A method of treating cancer with the indoline inhibitor KIF18A

Abstract

This disclosure relates to a series of indoline inhibitors of KIF18A and to methods of using them to treat diseases mediated by KIF18A (such as cancer).

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 508,233, filed on 14 June 2023, which is incorporated herein by reference in its entirety.

[0002] In some aspects, this disclosure relates to indoline inhibitors of KIF18A and methods of using them to treat diseases mediated by KIF18A (such as cancer). [Background technology]

[0003] KIF18A is a kinesin involved in supporting kinetochore-microtubule (kt-MT) binding and chromosome alignment during cell mitosis. Its cargo domain directly binds to protein phosphatase 1 (PP1), transporting it to the plus end of MT, where PP1 dephosphorylates Hec1 (a component of the kinetochore complex), further promoting kt-MT binding throughout metaphase and anaphase. Its MT-binding motor domain possesses ATPase activity that powers the translocation of KIF18A along the MT lattice, facilitated by its C-terminal MT-binding site, and caps and depolymerizes microtubules growing at the plus end, thereby weakening MT dynamics. This regulation of MT dynamics by KIF18A often occurs in the subsequent (or following) sister chromatid, thereby providing tension to balance the preceding sister chromatid movement catalyzed by another kinesin, Kif2C / MCAK. Loss of KIF18A function leads to defective kt-MT binding and loss of spindle tension in cells with high chromosomal instability (CIN), resulting in hyperstable, longer-lasting, and multipolar spindles, mitotic arrest, centrosome fragmentation, and spindle assembly checkpoint activation or cell death. KIF18A was identified as one of the essential top candidates for CIN-high cells from a reanalysis of DEPMAP RNAi data. Reports of synthetic lethality screening also selected KIF18A as a potential anti-cancer target, with KIF18A knockdown preferentially killing CIN-high aneuploid and whole-genome-duplicating cells (but not CIN-low cells). Cytotoxicity assays in allogeneic cell lines confirmed enhanced sensitivity of CIN-high cells to KIF18A inhibitors. In-progress in vivo mouse models using KIF18A inhibitors or knockdown demonstrated the inhibitory effect on tumor growth. Therefore, there is a need for new drugs and / or methods that are effective in treating diseases mediated by KIF18A. This application addresses this need and other needs. [Overview of the project]

[0004] In some embodiments, a method of treating cancer associated with chromosomal instability in a subject in need of treatment, the method comprising administering a therapeutically effective amount of a compound of formula (A): [Chemical Formula] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof [wherein, Ring A is C a1 , 1-6 , a21 , 3-10 , a19 , 1-6 , a18 , , a22 , 3-10 , a22 , a20 , 0-1 , 3-10 , 2-6 aryl or 5- to 12-membered heteroaryl, each of which is independently selected from the group consisting of halo, -OH, C 1-6 alkyl, 3- to 10-membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 , -NR a4 C(O)OR a5 , -NR a6 R a7 , -N=S(O)R a8 R a9 , -OR a10 , -S(O)R a11 , -S(O)(NR a12 )R a13 , -S(O)2NR a14 R a15 , -S(O)2R a16 , -(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 , -SR a21 , -C(O)R a22 , and C 1-6 alkyl (substituted with one or more substituents independently selected from the group consisting of -OH, cyano, C 3-10 cycloalkyl, and 3- to 10-membered heterocycloalkyl (optionally substituted with one or more halos)); and is optionally substituted with one or more substituents independently selected from the group consisting of: R a1 ~R a22 are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 3-10Cycloalkenyl, 3-10 member heterocycloalkyl, 3-10 member heterocycloalkenyl, C 6-14 These are aryls, or 5- to 12-membered heteroaryls, each consisting of a halo, cyano, -OH, and -O(C) 1-6 Alkyl), C 2-6 Alkenil, C 3-10 Cycloalkyl, -S(C 1-6 Alkyl), =CR 1a1 R 1a2 , and C 1-6 alkyl(halo, -OH, and -O(C) 1-6 Optionally substituted with one or more substituents independently selected from the group consisting of alkyl) and R 1a1 and R 1a2 Each of them independently consists of hydrogen or C 1-6 It is alkyl; Ring B is C 5-7 Cycloalkyl, C 5-7 A cycloalkenyl, or a 5- to 7-membered heterocycloalkyl, where one or two of the ring atoms are oxygen and the remaining ring atoms are carbon; m is 2; Two R's B The group is bonded to the same carbon atom on ring B, and together with the carbon atom to which they are bonded, C 3-7 Forms a cycloalkyl group; Y 1 is N or CR C1 and; Y 2 is N or CR C2 and; Y 3 is N or CR C3 and; Y 4 is N or CR C4 and; Y 1 , Y 2 , Y 3 , and Y 4 Three or fewer of these are N; R C1 ~R C4These are, independently, hydrogen, halo, cyano, -OH, -NO2, and -C(O)NR. c1 R c2 , -NR c3 R c4 , -NR c5 S(O)2R c6 ,-P(O)R c7 R c8 -N=S(O)R c9 R c10 -S(O)(NR c11 )R c12 -S(O)2R c13 , -NR c14 C(O)OR c15 , -NR c16 S(O)2(CH2) 1-6 NR c17 C(O)R c18 , or C 1-6 It is an alkyl group (optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH); R c1 ~R c18 These are, independently, hydrogen and C 3-10 Cycloalkyl, or C 1-6 [It is an alkyl group (optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH)] A method comprising administering to a target is provided herein.

[0005] In several variations, cancer is selected from the group consisting of progressive solid tumors, high-grade serous adenocarcinoma of the 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 the bladder, head and neck squamous cell carcinoma, ovarian carcinosarcoma, uterine carcinosarcoma, serous carcinoma of the uterine body, and endometrial cancer.

[0006] In some variations, a method of treating a cancer selected from the group consisting of progressive solid tumors, high-grade serous adenocarcinoma of the ovary, squamous non-small cell lung cancer, triple-negative breast cancer, gastric adenocarcinoma, colorectal adenocarcinoma, esophageal squamous carcinoma, esophageal adenocarcinoma, gastroesophageal junction adenocarcinoma, transitional epithelial carcinoma of the bladder, head and neck squamous carcinoma, ovarian carcinosarcoma, uterine carcinosarcoma, serous carcinoma of the uterine corpus, and endometrial carcinoma in a subject in need of treatment, comprising a therapeutically effective amount of a compound of formula (A): [Chemical Formula] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof [wherein, Ring A is C 6-14 aryl or 5- to 12-membered heteroaryl, each of which is independently selected from the group consisting of halo, -OH, C 1-6 alkyl, 3- to 10-membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 、-NR a4 C(O)OR a5 、-NR a6 R a7 、-N=S(O)R a8 R a9 、-OR a10 、-S(O)R a11 、-S(O)(NR a12 )R​​​​​​​​​​​​​​​​​​​​​​​​​​​​a1 ~R a22 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3-10 member heterocycloalkyl, 3-10 member heterocycloalkenyl, C 6-14 These are aryls, or 5- to 12-membered heteroaryls, each consisting of a halo, cyano, -OH, and -O(C) 1-6 Alkyl), C 2-6 Alkenil, C 3-10 Cycloalkyl, -S(C 1-6 Alkyl), =CR 1a1 R 1a2 , and C 1-6 alkyl(halo, -OH, and -O(C) 1-6 Optionally substituted with one or more substituents independently selected from the group consisting of alkyl) and R 1a1 and R 1a2 Each of them independently consists of hydrogen or C 1-6 It is alkyl; Ring B is C 5-7 Cycloalkyl, C 5-7 A cycloalkenyl, or a 5- to 7-membered heterocycloalkyl, where one or two of the ring atoms are oxygen and the remaining ring atoms are carbon; m is 2; Two R's B The group is bonded to the same carbon atom on ring B, and together with the carbon atom to which they are bonded, C 3-7 Forms a cycloalkyl group; Y 1 is N or CR C1 and; Y 2 is N or CR C2 and; Y 3 is N or CR C3 and; Y 4 is N or CR C4 and; Y1 , Y 2 , Y 3 , and Y 4 Three or fewer of these are N; R C1 ~R C4 These are, independently, hydrogen, halo, cyano, -OH, -NO2, and -C(O)NR. c1 R c2 , -NR c3 R c4 , -NR c5 S(O)2R c6 ,-P(O)R c7 R c8 -N=S(O)R c9 R c10 -S(O)(NR c11 )R c12 -S(O)2R c13 , -NR c14 C(O)OR c15 , -NR c16 S(O)2(CH2) 1-6 NR c17 C(O)R c18 , or C 1-6 It is an alkyl group (optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH); R c1 ~R c18 These are, independently, hydrogen and C 3-10 Cycloalkyl, or C 1-6 [It is an alkyl group (optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH)] A method comprising administering to a target is provided herein.

[0007] In several variations, the compound of formula (A) is administered to the subject in a 28-day cycle.

[0008] In some variations, the compound of formula (A) is the same as the compound of formula (A-1): [ka] or a pharmaceutically acceptable salt thereof.

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

[0010] In some embodiments, the compound of formula (A) is the compound of formula (A-3): [ka] or a pharmaceutically acceptable salt thereof. [Modes for carrying out the invention]

[0011] The following description is provided to enable those skilled in the art to fabricate and use various embodiments. The 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 skilled in the art, and the general principles defined herein may be applied to other examples and applications without departing from the spirit and scope of the various embodiments. Therefore, the various embodiments are not intended to be limited to the examples described and shown herein, but are given a scope that is not inconsistent with the claims.

[0012] I. Definition When used herein, the following words and phrases are generally intended to have the meanings described below, except to the extent indicated by the context in which they are used.

[0013] When used herein and in the appended claims, the singular forms "a," "an," and "the" include the plural form unless otherwise explicitly instructed by the context.

[0014] As used herein, and unless otherwise specified, the terms “about” and “approximately” mean, when used in relation to the dose, volume, or weight percentage of an ingredient in a composition or dosage form, a dose, volume, or weight percentage that would be recognized by those skilled in the art as providing an equivalent pharmacological effect to that obtained from a specified dose, volume, or weight percentage. Specifically, where applicable, the terms “about” and “approximately” mean, when used in this context, a dose, volume, or weight percentage that is no more than 15% of a specified dose, volume, or weight percentage.

[0015] Throughout this application, unless otherwise indicated by the context, references to compounds of formula (A) encompass all subgroups defined herein (e.g., formulas (B), (C), (A-1), (A-2), or (A-3)), including all substructures, subgenera, selections, embodiments, examples, and specific compounds defined and / or described herein. In some embodiments, unless otherwise indicated, references to compounds of formulas (A), (B), (C), (A-1), (A-2), or (A-3) and their subgroups encompass their ionic forms, polymorphs, pseudopolymorphs, amorphous forms, solvates, cocrystals, chelates, isomers, tautomers, oxides (e.g., N-oxides, S-oxides), esters, prodrugs, isotopes, and / or protected forms. In some embodiments, references to compounds of formula (A), (B), (C), (A-1), (A-2), or (A-3) and their subgroups include their polymorphs, isomers, cocrystals, isomers, tautomers, and / or oxides.

[0016] "Alkyl" encompasses linear and branched carbon chains having the indicated number of carbon atoms (e.g., 1 to 20 carbon atoms, or 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 3 carbon atoms). For example, C 1-6Alkyls encompass linear and branched alkyl groups with 1 to 6 carbon atoms. When an alkyl residue with a specific number of carbon atoms is named, it is intended that all branched and linear versions with that number of carbon atoms are included; therefore, for example, "propyl" includes n-propyl and isopropyl, and "butyl" includes n-butyl, sec-butyl, isobutyl, and t-butyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.

[0017] A range of values ​​is given (for example, C 1-6 In the case of alkyl, each value within the range, and the range between all of them, are included. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1-6 , C 2-6 , C 3-6 , C 4-6 , C 5-6 , C 1-5 , C 2-5 , C 3-5 , C 4-5 , C 1-4 , C 2-4 , C 3-4 , C 1-3 , C 2-3 , and C 1-2 It includes alkyl groups.

[0018] "Alkenyl" refers to an unsaturated branched or linear 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 have either a cis or trans configuration (Z configuration or E configuration) with respect to the double bond. Examples of 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., buto-1-en-1-yl, buto-1-en-2-yl, 2-methyl-prop-1-en-1-yl, buto-2-en-1-yl, buto-2-en-2-yl, buto-1,3-dien-1-yl, buto-1,3-dien-2-yl).

[0019] "Alkynyl" refers to an unsaturated branched or linear 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-carbon-carbon triple bond. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl (e.g., prop-1-in-1-yl, prop-2-in-1-yl), and butynyl (e.g., buto-1-in-1-yl, buto-1-in-3-yl, buto-3-in-1-yl).

[0020] "Cycloalkyl" refers to a non-aromatic, fully saturated carbocyclic ring having the indicated number of carbon atoms (e.g., 3-10, 3-8, or 3-6 ring carbon atoms). Cycloalkyl groups can be monocyclic or polycyclic (e.g., tricyclic, bicyclic). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, as well as crosslinked 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 that the polycyclic cycloalkyl group is bonded to the parent structure via non-aromatic carbon atoms. For example, the 1,2,3,4-tetrahydronaphthalene-1-yl group (which is bonded to the parent structure via non-aromatic carbon atoms) is a cycloalkyl group, while the 1,2,3,4-tetrahydronaphthalene-5-yl group (which is bonded to the parent structure via aromatic carbon atoms) is not considered a cycloalkyl group. Examples of polycyclic cycloalkyl groups consisting of cycloalkyl groups fused to an aromatic ring are described below.

[0021] "Cycloalkenyl" refers to a non-aromatic carbocyclic ring containing the indicated number of carbon atoms (e.g., 3-10, 3-8, or 3-6) and at least one carbon-carbon double bond. Cycloalkenyl groups can be monocyclic or polycyclic (e.g., tricyclic, bicyclic). Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, and cyclohexenyl, as well as bridging and caged ring groups (e.g., bicyclo[2.2.2]octene). In addition, one ring of a polycyclic alkenyl group can be aromatic, provided that the polycyclic cycloalkenyl group is bonded to the parent structure via non-aromatic carbon atoms. For example, indene-1-yl (the portion bonded to the parent structure via non-aromatic carbon atoms) is considered a cycloalkenyl group, while indene-4-yl (the portion bonded to the parent structure via aromatic carbon atoms) is not considered a cycloalkenyl group. Examples of polycyclic cycloalkenyl groups consisting of cycloalkenyl groups fused to an aromatic ring are described below.

[0022] "Aryl" refers to an aromatic carbocyclic ring having the indicated number of carbon atoms (e.g., 6-12 or 6-10 carbon atoms). Aryl groups can be monocyclic or polycyclic (e.g., tricyclic, bicyclic). In some examples, both rings of a polycyclic aryl group are aromatic (e.g., naphthyl). In other examples, a polycyclic aryl group may include a non-aromatic ring fused to the aromatic ring, provided that the polycyclic aryl group is bonded to the parent structure via atoms in the aromatic ring. Thus, the 1,2,3,4-tetrahydronaphthalene-5-yl group (where the portion is bonded to the parent structure via aromatic carbon atoms) is determined to be an aryl group, while the 1,2,3,4-tetrahydronaphthalene-1-yl group (where the portion is bonded to the parent structure via non-aromatic carbon atoms) is not determined to be an aryl group. Similarly, the 1,2,3,4-tetrahydroquinoline-8-yl group (where the portion is bonded to the parent structure via an aromatic carbon atom) is determined to be an aryl group, while the 1,2,3,4-tetrahydroquinoline-1-yl group (where the portion is bonded to the parent structure via a non-aromatic nitrogen atom) is not determined to be an aryl group. However, the term "aryl," regardless of the bonding site, does not encompass or overlap with "heteroaryl" as defined herein (for example, both quinoline-5-yl and quinoline-2-yl are heteroaryl groups). In some examples, the aryl is phenyl or naphthyl. In certain specific examples, the aryl is phenyl. Additional examples of aryl groups containing aromatic carbocyclic rings fused to non-aromatic rings are described below.

[0023] "Heteroaryl" refers to an aromatic ring containing the indicated number of atoms, consisting of one or more heteroatoms selected from N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms), with the remaining ring atoms being carbon. The heteroaryl group does not contain adjacent S and O atoms. In some embodiments, the total number of S and O atoms in the heteroaryl group is 2 or less. In some embodiments, the total number of S and O atoms in the heteroaryl group is 1 or less. Unless otherwise indicated, the heteroaryl group may be bonded to the parent structure by carbon or nitrogen atoms, as the valency allows. 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 examples, heteroaryl groups are 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 several examples, both rings of a polycyclic heteroaryl group are aromatic. Examples include indole, isoindole, indazole, benzimidazole, benzotriazole, benzofuran, benzoxazole, benzoxazole, 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, and 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, flo[2,3-b]pyridine, oxazolo[5,4- [b]pyridine, isoxazolo[5,4-b]pyridine, [1,2,3]oxadiazolo[5,4-b]pyridine, flou[3,2-b]pyridine, oxazolo[4,5-b]pyridine, isoxazolo[4,5-b]pyridine, [1,2,3]oxadiazolo[4,5-b]pyridine, flou[2,3-c]pyridine, oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine, [1,2,3]oxadiazolo[5,4-c]pyridine, flou[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,Examples include [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, quinazolin, 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.

[0026] In other examples, a polycyclic heteroaryl group may include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to the heteroaryl ring, provided that the polycyclic heteroaryl group is bonded to the parent structure via an atom in the aromatic ring. For example, the 4,5,6,7-tetrahydrobenzo[d]thiazole-2-yl group (where the portion is bonded to the parent structure via an aromatic carbon atom) is considered a heteroaryl group, while the 4,5,6,7-tetrahydrobenzo[d]thiazole-5-yl group (where the portion is bonded 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] "Hypercycloalkyl" refers to a non-aromatic, fully saturated ring (e.g., 3-10 or 3-7 membered heterocycloalkyl) having the indicated number of atoms, composed of one or more heteroatoms selected from N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms), with the remaining ring atoms being carbon. Heterocycloalkyl groups can be monocyclic or polycyclic (e.g., tricyclic, bicyclic). Examples of heterocycloalkyl groups include oxylanyl, azilidinyl, 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 that the polycyclic heterocycloalkyl group is bonded to the parent structure via a non-aromatic carbon or nitrogen atom. For example, the 1,2,3,4-tetrahydroquinoline-1-yl group (which is bonded to the parent structure via a non-aromatic nitrogen atom) is determined to be a heterocycloalkyl group, while the 1,2,3,4-tetrahydroquinoline-8-yl group (which is bonded to the parent structure via an aromatic carbon atom) is not determined to be a heterocycloalkyl group. Examples of polycyclic heterocycloalkyls consisting of heterocycloalkyls fused to an aromatic ring are described below.

[0028] A "heterocycloalkenyl" is a non-aromatic, fully saturated ring (e.g., 3-10 or 3-7 membered heterocycloalkenyl) having the indicated number of atoms, composed of one or more heteroatoms selected from N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms), with the remaining ring atoms being carbon, and at least one double bond being led by the removal of one molecule of hydrogen from an adjacent carbon atom, an adjacent nitrogen atom, or both adjacent carbon and nitrogen atoms of the corresponding heterocycloalkyl. Heterocycloalkenyl groups can be monocyclic or polycyclic (e.g., tricyclic, bicyclic). Examples of heterocycloalkenyl groups include dihydrofuranyl (e.g., 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dihydrothiophenyl (e.g., 2,3-dihydrothiophenyl, 2,5-dihydrothiophenyl), dihydropyrrolyl (e.g., 2,3-dihydro-1H-pyrrolyl, 2,5-dihydro-1H-pyrrolyl), dihydroimidazolyl (e.g., 2,3-dihydro-1H-imidazolyl), 4,5-dihydro-1H-imidazolyl, pyranyl, dihydropyranyl (e.g., 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl), tetrahydropyridinyl (e.g., 1,2,3,4-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl), and dihydropyridine (e.g., 1,2-dihydropyridine, 1,4-dihydropyridine). In addition, provided that the polycyclic heterocycloalkenyl group is bonded to the parent structure via a non-aromatic carbon or nitrogen atom, one of the rings in the polycyclic heterocycloalkenyl group can be aromatic (e.g., aryl or heteroaryl). For example, the 1,2-dihydroquinoline-1-yl group (which is bonded to the parent structure via a non-aromatic nitrogen atom) is considered a heterocycloalkenyl group, while the 1,2-dihydroquinoline-8-yl group (which is bonded to the parent structure via an aromatic carbon atom) is not considered a heterocycloalkenyl group. Examples of polycyclic heterocycloalkenyls consisting of heterocycloalkenyls fused to aromatic rings 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]dioxynyl, 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, 4,5,6,7tetrahydrobenzo[d]thiazolyl Azolyl, 5,6-dihydro-4H-pyrrolo[3,4-d]thiazolyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, indorin-2-one, indorin-3-one, isoindorin-1-one, 1,2-dihydroindazole-3-one, 1H-benzo[d]imidazole-2(3H)-one, benzofuran-2(3H)-one, benzofuran-3(2H)-one, isobenzofuran-1(3H)-one, benzo[c]isoxazole-3(1H)-one, benzo[d]isoxazole-3(2H)-one, benzo[d ]Oxazole-2(3H)-one, benzo[b]thiophene-2(3H)-one, benzo[b]thiophene-3(2H)-one, benzo[c]thiophene-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, quinoline-4(3H)-one, quinazolin-4(3H)-one, quinazolin-2,4(1H,Examples include 3H)-dione, quinoxaline-2(1H)-one, quinoxaline-2,3(1H,4H)-dione, cinnoline-4(3H)-one, pyridine-2(1H)-one, pyrimidine-2(1H)-one, pyrimidine-4(3H)-one, pyridazine-3(2H)-one, 1H-pyrrolo[3,2-b]pyridine-2(3H)-one, 1H-pyrrolo[3,2-c]pyridine-2(3H)-one, 1H-pyrrolo[2,3-c]pyridine-2(3H)-one, 1H-pyrrolo[2,3-b]pyridine-2(3H)-one, 1,2-dihydropyrzolo[3,4-d]thiazole-3-one, and 4,5-dihydropyrrolo[3,4-d]thiazole-6-one. As discussed herein, whether each ring is determined to be an aryl group, heteroaryl group, cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, or heterocycloalkenyl group is determined by the atom to which the part is bonded to the parent structure.

[0030] "Halogen" or "halo" refers to fluoro, chloro, bromo, or iodine.

[0031] A "haloalkyl" refers to an alkyl group substituted with one or more halogens. A haloalkyl group may have halogen substituents at any valency-permissible position on the alkyl group, and may have any number of halogen substituents ranging from 1 to the maximum valency-permissible number. A particular haloalkyl group may 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, and -CH2CCl3.

[0032] Unless otherwise indicated, the compounds disclosed and / or described herein encompass all possible enantiomers, diastereomers, mesoisomers, and other stereoisomers, including racemic mixtures, optically pure forms, and intermediate mixtures thereof. Enantiomers, diastereomers, mesoisomers, and other stereoisomers may be prepared using chiral synthons or chiral reagents, or may be divided using conventional techniques. Unless otherwise specified, if the compounds disclosed and / or described herein contain an olefinic double bond or other centers of geometric asymmetricity, the compounds are intended to encompass both E and Z isomers. If the compounds described herein contain a tautomerizable moiety, and unless otherwise specified, the compounds are intended to encompass all tautomers.

[0033] The term "protecting group" has a conventionally relevant meaning in organic synthesis, namely, a group that selectively blocks one or more reaction sites in a polyfunctional compound, allowing a chemical reaction to be selectively carried out on another unprotected reaction site, and which can be easily removed after the selective reaction is complete. Various protecting groups are disclosed, for example, in T. 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 hydroxyl group protected by a hydroxy-protecting group. Similarly, amines and other reaction groups can be protected in a similar manner.

[0034] The term “pharmaceutically acceptable salt” refers to any salt of a compound herein that is known to be non-toxic and is commonly used in pharmaceutical literature. In some embodiments, a pharmaceutically acceptable salt of a compound retains the biological efficacy of the compound described herein and is not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts can be found in Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19. Pharmaceutically acceptable acid addition salts can be formed from inorganic and organic acids. Examples of inorganic acids from which salts may be derived include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts may 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 from inorganic and organic bases. Inorganic bases from which salts may be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts may 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 salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0035] If the compounds described herein are obtained as acid addition salts, the free base can be obtained by basicizing a solution of the acidic salt. Conversely, if the compound is a free base, the addition salt (in particular a pharmaceutically acceptable addition salt) can be produced by dissolving the free base in a suitable organic solvent and treating the solution with acid according to 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 the various synthetic methodologies that can be used to prepare pharmaceutically acceptable addition salts.

[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 (monohydrates, dihydrates, and hemihydrates, etc.) having any ratio of compound to water.

[0037] The term "substituted" means that the specified group or part has one or more substituents, such substituents include, but are not limited to, alkoxy, acyl, acyloxy, alkoxycarbonyl, carbonylalkoxy, acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azide, 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 does not have substituents. When the term "substituted" is used to describe a structural system, substitution means that it occurs at any position in the system where a valency is permitted. When a group or part has two or more substituents, it is understood that the substituents may be the same as or different from each other. In some embodiments, the substituted group or part has 1 to 5 substituents. In some embodiments, the substituted group or part has one substituent. In some embodiments, the substituted group or part has two substituents. In some embodiments, the substituted group or part has three substituents. In some embodiments, the substituted group or part has four substituents. In some embodiments, the substituted group or part has five substituents.

[0038] The terms "optional" or "optionally" indicate whether the event or situation described thereafter may or may not occur, and that such description includes examples in which such event or situation occurs and examples in which it does not occur. For example, "optionally substituted alkyl" includes both "alkyl" and "substituted alkyl" as defined herein. With respect to any group containing one or more substituents, it will be understood that no substitution or substitution pattern is intended to introduce such group to be sterically impractical, synthetically unfeasible, and / or inherently unstable. If a group or part is optionally substituted, it will also be understood that this disclosure includes both embodiments with the group or part substituted and embodiments with the group or part unsubstituted.

[0039] The compounds disclosed and / or described herein may be enriched isotopes, for example 2 H, 3 H, 11 C, 13 C, and / or 14The C content may be enriched. In one embodiment, the compound contains at least one deuterium atom. Such a deuterated form may be prepared by the procedures described, for example, in U.S. Patent Nos. 5,846,514 and 6,334,997. Such deuterated compounds may improve the efficacy and increase the duration of action of the 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 terms “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” encompass any and all solvents, dispersions, coatings, antimicrobial and antifungal agents, isotonic and absorption retardants, and similar substances. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional medium or agent is incompatible with the active ingredient, its use in a pharmaceutical composition is intended. Supplementary active ingredients may also be incorporated into the pharmaceutical composition.

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

[0042] The terms “patient,” “individual,” and “subject” refer to animals (mammals, birds, or fish, etc.). In some embodiments, the patient or subject is a mammal. Examples of mammals include mice, rats, dogs, cats, pigs, sheep, horses, cattle, and humans. In some embodiments, the patient, individual, or subject is a human (e.g., a human who is or would be the object of treatment, observation, or experimentation). The compounds, compositions, and methods described herein may be useful in both human therapeutic and veterinary applications.

[0043] The terms “therapeutic dose” or “effective dose” refer to the amount of a compound disclosed and / or described herein that, when administered to a patient requiring such treatment as defined herein, is sufficient to have a therapeutic effect. The therapeutic dose of a compound may be sufficient to treat a disease that responds to the modulation (e.g., inhibition) of KIF18a. The therapeutic dose varies depending, for example, the subject being treated and the state of the disease, the subject’s weight and age, the severity of the disease state, the specific compound, the dosing regimen to be followed, the timing of administration, and the mode of administration, all of which can be readily determined by those skilled in the art. The therapeutic dose can be confirmed, for example, experimentally by assay of the blood concentration of the chemical or theoretically by calculation of its bioavailability.

[0044] "Treatment" (and related terms such as "treat", "treated", "treating", etc.) includes one or more of the following: inhibition of a disease or disorder; deceleration or cessation of the onset of clinical symptoms of a disease or disorder; and / or reduction of a disease or disorder (i.e., causing relief or regression of clinical symptoms). The term covers both complete and partial reduction of a condition or disorder, as well as complete or partial reduction of the clinical symptoms of a disease or disorder. Thus, the compounds described and / or disclosed herein may prevent an existing disease or disorder from worsening, may assist in the management of a disease or disorder, or may reduce or eliminate a disease or disorder.

[0045] It is understood that embodiments described herein as "comprising" include embodiments of "consisting of" and "consisting essentially of".

[0046] II. Methods of Treating Cancer In one aspect, a method of treating cancer in a subject that needs treatment, the method 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, is provided herein. In some embodiments, the cancer is mediated by KIF18A. In some embodiments, the cancer is associated with chromosomal instability.

[0047] The inhibitory activity of compounds provided herein (e.g., compounds of formula (A), (B), (C), (A-1), (A-2), or (A-3)), or their pharmaceutically acceptable salts, stereoisomers, or tautomers described herein, or their pharmaceutical compositions or formulations, or their crystalline forms, against KIF18A may be determined and measured by methods known in the art (including, but not limited to, inhibition of ATP hydrolysis in the presence of microtubules) (Hackney DD, Jiang W. (2001) Assays for Kinesin Microtubule-Stimulated ATPase Activity. In: Vernos I. (eds) Kinesin Protocols. Methods in Molecular Biology (trademark), vol 164. Humana Press. https: / / doi.org / 10.1385 / 1-59259-069-1:65).

[0048] In one embodiment, a method for inhibiting KIF18A is provided herein, comprising contacting cells with an effective amount of a compound provided herein (e.g., compounds of formula (A), (B), (C), (A-1), (A-2), or (A-3)), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof as described herein, or a pharmaceutical composition thereof. In one variation of the above embodiment, the cells are contacted in vitro. In another variation of the above embodiment, the cells are contacted in vivo.

[0049] In some embodiments, a method is provided for treating or preventing cancer in an individual (e.g., a treatment method) comprising administering 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 described herein, or a pharmaceutical composition thereof, to an individual in need of treatment or prevention. In another embodiment, a method is provided herein for treating or preventing a disease or condition in a subject in need of treatment or prevention, 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 described herein, or a pharmaceutical composition thereof. When used in a preventative manner, the compounds provided herein (e.g., compounds of formula (A), (B), (C), (A-1), (A-2), or (A-3)), or their pharmaceutically acceptable salts, stereoisomers, or tautomers described herein, or their pharmaceutical compositions or formulations, or their crystalline forms, may prevent the development of a disease or disorder in an individual at risk of developing such a disease or disorder, or reduce the severity 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, which is selected from the group consisting of progressive solid tumors, high-grade serous adenocarcinoma of the 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 the bladder, head and neck squamous cell carcinoma, ovarian carcinosarcoma, uterine carcinosarcoma, serous carcinoma of the uterine body, and endometrial cancer. In some embodiments, the disease or condition (e.g., cancer) is accompanied by chromosomal instability.

[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 hotspots or known hypermutator phenotypes. In some embodiments, the cancer does not have 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 hotspots or known hypermutator phenotypes.

[0053] Dosage In some variations of the methods provided herein, the compounds provided herein (e.g., compounds of formula (A), (B), (C), (A-1), (A-2), or (A-3)), or their pharmaceutically acceptable salts, stereoisomers, or tautomers, or their pharmaceutical compositions, are administered in therapeutically effective doses (e.g., doses sufficient to provide treatment for a disease condition (e.g., cancer)). For the chemical entities described herein, human dose levels will need to be optimized, but generally, daily doses range from about 0.01 to 100 mg / kg body weight, in some embodiments from about 0.05 to 10.0 mg / kg body weight, and in some embodiments from about 0.10 to 1.4 mg / kg body weight. Therefore, for administration to a person weighing 70 kg, in some embodiments the dosage range would be approximately 0.7 to 7000 mg per day, in some embodiments approximately 3.5 to 700.0 mg per day, and in some embodiments approximately 7 to 100.0 mg per day. The amount of chemical entity administered will depend, for example, on the subject being treated and the disease state, the severity of the illness, the mode and schedule of administration, and the discretion of the prescribing physician. For example, an exemplary dosage range for oral administration is approximately 5 mg to approximately 500 mg per day, and an exemplary dosage for intravenous administration is approximately 5 mg to approximately 500 mg per day, each depending on the pharmacokinetics of the compound.

[0054] The administration of the compounds provided herein (e.g., compounds of formulas (A), (B), (C), (A-1), (A-2), or (A-3)), or their pharmaceutically acceptable salts, stereoisomers, or tautomers described herein, or their pharmaceutical compositions, may be via any acceptable mode of administration for the therapeutic agent, including but not limited to oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration. In some embodiments, the compounds or formulations are administered orally or intravenously. In some embodiments, the compounds or formulations described herein are administered orally.

[0055] In some embodiments, the compounds provided herein (e.g., compounds of formula (A), (B), (C), (A-1), (A-2), or (A-3)), or their pharmaceutically acceptable salts, stereoisomers, or tautomers, or their pharmaceutical compositions, are administered periodically. In some embodiments, the compounds provided herein (e.g., compounds of formula (A), (B), (C), (A-1), (A-2), or (A-3)), or their pharmaceutically acceptable salts, stereoisomers, or tautomers, or their pharmaceutical compositions, are 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, administration of the compounds provided herein (e.g., compounds of formula (A), (B), (C), (A-1), (A-2), or (A-3)), or their pharmaceutically acceptable salts, stereoisomers, or tautomers, or pharmaceutical compositions thereof) is at intervals of 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. In some embodiments, the administration of the compounds provided herein (e.g., compounds of formula (A), (B), (C), (A-1), (A-2), or (A-3)), or their pharmaceutically acceptable salts, stereoisomers, or tautomers, or their pharmaceutical compositions, is at intervals of at least 28 days. In some embodiments, the compounds provided herein (e.g., compounds of formula (A), (B), (C), (A-1), (A-2), or (A-3)), or their pharmaceutically acceptable salts, stereoisomers, or tautomers, or pharmaceutical compositions thereof, are administered in cycles of 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 compounds provided herein (e.g., compounds of formula (A), (B), (C), (A-1), (A-2), or (A-3)), or their pharmaceutically acceptable salts, stereoisomers, or tautomers, or their pharmaceutical compositions, are administered in 28-day cycles.In some embodiments, the compounds provided herein (e.g., compounds of formula (A), (B), (C), (A-1), (A-2), or (A-3)), or their pharmaceutically acceptable salts, stereoisomers, or tautomers, or pharmaceutical compositions thereof, are administered orally in 28-day cycles.

[0057] In some variations of the methods provided herein, the compounds provided herein (e.g., compounds of formula (A), (B), (C), (A-1), (A-2), or (A-3)), or their pharmaceutically acceptable salts, stereoisomers, or tautomers, or their pharmaceutical compositions, may be administered alone or in combination with other therapies and / or therapeutic agents useful in treating the aforementioned disorders (e.g., cancer or cancer associated with chromosomal instability).

[0058] III.Compound In some embodiments, all uses of the compounds described herein are provided, which encompass 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 be referred to as a drug.

[0059] In some embodiments, the method provided herein involves a therapeutically effective amount of a compound of formula (A): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof [in the formula, Ring A is C 6-14 They are aryl or 5- to 12-membered heteroaryls, each consisting of a halo, -OH, and C. 1-6 Alkyl, 3-10 member heterocycloalkyl, -NR a1 C(O)NR a2 R a3, -NR a4 C(O)OR a5 , -NR a6 R a7 -N=S(O)R a8 R a9 , -OR a10 ,-S(O)R a11 -S(O)(NR a12 )R a13 -S(O)2NR a14 R a15 -S(O)2R a16 ,-(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 , -SR a21 , -C(O)R a22 , and C 1-6 Alkyl (-OH, cyano, C) 3-10 Optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyls and 3- to 10-membered heterocycloalkyls (optionally substituted with one or more halos); R a1 ~R a22 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3-10 member heterocycloalkyl, 3-10 member heterocycloalkenyl, C 6-14 These are aryls, or 5- to 12-membered heteroaryls, each consisting of a halo, cyano, -OH, and -O(C) 1-6 Alkyl), C 2-6 Alkenil, C 3-10 Cycloalkyl, -S(C 1-6 Alkyl), =CR 1a1 R 1a2 , and C 1-6 alkyl(halo, -OH, and -O(C) 1-6 Optionally substituted with one or more substituents independently selected from the group consisting of alkyl) and R1a1 and R 1a2 Each of them independently consists of hydrogen or C 1-6 It is alkyl; Ring B is C 5-7 Cycloalkyl, C 5-7 A cycloalkenyl, or a 5- to 7-membered heterocycloalkyl, where one or two of the ring atoms are oxygen and the remaining ring atoms are carbon; m is 2; Two R's B The group is bonded to the same carbon atom on ring B, and together with the carbon atom to which they are bonded, C 3-7 Forms a cycloalkyl group; Y 1 is N or CR C1 and; Y 2 is N or CR C2 and; Y 3 is N or CR C3 and; Y 4 is N or CR C4 and; Y 1 , Y 2 , Y 3 , and Y 4 Three or fewer of these are N; R C1 ~R C4 These are, independently, hydrogen, halo, cyano, -OH, -NO2, and -C(O)NR. c1 R c2 , -NR c3 R c4 , -NR c5 S(O)2R c6 ,-P(O)R c7 R c8 -N=S(O)R c9 R c10 -S(O)(NR c11 )R c12 -S(O)2R c13 , -NR c14 C(O)OR c15 , -NR c16 S(O)2(CH2) 1-6 NR c17 C(O)Rc18 or C 1-6 alkyl (optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH); R c1 ~R c18 are each independently hydrogen, C 3-10 cycloalkyl, or C 1-6 alkyl (optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH)] administering to a subject in need thereof.

[0060] In some embodiments of formula (A) or a pharmaceutically acceptable salt thereof, ring A is C 6-14 aryl or 5- to 12-membered heteroaryl, each optionally substituted as defined above or below. In some embodiments, ring A is optionally substituted C 6-14 aryl. 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 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 halo, -OH, C 1-6 alkyl, 3- to 10-membered heterocycloalkyl, -NR a1 C(O)NR a2 Ra3 , -NR a4 C(O)OR a5 , -NR a6 R a7 -N=S(O)R a8 R a9 , -OR a10 ,-S(O)R a11 -S(O)(NR a12 )R a13 -S(O)2NR a14 R a15 -S(O)2R a16 ,-(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 , -SR a21 , -C(O)R a22 , and C 1-6 Alkyl (-OH, cyano, C) 3-10 Optionally substituted with 1, 2, 3, 4, 5, or more substituents independently selected from the group consisting of cycloalkyls and 3- to 10-membered heterocycloalkyls (optionally substituted with one or more halos). In some embodiments, R a1 ~R a22 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3-10 member heterocycloalkyl, 3-10 member heterocycloalkenyl, C 6-14 These are aryls, or 5- to 12-membered heteroaryls, each consisting of a halo, cyano, -OH, and -O(C) 1-6 Alkyl), C 2-6 Alkenil, C 3-10 Cycloalkyl, -S(C 1-6 Alkyl), =CR 1a1 R 1a2 , and C 1-6 alkyl(halo, -OH, and -O(C) 1-6R 1a1 and R 1a2 Each of them independently consists of hydrogen or C 1-6 It is alkyl.

[0062] In some embodiments, -S(O)2NR a14 R a15 teeth, [ka] [ka] In some embodiments, -S(O)2NR a14 R a15 teeth, [ka] In some embodiments, R a14 and R a15 Each of them is independently of hydrogen;C 1-6 Alkyl, C 2-6 Alkenil, C 3-10 Cycloalkyl, -OH, -O(C 1-6 Alkyl), -S(C 1-6 C 1-6 Alkyl; C 2-6 Alkenil; C 2-6 Alkenil, C 3-10 Cycloalkyl, halo, cyano, -OH, -O(C 1-6 Alkyl), =CR 1a1 R 1a2 , and C 1-6 alkyl(-OH, -O(C) 1-6R 1a1 and R 1a2 However, each independently, hydrogen or C 1-6 C is an alkyl group 3-10 Cycloalkyl; C3-10 cycloalkenyl; or 1, 2, 3, 4, 5 or more C 1-6 A 3- to 12-membered heterocycloalkyl group optionally substituted with alkyl. In some embodiments, R a14 and R a15 Each of them independently consists of hydrogen or C 1-6 It is alkyl. In some embodiments, R a14 is hydrogen, and R a15 is butyl. In some embodiments, R a15 It is tert-butyl.

[0063] In some embodiments of formula (A) or its pharmaceutically acceptable salt, ring B is C 5-7 Cycloalkyl, C 5-7 A cycloalkenyl, or a 5-7 membered heterocycloalkyl, where one or two of the ring atoms are oxygen and the remaining ring atoms are carbon. In some embodiments, ring B is C 5-7 It is cycloalkyl. In some embodiments, ring B is cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, ring B is [ka] (In the formula, * represents a bonding point to the remainder of formula (A)). In some embodiments, ring B is C 5-7 It is a cycloalkenyl. In some embodiments, ring B is cyclopentenyl, cyclohexenyl, or cycloheptenyl. In some embodiments, ring B is [ka] (In the formula, * represents a bonding point to the remainder of formula (A)). In some embodiments, ring B is [ka] (In the formula, * represents a bond site to the remainder of formula (A)). In some embodiments, ring B is a 5- to 7-membered heterocycloalkyl. In some embodiments, ring B is a 5- to 7-membered heterocycloalkyl, where one or two of the ring atoms are oxygen and the remaining ring atoms are carbon. In some embodiments, ring B is tetrahydrofuranyl or 1,3-dioxanyl. In some embodiments, ring B is [ka] (In the equation, * represents a connection point to the remainder of equation (A)).

[0064] In some embodiments, ring B has two R B Substituted by the group, two R B The group is bonded to the same carbon atom on ring B, and together with the carbon atom to which they are bonded, C 3-7 Forms a cycloalkyl group. In some embodiments, two R B The group is bonded to the same carbon atom on ring B, and together with the carbon atom to which it is bonded, they form a cyclopropyl group.

[0065] In some embodiments, formula (A) [ka] teeth, [ka] (In the equation, * represents a connection point to the remainder of equation (A)).

[0066] In some embodiments of formula (A) or its pharmaceutically acceptable salt, Y 1 is N or CR C1 Y 2 is N or CR C2 Y 3 is N or CR C3 Y 4 is N or CR C4 In some embodiments, Y 1 , Y 2 , Y 3 , and Y 4 Three or fewer of these are N. In some embodiments, Y 1 , Y 2 , Y 3 , and Y 4 Two or fewer of these are N. In some embodiments, Y 1 , Y 2 , Y 3 , and Y 4 One or less of these is N. In some embodiments, Y 1 CR C1 Y 2 CR C2 Y 3 CR C3 Y 4 CR C4 That is the case.

[0067] In some embodiments, R C1 ~R C4 These are, independently, hydrogen, halo, cyano, -OH, -NO2, and -C(O)NR. c1 R c2 , -NR c3 R c4 , -NR c5 S(O)2R c6 ,-P(O)R c7 R c8 -N=S(O)R c9 R c10 -S(O)(NR c11 )R c12 -S(O)2R c13 , -NR c14 C(O)OR c15 , or C1-6 It is an alkyl group (optionally substituted with substituents 1, 2, 3, 4, 5, or more, independently selected from the group consisting of halo and -OH). In some embodiments, R c1 ~R c15 These are, independently, hydrogen and C 3-10 Cycloalkyl, or C 1-6 It is an alkyl group (optionally substituted with substituents 1, 2, 3, 4, 5, or more, independently selected from the group consisting of halo and -OH).

[0068] In some embodiments, R C1 , R C3 , and R C4 Each of them is hydrogen, and R C2 cyano, -OH, -CH2OH, bromo, -NO2, [ka] In some embodiments, R C1 , R C3 , and R C4 Each of them is hydrogen, and R C2 teeth, [ka] That is the case.

[0069] In one embodiment, the compound of formula (A) is the compound of formula (B): [ka] or a pharmaceutically acceptable salt thereof (wherein R a14 , R a15 , ring B, R B , m, and R C2 (This is defined for formula (A) or any variation or embodiment thereof). In some embodiments, R C2 These are halo, cyano, -OH, -NO2, and -C(O)NR. c1 R c2 , -NR c3 R c4, -NR c5 S(O)2R c6 ,-P(O)R c7 R c8 -N=S(O)R c9 R c10 -S(O)(NR c11 )R c12 -S(O)2R c13 , -NR c14 C(O)OR c15 , -NR c16 S(O)2(CH2) 1-6 NR c17 C(O)R c18 , or C 1-6 It is alkyl (optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH). In some embodiments, R C2 These are halo, cyano, -OH, -NO2, and -C(O)NR. c1 R c2 , -NR c3 R c4 , -NR c5 S(O)2R c6 ,-P(O)R c7 R c8 -N=S(O)R c9 R c10 -S(O)(NR c11 )R c12 -S(O)2R c13 , or C 1-6 It is alkyl (optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH). In some embodiments, R C2 -NR c5 S(O)2R c6 In some embodiments, R c5 is hydrogen, and R c6 C 1-6 It is alkyl. In some embodiments, R c5 is hydrogen, and R c6 is ethyl. In some embodiments, R c5 is hydrogen. In some embodiments, R c6 is ethyl. In some embodiments, R c6is methyl. In some embodiments, R a14 is hydrogen, and R a15 C 1-6 It is alkyl. In some embodiments, R a14 is hydrogen, and R a15 is tert-butyl. In some embodiments, R a14 is hydrogen. In some embodiments, R a15 is tert-butyl. In some embodiments, ring B is [ka] (In the formula, * represents a connection point to the remainder of formula (B)). In some embodiments, formula (B) [ka] teeth, [ka] That is the case.

[0070] In one embodiment, the compound of formula (A) is the compound of formula (C): [ka] or a pharmaceutically acceptable salt thereof (wherein R a14 , R a15 , and R c6 (This is as defined for formula (A) or any variation or embodiment thereof). In some embodiments, R a14 is hydrogen, and R a15 C 1-6 It is alkyl. In some embodiments, R a14 is hydrogen, and R a15 is tert-butyl. In some embodiments, R a14 is hydrogen. In some embodiments, R a15 is tert-butyl. In some embodiments, R a14 and Ra15 Each of them is independent of C 3-10 Cycloalkyl, C 3-10 The cycloalkenyl, a 3-10 membered heterocycloalkyl, or a 3-10 membered heterocycloalkenyl. In some embodiments, R a14 and R a15 These, together with the N atom to which they are bonded, form a 3- to 10-membered heterocycloalkyl group. In some embodiments, R c6 C is optionally replaced by one or more halos. 1-6 It is alkyl. In some embodiments, R c6 is unsubstituted C 1-6 It is alkyl. In some embodiments, R c6 is ethyl. In some embodiments, R c6 It is methyl.

[0071] In one embodiment, the compound of formula (A) is the compound of formula (A-1): [ka] That is the case.

[0072] In one embodiment, the compound of formula (A) is the compound of formula (A-2): [ka] That is the case.

[0073] In one embodiment, the compound of formula (A) is the compound of formula (A-3): [ka] That is the case.

[0074] In some variations, the compounds described herein (such as compounds of formulas (A), (B), (C), (A-1), (A-2), or (A-3)), or any of their variations, can be deuterated (for example, a hydrogen atom is replaced by deuterium). 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 that of preparations of the corresponding non-deuterated compounds. Hydrogen atoms can also be replaced by deuterium atoms using other methods known in the art.

[0075] Any formula given herein (e.g., formulas (A), (B), (C), (A-1), (A-2), or (A-3)) is intended to represent compounds having the structure illustrated by the structural formula, and specific variations or forms. In particular, any compound of any formula given herein has a chiral center and therefore may exist in different enantiomer or diastereomer forms. All optical and stereoisomers of a compound of a general formula, as well as mixtures thereof in any ratio, are considered to be within the range of the formula. Therefore, any formula given herein is intended to represent racemates, one or more enantiomers, one or more diastereomers, one or more atropisomers, and mixtures thereof in any ratio. Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers), tautomers, or atropisomers. In addition, any formula given herein is intended to refer to any one of the hydrates, solvates, amorphous and polymorphs of such compounds, as well as mixtures thereof, even if such forms are not explicitly listed. In some embodiments, the solvent is water and the solvate is the hydrate.

[0076] In one embodiment, it is understood that any of the compounds may be used in the methods detailed herein and, where applicable, may include an intermediate compound that can be isolated and administered to an organism.

[0077] The compounds shown herein may exist as salts even if salts are not indicated, and the compositions and methods provided herein are understood to encompass all salts and solvates of the compounds shown herein, as well as the unsalted and unsolvated forms of the compounds, as will be well understood by those skilled in the art. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts.

[0078] In one variation, the compounds described herein are synthetic compounds prepared for administration to an individual. In another variation, a composition containing the compound in a substantially pure form is provided. In yet another variation, a pharmaceutical composition comprising the compound detailed herein and a pharmaceutically acceptable carrier is provided. In yet another variation, a method for administering the compound is provided. The purified form, pharmaceutical composition, and method for administering the compound are suitable for any compound or form detailed herein.

[0079] Rings A, B, C, and R provided herein a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 , R a8 , R a9 , R a10 , R a11 , R a12 , R a13 , R a14 , R a15 , R a16 , R a17 , R a18 , R a19 , R a20 , R a21 , R a22 , R a23 , Ra24 , R a25 , R a26 , R a27 , R a28 , R a29 , R a30 , R a31 , R a32 , R a33 , R a34 , R a35 , R a36 , R a37 , R a38 , R a39 , R a40 , R 1a1 , R 1a2 , R 1a3 , R 1a4 , R B , m, X, Y 1 , Y 2 , Y 3 , Y 4 Z1, Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , R C1 , R C2 , R C3 , R C4 , R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , R c8 , R c9 , R c10 , R c11 , R c12 , R c13 , R c14 , R c15 , R c16 , R c17 , R c18 , R c19 , R D , R E , or R F Any variation or embodiment of the is ring A, ring B, ring C, R a1 , R a2 , R a3 , R a4 , R a5 , Ra6 、R a7 、R a8 、R a9 、R a10 、R a11 、R a12 、R a13 、R a14 、R a15 、R a16 、R a17 、R a18 、R a19 、R a20 、R a21 、R a22 、R a23 、R a24 、R a25 、R a26 、R a27 、R a28 、R a29 、R a30 、R a31 、R a32 、R a33 、R a34 、R a35 、R a36 、R a37 、R a38 、R a39 、R a40 、R 1a1 、R 1a2 、R 1a3 、R 1a4 、R B 、m、X、Y 1 、Y 2 、Y 3 、Y 4 、Z1、Z 2 、Z 3 、Z 4 、Z 5 、Z 6 、Z 7 、Z 8 、R C1 、R C2 、R C3 、R C4 、R c1 、R c2 、R c3 、R c4 、R c5 、R c6 、R c7 、R c8 、R c9 、R c10 、R c11 、Rc12 , R c13 , R c14 , R c15 , R c16 , R c17 , R c18 , R c19 , R D , R E , or R F It can be combined with all other variations or embodiments, as if each and every combination were described individually and specifically.

[0080] In this specification, if any variable appears more than once in a chemical formula, the definition for each appearance is independent of the definition for all other appearances.

[0081] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof may be synthesized by the method described in International Publication No. 2023 / 028564 (the contents thereof are incorporated herein by reference in their entirety). In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are potent inhibitors of KIF18A and have a small off rate or a very long dissociation half-life (ln(2) / k オフ This can achieve sub-nanomolar efficacy, potently induce cytotoxicity in KIF18a-sensitive cancer cell lines, and reduce tumor volume in mice. The KIF18A inhibitory efficacy, KIF18A binding kinetics, and in vivo activity of the compounds described herein or their pharmaceutically acceptable salts are disclosed in International Publication No. 2023 / 028564, which is incorporated herein by reference in its entirety. In some embodiments, the formulations, salts, or crystalline forms described herein may be prepared by the methods described in PCT / US2024 / 016952, which is incorporated herein by reference in its entirety.

[0082] In one embodiment, a crystalline form of the compound of formula (A-1) or a pharmaceutically acceptable salt thereof is provided herein.

[0083] In some embodiments, the crystalline morphology is characterized by having an XRPD pattern that includes peaks at 2θ angles 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 morphology is characterized by having an XRPD pattern that includes additional peaks at 2θ angles of 15.46±0.20 and 17.29±0.20 degrees. In some embodiments, the crystalline morphology is characterized by having an XRPD pattern that includes additional peaks at 2θ angles of 8.61±0.20 and 15.04±0.20 degrees.

[0084] In some embodiments, the crystalline morphology is characterized by having an endothermic onset at 188±2°C when determined by DSC. In some embodiments, the crystalline morphology is characterized by having an endothermic peak at 194±2°C when determined by DSC. In some embodiments, the crystalline morphology is characterized by having a weight loss of 0.01±0.005% at 52-150°C when determined by TGA. In some embodiments, the crystalline morphology is characterized by having a clear decomposition at 316±5°C when determined by TGA. In some embodiments, the crystalline morphology is characterized by having a weight increase of 0.095±0.005% at 5%RH-95%RH when determined by DVS. In some embodiments, the crystalline morphology is characterized by having a weight loss of 0.097±0.005% at 95%RH-5%RH when determined by DVS.

[0085] In some embodiments, the crystalline morphology is characterized by having an XRPD pattern that includes peaks at 2θ angles 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 morphology is characterized by having an XRPD pattern that includes additional peaks at 2θ angles of 17.50±0.20 and 21.13±0.20 degrees. In some embodiments, the crystalline morphology is characterized by having an XRPD pattern that includes additional peaks at 2θ angles of 8.23±0.20 and 11.72±0.20 degrees. In some embodiments, the crystalline morphology is characterized by having an endothermic onset at 196±2°C when determined by DSC. In some embodiments, the crystalline morphology is characterized by having an endothermic peak at 197±2°C when determined by DSC. In some embodiments, the crystalline morphology is characterized by having a weight loss of 0.05 ± 0.01% at 25–100°C, as determined by TGA. In some embodiments, the crystalline morphology is characterized by having a weight loss of 0.10 ± 0.05% at 100–180°C, as determined by TGA. In some embodiments, the crystalline morphology is characterized by having a weight gain of 0.030% ± 0.005% at 0.1%RH–95%RH, as determined by DVS. In some embodiments, the crystalline morphology is characterized by having a weight loss of 0.050% ± 0.005% at 95%RH–0.1%RH, as determined by DVS.

[0086] In some embodiments, the crystalline form includes the compound of formula (A-1).

[0087] In some embodiments, the crystalline form comprises the monosodium salt of the compound of formula (A-1).

[0088] In some embodiments, the crystalline form containing the monosodium salt of the compound of formula (A-1) is characterized by having an XRPD pattern including peaks at 2θ angles of 7.66±0.20, 8.45±0.20, 11.64±0.20, 17.92±0.20, and 22.82±0.20 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern including additional peaks at 2θ angles of 16.91±0.20 and 17.13±0.20 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern including additional peaks at 2θ angles of 13.60±0.20 and 18.34±0.20 degrees. In some embodiments, the crystalline form is characterized by having an endothermic onset at 186±2°C when determined by DSC. In some embodiments, the crystalline form is characterized by having an endothermic peak at 190±2°C when 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, when determined by TGA.

[0089] In some embodiments, the crystalline form containing the monosodium salt of the compound of formula (A-1) is characterized by having an XRPD pattern including peaks at 2θ angles 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 including additional peaks at 2θ angles of 18.61±0.20 and 27.38±0.20 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern including additional peaks at 2θ angles of 16.87±0.20 and 21.64±0.20 degrees. In some embodiments, the crystalline form is characterized by having an endothermic peak at 166±2°C when determined by DSC. In some embodiments, the crystalline form is characterized by having an endothermic peak at 192±2°C when determined by DSC. In some embodiments, the crystalline morphology is characterized by having an endothermic peak at 208±2°C when determined by DSC. In some embodiments, the crystalline morphology is characterized by having a weight loss of 0.3%±0.1% between 25°C and 80°C when determined by TGA. In some embodiments, the crystalline morphology is characterized by having a weight loss of 7.3%±0.1% between 80°C and 190°C when determined by TGA.

[0090] In some embodiments, the crystalline form containing the monosodium salt of the compound of formula (A-1) is characterized by having an XRPD pattern with peaks at 2θ angles 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 with additional peaks at 2θ angles of 18.51±0.20 and 20.95±0.20 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern with additional peaks at 2θ angles of 16.64±0.20 and 24.73±0.20 degrees. In some embodiments, the crystalline form is characterized by having an endothermic peak at 183±2°C when determined by DSC. In some embodiments, the crystalline form is characterized by having a weight loss of 0.7%±0.1% between 30°C and 120°C when determined by TGA. In some embodiments, the crystalline morphology is characterized by having a weight loss of 8.0% ± 0.1% at 120°C to 180°C, when determined by TGA. In some embodiments, the crystalline morphology is characterized by having a weight loss of 4.2% ± 0.1% at 180°C to 230°C, when determined by TGA.

[0091] In some embodiments, the crystalline form comprises the disodium salt of the compound of formula (A-1).

[0092] In some embodiments, the crystalline form containing the disodium salt of the compound of formula (A-1) is characterized by having an XRPD pattern including peaks at 2θ angles 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 including additional peaks at 2θ angles of 12.50±0.20 and 16.52±0.20 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern including additional peaks at 2θ angles of 13.48±0.20 and 14.34±0.20 degrees. In some embodiments, the crystalline form is characterized by having an endothermic peak at 60±2°C when determined by DSC. In some embodiments, the crystalline form is characterized by having an endothermic peak at 212±2°C when determined by DSC. In some embodiments, the crystalline morphology is characterized by having a weight loss of 3.3% ± 0.5% between 25°C and 48°C, when determined by TGA. In some embodiments, the crystalline morphology is characterized by having a weight loss of 2.1% ± 0.5% between 48°C and 100°C, when determined by TGA.

[0093] In some embodiments, the crystalline form containing the disodium salt of the compound of formula (A-1) is characterized by having an XRPD pattern including peaks at 2θ angles 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 including additional peaks at 2θ angles of 9.28±0.50 and 10.47±0.50 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern including additional peaks at 2θ angles 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% at 25°C to 140°C when determined by TGA.

[0094] In some embodiments, the crystalline form containing the disodium salt of the compound of formula (A-1) is characterized by having an XRPD pattern with peaks at 6.03±0.20, 7.66±0.20, 12.04±0.20, and 18.73±0.20 degrees at 2θ angles. In some embodiments, the crystalline form is characterized by having an XRPD pattern with additional peaks at 12.93±0.20 and 18.97±0.20 degrees at 2θ angles. In some embodiments, the crystalline form is characterized by having an XRPD pattern with additional peaks at 19.91±0.20 and 24.62±0.20 degrees at 2θ angles. In some embodiments, the crystalline form is characterized by having an endothermic peak at 52±2°C when determined by DSC. In some embodiments, the crystalline form is characterized by having an endothermic peak at 84±2°C when determined by DSC. In some embodiments, the crystalline morphology is characterized by having an endothermic peak at 104±2°C when determined by DSC. In some embodiments, the crystalline morphology is characterized by having an endothermic peak at 128±2°C when determined by DSC. In some embodiments, the crystalline morphology is characterized by having a weight loss of 11.9%±3.0% between 30°C and 110°C when determined by TGA.

[0095] In some embodiments, the crystalline form comprising the disodium salt of the compound of formula (A-1) is characterized by having an XRPD pattern including peaks at 2θ angles 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 including additional peaks at 2θ angles of 18.10±0.20 and 20.47±0.20 degrees. The crystalline form according to claim 138 or 139 is characterized by having an XRPD pattern including additional peaks at 2θ angles of 7.70±0.20 and 13.63±0.20 degrees. In some embodiments, the crystalline form is characterized by having an endothermic peak at 73±2°C when determined by DSC. In some embodiments, the crystalline morphology is characterized by having an endothermic peak at 99±2°C when determined by DSC. In some embodiments, the crystalline morphology is characterized by having an endothermic peak at 120±2°C when determined by DSC. In some embodiments, the crystalline morphology is characterized by having a weight loss of 0.6%±0.5% between 30°C and 48°C when determined by TGA. In some embodiments, the crystalline morphology is characterized by having a weight loss of 4.1%±0.5% between 48°C and 81°C when determined by TGA. In some embodiments, the crystalline morphology is characterized by having a weight loss of 2.7%±0.5% between 81°C and 140°C when determined by TGA. In some embodiments, the crystalline morphology is characterized by having a weight gain of 60%±5% between 1%RH and 95%RH when determined by DVS. In some embodiments, the crystalline form is characterized by having a weight loss of 58% ± 5% at 95% RH to 1% RH, as determined by DVS.

[0096] In some embodiments, the crystalline form containing the disodium salt of the compound of formula (A-1) is characterized by having an XRPD pattern including peaks at 2θ angles 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 including additional peaks at 2θ angles of 13.86±0.50 and 17.26±0.50 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern including additional peaks at 2θ angles 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% at 25°C to 64°C when determined by TGA. In some embodiments, the crystalline morphology is characterized by having a weight loss of 2.4% ± 0.1% at 65°C to 100°C, when determined by TGA. In some embodiments, the crystalline morphology is characterized by having a weight loss of 0.9% ± 0.1% at 100°C to 140°C, when determined by TGA.

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

[0098] In some embodiments, the crystalline form containing the monopotassium salt of the compound of formula (A-1) is characterized by having an XRPD pattern including peaks at 2θ angles 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 including additional peaks at 2θ angles of 12.25±0.20 and 19.69±0.20 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern including additional peaks at 2θ angles of 11.21±0.20 and 24.83±0.20 degrees. In some embodiments, the crystalline form is characterized by having an endothermic peak at 39±5°C when determined by DSC. In some embodiments, the crystalline form is characterized by having an endothermic peak at 156±5°C when determined by DSC. In some embodiments, the crystalline morphology is characterized by having a weight loss of 3.2% ± 0.1% between 25°C and 100°C, when determined by TGA.

[0099] In some embodiments, the crystalline form comprises the dipotassium salt of the compound of formula (A-1).

[0100] In some embodiments, the crystalline form containing the dipotassium salt of the compound of formula (A-1) is characterized by having an XRPD pattern including peaks at 2θ angles 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 including additional peaks at 2θ angles of 15.56±0.50 and 19.02±0.50 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern including additional peaks at 2θ angles of 13.56±0.50 and 25.27±0.50 degrees. In some embodiments, the crystalline form is characterized by having an endothermic peak at 70±10°C when determined by DSC. In some embodiments, the crystalline form is characterized by having a substantially continuous weight loss from 25°C to 300°C when determined by TGA.

[0101] In some embodiments, the crystalline form containing the dipotassium salt of the compound of formula (A-1) is characterized by having an XRPD pattern with peaks at 2θ angles 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 with additional peaks at 2θ angles of 13.12±0.20 and 19.99±0.20 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern with additional peaks at 2θ angles of 18.82±0.20 and 22.76±0.20 degrees. In some embodiments, the crystalline form is characterized by having an endothermic peak at 83±2°C when 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 when determined by TGA. In some embodiments, the crystalline morphology is characterized by having a weight loss of 2.7% ± 0.1% at 40°C to 75°C, when determined by TGA. In some embodiments, the crystalline morphology is characterized by having a weight loss of 3.1% ± 0.1% at 75°C to 170°C, when determined by TGA.

[0102] In some embodiments, the crystalline form containing the dipotassium salt of the compound of formula (A-1) is characterized by having an XRPD pattern including peaks at 2θ angles 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 including additional peaks at 2θ angles of 20.00±0.20 and 22.78±0.20 degrees. In some embodiments, the crystalline form is characterized by having an XRPD pattern including additional peaks at 2θ angles of 13.13±0.20 and 18.82±0.20 degrees. In some embodiments, the crystalline form is characterized by having an endothermic peak at 86±2°C when determined by DSC. In some embodiments, the crystalline morphology is characterized by having a weight loss of 0.7% or 0.7% ± 0.1% at 25°C to 42°C, as determined by TGA. In some embodiments, the crystalline morphology is characterized by having a weight loss of 6.0% ± 0.1% at 42°C to 94°C, as determined by TGA. In some embodiments, the crystalline morphology is characterized by having a weight gain of 62% ± 5% at 1%RH to 95%RH, as determined by DVS. In some embodiments, the crystalline morphology is characterized by having a weight loss of 70% ± 5% at 95%RH to 1%RH, as determined by DVS.

[0103] IV. Composition In some embodiments, the methods provided herein involve administering a therapeutically effective amount of a pharmaceutical composition containing a compound of formula (A) or any of its subgenuses or pharmaceutically acceptable salts thereof as described herein to a subject in need of treatment. In some embodiments, the pharmaceutical composition includes one or more additional agents, pharmaceuticals, adjuvants, carriers, excipients, and the like. Suitable medical and pharmaceutical agents are 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 saccharin, talc, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, and magnesium carbonate.

[0104] Pharmaceutically acceptable compositions include solid, semi-solid, liquid, and aerosol dosage forms (such as tablets, capsules, powders, liquids, suspensions, suppositories, and aerosols). Compounds disclosed and / or described herein may also be administered in sustained-release or controlled-release dosage forms (e.g., controlled / sustained-release pills, depot injections, osmotic pumps, or transdermal (including electrical transport) patches) for long-term timed administration and / or pulsed administration at a predetermined rate. In some embodiments, compositions are provided in unit dosage forms suitable for single doses of precise amounts.

[0105] The compounds disclosed and / or described herein may be administered alone or in combination with one or more conventional pharmaceutical carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, magnesium carbonate). If desired, pharmaceutical compositions may also contain small amounts of non-toxic auxiliary substances (humectants, emulsifiers, solubilizers, pH buffers, and similar substances (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate), etc.). Generally, depending on the intended mode of administration, pharmaceutical compositions will contain the compounds disclosed and / or described herein in an amount of about 0.005% to 95% or about 0.5% to 50% by weight. Practical methods for preparing such drug formulations are publicly known or obvious to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

[0106] In some embodiments, the compositions take the form of pills or tablets, and therefore the compositions may contain, together with the compounds disclosed and / or described herein, one or more of the following: diluents (e.g., lactose, sucrose, dicalcium phosphate), lubricants (e.g., magnesium stearate), and / or binders (e.g., starch, acacia gum, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives). Other solid dosage forms include powders encapsulated in gelatin capsules, marumes, solutions, or suspensions (e.g., in propylene carbonate, vegetable oil, or triglycerides).

[0107] Pharmaceutically administerable liquid compositions may be prepared by dissolving, dispersing, or suspending, for example, the compounds disclosed and / or described herein, as well as optional pharmaceutical additives, in a carrier (e.g., water, saline solution, aqueous dextrose, glycerol, glycol, ethanol, or similar) to form a solution or suspension. Injectables may be prepared in conventional forms, as a liquid solution or suspension, as an emulsion, or in a solid form suitable for dissolution or suspension in liquid before injection. The percentage of compounds contained in such parenteral compositions depends, for example, the physical properties of the compounds, the activity of the compounds, and the needs of the target. However, percentages of active ingredients between 0.01% and 10% are employable in solution, and may be higher if the composition is solid and subsequently diluted to other concentrations. In some embodiments, the composition will contain about 0.2% to 2% of the compounds disclosed and / or described herein in solution.

[0108] The pharmaceutical compositions of the compounds disclosed and / or described herein may also be administered to the airways, alone or in combination with an inert carrier (such as lactose), as an aerosol or solution for nebulizers, or as an ultrafine powder for inhalation. In such cases, the particles of the pharmaceutical composition may have a diameter of less than 50 microns, or in some embodiments, less than 10 microns.

[0109] In addition, the pharmaceutical composition may include the compounds disclosed and / or described herein, as well as one or more additional medicinal agents, pharmaceuticals, adjuvants, and similars. Preferred medicinal agents and pharmaceuticals include those described herein.

[0110] In some embodiments, the methods provided herein involve administering a therapeutically effective amount of a pharmaceutically acceptable composition containing a compound of formula (A), (B), (C), (A-1), (A-2), or (A-3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, to a subject in need of treatment. In some embodiments, the composition may contain synthetic intermediates that can be used in the preparation of the compounds described herein. The compositions described herein may also contain other suitable activators or deactivators.

[0111] Any of the compositions described herein may be sterilized or may contain sterilized components. Sterilization may be achieved by methods known in the art. Any of the compositions described herein may contain one or more substantially pure compounds.

[0112] In some embodiments, the pharmaceutical composition is packaged, and the package includes the pharmaceutical composition 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, pharmaceutically acceptable polymers include hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose (HPMC), or methacrylate-ethyl acrylate copolymers, or any combination thereof. In some embodiments, pharmaceutically acceptable polymers include HPMCAS. In some embodiments, HPMCAS is HPMCASM. In some embodiments, pharmaceutically acceptable polymers include HPMCP. In some embodiments, HPMCP is HPMCP-HP55. In some embodiments, pharmaceutically acceptable polymers include HPMC. In some embodiments, HPMC is HPMC E3LV. In some embodiments, pharmaceutically acceptable polymers include methacrylate-ethyl acrylate copolymers. In some embodiments, the methacrylate-ethyl acrylate copolymer is methacrylate-ethyl acrylate copolymer (1:1).

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

[0116] In some embodiments, the formulation contains the compound of formula (A) or a pharmaceutically acceptable salt thereof and methacrylate-ethyl acrylate copolymer (1:1) in a weight ratio of about 40:60. In some embodiments, the formulation contains the compound of formula (A) or a pharmaceutically acceptable salt thereof and methacrylate-ethyl acrylate copolymer (1:1) in a weight ratio of about 50:50. In some embodiments, the formulation contains the compound of formula (A) or a pharmaceutically acceptable salt thereof and methacrylate-ethyl acrylate copolymer (1:1) in a weight ratio of about 60:40. In some embodiments, the formulation contains the compound of formula (A) or a pharmaceutically acceptable salt thereof and methacrylate-ethyl acrylate copolymer (1:1) in a weight ratio of about 70:30. In some embodiments, the formulation contains the compound of formula (A) or a pharmaceutically acceptable salt thereof and HPMCAS in a weight ratio of about 25:75. In some embodiments, the formulation contains the compound of formula (A) or a pharmaceutically acceptable salt thereof and HPMCAS in a weight ratio of about 40:60. In some embodiments, the formulation contains the compound of formula (A) or a pharmaceutically acceptable salt thereof and HPMCAS in a weight ratio of about 50:50. In some embodiments, the formulation contains the compound of formula (A) or a pharmaceutically acceptable salt thereof and HPMCAS in a weight ratio of about 60:40. In some embodiments, the formulation contains the compound of formula (A) or a 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, two R B The group is bonded to the same carbon atom on ring B, and together with the carbon atom to which they are bonded, they form a cyclopropyl group. In some embodiments, ring A is one -S(O)2NR a14 R a15 C substituted with a group 6-14 It is Y. In some embodiments, 2 CR C2 And CR C2 -NR c5 S(O)2R c6In some embodiments, ring A is one -S(O)2NR a14 R a15 C substituted with a group 6-14 It is aryl, Y 2 CR C2 And CR C2 -NR c5 S(O)2R c6 In some embodiments, ring A is one -S(O)2NR a14 R a15 group (in the formula, R a14 H is R a15 is C 1-6 C substituted with alkyl 6-14 It is Ariel. Y 2 CR C2 And CR C2 -NR c5 S(O)2R c6 (In the formula, R c6 C is optionally substituted with one -OH group. 1-6 It is alkyl.

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

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

[0120] In one embodiment, a solid formulation or composition comprising a compound of formula (A) is provided.

[0121] In some embodiments, the formulation measures the area under the plasma concentration-time curve (AUC) of the compound of formula (A) in human subjects approximately 0 to 24 hours after administration of the formulation to the subject. 0-24 This is effective in achieving approximately 10 μmol·h / mL to approximately 100 μmol·h / mL.

[0122] In some embodiments, the compound of formula (A) or a pharmaceutically acceptable salt thereof is the compound of formula (A-1) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (A) or a pharmaceutically acceptable salt thereof is the 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 the 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.

[0124] V. Kit Products and kits are also provided that contain any of the compounds provided herein (e.g., compounds of formulas (A), (B), (C), (A-1), (A-2), or (A-3)), or their pharmaceutically acceptable salts, stereoisomers, or tautomers described herein, or their pharmaceutical compositions or formulations, or their crystalline forms. Products may include labeled containers. Suitable containers include, for example, bottles, vials, and test tubes. Containers may be formed from a variety of materials (e.g., glass or plastic). Containers may hold the pharmaceutical compositions provided herein. Labels on the containers may indicate that the pharmaceutical compositions may be used to prevent, treat, or suppress the conditions described herein, and may also indicate instructions for in vivo or in vitro use.

[0125] In one embodiment, a kit is provided herein 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 as described herein, or a pharmaceutical composition thereof, and instructions for use. The kit may contain instructions for use in the treatment of any disease or condition described herein in an individual requiring treatment. The kit may additionally contain any materials or equipment (such as vials, syringes, or intravenous bags) that can be used in administering the compound or composition. The kit may also contain sterile packaging. [Examples]

[0126] Example 1. Phase I / II study of compound (A-1) in patients with advanced cancer. A Phase I / II trial of compound (A-1) will be conducted to assess the safety, tolerability, and preliminary efficacy of compound (A-1) as monotherapy, and will consist of two parts: dose escalation and dose expansion. Dose escalation will examine the safety and tolerability of compound (A-1) in different solid tumor types at various dose levels through one series of dose escalation cohorts and backfill cohorts to identify the maximum tolerable dose (MTD) and select dose levels for dose expansion. Criteria for dose (decrease) escalation will be based on a Bayesian optimal interval (BOIN) design. Dose expansion will examine the safety, tolerability, drug interaction (DDI) risk, food effect (FE), and preliminary efficacy of compound (A-1) at different tumor types and / or dose levels of interest through various expansion cohorts. Compound (A-1) will be administered orally in 28-day cycles. Continue administering the medication until disease progression, unacceptable toxicity occurs, consent is withdrawn, or other criteria for discontinuation are met.

[0127] The conditions investigated under this study include advanced solid tumors, high-grade serous adenocarcinoma of the 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 the bladder, head and neck squamous cell carcinoma, ovarian carcinosarcoma, uterine carcinosarcoma, serous carcinoma of the uterine body, endometrial cancer, and chromosomal instability.

[0128] The study will include multiple groups, each receiving orally administered the compound in the form of a tablet of formula (A-1). The groups will include: (i) a dose-escalation cohort, enrolling subjects in various doses and / or schedules of the compound in formula (A-1). These dose-escalation cohorts will be used to identify the MTD and select dose levels for dose expansion. (ii) a backfill cohort.

[0129] Additional subjects may be enrolled at any dose level that does not meet the tapering or exclusion rules for the BOIN design. These backfill cohorts will be used to build additional data to support dose and / or tumor type selection for further trials in dose expansion. (iii) Exploratory cohort. Subjects of a selected single tumor type are randomized 1:1 to an exploratory cohort at two or more dose levels of interest. A subset of subjects may undergo additional assessments to examine the potential interactions of the compound of formula (A-1) with other drugs and the effect of food on the absorption of the compound of formula (A-1). and (iv) Development cohort. Subjects of other tumor types are enrolled at single dose levels of interest. These development cohorts will be used to examine the preliminary efficacy of the compound of formula (A-1) in various tumor types.

[0130] Several primary outcome measures will be recorded over the trial period, with a timeframe of up to 12 months. The primary outcome measures include: (1) Dose escalation: Incidence of dose-limiting toxicity (DLT) in DLT-evaluable subjects; (2) Dose escalation: Determination of the MTD of the compound according to 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 according to the NCI-CTCAE version 5.0; (5) Dose escalation: Frequency of treatment-induced AEs (TEAEs) graded according to the NCI-CTCAE version 5.0; (6) Dose escalation: Frequency of dose interruption and permanent treatment interruption; (7) Dose expansion: Frequency of trigger events (TEs); and (8) Dose expansion: Objective response rate (ORR) assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. For the primary outcome measure (8), the time frame is a maximum of 18 months.

[0131] Several secondary outcome measures will also be recorded during the trial. The secondary outcome measures and the time frame for each secondary outcome measure are as follows: (1) Dose escalation: ORR assessed by RECIST version 1.1 over a maximum 12-month time frame; (2) Dose expansion: Frequency of SAEs graded according to NCI-CTCAE version 5.0 over a maximum 18-month time frame; (3) Dose expansion: Frequency of treatment-related AEs graded according to NCI-CTCAE version 5.0 over a maximum 18-month time frame; (4) Dose expansion: Frequency of TEAEs graded according to NCI-CTCAE version 5.0 over a maximum 18-month time frame; (5) Dose expansion: Frequency of dose interruption and permanent treatment interruption over a maximum 18-month time frame; (6) Dose expansion: Area under the plasma concentration-time curve (AUC) of midazolam and its metabolite 1'-hydroxymidazolam over a maximum 18-month time frame; (7) Dose expansion: Maximum plasma concentration (C) of midazolam and its metabolite 1'-hydroxymidazolam over a maximum 18-month time frame max(8) Dose escalation: Evaluation of CA-125 response according to Gynecologic Cancer Inter Group (GCIG) criteria (high-grade serous ovarian cancer only) within a time frame of up to 18 months; (9) Dose escalation and dose expansion: Duration of response (DOR) assessed by RECIST version 1.1 within a time frame of up to 32 months; (10) Dose escalation and dose expansion: Disease control rate (DCR) assessed by RECIST version 1.1 within a time frame of up to 32 months; (11) Dose escalation and dose expansion: Progression-free survival (PFS) assessed by RECIST version 1.1 within a time frame of up to 32 months; (12) Dose escalation and dose expansion: C of compound (A-1) within a time frame of up to 32 months max (13) Dose escalation and dose expansion: AUC of the compound of formula (A-1) over a time frame of up to 32 months; (14) Dose escalation and dose expansion: Trough concentration (C) of the compound of formula (A-1) over a time frame of up to 32 months trough (15) Dose escalation and dose expansion: Time to reach maximum plasma concentration of compound (A-1) within a time frame of up to 32 months (t max (16) The ratio of total cholesterol to 4β-hydroxycholesterol in plasma over a maximum 32-month timeframe; (17) The increase in the number of phosphorylated histone 3-positive tumor cells over a maximum 32-month timeframe; (18) The frequency of micronucleated reticulocytes in the blood over a maximum 32-month timeframe; and (19) The increase in micronuclei in circulating tumor cells over a maximum 32-month timeframe.

[0132] The primary inclusion criteria for this study are age ≥ 18 years, ECOG performance status ≤ 1, at least one measurable site of disease as assessed by CT scan or MRI according to RECIST 1.1, and the ability to take oral medication without modification. Inclusion criteria for the dose-escalation study are the absence of available treatment options that provide a clinically meaningful benefit 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 cancer, esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastroesophageal junction cancer, bladder (transitional cell) cancer, head and neck squamous cell carcinoma (not nasopharyngeal, paranasal sinus, or lip cancer), ovarian carcinosarcoma, or high-CN endometrial / uterine cancer. Inclusion criteria for dose expansion studies include prior treatment with one of the following standard treatments specified in protocols for high-grade serous ovarian cancer, squamous non-small cell lung cancer, triple-negative breast cancer, gastric adenocarcinoma (not EBV+), colorectal cancer, esophageal squamous cell carcinoma, esophageal adenocarcinoma, head and neck squamous cell carcinoma (not nasopharyngeal, paranasal sinus, or lip cancer), or high-CN endometrial / uterine cancer.

[0133] The primary exclusion criteria for this study were: (a) the subject had high microsatellite instability (MSI-H), mismatch repair deficiency (dMMR), a mutated pole gene hotspot, or a known hypermutator phenotype; (b) the subject had previously taken a KIF18A inhibitor; (c) the subject currently had CNS metastasis or pia maternal disease; (d) the subject had cardiac parameters: MI or stroke ≤ 1 year, unstable angina / PE / DVT / CABG ≤ 6 months, and NYHA class ≥ II, LV. (e) The subject has an EF < 50%; (f) The subject is unable to comply with the restrictions on concomitant medications regarding strong inhibitors and inducers of CYP3A and clinical inhibitors of MDR1 (P-gp) and BCRP; (g) The subject has any clinically significant ascites or pleural effusion at the time of enrollment, or undergoes any therapeutic paracentesis or thoracentesis within 28 days of the planned first dose of the study drug; and (g) The subject has intestinal obstruction or gastrointestinal perforation within 6 months of the planned first dose of the study drug.

Claims

1. A method for treating cancer accompanied by chromosomal instability in a patient requiring treatment, comprising a compound of formula (A) in an effective therapeutic amount: 【Chemistry 1】 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof [in the formula, Ring A is C ６－１４ aryl or 5- to 12-membered heteroaryl, each of which is halo, -OH, C １－６ alkyl, 3- to 10-membered heterocycloalkyl, -NR ａ１ C(O)NR ａ２ R ａ３ , -NR ａ４ C(O)OR ａ５ , -NR ａ６ R ａ７ , -N=S(O)R ａ８ R ａ９ , -OR ａ１０ , -S(O)R ａ１１ , -S(O)(NR ａ１２ )R ａ１３ , -S(O) ２ NR ａ１４ R ａ１５ , -S(O) ２ R ａ１６ , -(CR ａ１７ R ａ１８ ) ０－１ C(O)NR ａ１９ R ａ２０ , -SR ａ２１ , -C(O)R ａ２２ , and C １－６ alkyl (optionally substituted by one or more substituents independently selected from the group consisting of -OH, cyano, C ３－１０ cycloalkyl, and 3- to 10-membered heterocycloalkyl (optionally substituted by one or more halos)) is optionally substituted by one or more substituents independently selected from the group consisting of; R ａ１ ~R ａ２２ These are, independently, hydrogen and C １－６ Alkyl, C ２－６ Alkenil, C ３－１０ Cycloalkyl, C ３－１０ Cycloalkenyl, 3-10 member heterocycloalkyl, 3-10 member heterocycloalkenyl, C ６－１４ These are aryls, or 5- to 12-membered heteroaryls, each consisting of a halo, cyano, -OH, and -O(C) １－６ Alkyl), C ２－６ Alkenil, C ３－１０ Cycloalkyl, -S(C) １－６ Alkyl), =CR １ａ１ R １ａ２ , and C １－６ Alkyl (halo, -OH, and -O(C) １－６ Optionally substituted with one or more substituents independently selected from the group consisting of alkyl) and R １ａ１ and R １ａ２ Each of them independently consists of hydrogen or C １－６ It is alkyl; Ring B is C ５－７ Cycloalkyl, C ５－７ A cycloalkenyl, or a 5- to 7-membered heterocycloalkyl, where one or two of the ring atoms are oxygen and the remaining ring atoms are carbon; m is 2; Two R's Ｂ The group is bonded to the same carbon atom on ring B, and together with the carbon atom to which they are bonded, C ３－７ Forms a cycloalkyl group; Y １ is N or CR Ｃ１ And; Y ２ is N or CR Ｃ２ And; Y ３ is N or CR Ｃ３ And; Y ４ is N or CR Ｃ４ And; Y １ , Y ２ , Y ３ , and Y ４ Three or fewer of these are N; R Ｃ１ ~R Ｃ４ are each independently hydrogen, halo, cyano, -OH, -NO ２ , -C(O)NR ｃ１ R ｃ２ , -NR ｃ３ R ｃ４ , -NR ｃ５ S(O) ２ R ｃ６ , -P(O)R ｃ７ R ｃ８ , -N = S(O)R ｃ９ R ｃ１０ , -S(O)(NR ｃ１１ )R ｃ１２ , -S(O) ２ R ｃ１３ , -NR ｃ１４ C(O)OR ｃ１５ , -NR ｃ１６ S(O) ２ (CH ２ ) １－６ NR ｃ１７ C(O)R ｃ１８ , or C １－６ alkyl (optionally substituted by one or more substituents independently selected from the group consisting of halo and -OH); R ｃ１ ~R ｃ１８ These are, independently, hydrogen and C ３－１０ Cycloalkyl, or C １－６ [It is an alkyl group (optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH)] The method comprising administering to the target.

2. A method for treating cancer selected from the group consisting of advanced solid tumors, high-grade serous adenocarcinoma of the 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 the bladder, head and neck squamous cell carcinoma, ovarian carcinosarcoma, uterine carcinosarcoma, serous carcinoma of the uterine body, and endometrial cancer, wherein the compound of formula (A) in a therapeutically effective amount: 【Chemistry 2】 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof [in the formula, Ring A is C ６－１４ aryl or 5- to 12-membered heteroaryl, each of which is halo, -OH, C １－６ alkyl, 3- to 10-membered heterocycloalkyl, -NR ａ１ C(O)NR ａ２ R ａ３ , -NR ａ４ C(O)OR ａ５ , -NR ａ６ R ａ７ , -N=S(O)R ａ８ R ａ９ , -OR ａ１０ , -S(O)R ａ１１ , -S(O)(NR ａ１２ )R ａ１３ , -S(O) ２ NR ａ１４ R ａ１５ , -S(O) ２ R ａ１６ , -(CR ａ１７ R ａ１８ ) ０－１ C(O)NR ａ１９ R ａ２０ , -SR ａ２１ , -C(O)R ａ２２ , and C １－６ alkyl (optionally substituted by one or more substituents independently selected from the group consisting of -OH, cyano, C ３－１０ cycloalkyl, and 3- to 10-membered heterocycloalkyl (optionally substituted by one or more halos)) is optionally substituted by one or more substituents independently selected from the group consisting of; R ａ１ ~R ａ２２ These are, independently, hydrogen and C １－６ Alkyl, C ２－６ Alkenil, C ３－１０ Cycloalkyl, C ３－１０ Cycloalkenyl, 3-10 member heterocycloalkyl, 3-10 member heterocycloalkenyl, C ６－１４ These are aryls, or 5- to 12-membered heteroaryls, each consisting of a halo, cyano, -OH, and -O(C) １－６ Alkyl), C ２－６ Alkenil, C ３－１０ Cycloalkyl, -S(C) １－６ Alkyl), =CR １ａ１ R １ａ２ , and C １－６ Alkyl (halo, -OH, and -O(C) １－６ Optionally substituted with one or more substituents independently selected from the group consisting of alkyl) and R １ａ１ and R １ａ２ Each of them independently consists of hydrogen or C １－６ It is alkyl; Ring B is C ５－７ Cycloalkyl, C ５－７ A cycloalkenyl, or a 5- to 7-membered heterocycloalkyl, where one or two of the ring atoms are oxygen and the remaining ring atoms are carbon; Two R's Ｂ The group is bonded to the same carbon atom on ring B, and together with the carbon atom to which they are bonded, C ３－７ Forms a cycloalkyl group; Y １ is N or CR Ｃ１ And; Y ２ is N or CR Ｃ２ And; Y ３ is N or CR Ｃ３ And; Y ４ is N or CR Ｃ４ And; Y １ , Y ２ , Y ３ , and Y ４ Three or fewer of these are N; R Ｃ１ ~R Ｃ４ These are, independently, hydrogen, halo, cyano, -OH, and -NO. ２ , -C(O)NR ｃ１ R ｃ２ , -NR ｃ３ R ｃ４ , -NR ｃ５ S(O) ２ R ｃ６ ,-P(O)R ｃ７ R ｃ８ -N=S(O)R ｃ９ R ｃ１０ , -S(O)(NR ｃ１１ ) R ｃ１２ , -S(O) ２ R ｃ１３ , -NR ｃ１４ C(O)OR ｃ１５ , -NR ｃ１６ S(O) ２ (CH ２ ) １－６ NR ｃ１７ C(O)R ｃ１８ , or C １－６ It is an alkyl group (optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH); R ｃ１ ~R ｃ１８ These are, independently, hydrogen and C ３－１０ Cycloalkyl, or C １－６ [It is an alkyl group (optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH)] The method comprising administering to the target.

3. The method according to claim 1 or 2, wherein the compound of formula (A) is administered to a subject in a 28-day cycle.

4. The compound of formula (A) is the compound of formula (A-1): 【Transformation 3】 The method according to any one of claims 1 to 3, wherein the salt is pharmaceutically acceptable or a pharmaceutically acceptable salt thereof.

5. The compound of formula (A) is the compound of formula (A-2): 【Chemistry 4】 The method according to any one of claims 1 to 3, wherein the salt is pharmaceutically acceptable or a pharmaceutically acceptable salt thereof.

6. The compound of formula (A) is the compound of formula (A-3): 【Transformation 5】 The method according to any one of claims 1 to 3, wherein the salt is pharmaceutically acceptable or a pharmaceutically acceptable salt thereof.

7. The method according to any one of claims 2 to 6, wherein the cancer is a progressive solid tumor.

8. The method according to any one of claims 2 to 6, wherein the cancer is a high-grade serous adenocarcinoma of the ovary.

9. The method according to any one of claims 2 to 6, wherein the cancer is squamous cell non-small cell lung cancer.

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

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

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

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

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

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

16. The method according to any one of claims 2 to 6, wherein the cancer is transitional cell carcinoma of the bladder.

17. The method according to any one of claims 2 to 6, wherein the cancer is squamous cell carcinoma of the head and neck.

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

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

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

21. The method according to any one of claims 2 to 6, wherein the cancer is endometrial cancer.

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