1-6 alkyl; R 4 is H, C 1-6 alkyl, C 1-6 haloalkyl or halo group; R 5 is H or C 1-6 alkyl; Each R 6 is independently C 1-6 alkyl, C 1-6 haloalkyl or halo group; Provided that when ring A is phenyl or 6-membered heteroaryl, then R 3 is 3. The compound according to claim 1, wherein the compound is represented by formula (I): or a pharmaceutically acceptable salt thereof, wherein: X 1 and X 2 each independently is 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- to 10-membered monocyclic or bicyclic heterocyclic group; Z is *-NHC(O)- or *-C(O)NH-, where *- represents the connection to Ring A; o is an integer from 0 to 3; R 1 is C 1-6 alkyl, C 3-6 cycloalkyl, a 3- to 6-membered monocyclic heterocyclic group, OR O1a , SO2R 1a , NR N1a SO2R 1a , NR N1a R N1b , -C(O)R 1a , a halogen group, a cyano group, wherein the C 1-6 alkyl, the C 3-6 cycloalkyl and the 3- to 6-membered monocyclic heterocyclic group are each optionally substituted by one or more R 1b substituents; R 1a is C 1-6 alkyl, NR N1a R N1b , OR O1a , C 3-6 cycloalkyl or a 3- to 6-membered monocyclic heterocyclic group, wherein the C 1-6 alkyl, the C 3-6 cycloalkyl and the 3- to 6-membered monocyclic heterocyclic group are each optionally substituted by one or more R 1b substituents; Each R 1b is independently selected from a halogen group, a hydroxyl group, a C 1-6 alkyl group, a C 1-6 alkoxy group, and a C 1-6 haloalkoxy group; or two Rs 1b which together with the atom to which it is attached forms a C 3-6 cycloalkyl group; R N1a and R N1b each independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more R 1b substituents; R O1a is H or C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted by one or more R 1b substituents; R 2 is H, C 1-6 alkyl, SO2R 2a , NR N2a SO2R 2a , OR O2a , halogen, cyano, -C(O)R 2a or NR N2a R N2b , wherein said C 1-6 alkyl is optionally substituted with 1 or more R 2b ; R 2a is C 1-6 alkyl, NR N2a R N2b , OR O2a , C 3-6 cycloalkyl or a 3- to 6-membered monocyclic heterocyclic group, wherein said C 1-6 alkyl, said C 3-6 cycloalkyl and said heterocyclic group are each optionally substituted with 1 or more R 2b substituents; Each R 2b is independently selected from C 1-6 alkyl, halogen, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy and -C(O)OC 1-6 alkyl; R N2a and R N2b each independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more R 2b substituents; R O2a is H or C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1 or more halo groups, hydroxy groups, C 1-6 alkoxy groups or C 1-6 haloalkoxy groups; R 3 is C 3-6 a cycloalkyl group, a phenyl group or a 3- to 6-membered monocyclic heterocyclic group, wherein the 3- to 6-membered monocyclic heterocyclic group is optionally substituted with one or more R 3a substituents; Each R 3a is independently selected from a halogen group or a C 1-6 alkyl group; or two Rs 3a together with the atom to which they are attached form a C 3-6 cycloalkyl group; R 4 is H, C 1-6 alkyl, C 1-6 haloalkyl or halogen; R 5 is H or C 1-6 alkyl; Each R 6 is independently C 1-6 alkyl, C 1-6 haloalkyl or halo group; Provided that when ring A is phenyl or 6-membered heteroaryl, R 3 is 4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein Z is *-C(O)NH-, where * represents the connection to ring A.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl, 6-membered heteroaryl or 6,5-bicyclic heteroaryl, each of which is substituted by R 2 , R 3 and 0 to 2 R 6 substituents.

6. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl, 6-membered heteroaryl or 6,5-bicyclic heteroaryl, each of which is substituted by R 2 , R 3 and 0 to 1 R 6 substituents.

7. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl, pyridyl, pyrazinyl or indazolyl, each of which is substituted by R 2 , R 3 and 0 to 2 R 6 substituents.

8. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl, pyridyl or indazolyl, each of which is substituted by R 2 , R 3 and 0 to 1 R 6 substituents.

9. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein ring A is represented by the following structural formula: each of which is substituted by R 2 , R 3 and 0 to 2 R 6 substituents.

10. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein ring A is represented by the following structural formula: each of which is substituted by R 2 , R 3 and 0 to 1 R 6 substituents.

11. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein ring A is represented by the following structural formula:

12. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein ring A is represented by the following structural formula:

13. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein ring A is represented by the following structural formula:

14. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein ring A is a phenyl group substituted by R 2 and R 3 .

15. A compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein ring A is represented by the following structural formula:

16. A compound according to any one of claims 1 to 15, wherein the compound is represented by formula (IA): or a pharmaceutically acceptable salt thereof.

17. A compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein: X 1 and X 2 both are N and X 3 is CR 4 ; or X 1 and X 3 both are N and X 2 is CR 5 .

18. A compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein one of X 3 is CR 4 , one of X 1 or X 2 is N, and the other is CR 5 .

19. A compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein X 3 is CR 4 , and both X 1 and X 2 are CR 5 .

20. A compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, wherein R 4 is H or -CH3 and R 5 is H, -F or -CH3.

21. A compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, wherein R 4 is H or -CH3 and R 5 is H or -CH3.

22. A compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, wherein R 4 is H and R 5 is H or -CH3.

23. A compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, wherein R 3 is optionally substituted by 1 to 3 R3a A substituted 5- or 6-membered monocyclic heterocyclic group.

24. The compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, wherein R 3 is a 6-membered monocyclic heterocyclic group optionally substituted with 1 to 3 R 3a groups.

25. The compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, wherein R 3 is piperidinyl, 1,3-azasilacyclopentyl or 1,4-azasilacyclohexyl, each optionally substituted with 1 to 3 R 3a groups.

26. The compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, wherein R 3 is piperidinyl or 1,4-azasilacyclohexyl, each optionally substituted with 1 to 3 R 3a groups.

27. The compound according to claim 25 or a pharmaceutically acceptable salt thereof, wherein R 3 is represented by the following structural formula: wherein j is 0 or 1, each optionally substituted with 1 to 3 R 3a groups.

28. The compound according to claim 26 or a pharmaceutically acceptable salt thereof, wherein R 3 is represented by the following structural formula: each optionally substituted with 1 to 3 R 3a groups.

29. The compound according to claim 27 or a pharmaceutically acceptable salt thereof, wherein R 3 is represented by the following structural formula: and each R 3a is C 1-3 alkyl, or two R 3a together with one or more atoms to which they are attached form a C 3b cycloalkyl group substituted with 1 to 3 R 3-6 groups.

30. The compound according to claim 28 or a pharmaceutically acceptable salt thereof, wherein R 3 is represented by the following structural formula: and each R 3a is C 1-3 alkyl, or two R 3a together with one or more atoms to which they are attached form a C 3b cycloalkyl group substituted with 1 to 3 R 3-6 groups.

31. The compound according to claim 28 or a pharmaceutically acceptable salt thereof, wherein R3 is represented by the following structural formula: and each R 3a is C 1-3 alkyl, or two Rs 3a together with the atom(s) to which they are attached form C 3-6 cycloalkyl.

32. The compound or a pharmaceutically acceptable salt thereof according to claim 30, wherein each R 3a is -CH3 or -CH2CH3, or two Rs 3a together with one or more atoms to which they are attached form a cyclopropyl or cyclobutyl group substituted with 1 to 3 Rs 3b and each R 3b is independently H, halogen, -CH3, -OCH3, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2OCH3 or -CH2OH.

33. The compound or a pharmaceutically acceptable salt thereof according to claim 31, wherein each R 3a is -CH3, or two Rs 3a together with one or more atoms to which they are attached form a cyclopropyl group substituted with 1 to 3 Rs 3b and each R 3b is independently H, halogen, -CH3, -CHF2 or -CH2OH.

34. The compound or a pharmaceutically acceptable salt thereof according to claim 31, wherein each R 3a is -CH3, or two Rs 3a together with the atom(s) to which they are attached form a cyclopropyl group.

35. The compound or a pharmaceutically acceptable salt thereof according to claim 32, wherein R 3 is represented by the following structural formula:

36. The compound or a pharmaceutically acceptable salt thereof according to claim 33, wherein R 3 is represented by the following structural formula:

37. The compound or a pharmaceutically acceptable salt thereof according to claim 34, wherein R 3 is represented by the following structural formula:

38. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 32 to 34, wherein each R 3a is -CH3.

39. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 38, wherein: R 1 is C 3-6 cycloalkyl, 3- to 6-membered monocyclic heterocyclic group, OR O1a or SO2R 1a , wherein said C 3-6 cycloalkyl and said 3- to 6-membered monocyclic heterocyclic group are each optionally substituted with 1 to 3 R 1b substituents; R 1a is -NHR N1b , C 3-6 cycloalkyl or a 3- to 6-membered monocyclic heterocyclic group, wherein the 3- to 6-membered monocyclic heterocyclic group is optionally substituted with 1 to 3 halogen groups; R N1b Optionally substituted by 1 or 2 R 1b substituted C 1-4 alkyl; R O1a Optionally substituted by 1 to 3 R 1b alkyl 1-3 groups; Each R 1b is independently selected from a halogen group, a cyano group, C 1-3 haloalkyl, and C 1-3 alkyl; or two Rs 1b which together with one or more atoms to which it is attached forms a C 3-6 cycloalkyl group.

40. A compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof, wherein: R 1 is C 3-6 cycloalkyl, 3- to 6-membered monocyclic heterocyclic group, OR O1a or SO2R 1a , wherein said C 3-6 cycloalkyl and said 3- to 6-membered monocyclic heterocyclic group are each optionally substituted with 1 to 3 R 1b substituents; R 1a is -NHR N1b , C 3-6 cycloalkyl or a 3- to 6-membered monocyclic heterocyclic group, wherein the 3- to 6-membered monocyclic heterocyclic group is optionally substituted with 1 to 3 halogen groups; R N1b optionally substituted by 1 or 2 R 1b alkyl 1-4 groups; R O1a Optionally substituted by 1 to 3 R 1b substituted C 1-3 alkyl; Each R 1b is independently selected from a halogen group and a C 1-3 alkyl group; or two Rs 1b which together with the atom to which it is attached forms a C 3-6 cycloalkyl group.

41. A compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof, wherein: R 1 is C 3-6 cycloalkyl, 3- to 6-membered monocyclic heterocyclic group, OR O1a or SO2R 1a , wherein said C 3-6 cycloalkyl and said 3- to 6-membered monocyclic heterocyclic group are each optionally substituted with 1 to 3 R 1b substituents; R 1a is - NHR N1b or C 3-6 cycloalkyl; R N1b Optionally substituted by 1 or 2 R 1b substituted C 1-4 alkyl; R O1a Optionally substituted by 1 to 3 R 1b alkyl 1-3 groups; Each R 1b is independently selected from a halogen group and C 1-3 alkyl; or two Rs 1b which together with the atom to which it is attached forms a C 3-6 cycloalkyl group.

42. A compound according to claim 39 or a pharmaceutically acceptable salt thereof, wherein: 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, wherein the cyclopropyl, the cyclohexyl, the morpholinyl, the piperidinyl, the piperidinyl of the -SO2-piperidinyl, the azetidinyl, the 3H-diazirinyl and the pyrrolidinyl are each optionally substituted with 1 to 3 R 1b substituents; and Each R 1b is -F, -CN, -CF3 or -CH3; or two Rs 1b which together with the atoms to which they are attached form a cyclopropyl group.

43. A compound according to claim 40 or a pharmaceutically acceptable salt thereof, wherein: R 1 is -S(O)2NHC(CH3)3, -SO2-cyclopentyl, -SO2-piperidinyl, -OCH2CH2CF3, cyclopropyl, cyclohexyl, morpholinyl, piperidinyl, azetidinyl or pyrrolidinyl, wherein the cyclopropyl, the cyclohexyl, the morpholinyl, the piperidinyl, the piperidinyl of the -SO2-piperidinyl, the azetidinyl and the pyrrolidinyl are each optionally substituted with 1 to 3 R 1b substituents; and Each R 1b is -F or -CH3; or two Rs 1b which together with the atom to which it is attached form a cyclopropyl group.

44. A compound according to claim 41 or a pharmaceutically acceptable salt thereof, wherein: R 1 is -S(O)2NHC(CH3)3, -SO2-cyclopentyl, -OCH2CH2CF3, cyclopropyl, cyclohexyl, morpholinyl, piperidinyl, azetidinyl or pyrrolidinyl, wherein the cyclopropyl, the cyclohexyl, the morpholinyl, the piperidinyl, the azetidinyl and the pyrrolidinyl are each optionally substituted with 1 to 3 R 1b substituents; and Each R 1b is -F or -CH3; or two Rs 1b which together with the atom to which it is attached forms a cyclopropyl group.

45. A compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof, wherein: R 1 is C 3-6 cycloalkyl, 3- to 6-membered monocyclic heterocyclic group or SO2R 1a , wherein said C 3-6 cycloalkyl and said 3- to 6-membered monocyclic heterocyclic group are each optionally substituted with 1 to 3 R 1b substituents; R 1a is - NHR N1b ; R N1b is C 1-4 alkyl; Each R 1b is independently a halogen group.

46. The compound according to claim 45 or a pharmaceutically acceptable salt thereof, wherein: R 1 is -S(O)2NHC(CH3)3, cyclohexyl, morpholinyl or piperidinyl, wherein the cyclohexyl, the morpholinyl and the piperidinyl are each optionally substituted with 1 to 3 R 1b substituents; and Each R 1b is -F.

47. The compound according to claim 45 or 46 or a pharmaceutically acceptable salt thereof, wherein R 1 is -S(O)2NHC(CH3)3, or R 1 is represented by the following structural formula:

48. The compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, wherein: R 2 is H, C 1-3 alkyl, NR N2a R N2b , SO2R 2a , S(O)(NH)R 2a or NHSO2R 2a , wherein said C 1-3 alkyl is optionally substituted with 1 to 3 R 2b substituents; R 2a is C 1-4 alkyl, -NHR N2b 、C 3-4 cycloalkyl or a 3- to 6-membered monocyclic heterocyclic group, wherein said C 1-3 alkyl and said 3- to 6-membered monocyclic heterocyclic group are each optionally substituted by 1 to 3 R 2b substituents; R N2a and R N2b each independently is H or optionally C 2b alkyl which is substituted by 1 to 3 R 1-3 groups; Each R 2b is independently selected from a hydroxyl group, -N(R N2c )2 and C 1-3 alkyl; Each R N2c is independently H, C 1-3 alkyl, -C(O)(C 1-3 alkyl).

49. The compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, wherein: R 2 is H, C 1-3 alkyl, SO2R 2a or NHSO2R 2a , wherein said C 1-3 alkyl is optionally substituted with 1 to 3 R 2b substituents; R 2a is C 1-4 alkyl, -NHR N2b or a 3- to 6-membered monocyclic heterocyclic group, wherein the C 1-3 alkyl and the 3- to 6-membered monocyclic heterocyclic group are each optionally substituted with 1 to 3 R 2b substituents; R N2b Optionally substituted by 1 to 3 R 2b substituted C 1-3 alkyl; Each R 2b is independently selected from a hydroxyl group and C 1-3 alkyl group.

50. The compound according to claim 48 or a pharmaceutically acceptable salt thereof, wherein R 2 is H, -NHS(O)2CH3, -NHS(O)2CH2CH2OH, -NHS(O)2CH2CH2NH2, -NHS(O)2CH2CH2NHCH3, NHS(O)2CH2CH2NHC(O)CH3, -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 represented by the following formula:

51. The compound according to claim 49 or a pharmaceutically acceptable salt thereof, wherein R 2is H, -NHS(O)2CH3, -NHS(O)2CH2CH2OH, -NHS(O)2C(CH3)3, -NHS(O)2NHCH2CH2OH, -S(O)2NHCH2CH2OH, -CH2CH2OH, or R 2 is represented by the formula:

52. The compound according to claim 49 or a pharmaceutically acceptable salt thereof, wherein R 2 is H, -NHS(O)2CH3, -NHS(O)2CH2CH2OH, -NHS(O)2C(CH3)3, -S(O)2NHCH2CH2OH, -CH2CH2OH, or R 2 is represented by the formula:

53. The compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, wherein: R 2 is NHSO2R 2a ; R 2a optionally substituted by 1 to 3 R 2b alkyl 1-4 groups; Each R 2b is a hydroxyl group.

54. The compound according to claim 53 or a pharmaceutically acceptable salt thereof, wherein R 2 is -NHS(O)2CH2CH2OH or -NHS(O)2C(CH3)3.

55. The compound according to any one of claims 1 to 54 or a pharmaceutically acceptable salt thereof, wherein R 4 is H or C 1-3 alkyl.

56. The compound according to claim 55 or a pharmaceutically acceptable salt thereof, wherein R 4 is H or -CH3.

57. The compound according to any one of claims 1 to 13 and 17 to 56 or a pharmaceutically acceptable salt thereof, wherein each R 6 is a halogen group.

58. The compound according to claim 57 or a pharmaceutically acceptable salt thereof, wherein each R 6 is -F.

59. The compound according to any one of claims 1 to 56 or a pharmaceutically acceptable salt thereof, wherein o is 0.

60. The compound according to claim 1, wherein the compound is represented by formula (II), formula (III) or formula (IV): or a pharmaceutically acceptable salt thereof, wherein: X 1 and X 2 are each independently CR 5 or N, and X 3 is CR 4 or N; R 1 is C 3-6 cycloalkyl, 3- to 6-membered monocyclic heterocyclic group or SO2R 1a , wherein said C 3-6 cycloalkyl and said 3- to 6-membered monocyclic heterocyclic group are each optionally substituted with 1 to 3 Rs 1b ; R 1a is - NHR N1b ; R N1b is C 1-4 alkyl; Each R 1b is independently a halogen group; R 2 is NHSO2R 2a ; R 2a Optionally substituted by 1 or 2 R 2b alkyl 1-4 groups; Each R 2b is a hydroxyl group; R 3b is H, a halogen group, C 1-3 alkyl or C 1-3 haloalkyl; R 4 is H or C 1-3 alkyl; R 5 is H or C 1-3 alkyl group.

61. The compound according to claim 1, wherein the compound is represented by formula (II) or formula (III): or a pharmaceutically acceptable salt thereof, wherein: X 1 and X 2 each independently is CR 5 or N, and X 3 is CR 4 or N; R 1 is C 3-6 cycloalkyl, 3- to 6-membered monocyclic heterocyclic group or SO2R 1a , wherein said C 3-6 cycloalkyl and said 3- to 6-membered monocyclic heterocyclic group are each optionally substituted with 1 to 3 R 1b substituents; R 1a is - NHR N1b ; R N1b is C 1-4 alkyl; Each R 1b is independently a halogen group; R 2 is NHSO2R 2a ; R 2a Optionally substituted by 1 or 2 R 2b alkyl 1-4 groups; Each R 2b is a hydroxyl group; R 3b is H, C 1-3 alkyl or C 1-3 haloalkyl; R 4 is H or C 1-3 alkyl; R 5 is H or C 1-3 alkyl group.

62. The compound according to claim 1, wherein the compound is represented by formula (II): or a pharmaceutically acceptable salt thereof, wherein: X 1 and X 2 are each independently CR 5 or N, and X 3 is CR 4 or N; R 1 is C 3-6 cycloalkyl, 3- to 6-membered monocyclic heterocyclic group or SO2R 1a , wherein said C 3-6 cycloalkyl and said 3- to 6-membered monocyclic heterocyclic group are each optionally substituted with 1 to 3 R 1b substituents; R 1a is - NHR N1b ; R N1b is C 1-4 alkyl; Each R 1b is independently a halogen group; R 2 is NHSO2R 2a ; R 2a Optionally substituted by 1 or 2 R 2b substituted C 1-4 alkyl; Each R 2b is a hydroxyl group; R 4 is H or C 1-3 alkyl; R 5 is H or C 1-3 alkyl group 63. The compound according to claim 60, wherein the compound is represented by formula (IIA), formula (IIB), formula (IIC), formula (IID), formula (IIE), formula (IIIA) or formula (IVA): or a pharmaceutically acceptable salt thereof.

64. The compound according to claim 61, wherein the compound is represented by formula (IIA), formula (IIB), formula (IIC), formula (IID), formula (IIE) or formula (IIIA): or a pharmaceutically acceptable salt thereof.

65. The compound according to claim 62, wherein the compound is represented by formula (IIA), formula (IIB), formula (IIC), formula (IID) or formula (IIE): or a pharmaceutically acceptable salt thereof.

66. The compound according to claim 63 or 64, wherein the compound is represented by formula (IIIA): or a pharmaceutically acceptable salt thereof.

67. The compound according to claim 63, wherein the compound is represented by formula (IVA): or a pharmaceutically acceptable salt thereof.

68. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 60 to 67, wherein: R 1 is -S(O)2NHC(CH3)3, cyclohexyl, morpholinyl or piperidinyl, wherein the cyclohexyl, the morpholinyl and the piperidinyl are each optionally substituted with 1 to 2 R 1b substituents; and Each R 1b is -F.

69. The compound or a pharmaceutically acceptable salt thereof according to claim 68, wherein R 1 is -S(O)2NHC(CH3)3, or R 1 is represented by the following structural formula:

70. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 60 to 69, wherein R 2 is -NHS(O)2CH2CH2OH or -NHS(O)2C(CH3)3.

71. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 60 to 70, wherein R 4and R 5 are each H or -CH3.

72. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 60 to 71, wherein R 3b is H, -F, -CH3, -CH2F or -CHF2.

73. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 60 to 71, wherein R 3b is H, -CH3 or -CHF2.

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

75. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 74 and a pharmaceutically acceptable excipient.

76. A method of treating a KIF18A-mediated disease or disorder in a subject, comprising administering to the subject the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 74 or the pharmaceutical composition according to claim 75.

77. The method according to claim 76, wherein the disease or disorder is cancer.

78. The method according to claim 77, wherein the cancer is chromosomally unstable cancer.

79. The method according to claim 76 or 77, wherein the cancer exhibits whole genome doubling.

80. The method according to any one of claims 77 to 79, wherein the cancer has a mutation in TP53, BRCA1, BRCA2, RB1 and / or an amplification in CCNE1.

81. The method according to any one of claims 77 to 80, wherein the cancer is small cell lung cancer, non-small cell lung cancer, pancreatic cancer, triple negative breast cancer, colorectal cancer, hepatobiliary duct 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, uterine cancer, cervical cancer or bone cancer.

82. The method according to claim 76, wherein the disease or disorder is (a) a solid or blood-borne tumor selected from bladder cancer, endometrial cancer, squamous cell lung cancer, 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) a hematopoietic tumor of lymphoid lineage selected from leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkitt's lymphoma; (c) a hematopoietic tumor of myeloid lineage selected from acute and chronic myelogenous leukemia, myelodysplastic syndrome, and promyelocytic leukemia; (d) a tumor of mesenchymal origin selected from fibrosarcoma and rhabdomyosarcoma; (e) a tumor of the central and peripheral nervous systems selected from astrocytoma, neuroblastoma, glioma, and schwannoma; or (f) melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, or Kaposi's sarcoma.

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