Spiroindoline inhibitors of KIF18A

Abstract

The present disclosure relates generally to inhibitors of KIF18A, compositions thereof, and methods of using said compounds and compositions thereof. More specifically, the present disclosure relates to indoline inhibitors of KIF18A and methods of using them to treat KIF18A-mediated diseases, such as cancer. [Formula 1] TIFF2024534840000455.tif55170

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 / 237,275, filed August 26, 2021, U.S. Provisional Patent Application No. 63 / 306,452, filed February 3, 2022, and U.S. Provisional Patent Application No. 63 / 344,435, filed May 20, 2022, the disclosures of which are incorporated herein by reference in their entireties.

[0002] The present disclosure relates generally to inhibitors of KIF18A, compositions thereof, and methods of using said compounds and compositions thereof. More specifically, the present disclosure relates to indoline 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 kinetophore complex), further enhancing kt-MT attachment throughout metaphase and anaphase. Its MT-binding motor domain possesses ATPase activity and 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), compositions thereof, and methods of using said compounds and compositions thereof for the treatment of diseases or conditions associated with KIF18a. In one aspect, provided is a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein ring A is independently selected from halo, —OH, C 1-6 Alkyl, 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 , -(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 , -SR a21 , -C(O)R a22 , and -OH, cyano, C 3-10 C 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. 1-6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 6-14 aryl or 5-12 membered heteroaryl; R a1 -R a22 are each independently hydrogen, or each independently 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 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 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 5-12 membered heteroaryl, where R 1a1 and R 1a2 are each independently hydrogen or C 1-6 ring B is a C alkyl group in which one or two ring atoms are each oxygen and the remaining ring atoms are each carbon; 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl; each R B The groups are independently halo, one or more halo, or C 2-6 C optionally substituted with alkenyl 1-6 alkyl; or two adjacent R B The groups, together with the carbon atoms to which they are attached, form C 3-10 Forming a cycloalkyl; or two geminal R B The groups, together with the carbon atoms to which they are attached, form C 3-10 forms a cycloalkyl; m is 0, 1, 2, 3, or 4 ;Y 1 is N or CR C1 and;Y 2 is N or CR C2 and;Y 3 is N or CR C3 and;Y 4 is N or CR C4 and Y 1 , Y 2 , Y 3 , and Y 4 3 or less is N; R C1 -R C4 are each independently hydrogen, halo, cyano, -OH, -NO2, or -C(O)NR c1 R c2 , -NR c3 R c4 , -NRc5 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 , -NR c14 C(O)OR c15 , -NR c16 S(O)2(CH2) 1-6 NR c17 C(O)R c18 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 c18 are independently hydrogen, C 3-10 C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halo, and —OH; 1-6 It is alkyl.

[0005] In another aspect, provided is a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein ring A is: [ka] where (1) Z 4 When is hydrogen, Z 1 and Z 3 At least one of them is R D and (2) Z 4 R D When Z 1 is R D Under the condition that 1 , Z 2 , Z 3 , and Z 4 are each independently hydrogen or R D In this case, R D is halo, -OH, -NR a4 C(O)ORa5 , -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 , -(CR a17 R a18 ) 0-1 C(O)NR a19 Ra 20 , -SR a21 , -C(O)R a22 , -P(O)(R a23 )(Ra 24 ), -C=NR a25 , or -OH, cyano, C 3-10 cycloalkyl and one or more halo or C 1-3 C substituted with one or more substituents independently selected from the group consisting of 3-10 membered heterocycloalkyl optionally substituted with alkyl 1-6 or (ii) is alkyl; [ka] In this case, [ka] is a single or double bond, and Z 5 is CH, N, O, S, or NX, where X is H or C 1-6 is alkyl, and Z 6 Ha-NR a26 C(O)NR a27 R a28 , -NR a29 C(O)OR a30 , -N=S(O)R a31 R a32 , -S(O)R a33 , -S(O)(NR a34 )R a35 , -S(O)NR a36 R a37 , -S(O)2Ra38 , -SR a39 , 3-10 membered heterocycloalkyl, -C(O)R a40 or -CH(Z 7 )(Z 8 ) and Z 7 is hydrogen or -OH, and Z 8 is C 1-6 alkyl, C optionally substituted with one or more halo 3-10 cycloalkyl, or 3-10 membered heterocycloalkyl optionally substituted with one or more halo, and ring C is one or more R E a 5- or 6-membered heteroaryl optionally substituted with substituents, wherein each R E The substituents are halo, -OH, and C 1-6 or two R E The substituents, together with the atoms to which they are attached, form C 5-6 Cycloalkyl, C 5-6 R forms a cycloalkenyl, a 5-6 membered heterocycloalkyl, a 5-6 membered heterocycloalkenyl, or a 5-6 membered heteroaryl; a4 -R a40 are each independently hydrogen, or each independently 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 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 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 5-12 membered heteroaryl, wherein R 1a1 and R 1a2are each independently hydrogen or C 1-6 ring B is a C alkyl group in which one or two ring atoms are each oxygen and the remaining ring atoms are each carbon; 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl; each R B The groups are independently halo or C optionally substituted with one or more halo. 1-6 or two alkyl groups Adjacent R B The groups, together with the carbon atoms to which they are attached, form C 3-10 Forming a cycloalkyl; or two geminal R B The groups, together with the carbon atoms to which they are attached, form C 3-10 Forming a cycloalkyl; or two geminal R B The base is together =CR 1a3 R 1a4 group, wherein R 1a3 and R 1a4 are each independently hydrogen or C 1-6 alkyl; m is 0, 1, 2, 3, or 4; Y 1 is N or CR C1 and;Y 2 is N or CR C2 and;Y 3 is N or CR C3 and;Y 4 is N or CR C4 and;Y 1 , Y 2 , Y 3 , and Y 4 3 or less is N; R C1 -R C4 are each independently hydrogen or R F In this case, R F are 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 c9R c10 , -S(O)(NR c11 )R c12 , -S(O)2R c13 , -NR c14 C(O)OR c15 , -NR c16 S(O)2(CH2) 1-6 NR c17 C(O)R c18 , -OS(O)2R c19 or C substituted with one or more substituents independently selected from the group consisting of halo and —OH 1-6 alkyl, and R c1 -R c19 are independently hydrogen, C 3-10 Cycloalkyl, or halo, -O(C 1-6 alkyl), -NHC(O)(C 1-6 C optionally substituted with one or more substituents independently selected from the group consisting of -alkyl, -C ... 1-6 (1) When ring B is unsubstituted cyclopentyl, ring A is [ka] In this case, Z 1 -Z 4 at least one of is -S(O)2-(3-10 membered heterocycloalkyl) substituted with one or more halo, (2) ring B is unsubstituted cyclohexyl and ring A is [ka] When R C1 -R C4 At least one of F and (3) Ring B is R 1 to 4 B When ring A is a 5- to 7-membered heterocycloalkyl optionally substituted with [ka] In this case, Z 1 -Z 4is -S(O)2-(3-10 membered heterocycloalkyl) optionally substituted with one or more halo.

[0006] In another aspect, provided is a pharmaceutical composition comprising a compound of Formula (I), Formula (I-1), Formula (Ia1), Formula (Ia2), Formula (I-3), Formula (Ia1), Formula (Ia2) or Formula (II) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0007] 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.

[0008] 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. [Brief explanation of the drawings]

[0009] [Figure 1A] 1 shows a graph of tumor volume in vehicle- and compound-treated mice plotted as a function of time after the start of treatment. 1 shows compound 22 (10 mg / kg BID, 30 mg / kg BID, 60 mg / kg BID) treatment of SCID Beige mice implanted with HCC15. [Figure 1B] Graphs of tumor volume in vehicle- and compound-treated mice plotted as a function of time after the start of treatment are shown. Compound 22 (10 mg / kg QD, 30 mg / kg QD, 60 mg / kg QD) treatment of OVCAR-3-implanted Balb / C nude mice is shown. [Figure 1C]1 shows a graph of tumor volume in vehicle- and compound-treated mice plotted as a function of time after the start of treatment. 1 shows compound 134 (10 mg / kg BID, 30 mg / kg BID, 60 mg / kg BID) treatment of SCID Beige mice implanted with HCC15. [Figure 1D] Graphs of tumor volume in vehicle- and compound-treated mice plotted as a function of time after the start of treatment are shown. Compound 134 (10 mg / kg BID, 30 mg / kg BID, 60 mg / kg BID) treatment of OVCAR-3-implanted Balb / C nude mice is shown. [Figure 1E] Graphs of tumor volume in vehicle- and compound-treated mice plotted as a function of time after the start of treatment are shown. Compound 134 (30 mg / kg BID, 30 mg / kg QD, 60 mg / kg QD) treatment of OVCAR-3-implanted Balb / C nude mice is shown. DETAILED DESCRIPTION OF THE INVENTION

[0010] 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.

[0011] 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.

[0012] Throughout this application, unless the context indicates otherwise, references to compounds of Formula (I), Formula (I-1), Formula (Ia1), Formula (Ia2), Formula (I-2), Formula (I-3), Formula (Ia1), Formula (Ia2), or Formula (II) include all subgroups defined herein, such as Formula (I-1), (Ia1) or (Ia2), including all substructures, subgenera, preferences, embodiments, examples and specific compounds defined and / or described herein. In some embodiments, references to compounds of Formula (I), Formula (I-1), Formula (Ia1), Formula (Ia2), Formula (I-2), Formula (I-3), Formula (Ia1), Formula (Ia2), or Formula (II) and subgroups thereof, such as, for example, Formula (I-1), Formula (Ia1), or Formula (Ia2), include ionic forms, polymorphs, pseudopolymorphs, amorphous forms, solvates, co-crystals, chelators, 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), Formula (I-1), Formula (Ia1), Formula (Ia2), Formula (I-2), Formula (I-3), Formula (Ia1), Formula (Ia2), or Formula (II) and subgroups thereof, such as, for example, Formula (I-1), Formula (Ia1), or Formula (Ia2), includes polymorphs, solvates, co-crystals, isomers, tautomers, and / or oxides thereof. In some embodiments, a reference to a compound of Formula (I), Formula (I-1), Formula (I-2), Formula (I-3), Formula (Ia1), Formula (Ia2), or Formula (II) and subgroups thereof, such as, for example, Formula (I-1), (Ia1), or (Ia2), includes polymorphs, solvates, and / or co-crystals thereof. In some embodiments, a reference to a compound of Formula (I), Formula (I-1), Formula (I-2), Formula (I-3), Formula (Ia1), Formula (Ia2), or Formula (II) and subgroups thereof, such as, for example, Formula (I-1), (Ia1), or (Ia2), includes isomers, tautomers, and / or oxides thereof. In some embodiments, a reference to a compound of Formula (I), Formula (I-1), Formula (I-2), Formula (I-3), Formula (Ia1), Formula (Ia2), or Formula (II) and subgroups thereof, such as, for example, Formula (I-1), (Ia1), or (Ia2), includes solvates thereof.

[0013] "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 forms 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.

[0014] 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.

[0015] "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).

[0016] "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).

[0017] "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 may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, as well as bridged and cage ring groups (e.g., norbornane, bicyclo[2.2.2]octene). In addition, one ring of a polycyclic cycloalkyl group may 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.

[0018] "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.

[0019] "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.

[0020] "Heteroaryl" refers to an aromatic ring (e.g., a 5- to 12-membered ring or a 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.

[0021] 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.

[0022] 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.

[0023] 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.

[0024] "Heterocycloalkyl" refers to a non-aromatic, fully saturated ring (e.g., a 3-10-membered or 3-7-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. Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide. Furthermore, one ring of a polycyclic heterocycloalkyl group can 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.

[0025] "Heterocycloalkenyl" refers to a non-aromatic ring having the indicated number of atoms (e.g., a 3- to 10-, or 3- to 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.

[0026] 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 through which the moiety is attached to the parent structure.

[0027] "Halogen" or "halo" refers to fluoro, chloro, bromo, and iodo.

[0028] "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.

[0029] 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.

[0030] "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.

[0031] 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.

[0032] 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.

[0033] 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.

[0034] 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 valence-allowed position of that system. 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.

[0035] "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.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] "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.

[0041] It is understood that embodiments described herein as "comprising" include "consisting of" and "consisting essentially of" the embodiment.

[0042] compound 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.

[0043] In one aspect, provided is a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein Ring A is halo, -OH, C 1-6 Alkyl, 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 , -(CR a17 R a18 ) 0-1 C(O)NR a19R a20 , -SR a21 , -C(O)R a22 , and -OH, cyano, C 3-10 C 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. 1-6 C, each optionally substituted with one or more substituents independently selected from the group consisting of alkyl 6-14 is an aryl or a 5-12 membered heteroaryl; R a1 -R a22 are each independently hydrogen, or each independently 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 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 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 5-12 membered heteroaryl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1-6 is alkyl; Ring B is C 5-7 Cycloalkyl, C 5-7 a cycloalkenyl, or a 5-7 membered heterocycloalkyl, wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon; Each R B The groups are independently selected from halo, C optionally substituted with one or more halo. 1-6 Alkyl or C 2-6alkenyl; or two adjacent R B The groups, together with the carbon atoms to which they are attached, form C 3-10 Forming a cycloalkyl; or two geminal R B The groups, together with the carbon atoms to which they are attached, form C 3-10 Forming a cycloalkyl; m is 0, 1, 2, 3 or 4; Y 1 is N or CR C1 and; Y 2 is N or CR C2 and; Y 3 is N or CR C3 and; Y 4 is N or CR C4 and; In the formula, Y 1 , Y 2 , Y 3 and Y 4 of which 3 or less are N; R C1 -R C4 are each independently hydrogen, halo, cyano, -OH, -NO2, or -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 , -NR c14 C(O)OR c15 , -NR c16 S(O)2(CH2) 1-6 NR c17 C(O)R c18 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 c18Each independently represents hydrogen, C 3-10 C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halo, and —OH; 1-6 It is alkyl.

[0044] In one aspect, provided is a compound of formula (I-1): [ka] or a pharmaceutically acceptable salt thereof, wherein Ring A is halo, -OH, C 1-6 Alkyl, 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 , and -(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 C, each optionally substituted with one or more substituents independently selected from the group consisting of 6-14 is an aryl or a 5-12 membered heteroaryl; R a1 -R a20 are each independently hydrogen, or each independently 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 1-6C 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 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 5-12 membered heteroaryl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1-6 is alkyl; Ring B is C 5-7 Cycloalkyl, C 5-7 a cycloalkenyl, or a 5-7 membered heterocycloalkyl, wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon; Each R B The groups are independently halo, C 1-6 Alkyl or C 2-6 alkenyl; or two adjacent R B The groups, together with the carbon atoms to which they are attached, form C 3-10 Forming a cycloalkyl; or two geminal R B The groups, together with the carbon atoms to which they are attached, form C 3-10 Forming a cycloalkyl; m is 0, 1, 2, 3 or 4; Y 1 is N or CR C1 and; Y 2 is N or CR C2 and; Y 3 is N or CR C3 and; Y 4 is N or CR C4 and; In the formula, Y 1 , Y 2 , Y 3 and Y 4 of which 3 or less are N; R C1 -R C4 are each independently hydrogen, halo, cyano, -OH, -NO2, or -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 C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halo, and —OH; 1-6 It is alkyl.

[0045] In another aspect, provided is a compound of formula (I-2): [ka] or a pharmaceutically acceptable salt thereof, wherein Ring A is halo, -OH, C 1-6 Alkyl, 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 , -(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 , -SR a21 , -C(O)R a22 , and -OH, cyano, C 3-10 C 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. 1-6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 6-14 is an aryl or a 5-12 membered heteroaryl; R a1 -R a22 are each independently hydrogen, or 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 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 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 5-12 membered heteroaryl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1-6 is alkyl; Ring B is C 5-7 Cycloalkyl, C 5-7 a cycloalkenyl, or a 5-7 membered heterocycloalkyl, wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon; Each RB The groups are independently selected from halo, C optionally substituted with one or more halo. 1-6 Alkyl or C 2-6 alkenyl; or two adjacent R B The groups, together with the carbon atoms to which they are attached, form C 3-10 Forming a cycloalkyl; or two geminal R B The groups, together with the carbon atoms to which they are attached, form C 3-10 Forming a cycloalkyl; m is 0, 1, 2, 3 or 4; Y 1 is N or CR C1 and; Y 2 is N or CR C2 and; Y 3 is N or CR C3 and; Y 4 is N or CR C4 and; In the formula, Y 1 , Y 2 , Y 3 and Y 4 of which 3 or less are N; R C1 -R C4 are each independently hydrogen, halo, cyano, -OH, -NO2, or -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 , -NR c14 C(O)OR c15 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 c15are independently hydrogen, C 3-10 C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halo, and —OH; 1-6 It is alkyl.

[0046] In another aspect, provided is a compound of formula (I-3): [ka] or a pharmaceutically acceptable salt thereof, wherein Ring A is halo, -OH, C 1-6 Alkyl, 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 , -(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 , -SR a21 , -C(O)R a22 , and -OH, cyano, C 3-10 C 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. 1-6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 6-14 is an aryl or a 5-12 membered heteroaryl; R a1 -R a22 are each independently hydrogen, or halo, cyano, -OH, -O(C 1-6alkyl), 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 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 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 5-12 membered heteroaryl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1-6 is alkyl; Ring B is C 5-7 Cycloalkyl, C 5-7 a cycloalkenyl, or a 5-7 membered heterocycloalkyl, wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon; m is 2; The Two R's B The groups are attached to the same carbon atom on ring B and together with the carbon atom to which they are attached form C 3-7 Forming a cycloalkyl; Y 1 is N or CR C1 and; Y 2 is N or CR C2 and; Y 3 is N or CR C3 and; Y 4 is N or CR C4 and; In the formula, Y 1 , Y 2 , Y 3 and Y 4 of which 3 or less are N; R C1-R C4 are each independently hydrogen, halo, cyano, -OH, -NO2, or -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 , -NR c14 C(O)OR c15 , -NR c16 S(O)2(CH2) 1-6 NR c17 C(O)R c18 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 c18 Each independently is hydrogen, C 3-10 C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halo, and —OH; 1-6 It is alkyl.

[0047] In some embodiments of Formula (I), Formula (I-1), Formula (I-2), and Formula (I-3), or a pharmaceutically acceptable salt thereof, Ring A is -SR a21 , -C(O)R a22 , and -OH, cyano, C 3-10 C 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, ring A is substituted with 1, 2, 3, 4, 5 or more substituents independently selected from the group consisting of alkyl. a21 , -C(O)R a22 , as well as -OH, cyano, C 3-10C 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, R a21 and R a22 are each independently hydrogen, or 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 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 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 5-12 membered heteroaryl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1-6 It is alkyl.

[0048] In some embodiments of Formula (I), Formula (I-1), Formula (I-2), and Formula (I-3), or a pharmaceutically acceptable salt thereof, one or more R B The groups are independently selected from C substituted with 1, 2, 3, 4, 5 or more halo groups. 1-6 In some embodiments, R B The group is a C substituted with 1, 2, 3, 4, 5 or more halo groups. 1-6 It is alkyl.

[0049] In some embodiments of Formula (I), Formula (I-1), Formula (I-2), and Formula (I-3), or a pharmaceutically acceptable salt thereof, R C2 Ha-NRc14 C(O)OR c15 In this case, R c14 and R c15 are independently hydrogen, C 3-10 C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halo, and —OH; 1-6 It is alkyl.

[0050] In some embodiments, the cycloalkyl or heterocycloalkyl group comprises a spiro group, hi some embodiments, the cycloalkyl or heterocycloalkyl group comprises a fused group.

[0051] In some embodiments of Formula (I), Formula (I-1), Formula (I-2), and Formula (I-3), or a pharmaceutically acceptable salt thereof, ring A is each optionally substituted C 1-14 In some embodiments, ring A is an optionally substituted C 6-14 In some embodiments, ring A is an optionally substituted aryl. In some embodiments, ring A is an optionally substituted 5-12 membered heteroaryl. In some embodiments, ring A is an optionally substituted 6 membered heteroaryl. In some embodiments, ring A is an optionally substituted 5 membered heteroaryl. In some embodiments, ring A is an optionally substituted indolyl, indazolyl, pyridinyl, thiophenyl, furanyl, pyrazolyl, pyrrolyl, oxazolyl, chromanyl, or quinolinyl, each of which is optionally substituted. In some embodiments, ring A is an optionally substituted thiophenyl.

[0052] In some embodiments of Formula (I), Formula (I-1), Formula (I-2), and Formula (I-3), Ring A is selected from the group consisting of halo, —OH, C 1-6 Alkyl, 3-10 membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 , -NR a4 C(O)OR a5 , -NR a6 Ra7 , -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 , -(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 , -SR a21 , -C(O)R a22 , and -OH, cyano, C 3-10 C 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. 1-6 In some embodiments, R is optionally substituted with 1, 2, 3, 4, 5, or more substituents independently selected from the group consisting of alkyl. a1 -R a22 are each independently hydrogen, or 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 1, 2, 3, 4, 5 or more substituents independently selected from the group consisting of alkyl 1-6 C optionally substituted with 1, 2, 3, 4, 5 or more substituents independently selected from the group consisting of alkyl 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 5-12 membered heteroaryl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1-6It is alkyl.

[0053] In some embodiments, the 3-10 membered heterocycloalkyl is piperidinyl. In some embodiments, the 3-10 membered heterocycloalkyl is [ka] In some embodiments, R a1 is hydrogen or C 1-6 In some embodiments, each R a1 is hydrogen. In some embodiments, R a2 and R a3 are each independently hydrogen, C 1-6 Alkyl, or C 3-10 In some embodiments, R a2 and R a3 are each independently hydrogen, cyclopropyl, ethyl, or isopropyl. In some embodiments, R a4 is hydrogen or C 1-6 In some embodiments, R a4 is hydrogen. In some embodiments, R a5 is hydrogen or C 1-6 In some embodiments, R a5 is tert-butyl. In some embodiments, R a6 and R a7 are each independently hydrogen, C1-6 Alkyl, or C 1-6 In some embodiments, R is a 5-12 membered heteroaryl optionally substituted with alkyl. a6 and R a7 are each independently hydrogen, imidazolyl, methylimidazolyl, or pyrimidinyl. a8 R a9 teeth [ka] In some embodiments, R a8 and Ra9 are each independently hydrogen, C 1-6 Alkyl, or C 3-10 In some embodiments, R a8 and R a9 are each independently methyl or cyclopentyl. a10 teeth [ka] In some embodiments, R a10 is C 3-10 In some embodiments, R a10 is cyclopentyl. In some embodiments, —S(O)R a11 teeth [ka] In some embodiments, R a11 is C 3-10 In some embodiments, R a11 is cyclopentyl. In some embodiments, —S(O)(NR a12 )R a13 teeth [ka] or [ka] In some embodiments, R a12 is hydrogen or C 1-6 In some embodiments, R a12 is hydrogen or methyl. In some embodiments, R a13 is C 3-10 In some embodiments, R a13 is cyclopentyl. In some embodiments, —S(O)NR a14 R a15 teeth [ka] [ka] In some embodiments, -S(O)NR a14 R a15 teeth, [ka] [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 , as well as -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 1-6 C 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 1-6In 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, -S(O)R a16 teeth, [ka] In some embodiments, R a16 is C 3-10 cycloalkyl; or C 1-6 In some embodiments, -(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 is -C(O)NR a19 R a20 or -(CR a17 R a18 )C(O)NR a19 R a20 In some embodiments, -(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 is -C(O)NR a19 R a20 In some embodiments, -(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 Ha-(CR a17 R a18 )C(O)NR a19 R a20 In some embodiments, R a17 and R a18are each independently hydrogen or C 1-6 In some embodiments, R a17 and R a18 are each hydrogen. In some embodiments, R a19 and R a20 are independently hydrogen, C 1-6 Alkyl, or C 3-10 In some embodiments, R a19 and R a20 are each independently hydrogen or cyclopropyl. a21 teeth [ka] In some embodiments, R a21 is C 3-10 In some embodiments, —C(O)R a22 teeth [ka] In some embodiments, R a22 is C 3-10 In some embodiments, optionally substituted C 1-6 Alkyl is [ka] In some embodiments, C 1-6 Alkyl is -OH, cyano, C 3-10and 3-10 membered heterocycloalkyl 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. In some embodiments, the 3-10 membered heterocycloalkyl is piperidinyl 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.

[0054] In some embodiments, Ring A is fluoro, chloro, —OH, amino, [ka] [ka] In some embodiments, Ring A is substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, -OH, amino, [ka] [ka] and optionally substituted with 1, 2, 3, 4, 5 or more substituents independently selected from the group consisting of:

[0055] In some embodiments of Formula (I), Formula (I-1), Formula (I-2), and Formula (I-3), or a pharmaceutically acceptable salt thereof, Ring B is C 5-7 Cycloalkyl, C 5-7 In some embodiments, ring B is a cycloalkenyl, or a 5-7 membered heterocycloalkyl, wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon. 5-7In some embodiments, Ring B is cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, Ring B is [ka] wherein * represents the point of attachment to the remainder of Formula (I), Formula (I-1), Formula (I-2), or Formula (I-3). In some embodiments, Ring B is C 5-7 In some embodiments, Ring B is cyclopentenyl, cyclohexenyl, or cycloheptenyl. In some embodiments, Ring B is [ka] wherein * represents the point of attachment to the remainder of Formula (I), Formula (I-1), Formula (I-2), or Formula (I-3). In some embodiments, Ring B is [ka] wherein * represents the point of attachment to the remainder of Formula (I), Formula (I-1), Formula (I-2), or Formula (I-3). In some embodiments, Ring B is a 5-7 membered heterocycloalkyl. In some embodiments, Ring B is a 5-7 membered heterocycloalkyl where one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon. In some embodiments, Ring B is tetrahydrofuranyl or 1,3-dioxanyl. In some embodiments, Ring B is [ka] where * represents the point of attachment to the remainder of formula (I), formula (I-1), formula (I-2), or formula (I-3).

[0056] In some embodiments, ring B is mR B groups, wherein each R B The groups are independently halo, C optionally substituted with 1, 2, 3, 4, 5 or more halo. 1-6 Alkyl or C 2-6alkenyl; or two adjacent R B The group, together with the carbon atom to which it is attached, is C 3-10 Forming a cycloalkyl; or two geminal R B The group, together with the carbon atom to which it is attached, is C 3-10 In some embodiments, R B In some embodiments, two adjacent R groups are methyl or ethyl. B In some embodiments, two geminal R groups together with the carbon atom to which they are attached form a cyclopropyl. B The groups together with the carbon atom to which they are attached form a cyclopropyl.

[0057] In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1.

[0058] In some embodiments, a compound of formula (I), formula (I-1), formula (I-2), or formula (I-3) [ka] teeth, [ka] wherein * represents the point of attachment to the remainder of formula (I), formula (I-1), formula (I-2), or formula (I-3). In some embodiments, [ka] teeth, [ka] where * represents the point of attachment to the remainder of formula (I), formula (I-1), formula (I-2), or formula (I-3).

[0059] In some embodiments of Formula (I), Formula (I-1), Formula (I-2), and Formula (I-3), or a pharmaceutically acceptable salt thereof, Y 1 is N or CR C1 and;Y 2 is N or CR C2 and;Y 3 is N or CR C3 and Y 4 is N or CR C4 In some embodiments, Y 1 , Y 2 , Y 3 , and Y 4 In some embodiments, Y 1 , Y 2 , Y 3 , and Y 4 In some embodiments, Y 1 , Y 2 , Y 3 , and Y 4 In some embodiments, Y 1 is CR C1 and;Y 2 is CR C2 and;Y 3 is CR C3 and Y 4 is CR C4 In some embodiments, Y 1 is N;Y 2 is CR C2 and;Y 3 is CR C3 and Y 4 is CR C4 In some embodiments, Y 1 is CR C1 and;Y 2 is N and:Y 3 is CR C3 and;Y 4 is CR C4 is.

[0060] In some embodiments, R C1 -R C4are each independently hydrogen, halo, cyano, -OH, -NO2, or -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 , -NR c14 C(O)OR c15 , -NR c16 S(O)2(CH2) 1-6 NR c17 C(O)R c18 or C optionally substituted with 1, 2, 3, 4, 5 or more substituents independently selected from the group consisting of halo and —OH 1-6 In some embodiments, R c1 -R c18 are independently hydrogen, C 3-10 C optionally substituted with 1, 2, 3, 4, 5 or more substituents independently selected from the group consisting of cycloalkyl, halo, and —OH 1-6 It is alkyl.

[0061] In some embodiments, R C1 -R C4 are each independently hydrogen, halo, cyano, -OH, -NO2, or -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 , -NR c14 C(O)OR c15or C optionally substituted with 1, 2, 3, 4, 5 or more substituents independently selected from the group consisting of halo and —OH 1-6 In some embodiments, R c1 -R c15 are independently hydrogen, C 3-10 C optionally substituted with 1, 2, 3, 4, 5 or more substituents independently selected from the group consisting of cycloalkyl, halo, and —OH 1-6 It is alkyl.

[0062] In some embodiments, R C1 is hydrogen or halo. In some embodiments, R C1 is hydrogen or fluoro. In some embodiments, R C3 is hydrogen. In some embodiments, R C4 is hydrogen or -NH. In some embodiments, R C1 , R C3 , and R C4 are each independently hydrogen, halo, or -NH2.

[0063] In some embodiments, R C2 are cyano, -OH, -CH2OH, bromo, -NO2, [ka] In some embodiments, R C2 are cyano, -OH, -CH2OH, bromo, -NO2, [ka] In some embodiments, R C2 Cyano, -OH, halo, -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 , -NR c14 C(O)OR c15 , -NR c16 S(O)2(CH2) 1-6 NR c17 C(O)R c18 or C optionally substituted with 1, 2, 3, 4, 5 or more substituents independently selected from the group consisting of halo and —OH 1-6 In some embodiments, R C2 Cyano, -OH, halo, -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 , -NR c14 C(O)OR c15 or C optionally substituted with 1, 2, 3, 4, 5 or more substituents independently selected from the group consisting of halo and —OH 1-6 It is alkyl.

[0064] In some embodiments, —C(O)NR c1 R c2 teeth [ka] In some embodiments, R c1 and R c2 are each independently hydrogen or C 1-6 In some embodiments, R c1 and R c2 are each independently hydrogen, methyl, or ethyl. In some embodiments, -NR c3 R c4 teeth [ka] In some embodiments, R c3 and R c4 are each independently hydrogen or C 1-6 In some embodiments, R c1 and R c2 are each independently hydrogen, methyl, or ethyl. In some embodiments, -NR c5 S(O)2R c6 teeth [ka] In some embodiments, R c5 is hydrogen or C 1-6 In some embodiments, R c5 is hydrogen, methyl, or ethyl. In some embodiments, R c6 is hydrogen, or C optionally substituted with 1, 2, 3, 4, 5 or more substituents independently selected from halo and —OH; 1-6 In some embodiments, R c5 is methyl or —CHCHOH. In some embodiments, R c5 is hydrogen. In some embodiments, R c6 is ethyl. In some embodiments, —P(O)R c7 R c8 teeth [ka] In some embodiments, R c7 and R c8 are each independently C 1-6 In some embodiments, R c7 and R c8 are each methyl. In some embodiments, -N=S(O)R c9 R c10 teeth [ka] In some embodiments, Rc9 and R c10 are each independently C 1-6 In some embodiments, R c9 and R c10 are each methyl. In some embodiments, —S(O)(NR c11 )R c12 teeth [ka] In some embodiments, R c11 is hydrogen or C 1-6 In some embodiments, R c11 is hydrogen or methyl. In some embodiments, R c12 is C 1-6 Alkyl or C 3-10 In some embodiments, R c12 is cyclopropyl. In some embodiments, —S(O)R c13 teeth [ka] In some embodiments, R c13 is C 1-6 In some embodiments, R c13 is methyl. In some embodiments, NR c14 C(O)OR c15 teeth [ka] In some embodiments, R c14 and R c15 are each independently hydrogen or C 1-6 In some embodiments, R c14 is hydrogen. In some embodiments, R c15 is ethyl. In some embodiments, —NR c16 S(O)2(CH2) 1-6 NR c17 C(O)R c18 teeth [ka] In some embodiments, -NR c16 S(O)2(CH2) 1-6 NR c17 C(O)R c18 Ha-NR c16 S(O)2(CH2) 1-3 NR c17 C(O)R c18 In some embodiments, R c16 , R c17 and R c18 are each independently hydrogen or C 1-6 In some embodiments, R c16 and R c17 is hydrogen. In some embodiments, R c18 is methyl.

[0065] In one aspect, provided is a compound of formula (Ia1): [ka] or a pharmaceutically acceptable salt thereof, wherein R a14 , R a15 , ring B, R B , m, and R C2 is as defined for formula (I) or any variation or embodiment thereof. In some embodiments, R C2 are 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 , -NR c14 C(O)OR c15 , -NR c16 S(O)2(CH2) 1-6 NRc17 C(O)R c18 or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH 1-6 In some embodiments, R C2 are 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 In some embodiments, R C2 Ha-NR c5 S(O)2R c6 In some embodiments, R c5 is hydrogen and R c6 is C 1-6 In some embodiments, R c5 is hydrogen and R c6 is ethyl. In some embodiments, R c5 is hydrogen. In some embodiments, R c6 is ethyl. In some embodiments, R c6 is methyl. In some embodiments, R a14 is hydrogen and R a15 is C 1-6 In some embodiments, R a14 hydrogen, R a15 is tert-butyl. In some embodiments, R a14 is hydrogen. In some embodiments, R a15 is tert-butyl. In some embodiments, ring B is [ka] wherein * represents the point of attachment to the remainder of formula (Ia1). In some embodiments, [ka] teeth [ka] is.

[0066] In one aspect, provided is a compound of formula (Ia2): [ka] or a pharmaceutically acceptable salt thereof, wherein R a16 , ring B, R B , m, and R C2 is as defined for formula (I) or any variation or embodiment thereof. In some embodiments, R C2 are 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 , -NR c14 C(O)OR c15 , -NR c16 S(O)2(CH2) 1-6 NR c17 C(O)R c18 or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH 1-6 In some embodiments, R C2 are 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.

[0067] In some embodiments, ring B is represented by *, which represents the point of attachment to the remainder of formula (I). [ka] In some embodiments, R C1 is not fluoro. In some embodiments, R C2 is not hydrogen. In some embodiments, ring B is a ring in which * indicates the point of attachment to the remainder of formula (I). represent [ka] rather than ; or R C1 is not fluoro; or R C2 is not hydrogen.

[0068] In some embodiments, the compound is 4'-fluoro-1'-[3-(piperidine-1-sulfonyl)benzoyl]-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; 3-cyclopropyl-1-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]urea; 1-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]-3-(propan-2-yl)urea; [4-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]-3-(propan-2-yl)urea. N-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]pyrimidin-2-amine; 4'-fluoro-1'-[3-(morpholine-4-sulfonyl)benzoyl]-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; or [3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]urea.

[0069] In some embodiments, the compound is 4'-fluoro-1'-[3-(piperidine-1-sulfonyl)benzoyl]-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; 3-cyclopropyl-1-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]urea; 1-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]-3-(propan-2-yl)urea; [4-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]-3-(propan-2-yl)urea 4'-Fluoro-1'-[3-(morpholine-4-sulfonyl)benzoyl]-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; or a salt of [3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]urea.

[0070] In another aspect, provided herein is a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein Ring A is [ka] wherein Z 1 , Z 2 , Z 3 , and Z 4 are each independently hydrogen or R D In this case, R D is halo, -OH, -NR a4 C(O)ORa5 , -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 , -(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 , -SR a21 , -C(O)R a22 , -P(O)(R a23 )(R a24 ), -C=NR a25 , or -OH, cyano, C 3-10 cycloalkyl and one or more halo or C 1-3 C substituted with one or more substituents independently selected from the group consisting of 3-10 membered heterocycloalkyl optionally substituted with alkyl 1-6 is alkyl, however, (1)Z 4 If is hydrogen, Z 1 and Z 3 At least one of D and (2) Z 4 If RD, then Z 1 is R D or [ka] wherein: [ka] is a single or double bond, Z 5 is CH, N, O, S, or NX, where X is H or C 1-6 is alkyl; Z 6 is -NR a26C(O)NR a27 R a28 , -NR a29 C(O)OR a30 , -N=S(O)R a31 R a32 , -S(O)R a33 , -S(O)(NR a34 )R a35 , -S(O)NR a36 R a37 , -S(O)2R a38 , -SR a39 , -C(O)R a40 , 3-10 membered heterocycloalkyl, or -CH(Z 7 )(Z 8 ) where Z 7 is hydrogen or -OH, and Z 8 is C 1-6 alkyl, C optionally substituted with one or more halo 3-10 cycloalkyl or 3-10 membered heterocycloalkyl optionally substituted with one or more halo; and Ring C is 1 or more R E a 5- or 6-membered heteroaryl optionally substituted with substituents, wherein each R E The substituents are halo, -OH, and C 1-6 or two R E The substituents, together with the atoms to which they are attached, form C 5-6 Cycloalkyl, C 5-6 forming a cycloalkenyl, a 5-6 membered heterocycloalkyl, a 5-6 membered heterocycloalkenyl, or a 5-6 membered heteroaryl; R a4 -R a40 are each independently hydrogen, or 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 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 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 5-12 membered heteroaryl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1-6 is alkyl; Ring B is C 5-7 Cycloalkyl, C 5-7 a cycloalkenyl, or a 5-7 membered heterocycloalkyl, wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon; Each R B The groups are independently halo, or C optionally substituted with one or more halo. 1-6 alkyl; or two adjacent R B The groups, together with the carbon atoms to which they are attached, form C 3-10 Forming a cycloalkyl; or two geminal R B The groups, together with the carbon atoms to which they are attached, form C 3-10 Forming a cycloalkyl; or two geminal R B The base is together =CR 1a3 R 1a4 group; wherein R 1a3 and R 1a4 are each independently hydrogen or C 1-6 is alkyl; m is 0, 1, 2, 3 or 4; Y 1 is N or CR C1 and; Y 2 is N or CR C2 and; Y 3 is N or CR C3 and; Y 4 is N or CR C4 and; In the formula, Y 1 , Y 2 , Y 3 and Y 4 of which 3 or less are N; R C1 -R C4 are each independently hydrogen or R F In this case, R F are 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 , -NR c14 C(O)OR c15 , -NR c16 S(O)2(CH2) 1-6 NR c17 C(O)R c18 , -OS(O)2R c19 or C substituted with one or more substituents independently selected from the group consisting of halo and —OH 1-6 is alkyl; R c1 -R c19 are independently hydrogen, C 3-10 Cycloalkyl, or halo, -O(C 1-6 alkyl), -NHC(O)(C 1-6 C optionally substituted with one or more substituents independently selected from the group consisting of -alkyl, -C ... 1-6 is alkyl; however, (1) When ring B is unsubstituted cyclopentyl, ring A is [ka] wherein Z 1 -Z 4at least one of is -S(O)2-(3-10 membered heterocycloalkyl) substituted with one or more halo; (2) Ring B is unsubstituted cyclohexyl and Ring A is [ka] If R C1 -R C4 At least one of F and (3) Ring B is R 1 to 4 B When ring A is a 5-7 membered heterocycloalkyl optionally substituted with [ka] In this case, Z 1 -Z 4 is -S(O)2-(3-10 membered heterocycloalkyl) optionally substituted with one or more halo.

[0071] In some embodiments of Formula (II), or a pharmaceutically acceptable salt thereof, Z 1 -Z 4 1, 2, 3 or 4 of -SR a21 , -C(O)R a22 , and -OH, cyano, C 3-10 C 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 alkyl. In some embodiments, ring A is independently selected from the group consisting of -SR a21 , -C(O)R a22 , or -OH, cyano, C 3-10 C 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, R a21 and R a22are each independently hydrogen, or 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 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 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 5-12 membered heteroaryl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1-6 It is alkyl.

[0072] In some embodiments of Formula (II), or a pharmaceutically acceptable salt thereof, Z 1 , Z 2 , Z 3 , and Z 4 are each independently hydrogen or R D In this case, R D is halo, -OH, -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 , -(CR a17 R a18 ) 0-1 C(O)NR a19 Ra20 , -SR a21 , -C(O)R a22 , -P(O)(R a23 )(R a24 ), -C=NR a25 , or -OH, cyano, C 3-10 cycloalkyl and one or more halo or C 1-3 C substituted with one or more substituents independently selected from the group consisting of 3-10 membered heterocycloalkyl optionally substituted with alkyl 1-6 alkyl, where R a4 -R a25 are each independently hydrogen, or 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 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 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 5-12 membered heteroaryl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1-6 It is alkyl.

[0073] In some embodiments of Formula (II), or a pharmaceutically acceptable salt thereof, Z 4 is hydrogen, and Z 1 and Z 3 At least one of D In this case, R Dis as defined elsewhere herein. In some embodiments of Formula (II), or a pharmaceutically acceptable salt thereof, Z 4 is Z 4 R D and Z 1 R D When R D is as defined elsewhere herein.

[0074] In some embodiments of Formula (II), or a pharmaceutically acceptable salt thereof, Z 5 is CH, N, O, S, or NX, where X is H or C 1-6 In some embodiments, X is alkyl. In some embodiments, X is H. In some embodiments, X is C 1-6 In some embodiments, X is alkyl. In some embodiments, X is methyl. In some embodiments of Formula (II), or a pharmaceutically acceptable salt thereof, Z 5 is CH, N, O, S, or NX, where X is H or C 1-6 is alkyl, and Z 6 Ha-NR a26 C(O)NR a27 R a28 , -NR a29 C(O)OR a30 , -N=S(O)R a31 R a32 , -S(O)R a33 , -S(O)(NR a34 )R a35 , -S(O)NR a36 R a37 , -S(O)2R a38 , -SR a39 , 3-10 membered heterocycloalkyl, C(O)R a40 , or -CH(Z 7 )(Z 8 ) where Z 7 is hydrogen or -OH, and Z 8 is C 1-6 alkyl, C optionally substituted with one or more halo 3-10 cycloalkyl, or 3-10 membered heterocycloalkyl optionally substituted with one or more halo, and ring C is one or more RE a 5- or 6-membered heteroaryl optionally substituted with substituents, wherein each R E The substituents are halo, -OH, and C 1-6 or two R E The substituents, together with the atoms to which they are attached, form a C 5-6 Cycloalkyl, C 5-6 forming a cycloalkenyl, a 5-6 membered heterocycloalkyl, a 5-6 membered heterocycloalkenyl, or a 5-6 membered heteroaryl; and R a26 -R a40 are each independently hydrogen, or each independently 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 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 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 5-12 membered heteroaryl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1-6 It is alkyl.

[0075] In some embodiments of Formula (II) or a pharmaceutically acceptable salt thereof, one or more R B The groups are independently selected from C substituted with 1, 2, 3, 4, 5 or more halo groups. 1-6 In some embodiments, R B The group is a C substituted with 1, 2, 3, 4, 5 or more halo groups. 1-6It is alkyl.

[0076] In some embodiments of Formula (II), or a pharmaceutically acceptable salt thereof, ring B is C 5-7 Cycloalkyl, C 5-7 In some embodiments of Formula (II), or a pharmaceutically acceptable salt thereof, one or more R B The groups are independently halo, or C optionally substituted with one or more halo. 1-6 In some embodiments of Formula (II), or a pharmaceutically acceptable salt thereof, two adjacent R B The groups, together with the carbon atoms to which they are attached, form C 3-10 Forming a cycloalkyl; or two geminal R B The groups, together with the carbon atoms to which they are attached, form C 3-10 Forming a cycloalkyl; or two geminal R B The base is together =CR 1a3 R 1a4 group, wherein R 1a3 and R 1a4 are each independently hydrogen or C 1-6 It is alkyl.

[0077] In some embodiments of Formula (II), or a pharmaceutically acceptable salt thereof, R C2 Ha-NR c14 C(O)OR c15 In this case, R c14 and R c15 are independently hydrogen, C 3-10 C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halo, and —OH; 1-6 It is alkyl.

[0078] In some embodiments of Formula (II), or a pharmaceutically acceptable salt thereof, R C1 -R C4 are each independently hydrogen or R FIn this case, R F are 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 , -NR c14 C(O)OR c15 , -NR c16 S(O)2(CH2) 1-6 NR c17 C(O)R c18 , -OS(O)2R c19 , or C substituted with one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl; R c1 -R c19 are independently hydrogen, C 3-10 Cycloalkyl, or halo, -O(C 1-6 alkyl), -NHC(O)(C 1-6 C optionally substituted with one or more substituents independently selected from the group consisting of -alkyl, -C ... 1-6 In some embodiments of Formula (II), or a pharmaceutically acceptable salt thereof, R C1 -R C4 are each independently hydrogen or R F In this case, R F are 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, -NR c14 C(O)OR c15 , -NR c16 S(O)2(CH2) 1-6 NR c17 C(O)R c18 , or C substituted with one or more substituents independently selected from the group consisting of halo and -OH 1-6 alkyl, and R c1 -R c19 is as defined elsewhere herein. In some embodiments of Formula (II), or a pharmaceutically acceptable salt thereof, R C1 -R C4 are each independently -OS(O)2R c19 where R c19 is as defined elsewhere herein.

[0079] In some embodiments of Formula (II), or a pharmaceutically acceptable salt thereof, ring B is unsubstituted cyclopentyl and Z 1 -Z 4 In some embodiments of Formula (II), or a pharmaceutically acceptable salt thereof, ring B is unsubstituted cyclohexyl and ring A is -S(O)2-(3-10 membered heterocycloalkyl) substituted with one or more halo. [ka] and R C1 -R C4 At least one of them is R F and R C1 -R C4 and R F is as defined elsewhere herein. In some embodiments of Formula (II), or a pharmaceutically acceptable salt thereof, ring B contains 1 to 4 R B and Z is a 5- to 7-membered heterocycloalkyl optionally substituted with 1 -Z 4 at least one of R is -S(O)-(3-10 membered heterocycloalkyl) optionally substituted with one or more halo; Bis as defined elsewhere herein.

[0080] In some embodiments, the cycloalkyl or heterocycloalkyl group comprises a spiro group, hi some embodiments, the cycloalkyl or heterocycloalkyl group comprises a fused group.

[0081] In some embodiments of Formula (II), or a pharmaceutically acceptable salt thereof, ring A is optionally substituted C 6-14 In some embodiments, ring A is an optionally substituted C 6-14 In some embodiments, ring A is an optionally substituted aryl. In some embodiments, ring A is an optionally substituted 5-12 membered heteroaryl. In some embodiments, ring A is an optionally substituted 6 membered heteroaryl. In some embodiments, ring A is an optionally substituted 5 membered heteroaryl. In some embodiments, ring A is an optionally substituted indolyl, indazolyl, pyridinyl, thiophenyl, furanyl, pyrazolyl, pyrrolyl, oxazolyl, chromanyl, or quinolinyl, each of which is optionally substituted. In some embodiments, ring A is an optionally substituted thiophenyl.

[0082] In some embodiments of Formula (II), or a pharmaceutically acceptable salt thereof, ring A is an optionally substituted phenyl. In some embodiments, ring A is an optionally substituted 5-12 membered heteroaryl. In some embodiments, ring A is an optionally substituted 6 membered heteroaryl. In some embodiments, ring A is an optionally substituted 5 membered heteroaryl. In some embodiments, ring A is pyridinyl, thiophenyl, furanyl, pyrazolyl, pyrrolyl, or oxazolyl. In some embodiments, ring A is [ka] is.

[0083] In some embodiments of Formula (II), R a4 is hydrogen or C 1-6 In some embodiments, R a4 is hydrogen. In some embodiments, R a5 is hydrogen or C 1-6 In some embodiments, R a5 is tert-butyl. In some embodiments, R 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 a7 are each independently hydrogen, imidazolyl, methylimidazolyl, or pyrimidinyl. In some embodiments, -N=S(O)R a8 R a9 teeth [ka] In some embodiments, R a8 and R a9 are independently hydrogen, C 1-6 Alkyl, or C 3-10 In some embodiments, R a8 and R a9 are each independently methyl or cyclopentyl. In some embodiments, -OR a10 teeth [ka] In some embodiments, R a10 is C 3-10 In some embodiments, R a10 is cyclopentyl. In some embodiments, —S(O)R a11 teeth [ka] In some embodiments, Ra11 is C 3-10 In some embodiments, R a11 is cyclopentyl. In some embodiments, —S(O)(NR a12 )R a13 teeth [ka] In some embodiments, R a12 is hydrogen or C 1-6 In some embodiments, R a12 is hydrogen or methyl. In some embodiments, R a13 is C 3-10 In some embodiments, R a13 is cyclopentyl. In some embodiments, —S(O)NR a14 R a15 teeth, [ka] [ka] In some embodiments, -S(O)NR a14 R a15 teeth, [ka] [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(C1-6 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 1-6 C 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, -S(O)R a16 teeth, [ka] In some embodiments, -S(O)R a16 teeth [ka] In some embodiments, R a16 is C 3-10 cycloalkyl; or C 1-6 In some embodiments, -(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 is -C(O)NR a19 R a20 or -(CR a17 R a18 )C(O)NR a19 R a20 In some embodiments, -(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 is -C(O)NR a19 R a20 In some embodiments, -(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 Ha-(CR a17 R a18 )C(O)NR a19 R a20 In some embodiments, R a17 and R a18 are each independently hydrogen or C 1-6 In some embodiments, R a17 and R a18 are each hydrogen. In some embodiments, R a19 and R a20 are independently hydrogen, C 1-6 Alkyl, or C 3-10 In some embodiments, R a21 is hydrogen, C 3-10 Cycloalkyl, or one or more C 3-10 C optionally substituted with cycloalkyl 1-6In some embodiments, -SR is alkyl. a21 teeth [ka] In some embodiments, R a22 is hydrogen, C 3-10 Cycloalkyl, or one or more C 3-10 C optionally substituted with cycloalkyl 1-6 In some embodiments, —C(O)R a22 teeth [ka] In some embodiments, R a23 and Ra 24 are independently hydrogen, C 3-10 Cycloalkyl, or one or more C 3-10 C optionally substituted with cycloalkyl 1-6 In some embodiments, —P(O)(R a23 )(R a24 )teeth [ka] In some embodiments, R a24 is hydrogen, C 3-10 Cycloalkyl, or one or more C 3-10 C optionally substituted with cycloalkyl 1-6 In some embodiments, —C═NR a25 teeth [ka] In some embodiments, Z 1 -Z 4 are each independently -OH, cyano, or C 3-10 cycloalkyl and one or more halo or C 1-3 C substituted with one or more substituents independently selected from the group consisting of 3-10 membered heterocycloalkyl optionally substituted with alkyl 1-6 In some embodiments, Z is alkyl.1 -Z 4 are each independently [ka] is.

[0084] In some embodiments of Formula (II), Z 6 is a 3-10 membered heterocycloalkyl. In some embodiments, Z 6 teeth [ka] In some embodiments, R a26 is hydrogen or C 1-6 In some embodiments, R a27 is hydrogen. In some embodiments, R a27 and R a28 are independently hydrogen, C 1-6 Alkyl, or C 3-10 In some embodiments, R a27 and R a28 are each independently hydrogen, cyclopropyl, ethyl, or isopropyl. In some embodiments, R a29 is hydrogen or C1-6 In some embodiments, R a29 is hydrogen. In some embodiments, R a30 is hydrogen or C 1-6 In some embodiments, R a30 is tert-butyl. In some embodiments, —N═S(O)R a31 R a32 teeth [ka] In some embodiments, R a31 and R a32 are independently hydrogen, C 1-6 Alkyl, or C 3-10 In some embodiments, R a31 and Ra32 are each independently methyl or cyclopentyl. In some embodiments, -S(O)R a33 teeth [ka] In some embodiments, R a33 is C 3-10 In some embodiments, R a33 is cyclopentyl. In some embodiments, —S(O)(NR a34 )R a35 teeth [ka] In some embodiments, R a34 is hydrogen or C 1-6 In some embodiments, R a34 is hydrogen or methyl. In some embodiments, R a35 is C 3-10 In some embodiments, R a35 is cyclopentyl. In some embodiments, —S(O)NR a34 R a35 teeth [ka] [ka] In some embodiments, -S(O)NR a34 R a35 teeth [ka] In some embodiments, -S(O)NR a34 R a35 teeth [ka] [ka] In some embodiments, R a36 and R a37 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 1-6 C 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. a36 and R a37 are each independently hydrogen or C 1-6 In some embodiments, R a36 is hydrogen and R a37 is butyl. In some embodiments, R a37 is tert-butyl. In some embodiments, —S(O)R a38 teeth [ka] In some embodiments, -S(O)R a38teeth [ka] In some embodiments, -S(O)R a38 teeth [ka] In some embodiments, R a38 is C 3-10 Cycloalkyl, or C 1-6 In some embodiments, -SR is a 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. a39 teeth [ka] In some embodiments, R a39 is C 3-10 In some embodiments, R a40 is C 3-10 In some embodiments, —C(O)R a40 teeth [ka] In some embodiments, Z 7 is hydrogen or -OH, and Z 8 C 1-6 alkyl, C optionally substituted with one or more halo 3-10 -CH(Z) is a cycloalkyl or a 3-10 membered heterocycloalkyl optionally substituted with one or more halo groups; 7 )(Z 8 In some embodiments, Z 7 is —OH. In some embodiments, Z 7 is H. In some embodiments, Z 8 is C 1-6 In some embodiments, Z is alkyl. 8is C optionally substituted with one or more halo groups 3-10 In some embodiments, Z is cycloalkyl. 8 is a 3-10 membered heterocycloalkyl optionally substituted with one or more halo. In some embodiments, —CH(Z 7 )(Z 8 )teeth, [ka] is.

[0085] In some embodiments of Formula (II), Z 1 , Z 2 , Z 3 and Z 4 are each independently fluoro, chloro, -OH, amino, -CH2OH, [ka] [ka] [ka] In some embodiments, Z is selected from the group consisting of 1 , Z 2 , Z 3 , and Z 4 are each independently -CH2OH, [ka] In some embodiments, ring A is selected from the group consisting of: [ka] is selected from the group consisting of:

[0086] In some embodiments of Formula (II), or a pharmaceutically acceptable salt thereof, ring B is 5-7 Cycloalkyl, C 5-7In some embodiments, ring B is a cycloalkenyl, or a 5-7 membered heterocycloalkyl, wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon. 5-7 In some embodiments, Ring B is cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, Ring B is [ka] wherein * represents the point of attachment to the remainder of formula (II). In some embodiments, ring B is C 5-7 In some embodiments, Ring B is cyclopentenyl, cyclohexenyl, or cycloheptenyl. In some embodiments, Ring B is [ka] wherein * represents the point of attachment to the remainder of formula (II). In some embodiments, ring B is [ka] where * represents the point of attachment to the remainder of Formula (II). In some embodiments, Ring B is a 5-7 membered heterocycloalkyl. In some embodiments, Ring B is a 5-7 membered heterocycloalkyl where one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon. In some embodiments, Ring B is tetrahydrofuranyl or 1,3-dioxanyl. In some embodiments, Ring B is [ka] where * represents the point of attachment to the remainder of formula (II).

[0087] In some embodiments of Formula (II), ring B is mR B groups, wherein each R B The groups are independently halo, C optionally substituted with 1, 2, 3, 4, 5 or more halo. 1-6 Alkyl or C2-6 alkenyl; or two adjacent R B The groups, together with the carbon atoms to which they are attached, form C 3-10 Forming a cycloalkyl; or two geminal R B The groups, together with the carbon atoms to which they are attached, form C 3-10 In some embodiments, R B is methyl or ethyl. In some embodiments, two adjacent R B In some embodiments, two geminal R groups together with the carbon atom to which they are attached form a cyclopropyl. B The groups together with the carbon atom to which they are attached form a cyclopropyl.

[0088] In some embodiments of Formula (II), m is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1.

[0089] In some embodiments, the compound of formula (II) [ka] where * represents the point of attachment to the remainder of formula (II). [ka] In some embodiments, the compound of formula (II) [ka] where * represents the point of attachment to the remainder of formula (II). [ka] In some embodiments, [ka] where * represents the point of attachment to the remainder of formula (II). [ka] is.

[0090] In some embodiments of Formula (II), or a pharmaceutically acceptable salt thereof, Y 1 is N or CR C1 and;Y 2 is N or CR C2 and;Y 3 is N or CR C3 and;Y 4 is N or CR C4 In some embodiments, Y 1 , Y 2 , Y 3 , and Y 4 In some embodiments, Y 1 , Y 2 , Y 3 , and Y 4 In some embodiments, Y 1 , Y 2 , Y 3 , and Y 4 In some embodiments, Y 1 is CR C1 and;Y 2 is CR C2 and;Y 3 is CR C3 and Y 4 is CR C4 In some embodiments, Y 1 is N;Y 2 is CR C2 and;Y 3 is CR C3 and;Y 4 is CR C4 In some embodiments, Y 1 is CR C1 and;Y 2 is N and:Y 3 is CR C3 and;Y 4 is CRC4 is.

[0091] In some embodiments of Formula (II), R C1 -R C4 are each independently hydrogen or R F In this case, R F are 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 , -NR c14 C(O)OR c15 , -NR c16 S(O)2(CH2) 1-6 NR c17 C(O)R c18 , -OS(O)2R c19 or C substituted with one or more substituents independently selected from the group consisting of halo and —OH 1-6 It is alkyl.

[0092] In some embodiments of Formula (II), R C1 is hydrogen or halo. In some embodiments, R C1 is hydrogen or fluoro. In some embodiments, R C3 is hydrogen. In some embodiments, R C4 is hydrogen or -NH. In some embodiments, R C1 , R C3 , and R C4 are each independently hydrogen, halo, or -NH2.

[0093] In some embodiments of Formula (II), R C2 are cyano, -OH, -CH2OH, fluoro, bromo, -NO2, [ka] In some embodiments, R C2 are cyano, -OH, -CH2OH, bromo, -NO2, [ka] In some embodiments, R C2 teeth [ka] In some embodiments, R C2 Cyano, -OH, halo, -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 , -NR c14 C(O)OR c15 , -NR c16 S(O)2(CH2) 1-6 NR c17 C(O)R c18 or C optionally substituted with 1, 2, 3, 4, 5 or more substituents independently selected from the group consisting of halo and —OH 1-6 In some embodiments, R C2 Cyano, -OH, halo, -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 , -NRc14 C(O)OR c15 or C optionally substituted with 1, 2, 3, 4, 5 or more substituents independently selected from the group consisting of halo and —OH 1-6 In some embodiments, R C2 -OS(O)2R c19 is.

[0094] In some embodiments, —C(O)NR c1 R c2 teeth [ka] In some embodiments, R c1 and R c2 are each independently hydrogen or C 1-6 In some embodiments, R c1 and R c2 are each independently hydrogen, methyl, or ethyl. In some embodiments, -NR c3 R c4 teeth [ka] In some embodiments, R c3 and R c4 are each independently hydrogen or C 1-6 In some embodiments, R c1 and R c2 are each independently hydrogen, methyl, or ethyl. In some embodiments, -NR c5 S(O)2R c6 teeth [ka] In some embodiments, -NR c5 S(O)2R c6 teeth [ka] In some embodiments, R c5 is hydrogen or C1-6 In some embodiments, R c5 is hydrogen, methyl, or ethyl. In some embodiments, R c6 is hydrogen, or halo, -OH, -O(C 1-6 alkyl), and -NHC(O)(C 1-6 C optionally substituted with 1, 2, 3, 4, 5 or more substituents independently selected from alkyl 1-6 In some embodiments, R c5 is methyl or —CHCHOH. In some embodiments, R c5 is hydrogen. In some embodiments, R c6 is ethyl. In some embodiments, R c6 is -CH2CH2F. In some embodiments, R c6 is —OCH. In some embodiments, —P(O)R c7 R c8 teeth [ka] In some embodiments, R c7 and R c8 are each independently C 1-6 In some embodiments, R c7 and R c8 are each methyl. In some embodiments, -N=S(O)R c9 R c10 teeth [ka] In some embodiments, R c9 and R c10 are each independently C 1-6 In some embodiments, R c9 and R c10 are each methyl. In some embodiments, —S(O)(NR c11 )R c12 teeth [ka] In some embodiments, R c11 is hydrogen or C 1-6 In some embodiments, R c11 is hydrogen or methyl. In some embodiments, R c12 is C 1-6 Alkyl or C 3-10 In some embodiments, R c12 is cyclopropyl. In some embodiments, —S(O)R c13 teeth [ka] In some embodiments, R c13 is C 1-6 In some embodiments, R c13 is methyl. In some embodiments, NR c14 C(O)OR c15 teeth [ka] In some embodiments, R c14 and R c15 are each independently hydrogen or C 1-6 In some embodiments, R c14 is hydrogen. In some embodiments, R c15 is ethyl. In some embodiments, —NR c16 S(O)2(CH2) 1-6 NR c17 C(O)R c18 teeth [ka] In some embodiments, -NR c16 S(O)2(CH2) 1-6 NR c17 C(O)R c18 Ha-NR c16 S(O)2(CH2) 1-3 NR c17 C(O)R c18In some embodiments, R c16 , R c17 and R c18 are each independently hydrogen or C 1-6 In some embodiments, R c16 and R c17 is hydrogen. In some embodiments, R c18 is methyl.

[0095] 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 1-25

Table 1-27

Table 1-30

Table 1-32

Table 1-34

Table 1-35

Table 1-36

Table 1-40

Table 1-43

Table 1-49

Table 1-53

Table 1-59

Table 1-63

Table 1-69

[0096] In some embodiments, provided herein are compounds and salts thereof set forth in Table 2. In some embodiments, compounds set forth herein are not compounds of Table 2. [Table 2]

[0097] In some variations, any of the compounds described herein, such as a compound of Formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2), or (II), or any variation thereof, or a compound in Table 1 or Table 2, 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 some 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.

[0098] Any formula presented herein, such as Formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2), or (II), is intended to represent a compound having the structure depicted by the structural formula and any particular variation or form. In particular, compounds of any formula presented 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 presented 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), a tautomer, or an atropisomeric form. Additionally, any formula given herein is intended to refer to any one of hydrates, solvates, and amorphous and polymorphic forms of such compounds, and mixtures thereof, even if such forms are not explicitly stated. In some embodiments, the solvent is water and the solvate is a hydrate.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] Ring A, ring B, ring C, R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 , R a8 , R a9 , R a10 , Ra11 , R a12 , R a13 , R a14 , R a15 , R a16 , R a17 , R a18 , R a19 , R a20 , R a21 , R a22 , R a23 , R a24 , R a25 , R a26 , R a27 , R a28 , R a29 , R a30 , R a31 , R a32 , R a33 , R a34 , R a35 , R a36 , R a37 , R a38 , R a39 , R a40 , R 1a1 , R 1a2 , R 1a3 , R 1a4 , R B , m, X, Y 1 , Y 2 , Y 3 , Y4 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , R C1 , R C2 , R C3 , R C4 , 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 , R c14 , R c15 , R c16 , R c17 , R c18 , R c19 , R D , R E , or R F Any variation or embodiment of the formula may include ring A, ring B, ring C, R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , 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 a21 , R a22 , Ra23, R a24 , R a25 , Ra 26 , R a27 , R a28 , R a29 , R a30 , R a31, R a32 , R a33 , R a34 , R a35 , R a36 , R a37 , R a38 , R a39 , R a40 , R 1a1 , R 1a2 , R 1a3 , R 1a4 , R B , m, X, Y 1 , Y 2 , Y 3 , Y 4 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , R C1 , R C2 , R C3 , R C4 , 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 , R c14 , R c15 , R c16 , R c17 , R c18 , R c19 , R D , R E , or R F It may be combined with all other variations or embodiments, as if each and every combination were individually and specifically described.

[0103] 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.

[0104] The compound names provided herein, including in Tables 1 and 2, are provided in Chemaxon Marvin Structure to Name 20 or ChemDraw Professional 20. One of ordinary skill 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).

[0105] composition 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.

[0106] In some embodiments, provided are pharmaceutically acceptable compositions comprising a compound of Formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2), or (II), or a compound of Table 1 or Table 2, 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.

[0107] Any of the compositions described herein may be sterile or may 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.

[0108] 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.

[0109] How to use 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.

[0110] 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).

[0111] 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), (I-1), (I-2), (I-3), (Ia1), (Ia2), or (II), or a compound in Table 1 or Table 2, or a pharmaceutically acceptable salt thereof. 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), (I-1), (I-2), (I-3), (Ia1), (Ia2), or (II), or a compound in Table 1 or Table 2, or a pharmaceutically acceptable salt thereof. In one variation of the foregoing embodiment, the cell is contacted in vitro. In one variation of the foregoing embodiment, the cell is contacted in vivo.

[0112] 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.

[0113] In some embodiments, provided herein are methods 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, provided herein are methods for 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), (I-1), (I-2), (I-3), (Ia1), (Ia2), or (II), or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods for treating or preventing a disease or condition in an individual, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2), or (II), or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.

[0114] 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 (e.g., 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 the myeloid lineage (acute and chronic myeloid leukemia, myelodysplasia, leukemia ... These may include, but are not limited to, tumors of any lineage, including leukemia, encephalopathy syndrome 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.

[0115] In some embodiments, provided are methods of treating or preventing cancer in an individual comprising administering to the individual a compound of Formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2), or (II), or a compound of Table 1 or Table 2, 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 compound described herein. Also provided herein is the use of a compound of Formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2), or (II), or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease in a subject.

[0116] In some embodiments, provided herein is a method of treating cancer comprising administering a compound of Formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2) or (II), or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt thereof, to an individual in need thereof. Also provided herein is the use of a compound of Formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2) or (II), or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.

[0117] 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.

[0118] 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, tumors of the neuroendocrine system, tumors of the endocrine system, 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.

[0119] Dosage 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.

[0120] 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.

[0121] 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.

[0122] 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.

[0123] In some embodiments, the compositions take the form of a pill or tablet, and thus 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.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] kit 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.

[0128] 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.

[0129] combination 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.

[0130] 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 the myeloid lineage (acute and chronic myeloid leukemia, myelodysplasia, leukemia ... These may include, but are not limited to, tumors of any lineage, including leukemia, encephalopathy syndrome 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.

[0131] General synthesis method Compounds of Formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2), or (II) will now be described by reference to the following exemplary synthetic schemes for the 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 may 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 respect to Formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2), or (II).

[0132] If it is desired to obtain a specific enantiomer of a compound, this can be achieved from the corresponding enantiomeric mixture by 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 a suitable 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.Alternatively, if desired, a specific enantiomer can be obtained by using a suitable chiral intermediate in one of the processes described.

[0133] 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.

[0134] General methods for preparing the compounds described herein are illustrated in the following exemplary methods. The variables in the schemes provided herein are defined as for formula (I), (I-1), (I-2), (I-3), (Ia1), (Ia2), or (II), or any variation thereof. Other compounds described herein may be prepared by similar methods.

[0135] In some embodiments, the compounds provided herein may be synthesized according to Scheme 1, Scheme 2, Scheme 3, and / or Scheme 4. The rings A, B, Y are preferably substituted or unsubstituted as shown in Schemes 1-4 below. 1 , Y 2 , Y 3 , Y 4 , m, R B and R C is as defined for compounds of formula I.

[0136] Scheme 1. [ka] Scheme 1 outlines an exemplary route to the synthesis of compounds of general formula I. Compounds of formula I are prepared by the reaction of a carboxylic acid of formula A (e.g., X = OH) with an indoline of formula B in the presence of a coupling reagent such as HATU with a base such as iPrNEt or EDCI with HOBt or DMAP. Alternatively, an acid halide of formula A (e.g., X = Cl or F) is reacted directly with a compound of formula B with an acid scavenger such as EtN.

[0137] Scheme 2. [ka] The indoline intermediate of formula B may be prepared via Fisher indole synthesis as described in Scheme 2. Aryl hydrazines of formula C (e.g., formulas Ci, C-ii, and C-iii) are reacted with a ring B-substituted carbaldehyde of formula D in the presence of an acid, followed by reaction with a reducing agent such as NaBH, Pd / C and H gas, or EtSiH. Para-monosubstituted aryl hydrazines of formula Ci provide indolines of formula Bi, while hydrazines of formula C-ii containing at least one meta-substituent and no ortho-substitution provide mixtures of indolines of formula B-ii-a and B-ii-b. Aryl hydrazines of formula C-iii substituted at one ortho-position provide indolines of formula B-iii.

[0138] Scheme 3. [ka] Indolines of Formula B may be prepared via the 3,3-dialkylation method described in Scheme 3. Indoles of Formula D are reacted with optionally substituted 3-6 atom aliphatic and heteroaliphatic linear chains bearing two terminal leaving groups "LG" (Formula E). LG may be Cl, Br, I, or a sulfonate ester, or another suitable group displaceable by a nucleophile. This transformation may be mediated by a trialkylboron such as EtB and a base such as potassium t-butoxide. Spirocyclization is followed by reaction with a reducing agent such as NaBH, Pd / C and H gas, or EtSiH.

[0139] Scheme 4. [ka] Indolines of formula B may also be prepared via enolate alkylation of indolin-2-ones of formula F. The indolin-2-ones of formula F are deprotonated with a strong base such as butyllithium, sodium hexamethylsilazide, or potassium t-butoxide and reacted with optionally substituted 3-6 atom aliphatic and heteroaliphatic linear chains bearing two terminal leaving groups "LG" (formula E). LG may be Cl, Br, I, or a sulfonate ester, or another suitable group displaceable by a nucleophile. This reaction may be mediated by an additive such as tetramethyldiaminoethane or hexamethylphosphorus triamide. Spirocyclization is followed by reaction with a reducing agent such as LiAlH or borane.

[0140] Enumeration of Embodiments The embodiments listed below are representative of some aspects of the present invention. 1. Formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein Ring A is halo, -OH, C 1-6 Alkyl, 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 , and -(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 C, each optionally substituted with one or more substituents independently selected from the group consisting of 6-14is an aryl or a 5-12 membered heteroaryl; R a1 -R a20 are each independently hydrogen, or each independently 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 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 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 5-12 membered heteroaryl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1-6 is alkyl; Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5-7 membered heterocycloalkyl, wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon; Each R B The groups are independently halo, C 1-6 Alkyl or C 2-6 alkenyl; or two adjacent R B The groups, together with the carbon atoms to which they are attached, form C 3-10 Forming a cycloalkyl; or two geminal R B The groups, together with the carbon atoms to which they are attached, form C 3-10 Forming a cycloalkyl; m is 0, 1, 2, 3 or 4; Y 1 is N or CR C1and; Y 2 is N or CR C2 and; Y 3 is N or CR C3 and; Y 4 is N or CR C4 and; In the formula, Y 1 , Y 2 , Y 3 and Y 4 of which 3 or less are N; R C1 -R C4 are each independently hydrogen, halo, cyano, -OH, -NO2, or -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 C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halo, and —OH; 1-6 The compound or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

[0141] 2. The compound is 4'-fluoro-1'-[3-(piperidine-1-sulfonyl)benzoyl]-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; 3-cyclopropyl-1-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]urea; 1-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]-3-(propan-2-yl)urea; [4-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]methanol; 4'-fluoro 4'-Fluoro-1'-[3-(morpholine-4-sulfonyl)benzoyl]-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; [3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]urea; or a salt of any of the foregoing, or a pharmaceutically acceptable salt thereof.

[0142] 3. Ring A is optionally substituted C 6-14 The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein:

[0143] 4. The compound of embodiment 3, or a pharmaceutically acceptable salt thereof, wherein ring A is optionally substituted phenyl.

[0144] 5. The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring A is an optionally substituted 5-10 membered heteroaryl.

[0145] 6. The compound of embodiment 5, or a pharmaceutically acceptable salt thereof, wherein Ring A is indolyl, indazolyl, pyridinyl, thiophenyl, furanyl, pyrazolyl, pyrrolyl, oxazolyl, chromanyl, or quinolinyl, each of which is optionally substituted.

[0146] 7.R a1 is hydrogen or C 1-6 alkyl; R a2 and R a3 are independently hydrogen, C 1-6 Alkyl, or C 3-10 is cycloalkyl; R a4 is hydrogen or C 1-6 alkyl; R a5 is hydrogen or C 1-6 alkyl; R a6 and R a7 are independently hydrogen, C 1-6 Alkyl, or C 1-6 R is a 5-12 membered heteroaryl optionally substituted with alkyl; a8 and R a9 are independently hydrogen, C 1-6 Alkyl, or C 3-10 is cycloalkyl; R a10 C 3-10 is cycloalkyl; R a11 C 3-10 is cycloalkyl; R a12 is hydrogen or C 1-6 alkyl; R a13 C 3-10 is cycloalkyl; R a16 C 3-10 Cycloalkyl or C 1-6 R is a 3- to 12-membered heterocycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of alkyl or halo; a17 and R a18 are each independently hydrogen or C 1-6 alkyl; and R a19 and R a20 are independently hydrogen, C 1-6 Alkyl, or C 3-107. The compound of any one of embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein:

[0147] 8.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 one 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 one or more substituents independently selected from the group consisting of alkyl, and halo 1-6 C optionally substituted with one 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 one or more C 1-6 The compound of any one of embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, wherein the heterocycloalkyl is a 3-12 membered ring optionally substituted with alkyl.

[0148] 9. Ring A is fluoro, chloro, -OH, methyl, amino, [ka] [ka] 9. The compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of:

[0149] 10. Ring B is C 5-7 The compound of any one of embodiments 1-9, or a pharmaceutically acceptable salt thereof, wherein:

[0150] 11. The compound according to any one of embodiments 1-9, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 5-7 membered heterocycloalkyl.

[0151] 12. Ring B is [ka] 10. The compound of any one of embodiments 1-9, or a pharmaceutically acceptable salt thereof, wherein * represents the point of attachment to the remainder of formula (I).

[0152] 13. Formula (I) [ka] but, [ka] 10. The compound of any one of embodiments 1-9, or a pharmaceutically acceptable salt thereof, wherein * represents the point of attachment to the remainder of formula (I).

[0153] 14.Y 1 is CR C1 and;Y 2 is CR C2 and;Y 3 is CR C3 and Y 4 is CR C4 14. The compound of any one of embodiments 1-13, wherein:

[0154] 15.Y 1 is N;Y 2is CR C2 and;Y 3 is CR C3 and Y 4 is CR C4 14. The compound of any one of embodiments 1-13, wherein:

[0155] 16.Y 1 is CR C1 and;Y 2 is N;Y 3 is CR C3 and Y 4 is CR C4 14. The compound of any one of embodiments 1-13, wherein:

[0156] 17.R C1 , R C3 , and R C4 17. The compound of any one of embodiments 1-16, or a pharmaceutically acceptable salt thereof, wherein each is independently hydrogen, halo, or -NH2.

[0157] 18.R C2 However, cyano, -OH, -CH2OH, bromo, -NO2, [ka] or a pharmaceutically acceptable salt thereof.

[0158] 19. The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of the compounds in Table 1.

[0159] 20. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of the compounds in Table 2.

[0160] 21. A pharmaceutical composition comprising a compound according to any one of embodiments 1-18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0161] 22. A method for inhibiting KIF18A, comprising contacting a cell with an effective amount of a compound described in any one of embodiments 1 to 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in embodiment 21.

[0162] 23. A method for treating a disease or condition mediated by KIF18A in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described in any one of embodiments 1 to 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in embodiment 21.

[0163] 24. A method for 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 1 to 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 21.

[0164] 25. The method of embodiment 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, 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, other tumors including retinoblastoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, and other cancer-related disorders that are a result of the presence or progression of cancer.

[0165] 26. Formula (I) [ka] or a pharmaceutically acceptable salt thereof, wherein Ring A is halo, -OH, C 1-6 Alkyl, 3-10 membered heterocycloalkyl, -NRa1C (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 , -(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 , -SR a21 , -C(O)R a22 , and -OH, cyano, C 3-10 C 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. 1-6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 6-14 is an aryl or a 5-12 membered heteroaryl; R a1 -R a22 are each independently hydrogen, or 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 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 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 5-12 membered heteroaryl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1-6 is alkyl; Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5-7 membered heterocycloalkyl, wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon; Each R B The groups are independently selected from halo, C optionally substituted with one or more halo. 1-6 Alkyl or C 2-6 alkenyl; or two adjacent R B The groups, together with the carbon atoms to which they are attached, form C 3-10 Forming a cycloalkyl; or two geminal R B The groups, together with the carbon atoms to which they are attached, form C 3-10 Forming a cycloalkyl; m is 0, 1, 2, 3 or 4; Y 1 is N or CR C1 and; Y 2 is N or CR C2 and; Y 3 is N or CR C3 and; Y 4 is N or CR C4 and; In the formula, Y 1 , Y 2 , Y 3 and Y 4 of which 3 or less are N; R C1 -R C4 are each independently hydrogen, halo, cyano, -OH, -NO2, or -C(O)NR c1 R c2 , -NR c3 R c4 , -NR c5S(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 , -NR c14 C(O)OR c15 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 c15 are independently hydrogen, C 3-10 cycloalkyl or C optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH; 1-6 alkyl, or a pharmaceutically acceptable salt thereof.

[0166] 27. Formula (I-1) [ka] or a pharmaceutically acceptable salt thereof, wherein Ring A is halo, -OH, C 1-6 Alkyl, 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 , and -(CR a17 R a18 ) 0-1 C(O)NR a19 R a20C, each optionally substituted with one or more substituents independently selected from the group consisting of 6-14 is an aryl or a 5-12 membered heteroaryl; R a1 -R a20 are each independently hydrogen, or each independently 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 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 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 5-12 membered heteroaryl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1-6 is alkyl; Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5-7 membered heterocycloalkyl, wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon; Each R B The groups are independently halo, C 1-6 Alkyl or C 2-6 alkenyl; or two adjacent R B The groups, together with the carbon atoms to which they are attached, form C 3-10 Forming a cycloalkyl; or two geminal R B The groups, together with the carbon atoms to which they are attached, form C 3-10 Forming a cycloalkyl; m is 0, 1, 2, 3 or 4; Y 1 is N or CR C1 and; Y 2 is N or CR C2 and; Y 3 is N or CR C3 and; Y 4 is N or CR C4 and; In the formula, Y 1 , Y 2 , Y 3 and Y 4 of which 3 or less are N; R C1 -R C4 are each independently hydrogen, halo, cyano, -OH, -NO2, or -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 C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halo, and —OH; 1-6 The compound or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

[0167] 28. The compound is 4'-fluoro-1'-[3-(piperidine-1-sulfonyl)benzoyl]-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; 3-cyclopropyl-1-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]urea; 1-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]-3-(propan-2-yl)urea; [4-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]methanol; 4'-fluoro-1' 28. The compound of embodiment 26 or 27, or a pharmaceutically acceptable salt thereof, which is not -(1H-indole-5-carbonyl)-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; N-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indol]-1'-yl}carbonyl)phenyl]pyrimidin-2-amine; 4'-fluoro-1'-[3-(morpholine-4-sulfonyl)benzoyl]-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; [3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indol]-1'-yl}carbonyl)phenyl]urea; or a salt of any of the foregoing.

[0168] 29. C in which ring A is optionally substituted 6-14 29. The compound of embodiment 26 or 28, or a pharmaceutically acceptable salt thereof, wherein:

[0169] 30. The compound according to embodiment 29, or a pharmaceutically acceptable salt thereof, wherein ring A is optionally substituted phenyl.

[0170] 31. The compound according to embodiment 26 or 28, or a pharmaceutically acceptable salt thereof, wherein ring A is an optionally substituted 5-10 membered heteroaryl.

[0171] 32. The compound according to embodiment 31, or a pharmaceutically acceptable salt thereof, wherein ring A is indolyl, indazolyl, pyridinyl, thiophenyl, furanyl, pyrazolyl, pyrrolyl, oxazolyl, chromanyl, or quinolinyl, each of which is optionally substituted.

[0172] 33.R a1 is hydrogen or C 1-6 alkyl; R a2 and R a3 are independently hydrogen, C 1-6 alkyl, or C3-10 is cycloalkyl; R a4 is hydrogen or C 1-6 alkyl; R a5 is hydrogen or C 1-6 alkyl; R a6 and R a7 are independently hydrogen, C 1-6 Alkyl, or C 1-6 R is a 5-12 membered heteroaryl optionally substituted with alkyl; a8 and R a9 are independently hydrogen, C 1-6 Alkyl, or C 3-10 is cycloalkyl; R a10 C 3-10 is cycloalkyl; R a11 C 3-10 is cycloalkyl; R a12 is hydrogen or C 1-6 alkyl; R a13 C 3-10 is cycloalkyl; R a16 C 3-10 Cycloalkyl or C 1-6 R is a 3- to 12-membered heterocycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of alkyl or halo; a17 and R a18 are each independently hydrogen or C 1-6 alkyl; R a19 and R a20 are independently hydrogen, C 1-6 Alkyl, or C 3-10is cycloalkyl; R a21 C 3-10 cycloalkyl; and R a22 C 3-10 The compound of any one of embodiments 26 and 28-32, or a pharmaceutically acceptable salt thereof, wherein is cycloalkyl.

[0173] 34.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 one 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 , as well as -OH, -O(C 1-6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl, and halo 1-6 C optionally substituted with one 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 one or more C 1-6 The compound of any one of embodiments 26 and 28-33, or a pharmaceutically acceptable salt thereof, wherein the heterocycloalkyl is a 3-12 membered ring optionally substituted with alkyl.

[0174] 35.R a14 is hydrogen and R a15 The compound of any one of embodiments 26 and 28-34, or a pharmaceutically acceptable salt thereof, wherein is tert-butyl.

[0175] 36. Ring A is fluoro, chloro, -OH, methyl, amino, [ka] [ka] 36. The compound of any one of embodiments 26 and 28-35, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of:

[0176] 37. Ring A [ka] 37. The compound of any one of embodiments 26 and 28-36, wherein R is phenyl substituted with R, or a pharmaceutically acceptable salt thereof.

[0177] 38. Ring B is C 5-7 The compound of any one of embodiments 26 and 28-37, or a pharmaceutically acceptable salt thereof, wherein is cycloalkyl.

[0178] 39. The compound according to any one of embodiments 26 and 28-37, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 5-7 membered heterocycloalkyl.

[0179] 40. Ring B is [ka] 38. The compound of any one of embodiments 26 and 28-37, wherein * represents the point of attachment to the remainder of formula (I), or a pharmaceutically acceptable salt thereof.

[0180] 41. Formula (I) [ka] but [ka] 38. The compound of any one of embodiments 26 and 28-37, wherein * represents the point of attachment to the remainder of formula (I), or a pharmaceutically acceptable salt thereof.

[0181] 42. Formula (I) [ka] but [ka] or a pharmaceutically acceptable salt thereof.

[0182] 43.Y 1 is CR C1 and;Y 2 is CR C2 and;Y 3 is CR C3 and Y 4 is CR C4 43. The compound of any one of embodiments 25 and 28-42, wherein:

[0183] 44.R C1 , R C3 , and R C4 is each independently hydrogen, halo, or —NH 2 , or a pharmaceutically acceptable salt thereof.

[0184] 45.R C1 , R C3 and R C4 45. The compound of embodiment 43 or 44, or a pharmaceutically acceptable salt thereof, wherein each is hydrogen.

[0185] 46.Y 1 is N;Y 2 is CR C2 and;Y 3 is CR C3 and Y 4 is CR C442. The compound of any one of embodiments 25 and 28-41, wherein:

[0186] 47.Y 1 is CR C1 and;Y 2 is N;Y 3 is CR C3 and Y 4 is CR C4 42. The compound of any one of embodiments 25 and 28-41, wherein:

[0187] 48.R C2 However, cyano, -OH, -CH2OH, bromo, -NO2, [ka] 48. The compound of any one of embodiments 25 and 28-47, wherein:

[0188] 49.R C2 but [ka] or a pharmaceutically acceptable salt thereof.

[0189] 50. The compound of embodiment 26 or 28, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of the compounds in Table 1.

[0190] 51. The compound of embodiment 26, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of the compounds in Table 2.

[0191] 52. A pharmaceutical composition comprising a compound according to any one of embodiments 26-51, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0192] 53. A method for inhibiting KIF18A, comprising contacting a cell with an effective amount of a compound described in any one of embodiments 26 to 51, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in embodiment 52.

[0193] 54. A method for treating a disease or condition mediated by KIF18A in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described in any one of embodiments 26 to 51, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in embodiment 52.

[0194] 55. A method for 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 26 to 51, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 52.

[0195] 56. The method of embodiment 55, 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, other tumors including retinoblastoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, and other cancer-related disorders that are a result of the presence or progression of cancer.

[0196] 57. Formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein Ring A is halo, -OH, C 1-6 Alkyl, 3-10 membered heterocycloalkyl, -NRa1 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 , -(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 , -SR a21 , -C(O)R a22 , as well as -OH, cyano, C 3-10 C 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. 1-6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 6-14 is an aryl or a 5-12 membered heteroaryl; R a1 -R a22 are each independently hydrogen, or 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 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 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 5-12 membered heteroaryl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1-6 is alkyl; Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5-7 membered heterocycloalkyl, wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon; Each R B The groups are independently halo, C optionally substituted with one or more halo. 1-6 Alkyl or C 2-6 alkenyl; or two adjacent R B The groups, together with the carbon atoms to which they are attached, form C 3-10 Forming a cycloalkyl; or two geminal R B The groups, together with the carbon atoms to which they are attached, form C 3-10 Forming a cycloalkyl; m is 0, 1, 2, 3 or 4; Y 1 is N or CR C1 and; Y 2 is N or CR C2 and; Y 3 is N or CR C3 and; Y 4 is N or CR C4 and; In the formula, Y 1 , Y 2 , Y 3 and Y 4 of which 3 or less are N; R C1 -R C4 are each independently hydrogen, halo, cyano, -OH, -NO2, or -C(O)NR c1 R c2 , -NR c3 R c4 , -NR c5S(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 , -NR c14 C(O)OR c15 , -NR c16 S(O)2(CH2) 1-6 NR c17 C(O)R c18 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 c18 are independently hydrogen, C 3-10 C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halo, and —OH; 1-6 alkyl, or a pharmaceutically acceptable salt thereof.

[0197] 58. Formula (I-2): [ka] or a pharmaceutically acceptable salt thereof, wherein Ring A is halo, -OH, C 1-6 Alkyl, 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 , -(CR a17 Ra18 ) 0-1 C(O)NR a19 R a20 , -SR a21 , -C(O)R a22 , as well as -OH, cyano, C 3-10 C 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. 1-6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 6-14 is an aryl or a 5-12 membered heteroaryl; R a1 -R a22 are each independently hydrogen, or 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 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 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 5-12 membered heteroaryl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1-6 is alkyl; Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5-7 membered heterocycloalkyl, wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon; Each R BThe groups are independently halo, C optionally substituted with one or more halo. 1-6 Alkyl or C 2-6 alkenyl; or two adjacent R B The groups, together with the carbon atoms to which they are attached, form C 3-10 Forming a cycloalkyl; or two geminal R B The groups, together with the carbon atoms to which they are attached, form C 3-10 Forming a cycloalkyl; m is 0, 1, 2, 3 or 4; Y 1 is N or CR C1 and; Y 2 is N or CR C2 and; Y 3 is N or CR C3 and; Y 4 is N or CR C4 and; In the formula, Y 1 , Y 2 , Y 3 and Y 4 of which 3 or less are N; R C1 -R C4 are each independently hydrogen, halo, cyano, -OH, -NO2, or -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 , -NR c14 C(O)OR c15 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 c15 are independently hydrogen, C3-10 cycloalkyl or C optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH; 1-6 alkyl, or a pharmaceutically acceptable salt thereof.

[0198] 59. Formula (I-1): [ka] or a pharmaceutically acceptable salt thereof, wherein Ring A is halo, -OH, C 1-6 Alkyl, 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 , and -(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 C, each optionally substituted with one or more substituents independently selected from the group consisting of 6-14 is an aryl or a 5-12 membered heteroaryl; R a1 -R a20 are each independently hydrogen, or each independently 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 1-6C 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 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 5-12 membered heteroaryl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1-6 is alkyl; Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5-7 membered heterocycloalkyl, wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon; Each R B The groups are independently halo, C 1-6 Alkyl or C 2-6 alkenyl; or two adjacent R B The groups, together with the carbon atoms to which they are attached, form C 3-10 Forming a cycloalkyl; or two geminal R B The groups, together with the carbon atoms to which they are attached, form C 3-10 Forming a cycloalkyl; m is 0, 1, 2, 3 or 4; Y 1 is N or CR C1 and; Y 2 is N or CR C2 and; Y 3 is N or CR C3 and; Y 4 is N or CR C4 and; In the formula, Y 1 , Y 2 , Y 3 and Y 4 of which 3 or less are N; R C1 -R C4 are each independently hydrogen, halo, cyano, -OH, -NO2, or -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 C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halo, and —OH; 1-6 The compound or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

[0199] 60. The compound is 4'-fluoro-1'-[3-(piperidine-1-sulfonyl)benzoyl]-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; 3-cyclopropyl-1-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]urea; 1-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]-3-(propan-2-yl)urea; [4-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole]-1'-yl}carbonyl)phenyl]methanol; 4'-fluoro-1' 59. The compound of embodiment 57 or 58, or a pharmaceutically acceptable salt thereof, which is not -(1H-indole-5-carbonyl)-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; N-[3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indol]-1'-yl}carbonyl)phenyl]pyrimidin-2-amine; 4'-fluoro-1'-[3-(morpholine-4-sulfonyl)benzoyl]-1',2'-dihydrospiro[cyclopentane-1,3'-indole]; [3-({4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indol]-1'-yl}carbonyl)phenyl]urea; or a salt of any of the foregoing.

[0200] 61. The compound according to embodiment 57 or 60, or a pharmaceutically acceptable salt thereof, wherein ring A is optionally substituted C6-14 aryl.

[0201] 62. The compound according to embodiment 61, or a pharmaceutically acceptable salt thereof, wherein ring A is optionally substituted phenyl.

[0202] 63. The compound according to embodiment 57 or 60, or a pharmaceutically acceptable salt thereof, wherein ring A is an optionally substituted 5-10 membered heteroaryl.

[0203] 64. The compound according to embodiment 63, or a pharmaceutically acceptable salt thereof, wherein ring A is indolyl, indazolyl, pyridinyl, thiophenyl, furanyl, pyrazolyl, pyrrolyl, oxazolyl, chromanyl, or quinolinyl, each of which is optionally substituted.

[0204] 65.R a1 is hydrogen or C 1-6 alkyl; R a2 and R a3 are independently hydrogen, C 1-6 Alkyl, or C 3-10 is cycloalkyl; R a4 is hydrogen or C 1-6 alkyl; R a5 is hydrogen or C 1-6 alkyl; R a6 and R a7 are independently hydrogen, C 1-6 Alkyl, or C 1-6 R is a 5-12 membered heteroaryl optionally substituted with alkyl; a8 and R a9 are independently hydrogen, C 1-6 Alkyl, or C 3-10 is cycloalkyl; R a10 C 3-10 is cycloalkyl; R a11 C 3-10 is cycloalkyl; R a12 is hydrogen or C 1-6 alkyl; R a13 C 3-10 is cycloalkyl; R a16 C 3-10 Cycloalkyl or C 1-6 R is a 3- to 12-membered heterocycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of alkyl or halo; a17 and R a18 are each independently hydrogen or C 1-6 alkyl; R a19 and R a20 are independently hydrogen, C 1-6 Alkyl, or C 3-10is cycloalkyl; R a21 C 3-10 cycloalkyl; and R a22 C 3-10 The compound of any one of embodiments 57 and 60-64, or a pharmaceutically acceptable salt thereof, wherein is cycloalkyl.

[0205] 66.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 one 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 , as well as -OH, -O(C 1-6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl, and halo 1-6 C optionally substituted with one 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 one or more C 1-6 The compound of any one of embodiments 57 and 60-65, or a pharmaceutically acceptable salt thereof, wherein the heterocycloalkyl is a 3-12 membered ring optionally substituted with alkyl.

[0206] 67.R a14 is hydrogen and R a15 The compound according to any one of embodiments 57 and 60-66, or a pharmaceutically acceptable salt thereof, wherein is tert-butyl.

[0207] 68. Ring A is fluoro, chloro, -OH, methyl, amino, [ka] [ka] 68. The compound of any one of embodiments 57 and 60-67, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of:

[0208] 69. Ring A [ka] 69. The compound of any one of embodiments 57 and 60-68, wherein R is phenyl substituted with R, or a pharmaceutically acceptable salt thereof.

[0209] 70. Ring B is C 5-7 The compound of any one of embodiments 57 and 60-69, or a pharmaceutically acceptable salt thereof, wherein is cycloalkyl.

[0210] 71. The compound according to any one of embodiments 57 and 60-69, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 5-7 membered heterocycloalkyl.

[0211] 72. Ring B is [ka] 70. The compound of any one of embodiments 57 and 60-69, wherein * represents the point of attachment to the remainder of formula (I), or a pharmaceutically acceptable salt thereof.

[0212] 73. Formula (I) [ka] but, [ka] 70. The compound of any one of embodiments 57 and 60-69, wherein * represents the point of attachment to the remainder of formula (I), or a pharmaceutically acceptable salt thereof.

[0213] 74. Formula (I) [ka] but [ka] or a pharmaceutically acceptable salt thereof.

[0214] 75.Y 1 is CR C1 and;Y 2 is CR C2 and;Y 3 is CR C3 and Y 4 is CR C4 75. The compound of any one of embodiments 57 and 60-74, wherein:

[0215] 76.R C1 , R C3 , and R C4 is each independently hydrogen, halo, or —NH 2 , or a pharmaceutically acceptable salt thereof.

[0216] 77.R C1 , R C3 and R C4が 77. The compound of embodiment 75 or 76, or a pharmaceutically acceptable salt thereof, wherein each is hydrogen.

[0217] 78.Y 1 is N;Y 2 is CR C2 and;Y 3 is CR C3 and Y 4 is CR C475. The compound of any one of embodiments 57 and 60-74, wherein:

[0218] 79.Y 1 is CR C1 and;Y 2 is N;Y 3 is CR C3 and Y 4 is CR C4 75. The compound of any one of embodiments 57 and 60-74, wherein:

[0219] 80.R C2 Cyano, -OH, -CH2OH, Bromo, -NO2, [ka] 80. The compound of any one of embodiments 57 and 60-79, wherein:

[0220] 81.R C2 but [ka] or a pharmaceutically acceptable salt thereof.

[0221] 82. The compound according to embodiment 57 or 60, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of the compounds in Table 1.

[0222] 83. The compound according to embodiment 57, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of the compounds in Table 2.

[0223] 84. A pharmaceutical composition comprising a compound according to any one of embodiments 57-83, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0224] 85. A method for inhibiting KIF18A, comprising contacting a cell with an effective amount of a compound described in any one of embodiments 57 to 83, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in embodiment 84.

[0225] 86. A method for treating a disease or condition mediated by KIF18A in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described in any one of embodiments 57 to 83, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in embodiment 84.

[0226] 87. A method for 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 57 to 83, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 84.

[0227] 88. The method of embodiment 87, 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, other tumors including retinoblastoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, and other cancer-related disorders that are a result of the presence or progression of cancer. [Example]

[0228] 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 DAST: Diaminosulfur trifluoride dba: dibenzylidene acetone DMF: dimethylformamide EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide ESI MS: Electrospray mass spectrometry HATU: 3-Oxidohexafluorophosphate 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium HOBT: 1-hydroxybenzotriazole HPLC: High-performance liquid chromatography I C 50 :50% inhibitory concentration LDA: lithium diisopropylamide mCPBA: meta-chloroperbenzoic acid MsCl: methanesulfonyl chloride MTBE: Methyl t-butyl ether NCS: N-chlorosuccinimide NCI: N-iodosuccinimide NMR: nuclear magnetic resonance PE: Petroleum ether THF: tetrahydrofuran TFA: Trifluoroacetic acid Xanthphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene Xphos Pd G4: Dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphanium; Methanesulfonic acid; N-methyl-2-phenylaniline; Palladium (CAS: 1599466-81-5)

[0229] Synthesis of intermediates Synthesis of 3-(piperidin-1-ylsulfonyl)benzoic acid (A-01) [ka] Step 1. A mixture of piperidine (0.25 mL, 2.6 mmol), CHCl (5.0 mL), iPrNEt (1.3 mL, 7.7 mmol), and methyl 3-chlorosulfonylbenzoate (900 mg, 3.84 mmol, 1.5 equiv) was stirred for 2 h, concentrated, poured into HO (20 mL), and extracted with EtOAc (2×10 mL). The extracts were combined, washed with brine (10.0 mL), dried over NaSO, filtered, and concentrated to give methyl 3-(1-piperidylsulfonyl)benzoate (0.95 g).

[0230] Step 2. A mixture of methyl 3-(1-piperidylsulfonyl)benzoate (0.90 g, 3.2 mmol), THF (6.0 mL), HO (2.0 mL), and LiOH·HO (0.67 g, 16 mmol) was stirred for 2 h and then concentrated. The mixture was treated with HCl (4 N) to pH 3, poured into HO (10 mL), and extracted with EtOAc (2 × 10 mL). The extracts were combined, washed with brine (10.0 mL), dried over NaSO, filtered, and concentrated to give 3-(1-piperidylsulfonyl)benzoic acid (A-01, 0.72 g). ESIMS m / z: 270.0 (M+H). +

[0231] The compounds in Table 3 were prepared in the same manner as A-01 from the indicated sulfonyl chloride and amine. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11]

[0232] Synthesis of 3-(cyclopentylsulfinyl)benzoic acid (A-51) [ka] Step 1. A mixture of methyl 3-cyclopentylsulfanylbenzoate (0.50 g, 2.1 mmol), CHCl (25 mL), and MnO (0.37 g, 4.2 mmol) was stirred at 20 °C for 16 h. The mixture was extracted with EtOAc (100 mL × 3), and the extracts were combined, dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (0–100% EtOAc / petroleum ether) to give methyl 3-cyclopentylsulfinylbenzoate (0.52 g).

[0233] Step 2. A mixture of methyl 3-cyclopentylsulfinylbenzoate (0.50 g, 2.0 mmol), THF (10 mL), HO (10 mL), and LiOH (95 mg, 4.0 mmol) was stirred at 25 °C for 2 h and then concentrated. The pH was adjusted to 3 with 2 M HCl, and the mixture was extracted with EtOAc (50 mL × 3). The combined extracts were dried over NaSO, filtered, and concentrated to give 3-cyclopentylsulfinylbenzoic acid (A-51, 83 mg).

[0234] Synthesis of 3-(cyclopentylsulfonyl)benzoic acid (A-52) [ka] Step 1. To a mixture of methyl 3-cyclopentylsulfanylbenzoate (0.50 g, 2.1 mmol) in HOAc (3.0 mL) was added HO (30%, 1.2 mL, 13 mmol). The mixture was stirred at 80 °C for 12 h, HO (20 mL) was added, and the mixture was extracted with EtOAc (10 mL × 3). The extracts were combined and washed with saturated NaCO (20 mL × 3), aqueous NaSO (20 mL × 3), and brine (30 mL). The extract was dried over NaSO, filtered, and concentrated to give methyl 3-cyclopentylsulfonylbenzoate (260 mg).

[0235] Step 2. A mixture of methyl 3-cyclopentylsulfonylbenzoate (0.28 g, 1.0 mmol), THF (5.0 mL), HO (5 mL), and LiOH (50 mg, 2.1 mmol) was stirred at 25 °C for 2 h. The reaction mixture was extracted with MTBE (10 mL × 2). The pH of the aqueous phase was adjusted to 3 with HCl, and it was extracted with EtOAc (3 × 20 mL). The extracts were combined, washed with 20 mL of brine, dried over NaSO, filtered, and concentrated to give 3-cyclopentylsulfonylbenzoic acid (0.29 g).

[0236] Synthesis of 3-(N-methylcyclopentanesulfonimidoyl)benzoic acid (A-53) [ka] Step 1. To a mixture of methyl 3-cyclopentylsulfanylbenzoate (0.85 g, 3.6 mmol), EtOH (2 mL), and PhI(OAc) (3.5 g, 11 mmol) was added NHOAc (1.1 g, 14 mmol). The mixture was stirred at 20 °C for 2 h, concentrated, combined with 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 silica chromatography (0–100% EtOAc in petroleum ether) to give methyl 3-(cyclopentylsulfonimidoyl)benzoate (0.50 g).

[0237] Step 2. To a 0° C. mixture of methyl 3-(cyclopentylsulfonimidoyl)benzoate (0.25 g, 0.94 mmol) and DMF (2 mL) was added NaH (60% in mineral oil, 45 mg, 1.1). The mixture was stirred at 0° C. for 0.5 h, and MeI (64 μL, 1.0 mmol) was added. The mixture was stirred at 20° C. for 12 h, poured into HO (30 mL), and extracted with EtOAc (2×30 mL). The extracts were combined, washed with brine (10 mL), dried over NaSO, and concentrated to give 3-(S-cyclopentyl-N-methyl-sulfonimidoyl)benzoic acid (A-53, 0.25 g).

[0238] Synthesis of 3-(cyclopentanecarbonyl)benzoic acid (A-54) [ka] Step 1. To a −50° C. mixture of methyl 3-cyanobenzoate (1.0 g, 6.2 mmol), CuI (0.37 g, 1.9 mmol), and THF (30 mL) was slowly added cyclopentylmagnesium bromide (1 M in THF, 24 mL, 24 mmol). The mixture was stirred at −50° C. for 5 h and then at 20° C. for 1 h, and saturated aqueous NH4Cl (10 mL) was added at 0° C. EtOAc (20 mL) was added and the layers were separated. The aqueous washes were extracted with EtOAc (10 mL), and the extracts were combined, washed with brine (15 mL × 2), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0–20% EtOAc / petroleum ether) to give methyl 3-(cyclopentanecarbonyl)benzoate (0.22 g).

[0239] Step 2. A degassed mixture of methyl 3-(cyclopentanecarbonyl)benzoate (0.22 g, 0.95 mmol), LiOH (0.11 g, 4.7 mmol), THF (0.9 mL), and HO (0.3 mL) was stirred at 25 °C for 4 h. The mixture was concentrated, combined with HO (10 mL), and extracted with MTBE (2 mL). The pH of the aqueous phase was adjusted to between 2 and 3 with 2 N HCl. The resulting precipitate was filtered and dried under vacuum to give 3-(cyclopentanecarbonyl)benzoic acid (A-54, 120 mg).

[0240] Synthesis of 3-(cyclobutanecarbonyl)benzoic acid (A-77) [ka] 3-(Cyclobutanecarbonyl)benzoic acid was prepared from methyl 3-cyanobenzoate and cyclobutanemagnesium bromide in a similar manner to A-54.

[0241] Synthesis of 3-(2-cyclobutylacetyl)benzoic acid (A-75) [ka] Step 1. To a mixture of 3-bromobenzonitrile (2.0 g, 11 mmol) and THF (10 mL) at −50° C. was added CuI (2.1 g, 11 mmol) and bromo(cyclobutylmethyl)magnesium (1 M, 13.2 mL). The mixture was stirred at −50° C. for 5 h and then at 20° C. for 1 h. The mixture was poured into HO (20 mL) and extracted with EtOAc (2×20 mL). The combined extracts were washed with brine (20 mL), dried over NaSO, concentrated, and purified by silica chromatography (0–20% EtOAc in PE) to give 1-(3-bromophenyl)-2-cyclobutylethan-1-one (1.3 g).

[0242] Step 2. A mixture of 1-(3-bromophenyl)-2-cyclobutylethan-1-one (1.1 g, 4.4 mmol), MeOH (4 mL), DMF (16 mL), EtN (1.8 mL, 13 mmol), 3-diphenylphosphanylpropyl-(diphenyl)phosphane (0.36 g, 0.87 mmol), and Pd(OAc) (0.20 g, 0.87 mmol) was stirred at 90 °C for 12 h under CO (50 psi). The mixture 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 (0–20% EtOAc in PE) to give methyl 3-(2-cyclobutylacetyl)benzoate (0.80 g).

[0243] Step 3. A mixture of methyl 3-(2-cyclobutylacetyl)benzoate (0.50 g, 2.2 mmol), THF (0.6 mL), HO (0.2 mL), and LiOH (0.16 g, 6.7 mmol) was stirred at 20 °C for 2 h. The mixture was concentrated to remove THF, and HCl (0.5 M, 5 mL) was added. The mixture was extracted with EtOAc (2 × 30 mL), and the combined extracts were washed with brine (10 mL), dried over NaSO, and concentrated to give 3-(2-cyclobutylacetyl)benzoic acid (0.36 g, 46% purity).

[0244] Synthesis of 3-(cyclopentyldifluoromethyl)benzoic acid (A-76) [ka] Step 1. To a mixture of methyl 3-(cyclopentanecarbonyl)benzoate (0.16 mg, 0.69 mmol) and CHCl (1 mL) was added BF·EtO (0.64 mL, 5.2 mmol) and ethane-1,2-dithiol (0.10 mL, 1.2 mmol). The mixture was stirred at 20 °C for 18 h, poured into water (20 mL), and extracted with CHCl (2 × 30 mL). The combined extracts were washed with brine (10 mL), dried over NaSO, concentrated, and purified by preparative TLC (10% EtOAc / PE) to give methyl 3-(2-cyclopentyl-1,3-dithiolan-2-yl)benzoate (0.20 g).

[0245] Step 2. To a mixture of methyl 3-(2-cyclopentyl-1,3-dithiolan-2-yl)benzoate (0.20 g, 0.65 mmol) and CHCl (10 mL) was added NIS (0.29 g, 1.3 mmol) and hydrofluorinated pyridine (0.33 mL, 2.6 mmol) at −70° C. The mixture was stirred at −70° C. for 0.5 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, concentrated, and purified by preparative TLC (10% EtOAc in PE) to give methyl 3-[cyclopentyl(difluoro)methyl]benzoate (80 mg).

[0246] Step 3. A mixture of methyl 3-[cyclopentyl(difluoro)methyl]benzoate (80 mg, 0.32 mmol), THF (3 mL), HO (1 mL), and LiOH (23 mg, 0.94 mmol) was stirred at 20 °C for 2 h. The mixture was concentrated, combined with HCl (0.5 M, 5 mL), and extracted with EtOAc (2 × 30 mL). The combined extracts were washed with brine (10 mL), dried over NaSO, and concentrated to give 3-[cyclopentyl(difluoro)methyl]benzoic acid (A-76, 91 mg).

[0247] Synthesis of 3-(cyclopentanesulfonimidoyl)benzoic acid (A-72) [ka] A mixture of methyl 3-(cyclopentylsulfonylimidoyl)benzoate (0.80 g, 3.0 mmol), THF (18 mL), HO (6 mL), and LiOH HO (0.38 g, 9.0 mmol) was stirred at 25 °C for 12 h, then poured into water (20 mL) and extracted with EtOAc (2 × 20 mL). The organic phase was washed with brine (20 mL), dried over NaSO, and concentrated to give 3-(cyclopentanesulfonimidoyl)benzoic acid (A-72, 0.3 g). 1 H NMR (DMSO-d 6 ,400MHz)δppm13.72-13.06(m,1H),8.40-8.38(s,1H),8.20-8.17(m,1H),8.13-8.09 (m,1H),7.76-7.72(m,1H),3.68-3.60(m,1H),1.91-1.70(m,4H),1.62-1.47(m,4H).

[0248] Synthesis of 2-(cyclopentyl(hydroxy)methyl)isonicotinic acid (A-78) [ka] Step 1. To a −60° C. mixture of methyl 2-formylisonicotinate (1.0 g, 6.0 mmol) and THF (25 mL) was added cyclopentylmagnesium bromide (1 M, 7.3 mL) over 15 minutes. The resulting mixture was stirred at −60° C. for 1.75 hours, poured into water (50 mL), and extracted with EtOAc (2×50 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 give methyl 2-(cyclopentyl(hydroxy)methyl)isonicotinate (0.20 g).

[0249] Step 2. A mixture of methyl 2-(cyclopentyl(hydroxy)methyl)isonicotinate (0.18 g, 0.77 mmol), THF (2 mL), HO (1 mL), and LiOH HO (96 mg, 2.0 mmol) was stirred at 25 °C for 2 h, poured into water (30 mL), and extracted with MTBE (2 × 20 mL). The aqueous layer was collected, and the pH was adjusted to 5 by careful addition of 2 N HCl. The mixture was concentrated to give 2-(cyclopentyl(hydroxy)methyl)isonicotinic acid (A-78).

[0250] Synthesis of 3-((3,3-difluorocyclobutyl)sulfonyl)benzoic acid (A-82) [ka] Step 1. A mixture of 3-bromobenzenethiol (3.4 mL, 33 mmol), 4-bromobut-1-ene (4.4 mL, 43 mmol), DMF (50 mL), and K2CO3 (6.8 g, 49 mmol) was stirred at 60 °C for 4 h, combined with 1 M aqueous Na2SO3 and saturated NaHCO3 (30 mL), and extracted with C2Cl2 (2 × 30 mL). The combined extracts were washed with brine (10 mL), dried over Na2SO4, concentrated, and purified by silica chromatography (0 to 100% EtOAc in PE) to give 1-bromo-3-but-3-enylsulfanyl-benzene (6.50 g).

[0251] Step 2. To a mixture of 1-bromo-3-but-3-enylsulfanyl-benzene (6.5 g, 27 mmol) and CHCl (50 mL) was added mCPBA (27 g, 0.13 mol, 85% purity). The mixture was stirred at 20 °C for 12 h, combined with 1 M aqueous NaSO and saturated aqueous NaHCO (30 mL), extracted with CHCl (2 × 30 mL), washed with brine (10 mL), dried over NaSO, concentrated, and purified by silica chromatography (0–100% EtOAc in PE) to give 2-[2-(3-bromophenyl)sulfonylethyl]oxirane (5.1 g).

[0252] Step 3. To a mixture of 2-[2-(3-bromophenyl)sulfonylethyl]oxirane (5.1 g, 18 mmol) and THF (5 mL) was added MeMgBr (3 M, 23 mL, 69 mmol) at -70 °C. The mixture was stirred at 20 °C for 12 h, poured into saturated aqueous NH4Cl (20 mL), and extracted with EtOAc (2 × 20 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 3-(3-bromophenyl)sulfonylcyclobutanol (4.3 g).

[0253] Step 4. To a mixture of 3-(3-bromophenyl)sulfonylcyclobutanol (1.00 g, 3.4 mmol), HO (10 mL), MeCN (5 mL), and CHCl (5 mL) was added RuCl·HO (8 mg, 34 μmol) and NaIO (3.7 g, 17 mmol) at 40 °C. The resulting mixture was stirred at 40 °C for 12 h, cold water (30 mL) was added, and the mixture was extracted with CHCl (2 × 30 mL). The combined extracts were washed with saturated aqueous NaHCO and brine, dried over NaSO, concentrated, and purified by silica chromatography (0–100% EtOAc in PE) to give 3-(3-bromophenyl)sulfonylcyclobutanone (0.64 g).

[0254] Step 5. To a mixture of 3-(3-bromophenyl)sulfonylcyclobutanone (0.64 g, 2.2 mmol) and CHCl (6 mL) was added DAST (0.88 mL, 6.6 mmol) at −70° C. over 0.5 h. The mixture was stirred for 1 h, then warmed to 20° C. and stirred for 16 h. The mixture was poured into saturated aqueous NaHCO (10 mL), extracted with CHCl (2 × 10 mL), and the combined extracts were washed with brine (10 mL), dried over NaSO, concentrated, and purified by silica chromatography (0–100% EtOAc in PE) to give 1-bromo-3-(3,3-difluorocyclobutyl)sulfonyl-benzene (0.60 g).

[0255] Step 6. CO gas was bubbled through a stirring mixture of 1-bromo-3-(3,3-difluorocyclobutyl)sulfonyl-benzene (0.55 g, 1.8 mmol), EtN (0.49 mL, 3.5 mmol), DMF (6 mL), MeOH (3 mL), bis(diphenylphosphino)propane (73 mg, 0.18 mmol), and Pd(OAc) (40 mg, 0.18 mmol) for 5 min, and then the mixture was heated at 80 °C under a CO atmosphere at 15 psi for 12 h. The mixture 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 (0–100% EtOAc in PE) to give methyl 3-(3,3-difluorocyclobutyl)sulfonylbenzoate (0.44 g).

[0256] Step 7. A mixture of methyl 3-(3,3-difluorocyclobutyl)sulfonylbenzoate (0.44 g, 1.5 mmol), THF (5 mL), HO (1.5 mL), and LiOH HO (0.25 g, 6.1 mmol) was stirred at 40 °C for 2 h, concentrated, combined with HO (30 mL), 2 N HCl was added until the pH was between 3 and 4, and the resulting mixture was extracted with EtOAc (2 × 30 mL). The combined extracts were washed with brine (10 mL), dried over NaSO, and concentrated to give 3-((3,3-difluorocyclobutyl)sulfonyl)benzoic acid (A-82, 0.33 g).

[0257] Synthesis of 5-(cyclopentylsulfonyl)thiophene-3-carboxylic acid (A-83) [ka] Step 1. A mixture of methyl 5-bromothiophene-3-carboxylate (1.0 g, 4.5 mmol), 1,4-dioxane (2.5 mL), iPrNEt (2.0 mL, 11 mmol), Pd(dba) (0.41 g, 0.45 mmol), cyclopentanethiol (0.73 mL, 6.8 mmol), and Xantphos (0.26 g, 0.45 mmol) was stirred at 110 °C for 12 h. The mixture was poured into HO (20 mL), extracted with EtOAc (2 × 10 mL), and the combined extracts were washed with brine (20 mL), dried over NaSO, concentrated, and purified by silica chromatography (5-50% EtOAc in PE) to give methyl 5-cyclopentylsulfanylthiophene-3-carboxylate (1.0 g).

[0258] Step 2. To a mixture of methyl 5-cyclopentylsulfanylthiophene-3-carboxylate (0.70 g, 2.9 mmol) and CHCl (20 mL) was added mCPBA (2.4 g, 12 mmol, 85% purity). The mixture was stirred at 20 °C for 12 h, poured into saturated NaSO (10 mL), and extracted with EtOAc (2 × 5 mL). The combined extracts were washed with brine (10 mL), dried over anhydrous NaSO, concentrated, and purified by silica chromatography (5–50% EtOAc in PE) to give methyl 5-cyclopentylsulfonylthiophene-3-carboxylate (0.70 g).

[0259] Step 3. A mixture of methyl 5-cyclopentylsulfonylthiophene-3-carboxylate (0.71 g, 2.6 mmol), THF (9 mL), HO (3 mL), and LiOH·HO (0.32 g, 7.7 mmol) was stirred at 20 °C for 12 h, poured into HO (10 mL), and the pH was adjusted to 3–4 with HCl (2 N). The resulting mixture was extracted with EtOAc (2 × 5 mL). The extracts were combined, washed with brine (5 mL), dried over NaSO, concentrated, and purified by silica chromatography (5–50% EtOAc in PE) to give 5-(cyclopentylsulfonyl)thiophene-3-carboxylic acid (A-83, 0.40 g).

[0260] Synthesis of 3-(cyano(cyclopentyl)methyl)benzoic acid (A-85) [ka] Step 1. To a mixture of methyl 3-(cyanomethyl)benzoate (0.10 g, 0.58 mmol) and DMF (2 mL) was added NaH (27 mg, 0.69 mmol, 285 μL, 60% purity, 1.2 equiv.) at 0 °C. After stirring for 0.5 h, bromocyclopentane (0.12 mL, 1.1 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 2 h, and saturated aqueous NH Cl (2 mL) and HO (10 mL) were added at 0 °C. The mixture was extracted with EtOAc (10 mL × 3), and the combined extracts were washed with brine (10 mL × 3), dried over Na SO , filtered, concentrated, and purified by silica chromatography (0–15% EtOAc in PE) to give methyl 3-(cyano(cyclopentyl)methyl)benzoate (0.10 g).

[0261] Step 2. A mixture of methyl 3-(cyano(cyclopentyl)methyl)benzoate (0.10 g, 0.41 mmol), THF (3 mL), HO (3 mL), and LiOH HO (35 mg, 0.82 mmol) was stirred at 20 °C for 4 h, concentrated, and the pH was adjusted to 4 by dropwise addition of 2 M HCl. The mixture was extracted with EtOAc (20 mL × 3), and the combined extracts were dried over NaSO, filtered, and concentrated to give 3-(cyano(cyclopentyl)methyl)benzoic acid (A-85, 0.11 g).

[0262] Synthesis of 3-(1-(4,4-difluoropiperidin-1-yl)ethyl)benzoic acid (A-86) [ka]

[0263] Step 1. A mixture of methyl 3-acetylbenzoate (1.0 g, 5.6 mmol), 4,4-difluoropiperidine hydrochloride (0.88 g, 5.6 mmol), 1,2-dichloroethane (20 mL), and Ti(OiPr) (6.6 mL, 23 mmol) was stirred at 80 °C for 12 h. NaBH(OAc) (3.6 g, 17 mmol) was added, and the mixture was stirred at 80 °C for 2 h, poured into water (20 mL), and extracted with EtOAc (2 × 20 mL). The combined extracts were washed with brine (10 mL), dried over NaSO, and concentrated to give isopropyl 3-[1-(4,4-difluoro-1-piperidyl)ethyl]benzoate (1.5 g).

[0264] Step 2. A mixture of isopropyl 3-[1-(4,4-difluoro-1-piperidyl)ethyl]benzoate (1.4 g, 4.6 mmol) and LiOH (0.33 g, 14 mmol) in THF (14 mL), MeOH (3.3 mL), and HO (3.3 mL) was stirred at 25 °C for 2 h. The mixture was concentrated, combined with HO (28 mL), and washed with EtOAc (2 x 28 mL). The aqueous solution was treated with 2 M HCl to pH 2, and the resulting mixture was concentrated to give 3-[1-(4,4-difluoro-1-piperidyl)ethyl]benzoic acid (A-86, 0.91 g).

[0265] Synthesis of 6-((4,4-difluoropiperidin-1-yl)methyl)picolinic acid (A-87) [ka]

[0266] Step 1. To a mixture of methyl 6-formylpyridine-2-carboxylate (0.50 g, 3.0 mmol) and 4,4-difluoropiperidine (477 mg, 3.0 mmol, 1.0 equiv, HCl) in MeOH (10 mL) was added HOAc (545 mg, 9.1 mmol, 519 uL, 3.0 equiv), NaOAc (745 mg, 9.1 mmol, 3.0 equiv), and then stirred at 25 °C for 1 h. NaBHCN (761 mg, 12.1 mmol, 4.0 equiv) was then added and the mixture was stirred at 25 °C for 1 h. The reaction was poured into water (10 mL), and the resulting mixture was extracted with EtOAc (2 × 10 mL). The organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give compound methyl 6-[(4,4-difluoro-1-piperidyl)methyl]pyridine-2-carboxylate (500 mg, crude) as a yellow solid.

[0267] Synthesis of 3-((3,3-difluoropyrrolidin-1-yl)methyl)benzoic acid (A-92) [ka] 3-((3,3-Difluoropyrrolidin-1-yl)methyl)benzoic acid (A-92) was prepared from methyl 3-formylbenzoate by the method described for the synthesis of A-87.

[0268] Synthesis of 2-((4,4-difluoropiperidin-1-yl)methyl)-6-methylpyrimidine-4-carboxylic acid (A-88) [ka] A mixture of potassium ((4,4-difluoropiperidin-1-yl)methyl)trifluoroborate (CAS: 1708960-44-4, 1.1 g, 4.6 mmol), methyl 2-chloro-6-methyl-pyrimidine-4-carboxylate (0.28 g, 1.5 mmol), HO (2 mL), THF (8 mL), CsCO (1.5 g, 4.6 mmol), and Xphos Pd G (65 mg, 76 μmol) was stirred at 80 °C for 12 h, diluted with water (10 mL), and extracted with EtOAc (10 mL × 3). The combined extracts were washed with brine (10 mL), dried over NaSO, filtered, concentrated, and purified by preparative HPLC (C, 1-10% MeCN in HO [formic acid]) to afford 2-((4,4-difluoropiperidin-1-yl)methyl)-6-methylpyrimidine-4-carboxylic acid (A-88, 50 mg).

[0269] Synthesis of 3-(Isoxazolidin-2-ylmethyl)benzoic acid (A-89) [ka] Step 1. A mixture of methyl 3-(bromomethyl)benzoate (0.30 g, 1.3 mmol), DMF (3 mL), isoxazolidine hydrochloride (0.14 g, 1.3), and iPrNEt (0.68 mL, 3.9 mmol) was stirred at 60 °C for 12 h. The mixture was combined with HO (10 mL) at 0 °C and extracted with EtOAc (10 mL × 2). The combined extracts were washed with HO (10 mL) and brine (10 mL), dried over NaSO, concentrated, and purified by silica chromatography (0 to 100% EtOAc in PE) to give methyl 3-(isoxazolidin-2-ylmethyl)benzoate (0.17 g).

[0270] Step 2. A mixture of methyl 3-(isoxazolidin-2-ylmethyl)benzoate (0.17 g, 0.77 mmol), 1,4-dioxane (1.5 mL), HO (0.5 mL), and LiOH HO (32 mg, 0.77 mmol) was stirred at 20 °C for 12 h, and then diluted with HO (5 mL) and MTBE (10 mL). The aqueous phase was collected, and the pH was adjusted to 6.0 by the addition of HCl (2 N). The aqueous phase was concentrated to give 3-(isoxazolidin-3-ylmethyl)benzoic acid (A-89, 0.17 g, crude).

[0271] Synthesis of 3-((6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)methyl)benzoic acid (A-96) [ka] The synthesis of 3-((6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)methyl)benzoic acid (A-96) was prepared in a similar manner to A-89, replacing isoxazolidine hydrochloride with 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride.

[0272] Synthesis of 3-(cyclopentylamino)benzoic acid (A-90) [ka] Step 1. A mixture of methyl 3-aminobenzoate (1.0 g, 6.6 mmol), cyclopentanone (2.9 mL, 33 mmol), MeOH (10 mL), and HOAc (0.38 mL, 6.6 mmol) was stirred for 3 h, and NaBHCN (0.62 g, 9.9 mmol) was added portionwise. The resulting mixture was stirred for 11 h, poured into water (50 mL), and extracted with EtOAc (2 × 25 mL). The extract was washed with brine (10 mL), dried over NaSO, concentrated, and purified by silica chromatography (5–50% EtOAc in PE) to give methyl 3-(cyclopentylamino)benzoate (1.33 g, 91.68% yield) as a white solid.

[0273] Step 2. A mixture of methyl 3-(cyclopentylamino)benzoate (0.10 g, 0.46 mmol), THF (0.9 mL), HO (0.3 mL), and LiOH HO (96 mg, 2.3 mmol) was stirred at 60 °C for 6 h, poured into HO (10 mL), and the pH was adjusted to 5–6 with HCl (2 N). The resulting mixture was extracted with EtOAc (2 × 5 mL), and the extract was washed with brine (5 mL), dried over NaSO, and concentrated to give 3-(cyclopentylamino)benzoic acid (A-90, 53 mg).

[0274] Synthesis of 3-(cyclopentyl(methyl)amino)benzoic acid (A-91) [ka] Step 1. To a mixture of methyl 3-(cyclopentylamino)benzoate (0.50 g, 2.0 mmol), paraformaldehyde (0.41 mg, 5 mmol), and dichloroethane (5 mL) was added HOAc (0.16 mL, 3.0 mmol) dropwise at 20 °C. After stirring for 1 h, NaBH(OAc) (0.97 g, 5 mmol) was added and the mixture was stirred at 60 °C for 11 h. The reaction was poured into water (20 mL), and the resulting mixture was extracted with EtOAc (2 × 15 mL). The organic phase was washed with brine (10 mL), dried over NaSO, concentrated, and purified by silica chromatography (5–50% EtOAc in PE) to give methyl 3-[cyclopentyl(methyl)amino]benzoate (0.42 g).

[0275] Step 2. A mixture of methyl 3-[cyclopentyl(methyl)amino]benzoate (0.23 g, 0.98 mmol), THF (3 mL), HO (1 mL), and LiOH HO (0.12 g, 3.0 mmol) was stirred at 60 °C for 2 h. The mixture was poured into water (10 mL), the pH was adjusted to 3–4 with HCl (2 N), and extracted with EtOAc (2 × 5 mL). The extract was washed with brine (5 mL), dried over NaSO, and concentrated to give 3-(cyclopentyl(methyl)amino)benzoic acid (A-91, 0.30 g).

[0276] Synthesis of 3-(3,3-difluorocyclobutane-1-carbonyl)benzoic acid (A-93) [ka] Step 1. To a mixture of 1-bromo-3-iodo-benzene (1.3 mL, 10 mmol) and THF (20 mL) at −70° C., BuLi (1 M, 10 mL) was added dropwise. The mixture was stirred for 30 min. 3,3-Difluoro-N-methoxy-N-methyl-cyclobutanecarboxamide (1.5 g, 8.4 mmol) in THF (10 mL) was added dropwise at −70° C. The resulting mixture was stirred at 20° C. for 1.5 h, poured into saturated aqueous 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 (3-bromophenyl)-(3,3-difluorocyclobutyl)methanone (1.1 g).

[0277] Step 2. A mixture of (3-bromophenyl)-(3,3-difluorocyclobutyl)methanone (1.0 g, 3.6 mmol), MeOH (5 mL), DMF (10 mL), EtN (1.5 mL, 11 mmol), 3-diphenylphosphanylpropyl(diphenyl)phosphane (0.30 g, 0.73 mmol), and Pd(OAc) (0.16 g, 0.73 mmol) was stirred at 80 °C for 12 hours under CO (50 psi). The mixture was concentrated, 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 TLC (10% EtOAc in PE) to give methyl 3-(3,3-difluorocyclobutanecarbonyl)benzoate (0.80 g).

[0278] Step 3. A mixture of methyl 3-(3,3-difluorocyclobutanecarbonyl)benzoate (0.80 g, 3.2 mmol), THF (0.6 mL), HO (0.2 mL), and LiOH HO (226 mg, 9.4 mmol, 3.0 equiv.) was stirred at 20 °C for 2 h, concentrated, and HCl (0.5 M, 5 mL) was added. The mixture was extracted with EtOAc (10 mL), and the extract was concentrated to give 3-(3,3-difluorocyclobutane-1-carbonyl)benzoic acid (A-93, 0.50 g).

[0279] Synthesis of 3-(1-methylcyclobutane-1-carbonyl)benzoic acid (A-94) [ka] 3-(1-Methylcyclobutane-1-carbonyl)benzoic acid (A-94) was prepared in a similar manner to A-93.

[0280] Synthesis of 4-(cyclopentanecarbonyl)thiophene-2-carboxylic acid (A-98) [ka] To 4-bromothiophene-2-carboxylic acid (0.80 g, 3.9 mmol) in THF (15 mL) was added nBuLi (2.5 M, 3.9 mL, 2.5 equiv.) dropwise over 5 min at −78 °C. The mixture was stirred for 25 min, and N-methoxy-N-methyl-cyclopentacarboxamide (0.91 g, 5.8 mmol) was added at −78 °C. The resulting mixture was stirred at 20 °C for 12 h, combined with 1 mL of saturated NH4Cl and HO (5 mL) at −78 °C, and extracted with EtOAc (10 mL × 3). The combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified by preparative HPLC (C18, 20–50% MeCN / HO [HCl]) to give 4-(cyclopentanecarbonyl)thiophene-2-carboxylic acid (A-98, 10%).

[0281] Synthesis of 5-(cyclopentyl(hydroxy)methyl)furan-2-carboxylic acid (A-99) [ka] To a mixture of furan-2-carboxylic acid (2.0 g, 18 mmol) and THF (20 mL) was added dropwise LDA (2 M, 13 mL) at −70 °C. The mixture was stirred for 0.5 h, and cyclopentanecarbaldehyde (2.6 g, 27 mmol) in THF (20 mL) was added dropwise at −70 °C. The resulting mixture was stirred at 20 °C for 1.5 h, poured into saturated NH4Cl (10 mL), and extracted with EtOAc (2 × 10 mL). The aqueous phase was purified by preparative HPLC (0.1% FA condition) to give 5-(cyclopentyl(hydroxy)methyl)furan-2-carboxylic acid (A-99, 0.38 g).

[0282] The compounds in Table 3.1 were prepared from furan-2-carboxylic acid and the indicated aldehyde in the manner described for the synthesis of A-99. [Table 4]

[0283] Synthesis of 3-(N-(3,3-difluorocyclobutyl)-N-methylsulfamoyl)benzoic acid (A-95) [ka] Step 1: To two mixtures of methyl 3-[(3,3-difluorocyclobutyl)sulfamoyl]benzoate (an intermediate from the synthesis of A-36, 0.30 and 0.10 g, 0.98 and 0.33 mmol) and DMF (4.0 and 1.3 mL) was added NaH (59 and 20 mg, 1.5 and 0.5 mmol, 60% purity) at 0 °C. The mixture was stirred for 30 min, and MeI (73 and 24 μL, 1.2 and 0.4 mmol) was added, followed by stirring at 20 °C for 30 min. The combined mixture was poured into water (10 mL) and extracted with EtOAc (10 mL × 2), and the combined extracts were washed with brine (10 mL), dried over Na2SO4, concentrated, and purified by silica chromatography (10–100% EtOAc in PE) to give methyl 3-[(3,3-difluorocyclobutyl)-methyl-sulfamoyl]benzoate (0.28 g).

[0284] Step 2: To two mixtures of methyl 3-[(3,3-difluorocyclobutyl)-methyl-sulfamoyl]benzoate (0.23 and 0.050 g, 0.72 and 0.16 mmol), THF (1.8 and 0.4 mL), and HO (0.6 and 0.13 mL), LiOH·HO (91 and 20 mg, 2.2 and 0.48 mmol) was added and stirred at 20 °C for 4 h. The mixtures were combined, partially concentrated, and the pH was adjusted to 3 by the addition of 2 N HCl. The mixture was extracted with EtOAc (2 × 10 mL), and the combined extracts were washed with brine (10 mL), dried over NaSO, and concentrated to give 3-(N-(3,3-difluorocyclobutyl)-N-methylsulfamoyl)benzoic acid (A-95, 0.29 g).

[0285] Synthesis of 3-((cyclobutylmethyl)(methyl)phosphoryl)benzoic acid (A-97) [ka] Step 1. To a mixture of 1-bromo-3-ethoxyphosphonoyl-benzene (1.8 g, 7.2 mmol) and DMF (20 mL) at 0 °C was added NaH (0.87 g, 22 mmol, 60% purity). The mixture was stirred for 30 min, and iodomethylcyclobutane (1.6 mL, 14 mmol) was added. The mixture was stirred at 0-20 °C for 60 min, poured into saturated NH4Cl (20 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 (5-50% EtOAc in PE) to give 1-bromo-3-[cyclobutylmethyl(ethoxy)phosphoryl]benzene (0.85 g).

[0286] Step 2. To a mixture of 1-bromo-3-[cyclobutylmethyl(ethoxy)phosphoryl]benzene (0.68 g, 2.1 mmol) and THF (6 mL) at 0 °C, MeMgBr (3 M, 6.4 mL) was added, stirred at 20 °C for 4 h, poured into saturated NH Cl (20 mL), and extracted with EtOAc (2 × 15 mL). The combined extracts were washed with brine (10 mL), dried over Na SO , concentrated, and purified by silica chromatography (5–50% EtOAc in PE) to give 1-bromo-3-[cyclobutylmethyl(methyl)phosphoryl]benzene (0.56 g).

[0287] Step 3. A mixture of 1-bromo-3-[cyclobutylmethyl(methyl)phosphoryl]benzene (0.49 g, 1.7 mmol), MeOH (4 mL), 1,4-dioxane (4 mL), Mo(CO) (0.11 g, 0.43 mmol), KPO (0.36 g, 1.7 mmol), DMAP (0.10 g, 0.85 mmol), Xantphos (99 mg, 0.17 mmol), and Pd(OAc) (19 mg, 85 μmol) was stirred for 3 h at 120 °C. The reaction was poured into water (20 mL), and the resulting mixture was extracted with EtOAc (2 × 15 mL). The organic phase was washed with brine (10 mL), dried over Na2SO4, concentrated, and purified by silica chromatography (5-10% MeOH in CH2Cl2) to give methyl 3-[cyclobutylmethyl(methyl)phosphoryl]benzoate (0.34 g).

[0288] Step 4. A mixture of methyl 3-[cyclobutylmethyl(methyl)phosphoryl]benzoate (0.32 g, 1.2 mmol), THF (3 mL), HO (1 mL), and LiOH HO (0.15 g, 3.6 mmol) was stirred for 12 h, poured into HO (10 mL), adjusted to pH 3–4 with HCl (2 N), and extracted with EtOAc (2 × 5 mL). The combined extracts were washed with brine (5 mL), dried over NaSO, and concentrated to give 3-((cyclobutylmethyl)(methyl)phosphoryl)benzoic acid (A-97, 0.17 g).

[0289] Synthesis of 4-(difluoromethyl)cyclohexane-1-carbaldehyde [ka] Step 1. To a 0°C mixture of methyl 4-formylcyclohexanecarboxylate (5.0 g, 29 mmol) and CHCl (50 mL) was slowly added DAST (12 mL, 88 mmol). The mixture was stirred at 20°C for 12 h, poured into saturated aqueous NaHCO (30 mL), and extracted with CHCl (2 × 80 mL). The combined extracts were washed with brine (30 mL), dried over NaSO, concentrated, and purified by silica chromatography (5–17% EtOAc in petroleum ether) to give methyl 4-(difluoromethyl)cyclohexanecarboxylate (3.2 g).

[0290] Step 2. A solution of 4-(difluoromethyl)cyclohexanecarboxylate (3.2 g, 17 mmol) in THF (10 mL) was slowly added to LiAlH (1.3 g, 33 mmol) in THF (20 mL) and then stirred at 25 °C for 2 h. HO (1.3 mL), aqueous NaOH (85%, 1.3 mL), and additional HO (1.3 mL) were added, and the mixture was filtered. The filtrate was concentrated to give [4-(difluoromethyl)cyclohexyl]methanol (1.80 g).

[0291] Step 3. To a mixture of [4-(difluoromethyl)cyclohexyl]methanol (1.6 g, 9.7 mmol), NaHCO3 (6.6 g, 78 mmol), and CHCl2 (50 mL) was added Dess-Martin periodinane (8.3 g, 20 mmol). The mixture was stirred at 25 °C for 2 h and then poured into a mixture of saturated aqueous NaHCO3 (15 mL) and saturated aqueous NaSO3 (15 mL). The resulting mixture was filtered and extracted with CHCl2 (2 × 30 mL). The combined extracts were washed with brine (10 mL), dried over NaSO4, concentrated, and purified by silica chromatography (5–17% EtOAc in petroleum ether) to give 4-(difluoromethyl)cyclohexanecarbaldehyde (1.4 g).

[0292] Synthesis of 4-fluoro-4-methylcyclohexane-1-carbaldehyde [ka] Step 1. To a mixture of ethyl 4-oxocyclohexanecarboxylate (4.7 mL, 29 mmol) in THF (30 mL) was added MeLi (1 M, 41 mL) slowly at −60° C. The mixture was stirred at −60° C. for 1 h, poured into NH4Cl (20 mL), and extracted with EtOAc (2×20 mL). The combined extracts were washed with brine (20 mL), dried over Na2SO4, concentrated, and purified by silica chromatography (13-50% EtOAc in PE) to give ethyl 4-hydroxy-4-methyl-cyclohexanecarboxylate (2.20 g).

[0293] Step 2. To a solution of ethyl 4-hydroxy-4-methyl-cyclohexanecarboxylate (2.4 g, 13 mmol) and CHCl (1 mL) was added DAST (1.7 mL, 13 mmol). The mixture was stirred at −40° C. for 1 h, poured into 1 M NaHCO (20 mL), and extracted with EtOAc (2×20 mL). The combined extracts were washed with brine (15 mL), dried over NaSO, concentrated, and purified by silica chromatography (15–50% EtOAc in PE) to give ethyl 4-fluoro-4-methyl-cyclohexanecarboxylate (1.60 g).

[0294] Step 3. To a 0° C. mixture of ethyl 4-fluoro-4-methyl-cyclohexanecarboxylate (1.4 g, 7.4 mmol) and THF (30 mL) was added LiAlH (0.57 g, 15 mmol). The mixture was stirred at 0° C. for 2 h, and 0.56 mL of HO, 0.56 mL of 15% aqueous NaOH, and an additional 1.7 mL of HO were added. The mixture was filtered, and the filtrate was concentrated, added to HO (10 mL), and extracted with EtOAc (2×15 mL). The combined extracts were washed with brine (15 mL), dried over NaSO, and concentrated to give (4-fluoro-4-methyl-cyclohexyl)methanol (0.80 g).

[0295] Step 4. A mixture of (4-fluoro-4-methyl-cyclohexyl)methanol (0.70 mg, 4.8 mmol), CHCl (20 mL), NaHCO (3.2 g, 38 mmol), and Dess-Martin periodinane (4.1 g, 9.6 mmol) was stirred at 25 °C for 2 hours. The mixture was poured into saturated NaHCO (5 mL) and saturated NaSO (5 mL), and the resulting mixture was filtered and extracted with CHCl (2 × 10 mL). The combined extracts were washed with brine (10 mL), dried over NaSO, and concentrated to give 4-fluoro-4-methyl-cyclohexanecarbaldehyde (0.60 g).

[0296] Synthesis of 5"-nitrodispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline] (B-01) [ka] Step 1. To a mixture of ZnEt (1 M in hexane, 180 mL) and CHCl (200 mL) under N was slowly added CHCl (26 mL, 320 mmol) in CHCl (60 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min, and ethyl 4-methylenecyclohexanecarboxylate (12 g, 71 mmol) in CHCl (50 mL) was slowly added. The mixture was stirred at 20 °C for 12 h, cooled to 0 °C, and saturated NHCl (100 mL) was added. The organic phase was separated, washed with water (50 mL × 2), brine (50 mL), dried over NaSO, filtered, concentrated, and purified by silica chromatography (1–10% CHCl in petroleum ether) to give compound ethyl spiro[2.5]octane-6-carboxylate (10 g).

[0297] Step 2. To a mixture of ethyl spiro[2.5]octane-6-carboxylate (10 g, 55 mmol) and THF (300 mL) was added LiAlH (3.1 g, 81 mmol) in portions under N at 0 °C. The resulting mixture was stirred at 0 °C for 1 h and then at 22 °C for an additional 1 h. 2 M aqueous NaOH (3.0 mL) was slowly added to the stirring mixture, followed by NaSO (30 g). The suspension was filtered, and the filtrate was concentrated to give spiro[2.5]octan-6-ylmethanol (7.5 g). 1 H NMR (DMSO-d 6 ,400MHz)δ3.51(d,J=6.38Hz,2H),1.82-1.68(m,4H),1.53(tdt,J=14.71,6.38,3.24Hz,1H),1 .40-1.29(m,1H),1.12-1.07(m,2H),0.96-0.84(m,2H),0.35-0.24(m,2H),0.23-0.12(m,2H).

[0298] Step 3. To a mixture of spiro[2.5]octan-6-ylmethanol (7.5 g, 54 mmol) and CHCl (250 mL) was added Dess-Martin periodinane (28 g, 66 mmol) at 0 °C. The mixture was stirred for 5 h while the temperature was raised to 25 °C. The mixture was filtered through Celite, and the filter cake was washed with CHCl (50 mL × 3). The filtrate was concentrated and purified by silica chromatography (0-10% EtOAc in petroleum ether) to give spiro[2.5]octane-6-carbaldehyde (7.30 g). 1 H NMR (DMSO-d 6 ,400MHz)δ9.68(d,J=1.25Hz,1H),2.35-2.23(m,1H),1.97-1.85(m,2H),1 .70-1.51(m,4H),1.12-1.03(m,2H),0.35-0.27(m,2H),0.26-0.18(m,2H).

[0299] Step 4.a) A mixture of (4-nitrophenyl)hydrazine (1.8 g, 12 mmol), TFA (4.5 mL, 61 mmol), CHCl (40 mL), and spiro[2.5]octane-6-carbaldehyde (2.0 g, 15 mmol) was stirred at 40 °C for 15 h. b) Additional TFA (6.3 mL, 85 mmol), CHCl, and EtSiH (6.3 mL, 4.6 mmol) were added at 0 °C, and the mixture was stirred at 25 °C for 2 h, then concentrated and purified by silica chromatography (0–15% [1:1 Me-THF in EtOAc] in petroleum ether) to give 5″-nitrodispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline] (B-01, 0.88 g).

[0300] Synthesis of spiro[cyclopentane-1,3'-indoline] (B-02) [ka] To a mixture of 1H-indole (1.0 g, 8.5 mmol) and THF (25 mL), t-BuOK (1 M in THF, 20 mL) was added dropwise, and the mixture was stirred at 20 °C for 0.5 h. EtB (1 M in THF, 17 mL) was added, and the mixture was stirred for 0.5 h. 1,4-Diiodobutane (1.2 mL, 9.4 mmol) was added, and the mixture was stirred at 70 °C for 13 h. MeOH (10 mL) and NaBH (0.97 g, 26 mmol) were added, and the mixture was stirred at 20 °C for 12 h. The mixture was concentrated and combined with EtOAc (20 mL) and 2 N HCl (20 mL). The pH was adjusted to 9 by slowly adding saturated aqueous NaHCO solution. The phases were separated, and the aqueous wash was extracted with EtOAc (2 × 30 mL). The extracts were combined, washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to give spiro[cyclopentane-1,3'-indoline] (B-02). 1HNMR:(DMSO-d6,400MHz)δ6.98(dd,J=7.32,0.81Hz,1H),6.90(td,J=7.57,1.25Hz,1H),6.55( td,J=7.35,0.94Hz,1H),6.49(d,J=7.75Hz,1H),5.43(s,1H),3.22(s,2H),1.84-1.62(m,8H).

[0301] The compounds in Table 4 were prepared from indoles and dihalides in the manner described for B-02. [Table 5]

[0302] Synthesis of dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline] (B-06) [ka] Step 1. Dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indole] was prepared from phenylhydrazine and spiro[2.5]octane-6-carbaldehyde as described in step 4a of the synthesis of B-01.

[0303] Step 2. To a mixture of dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indole] (1.0 g, 4.7 mmol) in MeOH (15 mL) and THF (15 mL) at 0° C. was added NaBHCN (0.90 g, 14 mmol) portionwise. The mixture was stirred at 20° C. for 12 h, then NaBHCN (0.50 g) and THF (15 mL) were added, and the mixture was stirred at 40° C. for 2 h. The reaction mixture was concentrated and purified by chromatography (silica, 0-15% [1:1 THF / EtOAc] in petroleum ether) to afford dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline] (B-06, 0.64 g).

[0304] The compounds in Table 5 were prepared from the indicated hydrazines and aldehydes by the method described for the synthesis of B-06. [Table 6-1] [Table 6-2]

[0305] Synthesis of tert-butyl 5"-bromodispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carboxylate (B-10) and N-(dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)-2-hydroxyethane-1-sulfonamide (B-11) [ka] Step 1. A mixture of B-07 (0.2 M, 3.4 mL) and BocO (0.30 g, 1.4 mmol), MeCN (10 mL), and EtN (0.40 mL, 2.9 mmol) was stirred at 25 °C for 12 hours. The mixture was concentrated and purified by silica chromatography (0-20% MTBE in petroleum ether) to give tert-butyl 5″-bromo-1″,2″-dihydrodispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indole]-1″-carboxylate (B-10, 0.23 g).

[0306] Step 2.a) A mixture of tert-butyl 5″-bromo-1″,2″-dihydrodispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indole]-1″-carboxylate (0.11 g, 0.27 mmol) and 2-[(tert-butyldimethylsilyl)oxy]ethane-1-sulfonamide (0.21 g, 0.88 mmol) in DMF (8.0 mL) was treated with CuI (57 mg, 0.30 mmol), KPO (0.21 g, 0.99 mmol), and N 1 ,N 2N-dimethylcyclohexane-1,2-diamine (48 mg, 0.34 mmol) was added. The reaction mixture was stirred at 140 °C in a microwave reactor for 3 h. The reaction mixture was diluted with 30 mL of water and extracted with 1:1 EtOAc / THF (15 mL × 2). The extracts were combined, washed with HO (10 mL × 3) and brine (10 mL), dried over NaSO, filtered, concentrated, and purified by silica chromatography (0–10% [1:1 THF / EtOAc] in petroleum ether) to give 2-[(tert-butyldimethylsilyl)oxy]-N-{1”,2”-dihydrodispiro[cyclopropane-1,1′-cyclohexane-4′,3”-indol]-5”-yl}ethane-1-sulfonamide (70 mg).

[0307] Step 3. A mixture of 2-[(tert-butyldimethylsilyl)oxy]-N-{1",2"-dihydrodispiro[cyclopropane-1,1'-cyclohexane-4',3"-indol]-5"-yl}ethane-1-sulfonamide (60 mg, 0.11 mmol), MeOH (1.0 mL), and HCl (4 M in MeOH, 1.0 mL) was stirred at 25 °C for 5 h. The mixture was concentrated to give N-{1",2"-dihydrodispiro[cyclopropane-1,1'-cyclohexane-4',3"-indol]-5"-yl}-2-hydroxyethane-1-sulfonamide hydrochloride (B-11, 47 mg).

[0308] Separation of B-24 into diastereomers Indoline B-24 was separated into (1s,4s) and (1r,4r) isomers by silica chromatography (0-100% EtOAc in PE). The configurations were not determined, but the first eluting isomer is B-24a and the second eluting isomer is B-24b.

[0309] Synthesis of tert-butyl 5'-bromospiro[cyclohexane-1,3'-indoline]-1'-carboxylate (B-12) and N-(spiro[cyclohexane-1,3'-indoline]-5'-yl)methanesulfonamide (B-13) [ka] t-Butyl 5′-bromospiro[cyclohexane-1,3′-indoline]-1′-carboxylate (B-12) and N-(spiro[cyclohexane-1,3′-indoline]-5′-yl)methanesulfonamide (B-13) were prepared from B-03 in the same manner as B-10 and B-11.

[0310] The intermediates in Table 5.1 were prepared from the indicated indolines and sulfonamides by the method described for the synthesis of B-11. [Table 7]

[0311] Synthesis of spiro[cyclohexane-1,3'-indolin]-5'-ol hydrochloride (B-15) [ka] Step 1. A mixture of B-12 (0.35 g, 0.96 mmol), NMP (8 mL), HO (4 mL), KOH (0.16 g, 2.9 mmol), Pd(dba) (88 mg, 96 μmol), and di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (81 mg, 0.19 mmol) was stirred at 110 °C for 12 h, diluted with 10 mL of water, and extracted with EtOAc (5 mL × 3). The combined extracts were washed with brine (5 mL), dried over NaSO, filtered, concentrated, and purified by preparative TLC (SiO in petroleum ether, 25% EtOAc) to give tert-butyl 5'-hydroxyspiro[cyclohexane-1,3'-indoline]-1'-carboxylate (80 mg).

[0312] Step 2. A mixture of tert-butyl 5'-hydroxyspiro[cyclohexane-1,3'-indoline]-1'-carboxylate (80 mg, 0.26 mmol) and 1 M HCl in EtOAc (2.0 mL) was stirred at 25 °C for 2 h and concentrated to give spiro[cyclohexane-1,3'-indolin]-5'-ol hydrochloride (B-15, 60 mg).

[0313] Synthesis of 3-(5"-(methylsulfonamido)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonyl chloride (C-01) [ka] Step 1. A mixture of 3-benzylsulfanylbenzoic acid (1.5 g, 6.1 mmol), DMF (10 mL), HATU (4.7 g, 13 mmol), and iPrNEt (3.2 mL, 18 mmol) was stirred at 25 °C for 15 min, and B-07 (1.8 g, 6.1 mmol) was added. The mixture was stirred at 25 °C for 2 h, then diluted with EtOAc (50 mL), washed with water (30 mL × 3) and brine (30 mL), dried over NaSO, filtered, concentrated, and purified by silica chromatography (8-10% EtOAc in petroleum ether) to give (3-(benzylthio)phenyl)(5"-bromodispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-yl)methanone (3.0 g).

[0314] Step 2. (3-(benzylthio)phenyl)(5"-bromodispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-yl)methanone (2.0 g, 3.9 mmol), DMF (10 mL), methanesulfonamide (1.1 g, 12 mmol), KPO (2.5 g, 12 mmol), N 1 ,N 2A mixture of N-dimethylcyclohexane-1,2-diamine (0.55 g, 3.9 mmol) and CuI (0.74 g, 3.9 mmol) was stirred at 160 °C for 2 h. The mixture was diluted with EtOAc (30 mL), washed with HO (30 mL × 3) and brine (30 mL), dried over NaSO, filtered, concentrated, and purified by silica chromatography (29–31% EtOAc in petroleum ether) to give N-(1″-(3-(benzylthio)benzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)methanesulfonamide (1.84 g).

[0315] Step 3. A mixture of N-(1″-(3-(benzylthio)benzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)methanesulfonamide (1.0 g, 1.9 mmol), NCS (0.50 g, 3.8 mmol), HOAc (1.8 mL), and HO (0.2 mL) was stirred at 30° C. for 2 hours. The mixture was diluted with EtOAc (50 mL) and diluted with HO (30 mL × 3), saturated After washing with aqueous NaHCO (30 mL) and brine (30 mL), it was dried over NaSO, filtered, concentrated, and purified by silica chromatography (25-35% EtOAc in petroleum ether) to give 3-(5"-(methylsulfonamido)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonyl chloride (C-01, 0.36 g).

[0316] The compounds in Table 5.2 were prepared from the indicated carboxylic acids and indolines in the same manner as described for C-01. [Table 8]

[0317] Synthesis of 2-methoxy-5-(5"-(methylsulfonamido)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonyl chloride (C-02) [ka] Step 1. A mixture of 3-benzylsulfanyl-4-methoxy-benzoic acid (0.32 mg, 1.2 mmol), B-14 (0.22 g, 0.73 mmol), DMF (3 mL), HOBt (0.26 g, 1.9 mmol), EDCI (0.37 g, 1.9 mmol), and EtN (0.54 mL, 3.9 mmol) was stirred at 25 °C for 2 h. The reaction 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 (40–45% EtOAc in PE) to give N-(1″-(3-(benzylthio)-4-methoxybenzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)methanesulfonamide (0.22 g).

[0318] Step 2. A mixture of N-(1"-(3-(benzylthio)-4-methoxybenzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (0.22 g, 0.36 mmol), NCS (0.14 g, 1.1 mmol), HO (0.05 mL), and HOAc (0.45 mL) was stirred at 25 °C for 2 h. The mixture was diluted with HO (10 ml). The residue was poured into 10 mL of HCl (1 L) and saturated NaHCO3 (10 mL), extracted with EtOAc (2 x 30 mL), and the combined extracts were washed with brine (10 mL), dried over Na2SO4, and concentrated to give 2-methoxy-5-(5"-(methylsulfonamido)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonyl chloride (C-02, 0.20 g).

[0319] Synthesis example S-001 Synthesis of (3-((4,4-difluoropiperidin-1-yl)sulfonyl)phenyl)(4'-fluorospiro[cyclopentane-1,3'-indoline]-1'-yl)methanone (Compound 1) [ka] A mixture of 3-[(4,4-difluoro-1-piperidyl)sulfonyl]benzoic acid (88 mg, 0.28 mmol), DMF (1.5 mL), EtN (0.11 mL, 0.78 mmol), and HATU (0.20 g, 0.52 mmol) was stirred at 20 °C for 30 min, and 4'-fluorospiro[cyclopentane-1,3'-indoline] (50 mg, 0.26 mmol) in DMF (1.0 mL) was added. The resulting mixture was stirred at 20 °C for 3.5 h, concentrated, and purified by preparative HPLC (45–75% MeCN in HO [10 mM NHHCO]) to give (3-((4,4-difluoropiperidin-1-yl)sulfonyl)phenyl)(4'-fluorospiro[cyclopentane-1,3'-indoline]-1'-yl)methanone (compound 1) (35 mg). ESI MS m / z: 479.2 (M+H).

[0320] The compounds in Table 6 were prepared from the indicated carboxylic acid and indoline analogs by the method described for the synthesis of Compound 1 (Synthesis Example S-001). [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5] [Table 9-6] [Table 9-7] [Table 9-8] [Table 9-9] [Table 9-10] [Table 9-11] [Table 9-12] [Table 9-13] [Table 9-14] [Table 9-15] [Table 9-16] [Table 9-17]

[0321] Synthesis example S-002 Synthesis of N-(1'-(3-((4,4-difluoropiperidin-1-yl)sulfonyl)benzoyl)spiro[cyclopentane-1,3'-indoline]-5'-yl)methanesulfonamide (Compound 18) [ka] Compound 2 (50 mg, 93 μmol), methanesulfonamide (13 mg, 0.14 mmol), CuI (9.0 mg, 46 μmol), KPO (59 mg, 0.28 mmol), N 1 ,N 2A degassed mixture of N-dimethylcyclohexane-1,2-diamine (7.0 mg, 46 μmol) and DMF (2.0 mL) was stirred at 150 °C in a microwave reactor for 2 h. This mixture was combined with HO (30 mL) and extracted with EtOAc (2 × 30 mL). The extracts were combined, washed with brine (10 mL), dried over NaSO (10 mL), concentrated, and purified by preparative HPLC (35–0% HO in MeCN [10 mM NHCO]) to give N-(1′-(3-((4,4-difluoropiperidin-1-yl)sulfonyl)benzoyl)spiro[cyclopentane-1,3′-indoline]-5′-methanesulfonamide (compound 18, 8.6 mg).

[0322] Synthesis example S-002a Synthesis of N-(tert-butyl)-3-(5"-(ethylsulfonamido)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide (Compound 134) [ka] Compound 2 (1.0 g, 1.9 mmol), ethanesulfonamide (0.60 g, 5.5 mmol), CuI (0.37 g, 1.9 mmol), KPO (1.3 g, 6.0 mmol), N 1 ,N 2 A degassed mixture of N-dimethylcyclohexane-1,2-diamine (0.27 g, 1.9 mmol) and DMF (14 mL) was stirred at 150 °C for 3 h. The mixture was combined with HO (40 mL). The resulting precipitate was filtered, washed with HO (5 mL × 3), dissolved in EtOAc (50 mL), washed with water (20 mL × 2), dried over NaSO, concentrated, and purified by preparative HPLC (50–20% HO in MeCN [0.1% formic acid]) to give N-(tert-butyl)-3-(5″-(ethylsulfonamido)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-1″-carbonyl)benzenesulfonamide (Compound 134, 1.3 g).

[0323] The compounds in Table 7 were prepared in the same manner as compound 18 from the indicated bromoindolines and primary sulfonamides. [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5] [Table 10-6] [Table 10-7] [Table 10-8] [Table 10-9] [Table 10-10] [Table 10-11] [Table 10-12] [Table 10-13] [Table 10-14] [Table 10-15] [Table 10-16] [Table 10-17] [Table 10-18]

[0324] Synthesis of N-(tert-butyl)-3-(6"-fluoro-5"-(methylsulfonamido)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide and N-(tert-butyl)-3-(4"-fluoro-5"-(methylsulfonamido)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide [ka] A 3:1 mixture of compound 307 and compound 308 (0.55 g, 1.0 mmol), methanesulfonamide (0.29 g, 3.0 mmol), CuI (0.11 g, 0.60 mmol), DMF (5 mL), N,N-dimethylcyclohexane-1,2-diamine (85 mg, 0.60 mmol), and KPO (0.64 g, 3.0 mmol) was stirred at 160 °C for 2 hours. The mixture was concentrated, combined with HO (10 mL), extracted with EtOAc (2 × 10 mL), and the combined extracts were washed with brine (10 mL), dried over NaSO, concentrated, and purified by preparative HPLC (35–65% MeCN / HO [formic acid]) to give N-(tert-butyl)-3-(6″-fluoro-5″-(methylsulfonamido)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-1″-carbonyl)benzenesulfonamide (Compound 309, 23.2 mg) and N-(tert-butyl)-3-(4″-fluoro-5″-(methylsulfonamido)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-1″-carbonyl)benzenesulfonamide (Compound 310, 5.1 mg).

[0325] Synthesis example S-002b Synthesis of N-(tert-butyl)-2-methoxy-5-(5"-(methylsulfonamido)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide (Compound 297) and N-(tert-butyl)-2-hydroxy-5-(5"-(methylsulfonamido)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide (Compound 298). [ka] Compound 296 (0.10 g, 0.18 mmol), methanesulfonamide (51 mg, 0.53 mmol), CuI (34 mg, 0.18 mmol), KPO (0.11 g, 0.53 mmol), N 1 ,N 2 A mixture of 2-dimethylcyclohexane-1,2-diamine (25 mg, 0.18 mmol) and DMF (2 mL) was stirred at 150° C. for 1.5 h. The mixture was then poured into 30 mL of HO and extracted with EtOAc (2 × 30 mL), and the extract was washed with brine (10 mL), dried over NaSO, filtered, concentrated, and purified by reverse-phase HPLC (C18, 30-60% MeCN / water [0.1 mM formic acid]) to give 13 mg of compound 297 and 26 mg of compound 298.

[0326] Synthesis example S-003 Synthesis of N-(1'-(3-((4,4-difluoropiperidin-1-yl)sulfonyl)benzoyl)spiro[cyclopentane-1,3'-indoline]-5'-yl)-2-hydroxyethane-1-sulfonamide (Compound 27) [ka]

[0327] Step 1. Compound 2 (50 mg, 93 μmol), 2-((tert-butyldimethylsilyl)oxy)ethane-1-sulfonamide (33 mg, 0.14 mmol), CuI (9 mg, 46 μmol), KPO (59 mg, 0.28 mmol), and N 1 ,N 2 A degassed mixture of N-dimethylcyclohexane-1,2-diamine (7 mg, 46 μmol) and DMF (2.0 mL) was stirred at 150 °C in a microwave reactor for 2 h. The mixture was poured into HO (30 mL) and extracted with EtOAc (2 × 30 mL). The extracts were combined, washed with brine (10 mL), dried over NaSO, and concentrated to give 2-((tert-butyldimethylsilyl)oxy)-N-(1'-(3-((4,4-difluoropiperidin-1-yl)sulfonyl)benzoyl)spiro[cyclopentane-1,3'-indoline]-5'-yl)ethane-1-sulfonamide (65 mg).

[0328] Step 2. A mixture of 2-((tert-butyldimethylsilyl)oxy)-N-(1'-(3-((4,4-difluoropiperidin-1-yl)sulfonyl)benzoyl)benzoyl)spiro[cyclopentane-1,3'-indoline]-5'-yl)ethane-1-sulfonamide (65 mg, 93 μmol), MeOH (5.0 mL), and HCl (2 M, 5.0 mL) was stirred at 20 °C for 1 h, concentrated, and the pH was adjusted to 9 by the addition of saturated aqueous NaHCO3. The mixture was extracted with EtOAc (2 × 30 mL), and the extracts were combined, washed with brine (10 mL), dried over NaSO, and purified by preparative HPLC (30–60% MeCN in HO [10 mM NHHCO]) to give N-(1′-(3-((4,4-difluoropiperidin-1-yl)sulfonyl)benzoyl)spiro[cyclopentane-1,3′-indoline]-5′-yl)-2-hydroxyethane-1-sulfonamide (compound 27, 8.5 mg).

[0329] The compounds in Table 7.1 were prepared in a similar manner to compound 29 from the indicated bromoindoline and 2-[(tert-butyldimethylsilyl)oxy]ethane-1-sulfonamide. [Table 11-1] [Table 11-2]

[0330] Synthesis example S-004 Synthesis of N-(1"-(3-((4,4-difluoropiperidin-1-yl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (Compound 28) [ka] Step 1. To a mixture of compound 12 (0.18 g, 0.33 mmol), Fe (0.20 g, 3.6 mmol), EtOH (10 mL), THF (10 mL), and HO (4.0 mL) was added NHCl (0.2 g, 3.7 mmol), and the mixture was stirred at 80° C. for 3 hours. The mixture was filtered through Celite, and the filter cake was washed with THF (10 mL × 2) and MeOH (10 mL × 2). The filtrate was concentrated to approximately 20 mL, diluted with EtOAc (30 mL), washed with HO (15 mL × 2), brine (15 mL), dried over NaSO, filtered, and concentrated to give (5″-aminodispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-1″-yl)(3-((4,4-difluoropiperidin-1-yl)sulfonyl)phenyl)methanone (0.17 g).

[0331] Step 2. To a mixture of (5″-aminodispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-1″-yl)(3-((4,4-difluoropiperidin-1-yl)sulfonyl)phenyl)methanone (0.15 g, 0.29 mmol), EtN (880.12 mL, 0.87 mmol), and CHCl (14 mL), a mixture of methanesulfonyl chloride (68 μg, 0.87 mmol) and CHCl (1.0 mL) was slowly added, and the mixture was stirred at 20° C. for 2 hours. The reaction mixture was poured into ice water and extracted with CHCl (15 mL), and the extract was washed with HO (5.0 mL × 2) and brine (5.0 mL), dried over NaSO, filtered, concentrated, and purified by preparative HPLC (40-70% MeCN in water [0.1% formic acid]) to give N-(1″-(3-((4,4-difluoropiperidin-1-yl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)methanesulfonamide (Compound 28, 55 mg).

[0332] Synthesis example S-005 N-(1″-(3-((4,4-difluoropiperidin-1-yl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)-2-hydroxyethane-1-sulfonamide (Compound 29) [ka] A mixture of A-04 (16 mg, 53 μmol), DMF (1.0 mL), HATU (46 mg, 0.12 mmol), and iPr2NEt (18 μg, 0.10 mmol) was stirred at 25 °C for 15 minutes, and a mixture of N-{1”,2”-dihydrodispiro[cyclopropane-1,1′-cyclohexane-4′,3”-indol]-5”-yl}-2-hydroxyethane-1-sulfonamide (42 mg, 48 μmol), iPr2NEt (89 μg, 0.51 μmol), and DMF (1.0 mL) was added. After stirring at 25 °C for 5 h, the mixture was filtered, and the filtrate was concentrated and purified by preparative HPLC (20-60% MeCN in HO [0.1% formic acid]) to give N-(1″-(3-((4,4-difluoropiperidin-1-yl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)-2-hydroxyethane-1-sulfonamide (Compound 29, 2 mg).

[0333] Synthesis example S-006 Synthesis of (3-((4,4-difluoropiperidin-1-yl)sulfonyl)phenyl)(5"-(ethylamino)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-yl)methanone (Compound 30) [ka] A mixture of compound 12 (0.15 g, 0.28 mmol), Pd / C (0.15 g, 10%), and EtOH (15 mL) was stirred under H (15 psi) at 25 °C for 12 h. The mixture was flushed with N, filtered through Celite, the filtrate was concentrated, and the minor product was isolated by preparative HPLC (45–80% MeCN in H2O [10 mM NH4HCO3]) and then by preparative HPLC (35–75% MeCN in H2O [0.1% formic acid]) to give (3-((4,4-difluoropiperidin-1-yl)sulfonyl)phenyl)(5"-(ethylamino)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-yl)methanone (compound 30, 7.9 mg).

[0334] Synthesis example S-007 Isolation of N-(tert-butyl)-3-(4-ethyl-5'-(methylsulfonamido)spiro[cyclohexane-1,3'-indolin]-3-ene-1'-carbonyl)benzenesulfonamide (compound 31) [ka] Purification of compound 22: Compound 31 was isolated as a by-product during preparative HPLC (40-60% MeCN in HO [10 mM NH4HCO3]).

[0335] Synthesis example S-008 Preparation of N,N-dimethyl-3-(5'-(methylsulfonamido)spiro[cyclohexane-1,3'-indoline]-1'-carbonyl)benzenesulfonamide (compound 42) [ka] To a mixture of A-10 (50 mg, 0.22 mmol) and DMF (3 mL) was added HATU (0.12 g, 0.33 mmol) and iPrNEt (0.11 mL, 0.65 mmol). After 20 min, B-13 (73 mg, 0.26 mmol) was added, and the mixture was stirred at 60 °C for 2 h, concentrated, and purified by preparative HPLC (45–65% MeCN in HO (0.1 M HCl)) to give N,N-dimethyl-3-(5'-(methylsulfonamido)spiro[cyclohexane-1,3'-indoline]-1'-carbonyl)benzenesulfonamide (compound 42, 50 mg).

[0336] The compounds in Table 7.2 were prepared in the same manner as compound 42 from the indicated indoline and carboxylic acid. [Table 12-1] [Table 12-2] [Table 12-3] [Table 12-4] [Table 12-5] [Table 12-6] [Table 12-7] [Table 12-8]

[0337] Preparation of N-(1"-(3-(1-(4,4-difluoropiperidin-1-yl)ethyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (Compound 341) [ka] A mixture of A-86 (0.55 g, 2.0 mmol), DMF (5.5 mL), EtN (0.85 mL, 6.1 mmol), EDCI (1.4 g, 7.1 mmol), and HOBt (0.96 g, 7.1 mmol) was stirred at 20 °C for 0.5 h, and then B-14 (0.25 g, 0.81 mmol) was added. The mixture was stirred at 20 °C for 12 h, poured into HO (16 mL), and extracted with EtOAc (2 × 16 mL). The combined extracts were washed with brine (10 mL), dried over NaSO, concentrated, and purified by preparative HPLC (C, 20-55% MeCN in HO [formic acid]) to give N-(1″-(3-(1-(4,4-difluoropiperidin-1-yl)ethyl)benzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)methanesulfonamide (Compound 341, 30 mg).

[0338] The compounds in Table 7.3 were prepared in the same manner as compound 341 from the indicated indolines and carboxylic acids. [Table 13-1] [Table 13-2] [Table 13-3] [Table 13-4]

[0339] Synthesis example S-009 Preparation of ethyl (1'-(3-(piperidin-1-ylsulfonyl)benzoyl)spiro[cyclohexane-1,3'-indoline]-5'-yl)carbamate (compound 141) [ka] A mixture of compound 142 (0.20 g, 0.39 mmol), dioxane (10 mL), CsCO (0.38 g, 1.2 mmol), Pd(dba) (35 mg, 39 μmol), Xantphos (22 mg, 39 μmol), and ethyl carbamate (52 mg, 0.58 mmol) was stirred at 110 °C for 12 h. The mixture was concentrated and purified by preparative HPLC (70–90% MeCN in HO [0.1 M HCl]) to give ethyl (1′-(3-(piperidin-1-ylsulfonyl)benzoyl)spiro[cyclohexane-1,3′-indoline]-5′-yl)carbamate (compound 141, 21 mg).

[0340] Synthesis example S-010 Preparation of N-(1'-(3-(cyclopentyl(hydroxy)methyl)benzoyl)spiro[cyclohexane-1,3'-indoline]-5'-yl)methanesulfonamide (Compound 157) [ka] A degassed mixture of compound 156 (0.10 g, 0.21 mmol), NaBH (16 mg, 0.42 mmol), and MeOH (2 mL) was stirred under a N atmosphere at 0 °C for 3 h. The mixture was concentrated and extracted with EtOAc (10 mL). The extract was washed with water (5 mL × 2) and brine (3 mL), dried over NaSO, filtered, concentrated, and purified by preparative HPLC (42–72% MeCN in HO [0.1% formic acid]) to give N-(1′-(3-(cyclopentyl(hydroxy)methyl)benzoyl)spiro[cyclohexane-1,3′-indoline]-5′-yl)methanesulfonamide (compound 157, 20 mg).

[0341] The compounds in Table 7.4 were prepared from the indicated ketones by the method described for the synthesis of compound 157. [Table 14]

[0342] Synthesis example S-011 Preparation of N-(bicyclo[1.1.1]pentan-1-yl)-3-(5"-(methylsulfonamido)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide [ka] To a mixture of bicyclo[1.1.1]pentan-1-amine (16 mg, 196 μmol), CHCl (1.0 mL), EtN (82 μg, 0.59 mmol), and C-01 (100 mg, 0.20 mmol) were added. The resulting mixture was stirred at 25 °C for 1 h, then concentrated and partitioned between HO (30 mL) and EtOAc (2 × 30 mL). The extracts were combined, washed with brine (10 mL), dried over NaSO, concentrated, and purified by preparative HPLC (35–65% MeCN in HO [0.1% formic acid]) to give N-(bicyclo[1.1.1]pentan-1-yl)-3-(5″-(methylsulfonamido)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-1″-carbonyl)benzenesulfonamide (Compound 223, 15 mg).

[0343] The compounds in Table 7.5 were prepared in the same manner as compound 223 from the indicated sulfonyl chloride and amine. [Table 15-1] [Table 15-2]

[0344] Synthesis example S-012 Preparation of N-(1"-(5-(cyclopentyl(hydroxy)methyl)thiophene-3-carbonyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (Compound 301) [ka] Step 1. To a mixture of 5-formylthiophene-3-carboxylic acid (0.12 mg, 0.74 mmol) and DMF (1.5 mL) were added HATU (0.42 g, 1.1 mmol) and iPrNEt (0.39 mL, 2.2 mmol). After stirring for 30 min, B-14 (0.27 mg, 0.88 mmol) was added, and the mixture was stirred at 80 °C for 1.5 h, diluted with HO (4 mL), and extracted with EtOAc (10 mL × 3). The combined extracts were washed with brine (30 mL), dried over NaSO, filtered, concentrated, and purified by silica chromatography (0–100% EtOAc / PE) to give N-(1″-(5-formylthiophene-3-carbonyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indolyl]-5″-yl)methanesulfonamide (0.31 g). 1 H NMR (400 MHz, DMSO-d 6 )δppm10.00-9.91(m,1H)8.14(s,1H)8.08-7.96(m,1H)7.26-7.19(m,2H)7.15-7. 00(m,1H)4.08(d,J=6.58Hz,2H)2.98(s,3H)1.27-1.24(m,8H)0.36-0.28(m,4H).

[0345] Step 2. To a mixture of N-(1"-(5-formylthiophene-3-carbonyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (0.25 g, 0.56 mmol) and THF (3 mL) was added bromo(cyclopentyl)magnesium (1 M, 2.8 mL). The mixture was stirred at -70°C for 2 hours, poured slowly onto ice (5 mL), and extracted with EtOAc (10 mL x 3). The combined extracts were washed with brine (30 mL), dried over NaSO, concentrated, and purified by preparative HPLC (C, 45% to 75% MeCN in HO[NHHCO]) to give N-(1″-(5-(cyclopentyl(hydroxy)methyl)thiophene-3-carbonyl)dispiro[cyclopropane-1,1-cyclohexane-4′,3″-indoline]-5″-yl)-methanesulfonamide (compound 301, 3.5 mg).

[0346] Preparation of N-(1"-(5-(cyclopentyl(hydroxy)methyl)furan-2-carbonyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (Compound 352) [ka] Step 1. A mixture of 5-formylfuran-2-carboxylic acid (0.20 g, 1.4 mmol), DMF (3 mL), EDCI (0.55 g, 2.9 mmol), HOBt (0.39 g, 2.9 mmol), and iPrNEt (0.75 mL, 4.3 mmol) was stirred at 20 °C for 30 min, and B-14 (0.44 g, 1.4 mmol) in DMF (0.5 mL) was added dropwise at 20 °C. The mixture was stirred at 20 °C for 12 h, poured into water (20 mL), and extracted with EtOAc (2 × 20 mL). The combined extracts were washed with brine (20 mL), dried over NaSO, concentrated, and purified by silica chromatography (10-50% EtOAc in PE) to give N-(1″-(3-formylbenzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)methanesulfonamide (0.23 g).

[0347] Step 2. To a mixture of N-(1"-(3-formylbenzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (0.20 g, 0.37 mmol) and THF (3 mL) was added bromo(cyclopentyl)magnesium (1 M, 0.47 mL). The mixture was stirred at -60 °C for 0.5 h, poured into saturated NH4Cl (5 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 preparative HPLC (C, 30–70% MeCN in HO [formic acid]) to give N-(1″-(5-(cyclopentyl(hydroxy)methyl)furan-2-carbonyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)-methanesulfonamide (Compound 352, 7.0 mg).

[0348] Synthesis example S-013 Preparation of N-(1"-(3-((3,3-difluoroazetidin-1-yl)sulfonyl)-4-hydroxybenzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (Compound 303) [ka] A mixture of two compounds, compound 302 (90 and 40 mg, 0.15 and 0.067 mmol), DMF (3 and 1.3 mL), and LiCl (19 and 8.5 mg, 0.45 and 0.20 mmol), was stirred at 160 °C for 4 h. The mixture was 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, concentrated, and purified by preparative HPLC (C18, 15–55% MeCN in HO [NHHCO]) to give N-(1″-(3-((3,3-difluoroazetidin-1-yl)sulfonyl)-4-hydroxybenzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)methanesulfonamide (compound 303, 10 mg).

[0349] Synthesis example S-014 Preparation of N-(1"-(3-(2-(3,3-difluoroazetidin-1-yl)-1-hydroxyethyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (Compound 314) [ka] Step 1. A mixture of 3-vinylbenzoic acid (0.13 g, 0.89 mmol), DMF (3 mL), B-14 (0.30 mg, 0.98 mmol), HOBt (0.24 mg, 1.8 mmol), EDCI (0.34 g, 1.8 mmol), and EtN (0.37 mL, 2.7 mmol) was stirred at 20 °C for 2 h, then 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 (0–40% EtOAc in PE) to give N-(1″-(3-vinylbenzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)methanesulfonamide (0.30 g).

[0350] Step 2. To a mixture of N-(1"-(3-vinylbenzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (0.15 g, 0.34 mmol) and CHCl (1 mL) was added m-CPBA (0.14 g, 0.60 mmol, purity 85%) at 0 °C. The mixture was stirred at 20 °C for 12 h, poured into NaSO (1 M, 30 mL), and diluted with EtOAc. The resulting mixture was extracted with Ac (2 × 30 mL). The combined extracts were washed with brine (10 mL), dried over NaSO, concentrated, and purified by silica chromatography (0–30% EtOAc in PE) to give N-(1″-(3-(oxiran-2-yl)benzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)methanesulfonamide (0.10 g).

[0351] Step 3. A mixture of 3,3-difluoroazetidine hydrochloride (39 mg, 0.30 mmol), iPrNEt (0.10 mL, 0.60 mmol), EtOH (1 mL), and N-(1″-(3-(oxiran-2-yl)benzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)methanesulfonamide (90 mg, 0.20 mmol) was heated at 80° C. The mixture was stirred at rt for 12 h. The mixture was concentrated and purified by preparative HPLC (35-65% MeCN in HO [formic acid]) to give N-(1″-(3-(2-(3,3-difluoroazetidin-1-yl)-1-hydroxyethyl)benzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)methanesulfonamide (compound 314, 22 mg).

[0352] Preparation of N-(1"-(3-(2-(4,4-difluoropiperidin-1-yl)-1-hydroxyethyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (Compound 315) [ka] (Compound 315) was prepared from N-(1″-(3-vinylbenzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)methanesulfonamide and 3,3-difluoropiperidine hydrochloride by the method described for compound 314.

[0353] Synthesis example S-015 Preparation of N-(1"-(3-((piperidin-1-ylimino)methyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (Compound 318) [ka] Step 1. Three mixtures of 3-formylbenzoic acid (0.20, 0.10, and 0.10 g, 1.3, 0.65, and 0.65 mmol), THF (10, 5, and 5 mL), EDCI (0.51, 0.25, and 0.25 g, 2.7, 1.4, and 1.4 mmol), HOBt (0.36, 0.18, and 0.18 g, 2.7, 1.4, and 1.4 mmol), and EtN (0.56, 0.28, and 0.28 mL, 4.0, 2.0, and 2.0 mmol) were stirred at 20 °C for 0.5 hours, and B-14 (0.41, 0.21, 0.21 g, 1.3, 0.65, and 0.65 mmol) was added, and the mixture was stirred at 20 °C for 12 hours. The mixtures were combined, poured into water (20 mL), and extracted with CHCl (2 × 20 mL). The combined extracts were washed with brine (10 mL), dried over NaSO, concentrated, and purified by silica chromatography (20–100% EtOAc in PE) to give N-(1″-(3-formylbenzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)methanesulfonamide (0.36 g).

[0354] Step 2. A mixture of N-(1"-(3-formylbenzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (0.31 g, 0.73 mmol), EtOAc (3 mL), TFA (81 μg, 1.1 mmol), and piperidin-1-amine (0.47 g, 4.4 mmol) was stirred at 80° C. for 12 hours. The mixture was concentrated and added to water (30 mL), and the EtOAc was added. c (2 × 30 mL), and the combined extracts were washed with brine (10 mL), dried over NaSO, concentrated, and purified by preparative HPLC (C18, 40–80% MeCN in HO [formic acid]) to give N-(1″-(3-((piperidin-1-ylimino)methyl)benzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)methanesulfonamide (0.17 g).

[0355] Synthesis example S-016 Preparation of N-(1"-(3-(1-cyclopentyl-1-hydroxyethyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (Compound 331) [ka] To compound 164 (50 mg, 99 μmol) in THF (1 mL) was added MeMgBr (3 M, 99 μL, 0.30 mmol) at 0° C. The mixture was stirred at 20° C. for 2 h, poured into HO (3 mL), concentrated, and purified by preparative HPLC (40-80% MeCN in HO [formic acid]) to give N-(1″-(3-(1-cyclopentyl-1-hydroxyethyl)benzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)methanesulfonamide (compound 331, 6 mg).

[0356] Synthesis example S-017 Preparation of N-(tert-butyl)-3-(5"-(1-hydroxyethyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide (Compound 332) [ka] Step 1. A degassed mixture of compound 9 (0.20 g, 0.38 mmol), tributyl(1-ethoxyvinyl)stannane (0.19 mL, 0.56 mmol), Pd(PPh)Cl (53 mg, 75 μmol), CsF (0.11 g, 0.75 mmol), and dioxane (4 mL) was stirred at 130° C. for 2 h under a N atmosphere. A solution of KF (0.10 g) in HO (20 mL) was added, and the mixture was stirred at 20° C. for 0.5 h. The mixture was extracted with EtOAc (20 × 2 mL), and the combined extracts were washed with brine (10 mL), dried over NaSO, filtered, concentrated, and purified by silica chromatography (0 to 50% EtOAc in PE) to give 3-(5″-acetyldispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-1″-carbonyl)-N-(tert-butyl)benzenesulfonamide (0.11 g).

[0357] Step 1. To a mixture of 3-(5″-acetyldispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-1″-carbonyl)-N-(tert-butyl)benzenesulfonamide (0.11 g, 0.22 mmol) and MeOH (10 mL) was added NaBH (25 mg, 0.67 mmol) slowly at 0° C. The mixture was stirred at 0° C. for 3 h, poured into saturated NH Cl (20 mL), and diluted with EtOAc (2×10 The combined extracts were washed with brine (10 mL), dried over NaSO, concentrated, and purified by preparative HPLC (C18, 45-75% MeCN in HO [formic acid]) to give N-(tert-butyl)-3-(5"-(1-hydroxyethyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide (Compound 332, 25 mg).

[0358] Synthesis example S-018 Preparation of N-(1"-(3-((cyclobutylmethyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (Compound 335) [ka] A mixture of compound 334 (0.20 g, 0.39 mmol), HOAc (2 mL), and 30% HO (0.11 mL, 1.2 mmol) was stirred at 20 °C for 2 h. The mixture was combined with saturated NaSO (20 mL) and 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 (C18, 35–65% MeCN in HO [formic acid]) to give N-(1″-(3-((cyclobutylmethyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)methanesulfonamide (compound 335, 76 mg, 35.40% yield, 99.00% purity) as a white solid.

[0359] Synthesis example S-019 Preparation of N-(tert-butyl)-3-(5"-(2,2,2-trifluoro-1-hydroxyethyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide (Compound 338) [ka] Step 1. A degassed mixture of compound 9 (0.50 g, 0.94 mmol), KBF(vinyl) (0.63 g, 4.7 mmol), KCO (0.65 g, 4.7 mmol), PdCl (0.12 g, 0.66 mmol), and DMSO (5 mL) was stirred at 100 °C under a N atmosphere for 3 h. The mixture was poured into HO (20 mL) and extracted with CHCl (2 × 20 mL). The combined extracts were washed with brine (10 mL), dried over NaSO, concentrated, and purified by silica chromatography (30-50% EtOAc in PE) to give N-(tert-butyl)-3-(5″-vinyldispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-1″-carbonyl)benzenesulfonamide (0.32 mg).

[0360] Step 2. A mixture of N-(t-butyl)-3-(5"-vinyldispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide (0.32 g, 0.67 mmol), CHCl (10 mL), and MeOH (10 mL) was treated with O (32 mg, 669 umol, 1.0 equiv) at 0 °C for 0.5 h. The solution was purged with O (21 mg, 669 umol, 1.0 equiv) at 0 °C for 0.5 h, then PPh (0.35 g, 1 The resulting mixture was stirred with 0.3 mmol) at 20 °C for 1 h, poured into HO (20 mL), and extracted with CHCl (2 × 20 mL). The combined extracts were washed with brine (10 mL), dried over NaSO, concentrated, and purified by silica chromatography (30-50% EtOAc in PE) to give N-(t-butyl)-3-(5″-formyldispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-1″-carbonyl)benzenesulfonamide (0.25 g).

[0361] Step 3. To a mixture of N-(tert-butyl)-3-(5"-formyldispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide (0.15 g, 0.31 mmol) and DMF (2 mL) was added TMSCF (89 mg, 0.62 mmol) and CsF (95 mg, 0.62 mmol) at 50 °C. The mixture was stirred at 50 °C for 12 h, concentrated, added to HO (30 mL) and EtOAc (2 × 3 The extract was extracted with 10 mL of hexane (20 mL). The combined extracts were washed with brine (10 mL), dried over NaSO, concentrated, and purified by preparative HPLC (C18, 35-75% MeCN in HO [formic acid]) to give N-(tert-butyl)-3-(5″-(2,2,2-trifluoro-1-hydroxyethyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-1″-carbonyl)benzenesulfonamide (Compound 338, 11 mg).

[0362] Synthesis example S-20 Preparation of N-(1"-(3-((3,3-difluoroazetidin-1-yl)methyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (Compound 345) [ka] Step 1. A mixture of compound 344 (0.28 g, 0.64 mmol), CHCl (5 mL), and PCC (0.27 g, 1.3 mmol) was stirred at 20 °C for 2 h, diluted with CHCl (10 mL), washed with HO (5 mL), saturated aqueous NaHCO (5 mL), brine (5 mL), then dried over NaSO, concentrated, and purified by flash silica chromatography (0-50% EtOAc in PE) to give N-(1″-(3-formylbenzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)methanesulfonamide (0.18 g).

[0363] Step 2. A mixture of N-(1"-(3-formylbenzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5'-yl)methanesulfonamide (0.10 g, 0.23 mmol), MeOH (1 mL), THF (1 mL), 3,3-difluoroazetidine hydrochloride (44 mg, 0.34 mmol), and HOAc (26 μL, 0.46 mmol) was stirred at 20 °C for 2 h, NaBHCN (43 mg, 0.68 mmol) was added, and the mixture was stirred at 20 °C for 10 h. The mixture was treated with HO (5 mL) at 0 °C and extracted with CHCl (10 mL). The combined extracts were washed with HO (10 mL) and brine (10 mL), dried over NaSO, concentrated, and purified by preparative HPLC (C18, 25-65% MeCN in HO [formic acid]) to give N-(1″-(3-((3,3-difluoroazetidin-1-yl)methyl)benzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)methanesulfonamide (Compound 345, 6 mg).

[0364] Synthesis example S-21 Preparation of 2-methyl-N-(3-(5"-(methylsulfonamido)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)phenyl)propane-2-sulfonamide (Compound 355) [ka]

[0365] Step 1. A mixture of B-14 (0.20 g, 0.65 mmol), CHCl (4 mL), iPrNEt (0.34 mL, 2.0 mmol), and 3-bromobenzoyl chloride (0.10 mL, 0.78 mmol) was stirred at 20 °C for 1 hour, then concentrated and poured into water (5 mL). The resulting mixture was extracted with EtOAc (10 mL × 2), and the combined extracts were washed with brine (10 mL), dried over NaSO, concentrated, and purified by silica chromatography (10 to 100% EtOAc in PE) to give N-(1″-(3-bromobenzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)methanesulfonamide (0.21 g).

[0366] Step 2. A degassed mixture of N-(1″-(3-bromobenzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)methanesulfonamide (0.10 g, 0.20 mmol), 2-methylpropane-2-sulfonamide (0.11 g, 0.82 mmol), CuI (78 mg, 0.41 mmol), N1,N2-dimethylcyclohexane-1,2-diamine dihydrochloride (88 mg, 0.41 mmol), K3PO4 (0.13 g, 0.61 mmol), and DMF (2 mL) was added to a 100 mL flask under a N2 atmosphere. The mixture was stirred at 160° C. for 2 h. The mixture was poured into water (10 mL) and extracted with EtOAc (10 mL × 2), and the combined extracts were washed with brine (10 mL), dried over NaSO, concentrated, and purified by preparative HPLC (C18, 35–65% MeCN in HO[NHCO]) to give 2-methyl-N-(3-(5″-(methylsulfonamido)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-1″-carbonyl)phenyl)propane-2-sulfonamide (Compound 355, 16 mg).

[0367] Synthesis example S-22 Preparation of N-(1"-(3-(1-hydroxy-3,3-dimethylbutyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (Compound 357) [ka]

[0368] To a mixture of N-(1"-(3-(oxiran-2-yl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-5"-yl)methanesulfonamide (50 mg, 0.11 mmol), CuCl (15 mg, 0.11 mmol), LiCl (5 mg, 0.11 mmol), and THF (1 mL) was added t-BuMgCl (1 M, 0.44 mL) dropwise. The mixture was stirred at 20 °C for 2 h and then saturated aqueous NH4Cl (2 The resulting mixture was poured into a 100 mL flask and extracted with EtOAc (2 × 20 mL). The combined extracts were washed with brine (10 mL), dried over NaSO, concentrated, and purified by preparative HPLC (C18, 45–85% MeCN in HO [formic acid]) to give N-(1″-(3-(1-hydroxy-3,3-dimethylbutyl)benzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-5″-yl)methanesulfonamide (8.0 mg).

[0369] Synthesis example S-23 Preparation of N-(tert-butyl)-3-(5"-((2-fluoroethyl)sulfonamido)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline]-1"-carbonyl)benzenesulfonamide (Compound 365) [ka] To a mixture of compound 148 (50 mg, 87 μmol) in CHCl (1.5 mL) at 0 °C was added DAST (23 μL, 0.18 mmol). The mixture was stirred under N at 20 °C for 1 h, 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 (C18, 45–75% MeCN in HO [formic acid]) to give N-(tert-butyl)-3-(5″-((2-fluoroethyl)sulfonamido)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indoline]-1″-carbonyl)benzenesulfonamide (compound 365, 13 mg).

[0370] Table 7c lists the chromatographic separation of the isomers for certain examples. [Table 16-1] [Table 16-2] [Table 16-3] [Table 17-1] [Table 17-2] [Table 17-3] [Table 17-4] [Table 17-5] [Table 17-6] [Table 17-7] [Table 17-8] [Table 17-9] [Table 17-10] [Table 17-11] [Table 17-12] [Table 17-13] [Table 17-14] [Table 17-15] [Table 17-16] [Table 17-17] [Table 17-18] [Table 17-19] [Table 17-20] [Table 17-21] [Table 17-22]

[0371] 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. 2.5 μL of enzyme mix (4 nM hKIF18A(1-374) in assay buffer) was added to 50 nL of compound in DMSO. After 30 minutes of incubation at room temperature, 2.5 μL of microtubule mix (0.2 mg / mL preformed microtubules in assay buffer, 2.0 mM ATP) was added, the plate was centrifuged for 30 seconds, and then incubated at 28°C for 60 minutes. 5 μL of Promega® ADP-GloMax® 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-GloMax® was added, the plate was centrifuged for 30 seconds, and incubated for 60 minutes at room temperature. Luminescence was measured on an Envision plate reader, and % inhibition was calculated for each well as ([Max-Min]-[Test-Min]) / [Max-Min]. IC values ​​were calculated from concentrations correlated to % inhibition data via a four-parameter variable slope model. 50 The value was calculated.

[0372] Table 9 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.

[0373] 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 a one-step slow binding inhibition to determine the on-rate k. on k value and off-rate off values ​​were derived (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).

[0374] The results from the binding kinetics assay are summarized in Table 10. The data in Table 10 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 on =0.059nM -1 h -1 ;k off =0.21h -1 ,dissociation t 1 / 2 =4.1h;K I =3.4nM.

[0375] 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.

[0376] 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 concentrations via an ATP standard curve (10 points, 2-fold dilutions from 5 μM). % inhibition was calculated for each well as ([max-min]-[test-min]) / [max-min]). IC was calculated from the concentrations correlated to the % 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.

[0377] Table 11 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 18-1] [Table 18-2] [Table 18-3] [Table 19-1] [Table 19-2]

[0378] 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 20-1] [Table 20-2]

[0379] 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.

[0380] Tumor cells were passaged twice a week. Cells growing in the exponential growth phase were harvested and counted for tumor inoculum.

[0381] Tumor cells (10 × 10) in 0.2 mL of PBS mixed with Matrigel (50:50) 6 Each mouse was subcutaneously inoculated with 1000 mg of 1000 mAb into the right flank. The average 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.

[0382] The compounds were administered orally once or twice daily (12 hours). The tumor growth inhibition (TGI) was calculated by the following formula: TGI (tumor growth inhibition) (%) = [1-(T N -T0) / (V N Tumor growth inhibition was calculated using the formula: T −V0)] × 100; N 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 treatment day 0, and V N is the mean tumor volume of the vehicle control group at the indicated time points, and V0 is the mean tumor volume of the vehicle group on treatment day 0. P values ​​were calculated based on tumor size by one-way ANOVA using GraphPad Prism 9.4.0 compared to the vehicle group, respectively. **** indicates p<0.0001.

[0383] Tumor volumes in vehicle-treated and compound-treated mice as a function of time after the start of treatment, and the results of treatment with selected compounds in SCID Beige or nude mice implanted with HCC15 or OVCAR-3, are shown in Figures 1A-1E. The calculated TGIs for treatment with selected compounds are shown in Table 12. [Table 21]

Claims

1. Formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein Ring A is halo, —OH, C １－６ Alkyl, 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) ２ NR ａ１４ R ａ１５ , -S(O) ２ R ａ１６ , -(CR ａ１７ R ａ１８ ) ０－１ C(O)NR ａ１９ R ａ２０ , -SR ａ２１ , -C(O)R ａ２２ , as well as —OH, cyano, C ３－１０ C 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. １－６ C optionally substituted with one or more substituents independently selected from the group consisting of alkyl ６－１４ is aryl; R ａ１ -R ａ２２ are each independently hydrogen, or each independently 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 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 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 5-12 membered heteroaryl, wherein R １ａ１ and R １ａ２ are each independently hydrogen or C １－６ is alkyl; Ring B is C ５－７ Cycloalkyl, C ５－７ cycloalkenyl, or 5-7 membered heterocycloalkyl, wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon; Each R Ｂ The groups are independently halo, C optionally substituted with one or more halo. １－６ Alkyl or C ２－６ alkenyl; or two adjacent R Ｂ The groups, together with the carbon atoms to which they are attached, form a C ３－１０ form a cycloalkyl; or two geminal R Ｂ The groups, together with the carbon atoms to which they are attached, form a C ３－１０ Forming a cycloalkyl; m is 0, 1, 2, 3 or 4; Y １ is N or CR Ｃ１ and Y ２ is N or CR Ｃ２ and Y ３ is N or CR Ｃ３ and Y ４ is N or CR Ｃ４ and In the formula, Y １ , Y ２ , Y ３ and Y ４ of which 3 or less are N; R Ｃ１ , R C3 , and R Ｃ４ each independently represents hydrogen, halo, cyano, —OH, or —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 , -NR ｃ１４ C(O)OR ｃ１５ , -NR ｃ１６ S (O) ２ (CH ２ ) １－６ NR ｃ１７ C(O)R ｃ１８ or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH １－６ is alkyl; R C2 is 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 , —NR c14 C(O)OR c15 , —NR c16 S(O) 2 (CH 2 ) 1-6 NR c17 C(O)R c18 , or C 1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH; and R ｃ１ -R ｃ１８ are each independently hydrogen, C ３－１０ C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halo, and —OH; １－６ alkyl, or a pharmaceutically acceptable salt thereof.

2. Formula (I-3): 【Chemistry 2】 or a pharmaceutically acceptable salt thereof, wherein Ring A is independently halo, —OH, C １－６ Alkyl, 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) ２ NR ａ１４ R ａ１５ , -S(O) ２ R ａ１６ , -(CR ａ１７ R ａ１８ ) ０－１ C(O)NR ａ１９ R ａ２０ , -SR ａ２１ , -C(O)R ａ２２ , as well as —OH, cyano, C ３－１０ C 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. １－６ C optionally substituted with one or more substituents independently selected from the group consisting of alkyl ６－１４ aryl or 5-12 membered heteroaryl; R ａ１ -R ａ２２ are each independently hydrogen, or each independently 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 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 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 5-12 membered heteroaryl, wherein R １ａ１ and R １ａ２ are each independently hydrogen or C １－６ is alkyl; Ring B is C ５－７ Cycloalkyl, C ５－７ cycloalkenyl, or 5-7 membered heterocycloalkyl, wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon; m is 2; Two R's Ｂ The groups are bonded to the same carbon atom on ring B and together with the carbon atom to which they are bonded form C ３－７ Forming a cycloalkyl; Y １ is N or CR Ｃ１ and Y ２ is N or CR Ｃ２ and Y ３ is N or CR Ｃ３ and Y ４ is N or CR Ｃ４ and In the formula, Y １ , Y ２ , Y ３ and Y ４ of which 3 or less are N; R Ｃ１ -R Ｃ４ each independently represents hydrogen, halo, cyano, —OH, or —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 , -NR ｃ１４ C(O)OR ｃ１５ , -NR ｃ１６ S (O) ２ (CH ２ ) １－６ NR ｃ１７ C(O)R ｃ１８ or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH １－６ alkyl; and R ｃ１ -R ｃ１８ are each independently hydrogen, C ３－１０ C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halo, and —OH; １－６ alkyl, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2, wherein the compound has formula (Ia1): 【Chemistry 3】 A compound of the formula: R ａ１４ and R ａ１５ are each independently hydrogen, or each independently 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 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 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 5-12 membered heteroaryl, wherein R １ａ１ and R １ａ２ are each independently hydrogen or C １－６ is alkyl; Ring B is C ５－７ Cycloalkyl, C ５－７ cycloalkenyl, or 5-7 membered heterocycloalkyl, wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon; Each R Ｂ The groups are independently halo, C optionally substituted with one or more halo. １－６ Alkyl or C ２－６ alkenyl; or two adjacent R Ｂ The groups, together with the carbon atoms to which they are attached, form a C ３－１０ form a cycloalkyl; or two geminal R Ｂ The groups, together with the carbon atoms to which they are attached, form a C ３－１０ Forming a cycloalkyl; m is 0, 1, 2, 3 or 4; RC ２ is 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 , -NR ｃ１４ C(O)OR ｃ１５ , -NR ｃ１６ S (O) ２ (CH ２ ) １－６ NR ｃ１７ C(O)R ｃ１８ or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH １－６ alkyl; and R ｃ１ -R ｃ１８ are each independently hydrogen, C ３－１０ C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halo, and —OH; １－６ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

4. R Ｃ２ Ga-NR ｃ５ S (O) ２ R ｃ６ and R ｃ５ and R ｃ６ are each independently hydrogen, C ３－１０ C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halo, and —OH; １－６ 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl; 5. The compound of claim 1, wherein the compound has formula (Ia2): 【Chemistry 4】 A compound of the formula: R ａ１６ are hydrogen, or 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 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 5-12 membered heteroaryl, wherein R １ａ１ and R １ａ２ are each independently hydrogen or C １－６ is alkyl; Each R Ｂ The groups are independently halo, C optionally substituted with one or more halo. １－６ Alkyl or C ２－６ alkenyl; or two adjacent R Ｂ The groups, together with the carbon atoms to which they are attached, form a C ３－１０ form a cycloalkyl; or two geminal R Ｂ The groups, together with the carbon atoms to which they are attached, form a C ３－１０ Forming a cycloalkyl; m is 0, 1, 2, 3 or 4; R Ｃ２ is 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 , -NR ｃ１４ C(O)OR ｃ１５ , -NR ｃ１６ S (O) ２ (CH ２ ) １－６ NR ｃ１７ C(O)R ｃ１８ or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH １－６ alkyl; and R ｃ１ -R ｃ１８ are each independently hydrogen, C ３－１０ C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halo, and —OH; １－６ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

6. R Ｃ２ Ga-NR ｃ５ S (O) ２ R ｃ６ and R ｃ５ and R ｃ６ are each independently hydrogen, C ３－１０ C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halo, and —OH; １－６ 6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

7. 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein Ring A is indolyl, indazolyl, pyridinyl, thiophenyl, furanyl, pyrazolyl, pyrrolyl, oxazolyl, chromanyl, or quinolinyl, each of which is optionally substituted.

8. R ａ１ is hydrogen or C １－６ alkyl; R ａ２ and R ａ３ are each independently hydrogen, C １－６ Alkyl, or C ３－１０ is cycloalkyl; R ａ４ is hydrogen or C １－６ alkyl; R ａ５ is hydrogen or C １－６ alkyl; R ａ６ and R ａ７ are each independently hydrogen, C １－６ Alkyl, or C １－６ R is a 5-12 membered heteroaryl optionally substituted with alkyl; ａ８ and R ａ９ are each independently hydrogen, C １－６ Alkyl, or C ３－１０ is cycloalkyl; R ａ１０ is C ３－１０ is cycloalkyl; R ａ１１ is C ３－１０ is cycloalkyl; R ａ１２ is hydrogen or C １－６ alkyl; R ａ１３ is C ３－１０ is cycloalkyl; R ａ１６ is C ３－１０ Cycloalkyl or C １－６ R is a 3- to 12-membered heterocycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of alkyl or halo; ａ１７ and R ａ１８ are each independently hydrogen or C １－６ alkyl; R ａ１９ and R ａ２０ are each independently hydrogen, C １－６ Alkyl, or C ３－１０ is cycloalkyl; R ａ２１ is C ３－１０ cycloalkyl; and R ａ２２ is C ３－１０ is cycloalkyl; and R a14 and R a15 are each independently hydrogen; C 1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, —OH, —O(C 1-6 alkyl), —S(C 1-6 alkyl), and halo; C 2-6 alkenyl; C 3-10 cycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of C 2-6 alkenyl, C 3-10 cycloalkyl, halo, cyano, —OH, —O(C 1-6 alkyl), ═CR 1a1 R 1a2 , and C 1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of —OH, —O(C 1-6 alkyl), and halo, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1-6 alkyl; C 3-10 cycloalkenyl; or a 3- to 12-membered heterocycloalkyl optionally substituted with one or more C 1-6 alkyl, or a pharmaceutically acceptable salt thereof.

9. Ring A is fluoro, chloro, —OH, methyl, amino, 【Chemistry 5】 【Chemistry 6】 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of:

10. Ring B 【Chemistry 7】 2. The compound of claim 1, wherein * represents the point of attachment to the remainder of formula (I), or a pharmaceutically acceptable salt thereof.

11. of formula (I) 【Chemistry 8】 but, 【Chemistry 9】 2. The compound of claim 1, wherein * represents the point of attachment to the remainder of formula (I), or a pharmaceutically acceptable salt thereof.

12. Y １ is CR Ｃ１ and Y ２ is CR Ｃ２ and Y ３ is CR Ｃ３ and Y ４ is CR Ｃ４ and R C1 , R C3 and R C4 are each independently hydrogen, halo, or —NH 2 ; or 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R C1 , R C3 and R C4 are each hydrogen.

13. Y １ is N; Y ２ is CR Ｃ２ and Y ３ is CR Ｃ３ and Y ４ is CR Ｃ４ or 2. The compound of claim 1, wherein Y 1 is CR C1 ; Y 2 is N; Y 3 is CR C3 ; and Y 4 is CR C4 , or a pharmaceutically acceptable salt thereof.

14. R Ｃ２ is cyano, -OH, -CH ２ OH, bromo, -NO ２ , 【Chemistry 10】 2. The compound of claim 1, wherein:

15. Formula (II): 【Chemistry 11】 or a pharmaceutically acceptable salt thereof, wherein Ring A is 【Chemistry 12】 wherein Z １ , Z ２ , Z ３ , and Z ４ are each independently hydrogen or R Ｄ where R Ｄ is halo, -OH, -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 , -(CR ａ１７ R ａ１８ ) ０－１ C(O)NR ａ１９ R ａ２０ , -SR ａ２１ , -C(O)R ａ２２ , -P(O)(R ａ２３ ) (R ａ２４ ), -C=NR ａ２５ , or —OH, cyano, C ３－１０ cycloalkyl and one or more halo or C １－３ C substituted with one or more substituents independently selected from the group consisting of 3-10 membered heterocycloalkyl optionally substituted with alkyl １－６ is alkyl, however, (1) Z ４ is hydrogen, Z １ and Z ３ At least one of Ｄ and (2) Z ４ If is RD, then Z １ is R Ｄ Or, 【Chemistry 13】 where: 【Chemistry 14】 is a single or double bond, Z ５ is C—H, N, O, S, or N—X, where X is H or C １－６ is alkyl; Z ６ is -NR ａ２６ C(O)NR ａ２７ R ａ２８ , -NR ａ２９ C(O)OR ａ３０ , -N=S(O)R ａ３１ R ａ３２ , -S(O)R ａ３３ , -S(O)(NR ａ３４ ) R ａ３５ , -S(O) ２ NR ａ３６ R ａ３７ , -S(O) ２ R ａ３８ , -SR ａ３９ , 3-10 membered heterocycloalkyl, —C(O)R ａ４０ , or -CH(Z ７ ) (Z ８ ) where Z ７ is hydrogen or —OH, and Z ８ is C １－６ alkyl, C optionally substituted with one or more halo ３－１０ cycloalkyl or a 3-10 membered heterocycloalkyl optionally substituted with one or more halo; and Ring C is one or more R Ｅ a 5-6 membered heteroaryl optionally substituted with substituents, wherein each R Ｅ The substituents are halo, —OH, and C １－６ alkyl, or two R Ｅ The substituents together with the atoms to which they are attached form a C ５－６ Cycloalkyl, C ５－６ forming a cycloalkenyl, a 5-6 membered heterocycloalkyl, a 5-6 membered heterocycloalkenyl, or a 5-6 membered heteroaryl; R ａ４ -R ａ４０ are each independently hydrogen, or each independently 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 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 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 5-12 membered heteroaryl, wherein R １ａ１ and R １ａ２ are each independently hydrogen or C １－６ is alkyl; Ring B is C ５－７ Cycloalkyl, C ５－７ cycloalkenyl, or 5-7 membered heterocycloalkyl, wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon; Each R Ｂ The groups are independently halo or C optionally substituted with one or more halo. １－６ alkyl; or two adjacent R Ｂ The groups, together with the carbon atoms to which they are attached, form a C ３－１０ form a cycloalkyl; or two geminal R Ｂ The groups, together with the carbon atoms to which they are attached, form a C ３－１０ form a cycloalkyl; or two geminal R Ｂ The foundation comes together = CR １ａ３ R １ａ４ group; wherein R １ａ３ and R １ａ４ are each independently hydrogen or C １－６ is alkyl; m is 0, 1, 2, 3 or 4; Y １ is N or CR Ｃ１ and Y ２ is N or CR Ｃ２ and Y ３ is N or CR Ｃ３ and Y ４ is N or CR Ｃ４ and In the formula, Y １ , Y ２ , Y ３ and Y ４ of which 3 or less are N; R Ｃ１ -R Ｃ４ are each independently hydrogen or R Ｆ where R Ｆ is 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 , -NR ｃ１４ C(O)OR ｃ１５ , -NR ｃ１６ S (O) ２ (CH ２ ) １－６ NR ｃ１７ C(O)R ｃ１８ , —O—S(O) ２ R ｃ１９ or C substituted with one or more substituents independently selected from the group consisting of halo and —OH １－６ is alkyl; R ｃ１ -R ｃ１９ are each independently hydrogen, C ３－１０ cycloalkyl, or halo, —O(C １－６ alkyl), -NHC(O)(C １－６ C optionally substituted with one or more substituents independently selected from the group consisting of -C, ... １－６ is alkyl; however, (1) When ring B is unsubstituted cyclopentyl, ring A is 【Chemistry 15】 wherein Z １ -Z ４ At least one of -S(O) is substituted with one or more halo. ２ -(3-10 membered heterocycloalkyl) That is, (2) Ring B is unsubstituted cyclohexyl and Ring A is 【Chemistry 16】 If R Ｃ１ -R Ｃ４ At least one of Ｆ and (3) Ring B is R Ｂ When ring A is a 5-7 membered heterocycloalkyl optionally substituted with 【Chemistry 17】 In this case, Z １ -Z ４ at least one of which is —S(O) optionally substituted with one or more halo ２ -(3-10 membered heterocycloalkyl), or a pharmaceutically acceptable salt thereof.

16. Ring A is 【Chemistry 18】 16. The compound of claim 15, wherein:

17. Z ４ is hydrogen, and Z １ and Z ３ At least one of Ｄ where R Ｄ is halo, -OH, -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 , -(CR ａ１７ R ａ１８ ) ０－１ C(O)NR ａ１９ R ａ２０ , -SR ａ２１ , -C(O)R ａ２２ , -P(O)(R ａ２３ ) (R ａ２４ ), -C=NR ａ２５ , or —OH, cyano, C ３－１０ cycloalkyl and one or more halo or C １－３ C substituted with one or more substituents independently selected from the group consisting of 3-10 membered heterocycloalkyl optionally substituted with alkyl １－６ 17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

18. Z ４ is R Ｄ and Z １ is R Ｄ where R Ｄ are independently halo, —OH, —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 , -(CR ａ１７ R ａ１８ ) ０－１ C(O)NR ａ１９ R ａ２０ , -SR ａ２１ , -C(O)R ａ２２ , -P(O)(R ａ２３ ) (R ａ２４ ), -C=NR ａ２５ , or —OH, cyano, C ３－１０ cycloalkyl and one or more halo or C １－３ C substituted with one or more substituents independently selected from the group consisting of 3-10 membered heterocycloalkyl optionally substituted with alkyl １－６ 17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

19. Z １ -Z ４ At least one of the following is fluoro, chloro, —OH, —NH ２ , -CH ２ OH, 【Chemistry 19】 【Chemistry 20】 【Chemical 21】 16. The compound of claim 15, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

20. Ring A is 【Chemical 22】 and ring C is one or more R Ｅ a 5-6 membered heteroaryl optionally substituted with substituents, wherein each R Ｅ The substituents are halo, —OH, and C １－６ alkyl, or two R Ｅ The substituents together with the atoms to which they are attached form a C ５－６ Cycloalkyl, C ５－６ The compound according to claim 15, which forms a cycloalkenyl, a 5-6 membered heterocycloalkyl, a 5-6 membered heterocycloalkenyl, or a 5-6 membered heteroaryl, or a pharmaceutically acceptable salt thereof.

21. Ring A is 【Chemical 23】 and ring C is one or more R Ｅ a 5-6 membered heteroaryl optionally substituted with substituents, wherein each R Ｅ The substituents are halo, —OH, and C １－６ 16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein each of the groups is independently selected from the group consisting of alkyl.

22. 21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein Ring C is pyridinyl, thiophenyl, furanyl, pyrazolyl, pyrrolyl, or oxazolyl, each of which is optionally substituted.

23. The one or more R Ｅ The substituents are halo, —OH, and C １－６ 21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein each of the groups is independently selected from the group consisting of alkyl.

24. The one or more R Ｅ 24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein the substituent is methyl.

25. Two R's Ｅ The substituents, together with the atoms to which they are attached, form a C ５－６ Cycloalkyl, C ５－６ The compound according to claim 20, which forms a cycloalkenyl, a 5-6 membered heterocycloalkyl, a 5-6 membered heterocycloalkenyl, or a 5-6 membered heteroaryl, or a pharmaceutically acceptable salt thereof.

26. Z ６ -CH(Z ７ ) (Z ８ ) where Z ７ is hydrogen or —OH, and Z ８ is C １－６ alkyl, C optionally substituted with one or more halo ３－１０ 21. The compound of claim 20, which is a cycloalkyl or a 3-10 membered heterocycloalkyl optionally substituted with one or more halo, or a pharmaceutically acceptable salt thereof.

27. Z ６ but 【Chemistry 24】 21. The compound of claim 20, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

28. Ring B is C ５－７ 16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, which is cycloalkyl.

29. 16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein ring B is a 5- to 7-membered heterocycloalkyl.

30. Ring B 【Chemistry 25】 16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein * represents the point of attachment to the remainder of formula (II).

31. of formula (II) 【Chemical 26】 but, 【Chemical 27】 16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein * represents the point of attachment to the remainder of formula (II).

32. Y １ is CR Ｃ１ and Y ２ is CR Ｃ２ and Y ３ is CR Ｃ３ and Y ４ is CR Ｃ４ and R C1 , R C3 and R C4 are each independently hydrogen, halo, or —NH 2 ; or 16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R C1 , R C3 and R C4 are each hydrogen.

33. Y １ is N; Y ２ is CR Ｃ２ and Y ３ is CR Ｃ３ and Y ４ is CR Ｃ４ or 16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein Y<1> is CR<C1>; Y<2> is N; Y<3> is CR<C3>; and Y<4> is CR<C4>.

34. R Ｃ１ or R C4 is halo or —NH 2 , or a pharmaceutically acceptable salt thereof.

35. R Ｃ２ is cyano, -OH, -CH ２ OH, Fluoro, Bromo, -NO ２ , 【Chemical formula 28】 16. The compound of claim 15, wherein:

36. A compound selected from the group consisting of the compounds of Table 1, or a pharmaceutically acceptable salt thereof.

37.

29. 2. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt thereof.

38.

30. 2. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt thereof.

39.

31. 2. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt thereof.

40. 【Catalog 32】 2. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt thereof.

41. 【Catalog 33】 2. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt thereof.

42. 42. A pharmaceutical composition comprising a compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

43. 42. A composition comprising a compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, for use in a method of inhibiting KIF18A, the method comprising contacting a cell with an effective amount of the compound, or a pharmaceutically acceptable salt thereof.

44. 42. A composition comprising a compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or condition mediated by KIF18A in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of said compound, or a pharmaceutically acceptable salt thereof.

45. 42. A composition comprising a compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of said compound, or a pharmaceutically acceptable salt thereof.

46. 46. ​​The composition of claim 45, 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, other tumors including retinoblastoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, and other cancer-related disorders that are a result of the presence or progression of cancer.

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