Method of treating cancer with indoline inhibitors of kif18a

Abstract

The present disclosure relates to a series of indoline inhibitors of KIF18A, and methods of their use for treating disease mediated by KIF18A, such as cancer.

Description

184102001940 METHOD OF TREATING CANCER WITH INDOLINE INHIBITORS OF KIF18A CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority benefit of United States Provisional Patent Application No. 63 / 508,233, filed June 14, 2023, the disclosure of which is hereby incorporated herein by reference in its entirety. FIELD

[0002] The present disclosure in some aspects relates to indoline inhibitors of KIF18A, and methods of their use for treating diseases mediated by KIF18A, such as cancer. BACKGROUND

[0003] KIF18A is a kinesin involved in assisting kinetochore-microtubule (kt-MT) attachment and chromosomal alignment during cell mitosis. Its cargo domain binds directly to protein phosphatase 1 (PP1) and carries it to the plus end of MT where PP1 dephosphorylates Hec1, a kinetochore complex component, further enhancing kt-MT attachment throughout metaphase and anaphase. Its MT-binding motor domain has ATPase activity that powers KIF18A translocation along the MT lattice, enhanced by its C-terminal MT-binding site, and caps and depolymerizes the 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. A 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 or knockdown demonstrated effect of inhibited tumor growth. Thus, there is a need for new 1 sf-5988480184102001940 agents and / or methods effective in treating diseases mediated by KIF18A. The present application addresses this and other needs. SUMMARY

[0004] In some aspects, provided herein is a method of treating cancer associated with chromosomal instability in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (A):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof, wherein: ring A is C6-14aryl or 5- to 12-membered heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, C1-6 alkyl, 3- to 10-membered heterocycloalkyl, -NRa1C(O)NRa2Ra3, -NRa4C(O)ORa5, -NRa6Ra7, - N=S(O)Ra8Ra9, -ORa10, -S(O)Ra11, -S(O)(NRa12)Ra13, -S(O)2NRa14Ra15, -S(O)2Ra16, - (CRa17Ra18)0-1C(O)NRa19Ra20, -SRa21, -C(O)Ra22, and C1-6 alkyl substituted with one or more substituents 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; Ra1to 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, C6-14aryl, 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(C1-6 alkyl), C2-6alkenyl, C3-10cycloalkyl, -S(C1-6alkyl), =CR1a1R1a2, and C1-6alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, and -O(C1-6 alkyl), wherein R1a1and R1a2are each independently hydrogen or C1-6 alkyl; 2 sf-5988480184102001940 ring B is C5-7cycloalkyl, C5-7cycloalkenyl, 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; m is 2; the two RBgroups are attached to the same carbon atom on ring B and are taken together with the carbon atom to which they are attached to form C3-7 cycloalkyl; Y1is N or CRC1; Y2is N or CRC2; Y3is N or CRC3; Y4is N or CRC4; wherein no more than three of Y1, Y2, Y3, and Y4are N; RC1-RC4are each independently hydrogen, halo, cyano, -OH, -NO2, -C(O)NRc1Rc2, -NRc3Rc4, -NRc5S(O)2Rc6, -P(O)Rc7Rc8, -N=S(O)Rc9Rc10, -S(O)(NRc11)Rc12, -S(O)2Rc13, - NRc14C(O)ORc15, -NRc16S(O)2(CH2)1- 6NRc17C(O)Rc18, or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and - OH; Rc1-Rc18are 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 some variations, the cancer is selected from the group consisting of advanced solid tumor, high grade serous adenocarcinoma of ovary, squamous non-small-cell lung cancer, triple negative breast cancer, gastric adenocarcinoma, colorectal adenocarcinoma, esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastroesophageal junction adenocarcinoma, transitional cell carcinoma of bladder, head and neck squamous cell carcinoma, ovarian carcinosarcoma, uterine carcinosarcoma, uterine serous carcinoma, and endometrium cancer.

[0006] In some variations, provided herein is a method of treating cancer selected from the group consisting of advanced solid tumor, high grade serous adenocarcinoma of ovary, 3 sf-5988480184102001940 squamous non-small-cell lung cancer, triple negative breast cancer, gastric adenocarcinoma, colorectal adenocarcinoma, esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastroesophageal junction adenocarcinoma, transitional cell carcinoma of bladder, head and neck squamous cell carcinoma, ovarian carcinosarcoma, uterine carcinosarcoma, uterine serous carcinoma, and endometrium cancer, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (A):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof, wherein: ring A is C6-14 aryl or 5- to 12-membered heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, C1-6alkyl, 3- to 10-membered heterocycloalkyl, -NRa1C(O)NRa2Ra3, -NRa4C(O)ORa5, -NRa6Ra7, - N=S(O)Ra8Ra9, -ORa10, -S(O)Ra11, -S(O)(NRa12)Ra13, -S(O)2NRa14Ra15, -S(O)2Ra16, - (CRa17Ra18)0-1C(O)NRa19Ra20, -SRa21, -C(O)Ra22, and C1-6 alkyl substituted with one or more substituents independently selected from the group consisting of -OH, cyano, C3-10cycloalkyl, and 3- to 10-membered heterocycloalkyl optionally substituted with one or more halo; Ra1to Ra22are each independently hydrogen, C1-6alkyl, C2-6alkenyl, C3-10cycloalkyl, C3-10cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C6-14 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(C1-6alkyl), C2-6alkenyl, C3-10cycloalkyl, -S(C1-6alkyl), =CR1a1R1a2, and C1-6alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, and -O(C1-6 alkyl), wherein R1a1and R1a2are each independently hydrogen or C1-6 alkyl; 4 sf-5988480184102001940 ring B is C5-7cycloalkyl, C5-7cycloalkenyl, 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; m is 2; the two RBgroups are attached to the same carbon atom on ring B and are taken together with the carbon atom to which they are attached to form C3-7 cycloalkyl; Y1is N or CRC1; Y2is N or CRC2; Y3is N or CRC3; Y4is N or CRC4; wherein no more than three of Y1, Y2, Y3, and Y4are N; RC1-RC4are each independently hydrogen, halo, cyano, -OH, -NO2, -C(O)NRc1Rc2, -NRc3Rc4, -NRc5S(O)2Rc6, -P(O)Rc7Rc8, -N=S(O)Rc9Rc10, -S(O)(NRc11)Rc12, -S(O)2Rc13, - NRc14C(O)ORc15, -NRc16S(O)2(CH2)1- 6NRc17C(O)Rc18, or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and - OH; Rc1-Rc18are 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.

[0007] In some variations, the compound of Formula (A) is administered to the subject in 28-day cycles.

[0008] In some variations, the compound of Formula (A) is a compound of Formula (A-1):5 sf-5988480184102001940 or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments, the compound of Formula (A) is a compound of Formula (A- 2):or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, the compound of Formula (A) is a compound of Formula (A-or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION

[0011] 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 general principles 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. 6 sf-5988480184102001940 I. Definition

[0012] 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.

[0013] As used herein and in the appended claims, the singular forms “a”, “an” and “the” include plural forms, unless the context clearly dictates otherwise.

[0014] As used herein, and unless otherwise specified, the terms “about” and “approximately”, when used in connection with doses, amounts, or weight percent of ingredients of a composition or a dosage form, mean a dose, amount, or weight percent that is recognized by those of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent. Specifically, where applicable, the terms “about” and “approximately,” when used in this context, contemplate a dose, amount, or weight percent within 15% of the specified dose, amount, or weight percent.

[0015] Throughout this application, unless the context indicates otherwise, references to a compound of Formula (A) include all subgroups defined herein, such as Formula (B), (C), (A-1), (A-2), or (A-3), including all substructures, subgenera, preferences, embodiments, examples and particular compounds defined and / or described herein. In some embodiments, unless indicated otherwise, references to a compound of Formula (A), (B), (C), (A-1), (A-2), or (A-3) and subgroups thereof, 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 (A), (B), (C), (A-1), (A-2), or (A-3) and subgroups thereof, include polymorphs, isomers, co-crystals, isomers, tautomers, and / or oxides thereof. In some embodiments, references to a compound of Formula (A), (B), (C), (A-1), (A-2), or (A-3) and subgroups thereof, include polymorphs, solvates, and / or co-crystals thereof.

[0016] “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, C1-6 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, sec- 7 sf-5988480184102001940 butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.

[0017] When a range of values is given (e.g., C1-6 alkyl), each value within the range as well as all intervening ranges are included. For example, “C1-6alkyl” includes C1, C2, C3, C4, C5, C6, C1-6, C2-6, C3-6, C4-6, C5-6, C1-5, C2-5, C3-5, C4-5, C1-4, C2-4, C3-4, C1-3, C2-3, and C1-2 alkyl.

[0018] “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-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2- yl), and butenyl (e.g., but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl).

[0019] “Alkynyl” refers to an unsaturated branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon triple bond. Alkynyl groups include, but are not limited to, ethynyl, propynyl (e.g., prop-1-yn-1-yl, prop-2-yn-1-yl) and butynyl (e.g., but-1-yn-1-yl, but-1-yn-3-yl, but-3- yn-1-yl).

[0020] “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-1-yl group (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is a cycloalkyl group, while 1,2,3,4-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.

[0021] “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, 8 sf-5988480184102001940 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.

[0022] “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 1,2,3,4-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-1-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is not considered an aryl group. Similarly, a 1,2,3,4-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-1-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.

[0023] “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 some embodiments, 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 9 sf-5988480184102001940 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.

[0024] 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.

[0025] 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, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine, 3H-imidazo[4,5-b]pyridine, 3H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-imidazo[4,5-b]pyridine, 1H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[2,3-c]pyridine, 1H-pyrazolo[3,4-c]pyridine, 3H-imidazo[4,5-c]pyridine, 3H- [1,2,3]triazolo[4,5-c]pyridine, 1H-pyrrolo[3,2-c]pyridine, 1H-pyrazolo[4,3-c]pyridine, 1H- imidazo[4,5-c]pyridine, 1H-[1,2,3]triazolo[4,5-c]pyridine, furo[2,3-b]pyridine, oxazolo[5,4- b]pyridine, isoxazolo[5,4-b]pyridine, [1,2,3]oxadiazolo[5,4-b]pyridine, furo[3,2-b]pyridine, oxazolo[4,5-b]pyridine, isoxazolo[4,5-b]pyridine, [1,2,3]oxadiazolo[4,5-b]pyridine, furo[2,3- c]pyridine, oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine, [1,2,3]oxadiazolo[5,4- c]pyridine, furo[3,2-c]pyridine, oxazolo[4,5-c]pyridine, isoxazolo[4,5-c]pyridine, [1,2,3]oxadiazolo[4,5-c]pyridine, thieno[2,3-b]pyridine, thiazolo[5,4-b]pyridine, isothiazolo[5,4-b]pyridine, [1,2,3]thiadiazolo[5,4-b]pyridine, thieno[3,2-b]pyridine, thiazolo[4,5-b]pyridine, isothiazolo[4,5-b]pyridine, [1,2,3]thiadiazolo[4,5-b]pyridine, thieno[2,3-c]pyridine, thiazolo[5,4-c]pyridine, isothiazolo[5,4-c]pyridine, [1,2,3]thiadiazolo[5,4-c]pyridine, thieno[3,2-c]pyridine, thiazolo[4,5-c]pyridine, isothiazolo[4,5-c]pyridine, [1,2,3]thiadiazolo[4,5-c]pyridine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine (e.g., 1,8-naphthyridine, 1,7- naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, 2,7-naphthyridine, 2,6-naphthyridine), imidazo[1,2-a]pyridine, 1H-pyrazolo[3,4-d]thiazole, 1H-pyrazolo[4,3-d]thiazole and imidazo[2,1-b]thiazole. 10 sf-5988480184102001940

[0026] 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.

[0027] “Heterocycloalkyl” indicates a non-aromatic, fully saturated 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. 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-1-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.

[0028] “Heterocycloalkenyl” indicates a non-aromatic ring having the indicated number of atoms (e.g., 3- to 10-, or 3- to 7-, membered heterocycloalkenyl) 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 adjacent carbon 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), 11 sf-5988480184102001940 dihydrothiophenyl (e.g., 2,3-dihydrothiophenyl, 2,5-dihydrothiophenyl), dihydropyrrolyl (e.g., 2,3-dihydro-1H-pyrrolyl, 2,5-dihydro-1H-pyrrolyl), dihydroimidazolyl (e.g., 2,3- dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl), pyranyl, dihydropyranyl (e.g., 3,4- dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl), tetrahydropyridinyl (e.g., 1,2,3,4- tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl) and dihydropyridine (e.g., 1,2- dihydropyridine, 1,4-dihydropyridine). 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-1-yl group (wherein the moiety is bound to the parent structure via a non-aromatic nitrogen atom) is considered a heterocycloalkenyl group, while 1,2-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.

[0029] Examples of polycyclic rings consisting of an aromatic ring (e.g., aryl or heteroaryl) fused to a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) include indenyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[1,4]dioxinyl, indolinyl, isoindolinyl, 2,3-dihydro-1H-indazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 2,3- dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 1,3-dihydrobenzo[c]isoxazolyl, 2,3-dihydrobenzo[d]isoxazolyl, 2,3-dihydrobenzo[d]oxazolyl, 2,3-dihydrobenzo[b]thiophenyl, 1,3-dihydrobenzo[c]thiophenyl, 1,3-dihydrobenzo[c]isothiazolyl, 2,3-dihydrobenzo[d]isothiazolyl, 2,3-dihydrobenzo[d]thiazolyl, 5,6-dihydro-4H-cyclopenta[d]thiazolyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, 5,6-dihydro-4H-pyrrolo[3,4-d]thiazolyl, 4,5,6,7- tetrahydrothiazolo[5,4-c]pyridinyl, indolin-2-one, indolin-3-one, isoindolin-1-one, 1,2- dihydroindazol-3-one, 1H-benzo[d]imidazol-2(3H)-one, benzofuran-2(3H)-one, benzofuran- 3(2H)-one, isobenzofuran-1(3H)-one, benzo[c]isoxazol-3(1H)-one, benzo[d]isoxazol-3(2H)- one, benzo[d]oxazol-2(3H)-one, benzo[b]thiophen-2(3H)-one, benzo[b]thiophen-3(2H)-one, benzo[c]thiophen-1(3H)-one, benzo[c]isothiazol-3(1H)-one, benzo[d]isothiazol-3(2H)-one, benzo[d]thiazol-2(3H)-one, 4,5-dihydropyrrolo[3,4-d]thiazol-6-one, 1,2-dihydropyrazolo[3,4- d]thiazol-3-one, quinolin-4(3H)-one, quinazolin-4(3H)-one, quinazoline-2,4(1H,3H)-dione, quinoxalin-2(1H)-one, quinoxaline-2,3(1H,4H)-dione, cinnolin-4(3H)-one, pyridin-2(1H)- 12 sf-5988480184102001940 one, pyrimidin-2(1H)-one, pyrimidin-4(3H)-one, pyridazin-3(2H)-one, 1H-pyrrolo[3,2- b]pyridin-2(3H)-one, 1H-pyrrolo[3,2-c]pyridin-2(3H)-one, 1H-pyrrolo[2,3-c]pyridin-2(3H)- one, 1H-pyrrolo[2,3-b]pyridin-2(3H)-one, 1,2-dihydropyrazolo[3,4-d]thiazol-3-one and 4,5- dihydropyrrolo[3,4-d]thiazol-6-one. As discussed herein, whether each ring is considered an aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl group is determined by the atom through which the moiety is bound to the parent structure.

[0030] “Halogen” or “halo” refers to fluoro, chloro, bromo or iodo.

[0031] “Haloalkyl” refers to alkyl substituted with one or more halogen. A haloalkyl group may have a halogen substituent at any valence-permitted location on the alkyl and may have any number of halogen substituents ranging from one to the maximum valence-permitted number. Particular haloalkyl groups have 1, 2, or 3 halogen substituents. Examples of haloalkyl groups include, but are not limited to, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3.

[0032] 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.

[0033] “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. 13 sf-5988480184102001940

[0034] 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 the pharmaceutical 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.

[0035] 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. 14 sf-5988480184102001940

[0036] 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.

[0037] 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.

[0038] 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.

[0039] The compounds disclosed and / or described herein can be enriched isotopic forms, e.g., enriched in the content of2H,3H,11C,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 15 sf-5988480184102001940 compounds may improve the efficacy and increase the duration of action of compounds disclosed and / or described herein. Deuterium substituted compounds can be synthesized using 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.

[0040] 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.

[0041] As used herein, the term “substantially free of” means that the composition comprising the crystalline form contains less than 50%, less than 40%, less than 30%, less than 20%, less than 15%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% by weight of the indicated substance or substances.

[0042] 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.

[0043] 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 16 sf-5988480184102001940 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.

[0044] “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.

[0045] It is understood that embodiments described herein as “comprising” include “consisting of” and “consisting essentially of” embodiments. II. Methods of Treating Cancer

[0046] In one aspect, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (e.g., a compound of Formula (A), (B), (C), (A-1), (A-2), or (A- 3)), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition or formulation thereof, or a crystalline form thereof. In some embodiments, the cancer is mediated by KIF18A. In some embodiments, the cancer is associated with chromosomal instability.

[0047] The inhibitory activity of the compound provided herein (e.g., a compound of Formula (A), (B), (C), (A-1), (A-2), or (A-3)), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition or formulation thereof, or a crystalline for thereof as 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: Vernos I. (eds) Kinesin Protocols. Methods in Molecular Biology™, vol 164. Humana Press. https: / / doi.org / 10.1385 / 1-59259- 069-1:65). 17 sf-5988480184102001940

[0048] In one aspect, provided herein is a method of inhibiting KIF18A comprising contacting a cell with an effective amount of a compound provided herein (e.g., a compound of Formula (A), (B), (C), (A-1), (A-2), or (A-3)), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof, as described herein. In one variation of the aforementioned embodiments, the cell is contacted in vitro. In other variations of the aforementioned embodiments, the cell is contacted in vivo.

[0049] In some embodiments, provided are methods of treating or preventing (e.g., method of treating) cancer in an individual, comprising administering to the individual in need thereof a compound provided herein (e.g., a compound of Formula (A), (B), (C), (A-1), (A- 2), or (A-3)), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof, as described herein. In another aspect, provided herein is a method of treating or preventing a disease or condition in a subject in need thereof, comprising administering an effective amount of a compound provided herein (e.g., a compound of Formula (A), (B), (C), (A-1), (A-2), or (A-3)), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof, as described herein. When used in a prophylactic manner, the compound provided herein (e.g., a compound of Formula (A), (B), (C), (A-1), (A-2), or (A-3)), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition or formulation thereof, or a crystalline form thereof, as 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.

[0050] In some embodiments, the disease or condition is mediated by KIF18A. In some embodiments, the disease or condition is cancer.

[0051] In some embodiments, the disease or condition is cancer, and the cancer is selected from the group consisting of advanced solid tumor, high grade serous adenocarcinoma of ovary, squamous non-small-cell lung cancer, triple negative breast cancer, gastric adenocarcinoma, colorectal adenocarcinoma, esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastroesophageal junction adenocarcinoma, transitional cell carcinoma of bladder, head and neck squamous cell carcinoma, ovarian carcinosarcoma, uterine carcinosarcoma, uterine serous carcinoma, and endometrium cancer. In some embodiments, the disease or condition (e.g., cancer) is associated with chromosomal instability. 18 sf-5988480184102001940

[0052] In some embodiments, the cancer is not caused by high microsatellite instability (MSI-H). In some embodiments, the cancer is not caused by mismatch repair deficiency (dMMR). In some embodiments, the cancer is not caused by mutated POLE gene hotspot, or known hypermutator phenotype. In some embodiments, the cancer does not have a low chromosomal instability (CIN). In some embodiments, the subject does not have high microsatellite instability (MSI-H). In some embodiments, the subject does not have mismatch repair deficiency (dMMR). In some embodiments, the subject does not have mutated POLE gene hotspot, or known hypermutator phenotype. Dosages

[0053] In some variations of the method provided herein, the compound provided herein (e.g., a compound of Formula (A), (B), (C), (A-1), (A-2), or (A-3)), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof is administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for the disease state (e.g., cancer). 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 pharmacokinetics.

[0054] Administration of the compound provided herein (e.g., a compound of Formula (A), (B), (C), (A-1), (A-2), or (A-3)), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof 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, 19 sf-5988480184102001940 intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration. In some embodiments, the compound or formulation is administered orally or intravenously. In some embodiments, the compound or formulation described herein is administered orally.

[0055] In some embodiments, the compound provided herein (e.g., a compound of Formula (A), (B), (C), (A-1), (A-2), or (A-3)), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof described herein is administered periodically. In some embodiments, the compound provided herein (e.g., a compound of Formula (A), (B), (C), (A-1), (A-2), or (A-3)), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof is administered daily.

[0056] In some embodiments, the compound or formulation is administered every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 days. In some embodiments, the compound or formulation is administered every 28 days. In some embodiments, administrations of the compound provided herein (e.g., a compound of Formula (A), (B), (C), (A-1), (A-2), or (A-3)), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof are at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 days apart. In some embodiments, administrations of the compound provided herein (e.g., a compound of Formula (A), (B), (C), (A-1), (A-2), or (A-3)), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof are at least 28 days apart. In some embodiments, the compound provided herein (e.g., a compound of Formula (A), (B), (C), (A-1), (A-2), or (A-3)), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof is administered in 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19-, 20-, 21-, 22-, 23-, 24-, 25-, 26-, 27-, 28-, 29-, 30-, 31-, 32-, 33-, 34-, 35-, or 36-day cycles. In some embodiments, the compound provided herein (e.g., a compound of Formula (A), (B), (C), (A- 1), (A-2), or (A-3)), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof is administered in 28-day cycles. In some embodiments, the compound provided herein (e.g., a compound of Formula (A), (B), (C), (A- 1), (A-2), or (A-3)), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof is administered orally in 28-day cycles. 20 sf-5988480184102001940

[0057] In some variations of the method provided herein, the compound provided herein (e.g., a compound of Formula (A), (B), (C), (A-1), (A-2), or (A-3)), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof may be administered alone or in combination with other therapies and / or therapeutic agents useful in the treatment of the aforementioned disorders (e.g., cancer or cancer associated with chromosomal instability). III. Compounds

[0058] In some aspect, 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. Any compound described herein may also be referred to as a drug.

[0059] In some aspects, the method provided herein comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (A) :or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof, wherein: ring A is C6-14aryl or 5- to 12-membered heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, C1-6alkyl, 3- to 10-membered heterocycloalkyl, -NRa1C(O)NRa2Ra3, -NRa4C(O)ORa5, -NRa6Ra7, - N=S(O)Ra8Ra9, -ORa10, -S(O)Ra11, -S(O)(NRa12)Ra13, -S(O)2NRa14Ra15, -S(O)2Ra16, - (CRa17Ra18)0-1C(O)NRa19Ra20, -SRa21, -C(O)Ra22, and C1-6alkyl substituted with one or more substituents 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; 21 sf-5988480184102001940 Ra1-Ra22are each independently hydrogen, C1-6alkyl, C2-6alkenyl, C3-10cycloalkyl, C3-10 cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C6-14 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(C1-6 alkyl), C2-6 alkenyl, C3-10 cycloalkyl, -S(C1-6 alkyl), =CR1a1R1a2, and C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, and -O(C1-6alkyl), wherein R1a1and R1a2are each independently hydrogen or C1-6 alkyl; ring B is C5-7 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; m is 2; the two RBgroups are attached to the same carbon atom on ring B and are taken together with the carbon atom to which they are attached to form C3-7cycloalkyl; Y1is N or CRC1; Y2is N or CRC2; Y3is N or CRC3; Y4is N or CRC4; wherein no more than three of Y1, Y2, Y3, and Y4are N; RC1-RC4are each independently hydrogen, halo, cyano, -OH, -NO2, -C(O)NRc1Rc2, - NRc3Rc4, -NRc5S(O)2Rc6, -P(O)Rc7Rc8, -N=S(O)Rc9Rc10, -S(O)(NRc11)Rc12, -S(O)2Rc13, - NRc14C(O)ORc15, -NRc16S(O)2(CH2)1- 6NRc17C(O)Rc18, or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and - OH; Rc1-Rc18are 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.

[0060] In some embodiments of Formula (A), or a pharmaceutically acceptable salt thereof, ring A is C6-14 aryl or 5- to 12-membered heteroaryl, each optionally substituted as defined above or below. In some embodiments, ring A is optionally substituted C6-14aryl. In some embodiments, ring A is phenyl optionally substituted as defined above or below. In some embodiments, ring A is 5- to 12-membered heteroaryl optionally substituted as defined above or below. In some embodiments, ring A is 6-membered heteroaryl optionally substituted as 22 sf-5988480184102001940 defined above or below. In some embodiments, ring A is 5-membered heteroaryl optionally substituted as defined above or below. In some embodiments, ring A is indolyl, indazolyl, pyridinyl, thiophenyl, furanyl, pyrazolyl, pyrrolyl, oxazolyl, chromanyl, or quinolinyl, each optionally substituted as defined above or below. In some embodiments, ring A is thiophenyl optionally substituted as defined above or below.

[0061] In some embodiments of Formula (A), 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, 3- to 10-membered heterocycloalkyl, -NRa1C(O)NRa2Ra3, - NRa4C(O)ORa5, -NRa6Ra7, -N=S(O)Ra8Ra9, -ORa10, -S(O)Ra11, -S(O)(NRa12)Ra13, - S(O)2NRa14Ra15, -S(O)2Ra16, -(CRa17Ra18)0-1C(O)NRa19Ra20, -SRa21, -C(O)Ra22, and C1-6alkyl substituted with one or more substituents 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. In some embodiments, Ra1-Ra22are each independently hydrogen, C1-6 alkyl, C2-6alkenyl, C3-10cycloalkyl, C3-10cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl C6-14 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(C1-6alkyl), C2-6alkenyl, C3-10cycloalkyl, -S(C1-6 alkyl), =CR1a1R1a2, 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(C1-6alkyl), wherein R1a1and R1a2are each independently hydrogen or C1-6alkyl.23 sf-598848018410200194024 sf-5988480184102001940some embodiments, Ra14and Ra15are each independently hydrogen; C1-6 alkyl optionally substituted with one, two, three, four, five, or more substituents independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C3-10 cycloalkyl, -OH, -O(C1-6 alkyl), -S(C1-6 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 C2-6alkenyl, C3-10cycloalkyl, halo, cyano, -OH, -O(C1-6alkyl), =CR1a1R1a2, and C1-6alkyl optionally substituted with one, two, three, four, five, or more substituents independently selected from the group consisting of -OH, -O(C1-6 alkyl), and halo, wherein R1a1and R1a2are each independently hydrogen or C1-6alkyl; C3-10cycloalkenyl; or 3- to 12-membered heterocycloalkyl optionally substituted with one, two, three, four, five, or more C1-6 alkyl. In some embodiments, Ra14and Ra15are each 25 sf-5988480184102001940 independently hydrogen or C1-6alkyl. In some embodiments, Ra14is hydrogen and Ra15is butyl. In some embodiments, Ra15is tert-butyl.

[0063] In some embodiments of Formula (A), or a pharmaceutically acceptable salt thereof, ring B is C5-7cycloalkyl, C5-7cycloalkenyl, 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 C5-7 cycloalkyl. In some embodiments, ring B is cyclopentyl,cyclohexyl, or cycloheptyl. In some embodiments, ring B is or , wherein * denotes the point of attachment to the rest of Formula (A). In some embodiments, ring B is C5-7 cycloalkenyl. In some embodiments, ring B is cyclopentenyl, cyclohexenyl, orcycloheptenyl. In some embodiments, ring B is , wherein * denotes the point ofattachment to the rest of Formula (A). In some embodiments, ring B is , wherein * denotes the point of attachment to the rest of Formula (A). In some embodiments, ring B is 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. In some embodiments, ring B is tetrahydrofuranyl or 1,3-dioxanyl. In some embodiments, ring B is or , wherein * denotes the point of attachment to the rest of Formula (A).

[0064] In some embodiments, ring B is substituted with two RBgroups, wherein the two RBgroups are attached to the same carbon atom on ring B and are taken together with the carbon atom to which they are attached to form C3-7cycloalkyl. In some embodiments, the two RBgroups are attached to the same carbon atom on ring B and are taken together with the carbon atom to which they are attached to form a cyclopropyl.

[0065] In some embodiments, of Formula (A) is , wherein * denotes the point of attachment to the rest of Formula (A). 26 sf-5988480184102001940

[0066] In some embodiments of Formula (A), or a pharmaceutically acceptable salt thereof, Y1is N or CRC1; Y2is N or CRC2; Y3is N or CRC3; and Y4is N or CRC4. In some embodiments, no more than three of Y1, Y2, Y3, and Y4are N. In some embodiments, no more 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 CRC4.

[0067] In some embodiments, RC1-RC4are each independently hydrogen, halo, cyano, -OH, -NO2, -C(O)NRc1Rc2, -NRc3Rc4, -NRc5S(O)2Rc6, -P(O)Rc7Rc8, -N=S(O)Rc9Rc10, - S(O)(NRc11)Rc12, -S(O)2Rc13, -NRc14C(O)ORc15, or C1-6 alkyl optionally substituted with one, two, three, four, five, or more substituents independently selected from the group consisting of halo and -OH. In some embodiments, Rc1-Rc15are each independently hydrogen, C3-10cycloalkyl, or C1-6 alkyl optionally substituted with one, two, three, four, five, or more substituents independently selected from the group consisting of halo and -OH.

[0068] In some embodiments, RC1, RC3, and RC4are each hydrogen, and RC2is cyano, -OH, ,

[0069] In one aspect, the compound of Formula (A) is a compound of Formula (B):or a pharmaceutically acceptable salt thereof, wherein Ra14, Ra15, ring B, RB, m, and RC2are as defined for Formula (A) or any variation or embodiment thereof. In some embodiments, 27 sf-5988480184102001940 RC2is halo, cyano, -OH, -NO2, -C(O)NRc1Rc2, -NRc3Rc4, -NRc5S(O)2Rc6, -P(O)Rc7Rc8, - N=S(O)Rc9Rc10, -S(O)(NRc11)Rc12, -S(O)2Rc13, -NRc14C(O)ORc15, -NRc16S(O)2(CH2)1- 6NRc17C(O)Rc18or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH. In some embodiments, RC2is halo, cyano, -OH, -NO2, -C(O)NRc1Rc2, -NRc3Rc4, -NRc5S(O)2Rc6, -P(O)Rc7Rc8, - N=S(O)Rc9Rc10, -S(O)(NRc11)Rc12, -S(O)2Rc13, or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and –OH. In some embodiments, RC2is -NRc5S(O)2Rc6. In some embodiments, Rc5is hydrogen and Rc6is C1-6 alkyl. In some embodiments, Rc5is hydrogen and Rc6is ethyl. In some embodiments, Rc5is hydrogen. In some embodiments, Rc6is ethyl. In some embodiments, Rc6is methyl. In some embodiments, Ra14is hydrogen and Ra15is C1-6alkyl. In some embodiments, Ra14is hydrogen and Ra15is tert-butyl. In some embodiments, Ra14is hydrogen. In some embodiments, Ra15istert-butyl. In some embodiments, ring B is , wherein * denotes the point of attachmentto the rest of Formula (B). In some embodiments, .

[0070] In one aspect, the compound of Formula (A) is a compound of Formula (C):or a pharmaceutically acceptable salt thereof, wherein Ra14, Ra15, and Rc6are as defined for Formula (A) or any variation or embodiment thereof. In some embodiments, Ra14is hydrogen and Ra15is C1-6 alkyl. In some embodiments, Ra14is hydrogen and Ra15is tert-butyl. In some embodiments, Ra14is hydrogen. In some embodiments, Ra15is tert-butyl. In some embodiments, Ra14and Ra15are each independently C3-10cycloalkyl, C3-10cycloalkenyl, 3- to 10-membered heterocycloalkyl, or 3- to 10-membered heterocycloalkenyl. In some embodiments, Ra14and Ra15are taken together with the N atom to which they are attached to form a 3- to 10-membered heterocycloalkyl. In some embodiments, Rc6is C1-6alkyl 28 sf-5988480184102001940 optionally substituted with one or more halo. In some embodiments, Rc6is unsubstituted C1-6alkyl. In some embodiments, Rc6is ethyl. In some embodiments, Rc6is methyl.

[0071] In one aspect, the compound of Formula (A) is a compound of Formula (A-1):

[0072] In one aspect, the compound of Formula (A) is a compound of Formula (A-2):

[0073] In one aspect, the compound of Formula (A) is a compound of Formula (A-3):

[0074] In some variations, any of the compounds described herein, such as a compound of Formula (A), (B), (C), (A-1), (A-2), or (A-3), or any variation thereof, 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 a manner 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. 29 sf-5988480184102001940

[0075] Any formula given herein, such as Formula (A), (B), (C), (A-1), (A-2), or (A-3), 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.

[0076] 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.

[0077] 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.

[0078] 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. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.

[0079] Any variation or embodiment of ring A, ring B, ring C, Ra1, Ra2, Ra3, Ra4, Ra5, Ra6, Ra7, Ra8, Ra9, Ra10, Ra11, Ra12, Ra13, Ra14, Ra15, Ra16, Ra17, Ra18, Ra19, Ra20, Ra21, Ra22, Ra23, Ra24, Ra25, Ra26, Ra27, Ra28, Ra29, Ra30, Ra31, Ra32, Ra33, Ra34, Ra35, Ra36, Ra37, Ra38, Ra39, Ra40, R1a1, R1a2, R1a3, R1a4, RB, m, X, Y1, Y2, Y3, Y4, Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, RC1, RC2, RC3, RC4, Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc8, Rc9, Rc10, Rc11, Rc12, Rc13, Rc14, Rc15, Rc16, Rc17, Rc18, Rc19, RD, 30 sf-5988480184102001940 RE, or RFprovided herein can be combined with every other variation or embodiment of ring A, ring B, ring C, Ra1, Ra2, Ra3, Ra4, Ra5, Ra6, Ra7, Ra8, Ra9, Ra10, Ra11, Ra12, Ra13, Ra14, Ra15, Ra16, Ra17, Ra18, Ra19, Ra20, Ra21, Ra22, Ra23, Ra24, Ra25, Ra26, Ra27, Ra28, Ra29, Ra30, Ra31, Ra32, Ra33, Ra34, Ra35, Ra36, Ra37, Ra38, Ra39, Ra40, R1a1, R1a2, R1a3, R1a4, RB, m, X, Y1, Y2, Y3, Y4, Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, RC1, RC2, RC3, RC4, Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc8, Rc9, Rc10, Rc11, Rc12, Rc13, Rc14, Rc15, Rc16, Rc17, Rc18, Rc19, RD, RE, or RF, the same as if each and every combination had been individually and specifically described.

[0080] 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.

[0081] In some embodiments, the compounds described herein, or a pharmaceutically acceptable salt thereof can be synthesized by the methods described in WO 2023 / 028564, the contents of which are hereby incorporated by reference in its entirety. In some embodiments, the compounds described herein, or a pharmaceutically acceptable salt thereof are potent inhibitors of KIF18A, can achieve sub-nanomolar potency with small off-rates or very long dissociation half-life (ln(2) / koff), and can potently induce cell killing for KIF18a-senstive cancer cell lines, and reduce tumor volumes in mice. The KIF18A inhibition potency, binding kinetics to KIF18A, and in vivo activities of the compounds described herein, or a pharmaceutically acceptable salt thereof are disclosed in WO 2023 / 028564, the contents of which are hereby incorporated by reference in its entirety. In some embodiments, the formulations, salts, or the crystalline forms described herein can be prepared by the methods described in PCT / US2024 / 016952, the contents of which are hereby incorporated by reference in its entirety.

[0082] In one aspect provided herein are crystalline forms of a compound of Formula (A- 1), or a pharmaceutically acceptable salt thereof.

[0083] In some embodiments, the crystalline form is characterized by having an XRPD pattern comprising peaks at angles 2-theta of 13.54±0.20, 17.89±0.20, 18.39±0.20, 19.39±0.20, and 19.73±0.20 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern comprising additional peaks at angles 2-theta of 15.46±0.20 and 17.29±0.20 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern comprising additional peaks at angles 2-theta of 8.61±0.20 and 15.04±0.20 degrees. 31 sf-5988480184102001940

[0084] In some embodiments, the crystalline form is characterized by having an endotherm onset at 188±2°C, as determined by DSC. In some embodiments, the crystalline form is characterized by having an endotherm peak at 194±2°C, as determined by DSC. In some embodiments, the crystalline form is characterized by having a weight loss of 0.01±0.005% between 52-150°C, as determined by TGA. In some embodiments, the crystalline form is characterized by having an apparent decomposition at 316±5°C, as determined by TGA. In some embodiments, the crystalline form is characterized by having a weight gain of 0.095±0.005% from 5% RH to 95% RH, as determined by DVS. In some embodiments, the crystalline form is characterized by having a weight loss of 0.097±0.005% from 95% RH to 5% RH, as determined by DVS.

[0085] In some embodiments, the crystalline form is characterized by having an XRPD pattern comprising peaks at angles 2-theta of 15.62±0.20, 16.60±0.20, 19.87±0.20, 20.11±0.20, and 25.76±0.20 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern comprising additional peaks at angles 2-theta of 17.50±0.20 and 21.13±0.20 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern comprising additional peaks at angles 2-theta of 8.23±0.20 and 11.72±0.20 degrees. In some embodiments, the crystalline form is characterized by having an endotherm onset at 196±2°C, as determined by DSC. In some embodiments, the crystalline form is characterized by having an endotherm peak at 197±2°C, as determined by DSC. In some embodiments, the crystalline form is characterized by having a weight loss of 0.05±0.01% between 25 and 100°C, as determined by TGA. In some embodiments, the crystalline form is characterized by having a weight loss of 0.10±0.05% between 100 and 180°C, as determined by TGA. In some embodiments, the crystalline form is characterized by having a weight gain of 0.030%±0.005% from 0.1% RH to 95% RH, as determined by DVS. In some embodiments, the crystalline form is characterized by having a weight loss of 0.050%±0.005% from 95 % RH to 0.1% RH, as determined by DVS.

[0086] In some embodiments, the crystalline form comprises a compound of Formula (A- 1).

[0087] In some embodiments, the crystalline form comprises a mono-sodium salt of the compound of Formula (A-1).

[0088] In some embodiments, the crystalline form comprising mono-sodium salt of the compound of Formula (A-1) is characterized by having an XRPD pattern comprising peaks at angles 2-theta of 7.66±0.20, 8.45±0.20, 11.64±0.20, 17.92±0.20, and 22.82±0.20 degrees. In 32 sf-5988480184102001940 some embodiments, the crystalline form is characterized by having an XRPD pattern comprising additional peaks at angles 2-theta of 16.91±0.20 and 17.13±0.20 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern comprising additional peaks at angles 2-theta of 13.60±0.20 and 18.34±0.20 degrees. In some embodiments, the crystalline form is characterized by having an endotherm onset at 186±2°C, as determined by DSC. In some embodiments, the crystalline form is characterized by having an endotherm peak at 190±2°C, as determined by DSC. In some embodiments, the crystalline form is characterized by having a weight loss of 0.7%±0.1% between 25 °C and 170 °C, as determined by TGA.

[0089] In some embodiments, the crystalline form comprising mono-sodium salt of the compound of Formula (A-1) is characterized by having an XRPD pattern comprising peaks at angles 2-theta of 14.19±0.20, 17.44±0.20, 17.70±0.20, and 18.14±0.20 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern comprising additional peaks at angles 2-theta of 18.61±0.20 and 27.38±0.20 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern comprising additional peaks at angles 2-theta of 16.87±0.20 and 21.64±0.20 degrees. In some embodiments, the crystalline form is characterized by having an endotherm peak at 166±2 °C, as determined by DSC. In some embodiments, the crystalline form is characterized by having an endotherm peak at 192±2 °C, as determined by DSC. In some embodiments, the crystalline form is characterized by having an endotherm peak at 208±2 °C, as determined by DSC. In some embodiments, the crystalline form is characterized by having a weight loss of 0.3%±0.1% between 25 °C and 80 °C, as determined by TGA. In some embodiments, the crystalline form is characterized by having a weight loss of 7.3%±0.1% between 80 °C and 190 °C, as determined by TGA.

[0090] In some embodiments, the crystalline form comprising mono-sodium salt of the compound of Formula (A-1) is characterized by having an XRPD pattern comprising peaks at angles 2-theta of 6.85±0.20, 11.74±0.20, 17.14±0.20, and 18.92±0.20 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern comprising additional peaks at angles 2-theta of 18.51±0.20 and 20.95±0.20 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern comprising additional peaks at angles 2-theta of 16.64±0.20 and 24.73±0.20 degrees. In some embodiments, the crystalline form is characterized by having an endotherm peak at 183±2 °C, as determined by DSC. In some embodiments, the crystalline form is characterized by 33 sf-5988480184102001940 having a weight loss of 0.7%±0.1% between 30 °C and 120 °C, as determined by TGA. In some embodiments, the crystalline form is characterized by having a weight loss of 8.0 %±0.1% between 120 °C and 180 °C, as determined by TGA. In some embodiments, the crystalline form is characterized by having a weight loss of 4.2 %±0.1% between 180 °C and 230 °C, as determined by TGA.

[0091] In some embodiments, the crystalline form comprises a di-sodium salt of the compound of Formula (A-1).

[0092] In some embodiments, the crystalline form comprising di-sodium salt of the compound of Formula (A-1) is characterized by having an XRPD pattern comprising peaks at angles 2-theta of 6.39±0.20, 6.89±0.20, 16.32±0.20, 17.01±0.20, and 22.82±0.20 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern comprising additional peaks at angles 2-theta of 12.50±0.20 and 16.52±0.20 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern comprising additional peaks at angles 2-theta of 13.48±0.20 and 14.34±0.20 degrees. In some embodiments, the crystalline form is characterized by having an endotherm peak at 60±2 °C, as determined by DSC. In some embodiments, the crystalline form is characterized by having an endotherm peak at 212±2°C, as determined by DSC. In some embodiments, the crystalline form is characterized by having a weight loss of 3.3%±0.5% between 25 °C and 48 °C as determined by TGA. In some embodiments, the crystalline form is characterized by having a weight loss of 2.1%±0.5% between 48 °C and 100 °C as determined by TGA.

[0093] In some embodiments, the crystalline form comprising di-sodium salt of the compound of Formula (A-1) is characterized by having an XRPD pattern comprising peaks at angles 2-theta of 5.26±0.50, 8.80±0.50, 16.75±0.50, and 17.72±0.50 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern comprising additional peaks at angles 2-theta of 9.28±0.50 and 10.47±0.50 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern comprising additional peaks at angles 2-theta of 8.37±0.50 and 21.32±0.50 degrees. In some embodiments, the crystalline form is characterized by having a weight loss of 5.4%±0.1% between 25 °C and 140 °C as determined by TGA.

[0094] In some embodiments, the crystalline form comprising di-sodium salt of the compound of Formula (A-1) is characterized by having an XRPD pattern comprising peaks at 34 sf-5988480184102001940 angles 2-theta of 6.03±0.20, 7.66±0.20, 12.04±0.20, and 18.73±0.20 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern comprising additional peaks at angles 2-theta of 12.93±0.20 and 18.97±0.20 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern comprising additional peaks at angles 2-theta of 19.91±0.20 and 24.62±0.20 degrees. In some embodiments, the crystalline form is characterized by having an endotherm peak at 52±2 °C, as determined by DSC. In some embodiments, the crystalline form is characterized by having an endotherm peak at 84±2 °C, as determined by DSC. In some embodiments, the crystalline form is characterized by having an endotherm peak at 104±2 °C, as determined by DSC. In some embodiments, the crystalline form is characterized by having an endotherm peak at 128±2 °C, as determined by DSC. In some embodiments, the crystalline form is characterized by having a weight loss of 11.9%±3.0% between 30 °C and 110 °C as determined by TGA.

[0095] In some embodiments, the crystalline form comprising di-sodium salt of the compound of Formula (A-1) is characterized by having an XRPD pattern comprising peaks at angles 2-theta of 6.07±0.20, 6.84±0.20, 12.07±0.20, 18.75±0.20, and 19.96±0.20 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern comprising additional peaks at angles 2-theta of 18.10±0.20 and 20.47±0.20 degrees. The crystalline form of claims 138 or 139, characterized by having an XRPD pattern comprising additional peaks at angles 2-theta of 7.70±0.20 and 13.63±0.20 degrees. In some embodiments, the crystalline form is characterized by having an endotherm peak at 73±2 °C, as determined by DSC. In some embodiments, the crystalline form is characterized by having an endotherm peak at 99±2 °C, as determined by DSC. In some embodiments, the crystalline form is characterized by having an endotherm peak at 120±2 °C, as determined by DSC. In some embodiments, the crystalline form is characterized by having a weight loss of 0.6%±0.5% between 30 °C and 48 °C as determined by TGA. In some embodiments, the crystalline form is characterized by having a weight loss of 4.1%±0.5% between 48 °C and 81°C as determined by TGA. In some embodiments, the crystalline form is characterized by having a weight loss of 2.7 %±0.5% between 81 °C and 140 °C as determined by TGA. In some embodiments, the crystalline form is characterized by having a weight gain of 60%±5% from 1% RH to 95% RH, as determined by DVS. In some embodiments, the crystalline form is characterized by having a weight loss of 58%±5% from 95% RH to 1% RH, as determined by DVS. 35 sf-5988480184102001940

[0096] In some embodiments, the crystalline form comprising di-sodium salt of the compound of Formula (A-1) is characterized by having an XRPD pattern comprising peaks at angles 2-theta of 66.93±0.50, 20.10±0.50, 32.35±0.50, and 37.94±0.50 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern comprising additional peaks at angles 2-theta of 13.86±0.50 and 17.26±0.50 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern comprising additional peaks at angles 2-theta of 20.80±0.50 and 32.53±0.50 degrees. In some embodiments, the crystalline form is characterized by having a weight loss of 2.7%±0.1% between 25 °C and 64 °C as determined by TGA. In some embodiments, the crystalline form is characterized by having a weight loss of 2.4%±0.1% between 65 °C and 100 °C as determined by TGA. In some embodiments, the crystalline form is characterized by having a weight loss of 0.9%±0.1% % between 100 °C and 140 °C as determined by TGA.

[0097] In some embodiments, the crystalline form comprises a mono-potassium salt of the compound of Formula (A-1).

[0098] In some embodiments, the crystalline form comprising mono-potassium salt of the compound of Formula (A-1) is characterized by having an XRPD pattern comprising peaks at angles 2-theta of 13.48±0.20, 16.62±0.20, and 16.62±0.20 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern comprising additional peaks at angles 2-theta of 12.25±0.20 and 19.69±0.20 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern comprising additional peaks at angles 2-theta of 11.21±0.20 and 24.83±0.20 degrees. In some embodiments, the crystalline form is characterized by having an endotherm peak at 39±5 °C, as determined by DSC. In some embodiments, the crystalline form is characterized by having an endotherm peak at 156±5 °C, as determined by DSC. In some embodiments, the crystalline form is characterized by having a weight loss of 3.2%±0.1%between 25 °C and 100 °C, as determined by TGA.

[0099] In some embodiments, the crystalline form comprises a di-potassium salt of the compound of Formula (A-1).

[0100] In some embodiments, the crystalline form comprising di-potassium salt of the compound of Formula (A-1) is characterized by having an XRPD pattern comprising peaks at angles 2-theta of 5.84±0.50, 5.91±0.50, 9.21±0.50, and 18.56±0.50 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern comprising 36 sf-5988480184102001940 additional peaks at angles 2-theta of 15.56±0.50 and 19.02±0.50 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern comprising additional peaks at angles 2-theta of 13.56±0.50 and 25.27±0.50 degrees. In some embodiments, the crystalline form is characterized by having an endotherm peak at 70±10 °C, as determined by DSC. In some embodiments, the crystalline form is characterized by having a substantially continuous weight loss between 25 °C and 300 °C, as determined by TGA.

[0101] In some embodiments, the crystalline form comprising di-potassium salt of the compound of Formula (A-1) is characterized by having an XRPD pattern comprising peaks at angles 2-theta of 6.66±0.20, 17.43±0.20, 19.31±0.20, and 23.72±0.20 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern comprising additional peaks at angles 2-theta of 13.12±0.20 and 19.99±0.20 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern comprising additional peaks at angles 2-theta of 18.82±0.20 and 22.76±0.20 degrees. In some embodiments, the crystalline form is characterized by having an endotherm peak at 83±2 °C, as determined by DSC. In some embodiments, the crystalline form is characterized by having a weight loss of 0.3%±0.1% between 25 °C and 40 °C, as determined by TGA. In some embodiments, the crystalline form is characterized by having a weight loss of 2.7%±0.1% between 40 °C and 75 °C, as determined by TGA. In some embodiments, the crystalline form is characterized by having a weight loss of 3.1%±0.1% between 75 °C and 170 °C, as determined by TGA.

[0102] In some embodiments, the crystalline form comprising di-potassium salt of the compound of Formula (A-1) is characterized by having an XRPD pattern comprising peaks at angles 2-theta of 6.65±0.20, 17.42±0.20, 19.30±0.20, and 23.75±0.20 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern comprising additional peaks at angles 2-theta of 20.00±0.20 and 22.78±0.20 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern comprising additional peaks at angles 2-theta of 13.13±0.20 and 18.82±0.20 degrees. In some embodiments, the crystalline form is characterized by having an endotherm peak at 86±2 °C, as determined by DSC. In some embodiments, the crystalline form is characterized by having a weight loss of 0.7% or 0.7%±0.1% between 25 °C and 42 °C, as determined by TGA. In some embodiments, the crystalline form is characterized by having a weight loss of 37 sf-5988480184102001940 6.0%±0.1% between 42 °C and 94 °C, as determined by TGA. In some embodiments, the crystalline form is characterized by having a weight gain of 62%±5% from 1% RH to 95% RH, as determined by DVS. In some embodiments, the crystalline form is characterized by having a weight loss of 70%±5% from 95% RH to 1% RH, as determined by DVS. IV. Compositions

[0103] In some aspects, the method provided herein comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (A) or any subgenus thereof, or a pharmaceutically acceptable salt thereof described herein. In some embodiments, the pharmaceutical composition comprises 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 crosscarmellose, glucose, gelatin, sucrose, and magnesium carbonate.

[0104] 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.

[0105] 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 crosscarmellose, 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 38 sf-5988480184102001940 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 in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

[0106] In some embodiments, the compositions will take the form of a pill or tablet and thus the composition may contain, along with a compounds 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.

[0107] 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.

[0108] 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.

[0109] 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. 39 sf-5988480184102001940

[0110] In some embodiments, the method provided herein comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutically acceptable composition comprising a compound of Formula (A), (B), (C), (A-1), (A-2), or (A-3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. In some aspects, the 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.

[0111] 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.

[0112] In some embodiments, the pharmaceutical composition is packaged, wherein the package comprises a pharmaceutical composition as described herein and instructions for using the composition to treat a patient suffering from a disease or condition described herein (e.g., cancer).

[0113] In some embodiments, the pharmaceutical composition or formulation comprises a compound of Formula (A) and a pharmaceutically acceptable polymer. In some embodiments,

[0114] In some embodiments, the pharmaceutically acceptable polymer comprises hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose (HPMC), or methacrylic acid-ethyl acrylate copolymer, or any combination thereof. In some embodiments, the pharmaceutically acceptable polymer comprises HPMCAS. In some embodiments, wherein the HPMCAS is HPMCAS-M. In some embodiments, the pharmaceutically acceptable polymer comprises HPMCP. In some embodiments, the HPMCP is HPMCP-HP55. In some embodiments, the pharmaceutically acceptable polymer comprises HPMC. In some embodiments, the HPMC is HPMC E3LV. In some embodiments, the pharmaceutically acceptable polymer comprises methacrylic acid-ethyl acrylate copolymer. In some embodiments, the methacrylic acid-ethyl acrylate copolymer is methacrylic acid-ethyl acrylate copolymer (1:1).

[0115] In some embodiments, the formulation has a weight ratio of the compound of Formula (A), or pharmaceutically acceptable salt thereof, to the pharmaceutically acceptable polymer of from about 20:80 to about 90:10. In some embodiments, the formulation has a weight ratio of the compound of Formula (A), or pharmaceutically acceptable salt thereof, to 40 sf-5988480184102001940 the pharmaceutically acceptable polymer of from about 25:75 to about 70:30. In some embodiments, the formulation has a weight ratio of the compound of Formula (A), or pharmaceutically acceptable salt thereof, to the pharmaceutically acceptable polymer of about 25:75. In some embodiments, the formulation has a weight ratio of the compound of Formula (A), or pharmaceutically acceptable salt thereof, to the pharmaceutically acceptable polymer of about 40:60. In some embodiments, the formulation has a weight ratio of the compound of Formula (A), or pharmaceutically acceptable salt thereof, to the pharmaceutically acceptable polymer of about 50:50. In some embodiments, the formulation has a weight ratio of the compound of Formula (A), or pharmaceutically acceptable salt thereof, to the pharmaceutically acceptable polymer of about 60:40. In some embodiments, the formulation has a weight ratio of the compound of Formula (A), or pharmaceutically acceptable salt thereof, to the pharmaceutically acceptable polymer of about 70:30. In some embodiments, the formulation comprises a compound of Formula (A), or pharmaceutically acceptable salt thereof, and HPMCP-HP55 in a weight ratio of about 25:75. In some embodiments, the formulation comprises a compound of Formula (A), or pharmaceutically acceptable salt thereof, and HPMCP-HP55 in a weight ratio of about 40:60. In some embodiments, the formulation comprises a compound of Formula (A), or pharmaceutically acceptable salt thereof, and HPMCP-HP55 in a weight ratio of about 50:50. In some embodiments, the formulation comprises a compound of Formula (A), or pharmaceutically acceptable salt thereof, and HPMCP-HP55 in a weight ratio of about 60:40. In some embodiments, the formulation comprises a compound of Formula (A), or pharmaceutically acceptable salt thereof, and HPMCP-HP55 in a weight ratio of about 70:30. In some embodiments, the formulation comprises a compound of Formula (A), or pharmaceutically acceptable salt thereof, and methacrylic acid-ethyl acrylate copolymer (1:1) in a weight ratio of about 25:75.

[0116] In some embodiments, the formulation comprises a compound of Formula (A), or pharmaceutically acceptable salt thereof, and methacrylic acid-ethyl acrylate copolymer (1:1) in a weight ratio of about 40:60. In some embodiments, the formulation comprises a compound of Formula (A), or pharmaceutically acceptable salt thereof, and methacrylic acid- ethyl acrylate copolymer (1:1) in a weight ratio of about 50:50. In some embodiments, the formulation comprises a compound of Formula (A), or pharmaceutically acceptable salt thereof, and methacrylic acid-ethyl acrylate copolymer (1:1) in a weight ratio of about 60:40. In some embodiments, the formulation comprises a compound of Formula (A), or pharmaceutically acceptable salt thereof, and methacrylic acid-ethyl acrylate copolymer (1:1) 41 sf-5988480184102001940 in a weight ratio of about 70:30. In some embodiments, the formulation comprises a compound of Formula (A), or pharmaceutically acceptable salt thereof, and HPMCAS in a weight ratio of about 25:75. In some embodiments, the formulation comprises a compound of Formula (A), or pharmaceutically acceptable salt thereof, and HPMCAS in a weight ratio of about 40:60. In some embodiments, the formulation comprises a compound of Formula (A), or pharmaceutically acceptable salt thereof, and HPMCAS in a weight ratio of about 50:50. In some embodiments, the formulation comprises a compound of Formula (A), or pharmaceutically acceptable salt thereof, and HPMCAS in a weight ratio of about 60:40. In some embodiments, the formulation comprises a compound of Formula (A), or pharmaceutically acceptable salt thereof, and HPMCAS in a weight ratio of about 70:30.

[0117] In some embodiments, ring B is cyclohexyl. In some embodiments, the two RBgroups are attached to the same carbon atom on ring B and are taken together with the carbon atom to which they are attached to form cyclopropyl. In some embodiments, ring A is C6-14 aryl substituted with one -S(O)2NRa14Ra15group. In some embodiments, Y2is CRC2, and CRC2is -NRc5S(O)2Rc6. In some embodiments, ring A is C6-14 aryl substituted with one - S(O)2NRa14Ra15group, and Y2is CRC2, and CRC2is -NRc5S(O)2Rc6. In some embodiments, ring A is C6-14aryl substituted with one -S(O)2NRa14Ra15group, wherein Ra14is H and Ra15is C1-6 alkyl; and Y2is CRC2, CRC2is -NRc5S(O)2Rc6, wherein Rc6is C1-6 alkyl optionally substituted with one -OH group.

[0118] In some embodiments, the compound of Formula (A) is a compound of Formula (A- 1). In some embodiments, the compound of Formula (A) is a compound of Formula (A-2). In some embodiments, the compound of Formula (A) is a compound of Formula (A-3).

[0119] In some embodiments, the compound of Formula (A) is in substantially amorphous form.

[0120] In one aspect, provided are solid formulations or compositions comprising a compound of Formula (A).

[0121] In some embodiments, the formulation is effective to achieve an area under a plasma concentration-time curve (AUC0-24) of the compound of Formula (A) in a human subject from about 10 µmol·hr / mL to about 100 µmol·hr / mL from about 0 hour to about 24 hours after administration of the formulation to the subject.

[0122] In some embodiments, the compound of Formula (A), or a pharmaceutically acceptable salt thereof, is a compound of Formula (A-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (A), or a pharmaceutically 42 sf-5988480184102001940 acceptable salt thereof, is a compound of Formula (A-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (A), or a pharmaceutically acceptable salt thereof, is a compound of Formula (A-3), or a pharmaceutically acceptable salt thereof.

[0123] In some embodiments, the formulation is administered to the subject without food. In some embodiments, the formulation is a spray-dried dispersion. V. Kits

[0124] Also provided are articles of manufacture and kits containing any of the compound provided herein (e.g., a compound of Formula (A), (B), (C), (A-1), (A-2), or (A-3)), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition or formulation thereof, or crystalline form thereof, as described 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.

[0125] In one aspect, provided herein are kits containing a compound provided herein (e.g., a compound of Formula (A), (B), (C), (A-1), (A-2), or (A-3)), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof, as 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. EXAMPLES Example 1. A phase I / II study of compound of Formula (A-1) in subjects with advanced cancer

[0126] A phase I / II study of compound of Formula (A-1) is carried out to assess the safety, tolerability and preliminary efficacy of Compound of Formula (A-1) monotherapy, which 43 sf-5988480184102001940 comprises two parts: Dose Escalation and Dose Expansion. Dose Escalation examines the safety and tolerability of Compound of Formula (A-1) in different solid tumor types at various dose levels through a series of Dose Escalation and Backfill Cohorts to identify the Maximum Tolerated Dose (MTD) and to select dose levels for Dose Expansion. The criteria for dose (de-) escalation is based on a Bayesian Optimal Interval (BOIN) design. Dose Expansion examines the safety, tolerability, Drug Drug Interaction (DDI) risk, Food Effect (FE) and preliminary efficacy of compound of Formula (A-1) in different tumor types and / or dose levels of interest through various expansion cohorts. Compound of Formula (A-1) is given orally in 28-day cycles. Dosing is continued until disease progression, unacceptable toxicity, withdrawal of consent, or other stopping criteria are met.

[0127] The conditions investigated under this study include: Advanced Solid Tumor, High Grade Serous Adenocarcinoma of Ovary, Squamous Non-small-cell Lung Cancer, Triple Negative Breast Cancer, Gastric Adenocarcinoma, Colorectal Adenocarcinoma, Esophageal Squamous Cell Carcinoma, Esophageal Adenocarcinoma, Gastroesophageal Junction Adenocarcinoma, Transitional Cell Carcinoma of Bladder, Head and Neck Squamous Cell Carcinoma, Ovarian Carcinosarcoma, Uterine Carcinosarcoma, Uterine Serous Carcinoma, Endometrium Cancer, and Chromosomal Instability.

[0128] The study involves multiple arms, wherein in each arm, the compound of Formula (A-1) tablet is given orally. The arms include: (i) Dose Escalation Cohorts Subjects are enrolled at various doses and / or schedules of compound of Formula (A-1). These Dose Escalation Cohorts are utilized to identify the MTD and to select dose levels for Dose Expansion; (ii) Backfill Cohorts:

[0129] Additional subjects may be enrolled at any dose level that does not meet de- escalation or elimination rules per the BOIN design. These Backfill Cohorts will be utilized to build additional data to support selection of doses and / or tumor types for further study in Dose Expansion; (iii) Exploration Cohorts: Subjects with a selected single tumor type are randomized 1:1 into Exploration Cohorts at two or more dose levels of interest. A subset of subjects may have additional assessments to examine the potential for compound of Formula (A-1) to interact with other drugs and the effect of food on compound of Formula (A-1) absorption; and (iv) Development Cohorts: Subjects with other tumor types are enrolled at a single dose level of interest. These Development Cohorts are utilized to examine the preliminary efficacy of compound of Formula (A-1) in various tumor types. 44 sf-5988480184102001940

[0130] Several primary outcomes measures are recorded during the study, with a time frame up to 12 months. The primary outcomes measures include: (1) Dose Escalation: Incidence of Dose Limiting Toxicities (DLTs) in DLT-evaluable subjects; (2) Dose Escalation: Determination of the MTD of compound of Formula (A-1); (3) Dose Escalation: Frequency of Serious Adverse Events (SAEs) graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0; (4) Dose Escalation: Frequency of Treatment-related Adverse Events (AEs) graded per NCI- CTCAE version 5.0; (5) Dose Escalation: Frequency of Treatment-Emergent AEs (TEAEs) graded per NCI-CTCAE version 5.0; (6) Dose Escalation: Frequency of Dose Interruptions and Permanent Treatment Discontinuations; (7) Dose Expansion: Frequency of Trigger Events (TEs); and (8) Dose Expansion: Objective Response Rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. For the primary outcome measure (8), the time frame is up to 18 months.

[0131] Several secondary outcomes measures are also recorded during the study. The secondary outcome measures and the time frame for each secondary outcome measure include: (1) Dose Escalation: ORR as assessed by RECIST version 1.1, with a time frame up to 12 months; (2) Dose Expansion: Frequency of SAEs graded according to NCI-CTCAE version 5.0, with a time frame up to 18 months; (3) Dose Expansion: Frequency of Treatment-related AEs graded according to NCI-CTCAE version 5.0, with a time frame up to 18 months; (4) Dose Expansion: Frequency of TEAEs graded according to NCI-CTCAE version 5.0, with a time frame up to 18 months; (5) Dose Expansion: Frequency of Dose Interruptions and Permanent Treatment Discontinuations, with a time frame up to 18 months; (6) Dose Expansion: Area Under the Plasma Concentration-Time Curve (AUC) of Midazolam and its metabolite 1’-hydroxymidazolam, with a time frame up to 18 months; (7) Dose Expansion: Maximum Plasma Concentration (Cmax) of Midazolam and its metabolite 1’-hydroxymidazolam, with a time frame up to 18 months; (8) Dose Expansion: Evaluation of CA-125 response by Gynecologic Cancer InterGroup (GCIG) criteria (High Grade Serous Ovarian Cancer only), with a time frame up to 18 months; (9) Dose Escalation & Dose Expansion: Duration of Response (DOR) as assessed by RECIST version 1.1, with a time frame up to 32 months; (10) Dose Escalation & Dose Expansion: Disease Control Rate (DCR) as assessed by RECIST version 1.1, with a time frame up to 32 months; (11) Dose Escalation & Dose Expansion: Progression Free Survival (PFS) as assessed by RECIST version 1.1, with a time frame up to 32 months; (12) Dose Escalation & Dose Expansion: 45 sf-5988480184102001940 Cmaxof Compound of Formula (A-1), with a time frame up to 32 months; (13) Dose Escalation & Dose Expansion: AUC of Compound of Formula (A-1), with a time frame up to 32 months; (14) Dose Escalation & Dose Expansion: Trough Concentration (Ctrough) of Compound of Formula (A-1), with a time frame up to 32 months; (15) Dose Escalation & Dose Expansion: Time to Maximum Plasma Concentration (Tmax) of Compound of Formula (A-1), with a time frame up to 32 months; (16) Dose Escalation & Dose Expansion: Ratio of Total Cholesterol to 4β-hydroxycholesterol in plasma, with a time frame up to 32 months; (17) Dose Escalation & Dose Expansion: Increase in the number of Phospho-Histone 3 positive tumor cells, with a time frame up to 32 months; (18) Dose Escalation & Dose Expansion: Frequency of Micronucleated Reticulocytes in blood, with a time frame up to 32 months; and (19) Dose Escalation & Dose Expansion: Increase in Micronuclei in Circulating Tumor Cells, with a time frame up to 32 months.

[0132] The key inclusion criteria for the study includes: age ≥ 18 years, ECOG Performance Status ≤ 1, at least 1 site of measurable disease evaluable by CT scan or MRI per RECIST 1.1, and able to take oral medication without alteration. The inclusion criteria for the dose escalation study includes that there are no available therapeutic options to provide clinically meaningful benefits in the following tumor types: High Grade Serous Ovarian Cancer, Squamous-Non Small Cell Lung Cancer, Triple Negative Breast Cancer, Gastric Adenocarcinoma (not EBV+), Colorectal, Esophageal Squamous Cell Carcinoma, Esophageal Adenocarcinoma, Gastroesophageal Junction, Bladder (transitional cell), Head and Neck Squamous Cell Carcinomas (not nasopharynx, sinonasal or lip), Ovarian Carcinosarcoma, or CN-high Endometrial / Uterine. The inclusion criteria for dose expansion study includes that the subject must have been previously treated with several lines of standard of care treatment specified in the protocol in the following tumor types: High Grade Serous Ovarian Cancer, Squamous Non-Small Cell Lung Cancer, Triple Negative Breast Cancer, Gastric Adenocarcinoma (not EBV+), Colorectal, Esophageal Squamous Cell Carcinoma, Esophageal Adenocarcinoma, Head and Neck Squamous Cell Carcinomas (not nasopharynx, sinonasal or lip), or CN-high Endometrial / Uterine.

[0133] The key exclusion criteria of this study include: (a) the subject has high microsatellite instability (MSI-H), mismatch repair deficient (dMMR), POLE gene hotspot mutated, or known hypermutator phenotype; (b) the subject previously received a KIF18A inhibitor; (c) the subject has current CNS metastases or leptomeningeal disease; (d) the subject has cardiac parameters: MI or stroke ≤ 1 year, unstable angina / PE / DVT / CABG ≤ 6 46 sf-5988480184102001940 months, and NYHA Class ≥ II, LVEF < 50%; (e) the subject is unable to comply with concomitant medication restrictions with respect to strong inhibitors and inducers of CYP3A, and clinical inhibitors of MDR1 (P-gp) and BCRP; (f) the subject has any clinically significant ascites or pleural effusions at time of enrollment, or any therapeutic paracentesis or thoracentesis within 28 days of planned first dose of study drug; and (g) the subject has bowel obstruction or GI perforation within 6 months of planned first dose of study drug. 47 sf-5988480

Claims

184102001940 CLAIMS 1. A method of treating cancer associated with chromosomal instability in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (A):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof, wherein: ring A is C6-14 aryl or 5- to 12-membered heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, C1-6alkyl, 3- to 10-membered heterocycloalkyl, - NRa1C(O)NRa2Ra3, -NRa4C(O)ORa5, -NRa6Ra7, -N=S(O)Ra8Ra9, -ORa10, -S(O)Ra11, - S(O)(NRa12)Ra13, -S(O)2NRa14Ra15, -S(O)2Ra16, -(CRa17Ra18)0-1C(O)NRa19Ra20, -SRa21, -C(O)Ra22, and C1-6alkyl substituted with one or more substituents 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; Ra1-Ra22are each independently hydrogen, C1-6alkyl, C2-6alkenyl, C3-10cycloalkyl, C3-10 cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10- membered heterocycloalkenyl, C6-14 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(C1-6alkyl), C2-6alkenyl, C3-10cycloalkyl, - S(C1-6 alkyl), =CR1a1R1a2, and C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, and - O(C1-6alkyl), wherein R1a1and R1a2are each independently hydrogen or C1-6alkyl; ring B is C5-7 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; m is 2; 48 sf-5988480184102001940 the two RBgroups are attached to the same carbon atom on ring B and are taken together with the carbon atom to which they are attached to form C3-7 cycloalkyl; Y1is N or CRC1; Y2is N or CRC2; Y3is N or CRC3; Y4is N or CRC4; wherein no more than three of Y1, Y2, Y3, and Y4are N; RC1-RC4are each independently hydrogen, halo, cyano, -OH, -NO2, - C(O)NRc1Rc2, -NRc3Rc4, -NRc5S(O)2Rc6, -P(O)Rc7Rc8, -N=S(O)Rc9Rc10, - S(O)(NRc11)Rc12, -S(O)2Rc13, -NRc14C(O)ORc15, -NRc16S(O)2(CH2)1- 6NRc17C(O)Rc18,or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH; Rc1-Rc18are each independently hydrogen, C3-10cycloalkyl, or C1-6alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH.

2. A method of treating cancer selected from the group consisting of advanced solid tumor, high grade serous adenocarcinoma of ovary, squamous non-small-cell lung cancer, triple negative breast cancer, gastric adenocarcinoma, colorectal adenocarcinoma, esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastroesophageal junction adenocarcinoma, transitional cell carcinoma of bladder, head and neck squamous cell carcinoma, ovarian carcinosarcoma, uterine carcinosarcoma, uterine serous carcinoma, and endometrium cancer, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (A):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof, wherein: 49 sf-5988480184102001940 ring A is C6-14aryl or 5- to 12-membered heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, C1-6 alkyl, 3- to 10-membered heterocycloalkyl, - NRa1C(O)NRa2Ra3, -NRa4C(O)ORa5, -NRa6Ra7, -N=S(O)Ra8Ra9, -ORa10, -S(O)Ra11, - S(O)(NRa12)Ra13, -S(O)2NRa14Ra15, -S(O)2Ra16, -(CRa17Ra18)0-1C(O)NRa19Ra20, -SRa21, -C(O)Ra22, and C1-6 alkyl substituted with one or more substituents independently selected from the group consisting of -OH, cyano, C3-10cycloalkyl, and 3- to 10- membered heterocycloalkyl optionally substituted with one or more halo; Ra1-Ra22are each independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C3-10cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10- membered heterocycloalkenyl, C6-14aryl, 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(C1-6 alkyl), C2-6 alkenyl, C3-10 cycloalkyl, - S(C1-6alkyl), =CR1a1R1a2, and C1-6alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, and - O(C1-6 alkyl), wherein R1a1and R1a2are each independently hydrogen or C1-6 alkyl; ring B is C5-7cycloalkyl, C5-7cycloalkenyl, 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; m is 2; the two RBgroups are attached to the same carbon atom on ring B and are taken together with the carbon atom to which they are attached to form C3-7 cycloalkyl; Y1is N or CRC1; Y2is N or CRC2; Y3is N or CRC3; Y4is N or CRC4; wherein no more than three of Y1, Y2, Y3, and Y4are N; RC1-RC4are each independently hydrogen, halo, cyano, -OH, -NO2, - C(O)NRc1Rc2, -NRc3Rc4, -NRc5S(O)2Rc6, -P(O)Rc7Rc8, -N=S(O)Rc9Rc10, - S(O)(NRc11)Rc12, -S(O)2Rc13, -NRc14C(O)ORc15, -NRc16S(O)2(CH2)1- 6NRc17C(O)Rc18,or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH; 50 sf-5988480184102001940 Rc1-Rc18are each independently hydrogen, C3-10cycloalkyl, or C1-6alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH.

3. The method of claims 1 or 2, wherein the compound of Formula (A) is administered to the subject in 28-day cycles.

4. The method of any one of claims 1-3, wherein the compound of Formula (A) is a compound of Formula (A-1):or a pharmaceutically acceptable salt thereof.

5. The method of any one of claims 1-3, wherein the compound of Formula (A) is a compound of Formula (A-2):or a pharmaceutically acceptable salt thereof.

6. The method of any one of claims 1-3, wherein the compound of Formula (A) is a compound of Formula (A-3): 51 sf-5988480184102001940or a pharmaceutically acceptable salt thereof.

7. The method of any one of claims 2-6, wherein the cancer is advanced solid tumor 8. The method of any one of claims 2-6, wherein the cancer is high grade serous adenocarcinoma of ovary 9. The method of any one of claims 2-6, wherein the cancer is squamous non-small-cell lung cancer.

10. The method of any one of claims 2-6, wherein the cancer is triple negative breast cancer.

11. The method of any one of claims 2-6, wherein the cancer is gastric adenocarcinoma.

12. The method of any one of claims 2-6, wherein the cancer is colorectal adenocarcinoma.

13. The method of any one of claims 2-6, wherein the cancer is esophageal squamous cell carcinoma.

14. The method of any one of claims 2-6, wherein the cancer is esophageal adenocarcinoma.

15. The method of any one of claims 2-6, wherein the cancer is gastroesophageal junction adenocarcinoma.

16. The method of any one of claims 2-6, wherein the cancer is transitional cell carcinoma of bladder. 52 sf-5988480184102001940 17. The method of any one of claims 2-6, wherein the cancer is head and neck squamous cell carcinoma.

18. The method of any one of claims 2-6, wherein the cancer is ovarian carcinosarcoma.

19. The method of any one of claims 2-6, wherein the cancer is uterine carcinosarcoma.

20. The method of any one of claims 2-6, wherein the cancer is uterine serous carcinoma.

21. The method of any one of claims 2-6, wherein the cancer is endometrium cancer. 53 sf-5988480

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