Combinations of checkpoint kinase 1 (chk1) inhibitors and uses thereof

Abstract

Provided herein is a method for treating cancer, comprising administering to a subject in need of cancer treatment a therapeutically effective amount of a Chk1 inhibitor disclosed herein in combination with an additional therapeutic agent.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 385,347, filed November 29, 2022, which is incorporated herein by reference in its entirety.

[0002] Described herein are combinations comprising compounds for inhibiting checkpoint kinase 1 (Chk1). [Background technology]

[0003] Some cancers have been found to be resistant to the therapeutic drugs used to treat them, hindering the efforts to maintain the sustained and progression-free survival of cancer patients.Patients whose tumors have oncogene amplification may prove to be particularly difficult to treat.For example, patients whose tumors have oncogene amplification on or derived from extrachromosomal DNA (ecDNA) may not respond to targeted therapy or immunotherapy and have poor prognosis.

[0004] Single-agent therapy may be less effective in some patient populations, or tumors or tumor cells may have a shorter durability before developing resistance.It is necessary to develop multiple attack points against such cancers.However, it has been found that combinations of therapeutic agents are also susceptible to the development of resistance or reduced responsiveness.

[0005] To address the need for safe and effective treatments for cancer, there is a need for combinations that are potent therapeutic treatments with increased durability and length of effect. Summary of the Invention

[0006] Disclosed herein are methods of treating a tumor or tumor cells, the methods comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a selected cancer-targeted therapeutic agent to a subject identified as having a tumor or tumor cells, wherein the tumor or tumor cells contain gene amplification, and the method reduces the growth or size of the tumor, or the growth or number of tumor cells.

[0007] Also disclosed herein is a method of delaying resistance to a selected cancer-targeted therapeutic agent, the method comprising administering to a subject a compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, in an amount sufficient to induce replication stress in a tumor or tumor cells, and administering the selected cancer-targeted therapeutic agent simultaneously with or after administration of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0008] Also disclosed herein is a method of treating a subject having a tumor or tumor cells that are unresponsive to a previous cancer-targeted therapeutic agent, the method comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a selected cancer-targeted therapeutic agent.

[0009] In some embodiments of the methods disclosed herein, the subject has received one or more previous cancer targeted therapeutic agents prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the tumor or tumor cells have become reduced in response to or have acquired resistance to the previous cancer targeted therapeutic agents.

[0010] Also disclosed herein is a method for inducing a response in a subject having a tumor or tumor cells that are unresponsive or have reduced responsiveness to a previous cancer targeted therapeutic agent, the method comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a selected cancer targeted therapeutic agent, wherein the previous cancer targeted therapeutic agent is the same as the selected cancer targeted therapeutic agent.

[0011] In some embodiments of the methods disclosed herein, prior to treatment with a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, the tumor or tumor cells contain a gene amplification and the previous cancer-targeted therapeutic agent has activity directed against a protein encoded by a gene contained within the gene amplification.

[0012] In some embodiments of the methods disclosed herein, the selected cancer targeted therapeutic agent is administered simultaneously with or after administration of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0013] In some embodiments of the methods disclosed herein, the selected cancer targeted therapeutic agent is administered prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0014] In some embodiments of the methods disclosed herein, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is administered in an amount sufficient to induce replicative stress in a tumor or tumor cells.

[0015] In some embodiments of the methods disclosed herein, the subject is identified as having a tumor or tumor cells that contain a gene amplification.

[0016] In some embodiments of the methods disclosed herein, the gene amplification is focal gene amplification.

[0017] In some embodiments of the methods disclosed herein, the gene amplification is amplification from ecDNA.

[0018] In some embodiments of the methods disclosed herein, the gene amplification is contained in ecDNA or homogeneously staining region (HSR).

[0019] In some embodiments of the methods disclosed herein, the tumor or tumor cells comprise an ecDNA signature.

[0020] In some embodiments of the methods disclosed herein, the selected cancer-targeting therapeutic agent is directed against a protein encoded by a gene contained within the gene amplification.

[0021] In some embodiments of the methods disclosed herein, the cells contained within the tumor or tumor cells are ecDNA competent.

[0022] In some embodiments of the methods disclosed herein, treatment with both a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a selected cancer targeted therapeutic agent has a greater effect or a longer duration of effect on reducing one or more of tumor growth, tumor size, number of tumor cells, or tumor metastasis compared to treatment with either the compound of Formula (I) or the selected cancer targeted therapeutic agent administered alone.

[0023] In some embodiments of the methods disclosed herein, the greater effect is a synergistic effect.

[0024] In some embodiments of the methods disclosed herein, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and / or the selected cancer targeted therapeutic agent is administered orally.

[0025] In some embodiments of the methods disclosed herein, the treatment comprises administering multiple doses of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and / or a selected cancer-targeted therapeutic agent over a treatment period.

[0026] In some embodiments of the methods disclosed herein, the gene amplification comprises amplification of a gene selected from the group consisting of ABCB1, AKT, ALK, AR, BCL-2, BCR-ABL, BRAF, CDK4, CDK6, c-MET, EGFR, ER, ERBB3, ERRB2, AK, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, GR, HRAS, IGF1R, KIT, KRAS, MCL-1, MDM2, MDM4, MTOR, MYC, MYCL, MYCN, NRAS, NRG1, NTRK1, NTRK2, NTRK3, PDGFR, PIK3Cδ, PIK3CA / B, RET, and ROS1.

[0027] In some embodiments of the methods disclosed herein, the gene amplification comprises amplification of a gene selected from the group consisting of CDK4, CDK6, c-MET, EGFR, FGFR1, FGFR2, FGFR3, and FGFR4.

[0028] In some embodiments of the methods disclosed herein, the selected cancer therapeutic agent is an FGFR inhibitor. In some embodiments of the methods disclosed herein, the FGFR inhibitor is infigratinib, futivatinib, or pemigatinib.

[0029] In some embodiments of the methods disclosed herein, the selected cancer therapeutic agent is a CDK4 / 6 inhibitor. In some embodiments of the methods disclosed herein, the CDK4 / 6 inhibitor is palbociclib or abemaciclib.

[0030] In some embodiments of the methods disclosed herein, the selected cancer therapeutic agent is an EGFR inhibitor. In some embodiments of the methods disclosed herein, the EGFR inhibitor is erlotinib.

[0031] In some embodiments of the methods disclosed herein, the selected cancer therapeutic agent is a c-MET inhibitor. In some embodiments of the methods disclosed herein, the c-MET inhibitor is tepotinib.

[0032] In some embodiments of the methods disclosed herein, prior to treatment, the tumor or tumor cells contain ecDNA, and the treatment results in a decrease in the amount of ecDNA in the tumor or tumor cells.

[0033] In some embodiments of the methods disclosed herein, prior to treatment, the tumor or tumor cells contain ecDNA, and the level or amount of ecDNA after treatment is not elevated compared to before treatment.

[0034] In some embodiments of the methods disclosed herein, the method further comprises evaluating a sample from the subject for the presence or level of one or more of gene amplification, local gene amplification, ecDNA, HSR, or ecDNA signature.

[0035] In some embodiments of the methods disclosed herein, the methods further include obtaining information about the presence or level of one or more of gene amplification, regional gene amplification, ecDNA, HSR, or ecDNA signature in a tumor or tumor cells from the subject before, during, or after administration of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0036] In some embodiments of the methods disclosed herein, the information is obtained from blood, tissue, or one or more cells.

[0037] In some embodiments of the methods disclosed herein, the information is obtained by liquid biopsy or tissue biopsy.

[0038] In some embodiments of the methods disclosed herein, the previous cancer targeted therapeutic agent is targeted to a protein encoded by a gene selected from the group consisting of ABCB1, AKT, ALK, AR, BCL-2, BCR-ABL, BRAF, CDK4, CDK6, c-MET, EGFR, ER, ERBB3, ERRB2, AK, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, GR, HRAS, IGF1R, KIT, KRAS, MCL-1, MDM2, MDM4, MTOR, MYC, MYCL, MYCN, NRAS, NRG1, NTRK1, NTRK2, NTRK3, PDGFR, PIK3Cδ, PIK3CA / B, RET, and ROS1.

[0039] In some embodiments of the methods disclosed herein, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is a compound of formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, as disclosed herein.

[0040] [ka] is.

[0041] In some embodiments of the methods disclosed herein, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is a compound of formula (Ib):

[0042] [ka] is a compound of

[0043] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is

[0044] [ka] or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0045] Incorporation by Reference All publications, patents, and patent applications mentioned herein are hereby incorporated by reference for the specific purposes identified herein. [Brief explanation of the drawings]

[0046] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings.

[0047] [Figure 1A] Figure 1A shows tumor volume after treatment with a combination of compound 31 (50 mg / kg PO Q2D) and the pan-FGFR inhibitor infigratinib (15 mg / kg PO QD) in the ecDNA+FGFR2-amplified gastric cancer SNU-16 CDX model. [Figure 1B]Figure 1B shows tumor volume after treatment with a combination of compound 31 (50 mg / kg PO Q2D) and the pan-FGFR inhibitor infigratinib (15 mg / kg PO QD) in the ecDNA+FGFR2-amplified gastric cancer CTG-0353 PDX model. [Figure 1C] Figure 1C shows survival curves following treatment with a combination of compound 31 (50 mg / kg PO Q2D) and the pan-FGFR inhibitor infigratinib (15 mg / kg PO QD) in the ecDNA+FGFR2-amplified gastric cancer CTG-0353 PDX model. [Figure 1D] FIG. 1D shows tumor volume after treatment with a combination of compound 31 (50 mg / kg PO Q2D) and the pan-FGFR inhibitor futibatinib (12.5 mg / kg PO QD) in the ecDNA+FGFR2-amplified gastric cancer SNU-16 CDX model. [Figure 1E] FIG. 1E shows tumor volume after treatment with a combination of compound 31 (50 mg / kg PO administered Q2D) and the pan-FGFR inhibitor pemigatinib (1 mg / kg PO administered QD) in the ecDNA+FGFR2-amplified gastric cancer SNU-16 CDX model. [Figure 2A] Figure 2A shows tumor volume after treatment with a combination of compound 31 (50 mg / kg PO administered Q2D) and the CDK4 / 6 inhibitor palbociclib (50 mg / kg PO administered QD) in an ecDNA+CDK4-amplified osteosarcoma SJSA-1 CDX tumor model. [Figure 2B] Figure 2B shows tumor volume after treatment with a combination of compound 31 (50 mg / kg PO Q2D) and the CDK4 / 6 inhibitor abemaciclib (10.5 mg / kg PO QD) in the ecDNA+CDK4-amplified osteosarcoma SJSA-1 CDX tumor model. [Figure 3] Figure 3 shows tumor volume after treatment with a combination of compound 31 (50 mg / kg PO administered Q2D) and the EGFR inhibitor erlotinib (50 mg / kg PO administered QD) in the ecDNA+EGFR amplified NSCLC PDX tumor model LU1206. [Figure 4]Figure 4 shows tumor volume after treatment with a combination of compound 31 (50 mg / kg PO Q2D) and the MET inhibitor tepotinib (25 mg / kg PO Q2D) in the ecDNA+MET-amplified NSCLC PDX tumor model LU1902. [Figure 5] FIG. 5 shows that combination treatment with infigratinib and compound 31 blocked the increase in FGFR2 copy number on ecDNA otherwise caused by single-agent infigratinib. DETAILED DESCRIPTION OF THE INVENTION

[0048] definition In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments. However, those skilled in the art will understand that the present invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless otherwise required by context, throughout the following specification and claims, the term "comprises" and variations thereof (such as "comprises" and "comprising") should be interpreted in an open and inclusive sense, i.e., "including, but not limited to." Furthermore, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0049] References throughout this specification to "some embodiments" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Similarly, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally used in its sense to include "and / or" unless the content clearly dictates otherwise.

[0050] As used herein, the following terms have the following meanings unless otherwise indicated.

[0051] "Oxo" refers to =O.

[0052] "Carboxyl" refers to --COOH.

[0053] "Cyano" refers to -CN.

[0054] "Alkyl" refers to a straight- or branched-chain saturated hydrocarbon monoradical having 1 to about 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl and octyl. Whenever appearing herein, "C1-C6 alkyl" or "C 1-6 Numerical ranges such as "alkyl" mean that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also includes occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is C 1-10 In some embodiments, alkyl is C 1-6 In some embodiments, alkyl is C 1-5 In some embodiments, alkyl is C 1-4 In some embodiments, alkyl is C 1-3and alkyl. Unless otherwise specified herein, alkyl groups can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkyl is optionally substituted with halogen.

[0055] "Alkenyl" refers to a straight or branched chain hydrocarbon monoradical having one or more carbon-carbon double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The group may be in either the cis or trans conformation about the double bond(s) and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH), 1-propenyl (-CHCH=CH), isopropenyl [-C(CH)=CH], butenyl, 1,3-butadienyl, and the like. Whenever appearing herein, "C-C alkenyl" or "C 2-6Numerical ranges such as "alkenyl" mean that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also includes occurrences of the term "alkenyl" when no numerical range is specified. Unless otherwise specified in the specification, alkenyl groups can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, an alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkenyl is optionally substituted with halogen.

[0056] "Alkynyl" refers to a straight or branched chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever it appears herein, "C2-C6 alkynyl" or "C 2-6Numerical ranges such as "alkynyl" mean that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also includes occurrences of the term "alkynyl" where no numerical range is specified. Unless otherwise specified in the specification, alkynyl groups can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkynyl is optionally substituted with oxo, halogen, -CN, COOH, -COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkynyl is optionally substituted with halogen.

[0057] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise specified in the specification, an alkylene group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkylene is optionally substituted with halogen.

[0058] "Alkoxy" is R a is an alkyl radical as defined by the formula -OR aUnless otherwise specified in the specification, an alkoxy group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkoxy is optionally substituted with halogen.

[0059] "Aryl" refers to a radical derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. Aryl radicals can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which can include fused ring systems (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is attached through an aromatic ring atom) or bridged ring systems. In some embodiments, an aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specified herein, an aryl can be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, an aryl is optionally substituted with halogen.

[0060] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include fused ring systems (when fused to an aryl or heteroaryl ring, the cycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems. In some embodiments, a cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls containing 3 to 15 carbon atoms (C3-C4). 15 Cycloalkyl or C3-C15 cycloalkenyl), 3 to 10 carbon atoms (C3-C 10 Cycloalkyl or C3-C 10Examples of cycloalkyl include cycloalkyls having 3 to 8 carbon atoms (C3-C8 cycloalkyl or C3-C8 cycloalkenyl), 3 to 6 carbon atoms (C3-C6 cycloalkyl or C3-C6 cycloalkenyl), 3 to 5 carbon atoms (C3-C5 cycloalkyl or C3-C5 cycloalkenyl), or 3 to 4 carbon atoms (C3-C4 cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, a cycloalkyl is a 3 to 10-membered cycloalkyl or a 3 to 10-membered cycloalkenyl. In some embodiments, a cycloalkyl is a 3 to 6-membered cycloalkyl or a 3 to 6-membered cycloalkenyl. In some embodiments, a cycloalkyl is a 5 to 6-membered cycloalkyl or a 5 to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specified in the specification, cycloalkyl can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —COOH, —COOMe, —CF, —OH, —OMe, —NH, or —NO.In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.

[0061] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0062] "Haloalkyl" refers to an alkyl radical, as defined above, substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0063] "Hydroxyalkyl" refers to an alkyl radical, as defined above, substituted with one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0064] "Aminoalkyl" refers to an alkyl radical, as defined above, substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0065] "Deuteroalkyl" refers to an alkyl radical, as defined above, that is substituted with one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums. Deuteroalkyls include, for example, CD3, CHD, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3.

[0066] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6 heteroalkyl, where the heteroalkyl consists of 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, and the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CHOCH3, -CH2CHOCH3, -CH2CHOCH2CHOCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise specified in the specification, a heteroalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, a heteroalkyl is optionally substituted with halogen.

[0067] "Heterocycloalkyl" refers to a 3- to 24-membered, partially or fully saturated ring radical containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, a heterocycloalkyl is fully saturated. In some embodiments, a heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heterocycloalkyl contains 1 to 3 nitrogens. In some embodiments, a heterocycloalkyl contains 1 or 2 nitrogens. In some embodiments, a heterocycloalkyl contains 1 nitrogen. In some embodiments, a heterocycloalkyl contains 1 nitrogen and 1 oxygen. Unless otherwise specified in the specification, a heterocycloalkyl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems; the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical can be optionally oxidized; and the nitrogen atom can be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having 2 to 15 carbon atoms (C2-C4). 15 Heterocycloalkyl or C2-C 15 heterocycloalkenyl), 2 to 10 carbon atoms (C2-C 10 Heterocycloalkyl or C2-C 10heterocycloalkenyl), heterocycloalkyl having 2 to 8 carbon atoms (C2-C8 heterocycloalkyl or C2-C8 heterocycloalkenyl), 2 to 7 carbon atoms (C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), 2 to 6 carbon atoms (C2-C6 heterocycloalkyl or C2-C6 heterocycloalkenyl), 2 to 5 carbon atoms (C2-C5 heterocycloalkyl or C2-C5 heterocycloalkenyl), or 2 to 4 carbon atoms (C2-C4 heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, and 2-oxopyrrolidinyl. 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl.The term "heterocycloalkyl" also includes cyclic forms of all carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, heterocycloalkyls have 2 to 10 carbons in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is noted that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). In some embodiments, a heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, a heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, a heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, a heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, a heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless otherwise specified in this specification, a heterocycloalkyl can be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0068] "Heteroaryl" refers to a 5-14 membered ring system radical containing 1-13 carbon atoms, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, a heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heteroaryl contains 1-3 nitrogens. In some embodiments, a heteroaryl contains 1 or 2 nitrogens. In some embodiments, a heteroaryl contains 1 nitrogen. A heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is joined by an aromatic ring atom) or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized. In some embodiments, the heteroaryl is a 5-10 membered heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5-6 membered heteroaryl. In some embodiments, the heteroaryl is a 6 membered heteroaryl. In some embodiments, the heteroaryl is a 5 membered heteroaryl.Examples, without limitation, include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoin dolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified in the specification, heteroaryl can be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe.In some embodiments, the heteroaryl is optionally substituted with halogen.

[0069] The term "optional" or "optionally" means that the event or circumstance described below may or may not occur, and the description includes both cases where the event or circumstance occurs and cases where the event or circumstance does not occur. For example, "optionally substituted alkyl" means either "alkyl" or "substituted alkyl" as defined above. Furthermore, an optionally substituted group may be unsubstituted (e.g., -CHCH), fully substituted (e.g., -CFCF), monosubstituted (e.g., -CHCHF), or substituted at any level between fully and monosubstituted (e.g., -CHCHF, -CHCF, -CFCH, -CFHCHF, etc.). It will be understood by those skilled in the art that with respect to any group containing one or more substituents, it is not intended that such group introduce any substitution or substitution pattern that is sterically impractical and / or synthetically infeasible (e.g., substituted alkyl is defined as including an optionally substituted cycloalkyl group, which in turn may include an infinite number of optionally substituted alkyl groups). Thus, any substituent described should generally be understood as having a maximum molecular weight of about 1,000 daltons, more typically up to about 500 daltons.

[0070] When referring to optional substituents, the term "one or more" means that the group in question is optionally substituted with one, two, three, four, or more substituents. In some embodiments, the group in question is optionally substituted with one, two, three, or four substituents. In some embodiments, the group in question is optionally substituted with one, two, or three substituents. In some embodiments, the group in question is optionally substituted with one or two substituents. In some embodiments, the group in question is optionally substituted with one substituent. In some embodiments, the group in question is optionally substituted with two substituents.

[0071] The terms "treat," "treated," "treatment," or "treating," as used herein, refer to therapeutic treatment, the purpose of which is to prevent or slow (reduce) an undesirable physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical result. For purposes described herein, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, whether detectable, undetectable, or either progression or amelioration of the disease, disorder, or disease; reduction in the extent of the disease, disorder, or disease; stabilization (i.e., not worsening) of the disease, disorder, or disease; delaying the onset or slowing the progression of the disease, disorder, or disease; amelioration of the disease, disorder, or disease; and remission (whether partial or total). Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment further includes prolonging survival compared to expected survival without treatment. The terms "treat," "treated," "treatment," or "treating," as well as words derived therefrom, as used herein, do not necessarily mean 100% or complete treatment. Rather, there are various degrees of treatment that one of skill in the art will recognize as having potential benefit or therapeutic effect. In this regard, the disclosed methods can provide any amount of any level of treatment for a disorder in a mammal. For example, the disorder, including its symptoms or disease, can be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%.

[0072] The terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufficient quantity of the compound being administered that will relieve to some extent one or more symptoms of the disease or disorder being treated, e.g., cancer or inflammatory disease. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic purposes is the quantity of a composition comprising a compound as disclosed herein that is required to result in a clinically significant reduction in a disease symptom. In some embodiments, an appropriate "effective" amount in any individual case is determined using techniques, such as a dose escalation study.

[0073] The term "biological sample," as used herein, generally refers to a sample derived from or obtained from a subject, such as a mammal (e.g., a human). Biological samples are intended to include, but are not limited to, hair, nails, skin, sweat, tears, eye fluid, nasal or nasopharyngeal swabs, sputum, throat swabs, saliva, mucus, blood, serum, plasma, placental fluid, amniotic fluid, umbilical cord blood, pleural fluid, emphatic fluids, body cavity fluids, earwax, oil, glandular secretions, bile, lymph, pus, microbiota, meconium, breast milk, bone marrow, bone, central nervous system tissue, cerebrospinal fluid, adipose tissue, synovial fluid, stool, gastric juice, urine, semen, vaginal secretions, stomach, small intestine, large intestine, rectum, pancreas, liver, kidney, bladder, lung, and other tissues and fluids derived from or taken from a subject.

[0074] As used herein, the term "tumor" or "tumor cells" generally refers to cells that grow and divide inappropriately more, or do not die when they should. In some cases, tumor cells exist in a solid mass, such as a solid tumor, while in other cases, tumor cells are found in a non-solid form, such as a blood cancer. Tumors or tumor cells can also include metastases, or metastatic cells, in which cancer cells can break away from the original (primary) tumor and form new tumors in other organs or tissues of the body.

[0075] As used herein, the term "ecDNA signature" refers to one or more characteristics common to tumors or tumor cells that are generally ecDNA+. In some cases, the ecDNA signature is selected from the group consisting of gene amplification; p53 loss-of-function mutation; absence of microsatellite instability (MSI-H); low levels of PD-L1 expression; low levels of tumor inflammation signature (TIS); low levels of tumor mutation burden (TMB); increased frequency of allelic substitutions, insertions, or deletions (indels); and combinations thereof. In some cases, the ecDNA signature may include increased copy number (gene amplification) in conjunction with specific structural mutations. In some cases, the ecDNA signature may include focal amplification. In some cases, the ecDNA signature includes detection or identification of ecDNA using imaging technology. In some cases, the ecDNA signature does not include any imaging or direct detection of ecDNA.

[0076] compound Described herein are Chk1 inhibitors that are useful in the treatment of cancer.

[0077] As used herein, the formula (I)

[0078] [ka] or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R 1 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d, -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R on the same atom 1 together to form an oxo n is 0 to 4, R 2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R 3 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R 4is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; W is N or CR W and R W are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R; X is N or CR X and R X are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)Ra , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R; Y is N or CR Y and R Y are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR bC(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R; Z is N or CR Z and R Z are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R; provided that at least one of W, X, Y, or Z is N, L is -O- or -NR 5 - and R 5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R 6 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NRc R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R on the same atom 6 together to form an oxo Or two R on the same carbon 6 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; Or two R on different atoms 6 together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; m is 0 to 8; Each R a is independently C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Each R bare independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and Each R c and R d are independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Or R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently selected from halogen, -CN, -OH, -OC1-C3 alkyl, -OC1-C3 haloalkyl, -SC1-C3 alkyl, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -C( =O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuteroalkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, or C3-C6 cycloalkyl; Alternatively, two R on the same atom form an oxo.

[0079] In some embodiments of the compounds of Formula (I), W is N. In some embodiments of the compounds of Formula (I), W is CR W is.

[0080] In some embodiments of the compound of Formula (I), X is N. In some embodiments of the compound of Formula (I), X is CR X is.

[0081] In some embodiments of the compound of Formula (I), Y is N. In some embodiments of the compound of Formula (I), Y is CR Y is.

[0082] In some embodiments of the compound of Formula (I), Z is N. In some embodiments of the compound of Formula (I), Z is CR Z is.

[0083] In some embodiments of the compound of Formula (I), the compound has the formula (Ia):

[0084] [ka] In some embodiments of the compound of Formula (I), the compound is a compound of Formula (Ib):

[0085] [ka] is a compound of

[0086] In some embodiments of the compound of Formula (I), the compound has the formula (Ic):

[0087] [ka] is a compound of

[0088] In some embodiments of the compound of Formula (I), the compound has the formula (Id):

[0089] [ka] is a compound of

[0090] In some embodiments of the compounds of Formula (I) or (Ia)-(Id), ring A is aryl or heteroaryl. In some embodiments of the compounds of Formula (I) or (Ia)-(Id), ring A is heteroaryl. In some embodiments of the compounds of Formula (I) or (Ia)-(Id), ring A is 6-membered heteroaryl. In some embodiments of the compounds of Formula (I) or (Ia)-(Id), ring A is pyrazinyl.

[0091] In some embodiments of compounds of Formula (I) or (Ia)-(Id), each R 1 are independently deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), each R 1 are independently -CN.

[0092] In some embodiments of a compound of Formula (I) or (Ia)-(Id), n is 0 to 2. In some embodiments of a compound of Formula (I) or (Ia)-(Id), n is 1 or 2. In some embodiments of a compound of Formula (I) or (Ia)-(Id), n is 0 or 1. In some embodiments of a compound of Formula (I) or (Ia)-(Id), n is 0. In some embodiments of a compound of Formula (I) or (Ia)-(Id), n is 1. In some embodiments of a compound of Formula (I) or (Ia)-(Id), n is 2. In some embodiments of a compound of Formula (I) or (Ia)-(Id), n is 3.

[0093] In some embodiments of compounds of Formula (I) or (Ia)-(Id), R 2 is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R 2 is hydrogen.

[0094] In some embodiments of compounds of Formula (I) or (Ia)-(Id), R 3 is hydrogen, deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R 3 is hydrogen.

[0095] In some embodiments of compounds of Formula (I) or (Ia)-(Id), R 4 is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R 4 is hydrogen.

[0096] In some embodiments of the compounds of Formula (I) or (Ia)-(Id), L is -O-. In some embodiments of the compounds of Formula (I) or (Ia)-(Id), L is -NR 5 -It is.

[0097] In some embodiments of compounds of Formula (I) or (Ia)-(Id), R 5 is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R 5 is hydrogen.

[0098] In some embodiments of compounds of Formula (I) or (Ia)-(Id), R W represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R W represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R W is hydrogen, deuterium, halogen, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R W is hydrogen, halogen, -OH, -OR a, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R W is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R W is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R W is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R W is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R W is hydrogen or halogen. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R W is hydrogen.

[0099] In some embodiments of compounds of Formula (I) or (Ia)-(Id), R W is hydrogen, halogen, -OH, -OR a , or -NR c R d In some embodiments of compounds of Formula (I) or (Ia)-(Id), R W is hydrogen, -OH, or -OR a In some embodiments of compounds of Formula (I) or (Ia)-(Id), R W is -OH or -OR a In some embodiments of compounds of Formula (I) or (Ia)-(Id), R W is halogen or -OR a is.

[0100] In some embodiments of compounds of Formula (I) or (Ia)-(Id), R X represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , -NR c Rd , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R X represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R X is hydrogen, deuterium, halogen, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R X is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R X is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R X is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R X is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), RX is hydrogen or halogen. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R X is hydrogen.

[0101] In some embodiments of compounds of Formula (I) or (Ia)-(Id), R Y represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R Y represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R Y is hydrogen, deuterium, halogen, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R Y is hydrogen, halogen, -OH, -ORa , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or cycloalkyl, wherein alkyl and cycloalkyl are optionally substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R Y is hydrogen, deuterium, halogen, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R Y is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R Y is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R Y is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R Y is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R Y is hydrogen or halogen. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R Y is hydrogen. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R Y is C1-C6 alkyl.

[0102] In some embodiments of compounds of Formula (I) or (Ia)-(Id), R Z represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R Z represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R Z is hydrogen, deuterium, halogen, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R Z is hydrogen, deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R Z is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R Z is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R Z is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R Z is hydrogen or halogen. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R Zis hydrogen. In some embodiments of compounds of Formula (I) or (Ia)-(Id), R Z is C1-C6 alkyl.

[0103] In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring B is cycloalkyl or heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring B is cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring B is monocyclic cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring B is bicyclic cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring B is 4- to 6-membered cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring B is monocyclic 4- to 5-membered cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Id), Ring B is monocyclic 4-membered cycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Id), Ring B is a monocyclic 5-membered cycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Id), Ring B is a monocyclic 6-membered cycloalkyl.

[0104] In some embodiments of compounds of Formula (I) or (Ia)-(Id), each R 6 are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), each R 6 are independently -OH and -OR a , or -NR c R d In some embodiments of compounds of Formula (I) or (Ia)-(Id), each R 6 independently -NR c R d is.

[0105] In some embodiments of a compound of Formula (I) or (Ia)-(Id), m is 0. In some embodiments of a compound of Formula (I) or (Ia)-(Id), m is 1. In some embodiments of a compound of Formula (I) or (Ia)-(Id), m is 2. In some embodiments of a compound of Formula (I) or (Ia)-(Id), m is 3. In some embodiments of a compound of Formula (I) or (Ia)-(Id), m is 0 or 1. In some embodiments of a compound of Formula (I) or (Ia)-(Id), m is 0 to 2. In some embodiments of a compound of Formula (I) or (Ia)-(Id), m is 1 or 2.

[0106] In some embodiments of the compounds disclosed herein, each R a is independently C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C hydroxyalkyl, C-C aminoalkyl, cycloalkyl, heterocycloalkyl, C-C alkylene(cycloalkyl), or C-C alkylene(heterocycloalkyl), where each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independently C-C alkyl, C-C haloalkyl, cycloalkyl, heterocycloalkyl, C-C alkylene(cycloalkyl), or C-C alkylene(heterocycloalkyl), where each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R ais independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, 1-C6 aminoalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independently C-C alkyl, C-C haloalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independently C-C alkyl, C-C haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R a are independently C1-C6 alkyl.

[0107] In some embodiments of the compounds disclosed herein, each R b are independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C hydroxyalkyl, C-C aminoalkyl, cycloalkyl, heterocycloalkyl, C-C alkylene(cycloalkyl), or C-C alkylene(heterocycloalkyl), where each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each Rb are independently hydrogen, C-C alkyl, C-C haloalkyl, cycloalkyl, heterocycloalkyl, C-C alkylene(cycloalkyl), or C-C alkylene(heterocycloalkyl), and each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b are independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C hydroxyalkyl, 1-C aminoalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b are independently hydrogen, C-C alkyl, C-C haloalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b is independently hydrogen, C-C alkyl, C-C haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R b is independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C hydroxyalkyl, or C-C aminoalkyl. In some embodiments of the compounds disclosed herein, each R b is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R b is independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R b is hydrogen. In some embodiments of the compounds disclosed herein, each Rb are independently C1-C6 alkyl.

[0108] In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C hydroxyalkyl, C-C aminoalkyl, cycloalkyl, heterocycloalkyl, C-C alkylene(cycloalkyl), or C-C alkylene(heterocycloalkyl), where each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen, C-C alkyl, C-C haloalkyl, cycloalkyl, heterocycloalkyl, C-C alkylene(cycloalkyl), or C-C alkylene(heterocycloalkyl), where each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C hydroxyalkyl, 1-C aminoalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen, C-C alkyl, C-C haloalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each Rc and R d is independently hydrogen, C-C alkyl, C-C haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R c and R d is independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C hydroxyalkyl, or C-C aminoalkyl. In some embodiments of the compounds disclosed herein, each R c and R d is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R c and R d is independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R c and R d is hydrogen. In some embodiments of the compounds disclosed herein, each R c and R d is independently C1-C6 alkyl. In some embodiments of the compounds disclosed herein, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R.

[0109] In some embodiments of the compounds disclosed herein, each R is independently halogen, —CN, —OH, —O—C—C alkyl, —O—C—C haloalkyl, —NH, —NHC—C alkyl, —N(C—C alkyl), —C(═O)C—C alkyl, —C(═O)OH, —C(═O)O—C alkyl, —C(═O)NH, —C(═O)NHC—C alkyl, —C(═O)N(C—C alkyl), C—C alkyl, C—C haloalkyl, C—C deuteroalkyl, C—C hydroxyalkyl, C—C aminoalkyl, C—C heteroalkyl, or C—C cycloalkyl; or two R on the same atom form oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -O-C alkyl, -O-C haloalkyl, -NH, -NHC-C alkyl, -N(C-C alkyl), C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, or C-C cycloalkyl; or two R on the same atom form oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -O-C alkyl, -O-C haloalkyl, -NH, C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, or C-C cycloalkyl, or two R on the same atom form an oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -O-C alkyl, -O-C haloalkyl, -NH, C-C alkyl, or C-C haloalkyl, or two R on the same atom form an oxo.In some embodiments of the compounds disclosed herein, each R is independently halogen, C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C hydroxyalkyl, C-C aminoalkyl, or C-C heteroalkyl, or two R on the same atom form an oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, —CN, —OH, —NH, C-C alkyl, or C-C haloalkyl, or two R on the same atom form an oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, C-C alkyl, or C-C haloalkyl, or two R on the same atom form an oxo.

[0110] In some embodiments of the compounds disclosed herein, the compound is selected from the group consisting of hydroxybenzoates, ...

[0111] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18] or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or a compound of Table 2

[0112] [Table 2-1] [Table 2-2] [Table 2-3] or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0113] In some embodiments, the CHK1 inhibitor is compound 31

[0114] [ka] or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. In some embodiments, the CHK1 inhibitor is compound 31

[0115] [ka] is.

[0116] Further forms of the compounds disclosed herein Isomers / stereoisomers In some embodiments, the compounds described herein exist as geometric isomers. In other embodiments, the compounds described herein possess one or more double bonds. The compounds provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers and their corresponding mixtures. In some circumstances, the compounds described herein contain one or more chiral centers, with each center existing in the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms and their corresponding mixtures. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers derived from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomer. In some embodiments, separable complexes are preferred. In some embodiments, diastereomers have distinctive physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be separated by taking advantage of these dissimilarities. In some embodiments, diastereomers are separated by chiral chromatography or, preferably, by separation / resolution techniques based on differences in solubility. In some embodiments, the optically pure enantiomers are then recovered along with the resolving agent.

[0117] labeled compound In some embodiments, the compounds described herein exist in isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating disease by administering isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds, which are identical to those listed herein except for the fact that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds described herein, or their solvates, tautomers, or stereoisomers, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, respectively. 2 H, 3 H, 13 C. 14 C. l5 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Cl, etc. Compounds described herein and pharmaceutically acceptable salts, solvates, solvates, or stereoisomers that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the disclosure. 3 H and 14 Certain isotopically labeled compounds, such as those incorporating C, are useful in drug and / or substrate tissue distribution assays. 3 H and carbon-14, i.e., 14 The C isotope is particularly preferred because it is easy to prepare and detect. 2Substitution with heavy isotopes such as H offers certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. In some embodiments, isotopically labeled compounds, or pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers thereof, are prepared by any suitable method.

[0118] In some embodiments, the compounds described herein are labeled by other means, including but not limited to, a chromophore or fluorescent moiety, a bioluminescent label, or a chemiluminescent label.

[0119] Pharmaceutically acceptable salts In some embodiments, the compounds described herein are present as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0120] In some embodiments, the compounds described herein possess acidic or basic groups and thus react with a number of inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared during the final isolation and purification of the compounds disclosed herein, or in situ by reacting the purified compound in free form with a suitable acid or base and isolating the salt thereby formed.

[0121] Examples of pharmaceutically acceptable salts include salts prepared by reacting a compound disclosed herein with a mineral, organic acid, or inorganic base, such as acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate. , gamma-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0122] Additionally, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids, including, but not limited to, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) Benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

[0123] In some embodiments, the compounds described herein containing free acid groups are reacted with a suitable base, such as a hydroxide, carbonate, bicarbonate, or sulfate salt of a pharmaceutically acceptable metal cation, ammonia, or a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium, and aluminum salts. Specific examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 Representative salts include the alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium, as well as the aluminum salt of tetrazole.

[0124] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water- or oil-soluble or dispersible products are obtained by such quaternization.

[0125] solvate In some embodiments, the compounds described herein exist as solvates. The present disclosure provides methods for treating diseases by administering such solvates. The present disclosure further provides methods for treating diseases by administering such solvates as pharmaceutical compositions.

[0126] Solvate comprises stoichiometric or non-stoichiometric amount of solvent such as water, ethanol, etc. Hydrate is formed when solvent is water, and alcoholate is formed when solvent is alcohol. The solvate of the compound described herein can be conveniently prepared or formed during the process described herein. In addition, the compound provided herein can exist in both solvated and non-solvated form. Generally, solvated form is considered to be equivalent to non-solvated form for the purpose of the compound and method provided herein.

[0127] tautomers In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that can be interconverted by the migration of a hydrogen atom, involving the switching of a single bond and an adjacent double bond. In bond structures that allow tautomerization, a chemical equilibrium of tautomers exists. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0128] Compound Preparation The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or from compounds described in the chemical literature.

[0129] Suitable references and scientific treatises detailing the synthesis of reactants useful in preparing the compounds described herein, or referencing articles describing their preparation, include, for example, "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York; S.R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H.O. House, "Modern Synthetic Reactions," 2nd Ed., W.A. Benjamin, Inc., Menlo Park, Calif., 1972; T.L.G. Gilchrist, "Heterocyclic Chemistry," 2nd Ed., John Wiley & Sons, New York, 1992; and J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable references and academic papers detailing the synthesis of or referencing articles describing the preparation of reactants useful in the preparation of the compounds described herein include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons, ISBN: 3-527-29074-5; Hoffman, RV. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations", 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J."Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992), John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor), "Modern Carbonyl Chemistry" (2000), Wiley-VCH, ISBN: 3-527-29871-1; Patai, S., "Patai’s 1992 Guide to the Chemistry of Functional Groups" (1992), Interscience, ISBN: 0-471-93022-9; Solomons, T.W.G., "Organic Chemistry" 7th Edition (2000), John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993), Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann’s Encyclopedia" (1999), John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942 - 2000), John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups", John Wiley & Sons, 73 volumes.

[0130] Specific and analogous reactants are identified in the index of known chemical products prepared by the Chemical Abstract Service of the American Chemical Society, which is available in most public and university libraries and online. Known but not catalog-sold chemical products are optionally prepared by custom chemical synthesis companies, and many of the standard drug supply companies (e.g., those listed above) offer custom synthesis services. For the preparation and selection of pharmaceutical salts of the compounds described herein, see P.H. Stahl & C.G. Wermuth, "Handbook of Pharmaceutical Salts," Verlag Helvetica Chimica Acta, Zurich, 2002.

[0131] Compounds of Formula I can be synthesized as described in the following general Schemes I-VI.

[0132] In some embodiments, compounds of Formula I can be prepared via metal-catalyzed carbon-carbon bond-forming cross-coupling reactions. In some embodiments, suitable cross-coupling reactions include Suzuki, Negishi, Stille, Kumada, or Heck reactions. In certain embodiments, the cross-coupling reaction is a Suzuki reaction between an appropriately substituted aryl bromide and an appropriately substituted aryl boronic acid or aryl boronic ester.

[0133] [ka]

[0134] The synthesis of appropriately substituted intermediate building blocks for the Suzuki reaction is described in Scheme I. Aryl bromides of Formula I-3 can be synthesized by the reaction between an appropriately substituted compound of Formula I-1 (where L represents a nucleophile) and a compound of Formula I-2 (where LG represents a suitable leaving group). In some embodiments of I-1, L is an oxygen or an optionally substituted nitrogen atom. In some embodiments, L is oxygen. In some embodiments of I-2, LG is an alkyl halide such as bromine or iodine, and in other embodiments, LG may be oxygen. In some embodiments of I-2 where LG is oxygen, it can be activated to increase its reactivity as a leaving group. Such activation can occur via the synthesis of an alkyl sulfonate, such as mesylate, tosylate, nosylate, brosylate, or other sulfonates known to those skilled in the art. Such alkyl sulfonates can be synthesized from the corresponding alkyl alcohol by reaction with an appropriate sulfonyl chloride or sulfonic anhydride (e.g., methanesulfonyl chloride or methanesulfonic anhydride). Such sulfonylation reactions typically occur in a solvent such as dichloromethane, tetrahydrofuran, or toluene in the presence of a base such as sodium hydride, triethylamine, diisopropylethylamine, pyridine, potassium carbonate, or another base known to those skilled in the art. The reaction typically proceeds at subambient or ambient temperatures, e.g., 0-25°C. The reaction is typically complete within 1-18 hours, and the product can be purified or, if unstable to purification, can be used directly without purification.

[0135] In other embodiments, aryl bromides of formula I-3 can be synthesized by reaction with a compound of formula I-2 (where LG represents an alcohol that is activated in situ without isolation, as in the Mitsunobu reaction). In the Mitsunobu reaction, activation of the alcohol occurs in the presence of an appropriate azodicarboxylate, such as diethyl azodicarboxylate or diisopropyl azodicarboxylate, and an appropriate phosphine, such as triphenylphosphine. In some embodiments, activation can be achieved using an appropriate phosphorane, such as (tributylphosphoranylidene)acetonitrile (CMBP) or (trimethylphosphoranylidene)acetonitrile (CMMP). The Mitsunobu reaction is typically carried out in a solvent such as dichloromethane, tetrahydrofuran, or toluene, and typically occurs at ambient or elevated temperatures, typically between 25 and 110°C. The reaction is typically complete within 1 to 18 hours.

[0136] In some embodiments, a compound of Formula I-3 can be synthesized by the reaction between a compound of Formula I-4 and a compound of Formula I-5. In some embodiments of I-4, LG is a halide such as fluorine, chlorine, bromine, or iodine. In some embodiments of I-5, L is nitrogen or oxygen. In some embodiments of I-5, L is oxygen. The reaction between I-4 and I-5 can proceed under cross-coupling conditions catalyzed by a suitable transition metal or by nucleophilic aromatic substitution. In some embodiments, a nucleophilic aromatic substitution reaction occurs when LG of I-4 is fluorine or chlorine and L of I-5 is oxygen. In some embodiments, LG of I-4 is fluorine. When L of I-5 is oxygen, the nucleophilic aromatic substitution reaction typically occurs in the presence of a strong base such as sodium hydride, lithium diisopropylamine, lithium bis(trimethylsilyl)amide, or a suitable base known to those skilled in the art. Such nucleophilic aromatic substitution reactions typically occur in solvents such as tetrahydrofuran, dimethyl sulfoxide, 1,4-dioxane, N,N-dimethylformamide, or N,N-dimethylacetamide. Such nucleophilic aromatic substitution reactions typically occur at low temperatures such as −78° C. or 0° C., although in some embodiments, the reactions can occur at ambient or elevated temperatures between 25 and 110° C. The reactions are typically complete within 1 to 18 hours.

[0137] Compounds of Formula I-8 can be synthesized from appropriately substituted aminopyrazoles of Formula I-6 via reaction with appropriately substituted compounds of Formula I-7, where Ring A contains a suitable leaving group LG. In some embodiments, such leaving group can be chloride, bromide, iodide, or an activated alcohol such as mesylate or tosylate. In some embodiments, Ring A can be aromatic, and the leaving group can be an aryl chloride. In some embodiments, the reaction can occur in the presence of a suitable base, such as sodium hydride, triethylamine, diisopropylethylamine, pyridine, potassium carbonate, or another base known to those skilled in the art. Such reactions typically occur in solvents such as tetrahydrofuran, dimethyl sulfoxide, 1,4-dioxane, N,N-dimethylformamide, or N,N-dimethylacetamide. The reaction can occur at ambient temperature or at elevated temperatures between 60 and 110°C. The reaction is typically complete within 1 to 18 hours.

[0138] Pyrazole boronic ester compounds of Formula I-9 can be synthesized from compounds of Formula I-8 by reaction with an appropriate boronating agent. In some embodiments, compounds of Formula I-9 can contain a mixture of pyrazole boronic ester and pyrazole boronic acid. In some embodiments, compounds of Formula I-9 can contain primarily pyrazole boronic acid. In some embodiments, compounds of Formula I-9 are synthesized by the Miyaura boronation reaction, where the appropriate boronating agent is bis(pinacolato)diboron. The Miyaura boronation reaction is carried out in the presence of a palladium catalyst complexed with a phosphine ligand, such as tetrakis(triphenylphosphine)palladium, bis(diphenylphosphino)ferrocene]dichloropalladium(II), or another catalytic system known to those skilled in the art. Such reactions typically proceed in the presence of a suitable base, such as sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium acetate, potassium acetate, or another base known to those skilled in the art. The Miyaura reaction is typically carried out in solvents such as 1,4-dioxane, ethyl acetate, or toluene at elevated temperatures, typically between 60 and 110° C. The reaction is typically complete within 6 to 24 hours.

[0139] [ka]

[0140] As shown in Scheme II, compounds of Formula I can be synthesized by the Suzuki reaction between compounds of Formula I-3 and I-9. Such reactions are typically carried out in the presence of a palladium catalyst complexed with a phosphine ligand, such as tetrakis(triphenylphosphine)palladium, bis(diphenylphosphino)ferrocene]dichloropalladium(II), RuPhos palladacycle G3, or another catalyst system known to those skilled in the art. Such reactions typically proceed in the presence of a suitable base, such as sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium acetate, potassium acetate, or another base known to those skilled in the art. Suzuki reactions are typically carried out in solvents such as 1,4-dioxane, ethyl acetate, or toluene. In all cases, water is used as an additive, independent of the solvent chosen. The reaction can occur at elevated temperatures, typically between 60 and 110 °C. The reaction is typically complete within 6 to 24 hours.

[0141] [ka]

[0142] In an alternative embodiment, as shown in Scheme III, a cyanoketone intermediate of Formula III-5 can be synthesized from a compound of Formula I-3. In some embodiments, a compound of Formula I-3 can be converted to a vinyl enol ether of Formula III-1. Such a reaction can occur between a compound of Formula I-3 and an appropriately substituted vinyl building block under palladium-catalyzed cross-coupling conditions. In some embodiments, the cross-coupling reaction can be a Suzuki or Stille reaction. In some embodiments, the vinyl component is substituted as a boronic ester, boronic acid, trifluoroborate, or alkylstannane. Such cross-coupling reactions typically occur in the presence of a palladium catalyst complexed with a phosphine ligand, such as tetrakis(triphenylphosphine)palladium, bis(diphenylphosphino)ferrocene]dichloropalladium(II), RuPhos palladacycle G3, or another catalytic system known to those skilled in the art. Such reactions typically proceed in the presence of a suitable base, such as sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium acetate, potassium acetate, or another base known to those skilled in the art. Cross-coupling reactions are typically carried out in solvents such as 1,4-dioxane, ethyl acetate, or toluene. The reaction typically occurs at elevated temperatures, typically between 60 and 110°C. The reaction is typically complete within 6 to 24 hours. The compound of formula III-1 may be purified or, if it may be unstable to standard purification conditions, may be used directly in the next step without purification.

[0143] The compound of formula III-1 can be converted to a ketone of formula III-2 via acidic hydrolysis. Such a reaction is typically carried out in an aqueous medium using a strong Bronsted acid, such as hydrochloric acid. The reaction can be carried out at subambient, ambient, or elevated temperatures, typically between 0 and 80°C. In some embodiments, the ketone of formula III-2 can be converted to an enamine compound of formula III-3 by reaction with N,N-dimethylformamide dimethyl acetal. In some embodiments, the reaction occurs at elevated temperatures, typically between 60 and 110°C, in N,N-dimethylformamide as the solvent. The reaction is typically complete in 2 to 24 hours. The compound of formula III-3 can be purified, or in some embodiments, can be used directly in the next step without purification, as it may be unstable to standard purification conditions.

[0144] Compounds of formula III-3 can be converted to isoxazoles of formula III-4 by reaction with hydroxylamine. In some embodiments, the reaction can use hydroxylamine as the free base or as a salt. In some embodiments, the reaction is carried out using hydroxylamine hydrochloride. The reaction typically proceeds at ambient or elevated temperatures, typically between 25 and 110°C, in a suitable solvent such as methanol, ethanol, isopropanol, n-butanol, tert-butanol, or toluene. The reaction is typically complete within 2 to 24 hours.

[0145] The isoxazole of formula III-4 can be converted to the cyanoketone of formula III-5 by treatment with a suitable base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide. In some embodiments, the base is potassium hydroxide. The reaction typically proceeds in a suitable solvent such as methanol, ethanol, isopropanol, n-butanol, tert-butanol, or toluene. The reaction can be carried out at ambient or elevated temperatures between 25 and 110 °C for a reaction time of 1 to 8 hours.

[0146] [ka]

[0147] In an alternative embodiment, the cyanoketone of Formula III-5 can be synthesized from an ester as shown in Scheme IV. The ester of Formula IV-5 can be synthesized from an appropriate building block of Formula IV-1, where L represents a nucleophile, and a compound of Formula IV-2, where LG represents a suitable leaving group. In some embodiments of IV-1, L is oxygen or an optionally substituted nitrogen atom. In some embodiments, L is oxygen. In some embodiments of IV-2, LG is an alkyl halide such as bromine or iodine, and in other embodiments, it can be oxygen. In some embodiments of IV-2 where LG is oxygen, it can be activated to increase its reactivity as a leaving group. Such activation can occur via the synthesis of alkyl sulfonates such as mesylate, tosylate, nosylate, brosylate, or other sulfonates known to those skilled in the art. Such alkyl sulfonates can be synthesized from the corresponding alkyl alcohol by reaction with an appropriate sulfonyl chloride or sulfonic anhydride (e.g., methanesulfonyl chloride or methanesulfonic anhydride). Such sulfonylation reactions typically occur in a solvent such as dichloromethane, tetrahydrofuran, or toluene in the presence of a base such as sodium hydride, triethylamine, diisopropylethylamine, pyridine, potassium carbonate, or another base known to those skilled in the art. The reaction typically proceeds at reduced or ambient temperature, e.g., 0°C. The reaction is typically complete within 1 to 18 hours, and the product can be purified or used directly without purification.

[0148] In other embodiments, esters of formula IV-5 can be synthesized by reaction with compounds of formula IV-2 (where LG represents an alcohol that is activated in situ without isolation, as in the Mitsunobu reaction). Activation of the alcohol occurs in the presence of an appropriate azodicarboxylate, such as diethyl azodicarboxylate or diisopropyl azodicarboxylate, and an appropriate phosphine, such as triphenylphosphine. In some embodiments, activation can be achieved using an appropriate phosphorane, such as (tributylphosphoranylidene)acetonitrile (CMBP) or (trimethylphosphoranylidene)acetonitrile (CMMP). The Mitsunobu reaction is typically carried out in a solvent such as dichloromethane, tetrahydrofuran, or toluene, and typically occurs at ambient or elevated temperatures, typically between 25 and 110 °C. The reaction is typically complete within 1 to 18 hours.

[0149] In some embodiments, a compound of formula IV-5 can be synthesized from a compound of formula IV-3 and a compound of formula IV-4. In some embodiments of IV-3, LG is a halide such as fluorine, chlorine, bromine, or iodine. In some embodiments of IV-4, L is nitrogen or oxygen. In some embodiments of I-5, L is oxygen. The reaction between IV-3 and IV-4 can proceed under cross-coupling conditions catalyzed by a suitable transition metal or by nucleophilic aromatic substitution. In some embodiments, a nucleophilic aromatic substitution reaction occurs when LG of IV-3 is fluorine or chlorine and L is oxygen. In some embodiments, LG of IV-3 is fluorine. When L is oxygen, the nucleophilic aromatic substitution reaction typically occurs in the presence of a strong base such as sodium hydride, lithium diisopropylamine, lithium bis(trimethylsilyl)amide, or a suitable base known to those skilled in the art. Such nucleophilic aromatic substitution reactions typically occur in solvents such as tetrahydrofuran, dimethyl sulfoxide, 1,4-dioxane, N,N-dimethylformamide, or N,N-dimethylacetamide. Such nucleophilic aromatic substitution reactions typically occur at low temperatures such as −78° C. or 0° C., although in some embodiments, the reactions can occur at elevated temperatures such as 100° C. The reactions are typically complete within 1 to 18 hours.

[0150] The ester of formula IV-5 can be converted to a cyanoketone of formula III-5 by reaction with the carbanion of an optionally substituted nitrile. In some embodiments, the nitrile is acetonitrile. In such reactions, the acetonitrile is deprotonated with a suitable strong base, such as sodium hydride, potassium tert-butoxide, n-butyllithium, sec-butyllithium, lithium diisopropylamine, lithium bis(trimethylsilyl)amide, or other suitable bases known to those skilled in the art. The reaction can be carried out using acetonitrile as a solvent or in another suitable solvent, such as tetrahydrofuran or diethyl ether. In some embodiments, the solvent is tetrahydrofuran. The reaction typically occurs at low temperatures, such as -78°C or 0°C; in some embodiments, the reaction can occur at ambient temperature. The reaction is typically complete within 1 to 18 hours.

[0151] [ka]

[0152] In some embodiments, the cyanoketone of Formula III-5 can be converted to an aminopyrazole of Formula VI as shown in Scheme V. Such a reaction may be carried out using an optionally substituted hydrazine to form the aminopyrazole. In some embodiments, the optionally substituted hydrazine is hydrazine or hydrazine monohydrate. The reaction is typically carried out in the presence of a Bronsted acid, such as acetic acid or hydrochloric acid. The reaction is carried out in a suitable solvent, such as methanol, ethanol, isopropanol, n-butanol, tert-butanol, or toluene. The reaction can be carried out at ambient or elevated temperatures, between 25 and 110°C. The reaction is typically complete within 2 to 18 hours.

[0153] A compound of Formula VI can be reacted with an appropriately substituted compound of Formula I-7 to give a compound of Formula I, where Ring A contains a suitable leaving group LG. In some embodiments, such leaving group LG can be chloride, bromide, iodide, or an activated alcohol such as mesylate or tosylate. In some embodiments, Ring A can be aromatic, and the leaving group can be an aryl chloride. In some embodiments, the reaction can occur in the presence of a suitable base, such as sodium hydride, triethylamine, diisopropylethylamine, pyridine, potassium carbonate, or another base known to those skilled in the art. Such reactions typically occur in solvents such as tetrahydrofuran, dimethyl sulfoxide, 1,4-dioxane, N,N-dimethylformamide, or N,N-dimethylacetamide. The reaction can occur at ambient temperature or at elevated temperatures between 60 and 110°C. The reaction is typically complete within 1 to 18 hours.

[0154] In some embodiments, the reaction between a compound of Formula VI and a compound of Formula I-7 can be carried out in the presence of a suitable transition metal catalyst. In some embodiments, the transition metal is a copper catalyst, as in the Ullmann reaction. In some embodiments, the catalyst is a palladium complex, as in the Buchwald reaction. Such cross-coupling reactions typically occur in the presence of a palladium catalyst in complex with a phosphine ligand, such as tetrakis(triphenylphosphine)palladium, bis(diphenylphosphino)ferrocene]dichloropalladium(II), BrettPhos palladacycle G3, or another catalytic system known to those skilled in the art. Such reactions typically proceed in the presence of a suitable base, such as sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium acetate, potassium acetate, triethylamine, or another base known to those skilled in the art. This reaction is typically carried out in a solvent such as 1,4-dioxane or toluene. The reaction typically occurs at elevated temperatures, typically between 60 and 110°C. The reaction is typically complete within 6 to 24 hours.

[0155] [ka]

[0156] Those skilled in the art will recognize that it may sometimes be necessary to mask reactive functional groups on a molecule with an appropriate protecting group. In some embodiments, the protecting group(s) may be carried through several synthetic steps. In some embodiments, all of the protecting group(s) may be removed in a single global deprotection step. In some embodiments, the protecting group masks an amine functionality. In some embodiments, the protecting group is a tert-butyl carbamate group. In some embodiments, the tert-butyl carbamate-protected amine will be on Ring B. The tert-butyl carbamate protecting group is typically removed by treatment with a Bronsted acid, such as trifluoroacetic acid, hydrogen chloride, or hydrochloric acid. A typical cleavage reaction occurs in a suitable solvent, such as ethyl acetate, 1,4-dioxane, diethyl ether, or dichloromethane. The reaction typically proceeds at subambient or ambient temperatures, but may also proceed at elevated temperatures, typically between 0 and 60°C. Compounds of Formula I prepared under such conditions may be purified by standard methods, including chromatography or recrystallization. In some embodiments, the compound of Formula I is isolated directly as a salt from the deprotection reaction. In some embodiments, the compound of Formula I is purified by preparative HPLC using appropriate column and eluent conditions.

[0157] Pharmaceutical Composition In certain embodiments, the compounds described herein are administered as pure chemicals. In some embodiments, the compounds described herein are administered as pure chemicals, e.g., as described in Remington: The Science and Practice of Pharmacy (Gennaro, 2011). stIn combination with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier), selected based on the chosen route of administration and standard pharmaceutical practice, as described in Ed. Mack Pub. Co., Easton, PA (2005).

[0158] Accordingly, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0159] In certain embodiments, the compounds provided herein are substantially pure in that they contain less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, such as, for example, unreacted intermediates or synthetic by-products produced in one or more steps of the synthetic method.

[0160] The pharmaceutical composition is administered in a manner appropriate for the disease to be treated (or prevented). The appropriate dosage and the appropriate duration and frequency of administration are determined by factors such as the patient's disease, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. In general, an appropriate dosage and treatment regimen provides the composition in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., improved clinical results such as an increased overall response rate, an increased duration of response, more frequent complete or partial remissions, or a longer disease-free period and / or overall survival, or a reduction in the severity of symptoms). The optimal dose can generally be determined using experimental models and / or clinical trials. The optimal dose may depend on the patient's body mass, body weight, or blood volume.

[0161] In some embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, pulmonary, intradermal, intrathecal, epidural, or intranasal administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical administration, or ocular administration. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection. In some embodiments, the pharmaceutical composition is formulated as a tablet, pill, capsule, liquid, inhalant, nasal spray solution, suppository, suspension, gel, colloid, dispersion, suspension, solution, emulsion, ointment, lotion, eye drop, or ear drop. In some embodiments, the pharmaceutical composition is formulated as a tablet.

[0162] Suitable dosage and administration regimen can be determined by conventional range-finding techniques known to those skilled in the art.Generally, treatment is initiated with smaller dosages that are less than the optimal dosage of the compounds disclosed herein.Then, dosage is increased by small increments until the optimal effect under the circumstances is reached.

[0163] method Disclosed herein is a method of treating a tumor or tumor cells, the method comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a cancer-targeted therapeutic agent to a subject identified as having a tumor or tumor cells, wherein the tumor or tumor cells contain gene amplification, and wherein the administering reduces the growth or size of the tumor, or the growth or number of tumor cells.

[0164] Also disclosed herein is a method of delaying resistance to a cancer-targeted therapeutic agent, the method comprising administering to a subject a compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, in an amount sufficient to induce replication stress in a tumor or tumor cells, and administering the cancer-targeted therapeutic agent simultaneously with or after administration of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0165] Disclosed herein is a method for treating a tumor or tumor cells in a subject, the method comprising administering a compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. Optionally, the subject has undergone one or more prior treatments with a first cancer-targeting therapeutic agent (also referred to herein as a "prior cancer-targeting therapeutic agent") prior to treatment with the compound of formula (I). Optionally, the compound of formula (I) is administered in conjunction with administration of a second cancer-targeting therapeutic agent (also referred to herein as a "selected cancer-targeting therapeutic agent").

[0166] Also disclosed herein is a method of treating a subject having a tumor or tumor cells that are non-responsive to a first (prior) cancer targeted therapeutic agent, the method comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a second (selected) cancer targeted therapeutic agent.

[0167] Also disclosed herein is a method for inducing a response in a subject having a tumor or tumor cells that are unresponsive or have reduced responsiveness to a first (prior) cancer targeted therapeutic agent, the method comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the first (prior) cancer targeted therapeutic agent.

[0168] In some embodiments of the methods disclosed herein, the cancer targeted therapeutic agent is administered simultaneously with or after administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0169] In some embodiments of the methods disclosed herein, the first (prior) cancer targeted therapeutic agent is administered simultaneously with or after administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0170] In some embodiments of the methods disclosed herein, the second (selected) cancer targeted therapeutic agent is administered simultaneously with or after administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0171] In some embodiments of the methods disclosed herein, a cancer targeted therapeutic agent is administered prior to the step of administering a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0172] In some embodiments of the methods disclosed herein, the first (prior) cancer targeted therapeutic agent is administered prior to the administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0173] In some embodiments of the methods disclosed herein, the second (selected) cancer targeted therapeutic agent is administered prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0174] In some embodiments of the methods disclosed herein, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is administered in an amount sufficient to induce replicative stress in a tumor or tumor cells.

[0175] In some embodiments of the methods disclosed herein, the subject is identified as having a tumor or tumor cells that contain a gene amplification.

[0176] In some embodiments of the methods disclosed herein, the gene amplification is local gene amplification.

[0177] In some embodiments of the methods disclosed herein, the gene amplification is amplification from ecDNA.

[0178] In some embodiments of the methods disclosed herein, the gene amplification is contained in ecDNA or HSR (homogeneously staining region).

[0179] In some embodiments of the methods disclosed herein, the cancer-targeting therapeutic agent is directed against a protein encoded by a gene contained within the gene amplification.

[0180] In some embodiments of the methods disclosed herein, the first (prior) cancer targeted therapeutic agent is directed against a protein encoded by a gene contained within the gene amplification.

[0181] In some embodiments of the methods disclosed herein, the second (selected) cancer targeted therapeutic agent is directed against a protein encoded by a gene contained within the gene amplification.

[0182] In some embodiments of the methods disclosed herein, the tumor or tumor cells comprise an ecDNA signature.

[0183] In some embodiments of the methods disclosed herein, cells contained within a tumor or tumor cells are ecDNA competent. For example, ecDNA competent tumor cells may have detectable levels of ecDNA amplification, or ecDNA competent tumor cells may have the ability to generate ecDNA amplification in response to selection pressure, such as a targeted therapy (e.g., a cancer-targeted therapeutic agent described herein).

[0184] In some embodiments of the methods disclosed herein, treatment with both a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a cancer targeted therapeutic agent has a greater effect or a longer duration of effect on reducing one or more of tumor growth, tumor size, number of tumor cells, or tumor metastasis compared to treatment with either the compound of Formula (I) or the cancer targeted therapeutic agent administered alone.

[0185] In some embodiments of the methods disclosed herein, treatment with both the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the first (prior) cancer targeted therapeutic agent has a greater effect or a longer duration of effect on reducing one or more of tumor growth, tumor size, number of tumor cells, or tumor metastasis compared to treatment with either the compound of Formula (I) or the first (prior) cancer targeted therapeutic agent administered alone.

[0186] In some embodiments of the methods disclosed herein, treatment with both a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a second (selected) cancer targeted therapeutic agent has a greater effect or a longer duration of effect on reducing one or more of tumor growth, tumor size, number of tumor cells, or tumor metastasis compared to treatment with either the compound of Formula (I) or the second (selected) cancer targeted therapeutic agent administered alone.

[0187] In some embodiments of the methods disclosed herein, the greater effect is a synergistic effect.

[0188] In some embodiments of the methods disclosed herein, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and / or the cancer targeted therapeutic agent is administered orally.

[0189] In some embodiments of the methods disclosed herein, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and / or the first (or prior) cancer targeted therapeutic agent is administered orally.

[0190] In some embodiments of the methods disclosed herein, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and / or the second (selected) cancer targeted therapeutic agent are administered orally.

[0191] In some embodiments of the methods disclosed herein, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and / or the cancer targeted therapeutic agent is administered parenterally.

[0192] In some embodiments of the methods disclosed herein, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and / or the first (or prior) cancer targeted therapeutic agent is administered parenterally.

[0193] In some embodiments of the methods disclosed herein, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and / or the second (selected) cancer targeted therapeutic agent are administered parenterally.

[0194] In some embodiments of the methods disclosed herein, the treatment comprises administering multiple doses of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and / or a cancer targeted therapeutic agent over a treatment period. In some embodiments of the methods disclosed herein, the treatment comprises administering multiple doses of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and / or a first (prior) cancer targeted therapeutic agent over a treatment period.

[0195] In some embodiments of the methods disclosed herein, the treatment comprises administering multiple doses of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and / or a second (selected) cancer-targeted therapeutic agent over a treatment period.

[0196] In some embodiments of the methods disclosed herein, the gene amplification comprises amplification of a gene selected from the group consisting of ABCB1, AKT, ALK, AR, BCL-2, BCR-ABL, BRAF, CDK4, CDK6, c-MET, EGFR, ER, ERBB3, ERRB2, AK, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, GR, HER2, HRAS, IGF1R, KIT, KRAS, MCL-1, MDM2, MDM4, MTOR, MYC, MYCL, MYCN, NRAS, NRG1, NTRK1, NTRK2, NTRK3, PDGFR, PIK3Cδ, PIK3CA / B, RET, and ROS1.

[0197] In some embodiments of the methods disclosed herein, the gene amplification comprises amplification of a gene selected from the group consisting of CDK4, CDK6, c-MET, EGFR, FGFR1, FGFR2, FGFR3, and FGFR4.

[0198] In some embodiments of the methods disclosed herein, the first (prior) cancer targeted therapeutic agent is different from the second (selected) cancer targeted therapeutic agent.

[0199] In some embodiments of the methods disclosed herein, the first (prior) cancer targeted therapeutic agent is the same as the second (selected) cancer targeted therapeutic agent.

[0200] In some embodiments of the methods disclosed herein, the cancer targeted therapeutic agent, the first (prior) cancer targeted therapeutic agent, the second cancer targeted therapeutic agent, or the selected cancer targeted therapeutic agent is abemaciclib, ado-trastuzumab emtansine, afatinib, alectinib, ALRN-6924, AMG232, AMG-510, apatinib, ARS-3248, AXL1717, AZD-3759, bevacizumab, BI 1701963, bortezomib, brigatinib, cabozantinib, capmatinib, ceritinib, cetuximab, CGM097, crizotinib, dabrafenib, dacomitinib, dasatinib, DS-3032b, encorafenib, entrectinib, ERAS-801, erdafitinib, erlotinib, everolimus, trastuzumab deruxtecan (fam-trastuzumab druxtecan), figitumumab, futibatinib, gefitinib, gossypol, HDM201, idasanutinib, imatinib, infigratinib, iniparib, lapatinib, larotrectinib, LEE011, lenvatinib, LGX818, lorlatinib, MEK162, MK-8242 SCH 900242, MRTX849, navitoclax, necitumumab, nilotinib, obatoclax, olaparib, OSI-906, osimertinib, palbociclib, panitumumab, PD-0332991, perisophrine, pertuzumab, PF-06873600, PF-07220060, PL225B, repotrectinib, ribociclib, RLY-4008 , RO5045337, salinomycin, salirasib, SAR405838, MI-77301, sorafenib, sotrasib, sunitinib, tamoxifen, temsirolimus, tipifarnib, tibanitab, tofacitinib, trametinib, trastuzumab, tucatinib, UPR1376, VAL-083, vemurafenib, vintafolide, and zoptarelin doxorubicin.

[0201] In some embodiments of the method disclosed herein, the cancer targeted therapeutic agent, the first (previous) cancer targeted therapeutic agent, the second cancer targeted therapeutic agent, or the selected cancer targeted therapeutic agent is an inhibitor of EFGR, FGFR, CDK4 / CDK6, or KRAS.In some cases, the EGFR inhibitor is erlotinib, gefitinib, or an analog thereof, or an antibody such as cetuximab, necitumumab, nimotuzumab, and panitumumab.In some cases, the FGFR inhibitor is erdafitinib, futibatinib, infigratinib, pemigatinib, RLY-4008, or an analog thereof.In some cases, the KRAS inhibitor is adagrasib, BI 1701963, sotorasib, or an analog thereof. In some cases, the CDK4 / CDK6 inhibitor is abemaciclib, palbociclib, ribociclib, PF-06873600, PF-07220060, or an analog thereof.

[0202] In some embodiments of the methods disclosed herein, the cancer targeted therapeutic agent, the first (previous) cancer targeted therapeutic agent, the second cancer targeted therapeutic agent, or the selected cancer targeted therapeutic agent is a BRAF inhibitor. In some embodiments, BRAF inhibitors include ASN-003, AZ-304, AZ-628, DP-2874, EBI-907, EBI-945, GDC-0879, LYN 204, NMS-P285, NMS-P730, PF-04880594, TL-241, UAI-201, and UB-941. In some embodiments, BRAF inhibitors include ABM-1310, agerafenib (RXDX-105), ARQ-736, BAL-3833, belvarafenib, BGB-3245, BI-882370, DAY101, lifirafenib, LUT-014, PF-07284890, PLX-8394, RX-208, VS-6766, and XL-281. In some embodiments, BRAF inhibitors include dabrafenib, encorafenib, and vemurafenib.

[0203] In some embodiments of the methods disclosed herein, the cancer targeted therapeutic agent, the first (previous) cancer targeted therapeutic agent, the second cancer targeted therapeutic agent, or the selected cancer targeted therapeutic agent is an inhibitor of MDM2 or MDM4. In some embodiments, MDM2 inhibitors include AD-021.32, CYC700, DS-5272, MI-1061, MI-219, MI-43, MD-224, MK-8242, NU-8231, OM-301, PXN-527, Rigel-3, RO-2468, RO-5353, RO-5963, and SIL-43. In some embodiments, MDM2 inhibitors include ALRN-6924, APG-115, ASTX-295, ATSP-7041, BI-907828, CGM-097, idasanutlin, KRT-232 (AMG-232), MI-77301 (SAR405838, SAR299155), NVP-CGM097, RAIN-32 (mirademetan), RG7112 (RO5045337), RG7388 (RG7775), serdemetan (JNJ-26854165), siremadlin, and UBX-0101. In some embodiments, MDM4 inhibitors include 17AAG, 489-PXN, CTX1, FL-118, Inulanolide A, K-178, and SAH-p53-8. In some embodiments, MDM4 inhibitors include APG-115, ALRN-6924, ATSP-7041, and BI-907828.

[0204] In some embodiments of the methods disclosed herein, the cancer targeted therapeutic agent, the first (previous) cancer targeted therapeutic agent, the second cancer targeted therapeutic agent, or the selected cancer targeted therapeutic agent is an inhibitor of MET. In some embodiments, the inhibitors include, but are not limited to, ABP-1130, BPI-1831, BPI-2021, BYON-3521, CG-203306, CX-1003, Debio-1144, EMD-94283, EMT-100, EMT-101, HE-003, LMV-12, LS-177, NX-125, OMO-2, PF-4254644, PRX-MET, PTX-2173, Q MET small molecule inhibitors such as BH-196, RP-1400, SAB-Y14, SAR-125844, SGX-126, SYD-3521, WXSH-0011, X-379, and XL-265, and anti-MET antibodies such as ABX-900, GB-263, FS-101, LY-3164530, LY-3343544, PMC-002, and SAIT-301. In some embodiments, ABN-401, ABT-700, AMG-208, AMG-337, ARGX-111, BAY-85-3474, BMS-817378, bozitinib, BPI-9016M, glumetinib, golvatinib tartrate, GST-HG161, HQP-8361, I-020, JNJ-38877605, kanitinib, merestinib, MK-2461, MK-8033, OMO-1, pamufetinib, S-49076, savolitinib, SPH-3348, tivantinib, SAR-125844, SCR These include MET small molecule inhibitors such as MET-1515, and TPX-0022, and anti-MET antibodies such as APL-101, CKD-702, EMB-01, EMI-137, ficlatuzumab, HLX-55, HS-10241, MCLA-129, MT-8633, NOV-1105, RC-108, REGN-5093, SHR-A1403, Sym-015, and telisotuzumab vedotin.In some embodiments, the MET small molecule inhibitors include amivantamab, capatinib, crizotinib, and tepotinib.

[0205] In some embodiments of the methods disclosed herein, the cancer targeted therapeutic agent, the first (previous) cancer targeted therapeutic agent, the second cancer targeted therapeutic agent, or the selected cancer targeted therapeutic agent is a CDK4 / 6 inhibitor. In some embodiments, CDK4 / 6 inhibitors include AG-122275, AM-5992, AU2-94, IIIM-985, IIIM-290, GW-491619, HEC-80797, MM-D37K, MS-140, NP-102, QHRD-110, R-547, RGB-286199, RGT-419B, riviciclib, RO-0505124, THR-53, THR-79, TQB-3303, TY-302, VS2-370, XH-30002, and WXWH-0240. In some embodiments, CDK4 / 6 inhibitors include auceliciclib, AT-7519, BEBT-209, BPI-1178, BPI-16350, CS-3002, fascaplysin, FCN-437, FN-1501, GLR-2007, HS-10342, lerociclib, milciclib maleate, NUV-422, ON-123300, PF-06842874, PF-06873600, PF-07220060, SHR-6390, TQB-3616, TY-302, voruciclib, and XZP-3287. In some embodiments, CDK4 / 6 inhibitors include abemaciclib, palbociclib, ribociclib, and trilaciclib.

[0206] In some embodiments of the methods disclosed herein, the cancer targeted therapeutic agent, the first (prior) cancer targeted therapeutic agent, the second cancer targeted therapeutic agent, or the selected cancer targeted therapeutic agent is palbociclib or abemaciclib.

[0207] In some embodiments of the methods disclosed herein, the cancer targeted therapeutic agent, the first (previous) cancer targeted therapeutic agent, the second cancer targeted therapeutic agent, or the selected cancer targeted therapeutic agent is an inhibitor of EGFR. In some embodiments, EGFR inhibitors include small molecule inhibitors such as APL-1898, BDTX-1535, BLU-701, BPI-361175, CH-7233163, DS-2087, E-10C, FWD-1509, IN-A008, JS-111, JS-113, LL-191, LYN 205, neptinib, NT-004, ORIC-114, PRB-001, SIM-200, TGRX-360, WJ-13404, yinlitinib maleate, and ZSP-0391, and anti-EGFR antibodies such as 705, 707, ABX-900, CMAB-017, GB-263, KN-023, SSGJ-612, and SHR-A1307.In some embodiments, the EGFR inhibitor is selected from the group consisting of abivertinib, alflutinib mesylate, ASK-120067, BBT-176, BDTX-189, BEBT-109, befortinib mesylate, beitatini, BPI-7711, BPI-D0316, BLU-945, CK-101, dositinib, DFP-17729, DZD-9008, epertinib, epitinib (HMPL-813), ES-072, FCN-411, FHND-9041, and flumone. Furmonertinib, GMA-204, Hemay-022, JRF-103, KP-673, larotinib, lazertinib, maihuatinib, marizomib, mobocertinib, naptinib tosylate, nazartinib, NRC-2694-A, OBX1-01 2, small molecule inhibitors such as orafeltinib, olmutinib, oritinib, pyrotinib, poziotinib, SPH-1188, tarloxotinib, teliatinib (HMPL-309), TAS-6417, TPC-064, TQB-3804, TY-9591, WSD-0922, XZP-5809, YK-029A, YZJ-0318, and zolifertinib, as well as anti-EGFR Antibodies include, for example, 602, C-005, CDP1, depatuxizumab, E01001, GC-1118A, GR-1401, HLX-07, HS-627, I-010, imgatuzumab, JMT-101, JZB-28, KN-026, MP-0274, QL-1203, SCT-200, cercultamab, SYN-004, and small molecule inhibitors such as TAD-011.In some embodiments, EGFR inhibitors include small molecule inhibitors such as afatinib, amivantamab, aumolertinib (almonertinib), dacomitinib, erlotinib, gefitinib, icotinib, lapatinib, osimertinib, and pyrotinib, and anti-EGFR antibodies such as cetuximab, necitumumab, nimotuzumab, and panitumumab.

[0208] In some embodiments of the methods disclosed herein, the cancer targeted therapeutic agent, the first (prior) cancer targeted therapeutic agent, the second cancer targeted therapeutic agent, or the selected cancer targeted therapeutic agent is erlotinib.

[0209] In some embodiments of the methods disclosed herein, the cancer targeted therapeutic agent, the first (previous) cancer targeted therapeutic agent, the second cancer targeted therapeutic agent, or the selected cancer targeted therapeutic agent is an inhibitor of FGFR.

[0210] In some embodiments, FGFR inhibitors include small molecule inhibitors such as ABSK-012, ABSK-061, AST-56100, BIO-1262, BGS-2219, EVT-601, FPI-1966, JAB-6000, KIN-3248, SAR-439115, SC-0011, and WXSH-0011, and anti-FGFR antibodies such as M-6123, OM-RCA-001. In some embodiments, the FGFR inhibitor is 3D-185, ABSK-011, ABSK-091, aldafermin, allofanib, AZD-4547, BFKB-8488A, BPI-17509, BPI-43487, CPL-304-110, derazantinib, E-7090, EVER-4010001, FGF-401, fisogatinib, futibatinib, or gangura. In some embodiments, FGFR inhibitors include small molecule inhibitors such as erdafitinib, pemigatinib, and small molecule inhibitors such as erdafitinib, pemigatinib, and small molecule inhibitors such as erdafitinib.

[0211] In some embodiments of the methods disclosed herein, the cancer targeted therapeutic agent, the first (prior) cancer targeted therapeutic agent, the second cancer targeted therapeutic agent, or the selected cancer targeted therapeutic agent is infigratinib, futibatinib, or pemigatinib.

[0212] In some embodiments of the methods disclosed herein, the cancer targeted therapeutic agent, the first (previous) cancer targeted therapeutic agent, the second cancer targeted therapeutic agent, or the selected cancer targeted therapeutic agent is an inhibitor of KRAS. In some embodiments, KRAS inhibitors include small molecule inhibitors such as ABREV01, ARS-1620, APG-1842, ATG-012, BBP-454, BEPT-607, BI-2852, BI-1823911, BPI-421286, BTX-2541, COTI-219, IMM-1811900, JAB-21000, JAB-22000, JAB-23000, JAB-BX300, JP-002, KR-12, LYN202, MRTX-1133, RAS-F, RMC-6236, RMC-6291, SDGR5, STX-301, and YL-15293, and anti-KRAS antibodies such as SBT-100, SBT-102, and SBT-300. In some embodiments, KRAS includes small molecule inhibitors such as adagrasib, ARS-3248, D-1553, GDC-6036, JDQ-443, LY3537982, sotalasib (AMG510), and BI 1701963.

[0213] In some embodiments of the methods disclosed herein, the cancer targeted therapeutic agent, the first (previous) cancer targeted therapeutic agent, the second cancer targeted therapeutic agent, or the selected cancer targeted therapeutic agent is an inhibitor of c-MET, HER2, androgen receptor (AR), KIT, PDGFRA PI3K, AKT, BCL2, or MCL1. In some embodiments, the c-MET inhibitor includes a monoclonal antibody against c-MET, such as crizotinib, tivantinib, cabozantinib, foretinib, or onartuzumab.

[0214] In some embodiments of the methods disclosed herein, the cancer targeted therapeutic agent, the first (prior) cancer targeted therapeutic agent, the second cancer targeted therapeutic agent, or the selected cancer targeted therapeutic agent is a cMET inhibitor.

[0215] In some embodiments of the methods disclosed herein, the cancer targeted therapeutic agent, the first (prior) cancer targeted therapeutic agent, the second cancer targeted therapeutic agent, or the selected cancer targeted therapeutic agent is tepotinib.

[0216] In some embodiments of the methods disclosed herein, the cancer targeted therapeutic agent, the first (prior) cancer targeted therapeutic agent, the second cancer targeted therapeutic agent, or the selected cancer targeted therapeutic agent targets a protein encoded by one or more genes presented in Table 3.

[0217] [Table 3-1] [Table 3-2]

[0218] In some embodiments of the methods disclosed herein, prior to treatment with a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, the tumor or tumor cells contain a gene amplification and the previous cancer-targeted therapeutic agent has activity directed against a protein encoded by a gene contained within the gene amplification.

[0219] In some embodiments of the methods disclosed herein, prior to treatment with a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, the tumor or tumor cells contain a gene amplification and the first (prior) cancer targeted therapeutic agent has activity directed against a protein encoded by a gene contained within the gene amplification.

[0220] In some embodiments of the methods disclosed herein, prior to treatment with a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, the tumor or tumor cells comprise a gene amplification, and the second cancer-targeted therapeutic agent has activity directed against a protein encoded by a gene contained within the gene amplification.

[0221] In some embodiments of the methods disclosed herein, prior to treatment with a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, the tumor or tumor cells contain a gene amplification, and the selected cancer-targeted therapeutic agent has activity directed against a protein encoded by a gene contained within the gene amplification.

[0222] In some embodiments of the methods disclosed herein, the subject has received one or more previous cancer targeted therapeutic agents prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the tumor or tumor cells have acquired resistance to the first (or previous) cancer targeted therapeutic agent.

[0223] In some embodiments of the methods disclosed herein, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is administered simultaneously with or prior to the administration of the cancer targeted therapeutic agent.

[0224] In some embodiments of the methods disclosed herein, a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is administered simultaneously with or prior to the administration of a selected cancer-targeted therapeutic agent.

[0225] In some embodiments of the methods disclosed herein, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is administered simultaneously with or prior to the administration of a first (prior) cancer targeted therapeutic agent.

[0226] In some embodiments of the methods disclosed herein, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is administered simultaneously with or prior to the administration of a second (selected) cancer-targeted therapeutic agent.

[0227] In some embodiments of the methods disclosed herein, the subject has received one or more administrations of a first (or prior) cancer targeted therapeutic agent(s) prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the tumor or tumor cells have developed reduced responsiveness or resistance to the first (or prior) cancer targeted therapeutic agent(s).

[0228] In some embodiments of the methods disclosed herein, treatment with both a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a cancer targeted therapeutic agent has a greater effect or a longer duration of effect on reducing one or more of tumor growth, tumor size, the number of tumor cells, or tumor metastasis, compared to treatment with either the compound of Formula (I) or the cancer targeted therapeutic agent alone. In some embodiments of the methods disclosed herein, treatment with both a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a first (or previous) cancer targeted therapeutic agent has a greater effect or a longer duration of effect on reducing one or more of tumor growth, tumor size, the number of tumor cells, or tumor metastasis, compared to treatment with either the compound of Formula (I) or the first (or previous) cancer targeted therapeutic agent alone.

[0229] In some embodiments of the methods disclosed herein, treatment with both a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a second (selected) cancer targeted therapeutic agent has a greater effect or a longer duration of effect on reducing one or more of tumor growth, tumor size, number of tumor cells, or tumor metastasis compared to treatment with either the compound of Formula (I) or the second (selected) cancer targeted therapeutic agent administered alone.

[0230] In certain embodiments, when a compound disclosed herein is administered in combination with a second (selected) therapeutic agent, different therapeutically effective doses of the compound disclosed herein will be utilized in the formulation of pharmaceutical compositions and / or treatment regimens. The therapeutically effective dosages of drugs and other agents used in combination treatment regimens are optionally determined by means similar to those specified above for the active ingredients themselves. Furthermore, the prevention / treatment methods described herein include the use of metronomic dosing, i.e., providing more frequent and lower doses to minimize toxic side effects. In some embodiments, a combination treatment regimen includes a treatment regimen in which administration of a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is initiated before, during, or after treatment with a second (selected) agent described herein, and continues until any time during or after treatment with the second (selected) agent. Combination treatment regimens also include treatments in which a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a second (selected) agent used in combination are administered simultaneously or at different times and / or at intervals that increase or decrease the duration of treatment. Combination treatments further include periodic treatments that are started and stopped at various times to aid in the clinical management of the patient.

[0231] It is understood that dosage regimens for treating, preventing, or ameliorating the condition for which relief is sought will be modified according to various factors (e.g., the disease, disorder, or condition from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject). Thus, in some instances, the dosage regimen utilized will vary, and in some embodiments, will deviate from the dosage regimens set forth herein. With respect to the combination treatments described herein, the dosage of the co-administered compounds will vary depending on the type of co-drug utilized, the particular drug utilized, the disease or condition being treated, etc.

[0232] The compounds described herein, or pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers thereof, and combination therapies, are administered before, during, or after the onset of a disease or disorder, and the timing of administration of compositions containing the compounds varies.

[0233] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is administered in combination with an adjuvant. In one embodiment, the therapeutic effect of one of the compounds described herein is enhanced by the administration of an adjuvant (i.e., the adjuvant has minimal therapeutic benefit by itself, but when combined with another therapeutic agent, enhances the overall therapeutic benefit to the patient).

[0234] In some embodiments, a subject identified as having a tumor or tumor cells has cancer. In some embodiments, cancer includes malignant tumors whose size can be reduced, whose growth or spread can be slowed or stopped, or whose symptoms can be ameliorated, alleviated, and / or completely cured by deleting, suppressing, and / or inhibiting the function of Chk1. Malignant tumors of interest include, but are not limited to, head and neck cancer, gastrointestinal cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder cancer, bile duct cancer, etc.), pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.)), lung cancer (non-small cell lung cancer, small cell lung cancer, squamous cell lung cancer, mesothelioma, etc.), breast cancer, genital cancer (ovarian cancer, uterine cancer, cervical cancer, endometrial cancer, etc.), urinary tract cancer (kidney cancer, bladder cancer, prostate cancer, testicular tumor, etc.), hematopoietic tumor (leukemia, malignant lymphoma, multiple myeloma, etc.), bone and soft tissue tumor (e.g., soft tissue sarcoma and osteosarcoma), skin cancer, brain tumor (e.g., glioblastoma), etc.

[0235] In some embodiments, the term cancer is used according to its ordinary and plain meaning in light of the present disclosure to refer to all types of cancers, neoplasms, or malignant tumors found in mammals, including leukemias, lymphomas, melanomas, neuroendocrine tumors, carcinomas, and sarcomas. Exemplary cancers that may be treated with the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers thereof, pharmaceutical compositions include acute myeloid leukemia, adrenocortical carcinoma, adrenal gland cancer, bladder cancer, bone cancer, cancer of the brain, breast cancer (e.g., ductal carcinoma, lobular carcinoma, primary, metastatic), breast cancer, cancer of the endocrine system, cancer of hepatic stellate cells, cancer of pancreatic stellate cells, cervical cancer, colon cancer, colorectal cancer, ductal carcinoma, endometrial cancer, esophageal cancer, gastric cancer, cancer of the genitourinary tract, glioblastoma, glioma, head and neck cancer, hepatocellular carcinoma, Hodgkin's disease, kidney cancer, leukemia (e.g., lymphoblastic leukemia, chronic lymphocytic leukemia, hairy cell leukemia), liver cancer (e.g., hepatocellular carcinoma), lobular carcinoma, lung cancer (e.g., non-small cell lung cancer, squamous cell lung carcinoma, adenocarcinoma, large cell lung cancer, small cell lung cancer, carcinoid, sarcoma), lymph node cancer, lymphoma (e.g., mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, marginal zone lymphoma, Burkitt's lymphoma, non-Hodgkin's lymphoma), malignant carcinoid, malignant hypercalcemia, malignant pancreatic insulinoma, medullary thyroid carcinoma, medulloblastoma, melanoma, mesothelioma, multiple myeloma, muscle carcinoma, neoplasms of the endocrine or exocrine pancreas, neuroblastoma, ovarian cancer, Paget's disease of the nipple, pancreatic cancer, papillary thyroid carcinoma, phyllodes tumor, premalignant skin lesions, primary thrombocythemia, prostate cancer (e.g., castration-resistant prostate cancer), rhabdomyosarcoma, salivary gland cancer, sarcoma, soft tissue sarcoma, squamous cell carcinoma (e.g., of the head, neck, or esophagus), gastric cancer, testicular cancer, thyroid cancer, bladder cancer, or uterine cancer. In embodiments, the cancer is selected from bladder cancer, breast cancer, colon cancer, esophageal cancer, glioblastoma, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, salivary gland cancer, soft tissue sarcoma, squamous cell lung cancer, gastric cancer, and uterine cancer.

[0236] Gene amplification plays a role in the response of tumors or tumor cells to cancer-directed therapies and in the acquisition of resistance to targeted therapy. In some cases, gene amplification involves the amplification of one or more genes, such as oncogenes, where the one or more oncogenes are in higher copy number, while the surrounding genetic material (e.g., from the chromosomal location of such amplified genes) is not amplified or is not at the same amplification level. Local amplification is derived from ecDNA or ecDNA (i.e., derived from ecDNA, such as ecDNA that reintegrates into one chromosome). ecDNA mediates an important and clinically distinct mechanism of resistance to targeted therapy. Tumor cells with ecDNA and / or ecDNA-derived amplification may be non-responsive, hyporesponsive, or resistant to targeted therapy. There are imminent therapeutic opportunities for utilizing the compound of formula (I), or its pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer, in combination with other therapies. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, can be used in combination with a therapeutic agent to treat ecDNA+ cancers, ecDNA+ tumors, or ecDNA+ tumor cells (i.e., tumor cells containing gene amplifications on or derived from ecDNA). A combination of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a therapeutic agent can be used to treat tumors having one or more amplified cancer genes (e.g., BRAF, CDK4, CDK6, EGFR, FGFR, HER2, KRAS, MET, MDM2 amplification), etc., where in some cases, the one or more amplified cancer genes include non-mutated cancer genes, and in some cases, the amplified cancer genes include mutated cancer genes. In some cases, the one or more amplified cancer genes are extrachromosomal (i.e., on ecDNA) and / or derived from ecDNA and located on a chromosome.In some embodiments herein, the therapeutic agent used in combination with a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is an inhibitor of a protein encoded by a gene amplified on ecDNA, or an inhibitor of ecDNA-derived amplification.

[0237] The combinations described herein can be used to treat tumors that have developed resistance to another therapy, such as resistance to a targeted agent. In some cases, tumors (or tumor cells) treated with a first (previous) targeted agent acquire resistance to the first (previous) targeted agent or become less responsive or unresponsive to the first (previous) targeted agent. In some cases, the first (previous) therapeutic agent is an inhibitor of a protein encoded by a gene amplified on ecDNA or an inhibitor of ecDNA-derived amplification, and a compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the first (previous) targeted agent can be used to treat such tumors or tumor cells. In some cases, the first (prior) therapeutic agent is an inhibitor of a protein encoded by a gene amplified on ecDNA or an inhibitor of ecDNA-derived amplification, and a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a second (selected) targeted agent may be used to treat such tumors or tumor cells, wherein the second (selected) targeted agent is an inhibitor of a protein that is different from the protein target of the first (prior) targeted agent.

[0238] Provided herein are methods in which inhibition by a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, exhibits synthetic lethality with a cancer-targeting agent. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, in combination with a cancer-targeting agent results in synthetic lethality. In some cases, the tumor background is identified as highly sensitive to Chk1 inhibitors, allowing for a therapeutic index sufficient to allow for an effective tolerated dose. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, in combination with a cancer-targeting agent results in synthetic lethality, wherein the tumor or tumor cells are ecDNA+ (i.e., contain ecDNA or ecDNA-derived gene amplification). In some cases, Chk1 inhibition results in a decrease in ecDNA copy number. In some cases, Chk1 inhibition results in enhanced cytotoxicity in ecDNA+ cells. In some cases, enhanced cytotoxicity results from the combination of Chk1 inhibition with the inhibition of a cancer target, such as an oncogene.

[0239] In some embodiments of the methods disclosed herein, prior to treatment, the tumor or tumor cells contain ecDNA, and the treatment results in a decrease in the amount of ecDNA in the tumor or tumor cells.

[0240] In some embodiments of the methods disclosed herein, prior to treatment, the tumor or tumor cells contain ecDNA, and the level or amount of ecDNA after treatment is not elevated compared to before treatment.

[0241] In some embodiments of the methods disclosed herein, the method further comprises evaluating a sample from the subject for the presence or level of one or more of gene amplification, local gene amplification, ecDNA, HSR, or ecDNA signature. Optionally, such evaluation is performed before treatment, during a course of treatment, or after treatment.

[0242] In some embodiments of the methods disclosed herein, the methods further include obtaining information on the presence or level of one or more of gene amplification, local gene amplification, ecDNA, HSR, or ecDNA signature in tumors or tumor cells from a subject before, during, or after administration of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. In some cases, such information is obtained prior to treatment with a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a targeted cancer therapeutic agent. In some cases, such information is obtained during a course of treatment with an inhibitor that is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a targeted cancer therapeutic agent. In some cases, such information is obtained after treatment with a first (prior) targeted cancer therapeutic agent but before treatment with a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and if the information indicates the presence of ecDNA or ecDNA-derived gene amplification, the subject is treated with a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, in combination with the first (prior) targeted cancer therapeutic agent, or is treated with a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, in combination with a second (selected) targeted cancer therapeutic agent.

[0243] In one embodiment of the methods described herein, a tumor or tumor cell is determined to have an ecDNA signature. In some cases, a tumor or tumor cell is determined to have an ecDNA signature when it has one or more characteristics associated with ecDNA+ tumor or tumor cell. For example, in some cases, the ecDNA signature is selected from the group consisting of gene amplification; local gene amplification; structural mutation characterization; p53 loss-of-function mutation; lack of microsatellite instability (MSI-H); low level of PD-L1 expression; low level of tumor inflammation signature (TIS); low level of tumor mutation burden (TMB); increased frequency of allelic substitution, insertion, or deletion (indel); or a combination thereof.

[0244] In one embodiment of the methods described herein, the tumor or tumor cells have an ecDNA signature. In some cases, the tumor or tumor cells acquire the ecDNA signature after administration of a first (previous) cancer-targeting therapeutic agent. In some cases, the tumor or tumor cells acquire the ecDNA signature before treatment.

[0245] In some embodiments of the methods disclosed herein, information regarding the presence or level of one or more of gene amplification, local gene amplification, ecDNA, HSR, or ecDNA signature in a tumor or tumor cells is obtained from blood, tissue, or one or more cells.

[0246] In some embodiments of the methods disclosed herein, information regarding the presence or level of one or more of gene amplification, local gene amplification, ecDNA, HSR, or ecDNA signature in a tumor or tumor cells is obtained by liquid biopsy or tissue biopsy.

[0247] Numbered Embodiments Embodiment 1: A method of treating a tumor or tumor cells, comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a cancer-targeted therapeutic agent to a subject identified as having a tumor or tumor cells, wherein the tumor or tumor cells contain gene amplification, and wherein the administering reduces tumor growth or size, or tumor cell growth or number.

[0248] Embodiment 2: The method of embodiment 1, wherein the cancer targeted therapeutic agent is administered simultaneously with or after administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0249] Embodiment 3: The method of embodiment 1 or embodiment 2, wherein the cancer targeted therapeutic agent is administered prior to the step of administering the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0250] Embodiment 4: The method of any one of embodiments 1-3, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is administered in an amount sufficient to induce replication stress in the tumor or tumor cells.

[0251] Embodiment 5: A method of delaying resistance to a cancer targeted therapeutic agent, comprising administering to a subject a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, in an amount sufficient to induce replication stress in a tumor or tumor cells, and administering the cancer targeted therapeutic agent simultaneously with or following administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0252] Embodiment 6: The method of embodiment 5, wherein the subject is identified as having a tumor or tumor cells that contain gene amplification.

[0253] Example 7: The method of any one of embodiments 1 to 4 or 6, wherein the gene amplification is local gene amplification.

[0254] Embodiment 8: The method of any one of embodiments 1 to 4, 6, or 7, wherein the gene amplification is amplification from ecDNA.

[0255] Embodiment 9: The method of any one of embodiments 1-4 or 6-8, wherein the gene amplification is contained in ecDNA or HSR (homogeneously staining region).

[0256] Embodiment 10: The method of any one of embodiments 1-4 or 6-9, wherein the cancer targeted therapeutic agent is directed against a protein encoded by a gene contained within the gene amplification.

[0257] Embodiment 11: The method of any one of embodiments 1 to 10, wherein the tumor or tumor cells comprise an ecDNA signature.

[0258] Embodiment 12: The method of any one of embodiments 1 to 11, wherein the cells contained within the tumor or tumor cells are ecDNA competent.

[0259] Embodiment 13: The method of any one of embodiments 1-12, wherein treatment with both the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the cancer therapeutic agent has a greater effect or a longer duration of effect on reducing one or more of tumor growth, tumor size, number of tumor cells, or tumor metastasis compared to treatment with either the compound of Formula (I) or the cancer therapeutic agent administered alone.

[0260] Embodiment 14: The method of embodiment 13, wherein the greater effect is a synergistic effect.

[0261] Embodiment 15: The method of any one of embodiments 1-14, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and / or the cancer targeted therapeutic agent is administered orally.

[0262] Embodiment 16: The method of any one of embodiments 1-14, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and / or the cancer targeted therapeutic agent is administered parenterally.

[0263] Embodiment 17: The method of any one of embodiments 1-16, wherein the treatment comprises administering multiple doses of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and / or a cancer targeted therapeutic agent over a treatment period.

[0264] Embodiment 18: The method of any one of embodiments 1 to 4 or 6 to 17, wherein the gene amplification comprises amplification of a gene selected from the group consisting of ABCB1, AKT, ALK, AR, BCL-2, BCR-ABL, BRAF, CDK4, CDK6, c-MET, EGFR, ER, ERBB3, ERRB2, AK, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, GR, HER2, HRAS, IGF1R, KIT, KRAS, MCL-1, MDM2, MDM4, MTOR, MYC, MYCL, MYCN, NRAS, NRG1, NTRK1, NTRK2, NTRK3, PDGFR, PIK3Cδ, PIK3CA / B, RET, and ROS1.

[0265] Embodiment 19: The cancer therapeutic agent is selected from the group consisting of abemaciclib, ado-trastuzumab emtansine, afatinib, alectinib, ALRN-6924, AMG232, AMG-510, apatinib, ARS-3248, AXL1717, AZD-3759, bevacizumab, BI 1701963, bortezomib, brigatinib, cabozantinib, capmatinib, ceritinib, cetuximab, CGM097, crizotinib, dabrafenib, dacomitinib, dasatinib, DS-3032b, encorafenib, entrectinib, ERAS-801, erdafitinib, erlotinib, everolimus, trastuzumab deruxtecan (fam-trastuzumab druxtecan), figitumumab, futibatinib, gefitinib, gossypol, HDM201, idasanutlin, imatinib, infigratinib, iniparib, lapatinib, larotrectinib, LEE011, lenvatinib, LGX818, lorlatinib, MEK162, MK-8242 SCH 900242, MRTX849, navitoclax, necitumumab, nilotinib, obatoclax, olaparib, OSI-906, osimertinib, palbociclib, panitumumab, PD-0332991, perisophrine, pertuzumab, PF-06873600, PF-07220060, PL225B, repotrectinib, ribociclib, RLY-4008 , RO5045337, salinomycin, salirasib, SAR405838, MI-77301, sorafenib, sotorasib, sunitinib, tamoxifen, temsirolimus, tipifarnib, tibanitab, tofacitinib, trametinib, trastuzumab, tucatinib, UPR1376, VAL-083, vemurafenib, vintafolide, and zoptarelin doxorubicin.

[0266] Embodiment 20: A method of treating a subject having a tumor or tumor cells that are non-responsive to a first cancer targeted therapeutic agent, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a second cancer targeted therapeutic agent.

[0267] Embodiment 21: The method of embodiment 20, wherein prior to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, the tumor or tumor cells comprise a gene amplification, and the first cancer targeted therapeutic agent has activity directed against a protein encoded by a gene contained within the gene amplification.

[0268] Embodiment 22: The method of embodiment 21, wherein the subject has received one or more administrations of a first cancer targeted therapeutic agent prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the tumor or tumor cells have acquired resistance to the first cancer targeted therapeutic agent.

[0269] Embodiment 23: The method of any one of embodiments 20-22, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is administered simultaneously with or prior to the administration of a second cancer targeted therapeutic agent.

[0270] Embodiment 24: The method of any one of embodiments 21 to 23, wherein the gene amplification is local gene amplification.

[0271] Embodiment 25: The method of any one of embodiments 21 to 24, wherein the gene amplification is amplification from ecDNA.

[0272] Embodiment 26: The method of any one of embodiments 21 to 25, wherein the gene amplification is contained in ecDNA or HSR (homogeneously staining region).

[0273] Embodiment 27: The method of any one of embodiments 21 to 26, wherein the second cancer-targeting therapeutic agent is directed against a protein encoded by a gene contained within the gene amplification.

[0274] Embodiment 28: The method of any one of embodiments 20 to 27, wherein the tumor or tumor cells comprise an ecDNA signature.

[0275] Embodiment 29: The method of any one of embodiments 20 to 28, wherein the cells contained within the tumor or tumor cells are ecDNA competent.

[0276] Embodiment 30: The method of any one of embodiments 20-29, wherein treatment with both the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the cancer therapeutic agent has a greater effect or a longer duration of effect on reducing one or more of tumor growth, tumor size, number of tumor cells, or tumor metastasis compared to treatment with either the compound of Formula (I) or the cancer therapeutic agent administered alone.

[0277] Embodiment 31: The method of embodiment 30, wherein the greater effect is a synergistic effect.

[0278] Embodiment 32: The method of any one of embodiments 20-31, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and / or the second cancer targeted therapeutic agent is administered orally.

[0279] Embodiment 33: The method of any one of embodiments 20-31, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and / or the second cancer targeted therapeutic agent is administered parenterally.

[0280] Embodiment 34: The method of any one of embodiments 20-33, wherein the treatment comprises administering multiple doses of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and / or the second cancer-targeted therapeutic agent over a treatment period.

[0281] Embodiment 35: The method of any one of embodiments 21 to 34, wherein the gene amplification comprises amplification of a gene selected from the group consisting of ABCB1, AKT, ALK, AR, BCL-2, BCR-ABL, BRAF, CDK4, CDK6, c-MET, EGFR, ER, ERBB3, ERRB2, AK, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, GR, HRAS, IGF1R, KIT, KRAS, MCL-1, MDM2, MDM4, MTOR, MYC, MYCL, MYCN, NRAS, NRG1, NTRK1, NTRK2, NTRK3, PDGFR, PIK3Cδ, PIK3CA / B, RET, and ROS1.

[0282] Embodiment 36: The first cancer targeted therapeutic agent is selected from the group consisting of abemaciclib, ado-trastuzumab emtansine, afatinib, alectinib, ALRN-6924, AMG232, AMG-510, apatinib, ARS-3248, AXL1717, AZD-3759, bevacizumab, BI 1701963, bortezomib, brigatinib, cabozantinib, capmatinib, ceritinib, cetuximab, CGM097, crizotinib, dabrafenib, dacomitinib, dasatinib, DS-3032b, encorafenib, entrectinib, ERAS-801, erdafitinib, erlotinib, everolimus, trastuzumab deruxtecan (fam-trastuzumab druxtecan), figitumumab, futibatinib, gefitinib, gossypol, HDM201, idasanutlin, imatinib, infigratinib, iniparib, lapatinib, larotrectinib, LEE011, lenvatinib, LGX818, lorlatinib, MEK162, MK-8242 SCH 900242, MRTX849, navitoclax, necitumumab, nilotinib, obatoclax, olaparib, OSI-906, osimertinib, palbociclib, panitumumab, PD-0332991, perisophrine, pertuzumab, PF-06873600, PF-07220060, PL225B, repotrectinib, ribociclib, RLY-4008 , RO5045337, salinomycin, salirasib, SAR405838, MI-77301, sorafenib, sotorasib, sunitinib, tamoxifen, temsirolimus, tipifarnib, tibanitab, tofacitinib, trametinib, trastuzumab, tucatinib, UPR1376, VAL-083, vemurafenib, vintafolide, and zoptarelin doxorubicin.

[0283] Embodiment 37: The second cancer targeted therapeutic agent is abemaciclib, ado-trastuzumab emtansine, afatinib, alectinib, ALRN-6924, AMG232, AMG-510, apatinib, ARS-3248, AXL1717, AZD-3759, bevacizumab, BI 1701963, bortezomib, brigatinib, cabozantinib, capatinib, ceritinib, cetuximab, CGM097, crizotinib, dabrafenib, dacomitinib, dasatinib, DS-3032b, encorafenib, entrectinib, ERAS-801, erdafitinib, erlotinib, everolimus, trastuzumab deruxtecan (fam-trastuzumab druxtecan), figitumumab, futibatinib, gefitinib, gossypol, HDM201, idasanutlin, imatinib, infigratinib, iniparib, lapatinib, larotrectinib, LEE011, lenvatinib, LGX818, lorlatinib, MEK162, MK-8242 SCH 900242, MRTX849, navitoclax, necitumumab, nilotinib, obatoclax, olaparib, OSI-906, osimertinib, palbociclib, panitumumab, PD-0332991, perisophrine, pertuzumab, PF-06873600, PF-07220060, PL225B, repotrectinib, ribociclib, RLY-4008 , RO5045337, salinomycin, salirasib, SAR405838, MI-77301, sorafenib, sotorasib, sunitinib, tamoxifen, temsirolimus, tipifarnib, tibanitab, tofacitinib, trametinib, trastuzumab, tucatinib, UPR1376, VAL-083, vemurafenib, vintafolide, and zoptarelin doxorubicin.

[0284] Embodiment 38: A method of eliciting a response in a subject having a tumor or tumor cells that are non-responsive or have reduced responsiveness to a first cancer targeted therapeutic agent, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the first cancer targeted therapeutic agent.

[0285] Embodiment 39: The method of embodiment 38, wherein prior to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, the tumor or tumor cells comprise a gene amplification, and the first cancer targeted therapeutic agent has activity directed against a protein encoded by a gene contained within the gene amplification.

[0286] Embodiment 40: The method of embodiment 38 or embodiment 39, wherein the subject has received one or more administrations of a first cancer targeted therapeutic agent prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the tumor or tumor cells have developed reduced responsiveness or resistance to the first cancer targeted therapeutic agent.

[0287] Embodiment 41: The method of embodiment 39 or embodiment 40, wherein the gene amplification is local gene amplification.

[0288] Embodiment 42: The method of any one of embodiments 39 to 41, wherein the gene amplification is amplification from ecDNA.

[0289] Embodiment 43: The method of any one of embodiments 39 to 42, wherein the gene amplification is contained in ecDNA or HSR (homogeneously staining region).

[0290] Embodiment 44: The method of any one of embodiments 38 to 43, wherein the tumor or tumor cells comprise an ecDNA signature.

[0291] Embodiment 45: The method of any one of embodiments 38 to 44, wherein the cells contained within the tumor or tumor cells are ecDNA competent.

[0292] Embodiment 46: The method of any one of embodiments 38-45, wherein treatment with both the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the first cancer targeted therapeutic agent has a greater effect or a longer duration of effect on reducing one or more of tumor growth, tumor size, tumor cell number, or tumor metastasis, compared to treatment with either the compound of Formula (I) or the first cancer targeted therapeutic agent administered alone.

[0293] Embodiment 47: The method of embodiment 46, wherein the greater effect is a synergistic effect.

[0294] Embodiment 48: The method of any one of embodiments 38-47, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and / or the first cancer targeted therapeutic agent is administered orally.

[0295] Embodiment 49: The method of any one of embodiments 38-47, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and / or the second cancer targeted therapeutic agent is administered parenterally.

[0296] Embodiment 50: The method of any one of embodiments 38-49, wherein the treatment comprises administering multiple doses of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and / or the first cancer targeted therapeutic agent over a treatment period.

[0297] Embodiment 51: The method of any one of embodiments 39 to 50, wherein the gene amplification comprises amplification of a gene selected from the group consisting of ABCB1, AKT, ALK, AR, BCL-2, BCR-ABL, BRAF, CDK4, CDK6, c-MET, EGFR, ER, ERBB3, ERRB2, AK, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, GR, HRAS, IGF1R, KIT, KRAS, MCL-1, MDM2, MDM4, MTOR, MYC, MYCL, MYCN, NRAS, NRG1, NTRK1, NTRK2, NTRK3, PDGFR, PIK3Cδ, PIK3CA / B, RET, and ROS1.

[0298] Embodiment 52: The first cancer targeted therapeutic agent is selected from the group consisting of abemaciclib, ado-trastuzumab emtansine, afatinib, alectinib, ALRN-6924, AMG232, AMG-510, apatinib, ARS-3248, AXL1717, AZD-3759, bevacizumab, BI 1701963, bortezomib, brigatinib, cabozantinib, capmatinib, ceritinib, cetuximab, CGM097, crizotinib, dabrafenib, dacomitinib, dasatinib, DS-3032b, encorafenib, entrectinib, ERAS-801, erdafitinib, erlotinib, everolimus, trastuzumab deruxtecan (fam-trastuzumab druxtecan), figitumumab, futibatinib, gefitinib, gossypol, HDM201, idasanutlin, imatinib, infigratinib, iniparib, lapatinib, larotrectinib, LEE011, lenvatinib, LGX818, lorlatinib, MEK162, MK-8242 SCH 900242, MRTX849, navitoclax, necitumumab, nilotinib, obatoclax, olaparib, OSI-906, osimertinib, palbociclib, panitumumab, PD-0332991, perisophrine, pertuzumab, PF-06873600, PF-07220060, PL225B, repotrectinib, ribociclib, RLY-4008 , RO5045337, salinomycin, salirasib, SAR405838, MI-77301, sorafenib, sotorasib, sunitinib, tamoxifen, temsirolimus, tipifarnib, tibanitab, tofacitinib, trametinib, trastuzumab, tucatinib, UPR1376, VAL-083, vemurafenib, vintafolide, and zoptarelin doxorubicin.

[0299] Embodiment 53: The method of any one of embodiments 1 to 52, wherein prior to the treatment, the tumor or tumor cells contain ecDNA, and the treatment results in a decrease in the amount of ecDNA in the tumor or tumor cells.

[0300] Embodiment 54: The method of any one of embodiments 1 to 52, wherein prior to treatment, the tumor or tumor cells contain ecDNA, and the level or amount of ecDNA after treatment is not elevated compared to before treatment.

[0301] Embodiment 55: The method of any one of embodiments 1 to 54, further comprising evaluating a sample from the subject for the presence or level of one or more of gene amplification, local gene amplification, ecDNA, HSR, or ecDNA signature.

[0302] Embodiment 56: The method of any one of embodiments 1 to 55, further comprising obtaining information on the presence or level of one or more of gene amplification, local gene amplification, ecDNA, HSR, or ecDNA signature in a tumor or tumor cells from the subject before, during, or after administration of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0303] Embodiment 57: The method of embodiment 55, wherein the information is obtained from blood, tissue, or one or more cells.

[0304] Embodiment 58: The method of embodiment 55, wherein the information is obtained by liquid biopsy or tissue biopsy. [Example]

[0305] Example 1: Kinase HTRF biochemical assay Chk1 enzyme activity was measured using the HTRF KinEASE assay (Cisbio, catalog no. 62ST1PEC). Full-length human CHK1 protein (GenBank accession no. NP_001265.1) was obtained from Carna Biosciences, Inc. (Kobe, Japan, catalog no. 02-117). Enzyme reactions were performed in assay buffer containing CHK1 enzyme (0.012 ng / μL), MgCl2 (5 mM), and DTT (1 mM) (final concentrations). To determine compound dose response, DMSO stock solutions were serially diluted in duplicate, 10-point concentration series. Compound solutions (50 nL) were added to a 384-well assay plate (Greiner, catalog no. 784075). Assay buffer solution (5 μL) was added to each well containing the compound solution. The plate was centrifuged at 1000 rpm for 1 minute and then incubated at room temperature for 10 minutes. The reaction was initiated by the addition of substrate buffer (5 μL / well) containing the STK substrate l-biotin (120 nM) and ATP (1 mM) (final concentrations). The assay plate was centrifuged at 1000 rpm for 1 min and then incubated at room temperature for 60 min. The reaction was stopped by the addition of detection buffer (Cisbio, 10 μL) containing STK antibody-cryptate (0.25 nM) and streptavidin-XL665 (7.5 nM) (final concentrations). The plate was centrifuged at 1000 rpm for 1 min and then incubated at 25°C for 2 h. HTRF signals were read in HTRF mode on an EnVision multimode plate reader (CisBio). The data were fitted to a dose-response curve using XLfit (IDBS, Surrey, UK) or Prism (GraphPad Software, La Jolla, CA, USA) to calculate IC50 values ​​for each compound tested.

[0306] Example 2: AlphaLisa Cell Assay Compound activity in cells was measured using the AlphaLISA® SureFire® Ultra™ p-CHK1 (Ser345) assay (Perkin Elmer, catalog number ALSU-PCHK1-A10K). HT29 cells were cultured in McCoy's 5A medium containing 10% FBS and 1% penicillin-streptomycin and seeded into a 96-well plate (Corning, catalog number 3599). Compounds were serially diluted in DMSO over a 10-point dose range in 3-fold dilutions, and the compound solution was added to each well containing cells. The plate was centrifuged at 1000 rpm for 30 seconds. The plate was incubated at 37°C for 16 hours. The supernatant was removed by flicking the plate against a paper towel. The wells were washed once with PBS solution. Freshly prepared lysis buffer was added to each well, and the plate was agitated at 400 rpm on a plate shaker for 30 minutes. The 96-well cell plate was centrifuged at 1500 rpm for 1 minute. 10 μL of lysate from each well was transferred to a 384-well Optiplate™ (PerkinElmer, Cat. No. 6007290). Acceptor Mix (5 μL) was added to each well, and the plate was sealed and wrapped in foil. The plate was agitated on a plate shaker for 2 minutes, then incubated at room temperature for 1 hour. Donor Mix (5 μL) was added to each well, and the plate was sealed and wrapped in foil. The plate was agitated on a plate shaker for 2 minutes, then incubated at room temperature for 1 hour. AlphaLisa signals were read on an EnVision multimode plate reader (PerkinElmer). IC of each compound tested was 50 Values ​​were calculated by fitting the data to a dose-response curve using XLfit (IDBS, Surrey, UK) or Prism (GraphPad Software, La Jolla, CA, USA).

[0307] The data from Examples 1 and 2 are shown in Table 4.

[0308] [Table 4-1] [Table 4-2] [Table 4-3]

[0309] Example 3: Synergistic activity of compound 31 with additional therapeutic agents The in vivo antitumor activity and tolerability of compound 31 in combination with various targeted agents were evaluated in mice using a series of cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) tumor models representing various solid tumors with localized amplification of ecDNA (e.g., focal amplification of one or more oncogenes). For each study, mice were implanted with tumor cells, and once tumors were established (e.g., approximately 100–350 mm), tumors were then cultured. 3 Once tumor volume reached 1000 mg / kg, mice began treatment regimens as further described below. For each study, synergy of the combination treatment compared to the corresponding single-agent arm was determined using the Fractional Product Method (Webb et al., 1963). A summary of the results is shown in Table 5. The fraction unaffected (fu) is the % where no tumor growth inhibition was observed. The observed fu of the combination treatment (fu)A+B ("observed fu") was compared to the expected fu, calculated as the product of the observed fu of the single treatments (fu)A × (fu)B. The combination was determined to be additive if (fu)A+B = (fu)A × (fu)B, and synergistic if (fu)A+B < (fu)A × (fu)B.

[0310] [Table 5]

[0311] Taken together, these findings demonstrate that the combination of compound 31 with targeted agents can result in significant and synergistic antitumor activity, including tumor regression, in tumors harboring oncogene amplification on ecDNA.

[0312] FGFR The combination of compound 31 (50 mg / kg PO Q2D) and the pan-FGFR inhibitor infigratinib (15 mg / kg PO QD) was evaluated in ecDNA+FGFR2-amplified gastric cancer SNU-16 CDX and CTG-0353 PDX models. The results are shown in Figure 1A and Figure 1B, respectively. The survival curve of the treated CTG-0353 PDX model is shown in Figure 1C. In both models, the combination treatment demonstrated sustained and significant tumor growth inhibition (including tumor regression) compared to vehicle. The combination of compound 31 and infigratinib was determined to be synergistic.

[0313] The combination of compound 31 (50 mg / kg PO Q2D) and the pan-FGFR inhibitor futibatinib (12.5 mg / kg PO QD) was evaluated in the ecDNA+FGFR2-amplified gastric cancer SNU-16 CDX model. Results are shown in Figure 1D. The combination treatment demonstrated sustained and significant tumor growth inhibition (including tumor regression) compared with vehicle or either agent alone.

[0314] The combination of compound 31 (50 mg / kg PO Q2D) and the pan-FGFR inhibitor pemigatinib (1 mg / kg PO QD) was evaluated in the ecDNA+FGFR2-amplified gastric cancer SNU-16 CDX model. Results are shown in Figure 1E. The combination treatment demonstrated sustained and significant tumor growth inhibition (including tumor regression) compared to vehicle or either agent alone.

[0315] CDK4 / 6 The combination of compound 31 (50 mg / kg PO Q2D) with the CDK4 / 6 inhibitor palbociclib (50 mg / kg PO QD) or abemaciclib (10.5 mg / kg PO QD) was evaluated in the ecDNA+CDK4-amplified osteosarcoma SJSA-1 CDX tumor model. The results are shown in Figure 2A (palbociclib) and Figure 2B (abemaciclib). The combination of compound 31 with palbociclib or abemaciclib resulted in significant antitumor activity, including tumor regression, compared to vehicle. The combination of compound 31 and abemaciclib was determined to be synergistic.

[0316] EGFR The combination of compound 31 (50 mg / kg PO Q2D) and the EGFR inhibitor erlotinib (50 mg / kg PO QD) was evaluated in the ecDNA+EGFR amplified NSCLC PDX tumor model LU1206. The results are shown in Figure 3. The combination treatment resulted in significant tumor growth inhibition when compared to vehicle, and the treatment was determined to be synergistic.

[0317] MET The combination of compound 31 (50 mg / kg PO Q2D) and the MET inhibitor tepotinib (25 mg / kg PO Q2D) was evaluated in the ecDNA+MET-amplified NSCLC PDX tumor model LU1902. The results are shown in Figure 4. The combination treatment resulted in significant tumor growth inhibition compared to vehicle, and the combination treatment with tepotinib resulted in complete tumor regression. The combination treatment was determined to be synergistic.

[0318] Example 4: Inhibition of ecDNA amplification Long-term treatment of SNU-16 tumor cells in vitro and SNU-16 CDX tumors in vivo with the pan-FGFR tyrosine kinase inhibitor infigratinib resulted in tumor cell stasis over a 1- to 2-week period, but acquired resistance to infigratinib treatment occurred, leading to re-initiation of tumor growth. Infigratinib resistance was directly correlated with increased FGFR2 amplification (copy number) on ecDNA. Combination treatment of infigratinib with compound 31 blocked the increase in FGFR2 copy number on ecDNA otherwise induced by single-agent infigratinib. Results for SNU-16 tumor cells in vitro are shown in Figure 5.

[0319] The examples and embodiments described herein are for illustrative purposes only, and in some embodiments, various improvements or modifications are intended to be encompassed within the scope of the disclosure and the appended claims.

Claims

1. A method of treating a tumor or tumor cells, comprising administering a compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a selected cancer-targeted therapeutic agent to a subject identified as having said tumor or tumor cells, wherein said tumor or tumor cells contain gene amplification, and said administering reduces the growth or size of said tumor, or the growth or number of tumor cells.

2. A method for delaying resistance to a selected cancer-targeted therapeutic agent, comprising administering to a subject a compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, in an amount sufficient to induce replication stress in a tumor or tumor cells, and administering the selected cancer-targeted therapeutic agent simultaneously with or after administration of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

3. A method of treating a subject having a tumor or tumor cells that are unresponsive to a previous cancer-targeted therapeutic agent, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a selected cancer-targeted therapeutic agent.

4. 4. The method of claim 3, wherein the subject has received one or more of the previous cancer targeted therapeutic agents prior to administration of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the tumor or tumor cells have acquired reduced responsiveness or resistance to the previous cancer targeted therapeutic agents.

5. A method for inducing a response in a subject having a tumor or tumor cells that are unresponsive or have reduced responsiveness to a previous cancer targeted therapeutic agent, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a selected cancer targeted therapeutic agent, wherein the previous cancer targeted therapeutic agent is the same as the selected cancer targeted therapeutic agent.

6. 6. The method of any one of claims 3 to 5, wherein prior to treatment with the compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, the tumor or tumor cells comprise a gene amplification, and the previous cancer targeted therapeutic agent has activity directed against a protein encoded by a gene contained in the gene amplification.

7. 7. The method of any one of claims 1 to 6, wherein the selected cancer targeted therapeutic agent is administered simultaneously with or after administration of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

8. 7. The method of any one of claims 1 to 6, wherein the selected cancer targeted therapeutic agent is administered prior to the step of administering the compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

9. 9. The method of any one of claims 1 to 8, wherein the compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is administered in an amount sufficient to induce replication stress in the tumor or tumor cells.

10. The method of any one of claims 1 to 9, wherein the subject is identified as having the tumor or tumor cells that contain gene amplification.

11. The method of claim 10, wherein the gene amplification is local gene amplification.

12. The method according to claim 10 or 11, wherein the gene amplification is an amplification derived from ecDNA.

13. The method according to any one of claims 10 to 12, wherein the gene amplification is contained in ecDNA or HSR (homogeneously staining region).

14. The method of any one of claims 10 to 13, wherein the tumor or tumor cells comprise an ecDNA signature.

15. The method of any one of claims 10 to 14, wherein the selected cancer targeted therapeutic agent is directed against a protein encoded by a gene contained in the gene amplification.

16. The method of any one of claims 10 to 15, wherein cells contained within the tumor or tumor cells are ecDNA competent.

17. 17. The method of any one of claims 1 to 16, wherein treatment with both the compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the selected cancer targeted therapeutic agent has a greater effect or a longer duration of effect on reducing one or more of tumor growth, tumor size, number of tumor cells, or tumor metastasis compared to treatment with either the compound of formula (I) or the selected cancer targeted therapeutic agent when administered alone.

18. 18. The method of claim 17, wherein the greater effect is a synergistic effect.

19. 19. The method of any one of claims 1 to 18, wherein the compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and / or the selected cancer targeted therapeutic agent is administered orally.

20. 20. The method of any one of claims 1 to 19, wherein the treatment comprises administering multiple doses of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and / or the selected cancer targeted therapeutic agent over a treatment period.

21. 21. The method of any one of claims 1 to 20, wherein the gene amplification comprises amplification of a gene selected from the group consisting of ABCB1, AKT, ALK, AR, BCL-2, BCR-ABL, BRAF, CDK4, CDK6, c-MET, EGFR, ER, ERBB3, ERRB2, AK, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, GR, HRAS, IGF1R, KIT, KRAS, MCL-1, MDM2, MDM4, MTOR, MYC, MYCL, MYCN, NRAS, NRG1, NTRK1, NTRK2, NTRK3, PDGFR, PIK3Cδ, PIK3CA / B, RET, and ROS1.

22. 22. The method of any one of claims 1 to 21, wherein the gene amplification comprises amplification of a gene selected from the group consisting of CDK4, CDK6, c-MET, EGFR, FGFR1, FGFR2, FGFR3, and FGFR4.

23. The method of any one of claims 1 to 22, wherein the selected cancer therapeutic agent is an FGFR inhibitor.

24. 24. The method of claim 23, wherein the FGFR inhibitor is infigratinib, futibatinib, or pemigatinib.

25. The method of any one of claims 1 to 22, wherein the selected cancer therapeutic agent is a CDK4 / 6 inhibitor.

26. 26. The method of claim 25, wherein the CDK4 / 6 inhibitor is palbociclib or abemaciclib.

27. The method of any one of claims 1 to 22, wherein the selected cancer therapeutic agent is an EGFR inhibitor.

28. 28. The method of claim 27, wherein the EGFR inhibitor is erlotinib.

29. The method of any one of claims 1 to 22, wherein the selected cancer therapeutic agent is a c-MET inhibitor.

30. 30. The method of claim 29, wherein the c-MET inhibitor is tepotinib.

31. 31. The method of any one of claims 1 to 30, wherein prior to treatment, the tumor or tumor cells contain ecDNA, and the treatment results in a reduction in the amount of ecDNA in the tumor or tumor cells.

32. 31. The method of any one of claims 1 to 30, wherein prior to treatment, the tumor or tumor cells comprise ecDNA, and the level or amount of ecDNA after said treatment is not elevated compared to before said treatment.

33. 33. The method of any one of claims 1-32, further comprising assessing a sample from the subject for the presence or level of one or more of gene amplification, local gene amplification, ecDNA, HSR, or an ecDNA signature.

34. 34. The method of any one of claims 1 to 33, further comprising obtaining information on the presence or level of one or more of gene amplification, local gene amplification, ecDNA, HSR, or ecDNA signature in said tumor or tumor cells from said subject before, during, or after administration of said compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

35. 35. The method of claim 34, wherein the information is obtained from blood, tissue, or one or more cells.

36. 35. The method of claim 34, wherein the information is obtained by liquid biopsy or tissue biopsy.

37. 37. The method of any one of claims 1-36, wherein the previous cancer targeted therapeutic agent is targeted to a protein encoded by a gene selected from the group consisting of ABCB1, AKT, ALK, AR, BCL-2, BCR-ABL, BRAF, CDK4, CDK6, c-MET, EGFR, ER, ERBB3, ERRB2, AK, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, GR, HRAS, IGF1R, KIT, KRAS, MCL-1, MDM2, MDM4, MTOR, MYC, MYCL, MYCN, NRAS, NRG1, NTRK1, NTRK2, NTRK3, PDGFR, PIK3Cδ, PIK3CA / B, RET, and ROS1.

38. The compound of formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is 【Chemistry 1】 wherein: Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R １ are independently deuterium, halogen, -CN, -NO ２ , —OH, —OR ａ , —OC(═O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (= O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R on the same atom １ come together to form oxo, n is 0 to 4; R ２ But hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ heteroalkyl, cycloalkyl, or heterocycloalkyl; R ３ But hydrogen, deuterium, halogen, -CN, -NO ２ , —OH, —OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ heteroalkyl, cycloalkyl, or heterocycloalkyl; R ４ But hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ heteroalkyl, cycloalkyl, or heterocycloalkyl; W is N or CR Ｗ and R Ｗ But hydrogen, deuterium, halogen, -CN, -NO ２ , —OH, —OR ａ , —OC(═O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (= O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R; X is N or CR Ｘ and R Ｘ But hydrogen, deuterium, halogen, -CN, -NO ２ , —OH, —OR ａ , —OC(═O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (= O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R; Y is N or CR Ｙ and R Ｙ But hydrogen, deuterium, halogen, -CN, -NO ２ , —OH, —OR ａ , —OC(═O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (= O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R; Z is N or CR Ｚ and R Ｚ But hydrogen, deuterium, halogen, -CN, -NO ２ , —OH, —OR ａ , —OC(═O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (= O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R; provided that at least one of W, X, Y, or Z is N; L is —O— or —NR ５ - and R ５ But hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ heteroalkyl, cycloalkyl, or heterocycloalkyl; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R ６ are independently deuterium, halogen, -CN, -NO ２ , —OH, —OR ａ , —OC(═O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (= O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R on the same atom ６ come together to form oxo, Or two R on the same carbon ６ together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; Or two R on different atoms ６ together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; m is 0 to 8; Each R ａ However, independently C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Each R ｂ are independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Each R ｃ and R ｄ are independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Or R ｃ and R ｄ together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently a halogen, —CN, —OH, or —OC １ -C ３ Alkyl, —OC １ -C ３ Haloalkyl, -SC １ -C ３ Alkyl, —S(═O)C １ -C ３ Alkyl, —S(═O) ２ C １ -C ３ Alkyl, —S(═O) ２ NH ２ , -S(=O) ２ NHC １ -C ３ Alkyl, —S(═O) ２ N (C １ -C ３ alkyl) ２ , -NH ２ , -NHC １ -C ３ Alkyl, —N(C １ -C ３ alkyl) ２ , -C(=O)C １ -C ３ Alkyl, —C(═O)OH, —C(═O)OC １ -C ３ Alkyl, —C(═O)NH ２ , -C(=O)NHC １ -C ３ Alkyl, —C(═O)N(C １ -C ３ alkyl) ２ , C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Deuteroalkyl, C １ -C ３ Hydroxyalkyl, C １ -C ３ Aminoalkyl, C １ -C ３ heteroalkyl, or C ３ -C ６ is cycloalkyl, Alternatively, two R on the same atom form an oxo.

39. The compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is represented by formula (Ib): 【Chemistry 2】 The method of any one of claims 1 to 37, wherein the compound is

40. The compound of formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is 【Transformation 3】 40. The method of any one of claims 1 to 39, wherein the compound is: or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

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