Compounds for inhibiting KIF18A

Abstract

The present disclosure relates broadly to inhibitors of KIF18A, compositions thereof, and methods of using said compounds and compositions thereof. More specifically, the present disclosure relates to inhibitors of KIF18A and methods of using them to treat KIF18A-mediated diseases, such as cancer. (I) [Formula 1] TIFF2025515484000513.tif60170

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 336,183, filed April 28, 2022, U.S. Provisional Patent Application No. 63 / 389,237, filed July 14, 2022, and U.S. Provisional Patent Application No. 63 / 456,342, filed March 31, 2023, the disclosures of each of which are incorporated herein by reference in their entirety.

[0002] The present disclosure relates generally to inhibitors of KIF18A, compositions thereof, and methods of using such compounds and compositions thereof. More specifically, the present disclosure relates to inhibitors of KIF18A and methods of using them to treat KIF18A-mediated diseases, such as cancer. [Background technology]

[0003] KIF18A is a kinesin involved in supporting kinetochore microtubule (kt-MT) attachment and chromosome alignment during cell mitosis. Its cargo domain directly binds to protein phosphatase 1 (PP1) and delivers it to the plus ends of MTs, where PP1 dephosphorylates Hec1 (a component of the kinetochore complex), further enhancing kt-MT attachment throughout metaphase and anaphase. Its MT-binding motor domain possesses ATPase activity, which powers KIF18A's movement along the MT lattice, enhanced by its C-terminal MT-binding site. It caps and depolymerizes growing microtubules at the plus end, dampening MT dynamics. This regulation of MT dynamics by KIF18A often occurs at the next (or subsequent) sister chromatid, thereby providing counterbalancing tension against the movement of the preceding sister chromatid, which is catalyzed by another kinesin, Kif2C / MCAK. Loss of KIF18A function causes defective kT-MT binding and loss of intramitotic spindle tension in cells with high chromosomal instability (CIN), resulting in hyperstable, elongated, and multipolar spindles, mitotic arrest, centrosome fragmentation, and spindle assembly checkpoint activation or cell death. KIF18A was identified from a reanalysis of DEPMAP RNAi data as one of the top candidates essential for CIN-high cells. A reported synthetic lethality screen also identified KIF18A as a potential anticancer drug target, whose knockdown preferentially kills CIN-high (but not CIN-low) cells, aneuploid cells, and whole-genome-doubled cells. Cytotoxicity assays in isogenic cell lines confirmed the enhanced sensitivity of CIN-high cells to KIF18A inhibitors. Ongoing in vivo mouse models using KIF18A inhibitors or knockdown demonstrated the effects of inhibited tumor growth. Therefore, there is a need for new compounds for use in the treatment of KIF18A-mediated diseases. Summary of the Invention

[0004] The present disclosure provides compounds of formula (I), (II), and (III), compositions thereof, and methods of using the compounds and compositions thereof for treating diseases or conditions associated with KIF18a. In one aspect, a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein X and Z are independently O, N, or CH; Y is NH, N, or CH; V and W are independently N or C; wherein at least one of X and Z is N or Y is NH; and ring A is [ka] where A 1 , A 3 , and A 4 One, two, or three of these are independently N, NR A1 , O, or S, and if present, A 1 , A 3 , and A 4 The remaining one or two are independently CH or CR 2 where R A1 is H or C 1~3 Alkyl; A 2 is N or C; A 5 ~A 8 are CH, CR independently 2 , N, or NR A2 where A 5 , A 6 , A 7 , and A 8 At least two of these are CH or CR 2 and if it exists, A 5 , A 6 , A 7 , and A 8 The remaining one or two are N or NR A2 where R A2 is =O; where "*" indicates the point of attachment to V; B 1 and B 2 are each independently N, CH, or CRB where R B is a halogen; R 1 is C 1~6 Alkyl, C 3~6 Cycloalkyl, C 3~10 Cycloalkenyl, 3-10 membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 , -NR a4 C(O)OR a5 , -NR a6 R a7 , -N=S(O)R a8 R a9 , -OR a10 , -S(O)R a11 , -S(O)(NR a12 )R a13 , -S(O)NR a14 R a15 , -S(O)2R a16 , or -(CR a17 R a18 ) 0~1 C(O)NR a19 R a20 where R 1 C1-C6 alkyl is halogen, -OH, oxo, cyano, C 3~10 optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo; 1 C 3~6 The cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; 1 C 3~10 The cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; and 1 The 3- to 10-membered heterocycloalkyl may be halogen, C 1~6 Alkyl, and C 1~6 optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl; R a1 ~R a20 are each independently hydrogen, C 1~6 Alkyl, C 2~6Alkenyl, C 3~10 Cycloalkyl, C 3~10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 6~14 aryl, or 5- to 12-membered heteroaryl, each of which is halo, cyano, -OH, -O(C 1~6 alkyl), C 2~6 Alkenyl, C 3~10 Cycloalkyl, -S(C 1~6 alkyl), =CR 1a1 R 1a2 , and halo, -OH, and -O(C 1~6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkyl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1~6 alkyl; or R a14 and R a15 together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl optionally substituted with one or more halo; each R 2 are independently halogens, C 1~3 Alkyl, C 3~5 Cycloalkyl, cyano, C 1~3 Alkyloxy, C 3~5 Cycloalkyloxy, hydroxy, or NR b1 R b2 where R 2 C 1~3 The alkyl is optionally substituted with one or more substituents selected from the group consisting of —OH and oxo, where R b1 and R b2 are independently optionally substituted with C1-C3 alkyl, or R b1 and R b2 form a 3- to 6-membered ring together with the nitrogen to which they are attached; or A 5 R 1 and R 2together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 10-membered heterocycloalkyl; R 3 is piperidinyl, pyrrolidinyl, or azepanyl, where piperidinyl, pyrrolidinyl, or azepanyl is C 3~10 optionally substituted with cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 3~10 The cycloalkyl or 3- to 10-membered heterocycloalkyl may form a spirocyclic or fused bicyclic ring system with piperidinyl, pyrrolidinyl, or azepanyl, or wherein the piperidinyl, pyrrolidinyl, or azepanyl is optionally C 1~2 substituted with alkylene to form a bridged piperidinyl, pyrrolidinyl, or azepanyl ring system, wherein piperidinyl, pyrrolidinyl, azepanyl, or C 3~10 Cycloalkyl, 3-10 membered heterocycloalkyl, or C 1~2 The spirocyclic, fused, or bridged bicyclic ring system formed by alkylene and piperidinyl, pyrrolidinyl, or azepanyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and halo; R 4 is H, halo, cyano, -OH, -NO2, -C(O)NR c1 R c2 , -NR c3 R c4 , -NR c5 S(O)2R c6 , -P(O)R c7 R c8 , -N=S(O)R c9 R c10 , -S(O)(NR c11 )R c12 , -S(O)2R c13 or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH 1~6 alkyl; R c1 ~R c13 are independently hydrogen, C 3~10 Cycloalkyl, or C 1~6 alkyl, where R c1~R c13 each C1-C6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, —OH, and —C(O)—O—C1-C3 alkyl, wherein each C 3~10 The cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkylene-OH. In some embodiments, when X is N, Y is N, and Z is O, then R 4 is not H.

[0005] In another embodiment, the compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein X and Z are independently O, N, or CH; Y is NH or CH; V and W are independently N or C; wherein at least one of X and Z is N or Y is NH; and ring A is [ka] where A 1 , A 3 , and A 4 one or two of which are independently N, O, or S, and A 1 , A 3 , and A 4 The remaining one or two are independently CH or CR 2 and;A 2 is N or C; A 5 ~A 8 are independently CH, CR 2 , or N, where A 5 , A 6 , A 7 , and A 8 At least two of these are CH or CR 2 and if it exists, A 5 , A 6 , A 7 , and A 8 and the remaining one or two of these are N; where "*" indicates the point of attachment to V; B 1and B 2 are each independently N or CH; R 1 is C 1~6 Alkyl, C 3~6 Cycloalkyl, 3-10 membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 , -NR a4 C(O)OR a5 , -NR a6 R a7 , -N=S(O)R a8 R a9 , -OR a10 , -S(O)R a11 , -S(O)(NR a12 )R a13 , -S(O)NR a14 R a15 , -S(O)2R a16 , or -(CR a17 R a18 ) 0~1 C(O)NR a19 R a20 where R 1 C1-C6 alkyl is halogen, -OH, cyano, C 3~10 optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo; 1 C 3~6 Cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; 1 R is a 3- to 10-membered heterocycloalkyl optionally substituted with one or more halogens; a1 ~R a20 are each independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 3~10 Cycloalkyl, C 3~10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 6~14 aryl, or 5- to 12-membered heteroaryl, each of which is halo, cyano, -OH, -O(C 1~6 alkyl), C 2~6Alkenyl, C 3~10 Cycloalkyl, -S(C 1~6 alkyl), =CR 1a1 R 1a2 , and halo, -OH, and -O(C 1~6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkyl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1~6 alkyl; or R a14 and R a15 together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl optionally substituted with one or more halo; each R 2 are independently halogens, C 1~3 Alkyl, C 3~5 Cycloalkyl, cyano, C 1~3 Alkyloxy, C 3~5 Cycloalkyloxy, hydroxy, or NR b1 R b2 where R b1 and R b2 are independently optionally substituted with C1-C3 alkyl, or R b1 and R b2 form a 3- to 6-membered ring together with the nitrogen to which they are attached; or A 5 R 1 and R 2 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocycloalkyl; R 3 is piperidinyl, pyrrolidinyl, or azepanyl, where piperidinyl, pyrrolidinyl, or azepanyl is C 3~10 optionally substituted with cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 3~10 A cycloalkyl or a 3- to 10-membered heterocycloalkyl may form a spirocyclic or fused bicyclic ring system with piperidinyl, pyrrolidinyl, or azepanyl, where piperidinyl, pyrrolidinyl, azepanyl, or C3~10 The spirocyclic or fused bicyclic ring system formed by cycloalkyl or 3-10 membered heterocycloalkyl and piperidinyl, pyrrolidinyl, or azepanyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl and C1-C3 haloalkyl; R 4 is H, halo, cyano, -OH, -NO2, -C(O)NR c1 R c2 , -NR c3 R c4 , -NR c5 S(O)2R c6 , -P(O)R c7 R c8 , -N=S(O)R c9 R c10 , -S(O)(NR c11 )R c12 , -S(O)2R c13 or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH 1~6 alkyl; R c1 ~R c13 are each independently hydrogen, C 3~10 Cycloalkyl, or C 1~6 alkyl, where R c1 ~R c13 wherein each C1-C6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, and -C(O)-O-C1-C3 alkyl.

[0006] In yet another embodiment, a compound of formula (III): [ka] or a pharmaceutically acceptable salt thereof, wherein ring A is [ka] where A 1 , A 3 , and A 4 One, two, or three of these are independently N, NR A1, O, or S, and if present, A 1 , A 3 , and A 4 The remaining one or two are independently CH or CR 2 where R A1 is H or C 1~3 Alkyl; A 2 is N or C; A 5 ~A 8 are CH, CR independently 2 , N, or NR A2 where A 5 , A 6 , A 7 , and A 8 At least two of these are CH or CR 2 and if it exists, A 5 , A 6 , A 7 , and A 8 The remaining one or two are N or NR A2 where R A2 is =O; where "*" indicates the point of attachment to V; B 1 and B 2 are each independently N, CH, or CR B where R B is a halogen; R 1 is C 1~6 Alkyl, C 3~6 Cycloalkyl, C 3~10 Cycloalkenyl, 3-10 membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 , -NR a4 C(O)OR a5 , -NR a6 R a7 , -N=S(O)R a8 R a9 , -OR a10 , -S(O)R a11 , -S(O)(NR a12 )R a13 , -S(O)NR a14 R a15 , -S(O)2R a16 , or -(CR a17 Ra18 ) 0~1 C(O)NR a19 R a20 where R 1 C1-C6 alkyl is halogen, -OH, oxo, cyano, C 3~10 optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo; 1 C 3~6 The cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; 1 C 3~10 The cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; and 1 The 3- to 10-membered heterocycloalkyl may be halogen, C 1~6 Alkyl, and C 1~6 optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl; R a1 ~R a20 are each independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 3~10 Cycloalkyl, C 3~10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 6~14 aryl, or 5- to 12-membered heteroaryl, each of which is halo, cyano, -OH, -O(C 1~6 alkyl), C 2~6 Alkenyl, C 3~10 Cycloalkyl, -S(C 1~6 alkyl), =CR 1a1 R 1a2 , and halo, -OH, and -O(C 1~6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkyl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1~6alkyl; or R a14 and R a15 together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl optionally substituted with one or more halo; each R 2 are independently halogens, C 1~3 Alkyl, C 3~5 Cycloalkyl, cyano, C 1~3 Alkyloxy, C 3~5 Cycloalkyloxy, hydroxy, or NR b1 R b2 where R 2 C 1~3 The alkyl is optionally substituted with one or more substituents selected from the group consisting of —OH and oxo, where R b1 and R b2 are independently optionally substituted with C1-C3 alkyl, or R b1 and R b2 form a 3- to 6-membered ring together with the nitrogen to which they are attached; or A 5 R 1 and R 2 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 10-membered heterocycloalkyl; d1 are independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and halo; or two R d1 Together they form C 3~10 cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 3~10 The cycloalkyl or 3- to 10-membered heterocycloalkyl may form a spirocyclic or fused bicyclic ring system with the piperidinyl; or two R d1 Together they form C 1~2 Forming alkylene, C 1~2 The alkylene forms a bridged piperidinyl ring system, where C 3~10cycloalkyl, 3-10 membered heterocycloalkyl, or the spirocyclic, fused, or bridged bicyclic ring system formed by C1-2 alkylene and piperidinyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and halo; R 4 is H, halo, cyano, -OH, -NO2, -C(O)NR c1 R c2 , -NR c3 R c4 , -NR c5 S(O)2R c6 , -P(O)R c7 R c8 , -N=S(O)R c9 R c10 , -S(O)(NR c11 )R c12 , -S(O)2R c13 or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH 1~6 alkyl; R c1 ~R c13 are each independently hydrogen, C 3~10 Cycloalkyl, or C 1~6 alkyl, where R c1 ~R c13 each C1-C6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, —OH, and —C(O)—O—C1-C3 alkyl, wherein each C 3~10 The cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkylene-OH.

[0007] In another aspect, provided is a pharmaceutical composition comprising a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0008] In another aspect, provided herein is a method for inhibiting KIF18A, comprising contacting a cell with an effective amount of a compound or pharmaceutical composition described herein.

[0009] In another aspect, provided herein is a method for treating or preventing a disease or condition in an individual, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein.In some embodiments, the disease or condition is mediated by KIF18A.In some embodiments, the disease or condition is cancer.In some embodiments, the disease or condition is a cell proliferation disorder.

[0010] The drawings illustrate certain features and advantages of the present disclosure. These embodiments are not intended to limit the scope of the appended claims in any way. [Brief explanation of the drawings]

[0011] [Figure 1] 1 shows a plot of tumor volume over time in an in vivo xenograft ovarian cancer cell line model (OVCAR3) in Balb / c mice treated with compound 47 (at doses of 3, 10, and 30 mg / kg QD PO) compared to vehicle control. [Figure 2] 1 shows a plot of tumor volume over time in an in vivo xenograft non-small cell lung cancer cell line model (HCC15) in Balb / c mice treated with compound 47 (at doses of 3, 10, and 30 mg / kg QD PO) compared to vehicle control. DETAILED DESCRIPTION OF THE INVENTION

[0012] The following description is presented to enable any person skilled in the art to make and use various embodiments. Descriptions of specific devices, techniques, and applications are provided as examples only. Various modifications to the examples described herein will be readily apparent to those skilled in the art, and the general principles defined herein may be applied to other examples and applications without departing from the spirit and scope of the various embodiments. Accordingly, the various embodiments are not intended to be limited to the examples described and shown herein, but rather should be accorded the scope consistent with the appended claims.

[0013] As used herein, the following words and phrases are generally intended to have the meanings set forth below, unless the context in which they are used dictates otherwise.

[0014] Throughout this application, unless the context dictates otherwise, a reference to a compound of Formula (I) includes all subgroups of Formula (I) defined herein, including all substructures, subgenera, selections, embodiments, examples, and specific compounds defined and / or described herein. In some embodiments, a reference to a compound of Formula (I) and its subgroups includes ionic forms, polymorphs, pseudopolymorphs, amorphous forms, solvates, co-crystals, chelates, isomers, tautomers, oxides (e.g., N-oxides, S-oxides), esters, prodrugs, isotopes, and / or protected forms thereof. In some embodiments, a reference to a compound of Formula (I) and its subgroups includes polymorphs, solvates, co-crystals, isomers, tautomers, and / or oxides thereof. In some embodiments, a reference to a compound of Formula (I) and its subgroups includes polymorphs, solvates, and / or co-crystals thereof. In some embodiments, a reference to compounds of Formula (I) and subgroups thereof includes their isomers, tautomers, and / or oxides. In some embodiments, a reference to compounds of Formula (I) and subgroups thereof includes their solvates.

[0015] "Alkyl" includes straight and branched carbon chains having the indicated number of carbon atoms, e.g., 1 to 20 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 3 carbon atoms. For example, C 1~6 Alkyl includes both straight-chain and branched-chain alkyls of 1 to 6 carbon atoms. When an alkyl residue having a specific number of carbon atoms is specified, all branched and straight-chain versions having that number of carbon atoms are intended to be included; thus, for example, "propyl" includes N-propyl and isopropyl, and "butyl" includes n-butyl, sec-butyl, isobutyl, and t-butyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, N-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.

[0016] If a range of values ​​is specified (e.g., C 1~6 alkyl), each value within that range, as well as all ranges therebetween. For example, "C 1-6 "Alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 , C 2-6 , C 3-6 , C 4-6 , C 5-6 , C 1-5 , C 2-5 , C 3-5 , C 4-5 , C 1-4 , C 2-4 , C 3-4 , C 1-3 , C 2-3 , and C 1-2 Contains alkyl.

[0017] "Alkenyl" refers to an unsaturated branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8, or 2 to 6 carbon atoms) and at least one carbon-carbon double bond. The group can be in either the cis or trans configuration (Z or E configuration) about the double bond(s). Alkenyl groups include, but are not limited to, ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl), and butenyl (e.g., but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl).

[0018] "Alkynyl" refers to an unsaturated branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon triple bond. Alkynyl groups include, but are not limited to, ethynyl, propynyl (e.g., prop-1-yn-1-yl, prop-2-yn-1-yl), and butynyl (e.g., but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl).

[0019] "Cycloalkyl" refers to a non-aromatic, fully saturated carbocyclic ring having the indicated number of carbon atoms, e.g., 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms. Cycloalkyl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, as well as polycyclic spiro, fused, bridged, and cage ring groups (e.g., norbornane, bicyclo[2.2.2]octane). In addition, one ring of a polycyclic cycloalkyl group can be aromatic, provided that the polycyclic cycloalkyl group is attached to the parent structure through a non-aromatic carbon atom. For example, 1,2,3,4-tetrahydronaphthalen-1-yl (where the moiety is attached to the parent structure through a non-aromatic carbon atom) is a cycloalkyl group, while 1,2,3,4-tetrahydronaphthalen-5-yl (where the moiety is attached to the parent structure through an aromatic carbon atom) is not considered a cycloalkyl group. Examples of polycyclic cycloalkyl groups consisting of a cycloalkyl group fused to an aromatic ring are described below.

[0020] "Cycloalkenyl" refers to a non-aromatic carbocyclic ring containing the indicated number of carbon atoms (e.g., 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms) and at least one carbon-carbon double bond. Cycloalkenyl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, and cyclohexenyl, as well as bridged and caged ring groups (e.g., bicyclo[2.2.2]octene). Furthermore, one ring of a polycyclic cycloalkenyl group can be aromatic, provided that the polycyclic alkenyl group is connected to the parent structure through a non-aromatic carbon atom. For example, inden-1-yl (which moiety is connected to the parent structure through a non-aromatic carbon atom) is considered a cycloalkenyl group, while inden-4-yl (which moiety is connected to the parent structure through an aromatic carbon atom) is not considered a cycloalkenyl group. Examples of polycyclic cycloalkenyl groups consisting of a cycloalkenyl group fused to an aromatic ring are provided below.

[0021] "Aryl" refers to an aromatic carbocyclic ring having the indicated number of carbon atoms, e.g., 6 to 12 or 6 to 10 carbon atoms. Aryl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In some cases, both rings in a polycyclic aryl group are aromatic (e.g., naphthyl). In other cases, a polycyclic aryl group may contain a non-aromatic ring fused to an aromatic ring, provided that the polycyclic aryl group is attached to the parent structure through an atom in the aromatic ring. Thus, a 1,2,3,4-tetrahydronaphthalen-5-yl group (which is attached to the parent structure through an aromatic carbon atom) is considered an aryl group, while a 1,2,3,4-tetrahydronaphthalen-1-yl group (which is attached to the parent structure through a non-aromatic carbon atom) is not considered an aryl group. Similarly, a 1,2,3,4-tetrahydroquinolin-8-yl group (which moiety is attached to the parent structure through an aromatic carbon atom) is considered an aryl group, while a 1,2,3,4-tetrahydroquinolin-1-yl group (which moiety is attached to the parent structure through a non-aromatic nitrogen atom) is not considered an aryl group. However, the term "aryl" does not encompass or overlap with "heteroaryl," as defined herein, regardless of the point of attachment (e.g., both quinolin-5-yl and quinolin-2-yl are heteroaryl groups). In some instances, an aryl is phenyl or naphthyl. In certain instances, an aryl is phenyl. Further examples of aryl groups comprising an aromatic carbocyclic ring fused to a non-aromatic ring are described below.

[0022] "Heteroaryl" refers to an aromatic ring (e.g., a 5- to 12-membered or 5- to 10-membered heteroaryl) containing the indicated number of atoms, composed of one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) selected from N, O, and S, with the remaining ring atoms being carbon. Heteroaryl groups do not contain adjacent S and O atoms. In some embodiments, the total number of S and O atoms in a heteroaryl group is 2 or less. In some embodiments, the total number of S and O atoms in a heteroaryl group is 1 or less. Unless otherwise stated, a heteroaryl group may be attached to the parent structure by a carbon or nitrogen atom, valence permitting. For example, "pyridyl" includes 2-pyridyl, 3-pyridyl, and 4-pyridyl groups, and "pyrrolyl" includes 1-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl groups.

[0023] In some cases, the heteroaryl group is monocyclic. Examples include pyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-triazole, 1,2,4-triazole, 1,2,4-triazole), tetrazole, furan, isoxazole, oxazole, oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole), thiophene, isothiazole, thiazole, thiadiazole (e.g., 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (e.g., 1,2,4-triazine, 1,3,5-triazine), and tetrazine.

[0024] In some cases, both rings of the polycyclic heteroaryl group are aromatic. Examples include indole, isoindole, indazole, benzimidazole, benzotriazole, benzofuran, benzoxazole, benzisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzisothiazole, benzothiadiazole, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine, 3H-imidazo[4,5-b]pyridine, 3H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-pyrrolo[3,4-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-pyrazolo[3,4 ... Pyridine, 1H-imidazo[4,5-b]pyridine, 1H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[2,3-c]pyridine, 1H-pyrazolo[3,4-c]pyridine, 3H-imidazo[4,5-c]pyridine, 3H-[1,2,3]triazolo[4,5-c]pyridine, 1H-pyrrolo[3,2-c]pyridine, 1H-pyrazolo[4,3-c]pyridine, 1H-imidazo[4,5-c]pyridine, 1H-[1,2,3]triazolo[4,5-c]pyridine, furo[2,3-b]pyridine, oxazolo[5,4- b]pyridine, isoxazolo[5,4-b]pyridine, [1,2,3]oxadiazolo[5,4-b]pyridine, furo[3,2-b]pyridine, oxazolo[4,5-b]pyridine, isoxazolo[4,5-b]pyridine, [1,2,3]oxadiazolo[4,5-b]pyridine, furo[2,3-c]pyridine, oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine, [1,2,3]oxadiazolo[5,4-c]pyridine, furo[3,2-c]pyridine, oxazolo[4,5-c]pyridine, isoxazolo thiazolo[4,5-c]pyridine, [1,2,3]oxadiazolo[4,5-c]pyridine, thieno[2,3-b]pyridine, thiazolo[5,4-b]pyridine, isothiazolo[5,4-b]pyridine, [1,2,3]thiadiazolo[5,4-b]pyridine, thieno[3,2-b]pyridine, thiazolo[4,5-b]pyridine, isothiazolo[4,5-b]pyridine, [1,2,3]thiadiazolo[4,5-b]pyridine, thieno[2,3-c]pyridine, thiazolo[5,4-c]pyridine, isothiazolo[5,4-c]pyridine, [1,2,3]thiadiazolo[5,4-c]pyridine, thieno[3,2-c]pyridine, thiazolo[4,5-c]pyridine, isothiazolo[4,5-c]pyridine, [1,2,3]thiadiazolo[4,5-c]pyridine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine (e.g., 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, 2,7-naphthyridine, 2,6-naphthyridine), imidazo[1,2-a]pyridine, 1H-pyrazolo[3,4-d]thiazole, 1H-pyrazolo[4,3-d]thiazole, and imidazo[2,1-b]thiazole.

[0025] In other cases, polycyclic heteroaryl groups can contain non-aromatic rings (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to the heteroaryl ring, provided that the polycyclic heteroaryl group is attached to the parent structure through an atom in the aromatic ring. For example, 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl (which is attached to the parent structure through an aromatic carbon atom) is considered a heteroaryl group, while 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (which is attached to the parent structure through a non-aromatic carbon atom) is not considered a heteroaryl group. Examples of polycyclic heteroaryl groups consisting of heteroaryl rings fused to non-aromatic rings are described below.

[0026] "Heterocycloalkyl" refers to a non-aromatic, fully saturated ring (e.g., a 3- to 10-membered or 3- to 7-membered heterocycloalkyl) having the indicated number of atoms, composed of one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) selected from N, O, and S, with the remaining ring atoms being carbon. Heterocycloalkyl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocycloalkyl groups include oxiranyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl, as well as polycyclic spiro, fused, bridged, and cage ring groups. Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide. Additionally, one ring of a polycyclic heterocycloalkyl group may be aromatic (e.g., aryl or heteroaryl), provided that the polycyclic heterocycloalkyl group is attached to the parent structure through a non-aromatic carbon or nitrogen atom. For example, a 1,2,3,4-tetrahydroquinolin-1-yl group (which is attached to the parent structure through a non-aromatic nitrogen atom) is considered a heterocycloalkyl group, while a 1,2,3,4-tetrahydroquinolin-8-yl group (which is attached to the parent structure through an aromatic carbon atom) is not considered a heterocycloalkyl group. Examples of polycyclic heterocycloalkyl groups consisting of a heterocycloalkyl group fused to an aromatic ring are described below.

[0027] "Heterocycloalkenyl" refers to a non-aromatic ring having the indicated number of atoms (e.g., 3-10 or 3-7 membered heterocycloalkyl) composed of one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) selected from N, O, and S, the remaining ring atoms being carbon, and having at least one double bond derived by removing one hydrogen atom from the adjacent carbon atom, adjacent nitrogen atom, or adjacent carbon and nitrogen atom of the corresponding heterocycloalkyl. Heterocycloalkenyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocycloalkenyl groups include dihydrofuranyl (e.g., 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dihydrothiophenyl (e.g., 2,3-dihydrothiophenyl, 2,5-dihydrothiophenyl), dihydropyrrolyl (e.g., 2,3-dihydro-1H-pyrrolyl, 2,5-dihydro-1H-pyrrolyl), dihydroimidazolyl (e.g., 2,3-dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl), pyranyl, dihydropyranyl (e.g., 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl), tetrahydropyridinyl (e.g., 1,2,3,4-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl), and dihydropyridine (e.g., 1,2-dihydropyridine, 1,4-dihydropyridine). Additionally, one ring of a polycyclic heterocycloalkenyl group may be aromatic (e.g., aryl or heteroaryl), provided that the polycyclic heterocycloalkenyl group is attached to the parent structure through a non-aromatic carbon or nitrogen atom. For example, a 1,2-dihydroquinolin-1-yl group (which is attached to the parent structure through a non-aromatic nitrogen atom) is considered a heterocycloalkenyl group, while a 1,2-dihydroquinolin-8-yl group (which is attached to the parent structure through an aromatic carbon atom) is not considered a heterocycloalkenyl group. Examples of polycyclic heterocycloalkenyl groups consisting of a heterocycloalkenyl group fused to an aromatic ring are described below.

[0028] Examples of polycyclic rings consisting of an aromatic ring (e.g., aryl or heteroaryl) fused to a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) include indenyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[1,4]dioxinyl, indolinyl, isoindolinyl, 2,3-dihydro-1H-indazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 2, 3-Dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 1,3-dihydrobenzo[c]isoxazolyl, 2,3-dihydrobenzo[d]isoxazolyl, 2,3-dihydrobenzo[d]oxazolyl, 2,3-dihydrobenzo[b]thiophenyl, 1,3-dihydrobenzo[c]thiophenyl, 1,3-dihydrobenzo[c]isothiazolyl, 2,3-dihydrobenzo[d]isothiazolyl, 2,3-dihydrobenzo[d]thiazolyl, 5,6-dihydro-4H-cyclopenta[d]thiazolyl, 4,5,6,7-tetrahydrobenzo [d]thiazolyl, 5,6-dihydro-4H-pyrrolo[3,4-d]thiazolyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, indolin-2-one, indolin-3-one, isoindolin-1-one, 1,2-dihydroindazol-3-one, 1H-benzo[d]imidazol-2(3H)-one, benzofuran-2(3H)-one, benzofuran-3(2H)-one, isobenzofuran-1(3H)-one, benzo[c]isoxazol-3(1H)-one, benzo[d]isoxazol-3(2H)-one, benzo [d]oxazol-2(3H)-one, benzo[b]thiophen-2(3H)-one, benzo[b]thiophen-3(2H)-one, benzo[c]thiophen-1(3H)-one, benzo[c]isothiazol-3(1H)-one, benzo[d]isothiazol-3(2H)-one, benzo[d]thiazol-2(3H)-one, 4,5-dihydropyrrolo[3,4-d]thiazol-6-one, 1,2-dihydropyrazolo[3,4-d]thiazol-3-one, quinolin-4(3H)-one, quinazolin-4(3H)-one, quinazolin-2,4(1H,3H)-dione, quinoxalin-2(1H)-one, quinoxalin-2,3(1H,4H)-dione, cinnolin-4(3H)-one, pyridin-2(1H)-one, pyrimidin-2(1H)-one, pyrimidin-4(3H)-one, pyridazin-3(2H)-one, 1H-pyrrolo[3,2-b]pyridin-2(3H)-one, 1H-pyrrolo[3,2-c]pyridin-2(3H)-one, 1H-pyrrolo[2,3-c]pyridin-2(3H)-one, 1H-pyrrolo[2,3-b]pyridin-2(3H)-one, 1,2-dihydropyrazolo[3,4-d]thiazol-3-one and 4,5-dihydropyrrolo[3,4-d]thiazol-6-one. As discussed herein, whether each ring is considered an aryl group, heteroaryl group, cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, or heterocycloalkenyl group is determined by the atom to which the moiety is attached to the parent structure.

[0029] "Halogen" or "halo" refers to fluoro, chloro, bromo, or iodo.

[0030] "Haloalkyl" refers to an alkyl substituted with one or more halogens. Haloalkyl groups may have halogen substituents at any valence-allowed position on the alkyl and any number of halogen substituents ranging from one to the maximum number of valences allowed. Particular haloalkyl groups have one, two, or three halogen substituents. Examples of haloalkyl groups include, but are not limited to, -CHF, -CHF, -CF, -CHCHF, -CHCHF, -CHCF, -CHCl, -CHCl, -CCl, -CHCHCl, -CHCHCl, -CHCCl.

[0031] Unless otherwise indicated, the compounds disclosed and / or described herein include all possible enantiomers, diastereomers, mesoisomers, and other stereoisomeric forms, including racemic mixtures, optically pure forms, and intermediate mixtures thereof. Enantiomers, diastereomers, mesoisomers, and other stereoisomeric forms can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. Unless otherwise specified, when a compound disclosed and / or described herein contains an olefinic double bond or other center of geometric asymmetry, it is intended that the compound include both the E and Z isomers. When a compound described herein contains a moiety capable of tautomerization, it is intended that the compound include all possible tautomers, unless otherwise specified.

[0032] "Protecting group" has the meaning customarily associated with it in organic synthesis, i.e., a group that selectively blocks one or more reactive sites in a polyfunctional compound, allowing a chemical reaction to be selectively carried out at an otherwise unprotected reactive site, and that allows the group to be easily removed after the selective reaction is complete. Various protecting groups are disclosed, for example, in T.H. Greene and P.G.M. Buts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999). For example, a "hydroxy-protected form" comprises at least one hydroxy group protected with a hydroxy-protecting group. Similarly, amines and other reactive groups can be similarly protected.

[0033] The term "pharmaceutically acceptable salt" refers to any salt of the compounds herein that is known to be non-toxic and commonly used in the pharmaceutical literature. In some embodiments, a pharmaceutically acceptable salt of a compound retains the biological effectiveness of the compounds described herein and is not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts can be found in Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January, 1977, 66(1), 1-19. Pharmaceutically acceptable acid addition salts can be formed using inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethylsulfonic acid, p-toluenesulfonic acid, stearic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines such as naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0034] When the compounds described herein are obtained as acid addition salts, the solution of the acid salt can be basified to obtain the free base. Conversely, when the compound is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to the conventional procedure for preparing acid addition salts from basic compounds (see, for example, Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January, 1977, 66(1), 1-19). Those skilled in the art will recognize various synthetic methods that can be used to prepare pharmaceutically acceptable addition salts.

[0035] A "solvate" is formed by the interaction of a solvent and a compound. Suitable solvents include, for example, water and alcohols (e.g., ethanol). Solvates include hydrates of any ratio of water to the compound, such as monohydrates, dihydrates, and hemihydrates.

[0036] The term "substituted" means that the specified group or moiety bears one or more substituents, including, but not limited to, alkoxy, acyl, acyloxy, alkoxycarbonyl, carbonylalkoxy, acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azido, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, alkyl, alkenyl, alkynyl, heterocycloalkyl, heterocycloalkenyl, aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, and the like. The term "unsubstituted" means that the specified group bears no substituents. When the term "substituted" is used to describe a structural system, substitution is meant to occur at any position in that system where valency allows. When a group or moiety bears multiple substituents, it is understood that the substituents can be the same or different from one another. In some embodiments, a substituted group or moiety bears 1 to 5 substituents. In some embodiments, a substituted group or moiety has one substituent. In some embodiments, a substituted group or moiety has two substituents. In some embodiments, a substituted group or moiety has three substituents. In some embodiments, a substituted group or moiety has four substituents. In some embodiments, a substituted group or moiety has five substituents.

[0037] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes cases where the event or circumstance occurs and cases where it does not. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl" as defined herein. With respect to any group containing one or more substituents, it will be understood by those of skill in the art that such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical, synthetically infeasible, and / or inherently unstable. When a group or moiety is optionally substituted, it will also be understood that the present disclosure includes both embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is not substituted.

[0038] The compounds disclosed and / or described herein may be present in isotopically enriched form, e.g. 2 H, 3 H, 11 C. 13 C and / or 14The compound may be enriched in C. In one embodiment, the compound contains at least one deuterium atom. Such deuterated forms can be made, for example, by the means described in U.S. Patent Nos. 5,846,514 and 6,334,997. Such deuterated compounds can improve the efficacy and increase the duration of action of the compounds disclosed and / or described herein. Deuterium-substituted compounds can be synthesized using a variety of methods, such as those described in Dean, D., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development, Curr. Pharm. Des., 2000;6(10); Kabalka, G. et al., The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989,45(21),6601-21; and Evans, E., Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981,64(1-2),9-32.

[0039] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the pharmaceutical compositions is contemplated. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.

[0040] The terms "patient," "individual," and "subject" refer to an animal such as a mammal, bird, or fish. In some embodiments, a patient or subject is a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows, and humans. In some embodiments, a patient, individual, or subject is a human, e.g., a human who has been the object of treatment, observation, or experiment, or a human subject. The compounds, compositions, and methods described herein can be useful in both human therapy and veterinary applications.

[0041] The term "therapeutically effective amount" or "effective amount" refers to an amount of a compound disclosed and / or described herein that, when administered to a patient in need of treatment as defined herein, is sufficient to affect such treatment. A therapeutically effective amount of a compound may be an amount sufficient to treat a disease that responds to modulation (e.g., inhibition) of KIF18a. A therapeutically effective amount will vary depending, for example, on the subject and condition being treated, the subject's weight and age, the severity of the condition, the particular compound, the dosing regimen to be followed, the timing of administration, and the mode of administration, all of which can be readily determined by one skilled in the art. A therapeutically effective amount can be ascertained experimentally, for example, by assaying the blood concentration of the chemical substance, or theoretically by calculating bioavailability.

[0042] "Treatment" (and related terms such as "treat," "treated," and "treating") includes one or more of inhibiting the disease or disorder, delaying or preventing the onset of clinical symptoms of the disease or disorder, and / or alleviating the disease or disorder (i.e., causing a reduction or regression of clinical symptoms). The term encompasses both complete and partial alleviation of the condition or disorder, and complete or partial alleviation of clinical symptoms of the disease or disorder. Thus, the compounds described and / or disclosed herein may prevent the worsening of an existing disease or disorder, may assist in the management of the disease or disorder, or may reduce or eliminate the disease or disorder.

[0043] It is understood that embodiments described herein as "comprising" include "consisting of" and "consisting essentially of" the embodiment. compound

[0044] Compounds and salts thereof (e.g., pharmaceutically acceptable salts) are described in detail herein, including in the Summary and the accompanying Claims. Also provided are all uses of the compounds described herein, including any and all stereoisomers, including geometric isomers (cis / trans), E / Z isomers, enantiomers, diastereomers, and mixtures thereof in any ratio, including racemic mixtures, salts, and solvates, as well as methods for making such compounds. Any compound described herein may also be referred to as a drug.

[0045] In one aspect, provided is a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: X and Z are independently O, N, or CH; Y is NH, N, or CH; V and W are independently N or C; wherein at least one of X and Z is N or Y is NH; Ring A is [ka] where: A 1 , A 3 , and A 4 One, two, or three of these are independently N, NR A1 , O, or S, and if present, A 1 , A 3 , and A 4The remaining one or two are independently CH or CR 2 where R A1 is H or C 1~3 is alkyl; A 2 is N or C; A 5 ~A 8 are CH, CR independently 2 , N, or NR A2 where A 5 , A 6 , A 7 , and A 8 At least two of these are CH or CR 2 and if it exists, A 5 , A 6 , A 7 , and A 8 The remaining one or two are N or NR A2 where R A2 is =O; where "*" indicates the point of attachment to V; B 1 and B 2 are each independently N, CH, or CR B where R B is a halogen; R 1 is C 1~6 Alkyl, C 3~6 Cycloalkyl, C 3~10 Cycloalkenyl, 3-10 membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 , -NR a4 C(O)OR a5 , -NR a6 R a7 , -N=S(O)R a8 R a9 , -OR a10 , -S(O)R a11 , -S(O)(NR a12 )R a13 , -S(O)NR a14 R a15 , -S(O)2R a16 , or -(CR a17 Ra18 ) 0~1 C(O)NR a19 R a20 and where R 1 C1-C6 alkyl is halogen, -OH, oxo, cyano, C 3~10 optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo; 1 C 3~6 The cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; 1 C 3~10 The cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; and 1 The 3- to 10-membered heterocycloalkyl may be halogen, C 1~6 Alkyl, and C 1~6 optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl; R a1 ~R a20 are each independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 3~10 Cycloalkyl, C 3~10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 6~14 aryl, or 5- to 12-membered heteroaryl, each of which is halo, cyano, -OH, -O(C 1~6 alkyl), C 2~6 Alkenyl, C 3~10 Cycloalkyl, -S(C 1~6 alkyl), =CR 1a1 R 1a2 , and halo, -OH, and -O(C 1~6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkyl, wherein R 1a1 and R 1a2are each independently hydrogen or C 1~6 alkyl; or R a14 and R a15 together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl optionally substituted with one or more halo; Each R 2 are independently halogens, C 1~3 Alkyl, C 3~5 Cycloalkyl, cyano, C 1~3 Alkyloxy, C 3~5 Cycloalkyloxy, hydroxy, or NR b1 R b2 where R 2 C 1~3 The alkyl is optionally substituted with one or more substituents selected from the group consisting of —OH and oxo, where R b1 and R b2 are independently optionally substituted with C1-C3 alkyl, or R b1 and R b2 form a 3- to 6-membered ring together with the nitrogen to which they are attached; or A 5 R 1 and R 2 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3-10 membered heterocycloalkyl; R 3 is piperidinyl, pyrrolidinyl, or azepanyl, where piperidinyl, pyrrolidinyl, or azepanyl is C 3~10 optionally substituted with cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 3~10 A cycloalkyl or a 3- to 10-membered heterocycloalkyl may form a spirocyclic or fused bicyclic ring system with piperidinyl, pyrrolidinyl, or azepanyl; or wherein piperidinyl, pyrrolidinyl, or azepanyl is optionally C 1~2 substituted with alkylene to form a bridged piperidinyl, pyrrolidinyl, or azepanyl ring system; where piperidinyl, pyrrolidinyl, azepanyl, or C 3~10 Cycloalkyl, 3-10 membered heterocycloalkyl, or C 1~2 The spirocyclic, fused, or bridged bicyclic ring system formed by the alkylene and piperidinyl, pyrrolidinyl, or azepanyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and halo; R 4 is H, halo, cyano, -OH, -NO2, -C(O)NR c1 R c2 , -NR c3 R c4 , -NR c5 S(O)2R c6 , -P(O)R c7 R c8 , -N=S(O)R c9 R c10 , -S(O)(NR c11 )R c12 , -S(O)2R c13 or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH 1~6 is alkyl; R c1 ~R c13 are each independently hydrogen, C 3~10 Cycloalkyl, or C 1~6 alkyl, where R c1 ~R c13 each C1-C6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, —OH, and —C(O)—O—C1-C3 alkyl, wherein each C 3~10 The cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkylene-OH.

[0046] In some embodiments, when Y is N, R 4 is not H. In some embodiments, when X is N, Y is N, and Z is O, then R 4 is not H. In some embodiments, when Y is N, R 3teeth [ka] In some embodiments, when X is N, Y is N, and Z is O, R 3 teeth [ka] In some embodiments, each R d1 are independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and halo. d1 Together they form C 3~10 cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 3~10 The cycloalkyl or 3-10 membered heterocycloalkyl forms a spirocyclic or fused bicyclic ring system with the piperidinyl. In some embodiments, two R d1 Together they form C 1~2 Forms an alkylene, where C 1~2 The alkylene forms a bridged piperidinyl ring system. In some embodiments, C 3~10 The cycloalkyl, 3- to 10-membered heterocycloalkyl, or spirocyclic, fused, or bridged bicyclic ring system formed by C1-2 alkylene and piperidinyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and halo. In some embodiments, when Y is N, R 3 teeth [ka] In some embodiments, when X is N, Y is N, and Z is O, R 3 teeth [ka] is.

[0047] In some embodiments, the compound is not 3-(5-methylfuran-2-yl)-5-(2-(piperidin-4-yl)pyridin-3-yl)-1,2,4-oxadiazole. In some embodiments, the compound is not 3-(3-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl)-5-(2-(pyrrolidin-1-yl)phenyl)-1,2,4-oxadiazole. In some embodiments, the compound is not 3-(5-methylfuran-2-yl)-5-(2-(piperidin-4-yl)pyridin-3-yl)-1,2,4-oxadiazole or 3-(3-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl)-5-(2-(pyrrolidin-1-yl)phenyl)-1,2,4-oxadiazole.

[0048] In some embodiments, the compound is not a salt of 3-(5-methylfuran-2-yl)-5-(2-(piperidin-4-yl)pyridin-3-yl)-1,2,4-oxadiazole. In some embodiments, the compound is not a salt of 3-(3-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl)-5-(2-(pyrrolidin-1-yl)phenyl)-1,2,4-oxadiazole. In some embodiments, the compound is not a salt of 3-(5-methylfuran-2-yl)-5-(2-(piperidin-4-yl)pyridin-3-yl)-1,2,4-oxadiazole or 3-(3-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl)-5-(2-(pyrrolidin-1-yl)phenyl)-1,2,4-oxadiazole.

[0049] In some embodiments, the compound of formula (I) is a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof.

[0050] In one aspect, provided is a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein: X and Z are independently O, N, or CH; Y is NH or CH; V and W are independently N or C; wherein at least one of X and Z is N or Y is NH; Ring A is [ka] where: A 1 , A 3 , and A 4 one or two of which are independently N, O, or S, and A 1 , A 3 , and A 4 The remaining one or two are independently CH or CR 2 and; A 2 is N or C; A 5 ~A 8 are independently CH, CR 2 , or N, where A 5 , A 6 , A 7 , and A 8 At least two of these are CH or CR 2 and if it exists, A 5 , A 6 , A 7 , and A 8 of which the remaining one or two are N; where "*" indicates the point of attachment to V; B 1 and B 2 are each independently N or CH; R 1 is C 1~6 Alkyl, C 3~6 Cycloalkyl, 3-10 membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 , -NR a4C(O)OR a5 , -NR a6 R a7 , -N=S(O)R a8 R a9 , -OR a10 , -S(O)R a11 , -S(O)(NR a12 )R a13 , -S(O)NR a14 R a15 , -S(O)2R a16 , or -(CR a17 R a18 ) 0~1 C(O)NR a19 R a20 and where R 1 C1-C6 alkyl is halogen, -OH, cyano, C 3~10 optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo; 1 C 3~6 Cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; 1 wherein the 3- to 10-membered heterocycloalkyl is optionally substituted with one or more halogens; R a1 ~R a20 are each independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 3~10 Cycloalkyl, C 3~10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 6~14 aryl, or 5- to 12-membered heteroaryl, each of which is halo, cyano, -OH, -O(C 1~6 alkyl), C 2~6 Alkenyl, C 3~10 Cycloalkyl, -S(C 1~6 alkyl), =CR 1a1 R 1a2 , and halo, -OH, and -O(C 1~6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkyl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1~6 is alkyl; or R a14 and R a15 together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl optionally substituted with one or more halo; Each R 2 are independently halogens, C 1~3 Alkyl, C 3~5 Cycloalkyl, cyano, C 1~3 Alkyloxy, C 3~5 Cycloalkyloxy, hydroxy, or NR b1 R b2 where R b1 and R b2 are independently optionally substituted with C1-C3 alkyl, or R b1 and R b2 form a 3- to 6-membered ring together with the nitrogen to which they are attached; or A 5 R 1 and R 2 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3-6 membered heterocycloalkyl; R 3 is piperidinyl, pyrrolidinyl, or azepanyl, where piperidinyl, pyrrolidinyl, or azepanyl is C 3~10 optionally substituted with cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 3~10 a cycloalkyl or a 3- to 10-membered heterocycloalkyl forms a spirocyclic or fused bicyclic ring system with piperidinyl, pyrrolidinyl, or azepanyl; where piperidinyl, pyrrolidinyl, azepanyl, or C 3~10The spirocyclic or fused bicyclic ring system formed by the cycloalkyl or 3-10 membered heterocycloalkyl and piperidinyl, pyrrolidinyl, or azepanyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl and C1-C3 haloalkyl; R 4 is H, halo, cyano, -OH, -NO2, -C(O)NR c1 R c2 , -NR c3 R c4 , -NR c5 S(O)2R c6 , -P(O)R c7 R c8 , -N=S(O)R c9 R c10 , -S(O)(NR c11 )R c12 , -S(O)2R c13 or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH 1~6 is alkyl, R c1 ~R c13 are independently hydrogen, C 3~10 Cycloalkyl, or C 1~6 alkyl, where R c1 ~R c13 wherein each C1-C6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, and -C(O)-O-C1-C3 alkyl.

[0051] In some embodiments, X and Z are independently O, N, or CH and Y is NH, N, or CH, where at least one of X and Z is N or Y is NH.

[0052] In some embodiments, X is O, N, or CH. In some embodiments, X is O or N. In other embodiments, X is O or CH. In still other embodiments, X is N or CH. In some embodiments, X is N. In other embodiments, X is O. In still other embodiments, X is CH.

[0053] In some embodiments, Z is O, N, or CH. In some embodiments, Z is O or N. In other embodiments, Z is O or CH. In still other embodiments, Z is N or CH. In some embodiments, Z is N. In other embodiments, Z is O. In still other embodiments, Z is CH.

[0054] In some embodiments, Y is NH or CH. In some embodiments, Y is NH. In other embodiments, Y is CH.

[0055] In some embodiments, V is N or C. In some embodiments, V is N. In other embodiments, V is C.

[0056] In some embodiments, W is N or C. In some embodiments, W is N. In other embodiments, W is C.

[0057] In some embodiments, the ring [ka] teeth, [ka] In some embodiments, the ring [ka] teeth, [ka] In certain embodiments, the ring [ka] teeth, [ka] In some embodiments, the ring [ka] teeth, [ka] In certain embodiments, the ring [ka] teeth, [ka] In certain embodiments, the ring [ka] teeth, [ka] In any embodiment where Y is NH, the ring [ka] It should be recognized that the formula (I) can encompass any of its available tautomers, such as, for example, where Y is N and X or Z is NH. For example, in some embodiments, the ring [ka] teeth, [ka] is.

[0058] In some embodiments of any of the above, the compound of Formula (I) is a compound of Formula (Ia): [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is [ka] where: A 1 , A 3 , and A 4 One, two, or three of these are independently N, NR A1 , O, or S, and if present, A 1 , A 3 , and A 4 The remaining one or two are independently CH or CR 2 where R A1 is H or C 1~3 is alkyl; A 2 is N or C; A 5 ~A 8 are CH, CR independently 2 , N, or NR A2 where A 5 , A 6 , A 7 , and A 8 At least two of these are CH or CR 2 and if it exists, A 5 , A 6 , A 7 , and A 8 The remaining one or two are N or NR A2 where R A2 is =O; where "*" indicates the point of attachment to V; B 1 and B 2 are each independently N, CH, or CR B where R B is a halogen; R 1 is C1~6 Alkyl, C 3~6 Cycloalkyl, C 3~10 Cycloalkenyl, 3-10 membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 , -NR a4 C(O)OR a5 , -NR a6 R a7 , -N=S(O)R a8 R a9 , -OR a10 , -S(O)R a11 , -S(O)(NR a12 )R a13 , -S(O)NR a14 R a15 , -S(O)2R a16 , or -(CR a17 R a18 ) 0~1 C(O)NR a19 R a20 and where R 1 C1-C6 alkyl is halogen, -OH, oxo, cyano, C 3~10 optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo; 1 C 3~6 The cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; 1 C 3~10 The cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; and 1 The 3- to 10-membered heterocycloalkyl may be halogen, C 1~6 Alkyl, and C 1~6 optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl; R a1 ~R a20 are each independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 3~10 Cycloalkyl, C3~10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 6~14 aryl, or 5- to 12-membered heteroaryl, each of which is halo, cyano, -OH, -O(C 1~6 alkyl), C 2~6 Alkenyl, C 3~10 Cycloalkyl, -S(C 1~6 alkyl), =CR 1a1 R 1a2 , and halo, -OH, and -O(C 1~6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkyl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1~6 is alkyl; or R a14 and R a15 together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl optionally substituted with one or more halo; Each R 2 are independently halogens, C 1~3 Alkyl, C 3~5 Cycloalkyl, cyano, C 1~3 Alkyloxy, C 3~5 Cycloalkyloxy, hydroxy, or NR b1 R b2 where R 2 C 1~3 The alkyl is optionally substituted with one or more substituents selected from the group consisting of —OH and oxo, where R b1 and R b2 are independently optionally substituted with C1-C3 alkyl, or R b1 and R b2 form a 3- to 6-membered ring together with the nitrogen to which they are attached; or A 5 R 1 and R 2together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3-10 membered heterocycloalkyl; R 3 is piperidinyl, pyrrolidinyl, or azepanyl, where piperidinyl, pyrrolidinyl, or azepanyl is C 3~10 optionally substituted with cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 3~10 A cycloalkyl or a 3- to 10-membered heterocycloalkyl may form a spirocyclic or fused bicyclic ring system with piperidinyl, pyrrolidinyl, or azepanyl; or wherein piperidinyl, pyrrolidinyl, or azepanyl is optionally C 1~2 substituted with alkylene to form a bridged piperidinyl, pyrrolidinyl, or azepanyl ring system; where piperidinyl, pyrrolidinyl, azepanyl, or C 3~10 Cycloalkyl, 3-10 membered heterocycloalkyl, or C 1~2 The spirocyclic, fused, or bridged bicyclic ring system formed by the alkylene and piperidinyl, pyrrolidinyl, or azepanyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and halo; R 4 is H, halo, cyano, -OH, -NO2, -C(O)NR c1 R c2 , -NR c3 R c4 , -NR c5 S(O)2R c6 , -P(O)R c7 R c8 , -N=S(O)R c9 R c10 , -S(O)(NR c11 )R c12 , -S(O)2R c13 or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH 1~6 is alkyl, R c1 ~R c13are each independently hydrogen, C 3~10 Cycloalkyl, or C 1~6 alkyl, where R c1 ~R c13 each C1-C6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, —OH, and —C(O)—O—C1-C3 alkyl, wherein each C 3~10 The cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkylene-OH.

[0059] In some embodiments of any of the above, the compound of Formula (I) is a compound of Formula (Ib): [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is [ka] where: A 1 , A 3 , and A 4 One, two, or three of these are independently N, NR A1 , O, or S, and if present, A 1 , A 3 , and A 4 The remaining one or two are independently CH or CR 2 where R A1 is H or C 1~3 is alkyl; A 2 is N or C; A 5 ~A 8 are CH, CR independently 2 , N, or NR A2 where A 5 , A 6 , A 7 , and A 8 At least two of these are CH or CR 2 and if it exists, A 5, A 6 , A 7 , and A 8 The remaining one or two are N or NR A2 where R A2 is =O; where "*" indicates the point of attachment to V; B 1 and B 2 are each independently N, CH, or CR B where R B is a halogen; R 1 is C 1~6 Alkyl, C 3~6 Cycloalkyl, C 3~10 Cycloalkenyl, 3-10 membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 , -NR a4 C(O)OR a5 , -NR a6 R a7 , -N=S(O)R a8 R a9 , -OR a10 , -S(O)R a11 , -S(O)(NR a12 )R a13 , -S(O)NR a14 R a15 , -S(O)2R a16 , or -(CR a17 R a18 ) 0~1 C(O)NR a19 R a20 and where R 1 C1-C6 alkyl is halogen, -OH, oxo, cyano, C 3~10 optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo; 1 C 3~6 The cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; 1 C 3~10The cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; and 1 The 3- to 10-membered heterocycloalkyl may be halogen, C 1~6 Alkyl, and C 1~6 optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl; R a1 ~R a20 are each independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 3~10 Cycloalkyl, C 3~10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 6~14 aryl, or 5- to 12-membered heteroaryl, each of which is halo, cyano, -OH, -O(C 1~6 alkyl), C 2~6 Alkenyl, C 3~10 Cycloalkyl, -S(C 1~6 alkyl), =CR 1a1 R 1a2 , and halo, -OH, and -O(C 1~6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkyl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1~6 is alkyl; or R a14 and R a15 together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl optionally substituted with one or more halo; Each R 2 are independently halogens, C 1~3 Alkyl, C 3~5 Cycloalkyl, cyano, C 1~3 Alkyloxy, C 3~5 Cycloalkyloxy, hydroxy, or NR b1 R b2 where R2 C 1~3 The alkyl is optionally substituted with one or more substituents selected from the group consisting of —OH and oxo, where R b1 and R b2 are independently optionally substituted with C1-C3 alkyl, or R b1 and R b2 form a 3- to 6-membered ring together with the nitrogen to which they are attached; or A 5 R 1 and R 2 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3-10 membered heterocycloalkyl; R 3 is piperidinyl, pyrrolidinyl, or azepanyl, where piperidinyl, pyrrolidinyl, or azepanyl is C 3~10 optionally substituted with cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 3~10 A cycloalkyl or a 3- to 10-membered heterocycloalkyl may form a spirocyclic or fused bicyclic ring system with piperidinyl, pyrrolidinyl, or azepanyl; or wherein piperidinyl, pyrrolidinyl, or azepanyl is optionally C 1~2 substituted with alkylene to form a bridged piperidinyl, pyrrolidinyl, or azepanyl ring system; where piperidinyl, pyrrolidinyl, azepanyl, or C 3~10 Cycloalkyl, 3-10 membered heterocycloalkyl, or C 1~2 The spirocyclic, fused, or bridged bicyclic ring system formed by the alkylene and piperidinyl, pyrrolidinyl, or azepanyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and halo; R 4 is H, halo, cyano, -OH, -NO2, -C(O)NR c1 R c2 , -NR c3 R c4 , -NR c5 S(O)2Rc6 , -P(O)R c7 R c8 , -N=S(O)R c9 R c10 , -S(O)(NR c11 )R c12 , -S(O)2R c13 or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH 1~6 is alkyl, R c1 ~R c13 are each independently hydrogen, C 3~10 Cycloalkyl, or C 1~6 alkyl, where R c1 ~R c13 each C1-C6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, —OH, and —C(O)—O—C1-C3 alkyl, wherein each C 3~10 The cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkylene-OH.

[0060] In some embodiments of any of the above, the compound of Formula (I) is a compound of Formula (Ic): [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is [ka] where: A 1 , A 3 , and A 4 One, two, or three of these are independently N, NR A1 , O, or S, and if present, A 1 , A 3 , and A 4 The remaining one or two are independently CH or CR 2 where R A1 is H or C 1~3 is alkyl; A 2 is N or C; A 5 ~A 8 are CH, CR independently 2 , N, or NR A2 where A 5 , A 6 , A 7 , and A 8 At least two of these are CH or CR 2 and if it exists, A 5 , A 6 , A 7 , and A 8 The remaining one or two are N or NR A2 where R A2 is =O; where "*" indicates the point of attachment to V; B 1 and B 2 are each independently N, CH, or CR B where R B is a halogen; R 1 is C 1~6 Alkyl, C 3~6 Cycloalkyl, C 3~10 Cycloalkenyl, 3-10 membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 , -NR a4 C(O)OR a5 , -NR a6 R a7 , -N=S(O)R a8 R a9 , -OR a10 , -S(O)R a11 , -S(O)(NR a12 )R a13 , -S(O)NR a14 R a15 , -S(O)2R a16 , or -(CR a17 R a18 ) 0~1 C(O)NR a19 R a20 and where R 1C1-C6 alkyl is halogen, -OH, oxo, cyano, C 3~10 optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo; 1 C 3~6 The cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; 1 C 3~10 The cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; and 1 The 3- to 10-membered heterocycloalkyl may be halogen, C 1~6 Alkyl, and C 1~6 optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl; R a1 ~R a20 are each independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 3~10 Cycloalkyl, C 3~10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 6~14 aryl, or 5- to 12-membered heteroaryl, each of which is halo, cyano, -OH, -O(C 1~6 alkyl), C 2~6 Alkenyl, C 3~10 Cycloalkyl, -S(C 1~6 alkyl), =CR 1a1 R 1a2 , and halo, -OH, and -O(C 1~6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkyl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1~6 is alkyl; or R a14 and R a15together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl optionally substituted with one or more halo; Each R 2 are independently halogens, C 1~3 Alkyl, C 3~5 Cycloalkyl, cyano, C 1~3 Alkyloxy, C 3~5 Cycloalkyloxy, hydroxy, or NR b1 R b2 where R 2 C 1~3 The alkyl is optionally substituted with one or more substituents selected from the group consisting of —OH and oxo, where R b1 and R b2 are independently optionally substituted with C1-C3 alkyl, or R b1 and R b2 form a 3- to 6-membered ring together with the nitrogen to which they are attached; or A 5 R 1 and R 2 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3-10 membered heterocycloalkyl; R 3 is piperidinyl, pyrrolidinyl, or azepanyl, where piperidinyl, pyrrolidinyl, or azepanyl is C 3~10 optionally substituted with cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 3~10 A cycloalkyl or a 3- to 10-membered heterocycloalkyl may form a spirocyclic or fused bicyclic ring system with piperidinyl, pyrrolidinyl, or azepanyl; or wherein piperidinyl, pyrrolidinyl, or azepanyl is optionally C 1~2 substituted with alkylene to form a bridged piperidinyl, pyrrolidinyl, or azepanyl ring system; where piperidinyl, pyrrolidinyl, azepanyl, or C 3~10 Cycloalkyl, 3-10 membered heterocycloalkyl, or C 1~2The spirocyclic, fused, or bridged bicyclic ring system formed by the alkylene and piperidinyl, pyrrolidinyl, or azepanyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and halo; R 4 is H, halo, cyano, -OH, -NO2, -C(O)NR c1 R c2 , -NR c3 R c4 , -NR c5 S(O)2R c6 , -P(O)R c7 R c8 , -N=S(O)R c9 R c10 , -S(O)(NR c11 )R c12 , -S(O)2R c13 or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH 1~6 is alkyl, R c1 ~R c13 are each independently hydrogen, C 3~10 Cycloalkyl, or C 1~6 alkyl, where R c1 ~R c13 each C1-C6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, —OH, and —C(O)—O—C1-C3 alkyl, wherein each C 3~10 The cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkylene-OH.

[0061] In some embodiments, the compound of Formula (II) is a compound of Formula (II-a): [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is [ka] where: A 1 , A 3 , and A 4 one or two of which are independently N, O, or S, and A 1 , A 3 , and A 4 The remaining one or two are independently CH or CR 2 and;A 2 is N or C; A 5 ~A 8 are independently CH, CR 2 , or N, where A 5 , A 6 , A 7 , and A 8 At least two of these are CH or CR 2 and if it exists, A 5 , A 6 , A 7 , and A 8 and the remaining one or two of these are N; where "*" indicates the point of attachment to V; B 1 and B 2 are each independently N or CH; R 1 is C 1~6 Alkyl, C 3~6 Cycloalkyl, 3-10 membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 , -NR a4 C(O)OR a5 , -NR a6 R a7 , -N=S(O)R a8 R a9 , -OR a10 , -S(O)R a11 , -S(O)(NR a12 )R a13 , -S(O)NR a14 R a15 , -S(O)2R a16 , or -(CR a17 R a18 ) 0~1 C(O)NR a19 R a20 where R 1 C1-C6 alkyl is halogen, -OH, cyano, C3~10 optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo; 1 C 3~6 Cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; 1 R is a 3- to 10-membered heterocycloalkyl optionally substituted with one or more halogens; a1 ~R a20 are each independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 3~10 Cycloalkyl, C 3~10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 6~14 aryl, or 5- to 12-membered heteroaryl, each of which is halo, cyano, -OH, -O(C 1~6 alkyl), C 2~6 Alkenyl, C 3~10 Cycloalkyl, -S(C 1~6 alkyl), =CR 1a1 R 1a2 , and halo, -OH, and -O(C 1~6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkyl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1~6 alkyl; or R a14 and R a15 together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl optionally substituted with one or more halo; each R 2 are independently halogens, C 1~3 Alkyl, C 3~5 Cycloalkyl, cyano, C 1~3 Alkyloxy, C 3~5 Cycloalkyloxy, hydroxy, or NR b1 R b2where R b1 and R b2 are independently optionally substituted with C1-C3 alkyl, or R b1 and R b2 form a 3- to 6-membered ring together with the nitrogen to which they are attached; or A 5 R 1 and R 2 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocycloalkyl; R 3 is piperidinyl, pyrrolidinyl, or azepanyl, where piperidinyl, pyrrolidinyl, or azepanyl is C 3~10 optionally substituted with cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 3~10 A cycloalkyl or a 3- to 10-membered heterocycloalkyl may form a spirocyclic or fused bicyclic ring system with piperidinyl, pyrrolidinyl, or azepanyl, where piperidinyl, pyrrolidinyl, azepanyl, or C 3~10 The spirocyclic or fused bicyclic ring system formed by the cycloalkyl or 3-10 membered heterocycloalkyl and piperidinyl, pyrrolidinyl, or azepanyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl and C1-C3 haloalkyl; R 4 is H, halo, cyano, -OH, -NO2, -C(O)NR c1 R c2 , -NR c3 R c4 , -NR c5 S(O)2R c6 , -P(O)R c7 R c8 , -N=S(O)R c9 R c10 , -S(O)(NR c11 )R c12 , -S(O)2R c13 or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH 1~6 is alkyl, R c1 ~Rc13 are each independently hydrogen, C 3~10 Cycloalkyl, or C 1~6 alkyl, where R c1 ~R c13 Each C 1 ~C 6 The alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, and -C(O)-O-C1-C3 alkyl.

[0062] In some embodiments, the compound of Formula (II) is a compound of Formula (II-b): [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is [ka] where: A 1 , A 3 , and A 4 one or two of which are independently N, O, or S, and A 1 , A 3 , and A 4 The remaining one or two are independently CH or CR 2 and; A 2 is N or C; A 5 ~A 8 are independently CH, CR 2 , or N, where A 5 , A 6 , A 7 , and A 8 At least two of these are CH or CR 2 and if it exists, A 5 , A 6 , A 7 , and A 8 of which the remaining one or two are N; where "*" indicates the point of attachment to V; B 1 and B2 are each independently N or CH; R 1 is C 1~6 Alkyl, C 3~6 Cycloalkyl, 3-10 membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 , -NR a4 C(O)OR a5 , -NR a6 R a7 , -N=S(O)R a8 R a9 , -OR a10 , -S(O)R a11 , -S(O)(NR a12 )R a13 , -S(O)NR a14 R a15 , -S(O)2R a16 , or -(CR a17 R a18 ) 0~1 C(O)NR a19 R a20 and where R 1 C1-C6 alkyl is halogen, -OH, cyano, C 3~10 optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo; 1 C 3~6 The cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; 1 wherein the 3- to 10-membered heterocycloalkyl is optionally substituted with one or more halogens; R a1 ~R a20 are each independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 3~10 Cycloalkyl, C 3~10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 6~14 aryl, or 5- to 12-membered heteroaryl, each of which is halo, cyano, -OH, -O(C1~6 alkyl), C 2~6 Alkenyl, C 3~10 Cycloalkyl, -S(C 1~6 alkyl), =CR 1a1 R 1a2 , and halo, -OH, and -O(C 1~6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkyl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1~6 is alkyl; or R a14 and R a15 together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl optionally substituted with one or more halo; Each R 2 are independently halogens, C 1~3 Alkyl, C 3~5 Cycloalkyl, cyano, C 1~3 Alkyloxy, C 3~5 Cycloalkyloxy, hydroxy, or NR b1 R b2 where R b1 and R b2 are independently optionally substituted with C1-C3 alkyl, or R b1 and R b2 form a 3- to 6-membered ring together with the nitrogen to which they are attached; or A 5 R 1 and R 2 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3-6 membered heterocycloalkyl; R 3 is piperidinyl, pyrrolidinyl, or azepanyl, where piperidinyl, pyrrolidinyl, or azepanyl is C 3~10 optionally substituted with cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 3~10a cycloalkyl or a 3- to 10-membered heterocycloalkyl forms a spirocyclic or fused bicyclic ring system with piperidinyl, pyrrolidinyl, or azepanyl; where piperidinyl, pyrrolidinyl, azepanyl, or C 3~10 The spirocyclic or fused bicyclic ring system formed by the cycloalkyl or 3-10 membered heterocycloalkyl and piperidinyl, pyrrolidinyl, or azepanyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl and C1-C3 haloalkyl; R 4 is H, halo, cyano, -OH, -NO2, -C(O)NR c1 R c2 , -NR c3 R c4 , -NR c5 S(O)2R c6 , -P(O)R c7 R c8 , -N=S(O)R c9 R c10 , -S(O)(NR c11 )R c12 , -S(O)2R c13 or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH 1~6 is alkyl, R c1 ~R c13 are each independently hydrogen, C 3~10 Cycloalkyl, or C 1~6 alkyl, where R c1 ~R c13 wherein each C1-C6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, and -C(O)-O-C1-C3 alkyl.

[0063] In some embodiments, the compound of Formula (II) is a compound of Formula (II-c): [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is [ka] where: A 1 , A 3 , and A 4 one or two of which are independently N, O, or S, and A 1 , A 3 , and A 4 The remaining one or two are independently CH or CR 2 and; A 2 is N or C; A 5 ~A 8 are independently CH, CR 2 , or N, where A 5 , A 6 , A 7 , and A 8 At least two of these are CH or CR 2 and if it exists, A 5 , A 6 , A 7 , and A 8 of which the remaining one or two are N; where "*" indicates the point of attachment to V; B 1 and B 2 are each independently N or CH; R 1 is C 1~6 Alkyl, C 3~6 Cycloalkyl, 3-10 membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 , -NR a4 C(O)OR a5 , -NR a6 R a7 , -N=S(O)R a8 R a9 , -OR a10 , -S(O)R a11 , -S(O)(NR a12 )R a13 , -S(O)NR a14 R a15 , -S(O)2Ra16 , or -(CR a17 R a18 ) 0~1 C(O)NR a19 R a20 and where R 1 C1-C6 alkyl is halogen, -OH, cyano, C 3~10 optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo; 1 C 3~6 The cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; 1 wherein the 3- to 10-membered heterocycloalkyl is optionally substituted with one or more halogens; R a1 ~R a20 are each independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 3~10 Cycloalkyl, C 3~10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 6~14 aryl, or 5- to 12-membered heteroaryl, each of which is halo, cyano, -OH, -O(C 1~6 alkyl), C 2~6 Alkenyl, C 3~10 Cycloalkyl, -S(C 1~6 alkyl), =CR 1a1 R 1a2 , and halo, -OH, and -O(C 1~6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkyl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1~6 alkyl; or R a14 and R a15together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl optionally substituted with one or more halo; Each R 2 are independently halogens, C 1~3 Alkyl, C 3~5 Cycloalkyl, cyano, C 1~3 Alkyloxy, C 3~5 Cycloalkyloxy, hydroxy, or NR b1 R b2 where R b1 and R b2 are independently optionally substituted with C1-C3 alkyl, or R b1 and R b2 form a 3- to 6-membered ring together with the nitrogen to which they are attached; or A 5 R 1 and R 2 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3-6 membered heterocycloalkyl; R 3 is piperidinyl, pyrrolidinyl, or azepanyl, where piperidinyl, pyrrolidinyl, or azepanyl is C 3~10 optionally substituted with cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 3~10 a cycloalkyl or a 3- to 10-membered heterocycloalkyl forms a spirocyclic or fused bicyclic ring system with piperidinyl, pyrrolidinyl, or azepanyl; where piperidinyl, pyrrolidinyl, azepanyl, or C 3~10 The spirocyclic or fused bicyclic ring system formed by the cycloalkyl or 3-10 membered heterocycloalkyl and piperidinyl, pyrrolidinyl, or azepanyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl and C1-C3 haloalkyl; R 4 is H, halo, cyano, -OH, -NO2, -C(O)NR c1 R c2 , -NR c3 R c4, -NR c5 S(O)2R c6 , -P(O)R c7 R c8 , -N=S(O)R c9 R c10 , -S(O)(NR c11 )R c12 , -S(O)2R c13 or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH 1~6 is alkyl, R c1 ~R c13 are independently hydrogen, C 3~10 Cycloalkyl, or C 1~6 alkyl, where R c1 ~R c13 wherein each C1-C6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, and -C(O)-O-C1-C3 alkyl.

[0064] In some embodiments, ring A is [ka] where A 1 , A 3 , and A 4 One, two, or three of these are independently N, NR A1 , O, or S, and if present, A 1 , A 3 , and A 4 The remaining one or two are independently CH or CR 2 where R A1 is H or C 1~3 Alkyl; A 2 is N or C; A 5 ~A 8 are independently CH, CR 2 , N, or NR A2 and A 5 , A 6 , A 7 , and A 8 At least two of these are CH or CR 2and if it exists, A 5 , A 6 , A 7 , and A 8 The remaining one or two are N or NR A2 where R A2 is ═O; where “*” indicates the point of attachment to V.

[0065] In some embodiments, ring A is [ka] where A 1 , A 3 , and A 4 one or two of which are independently N, O, or S, and A 1 , A 3 , and A 4 The remaining one or two are independently CH or CR 2 and A 2 is N or C; A 5 ~A 8 are independently CH, CR 2 , or N and A 5 , A 6 , A 7 , and A 8 At least two of these are CH or CR 2 and if it exists, A 5 , A 6 , A 7 , and A 8 and the remaining one or two of are N; where "*" indicates the point of attachment to V.

[0066] In some embodiments, ring A is [ka] where A 1 , A 3 , and A 4 One, two, or three of these are independently N, NR A1 , O, or S, and if present, A 1 , A 3 , and A4 The remaining one or two are independently CH or CR 2 where R A1 is H or C 1~3 Alkyl; A 2 is N or C. In certain embodiments, ring A is [ka] where A 1 , A 3 , and A 4 one or two of which are independently N, O, or S, and A 1 , A 3 , and A 4 The remaining one or two are independently CH or CR 2 and A 2 is N or C. In some embodiments, A 1 , A 3 , and A 4 One of them is independently N, NR A1 , O, or S, and A 1 , A 3 , and A 4 The remaining two are independently CH or CR 2 In certain embodiments, A 1 , A 3 , and A 4 one of which is independently N, O, or S, and A 1 , A 3 , and A 4 The remaining two are independently CH or CR 2 In other embodiments, A 1 , A 3 , and A 4 Two of them are independently N and NR A1 , O, or S, and A 1 , A 3 , and A 4 The remaining one of them is independently CH or CR 2 In certain embodiments, A 1 , A 3 , and A 4 two of which are independently N, O, or S, and A1 , A 3 , and A 4 The remaining one of them is independently CH or CR 2 In yet another embodiment, A 1 , A 3 , and A 4 Three of them are N and NR independently. A1 , O, or S. In some embodiments, when present, R A1 is H or C 1~3 In certain embodiments, R A1 is H or -CH3.

[0067] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In certain embodiments, ring A is [ka] In certain embodiments, ring A is [ka] is.

[0068] In some embodiments, ring A is [ka] wherein A 5 ~A 8 are independently CH, CR 2 , N, or NR A2 and A 5 , A 6 , A 7 , and A 8 At least two of these are CH or CR 2 and if it exists, A 5 , A 6 , A 7 , and A 8 The remaining one or two are N or NR A2 where R A2 In some embodiments, ring A is: [ka] wherein A 5 ~A 8 are independently CH, CR 2 , or N and A 5 , A 6 , A 7 , and A 8 At least two of these are CH or CR 2 and if it exists, A 5 , A 6 , A 7 , and A 8 and the remaining one or two of A are N. 5 , A 6 , A 7 , and A 8 Two of them are CH or CR 2and A 5 , A 6 , A 7 , and A 8 The remaining two are N or NR A2 where R A2 is ═O. In certain embodiments, A 5 , A 6 , A 7 , and A 8 Two of them are CH or CR 2 and A 5 , A 6 , A 7 , and A 8 The remaining two of A are N. 5 , A 6 , A 7 , and A 8 Three of them are CH or CR 2 and A 5 , A 6 , A 7 , and A 8 The remaining one is N or NR A2 where R A2 is ═O. In certain embodiments, A 5 , A 6 , A 7 , and A 8 Three of them are CH or CR 2 and A 5 , A 6 , A 7 , and A 8 The remaining one of A is N. 5 , A 6 , A 7 , and A 8 is CH or CR 2 is.

[0069] In other embodiments, ring A is [ka] In some embodiments, ring A is [ka] [ka] [ka] [ka] [ka] In other embodiments, ring A is: [ka] In some embodiments, ring A is [ka] [ka] [ka] In some embodiments, ring A is [ka] [ka] In certain embodiments, ring A is [ka] In certain embodiments, ring A is [ka] is.

[0070] In some embodiments, R 1 is C 1~6 Alkyl, C 3~6 Cycloalkyl, C 3~10 Cycloalkenyl, 3-10 membered heterocycloalkyl, -NR a1C(O)NR a2 R a3 , -NR a4 C(O)OR a5 , -NR a6 R a7 , -N=S(O)R a8 R a9 , -OR a10 , -S(O)R a11 , -S(O)(NR a12 )R a13 , -S(O)NR a14 R a15 , -S(O)2R a16 , or -(CR a17 R a18 ) 0~1 C(O)NR a19 R a20 where R 1 C1-C6 alkyl is halogen, -OH, oxo, cyano, C 3~10 optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo; 1 C 3~6 The cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; 1 C 3~10 The cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; and 1 The 3- to 10-membered heterocycloalkyl may be halogen, C 1~6 Alkyl, and C 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl. In some embodiments, the cycloalkyl group, cycloalkenyl group, or heterocycloalkyl group comprises a spiro group. In some embodiments, the cycloalkyl group, cycloalkenyl group, or heterocycloalkyl group comprises a fused bicyclic group. In some embodiments, the cycloalkyl group, cycloalkenyl group, or heterocycloalkyl group comprises a bridging group.

[0071] In some embodiments, R 1 teeth,1~6 Alkyl, C 3~6 Cycloalkyl, 3-10 membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 , -NR a4 C(O)OR a5 , -NR a6 R a7 , -N=S(O)R a8 R a9 , -OR a10 , -S(O)R a11 , -S(O)(NR a12 )R a13 , -S(O)NR a14 R a15 , -S(O)2R a16 , or -(CR a17 R a18 ) 0~1 C(O)NR a19 R a20 where R 1 C1-C6 alkyl is halogen, -OH, cyano, C 3~10 optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo; 1 C 3~6 Cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; 1 wherein the 3-10 membered heterocycloalkyl is optionally substituted with one or more halogens. In some embodiments, the cycloalkyl or heterocycloalkyl group comprises a spiro group. In some embodiments, the cycloalkyl or heterocycloalkyl group comprises a fused bicyclic group.

[0072] In some embodiments, R 1 is C 1~6 Alkyl, C 3~6 Cycloalkyl, C 3~10 Cycloalkenyl, 3-10 membered heterocycloalkyl, -NR a6 R a7 , -OR a10 , -S(O)NR a14 Ra15 , or -S(O)2R a16 where R 1 C1-C6 alkyl is halogen, -OH, oxo, cyano, C 3~10 optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo; 1 C 3~6 The cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; 1 C 3~10 The cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; and 1 The 3- to 10-membered heterocycloalkyl may be halogen, C 1~6 Alkyl, and C 1~6 In some embodiments, R is optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl. 1 is C 1~6 Alkyl, C 3~6 Cycloalkyl, 3-10 membered heterocycloalkyl, -NR a6 R a7 , -S(O)NR a14 R a15 , or -S(O)2R a16 where R 1 C1-C6 alkyl is halogen, -OH, cyano, C 3~10 optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo; 1 C 3~6 Cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; 1 The 3- to 10-membered heterocycloalkyl is optionally substituted with one or more halogens.

[0073] In some embodiments, R a1 ~R a20 are each independently hydrogen, C1~6 Alkyl, C 2~6 Alkenyl, C 3~10 Cycloalkyl, C 3~10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 6~14 aryl, or 5- to 12-membered heteroaryl, each of which is halo, cyano, -OH, -O(C 1~6 alkyl), C 2~6 Alkenyl, C 3~10 Cycloalkyl, -S(C 1~6 alkyl), =CR 1a1 R 1a2 , and halo, -OH, and -O(C 1~6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkyl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1~6 It is alkyl.

[0074] In other embodiments, R a14 and R a15 taken together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl optionally substituted with one or more halo.

[0075] In some embodiments, R a6 and R a7 are each independently hydrogen, C 1~6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl, halo 3~6 Cycloalkyl, or C 1~6 In some embodiments, R is a 5-12 membered heteroaryl optionally substituted with alkyl. a6 and R a7 are independently hydrogen, C 1~6 Alkyl, or C 1~6 In some embodiments, R is a 5-12 membered heteroaryl optionally substituted with alkyl. a6 and R a7are each independently hydrogen, methyl, cyclobutyl optionally substituted with one or more fluoro, imidazolyl, methylimidazolyl, or pyrimidinyl. a6 and R a7 are each independently hydrogen, imidazolyl, methylimidazolyl, or pyrimidinyl. a6 R a7 teeth, [ka] In some embodiments, R a10 is C 3~10 In some embodiments, -OR is cycloalkyl. a10 teeth [ka] In some embodiments, -S(O)NR a14 R a15 teeth [ka] In some embodiments, R a14 and R a15 are each independently hydrogen; C 1~6 Alkyl, C 2~6 Alkenyl, C 3~10 Cycloalkyl, -OH, -O(C 1~6 alkyl), -S(C 1~6 C optionally substituted with 1, 2, 3, 4, 5 or more substituents independently selected from the group consisting of alkyl, and halo 1~6 Alkyl; C 2~6 Alkenyl; C 2~6 Alkenyl, C 3~10 Cycloalkyl, halo, cyano, -OH, -O(C 1~6 alkyl), =CR 1a1 R 1a2 , and -OH, -O(C 1~6 C optionally substituted with 1, 2, 3, 4, 5 or more substituents independently selected from the group consisting of alkyl, and halo 1~6C optionally substituted with 1, 2, 3, 4, 5 or more substituents independently selected from the group consisting of alkyl 3~10 cycloalkyl, where R 1a1 and R 1a2 are each independently hydrogen or C 1~6 Alkyl; C 3~10 cycloalkenyl; or 1, 2, 3, 4, 5 or more C 1~6 In some embodiments, R is a 3- to 12-membered heterocycloalkyl optionally substituted with alkyl. a14 and R a15 are each independently hydrogen or C 1~6 In some embodiments, R a14 is hydrogen and R a15 is butyl. In some embodiments, R a15 is tert-butyl. In some embodiments, —S(O)R a16 teeth [ka] In some embodiments, R a16 is C 3~10 cycloalkyl; or C 1~6 and 3-12 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4, 5 or more substituents independently selected from the group consisting of alkyl or halo.

[0076] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is halogen, -OH, oxo, cyano, C 3~10In some embodiments, R is C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo. 1 -OH, cyano, C 3~10 C optionally substituted with 1, 2, 3, 4, 5 or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4, 5 or more halo. 1~6 In some embodiments, the 3-10 membered heterocycloalkyl is piperidinyl optionally substituted with 1, 2, 3, 4, 5, or more halo. In other embodiments, the 3-10 membered heterocycloalkyl is pyrrolidinyl optionally substituted with 1, 2, 3, 4, 5, or more halo. In other embodiments, the 3-10 membered heterocycloalkyl is azetidinyl optionally substituted with 1, 2, 3, 4, 5, or more halo. In some embodiments, the 3-10 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, or more fluoro. In some embodiments, the 3-10 membered heterocycloalkyl is piperidinyl optionally substituted with 1, 2, 3, 4, 5, or more fluoro. In some embodiments, the 3-10 membered heterocycloalkyl is pyrrolidinyl optionally substituted with 1, 2, 3, 4, 5, or more fluoro. In some embodiments, the 3-10 membered heterocycloalkyl is azetidinyl optionally substituted with 1, 2, 3, 4, 5 or more fluoro.

[0077] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 are halo, cyano, -OH, -O(C 1~6 alkyl), C 2~6 Alkenyl, C 3~10 Cycloalkyl, -S(C 1~6 alkyl), =CR 1a1 R 1a2 , and halo, -OH, and -O(C1~6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 1~6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 3~6 cycloalkyl, where R 1a1 and R 1a2 are each independently hydrogen or C 1~6 It is alkyl.

[0078] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is C optionally substituted with one or more substituents independently selected from the group consisting of halogens 3~10 It is a cycloalkenyl.

[0079] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is a halogen, C 1~6 Alkyl, and C 1~6 and 3-10 membered heterocycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl.

[0080] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0081] In some embodiments, each R 2are independently halogens, C 1~3 Alkyl, C 3~5 Cycloalkyl, cyano, C 1~3 Alkyloxy, C 3~5 Cycloalkyloxy, hydroxy, or NR b1 R b2 where R 2 C 1~3 The alkyl is optionally substituted with one or more substituents selected from the group consisting of —OH and oxo, where R b1 and R b2 are independently optionally substituted with C1-C3 alkyl, or R b1 and R b2 are taken together with the nitrogen to which they are attached to form a 3- to 6-membered ring. In some embodiments, each R 2 are independently halogens, C 1~3 Alkyl, C 3~5 Cycloalkyl, cyano, C 1~3 Alkyloxy, C 3~5 Cycloalkyloxy, hydroxy, or NR b1 R b2 where R b1 and R b2 are independently optionally substituted with C1-C3 alkyl, or R b1 and R b2 are taken together with the nitrogen to which they are attached to form a 3- to 6-membered ring. In some embodiments, each R 2 are independently halogens, C 1~3 Alkyl, cyano, hydroxy, or NR b1 R b2 where R b1 and R b2 is independently optionally substituted with C1-C3 alkyl. In some embodiments, each R 2 independently C 1~3 Alkyl, C 3~5 Cycloalkyl, C 1~3 Alkyloxy, C 3~5 Cycloalkyloxy, or NR b1 R b2 where R b1 and R b2are taken together with the nitrogen to which they are attached to form a 3- to 6-membered ring. In some embodiments, each R 2 is halogen. In some embodiments, each R 2 is fluoro. In some embodiments, each R 2 is C optionally substituted with one or more substituents independently selected from the group consisting of —OH and oxo; 1~3 In other embodiments, each R 2 is independently C 1~3 In certain embodiments, each R 2 is independently —CH. In some embodiments, R 2 is —CHOH. In other embodiments, each R 2 is -C(O)OH.

[0082] In yet other embodiments, A 5 R 1 and R 2 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3-6 membered heterocycloalkyl. In certain embodiments, ring A is [ka] In certain other embodiments, ring A is [ka] In still other embodiments, ring A is: [ka] In certain other embodiments, ring A is [ka] is.

[0083] In some embodiments, B 1 and B 2 are each independently N, CH, or CR B where R Bis a halogen. In some embodiments, B 1 and B 2 are each independently N or CH.

[0084] In some embodiments, B 1 is N or CH. In some embodiments, B 1 is N. In other embodiments, B 1 is CH. In some embodiments, B 1 is CR B where R B is halogen. In certain embodiments, B 1 is CR B where R B is fluoro.

[0085] In some embodiments, B 2 is N or CH. In some embodiments, B 2 is N. In other embodiments, B 2 is CH. In some embodiments, B 2 is CR B where R B is halogen. In certain embodiments, B 2 is CR B where R B is fluoro.

[0086] In some embodiments, the ring [ka] teeth, [ka] In some embodiments, the ring [ka] teeth, [ka] In certain embodiments, the ring [ka] teeth, [ka] In certain embodiments, the ring [ka] teeth, [ka] In some embodiments, the ring [ka] teeth, [ka] In some embodiments, the ring [ka] teeth, [ka] In some embodiments, the ring [ka] teeth, [ka] In some embodiments, the ring [ka] teeth, [ka] In some embodiments, the ring [ka] teeth, [ka] is.

[0087] In some embodiments, R 3 is piperidinyl, pyrrolidinyl, or azepanyl, where piperidinyl, pyrrolidinyl, or azepanyl is C 3~10 optionally substituted with cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 3~10 The cycloalkyl or 3- to 10-membered heterocycloalkyl may form a spirocyclic or fused bicyclic ring system with piperidinyl, pyrrolidinyl, or azepanyl, or wherein the piperidinyl, pyrrolidinyl, or azepanyl is optionally C 1~2 substituted with alkylene to form a bridged piperidinyl, pyrrolidinyl, or azepanyl ring system, wherein piperidinyl, pyrrolidinyl, azepanyl, or C 3~10 Cycloalkyl, 3-10 membered heterocycloalkyl, or C 1~2 The spirocyclic, fused, or bridged bicyclic ring system formed by the alkylene and piperidinyl, pyrrolidinyl, or azepanyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and halo. 3 is piperidinyl, pyrrolidinyl, or azepanyl, where piperidinyl, pyrrolidinyl, or azepanyl is C 3~10 optionally substituted with cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 3~10 A cycloalkyl or a 3- to 10-membered heterocycloalkyl may form a spirocyclic or fused bicyclic ring system with piperidinyl, pyrrolidinyl, or azepanyl, where piperidinyl, pyrrolidinyl, azepanyl, or C 3~10The spirocyclic or fused bicyclic ring system formed by the cycloalkyl or 3- to 10-membered heterocycloalkyl and piperidinyl, pyrrolidinyl, or azepanyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and halo.

[0088] In some embodiments, R 3 is piperidinyl, where piperidinyl is C 3~10 optionally substituted with cycloalkyl or 3-10 membered heterocycloalkyl, where C 3~10 The cycloalkyl or 3-10 membered heterocycloalkyl may form a spirocyclic or fused bicyclic ring system with the piperidinyl, or the piperidinyl may optionally be C 1~2 substituted with alkylene to form a bridged piperidinyl ring system, wherein piperidinyl, or C 3~10 Cycloalkyl, 3-10 membered heterocycloalkyl, or C 1~2 The spirocyclic, fused, or bridged bicyclic ring system formed by the alkylene and piperidinyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and halo. In some embodiments, R 3 is piperidinyl, where piperidinyl is C 3~10 optionally substituted with cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 3~10 The cycloalkyl or 3- to 10-membered heterocycloalkyl forms a spirocyclic or fused bicyclic ring system with the piperidinyl, where the piperidinyl, or C 3~10 The spirocyclic or fused bicyclic ring system formed by the cycloalkyl or 3-10 membered heterocycloalkyl and piperidinyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and halo. In some embodiments, R 3is piperidinyl, wherein the piperidinyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and halo. 3 is C 3~10 piperidinyl substituted with cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 3~10 The cycloalkyl or 3- to 10-membered heterocycloalkyl forms a spirocyclic or fused bicyclic ring system with the piperidinyl, and C 3~10 The spirocyclic or fused bicyclic ring system formed by the cycloalkyl or 3-10 membered heterocycloalkyl and pyrrolidinyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and halo. In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In certain embodiments, R 3 teeth [ka] In certain other embodiments, R 3 teeth [ka] is.

[0089] In some embodiments, R 3 is pyrrolidinyl, where pyrrolidinyl is C 3~10optionally substituted with cycloalkyl or 3-10 membered heterocycloalkyl, where C 3~10 The cycloalkyl or 3- to 10-membered heterocycloalkyl may form a spirocyclic or fused bicyclic ring system with the pyrrolidinyl, or the pyrrolidinyl may optionally be C 1~2 substituted with alkylene to form a bridged pyrrolidinyl ring system, wherein pyrrolidinyl, or C 3~10 Cycloalkyl, 3-10 membered heterocycloalkyl, or C 1~2 The spirocyclic, fused, or bridged bicyclic ring system formed by the alkylene and pyrrolidinyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and halo. 3 is pyrrolidinyl, where pyrrolidinyl is C 3~10 optionally substituted with cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 3~10 The cycloalkyl or 3- to 10-membered heterocycloalkyl forms a spirocyclic or fused bicyclic ring system with pyrrolidinyl, where pyrrolidinyl, or C 3~10 The spirocyclic or fused bicyclic ring system formed by the cycloalkyl or 3-10 membered heterocycloalkyl and pyrrolidinyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and halo. In some embodiments, R 3 is pyrrolidinyl, wherein the pyrrolidinyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and halo. In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In certain embodiments, R 3 teeth [ka] In certain other embodiments, R 3 teeth [ka] In other embodiments, R 3 is C 3~10 pyrrolidinyl substituted with cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 3~10 The cycloalkyl or 3-10 membered heterocycloalkyl forms a spirocyclic or fused bicyclic ring system with the pyrrolidinyl, wherein C 3~10 The spirocyclic or fused bicyclic ring system formed by the cycloalkyl or 3-10 membered heterocycloalkyl and pyrrolidinyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and halo.

[0090] In yet other embodiments, R 3 is azepanil, where azepanil is C 3~10 optionally substituted with cycloalkyl or 3-10 membered heterocycloalkyl, where C 3~10 The cycloalkyl or 3-10 membered heterocycloalkyl may form a spirocyclic or fused bicyclic ring system with the azepanyl, or the azepanyl may optionally be C 1~2 substituted with alkylene to form a bridged azepanyl ring system, where azepanyl, or C 3~10 Cycloalkyl, 3-10 membered heterocycloalkyl, or C 1~2 The spirocyclic, fused, or bridged bicyclic ring system formed by the alkylene and azepanyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and halo. In some embodiments, R 3 is azepanil, where azepanil is C 3~10 optionally substituted with cycloalkyl or 3-10 membered heterocycloalkyl, wherein C3~10 The cycloalkyl or 3- to 10-membered heterocycloalkyl forms a spirocyclic or fused bicyclic ring system with azepanyl, where azepanyl, or C 3~10 The spirocyclic or fused bicyclic ring system formed by the cycloalkyl or 3-10 membered heterocycloalkyl and azepanyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and halo. In some embodiments, R 3 is azepanyl, wherein the azepanyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and halo. In some embodiments, R 3 teeth [ka] In other embodiments, R 3 is C 3~10 azepanyl substituted with cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 3~10 The cycloalkyl or 3-10 membered heterocycloalkyl forms a spirocyclic or fused bicyclic ring system with the azepanyl, wherein C 3~10 The spirocyclic or fused bicyclic ring system formed by the cycloalkyl or 3-10 membered heterocycloalkyl and the azepanyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and halo.

[0091] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] is.

[0092] In one aspect, provided is a compound of formula (III): [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is [ka] where: A 1 , A 3 , and A 4 One, two, or three of these are independently N, NR A1 , O, or S, and if present, A 1 , A 3 , and A 4 The remaining one or two are independently CH or CR 2 where R A1 is H or C 1~3 is alkyl; A 2 is N or C; A 5 ~A 8 are CH, CR independently 2 , N, or NR A2 where A 5 , A 6 , A 7 , and A 8 At least two of these are CH or CR 2 and if it exists, A 5 , A 6 , A 7 , and A 8 The remaining one or two are N or NR A2 where R A2 is =O; where "*" indicates the point of attachment to V; B 1 and B 2 are each independently N, CH, or CR B where R B is a halogen; R 1 is C 1~6 Alkyl, C3~6 Cycloalkyl, C 3~10 Cycloalkenyl, 3-10 membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 , -NR a4 C(O)OR a5 , -NR a6 R a7 , -N=S(O)R a8 R a9 , -OR a10 , -S(O)R a11 , -S(O)(NR a12 )R a13 , -S(O)NR a14 R a15 , -S(O)2R a16 , or -(CR a17 R a18 ) 0~1 C(O)NR a19 R a20 and where R 1 C1-C6 alkyl is halogen, -OH, oxo, cyano, C 3~10 optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo; 1 C 3~6 The cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; 1 C 3~10 The cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; and 1 The 3- to 10-membered heterocycloalkyl may be halogen, C 1~6 Alkyl, and C 1~6 optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl; R a1 ~R a20 are each independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 3~10 Cycloalkyl, C 3~10Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 6~14 aryl, or 5- to 12-membered heteroaryl, each of which is halo, cyano, -OH, -O(C 1~6 alkyl), C 2~6 Alkenyl, C 3~10 Cycloalkyl, -S(C 1~6 alkyl), =CR 1a1 R 1a2 , and halo, -OH, and -O(C 1~6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkyl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1~6 is alkyl; or R a14 and R a15 together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl optionally substituted with one or more halo; Each R 2 are independently halogens, C 1~3 Alkyl, C 3~5 Cycloalkyl, cyano, C 1~3 Alkyloxy, C 3~5 Cycloalkyloxy, hydroxy, or NR b1 R b2 where R 2 C 1~3 The alkyl is optionally substituted with one or more substituents selected from the group consisting of —OH and oxo, where R b1 and R b2 are independently optionally substituted with C1-C3 alkyl, or R b1 and R b2 form a 3- to 6-membered ring together with the nitrogen to which they are attached; or A 5 R 1 and R 2together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3-10 membered heterocycloalkyl; Here, each R d1 are independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and halo, or two R d1 Together they form C 3~10 cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 3~10 The cycloalkyl or 3- to 10-membered heterocycloalkyl may form a spirocyclic or fused bicyclic ring system with the piperidinyl, or two R d1 Together they form C 1~2 Forming alkylene, C 1~2 The alkylene forms a bridged piperidinyl ring system; where C 3~10 cycloalkyl, 3-10 membered heterocycloalkyl, or spirocyclic, fused, or bridged bicyclic ring system formed by C1-2 alkylene and piperidinyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and halo; R 4 is H, halo, cyano, -OH, -NO2, -C(O)NR c1 R c2 , -NR c3 R c4 , -NR c5 S(O)2R c6 , -P(O)R c7 R c8 , -N=S(O)R c9 R c10 , -S(O)(NR c11 )R c12 , -S(O)2R c13 or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH 1~6 is alkyl, R c1 ~R c13 are each independently hydrogen, C 3~10 Cycloalkyl, or C 1~6 alkyl, where Rc1 ~R c13 Each C 1 ~C 6 The alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, —OH, and —C(O)—O—C1-C3 alkyl, wherein each C 3~10 The cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkylene-OH.

[0093] In some embodiments, R 4 is hydrogen, halo, cyano, -OH, -NO2, -C(O)NR c1 R c2 , -NR c3 R c4 , -NR c5 S(O)2R c6 , -P(O)R c7 R c8 , -N=S(O)R c9 R c10 , -S(O)(NR c11 )R c12 , -S(O)2R c13 or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH 1~6 It is alkyl.

[0094] In some embodiments, R c1 ~R c13 are each independently hydrogen, C 3~10 Cycloalkyl, or C 1~6 alkyl, where R c1 ~R c13 each C1-C6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, —OH, and —C(O)—O—C1-C3 alkyl, wherein each C 3~10 The cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkylene-OH. In some embodiments, R c1 ~R c13 are each independently hydrogen, C 3~10 Cycloalkyl, or C 1~6alkyl, where R c1 ~R c13 wherein each C1-C6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, and -C(O)-O-C1-C3 alkyl.

[0095] In some embodiments, R 4 is hydrogen, halo, or -NR c5 S(O)2R c6 In some embodiments, R 4 is hydrogen. In other embodiments, R 4 is halo. In some embodiments, R 4 Ha-NR c5 S(O)2R c6 In some embodiments, R c5 is hydrogen or C 1~6 alkyl, wherein the C alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo. c5 is hydrogen. In some embodiments, R c5 is hydrogen. In some embodiments, R c6 is C 1~6 alkyl, where the C1-C6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, —OH, and —C(O)—O—C1-C3 alkyl. In some embodiments, R c6 is C 1~6 alkyl, where the C1-C6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, —OH, and —C(O)—O—C1-C3 alkyl. In some embodiments, R c6 is C 1~6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of —OH, and —C(O)—O—C1-C3 alkyl. In certain embodiments, R c6 is a C optionally substituted with one or more substituents independently selected from the group consisting of —OH and —C(O)—O—C1-C3 alkyl; 1~6In some embodiments, R c6 is methyl or ethyl. In other embodiments, R c6は , methyl substituted with —C(O)—O—C1-C3 alkyl. In some embodiments, R c6 is ethyl substituted with -OH or propyl substituted with -OH. In still other embodiments, R c6 is ethyl substituted with -OH. In yet other embodiments, R c6 is each C optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkylene-OH 3~10 In some embodiments, R c6 is C 3~10 In certain embodiments, R c6 is cyclopropyl. In other embodiments, R c6 is each C substituted with one or more substituents independently selected from the group consisting of C1-C6 alkylene-OH 3~10 In some embodiments, R c6 is cyclopropyl substituted with one or more substituents independently selected from the group consisting of: —CHOH. In some embodiments, R 4 teeth, [ka] In some embodiments, NR c5 S(O)2R c6 teeth, [ka] is.

[0096] In some embodiments, R 4 H, Br, [ka] In some embodiments, R 4 H, Br, [ka] In certain embodiments, R 4 teeth, [ka] In certain embodiments, R 4 teeth, [ka] is.

[0097] In some embodiments of this aspect of the invention, the ring [ka] teeth, [ka] and ring A is [ka] [ka] and R 1 teeth, [ka] and the ring [ka] teeth, [ka] and R 3 teeth, [ka] and R 4 H, Br, [ka] is.

[0098] In some embodiments of this aspect of the invention, the ring [ka] teeth, [ka] and ring A is [ka] and R 1 teeth, [ka] and the ring [ka] teeth, [ka] and R 3 teeth, [ka] and R 4 H, Br, [ka] is.

[0099] In some embodiments, provided herein are compounds set forth in Table 1 and pharmaceutically acceptable salts thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38

[0100] In some variations, any of the compounds described herein, such as a compound of Formula (I), Formula (II), Formula (III), or any variation thereof, or a compound in Table 1, may be deuterated (e.g., a hydrogen atom is replaced with a deuterium atom). In some of these variations, the compound is deuterated at a single site. In other variations, the compound is deuterated at multiple sites. Deuterated compounds can be prepared from deuterated starting materials in a manner similar to the preparation of the corresponding non-deuterated compounds. Other methods known in the art may also be used to replace hydrogen atoms with deuterium atoms.

[0101] Any formula provided herein, for example, Formula (I), Formula (II), or Formula (III), is intended to represent a compound having the structure depicted by the structural formula, as well as certain variations or forms. In particular, compounds of any formula depicted herein may have asymmetric centers and, therefore, may exist in different enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of a compound of a general formula, as well as mixtures thereof in any ratio, are considered within the scope of the formula. Thus, any formula depicted herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof in any ratio. Furthermore, a particular structure may exist as a geometric isomer (i.e., cis and trans isomers), tautomer, or atropisomer. Furthermore, any formula depicted herein is intended to refer to any one of hydrates, solvates, and amorphous and polymorphic forms of such a compound, as well as mixtures thereof, even if such forms are not explicitly stated. In some embodiments, the solvent is water and the solvate is a hydrate.

[0102] Representative examples of the compounds detailed herein, including intermediate and final compounds, are shown in the Tables and elsewhere herein. In one aspect, it is understood that any of the compounds, including intermediate compounds that may be isolated and administered to an individual, may be used in the methods detailed herein, if applicable.

[0103] The compounds provided herein may exist as salts whether or not the salts are provided, and it is understood that the compositions and methods provided herein encompass all salts and solvates of the compounds provided herein, as well as non-salt and non-solvated forms of the compounds, as will be appreciated by one of ordinary skill in the art. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts.

[0104] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual. In another variation, compositions containing the compounds in substantially pure form are provided. In another variation, pharmaceutical compositions are provided that include the compounds detailed herein and a pharmaceutically acceptable carrier. In another variation, methods of administering the compounds are provided. Purified forms, pharmaceutical compositions, and methods of administering the compounds are suitable for any of the compounds or forms thereof detailed herein.

[0105] V, W, X, Y, Z, ring A, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8 , R A1 , R A2 , B 1 , B 2 , R B , R 1 , R 2 , R 3 , R 4 , R a1 , R a2 , R a3 , R a4 , R a5 , Ra6 , R a7 , R a8 , R a9 , R a10 , R a11 , R a12 , R a13 , R a14 , R a15 , R a16 , R a17 , R a18 , R a19 , R a20 , R 1a1 , R 1a2 , R b1 , R b2 , R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , R c8 , R c9 , R c10 , R c11 , R c12 , R c13 , or R d1 Any variation or embodiment of V, W, X, Y, Z, ring A, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8 , R A1 , R A2 , B 1 , B 2 , R B , R 1 , R 2 , R 3 , R 4 , R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 , R a8 , R a9 , R a10 , R a11 , R a12 , Ra13 , R a14 , R a15 , R a16 , R a17 , R a18 , R a19 , R a20 , R 1a1 , R 1a2 , R b1 , R b2 , R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , R c8 , R c9 , R c10 , R c11 , R c12 , R c13 , or R d1 It is possible to combine it with all other variations or embodiments of the above.

[0106] As used herein, when any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence.

[0107] The compound names provided herein, including in Table 1, are provided by Chemaxon Marvin Structure to Name 20 or ChemDraw Professional 21. Those skilled in the art will understand that compounds may be named or identified using a variety of commonly recognized nomenclature systems and symbols. By way of example, compounds may be named or identified by common name, systematic name, or non-systematic name. Nomenclature systems and symbols commonly recognized in the chemical arts include, for example, Chemical Abstract Service (CAS), ChemBioDraw Ultra, and International Union of Pure and Applied Chemistry (IUPAC). composition

[0108] Compositions, such as pharmaceutical compositions, containing a compound disclosed and / or described herein and one or more additional agents, pharmaceuticals, adjuvants, carriers, excipients, etc. are also provided. Suitable agents and pharmaceuticals include those described herein. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable excipient or adjuvant and at least one chemical entity described herein. Examples of pharmaceutically acceptable excipients include, but are not limited to, mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, and magnesium carbonate. In some embodiments, provided are compositions, such as pharmaceutical compositions, containing one or more compounds described herein, or pharmaceutically acceptable salts thereof.

[0109] In some embodiments, provided are pharmaceutically acceptable compositions comprising a compound of Formula (I), Formula (II), Formula (III), or a compound in Table 1, or a pharmaceutically acceptable salt thereof. In some aspects, the compositions may contain synthetic intermediates that may be used in the preparation of the compounds described herein. The compositions described herein may also include any other suitable active or inactive agents.

[0110] Any of the compositions described herein may be sterile or contain sterile components.Sterilization can be achieved by methods known in the art.Any of the compositions described herein may contain one or more compounds that are substantially pure.

[0111] Also provided is a packaged pharmaceutical composition comprising a pharmaceutical composition described herein and instructions for using the composition to treat a patient suffering from a disease or condition described herein. How to use

[0112] As described herein, the compounds of the present disclosure are inhibitors of KIF18A. In one embodiment, the compounds and pharmaceutical compositions of the present disclosure may be used to inhibit KIF18A. In another embodiment, the compounds and pharmaceutical compositions of the present disclosure may be used to treat or prevent a disease or condition in an individual.

[0113] The inhibitory activity of the compounds described herein against KIF18A may be determined and measured by methods known in the art, including, but not limited to, inhibition of ATP hydrolysis in the presence of microtubules (Hackney DD, Jiang W. (2001), Assays for Kinesin Microtubule-Stimulated ATPase Activity. In: Vernos I. (eds), Kinesin Protocols. Methods in Molecular Biology™, vol 164. Humana Press. https: / / doi.org / 10.1385 / 1-59259-069-1:65).

[0114] In one aspect, provided herein is a method for inhibiting KIF18A, comprising contacting a cell with an effective amount of a compound or pharmaceutical composition described herein. In some embodiments, provided herein is a method for inhibiting KIF18A, comprising contacting a cell with an effective amount of a compound of Formula (I), Formula (II), Formula (III), or Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method for inhibiting KIF18A, comprising contacting a cell with a pharmaceutical composition comprising an effective amount of a compound of Formula (I), Formula (II), Formula (III), or Table 1, or a pharmaceutically acceptable salt thereof. In one variation of the foregoing embodiment, the cell is contacted in vitro. In another variation of the foregoing embodiment, the cell is contacted in vivo.

[0115] In another aspect, the compounds and pharmaceutical compositions herein may be used to treat or prevent a disease or condition in an individual, comprising administering an effective amount of a compound or pharmaceutical composition described herein. When used prophylactically, the compounds disclosed and / or described herein may prevent a disease or disorder from occurring in an individual at risk of developing it, or may reduce the severity of the disease or disorder that may occur.

[0116] In some embodiments, provided herein are methods of treating or preventing a disease or condition in an individual, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein. In some embodiments, provided herein are methods of treating or preventing a disease or condition in an individual, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), Formula (II), Formula (III), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of treating or preventing a disease or condition in an individual, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), Formula (II), Formula (III), or a compound of Table 1, or a pharmaceutically acceptable salt thereof.

[0117] In some embodiments, the disease or condition is mediated by KIF18A. In some embodiments, the disease or condition is cancer. In some embodiments, the disease or condition is a cell proliferation disorder, including uncontrolled cell proliferation, aberrant cell cycle regulation, centrosome abnormalities (structure and / or number, fragmentation), solid tumors, hematopoietic cancers, and hyperproliferative disorders, such as thyroid hyperplasia (particularly Graves' disease), and cysts (such as hypervascularity of the ovarian stroma, a feature of polycystic ovary syndrome (Stein-Leventhal syndrome)). Solid tumors such as carcinomas and hematologically derived tumors include cancers of the anus, bladder, breast, colon, small intestine, appendix, kidney, renal pelvis, ureter, allantois, liver, lung (including squamous cell and small cell lung cancer), pleura, esophagus, head and neck, nasopharynx, oropharynx, hypopharynx, oral cavity, larynx, biliary duct, gallbladder, ovary, testis, germ cell, uterus, pancreas, stomach, cervix, thyroid, prostate, salivary gland, and skin (including squamous cell carcinoma); hematopoietic tumors of lymphoid lineage (including 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); hematopoietic tumors of myeloid lineage (acute and chronic myeloid leukemia, myelodysplastic syndromes, myeloatherosclerosis, and thyroid cancer); and promyelocytic leukemia), hematopoietic tumors of any lineage, myeloma, mesenchymal tumors (including fibrosarcoma and rhabdomyosarcoma, and other sarcomas, e.g., tumors of soft tissue and bone), tumors of the central and peripheral nervous system (including astrocytoma, neuroblastoma, glioma, and schwannoma), tumors of the neuroendocrine system, tumors of the endocrine system, small cell tumors, tumors of unknown primary, other tumors (including retinoblastoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, Ewing's sarcoma, Kaposi's sarcoma), and other cancer-related disorders that are a result of the presence or progression of cancer, such as tumor-induced pleural or pericardial effusion, and malignant ascites.

[0118] In some embodiments, provided are methods of treating or preventing cancer in an individual comprising administering to the individual a compound of Formula (I), Formula (II), Formula (III), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided are methods of treating or preventing cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one chemical entity described herein. Also provided herein is the use of a compound of Formula (I), Formula (II), Formula (III), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease in a subject.

[0119] In some embodiments, provided herein is a method of treating cancer comprising administering a compound of Formula (I), Formula (II), Formula (III), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, to an individual in need thereof. Also provided herein is the use of a compound of Formula (I), Formula (II), Formula (III), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.

[0120] In some embodiments, provided herein is a method for treating a KIF18A-mediated disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein.

[0121] In some embodiments, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein. In some embodiments, the cancer is selected from the group consisting of carcinoma, cancer of the anus, bladder, breast, colon, small intestine, appendix, kidney, renal pelvis, ureter, urothelium, liver, lung, pleura, esophagus, head and neck, nasopharynx, oropharynx, hypopharynx, oral cavity, larynx, biliary tract, gallbladder, ovary, testis, germ cell, uterus, pancreas, stomach, cervix, thyroid, prostate, salivary gland, or skin, hematopoietic tumors of lymphoid lineage, hematopoietic tumors of myeloid lineage, hematopoietic tumors of any lineage, myeloma, mesenchymal tumors including sarcoma, tumors of the central and peripheral nervous system, neuroendocrine tumors, endocrine tumors, small cell tumors, tumors of unknown primary, retinoblastoma, melanoma, seminoma, teratocarcinoma, other tumors including osteosarcoma, and other cancer-related disorders that are a result of the presence or progression of cancer. Dosage

[0122] The compounds and compositions disclosed and / or described herein are administered at therapeutically effective doses, e.g., at doses sufficient to treat a medical condition. While human dosage levels for the chemical compounds described herein have not yet been optimized, generally, daily doses range from about 0.01 to 100 mg / kg body weight, in some embodiments, from about 0.05 to 10.0 mg / kg body weight, and in some embodiments, from about 0.10 to 1.4 mg / kg body weight. Thus, for a 70 kg human, the dosage range is, in some embodiments, from about 0.7 to 7000 mg per day, in some embodiments, from about 3.5 to 700.0 mg per day, and in some embodiments, from about 7 to 100.0 mg per day. The amount of chemical compound administered will depend, for example, on the subject and medical condition being treated, the severity of the condition, the mode and schedule of administration, and the judgment of the prescribing physician. For example, exemplary dosage ranges for oral administration are from about 5 mg to about 500 mg per day, and exemplary dosages for intravenous administration are from about 5 mg to about 500 mg per day, depending on the pharmacokinetics of each compound.

[0123] Administration of the compounds and compositions disclosed and / or described herein can be via any accepted mode of administration for therapeutic agents, including, but not limited to, oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration. In some embodiments, the compounds or compositions are administered orally or intravenously. In some embodiments, the compounds or compositions disclosed and / or described herein are administered orally.

[0124] Pharmaceutically acceptable compositions include solid, semi-solid, liquid, and aerosol dosage forms, such as tablets, capsules, powders, solutions, suspensions, suppositories, and aerosol forms. The compounds disclosed and / or described herein can also be administered in sustained- or controlled-release dosage forms (e.g., controlled-release / sustained-release pills, depot injections, osmotic pumps, or transdermal (including electrotransport) patch forms) for extended timed administration and / or pulsed administration at a predetermined rate. In some embodiments, the compositions are provided in unit dosage forms suitable for single administration of precise doses.

[0125] The compounds disclosed and / or described herein may be administered alone or in combination with one or more conventional pharmaceutical carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, saccharin sodium, talcum, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, magnesium carbonate). If desired, pharmaceutical compositions may contain minor amounts of non-toxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents, and the like (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate). Generally, pharmaceutical compositions will contain about 0.005% to 95% by weight, or about 0.5% to 50% by weight, of the compounds disclosed and / or described herein, depending on the intended mode of administration. Actual methods for preparing such dosage forms are known, or will become apparent, to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

[0126] In some embodiments, the composition takes the form of a pill or tablet, and thus the composition may contain one or more of a diluent (e.g., lactose, sucrose, dicalcium phosphate), a lubricant (e.g., magnesium stearate), and / or a binder (e.g., starch, gum arabic, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives) along with a compound disclosed and / or described herein. Other solid dosage forms include powders, marume, solutions or suspensions (e.g., in propylene carbonate, vegetable oils, or triglycerides) enclosed in gelatin capsules.

[0127] Liquid pharmaceutically administrable compositions can be prepared, for example, by dissolving, dispersing, or suspending a compound disclosed and / or described herein and optional pharmaceutical excipients in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycol, ethanol, etc.) to form a solution or suspension. Injectables can be prepared in conventional forms: as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection. The percentage of compound contained in such parenteral compositions depends, for example, on the physical properties of the compound, the activity of the compound, and the needs of the subject. However, percentages of active ingredient between 0.01% and 10% in solution are usable, and may be higher if the composition is solid and will later be diluted to another concentration. In some embodiments, the composition contains about 0.2-2% of a compound disclosed and / or described herein in solution.

[0128] Pharmaceutical compositions of the compounds disclosed and / or described herein may be administered to the respiratory tract as aerosols or solutions for nebulizers, or as ultrafine powders for insufflation, either alone or in combination with an inert carrier such as lactose.In such cases, the particles of the pharmaceutical composition may have a diameter of less than 50 microns, or in some embodiments, less than 10 microns.

[0129] Additionally, pharmaceutical compositions may include a compound disclosed and / or described herein, as well as one or more additional drugs, pharmaceutical agents, adjuvants, etc. Suitable drugs and pharmaceutical agents include those described herein. kit

[0130] Also provided are articles of manufacture and kits containing any of the compounds or pharmaceutical compositions provided herein. The articles of manufacture may include a container with a label. Suitable containers include, for example, bottles, vials, and test tubes. The container may be formed from a variety of materials, such as glass or plastic. The container may hold a pharmaceutical composition provided herein. The label on the container may indicate that the pharmaceutical composition is used to prevent, treat, or inhibit a condition described herein, and may indicate instructions for either in vivo or in vitro use.

[0131] In one aspect, the present invention provides a kit that contains the compound or composition described herein and instructions for use.The kit can also contain instructions for use in treating any disease or condition described herein in an individual in need thereof.The kit can also contain any material or equipment that can be used in administering the compound or composition, such as vials, syringes, or IV bags.The kit can also contain sterile packaging. combination

[0132] The compounds and compositions described and / or disclosed herein may be administered alone or in combination with other therapies and / or therapeutic agents useful in the treatment of the aforementioned disorders.

[0133] The compounds and compositions described and / or disclosed herein may be combined with one or more other therapies to treat the diseases or conditions described herein. In some embodiments, the disease or condition is cancer. In some embodiments, the disease or condition is a cell proliferation disorder, including uncontrolled cell proliferation, abnormal cell cycle regulation, centrosome abnormalities (structure and / or number, fragmentation), solid tumors, hematopoietic cancers, and hyperproliferative disorders, such as thyroid hyperplasia (particularly Graves' disease), and cysts (such as hypervascularity of the ovarian stroma, a feature of polycystic ovary syndrome (Stein-Leventhal syndrome)). Solid tumors such as carcinomas and hematologically derived tumors include cancers of the anus, bladder, breast, colon, small intestine, appendix, kidney, renal pelvis, ureter, allantois, liver, lung (including squamous cell and small cell lung cancer), pleura, esophagus, head and neck, nasopharynx, oropharynx, hypopharynx, oral cavity, larynx, biliary duct, gallbladder, ovary, testis, germ cell, uterus, pancreas, stomach, cervix, thyroid, prostate, salivary gland, and skin (including squamous cell carcinoma); hematopoietic tumors of lymphoid lineage (including 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); hematopoietic tumors of myeloid lineage (acute and chronic myeloid leukemia, myelodysplastic syndromes, myeloatherosclerosis, and thyroid cancer); and promyelocytic leukemia), hematopoietic tumors of any lineage, myeloma, mesenchymal tumors (including fibrosarcoma and rhabdomyosarcoma, and other sarcomas, e.g., tumors of soft tissue and bone), tumors of the central and peripheral nervous system (including astrocytoma, neuroblastoma, glioma, and schwannoma), tumors of the neuroendocrine system, tumors of the endocrine system, small cell tumors, tumors of unknown primary, other tumors (including retinoblastoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, Ewing's sarcoma, Kaposi's sarcoma), and other cancer-related disorders that are a result of the presence or progression of cancer, such as tumor-induced pleural or pericardial effusion, and malignant ascites. General synthesis method

[0134] The compounds of formula (I) will now be described by reference to the following exemplary synthetic schemes for general preparation, followed by specific examples. Those skilled in the art will recognize that to obtain the various compounds herein, starting materials may be suitably selected so that the desired substituents ultimately carry through the reaction scheme, with or without protection, as appropriate, to produce the desired product. Alternatively, it may be necessary or desirable to employ, in place of the ultimately desired substituent, a suitable group that will carry through the reaction scheme and that may be replaced with the desired substituent, as appropriate. Furthermore, those skilled in the art will recognize that protecting groups can be used to protect certain functional groups (amino, carboxy, or side chain groups) from the reaction conditions, and that such groups are removed under standard conditions, as appropriate. Unless otherwise specified, variables are as defined above with reference to formula (I).

[0135] If it is desired to obtain a specific enantiomer of a compound, this can be achieved from the corresponding enantiomeric mixture using any conventional procedure suitable for separating or resolving enantiomers.Thus, for example, diastereomeric derivatives can be produced by reacting a mixture of enantiomers, such as a racemate, with an appropriate chiral compound.The diastereomers can then be separated by any convenient means, such as crystallization, and the desired enantiomer can be recovered.In another resolution process, a racemate can be separated using chiral high-performance liquid chromatography (HPLC).Alternatively, if desired, a specific enantiomer can be obtained by using an appropriate chiral intermediate in one of the processes described.

[0136] Chromatography, recrystallization, and other conventional separation procedures may also be used on intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify the product of a reaction.

[0137] General methods for preparing the compounds described herein are shown in the following exemplary methods. The variable groups in the schemes provided herein are defined as in formula (I), or any variation thereof. Other compounds described herein can be prepared by similar methods.

[0138] In some embodiments, the compounds provided herein may be synthesized according to Scheme 1, Scheme 2, Scheme 3, Scheme 4, Scheme 5, Scheme 6, Scheme 7, Scheme 8, and / or Scheme 9. The rings A, A, and B shown in Schemes 1-9 below are also suitable for synthesis. 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , V, W, X, Y, Z, R 1 , R 2 , R 3 , R 4 , B 1 , B 2 , R a1 ~R a20 , and R c1 ~R c13 is as defined for compounds of formula (I).

[0139] Scheme 1 [ka] Scheme 1 outlines an exemplary synthetic route to compounds of Formula I where Y is "NH" and X and Z are both "N". Acylhydrazine A can be condensed with imidate ester B by heating with a suitable base such as iPrNEt to give the 1,2,4-triazole product. The radical r b is R 3 and the compound of formula I is directly produced. b may be a halogen, in which case intermediate C is obtained. Scheme 2 [ka]

[0140] Acylhydrazine A can be converted to an ester (r c =O-alkyl), activated chloride (r c =Cl), or carboxylic acid (r c =OH). When D is an ester, A can be prepared by heating D with excess hydrazine hydrate in an alcohol solvent. When D is an acid chloride, A can be prepared by reacting it with excess hydrazine hydrate and a base such as iPrNEt, or A can be prepared by reacting it with a protected hydrazine such as Boc-hydrazine, followed by deprotection, such as by treatment with an acid. When D is a carboxylic acid, D can be activated with, for example, a carbodiimide, such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or diisopropylcarbodiimide, and an activating group such as 4-dimethylaminopyridine, hydroxybenzotriazole, or pentafluorophenol. The in situ generated acyl transfer reagent is then treated with hydrazine hydrate to afford A.

[0141] Scheme 3 [ka] Imidate esters B can be prepared by the route outlined in Scheme 3. Nitrile compounds E can be prepared by the reaction of HCl with approximately stoichiometric amounts of alkyl alcohols r d OH (in the formula, r d is alkyl) to give imidate ester B as the hydrochloride salt. a The amide F can be reacted with Mehrwein salt (Me3OBF4) to give the methyl imidate B as the tetrafluoroborate salt. b can be obtained.

[0142] Scheme 4 [ka] Scheme 4 outlines an exemplary synthetic route for compounds of Formula I where Y is "NH" and Z is "N". a is a halogen) can be heated with amidine B containing an acid scavenger such as iPrNEt to give the imidazole product. b R 3 is one of the groups defined for e R 4 If r is one of the groups defined for b may be halogen, and / or r e may be a nitro group, in which case intermediate J is obtained.

[0143] Scheme 5 [ka] Scheme 5 outlines the synthesis of compounds of Formula I where Y is "CH" and X, Z, and W are "N". Alkyne K and azide L can be reacted with a copper reagent such as CuSO4 and sodium ascorbate to give 1,2,3-triazole M. b R 3 is one of the groups defined for e R 4 If r is one of the groups defined for b may be halogen, and / or r e may be a nitro group, in which case intermediate M is obtained.

[0144] Scheme 6 [ka] Schemes 6 and 7 illustrate the derivatization of intermediates C, J, and M to give compounds of formula I. Scheme 6 illustrates the derivatization of intermediates C, J, and M to give compounds of formula I. b Scheme 7 shows the derivatization of intermediates C, J, and M when r is a halogen.e In Scheme 6, the derivatization of intermediates C, J, and M when r is nitro is shown. b When R is F or Cl, the intermediate and the amine (R 3 H) or amine hydrochloride (R 3 HHCl), S N The compound of formula I is obtained via the Ar reaction. b is bromine or iodine, compounds of formula I can be prepared by reacting C, J, or M with R in the presence of a base and a suitable catalyst (typically derived from a palladium salt such as Pd(OAc) or Pd(dba) and a hindered phosphine ligand such as tri(tert-butyl)phosphine or 2,2′-bis-(diphenylphosphino)-1,1′-binaphthyl). 3 It can be prepared by cross-coupling by reacting with H.

[0145] Scheme 7 [ka] In Scheme 7, intermediates C, J, or M are e When R is nitro, the nitro group can be reduced to the aniline using, for example, H gas and a catalyst such as Pd / C, or zinc and acetic acid. The aniline can be converted to a sulfonyl chloride (R c6 SO2Cl) and an acid scavenger such as iPr2NEt to form R 4 Ga-NHS(O)2R c6 Compounds of formula I can be obtained which are

[0146] Scheme 8 [ka] As shown in Scheme 8, the substituent on ring A is a substituent R 1Precursors of the formula (I) can also be carried. In that case, compounds of formula I can be prepared by conversion of these precursors. For example, thioethers N can be converted to sulfonyl chlorides O by reaction with N-chlorosuccinimide (NCS), and O can be converted to sulfonamides R by reaction with an amine and a suitable base such as iPrNEt. 1 can be converted to a compound of formula I having the formula:

[0147] Scheme 9 [ka] Another example of modification of the substituents on ring A is described in Scheme 9. For compounds of structure P where X is F or Cl, the intermediate can be converted to an amine (R a7 R a6 NH), S N Compounds of formula I can be obtained via the Ar reaction. When X is bromine or iodine, compounds of formula I can be obtained by the reaction of P and R in the presence of a base and a suitable catalyst (typically derived from a palladium salt such as Pd(OAc) or Pd(dba) and a hindered phosphine ligand such as tri(tert-butyl)phosphine or 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl). a7 R a6 It can be prepared by cross-coupling by reacting with NH.

[0148] Enumeration of Embodiments The embodiments listed below are representative of some aspects of the present invention. A1. A compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, X and Z are independently O, N, or CH; Y is NH or CH; V and W are independently N or C; wherein at least one of X and Z is N or Y is NH; Ring A is [ka] where: A 1 , A 3 , and A 4 one or two of which are independently N, O, or S, and A 1 , A 3 , and A 4 The remaining one or two are independently CH or CR 2 and; A 2 is N or C; A 5 ~A 8 are independently CH, CR 2 , or N, where A 5 , A 6 , A 7 , and A 8 At least two of these are CH or CR 2 and if it exists, A 5 , A 6 , A 7 , and A 8 of which the remaining one or two are N; where "*" indicates the point of attachment to V; B 1 and B 2 are each independently N or CH; R 1 is C 1~6 Alkyl, C 3~6 Cycloalkyl, 3-10 membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 , -NR a4 C(O)OR a5 , -NR a6 R a7 , -N=S(O)R a8 R a9 , -OR a10 , -S(O)R a11 , -S(O)(NR a12 )Ra13 , -S(O)NR a14 R a15 , -S(O)2R a16 , or -(CR a17 R a18 ) 0~1 C(O)NR a19 R a20 and where R 1 The C1 to C6 alkyl is selected from halogen, —OH, cyano, C 3~10 optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo; 1 The above C 3~6 The cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; 1 wherein said 3 to 10 membered heterocycloalkyl is optionally substituted with one or more halogens; R a1 ~R a20 are each independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 3~10 Cycloalkyl, C 3~10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 6~14 aryl, or 5- to 12-membered heteroaryl, each of which is halo, cyano, -OH, -O(C 1~6 alkyl), C 2~6 Alkenyl, C 3~10 Cycloalkyl, -S(C 1~6 alkyl), =CR 1a1 R 1a2 , and halo, -OH, and -O(C 1~6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkyl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1~6 Is it alkyl; Alternatively, Ra14 and R a15 together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl optionally substituted with one or more halo; Each R 2 are independently halogens, C 1~3 Alkyl, C 3~5 Cycloalkyl, cyano, C 1~3 Alkyloxy, C 3~5 Cycloalkyloxy, hydroxy, or NR b1 R b2 where R b1 and R b2 are independently optionally substituted with C1-C3 alkyl, or R b1 and R b2 form a 3- to 6-membered ring together with the nitrogen to which they are attached; or A 4 R 1 and R 2 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3-6 membered heterocycloalkyl; R 3 is piperidinyl, pyrrolidinyl, or azepinyl, wherein said piperidinyl, said pyrrolidinyl, or said azepinyl is C 3~10 cycloalkyl or 3-10 membered heterocycloalkyl, wherein 3~10 cycloalkyl or 3-10 membered heterocycloalkyl forms a spirocyclic or fused bicyclic ring system with said piperidinyl, pyrrolidinyl, or azepinyl; wherein the piperidinyl, the pyrrolidinyl, the azepinyl, or C 3~10 The spirocyclic or fused bicyclic ring system formed by the cycloalkyl or 3-10 membered heterocycloalkyl and piperidinyl, pyrrolidinyl, or azepinyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl and C1-C3 haloalkyl; R 4 is hydrogen, halo, cyano, -OH, -NO2, -C(O)NR c1R c2 , -NR c3 R c4 , -NR c5 S(O)2R c6 , -P(O)R c7 R c8 , -N=S(O)R c9 R c10 , -S(O)(NR c11 )R c12 , -S(O)2R c13 or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH 1~6 is alkyl, R c1 ~R c13 are each independently hydrogen, C 3~10 Cycloalkyl, or C 1~6 alkyl, where R c1 ~R c13 wherein each C1-C6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, and -C(O)-O-C1-C3 alkyl, or a pharmaceutically acceptable salt thereof. A2. A compound according to embodiment A1, wherein X is N, or a pharmaceutically acceptable salt thereof. A3. A compound according to embodiment A1 or A2, wherein Z is N, or a pharmaceutically acceptable salt thereof. A4. A compound according to any one of embodiments A1-A3, or a pharmaceutically acceptable salt thereof, wherein Y is NH. A5. The ring [ka] but, [ka] The compound of embodiment A1, wherein: embedded image or a pharmaceutically acceptable salt thereof. A6.The ring [ka] but, [ka] The compound of embodiment A1, wherein: embedded image or a pharmaceutically acceptable salt thereof. A7. Ring A is [ka] The compound of any one of embodiments A1 to A6, wherein: embedded image or a pharmaceutically acceptable salt thereof. A8. Ring A [ka] [ka] A compound according to any one of embodiments A1 to A7, wherein: embedded image or a pharmaceutically acceptable salt thereof. A9. Ring A is [ka] A compound according to any one of embodiments A1 to A8, wherein: embedded image or a pharmaceutically acceptable salt thereof. A10. Ring A is [ka] The compound of any one of embodiments A1 to A6, wherein: embedded image or a pharmaceutically acceptable salt thereof. A11. Ring A is [ka] [ka] [ka] A compound according to any one of embodiments A1 to A6 and A10, wherein: embedded image or a pharmaceutically acceptable salt thereof. A12. Ring A is [ka] A compound according to any one of embodiments A1 to A6 and A10 to A11, wherein: or a pharmaceutically acceptable salt thereof. A13.R 1 But C 1~6 Alkyl, C 3~6 Cycloalkyl, 3-10 membered heterocycloalkyl, -NR a6 R a7 , -S(O)NR a14 R a15 , or -S(O)2R a16 where R 1 The C1 to C6 alkyl is selected from halogen, —OH, cyano, C 3~10 optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo; 1 The above C 3~6 Cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; 1 A compound according to any one of embodiments A1 to A12, or a pharmaceutically acceptable salt thereof, wherein said 3 to 10 membered heterocycloalkyl is optionally substituted with one or more halogen. A14. The above R 1 but, [ka] A compound according to any one of embodiments A1 to A13, wherein: embedded image or a pharmaceutically acceptable salt thereof. A15. The ring [ka] but, [ka] A compound according to any one of embodiments A1 to A14, wherein: embedded image or a pharmaceutically acceptable salt thereof. A16. The ring [ka] but, [ka] A compound according to any one of embodiments A1 to A15, wherein: embedded image or a pharmaceutically acceptable salt thereof. A17.R 3 is piperidinyl, and said piperidinyl is C 3~10 cycloalkyl or 3-10 membered heterocycloalkyl, wherein 3~10 the cycloalkyl or 3-10 membered heterocycloalkyl forms a spirocyclic or fused bicyclic ring system with the piperidinyl; wherein said piperidinyl, or said C 3~10 A compound according to any one of embodiments A1-A15, or a pharmaceutically acceptable salt thereof, wherein the spirocyclic or fused bicyclic ring system formed by the cycloalkyl or 3-10 membered heterocycloalkyl and piperidinyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, and C1-C3 haloalkyl. A18.R 3 but, [ka] A compound according to any one of embodiments A1 to A16, wherein: embedded image or a pharmaceutically acceptable salt thereof. A19.R 3 is pyrrolidinyl, and said pyrrolidinyl is C 3~10 cycloalkyl or 3-10 membered heterocycloalkyl, wherein 3~10 the cycloalkyl or 3- to 10-membered heterocycloalkyl forms a spirocyclic or fused bicyclic ring system with the pyrrolidinyl; wherein the pyrrolidinyl or the C 3~10A compound according to any one of embodiments A1-A15, or a pharmaceutically acceptable salt thereof, wherein the spirocyclic or fused bicyclic ring system formed by the cycloalkyl or 3-10 membered heterocycloalkyl and pyrrolidinyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, and C1-C3 haloalkyl. A20.R 3 but, [ka] A compound according to any one of embodiments A1 to A15 and A19, wherein: embedded image or a pharmaceutically acceptable salt thereof. A21.R 3 is azepinyl, and said azepinyl is C 3~10 cycloalkyl or 3-10 membered heterocycloalkyl, wherein 3~10 the cycloalkyl or 3-10 membered heterocycloalkyl forms a spirocyclic or fused bicyclic ring system with the azepinyl; wherein said azepinyl, or C 3~10 A compound according to any one of embodiments A1-A15, or a pharmaceutically acceptable salt thereof, wherein the spirocyclic or fused bicyclic ring system formed by the cycloalkyl or 3-10 membered heterocycloalkyl and the azepinyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, and C1-C3 haloalkyl. A22.R 3 but, [ka] A compound according to any one of embodiments A1 to A15 and A21, wherein: embedded image or a pharmaceutically acceptable salt thereof. A23.R 4 is hydrogen, halo, or -NR c5 S(O)2R c6 A compound according to any one of embodiments A1 to A22, wherein: embedded image or a pharmaceutically acceptable salt thereof. A24.R 4 But H, Br, [ka] A compound according to any one of embodiments A1 to A23, wherein: embedded image or a pharmaceutically acceptable salt thereof. A25.R 4 but [ka] A compound according to any one of embodiments A1 to A24, wherein: embedded image or a pharmaceutically acceptable salt thereof. A26. The compound according to embodiment A1, wherein said compound is selected from the group consisting of compounds 1-48 in Table 1, or a pharmaceutically acceptable salt thereof. A27. A pharmaceutical composition comprising a compound according to any one of embodiments A1 to A26, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. A28. A method for inhibiting KIF18A, comprising contacting a cell with an effective amount of a compound according to any one of embodiments A1 to A26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment A27. A29. A method for treating a KIF18A-mediated disease or condition in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound described in any one of embodiments A1 to A26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in embodiment A27. A30. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments A1 to A26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment A27. A31. The method of embodiment A30, wherein the cancer is selected from the group consisting of carcinoma, cancer of the anus, bladder, breast, colon, small intestine, appendix, kidney, renal pelvis, ureter, urothelium, liver, lung, pleura, esophagus, head and neck, nasopharynx, oropharynx, hypopharynx, oral cavity, larynx, biliary tract, gallbladder, ovary, testis, germ cell, uterus, pancreas, stomach, cervix, thyroid, prostate, salivary gland, or skin, hematopoietic tumors of lymphoid lineage, hematopoietic tumors of myeloid lineage, hematopoietic tumors of any lineage, myeloma, mesenchymal tumors including sarcoma, tumors of the central and peripheral nervous system, neuroendocrine tumors, endocrine tumors, small cell tumors, tumors of unknown primary, retinoblastoma, melanoma, seminoma, teratocarcinoma, other tumors including osteosarcoma, and other cancer-related disorders that are a result of the presence or progression of cancer. B1. Compound of Formula (I): [ka] or a pharmaceutically acceptable salt thereof, X and Z are independently O, N, or CH; Y is NH or CH; V and W are independently N or C; wherein at least one of X and Z is N or Y is NH; Ring A is [ka] where: A 1 , A 3 , and A 4 One, two, or three of these are independently N, NR a , O, or S, and if present, A 1 , A 3 , and A 4 The remaining one or two are independently CH or CR 2 where R A1 is H or C 1~3 is alkyl; A 2 is N or C; A 5 ~A 8 are CH, CR independently 2, N, or NR A2 where A 5 , A 6 , A 7 , and A 8 At least two of these are CH or CR 2 and if it exists, A 5 , A 6 , A 7 , and A 8 The remaining one or two are N or NR A2 where R A2 is =O; where "*" indicates the point of attachment to V; B 1 and B 2 are each independently N, CH, or CR B where R B is a halogen; R 1 is C 1~6 Alkyl, C 3~6 Cycloalkyl, C 3~10 Cycloalkenyl, 3-10 membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 , -NR a4 C(O)OR a5 , -NR a6 R a7 , -N=S(O)R a8 R a9 , -OR a10 , -S(O)R a11 , -S(O)(NR a12 )R a13 , -S(O)NR a14 R a15 , -S(O)2R a16 , or -(CR a17 R a18 ) 0~1 C(O)NR a19 R a20 and where R 1 The C1 to C6 alkyl is selected from halogen, —OH, oxo, cyano, C 3~10optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo; 1 The above C 3~6 The cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; 1 The above C 3~10 The cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; and 1 The 3 to 10-membered heterocycloalkyl is selected from halogen, C 1~6 Alkyl, and C 1~6 optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl; R a1 ~R a20 are each independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 3~10 Cycloalkyl, C 3~10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 6~14 aryl, or 5- to 12-membered heteroaryl, each of which is halo, cyano, -OH, -O(C 1~6 alkyl), C 2~6 Alkenyl, C 3~10 Cycloalkyl, -S(C 1~6 alkyl), =CR 1a1 R 1a2 , and halo, -OH, and -O(C 1~6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkyl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1~6 is alkyl; or R a14 and R a15together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl optionally substituted with one or more halo; Each R 2 are independently halogens, C 1~3 Alkyl, C 3~5 Cycloalkyl, cyano, C 1~3 Alkyloxy, C 3~5 Cycloalkyloxy, hydroxy, or NR b1 R b2 where R 2 The above C 1~3 The alkyl is optionally substituted with one or more substituents selected from the group consisting of —OH and oxo, where R b1 and R b2 are independently optionally substituted with C1-C3 alkyl, or R b1 and R b2 form a 3- to 6-membered ring together with the nitrogen to which they are attached; or A 5 R 1 and R 2 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3-10 membered heterocycloalkyl; R 3 is piperidinyl, pyrrolidinyl, or azepanyl, wherein said piperidinyl, said pyrrolidinyl, or said azepanyl is C 3~10 cycloalkyl or 3-10 membered heterocycloalkyl, wherein 3~10 a cycloalkyl or a 3- to 10-membered heterocycloalkyl may form a spirocyclic or fused bicyclic ring system with said piperidinyl, pyrrolidinyl, or azepanyl; or wherein said piperidinyl, pyrrolidinyl, or azepanyl is optionally C 1~2 substituted with alkylene to form a bridged piperidinyl, pyrrolidinyl, or azepanyl ring system; wherein the piperidinyl, the pyrrolidinyl, the azepanyl, or the C 3~10The spirocyclic, fused, or bridged bicyclic ring system formed by cycloalkyl or 3-10 membered heterocycloalkyl and piperidinyl, pyrrolidinyl, or azepanyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl and C1-C3 haloalkyl; R 4 is H, halo, cyano, -OH, -NO2, -C(O)NR c1 R c2 , -NR c3 R c4 , -NR c5 S(O)2R c6 , -P(O)R c7 R c8 , -N=S(O)R c9 R c10 , -S(O)(NR c11 )R c12 , -S(O)2R c13 or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH 1~6 is alkyl, R c1 ~R c13 are each independently hydrogen, C 3~10 Cycloalkyl, or C 1~6 alkyl, where R c1 ~R c13 Each C 1 ~C 6 The alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, —OH, and —C(O)—O—C1-C3 alkyl, wherein each C 3~10 The compound, or a pharmaceutically acceptable salt thereof, wherein cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkylene-OH. B2. A compound according to embodiment B1, wherein X is N, or a pharmaceutically acceptable salt thereof. B3. A compound according to embodiment B1 or B2, wherein Z is N, or a pharmaceutically acceptable salt thereof. B4. The compound according to any one of embodiments B1-B3, or a pharmaceutically acceptable salt thereof, wherein Y is NH. B5. The ring [ka] but, [ka] The compound according to embodiment B1, wherein: embedded image or a pharmaceutically acceptable salt thereof. B6. The ring [ka] but, [ka] The compound according to embodiment B1, wherein: embedded image or a pharmaceutically acceptable salt thereof. B7. The compound according to embodiment B1, or a pharmaceutically acceptable salt thereof, wherein said compound of Formula (I) is a compound of Formula (Ia): [ka] B8. The compound according to embodiment B1, or a pharmaceutically acceptable salt thereof, wherein said compound of Formula (I) is a compound of Formula (Ib): [ka] B9. The compound according to embodiment B1, or a pharmaceutically acceptable salt thereof, wherein said compound of Formula (I) is a compound of Formula (Ic): [ka] B10. Ring A [ka] The compound of any one of embodiments B1 to B9, wherein: embedded image or a pharmaceutically acceptable salt thereof. B11. Ring A is [ka] [ka] The compound of any one of embodiments B1 to B10, wherein: B12. Ring A is [ka] The compound of any one of embodiments B1 to B11, wherein: embedded image or a pharmaceutically acceptable salt thereof. B13. Ring A [ka] The compound of any one of embodiments B1 to B9, wherein: embedded image or a pharmaceutically acceptable salt thereof. B14. Ring A is [ka] [ka] [ka] [ka] A compound according to any one of embodiments B1 to B9 and B13, wherein: embedded image or a pharmaceutically acceptable salt thereof. B15. Ring A is [ka] A compound according to any one of embodiments B1 to B9 and B13 to B14, wherein: B16.R 1 But C 1~6 Alkyl, C 3~6 Cycloalkyl, C 3~10 Cycloalkenyl, 3-10 membered heterocycloalkyl, -NR a6 R a7 , -OR a10 , -S(O)NR a14 R a15 , or -S(O)2R a16and where R 1 The C1 to C6 alkyl is selected from halogen, —OH, oxo, cyano, C 3~10 optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo; 1 The above C 3~6 The cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; 1 The above C 3~10 The cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; and 1 The 3 to 10-membered heterocycloalkyl is selected from halogen, C 1~6 Alkyl, and C 1~6 A compound according to any one of embodiments B1 through B15, or a pharmaceutically acceptable salt thereof, optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl. B17.R 1 teeth, [ka] The compound of any one of embodiments B1 to B16, wherein: embedded image or a pharmaceutically acceptable salt thereof. B18. The ring [ka] but, [ka] The compound of any one of embodiments B1 to B17, wherein: embedded image or a pharmaceutically acceptable salt thereof. B19. The ring [ka] but, [ka] The compound of any one of embodiments B1 to B18, wherein: embedded image or a pharmaceutically acceptable salt thereof. B20.R 3 is piperidinyl, and said piperidinyl is C 3~10 cycloalkyl or 3-10 membered heterocycloalkyl, wherein 3~10 The cycloalkyl or 3-10 membered heterocycloalkyl may form a spirocyclic or fused bicyclic ring system with said piperidinyl, or said piperidinyl may optionally be C 1~2 substituted with alkylene to form a bridged piperidinyl ring system, wherein said piperidinyl, or C 3~10 Cycloalkyl, 3-10 membered heterocycloalkyl, or C 1~2 A compound according to any one of embodiments B1-B19, or a pharmaceutically acceptable salt thereof, wherein the spirocyclic, fused, or bridged bicyclic ring system formed by the alkylene and piperidinyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, and C1-C3 haloalkyl. B21.R 3 teeth, [ka] The compound of any one of embodiments B1 to B20, wherein: embedded image or a pharmaceutically acceptable salt thereof. B22.R 3 is pyrrolidinyl, and said pyrrolidinyl is C 3~10 cycloalkyl or 3-10 membered heterocycloalkyl, wherein 3~10 The cycloalkyl or 3-10 membered heterocycloalkyl may form a spirocyclic or fused bicyclic ring system with said pyrrolidinyl, or said pyrrolidinyl may optionally be C 1~2 substituted with alkylene to form a bridged pyrrolidinyl ring system, wherein said pyrrolidinyl, or said C 3~10 Cycloalkyl, 3-10 membered heterocycloalkyl, or C 1~2The compound of any one of embodiments B1-B19, or a pharmaceutically acceptable salt thereof, wherein the spirocyclic, fused, or bridged bicyclic ring system formed by the alkylene and the pyrrolidinyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, and C1-C3 haloalkyl. B23.R 3 teeth, [ka] The compound according to any one of embodiments B1 to B19, and B22, wherein: B24.R 3 is azepanil, and said azepanil is C 3~10 cycloalkyl or 3-10 membered heterocycloalkyl, wherein 3~10 The cycloalkyl or 3-10 membered heterocycloalkyl may form a spirocyclic or fused bicyclic ring system with said azepanyl, or said azepanyl may optionally be C 1~2 substituted with alkylene to form a bridged azepanyl ring system, wherein said azepanyl, or said C 3~10 Cycloalkyl, 3-10 membered heterocycloalkyl or C 1~2 The compound of any one of embodiments B1-B19, or a pharmaceutically acceptable salt thereof, wherein the spirocyclic, fused, or bridged bicyclic ring system formed by the alkylene and the azepanyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, and C1-C3 haloalkyl. B25.R 3 teeth [ka] The compound according to any one of embodiments B1 to B19, and B24, wherein: embedded image or a pharmaceutically acceptable salt thereof. B26.R 4 is hydrogen, halo, or -NR c5 S(O)2R c6The compound of any one of embodiments B1 to B25, wherein: embedded image or a pharmaceutically acceptable salt thereof. B27.H, Br, [ka] The compound of any one of embodiments B1 to B26, wherein: embedded image or a pharmaceutically acceptable salt thereof. B28.R 4 teeth, [ka] The compound of any one of embodiments B1 to B27, wherein: embedded image or a pharmaceutically acceptable salt thereof. B29. Compound of formula (III): [ka] or a pharmaceutically acceptable salt thereof, Ring A is [ka] where: A 1 , A 3 , and A 4 One, two, or three of these are independently N, NR a , O, or S, and if present, A 1 , A 3 , and A 4 The remaining one or two are independently CH or CR 2 where R A1 is H or C 1~3 is alkyl; A 2 is N or C; A 5 ~A 8 are CH, CR independently 2 , N, or NR A2 where A 5 , A 6 , A 7 , and A 8 At least two of these are CH or CR2 and if it exists, A 5 , A 6 , A 7 , and A 8 The remaining one or two are N or NR A2 where R A2 is =O; where "*" indicates the point of attachment to V; B 1 and B 2 are each independently N, CH, or CR B where R B is a halogen; R 1 is C 1~6 Alkyl, C 3~6 Cycloalkyl, C 3~10 Cycloalkenyl, 3-10 membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 , -NR a4 C(O)OR a5 , -NR a6 R a7 , -N=S(O)R a8 R a9 , -OR a10 , -S(O)R a11 , -S(O)(NR a12 )R a13 , -S(O)NR a14 R a15 , -S(O)2R a16 , or -(CR a17 R a18 ) 0~1 C(O)NR a19 R a20 and where R 1 The C1 to C6 alkyl is selected from halogen, —OH, oxo, cyano, C 3~10 optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo; 1 The above C 3~6 The cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen;1 The above C 3~10 The cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; and 1 The 3 to 10-membered heterocycloalkyl is selected from halogen, C 1~6 Alkyl, and C 1~6 optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl; R a1 ~R a20 are each independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 3~10 Cycloalkyl, C 3~10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 6~14 aryl, or 5- to 12-membered heteroaryl, each of which is halo, cyano, -OH, -O(C 1~6 alkyl), C 2~6 Alkenyl, C 3~10 Cycloalkyl, -S(C 1~6 alkyl), =CR 1a1 R 1a2 , and halo, -OH, and -O(C 1~6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkyl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1~6 is alkyl; or R a14 and R a15 together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl optionally substituted with one or more halo; Each R 2 are independently halogens, C 1~3 Alkyl, C 3~5 Cycloalkyl, cyano, C 1~3 Alkyloxy, C 3~5 Cycloalkyloxy, hydroxy, or NR b1 Rb2 where R 2 The above C 1~3 The alkyl is optionally substituted with one or more substituents selected from the group consisting of —OH and oxo, where R b1 and R b2 are independently optionally substituted with C1-C3 alkyl, or R b1 and R b2 form a 3- to 6-membered ring together with the nitrogen to which they are attached; or A 5 R 1 and R 2 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3-10 membered heterocycloalkyl; Here, each R d1 are independently selected from the group consisting of C1-C3 alkyl and C1-C3 haloalkyl, or two R d1 Together they form C 3~10 cycloalkyl or 3- to 10-membered heterocycloalkyl, wherein said C 3~10 The cycloalkyl or 3- to 10-membered heterocycloalkyl may form a spirocyclic or fused bicyclic ring system with the piperidinyl, or two R d1 Together they form C 1~2 alkylene, wherein said C 1~2 The alkylene forms a bridged piperidinyl ring system; Here, the C 3~10 cycloalkyl, 3-10 membered heterocycloalkyl, or spirocyclic, fused, or bridged bicyclic ring system formed by C1-2 alkylene and piperidinyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl and C1-C3 haloalkyl; R 4 is H, halo, cyano, -OH, -NO2, -C(O)NR c1 R c2 , -NR c3 R c4 , -NR c5 S(O)2R c6 , -P(O)R c7 Rc8 , -N=S(O)R c9 R c10 , -S(O)(NR c11 )R c12 , -S(O)2R c13 or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH 1~6 is alkyl, R c1 ~R c13 are each independently hydrogen, C 3~10 Cycloalkyl, or C 1~6 alkyl, where R c1 ~R c13 each C1-C6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, —OH, and —C(O)—O—C1-C3 alkyl, wherein each C 3~10 The compound, or a pharmaceutically acceptable salt thereof, wherein cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkylene-OH. B30. Compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, X and Z are independently O, N, or CH; Y is NH or CH; V and W are independently N or C; wherein at least one of X and Z is N or Y is NH; Ring A is [ka] where: A 1 , A 3 , and A 4 one or two of which are independently N, O, or S, and A 1 , A 3 , and A 4 The remaining one or two are independently CH or CR 2 and; A 2 is N or C; A 5 ~A 8 are independently CH, CR 2 , or N, where A 5 , A 6 , A 7 , and A 8 At least two of these are CH or CR 2 and if it exists, A 5 , A 6 , A 7 , and A 8 of which the remaining one or two are N; where "*" indicates the point of attachment to V; B 1 and B 2 are each independently N or CH; R 1 is C 1~6 Alkyl, C 3~6 Cycloalkyl, 3-10 membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 , -NR a4 C(O)OR a5 , -NR a6 R a7 , -N=S(O)R a8 R a9 , -OR a10 , -S(O)R a11 , -S(O)(NR a12 )R a13 , -S(O)NR a14 R a15 , -S(O)2R a16 , or -(CR a17 R a18 ) 0~1 C(O)NR a19 R a20 and where R 1 The C1 to C6 alkyl is selected from halogen, —OH, cyano, C 3~10 optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo;1 The above C 3~6 The cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; 1 wherein said 3 to 10 membered heterocycloalkyl is optionally substituted with one or more halogens; R a1 ~R a20 are each independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 3~10 Cycloalkyl, C 3~10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 6~14 aryl, or 5- to 12-membered heteroaryl, each of which is halo, cyano, -OH, -O(C 1~6 alkyl), C 2~6 Alkenyl, C 3~10 Cycloalkyl, -S(C 1~6 alkyl), =CR 1a1 R 1a2 , and halo, -OH, and -O(C 1~6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkyl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1~6 Is it alkyl; Alternatively, R a14 and R a15 together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl optionally substituted with one or more halo; Each R 2 are independently halogens, C 1~3 Alkyl, C 3~5 Cycloalkyl, cyano, C 1~3 Alkyloxy, C 3~5 Cycloalkyloxy, hydroxy, or NR b1 R b2 where R b1 and R b2are independently optionally substituted with C1-C3 alkyl, or R b1 and R b2 form a 3- to 6-membered ring together with the nitrogen to which they are attached; or A 5 R 1 and R 2 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3-6 membered heterocycloalkyl; R 3 is piperidinyl, pyrrolidinyl, or azepanyl, wherein said piperidinyl, said pyrrolidinyl, or said azepanyl is C 3~10 cycloalkyl or 3-10 membered heterocycloalkyl, wherein 3~10 wherein the cycloalkyl or 3- to 10-membered heterocycloalkyl forms a spirocyclic or fused bicyclic ring system with said piperidinyl, pyrrolidinyl, or said azepanyl; wherein the piperidinyl, the pyrrolidinyl, the azepanyl, or the C 3~10 The spirocyclic or fused bicyclic ring system formed by cycloalkyl or 3-10 membered heterocycloalkyl and piperidinyl, pyrrolidinyl, or azepanyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl and C1-C3 haloalkyl; R 4 is hydrogen, halo, cyano, -OH, -NO2, -C(O)NR c1 R c2 , -NR c3 R c4 , -NR c5 S(O)2R c6 , -P(O)R c7 R c8 , -N=S(O)R c9 R c10 , -S(O)(NR c11 )R c12 , -S(O)2R c13 or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH 1~6 is alkyl, R c1 ~R c13 are each independently hydrogen, C 3~10 Cycloalkyl, or C 1~6 alkyl, where R c1 ~R c13 wherein each C1-C6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, and -C(O)-O-C1-C3 alkyl, or a pharmaceutically acceptable salt thereof. B31. A compound according to embodiment B30, wherein X is N, or a pharmaceutically acceptable salt thereof. B32. A compound according to embodiment B30 or B31, wherein Z is N, or a pharmaceutically acceptable salt thereof. B33. A compound according to any one of embodiments B30 to B32, or a pharmaceutically acceptable salt thereof, wherein Y is NH. B34. The ring [ka] but, [ka] The compound according to embodiment B30, wherein: embedded image or a pharmaceutically acceptable salt thereof. B35. The ring [ka] but, [ka] The compound according to embodiment B30, wherein: embedded image or a pharmaceutically acceptable salt thereof. B36. The compound according to embodiment B30, or a pharmaceutically acceptable salt thereof, wherein said compound of Formula (II) is a compound of Formula (II-a). [ka] B37. The compound according to embodiment B30, or a pharmaceutically acceptable salt thereof, wherein said compound of Formula (II) is a compound of Formula (II-b): [ka] B38. The compound according to embodiment B30, or a pharmaceutically acceptable salt thereof, wherein said compound of Formula (II) is a compound of Formula (II-c): [ka] B39. Ring A [ka] The compound according to any one of embodiments B30 to B38, wherein: embedded image or a pharmaceutically acceptable salt thereof. B40. Ring A is [ka] [ka] The compound according to any one of embodiments B30 to B39, wherein: embedded image or a pharmaceutically acceptable salt thereof. B41. Ring A [ka] The compound according to any one of embodiments B30 to B40, wherein: embedded image or a pharmaceutically acceptable salt thereof. B42. Ring A [ka] The compound according to any one of embodiments B30 to B38, wherein: embedded image or a pharmaceutically acceptable salt thereof. B43. Ring A is [ka] [ka] [ka] The compound according to any one of embodiments B30 to B38, and B42, wherein: embedded image or a pharmaceutically acceptable salt thereof. B44. Ring A is [ka] The compound according to any one of embodiments B30 to B38 and B42 to B43, wherein: embedded image or a pharmaceutically acceptable salt thereof. B45.R 1 But C 1~6 Alkyl, C 3~6 Cycloalkyl, 3-10 membered heterocycloalkyl, -NR a6 R a7 , -S(O)NR a14 R a15 , or -S(O)2R a16 where R 1 The C1 to C6 alkyl is selected from halogen, —OH, cyano, C 3~10 optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo; 1 The above C 3~6 The cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen; 1 A compound according to any one of embodiments B30 to B44, or a pharmaceutically acceptable salt thereof, wherein said 3 to 10 membered heterocycloalkyl is optionally substituted with one or more halogen. B46.R 1 teeth, [ka] The compound according to any one of embodiments B30 to B45, wherein: embedded image or a pharmaceutically acceptable salt thereof. B47. The ring [ka] but, [ka] The compound according to any one of embodiments B30 to B46, wherein: embedded image or a pharmaceutically acceptable salt thereof. B48.The ring [ka] but, [ka] The compound according to any one of embodiments B30 to B47, wherein: embedded image or a pharmaceutically acceptable salt thereof. B49.R 3 is piperidinyl, and said piperidinyl is C 3~10 cycloalkyl or 3-10 membered heterocycloalkyl, wherein 3~10 the cycloalkyl or 3-10 membered heterocycloalkyl forms a spirocyclic or fused bicyclic ring system with the piperidinyl; wherein said piperidinyl, or said C 3~10 A compound according to any one of embodiments B30-B48, or a pharmaceutically acceptable salt thereof, wherein said spirocyclic or fused bicyclic ring system formed by the cycloalkyl or 3-10 membered heterocycloalkyl and piperidinyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, and C1-C3 haloalkyl. B50.R 3 teeth, [ka] The compound according to any one of embodiments B30 to B49, wherein: embedded image or a pharmaceutically acceptable salt thereof. B51.R 3 is pyrrolidinyl, and said pyrrolidinyl is C 3~10 cycloalkyl or 3-10 membered heterocycloalkyl, wherein 3~10 the cycloalkyl or 3- to 10-membered heterocycloalkyl forms a spirocyclic or fused bicyclic ring system with the pyrrolidinyl; wherein the pyrrolidinyl or the C3~10 A compound according to any one of embodiments B30-B48, or a pharmaceutically acceptable salt thereof, wherein the spirocyclic or fused bicyclic ring system formed by the cycloalkyl or 3-10 membered heterocycloalkyl and pyrrolidinyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, and C1-C3 haloalkyl. B52.R 3 teeth [ka] The compound according to any one of embodiments B30 to B48, and B51, wherein: embedded image or a pharmaceutically acceptable salt thereof. B53.R 3 is azepanil, and said azepanil is C 3~10 cycloalkyl or 3-10 membered heterocycloalkyl, wherein 3~10 the cycloalkyl or 3- to 10-membered heterocycloalkyl forms a spirocyclic or fused bicyclic ring system with the azepanyl; wherein the azepanil or the C 3~10 A compound according to any one of embodiments B30-B48, or a pharmaceutically acceptable salt thereof, wherein the spirocyclic or fused bicyclic ring system formed by the cycloalkyl or 3-10 membered heterocycloalkyl and azepanyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl, and C1-C3 haloalkyl. B54.R 3 teeth [ka] The compound according to any one of embodiments B30 to B48, and B53, wherein: B55.R 4 is hydrogen, halo, or -NR c5 S(O)2R c6 The compound according to any one of embodiments B30 to B54, wherein: embedded image or a pharmaceutically acceptable salt thereof. B56.R4 But H, Br, [ka] The compound according to any one of embodiments B30 to B55, wherein: embedded image or a pharmaceutically acceptable salt thereof. B57.R 4 teeth [ka] The compound according to any one of embodiments B30 to B56, wherein: embedded image or a pharmaceutically acceptable salt thereof. B58. The compound according to embodiment B1, wherein said compound is selected from the group consisting of the compounds in Table 1, or a pharmaceutically acceptable salt thereof. B59. A pharmaceutical composition comprising a compound according to any one of embodiments B1 to B58, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. B60. A method for inhibiting KIF18A, comprising contacting a cell with an effective amount of a compound according to any one of embodiments B1 to B58, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment B59. B61. A method for treating a KIF18A-mediated disease or condition in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments B1 to B58, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment B59. B62. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments B1 to B58, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment B59. B63. The method of embodiment B62, wherein the cancer is selected from the group consisting of carcinoma, cancer of the anus, bladder, breast, colon, small intestine, appendix, kidney, renal pelvis, ureter, urothelium, liver, lung, pleura, esophagus, head and neck, nasopharynx, oropharynx, hypopharynx, oral cavity, larynx, biliary tract, gallbladder, ovary, testis, germ cell, uterus, pancreas, stomach, cervix, thyroid, prostate, salivary gland, or skin, hematopoietic tumors of lymphoid lineage, hematopoietic tumors of myeloid lineage, hematopoietic tumors of any lineage, myeloma, mesenchymal tumors including sarcoma, tumors of the central and peripheral nervous system, neuroendocrine tumors, endocrine tumors, small cell tumors, tumors of unknown primary, retinoblastoma, melanoma, seminoma, teratocarcinoma, other tumors including osteosarcoma, and other cancer-related disorders that are a consequence of the presence or progression of cancer. [Example]

[0149] The following examples are presented to illustrate, but not limit, the compositions, uses, and methods provided herein. Compounds are prepared using the general methods described above. Shorthand: BSA: bovine serum albumin DMF: dimethylformamide ESI MS: Electrospray mass spectrometry HPLC: High-performance liquid chromatography I C 50 :50% inhibitory concentration Ms: methanesulfonyl MsCl: methanesulfonyl chloride NBS: N-bromosuccinimide NCS: N-chlorosuccinimide NMP: N-methylpyrrolidinone NMR: nuclear magnetic resonance PE: Petroleum ether TBAF: tetra-n-butylammonium fluoride THF: tetrahydrofuran TFA: Trifluoroacetic acid

[0150] Synthesis of intermediates Synthesis of ethyl 4-bromo-2-fluorobenzimidate hydrochloride (I01.01) [ka] HCl gas was bubbled through a mixture of 4-bromo-4-fluorobenzonitrile (1.0 g, 5.0 mmol), CHCl (20 mL), and EtOH (10 mL) at 15 psi for 2 hours at 0° C. The mixture was stirred at 0° C. for 2 hours, then at 20° C. for 12 hours and concentrated to give 1.2 g of 4-bromo-2-fluorobenzimidate hydrochloride (I01.01).

[0151] The imidate esters in Table 2 were prepared from the corresponding nitriles in the same manner as I01.01. [Table 2]

[0152] Synthesis of 6-morpholinopicolinohydrazide (I02.01) [ka] A mixture of methyl 6-morpholinopyridine-2-carboxylate (4.0 g, 18 mmol), EtOH (20 mL), and hydrazine hydrate (3.1 mL, 63 mmol) was stirred at 80° C. for 6 hours. The mixture was cooled to 0° C. and allowed to stand for 1 hour. The resulting precipitate was filtered, washed with EtOH (3×2 mL), and dried under vacuum to give 3.0 g of 6-morpholinopicolinohydrazide (I02.01). 1 H NMR (DMSO-d 6 , 400 MHz) δ 9.65 (s, 1H), 7.75-7.60 (m, 1H), 7.28 (d, J = 7.2 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 4.49 (br s, 2H), 3.80-3.63 (m, 4H), 3.60-3.49 (m, 4H).

[0153] The compounds in Table 3 were prepared from the corresponding methyl esters in the same manner as I02.01. [Table 3]

[0154] Synthesis of 2-bromo-1-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)ethan-1-one (I03.02) [ka] Step 1. A mixture of 1-(6-bromo-2-pyridyl)ethanone (2.0 g, 10 mmol), DMF (20 mL), KCO (2.7 g, 20 mmol), and 4,4-difluoropiperidine hydrochloride (1.6 g, 10 mmol) was stirred at 130 °C for 12 h. The mixture was poured into 30 mL of HO and extracted with EtOAc (2 × 20 mL). The extracts were combined, washed with brine (10 mL), dried over NaSO, filtered, concentrated, and purified by silica chromatography (0 to 100% EtOAc in PE) to afford 1.6 g of 1-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)ethan-1-one (I03.01).

[0155] Step 2. Br2 (0.31 mL, 6.0 mmol) was added to I03.01 (1.6 g, 6.7 mmol), HBr (12 mL), and dioxane (6 mL). The mixture was stirred at 60 °C for 12 h. Aqueous NaHSO3 (10 mL) was added, the pH was adjusted to 7 with Na2CO3, and the mixture was combined with 30 mL of water and extracted with EtOAc (2 x 30 mL). The combined extracts were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0-100% EtOAc in PE) followed by reverse-phase HPLC (C18, 30-70% MeCN [0.1% formic acid] in HO) to afford 0.54 g of 2-bromo-1-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)ethan-1-one (I03.02).

[0156] The compounds in Table 4 were prepared from the corresponding ketones in the same manner as I03.02. [Table 4]

[0157] Synthesis of 3-(2-bromoacetyl)-N-(tert-butyl)benzenesulfonamide (I03.06). [ka] Step 1. A mixture of 3-(tert-butylsulfamoyl)benzoic acid (2.0 g, 7.8 mmol), DMF (20 mL), HATU (4.5 g, 12 mmol), and iPrNEt (5.4 mL, 31 mmol) was stirred for 0.5 h at 20 °C. N-Methoxymethanamine hydrochloride (1.1 g, 11 mmol) was added, and the mixture was stirred at 20 °C for 12 h, combined with EtOAc (30 mL), washed with HO (15 mL × 2) and brine (15 mL), dried over NaSO, filtered, concentrated, and purified by silica chromatography (0–50% EtOAc / PE) to give 3-(tert-butylsulfamoyl)-N-methoxy-N-methyl-benzamide (103.04, 2.1 g). 1 H NMR: (CDCl3, 400 MHz) δ ppm 8.24 (s, 1H), 7.99 (dd, J = 7.6, 1.25 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 4.65 (br s, 1H), 3.54 (s, 3H), 3.39 (s, 3H), 1.24 (s, 9H).

[0158] Step 2. To a mixture of I03.04 (1.0 g, 3.3 mmol) and THF (15 mL) at 0° C. was added MeMgBr (3 M, 3.3 mL). The mixture was stirred at 20° C. for 5 h, and saturated NH4Cl (20 mL) was added at 0° C. EtOAc (40 mL) was added, and the organic phase was separated, washed with brine (15 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0-30% EtOAc / PE) to give 3-acetyl-N-tert-butyl-benzenesulfonamide (I03.05, 0.75 g). 1H NMR: (CDCl3, 400 MHz) δ ppm 8.51-8.41 (m, 1 H), 8.18-8.04 (m, 2H), 7.67-7.56 (m, 1H), 4.72 (s, 1 H) 2.66 (s, 3 H) 1.26 (s, 9 H).

[0159] Step 3. To a mixture of I03.05 (0.5 g, 2.0 mmol) and THF (15 mL) was added phenyltrimethylammonium perbromide (0.77 g, 2.1 mmol), and the mixture was stirred for 12 hours at 20° C. The mixture was filtered, and the filtrate was concentrated and purified by silica chromatography (0-40% EtOAc / PE) to afford 3-(2-bromoacetyl)-N-tert-butylbenzenesulfonamide (I03.06, 0.55 g). 1 H NMR (CDCl3, 400 MHz) δ ppm 8.49 (s, 1 H) 8.16 (br t, J=9.19 Hz, 2 H) 7.66 (t, J=7.82 Hz, 1 H) 4.85 (br s, 1 H) 4.47 (s, 2 H) 1.26 (s, 9 H). Synthesis of 2-bromo-1-[6-[(3,3-difluorocyclobutyl)amino]-2-pyridyl]ethanone (I03.09) [ka]

[0160] Step 1. A mixture of 3,3-difluorocyclobutanamine hydrochloride (4.9 g, 34 mmol), iPrOH (15 mL), iPrNEt (5.9 mL, 34 mmol), and 2-bromo-6-fluoropyridine (2.0 g, 11 mmol) was stirred at 90 °C for 12 h, poured into water (10 mL), and extracted with EtOAc (2 × 10 mL). The organic phase was washed with brine (10 mL), dried over NaSO, concentrated, and purified by silica chromatography (10–50% EtOAc in PE) to give 6-bromo-N-(3,3-difluorocyclobutyl)pyridin-2-amine (103.07, 1.6 g).

[0161] Step 2. A mixture of I03.07 (0.60 g, 2.3 mmol) and tributyl(1-ethoxyvinyl)stannane (1.2 mL, 3.4 mmol) in dioxane (10 mL), CsF (0.69 mg, 4.6 mmol), Pd(PPh3)4 (0.13 g, 0.11 mmol) was stirred at 130 °C for 2 h. To the reaction mixture was added a solution of KF (0.4 g) in water (50 mL), and the mixture was stirred at 20 °C for 0.5 h. The mixture was diluted with EtOAc (10 mL), washed with brine (10 mL × 2), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (10-50% EtOAc in PE) to give N-(3,3-difluorocyclobutyl)-6-(1-ethoxyvinyl)pyridin-2-amine (I03.08, 0.55 g).

[0162] Step 3. To a mixture of I03.08 (0.55 g, 2.2 mmol), THF (5 mL), and HO (2 mL) was added NBS (0.31 g, 1.7 mmol). The mixture was stirred at 20 °C for 2 h, poured into water (10 mL), and extracted with EtOAc (2 × 10 mL). The organic phase was washed with brine (10 mL), dried over NaSO, concentrated, and purified by silica chromatography (10-50% EtOAc in PE) to give 2-bromo-1-[6-[(3,3-difluorocyclobutyl)amino]-2-pyridyl]ethanone (I03.09, 0.25 g).

[0163] Synthesis of 2-bromo-1-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)ethan-1-one (I03.13) [ka] I03.13 was prepared in the same manner as I03.09 by substituting 4,4-difluoropiperidine hydrochloride for 3,3-difluorocyclobutanamine hydrochloride and 2-bromo-6-fluoropyridine for 2-bromo-4-methyl-6-fluoropyridine.

[0164] Synthesis of 2-bromo-1-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)ethan-1-one (I03.16) [ka] I03.16 was prepared in the same manner as I03.09 by replacing 2-bromo-6-fluoropyridine with 2,6-dichloro-4-methylpyrimidine and changing the reaction sequence as shown in the scheme above.

[0165] Synthesis of 4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzimidamide (I04.02) [ka] Step 1. A mixture of 2-fluoro-4-nitrobenzonitrile (5.0 g, 30 mmol), DMF (30 mL), KCO (8.3 g, 60 mmol), and 6-azaspiro[2.5]octane hydrochloride (4.4 g, 30 mmol) was stirred at 120° C. for 12 h. The mixture was poured into HO (80 mL), extracted with EtOAc (2×100 mL), and the combined extracts were washed with brine (50 mL), dried over NaSO, filtered, concentrated, and triturated with MeOH (25 mL) for 0.5 h to give 6.8 g of 4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzonitrile (I04.01). 1 H NMR (DMSO-d 6 , 400 MHz) ppm δ 8.04 - 7.92 (m, 1 H), 7.86 - 7.73 (m, 2 H), 3.36 - 3.28 (m, 4 H), 1.58 - 1.47 (m, 4 H), 0.37 (s, 4 H).

[0166] Step 2. To a mixture of I04.01 (6.5 g, 25 mmol) and THF (60 mL) was added 1 M LiHMDS (130 mL, 130 mmol). The mixture was stirred at 20 °C for 12 h, and 2 M HCl (40 mL) was added at a rate to maintain the internal temperature below 30 °C. The mixture was partially concentrated, then washed with EtOAc, and the pH was adjusted to 8 by the slow addition of saturated NaHCO (30 mL). The resulting organic phase was collected and concentrated to give 1.7 g of 4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzimidamide (I04.02).

[0167] Synthesis of 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzimidamide (I04.05). [ka] Step 1. A mixture of 6-azaspiro[2.5]octane hydrochloride (2.7 g, 18 mmol), iPrNEt (13 mL, 75 mmol), DMSO (30 mL), and 4-bromo-2-fluorobenzonitrile (3.0 g, 15 mmol) was stirred at 140 °C for 12 h, poured into water (100 mL), and extracted with EtOAc (2 × 10 mL). The organic phase was washed with brine (10 mL), dried over NaSO, concentrated, and purified by flash silica chromatography (0–20% EtOAc in PE) to give 2-(6-azaspiro[2.5]octan-6-yl)-4-bromo-benzonitrile (104.03, 4.0 g).

[0168] Step 2. A mixture of I04.03 (4.0 g, 14 mmol), hydroxylamine (50% in HO, 1.8 g, 28 mmol), and EtOH (40 mL) was stirred at 100° C. for 12 hours, poured into water (150 mL), and extracted with EtOAc (2×150 mL). The organic phase was washed with brine (10 mL), dried over NaSO, concentrated, and triturated with CHCl (20 mL) at 20° C. for 0.5 hours to give 2-(6-azaspiro[2.5]octan-6-yl)-4-bromo-N-hydroxybenzamidine (I04.04, 3.0 g).

[0169] Step 3. A degassed mixture of I04.04 (3.0 g, 9.3 mmol), Zn (6.1 g, 93 mmol), and HOAc (30 mL) was degassed and stirred at 80° C. under a N atmosphere for 0.5 h. The mixture was cooled, filtered through a pad of Celite, poured into water (50 mL), and extracted with EtOAc (2×50 mL). The extract was washed with brine (10 mL), dried over NaSO, concentrated, and triturated with 10:1 EtOAc / PE at 20° C. for 30 min to provide 2-(6-azaspiro[2.5]octan-6-yl)-4-bromobenzamidine (I04.05, 2.1 g).

[0170] Synthesis of 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzaldehyde (I04.06) [ka] To a mixture of I04.03 (2.2 g, 7.6 mmol) and CHCl (30 mL) was added DIBAL-H (1 M, 11 mL) at -5 °C, and the mixture was stirred under a N atmosphere at -5 °C for 2 h. Aqueous HCl (2 N, 10 mL) was slowly added to the mixture, and then the mixture was poured into saturated NaCO (50 mL). The resulting mixture was extracted with CHCl (2 × 50 mL), and the combined extracts were washed with brine (30 mL), dried over NaSO, concentrated, and purified by silica chromatography (0–50% EtOAc in PE) to give 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzaldehyde (I04.06, 1.5 g, 91% purity).

[0171] Synthesis of 4-bromo-2-(4-methyl-1-piperidyl)benzaldehyde (I04.08) [ka] A mixture of 4-bromo-2-fluorobenzaldehyde (2.0 g, 10 mmol), 4-methylpiperidine (1.0 mL, 10 mmol), DMF (40 mL), and K2CO3 (4 g, 30 mmol) was stirred at 100 °C for 12 h, cooled, combined with HO (100 mL), and extracted with EtOAc (2 x 50 mL). The extracts were combined, washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (5-50% EtOAc in PE) to give 4-bromo-2-(4-methyl-1-piperidyl)benzaldehyde (104.08, 2.3 g).

[0172] Synthesis of 4-iodospiro[benzo[d][1,3]dioxole-2,1'-cyclohexane] (I04.07) [ka] To a mixture of spiro[1,3-benzodioxole-2,1'-cyclohexane] (2.0 g, 11 mmol) and THF (20 mL) was added sBuLi (1.3 M, 12 mL, 16 mmol) under Ar at −75 °C. The mixture was stirred under Ar for 2 h, followed by the addition of I (2.7 g, 11 mmol) at −75 °C. The mixture was stirred at −75 °C for 2 h, warmed, poured into HO (30 mL), and the resulting mixture was extracted with EtOAc (2 × 30.0 mL). The extracts were combined, washed with brine (10 mL), dried over NaSO, filtered, concentrated, and purified by silica chromatography (0–100% EtOAc in PE) to give 4-iodospiro[1,3-benzodioxole-2,1'-cyclohexane] (I 4.07, 0.73 mg). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.03 - 7.13 (m, 1 H) 6.76 - 6.89 (m, 1 H) 6.50 - 6.64 (m, 1 H) 1.80 -1.97 (m, 4 H) 1.56 - 1.72 (m, 4 H) 1.39 - 1.50 (m, 2 H)

[0173] Alkyne Synthesis Method I05A: Synthesis of 2-(4,4-difluoropiperidin-1-yl)-6-ethynylpyridine (I05.03) [ka] Step 1. A degassed mixture of 2-bromo-6-fluoropyridine (2.0 g, 11 mmol), 4,4-difluoropiperidine hydrochloride (2.7 g, 17 mmol), K2CO3 (4.7 g, 34 mmol), and DMF (20 mL) was stirred under N2 at 130 °C for 12 h. The mixture was cooled, concentrated, and purified by silica chromatography (0-30% EtOAc in PE) to afford 2.0 g of 2-bromo-6-(4,4-difluoropiperidin-1-yl)pyridine (105.01).

[0174] Step 2. A degassed mixture of I05.01 (1.1 g, 4.0 mmol), ethynyltrimethylsilane (1.7 mL, 12 mmol), Pd(PPh)Cl (0.28 g, 0.40 mmol), CuI (75 mg, 0.40 mmol), EtN (1.7 mL, 12 mmol), and THF (15 mL) was stirred under N at 55° C. for 12 h. The mixture was concentrated and purified by silica chromatography (0-30% EtOAc in PE) to afford 0.50 g of 2-(4,4-difluoropiperidin-1-yl)-6-((trimethylsilyl)ethynyl)pyridine (I05.02).

[0175] Step 3. A mixture of I05.02 (0.46 g, 1.6 mmol), K2CO3 (0.43 g, 3.1 mmol), and MeOH was stirred for 12 h at 20° C. The mixture was concentrated and purified by silica chromatography (0-30% EtOAc in PE) to afford 0.25 g of 2-(4,4-difluoropiperidin-1-yl)-6-ethynylpyridine (I05.03).

[0176] Synthesis of 2-(4,4-difluoropiperidin-1-yl)-4-ethynylthiazole (R-038) [ka] Step 1. A mixture of 2,4-dibromothiazole (1.0 g, 4.1 mmol), 4,4-difluoropiperidine hydrochloride (1.3 g, 8.2 mmol), DMF (10 mL), and EtN (2.3 g, 17 mmol) was stirred at 80 °C for 16 h. The mixture was combined with HO (50 mL) and extracted with EtOAc (30 mL × 3). The combined extracts were washed with brine (30 mL × 3), dried over NaSO, filtered, concentrated, and purified by silica chromatography (0-5% EtOH in PE) to give 4-bromo-2-(4,4-difluoro-1-piperidyl)thiazole (R-036; 1.0 g).

[0177] Steps 2-3. 2-(4,4-Difluoropiperidin-1-yl)-4-ethynylthiazole (R-038) was prepared in two steps as described in steps 2 and 3 of alkyne preparation method I05A by using R-036 instead of I05.01.

[0178] Synthesis of 2-(cyclopentyloxy)-6-ethynylpyrazine (I05.66) [ka] Step 1. A mixture of 2,6-dibromopyrazine (1.5 g, 6.3 mmol), cyclopentanol (0.57 mL, 6.3 mmol), DMF (20 mL), and CsCO (4.1 g, 13 mmol) was stirred at 100 °C for 6 h, then poured into HO (50 mL) and extracted with EtOAc (2 × 25 mL). The extracts were combined, washed with brine (10 mL), dried over NaSO, concentrated, and purified by silica chromatography (10–50% EtOAc in PE) to give 2-bromo-6-(cyclopentoxy)pyrazine (105.64, 0.59 g).

[0179] Steps 2-3. 2-(Cyclopentyloxy)-6-ethynylpyrazine (I05.66) was prepared in two steps as described in steps 2 and 3 of alkyne preparation method I05A by using I05.64 instead of I05.01.

[0180] Alkyne Synthesis Method I05B: Synthesis of 1-((3-ethynylphenyl)sulfonyl)-3,3-difluoroazetidine (I05.05) [ka] Step 1. A mixture of 1-(3-bromophenyl)sulfonyl-3,3-difluoroazetidine (0.87 g, 2.8 mmol), MeCN (3 mL), Xantphos Pd G (0.27 g, 0.28 mmol), CsCO (2.7 g, 8.4 mmol), ethynyl(triisopropyl)silane (3.1 mL, 14 mmol), and CuI (53 mg, 0.28 mmol) was stirred at 100 °C for 12 h. The mixture was poured into HO (30 mL) and extracted with EtOAc (2 × 30 mL). The extract was washed with brine (10 mL), dried over NaSO, and concentrated to give 2-[3-(3,3-difluoroazetidin-1-yl)sulfonylphenyl]ethynyl-triisopropyl-silane (105.04, 3.2 g).

[0181] Step 2. A mixture of I05.04 (1.2 g, 2.2 mmol), THF (10 mL), and TBAF (1 M, 11 mL, 11 mmol) was stirred at 25 °C for 2 h. The mixture was poured into HO (30 mL) and extracted with EtOAc (30 mL × 3), and the combined extracts were washed with brine (30 mL × 2), dried over NaSO, filtered, and concentrated. Another residue was prepared from 0.2 g of I05.04 in the same manner. The combined residue was purified by silica chromatography (5-10% EtOAc in PE) to give 1-(3-ethynylphenyl)sulfonyl-3,3-difluoroazetidine (I05.05, 0.37 g). Alkyne Synthesis Method I05C:

[0182] Synthesis of 2-(4,4-difluoro-1-piperidyl)-6-ethynyl-4-methylpyridine (I05.08) [ka] Step 1. 2-Bromo-6-(4,4-difluoro-1-piperidyl)-4-methyl-pyridine (I05.06) was prepared from 2-bromo-6-fluoro-4-methylpyridine in the same manner as described for I05.01. A degassed mixture of I05.06 (1.0 g, 3.4 mmol), 2-methylbut-3-yn-2-ol (2.0 mL, 21 mmol), CuI (65 mg, 0.34 μmol), EtN (1.4 mL, 10 mmol), Pd(PPh)Cl (0.24 g, 0.34 mmol), and DMF (10 mL) was stirred in a microwave reactor at 140 °C for 1.2 h. The mixture was concentrated and purified by silica chromatography (0-30% EtOAc in PE) to give 4-[6-(4,4-difluoro-1-piperidyl)-4-methyl-2-pyridyl]-2-methyl-but-3-yn-2-ol (105.07, 0.50 g).

[0183] Step 2. To a mixture of I05.07 (0.50 g, 1.7 mmol) and toluene (1 mL) was added NaOH (0.10 g, 2.5 mmol). The mixture was stirred at 110° C. for 12 hours, then concentrated, diluted with water (50 mL), and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated to give 2-(4,4-difluoro-1-piperidyl)-6-ethynyl-4-methyl-pyridine (I05.08, 0.40 mg).

[0184] Synthesis of 1-(4,4-difluorocyclohexyl)-3-ethynyl-1H-pyrazole (I05.24) [ka] Step 1. A mixture of 3-iodo-1H-pyrazole (2.0 g, 10 mmol), DMF (20 mL), CsCO (10 g, 31 mmol), and (4,4-difluorocyclohexyl)-4-methylbenzenesulfonate (4.5 g, 16 mmol) was stirred at 90 °C for 12 h. The mixture was concentrated, combined with HO (50 mL), and extracted with EtOAc (50 mL × 3). The combined extracts were washed with brine (30 mL), dried over NaSO, filtered, concentrated, and purified by silica chromatography (5-25% EtOAc in PE) to give 1-(4,4-difluorocyclohexyl)-3-iodo-pyrazole (R-033, 2.0 g).

[0185] Steps 2-3 were carried out using alkyne synthesis method I05C with R-033 in place of I05.06 to give I05.24.

[0186] Alkyne Synthesis Method I05D: Synthesis of 2-(4,4-difluoropiperidin-1-yl)-4-ethynyl-6-methylpyrimidine (I05.11) [ka] Step 1. To a mixture of 2,4-dichloro-6-methylpyrimidine (2.0 g, 12 mmol), ethynyl(triisopropyl)silane (8.3 mL, 37 mmol), and THF (20 mL), Pd(PPh)Cl (0.43 g, 0.61 mmol), CuI (0.23 mg, 1.2 mmol), and EtN (5.1 mL, 37 mmol) were added and stirred at 50 °C for 12 h. The mixture was poured into HO (10 mL) and extracted with EtOAc (2 × 10 mL). The extract was washed with brine (10 mL), dried over NaSO, concentrated, and purified by silica chromatography (0–10% EtOAc in PE) to give 2-(2-chloro-6-methyl-pyrimidin-4-yl)ethynyl-triisopropyl-silane (105.09, 1.2 g).

[0187] Step 2. A mixture of 4,4-difluoropiperidine (0.57 g, 4.7 mmol), DMF (5 mL), iPrNEt (2.0 mL, 12 mmol), and I05.09 (1.2 g, 3.9 mmol) was stirred at 120 °C for 1 h. The mixture was poured into water (10 mL) and extracted with EtOAc (2 × 10 mL). The combined extracts were washed with brine (10 mL), dried over NaSO, filtered, concentrated, and purified by silica chromatography (0 to 100% EtOAc in PE) to give 2-[2-(4,4-difluoro-1-piperidyl)-6-methyl-pyrimidin-4-yl]ethynyl-triisopropyl-silane (I05.10, 1.5 g).

[0188] Step 3. A mixture of I05.10 (1.5 g, 3.8 mmol), THF (5 mL), and TBAF (1 M, 19 mL, 19 mmol) was stirred at 20 °C for 4 h. The mixture was poured into HO (10 mL) and extracted with EtOAc (2 × 10 mL). The combined extracts were washed with brine (10 mL), dried over NaSO, concentrated, and purified by silica chromatography (0-10% EtOAc in PE) to afford 2-(4,4-difluoro-1-piperidyl)-4-ethynyl-6-methyl-pyrimidine (I05.11, 0.60 g).

[0189] Synthesis of 2-(cyclopentyloxy)-4-ethynyl-6-methylpyrimidine (I05.37) [ka] Step 1. A degassed mixture of I05.09 (1.0 g, 4.0 mmol), cyclopentanol (0.96 g, 11 mmol), dioxane (25 mL), and CsCO (3.0 g, 9.2 mmol) was stirred at 100 °C under a N atmosphere for 12 h. The mixture was diluted with EtOAc (40 mL) and filtered. The filtrate was washed with HO (20 mL), brine (20 mL), dried over NaSO, filtered, concentrated, and purified by silica chromatography (0-10% EtOAc in PE) to give 2-(cyclopentyloxy)-4-methyl-6-((triisopropylsilyl)ethynyl)pyrimidine (I05.14, 1.0 g).

[0190] Step 2. 2-(Cyclopentyloxy)-4-ethynyl-6-methylpyrimidine (I05.37) was prepared from I05.14 by treatment with TBAF in the manner described in Step 3 of the synthesis of I05.11.

[0191] Alkyne Synthesis Method I05E: Synthesis of 3-(4,4-difluoropiperidin-1-yl)-5-ethynyl-2-methylpyrazine [ka] Step 1. A mixture of 3,5-dichloro-2-methylpyrazine (2.0 g, 12 mmol), 4,4-difluoropiperidine hydrochloride (1.9 g, 12 mmol), DMSO (40 mL), and K2CO3 (5.1 g, 37 mmol) was stirred at 100 °C for 12 h, then cooled and poured into HO (20 mL), and the resulting mixture was extracted with EtOAc (2 x 25 mL). The combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (10-50% EtOAc in PE) to give 5-chloro-3-(4,4-difluoro-1-piperidyl)-2-methyl-pyrazine (105.48, 1.0 g).

[0192] Step 2. A degassed mixture of I05.48 (0.81 g, 3.3 mmol), 2-methylbut-3-yn-2-ol (0.96 mL, 9.8 mmol), CuI (62 mg, 0.33 mmol), Pd(dppf)Cl2 (0.24 g, 0.33 mmol), KF (0.38 g, 6.5 mmol), PPh3 (86 mg, 0.33 mmol), iPr2NEt (1.1 mL, 6.5 mmol), and DMF (16 mL) was stirred at 120 °C under a N2 atmosphere for 2 hours. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (2 × 15 mL), the extracts were combined, washed with brine (10 mL), dried over NaSO, concentrated and purified by silica chromatography (10-100% EtOAc in PE) to give 4-[6-(4,4-difluoro-1-piperidyl)-5-methyl-pyrazin-2-yl]-2-methyl-but-3-yn-2-ol (105.49, 0.68 g).

[0193] Step 3. A mixture of I05.49 (0.68 g, 2.3 mmol), toluene (7 mL), and NaOH (0.18 g, 4.6 mmol) was stirred for 1 hour at 120° C. The mixture was poured into HO (10 mL), extracted with EtOAc (2×15 mL), and the extracts were combined, washed with brine (10 mL), dried over NaSO, filtered, and concentrated to provide 3-(4,4-difluoropiperidin-1-yl)-5-ethynyl-2-methylpyrazine (I05.50, 0.39 g).

[0194] Alkyne Synthesis Method I05F: Synthesis of 3-(6-ethynyl-3-fluoropyridin-2-yl)-3-azabicyclo[3.1.0]hexane (I05.74) [ka] Step 1. A mixture of 2,6-dibromo-3-fluoropyridine (1.0 g, 4.0 mmol), 3-azabicyclo[3.1.0]hexane hydrochloride (0.48 g, 4.0 mmol), DMF (15 mL), and KCO (1.6 g, 12 mmol) was stirred at 100 °C for 12 h, poured into HO (30 mL), and extracted with EtOAc (2 × 30 mL). The combined extracts were washed with brine (20 mL), dried over NaSO, filtered, concentrated, and purified by silica chromatography (0 to 100% EtOAc in PE) to give 3-(6-bromo-3-fluoro-2-pyridyl)-3-azabicyclo[3.1.0]hexane (105.72, 0.95 g).

[0195] Step 2. A mixture of I05.72 (0.50 g, 2.0 mmol), ethynyl(triisopropyl)silane (1.0 mL, 6.0 mmol), Pd(PPh)Cl (0.14 g, 0.19 mmol), EtN (0.81 mL, 6.0 mmol), CuI (74 mg, 0.39 mmol), and THF (10 mL) was heated in a microwave reactor at 60° C. for 2 hours. The mixture was poured into HO (100 mL) and extracted with EtOAc (2×100 mL). The combined extracts were washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0-100% EtOAc in PE) to give 2-[6-(3-azabicyclo[3.1.0]hexan-3-yl)-5-fluoro-2-pyridyl]ethynyl-triisopropyl-silane (105.73, 1.2 g).

[0196] Step 3. A mixture of I05.73 (1.1 g, 3.0 mmol), THF (12 mL), and TBAF (1 M, 9 mL, 9 mmol) was stirred at 20 °C for 2 h, then poured into HO (30 mL) and extracted with EtOAc (2 x 30 mL). The combined extracts were washed with brine (10 mL), dried over NaSO, filtered, concentrated, and purified by silica chromatography (0-50% EtOAc in PE) to afford 3-(6-ethynyl-3-fluoropyridin-2-yl)-3-azabicyclo[3.1.0]hexane (I05.74, 0.33 g).

[0197] The alkynes in Table 4A were prepared as shown by method AI05-E. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6]

[0198] Synthesis of 1-azido-4-bromo-2-fluorobenzene (I05.19) [ka] Step 1. To a mixture of 2-(5-bromo-2-furyl)-1,3-dioxolane (1.4 g, 6.4 mmol), N,N,N',N'-tetramethylethane-1,2-diamine (0.97 mL, 6.4 mmol), and THF (20 mL) was added BuLi (1 M, 9.6 mL) at −70° C., followed by the dropwise addition of N-methoxy-N-methyl-cyclopentanecarboxamide (1.5 g, 9.6 mmol) in THF (20 mL) at −70° C. The mixture was stirred at 20° C. for 1 h, poured into saturated NH4Cl (10 mL), and extracted with EtOAc (2 × 10 mL). The combined extracts were washed with brine (10 mL), dried over Na2SO4, concentrated, and purified by silica chromatography (0-100% EtOAc in PE) to give cyclopentyl-[5-(1,3-dioxolan-2-yl)-2-furyl]methanone (105.17, 0.25 g).

[0199] Step 2. A mixture of I05.17 (0.25 g, 1.0 mmol), THF (0.8 mL), HO (0.5 mL), and 3 M HCl (1.0 mL, 3.0 mmol) was stirred at 20 °C for 4 h. The mixture was poured into water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined extracts were washed with brine (10 mL), dried over NaSO, concentrated, and purified by silica chromatography (0-100% EtOAc in PE) to afford 5-(cyclopentanecarbonyl)furan-2-carbaldehyde (I05.18, 0.19 g).

[0200] Step 3. A mixture of I05.18 (0.19 g, 0.99 mmol), MeOH (0.5 mL), KCO (0.27 g, 2.0 mmol), and 1-diazo-1-dimethoxyphosphorylpropan-2-one (0.23 g, 1.2 mmol) was stirred at 20 °C for 12 hours. The mixture was poured into HO (10 mL) and extracted with EtOAc (2 × 10 mL). The combined extracts were washed with brine (10 mL), dried over NaSO, filtered, concentrated, and purified by preparative TLC (20% EtOAc in PE) to afford cyclopentyl-(5-ethynyl-2-furyl)methanone (I05.19, 0.18 g).

[0201] Synthesis of 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzaldehyde (I05.20) [ka] A mixture of I04.06 (0.50 g, 1.7 mmol), MeOH (10 mL), 1-diazo-1-dimethoxyphosphorylpropan-2-one (0.39 g, 2.0 mmol), and KCO (0.47 g, 3.4 mmol) was stirred at 20 °C for 12 h. The mixture was poured into HO (30 mL) and extracted with EtOAc (2 × 30 mL). The combined extracts were washed with brine (10 mL), dried over NaSO, filtered, concentrated, and purified by silica chromatography (0–30% EtOAc in PE) to give 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzaldehyde (I05.20, 0.33 g).

[0202] Synthesis of 1-(4-ethynyl-1-methyl-1H-imidazol-2-yl)-4,4-difluoropiperidine (I05.46) [ka] Step 1. A mixture of 2,4-dibromo-1-methyl-1H-imidazole (1.2 g, 5.0 mmol), NMP (1 mL), DBU (14 mL, 96 mmol), and 4,4-difluoropiperidine hydrochloride (4.8 g, 31 mmol) was stirred at 220 °C for 3 h, cooled, and poured into HO (100 mL). The resulting mixture was extracted with EtOAc (2 × 100 mL), and the extracts were combined, washed with brine (10 mL), dried over NaSO, filtered, concentrated, and purified by silica chromatography (0 to 25% EtOAc in PE) to give 1-(4-bromo-1-methyl-1H-imidazol-2-yl)-4,4-difluoropiperidine (105.44, 0.96 g).

[0203] Step 2. n-BuLi (2.5 M, 1.1 mL, 2.8 mmol) was added dropwise to a stirred mixture of I05.44 (0.70 g, 2.5 mmol) in THF (10 mL) at −78 °C under N2. After stirring at −78 °C for 20 min, DMF (0.60 mL, 7.5 mmol) was added dropwise and the mixture was stirred at −78 °C for 15 min, warmed to 25 °C, and stirred for 1 h. The reaction was quenched with HO and saturated NH4Cl and extracted with EtOAc (2 × 50 mL). The extract was washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0-80% EtOAc in PE) to give 2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-imidazole-4-carbaldehyde (105.45, 0.18 g).

[0204] Step 3. To a mixture of I05.45 (0.17 g, 0.74 mmol) and MeOH (2 mL) was added 1-diazo-1-dimethoxyphosphorylpropan-2-one (0.17 g, 0.89 mmol) and KCO (0.2 g, 1.5 mmol). The mixture was stirred at 25 °C for 12 h, poured into HO (30 mL), extracted with EtOAc (2 × 30 mL), dried over NaSO, filtered, and concentrated to provide 1-(4-ethynyl-1-methyl-1H-imidazol-2-yl)-4,4-difluoropiperidine (I05.46, 0.15 g).

[0205] Synthesis of 6-(6-bromo-3-ethynylpyridin-2-yl)-6-azaspiro[2.5]octane (I05.42) [ka] Step 1. A mixture of 2,6-dibromo-3-nitropyridine (1.0 g, 3.5 mmol), 6-azaspiro[2.5]octane hydrochloride (0.42 g, 3.5 mmol), EtOH (30 mL), and EtN (1.5 mL, 11 mmol) was stirred at 25 °C for 12 h, then diluted with EtOAc (30 mL) and washed with HO (40 mL). The aqueous wash was extracted with EtOAc (20 mL). The combined extracts were washed with HO (20 mL) and brine (20 mL), dried over NaSO, filtered, concentrated, and purified by silica chromatography (0–8% EtOAc in PE) to give 6-(6-bromo-3-nitropyridin-2-yl)-6-azaspiro[2.5]octane (105.38, 0.90 g).

[0206] Step 2. To a mixture of I05.38 (0.80 g, 2.6 mmol), EtOH (24 mL), and HO (6 mL) was added Fe powder (1.5 g, 27 mmol) and NHCl (1.4 g, 26 mmol). The mixture was stirred at 70 °C for 2 h, cooled, filtered through Celite, and the filter cake was washed with MeOH (15 mL × 3). The filtrate was concentrated and purified by silica chromatography (0-20% EtOAc in PE) to give 6-bromo-2-(6-azaspiro[2.5]octan-6-yl)pyridin-3-amine (I05.39, 0.60 g).

[0207] Step 3. To a mixture of I05.39 (0.430 g, 1.5 mmol) in 6 M HCl (2.6 mL, 16 mmol) at 0 °C, a solution of NaNO2 (0.14 g, 2.1 mmol) in HO (1 mL) was added over 15 min. After stirring at 0 °C for 15 min, KI (1.0 g, 6.2 mmol) in HO (4.5 mL) was added over 15 min. The mixture was warmed to 25 °C, stirred for 1.3 h, and extracted with EtOAc (25 mL × 2). The combined extracts were washed with saturated NaHCO (15 mL × 2), HO (15 mL), and brine (10 mL), then dried over NaSO, filtered, concentrated, and purified by silica chromatography (0–18% EtOAc in PE) to give 6-(6-bromo-3-iodopyridin-2-yl)-6-azaspiro[2.5]octane (105.40, 0.22 g).

[0208] Steps 4 and 5 were carried out as described in alkyne synthesis method I05B to prepare 6-(6-bromo-3-ethynylpyridin-2-yl)-6-azaspiro[2.5]octane (I05.42) from I05.40.

[0209] Synthesis of 2-(cyclopent-1-en-1-yl)-5-ethynylfuran (I05.52) [ka]

[0210] Step 1. A degassed mixture of 5-bromofuran-2-carbaldehyde (2.0 g, 11 mmol), cyclopenten-1-ylboronic acid (1.4 g, 13 mmol), KCO (3.8 g, 27 mmol), RuPhos (0.53 g, 1.1 mmol), Pd(OAc) (77 mg, 0.34 mmol), toluene (18 mL), and HO (2 mL) was stirred at 120 °C under a N atmosphere for 12 h. The reaction was poured into water (30 mL), and the resulting mixture was extracted with EtOAc (2 × 30.0 mL). The extract was washed with brine (10 mL), dried over NaSO, filtered, concentrated, and purified by silica chromatography (0–30% EtOAc in PE) to give 5-(cyclopenten-1-yl)furan-2-carbaldehyde (105.51, 1.4 g).

[0211] Step 2 was carried out as described for the synthesis of I05.20 to prepare I05.52 from I05.51.

[0212] Synthesis of N-(tert-butyl)-5-ethynylfuran-2-sulfonamide (I05.57) [ka] Step 1. To a mixture of methyl 5-(tert-butylsulfamoyl)furan-2-carboxylate (0.56 g, 2.1 mmol) and THF (6 mL) at 0° C. was added LiBH (0.14 g, 6.4 mmol) in portions. The mixture was stirred at 40° C. for 1 h, cooled to 0° C., saturated NH Cl (8 mL) and HO (10 mL) were added, and the mixture was extracted with EtOAc (2×15 mL). The combined extracts were washed with brine (10 mL), dried over Na SO , and concentrated to give N-tert-butyl-5-(hydroxymethyl)furan-2-sulfonamide (105.55, 0.54 g).

[0213] Step 2. A mixture of I05.55 (0.30 g, 1.3 mmol), dioxane (3 mL), and MnO (1.7 g, 19 mmol) was stirred at 100 °C for 1 h, cooled, filtered, combined with HO (15 mL), and extracted with EtOAc (15 mL x 2). The combined extracts were washed with brine (10 mL), dried over NaSO, filtered, and concentrated to provide N-tert-butyl-5-formyl-furan-2-sulfonamide (I05.56, 0.16 g).

[0214] Step 3 was carried out as described for the synthesis of I05.20 to prepare I05.57 from I05.56.

[0215] The compounds in the following table were prepared from the indicated aldehydes in the same manner as I05.20. [Table 6]

[0216] Synthesis of 2-((3,3-difluoroazetidin-1-yl)methyl)-4-ethynyl-6-methylpyrimidine (I05.71) [ka] Step 1. To a mixture of I05.09 (4.7 g, 15 mmol) and MeOH (10 mL), PdCl (0.14 g, 0.76 mmol), [1-(2-diphenylphosphanyl-1-naphthyl)-2-naphthyl]-diphenylphosphane (947 mg, 1.5 mmol), and EtN (6.4 mL, 46 mmol) were added, and the mixture was stirred at 80 °C under CO (50 psi) for 12 h. Subsequently, the mixture was added to HO (10 mL) and extracted with EtOAc (2 × 10 mL). The extracts were combined, washed with brine (10 mL), dried over NaSO, filtered, concentrated, and purified by silica chromatography (0 to 30% EtOAc in PE) to give 4-methyl-6-((triisopropylsilyl)ethynyl)pyrimidine-2-carboxylate (I05.67, 1.9 g).

[0217] Step 2. A mixture of I05.67 (1.0 g, 3.0 mmol), EtOH (10 mL), and NaBH (0.23 g, 6.0 mmol) was stirred at 0 °C for 0.5 h, followed by stirring at 25 °C for 1.5 h. The mixture was poured into HO (30 mL) and extracted with EtOAc (2 x 30 mL). The extracts were combined, washed with brine (30 mL), dried over NaSO, concentrated, and purified by silica chromatography (0-30% EtOAc in PE) to afford (4-methyl-6-((triisopropylsilyl)ethynyl)pyrimidin-2-yl)methanol (I05.68, 0.90 g).

[0218] Step 3. A mixture of I05.68 (0.60 g, 2.0 mmol), CHCl (1.0 mL), EtN (0.55 mL, 4.0 mmol), and 4-methylbenzenesulfonyl chloride (0.75 g, 4.0 mmol) was stirred at 0° C. for 0.5 h, followed by stirring at 25° C. for 3.5 h. The mixture was combined with HO (10 mL) and extracted with EtOAc (10 mL × 2). The extracts were combined, washed with brine (10 mL), dried over NaSO, filtered, and concentrated to provide (4-methyl-6-((triisopropylsilyl)ethynyl)pyrimidin-2-yl)methyl 4-methylbenzenesulfonate (I05.69, 1.3 g).

[0219] Step 4. A mixture of I05.69 (1.2 g, 3.0 mmol), 3,3-difluoroazetidine hydrochloride (0.36 g, 3.0 mmol), CHCN (10 mL), and CsCO (1.7 g, 5.0 mmol) was stirred at 80 °C for 12 hours, diluted with HO (30 mL), and extracted with EtOAc (30 mL × 2). The extract was washed with brine (30 mL), dried over NaSO, filtered, concentrated, and purified by silica chromatography (49-60% EtOAc in PE) to afford 2-((3,3-difluoroazetidin-1-yl)methyl)-4-methyl-6-((triisopropylsilyl)ethynyl)pyrimidine (I05.70, 0.35 g).

[0220] Step 5. A mixture of I05.70 (0.15 g, 0.40 mmol), TBAF (3.0 mL, 4.0 mmol) was stirred at 25° C. for 2 hours, diluted with HO (10 mL), and extracted with EtOAc (10 mL×2). The combined extracts were washed with brine (10 mL), dried over NaSO, filtered, and concentrated to provide 2-((3,3-difluoroazetidin-1-yl)methyl)-4-ethynyl-6-methylpyrimidine (I05.71, 60 mg).

[0221] Synthesis of 2-(4,4-difluorocyclohex-1-en-1-yl)-4-ethynyl-6-methylpyrimidine (I05.77) [ka] Step 1. A mixture of I05.09 (0.50 g, 2.1 mmol), dioxane (20 mL), HO (4.0 mL), NaCO (0.65 g, 6.2 mmol), and Pd(dppf)Cl (0.17 g, 0.21 mmol) was stirred at 100 °C for 2 h, then poured into HO (30 mL) and extracted with EtOAc (2 × 25 mL). The extracts were combined, washed with brine (10 mL), dried over NaSO, filtered, concentrated, and purified by silica chromatography (5-50% EtOAc in PE) to give 2-(4,4-difluorocyclohex-1-en-1-yl)-4-methyl-6-((triisopropylsilyl)ethynyl)pyrimidine (I05.76, 0.89 g).

[0222] Step 2. A mixture of I05.76 (0.20 g, 0.51 mmol), THF (2 mL), and TBAF (1 M, 1.5 mL, 1.5 mmol) was stirred at 0° C. for 2 hours, diluted with 30 mL of water, and extracted with EtOAc (2×30 mL). The extracts were combined, washed with brine (10 mL), dried over NaSO, filtered, and concentrated to provide 2-(4,4-difluorocyclohex-1-en-1-yl)-4-ethynyl-6-methylpyrimidine (I05.77, 0.20 g).

[0223] Synthesis of a mixture of 2-(4,4-difluorocyclohex-1-en-1-yl)-6-ethynyl-3-fluoropyridine (I05.80) and 6-(4,4-difluorocyclohex-1-en-1-yl)-2-ethynyl-3-fluoropyridine (I05.81) [ka] Step 1. A degassed mixture of 2,6-dibromo-3-fluoro-pyridine (1.0 g, 3.9 mmol), 2-(4,4-difluorocyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.96 g, 3.9 mmol), Na2CO3 (1.3 g, 12 mmol), HO (1 mL), dioxane (5 mL), Pd(dppf)Cl2-CHCl2 (0.32 g, 0.39 mmol) was stirred at 100 °C for 4 h, poured into HO (50 mL), and extracted with EtOAc (2 × 50 mL). The combined extracts were washed with brine (50 mL), dried over NaSO, concentrated, and purified by preparative HPLC (40-70% EtOAc [NHHCO] in HO) to give 0.27 g of a mixture of 6-bromo-2-(4,4-difluorocyclohexen-1-yl)-3-fluoropyridine (105.78) and 2-bromo-6-(4,4-difluorocyclohex-1-en-1-yl)-3-fluoropyridine (105.79).

[0224] Step 2. A mixture of I05.78 and I05.79 (0.25 g, 0.86 mmol), ethynyl(triisopropyl)silane (0.58 mL, 2.6 mmol), CuI (33 mg, 0.17 mmol), Pd(PPh)Cl (60 mg, 86 μmol), EtN (0.35 mL, 2.6 mmol), and DMF (3 mL) was heated in a microwave reactor at 60° C. for 2 h. The mixture was poured into HO (30 mL), extracted with EtOAc (2 × 30 mL), and the extract was washed with brine (30 mL), dried over NaSO, concentrated, and purified by silica chromatography (0–30% EtOAc in PE) to give 0.26 g of a mixture of 2-(4,4-difluorocyclohex-1-en-1-yl)-3-fluoro-6-((triisopropylsilyl)ethynyl)pyridine and 2-bromo-6-(4,4-difluorocyclohex-1-en-1-yl)-3-((triisopropylsilyl)ethynyl)pyridine.

[0225] Step 3. The product mixture from step 2 was subjected to the conditions described in step 2 of the synthesis of I05.77 to give a mixture of I05.80 and 6-(4,4-difluorocyclohex-1-en-1-yl)-2-ethynyl-3-fluoropyridine (I05.81).

[0226] 3-(Cyclopent-1-en-1-yl)-5-ethynyl-2-methylpyrazine (I05.83) was prepared from 3,5-dichloro-2-methylpyrazine and 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane by the same three-step procedure described for the synthesis of I05.80 and I05.81. [ka]

[0227] Synthesis of 1-azido-4-bromo-2-fluorobenzene (I06.01) [ka] To a mixture of 4-bromo-2-fluoroaniline (0.20 g, 1.1 mmol) and TFA (3 mL) at 0 °C, NaNO (80 mg, 1.2 mmol) was added slowly in portions. After stirring at 0 °C for 0.5 h, NaN (80 mg, 1.2 mmol) in 1.5 mL of HO was added slowly. The mixture was stirred at 0 °C for 1 h, CHCl (15 mL) was added, and the pH was adjusted to 9 by adding saturated aqueous NaCO. The organic extract was washed with saturated aqueous NaCO (2 × 5 mL), brine (2 × 5 mL), dried over NaSO, filtered, and concentrated to give 0.22 mg of 1-azido-4-bromo-6-fluorobenzene (I06.01).

[0228] Synthesis of 6-(3-azido-6-bromopyridin-2-yl)-6-azaspiro[2.5]octane (I06.04) [ka] Step 1. A mixture of 2,6-dibromo-3-nitropyridine (2.0 g, 7.1 mmol), EtOH (20 mL), EtN (2.0 mL, 14 mmol), and 6-azaspiro[2.5]octane hydrochloride (1.1 g, 7.1 mmol) was stirred at 20 °C for 12 h. The mixture was poured into water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined extracts were washed with brine (20 mL), dried over NaSO, concentrated, and purified by silica chromatography (0 to 100% EtOAc in PE) to give 6-(6-bromo-3-nitro-2-pyridyl)-6-azaspiro[2.5]octane (106.02, 1.80 g).

[0229] Step 2. A mixture of I06.02 (0.40 g, 1.3 mmol), EtOH (3.2 mL), HO (0.8 mL), Fe (0.72 g, 13 mmol), and NHCl (0.55 g, 10 mmol) was stirred at 80 °C for 4 h. THF (20 mL) was added, the mixture was filtered through Celite, and the filtrate was poured into water (30 mL) and extracted with EtOAc (2 × 30 mL). The combined extracts were washed with brine (10 mL), dried over NaSO, concentrated, and purified by silica chromatography (0 to 100% EtOAc in PE) to afford 2-(6-azaspiro[2.5]octan-6-yl)-6-bromo-pyridin-3-amine (I06.03, 0.29 g).

[0230] Step 3. To a 0° C. mixture of I06.03 (0.28 mg, 0.99 mmol) and TFA (4.2 mL) was added NaNO (75 mg, 1.1 mmol) in portions. The mixture was stirred at 0° C. for 0.75 h, and a solution of NaN (80 mg, 1.2 mmol) in cold HO (1.4 mL) was added dropwise. The mixture was stirred at 0° C. for 2.3 h, and the pH was adjusted to >9 by adding CHCl (20 mL) and saturated NaCO solution. The organic phase was separated, washed with saturated aqueous NaHCO (20 mL × 2) and brine (20 mL × 2), dried over NaSO, filtered, concentrated, and purified by silica chromatography (10–100% EtOAc in PE) to give 6-(3-azido-6-bromo-2-pyridyl)-6-azaspiro[2.5]octane (106.04, 100 mg).

[0231] The aryl azides in Table 4B were prepared from the indicated 2-halonitroarenes by the method described for the synthesis of I06.04. [Table 7-1] [Table 7-2] [Table 7-3]

[0232] Synthesis of 6-(5-bromo-2-nitrophenyl)-6-azaspiro[2.5]octane (I06.10) [ka] Step 1. A mixture of 6-azaspiro[2.5]octane hydrochloride (0.85 g, 5.8 mmol), 4-bromo-2-fluoro-1-nitrobenzene (1.0 g, 4.6 mmol), DMF (15 mL), and KCO (1.9 g, 14 mmol) was stirred at 120 °C for 4 h. The mixture was combined with HO (40 mL) and extracted with EtOAc (20 mL × 2). The combined extracts were washed with water (20 mL × 3) and brine (20 mL), dried over NaSO, filtered, concentrated, and purified by silica chromatography (0–15% EtOAc / PE) to give 6-(5-bromo-2-nitro-phenyl)-6-azaspiro[2.5]octane (R-029, 1.3 g, 75% purity).

[0233] Step 2. R-029 (1.2 g, 4.0 mmol), methanesulfonamide (1.2 g, 13 mmol), CuI (0.84 g, 4.4 mmol), N 1 ,N 2 A mixture of 1,2-dimethylcyclohexane-1,2-diamine (0.64 g, 4.5 mmol), KPO (2.6 g, 12 mmol), and DMF (15 mL) was stirred at 140 °C under N for 2.5 h. The mixture was combined with EtOAc (40 mL) and HO (30 mL) and filtered. The filtrate was separated, and the organic phase was washed with HO (20 mL × 2), brine (20 mL), dried over NaSO, filtered, concentrated, and purified by silica chromatography (0–50% EtOAc / PE) to give N-[3-(6-azaspiro[2.5]octan-6-yl)-4-nitro-phenyl]methanesulfonamide (R-030, 0.6 g).

[0234] Step 3. A mixture of R-030 (0.55 g, 1.7 mmol), EtOH (25 mL), HO (5 mL), Fe (0.80 g, 14 mmol), and NHCl (1.0 g, 19 mmol) was stirred at 90° C. for 3 h. The mixture was filtered through Celite, and the filtrate was concentrated, combined with EtOAc (30 mL), washed with HO (15 mL × 2) and brine (15 mL), dried over NaSO, filtered, and concentrated to give N-[4-amino-3-(6-azaspiro[2.5]octan-6-yl)phenyl]methanesulfonamide (R-031, 0.51 g).

[0235] Step 4. To a mixture of R-031 (0.45 mg, 1.5 mmol) and MeCN (35 mL) was added TMSN3 (0.48 mL, 3.7 mmol) in MeCN (2.5 mL) at 0 °C. After stirring at 0 °C for 0.5 h, t-butyl nitrite (0.44 mL, 3.7 mmol) in MeCN (2.5 mL) was added dropwise. The mixture was stirred at 20 °C for 9.5 h, diluted with HO (40 mL), extracted with CHCl (40 mL × 2), and the combined extracts were washed with HO (20 mL), brine (20 mL), dried over NaSO, filtered, and concentrated to give N-[3-(6-azaspiro[2.5]octan-6-yl)-4-azido-phenyl]methanesulfonamide (106.10, 0.48 g).

[0236] The following compounds were prepared from the indicated 2-halo-nitroarenes in the same four-step procedure as described in I06.10. [Table 8]

[0237] Synthesis of 4-azido-2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine (I06.16). [ka] Step 1. A mixture of 2,4-dichloro-6-methylpyrimidine (3.0 g, 18 mmol), DMF (30 mL), CsCO (18 g, 55 mmol), and 4,4-difluoropiperidine (2.2 g, 18 mmol) was stirred at 100 °C for 12 h, then poured into HO (50 mL) and extracted with EtOAc (2 x 50 mL). The combined extracts were washed with brine (50 mL), dried over NaSO, concentrated, and purified by silica chromatography (10:1 to 1:1 EtOAc / PE) to give 4-chloro-2-(4,4-difluoro-1-piperidyl)-6-methylpyrimidine (106.14, 0.64 g).

[0238] Step 2. A mixture of I06.14 (0.10 g, 0.40 mmol), dioxane (1.5 mL), and NHNH-hydrate (40 μL, 0.81 mmol) was stirred at 110° C. for 4 hours. The pH was adjusted to 2 with 2 M HCl, and HO (10 mL) was added. The mixture was extracted with EtOAc (20 mL × 2), and the combined extracts were washed with brine (20 mL), dried over NaSO, filtered, and concentrated to provide 2-(4,4-difluoropiperidin-1-yl)-4-hydrazinyl-6-methylpyrimidine (I06.15, 85 mg).

[0239] Step 3. To a mixture of I06.15 (85 mg, 0.35 mmol), HOAc (0.5 mL), and HO (0.5 mL) was added NaNO (36 mg, 0.52 mmol). The mixture was stirred at 0 °C for 4 hours, then poured into ice water (20 mL) and extracted with CHCl (2 × 20 mL). The combined extracts were washed with brine (20 mL), dried over NaSO, filtered, and concentrated to provide 4-azido-2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine (I06.16, 80 mg).

[0240] The following heterocyclic azides were prepared from the indicated heterocyclic halides and amines in the same manner as described in I06.16. [Table 9]

[0241] Synthesis of 2-azido-6-(4,4-difluoropiperidin-1-yl)-4-methylpyridine (I06.22) [ka] Step 1. A mixture of 2,6-dichloro-4-methylpyridine (1.0 g, 6.2 mmol), 4,4-difluoropiperidine hydrochloride (1.1 g, 6.8 mmol), NMP (20 mL), and iPrNEt (4.3 mL, 25 mmol) was stirred at 140 °C for 12 h, poured into 25 mL of HO, and extracted with EtOAc (2 x 25 mL). The extracts were combined, washed with brine (10 mL), dried over NaSO, filtered, concentrated, and purified by silica chromatography (9-17% EtOAc in PE) to give 2-chloro-6-(4,4-difluoro-1-piperidyl)-4-methyl-pyridine (106.20, 0.95 g).

[0242] Step 2a. A degassed mixture of I06.20 (0.50 g, 2.0 mmol), BINAP (0.13 g, 0.20 mmol), Pd(OAc)2 (45 mg, 0.20 mmol), Cs2CO3 (1.3 g, 4.1 mmol), and BocNHNH2 (0.40 g, 3.0 mmol) in dioxane (10 mL) was stirred at 100 °C for 12 h under a N2 atmosphere. The mixture was poured into 15 mL of HO and extracted with EtOAc (2 × 15 mL). The extracts were combined, washed with brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (9–17% EtOAc in PE) to give tert-butyl N-[[6-(4,4-difluoro-1-piperidyl)-4-methyl-2-pyridyl]amino]carbamate (0.32 g).

[0243] Step 2b. To a mixture of tert-butyl N-[[6-(4,4-difluoro-1-piperidyl)-4-methyl-2-pyridyl]amino]carbamate (0.27 g, 0.79 mmol) and EtOAc (1 mL) was added HCl / EtOAc (4 M, 20 mL), and the mixture was stirred at 25 °C for 2 h. The reaction was poured into NaHCO (15 mL) and extracted with EtOAc (2 × 15 mL). The extracts were combined, washed with brine (10 mL), dried over NaSO, filtered, concentrated, and purified by silica chromatography (9–50% MeOH in CHCl) to give [6-(4,4-difluoro-1-piperidyl)-4-methyl-2-pyridyl]hydrazine (106.21, 0.18 g).

[0244] Step 3. 2-Azido-6-(4,4-difluoropiperidin-1-yl)-4-methylpyridine (I06.22) was prepared from I06.21 in the same manner as described in I06.16 (Step 3).

[0245] The following heterocyclic azides were prepared from the indicated heterocyclic halides and amines in the same manner as described in I06.22. [Table 10]

[0246] Synthesis of 2-azido-6-(4,4-difluoropiperidin-1-yl)pyrazine (I06.24) [ka] Step 1. A mixture of 2,6-dichloropyrazine (1.0 g, 6.7 mmol), 4,4-difluoropiperidine hydrochloride (1.2 g, 7.4 mmol), KCO (2.8 g, 20 mmol), and DMF (10 mL) was stirred at 25 °C for 2 h, then combined with 50 mL of HO and extracted with EtOAc (2 x 50 mL). The extracts were combined, washed with brine (20 mL), dried over NaSO, filtered, and purified by silica chromatography (0 to 100% EtOAc in PE) to give 2-chloro-6-(4,4-difluoro-1-piperidyl)pyrazine (106.23, 0.77 g).

[0247] Step 2. A degassed mixture of I06.23 (0.20 g, 0.86 mmol), DMF (5 mL), and NaN (0.17 g, 2.6 mmol) was stirred at 120 °C under a N atmosphere for 12 h. The mixture was poured into HO (30 mL) and extracted with EtOAc (2 x 30 mL). The extracts were combined, washed with brine (10 mL), dried over NaSO, filtered, and concentrated to a volume of 2 mL. Three cycles of adding 10 mL of CHCl and concentrating to 2 mL gave a crude solution of approximately 0.86 mmol of 2-azido-6-(4,4-difluoro-1-piperidyl)pyrazine (I06.24) in 2 mL of CHCl.

[0248] Synthesis of 1-(2-fluoro-4-nitro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (I07.02) [ka] Step 1. To a mixture of 4-iodo-1H-pyrazole (2.4 g, 13 mmol) and DMSO (40 mL) was added KCO (3.5 g, 25 mmol) and 1,2-difluoro-4-nitrobenzene (1.4 mL, 13 mmol) at 20 °C. The mixture was stirred at 90 °C for 2.5 h, then poured into HO (100 mL) and extracted with EtOAc (40 mL × 3). The combined extracts were washed with brine (100 mL × 3), dried over NaSO, filtered, concentrated, and purified by silica chromatography (0-10% EtOH in PE) to give 1-(2-fluoro-4-nitro-phenyl)-4-iodo-pyrazole (107.01, 3.8 g).

[0249] Step 2. To a mixture of I07.01 (1.0 g, 3.0 mmol), bis(pinacolato)diboron (1.1 g, 4.5 mmol), and DMF (10 mL) was added KOAc (0.88 g, 9.0 mmol) and Pd(dppf)Cl (0.22 g, 0.30 mmol). The mixture was stirred at 90 °C under N for 2 hours, poured into HO (50 mL), and extracted with EtOAc (20 mL × 3). The combined extracts were washed with brine (30 mL × 3), dried over NaSO, filtered, concentrated, and purified by silica chromatography (0 to 15% EtOAc in PE) to give 1-(2-fluoro-4-nitro-phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (I07.02, 0.64 g).

[0250] Synthesis of 1-(3-azidophenyl)-4,4-difluoropiperidine (I09.03) [ka] Step 1. Two mixtures of 1-fluoro-3-nitrobenzene (1.5 mL, 14 mmol each), DMSO (20 mL each), KCO (5.9 g, 43 mmol each), and 4,4-difluoropiperidine hydrochloride (2.7 g, 17 mmol each) were stirred at 90 °C for 12 hours. The mixtures were cooled, combined, poured into HO (300 mL), and extracted with EtOAc (2 × 300 mL). The combined extracts were washed with brine (100 mL), dried over NaSO, concentrated, and purified by silica chromatography (0–100% EtOAc in PE) to give 4,4-difluoro-1-(3-nitrophenyl)piperidine (109.01, 1.3 g).

[0251] Step 2. To a mixture of I09.01 (1.2 g, 5.0 mmol), EtOH (10 mL), and HO (2 mL) was added Fe (2.8 g, 50 mmol) and NHCl (1.3 g, 25 mmol). The mixture was stirred at 80 °C for 2 h, THF (20 mL) was added, the mixture was filtered, and the pad was washed with THF (50 mL × 2). The combined filtrate was concentrated to provide 3-(4,4-difluoro-1-piperidyl)aniline (I09.02, 1.0 g).

[0252] Step 3. To a 0°C mixture of I09.02 (1.0 g, 4.7 mmol) and MeCN (10 mL) was added a solution of TMSN3 (1.5 mL, 11 mmol) in MeCN (2 mL). After stirring at 0°C for 0.5 h, a solution of tBuONO (1.3 mL, 11 mmol) in MeCN (2 mL) was slowly added. The mixture was stirred at 20°C for 12 h, poured into water (300 mL), partially concentrated, and extracted with EtOAc (2 x 100 mL). The combined extracts were washed with brine (50 mL), dried over NaSO, and concentrated to give 1-(3-azidophenyl)-4,4-difluoro-piperidine (I09.03, 1.0 g).

[0253] Synthesis of 1-((5-azido-2-fluorophenyl)sulfonyl)-3,3-difluoroazetidine (I09.07) [ka] Step 1. A 0 °C mixture of 2-fluoro-5-nitrobenzenesulfonyl chloride (0.80 g, 3.3 mmol), EtN (0.47 mL, 3.3 mmol), and CHCl (20 mL) was slowly added to a stirred mixture of 3,3-difluoroazetidine hydrochloride (0.42 g, 3.2 mmol), EtN (1.4 mL, 10 mmol), and CHCl (10 mL). The new mixture was stirred for 1 h, diluted with CHCl (30 mL), washed with HO (20 mL) and brine (20 mL), dried over NaSO, filtered, concentrated, and purified by silica chromatography (0–30% EtOAc in PE) to give 3,3-difluoro-1-((2-fluoro-5-nitrophenyl)sulfonyl)azetidine (109.05, 0.75 g).

[0254] Step 2. A mixture of I09.05 (0.69 g, 2.3 mmol), NHCl (1.0 g, 19 mmol), Fe powder (1.3 g, 23 mmol), and EtOH (20 mL) was stirred at 70 °C for 10 h, cooled, and filtered through Celite. The filter pad was washed with MeOH (3 × 10 mL), and the combined filtrates were concentrated and purified by silica chromatography (0-25% EtOAc in PE) to give (I09.06, 0.45 g).

[0255] The following compounds were prepared from the indicated anilines using the method described for the preparation of I09.03. [Table 11]

[0256] Example 1 Synthesis of 4-(6-(5-(4-bromo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)morpholine (Compound 1) and N-(4-(5-(6-morpholinopyridin-2-yl)-4H-1,2,4-triazol-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)methanesulfonamide (Compound 2) [ka] Step 1. A mixture of ethyl 4-bromo-2-fluorobenzenecarboximidate hydrochloride (I01.01) (1.0 g, 4.0 mmol), 6-morpholinopicolinohydrazide (I02.01) (0.5 g, 2.3 mmol), and EtN (2.0 mL, 14 mmol) was stirred at 130 °C for 3 h, followed by concentration and purification by silica gel chromatography (0-40% [10% MeOH in EtOAc] / PE) to afford 0.28 g of 4-[6-[5-(4-bromo-2-fluoro-phenyl)-4H-1,2,4-triazol-3-yl]-2-pyridyl]morpholine (E01.01).

[0257] Step 2. A mixture of E01.01 (0.24 g, 0.59 mmol), 6-azaspiro[2.5]octane hydrochloride (0.19 g, 1.3 mmol), KCO (0.30 g, 2.2 mmol), and DMF (6 mL) was stirred in a microwave reactor at 140° C. for 3 hours. Additional 6-azaspiro[2.5]octane hydrochloride (0.17 g, 1.2 mmol) was added, and the mixture was heated in a microwave reactor at 140° C. for an additional 3 hours. The mixture was combined with 30 mL of EtOAc and filtered. The filtrate was washed with HO (3 × 15 mL) and brine (15 mL), dried over NaSO, concentrated, and purified by silica chromatography (0–35% [50% THF in EtOAc] / PE) to give 77 mg of 4-(6-(5-(4-bromo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)morpholine (compound 1).

[0258] Step 3. Compound 1 (57 mg, 0.12 mmol), methanesulfonamide (30 mg, 0.32 mmol), CuI (16 mg, 0.084 mmol), N 1 ,N 2A degassed mixture of 1,2-dimethylcyclohexane-1,2-diamine (12 mg, 0.084 mmol), KPO (74 mg, 0.35 mmol), and DMF (2.5 mL) was stirred in a microwave reactor at 150 °C for 2 h. The mixture was cooled, filtered, concentrated, and purified by reverse-phase HPLC (C18, 30-60% MeCN [1 mM NHCO] in HO) to give 2.5 mg of N-(4-(5-(6-morpholinopyridin-2-yl)-4H-1,2,4-triazol-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)methanesulfonamide (compound 2).

[0259] The following compounds were prepared from the appropriate imidate ester and acylhydrazine in the manner described for compound 2 in Example 1. [Table 12]

[0260] Example 2: Synthesis of 4-(6-(5-(2-(6-azaspiro[2.5]octan-6-yl)pyridin-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)morpholine (Compound 4) [ka] Step 1. E02.01 was prepared from I01.02 and I02.01 as described for E01.01 in Step 1 of Example 1.

[0261] Step 2. Compound 4 was prepared from E02.01 and 6-azaspiro[2.5]octane hydrochloride in the manner described for compound 1 in Step 2 of Example 1.

[0262] Example 3. Synthesis of N-(4-(5-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-1H-1,2,4-triazol-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)methanesulfonamide (Compound 5) [ka] Step 1. I02.04 (0.36 g, 1.4 mmol), ethyl 2-fluoro-4-nitrobenzimidate hydrochloride (I01.03) (0.45 g, 2.1 mmol), and CHCl (1 mL) were combined and concentrated, and the resulting residue was combined with iPrNEt (1 mL) and heated at 150° C. for 1 h, then 180° C. for 2 h, then poured into 30 mL of HO and extracted with EtOAc (2×30 mL). The extracts were combined, washed with brine (10 mL), dried over NaSO, filtered, and concentrated. Purification by silica chromatography (0-100% EtOAc in PE) gave 0.86 g of 2-(4,4-difluoropiperidin-1-yl)-6-(5-(2-fluoro-4-nitrophenyl)-4H-1,2,4-triazol-3-yl)pyridine (E03.01).

[0263] Step 2. A mixture of E03.01 (0.20 g, 0.49 mmol), 6-azaspiro[2.5]octane hydrochloride (95 mg, 0.64 mmol), NMP (2 mL), and KCO (0.21 g, 1.5 mmol) was stirred at 140 °C for 4 hours and then poured into 40 mL of HO. The mixture was extracted with EtOAc (2 × 30 mL), and the combined extracts were washed with brine (10 mL), dried over NaSO, filtered, concentrated, and purified by silica chromatography (0-11% EtOAc in PE) to give 245 mg of 6-(2-(5-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-4H-1,2,4-triazol-3-yl)-5-nitrophenyl)-6-azaspiro[2.5]octane (E03.02).

[0264] Step 3. Iron powder (0.23 g, 4.0 mmol) and NH4Cl (0.11 g, 2.0 mmol) were added to E03.02 (0.20 g, 0.40 mmol), EtOH (6 mL), and HO (1.2 mL), and the mixture was stirred at 80° C. for 2 h. THF (30 mL) was added, and the mixture was filtered, concentrated, combined with HO (30 mL), and extracted with EtOAc (2×30 mL). The combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0-100% EtOAc in PE) to give 0.10 g of 4-(5-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-4H-1,2,4-triazol-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)aniline (E03.03).

[0265] Step 4. A mixture of E03.03 (90 mg, 0.19 mmol), CHCl (2 mL), MsCl (67 mg, 0.58 mmol), and pyridine (0.12 mg, 1.6 mmol) was stirred at 50 °C for 1 hour, then poured into 10 mL of HO and extracted with EtOAc (2 × 10 mL). The combined extracts were washed with brine, dried over NaSO, filtered, concentrated, and purified by reverse-phase HPLC (C18, 25–55% MeCN [1 mM NHCO] in HO) to provide 20 mg of N-(4-(5-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-1H-1,2,4-triazol-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)methanesulfonamide (Compound 5).

[0266] Example 4. Synthesis of N-(4-(5-(6-methyl-2-morpholinopyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)methanesulfonamide (Compound 6) [ka] Steps 1-3 were carried out as described for the synthesis of E03.03 (Example 3) to give E04.03.

[0267] Step 4. A mixture of E04.03 (30 mg, 67 μmol), CHCl (0.2 mL), EtN (28 μL, 0.20 mmol), and MsCl (5 μL, 67 μmol) was stirred for 2 h, and an additional 94 μL of MsCl (1.2 mmol) was added slowly at 0° C. The mixture was stirred at 20° C. for 2 h, poured into 5 mL of saturated aqueous NaHCO, and extracted with 10:1 CHCl / MeOH (2 × 5 mL). The combined extracts were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated to give 40 mg of N-(4-(5-(6-methyl-2-morpholinopyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-N-(methylsulfonyl)methanesulfonamide (E04.04).

[0268] Step 5. A mixture of E04.04 (27 mg, 44 μmol), THF (0.1 mL), and 2 M NaOH (44 μmol, 22 μL) was stirred for 1 hour, poured into 5 mL of HO, and the pH was adjusted to 7 with 2 M HCl. The mixture was extracted with 10:1 CHCl / MeOH (2 × 5 mL), and the combined extracts were washed with brine, dried over NaSO, filtered, concentrated, and purified by reverse-phase HPLC (C18, 1–40% MeCN in HO [0.1% formic acid]) to provide 3.7 mg of N-(4-(5-(6-methyl-2-morpholinopyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)methanesulfonamide (Compound 6).

[0269] Example 5 Synthesis of ethyl 2-(N-(4-(5-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-4H-1,2,4-triazol-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)acetate (Compound 7) and N-(4-(5-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-4H-1,2,4-triazol-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 8) [ka] Step 1. A mixture of E03.03 (0.10 g, 0.22 mmol), ethyl 2-chlorosulfonyl acetate (48 μg, 0.26 mmol), CHCl (2 mL), and pyridine (68 mg, 0.86 mmol) was stirred for 2 hours. The mixture was poured into HO (10 mL) and extracted with EtOAc (2 × 10 mL). The combined extracts were washed with brine (10 mL), dried over NaSO, filtered, concentrated, and purified by silica chromatography (0 to 100% EtOAc in PE) to provide 80 mg of ethyl 2-(N-(4-(5-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-4H-1,2,4-triazol-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)acetate (Compound 7).

[0270] Step 2. To a mixture of compound 7 (70 mg, 0.11 mmol) and THF (2 mL) at 0 °C was added LiBH (7 mg, 0.34 mmol). The mixture was warmed to 20 °C and stirred for 2 h, poured into saturated aqueous NH Cl (20 mL), and extracted with EtOAc (2 × 20 mL). The combined extracts were washed with brine (10 mL), dried over Na SO , filtered, concentrated, and purified by reverse-phase HPLC (C18, 30–60% EtOAc in HO [0.1% formic acid]) to give 14 mg of N-(4-(5-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-4H-1,2,4-triazol-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (compound 8).

[0271] Example 6 Synthesis of N-(4-(5-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-1H-imidazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)methanesulfonamide (Compound 9) [ka] Step 1. Three separate mixtures each consisting of I04.02 (0.19 g, 0.69 mmol), DMF (8.5 mL), K2CO3 (0.22 g, 1.6 mmol), and I03.02 (0.17 g, 0.53 mmol) were stirred for 12 h. The mixtures were poured into water (20 mL), extracted with EtOAc (2 x 15 mL), washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0-50% EtOAc in PE) to give 0.11 g of combined 6-(2-(5-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-1H-imidazol-2-yl)-5-nitrophenyl)-6-azaspiro[2.5]octane (E06.01).

[0272] Step 2. A mixture of E06.01 (0.11 mg, 0.22 mmol), EtOH (5 mL), HO (1 mL), Fe powder (0.12 g, 2.2 mmol), and NHCl (59 mg, 1.1 mmol) was stirred for 2 hours at 80° C. The mixture was filtered, and the filtrate was concentrated to give 86 mg of 4-(5-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-1H-imidazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)aniline (E06.02).

[0273] Step 3. To a 0° C. mixture of E06.02 (0.10 g, 0.22 mmol) and CHCl (3 mL) was added MsCl (74 mg, 0.65 mmol) and EtN (0.13 mg, 1.3 mmol). The resulting mixture was stirred at 20° C. for 1 h, poured into saturated HO (10 mL), and extracted with EtOAc (2×10 mL). The combined extracts were washed with brine (10 mL), dried over NaSO, filtered, and concentrated. The resulting residue was combined with MeOH (1.5 mL) and KCO (0.12 g, 0.88 mmol), stirred for 1 h, poured into HO (10 mL), and extracted with EtOAc (2×10 mL). The combined extracts were washed with brine (10 mL), dried over NaSO, filtered, concentrated, and purified by reverse-phase HPLC (C, 30-53% MeCN in HO [0.1% formic acid]) to give 8.5 mg of N-(4-(5-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-1H-imidazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)methanesulfonamide (compound 9).

[0274] The compounds in Table 6 were prepared from the appropriate amidine and α-bromoketone in the same manner as compound 9. [Table 13]

[0275] Example 6A: Synthesis of N-(4-(4-(6-(cyclopentyl(hydroxy)methyl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)methanesulfonamide (Compound 22) [ka] A mixture of I06.10 (0.10 g, 0.31 mmol), I05.16 (70 mg, 0.35 mmol), CHCl (4 mL), HO (4 mL), CuSO HO (11 mg, 45 umol), and sodium ascorbate (80 mg, 0.40 mmol) was stirred at 25 °C for 12 h. The mixture was combined with EtOAc (20 mL) and HO (10 mL), filtered, and the organic phase was separated, washed with HO (10 mL × 3) and brine (10 mL), dried over NaSO, filtered, concentrated, and purified by preparative HPLC (C18; 40-75% MeCN(NHHCO) in HO) to give N-(4-(4-(6-(cyclopentyl(hydroxy)methyl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)methanesulfonamide (compound 22, 53 mg).

[0276] The compounds in Table 6X were prepared from the appropriate alkyne and azide in the same manner as compound 22. [Table 14-1] [Table 14-2] [Table 14-3] [Table 14-4]

[0277] Synthesis of a mixture of 6-(5-bromo-2-(4-(6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridin-2-yl)-1H-1,2,3-triazol-1-yl)phenyl)-6-azaspiro[2.5]octane (T6X.14) and 6-(5-bromo-2-(4-(6-(4,4-difluorocyclohex-1-en-1-yl)-3-fluoropyridin-2-yl)-1H-1,2,3-triazol-1-yl)phenyl)-6-azaspiro[2.5]octane (T6X.15) [ka] The reaction of alkynes I05.80 and I05.81 (70 mg, 0.30 mmol) and azide I06.06 in the same manner as for compound 22 gave a mixture of 6-(5-bromo-2-(4-(6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridin-2-yl)-1H-1,2,3-triazol-1-yl)phenyl)-6-azaspiro[2.5]octane (T6X.14) and 6-(5-bromo-2-(4-(6-(4,4-difluorocyclohex-1-en-1-yl)-3-fluoropyridin-2-yl)-1H-1,2,3-triazol-1-yl)phenyl)-6-azaspiro[2.5]octane (T6X.15). The products were separated by silica chromatography (0-30% EtOAc in PE) to give 27 mg of T6X.14 and 70 mg of T6X.15.

[0278] Example 7. Synthesis of N-(4-(4-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)methanesulfonamide (Compound 11) [ka] Step 1. A mixture of I06.01 (0.18 g, 0.83 mmol), I05.03 (0.37 g, 0.83 mmol), CHCl (2 mL), HO (2 mL), CuSO pentahydrate (21 mg, 83 μmol), and sodium ascorbate (0.17 g, 0.83 mmol) was stirred for 12 h. The mixture was filtered, concentrated, and purified by silica chromatography (0-30% EtOAc in PE) to afford 0.10 g of 2-(1-(4-bromo-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)-6-(4,4-difluoropiperidin-1-yl)pyridine (E07.01).

[0279] Step 2. A mixture of E07.01 (0.10 g, 0.23 mmol), 6-azaspiro[2.5]octane hydrochloride (67 mg, 0.46 mmol), DMF (3 mL), and KCO (95 mg, 0.65 mmol) was stirred for 12 hours at 120° C. The mixture was filtered, concentrated, and purified by silica chromatography (0 to 30% EtOAc in PE) to give 100 mg of 6-(5-bromo-2-(4-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)phenyl)-6-azaspiro[2.5]octane (E07.02).

[0280] Step 3. E07.02 (90 mg, 0.17 mmol), methanesulfonamide (40 mg, 0.42 mmol), CuI (1.6 mg, 9 μmol), N 1 ,N 2A degassed mixture of N-dimethylcyclohexane-1,2-diamine (2.4 mg, 17 μmol), KPO (0.11 mg, 0.51 mmol), and DMF (2 mL) was stirred under N at 140 °C for 2 h. The mixture was combined with HO (10 mL) and extracted with EtOAc (3 × 10 mL). The extracts were combined, washed with brine (10 mL), dried over NaSO, filtered, concentrated, and purified by reverse-phase HPLC (C18, 55–80% MeCN [HCl] in HO) to give N-(4-(4-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)methanesulfonamide (Compound 11).

[0281] The compounds in Table 6A were prepared in the same manner as compound 11 from the appropriate alkyne and azide in step 1, an amine in step 2, and a sulfonamide in step 3. [Table 15-1] [Table 15-2] [Table 15-3] [Table 15-4]

[0282] Example 7A: Synthesis of N-(4-(4-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 45) [ka] E07.02 (0.20 g, 0.38 mmol), 2-[tert-butyl(dimethyl)silyl]oxyethanesulfonamide (0.27 g, 1.1 mmol), CuI (80 mg, 0.42 mmol), N 1 ,N 2 A degassed mixture of -dimethylcyclohexane-1,2-diamine (60 mg, 0.42 mmol), KPO (0.24 g, 1.1 mmol), and DMF (4 mL) was stirred under N at 140 °C for 4 h. Another mixture was prepared in the same manner from 20 mg of E07.02. The two mixtures were combined, filtered, and the filtrate was diluted with EtOAc (40 mL). The mixture was washed with water (20 mL × 3) and brine (20 mL), dried over NaSO, filtered, concentrated, and purified by preparative HPLC (C18: 40-70% MeCN in HO [10 mM NH4HCO3]) to give N-(4-(4-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (compound 45, 50 mg).

[0283] Example 7B: Synthesis of N-(4-(4-(2-(4,4-difluoropiperidin-1-yl)-5-fluorothiazol-4-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 93) [ka] Step 1. To a mixture of T6X.06 (0.90 g, 2 mmol) and DMF (15 mL) was added 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium ditetrafluoroborate (0.60 g, 2 mmol) and 2,6-dimethylpyridine (0.39 mL, 3 mmol) at 0° C. The mixture was stirred at 25° C. for 12 h, poured into HO (60 mL), and extracted with EtOAc (2×35 mL). The combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (5–50% EtOAc in PE) to give 4-[1-[2-(6-azaspiro[2.5]octan-6-yl)-4-bromo-phenyl]triazol-4-yl]-2-(4,4-difluoro-1-piperidyl)-5-fluorothiazole (E7B.01, 0.56 g).

[0284] Step 2. E7B.01 (0.46 g, 0.83 mmol) and 2-hydroxyethanesulfonamide (0.21 g, 2 mmol), DMF (10 mL), CuI (0.11 g, 0.58 mmol), N 1 A mixture of N-dimethylcyclohexane-1,2-diamine (83 mg, 0.58 mmol) and KPO (0.53 g, 2 mmol) was stirred at 130 °C for 2 h, poured into 40 mL of HO, and extracted with EtOAc (2 × 15 mL). The combined extracts were washed with brine (20 mL), dried over NaSO, filtered, concentrated, and purified by preparative HPLC (C18; 45–65% MeCN [NHHCO] in HO) to give N-(4-(4-(2-(4,4-difluoropiperidin-1-yl)-5-fluorothiazol-4-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (compound 93, 0.18 g).

[0285] Example 8: Synthesis of N-(tert-butyl)-3-(2-(4-(methylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-1H-imidazol-5-yl)benzenesulfonamide (Compound 34) [ka] Step 1. A mixture of I03.04 (0.20 g, 0.60 mmol), THF (8 mL), and iPrNEt (0.45 mL, 2.6 mmol) was stirred at 80° C. for 15 minutes, and I04.05 (0.19 g, 0.60 mmol) was added. The mixture was stirred at 80° C. for 12 hours. Another mixture was prepared from 19 mg of I03.04 and 19 mg of I04.05. The two reaction mixtures were combined, diluted with EtOAc (20 mL), washed with brine (10 mL × 2), dried over NaSO, filtered, concentrated, and purified by preparative TLC (33% EtOAc in PE) to give 3-[2-[2-(6-azaspiro[2.5]octan-6-yl)-4-bromo-phenyl]-1H-imidazol-5-yl]-N-tert-butylbenzenesulfonamide (E07.01, 85 mg, 65% purity).

[0286] Step 2. E07.01 (65 mg, 0.12 mmol), methanesulfonamide (58 mg, 0.61 mmol), CuI (26 mg, 0.14 mmol), N 1 ,N 2 A mixture of 1,2-dimethylcyclohexane-1,2-diamine (20 mg, 0.14 mmol), KPO (78 mg, 0.37 mmol), and DMF (2 mL) was stirred under N at 120 °C for 3.5 h. Another mixture was prepared from 10 mg of E07.01 in the same manner. Both mixtures were combined and filtered. The filtrate was concentrated and purified by preparative HPLC (C, 40–70% MeCN in HO [10 mM NHHCO]) to give N-(tert-butyl)-3-(2-(4-(methylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-1H-imidazol-5-yl)benzenesulfonamide (Compound 34, 20 mg).

[0287] The compounds in Table 6B were prepared in the same manner as compound 34 from the appropriate amidines, α-bromoketones, and sulfonamides. [Table 16]

[0288] Example 9. Synthesis of N-(4-(5-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-1H-imidazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 35) [ka] A mixture of E08.02 (50 mg, 73 μmol), EtOAc (0.5 mL), and 6 M HCl in EtOAc (12 μL, 73 μmol) was stirred at 25° C. for 1 h. Another mixture was prepared from 10 mg of E08.02 in the same manner. The mixtures were combined, concentrated, poured into water (30 mL), and extracted with EtOAc (2×30 mL). The organic phase was washed with brine (10 mL), dried over NaSO, concentrated, and purified by preparative HPLC (C18; 1-50% MeCN in HO [0.1% formic acid]) to give N-(4-(5-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-1H-imidazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (compound 35, 3.8 mg).

[0289] Example 10. Synthesis of N-(4-(4-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-1H-pyrazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)methanesulfonamide (Compound 17) [ka] Step 1. A mixture of I07.02 (0.55 g, 1.7 mmol), I05.01 (0.55 g, 2.0 mmol), NaCO (0.53 mg, 5.0 mmol), HO (5 mL), dioxane (15 mL), and Pd(PPh) (0.19 g, 0.17 mmol) was heated at 90 °C for 2 h under N. The mixture was poured into HO (20 mL), extracted with EtOAc (10 mL × 3), and the combined extracts were washed with brine (20 mL × 2), dried over NaSO, filtered, concentrated, and purified by silica chromatography (0 to 40% EtOAc in PE) to afford 2-(4,4-difluoro-1-piperidyl)-6-[1-(2-fluoro-4-nitro-phenyl)pyrazol-4-yl]pyridine (E10.01, 0.47 g).

[0290] Step 2. To a mixture of 6-azaspiro[2.5]octane hydrochloride (0.59 g, 4.0 mmol) and DMF (7 mL) was added KCO (0.74 g, 5.4 mmol) and E10.01 (0.54 g, 1.3 mmol). The mixture was stirred at 120 °C for 16 h and poured into HO (10 mL) and EtOAc (10 mL). The resulting precipitate was filtered and dried to give 6-[2-[4-[6-(4,4-difluoro-1-piperidyl)-2-pyridyl]pyrazol-1-yl]-5-nitrophenyl]-6-azaspiro[2.5]octane (E10.02, 0.40 g).

[0291] Step 3. To a mixture of E10.02 (0.4 g, 0.81 mmol), NH4Cl (0.22 g, 4.0 mmol), EtOH (15 mL), and HO (7.5 mL) was added Fe (0.45 g, 8.1 mmol). The mixture was heated at 70 °C for 1.5 h. The mixture was filtered through Celite, and the filtrate was concentrated, dissolved in EtOAc (10 mL), washed with HO (10 mL × 2), brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0 to 70% EtOAc in PE) to give 3-(6-azaspiro[2.5]octan-6-yl)-4-[4-[6-(4,4-difluoro-1-piperidyl)-2-pyridyl]pyrazol-1-yl]aniline (E10.03, 0.36 g).

[0292] To a mixture of E10.03 (0.05 g, 0.11 mmol), EtN (45 μg, 0.32 mmol), and CHCl (1 mL) was added methylsulfonylmethanesulfonate (23 mg, 0.13 mmol) in CHCl (1 mL) dropwise at 0 °C. The mixture was stirred at 20 °C for 1.5 h. Additional methylsulfonylmethanesulfonate (23 mg, 0.13 mmol) and EtN (45 μg, 0.32 mmol) were added, and the mixture was stirred at 20 °C for 4.5 h, then heated to 40 °C for 17 h. The mixture was poured into HO (10 mL) and extracted with EtOAc (10 mL × 2). The combined extracts were washed with brine (10 mL × 3), dried over NaSO, filtered, concentrated, and purified by preparative HPLC (C18, 40-70% MeCN[HCl] in HO) to give N-(4-(4-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-1H-pyrazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)methanesulfonamide (Compound 17, 5.8 mg).

[0293] N-(4-(4-(4-(4,4-difluoropiperidin-1-yl)pyrimidin-2-yl)-1H-pyrazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)methanesulfonamide (Compound 66) was prepared from I07.02 and 2-chloro-4-(4,4-difluoropiperidin-1-yl)pyrimidine in the same manner as Compound 17. [ka]

[0294] Example 11. Synthesis of N-(5-(4-(5-(cyclopentyl(hydroxy)methyl)furan-2-yl)-1H-1,2,3-triazol-1-yl)-6-(6-azaspiro[2.5]octan-6-yl)pyridin-2-yl)methanesulfonamide (Compound 49) [ka]

[0295] A mixture of T6A.01 (60 mg, 0.12 mmol), MeOH (0.5 mL), and NaBH (9 mg, 0.24 mmol) at 0 °C was stirred at 20 °C for 2 h. The mixture was poured into HO (10 mL) and extracted with EtOAc (2 × 10 mL). The combined extracts were washed with brine (10 mL), dried over NaSO, concentrated, and purified by preparative HPLC (C18, 40% to 70% MeCN[NHHCO] in HO) to give N-(5-(4-(5-(cyclopentyl(hydroxy)methyl)furan-2-yl)-1H-1,2,3-triazol-1-yl)-6-(6-azaspiro[2.5]octan-6-yl)pyridin-2-yl)methanesulfonamide (Compound 49, 12 mg). The compounds in Table 6C were prepared from ketones in the same manner as compound 49. [Table 17]

[0296] Example 12. Synthesis of N-(4-(4-(6-morpholinopyridin-2-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)methanesulfonamide (Compound 54) [ka] A mixture of T6X.02 (90 mg, 0.20 mmol), morpholine (0.14 mL, 1.6 mmol), DMF (5 mL), and KCO (84 mg, 0.61 mmol) was stirred at 120 °C for 12 h. The mixture was poured into HO (30 mL) and extracted with EtOAc (2 × 30 mL). The combined extracts were washed with brine (10 mL), dried over NaSO, filtered, concentrated, and purified by preparative HPLC (C18; 45–60% MeCN in water [formic acid]) to give N-(4-(4-(6-morpholinopyridin-2-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)methanesulfonamide (Compound 54; 14 mg).

[0297] The compounds in Table 6D were prepared in the same manner as compound 54 from the indicated aryl fluoride and the indicated nucleophile. [Table 18]

[0298] Example 13 Synthesis of N-(5-(4-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)-4-(6-azaspiro[2.5]octan-6-yl)pyridin-2-yl)methanesulfonamide (Compound 59) [ka] Step 1. Two mixtures of I05.03 (0.12 g, 0.54 mmol and 0.05 g, 0.23 mmol), I06.05 (0.20 g, 0.65 mmol and 0.08 g, 0.27 mmol), CHCl (2 mL and 0.85 mL), HO (2 mL and 0.85 mL), sodium ascorbate (0.11 g, 0.54 mmol and 0.045 g, 0.23 mmol), and CuSO 5HO (14 mg, 54 μmol and 5.8 mg, 23 μmol) were stirred for 2.5 hours at 20° C. The reaction mixtures were combined, poured into HO (10 mL), and extracted with EtOAc (2×10 mL). The combined extracts were washed with brine (10 mL), dried over NaSO, filtered, concentrated, and purified by silica chromatography (0–50% EtOAc in PE) to give 6-[2-bromo-5-[4-[6-(4,4-difluoro-1-piperidyl)-2-pyridyl]triazol-1-yl]-4-pyridyl]-6-azaspiro[2.5]octane (E13.01, 0.20 g).

[0299] Step 2. Two mixtures of methanesulfonamide (38 mg, 0.40 mmol and 13.01), E13.01 (70 mg, 0.13 mmol and 20 mg, 0.04 mmol), (1R,2R)-N,N-dimethylcyclohexane-1,2-diamine (11 mg, 79 μmol and 3.1 mg, 23 μmol), DMF (0.5 mL and 0.15 mL), CuI (15 mg, 79 μmol and 4.3 mg, 23 μmol), and KPO (84 mg, 0.40 mmol and 24 mg, 0.11 mmol) were stirred at 140° C. for 2 hours. The mixtures were combined, poured into HO (30 mL), and extracted with EtOAc (2×30 mL). The combined extracts were washed with brine (10 mL), dried over NaSO, concentrated, and purified by preparative HPLC (C, 35-65% MeCN [formic acid] in HO) to give N-(5-(4-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)-4-(6-azaspiro[2.5]octan-6-yl)pyridin-2-yl)methanesulfonamide (compound 59, 25 mg).

[0300] The compounds in Table 6E were prepared in the same manner as compound 59 from the indicated azide, alkyne, and sulfonamide. [Table 19-1] [Table 19-2] [Table 19-3] [Table 19-4] [Table 19-5] [Table 19-6] [Table 19-7] [Table 19-8] [Table 19-9] [Table 19-10] [Table 19-11] [Table 19-12] [Table 19-13] [Table 19-14] [Table 19-15]

[0301] Example 14 Synthesis of N-(4-(1-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)methanesulfonamide (Compound 29) [ka] Step 2. A mixture of E14.01 (0.28 g, 0.63 mmol), 4,4-difluoropiperidine hydrochloride (0.20 g, 1.3 mmol), DMSO (5 mL), and CsF (0.29 mg, 1.9 mmol) was stirred at 120° C. for 12 hours. The mixture was poured into HO (30 mL), extracted with EtOAc (2×30 mL), and the combined extracts were washed with brine (10 mL), dried over NaSO, concentrated, and purified by silica chromatography (0 to 40% EtOAc in PE) to give compound 6-(5-bromo-2-(1-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-1H-1,2,3-triazol-4-yl)phenyl)-6-azaspiro[2.5]octane (E14.02, 0.17 g).

[0302] Step 3. N-(4-(1-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)methanesulfonamide (Compound 29) was prepared from E14.02 and methanesulfonamide by the method described in Step 2 of Example 13.

[0303] The compounds in Table 6F were prepared in the same manner as compound 29 from the indicated intermediate, amine, and sulfonamide. [Table 20-1] [Table 20-2]

[0304] Example 15 Synthesis of N-(4-(4-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-1-(hydroxymethyl)cyclopropane-1-sulfonamide (Compound 62) [ka] To a mixture of T6A.03 (50 mg, 80 μmol and 20 mg, 32 μmol) and THF (1 mL and 0.4 mL) was added LiBH (10 mg, 0.48 mmol and 4 mg, 0.19 mmol) at −78° C. The mixture was allowed to warm slowly to 25° C. over 2 h. The mixture was combined, poured into saturated aqueous NH Cl (20 mL), and extracted with EtOAc (2×10 mL). The combined extracts were washed with brine (10 mL), dried over NaSO, concentrated, and purified by preparative HPLC (C, 45-75% MeCN [formic acid] in HO) to give N-(4-(4-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-1-(hydroxymethyl)cyclopropane-1-sulfonamide (Compound 62, 8 mg).

[0305] The compounds in Table 6H were prepared from the indicated esters in the same manner as compound 62. [Table 21]

[0306] Example 15A: Synthesis of N-(4-(4-(6-(cyclopentyloxy)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 100) [ka] Step 1. To a mixture of T6X.03 (0.50 g, 1.2 mmol, 1.00 eq), cyclopentanol (0.15 g, 1.8 mmol), and THF (10 mL) was added KOtBu (0.46 g, 4.1 mmol). The mixture was stirred at 80 °C for 3 h, poured into HO (50 mL), and extracted with EtOAc (2 × 50 mL). The extracts were combined, washed with brine (30 mL), dried over NaSO, concentrated, and purified by silica chromatography (0–100% EtOAc in PE) to give 6-[5-bromo-2-[4-[6-(cyclopentoxy)-2-pyridyl]triazol-1-yl]phenyl]-6-azaspiro[2.5]octane (E15A.01, 0.40 g).

[0307] Step 2. A degassed mixture of E15A.01 (0.20 g, 0.40 mmol), 2-[tert-butyl(dimethyl)silyl]oxyethanesulfonamide (0.12 g, 0.49 mmol), Pd(dba) (5 mg, 8 μmol), t-BuXphos (7 mg, 16 μmol), KCO (0.11 g, 0.81 mmol), and 2-MeTHF (5 mL) was stirred at 100° C. for 12 hours under a N atmosphere. The reaction was poured into HO (30 mL) and extracted with EtOAc (2×30 mL). The combined extracts were washed with brine (10 mL), dried over NaSO, filtered, and concentrated. The residue was stirred in 5 mL of EtOAc and 5 mL of 2 M HCl for 2 hours. HO (30 mL) was added, and the mixture was extracted with EtOAc (2×30 mL). The combined extracts were washed with brine (10 mL), dried over NaSO, filtered, concentrated, and purified by preparative HPLC (C; 50–85% MeCN in HO [0.1% formic acid]) to give N-(4-(4-(6-(cyclopentyloxy)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 100, 36 mg).

[0308] Synthesis of N-(4-(1-(6-(cyclopentyloxy)pyridin-2-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 113) [ka] Compound 113 was prepared in two steps from E14.01 as described for compound 100.

[0309] Synthesis of methyl 1-(N-(4-(4-(3-(N-(tert-butyl)sulfamoyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)cyclopropane-1-carboxylate (E15.01) [ka] A degassed mixture of T6X.09 (0.20 g, 0.37 mmol), methyl 1-sulfamoylcyclopropane-1-carboxylate (80 mg, 0.45 mmol), Pd2(dba)3 (17 mg, 19 μmol), t-BuXphos (13 mg, 30 μmol), K2CO3 (0.10 g, 0.74 mmol), and 2-MeTHF (4 mL) was stirred at 100 °C for 3 h under a N2 atmosphere. The mixture was combined with HO (30 mL) and extracted with EtOAc (2 × 30 mL), and the combined extracts were washed with brine (10 mL), dried over NaSO, concentrated, and purified by silica chromatography (0–45% EtOAc in PE) to give methyl 1-(N-(4-(4-(3-(N-(tert-butyl)sulfamoyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)cyclopropane-1-carboxylate (E15.01, 0.25 g).

[0310] The compounds in the following table were prepared from the indicated aryl halides via the procedure described for the synthesis of E15.01. [Table 22-1] [Table 22-2]

[0311] Example 15B. Synthesis of N-(4-(4-(5-cyclopentylfuran-2-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 126) [ka] A N-purged mixture of compound 125 (20 mg, 39 μmol), MeOH (2 mL), and 10% Pd / C (3 mg) was stirred under H (15 Psi) at 25° C. for 2 h. The mixture was filtered, concentrated, and purified by preparative HPLC (C18; 55–85% MeCN in HO [HCl modifier]) to give N-(4-(4-(5-cyclopentylfuran-2-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (compound 126, 11 mg).

[0312] Example 15C. Synthesis of N-(4-(4-(6-(4,4-difluoropiperidin-1-yl)-4-(hydroxymethyl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)ethanesulfonamide (Compound 131) [ka] To a mixture of T6A.07 (34 mg, 57 μmol) and THF (2 mL) was added BH3-Me2S (10 M, 0.28 mL, 35 mmol) at 0 °C. The mixture was stirred at 80 °C for 2 h, and then 2 N HCl (1 mL) was added slowly at 5–10 °C. Next, HO (10 mL) was added, and the mixture was extracted with EtOAc (20 mL × 2). The combined extracts were washed with brine (20 mL), dried over NaSO, filtered, concentrated, and purified by preparative HPLC (40-70% MeCN in HO [HCl modifier]) to give N-(4-(4-(6-(4,4-difluoropiperidin-1-yl)-4-(hydroxymethyl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)ethanesulfonamide (Compound 131, 6 mg).

[0313] Example 15D. Synthesis of 3-(4,4-difluoropiperidin-1-yl)-5-(1-(4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-1H-1,2,3-triazol-4-yl)pyrazine 1-oxide (Compound 146) [ka] Step 1. To a 0°C mixture of T6X.11 (0.20 g, 0.38 mmol) and CHCl3 (30 mL) was added m-CPBA (0.11 g, 0.57 mmol, 85% purity). The mixture was stirred at 20°C for 3 h, poured into 1 M Na2SO3 (10 mL), and the resulting mixture was extracted with CHCl2 (2 × 10 mL). The extracts were combined, washed with brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0–50% EtOAc in PE) to give 6-[5-bromo-2-[4-[6-(4,4-difluoro-1-piperidyl)-4-oxido-pyrazin-4-ium-2-yl]triazol-1-yl]phenyl]-6-azaspiro[2.5]octane (E15.02, 0.17 g).

[0314] Step 2. 3-(4,4-Difluoropiperidin-1-yl)-5-(1-(4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-1H-1,2,3-triazol-4-yl)pyrazine 1-oxide (compound 146) was prepared from E15.02 and ethanesulfonamide by the method described in Step 2 of Example 13.

[0315] Example 16: Synthesis of N-(4-(3-(6-morpholinopyridin-2-yl)-1,2,4-oxadiazol-5-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)methanesulfonamide (Compound 163) [ka] Step 1. To a mixture of 6-fluoropyridine-2-carbonitrile (5.0 g, 41 mmol) and EtOH (4 mL) was added iPrNEt (21 mL, 123 mmol) and NHOH hydrochloride (5.7 g, 82 mmol). The mixture was stirred at 25 °C for 12 h and then combined with HO (0.5 L). The mixture was extracted with EtOAc (0.4 L × 3). The combined extracts were washed with brine (0.4 L), dried over NaSO, filtered, and concentrated to give 6-fluoro-N'-hydroxy-pyridine-2-carboxamidine (E16.01, 9.8 g).

[0316] Step 2. To a mixture of E16.01 (1.0 g, 6.5 mmol), CHCl (30 mL), and iPrNEt (2.3 mL, 13 mmol) at 0° C. was added 4-bromo-2-fluorobenzoyl chloride (1.8 g, 7.7 mmol) dropwise. The resulting mixture was stirred at 0° C. for 12 hours and then concentrated to give [(E)-[amino-(6-fluoro-2-pyridyl)methylene]amino]4-bromo-2-fluorobenzoate (E16.02, 5.8 g, crude).

[0317] Step 3. A mixture of E16.02 (5.80 g, 16 mmol), toluene (50 mL), and K2CO3 (6.8 g, 49 mmol) was stirred at 110 °C for 12 hours. The mixture was cooled and combined with CHCl2 (100 mL × 2). The combined extracts were washed with saturated NaHCO3 (200 mL), concentrated, and purified by silica chromatography (0 to 100% EtOAc in PE) to give 5-(4-bromo-2-fluoro-phenyl)-3-(6-fluoro-2-pyridyl)-1,2,4-oxadiazole (E16.03, 1.4 g).

[0318] Step 4. A mixture of E16.03 (1.1 g, 3.3 mmol), DMF (25 mL), KCO (1.4 g, 9.8 mmol), and 6-azaspiro[2.5]octane (0.54 g, 4.9 mmol) was stirred for 12 hours at 60° C. The mixture was concentrated and purified by silica chromatography (0 to 100% EtOAc in PE) to give 5-[2-(6-azaspiro[2.5]octan-6-yl)-4-bromo-phenyl]-3-(6-fluoro-2-pyridyl)-1,2,4-oxadiazole (E16.04, 0.35 mg).

[0319] Step 5. A mixture of E16.04 (0.27 g, 0.63 mmol), DMF (13 mL), KCO (0.26 g, 1.9 mmol), and morpholine (82 mg, 0.94 mmol) was stirred at 110 °C for 24 h, concentrated, and purified by silica chromatography (0 to 100% EtOAc in PE) to give 4-[6-[5-[2-(6-azaspiro[2.5]octan-6-yl)-4-bromo-phenyl]-1,2,4-oxadiazol-3-yl]-2-pyridyl]morpholine (E16.05, 0.24 g).

[0320] Step 6. E16.04 (0.24 g, 0.49 mmol), methanesulfonamide (0.14 g, 1.5 mmol), N 1 ,N 2A degassed mixture of 1,2-dimethylcyclohexane-1,2-diamine (70 mg, 0.49 mmol), DMA (20 mL), bis[(tetrabutylammonium iodide)copper(I) iodide] (0.55 g, 0.49 mmol), and CsCO (0.40 g, 1.2 mmol) was stirred under a N atmosphere at 100 °C for 2 h. The mixture was diluted with 10 mL of HO and extracted with EtOAc (10 mL × 3). The combined extracts were washed with brine (30 mL), dried over NaSO, filtered, concentrated, and purified by preparative HPLC (C, 40-70% MeCN in HO [0.1% formic acid]) to give N-(4-(3-(6-morpholinopyridin-2-yl)-1,2,4-oxadiazol-5-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)methanesulfonamide (compound 163, 46 mg).

[0321] Example 17. Synthesis of N-(4-(5-(6-morpholinopyridin-2-yl)-1,2,4-oxadiazol-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)methanesulfonamide (Compound 164) [ka] Step 1. A mixture of 2-fluoro-4-nitrobenzonitrile (2.0 g, 12 mmol) and NHOH hydrochloride (2.6 g, 37 mmol), EtOH (18 mL), and NaHCO (3.2 g, 38 mmol) in 1.5 mL of HO. The mixture was stirred at 85 °C for 6 h and concentrated to remove EtOH. The residue was dissolved in EtOAc (30 mL), and the solution was washed with water (15 mL), dried over NaSO, filtered, concentrated, and triturated with iPrOH (10 mL) at 0 °C for 20 min. The suspension was filtered, and the filter cake was washed with chilled iPrOH (1 mL × 3) and dried under reduced pressure to give 2-fluoro-N'-hydroxy-4-nitrobenzimidamide (E17.01, 1.9 g).

[0322] Step 2. A mixture of E17.01 (1.3 g, 6.5 mmol), THF (60 mL), and NaOEt (2.0 g, 29 mmol) was stirred at 20 °C for 15 minutes. 6-Morpholinopicolinoyl chloride hydrochloride (2.0 g, 7.6 mmol) was added portionwise. The mixture was stirred at 80 °C for 12 hours, diluted with THF (80 mL) and EtOAc (50 mL), and 2 M HCl was added until the pH was neutral. The organic phase was washed with brine (50 mL × 2), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0-80% in PE [1:1 EtOAc / THF]) to give 4-[6-[3-(2-fluoro-4-nitro-phenyl)-1,2,4-oxadiazol-5-yl]-2-pyridyl]morpholine (E17.02, 1 g).

[0323] Step 3. A mixture of E17.02 (0.60 g, 1.6 mmol) and 6-azaspiro[2.5]octane hydrochloride (0.60 g, 4.1 mmol), NMP (12 mL), and KCO (1.1 g, 8.1 mmol) was stirred at 120 °C for 12 h. HO (36 mL) was added dropwise, and the resulting mixture was filtered and washed with water (5 mL × 3). The filter cake was dissolved in EtOAc (40 mL), washed with brine (10 mL), concentrated, and triturated with MTBE (5 mL) at 20 °C for 15 min. The suspension was filtered, and the filter cake was washed with MTBE (3 mL × 2) and dried to give 4-(6-(3-(4-nitro-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-1,2,4-oxadiazol-5-yl)pyridin-2-yl)morpholine (E17.03, 0.31 g).

[0324] Step 4. A mixture of E17.03 (0.30 g, 0.65 mmol), SnCl dihydrate (1.7 g, 7.5 mmol), THF (7 mL), and EtOH (20 mL) was stirred at 100 °C for 12 hours. Saturated NaHCO (60 mL) was added, and the resulting suspension was filtered through Celite. The filtrate was extracted with 50 mL of EtOAc (50 mL), and the extract was concentrated and purified by silica chromatography (0-40% MeOH in CHCl) to give 4-(5-(6-morpholinopyridin-2-yl)-1,2,4-oxadiazol-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)aniline (E17.04, 80 mg).

[0325] Step 5. To a mixture of E17.04 (60 mg, 0.14 mmol), CHCl (3 mL), and EtN (42 mg, 0.42 mol) was added MsCl (50 mg, 0.44 mmol), and the mixture was stirred at 20 °C for 1 hour. HO (5 mL) was added, and the mixture was extracted with CHCl (10 mL). The extract was washed with brine (5 mL), filtered, concentrated, and purified by preparative TLC (SiO, 8:1 CHCl / MeOH) to give N-(4-(5-(6-morpholinopyridin-2-yl)-1,2,4-oxadiazol-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)methanesulfonamide (Compound 164, 2.1 mg).

[0326] Table 6G describes the chromatographic separation of the isomers for certain examples. [Table 23] [Table 24-1] [Table 24-2] [Table 24-3] [Table 24-4] Table 24-5 Table 24-6 Table 24-7 Table 24-8 Table 24-9 Table 24-10 Table 24-11 Table 24-12 Table 24-13 Table 24-14 Table 24-15 Table 24-16 Table 24-17 Table 24-18 Table 24-19 Table 24-20 Table 24-21 Table 24-22 Table 24-23 Table 24-24 Table 24-25 Table 24-26 Table 24-27 Table 24-28 Table 24-29 Table 24-30 Table 24-31 Table 24-32 Table 24-33 Table 24-34 Table 24-35 Table 24-36 Table 24-37 [Table 24-38] [Table 24-39] [Table 24-40] [Table 24-41] [Table 24-42] [Table 24-43] [Table 24-44] [Table 24-45] [Table 24-46] [Table 24-47] [Table 24-48] [Table 24-49] [Table 24-50] [Table 24-51]

[0327] Biological assays Inhibition of KIF18A microtubule-dependent ATPase activity Test compounds were added to a 384-well plate in a 3-fold dilution scheme. Assay buffer: 80 mM PIPES (pH 6.9), 1 mM MgCl, 75 mM KCl, 1 mM EGTA, 1 mM DTT, 0.01% BSA, 0.005% Tween-20, 1 μM Taxol in HO. To 50 nL of compound in DMSO, 2.5 μL of enzyme mix (4 nM hKIF18A(1-374) in assay buffer) was added. After 30 minutes of incubation at room temperature, 2.5 μL of microtubule mix (0.2 mg / mL preformed microtubules, 2.0 mM ATP in assay buffer) was added, the plate was centrifuged for 30 seconds, and then incubated at 28°C for 60 minutes. 5 μL of Promega® ADP-Glo ​​Max R1 was added, the plate was centrifuged for 30 seconds, and the mixture was incubated at room temperature for 4 hours. 10 μL of Promega® ADP-Glo ​​Max R2 was added, the plate was centrifuged for 30 seconds, and incubated at room temperature for 60 minutes. Luminescence was measured on an Envision plate reader, and the % inhibition for each well was calculated as ([max-min]-[test-min]) / [max-min]. IC50 values ​​were calculated from the concentration-coupled % inhibition data via a four-parameter variable slope model. Results from the biological assays are summarized in Table 8.

[0328] Table 8 shows that the compounds provided herein are potent inhibitors of KIF18a. In comparison, the data for AMG650 (2-{6-azaspiro[2.5]octan-6-yl}-N-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-4-(2-hydroxyethanesulfonamido)benzamide) is 17 nM.

[0329] Binding kinetics to the KIF18a-microtubule complex Compound binding kinetic parameters (k on and k offThe on-rate k was determined by global progress curve analysis (GPCA). KIF18A (0.25 nM) was incubated with serially diluted compounds in an assay buffer containing 80 mM PIPES, pH 6.9, 1 mM ATP, 0.1 mg / ml preformed microtubules (cytoskeleton) from porcine brain, 1 mM MgCl, 1 μM taxol, 75 mM KCl, 1 mM EGTA, 1 mM DTT, 0.01% BSA, and 0.005% Tween-20 for up to 24 hours. The level of ADP product was determined by the Promega® ADP-Glo ​​assay. The time / dose-dependent progress curves were then globally fitted to a Michaelis-Menten kinetic model with one-step slow binding inhibition to determine the on-rate k. on value and off-rate k off The values ​​were derived from Zhang, R., Wong, K. (2017): “High performance enzyme kinetics of turnover, activation and inhibition for translational drug discovery”, Expert Opinion on Drug Discovery, 2017 Jan;12(1):17-37. doi:10.1080 / 17460441.2017.1245721).

[0330] The results from the binding kinetics assay are summarized in Table 9. The data in Table 9 demonstrate that the compounds provided herein exhibit low off-rates or very long dissociation half-lives (ln(2) / k off ) can achieve subnanomolar potency. By comparison, data for AMG650 (2-{6-azaspiro[2.5]octan-6-yl}-N-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-4-(2-hydroxyethanesulfonamido)benzamide) show that k on =0.059nM -1 h -1 ;k off =0.21h -1 ,dissociation t 1 / 2 =4.1h;K I =3.4nM.

[0331] Cell viability of KIF18a-sensitive cell lines Twenty-four hours before compound treatment, cell lines were seeded as follows: HCC15 (Korean Cell Line Bank), 600 cells / well in 95 μL of RPMI-1640 medium supplemented with 100 units / mL penicillin, 100 units / mL streptomycin, and 10% FBS; NIH:OVCAR-3 (ATCC), 1,000 cells / well in 95 μL of RPMI-1640 medium supplemented with 100 units / mL penicillin, 100 units / mL streptomycin, 0.01 mg / mL bovine insulin, and 20% FBS; and JIMT-1 (Addexbio), 1,000 cells / well in 95 μL of DMEM medium supplemented with 100 units / mL penicillin, 100 units / mL streptomycin, and 10% FBS.

[0332] Test compounds were added to cells in a 20-fold dilution scheme by adding 5 μL of serially diluted compound to the plate, and the treated cells were incubated for an additional 7 days in a 37°C, 5% CO2 incubator. DMSO was used as a negative control (0% effect), and wells without cells were used as positive controls (100% effect). Cells were incubated for 7 days, and cell viability was determined via the Promega Cell Titre-Glo® Assay Kit. Luminescence units were converted to ATP concentration via an ATP standard curve (10 points, 2-fold dilutions from 5 μM). % inhibition for each well was calculated as ([max-min]-[test-min]) / [max-min]). IC values ​​were calculated from concentrations correlated to % inhibition data via a 4-parameter variable slope model. 50 The values ​​were calculated. The results from the biological assays are summarized in Table 10.

[0333] Table 10 shows that the compounds provided herein potently inhibit cell proliferation or induce cell death in KIF18a-sensitive cancer cell lines. For comparison, the data for AMG650 (2-{6-azaspiro[2.5]octan-6-yl}-N-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-4-(2-hydroxyethanesulfonamido)benzamide) are: HCC-15, 0.066 μM; JIMT-1, 0.13 μM; NIH:OVCAR3, 0.10 μM. [Table 25-1] [Table 25-2] [Table 25-3] [Table 26]

[0334] a) On-rate from binding kinetics assay. b) Off-rate from binding kinetics assay. c) Dissociation half-life ln(2) / k off d) k of binding kinetics assay off / k on K determined from I . [Table 27-1] [Table 27-2]

[0335] In vivo activity assessment OVCAR-3 (ATCC) tumor cells were maintained in vitro in RPMI-1640 medium supplemented with 20% fetal bovine serum, 0.01 mg / mL bovine insulin, and 1% ATP at 37°C in an atmosphere of 5% CO2 in air. HCC15 (DSMZ) tumor cells were maintained in vitro in RPMI-1640 medium supplemented with 10% fetal bovine serum and 1% ATP at 37°C in an atmosphere of 5% CO2 in air.

[0336] Tumor cells were passaged twice a week. Exponentially growing cells were harvested and counted for tumor inoculum.

[0337] Tumor cells (10 × 10 cells) in 0.2 mL of PBS mixed with Matrigel (50:50) were inoculated subcutaneously into the right flank of each mouse. The mean tumor volume was 110–175 mm. 3 When the sigma-positive cells reached 10, the animals were randomized into groups of 10 and treatment was initiated. Balb / C nude mice were implanted with OVCAR-3 cells, and SCID Beige mice were implanted with HCC15 cells.

[0338] Compounds were administered orally once or twice daily (12 hours). Tumor growth inhibition (TGI) was calculated using the following formula: TGI (%) = [1-(TN-T0) / (VN-V0)] x 100; TN is the mean tumor volume of the treatment group at the indicated time point, T0 is the mean tumor volume of the treatment group on day 0 of treatment, VN is the mean tumor volume of the vehicle control group at the indicated time point, and V0 is the mean tumor volume of the vehicle group on day 0 of treatment. P values ​​were calculated based on tumor size by one-way ANOVA using GraphPad Prism 9.4.0, respectively, compared with the vehicle group. **** indicates p<0.0001.

[0339] Tumor volumes in vehicle-treated and compound-treated mice as a function of time after treatment initiation, and the results of treatment with selected compounds in SCID Beige or nude mice engrafted with HCC15 or OVCAR-3, are shown in Figures 1 and 2. The calculated TGIs...

Claims

1. Compound of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, X and Z are independently O, N, or CH; Y is NH, N, or CH; V and W are independently N or C; Here, at least one of X and Z is N, or Y is NH; Ring A is, 【Chemistry 2】 And here, A １ , A ３ , and A ４ , one, two, or three of which are independently N, NR Ａ１ , O, or S, and when present, A １ , A ３ , and A ４ , the remaining one or two of which are independently CH or CR ２ , where R Ａ１ is H or C １～３ alkyl; A ２ is N or C; A ５ ~A ８ CH and CR are independent. ２ , N, or NR Ａ２ And here A ５ A ６ A ７ , and A ８ At least two of them are CH or CR ２ And if it exists, A ５ A ６ A ７ , and A ８ Of these, one or two are N or NR Ａ２ And here R Ａ２ ga = O; Here, "*" indicates the connection point to V; B １ and B ２ Each is independently N, CH, or CR Ｂ And here R Ｂ It is a halogen; R １ C １～６ Alkyl, C ３～６ Cycloalkyl, C ３～１０ Cycloalkenyl, 3-10 member heterocycloalkyl, -NR ａ１ C(O)NR ａ２ R ａ３ , -NR ａ４ C(O)OR ａ５ , -NR ａ６ R ａ７ -N=S(O)R ａ８ R ａ９ , -OR ａ１０ , -S(O)R ａ１１ , -S(O)(NR ａ１２ ) R ａ１３ , -S(O) ２ NR ａ１４ R ａ１５ , -S(O) ２ R ａ１６ , or - (CR ａ１７ R ａ１８ ) ０～１ C(O)NR ａ１９ R ａ２０ And, Here, R １ C １ ~C ６ Alkyls are halogens, -OH, oxo, cyano, and C. ３～１０ Optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyls and 3- to 10-membered heterocycloalkyls optionally substituted with one or more halos; where R １ C ３～６ The cycloalkyl group is optionally substituted with one or more substituents independently selected from the group consisting of halogens; where R １ C ３～１０ The cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogens; and, where R １ The aforementioned 3- to 10-membered heterocycloalkyl group is a halogen, C １～６ Alkyl and C １～６ Optionally substituted with one or more substituents independently selected from the group consisting of haloalkyls; R ａ１ ~R ａ２０ These are, independently, hydrogen and C １～６ Alkyl, C ２～６ Alkenil, C ３～１０ Cycloalkyl, C ３～１０ Cycloalkenyl, 3-10 member heterocycloalkyl, 3-10 member heterocycloalkenyl, C ６～１４ These are aryl groups or 5- to 12-membered heteroaryl groups, respectively, halo, cyano, -OH, and -O(C) １～６ Alkyl), C ２～６ Alkenil, C ３～１０ Cycloalkyl, -S(C １～６ Alkyl), =CR １ａ１ R １ａ２ , as well as halo, -OH, and -O(C) １～６ C (alkyl) is optionally substituted with one or more substituents independently selected from the group consisting of alkyl １～６ R is optionally substituted with one or more substituents independently selected from the group consisting of alkyl groups, where R １ａ１ and R １ａ２ Each is independently either hydrogen or C １～６ It is alkyl; or, R ａ１４ and R ａ１５ These, together with the nitrogen to which they are bound, form a 3- to 10-membered heterocycloalkyl group optionally substituted with one or more halos; Each R ２ is independently halogen, C １～３ alkyl, C ３～５ cycloalkyl, cyano, C １～３ alkyloxy, C ３～５ cycloalkyloxy, hydroxy, or NR ｂ１ R ｂ２ wherein the C ２ alkyl of R １～３ is optionally substituted with one or more substituents selected from the group consisting of -OH and oxo, wherein R ｂ１ and R ｂ２ are independently optionally substituted with C １ -C ３ alkyl, or R ｂ１ and R ｂ２ together with the nitrogen to which they are attached form a 3- to 6-membered ring; or A ５ R １ and R ２ Together with the carbon atoms to which they are bonded, C ３ ~C ６ Forming cycloalkyl or 3- to 10-membered heterocycloalkyl groups; R ３ is piperidinil, pyrrolidinil, or azepanil, where piperidinil, pyrrolidinil, or azepanil is C ３～１０ Optionally substituted with a cycloalkyl or a 3- to 10-membered heterocycloalkyl, where C ３～１０ Cycloalkyls or 3- to 10-membered heterocycloalkyls form spirocyclic or fused bicyclic ring systems with piperidinyl, pyrrolidinyl, or azepanyl, or Here, piperidinil, pyrrolidinil, or azepanil may optionally be C １～２ Substituted with alkylene to form a crosslinked piperidinyl, pyrrolidinyl, or azepanyl ring system, where the piperidinyl, pyrrolidinyl, azepanyl, or C ３～１０ Cycloalkyl groups, 3-10 member heterocycloalkyl groups, or C １～２ The spirocyclic, condensed, or crosslinked bicyclic ring system formed by alkylene and piperidinil, pyrrolidinil, or azepanil is C １ ~C ３ Alkyl, C １ ~C ３ Optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl and halo; R ４ H, halo, cyano, -OH, -NO ２ , -C(O)NR ｃ１ R ｃ２ , -NR ｃ３ R ｃ４ , -NR ｃ５ S(O) ２ R ｃ６ ,-P(O)R ｃ７ R ｃ８ -N=S(O)R ｃ９ R ｃ１０ , -S(O)(NR ｃ１１ ) R ｃ１２ , -S(O) ２ R ｃ１３ or C optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH １～６ It is alkyl, Here, if X is N, Y is N, and Z is O, then R ４ It is not H; R ｃ１ ~R ｃ１３ These are hydrogen and C, respectively, independently. ３～１０ Cycloalkyl, or C １～６ It is alkyl, and here, R ｃ１ ~R ｃ１３ Each C １ ~C ６ Alkyl groups include halo, -OH, and -C(O)-O-C １ ~C ３ It is optionally substituted with one or more substituents independently selected from the group consisting of alkyl groups, where each C ３～１０ Cycloalkyl is C １ ~C ６ The compound, or a pharmaceutically acceptable salt thereof, optionally substituted with one or more substituents independently selected from the group consisting of alkylene-OH groups.

2. The ring 【Transformation 3】 but, 【Chemistry 4】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (I-a), (I-b), or (I-c). 【Transformation 5】

4. Ring A 【Transformation 6】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

5. Ring A is 【Transformation 7】 【change】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6. Ring A is 【Transformation 8】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

7. Ring A is 【Chemistry 9】 【change】 【change】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

8. R １ However, C １～６ Alkyl, C ３～６ Cycloalkyl, C ３～１０ Cycloalkenyl, 3-10 member heterocycloalkyl, -NR ａ６ R ａ７ , -OR ａ１０ , -S(O) ２ NR ａ１４ R ａ１５ , or -S(O) ２ R ａ１６ And here, R １ C １ ~C ６ Alkyls are halogens, -OH, oxo, cyano, and C. ３～１０ Optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyls and 3- to 10-membered heterocycloalkyls optionally substituted with one or more halos; where R １ C ３～６ The cycloalkyl group is optionally substituted with one or more substituents independently selected from the group consisting of halogens; where R １ C ３～１０ The cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogens; and, where R １ The aforementioned 3- to 10-membered heterocycloalkyl group is a halogen, C １～６ Alkyl and C １～６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, optionally substituted with one or more substituents independently selected from the group consisting of haloalkyls.

9. R １ but, 【Chemistry 10】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

10. The ring 【Chemistry 11】 but, 【Chemistry 12】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

11. R ３ is piperidinyl, and the piperidinyl is C ３～１０ Optionally substituted with a cycloalkyl or a 3- to 10-membered heterocycloalkyl, where C ３～１０ A cycloalkyl or a 3- to 10-membered heterocycloalkyl may form a spirocyclic or fused bicyclic ring system with piperidinyl, or the piperidinyl may optionally be C １～２ Substituted with alkylene to form a crosslinked piperidinyl ring system, where the piperidinyl or the C ３～１０ Cycloalkyl groups, 3-10 member heterocycloalkyl groups, or C １～２ The spirocyclic, condensed, or bridging bicyclic ring system formed by alkylene and piperidinyl is C １ ~C ３ Alkyl, C １ ~C ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl and halo.

12. R ３ This is pyrrolidinyl, and the pyrrolidinyl is C ３～１０ Optionally substituted with a cycloalkyl or a 3- to 10-membered heterocycloalkyl, where C ３～１０ A cycloalkyl or a 3- to 10-membered heterocycloalkyl may form a spirocyclic or fused bicyclic ring system with the pyrrolidinyl, or the pyrrolidinyl may optionally be C １～２ Substituted with alkylene to form a crosslinked pyrrolidinyl ring system, where the pyrrolidinyl or the C ３～１０ Cycloalkyl groups, 3-10 member heterocycloalkyl groups, or C １～２ The spirocyclic, condensed, or crosslinked bicyclic ring system formed by the alkylene and the pyrrolidinyl is C １ ~C ３ Alkyl, C １ ~C ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl and halo.

13. R ３ is azepanil, and the azepanil is C ３～１０ Optionally substituted with a cycloalkyl or a 3- to 10-membered heterocycloalkyl, where C ３～１０ A cycloalkyl or a 3- to 10-membered heterocycloalkyl may form a spirocyclic or fused bicyclic ring system with the azepanyl, or the azepanyl may optionally be C １～２ Substituted with alkylene to form a crosslinked azepanyl ring system, where the azepanyl or the C ３～１０ Cycloalkyl, 3-10 member heterocycloalkyl, or C １～２ The spirocyclic, condensed, or crosslinked bicyclic ring system formed by alkylene and azepanyl is C １ ~C ３ Alkyl, C １ ~C ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl and halo.

14. R ３ teeth, 【Chemistry 13】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

15. R ４ However, hydrogen, halo, or -NR ｃ５ S(O) ２ R ｃ６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is -NR c5 S(O) 2 R c6.

17. R ４ However, H, Br, 【Chemistry 14】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

18. Compound of formula (III) 【Chemistry 15】 or a pharmaceutically acceptable salt thereof, Ring A is, 【Chemistry 16】 And here, A １ A ３ , and A ４ One, two, or three of these independently constitute N, NR Ａ１ , O, or S, and if present, A １ A ３ , and A ４ Of these, one or two independently become CH or CR ２ And here, R Ａ１ is H or C １～３ It is alkyl; A ２ is N or C; A ５ ~A ８ CH and CR are independent. ２ , N, or NR Ａ２ And here, A ５ A ６ A ７ , and A ８ At least two of them are CH or CR ２ And if it exists, A ５ A ６ A ７ , and A ８ Of these, one or two are N or NR Ａ２ And here R Ａ２ ga = O; Here, "*" indicates the connection point to V; B １ and B ２ Each is independently N, CH, or CR Ｂ And here R Ｂ It is a halogen; R １ C １～６ Alkyl, C ３～６ Cycloalkyl, C ３～１０ Cycloalkenyl, 3-10 member heterocycloalkyl, -NR ａ１ C(O)NR ａ２ R ａ３ , -NR ａ４ C(O)OR ａ５ , -NR ａ６ R ａ７ -N=S(O)R ａ８ R ａ９ , -OR ａ１０ , -S(O)R ａ１１ , -S(O)(NR ａ１２ ) R ａ１３ , -S(O) ２ NR ａ１４ R ａ１５ , -S(O) ２ R ａ１６ , or - (CR ａ１７ R ａ１８ ) ０～１ C(O)NR ａ１９ R ａ２０ And, Here, R １ C １ ~C ６ Alkyls are halogens, -OH, oxo, cyano, and C. ３～１０ Optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyls and 3- to 10-membered heterocycloalkyls optionally substituted with one or more halos; where R １ C ３～６ The cycloalkyl group is optionally substituted with one or more substituents independently selected from the group consisting of halogens; where R １ C ３～１０ The cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogens; and, where R １ The aforementioned 3- to 10-membered heterocycloalkyl group is a halogen, C １～６ Alkyl and C １～６ Optionally substituted with one or more substituents independently selected from the group consisting of haloalkyls; R ａ１ ~R ａ２０ These are, independently, hydrogen and C １～６ Alkyl, C ２～６ Alkenil, C ３～１０ Cycloalkyl, C ３～１０ Cycloalkenyl, 3-10 member heterocycloalkyl, 3-10 member heterocycloalkenyl, C ６～１４ These are aryl groups or 5- to 12-membered heteroaryl groups, respectively, halo, cyano, -OH, and -O(C) １～６ Alkyl), C ２～６ Alkenil, C ３～１０ Cycloalkyl, -S(C １～６ Alkyl), =CR １ａ１ R １ａ２ , as well as halo, -OH, and -O(C) １～６ C (alkyl) is optionally substituted with one or more substituents independently selected from the group consisting of alkyl １～６ R is optionally substituted with one or more substituents independently selected from the group consisting of alkyl groups, where R １ａ１ and R １ａ２ Each is independently either hydrogen or C １～６ Is it alkyl; or R ａ１４ and R ａ１５ These, together with the nitrogen to which they are bound, form a 3- to 10-membered heterocycloalkyl group optionally substituted with one or more halos; Each R ２ These are halogens and C １～３ Alkyl, C ３～５ Cycloalkyl, cyano, C １～３ Alkyloxy, C ３～５ Cycloalkyloxy, hydroxy, or NR ｂ１ R ｂ２ And here, R ２ C １～３ The alkyl group is optionally substituted with one or more substituents selected from the group consisting of -OH and oxo, where R ｂ１ and R ｂ２ C is independent １ ~C ３ It can be optionally substituted with alkyl, or R ｂ１ and R ｂ２ They either form a 3- to 6-membered ring together with the nitrogen to which they are bonded; or A ５ R １ and R ２ Together with the carbon atoms to which they are bonded, C ３ ~C ６ Forming cycloalkyl or 3- to 10-membered heterocycloalkyl groups; Here, each R ｄ１ C １ ~C ３ Alkyl, C １ ~C ３ Independently selected from the group consisting of haloalkyl and halo, or two R ｄ１ together C ３～１０ A cycloalkyl or 3- to 10-membered heterocycloalkyl is formed, where the C ３～１０ Cycloalkyl or 3- to 10-membered heterocycloalkyl groups form a spirocyclic or fused bicyclic ring system with piperidinyl, or two R groups. ｄ１ together C １～２ Forms alkylene, and the C １～２ Alkylenes form a cross-linked piperidinyl ring system. Here, C ３～１０ Cycloalkyl groups, 3-10 member heterocycloalkyl groups, or C １ ~ ２ The spirocyclic, condensed, or crosslinked bicyclic ring system formed by the alkylene and the piperidinil is C １ ~C ３ Alkyl, C １ ~C ３ Optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl and halo; R ４ H, halo, cyano, -OH, -NO ２ , -C(O)NR ｃ１ R ｃ２ , -NR ｃ３ R ｃ４ , -NR ｃ５ S(O) ２ R ｃ６ ,-P(O)R ｃ７ R ｃ８ -N=S(O)R ｃ９ R ｃ１０ , -S(O)(NR ｃ１１ ) R ｃ１２ , -S(O) ２ R ｃ１３ or C optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH １～６ It is alkyl, R ｃ１ ~R ｃ１３ These are hydrogen and C, respectively, independently. ３～１０ Cycloalkyl, or C １～６ It is alkyl, and here, R ｃ１ ~R ｃ１３ Each C １ ~C ６ Alkyl groups include halo, -OH, and -C(O)-O-C １ ~C ３ It is optionally substituted with one or more substituents independently selected from the group consisting of alkyl groups, where each C ３～１０ Cycloalkyl is C １ ~C ６ The compound, or a pharmaceutically acceptable salt thereof, optionally substituted with one or more substituents independently selected from the group consisting of alkylene-OH groups.

19. Compound of formula (II): 【Chemistry 17】 or a pharmaceutically acceptable salt thereof, X and Z are independently O, N, or CH; Y is either NH or CH; V and W are independently N or C; Here, at least one of X and Z is N, or Y is NH; Ring A is, [Chemistry 18] And here, A １ A ３ , and A ４ One or two of these are independently N, O, or S, and A １ A ３ , and A ４ Of these, one or two independently become CH or CR ２ And; A ２ is N or C; A ５ ~A ８ CH and CR are independent. ２ , or N, where A ５ A ６ A ７ , and A ８ At least two of them are CH or CR ２ And if it exists, A ５ A ６ A ７ , and A ８ One or two of the remaining ones are N; Here, "*" indicates the connection point to V; B １ and B ２ Each is independently N or CH; R １ C １～６ Alkyl, C ３～６ Cycloalkyl, 3-10 member heterocycloalkyl, -NR ａ１ C(O)NR ａ２ R ａ３ , -NR ａ４ C(O)OR ａ５ , -NR ａ６ R ａ７ -N=S(O)R ａ８ R ａ９ , -OR ａ１０ , -S(O)R ａ１１ , -S(O)(NR ａ１２ ) R ａ１３ , -S(O) ２ NR ａ１４ R ａ１５ , -S(O) ２ R ａ１６ , or - (CR ａ１７ R ａ１８ ) ０～１ C(O)NR ａ１９ R ａ２０ And, Here, R １ C １ ~C ６ Alkyl compounds include halogens, -OH, cyano, and C. ３～１０ Optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyls and 3- to 10-membered heterocycloalkyls optionally substituted with one or more halos; where R １ C ３～６ The cycloalkyl group is optionally substituted with one or more substituents independently selected from the group consisting of halogens; where R １ The aforementioned 3- to 10-membered heterocycloalkyl group is optionally substituted with one or more halogens; R ａ１ ~R ａ２０ These are, independently, hydrogen and C １～６ Alkyl, C ２～６ Alkenil, C ３～１０ Cycloalkyl, C ３～１０ Cycloalkenyl, 3-10 member heterocycloalkyl, 3-10 member heterocycloalkenyl, C ６～１４ These are aryl groups or 5- to 12-membered heteroaryl groups, respectively, halo, cyano, -OH, and -O(C) １～６ Alkyl), C ２～６ Alkenil, C ３～１０ Cycloalkyl, -S(C １～６ Alkyl), =CR １ａ１ R １ａ２ , as well as halo, -OH, and -O(C) １～６ C (alkyl) is optionally substituted with one or more substituents independently selected from the group consisting of alkyl １～６ R is optionally substituted with one or more substituents independently selected from the group consisting of alkyl groups, where R １ａ１ and R １ａ２ Each is independently either hydrogen or C １～６ Is it alkyl? Alternatively, R ａ１４ and R ａ１５ These, together with the nitrogen to which they are bound, form a 3- to 10-membered heterocycloalkyl group optionally substituted with one or more halos; Each R ２ These are halogens and C １～３ Alkyl, C ３～５ Cycloalkyl, cyano, C １～３ Alkyloxy, C ３～５ Cycloalkyloxy, hydroxy, or NR ｂ１ R ｂ２ And here, R ｂ１ and R ｂ２ C is independent １ ~C ３ It can be optionally substituted with alkyl, or R ｂ１ and R ｂ２ They either form a 3- to 6-membered ring together with the nitrogen to which they are bonded; or A ５ R １ and R ２ Together with the carbon atoms to which they are bonded, C ３ ~C ６ Forming cycloalkyl or 3- to 6-membered heterocycloalkyl groups; R ３ is piperidinil, pyrrolidinil, or azepanil, where piperidinil, pyrrolidinil, or azepanil is C ３～１０ Optionally substituted with a cycloalkyl or a 3- to 10-membered heterocycloalkyl, where C ３～１０ A cycloalkyl or a 3- to 10-membered heterocycloalkyl forms a spirocyclic or condensed bicyclic ring system with piperidinyl, pyrrolidinyl, or azepanyl. Here, piperidinil, pyrrolidinil, azepanil, or C ３～１０ The spirocyclic or fused bicyclic ring system formed by a cycloalkyl or a 3- to 10-membered heterocycloalkyl and piperidinyl, pyrrolidinyl, or azepanyl is C １ ~C ３ Alkyl and C １ ~C ３ Optionally substituted with one or more substituents independently selected from the group consisting of haloalkyls; R ４ These are hydrogen, halo, cyano, -OH, and -NO. ２ , -C(O)NR ｃ１ R ｃ２ , -NR ｃ３ R ｃ４ , -NR ｃ５ S(O) ２ R ｃ６ ,-P(O)R ｃ７ R ｃ８ -N=S(O)R ｃ９ R ｃ１０ , -S(O)(NR ｃ１１ ) R ｃ１２ , -S(O) ２ R ｃ１３ or C optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH １～６ It is alkyl, R ｃ１ ~R ｃ１３ These are hydrogen and C, respectively, independently. ３～１０ Cycloalkyl, or C １～６ It is alkyl, and here, R ｃ１ ~R ｃ１３ Each C １ ~C ６ Alkyl groups include halo, -OH, and -C(O)-O-C １ ~C ３ The compound, or a pharmaceutically acceptable salt thereof, optionally substituted with one or more substituents independently selected from the group consisting of alkyl groups.

20. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of the compounds in Table 1.

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

22. A method for inhibiting KIF18A, comprising contacting cells with an effective amount of a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof (excluding medical procedures on humans).

23. A pharmaceutical composition for treating a disease or condition mediated by KIF18A, comprising a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition for treating cancer in a person requiring cancer treatment, comprising a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof.

25. The pharmaceutical composition according to claim 24, wherein the cancer is selected from the group consisting of carcinoma, cancer of the anus, bladder, breast, colon, small intestine, appendix, kidney, renal pelvis, ureter, urothelium, liver, lung, pleura, esophagus, head and neck, nasopharynx, oropharynx, hypopharynx, oral cavity, larynx, biliary tract, gallbladder, ovary, testis, germ cell, uterus, pancreas, stomach, cervix, thyroid gland, prostate, salivary gland, or skin, hematopoietic malignancies of the lymphoid lineage, hematopoietic malignancies of the myeloid lineage, hematopoietic malignancies of any lineage, mesenchymal tumors including myeloma, sarcoma, tumors of the central and peripheral nervous systems, neuroendocrine tumors, endocrine tumors, small cell tumors, tumors of unknown primary origin, other tumors including retinoblastoma, melanoma, seminomas, teratocarcinoma, osteosarcoma, and other cancer-related disorders resulting from the presence or progression of cancer.

26. A method for synthesizing a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, comprising the following steps: (1) Compound of formula (A): 【Chemistry 19】 Compound of formula (B): 【Chemistry 20】 When brought into contact with, a compound of formula (C) or (I): 【Chemistry 21】 (In the formula, Y is NH, X is N, and Z is N) The process of generating; (2) Compound of formula (D): 【Chemistry 22】 The compound of formula (A): 【Chemistry 23】 The process of converting; (3) Compound of formula (E): 【Chemistry 24】 Compound of formula (Ba): 【Chemistry 25】 The process of converting; (4) Compound of formula (F): 【Chemistry 26】 Compound of formula (Bb): 【Chemistry 27】 The process of converting; (5) Compound of formula (G): 【Chemistry 28】 The compound of formula (H): 【Chemistry 29】 When brought into contact with, a compound of formula (J) or (I): 【Transformation 30】 (In the formula, Y is NH and Z is N) The process of generating; (6) Compound of formula (K): 【Chemistry 31】 Compound of formula (L): 【Chemistry 32】 When brought into contact with, a compound of formula (M) or (I): 【Transformation 33】 (In the formula, Y is CH, X is N, Z is N, and W is N) The process of generating; (7) Compounds of formula (C), (J), or (M): 【Transformation 34】 The compound of formula (I) 【change】 The process of converting; (8) Compounds of formula (C), (J), or (M): 【Chemistry 35】 The compound of formula (I): 【Transformation 36】 The process of converting; (9) Compound of formula (N): 【Chemistry 37】 Compound of formula (O): 【Transformation 38】 The process of converting; (10) Compound of formula (O): 【Chemistry 39】 The compound of formula (I): 【Chemistry 40】 The process of converting to; or (11) Compound of formula (P): 【Chemistry 41】 The compound of formula (I): 【Chemistry 42】 The process of converting to; or Any combination of the above steps (1) to (10) The above method, including.

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