Aryl indol-3-yl ketone and aryl indazol-3-yl ketone 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 indole and indazole inhibitors of KIF18A and methods of their use for treating disease mediated by KIF18A, such as cancer.

Description

ARYL INDOL-3-YL KETONE AND ARYL INDAZOL-3-YL KETONE INHIBITORS OF KIF18ACROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority benefit of United States Provisional Patent Application No. 63 / 524,077, filed June 29, 2023, the disclosure of which is hereby incorporated herein by reference in its entirety.FIELD

[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 indole and indazole inhibitors of KIF18A and methods of their use for treating disease mediated by KIF18A, such as cancer.BACKGROUND

[0003] KIF18A is a kinesin involved in assisting the kinetochore-microtubule (kt- MT) attachment and chromosomal alignment during cell mitosis. Its cargo domain binds directly to protein phosphatase 1 (PPI) and carries it to the plus end of MT where PPI dephosphorylates Heel, a kinetochore complex component, further enhancing kt- MT attachment throughout metaphase and anaphase. Its MT-binding motor domain has ATPase activity that powers the KIF18A translocation along MT lattice, enhanced by its C-terminal MT-binding site, and caps and depolymerizes growing microtubule at the plus end, thus dampening MT dynamics. This modulation of MT dynamics by KIF18A often occurs at the following (or trailing) sister chromatid, thereby providing a counterbalancing tension to the leading sister chromatid movement catalyzed by another kinesin Kif2C / MCAK. Loss of KIF18A function causes defective kt-MT attachments and loss of tension within the spindle in cells of high chromosome instability (CIN), leading to hyper stable, longer and multipolar spindles, mitotic arrest, centrosome fragmentation and spindle assembly checkpoint activation or cell death. KIF18A is identified from DEPMAP RNAi data re-analysis as one of the top candidates essential for CIN-high cells. Reported synthetic lethality screens also singled out KIF18A as a potential anticancer target whose knockdown preferentially renders CIN-high (but not CIN-low), aneuploid and whole-genome doubled cells vulnerable to death. Cellular toxicity assay in isogenic cell lines confirmed the enhanced sensitivity of CIN-high cells to KIF18A inhibitors. Ongoing in vivo mouse models using KIF18A inhibitor orknockdown demonstrated effect of inhibited tumor growth. Thus, there is a need for new compounds for use in treating diseases mediated by KIF18A.BRIEF SUMMARY

[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):or a pharmaceutically acceptable salt thereof, wherein: ring A is Ce-14 aryl or 5- to 12- membered heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, Ci-6 alkyl optionally substituted with one or more substituents T1, 3- to 10-membered heterocycloalkyl optionally substituted with one or more substituents T2, -NRalC(O)NRa2Ra3, -NRa4C(O)ORa5, -NRa6Ra7, -N=S(O)Ra8Ra9, -ORal°, -S(O)Ra11, -S(O)(NRal2)Ra13, -S(O)2NRal4Ra15, -S(O)2Ra16, - (CRal7Ral8)o-iC(0)NRal9Ra2°, -SRa21, and -C(O)Ra22, each T1is independently selected from the group consisting of -OH, cyano, C3-10 cycloalkyl, and 3- to 10-membered heterocycloalkyl optionally substituted with one or more halo; each T2is independently halo;Ral_Ra22are each independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocyclo alkenyl Ce-14 aryl, or 5- to 12-membered heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(Ci-6 alkyl), C2-6 alkenyl, C3-10 cycloalkyl, -S(Ci-6 alkyl), =CRlalRla2, and C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, and -O(Ci-6 alkyl), wherein Rlaland Rla2are each independently hydrogen or C1-6 alkyl; L is a bond, CRblRb2, or O; Rbland Rb2are each independently H or C1-3 alkyl; ring Bis C3-8 cycloalkyl, C5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon; each RBgroup is independently halo, C1-6 alkyl, or C2-6 alkenyl; or two vicinal RBgroups are taken together with the carbon atoms to which they are attached to form C3-10 cycloalkyl; or two geminal RBgroups are taken together with the carbon atom to which they are attached to form C3-10 cycloalkyl; m is 0, 1, 2, 3, or 4; Y1is N or CRC1; Y2is N or CRC2; Y3is N or CRC3; Y4is N or CH; RC1, RC2, and RC3are each independently hydrogen, halo, cyano, -OH, -OC1-6 alkyl, or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH; Rcis halo, cyano, -OH, -NO2, - C(O)NRclRc2, -NRC3RC4, -NRC5S(O)2RC6, -P(O)RC7RC8, -N=S(O)RC9RC1°, -S(O)(NRC11)RC12, - S(O)2RC13, -NRC14C(O)ORC15, or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH; and Rcl-Rc15are each independently hydrogen, C3-10 cycloalkyl, or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH.

[0005] In another aspect, provided is pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0006] In another aspect, provided herein is a method of inhibiting KIF18A comprising contacting a cell with an effective amount of a compound or a pharmaceutical composition as described herein.

[0007] In another aspect, provided herein are methods of treating or preventing a disease or condition in an individual, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition as 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 cellular proliferation disorder.DETAILED DESCRIPTION

[0008] The following description is presented to enable a person of ordinary skill in the art to make and use the various embodiments. Descriptions of specific devices, techniques, and applications are provided only as examples. Various modifications to the examples described herein will be readily apparent to those of ordinary skill in the art, and the generalprinciples defined herein may be applied to other examples and applications without departing from the spirit and scope of the various embodiments. Thus, the various embodiments are not intended to be limited to the examples described herein and shown, but are to be accorded the scope consistent with the claims.

[0009] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0010] Throughout this application, unless the context indicates otherwise, references to a compound of Formula (I) includes all subgroups of Formula (I) defined herein, such as Formula (la), including all substructures, subgenera, preferences, embodiments, examples and particular compounds defined and / or described herein. In some embodiments, references to a compound of Formula (I) and subgroups thereof, such as Formula (la), include ionic forms, polymorphs, pseudopolymorphs, amorphous forms, solvates, co-crystals, chelates, isomers, tautomers, oxides (e.g., N-oxides, S-oxides), esters, prodrugs, isotopes and / or protected forms thereof. In some embodiments, references to a compound of Formula (I) and subgroups thereof, such as Formula (la), include polymorphs, solvates, co-crystals, isomers, tautomers and / or oxides thereof. In some embodiments, references to a compound of Formula (I) and subgroups thereof, such as Formula (la), include polymorphs, solvates, and / or cocrystals thereof. In some embodiments, references to a compound of Formula (I) and subgroups thereof, such as Formula (la), include isomers, tautomers and / or oxides thereof. In some embodiments, references to a compound of Formula (I) and subgroups thereof, such as Formula (la), include solvates thereof.

[0011] “Alkyl” encompasses straight and branched carbon chains having the indicated number of carbon atoms, for example, from 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, Ci-6 alkyl encompasses both straight and branched chain alkyl of from 1 to 6 carbon atoms. When an alkyl residue having a specific number of carbons is named, all branched and straight chain versions having that number of carbons are intended to be encompassed; 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, secbutyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3 -methylpentyl.

[0012] When a range of values is given (e.g., Ci-6 alkyl), each value within the range as well as all intervening ranges are included. For example, “Ci-6 alkyl” includes Ci, C2, C3, C4, C5, C6, C1-6, C2-6, C3-6, C4-6, C5-6, Ci-5, C2-5, C3-5, C4-5, C , C2-4, C3-4, C1-3, C2-3, and C1-2 alkyl.

[0013] “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 may 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-l-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), prop-2-en-2- yl), and butenyl (e.g., but-l-en-l-yl, but-l-en-2-yl, 2-methyl-prop-l-en-l-yl, but-2-en-l-yl, but-2-en-l-yl, but-2-en-2-yl, buta-l,3-dien-l-yl, buta-l,3-dien-2-yl).

[0014] “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-l-yn-l-yl, prop-2-yn-l-yl) and butynyl (e.g., but-l-yn-l-yl, but-l-yn-3-yl, but-3- yn-l-yl).

[0015] “Cycloalkyl” indicates a non-aromatic, fully saturated carbocyclic ring having the indicated number of carbon atoms, for example, 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 caged ring groups (e.g., norbornane, bicyclo[2.2.2]octane). In addition, one ring of a polycyclic cycloalkyl group may be aromatic, provided the polycyclic cycloalkyl group is bound to the parent structure via a non-aromatic carbon. For example, a 1,2,3,4-tetrahydronaphthalen-l-yl group (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is a cycloalkyl group, while l,2,3,4-tetrahydronaphthalen-5- yl (wherein the moiety is bound to the parent structure via 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.

[0016] “Cycloalkenyl” indicates 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 may 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). In addition, one ring of a polycyclic cycloalkenyl group may be aromatic, provided the polycyclic alkenyl group is bound to the parent structure via a non-aromatic carbon atom. For example, inden- 1-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is considered a cycloalkenyl group, while inden-4-yl (wherein the moiety is bound to the parent structure via 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 described below.

[0017] “Aryl” indicates an aromatic carbocyclic ring having the indicated number of carbon atoms, for example, 6 to 12 or 6 to 10 carbon atoms. Aryl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In some instances, both rings of a polycyclic aryl group are aromatic (e.g., naphthyl). In other instances, polycyclic aryl groups may include a non-aromatic ring fused to an aromatic ring, provided the polycyclic aryl group is bound to the parent structure via an atom in the aromatic ring. Thus, a l,2,3,4-tetrahydronaphthalen-5- yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered an aryl group, while 1,2,3,4-tetrahydronaphthalen-l-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is not considered an aryl group. Similarly, a l,2,3,4-tetrahydroquinolin-8-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered an aryl group, while 1 ,2,3,4- tetrahydroquinolin-l-yl group (wherein the moiety is bound to the parent structure via 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, aryl is phenyl or naphthyl. In certain instances, aryl is phenyl. Additional examples of aryl groups comprising an aromatic carbon ring fused to a non-aromatic ring are described below.

[0018] “Heteroaryl” indicates an aromatic ring containing the indicated number of atoms (e.g., 5 to 12, or 5 to 10 membered heteroaryl) made up of one or more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, O and S and 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 the heteroaryl group is not more than 2. In someembodiments, the total number of S and O atoms in the heteroaryl group is not more than 1. Unless otherwise indicated, heteroaryl groups may be bound to the parent structure by a carbon or nitrogen atom, as valency permits. For example, “pyridyl” includes 2-pyridyl, 3- pyridyl and 4-pyridyl groups, and “pyrrolyl” includes 1 -pyrrolyl, 2-pyrrolyl and 3-pyrrolyl groups.

[0019] In some instances, a 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.

[0020] In some instances, both rings of a polycyclic heteroaryl group are aromatic. Examples include indole, isoindole, indazole, benzoimidazole, benzotriazole, benzofuran, benzoxazole, benzoisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzoisothiazole, benzothiadiazole, lH-pyrrolo[2,3-b]pyridine, lH-pyrazolo[3,4-b]pyridine, 3H-imidazo [4,5-b]pyridine, 3H- [ 1 ,2,3 ] triazolo [4,5-b]pyridine, 1 H-pyrrolo [3 ,2-b]pyridine, 1 H-pyrazolo [4,3-b]pyridine, 1 H-imidazo [4,5-b]pyridine, 1 H- [ 1 ,2,3] triazolo [4,5-b]pyridine, lH-pyrrolo[2,3-c]pyridine, lH-pyrazolo[3,4-c]pyridine, 3H-imidazo[4,5-c]pyridine, 3H-[1.2.3]triazolo[4,5-c]pyridine, lH-pyrrolo[3,2-c]pyridine, lH-pyrazolo[4,3-c]pyridine, 1H- imidazo[4,5-c]pyridine, lH-[l,2,3]triazolo[4,5-c]pyridine, furo[2,3-b]pyridine, oxazolo[5,4- b]pyridine, isoxazolo[5,4-b]pyridine, [l,2,3]oxadiazolo[5,4-b]pyridine, furo[3,2-b]pyridine, oxazolo[4,5-b]pyridine, isoxazolo[4,5-b]pyridine, [l,2,3]oxadiazolo[4,5-b]pyridine, furo[2,3- c]pyridine, oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine, [l,2,3]oxadiazolo[5,4- c]pyridine, furo[3,2-c]pyridine, oxazolo[4,5-c]pyridine, isoxazolo[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, [l,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, [l,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[l,2-a]pyridine, IH-pyrazolo [3, 4-d] thiazole, lH-pyrazolo[4,3-d]thiazole and imidazo[2, l-b]thiazole.

[0021] In other instances, polycyclic heteroaryl groups may include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to a heteroaryl ring, provided the polycyclic heteroaryl group is bound to the parent structure via an atom in the aromatic ring. For example, a 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered a heteroaryl group, while 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is not considered a heteroaryl group. Examples of polycyclic heteroaryl groups consisting of a heteroaryl ring fused to a non- aromatic ring are described below.

[0022] “Heterocycloalkyl” indicates a non-aromatic, fully saturated ring having the indicated number of atoms (e.g., 3 to 10, or 3 to 7, membered heterocyclo alkyl) made up of one or more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, O and S and with the remaining ring atoms being carbon. Heterocycloalkyl groups may 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. In addition, one ring of a polycyclic heterocycloalkyl group may be aromatic (e.g., aryl or heteroaryl), provided the polycyclic heterocycloalkyl group is bound to the parent structure via a non-aromatic carbon or nitrogen atom. For example, a 1 ,2,3,4- tetrahydroquinolin-l-yl group (wherein the moiety is bound to the parent structure via a non- aromatic nitrogen atom) is considered a heterocycloalkyl group, while 1, 2,3,4- tetrahydroquinolin-8-yl group (wherein the moiety is bound to the parent structure via 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.

[0023] “Heterocycloalkenyl” indicates a non-aromatic ring having the indicated number of atoms (e.g., 3 to 10, or 3 to 7, membered heterocycloalkyl) made up of one or more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, O and S and with the remaining ring atoms being carbon, and at least one double bond derived by the removal of one molecule of hydrogen from adjacent carbon atoms, adjacent nitrogen atoms, or adjacentcarbon and nitrogen atoms 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-lH-pyrrolyl, 2,5-dihydro-lH-pyrrolyl), dihydroimidazolyl (e.g., 2,3- dihydro-lH-imidazolyl, 4,5-dihydro-lH-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). In addition, one ring of a polycyclic heterocycloalkenyl group may be aromatic (e.g., aryl or heteroaryl), provided the polycyclic heterocycloalkenyl group is bound to the parent structure via a non-aromatic carbon or nitrogen atom. For example, a 1,2-dihydroquinolin-l-yl group (wherein the moiety is bound to the parent structure via a non-aromatic nitrogen atom) is considered a heterocycloalkenyl group, while l,2-dihydroquinolin-8-yl group (wherein the moiety is bound to the parent structure via 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.

[0024] 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-lH-indenyl, 1,2,3,4-tetrahydronaphthalenyl, benzo[l,3]dioxolyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[l,4]dioxinyl, indolinyl, isoindolinyl, 2,3-dihydro-lH-indazolyl, 2,3-dihydro-lH-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, l,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-l-one, 1,2- dihydroindazol-3-one, lH-benzo[d]imidazol-2(3H)-one, benzofuran-2(3H)-one, benzofuran- 3(2H)-one, isobenzofuran- l(3H)-one, benzo[c]isoxazol-3(lH)-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-l(3H)-one, benzo[c]isothiazol-3(lH)-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, quinazoline-2,4(lH,3H)-dione, quinoxalin-2(lH)-one, quinoxaline-2,3(lH,4H)-dione, cinnolin-4(3H)-one, pyridin-2(lH)- one, pyrimidin-2(lH)-one, pyrimidin-4(3H)-one, pyridazin-3(2H)-one, lH-pyrrolo[3,2- b]pyridin-2(3H)-one, lH-pyrrolo[3,2-c]pyridin-2(3H)-one, lH-pyrrolo[2,3-c]pyridin-2(3H)- one, lH-pyrrolo[2,3-b]pyridin-2(3H)-one, l,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, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl group is determined by the atom through which the moiety is bound to the parent structure.

[0025] “Halogen” or “halo” refers to fluoro, chloro, bromo or iodo.

[0026] Unless otherwise indicated, compounds disclosed and / or described herein include all possible enantiomers, diastereomers, meso isomers and other stereoisomeric forms, including racemic mixtures, optically pure forms and intermediate mixtures thereof.Enantiomers, diastereomers, meso isomers and other stereoisomeric forms can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Unless specified otherwise, when the compounds disclosed and / or described herein contain olefinic double bonds or other centers of geometric asymmetry, it is intended that the compounds include both E and Z isomers. When the compounds described herein contain moieties capable of tautomerization, and unless specified otherwise, it is intended that the compounds include all possible tautomers.

[0027] “Protecting group” has the meaning conventionally associated with it in organic synthesis, i.e., a group that selectively blocks one or more reactive sites in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site, and such that the group can readily be removed after the selective reaction is complete. A variety of protecting groups are disclosed, for example, in T.H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999). For example, a “hydroxy protected form” contains at least one hydroxy group protected with a hydroxy protecting group. Likewise, amines and other reactive groups may similarly be protected.

[0028] The term “pharmaceutically acceptable salt” refers to a salt of any of the compounds herein which are known to be non-toxic and are commonly used in thepharmaceutical literature. In some embodiments, the pharmaceutically acceptable salt of a compound retains the biological effectiveness of the compounds described herein and are 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 with inorganic acids 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 with 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 including 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.

[0029] If the compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the compound is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds (see, e.g., Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19). Those skilled in the art will recognize various synthetic methodologies that may be used to prepare pharmaceutically acceptable addition salts.

[0030] 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 having any ratio of compound to water, such as monohydrates, dihydrates and hemi-hydrates.

[0031] The term “substituted” means that the specified group or moiety bears one or more substituents including, but not limited to, substituents such as 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. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. When a group or moiety bears more than one substituent, it is understood that the substituents may be the same or different from one another. In some embodiments, a substituted group or moiety bears from one to five substituents. In some embodiments, a substituted group or moiety bears one substituent. In some embodiments, a substituted group or moiety bears two substituents. In some embodiments, a substituted group or moiety bears three substituents. In some embodiments, a substituted group or moiety bears four substituents. In some embodiments, a substituted group or moiety bears five substituents.

[0032] By “optional” or “optionally” is meant that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” encompasses both “alkyl” and “substituted alkyl” as defined herein. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible, and / or inherently unstable. It will also be understood that where a group or moiety is optionally substituted, the disclosure includes both embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is unsubstituted.

[0033] The compounds disclosed and / or described herein can be enriched isotopic forms, e.g., enriched in the content of2H,3H,nC,13C and / or14C. In one embodiment, the compound contains at least one deuterium atom. Such deuterated forms can be made, for example, by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. Such deuterated compounds may improve the efficacy and increase the duration of action of compounds disclosed and / or described herein. Deuterium substituted compounds can be synthesizedusing various 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.

[0034] 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 pharmaceutical compositions is contemplated. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.

[0035] The terms “patient,” “individual,” and “subject” refer to an animal, such as a mammal, bird, or fish. In some embodiments, the patient or subject is a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows and humans. In some embodiments, the patient, individual, or subject is a human, for example a human that has been or will be the object of treatment, observation or experiment. The compounds, compositions and methods described herein can be useful in both human therapy and veterinary applications.

[0036] The term “therapeutically effective amount” or “effective amount” refers to that amount of a compound disclosed and / or described herein that is sufficient to affect treatment, as defined herein, when administered to a patient in need of such treatment. A therapeutically effective amount of a compound may be an amount sufficient to treat a disease responsive to modulation (e.g., inhibition) of KIF18A. The therapeutically effective amount will vary depending upon, for example, the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound, the dosing regimen to be followed, timing of administration, the manner of administration, all of which can readily be determined by one of ordinary skill in the art. The therapeutically effective amount may be ascertained experimentally, for example by assaying blood concentration of the chemical entity, or theoretically, by calculating bioavailability.

[0037] ‘Treatment” (and related terms, such as “treat,” “treated,” “treating”) includes one or more of: inhibiting a disease or disorder; slowing or arresting the development of clinical symptoms of a disease or disorder; and / or relieving a disease or disorder (i.e., causing relief from or regression of clinical symptoms). The term covers both complete and partial reduction of the condition or disorder, and complete or partial reduction of clinical symptoms of a disease or disorder. Thus, compounds described and / or disclosed herein may prevent an existing disease or disorder from worsening, assist in the management of the disease or disorder, or reduce or eliminate the disease or disorder.

[0038] It is understood that embodiments described herein as “comprising” include “consisting of’ and “consisting essentially of’ embodiments.Compounds

[0039] Compounds and salts thereof (such as pharmaceutically acceptable salts) are detailed herein, including in the Brief Summary and in the appended claims. Also provided are the use of all 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 of the compounds described herein, as well as methods of making such compounds. Any compound described herein may also be referred to as a drug.

[0040] In one aspect, provided are compounds of Formula (I):or a pharmaceutically acceptable salt thereof, wherein ring A is Ce-14 aryl or 5- to 12-membered heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, Ci-6alkyl optionally substituted with one or more substituents T1, 3- to 10-membered heterocycloalkyl optionally substituted with one or more substituents T2, -NRalC(O)NRa2Ra3, -NRa4C(O)ORa5, -NRa6Ra7, -N=S(O)Ra8Ra9, -ORal°, -S(O)Ra11, -S(O)(NRal2)Ra13, - S(O)2NRal4Ra15, -S(O)2Ra16, -(CRal7Ral8)o-iC(0)NRal9Ra2°, -SRa21, and -C(O)Ra22; each T1is independently selected from the group consisting of -OH, cyano, C3-10 cycloalkyl, and 3- to 10-membered heterocycloalkyl optionally substituted with one or more halo; and each T2is independently halo;Ral _Ra22are each independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, Ce-14 aryl, or 5- to 12-membered heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(Ci-6 alkyl), C2-6 alkenyl, C3-10 cycloalkyl, -S(Ci-6 alkyl), =CRlalRla2, and C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, and -O(Ci-6 alkyl), wherein Rlaland Rla2are each independently hydrogen or C1-6 alkyl;L is a bond, CRblRb2, or O;Rbland Rb2are each independently H or C1-3 alkyl; ring B is C3-8 cycloalkyl, C5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon; each RBgroup is independently halo, C1-6 alkyl optionally substituted with one or more halo, or C2-6 alkenyl; or two vicinal RBgroups are taken together with the carbon atoms to which they are attached to form C3-10 cycloalkyl; or two geminal RBgroups are taken together with the carbon atom to which they are attached to form C3-10 cycloalkyl; m is 0, 1, 2, 3, or 4;Y1is N or CRcl;Y2is N or CRC2;Y3is N or CRC3;Y4is N or CH;RC1, RC2, and RC3are each independently hydrogen, halo, cyano, -OH, -OCi-6 alkyl, or Ci-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH;Rcis halo, cyano, -OH, -NO2, -C(O)NRclRc2, -NRc3Rc4, -NRc5S(O)2Rc6, -P(O)Rc7Rc8, -N=S(O)RC9RC1°, -S(O)(NRC11)RC12, -S(O)2RC13, -NRC14C(O)ORC15, or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH; andRcl-Rc15are each independently hydrogen, C3-10 cycloalkyl, or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH.

[0041] In some embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, ring A is Ce-14 aryl or 5- to 12-membered heteroaryl, each optionally substituted. In some embodiments, ring A is optionally substituted Ce-14 aryl. In some embodiments, ring A is optionally substituted phenyl. In some embodiments, ring A is optionally substituted 5- to 12-membered heteroaryl. In some embodiments, ring A is optionally substituted 5- to 10- membered heteroaryl. In some embodiments, ring A is optionally substituted 6-membered heteroaryl. In some embodiments, ring A is optionally substituted 5-membered heteroaryl. In some embodiments, ring A is indolyl, indazolyl, pyridinyl, thiophenyl, furanyl, pyrazolyl, pyrrolyl, oxazolyl, chromanyl, or quinolinyl, each optionally substituted. In some embodiments, ring A is furanyl or pyridyl, each optionally substituted. In some embodiments, ring A is Ce-14 aryl. In some embodiments, ring A is phenyl. In some embodiments, ring A is 5- to 12-membered heteroaryl. In some embodiments, ring A is 5- to 10-membered heteroaryl. In some embodiments, ring A is 6-membered heteroaryl. In some embodiments, ring A is 5-membered heteroaryl. In some embodiments, ring A is indolyl, indazolyl, pyridinyl, thiophenyl, furanyl, pyrazolyl, pyrrolyl, oxazolyl, chromanyl, or quinolinyl. In some embodiments, ring A is furanyl or pyridyl.

[0042] In some embodiments, ring A is optionally substituted with one, two, three, four, five, or more substituents independently selected from the group consisting of halo, -OH, C1-6 alkyl optionally substituted with one or more substituents T1, 3- to 10-membered heterocycloalkyl optionally substituted with one or more substituents T2, -NRalC(O)NRa2Ra3, -NRa4C(O)ORa5, -NRa6Ra7, -N=S(O)Ra8Ra9, -ORal°, -S(O)Ra11, -S(O)(NRal2)Ra13, - S(O)2NRal4Ra15, -S(O)2Ra16, and -(CRal7Ral8)o-iC(0)NRal9Ra2°, -SRa21, and -C(O)Ra22. Insome embodiments, ring A is optionally substituted with one or two substituents independently selected from the group consisting of -S(O)2NRal4Ra15, -S(O)2Ra16, Ci-6 alkyl optionally substituted with one or more substituents T1, and 3- to 10-membered heterocycloalkyl optionally substituted with one or more substituents T2. In some embodiments, ring A is substituted with one or two substituents independently selected from the group consisting of -S(O)2NRal4Ra15, -S(O)2Ra16, Ci-6 alkyl substituted with one or more substituents T1, and 3- to 10-membered heterocycloalkyl substituted with one or more substituents T2. In some embodiments, each T1is independently selected from the group consisting of C3-10 cycloalkyl and -OH. In some embodiments, each T2is independently halo. In some embodiments, each T1is independently selected from the group consisting of -OH and cyclopentyl. In some embodiments, each T2is fluoro. In some embodiments, ring A is substituted with one or more substituents selected from the group consisting of - S(O)2NRal4Ra15, -S(O)2Ra16, C1-6 alkyl optionally substituted with one or more substituents T1, and 3- to 10-membered heterocycloalkyl optionally substituted with one or more substituents T2; wherein each T1is independently selected from the group consisting of C3-10 cycloalkyl and -OH; and each T2is independently halo. In some embodiments, ring A is substituted with one or more substituents selected from the group consisting of - S(O)2NRal4Ra15, -S(O)2Ra16, piperidinyl optionally substituted with one or more fluoro, and alkyl optionally substituted with one or more substituents selected from the group consisting of -OH and cyclopentyl. In some embodiments, Ral-Ra22are each independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl Ce-14 aryl, or 5- to 12-membered heteroaryl, each optionally substituted with one, two, three, four, five, or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(Ci-6 alkyl), C2-6 alkenyl, C3-10 cycloalkyl, -S(Ci-6 alkyl), =CRlalRla2, and C1-6 alkyl optionally substituted with one, two, three, four, five, or more substituents independently selected from the group consisting of halo, -OH, and -O(Ci-6 alkyl), wherein Rlaland Rla2are each independently hydrogen or C1-6 alkyl.

[0043] In some embodiments, the 3- to 10-membered heterocycloalkyl optionally substituted with one or more substituents T2is piperidinyl. In some embodiments, the 3- to 10-membered heterocycloalkyl optionally substituted with one or more substituents T2is. In some embodiments, the optionally substituted 3- to 10-membered heterocycloalkyl optionally substituted with one or more substituentssome embodiments, Ralis hydrogen or Ci-6 alkyl. In some embodiments, Ralis hydrogen. In some embodiments, Ra2and Ra3are each independently hydrogen, Ci-6 alkyl, or C3-10 cycloalkyl. In some embodiments, Ra2and Ra3are each independently hydrogen, cyclopropyl, ethyl, or isopropyl. In some embodiments, Ra4is hydrogen or C1-6 alkyl. In some embodiments, Ra4is hydrogen. In some embodiments, Ra5is hydrogen or C1-6 alkyl. In some embodiments, R35is tert-butyl. In some embodiments, Ra6and Ra7are each independently hydrogen, C1-6 alkyl, or 5- to 12- membered heteroaryl optionally substituted with C1-6 alkyl. In some embodiments, Ra6and Ra7are each independently hydrogen, imidazolyl, methylimidazolyl, or pyrimidinyl. In some embodiments,some embodiments, Ra8and Ra9are each independently hydrogen, C1-6 alkyl, or C3-10 cycloalkyl. In some embodiments, Ra8and Ra9are each independently methyl or cyclopentyl. In some embodiments, -ORal° is. In some embodiments, Ral° is C3-10 cycloalkyl. In some embodiments, Ral° is cyclopentyl. In some embodiments, -S(O)Ra11is. In some embodiments, Ral1is C3-10 cycloalkyl.In some embodiments, Ral1is cyclopentyl. In some embodiments, -S(O)(NRal2)Ra13is 17some embodiments, R is hydrogen or C1-6 alkyl. In some embodiments, Ral2is hydrogen or methyl. In some embodiments, Ral3is C3-10 cycloalkyl. In some embodiments, Ral3is cyclopentyl. In some embodiments, -some embodiments, -some embodiments, Ral4and Ral5are each independently hydrogen; Ci-6 alkyl optionally substituted with one, two, three, four, five, or more substituents independently selected from the group consisting of Ci-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, -OH, -O(Ci-6 alkyl), -S(Ci-6 alkyl), and halo; C2-6 alkenyl; C3-10 cycloalkyl optionally substituted with one, two, three, four, five, or more substituents independently selected from the group consisting of C2-6 alkenyl, C3-10 cycloalkyl, halo, cyano, -OH, -O(Ci-6 alkyl), =CRlalRla2, and C1-6 alkyl optionally substituted with one, two, three, four, five, or more substituents independently selected from the group consisting of -OH, -O(Ci-6 alkyl), and halo, wherein Rlaland Rla2are each independently hydrogen or C1-6 alkyl; C3-10 cycloalkenyl; or 3- to 12-membered heterocycloalkyl optionally substituted with one, two, three, four, five, or more C1-6 alkyl. In some embodiments, Ral4and Ral5are each independently hydrogen or C1-6 alkyl. In some embodiments, -S(O)2Ra16isIn some embodiments, -some embodiments, Ral6is C3-10 cycloalkyl; or 3- to 12-membered heterocycloalkyl optionally substituted with one, two, three, four, five, or more substituents independently selected from the group consisting of Ci- 6 alkyl and halo. In some embodiments, Ral6is C3-10 cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of C1-6 alkyl andhalo. In some embodiments, -(CRal7Ral8)o-iC(0)NRal9Ra2° is -C(O)NRal9Ra20or - (CRal7Ral8)C(O)NRal9Ra20. In some embodiments, -(CRal7Ral8)o-iC(0)NRal9Ra2° is - C(O)NRal9Ra20. In some embodiments, -(CRal7Ral8)o-iC(0)NRal9Ra2° is - (CRal7Ral8)C(O)NRal9Ra20. In some embodiments, Ral7and Ral8are each independently hydrogen or Ci-6 alkyl. In some embodiments, Ral7and Ral8are each hydrogen. In some embodiments, Ral9and Ra20are each independently hydrogen, Ci-6 alkyl, or C3-10 cycloalkyl. In some embodiments, Ral9and Ra20are each independently hydrogen or cyclopropyl. In some embodiments, -SR2121is. In some embodiments, Ra21is C3-10 cycloalkyl. In some embodiments, -C(O)Ra22is. In some embodiments, Ra22is C3-10 cycloalkyl.In some embodiments, Ral4is hydrogen; R15is tert-butyl; and R16is azetidine optionally substituted with one or more halo.

[0044] In some embodiments, ring A is optionally substituted with one, two, three, four, five, or more substituents independently selected from the group consistingsubstituent with one or two substituents independently selected from the group consisting of

[0045] In some embodiments, ring A is substituted with one, two, three, four, five, or more substituents independently selected from the group consistingsome embodiments, ring A is substituent with one or two substituents independently selected from the group consisting

[0046] In some embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, L is a bond, CRblRb2, or O. In some embodiments, L is a bond. In some embodiments, L is CRblRb2. In some embodiments, Rbland Rb2are each independently H or C1-3 alkyl. In some embodiments, Rbland Rb2are each independently H. In some embodiments, L is O.

[0047] In some embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, ring B is C3-8 cycloalkyl, C5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon. In some embodiments, ring B is C3-8 cycloalkyl. In some embodiments, ring B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, ring B is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, ring B is, , , or , wherein * denotes the point of attachment to the rest ofFormula (I). In some embodiments, ring B is C3-8 cycloalkenyl. In some embodiments, ring Bis 5- to 7-membered heterocycloalkyl. In some embodiments, ring B is 5- to 7-membered heterocycloalkyl wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon.

[0048] In some embodiments, ring B is substituted with m RBgroups, wherein each RBgroup is independently halo, Ci-6 alkyl, or C2-6 alkenyl; or two vicinal RBgroups are taken together with the carbon atoms to which they are attached to form C3-10 cycloalkyl; or two geminal RBgroups are taken together with the carbon atom to which they are attached to form C3-10 cycloalkyl. In some embodiments, two geminal RBgroups are taken together with the carbon atom to which they are attached to form C3-10 cycloalkyl. In some embodiments, an RBgroup is methyl or ethyl. In some embodiments, an RBgroup is fluoro. In some embodiments, two vicinal RBgroups are taken together with the carbon atoms to which they are attached to form cyclopropyl. In some embodiments, two geminal RBgroups are taken together with the carbon atom to which they are attached to form cyclopropyl or cyclobutyl. In some embodiments, two geminal RBgroups are taken together with the carbon atom to which they are attached to form cyclopropyl. In some embodiments, two geminal RBgroups are taken together with the carbon atom to which they are attached to form cyclobutyl.

[0049] 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. In some embodiments, m is 2.wherein * denotes the point of attachment to the rest of Formula (I).

[0051] In some embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, Y1is N or CRC1; Y2is N or CRC2; Y3is N or CRC3; and Y4is N or CH. In some embodiments, no more than three of Y1, Y2, Y3, and Y4are N. In some embodiments, nomore than two of Y1, Y2, Y3, and Y4are N. In some embodiments, no more than one of Y1, Y2, Y3, and Y4is N. In some embodiments, Y1is CRC1; Y2is CRC2; Y3is CRC3; and Y4is CH. In some embodiments, Y1is CRC1; Y2is CRC2; Y3is CRC3; and Y4is N. In some embodiments, Y1is N; Y2is CRC2; Y3is CRC3; and Y4is CH. In some embodiments, Y1is CRcl; Y2is N; Y3is CRC3; and Y4is CH.

[0052] In some embodiments, RC1, RC2, and RC3are each independently hydrogen, halo, cyano, -OH, -OCi-6 alkyl, or Ci-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH. In some embodiments, RC1, RC2, and RC3are each independently hydrogen.

[0053] In some embodiments, Rcis halo, cyano, -OH, -NO2, -C(O)NRclRc2, -NRc3Rc4, - NRC5S(O)2RC6, -P(O)RC7RC8, -N=S(O)RC9RC1°, -S(O)(NRC11)RC12, -S(O)2RC13, - NRC14C(O)ORC15, or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH. In some embodiments, Rcis NRC5S(O)2RC6. In some embodiments,some embodiments,

[0054] In some embodiments, Rcl-Rc15are each independently hydrogen, C3-10 cycloalkyl, or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH. In some embodiments, Rcl-Rc15are each independently hydrogen or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH.H

[0055] In some embodiments, C(O)NRclRc2is O . In some embodiments, RclandRc2are each independently hydrogen or C1-6 alkyl. In some embodiments, Rcland Rc2are / "M7each independently hydrogen, methyl, or ethyl. In some embodiments, -NRc3Rc4is HIn some embodiments, Rc3and Rc4are each independently hydrogen or C1-6 alkyl. In some embodiments, Rcland Rc2are each independently hydrogen, methyl, or ethyl.

[0056] In some embodiments,. In some embodiments, -NRc5S(O)2Rc6is H . In some embodiments, Rc5is hydrogen or C1-6 alkyl. In some embodiments, Rc5is hydrogen, methyl, or ethyl. In some embodiments, Rc5is hydrogen. In some embodiments, Rc6is hydrogen or C1-6 alkyl optionally substituted with one, two, three, four, five, or more substituents independently selected from halo and - OH. In some embodiments, Rc5is methyl or -CH2CH2OH. In some embodiments, Rc5is methyl.

[0057] In some embodiments, -P(O)Rc7Rc8is I . In some embodiments, Rc7and Rc8are each independently C1-6 alkyl. In some embodiments, Rc7and Rc8are each methyl. InOs / £ X some embodiments, -N=S(O)Rc9Rcl° is * ‘N . In some embodiments, Rc9and Rcl° are each independently C1-6 alkyl. In some embodiments, Rc9and Rcl° are each methyl. In some embodiments, -S(O)(NRcl l)Rc12is. In some embodiments, Rcl 1is hydrogen or C1-6 alkyl. In some embodiments, Rcl 1is hydrogen or methyl. In some embodiments, Rcl2is C1-6 alkyl or C3-10 cycloalkyl. In some embodiments, Rcl2is cyclopropyl. In some embodiments, -S(O)2Rc13is. in some embodiments, Rcl3is C1-6 alkyl. In some embodiments, Rcl3is methyl. In some embodiments, Rcl4and Rcl5are each independently hydrogen, C3-10 cycloalkyl, or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH.

[0058] In some embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, ring A is phenyl substituted with S(O)2NRal4Ra15. In some embodiments, ring A is phenyl substitutedsome embodiments, ring A is phenyl substituted with, and L is a bond. In some embodiments, L is a bond, and ring B is cyclopentyl. In some embodiments, L is a bond, and ring B is cyclohexyl. In some embodiments, ring A is phenyl substitutedbond, ring B is cyclopentyl or cyclohexyl, and Rcis -NRC5S(O)2RC6. In some embodiments, ring A is phenyl substitutedbond,ring B is cyclopentyl or cyclohexyl, and R is . In some embodiments, ring A is phenyl, and L is a bond.

[0059] In one aspect, provided are compounds of Formula (la):or a pharmaceutically acceptable salt thereof, wherein Ral4, Ral5, ring B, RB, m, and Rcare as defined for Formula (I) or any variation or embodiment thereof.

[0060] In some embodiments, provided herein are compounds and pharmaceutically acceptable salts thereof described in Table 1.Table 1.

[0061] In some variations, any of the compounds described herein, such as a compound of Formula (I) or (la), or any variation thereof, or a compound of Table 1 may be deuterated (e.g., a hydrogen atom is replaced by a deuterium atom). In some of these variations, the compound is deuterated at a single site. In other variations, the compound is deuterated at multiple sites. Deuterated compounds can be prepared from deuterated starting materials in amanner similar to the preparation of the corresponding non-deuterated compounds. Hydrogen atoms may also be replaced with deuterium atoms using other method known in the art.

[0062] Any formula given herein, such as Formula (I) or (la), is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms. In particular, compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof in any ratio, are considered within the scope of the formula. Thus, any formula given 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, certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers. Additionally, any formula given herein is intended to refer also to any one of hydrates, solvates, and amorphous and polymorphic forms of such compounds, and mixtures thereof, even if such forms are not listed explicitly. In some embodiments, the solvent is water and the solvates are hydrates.

[0063] Representative examples of compounds detailed herein, including intermediates and final compounds, are depicted in the tables and elsewhere herein. It is understood that in one aspect, any of the compounds may be used in the methods detailed herein, including, where applicable, intermediate compounds that may be isolated and administered to an individual.

[0064] The compounds depicted herein may be present as salts even if salts are not depicted, and it is understood that the compositions and methods provided herein embrace all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts.

[0065] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual. In another variation, compositions are provided containing a compound in substantially pure form. In another variation, provided are pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another variation, methods of administering a compound are provided. Thepurified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.

[0066] Any variation or embodiment of ring A, Ral, Ra2, Ra3, Ra4, R35, Ra6, Ra7, Ra8, Ra9,Rcl4, or Rcl5, as if each combination had been individually and specifically described.

[0067] 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.

[0068] Compound names provided herein, including in Table 1, are provided by Chemaxon Marvin Structure to Name 20 or ChemDraw Professional 22. One of skilled in the art would understand that the compounds may be named or identified using various commonly recognized nomenclature systems and symbols. By way of example, the compounds may be named or identified with common names, systematic or non-systematic names. The nomenclature systems and symbols that are commonly recognized in the art of chemistry include, for example, Chemical Abstract Service (CAS), ChemBioDraw Ultra, and International Union of Pure and Applied Chemistry (IUPAC).Compositions

[0069] Also provided are compositions, such as pharmaceutical compositions, that include a compound disclosed and / or described herein and one or more additional medicinal agents, pharmaceutical agents, adjuvants, carriers, excipients, and the like. Suitable medicinal and pharmaceutical agents include those described herein. In some embodiments, the pharmaceutical composition includes a pharmaceutically acceptable excipient or adjuvant and at least one chemical entity as described herein. Examples of pharmaceutically acceptable excipients include, but are not limited to, mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium croscarmellose, glucose, gelatin, sucrose, and magnesium carbonate. In some embodiments, provided are compositions, such aspharmaceutical compositions that contain one or more compounds described herein, or a pharmaceutically acceptable salt thereof.

[0070] In some embodiments, provided is a pharmaceutically acceptable composition comprising a compound of Formula (I) or (la), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some aspects, a composition may contain a synthetic intermediate that may be used in the preparation of a compound described herein. The compositions described herein may contain any other suitable active or inactive agents.

[0071] Any of the compositions described herein may be sterile or contain components that are sterile. 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.

[0072] Also provided are packaged pharmaceutical compositions, comprising a pharmaceutical composition as described herein and instructions for using the composition to treat a patient suffering from a disease or condition described herein.Methods of Use

[0073] As described herein, the compounds of the present disclosure are inhibitors of KIF18A. In one aspect, the compounds and pharmaceutical compositions herein may be used to inhibit KIF18A. In another aspect, the compounds and pharmaceutical compositions herein may be used to treat or prevent a disease or condition in an individual.

[0074] 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 D.D., Jiang W.(2001) Assays for Kinesin Microtubule-Stimulated ATPase Activity. In: Vemos I. (eds) Kinesin Protocols. Methods in Molecular Biology™, vol 164. Humana Press. https: / / doi.Org / 10.1385 / l-59259-069-l:65).

[0075] In one aspect, provided herein is a method of inhibiting KIF18A comprising contacting a cell with an effective amount of a compound or a pharmaceutical composition as described herein. In some embodiments, provided herein are methods of inhibiting KIF18A comprising contacting a cell with an effective amount of a compound Formula (I) or (la), or acompound of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of inhibiting KIF18A comprising contacting a cell with an effective amount of a pharmaceutical composition comprising a compound a compound Formula (I) or (la), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In one variations of the aforementioned embodiments, the cell is contacted in vitro. In other variations of the aforementioned embodiments, the cell is contacted in vivo.

[0076] 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 a pharmaceutical composition as described herein. When used in a prophylactic manner, the compounds disclosed and / or described herein may prevent a disease or disorder from developing in an individual at risk of developing the disease or disorder, or lessen the extent of a disease or disorder that may develop.

[0077] In some embodiments, provided herein are methods of treating or preventing a disease or condition in an individual, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition as described herein. In some embodiments, provided herein are methods of treating or preventing a disease or condition in an individual, comprising administering to the subject a therapeutically effective amount of a compound Formula (I) or (la), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of treating or preventing a disease or condition in an individual, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound a compound Formula (I) or (la), or a compound of Table 1, or a pharmaceutically acceptable salt thereof.

[0078] 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 cellular proliferation disorder, including uncontrolled cell growth, aberrant cell cycle regulation, centrosome abnormalities (structural and or numeric, fragmentation), a solid tumor, hematopoietic cancer and hyperproliferative disorder, such as thyroid hyperplasia (especially Grave's disease), and cyst (such as hypervascularity of ovarian stroma, characteristic of polycystic ovarian syndrome (Stein-Leventhal syndrome). Solid and hematologically derived tumors, such as carcinomas, may include but are not limited to cancer of the anus, bladder, breast, colon, small intestine, appendix, kidney, renal pelvis,ureter, urothelium, liver, lung (including squamous cell and small cell lung cancer), pleura, esophagus, head and neck, nasopharynx, oropharynx, hypopharynx, oral cavity, larynx, biliary tract, gall-bladder, ovary, testicle, 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 Burkett's lymphoma), hematopoietic tumors of myeloid lineage (including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia), hematopoietic tumors of any lineage, myeloma, tumors of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma, and other sarcomas, e.g., soft tissue and bone), tumors of the central and peripheral nervous system (including astrocytoma, neuroblastoma, glioma and schwannomas), tumor of neuroendocrine origin, tumor of endocrine origin, small cell tumors, tumors of unknown primary, other tumors (including retinoblastoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, thyroid follicular cancer, Ewing's sarcoma, Kaposi's sarcoma), and other cancer-related disorders that are a consequence of cancer presence or progression such as tumor- induced pleural or pericardial effusions, and malignant ascites.

[0079] In some embodiments, provided are methods of treating or preventing cancer in an individual, comprising administering to the individual in need thereof a compound of Formula Formula (I) or (la), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided are methods of treating or preventing cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one chemical entity as described herein. Also provided herein is the use of a compound of Formula (I) or (la), or a compound of Table 1, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treatment of a disease in a subject.

[0080] In some embodiments, provided herein are methods of treating cancer, comprising administering to an individual in need thereof a compound of Formula (I) or (la), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. Also provided herein is the use of a compound of Formula (I) or (la), or a compound of Table 1, or apharmaceutically acceptable salt thereof in the manufacture of a medicament for treatment of a cancer.

[0081] In some embodiments, provided herein are methods of 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 or a pharmaceutical composition as described herein.

[0082] 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 a pharmaceutical composition as described herein. In some embodiments, the cancer is selected from the group consisting of carcinomas, 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, gall-bladder, ovary, testicle, 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, tumors of mesenchymal origin including sarcomas, tumors of the central and peripheral nervous system, tumor of neuroendocrine origin, tumor of endocrine origin, small cell tumors, tumors of unknown primary, other tumors comprising retinoblastoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, and other cancer-related disorders that are a consequence of cancer presence or progression.Dosages

[0083] The compounds and compositions disclosed and / or described herein are administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for the disease state. While human dosage levels have yet to be optimized for the chemical entities described herein, generally, a daily dose ranges from about 0.01 to 100 mg / kg of body weight; in some embodiments, from about 0.05 to 10.0 mg / kg of body weight, and in some embodiments, from about 0.10 to 1.4 mg / kg of body weight. Thus, for administration to a 70 kg person, in some embodiments, the dosage range would be about from 0.7 to 7000 mg per day; in some embodiments, about from 3.5 to 700.0 mg per day, and in some embodiments, about from 7 to 100.0 mg per day. The amount of the chemical entity administered will be dependent, for example, on the subject and disease state being treated,the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician. For example, an exemplary dosage range for oral administration is from about 5 mg to about 500 mg per day, and an exemplary intravenous administration dosage is from about 5 mg to about 500 mg per day, each depending upon the compound pharmacokinetic s .

[0084] 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 compound or composition is administered orally or intravenously. In some embodiments, the compound or composition disclosed and / or described herein is administered orally.

[0085] Pharmaceutically acceptable compositions include solid, semi-solid, liquid and aerosol dosage forms, such as tablet, capsule, powder, liquid, suspension, suppository, and aerosol forms. The compounds disclosed and / or described herein can also be administered in sustained or controlled release dosage forms (e.g., controlled / sustained release pill, depot injection, osmotic pump, or transdermal (including electrotransport) patch forms) for prolonged timed, and / or pulsed administration at a predetermined rate. In some embodiments, the compositions are provided in unit dosage forms suitable for single administration of a precise dose.

[0086] The compounds disclosed and / or described herein can be administered either alone or in combination with one or more conventional pharmaceutical carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium croscarmellose, glucose, gelatin, sucrose, magnesium carbonate). If desired, the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate). Generally, depending on the intended mode of administration, the pharmaceutical composition will contain about 0.005% to 95%, or about 0.5% to 50%, by weight of a compound disclosed and / or described herein. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled inthis art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

[0087] In some embodiments, the compositions will take the form of a pill or tablet and thus the composition may contain, along with a compound disclosed and / or described herein, 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 acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives). Other solid dosage forms include a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils or triglycerides) encapsulated in a gelatin capsule.

[0088] Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing or suspending etc. a compound disclosed and / or described herein and optional pharmaceutical additives in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution or suspension. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection. The percentage of the compound contained in such parenteral compositions depends, for example, on the physical nature of the compound, the activity of the compound and the needs of the subject. However, percentages of active ingredient of 0.01% to 10% in solution are employable, and may be higher if the composition is a solid which will be subsequently diluted to another concentration. In some embodiments, the composition will comprise from about 0.2 to 2% of a compound disclosed and / or described herein in solution.

[0089] Pharmaceutical compositions of the compounds disclosed and / or described herein may also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the pharmaceutical composition may have diameters of less than 50 microns, or in some embodiments, less than 10 microns.

[0090] In addition, pharmaceutical compositions can include a compound disclosed and / or described herein and one or more additional medicinal agents, pharmaceutical agents, adjuvants, and the like. Suitable medicinal and pharmaceutical agents include those described herein.Kits

[0091] Also provided are articles of manufacture and kits containing any of the compounds or pharmaceutical compositions provided herein. The article of manufacture may comprise a container with a label. Suitable containers include, for example, bottles, vials, and test tubes. The containers 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 for preventing, treating or suppressing a condition described herein, and may also indicate directions for either in vivo or in vitro use.

[0092] In one aspect, provided herein are kits containing a compound or composition described herein and instructions for use. The kits may contain instructions for use in the treatment of any disease or condition described herein in an individual in need thereof. A kit may additionally contain any materials or equipment that may be used in the administration of the compound or composition, such as vials, syringes, or IV bags. A kit may also contain sterile packaging.Combinations

[0093] 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.

[0094] 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 cellular proliferation disorder, including uncontrolled cell growth, aberrant cell cycle regulation, centrosome abnormalities (structural and or numeric, fragmentation), a solid tumor, hematopoietic cancer and hyperproliferative disorder, such as thyroid hyperplasia (especially Grave's disease), and cyst (such as hypervascularity of ovarian stroma, characteristic of polycystic ovarian syndrome (Stein-Leventhal syndrome). Solid and hematologically derived tumors, such as carcinomas, may include but are not limited to cancer of the anus, bladder, breast, colon, small intestine, appendix, kidney, renal pelvis, ureter, urothelium, liver, lung (including squamous cell and small cell lung cancer), pleura, esophagus, head and neck, nasopharynx, oropharynx, hypopharynx, oral cavity, larynx, biliary tract, gall-bladder, ovary, testicle, 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 Burkett's lymphoma), hematopoietic tumors of myeloid lineage (including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia), hematopoietic tumors of any lineage, myeloma, tumors of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma, and other sarcomas, e.g., soft tissue and bone), tumors of the central and peripheral nervous system (including astrocytoma, neuroblastoma, glioma and schwannomas), tumor of neuroendocrine origin, tumor of endocrine origin, small cell tumors, tumors of unknown primary, other tumors (including retinoblastoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, thyroid follicular cancer, Ewing's sarcoma, Kaposi's sarcoma), and other cancer-related disorders that are a consequence of cancer presence or progression such as tumor- induced pleural or pericardial effusions, and malignant ascites.General Synthetic Methods

[0095] Compounds of Formula (I) or (la) will now be described by reference to illustrative synthetic schemes for their general preparation below and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. In addition, one of skill in the art will recognize that protecting groups may be used to protect certain functional groups (amino, carboxy, or side chain groups) from reaction conditions, and that such groups are removed under standard conditions when appropriate. Unless otherwise specified, the variables are as defined above in reference to Formula (I) or (la).

[0096] Where it is desired to obtain a particular enantiomer of a compound, this may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g., a racemate, and anappropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered. In another resolution process, a racemate may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.

[0097] Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.

[0098] General methods of preparing compounds described herein are depicted in exemplified methods below. Variable groups in the schemes provided herein are defined as for Formula (I) or (la), or any variation thereof. Other compounds described herein may be prepared by similar methods.

[0099] In some embodiments, compounds provided herein may be synthesized according to Scheme 1, Scheme 2, Scheme 3, and / or Scheme 4. The groups RC6, Ring A, L, Ring B, Y4, m, RB, Ral5, and Ral6, as shown in Schemes 1-4 below, are as defined for the compounds of Formula I.Scheme 1.

[0100] Exemplary routes to compounds of Formula I when Y4is CH are described in Scheme 1. A 6-Bromoindole 1-A is treated with an aldehyde or ketone (R=O, wherein R represents L, ring B, and 0 to 4 RB) under reductive amination conditions, such as NaBH(OAc)3 and acetic acid, to provide a N-alkyl indoline 1-B. Compound 1-B is converted to sulfonamide 1-F in two steps, such as the copper-mediated coupling of primary sulfonamide 1-D to generate indoline sulfonamide 1-C followed by oxidation, for example with DDQ. The order of steps may be reversed such that oxidation of 1-B provides indole 1- E, followed by cross-coupling with sulfonamide 1-D to provide 1-F. Finally, the Pd- catalyzed addition of indole 1-F to aryl nitrile 1-G, for example with heat, Pd(OAc)2, and a ligand such as 2,2-bipyridyl, may provide compounds of Formula I.Scheme 2.

[0101] An alternate route to compounds of Formula I proceeds from 6-nitroindole 2-A via two steps to provide ketone 2-E, as outlined in Scheme 2. A Pd-catalyzed addition of 2-A to an aryl nitrile 2-C provides ketone 2-D, followed by alkylation with a base, such as NaH, and an alkylating agent, such as alkyl bromide, to provide 2-E (wherein R represents L, ring B, and 0 to 4 RB). The steps may also be reversed, where alkylation of 2-A provides indole 2- B and the subsequent Pd-catalyzed addition of 2-B to aryl nitrile 2-C provides 2-E.Reduction of 2-E, for example with H2 gas and Pd-C or with Fe and HO Ac, provides aniline 2-F, which may be reacted with sulfonylating agents such as sulfonyl chlorides or sulfonic acid anhydrides in the presence of a base, such as iPr NEt, to provide compounds of Formula I.Scheme 3.

[0102] A route to compounds of Formula I where Y4is N is depicted in Scheme 3. 6- Nitro-indazole-2-carbaldehyde 3-A is alkylated with a base and alkylating agent to provide alkyl indazole 3-B (wherein R represents L, ring B, and 0 to 4 RB). Addition of an aryl nucleophile, such as an arylmagnesium halide, provides alcohols 3-C. Oxidation of 3-C, for example with PCC, provides ketone 3-D. Reduction of 3-D, for example with H2 gas and Pd- C or with Fe and HOAc, provides aniline 3-E, which is reacted with a sulfonylating agent such as a sulfonyl chloride or sulfonic acid anhydride in the presence of a base, such as i Pr NEt, to provide compounds of Formula I.Scheme 4.

[0103] An aryl ring A may contain functional groups that can be transformed into other substituents. One example is described in Scheme 4. When intermediate 2-E of Scheme 2 or 3-D of Scheme 3 contains a bromo substituent, as in 4-Ai or 4-Aii, the bromide can be converted to a a benzylthioether, for example with benzylthiol and a catalyst such as Pd2(dba)3 and Xantphos, to provide 4-Bi and 4-Bii respectively (wherein R represents L, ringB, and 0 to 4 RB). Treatment of thioether 4-Bi or 4-Bii with NCS generates a sulfonyl chloride 4-Ci or 4-Cii, and subsequent treatment with an amine (Ral5Ral6NH) and an appropriate base, such as iPr2NEt, provides sulfonamide 4-D1 or 4-Dii. Compound 4-D1 can be converted to a compound of Formula I as described in Scheme 2, and Compound 4-Dii can be converted to a compound of Formula I as described in Scheme 3.ENUMERATED EMBODIMENTS

[0104] The following enumerated embodiments are representative of some aspects of the invention.1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein ring A is Ce-14 aryl or 5- to 12-membered heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, Ci-6 alkyl optionally substituted with one or more substituents T1, 3- to 10-membered heterocycloalkyl optionally substituted with one or more substituents T2, -NRalC(O)NRa2Ra3, -NRa4C(O)ORa5, -NRa6Ra7, -N=S(O)Ra8Ra9, -ORal°, -S(O)Ra11, -S(O)(NRal2)Ra13, - S(O)2NRal4Ra15, -S(O)2Ra16, -(CRal7Ral8)o-iC(0)NRal9Ra2°, -SRa21, and -C(O)Ra22; each T1is independently selected from the group consisting of -OH, cyano, C3-10 cycloalkyl, and 3- to 10-membered heterocycloalkyl optionally substituted with one or more halo; and each T2is independently halo;Ral _Ra22 are each independently hydrogen, Ci-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, Ce-14 aryl, or 5- to 12-membered heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(Ci-6 alkyl), C2-6 alkenyl, C3-10 cycloalkyl, -S(Ci-6 alkyl), =CRlalRla2, and C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, and -O(Ci-6 alkyl), wherein Rlaland Rla2are each independently hydrogen or C1-6 alkyl;L is a bond, CRblRb2, or O;Rbland Rb2are each independently H or C1-3 alkyl; ring B is C3-8 cycloalkyl, C5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon; each RBgroup is independently halo, C1-6 alkyl optionally substituted with one or more halo, or C2-6 alkenyl; or two vicinal RBgroups are taken together with the carbon atoms to which they are attached to form C3-10 cycloalkyl; or two geminal RBgroups are taken together with the carbon atom to which they are attached to form C3-10 cycloalkyl; m is 0, 1, 2, 3, or 4;Y1is N or CRcl;Y2is N or CRC2;Y3is N or CRC3;Y4is N or CH;RC1, RC2, and RC3are each independently hydrogen, halo, cyano, -OH, -OC1-6 alkyl, or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH;Rcis halo, cyano, -OH, -NO2, -C(O)NRclRc2, -NRc3Rc4, -NRc5S(O)2Rc6, -P(O)Rc7Rc8, -N=S(O)RC9RC1°, -S(O)(NRC11)RC12, -S(O)2RC13, -NRC14C(O)ORC15, or C1-6 alkyl optionallysubstituted with one or more substituents independently selected from the group consisting of halo and -OH; andRcl-Rc15are each independently hydrogen, C3-10 cycloalkyl, or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH.2. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein ring A is optionally substituted Ce-14 aryl.3. The compound of embodiment 2, or a pharmaceutically acceptable salt thereof, wherein ring A is optionally substituted phenyl.4. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein ring A is optionally substituted 5- to 10- membered heteroaryl.5. The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein ring A is optionally substituted pyridyl or optionally substituted furanyl.6. The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein ring A is substituted with one or more substituents selected from the group consisting of -S(O)2NRal4Ra15, -S(O)2Ra16, C1-6 alkyl optionally substituted with one or more substituents T1, and 3- to 10-membered heterocycloalkyl optionally substituted with one or more substituents T2; wherein each T1is independently selected from the group consisting of C3-10 cycloalkyl and -OH; and each T2is independently halo.7. The compound of embodiment 6, or a pharmaceutically acceptable salt thereof, wherein ring A is substituted with one or more substituents selected from the group consisting of - S(O)2NRal4Ra15, -S(O)2Ra16, piperidinyl optionally substituted with one or more fluoro, and alkyl optionally substituted with one or more substituents selected from the group consisting of -OH and cyclopentyl.8. The compound of any one of embodiments 1-7, or a pharmaceutically acceptable salt thereof, wherein Ral4is hydrogen; R15is tert-butyl; and R16is azetidine optionally substituted with one or more halo.9. The compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt thereof, wherein ring A is substituted with one or more substituents independently selected from the group consisting10. The compound of any one of embodiments 1-9, or a pharmaceutically acceptable salt thereof, wherein L is a bond.11. The compound of any one of embodiments 1-10, or a pharmaceutically acceptable salt thereof, wherein ring B is C3-8 cycloalkyl.12. The compound of embodiment 11, or a pharmaceutically acceptable salt thereof, wherein ring B is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.13. The compound of any one of embodiments 1-12, or a pharmaceutically acceptable salt thereof, wherein m is 0.14. The compound of any one of embodiments 1-12, or a pharmaceutically acceptable salt thereof, wherein m is 2.15. The compound of embodiment 14, or a pharmaceutically acceptable salt thereof, wherein two geminal RBgroups are taken together with the carbon atom to which they are attached to form C3-10 cycloalkyl.16. The compound of embodiment 15, or a pharmaceutically acceptable salt thereof, wherein two geminal RBgroups are taken together with the carbon atom to which they are attached to form cyclopropyl or cyclobutyl.17. The compound of any one of embodiments 1-12, or a pharmaceutically acceptable saltwherein * denotes the point of attachment to the rest of Formula (I).18. The compound of embodiment 17, or a pharmaceutically acceptable salt thereof, wherein19. The compound of any one of embodiments 1-18, or a pharmaceutically acceptable salt thereof, wherein Y1is CRC1; Y2is CRC2; Y3is CRC3; and Y4is CH.20. The compound of any one of embodiments 1-18, or a pharmaceutically acceptable salt thereof, wherein Y1is CRC1; Y2is CRC2; Y3is CRC3; and Y4is N.21. The compound of any one of embodiments 1-18, or a pharmaceutically acceptable salt thereof, wherein Y1is N; Y2is CRC2; Y3is CRC3; and Y4is CH.22. The compound of any one of embodiments 1-18, or a pharmaceutically acceptable salt thereof, wherein Y1is CRC1; Y2is N; Y3is CRC3; and Y4is CH.23. The compound of any one of embodiments 1-18, or a pharmaceutically acceptable salt thereof, wherein RC1, RC2, and RC3are each independently hydrogen.24. The compound of any one of embodiments 1-23, or a pharmaceutically acceptable salt thereof, wherein25. The compound of embodiment 24, or a pharmaceutically acceptable salt thereof, wherein26. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds of Table 1.27. A pharmaceutical composition comprising a compound of any one of embodiments 1-26, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.28. A method of inhibiting KIF18A comprising contacting a cell with an effective amount of a compound of any one of embodiments 1-26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 27.29. A method of 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 of any one of embodiments 1-26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 27.30. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 27.31. The method of embodiment 30, wherein the cancer is selected from the group consisting of carcinomas, 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, gall-bladder, ovary, testicle, 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, tumors of mesenchymal origin including sarcomas, tumors of the central and peripheral nervous system, tumor of neuroendocrine origin, tumor of endocrine origin, small cell tumors, tumors of unknown primary, other tumors comprising retinoblastoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, and other cancer-related disorders that are a consequence of cancer presence or progression.EXAMPLES

[0105] The following examples are offered to illustrate but not to limit the compositions, uses, and methods provided herein. The compounds are prepared using the general methods described above.Abbreviations:CSA: camphor sulfonic acidDDQ: 2,3-Dichloro-5,6-dicyano-l,4-benzoquinoneDMA: dimethylacetamideBSA: bovine serum albuminMS: mass spectrometryHPLC: high-performance liquid chromatographyIC50: 50% inhibitory concentrationNMR: nuclear magnetic resonancePCC: pyridinium chlorochromatePE: petroleum ether(Phen): 1,10-phenanthrolineTFA: trifluoroacetic acidSynthesis of IntermediatesSynthesis of (3-bromophenyl)(l-cyclopentyl-6-nitro-lH-indol-3-yl)methanone (A-02)A-01 A-02

[0106] Step 1. To a mixture of 3 -bromobenzonitrile (3.4 g, 19 mmol), 6-nitro- 1 / -indole(1.0 g, 6.2 mmol), and DMA (10 mL) was added Pd(OAc)2 (69 mg, 0.31 pmol,), 2-(2-pyridyl)pyridine (58 mg, 0.37 pmol) CSA (2.2 g, 9.3 mmol), H2O (0.22 mL, 12 mmol). The mixture was stirred at 120 °C for 36 h, then was cooled and combined with EtOAc (20 mL), washed with H2O (10 mL x 3) and brine (10 mL), concentrated, and purified by silica chromatography (25-50% EtOAc in PE) to provide (3-bromophenyl)(6-nitro-1H -indol-3- yl)methanone (A-01, 1.1 g, 85% pure).

[0107] Step 2. To a mixture of A-01 (0.86 g, 2.5 mmol), bromocyclopentane (0.35 pL, 3.2 mmol), and DMF (6 mL) was added tetrabutylammonium iodide (27 mg, 74 pmol), K- 2CO3 (1.5 g, 11 mmol). The mixture was stirred at 90 °C for 12 h, combined with EtOAc (20 mL), washed with H2O (10 mL x 3) and brine (10 mL), concentrated under reduced pressure to give a residue. The residue was purified by flash silica chromatography (10-20 % EtOAC in PE) to provide (3-bromophenyl)(l-cyclopentyl-6-nitro-1H -indol-3-yl)methanone (A-02, 0.76 g).Synthesis of (3-bromophenyl)( l-cyclohexyl-6-nitro- lH-indazol-3-yl )methanone (A-03)

[0108] Step 1. To a mixture of 6-nitro-177-indazole-3-carbaldehyde (4.0 g, 21 mmol) and bromocyclohexane (4.7 mL, 38 mmol), and DME (40 mL) was added K2CO3 (11 g, 77mmol), and tetrabutylammonium iodide (2.5 g, 6.6 mmol). The mixture was stirred at 90 °C for 6 h. H2O (80 mL) and EtOAc (150 mL) were added, the mixture was filtered. The organic phase was separated from the filtrate, then was washed with brine (60 mL), dried over Na2SO4, concentrated, and purified by silica chromatography (0-100% EtOAc in PE) to provide l-cyclohexyl-6-nitro-177-indazole-3-carbaldehyde (A-04, 1.5 g).

[0109] Step 2. 1 -Bromo-3-iodo-benzene (1.8 mL, 14 mmol) was added to a solution of lithium chloro (isopropyl)magnesium chloride (1.3 M, 20 mL) and THF (8 mL). The mixture was stirred at -78 °C for 2 h to provide 28 mL of 0.5 M (3-bromophenyl)-magnesium chloride in THF.

[0110] To a mixture of A-04 (1.50 g, 5.5 mmol) and THF (15 mL) was added (3- bromophenyl)-chloro-magnesium (0.5 M, 22 mL). The mixture was stirred at -78 °C for 1 h, poured into water (30 mL), and extracted with EtOAc (2 x 20 mL). The combined extracts were washed with brine (20 mL), dried over Na2SO4, concentrated, and purified by silica chromatography (5%-50% EtOAc in PE) to provide (3-bromophenyl)(l-cyclohexyl-6-nitro- 177-indazol-3-yl)methanol (A-05, 2.1 g).

[0111] Step 3. To a mixture of A-05 (1.70 g, 4.0 mmol, 1.0 eq) in CH2CI2 (15 mL) was added PCC (1.7 g, 7.9 mmol). The mixture was stirred at 20 °C for 2 h, concentrated, and purified by silica chromatography (0-100% EtOAc in PE) to afford the compound (3- bromophenyl)(l-cyclohexyl-6-nitro-177-indazol-3-yl)methanone (A-03, 1.3 g).

[0112] Compounds in Table 1A were prepared in the same manner as A-03 from 6-nitro- 177-indazole-3-carbaldehyde, the indicated cycloalkyl bromide, and the indicated aryl iodide.Synthesis of (5-bromofuran-2-yl)( l-cyclohexyl-6-nitro- lH-indazol-3-y 1 )methanone (A- 08):

[0113] Step 1. To a mixture of 2-bromofuran (4.0 g, 26 mmol) and THF (50 mL) at -40 °C was added dropwise LDA (2 M, 16 mL, 32 mmol) and A-04 (4.0 g, 13 mmol). The mixture was stirred at -40 °C for 1 h, concentrated, treated with aqueous NaHCOa (30 mL), and extracted with EtOAc (2 x 30 mL). The extracts were combined, washed with brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified by silic chromatography (33- 50% EtOAc in PE) to provide (5-bromofuran-2-yl)(l-cyclohexyl-6-nitro-177-indazol-3- yl)methanol (A-07.2, 5.5 g).

[0114] Step 2. To a 0 °C mixture of A-07.2 (3.0 g, 6.0 mmol) and CH2CI2 (30 mL) was added PCC (3.0 g, 12 mmol), silica gel (4 g), and NaOAc (1.0 g, 18 mmol). The mixture was stirred at 20°C for 30 min, The reaction mixture was filtered and concentrated to a volume of 5 mL, the was poured into water (30.0 mL) and the resulting mixture was extracted with EtOAc (2 x 30.0 mL). The organic phase was washed with brine (10.0 mL), dried over anhydrous Na2SO4, concentrated in vacuum to give a residue. The residue was purified by preparative HPLC (C18; 50-80% MeCN in H2O [0.2% formic acid]) to provide (5- bromofuran-2-yl)(l-cyclohexyl-6-nitro-177-indazol-3-yl)methanone (A-08, 0.40 g).Synthesis of A-(tert-butyl)-3-(l-cyclopentyl-6-nitro-lH-indole-3- carbonyl)benzenesulfonamide (A-09) :A-11 A-09

[0115] Step 1. A mixture of A-02 (0.45 g, 1.1 mmol), phenylmethanethiol (0.19 mL, 1.6 mmol), dioxane (3 mL), iPnNEt (0.48 mL, 2.7 mmol), Xantphos (63 mg, 0.11 mmol), Pd2(dba)3 (50 mg, 55 pmol) was stirred at 110 °C for 12 h. The mixture was poured into H2O (30 mL) and extracted with EtOAc (2 x 30 mL). The combined extracts were washed with brine (10 mL), dried over Na2SO4, concentrated, and purified by silica chromatography (20-30% EtOAc / PE) to provide (3-(benzylthio)phenyl)(l-cyclopentyl-6-nitro-lH-indol-3- yl)methanone (A-10, 0.33 g).

[0116] Step 2. To a mixture of A-10 (0.32 g, 0.71 mmol), HO Ac (0.9 mL), and H2O (0.1 mL) was added NCS (0.28 g, 2.1 mmol) and mixture was stirred at 25 °C for 2 h, poured into H2O (30 mL), and extracted with EtOAc (2 x 30 mL). The combined extracts were washed with brine (10 mL), dried over Na2SO4, and concentrated to provide crude 3-(l-cyclopentyl- 6-nitro-1H -indole-3-carbonyl)benzenesulfonyl chloride (A-ll, 0.58 g).

[0117] Step 3. A mixture of A-ll (0.18 g, 0.40 mmol), 2- methylpropan-2-amine (50 pL, 0.48 mmol), CH2CI2 (1 mL) was added iPnNEt (0.21 mL, 1.2 mmol). The mixture was stirred at 25 °C for 1 h, poured into water (30 mL), and extracted with EtOAc (2 x 30 mL). The combined extracts were washed with brine (10 mL), dried over Na2SO4, concentrated, and purified by silica (25-30% EtOAc / PE) to provide A-(tert-butyl)-3-( 1 -cyclopentyl-6-nitro-1H -indole-3-carbonyl)benzenesulfonamide (A-09, 0.13 g).

[0118] Compounds in Table 2 were prepared in the same manner as A-09 from the indicated aryl bromide via the indicated sulfonyl chloride intermediate and amine.Table 2.Synthesis of 3-(6-amino-l-cyclopentyl-lH-indole-3-carbonyl)-N-(tert- butyl)benzenesulfonamide (A-15)

[0119] A mixture of A-09 (0.10 g, 0.21 mmol), MeOH (4 mL), 10% Pd / C (50 mg) was stirred under th (15 psi) at 25 °C for 1.5 h. The mixture was purged with N2, filtered through celite, and concentrated to provide -(6-amino- l -cyclopcntyl- / / H-indolc-3-carbonyl)- N-(tert-butyl) benzenesulfonamide (A-15, 95 mg).Synthesis of 3-(6-amino-l-cyclohexyl-lH-indazole-3-carbonyl)- N-( rt- butyl)benzenesulfonamide (A-16)A-12 A-16

[0120] Two mixtures of A-12 (25 & 10 mg, 52 & 21 pmol), EtOH (1 & 0.4 mL), Fe (58 & 23 mg, 1.0 & 0.4 mmol), and NH4CI (55 & 22 mg, 1.0 & 0.4 mmol) were stirred at 80 °C for 2 h. The mixtures were combined and filtered, and the filtrate was concentrated and purified by preparative TLC (1:1 EtOAc / PE) to provide 3-(6-amino-l -cyclohexyl- J / / - indazole-3-carbonyl)-A-(tert-butyl)benzenesulfonamide (A-16, 41 mg).

[0121] Compounds in Table 2.1 were prepared in the same manner as A-16 from the indicated nitro-compound.Table 2.1Synthesis of 6-bromo-l -cyclohexylindoline (A-19)

[0122] A mixture of 6-bromoindoline (1.0 g, 5.1 mmol), cyclohexanone (0.6 mL, 6.1 mmol), HOAc (0.30 mL, 5.3 mmol), and 1,2-dichloroethane (20 mL) was stirred at 20 °C for 1 h, and NaBH(OAc)3 (2.1 g, 9.9 mmol) was added and the resulting mixture was stirred at 20 °C for 11 h. The pH of was adjusted to 7 by adding NaHCOa (20 mL), and the mixture was extracted with EtOAc (25 mL x 2). The combined extracts were washed with water (20 mL x 3) and brine (20 mL), dried over Na2SO4, filtered, concentrated, purified by silica chromatography (0-20% EtOAc / PE) to provide 6-bromo-l -cyclohexylindoline (A-19, 2.7 g).

[0123] Compounds in Table 3 were prepared in the same manner as A-19 from 6- bromoindole and the indicated ketone.Table 3.Synthesis of 2V-(l-(spiro[3.3]heptan-2-yl)indolin-6-yl)methanesulfonamide (A-27)

[0124] A mixture of A-22 (0.40 g, 1.4 mmol), methanesulfonamide (0.40 g, 4.2 mmol), DMF (8 mL), Cui (0.27 g, 1.4 mmol), A7,A2-dimethylcyclohexanel,2-diamine (0.20 g, 1.4 mmol) and K3PO4 (0.88 g, 4.2 mmol) was stirred t 150 °C for 1.5 h in a microwave reactor.The mixture was diluted with EtOAc (30 mL), washed with water (15 mL) and brine (15 mL), and the extract was dried over Na2SO4, filtered, and concentrated, and purified by silica chromatography (0-25% EtOAc / PE) to provide N-( 1 -(spiro[3.3]heptan-2-yl)indolin-6- yl)methanesulfonamide (A-27, 0.27 g).Synthesis of N-(l-(3,3-dimethylcyclopentyl)indolin-6-yl)methanesulfonamide (A-28)A-(l-(3,3-dimethylcyclopentyl)indolin-6-yl)methanesulfonamide (A-28) was prepared fromA-23 in the manner described for A-27.Synthesis of 6-bromo- 1 -cyclohexyl-1H -indole (A-29)

[0125] Two mixtures of A-19 (1.5 & 0.21 g, 5.2 & 0.73 mmol), THF (35 & 5 mL), and DDQ (1.3 g, 5.8 mmol) was stirred at 20 °C for 3 h. The mixtures were combined, diluted with EtOAc (30 mL) and washed with saturated NaHCOa (20 mL x 2) and brine (20 mL x 2), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0-30% EtOAc / PE) to provide 6-bromo- 1 -cyclohexyl- 1H -indole (1.4 g, A-29).

[0126] Compounds in Table 4 were prepared in the same manner as A-29 from the indicated indoline.Table 4.Synthesis of N-(l-cyclopentyl-lH-indol-6-yl)ethanesulfonamide (A-34)A-16 A-34

[0127] A degassed mixture of A-26 (0.30 g, 1.1 mmol), ethanesulfonamide (0.31 g, 2.8 mmol), Cui (11 mg, 56 υmol), A7,A2-dimethylcyclohexane-l,2-diamine (16 mg, 0.11 mmol), K3PO4 (0.72 mg, 3.4 mmol), DMF (5 mL), was stirred at 140 °C for 2 h under an N2 atmosphere. The mixture was diluted with H2O 50 mL, extracted with EtOAc (10 mL x 3), and the combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified by preparative HPLC (C18, 55-80% MeCN in water (HC1)) provided A-(l -cyclopentyl- 1H -indol-6-yl)ethanesulfonamide (0.15 g, A-34).

[0128] Compounds in Table 5 were prepared in the same manner as A-34 from the indicated bromoindoline in place of dihydroindole A-16 and sulfonamide.Table 5.Synthesis of l-(cyclopropylmethyl)-6-nitro-7H-indole (A-37)

[0129] A mixture of 6-nitro- 1H -indole (0.50 g, 3.1 mmol) and bromomethylcyclopropane (0.44 mL, 4.6 mmol), DMF (10 mL), BU4NI (34 mg, 93 pmol), and K2CO3 (1.9 g, 14 mmol) was stirred at 90 °C for 12 h, poured into water (30 mL) and extracted with EtOAc (2 x 30 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 provide 1- (cyclopropylmethyl)-6-nitro-1H -indole (0.65 g, A-37).

[0130] Compounds in Table 6 were prepared in the same manner as A-37 from the indicated bromoalkene.Table 6.Synthesis of 6-bromo- 1 -cyclopentyl- IH-py rrolo[2, 3-b ]pyridine (A-40)

[0131] To a 0 °C mixture of 6-bromo- 1H -pyrrolo[2,3- b]pyridine (0.85 g, 4.3 mmol), DMF (15 mL) was in portions 60% NaH (0.26 g, 6.5 mmol). The mixture was stirred at 0 °C for 0.5 h and bromocyclopentane (0.93 mL, 8.6 mmol) was added dropwise, and the mixture was stirred at 25 °C for 4 h. Saturated aqueous NH4CI (40 mL) was added at 0 °C, and the mixture was extracted by CH2Q2 (13 mL x 2). The extracts were washed brine (20 mL x 2), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (1-15% EtOAc / PE) to provide 6-bromo-l-cyclopentyl-lH-pyrrolo[2,3-b]pyridine (A-40, 0.96 g).Synthesis of 6-bromo- 1 -cyclo pentyl- IH-py rrolo[ 3, 2-c] pyridine (A-40.1)TQQB

[0132] 6-bromo- 1 -cyclopentyl- IH-pyrrolo [3, 2-c]pyridine (A-40.1) was prepared from 6- bromo- 1 H-pyrrolo| 3, 2-c| pyridine and bromocyclopentane in the manner described for A-40.Synthesis of N-( 1 -cyclohexyl- 1 / / -indol-6-yl)methanesull'onamide (A-41)A-29 A-41

[0133] A degassed mixture of A-29 (1.6 g, 5.8 mmol), methanesulfonamide (1.6 g, 17 mmol), Cui (0.44 g, 2.3 mmol), K3PO4 (1.2 g, 5.8 mmol) and A7,A2-dimethylcyclohexane- 1,2-diamine dihydrochloride (0.61 g, 2.9 mmol), and DMF (3 mL) was stirred at 160 °C for 3 h under an N2 atmosphere. The mixture was poured into H2O (30 mL), extracted with EtOAc (2 x 30 mL), and the combined extracts were washed with brine (10 mL), dried over Na2SO4, concentrated, and purified by silica chromatography (0-50% EtOAc / PE) to provide A-(l- cyclohexylindol-6-yl)methanesulfonamide (A-41, 1.2 g).

[0134] Compounds in Table 7 were prepared in the same manner as A-41 from the indicated sulfonamide and bromoindole.Table 7.Synthesis of l-(cyclopropylmethyl)-7H-indol-6-amine (A-46)

[0135] A mixture of A-37 (0.63 g, 2.9 mmol), EtOH (8 mL), Fe (1.6 g, 29 mmol), NH4CI (1.3 g, 23 mmol), and H2O (2 mL) was stirred at 70 °C for 2 h. The reaction was diluted with THF (30 mL), filtered, and filtrate was concentrated, combined with H2O (30 mL), and extracted with EtOAc (2 x 30 mL). The combined extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, concentrated, and purified by silica chromatography (0-100% EtOAc / PE) to provide 1 -(cyclopropyl methyl)- 1H -indol-6-amine (A-46, 0.52 g).

[0136] Compounds in Table 8 were prepared in the same manner as A-46 from the indicated nitroindole.Synthesis of \-( 1 -cyclopentyl-1H -indol-6-yl)methanesulfonamide (A-50)

[0137] A mixture of A-49 (0.45 g, 2.3 mmol), CH2CI2 (5 mL), EhN (1.3 mL, 9.0 mmol) and methylsulfonyl methanesulfonate (0.59 g, 3.4 mmol) was stirred at 20 °C for 1 h. The mixture was poured into H2O (30 mL), extracted with CH2CI2 (2 x 30 mL), and the combined extracts were washed with brine (10 mL), dried over Na2SO4, concentrated, and purified by silica chromatography (0-50% EtOAc / PE) followed by preparative HPLC (C18, 30-60% MeCN / thO [TLA 0.1%]) to provide A-(l -cyclopentyl- J77-indol-6-yl)methanesulfonamide (A-50, 0.11 g).

[0138] Compounds in Table 9 were prepared in the same manner as A-50 from the indicated aminoindole and sulfonylating reagent.Table 9.Example 1: Synthesis of 2V-(tert-butyl)-3-(l-cyclopentyl-6-(methylsulfonamido)-lH- indazole-3-carbonyl)benzenesulfonamide (Compound 17)A-18 Compound 17

[0139] A mixture of A-18 (35 mg, 79 pmol), CH2CL2 (2 mL), EhN (55 pL, 0.40 mmol), and methylsulfonyl methanesulfonate (28 mg, 0.16 mmol) was stirred at 25 °C for 1 h, poured into H2O (10 mL), and extracted with EtOAc (2 x 10 mL). The combined extracts were washed with brine (10 mL), dried over Na2SO4, and concentrated. The resulting residue was stirred in MeOH (2 mL) with K2CO3 (93 mg, 0.67 mmol) for 2 h, then was poured into H2O (10 mL), dried over Na2SO4, concentrated, and purified by preparative HPLC (C18, 50- 70% MeCN / thO [HC1]) to provide A-(tert-butyl)-3-( 1-cy clopentyl-6-(methylsulfonamido)- 1H -indazole-3-carbonyl)benzenesulfonamide (Compound 17, 18 mg).

[0140] Compounds in Table 10 were prepared in the same manner as Compound 17 from the indicated aminoindole and sulfonylating reagent.Table 10.Example 2: Synthesis of 2V-(l-cyclopentyl-3-(3-((3,3-difluoroazetidin-l- y 1 )su 11'onyl )benzoyl)-lH-indol -6-yl) met hanesullonam ide

[0141] A degassed mixture of A-53 (40 mg, 0.14 mmol), 3-(3,3-difluoroazetidin-l- yl)sulfonylbenzonitrile (0.11 g, 0.43 mmol), [(Phen)Pd(OAc)2] (5 mg), AcOH (25 pL, 0.43 mmol), 1,4-dioxane (3 mL), H2O (0.1 mL) was stirred at 140 °C for 2 h in a microwave reactor. The mixture was concentrated and purified by preparative HPLC (C18, 30-60% MeCN in H2O [HC1]) to provide A-( 1 -cyclopentyl-3-(3-((3,3-difluoroazetidin- 1 - yl)sulfonyl)benzoyl)-J / / -indol-6-yl)methanesulfonamide (22 mg).

[0142] Compounds in Table 11 were prepared in the same manner as Compound 19 from indicated indole and aryl nitrile.Table 11.Example 3: Synthesis of N -(l-cyclohexyl-3-(3-((3,3-difhioroazetidin-l- yl)sull'onyl)benzoyl)-1H -indol-6-yl)-2-hydroxyethane- 1 -sulfonamide (Compound 20)

[0143] To a mixture of A-44 (0.15 g, 0.58 mmol) and DMA (2 mL) was added 2-(2- pyridyl)pyridine (5 mg, 32 pmol), CSA (90 mg, 0.39 mmol), Pd(OAc)2 (8 mg, 36 pmol), andHoO (40 p L, 2.2 mmol). The mixture was stirred at 135 °C for 2.5 hours in a microwave reactor. The mixture was diluted with EtOAc (20 mL), washed with water (10 mL x 3) and brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified with the scale batch by preparative TLC (2:1 EtOAc / PE), followed preparative HPLC (Cl 8, 35-65% MeCN / thO [NH4HCO3]) to provide A-(l-cyclohexyl-3-(3-((3,3-difluoroazetidin-l-yl)sulfonyl)benzoyl)- 1H -indol-6-yl)-2-hydroxyethane-l-sulfonamide (Compound 20, 18 mg).

[0144] Compounds in Table 12 were prepared in the same manner as Compound 20 from indicated indole and aryl nitrile.Table 12.

[0145] Example 4: N-(tert-butyl)-3-( l-cyclopentyl-6-(methylsulfonamido)- 1H- pyrrolo[3,2-c]pyridine-3-carbonyl)benzenesulfonamide (Compound 38)

[0146] Step 1. To a mixture of A-40.1 (1.2 g, 4.5 mmol) and dichloroethane (50 mL) was added dropwise AlCh (1.2 mL, 23 mmol) and the mixture was stirred at 25 °C for 0.5 h. 3- bromobenzoyl chloride (1.7 mL, 13 mmol) was added dropwise at 25 °C and the mixture was stirred at 80 °C for 2 h. The mixture was poured into ice-water (20 mL), the pH was adjust to 3 with 1 M HC1, EtOAc (20 mL) added, and a precipitate removed by filtration. The filtrate was washed with H2O (10 mL x 2) and brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0-60% [1:1 THF / EtOAc] in PE) to provide the (6-bromo- l-cyclopentyl-pyrrolo[3,2-c]pyridin-3-yl)-(3-bromophenyl)methanone (A-54, 1.4 g).

[0147] Step 2. A mixture of A-54 (0.60 g, 1.3 mmol), dioxane (23 mL), Xantphos (0.13 g, 0.25 mmol), Pd2(dba)3 (0.13 g, 0.14 mmol), iP NEt (0.60 mL, 3.4 mmol), and phenylmethanethiol (0.15 mL, 1.3 mmol) was stirred under N2 at 70 °C for 6 h, combined with with H2O (50 mL) and extracted with EtOAc (30 mL). The extract was washed with brine (20 mL x 2), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0-20% [1:1 THF / EtOAc] in PE) to provide compound (3- benzylsulfanylphenyl)-(6-bromo-l-cyclopentyl-pyrrolo[3,2-c]pyridin-3-yl)methanone (A-55, 0.25 g).

[0148] Step 3. A mixture of A-55 (0.23 g, 0.47 mmol), H2O (0.5 mL), HOAc (5 mL), and NCS (0.19 g, 1.4 mmol) at 0 °C was stirred at 25 °C for 1 h, diluted with H2O (50 mL), and extracted with EtOAc (30 mL). The extract was washed with saturated NaHCOa (10 mL x 2), water (10 mL), and brine (10 mL), then dried over Na2SO4, and filtered to provide a solution of 3-(6-bromo-l-cyclopentyl-177-pyrrolo[3,2-c]pyridine-3-carbonyl)benzene-l-sulfonyl chloride in ~30 mL of EtOAc. EtaN (0.20 mL, 1.9 mmol) and 2-methylpropan-2-amine (0.20 mL, 1.9 mmol) were added and the mixture was stirred at 25 °C for 2 h. The mixture was washed with water (10 mL x 2), brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0-80% EtOAc in PE) to provide 3-(6-bromo-l- cyclopentyl-pyrrolo[3,2-c]pyridine-3-carbonyl)-N-tert-butyl-benzenesulfonamide (A-56, 64 mg).

[0149] Step 4. A mixture of A-56 (42 mg, 83 umol), methanesulfonamide (28 mg, 0.29 mmol), Cui (20 mg, 0.11 mmol), N N2-dimethylcyclohexane-l,2-diamine (15 mg, 0.11 mmol), K3PO4 (60 mg, 0.28 mmol), and DMF (2 mL) was stirred under N2 at 140 °C for 2.5 h. The mixture was diluted with EtOAc (20 mL) washed with H2O (10 mL x 3) and brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified by preparative HPLC (C18; 35- 70% MeCN in H2O [0.1% formic acid]) to provide A-(tert-butyl)-3-(l-cyclopentyl-6- (methylsulfonamido)- 177-pyrrolo [3 ,2- c]pyridine-3 -carbonyl)benzenesulfonamide (Compound 38, 27 mg).

[0150] MS and NMR characterization data for exemplary compounds of Formula (I) are provided in Table 13.Table 13.Biological AssaysInhibition of KIF18A microtubule-dependent ATPase activity:

[0151] Test compounds were plated in a 3x dilution scheme in a 384-well plate. Assay buffer: 80 mM PIPES (pH 6.9), 1 mM MgCl2, 75 mM KC1, 1 mM EGTA, 1 mM DTT, 0.01% BSA, 0.005% Tween-20, 1 pM Taxol in H2O. To 50 nL of compound in DMSO was added 2.5 pL of enzyme mix [4 nM hKIF18A (1-374) in assay buffer]. After incubation at room temperature for 30 min, 2.5 pL of microtubule mix was added [0.2 mg / mL pre-formed microtubules, 2.0 mM ATP in assay buffer], the plate was centrifuged for 30 s and then incubated at 28 °C for 60 min. 5 pL of Promega® ADP-Glo Max R1 was added, the plate was centrifuged for 30s, and the mixture incubated for 4 h at room temperature. 10 pL of Promega® ADP-Glo Max R2 was added, the plate centrifuged for 30 s, and incubated for 60min at room temperature. Luminescence was measured with an Envision plate reader, and %Inhibition was calculated for each well as: (([max - min] - [test - min]) / [max - min]. IC50 values were calculated from concentration vs. % Inhibition data via a four-parameter variable slope model.Cell Viability of KIF18a-sensitive cell lines:

[0152] Cell lines were seeded as follows 24 hours before compound treatment: HCC15 (Korean Cell Line Bank) 600 cell / well, 95 pL of RPML1640 media supplemented with 100 units / mL penicillin, 100 units / mL streptomycin and 10% FBS; NIH:OVCAR-3 (ATCC), 1000 cell / well, 95 pL of RPML1640 media supplemented with 100 units / mL penicillin, 100 units / mL streptomycin, 0.01 mg / mL bovine insulin, and 20% FBS; JIMT-1 (Addexbio) 1000 cell / well, 95 pL of DMEM media supplemented with 100 units / mL penicillin, 100 units / mL streptomycin, and 10% FBS.

[0153] Test compounds were added to cells in a 20x dilution scheme by adding 5 pL 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 the negative control (0% effect), and wells omitting cells were used as the positive control (100% effect). The cells were incubated for seven days, and cell viability determined via the Promega Cell Titre-Gio® Assay kit. Luminescence units were converted to ATP concentrations via an ATP standard curve (10 point, 2-fold dilution from 5 uM). %Inhibition was calculated for each well as: ([max - min] - [test - min]) / [max - min]. IC50 values were calculated from concentration vs. %Inhibition data via a four-parameter variable slope model.

[0154] Results from the biological assays are summarized in Table 14.Table 14.

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein ring A is Ce-14 aryl or 5- to 12-membered heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, Ci-6 alkyl optionally substituted with one or more substituents T1, 3- to 10-membered heterocycloalkyl optionally substituted with one or more substituents T2, -NRalC(O)NRa2Ra3, -NRa4C(O)ORa5, -NRa6Ra7, -N=S(O)Ra8Ra9, -ORal°, -S(O)Ra11, -S(O)(NRal2)Ra13, - S(O)2NRal4Ra15, -S(O)2Ra16, -(CRal7Ral8)o-iC(0)NRal9Ra2°, -SRa21, and -C(O)Ra22; each T1is independently selected from the group consisting of -OH, cyano, C3-10 cycloalkyl, and 3- to 10-membered heterocycloalkyl optionally substituted with one or more halo; and each T2is independently halo;Ral _Ra22are each independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, Ce-14 aryl, or 5- to 12-membered heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(Ci-6 alkyl), C2-6 alkenyl, C3-10 cycloalkyl, -S(Ci-6 alkyl), =CRlalRla2, and C1-6 alkyl optionally substituted with one or more substituents independently selected from thegroup consisting of halo, -OH, and -O(Ci-6 alkyl), wherein Rlaland Rla2are each independently hydrogen or C1-6 alkyl;L is a bond, CRblRb2, or O;Rbland Rb2are each independently H or C1-3 alkyl; ring B is C3-8 cycloalkyl, C5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon; each RBgroup is independently halo, C1-6 alkyl optionally substituted with one or more halo, or C2-6 alkenyl; or two vicinal RBgroups are taken together with the carbon atoms to which they are attached to form C3-10 cycloalkyl; or two geminal RBgroups are taken together with the carbon atom to which they are attached to form C3-10 cycloalkyl; m is 0, 1, 2, 3, or 4;Y1is N or CRcl;Y2is N or CRC2;Y3is N or CRC3;Y4is N or CH;RC1, RC2, and RC3are each independently hydrogen, halo, cyano, -OH, -OC1-6 alkyl, or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH;Rcis halo, cyano, -OH, -NO2, -C(O)NRclRc2, -NRc3Rc4, -NRc5S(O)2Rc6, -P(O)Rc7Rc8, -N=S(O)RC9RC1°, -S(O)(NRC11)RC12, -S(O)2RC13, -NRC14C(O)ORC15, or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH; andRcl-Rc15are each independently hydrogen, C3-10 cycloalkyl, or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is optionally substituted Ce-14 aryl.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein ring A is optionally substituted phenyl.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is optionally substituted 5- to 10- membered heteroaryl.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein ring A is optionally substituted pyridyl or optionally substituted furanyl.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein ring A is substituted with one or more substituents selected from the group consisting of -S(O)2NRal4Ra15, -S(O)2Ra16, Ci-6 alkyl optionally substituted with one or more substituents T1, and 3- to 10-membered heterocycloalkyl optionally substituted with one or more substituents T2; wherein each T1is independently selected from the group consisting of C3-10 cycloalkyl and -OH; and each T2is independently halo.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein ring A is substituted with one or more substituents selected from the group consisting of - S(O)2NRal4Ra15, -S(O)2Ra16, piperidinyl optionally substituted with one or more fluoro, and alkyl optionally substituted with one or more substituents selected from the group consisting of -OH and cyclopentyl.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein Ral4is hydrogen; R15is tert-butyl; and R16is azetidine optionally substituted with one or more halo.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein ring A is substituted with one or more substituents independently selected from the group consisting10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein L is a bond.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein L is -CH2-.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein ring B is C3-8 cycloalkyl.

14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein ring B is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein m is 0.

16. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein m is 2.

17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein two geminal RBgroups are taken together with the carbon atom to which they are attached to form C3-10 cycloalkyl.

18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein two geminal RBgroups are taken together with the carbon atom to which they are attached to form cyclopropyl or cyclobutyl.

19. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof,wherein * denotes the point of attachment to the rest of Formula (I).

20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein Y1is CRC1; Y2is CRC2; Y3is CRC3; and Y4is CH.

22. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein Y1is CRC1; Y2is CRC2; Y3is CRC3; and Y4is N.

23. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein Y1is N; Y2is CRC2; Y3is CRC3; and Y4is CH.

24. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein Y1is CRC1; Y2is N; Y3is CRC3; and Y4is CH.

25. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein RC1, RC2, and RC3are each hydrogen.

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein27. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein Rcis28. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of the compounds of Table 1.

29. A pharmaceutical composition comprising a compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

30. A method of inhibiting KIF18A comprising contacting a cell with an effective amount of a compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 29.

31. A method of 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 of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 29.

32. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 29.

33. The method of claim 32, wherein the cancer is selected from the group consisting of carcinomas, 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, gall-bladder, ovary, testicle, 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, tumors of mesenchymal origin including sarcomas, tumors of the central and peripheral nervous system, tumor of neuroendocrine origin, tumor of endocrine origin, small cell tumors, tumors of unknown primary, other tumors comprising retinoblastoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, and other cancer-related disorders that are a consequence of cancer presence or progression.

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