Inhibitors of POLO-like kinase 4 (PLK4) for the treatment of cancer

Abstract

Disclosed herein are methods of treating cancer in a subject, wherein the cancer in the subject has progressed following administration to the subject of a cyclin-dependent kinase inhibitor, comprising administering to the subject an inhibitor of polo -like kinase 4 (PLK4).

Description

INHIBITORS OF POLO-LIKE KINASE 4 (PLK4) FOR THE TREATMENT OF CANCERCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 569,988 filed March 26, 2024; which is hereby incorporated by reference in its entirety.BACKGROUND OF THE INVENTION

[0002] Abnormal activation of the cyclin-dependent kinases (CDKs), including CDK4 and CDK6, in subjects may result in aberrant cell proliferation and the development of cancer. There are currently several therapeutics approved for use in treating subjects having certain types of cancer, such as human epidermal growth factor receptor 2 negative (ER+ HER2-) breast cancer, which inhibit the activity of CDKs. While CDK inhibitors have proven successful in treating subjects having certain types of cancer, the effectiveness of such inhibitors is limited in some subjects due to the development of acquired resistance to such CDK inhibitors which can lead to progression of the cancer in such subjects. Thus, there remains a need to develop therapeutic strategies to address the treatment of subjects having cancer, wherein the cancer has progressed following treatment of the subject with at least one CDK inhibitor, or wherein the cancer has been determined to be resistant to at least one CDK inhibitor.

[0003] The Polo-like kinases (PUKs) are a family of serine / threonine kinases that play a critical role in cell cycle regulation and cellular responses under stress. Mammalian cells express five PUK family members (PUK 1-5). All PUKs share a similar structure, with an N-terminal kinase catalytic domain and C-terminal Polo-box domains (PBDs). Polo-like kinase 4 (PUK4), also known as SAK, is a regulator of centriole duplication. In proliferating tissues, PUK4 is expressed as a low -abundance enzyme under normal conditions and is required for centriole biogenesis via phosphorylation and interaction with centriolar proteins. Overexpression of PUK4 results in centriole amplification and further genomic instability and tumorigenesis. Aberrant PUK4 expression has been reported to be involved in several common human cancers. In addition, other cancer-associated aberrations have been shown to generate a synthetic lethal context that relies on PUK4 activity. Thus, strong evidence supports the critical role of PUK4 in carcinogenesis and therapeutic invention for the treatment of cancer.

[0004] The present disclosure relates to methods of treating cancer in a subject, wherein the cancer in the subject has progressed following administration to the subject of a cyclin-dependent kinase inhibitor, comprising administering to the subject an inhibitor of polo-like kinase 4 (PUK4).SUMMARY OF THE INVENTION

[0005] Disclosed herein are methods of treating cancer in a subject, wherein the cancer in the subject has progressed following administration to the subject of a cyclin-dependent kinase inhibitor, comprising administering to the subject an inhibitor of polo -like kinase 4 (PUK4).

[0006] Further disclosed herein are methods of treating cancer in a subject, wherein the cancer in the subject has been determined to be resistant to at least one cyclin -dependent kinase inhibitor, comprising administering to the subject an inhibitor of polo -like kinase 4 (PLK4).

[0007] Also disclosed herein are methods of treating cancer in a subject, wherein the cancer in the subject has (a) progressed following administration to the subject of a cyclin-dependent kinase inhibitor, and (b) been determined to be resistant to at least one cyclin-dependent kinase inhibitor, comprising administering to the subject an inhibitor of polo -like kinase 4 (PLK4).

[0008] Further disclosed herein are methods of treating cancer in a subject, comprising administering to the subject an inhibitor of polo-like kinase 4 (PLK4), wherein the cancer in the subject has progressed following administration to the subject of a cyclin-dependent kinase inhibitor prior to administration to the subject of the inhibitor of polo-like kinase 4 (PLK4).

[0009] Also disclosed herein are methods of treating cancer in a subject, comprising administering to the subject an inhibitor of polo-like kinase 4 (PLK4), wherein the cancer in the subject has been determined to be resistant to at least one cyclin-dependent kinase inhibitor prior to administration to the subject of the inhibitor of polo-like kinase 4 (PLK4).

[0010] Further disclosed herein are methods of treating cancer in a subject, comprising administering to the subject an inhibitor of polo-like kinase 4 (PLK4), wherein prior to administration to the subject of the inhibitor of polo-like kinase 4 (PLK4) the cancer in the subject has (a) progressed following administration to the subject of a cyclin-dependent kinase inhibitor, and (b) been determined to be resistant to at least one cyclin-dependent kinase inhibitor.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. 1 demonstrates elevation of Cyclin E 1 protein level in protein lysates extracted from MCF7 parental or palbociclib-resistant cells, as calculated by western blot densitometry of Cyclin El protein levels normalized to its respective aActinin loading control, according to Example No. 1.

[0012] FIG. 2 demonstrates the relative potency of Compound 11 in MCF7 parental or palbociclib- resistant cells as determined by CellTiter-Glo 2.0 cell viability assay, according to Example No. 1.

[0013] FIG. 3 demonstrates that in a palbociclib-resistant patient derived xenograft (PDX) model of breast cancer in mice as described in Example No. 2, 52-day daily repeated oral administration of Compound 11 at 250 mg / kg and 150mg / kg exhibited robust tumor growth inhibition of 64% and 48% respectively when compared to the vehicle control.

[0014] FIG. 4 demonstrates that in a palbociclib-resistant patient derived xenograft (PDX) model of breast cancer in mice as described in Example No. 2, 52-day daily repeated oral administration of Compound 11 was well tolerated, resulting in an average maximal body weight loss (BWL) of 3.6% for the vehicle group, 16.4% for the Compound 11 at 250 mg / kg group and 10.2% for the Compound 11 at 150 mg / kg group.

[0015] FIG. 5 demonstrates that in a palbociclib-resistant patient derived xenograft (PDX) model of breast cancer in mice as described in Example No. 2, 52-day daily repeated oral administration ofCompound 11 resulted in a statistically significant decrease in end of study tumor volumes for both the 250 mg / kg group (p = 0.0003) and the 150 mg / kg group (p = 0.0052) compared to vehicle control.INCORPORATION BY REFERENCE

[0016] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.DETAILED DESCRIPTION OF THE INVENTION

[0017] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0018] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and sub -combinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of’ or “consist essentially of’ the described features.

[0019] “Administering” when used in conjunction with a therapeutic means to administer a therapeutic systemically or locally, as directly into or onto a target tissue, or to administer a therapeutic to a subject whereby the therapeutic positively impacts the tissue to which it is targeted. Thus, as used herein, the term “administering,” when used in conjunction with a composition described herein, can include, but is not limited to, providing a composition into or onto the target tissue; providing a composition systemically to a subject by, e.g., oral administration whereby the therapeutic reaches the target tissue or cells. “Administering” a composition may be accomplished by injection, topical administration, and oral administration or by other methods alone or in combination with other known techniques.

[0020] The term “cyclin-dependent kinase inhibitor” as used herein means an agent that inhibits one or more cyclin-dependent kinases. Such an inhibitor may be selected from peptides, polypeptides, proteins, small molecules, antibodies, and antibody fragments. In some embodiments, the cyclin-dependent kinase inhibitor is a small molecule. It is understood by those having ordinary skill in the art that a cyclin- dependent kinase inhibitor used in the methods disclosed herein may be an inhibitor of one or morecyclin-dependent kinase inhibitor types, including CDK2, CDK4, CDK6. For example, in some embodiments the cyclin-dependent kinase inhibitor used in the methods disclosed herein may be a selective inhibitor of CDK2, a selective inhibitor of CDK4, or a selective inhibitor CDK6. In other embodiments, the cyclin-dependent kinase inhibitor used in the methods disclosed herein may be an inhibitor of CDK2 and CDK4, or an inhibitor CDK2 and CDK6, or an inhibitor of CDK4 and CDK6, or an inhibitor of CDK2, CDK4, and CDK6. In some embodiments, the cyclin-dependent kinase inhibitor is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, dinaciclib, PF-07I0409I, BLU-222, and PF-07220060.

[0021] The term “C2-C6alkenyl” as used herein, means an alkyl moiety comprising 2 to 6 carbon atoms having at least one carbon-carbon double bond. The carbon-carbon double bond in such a group may be anywhere along the 2 to 6 carbon atom chain that will result in a stable compound. Examples of such groups include, but are not limited to, ethenyl, propenyl, butenyl, allyl, and pentenyl. The alkenyl may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples of alkenyls include, but are not limited to ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. In some embodiments, the alkenyl is a C2-C10 alkenyl, a C2-C9 alkenyl, a C2-C8 alkenyl, a C2-C7 alkenyl, a C2-C6 alkenyl, a C2-C5 alkenyl, a C2-C4 alkenyl, a C2-C3 alkenyl, or a C2 alkenyl.

[0022] The term “Ci-Cealkyl,” as used herein, refers to a straight or branched chain hydrocarbon monoradical, which may be fully saturated or unsaturated, having from one to about ten carbon atoms, or from one to six carbon atoms. Examples of saturated hydrocarbon monoradical include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2 -m ethyl- 1 -propyl, 2-methyl -2 -propyl, 2-methyl-l-butyl, 3- methyl-1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l -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-l -butyl, 3,3- dim ethyl- 1 -butyl, 2-ethyl-l -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as “Ci-Ce alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.

[0023] The term “C2-Cealkynyl,” as used herein, means an alkyl moiety comprising from 2 to 6 carbon atoms and having at least one carbon-carbon triple bond. The carbon-carbon triple bond in such a group may be anywhere along the 2 to 6 carbon chain that will result in a stable compound. Examples of such groups include, but are not limited to, ethyne, propyne, 1 -butyne, 2-butyne, 1 -pentyne, 2-pentyne, 1- hexyne, 2-hexyne, and 3-hexyne, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkynyl” means that the alkynyl group may consist of2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.

[0024] The term “Ce-Cioaryl,” as used herein, refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 10 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl. 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. In some embodiments, the aryl is phenyl.

[0025] The term “Ci-Ce aminoalkyl,” as used herein, refers to a alkyl radical, C as1-6 defined above, that is substituted with one or more amino groups. The amino groups in such aminoalkyl groupsC1-6 may be unsubstituted, mono-substituted, or disubstituted. Examples of aminoalkyl groupsC in1c-6lude, but are not limited to, -CH2NH2, -CH2N(H)CH3, -CH2N(CH3)2, and the like.

[0026] The term “C6-10 cycloalkyl” refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring comprising from 3 to 10 carbon atoms, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. Representative cycloalkyls include. In some embodiments, the cycloalkyl is a 3 - to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5 - to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo [4.3.0] nonane, cis-decalin, trans-decalin, bicy clo [2. 1. 1] hexane, bicyclo[2.2. l]heptane, bicy clo [2.2.2] octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2. l]heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl

[0027] The term “Ci-Cedeuteroalkyl,” as used herein, means a alkyl group asC d1e-6fined herein wherein one or more hydrogen atoms in the alkyl groCu1p-6 is replaced with a deuterium atom.

[0028] The term “Ci-Ce haloalkyl,” as used herein, refers to a alkyl radical, aCs1 d-6efined above, that is 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.

[0029] The term “Ci-Ce hydroxyalkyl,” as used herein, refers to a alkyl radical, asC d1-e6fined above, that is substituted with one or more hydroxy groups.

[0030] The term “animal” as used herein includes, but is not limited to, humans and non-human vertebrates such as wild, domestic and farm animals. As used herein, the terms “subject,” “subject” and “individual” are intended to include living organisms in which certain conditions as described herein can occur. Examples include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats, and transgenicspecies thereof. In a preferred embodiment, the subject is a primate. In certain embodiments, the primate or subject is a human. In certain instances, the human is an adult. In certain instances, the human is child. In further instances, the human is under the age of 12 years. In certain instances, the human is elderly. In other instances, the human is 60 years of age or older. Other examples of subjects include experimental animals such as mice, rats, dogs, cats, goats, sheep, pigs, and cows. The experimental animal can be an animal model for a disorder, e.g., a transgenic mouse with hypertensive pathology.

[0031] A “cyano” group refers to a -CN group.

[0032] The term “halo” or “halogen,” as used herein, refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0033] The term “heterocycloalkyl,” as used herein, refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from boron, nitrogen, oxygen, phosphorous, and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heterocycloalkyl is a 3 - to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl [1, 3 ]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindo lyl, octahydroisoindo lyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1, 1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-l-yl, 3- oxo-1, 3-dihydroisobenzofuran-l-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring).

[0034] The term “Ci-Ceheteroalkyl,” as used herein, means an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., boron, oxygen, nitrogen (e.g. -NH-, - N(alkyl)-), sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a heteroalkyl whereCin1- t6he heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.

[0035] The term “heteroaryl,” as used herein refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from boron, nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[I,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1 -oxidopyridinyl, 1-oxidopyrimidinyl, 1 -oxidopyrazinyl, 1-oxidopyridazinyl, 1 -phenyl- IH-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).

[0036] By “pharmaceutically acceptable,” as used herein, is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0037] The term “pharmaceutical composition” means a composition comprising at least one active ingredient, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human) . Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan.

[0038] The term “pharmaceutically acceptable salt,” as used herein, means a salt of a compound of the present invention that retains the biological effectiveness of the free acids and bases of the specified derivative and that is not biologically or otherwise undesirable.

[0039] The term “PLK4,” as used herein, means the human protein known to those of ordinary skill in the art as polo-like kinase 4, and that is encoded by the PLK4 gene

[0040] The term “oxo,” as used herein, refers to a carbonyl moiety such that alkyl substituted by oxo refers to a ketone group.

[0041] The term “solvate,” as used herein, means a molecular complex between compounds of the present invention and solvent molecules. Examples of solvates include, but are not limited to, compounds of the invention in combination water, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term “hydrate” can be used when said solventis water. It is specifically contemplated that in the present invention one solvent molecule can be associated with one molecule of the compounds of the present invention, such as a hydrate. Furthermore, it is specifically contemplated that in the present invention, more than one solvent molecule may be associated with one molecule of the compounds of the present invention, such as a dihydrate. Additionally, it is specifically contemplated that in the present invention less than one solvent molecule may be associated with one molecule of the compounds of the present invention, such as a hemihydrate. Furthermore, solvates of the present invention are contemplated as solvates of compounds of the present invention that retain the biological effectiveness of the non-hydrate form of the compounds.

[0042] Where a compound of the invention contains an alkenyl group, geometric cis / trans (or Z / E) isomers are possible. Where the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism ( tautomerism ) can occur. Examples of tautomerism include keto and enol tautomers. A single compound may exhibit more than one type of isomerism. Included within the scope of the invention are all stereoisomers, geometric isomers, and tautomeric forms of the inventive compounds, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

[0043] The term “stereoisomers” refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of their atoms or groups in space. In particular, the term “enantiomers” refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. The terms “racemic” or “racemic mixture,” as used herein, refer to a 1: 1 mixture of enantiomers of a particular compound. A mixture of racemates in which one racemate is present in a greater amount than the other racemate in such mixture may be described as “enantiomerically enriched.” The term “diastereomers,” on the other hand, refers to the relationship between a pair of stereoisomers that comprise two or more asymmetric centers and are not mirror images of one another. Designations that are conventional in the art may be used to describe stereoisomers of compounds, or the stereochemistry of a particular asymmetric carbon atom, of the compounds disclosed herein, or mixtures thereof. For example, a single racemate or stereocenter of a compound, may be described as of the (+), the (-), the (R)-, or the (S) configuration. A mixture of racemates may be described by use of the (±) symbol.

[0044] The compounds of the present invention may have asymmetric carbon atoms. The carbon-carbon bonds of the compounds of the present invention may be depicted herein using a solid line ( - ), a solid wedge ( or a dotted wedge ( ' '1 1 1I ). The use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers (e.g. specific enantiomers, racemic mixtures, etc.) at that carbon atom are included. The use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms is meant to indicate that only the stereoisomer shown is meant to be included. It is possible that compounds of the invention may contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included. For example, unless statedotherwise, it is intended that the compounds of the present invention can exist as enantiomers and diastereomers or as racemates and mixtures thereof. The use of a solid line to depict bonds to one or more asymmetric carbon atoms in a compound of the invention and the use of a solid or dotted wedge to depict bonds to other asymmetric carbon atoms in the same compound is meant to indicate that a mixture of diastereomers is present.

[0045] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1 -phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and / or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art. Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture. Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art. See, e.g. “Stereochemistry of Organic Compounds” by E L Eliel (Wiley, New York, 1994), the disclosure of which is incorporated herein by reference in its entirety.

[0046] The term “substituted,” as used herein, means that the specified group or moiety bears one or more substituents. The term “unsubstituted,” means that the specified group bears no substituents. The term “optionally substituted” means that the specified group is unsubstituted or substituted by one or more substituents. It is to be understood that in the compounds of the present invention when a group is said to be “unsubstituted,” or is “substituted” with fewer groups than would fill the valencies of all the atoms in the compound, the remaining valencies on such a group are filled by hydrogen. For example, if a Cearyl group, also called “phenyl” herein, is substituted with one additional substituent, one of ordinary skill in the art would understand that such a group has 4 open positions left on carbon atoms of the Cearyl group (6 initial positions, minus one to which the remainder of the compound of the present invention is bonded, minus an additional substituent, to leave 4). In such cases, the remaining 4 carbon atoms are each bound to one hydrogen atom to fill their valencies. Similarly, if a Cearyl group in the present compounds is said to be “disubstituted,” one of ordinary skill in the art would understand it to mean that the Cearyl group has 3 carbon atoms remaining that are unsubstituted. Those three unsubstituted carbon atoms are each bound to one hydrogen atom to fill their valencies.

[0047] In accordance with a convention used in the art, the symbolis used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure. In accordance with another convention, in some structural formulae herein the carbon atoms and their bound hydrogen atoms are not explicitly depicted, e.g.,represents a methyl group,represents an ethyl group, andrepresents a cyclopentyl group, etc.

[0048] If a group, as for example, (Rx)n is depicted as “floating” Ring A in the formula:then, unless otherwise defined, the substituent R1may reside on any atom of the ring system, assuming replacement of a depicted, implied, or expressly defined hydrogen from one of the ring atoms, so long as a stable structure is formed. A ring system A may be, for example, but not limited to aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, spirocyclyl or a fused ring system.

[0049] If a group “R” is depicted as “floating” on a ring system A as shown above in the compounds of Formulae (I) and (II), and Ring A contains saturated carbons, then “n” can be more than one, assuming each replaces a currently depicted, implied, or expressly defined hydrogen the ring A; then, unless otherwise defined, where the resulting structure is stable, two R1groups may reside on the same carbon. For example, when R1is a methyl group, there can exist a germinal dimethyl on a carbon of the ring A. In another example, two R1groups on the same carbon, including that carbon, may form a ring, thus creating a spirocyclic ring (a “spirocyclyl group”). It is to be understood that in the compounds of Formulae (I) and (II), if n is less than the number of substitutable atoms on Ring A, the other substitutable positions on Ring A are bonded to a hydrogen atom.

[0050] As used herein, the term “therapeutic” means an agent utilized to treat, combat, ameliorate, prevent, or improve an unwanted condition or disease of a subject.

[0051] A “therapeutically effective amount” or “effective amount” as used herein refers to the amount of active compound or pharmaceutical agent that elicits a biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease, (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individualthat is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptomatology), and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology).

[0052] The terms “treat,” “treated,” “treatment,” or “treating” as used herein refers to both therapeutic treatment in some embodiments and prophylactic or preventative measures in other embodiments, wherein the object is to prevent or slow (lessen) an undesired physiological condition, disorder, or disease, or to obtain beneficial or desired clinical results. For the purposes described herein, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. A prophylactic benefit of treatment includes prevention of a condition, retarding the progress of a condition, stabilization of a condition, or decreasing the likelihood of occurrence of a condition. As used herein, “treat,” “treated,” “treatment,” or “treating” includes prophylaxis in some embodiments.

[0053] The term “TRIM37,” as used herein, means the human protein known those of ordinary skill in the art as tripartite motif-containing protein 37, an E3 ubiquitin ligase that is encoded by the TRIM37 gene.

[0054] The terms “ocifisertib” “CFI-400495” means the compound having the Chemical Abstract Service Registry No. 1338806-73-7, the structure shown below, and the chemical name (( lR,2S)-2-[3- [(lE)-2-[4-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl]phenyl] ethenyl] -lH-indazol-6-yl]-5'-methoxy- spiro[cyclopropane-l,3'-[3H]indol]-2'(TH)-one). The preparation of the compound is described in PCT Application Publication No. WO 2011 / 123946 and is commercially available for purchase.Methods of Treatment

[0055] Disclosed herein are methods of treating cancer in a subject, wherein the cancer in the subject has progressed following administration to the subject of a cyclin-dependent kinase inhibitor, comprising administering to the subject an inhibitor of polo -like kinase 4 (PLK4).

[0056] Further disclosed herein are methods of treating cancer in a subject, wherein the cancer in the subject has been determined to be resistant to at least one cyclin-dependent kinase inhibitor, comprising administering to the subject an inhibitor of polo -like kinase 4 (PLK4).

[0057] Also disclosed herein are methods of treating cancer in a subject, wherein the cancer in the subject has (a) progressed following administration to the subject of a cyclin-dependent kinase inhibitor, and (b) been determined to be resistant to at least one cyclin-dependent kinase inhibitor, comprising administering to the subject an inhibitor of polo-like kinase 4 (PLK4).

[0058] Further disclosed herein are methods of treating cancer in a subject, comprising administering to the subject an inhibitor of polo-like kinase 4 (PLK4), wherein the cancer in the subject has progressed following administration to the subject of a cyclin-dependent kinase inhibitor prior to administration to the subject of the inhibitor of polo-like kinase 4 (PLK4).

[0059] Also disclosed herein are methods of treating cancer in a subject, comprising administering to the subject an inhibitor of polo-like kinase 4 (PLK4), wherein the cancer in the subject has been determined to be resistant to at least one cyclin-dependent kinase inhibitor prior to administration to the subject of the inhibitor of polo-like kinase 4 (PLK4).

[0060] Further disclosed herein are methods of treating cancer in a subject, comprising administering to the subject an inhibitor of polo-like kinase 4 (PLK4), wherein prior to administration to the subject of the inhibitor of polo-like kinase 4 (PLK4) the cancer in the subject has (a) progressed following administration to the subject of a cyclin-dependent kinase inhibitor, and (b) been determined to be resistant to at least one cyclin-dependent kinase inhibitor.

[0061] In some embodiments of the methods disclosed herein, the cancer in the subject has been further determined to exhibit an overexpression of the gene that encodes the tripartite motif-containing protein 37 (TRIM37) prior to administration to the subject of the inhibitor of polo -like kinase 4 (PLK4).

[0062] In some embodiments of the methods disclosed herein, the cancer in the subject has been further determined to exhibit an amplification of the gene that encodes the tripartite motif-containing protein 37 (TRIM37) prior to administration to the subject of the inhibitor of polo-like kinase 4 (PLK4).

[0063] In some embodiments of the methods disclosed herein, the cancer in the subject has been further determined to overexpress the gene that encodes the tripartite motif-containing protein 37 (TRIM37) prior to administration to the subject of the inhibitor of polo-like kinase 4 (PLK4).

[0064] Also disclosed herein are methods of treating cancer in a subject, comprising administering to the subject an inhibitor of polo-like kinase 4 (PLK4), wherein prior to administration to the subject of the inhibitor of polo-like kinase 4 (PLK4) the cancer in the subject has (a) progressed following administration to the subject of a cyclin-dependent kinase inhibitor, (b) been determined to be resistant toat least one cyclin-dependent kinase inhibitor, and (c) been determined to exhibit an overexpression of the gene that encodes the tripartite motif-containing protein 37 (TRIM37).

[0065] Further disclosed herein are methods of treating cancer in a subject, comprising administering to the subject an inhibitor of polo-like kinase 4 (PLK4), wherein prior to administration to the subject of the inhibitor of polo-like kinase 4 (PLK4) the cancer in the subject has (a) progressed following administration to the subject of a cyclin-dependent kinase inhibitor, (b) been determined to be resistant to at least one cyclin-dependent kinase inhibitor, and (c) been determined to exhibit an amplification of the gene that encodes the tripartite motif-containing protein 37 (TRIM37).

[0066] Also disclosed herein are methods of treating cancer in a subject, comprising administering to the subject an inhibitor of polo-like kinase 4 (PLK4), wherein prior to administration to the subject of the inhibitor of polo-like kinase 4 (PLK4) the cancer in the subject has (a) progressed following administration to the subject of a cyclin-dependent kinase inhibitor, (b) been determined to be resistant to at least one cyclin-dependent kinase inhibitor, and (c) been determined to overexpress the gene that encodes the tripartite motif-containing protein 37 (TRIM37).

[0067] In some embodiments of the methods disclosed herein, the cancer in the subject is selected from chordoma, small-cell lung cancer, large cell neuroendocrine lung carcinoma, extrapulmonary small cell carcinoma, glioblastoma, glioma, head and neck cancer, esophagus squamous cell carcinoma, oligodendroglioma, oligoastrocytoma, prostate cancer, colorectal cancer, endometrial cancer, melanoma, breast cancer, neuroblastoma, non-squamous cell lung carcinoma, bladder cancer, and liver cancer.

[0068] In some embodiments of the methods disclosed herein, the cancer in the subject is breast cancer. In some embodiments, the breast cancer in the subject is selected from (a) hormone receptor (HR)- positive, human epidermal growth factor receptor 2 (HER2) -positive breast cancer (b) hormone receptor (HR) -positive, human epidermal growth factor receptor 2 (HER2) -negative breast cancer; (c) hormone receptor (HR)-positive breast cancer, (d) hormone receptor (HR)-negative breast cancer, (e) HER2- positive breast cancer, (f) human epidermal growth factor receptor 2 (HER2) -negative advanced or metastatic breast cancer, (g) human epidermal growth factor receptor 2 (HER2) -negative, node-positive, early breast cancer at high risk of recurrence, (h) hormone receptor (HR) -positive, human epidermal growth factor receptor 2 (HE R2) -negative advanced or metastatic breast cancer with disease progression following endocrine therapy; (i) hormone receptor (HR) -positive, human epidermal growth factor receptor 2 (HE R2) -negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting; (j) hormone receptor (HR) -positive, human epidermal growth factor receptor 2 (HER2) -negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine -based therapy; (k) fulvestrant as initial endocrine-based therapy or following disease progression on endocrine therapy in postmenopausal women or in men; (1) HER2-low breast cancer, (m) triple -negative breast cancer, (n) BRCA1 -mutated breast cancer, and (o) BRCA2 -mutated breast cancer. In some embodiments of the methods disclosed herein the breast cancer is hormone receptor (HR) -positive, human epidermal growth factor receptor 2 (HER2) -positive breast cancer. In some embodiments of the methods disclosed herein, the breast canceris hormone receptor (HR) -positive, human epidermal growth factor receptor 2 (HE R2) -negative breast cancer. In some embodiments of the methods disclosed herein, the breast cancer is hormone receptor (HR)-positive breast cancer. In some embodiments of the methods disclosed herein, the breast cancer is hormone receptor (HR)-negative breast cancer. In some embodiments of the methods disclosed herein, the breast cancer is HER2-positive breast cancer. In some embodiments of the methods disclosed herein, the breast cancer is human epidermal growth factor receptor 2 (HER2) -negative advanced or metastatic breast cancer. In some embodiments of the methods disclosed herein, the breast cancer is human epidermal growth factor receptor 2 (HER2) -negative, node-positive, early breast cancer at high risk of recurrence. In some embodiments of the methods disclosed herein, the breast cancer is hormone receptor (HR) -positive, human epidermal growth factor receptor 2 (HER2) -negative advanced or metastatic breast cancer with disease progression following endocrine therapy. In some embodiments of the methods disclosed herein, the breast cancer is hormone receptor (HR) -positive, human epidermal growth factor receptor 2 (HE R2) -negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. In some embodiments of the methods disclosed herein, the breast cancer is hormone receptor (HR) -positive, human epidermal growth factor receptor 2 (HE R2) -negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine -based therapy. In some embodiments of the methods disclosed herein, the breast cancer is fulvestrant as initial endocrine -based therapy or following disease progression on endocrine therapy in postmenopausal women or in men. In some embodiments of the methods disclosed herein, the breast cancer is HER2-low breast cancer. In some embodiments of the methods disclosed herein, the breast cancer is triple-negative breast cancer. In some embodiments of the methods disclosed herein, the breast cancer is BRCA 1 -mutated breast cancer. In some embodiments of the methods disclosed herein, the breast cancer is BRCA2 -mutated breast cancer.

[0069] In some embodiments of the methods disclosed herein, the cancer in the subject expresses polo- like kinase 4 (PLK4). In some embodiments, the cancer in the subject has been determined to express polo-like kinase 4 (PLK4) prior to administering to the subject an inhibitor of PLK4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the cancer in the subject exhibits an overexpression of the E3 ubiquitin-protein ligase (TRIM37) protein. In some embodiments, the cancer in the subject exhibits an overexpression of the gene that encodes the tripartite motif-containing protein 37 (TRIM37). In some embodiments, the cancer in the subject exhibits an amplification of the gene that encodes the tripartite motif-containing protein 37 (TRIM37).

[0070] In some embodiments are provided such methods described herein, wherein the cancer in the subject has been determined to express polo-like kinase 4 (PLK4) prior to administering to the subject the inhibitor of polo-like kinase 4 (PLK4), wherein the cancer in the subject exhibits an overexpression of the E3 ubiquitin-protein ligase (TRIM37) protein. In some embodiments are provided such methods disclosed herein, wherein the cancer in the subject exhibits an overexpression of the gene that encodes the tripartite motif-containing protein 37 (TRIM37). In some embodiments are provided such methods disclosed herein, wherein the cancer in the subject exhibits an amplification of the gene that encodes thetripartite motif-containing protein 37 (TRIM37). In some embodiments are provided such methods disclosed herein, wherein the cancer in the subject has been determined to overexpress the gene that encodes the tripartite motif-containing protein 37 (TRIM37) prior to administration to the subject of the inhibitor of polo-like kinase 4 (PLK4). In some embodiments are provided such methods disclosed herein, wherein the cancer is neuroblastoma or breast cancer. In some embodiments are provided such methods disclosed herein, wherein the cancer is neuroblastoma. In some embodiments are provided such compounds or pharmaceutical compositions for such use, wherein the cancer is breast cancer.

[0071] Further provided herein are uses of an inhibitor of polo-like kinase 4 (PLK4), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in the manufacture of a medicament for the treatment of cancer in a subject in need thereof, wherein the cancer in the subject has progressed following administration to the subject of a cyclin -dependent kinase inhibitor.

[0072] Further provided herein are uses of an inhibitor of polo-like kinase 4 (PLK4), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in the manufacture of a medicament for the treatment of cancer in a subject in need thereof, wherein the cancer in the subject has been determined to be resistant to at least one cyclin-dependent kinase inhibitor.

[0073] Further provided herein are uses of an inhibitor of polo-like kinase 4 (PLK4), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in the manufacture of a medicament for the treatment of cancer in a subject in need thereof, wherein the cancer in the subject has (a) progressed following administration to the subject of a cyclin-dependent kinase inhibitor, and (b) been determined to be resistant to at least one cyclin-dependent kinase inhibitor.

[0074] Further provided herein are uses of an inhibitor of polo-like kinase 4 (PLK4), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in the manufacture of a medicament for the treatment of cancer in a subject in need thereof, wherein the cancer in the subject has progressed following administration to the subject of a cyclin-dependent kinase inhibitor.

[0075] Further provided herein are uses of an inhibitor of polo-like kinase 4 (PLK4), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in the manufacture of a medicament for the treatment of cancer in a subject in need thereof, wherein the cancer in the subject has been determined to be resistant to at least one cyclin-dependent kinase inhibitor.

[0076] Further provided herein are uses of an inhibitor of polo-like kinase 4 (PLK4), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in the manufacture of a medicament for the treatment of cancer in a subject in need thereof, wherein the cancer in the subject has (a) progressed following administration to the subject of a cyclin-dependent kinase inhibitor, and (b) been determined to be resistant to at least one cyclin-dependent kinase inhibitor.

[0077] Further provided herein are uses of an inhibitor of polo -like kinase 4 (PLK4), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in the manufacture of a medicament for the treatment of cancer in a subject in need thereof, wherein the cancer in the subject has (a) progressed following administration to the subject of a cyclin-dependent kinase inhibitor, (b) beendetermined to be resistant to at least one cyclin-dependent kinase inhibitor, and (c) been determined to exhibit an overexpression of the gene that encodes the tripartite motif-containing protein 37 (TRIM37).

[0078] Further provided herein are uses of an inhibitor of polo-like kinase 4 (PLK4), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in the manufacture of a medicament for the treatment of cancer in a subject in need thereof, wherein the cancer in the subject has (a) progressed following administration to the subject of a cyclin-dependent kinase inhibitor, (b) been determined to be resistant to at least one cyclin-dependent kinase inhibitor, and (c) been determined to exhibit an amplification of the gene that encodes the tripartite motif-containing protein 37 (TRIM37).

[0079] Further provided herein are uses of an inhibitor of polo-like kinase 4 (PLK4), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in the manufacture of a medicament for the treatment of cancer in a subject in need thereof, wherein the cancer in the subject has (a) progressed following administration to the subject of a cyclin-dependent kinase inhibitor, (b) been determined to be resistant to at least one cyclin-dependent kinase inhibitor, and (c) been determined to overexpress the gene that encodes the tripartite motif-containing protein 37 (TRIM37).

[0080] In some embodiments are provided such uses, wherein the cancer is neuroblastoma, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, or pituitary adenoma. In some embodiments the cancer is neuroblastoma or breast cancer. In some embodiments the cancer is neuroblastoma. In some embodiments the cancer is breast cancer.

[0081] In some embodiments of the methods disclosed herein, the cyclin-dependent kinase inhibitor is selected from an inhibitor of one or more of cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 4 (CDK4), and cyclin-dependent kinase 6 (CDK6). In some embodiments, the cyclin-dependent kinase inhibitor is selected from an inhibitor of cyclin-dependent kinase 2 (CDK2). In some embodiments, the cyclin-dependent kinase inhibitor is selected from an inhibitor of cyclin-dependent kinase 4 (CDK4). In some embodiments, the cyclin-dependent kinase inhibitor is selected from an inhibitor of cyclin- dependent kinase 6 (CDK6). In some embodiments, the cyclin-dependent kinase inhibitor is selected from an inhibitor of cyclin dependent kinase 4 and 6 (CDK4 / 6).

[0082] In some embodiments of the methods disclosed herein, the cyclin-dependent kinase inhibitor is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, dinaciclib, PF-07104091, BLU-222, and PF-07220060. In some embodiments, the cyclin-dependent kinase inhibitor is palbociclib. In some embodiments, the cyclin-dependent kinase inhibitor is ribociclib. In some embodiments, the cyclin-dependent kinase inhibitor is abemaciclib. In some embodiments, the cyclin-dependent kinase inhibitor is trilaciclib. In some embodiments, the cyclin-dependent kinase inhibitor is dinaciclib. In some embodiments, the cyclin-dependent kinase inhibitor is PF-07104091. In some embodiments, the cyclin- dependent kinase inhibitor is BLU-222. In some embodiments, the cyclin-dependent kinase inhibitor is PF-07220060.

[0083] In some embodiments, the inhibitor of polo-like kinase 4 (PLK4) is used in combination with one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents is selected from: (a) an aromatase inhibitor: (b) fulvestrant; (c) luteinizing hormone -releasing hormone (LHRH) agonists. In some embodiments, the one or more additional therapeutic agents is an aromatase inhibitor. In some embodiments, the aromatase inhibitor is selected from anastrozole, exemestane, letrozole, vorozole, formestane, fadrozole, aminoglutethimide, testolactone, 1,4,6- androstatrien-3, 17-dione, and 4-androstene-3, 6, 17-trione. In some embodiments, the aromatase inhibitor is anastrozole. In some embodiments, the aromatase inhibitor is anastrozole. In some embodiments, the aromatase inhibitor is exemestane. In some embodiments, the aromatase inhibitor is letrozole. In some embodiments, the aromatase inhibitor is vorozole. In some embodiments, the aromatase inhibitor is formestane. In some embodiments, the aromatase inhibitor is fadrozole. In some embodiments, the aromatase inhibitor is aminoglutethimide. In some embodiments, the aromatase inhibitor is testolactone. In some embodiments, the aromatase inhibitor is 1, 4, 6-androstatrien-3, 17-dione. In some embodiments, the aromatase inhibitor is and 4-androstene-3, 6, 17-trione. In some embodiments, the one or more additional therapeutic agents is fulvestrant. In some embodiments, the one or more additional therapeutic agents is one or more luteinizing hormone-releasing hormone (LHRH) agonists. In some embodiments, the one or more luteinizing hormone-releasing hormone (LHRH) agonists are selected from leuprolide, goserelin, triptorelin, histrelin, buserelin, and triptorelin. In some embodiments, the luteinizing hormone- releasing hormone (LHRH) agonist is leuprolide. In some embodiments, the luteinizing hormone- releasing hormone (LHRH) agonist is goserelin. In some embodiments, the luteinizing hormone- releasing hormone (LHRH) agonist is triptorelin. In some embodiments, the luteinizing hormone- releasing hormone (LHRH) agonist is histrelin. In some embodiments, the luteinizing hormone-releasing hormone (LHRH) agonist is buserelin. In some embodiments, the luteinizing hormone-releasing hormone (LHRH) agonist is triptorelin.

[0084] In some embodiments, the inhibitor of polo-like kinase 4 (PLK4) is used in combination with one or more additional therapeutic agents selected from at least one cyclin-dependent kinase inhibitor that is the same or different than the cyclin-dependent kinase inhibitor that had been previously administered to the subject or to which the cancer in the subject has become resistant. In some embodiments, the inhibitor of polo-like kinase 4 (PLK4) is used in combination with at least one cyclin-dependent kinase inhibitor that is the same as the cyclin-dependent kinase inhibitor that had been previously administered to the subject or to which the cancer in the subject has become resistant. In some embodiments, the inhibitor of polo-like kinase 4 (PLK4) is used in combination with at least one cyclin-dependent kinase inhibitor that is different than the cyclin-dependent kinase inhibitor that had been previously administered to thesubject or to which the cancer in the subject has become resistant. In some embodiments, the cyclin- dependent kinase inhibitor is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, dinaciclib, PF- 07104091, BLU-222, and PF-07220060. In some embodiments, the cyclin-dependent kinase inhibitor is palbociclib. In some embodiments, the cyclin-dependent kinase inhibitor is ribociclib. In some embodiments, the cyclin-dependent kinase inhibitor is abemaciclib. In some embodiments, the cyclin- dependent kinase inhibitor is trilaciclib. In some embodiments, the cyclin-dependent kinase inhibitor is dinaciclib. In some embodiments, the cyclin-dependent kinase inhibitor is PF-07104091. In some embodiments, the cyclin-dependent kinase inhibitor is BLU-222. In some embodiments, the cyclin- dependent kinase inhibitor is PF-07220060.

[0085] In some embodiments of the methods disclosed herein, the inhibitor of polo-like kinase 4 (PLK4) is selected from a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (I), wherein:Ring A is C6-10 aryl, heteroaryl, C6-10 cycloalkyl, or heterocycloalkyl; each R1is independently deuterium, halogen, -CN, oxo, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -P(O)(Ra)2, - P(O)2(Ra)2, C1a-6lkyl, hCa1l-o6alkyl, -OCi-Cehaloalkyl, Ci -Cedeuteroalkyl, hydroxyalkyl, C1-6C1-6 aminoalkyl, Ch1-e6teroalkyl, C2-Cealkenyl, C2-Cealkynyl, C6-10 cycloalkyl, heterocycloalkyl,C6-10 aryl, or heteroaryl; wherein each of the alkyl, C2C-C1-e6alkenyl, C2-Cealkynyl, C3- Ciocycloalkyl, heterocycloalkyl, aryCl,6- a1n0d heteroaryl is optionally and independently substituted with one or more Rla; or two R1on adjacent atoms are taken together to form a C6-10 cycloalkyl or heterocycloalkyl; each optionally substituted with one or more Rlb; each Rlais independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl,C1-6 haloalkyl, Ci -Cedeuteroalkyl, hydrCox1-y6alkyl, aminoalkyCl1,-6 heteroalkyl, C2C-1-6 Cealkenyl, C2-Cealkynyl, C6-10 cycloalkyl, heterocycloalkyl, aryl, or heteCr6o-a10ryl; or two Rlaon the same atom are taken together to form an oxo;each Rlbis independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, C1-6 haloalkyl, Ci -Cedeuteroalkyl, hydrCox1-y6alkyl, aminoalkyCl1,-6 heteroalkyl, C2C-1-6 Cealkenyl, C2-Cealkynyl, C6-10 cycloalkyl, heterocycloalkyl, aryl, or heteCr6o-a10ryl; or two Rlbon the same atom are taken together to form an oxo; n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;R2is hydrogen, Ca1-l6kyl, haCl1o-a6lkyl, or Ci -Cedeuteroalkyl;R3is hydrogen, Ca1-l6kyl, haCl1o-a6lkyl, or Ci -Cedeuteroalkyl; each of R4a, R4b, and R4cis independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, alkyCl,1-6 haloalkCy1l-,6 Ci -Cedeuteroalkyl, C1-6 hydroxyalkyl, Ca1m-6inoalkyl, or heterCo1a-6lkyl;R5is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, alkyl, Ch1a-l6oalkyl, C1-6 Ci -Cedeuteroalkyl, Chy1-d6roxyalkyl, aminoCa1l-k6yl, or heteroalkylC;1-6 each R6is independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, alkyl, C1-6C1-6 haloalkyl, Ci -Cedeuteroalkyl, hydrCox1-y6alkyl, aminoalkyCl1,-6 or heteroalkyl; C1-6R7is hydrogen, Ca1l-k6yl, haClo1a-6lkyl, Ci -Cedeuteroalkyl, hydroxyalkyl, oCr1-6 aminoalkyl; C1-6 each ofR8a, R8b, R8c, andR8dis independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, - OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2a, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-a6lkyl, hCal1o-6alkyl, Ci -Cedeuteroalkyl, hydroxyalkylC, 1-6 aminoalkyl, C1-6C1-6 heteroalkyl, C2-Cealkenyl, C2-Cealkynyl, C6-10 cycloalkyl, heterocycloalkyl, aryl, or C6-10 heteroaryl; each Rais independently alkCyl1,-6 haloalCk1y-6l, Ci -Cedeuteroalkyl, hydroxyalkyl, C1-6 C1-6 aminoalkyl, Ch1-e6teroalkyl, C2-Cealkenyl, C2-Cealkynyl, C6-10 cycloalkyl, heterocycloalkyl, C6-10 aryl, heteroaryl, alCky1-l6(C3-Ciocycloalkyl), alkyl(heteCro1c-6ycloalkyl), alkyl(Ce- C1-6 Cioaryl), or C1-6alkyl(heteroaryl); wherein each of the alkyl, C2-CeaClk1-e6nyl, C2-Cealkynyl, C3- Ciocycloalkyl, heterocycloalkyl, aryCl,6- a1n0d heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-6 alkyl, C1-6haloalkyl, Ci -Cedeuteroalkyl, hydroxCya1l-6kyl, aminoalkyl,C or1-6 C1-6 heteroalkyl; each Rbis independently hydrogen, alkyl, C1-6 haloalkyl,C C1i-6 -Cedeuteroalkyl, hydroxyalkyl, C1-6C1-6 aminoalkyl, Ch1-e6teroalkyl, C2-Cealkenyl, C2-Cealkynyl, C6-10 cycloalkyl, heterocycloalkyl, C6-10 aryl, heteroaryl, alCky1-l6(C3-Ciocycloalkyl), alkyl(heteCro1c-6ycloalkyl), alkyl(Ce- C1-6 Cioaryl), or C1-6alkyl(heteroaryl); wherein each of the alkyl, C2-CeaClk1-e6nyl, C2-Cealkynyl, C3- Ciocycloalkyl, heterocycloalkyl, aryCl,6- a1n0d heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2,-S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-6 alkyl, C1-6haloalkyl, Ci -Cedeuteroalkyl, hydroxCya1l-6kyl, aminoalkyl, C or1-6 C1-6 heteroalkyl; and each Rcand Rdare independently hydrogen, alkyl, C1-h6aloalkyl, CCi -1C-6edeuteroalkyl, C1-6 hydroxyalkyl, Ca1-l6koxy, amCin1-o6alkyl, alkylamCi1n-o6 , heteroalkyl,C C12-6- Cealkenyl, C2-Cealkynyl, C3-Ciocycloalkyl, heterocycloalkyl, aryl, heteroarCyl6,-1 C0i-Cealkyl(C3- Ciocycloalkyl), Ci-C6alkyl(heterocycloalkyl), alkyl(CCe1--6Cioaryl), or Ci-C6alkyl(heteroaryl); wherein each of the aClk1y-6l, C2-Cealkenyl, C2-Cealkynyl, C3-Ciocycloalkyl, heterocycloalkyl, Ce- Cioaryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, alkyl, C1-6C1-6 haloalkyl, Ci -Cedeuteroalkyl, hydrCox1-y6alkyl, aminoalkyCl1,-6 or heteroalkyl; C1-6 or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, - S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, - C(=O)OH, -C(=O)OCH3, Ca1l-k6yl, haClo1a-6lkyl, deuterCoa1l-6kyl, hydroxyalkyCl,1-6 C1-6 aminoalkyl, or Ch1e-6teroalkyl.

[0086] In some embodiments of the methods disclosed herein, the inhibitor of polo-like kinase 4 (PLK4) is selected from (lR,2S)-5'-methoxy-2-{3-[(5-methoxypyrimidin-4-yl)amino]-lH-indazol-6- yl}spiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-5'-methoxy-2-{3-[(5-methylpyrimidin-4- yl)amino]-lH-indazol-6-yl}spiro[cyclopropane-l,3'-indol]-2'(lH)-one; (lR,2S)-2-{3-[(5- chloropyrimidin-4-yl)amino]-lH-indazol-6-yl}-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-2-{3-[(5-ethoxypyrimidin-4-yl)amino]-lH-indazol-6-yl}-5'-methoxyspiro[cyclopropane-l,3'- indol]-2'(rH)-one; (lR,2S)-2-{3-[(5-cyclopropylpyrimidin-4-yl)amino]-lH-indazol-6-yl}-5'- methoxyspiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-2-{3-[(5-chloropyrimidin-4-yl)amino]-lH- indazol-6-yl}-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(lH)-one; (lS,2R)-5'-methoxy-2-{3-[(5- methoxypyrimidin-4-yl)amino]-lH-indazol-6-yl}spiro[cyclopropane-l,3'-indol]-2'(lH)-one; (lR,2S)-2- (3-{[5-chloro-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-lH-indazol-6-yl)-5'- methoxyspiro[cyclopropane-l,3'-indol]-2'(lH)-one; (lR,2S)-2-{3-[(2-chloro-5-methoxypyrimidin-4- yl)amino]-lH-indazol-6-yl}-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(lH)-one; (lR,2S)-5'-methoxy- 2-(3-{[5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-lH-indazol-6-yl)spiro[cyclopropane-l,3'- indol]-2'(rH)-one; (lR,2S)-5'-methoxy-2-(3-{[5-methoxy-6-(piperidin-l-yl)pyrimidin-4-yl]amino}-lH- indazol-6-yl)spiro[cyclopropane-l,3'-indol]-2'(lH)-one; (lR,2S)-5'-methoxy-2-{3-[(3-methoxypyrazin- 2-yl)amino]-lH-indazol-6-yl}spiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-5'-methoxy-2-{3-[(6- methoxypyrimidin-4-yl)amino]-lH-indazol-6-yl}spiro[cyclopropane-l,3'-indol]-2'(lH)-one; (lR,2S)-2- {3-[(6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino]-lH-indazol-6-yl}-5'- methoxyspiro[cyclopropane-l,3'-indol]-2'(lH)-one; (lR,2S)-2-{3-[(2,3-dihydro-l-benzofuran-7- yl)amino]-lH-indazol-6-yl}-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(lH)-one; (lR,2S)-5'-methoxy-2-{3-[(3-methoxypyridin-2-yl)amino]-lH-indazol-6-yl}spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-5'-methoxy-2-{3-[(4-methoxypyridin-3-yl)amino]-lH-indazol-6-yl}spiro[cyclopropane-l,3'- indol]-2'(l'H)-one; (lR,2S)-5'-methoxy-2-{3-[(3-methoxypyridin-4-yl)amino]-lH-indazol-6- yl}spiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-2-(3-{[5-chloro-6-(4-methylpiperazin-l- yl)pyrimidin-4-yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-5'-methoxy-2-{3-[(l,3,5-trimethyl-lH-pyrazol-4-yl)amino]-lH-indazol-6- yl}spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-5'-methoxy-2-(3-{[5-(trifluoromethyl)pyrimidin- 4-yl]amino}-lH-indazol-6-yl)spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-{3-[(5-chloro-2- methoxypyrimidin-4-yl)amino]-lH-indazol-6-yl}-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-5'-methoxy-2-{3-[(2-methoxypyridin-3-yl)amino]-lH-indazol-6-yl}spiro[cyclopropane-l,3'- indol]-2'(l'H)-one; (lR,2S)-2-{3-[(l-benzofuran-7-yl)amino]-lH-indazol-6-yl}-5'- methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-5'-methoxy-2-{3-[(3-methoxy-l-methyl- lH-pyrazol-4-yl)amino]-lH-indazol-6-yl} spiro [cyclopropane-1, 3'-indol]-2'(l'H)-one; (lR,2S)-2-{3-[(3- hydroxy-2,3-dihydro-l-benzofuran-7-yl)amino]-lH-indazol-6-yl}-5'-methoxyspiro[cyclopropane-l,3'- indol]-2'(l'H)-one; (lR,2S)-2-(3-{[(3S)-3-hydroxy-2,3-dihydro-l-benzofuran-7-yl]amino}-lH-indazol-6- yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-2-(3-{[(3R)-3-hydroxy-2,3-dihydro- l-benzofuran-7-yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one;(lR,2S)-2-{3-[(2,3-dihydropyrazolo[5,l-b][l,3]oxazol-7-yl)amino]-lH-indazol-6-yl}-5'- methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-5'-methoxy-2-{3-[(3-oxo-2,3-dihydro-l- benzofuran-7-yl)amino]-lH-indazol-6-yl}spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-{3-[(2,3- dihydrofuro[2,3-c]pyridin-7-yl)amino]-lH-indazol-6-yl}-5'-methoxyspiro[cyclopropane-l,3'-indol]- 2'(l'H)-one; (lR,2S)-2-(3-{[(3S)-3-(hydroxymethyl)-2,3-dihydrofuro[2,3-c]pyridin-7-yl]amino}-lH- indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-(3-{[(3R)-3- (hydroxym ethyl) -2, 3 -dihydrofuro [2,3 -c] pyridin-7-yl] amino } - 1 H-indazol-6-yl) -5 methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-5'-methoxy-2-(3-{[6-(3-methoxyazetidin-l- yl)pyrimidin-4-yl]amino}-lH-indazol-6-yl)spiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-2-(3-{[6- (3-hydroxyazetidin-l-yl)pyrimidin-4-yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'- indol]-2'(l'H)-one; (lR,2S)-2-(3-((6-(3-oxa-8-azabicyclo[3.2. l]octan-8-yl)-5-methoxypyrimidin-4- yl)amino)-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indolin]-2'-one; (lR,2S)-2-(3-{[6-(2- hydroxyethoxy)pyrimidin-4-yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]- 2'(l'H)-one; (lR,2S)-2-(3-((6-(l,l-dioxidothiomorpholino)pyrimidin-4-yl)amino)-lH-indazol-6-yl)-5'- methoxyspiro[cyclopropane-l,3'-indolin]-2'-one); (lR,2S)-5'-methoxy-2-(3-{[6-(l,4-oxazepan-4- yl)pyrimidin-4-yl]amino}-lH-indazol-6-yl)spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-5 - methoxy-2-(3-{[5-methoxy-2-methyl-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-lH-indazol-6- yl)spiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-2-(3-{[6-(azetidin-l-yl)-5-methoxypyrimidin-4- yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-(3-{[6-(3- hydroxyazetidin- 1 -yl) -5 -methoxypyrimidin-4-yl] amino } - 1 H-indazol-6-yl) -5 methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-5'-methoxy-2-(3-{[5-methoxy-6-(l,4-oxazepan-4-yl)pyrimidin-4-yl]amino}-lH-indazol-6-yl)spiro[cyclopropane-l,3'-indol]-2'(rH)-one;(lR,2S)-2-(3-{[6-(azetidin-l-yl)pyrimidin-4-yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane- l,3'-indol]-2'(l'H)-one; (lR,2S)-2-(3-{[5-chloro-6-(3-hydroxyazetidin-l-yl)pyrimidin-4-yl]amino}-lH- indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-(3-{[5-chloro-6-(3- methoxyazetidin-l-yl)pyrimidin-4-yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'- indol]-2'(l'H)-one; (lR,2S)-2-(3-{[2-chloro-5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-lH- indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-2-(3-{[4-chloro-5-methoxy- 6-(morpholin-4-yl)pyrimi din-2 -yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]- 2'(l'H)-one; (lR,2S)-2-(3-{[l-(2-hydroxyethyl)-3-methoxy-lH-pyrazol-4-yl]amino}-lH-indazol-6-yl)-5- methoxyspirofcyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-2-(3-{[2-cyclopropyl-5-methoxy-6- (morpholin-4-yl)pyrimidin-4-yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]- 2'(l'H)-one; (lR,2S)-2-[3-({6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-5-methoxypyrimidin-4-yl}amino)- lH-indazol-6-yl]-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-2-(3-((5-chloro-6-(l,l- dioxidothiomorpholino)pyrimidin-4-yl)amino)-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'- indolin]-2'-one; (lR,2S)-2-(3-((6-(l,l-dioxidothiomorpholino)-5-methoxypyrimidin-4-yl)amino)-lH- indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indolin]-2'-one; (lR,2S)-2-(3-{[5-(2-hydroxyethyl)-3- methoxypyrazin-2-yl] amino } - lH-indazol-6-yl)-5 '-methoxyspiro [cyclopropane- 1 ,3 -indol] -2'( 1 'H)-one; (lR,2S)-2-(3-{[6-(2-hydroxyethyl)-3-methoxypyrazin-2-yl]amino}-lH-indazol-6-yl)-5'- methoxyspiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-2-(3-((6-(l,l-dioxidothiomorpholino)-5- methoxy-2-methylpyrimidin -4-yl)amino)-lH-indazol-6-yl)-5'-methoxy spiro [cyclopropane- l,3'-indolin]- 2'-one; (lR,2S)-2-(3-((5-chloro-6-(l,l-dioxidothiomorpholino)-2-methylpyrimidin-4-yl)amino)-lH- indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indolin]-2'-one; (lR,2S)-2-(3-((2-cyclopropyl-6-(l,l- dioxidothiomorpholino)pyrimidin-4-yl)amino)-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'- indolin]-2'-one; (lR,2S)-2-(3-((6-(l,l-dioxidothiomorpholino)-2-methylpyrimidin-4-yl)amino)-lH- indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indolin]-2'-one; 5-methoxy-4-({6-[(lR,2S)-5'-methoxy- 2-oxo- l',2'-dihydrospiro [cyclopropane- 1,3 -indol] -2-yl]- lH-indazol-3-yl}amino)-6-(morpholin-4- yl)pyrimidine-2-carbonitrile; 4-(l, l-dioxidothiomorpholino)-5-methoxy-6-((6-((lR,2S)-5'-methoxy-2'- oxospiro[cyclopropane-l,3'-indolin]-2-yl)-lH-indazol-3-yl)amino)pyrimidine-2-carbonitrile; (lR,2S)-2- {3-[(l,3-dimethyl-lH-pyrazol-4-yl)amino]-lH-indazol-6-yl}-5'-methoxyspiro[cyclopropane-l,3'-indol]- 2'(l'H)-one; (lR,2S)-5'-methoxy-2-(3-{[l-methyl-3-(trifluoromethyl)-lH-pyrazol-4-yl]amino}-lH- indazol-6-yl)spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-5'-methoxy-2-{3-[(l-methyl-lH- pyrazol-4-yl)amino]-lH-indazol-6-yl}spiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; 4-({6-[(lR,2S)-5'- methoxy-2'-oxo- l',2'-dihydrospiro [cyclopropane- 1 ,3'-indol]-2-yl]- lH-indazol-3-yl}amino)- 1 -methyl- 1H- pyrazole-3-carbonitrile; (lR,2S)-2-[3-({6-[(2R,6S)-2,6-dimethyhnorpholin-4-yl]-5-methoxy-2- methylpyrimidin-4-yl} amino)- lH-indazol-6-yl]-5'-methoxyspiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-2-(3-{[2-(2-hydroxyethyl)-5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-lH-indazol-6- yl)-5'-methoxyspiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-2-(3-((2-cyclopropyl-6-(l,l- dioxidothiomorpholino)-5-methoxypyrimidin-4-yl)amino)-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indolin]-2'-one; (lR,2S)-2-(3-((5-chloro-2-cyclopropyl-6-(l,l- dioxidothiomorpholino)pyrimidin-4-yl)amino)-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'- indolin]-2'-one; (lR,2S)-5'-methoxy-2-{3-[(3-methoxy-6-methylpyrazin-2-yl)amino]-lH-indazol-6- yl}spiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-2-(3-{[5-chloro-6-(3-hydroxyazetidin-l-yl)-2- methylpyrimidin-4-yl] amino } - lH-indazol-6-yl)-5 '-methoxyspiro [cyclopropane- 1 ,3 -indol] -2'( 1 'H)-one; ( lR,2S)-2-(3-{ [6-(3-hydroxyazetidin- 1 -yl)-5-methoxy-2-methylpyrimidin-4-yl]amino}- lH-indazol-6-yl)- 5'-methoxyspiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-2-{3-[(l,3-dimethyl-lH-pyrazol-5- yl)amino]-lH-indazol-6-yl}-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-5'-methoxy- 2-{ 3-[(4-methoxy-l -methyl- lH-pyrazol-5-yl)amino]-lH-indazol-6-yl}spiro[cyclopropane-l,3'-indol]- 2'(l'H)-one; (lR,2S)-2-(3-{[5-chloro-2-cyclopropyl-6-(3-hydroxyazetidin-l-yl)pyrimidin-4-yl]amino}- lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-2-[3-({2-cyclopropyl-6- [(2R,6S)-2,6-dimethylmorpholin-4-yl]-5-methoxypyrimidin-4-yl}amino)-lH-indazol-6-yl]-5'- methoxyspiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-2-(3-((5-chloro-6-(l,l- dioxidothiomorpholino)-2-isopropylpyrimidin-4-yl)amino)-lH-indazol-6-yl)-5'- methoxyspiro[cyclopropane-l,3'-indolin]-2'-one; (lR,2S)-5'-methoxy-2-{3-[(4-methoxy-l-methyl-lH- pyrazol-3-yl)amino]-lH-indazol-6-yl}spiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-2-{3-[(6- cyclopropyl-3-methoxypyrazin-2-yl)amino]- lH-indazol-6-yl}-5'-methoxy spiro [cyclopropane-1, 3'-indol]- 2'(l'H)-one; (lR,2S)-2-(3-{[2-cyclopropyl-6-(3-hydroxyazetidin-l-yl)-5-methoxypyrimidin-4-yl]amino}- lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-2-{3-[(3,6- dimethylpyrazin-2-yl)amino]-lH-indazol-6-yl} -5'-methoxy spirofcyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-5'-methoxy-2-(3-{[3-methoxy-6-(propan-2-yl)pyrazin-2-yl]amino}-lH-indazol-6- yl)spiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-2-(3-((6-(l,l-dioxidothiomorpholino)-2- isopropyl-5-methoxypyrimidin-4-yl)amino)-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'- indolin]-2'-one; (lR,2S)-5'-methoxy-2-(3-{[5-methoxy-6-(morpholin-4-yl)-2-(propan-2-yl)pyrimidin-4- yl]amino}-lH-indazol-6-yl)spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-5'-methoxy-2-{3-[(5- methoxy-2-methylpyridin-4-yl)amino]-lH-indazol-6-yl}spiro[cyclopropane-l,3'-indol]-2'(l'H)-one;(lR,2S)-5'-methoxy-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-lH-indazol-6- yl}spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-5'-methoxy-2-{3-[(3-methoxy-6-methylpyridin-2- yl)amino]-lH-indazol-6-yl} spiro [cyclopropane- l,3'-indol]-2'(l'H)-one; (lR,2S)-5'-methoxy-2-{3-[(2- methoxy-5-methylpyridin-3-yl)amino]-lH-indazol-6-yl}spiro[cyclopropane-l,3'-indol]-2'(l'H)-one;( 1 R, 2S) -5 '-methoxy-2- {3 - [(4-methoxypyridazin-3 -yl)amino] - 1 H-indazol-6-yl } spiro [cyclopropane- 1,3'- indol]-2'(l'H)-one; (lR,2S)-2-{3-[(3-cyclopropyl-l-methyl-lH-pyrazol-5-yl)amino]-lH-indazol-6-yl}-5'- methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-{3-[(3-cyclopropyl-l-ethyl-lH-pyrazol-5- yl)amino]-lH-indazol-6-yl}-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-(3-{[2-(2- hydroxy-2-methylpropyl)-5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-lH-indazol-6-yl)-5'- methoxyspirofcyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-5'-methoxy-2-(3-{[3-methoxy-5- (morpholin-4-yl)pyrazin-2-yl] amino } - lH-indazol-6-yl)spiro [cyclopropane- 1 ,3 -indol] -2'( 1 'H)-one; (lR,2S)-5'-methoxy-2-(3-{[3-methoxy-2-(morpholin-4-yl)pyridin-4-yl]amino}-lH-indazol-6-yl)spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-{3-[(5-chloro-2-methylpyridin-4-yl)amino]-lH- indazol-6-yl}-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-5'-methoxy-2-(3-{[5- methoxy-2-(morpholin-4-yl)pyrimidin-4-yl] amino} -lH-indazol-6-yl)spiro[cyclopropane- 1,3 -indol] - 2'(l'H)-one; (lR,2S)-2-{3-[(5-chloro-2-methylpyrimidin-4-yl)amino]-lH-indazol-6-yl}-5'- methoxyspiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-5'-methoxy-2-(3-{[3-methoxy-6- (morpholin-4-yl)pyrazin-2-yl] amino } - lH-indazol-6-yl)spiro [cyclopropane- 1 ,3 -indol] -2'( 1 'H)-one; (lR,2S)-5'-methoxy-2-(3-{[3-methoxy-6-(oxetan-3-yl)pyrazin-2-yl]amino}-lH-indazol-6- yl)spiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-5'-methoxy-2-(3-{[3-methoxy-6-(propan-2- yl)pyridazin-4-yl]amino}-lH-indazol-6-yl)spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-5 - methoxy-2-(3-{[6-(morpholin-4-yl)-2-(propan-2-yl)pyrimidin-4-yl]amino}-lH-indazol-6- yl)spiro[cyclopropane-l,3'-indol]-2'( H)-one; (lR,2S)-2-(3-{[5-chloro-2-(morpholin-4-yl)pyrimidin-4- yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-(3-{[5-(3- hydroxyazetidin-l-yl)-3-methoxypyridin-2-yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane- l,3'-indol]-2'(l'H)-one; (lR,2S)-5'-methoxy-2-(3-{[3-methyl-6-(propan-2-yl)pyrazin-2-yl]amino}-lH- indazol-6-yl)spiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-5'-methoxy-2-(3-{[6-(propan-2- yl)pyrazin-2-yl]amino}-lH-indazol-6-yl)spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-(3-{[5- chloro-6-(3-hydroxyazetidin-l-yl)pyrimidin-4-yl]amino}-lH-indazol-6-yl)-5'-methoxy-r- methylspiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-2-(3-{[5-chloro-6-(3-hydroxyazetidin-l- yl)pyrimidin-4-yl]amino}-lH-indazol-6-yl)-r-ethyl-5'-methoxyspiro[cyclopropane- 1,3 -indol] -2'(1'H)- one; (lR,2S)-2-(3-{[5-(difhioromethoxy)-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-lH-indazol-6-yl)-5'- methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-(3-{[6-(azetidin-3-yl)-3-methoxypyrazin- 2-yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; and (lR,2S)-2-(3- {[6-(3-hydroxyazetidin-l-yl)-2-(propan-2-yl)pyrimidin-4-yl]amino}-lH-indazol-6-yl)-5'- methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one, or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments of the methods disclosed herein, the inhibitor of polo-like kinase 4 (PLK4) is selected from (lR,2S)-2-(3-{[l-(2,2-difhioroethyl)-3-methyl-lH-pyrazol-5-yl]amino}-lH-indazol-6- yl)-5'-methoxyspiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-5'-methoxy-2-(3-{[5-methoxy-6- (morpholin-4-yl)pyrimidin-4-yl]amino}-lH-indazol-6-yl)-r-methylspiro[cyclopropane-l,3'-indol]- 2'(l'H)-one; (lR,2S)-2-(3-{[2-(3-hydroxyazetidin-l-yl)-5-methoxypyrimidin-4-yl]amino}-lH-indazol-6- yl)-5'-methoxyspiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-5'-methoxy-2-(3-{[6-(oxetan-3- yl)pyrazin-2-yl]amino}-lH-indazol-6-yl)spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-(3-{[5- chloro-2-(propan-2-yl)pyrimidin-4-yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'- indol]-2'(l'H)-one; (lR,2S)-2-(3-{[5-chloro-2-(oxetan-3-yl)pyrimidin-4-yl]amino}-lH-indazol-6-yl)-5'- methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-5'-methoxy-2-(3-{[5-methoxy-2-(oxetan-3- yl)pyrimidin-4-yl]amino}-lH-indazol-6-yl)spiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-2-(3-{[5- chloro-2-(3-hydroxyazetidin-l-yl)pyrimidin-4-yl]amino}-lH-indazol-6-yl)-5'- methoxyspirofcyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-2-(3-{[5-(difhroromethoxy)-2- methylpyrimidin-4-yl] amino } - lH-indazol-6-yl)-5 '-methoxyspiro [cyclopropane- 1 ,3 -indol] -2'( 1 'H)-one;(lR,2S)-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-lH-indazol-6-yl}-r- methylspiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2R)-2-{7-fluoro-3-[(5-methoxy-2- methylpyrimidin-4-yl)amino]-lH-indazol-6-yl}-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-lH-indazol-6-yl}spiro[cyclopropane-l,3'- indol]-2'(l'H)-one; (lR,2S)-5'-methoxy-2-(3-{[5-methoxy-2-(propan-2-yl)pyrimidin-4-yl]amino}-lH- indazol-6-yl)spiro|cyclopropanc-l.3'-indol |-2'( l 'H)-oncl (lR,2S)-2-{3-[(5-methoxy-2-methylpyrimidin- 4-yl)amino]-lH-indazol-6-yl}-5'-methylspiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lS,2S)-2-{3-[(5- methoxy-2-methylpyrimidin-4-yl)amino]-lH-indazol-6-yl}-5'-methylspiro[cyclopropane-l,3'-indol]- 2'(l'H)-one; (lR,2S)-2-(3-{[5-(difluoromethoxy)-2-(propan-2-yl)pyrimidin-4-yl]amino}-lH-indazol-6- yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-4'-fluoro-2-{3-[(5-methoxy-2- methylpyrimidin-4-yl)amino] - lH-indazol-6-yl} spiro[cyclopropane- 1 , 3 '-indol] -2'( 1 H)-one; ( 1 S,2S)-4'- fluoro-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-lH-indazol-6-yl}spiro[cyclopropane-l,3'- indol] -2'(l'H)-one; (lR,2S)-6'-fluoro-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-lH-indazol-6- yl}spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-(3-{[5-chloro-6-(2-oxa-6-azaspiro[3.3]heptan- 6-yl)pyrimidin-4-yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-5'-fluoro-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-lH-indazol-6- yl}spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-{3-[(5-ethoxy-2-methylpyrimidin-4-yl)amino]- lH-indazol-6-yl}-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-2-(3-{[5- (difluoromethoxy)-2-methylpyrimidin-4-yl]amino}-lH-indazol-6-yl)-5'-fluorospiro[cyclopropane-l,3'- indol] -2'(l'H)-one; (lR,2S)-5'-methoxy-2-[3-({2-methyl-5-[(propan-2-yl)oxy]pyrimidin-4-yl}amino)-lH- indazol-6-yl |spiro| cyclopropane- 1.3'-indol |-2'( I 'H)-onc: (lR,2S)-2-{3-[(5-methoxy-2-methylpyrimidin- 4-yl)amino]-lH-indazol-6-yl}-5'-(trifluoromethyl)spiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-2- {3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-lH-indazol-6-yl}-5'- (trifluoromethoxy)spiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lS,2S)-2-{3-[(5-methoxy-2- methylpyrimidin-4-yl)amino] - lH-indazol-6-yl } -5 '-(trifluoromethoxy) spiro [cyclopropane -1,3 -indol] - 2'(l'H)-one; (lR,2S)-2-{3-[(5-cyclopropyl-2-methylpyrimidin-4-yl)amino]-lH-indazol-6-yl}-5'- methoxyspiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-2-(3-{[5-(difluoromethoxy)-2-(oxetan-3- yl)pyrimidin-4-yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one;(lR,2R)-5'-fluoro-2-{7-fluoro-3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-lH-indazol-6- yl}spiro[cyclopropane-l,3'-indol]-2'(rH)-one; and (lR,2R)-2-(3-{[5-(difluoromethoxy)-2- methylpyrimidin-4-yl] amino} -7-fluoro- lH-indazol-6-yl)-5'- fluoro spiro[cyclopropane- l,3'-indol]-2'( 1'H)- one, or a pharmaceutically acceptable salt thereof.

[0088] In some embodiments of the methods disclosed herein, the inhibitor of polo-like kinase 4 (PLK4) is selected from (lR,2R)-2-{5-fluoro-3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-lH-indazol-6-yl}- 5'-methoxyspiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-5'-methoxy-2-{3-[(3-methoxy-6- methylpyridazin-4-yl)amino]-lH-indazol-6-yl}spiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-2-(3- { [5-(cyclopropyhnethoxy)-2-methylpyrimidin-4-yl]amino} - lH-indazol-6-yl)-5'- methoxyspirofcyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-2-(3-{[5-(2,2-difluoroethoxy)-2-methylpyrimidin-4-yl] amino } - lH-indazol-6-yl)-5 '-methoxyspiro [cyclopropane- 1 ,3 -indol] -2'( 1 'H)-one; ( 1 R, 2S) -5 '-methoxy-2- [3 -(2-methoxy-5-methylanilino) - IH-indazo 1-6-yl] spiro [cyclopropane- 1 , 3 -indol] - 2'(l'H)-one; (lR,2S)-5'-methoxy-2-(3-{ [2-methyl-5-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]amino}-lH- indazol-6-yl)spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-5'-methoxy-2-{3-[(2-methoxy-6- methylpyridin-3-yl)amino]-lH-indazol-6-yl}spiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-5 - methoxy-2-(3-{ [2-methyl-6-(propan-2-yl)pyrimidin-4-yl]amino}-lH-indazol-6-yl)spiro[cyclopropane- l,3'-indol]-2'(l'H)-one; (lR,2S)-2-{3-[(5-ethyl-2-methylpyrimidin-4-yl)amino]-lH-indazol-6-yl}-5'- methoxyspirofcyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-5'-methoxy-2-{3-[(2-methyl-6,7- dihydrofuro[3, 2-d]pyrimidin-4-yl)amino]-lH-indazol-6-yl}spiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-5'-methoxy-2-(3-{[5-methoxy-2-(oxan-4-yl)pyrimidin-4-yl]amino}-lH-indazol-6- yl)spiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-5'-methoxy-2-(3-{[5-methoxy-2- (methylsulfanyl)pyrimidin-4-yl] amino} - lH-indazol-6-yl)spiro[cyclopropane- 1 ,3'-indol] -2'( 1 H)-one; (lR,2S)-2-{3-[(2,5-dimethoxypyrimidin-4-yl)amino]-lH-indazol-6-yl}-5'-methoxyspiro[cyclopropane- l,3'-indol]-2'(l'H)-one; (lR,2S)-2-(3-{[2-(azetidin-l-yl)-5-methoxypyrimidin-4-yl]amino}-lH-indazol-6- yl)-5'-methoxyspiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-5'-methoxy-2-(3-{[3-methoxy-5- (trifluoromethyl)pyridin-2-yl]amino}-lH-indazol-6-yl)spiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-5'-methoxy-2-{3-[(2-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino]-lH-indazol-6- yl}spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-{3-[(2-ethyl-5-methoxypyrimidin-4-yl)amino]- lH-indazol-6-yl}-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-5'-methoxy-2-{3-[(7- methoxyquinolin-6-yl)amino]-lH-indazol-6-yl}spiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-5 - methoxy-2-(3-{ [2-methyl-5-(methylsulfanyl)pyrimidin-4-yl] amino }-lH-indazol-6- yl)spiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-5'-methoxy-2-{3-[(3-methoxyquinolin-2- yl)amino]-lH-indazol-6-yl}spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-{3-[(2,5- dimethoxypyridin-3-yl)amino]-lH-indazol-6-yl}-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-2-{3-[(2-chlorofuro[3,2-d]pyrimidin-4-yl)amino]-lH-indazol-6-yl}-5'- methoxyspiro[cyclopropane-l,3'-indol]-2'(rH)-one; 6-methoxy-5-({6-[(lR,2S)-5'-methoxy-2'-oxo-r,2'- dihydrospiro[cyclopropane-l,3'-indol]-2-yl]-lH-indazol-3-yl}amino)-N,N-dimethylpyridine-2- carboxamide; (lR,2S)-5'-methoxy-2-(3-{[5-methoxy-2-(pyrrolidin-l-yl)pyrimidin-4-yl]amino}-lH- indazol-6-yl)spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-(3-{[6-(methanesulfonyl)-2- methoxypyridin-3-yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-[3-({2-[(3R)-3-fluoropyrrolidin-l-yl]-5-methoxypyrimidin-4-yl}amino)-lH-indazol-6-yl]-5'- methoxyspirofcyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-2-(3-{ [2-(3,3-difluoropyrrolidin-l-yl)-5- methoxypyrimidin-4-yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-2-{3-[(2-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino]-lH-indazol-6-yl}-5'- methoxyspiro[cyclopropane-l,3'-indol]-2'(rH)-one; 5-methoxy-4-({6-[(lR,2S)-5'-methoxy-2'-oxo-r,2'- dihydrospiro [cyclopropane- 1, 3 -indol] -2-yl] -lH-indazol-3-yl}amino)pyrimidine-2-carbonitrile; (1R,2S)- 2-(3-{[2-(3,3-difluoroazetidin-l-yl)-5-methoxypyrimidin-4-yl]amino}-lH-indazol-6-yl)-5'- methoxyspirofcyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-2-(3-{ [2-(3-fluoroazetidin-l-yl)-5-methoxypyrimidin-4-yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-2-{3-[5-(ethanesulfonyl)-2-methoxyanilino]-lH-indazol-6-yl}-5'-methoxyspiro[cyclopropane- l,3'-indol]-2'(l'H)-one; 4-methoxy-3-({6-[(lR,2S)-5'-methoxy-2'-oxo-l 2'-dihydrospiro[cyclopropane- l,3'-indol]-2-yl]-lH-indazol-3-yl}amino)-N,N-dimethylbenzamide; 4-methoxy-3-({6-[(lR,2S)-5'- methoxy-2'-oxo-r,2'-dihydrospiro[cyclopropane-l,3'-indol]-2-yl]-lH-indazol-3-yl}amino)-N- methylbenzamide; (lR,2S)-5'-methoxy-2-{3-[2-methoxy-5-(propane-2-sulfonyl)anilino]-lH-indazol-6- yl}spiro[cyclopropane-l,3'-indol]-2'(rH)-one; 4-methoxy-3-({6-[(lR,2S)-5'-methoxy-2'-oxo-r,2'- dihydrospiro [cyclopropane- 1 , 3 -indol] -2-yl] - lH-indazol-3 -yl } amino) -N,N-dim ethylbenzene- 1 - sulfonamide; (lR,2S)-5'-methoxy-2-{3-[2-methoxy-5-(morpholine-4-carbonyl)anilino]-lH-indazol-6- yl}spiro[cyclopropane-l,3'-indol]-2'(rH)-one; 6-methoxy-5-({6-[(lR,2S)-5'-methoxy-2'-oxo-r,2'- dihydrospiro[cyclopropane-l,3'-indol]-2-yl]-lH-indazol-3-yl}amino)-N,N-dimethylpyridine-3- carboxamide; (lR,2S)-2-(3-{[2-(dimethylamino)-5-methylpyrimidin-4-yl]amino}-lH-indazol-6-yl)-5'- methoxyspiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-5'-methoxy-2-(3-{[2-methoxy-6- (morpholine-4-carbonyl)pyridin-3-yl]amino}-lH-indazol-6-yl)spiro[cyclopropane-l,3'-indol]-2'(l'H)- one; (lR,2S)-2-(3-{[6-(3,3-difluoroazetidine-l-carbonyl)-2-methoxypyridin-3-yl]amino}-lH-indazol-6- yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-2-(3-{[6-(4,4-difluoropiperidine-l- carbonyl)-2-methoxypyridin-3-yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]- 2'(l'H)-one; (lR,2S)-2-(4-fluoro-3-{[5-methoxy-2-(methylsulfanyl)pyrimidin-4-yl]amino}-lH-indazol-6- yl)-5'-methoxyspiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-5'-methoxy-2-{3-[(2-methoxy-5- methylpyrimidin-4-yl)amino]-lH-indazol-6-yl}spiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-5 - methoxy-2-(3-{[2-methoxy-6-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)pyridin-3-yl]amino}-lH- indazol-6-yl)spiro[cyclopropane-l,3'-indol ]-2'( lH)-one; (lR,2S)-2-(3-{[2-(4,4-difluoropiperidin-l-yl)-5- methoxypyrimidin-4-yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(rH)-one; 4-[5-methoxy-4-({6-[(lR,2S)-5'-methoxy-2'-oxo- l',2'-dihydrospiro[cyclopropane- 1,3 -indol] -2-yl] -1H- indazol-3-yl}amino)pyrimidin-2-yl]-lX6-thiomorpholine- 1,1 -dione; 6-methoxy-5-({6-[(lR,2S)-5'- methoxy-2'-oxo-r,2'-dihydrospiro[cyclopropane-l,3'-indol]-2-yl]-lH-indazol-3-yl}amino)-N- methylpyridine-2-carboxamide; (lR,2S)-5'-methoxy-2-(3-{[5-methoxy-2-(2-oxa-6-azaspiro[3.3]heptan- 6-yl)pyrimidin-4-yl]amino}-lH-indazol-6-yl)spiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-2-(3- {[5-(methanesulfonyl)-3-methoxypyridin-2-yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane- l,3'-indol]-2'(l'H)-one; 6-methoxy-5-({6-[(lR,2S)-5'-methoxy-2'-oxo-r,2'-dihydrospiro[cyclopropane- l,3'-indol]-2-yl]-lH-indazol-3-yl}amino)-N-methyl-N-(propan-2-yl)pyridine-2-carboxamide; (lR,2S)-2- (3-{[5-ethoxy-2-(methylsulfanyl)pyrimidin-4-yl]amino}-lH-indazol-6-yl)-5'- methoxyspiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-2-(3-{[6-(methanesulfonyl)-3- methoxypyridin-2-yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(rH)-one; 5- methoxy-6-( {6-[( lR,2S)-5'-methoxy-2'-oxo- l',2'-dihydrospiro [cyclopropane- 1,3 -indol] -2-yl]- 1H- indazol-3-yl}amino)-N,N-dimethylpyridine-3-carboxamide; 5-methoxy-4-({6-[(lR,2S)-5'-methoxy-2'- oxo-r,2'-dihydrospiro[cyclopropane-l,3'-indol]-2-yl]-lH-indazol-3-yl}amino)-N,N-dimethylpyridine-2- carboxamide; (lR,2S)-5'-methoxy-2-{3-[2-methoxy-4-(morpholine-4-carbonyl)anilino]-lH-indazol-6-yl}spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; Diastereomer 1 : (lR,2S)-5'-methoxy-2-(3-{[5-methoxy-2- (oxolan-3-yl)pyrimidin-4-yl]amino}-lH-indazol-6-yl)spiro[cyclopropane-l,3'-indol]-2'(rH)-one;Diastereomer 2: (lR,2S)-5'-methoxy-2-(3-{[5-methoxy-2-(oxolan-3-yl)pyrimidin-4-yl]amino}-lH- indazol-6-yl)spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-(3-{[2-ethoxy-6-(methanesulfonyl)pyridin-3-yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]- 2'(l'H)-one; 5-ethoxy-6-({6-[(lR,2S)-5'-methoxy-2'-oxo-r,2'-dihydrospiro[cyclopropane-l,3'-indol]-2- yl]-lH-indazol-3-yl}amino)-N,N-dimethylpyridine-3-carboxamide; 5-methoxy-6-({6-[(lR,2S)-5'- methoxy-2'-oxo-r,2'-dihydrospiro[cyclopropane-l,3'-indol]-2-yl]-lH-indazol-3-yl}amino)-N,N- dimethylpyridine-3-sulfonamide; (lR,2S)-2-(3-{[6-(dimethylphosphoryl)-2-methoxypyridin-3- yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; 2-fluoro-5-methoxy- 4-({6-[(lR,2S)-5'-methoxy-2'-oxo-l 2'-dihydrospiro[cyclopropane-l,3'-indol]-2-yl]-lH-indazol-3- yl}amino)-N,N-dimethylbenzamide; (lR,2S)-2-{3-[5-fluoro-2-methoxy-4-(morpholine-4- carbonyl)anilino]-lH-indazol-6-yl}-5'-methoxyspiro[cyclopropane- l,3'-indol ]-2'( lH)-one; and (1R,2S)- 2-(3-{[3-ethoxy-5-(methanesulfonyl)pyridin-2-yl]amino}-lH-indazol-6-yl)-5'- methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one, or a pharmaceutically acceptable salt thereof.

[0089] In some embodiments of the methods disclosed herein, the inhibitor of polo-like kinase 4 (PLK4) is selected from (lR,2S)-2-(3-{[6-(ethanesulfonyl)-2-methoxypyridin-3-yl]amino}-lH-indazol-6-yl)-5'- methoxyspiro[cyclopropane-l,3'-indol]-2'(rH)-one; 5-methoxy-4-({6-[(lR,2S)-5'-methoxy-2'-oxo-r,2'- dihydrospiro [cyclopropane- 1 , 3 -indol] -2-yl] - lH-indazol-3 -yl } amino) -N,2-dimethylbenzene- 1 - sulfonamide; (lR,2S)-2-{3-[(2,5-dimethyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)amino]-lH-indazol-6- yl } -5 '-methoxyspiro [ cyclopropane- 1, 3'-indol ]-2'( 1 H)-one; 2,5-dimethoxy-4-({6-[(lR,2S)-5'-methoxy-2'- oxo- l',2'-dihydrospiro[cyclopropane- 1 ,3'-indol] -2-yl] - lH-indazol-3-yl} amino)benzene- 1 -sulfonamide; (lR,2S)-2-(3-{[2-(dimethylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]amino}-lH-indazol-6- yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(rH)-one; 6-ethoxy-5-({6-[(lR,2S)-5'-methoxy-2'-oxo- 1 2'-dihydrospiro [cyclopropane- 1 , 3 -indol] -2-yl] - 1 H-indazol-3 -yl } amino) -N,N -dimethylpyridine-2- carboxamide; (lR,2S)-5'-methoxy-2-(3-{[2-methoxy-6-(2-oxopyrrolidin-l-yl)pyridin-3-yl]amino}-lH- indazol-6-yl)spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-5'-methoxy-2-{3-[2-methoxy-5- (morpholine-4-sulfonyl)anilino]-lH-indazol-6-yl}spiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-5 - methoxy-2-{3-[(3-methoxy-l,5-naphthyridin-2-yl)amino]-lH-indazol-6-yl}spiro[cyclopropane-l,3'- indol]-2'(rH)-one; N,6-dimethoxy-5-({6-[(lR,2S)-5'-methoxy-2'-oxo-r,2'-dihydrospiro[cyclopropane- l,3'-indol]-2-yl]-lH-indazol-3-yl}amino)-N-methylpyridine-2-carboxamide; 6-methoxy-5-({6-[(lR,2S)- 5'-methoxy-2'-oxo-r,2'-dihydrospiro[cyclopropane-l,3'-indol]-2-yl]-lH-indazol-3-yl}amino)-N'-(propan-2-yl)pyridine-2-carbohydrazide; (lR,2S)-5'-methoxy-2-(3-{[2-methoxy-5-(2-oxopyrrolidin-l-yl)pyridin-3-yl]amino}-lH-indazol-6-yl)spiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-5'-methoxy-2-(3-{[2- methoxy-5-(3-methyl-2-oxoimidazolidin-l-yl)pyridin-3-yl]amino}-lH-indazol-6-yl)spiro[cyclopropane- l,3'-indol]-2'(l'H)-one; 6-methoxy-5-({6-[(lR,2S)-5'-methoxy-2'-oxo-r,2'-dihydrospiro[cyclopropane- l,3'-indol]-2-yl]-lH-indazol-3-yl}amino)-N,N-dimethylpyridine-2-sulfonamide; 6-ethoxy-5-({6-[(lR,2S)-5'-methoxy-2'-oxo-r,2'-dihydrospiro[cyclopropane- 1,3 -indol] -2-yl] -lH-indazol-3-yl}amino)-N,N-dimethylpyridine-2-sulfonamide; (lR,2S)-5'-methoxy-2-{3-[2-methoxy-5-(oxane-4- sulfonyl)anilino]-lH-indazol-6-yl}spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-(3-{[5- (dimethylphosphoryl)-3-methoxypyridin-2-yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane- l,3'-indol]-2'(l'H)-one; (lR,2S)-2-(3-{[5-(2-hydroxypropan-2-yl)-2-methoxypyridin-3-yl]amino}-lH- indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-(3-{[6- (methanesulfonyl)-2-methoxy-5-methylpyridin-3-yl]amino}-lH-indazol-6-yl)-5'- methoxyspirofcyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-2-(3-{[5-(ethanesulfonyl)-3- methoxypyridin-2-yl]amino}-lH-indazol-6-yl)-5'-methoxy spiro [cyclopropane- l,3'-indol]-2'(l'H) -one; (lR,2S)-2-(3-{[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]amino}-lH-indazol-6-yl)-5'- methoxyspiro[cyclopropane-l,3'-indol]-2'(rH)-one; N-(cyclopropylmethyl)-6-methoxy-5-({6-[(lR,2S)- 5'-methoxy-2'-oxo-r,2'-dihydrospiro[cyclopropane-l,3'-indol]-2-yl]-lH-indazol-3-yl}amino)pyridine-2- carboxamide; 6-methoxy-5-({6-[(lR,2S)-5'-methoxy-2'-oxo-r,2'-dihydrospiro[cyclopropane-l,3'-indol]- 2-yl]-lH-indazol-3-yl}amino)-N-(propan-2-yl)pyridine-2-carboxamide; (lR,2S)-5'-methoxy-2-(3-{[2- methoxy-6-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)pyridin-3-yl]amino}-lH-indazol-6- yl)spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-5'-methoxy-2-{3-[(4-methoxy-l-methyl-6-oxo- l,6-dihydropyridazin-3-yl)amino]-lH-indazol-6-yl}spiro[cyclopropane-l,3'-indol]-2'(rH)-one; (1R,2S)- 5'-methoxy-2-(3-{[2-methoxy-5-(l,3-oxazol-2-yl)pyridin-3-yl]amino}-lH-indazol-6- yl)spiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-5'-methoxy-2-(3-{[3-methoxy-5-(3- methoxyazetidine- 1 -carbonyl)pyridin-2-yl] amino} - lH-indazol-6-yl)spiro[cyclopropane- 1 ,3'-indol] - 2'(l'H)-one; 6-methoxy-5-({6-[(lR,2S)-5'-methoxy-2'-oxo-r,2'-dihydrospiro[cyclopropane-l,3'-indol]-2- yl]-lH-indazol-3-yl}amino)-N,N-dimethylpyrazine-2-carboxamide; 6-ethoxy-5-({6-[(lR,2S)-5'- methoxy-2'-oxo-r,2'-dihydrospiro[cyclopropane-l,3'-indol]-2-yl]-lH-indazol-3-yl}amino)-N,N- dimethylpyrazine-2-carboxamide; 6-methoxy-5-({6-[(lR,2S)-5'-methoxy-2'-oxo-r,2'- dihydrospiro [cyclopropane- 1 , 3 -indol] -2-yl] - lH-indazol-3 -yl } amino) -N,N, 3 -trimethylpyridine-2- carboxamide; (lR,2S)-2-(3-{[6-(methanesulfinyl)-2-methoxypyridin-3-yl]amino}-lH-indazol-6-yl)-5'- methoxyspirofcyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-2-(3-{[6-(methanesulfinyl)-2- methoxypyridin-3-yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-(3-{[6-(methanesulfonyl)-4-methoxypyridin-3-yl]amino}-lH-indazol-6-yl)-5'- methoxyspirofcyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-2-(3-{[5-(methanesulfonyl)-3- methoxypyrazin-2-yl] amino } - lH-indazol-6-yl)-5 '-methoxyspiro [cyclopropane- 1 ,3 -indol] -2'( 1 'H)-one; N,N-dicyclopropyl-6-methoxy-5-({6-[(lR,2S)-5'-methoxy-2'-oxo-r,2'-dihydrospiro[cyclopropane-l,3'- indol] -2-yl] -lH-indazol-3-yl}amino)pyridine-2-carboxamide; N-(2,2-difluoroethyl)-6-methoxy-5-({6- [(lR,2S)-5'-methoxy-2'-oxo-r,2'-dihydrospiro[cyclopropane-l,3'-indol]-2-yl]-lH-indazol-3- yl}amino)pyridine-2-carboxamide; (lR,2S)-2-[3-({6-[(2R,6S)-2,6-dimethylpiperidine-l-carbonyl]-2- methoxypyridin-3-yl}amino)-lH-indazol-6-yl]-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-5'-methoxy-2-(3-{[2-methoxy-6-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)pyridin-3- yl]amino}-lH-indazol-6-yl)spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-(3-{[3-chloro-5- (methanesulfonyl)pyridin-2-yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-5'-methoxy-2-(3-{[3-methoxy-5-(propane-2-sulfonyl)pyridin-2-yl]amino}-lH- indazol-6-yl)spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-(3-{[6-(dimethylphosphoryl)-4- methoxypyridin-3-yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(rH)-one; N- (l,3-difluoropropan-2-yl)-6-methoxy-5-({6-[(lR,2S)-5'-methoxy-2'-oxo-r,2'-dihydrospiro[cyclopropane- l,3'-indol]-2-yl]-lH-indazol-3-yl}amino)pyridine-2-carboxamide; 6-chloro-5-({6-[(lR,2S)-5'-methoxy- 2-oxo- r,2'-dihydrospiro[cyclopropane-l,3'-indol]-2-yl]-lH-indazol-3-yl}amino)-N,N-dimethylpyridine-2-carboxamide; (lR,2S)-2-{3-[(5-chloro-2-methyl-l,3-benzoxazol-6-yl)amino]-lH-indazol-6-yl}-5'- methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; 4-methoxy-5-({6-[(lR,2S)-5'-methoxy-2'-oxo-r,2'- dihydrospiro[cyclopropane-l,3'-indol]-2-yl]-lH-indazol-3-yl}amino)-N,N-dimethylpyridine-2- carboxamide; 3-[6-methoxy-5-({6-[(lR,2S)-5'-methoxy-2'-oxo-r,2'-dihydrospiro[cyclopropane-l,3'- indol]-2-yl]-lH-indazol-3-yl}amino)pyrazin-2-yl]-lX6-thietane-l,l-dione; (lR,2S)-5'-methoxy-2-(3-{[3- methoxy-5-(morpholine-4-sulfonyl)pyridin-2-yl]amino}-lH-indazol-6-yl)spiro[cyclopropane-l,3'-indol]- 2'(l'H)-one; (lR,2S)-5'-methoxy-2-(3-{[3-methoxy-5-(8-oxa-3-azabicyclo[3.2. l]octane-3- sulfonyl)pyridin-2-yl]amino}-lH-indazol-6-yl)spiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-2-(3- { [6-(diethylphosphoryl) -2-methoxypyridin-3 -y 1] amino } - 1 H-indazol-6-yl) -5 '- methoxyspiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-2-(3-{[5-(cyclopropanesulfonyl)-3- methoxypyridin-2-yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-5'-methoxy-2-(3-{[3-methoxy-5-(oxane-4-sulfonyl)pyridin-2-yl]amino}-lH-indazol-6- yl)spiro[cyclopropane-l,3'-indol]-2'(rH)-one; 6-methoxy-5-({6-[(lR,2S)-5'-methoxy-2'-oxo-r,2'- dihydrospiro[cyclopropane-l,3'-indol]-2-yl]-lH-indazol-3-yl}amino)pyridine-2-carbonitrile; (lR,2S)-2- {3-[5-(diethylphosphoryl)-2-methoxyanilino]-lH-indazol-6-yl}-5'-methoxyspiro[cyclopropane-l,3'- indol]-2'(l'H)-one; (lR,2S)-2-(3-{[6-(ethanesulfonyl)-4-methoxypyridin-3-yl]amino}-lH-indazol-6-yl)- 5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-2-(3-{[5-(azetidine-l-carbonyl)-3- methoxypyridin-2-yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-5'-methoxy-2-(3-{[3-methoxy-5-(morpholine-4-carbonyl)pyridin-2-yl]amino}-lH-indazol-6- yl)spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-5'-methoxy-2-{3-[(6-methoxy-2-methyl-l-oxo- 2,3-dihydro-lH-isoindol-5-yl)amino]-lH-indazol-6-yl}spiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-5'-methoxy-2-{3-[(4-methoxy-2-methyl-l-oxo-2,3-dihydro-lH-isoindol-5-yl)amino]-lH- indazol-6-yl} spiro[cyclopropane- 1, 3 -indol] -2'( l'H)-one; ( lR,2S)-5'-methoxy-2-(3- { [3-methoxy-5-(l,2- oxazolidine-2-sulfonyl)pyridin-2-yl]amino}-lH-indazol-6-yl)spiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-2-(3-{[5-(azetidine-l-sulfonyl)-3-methoxypyridin-2-yl]amino}-lH-indazol-6-yl)-5'- methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; 5-methoxy-6-({6-[(lR,2S)-5'-methoxy-2'-oxo-r,2'- dihydrospiro [cyclopropane- 1, 3 -indol] -2-yl] -lH-indazol-3-yl}amino)-N-(3-methyloxetan-3-yl)pyri dine-3-sulfonamide; 5-methoxy-6-({6-[(lR,2S)-5'-methoxy-2'-oxo-r,2'-dihydrospiro[cyclopropane-l,3'- indol] -2-yl] -lH-indazol-3-yl}amino)-N-methyl-N-(3-methyloxetan-3-yl)pyridine-3-sulfonamide; (lR,2S)-2-(3-{[5-(l-hydroxyethyl)-2-methoxypyridin-3-yl]amino}-lH-indazol-6-yl)-5'- methoxyspiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-2-{3-[2-ethoxy-4- (methanesulfonyl)anilino]-lH-indazol-6-yl} -5'-methoxyspiro[cyclopropane- 1,3 -indol] -2'(l'H)-one;(lR,2S)-2-(3-{[3-ethoxy-5-(4-methylpiperazine-l-sulfonyl)pyridin-2-yl]amino}-lH-indazol-6-yl)-5'- methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-(3-{[5-(ethanesulfonyl)-3-ethoxypyridin- 2-yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; 5-ethoxy-6-({6- [(lR,2S)-5'-methoxy-2'-oxo-r,2'-dihydrospiro[cyclopropane-l,3'-indol]-2-yl]-lH-indazol-3-yl}amino)- N-methylpyridine-3-sulfonamide; (lR,2S)-5'-chloro-2-(3-{[3-ethoxy-5-(methanesulfonyl)pyridin-2- yl]amino}-lH-indazol-6-yl)spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-{3-[(4-ethoxy-l- methyl-6-oxo-l,6-dihydropyridazin-3-yl)amino]-lH-indazol-6-yl}-5'-methoxyspiro[cyclopropane-l,3'- indol]-2'(l'H)-one; (lR,2S)-2-(3-{[6-(2-hydroxypropan-2-yl)-3-methoxypyridin-2-yl]amino}-lH- indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-(3-{[4-ethoxy-6- (methanesulfonyl)pyridin-3-yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]- 2'( l'H)-one; and ( lR,2S)-2-(3- { [5-(difluoromethanesulfonyl)-3-methoxypyridin-2-yl]amino} - 1H- indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one, or a pharmaceutically acceptable salt thereof.

[0090] In some embodiments of the methods disclosed herein, the inhibitor of polo-like kinase 4 (PLK4) is selected from the group consisting of:

[0091] In some embodiments of the methods disclosed herein, the inhibitor of polo -like kinase 4 (PLK4)(Compound 1), or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments of the methods disclosed herein, the inhibitor of polo -like kinase 4 (PLK4)(Compound 2), or a pharmaceutically acceptable salt thereof.

[0093] In some embodiments of the methods disclosed herein, the inhibitor of polo -like kinase 4 (PLK4)(Compound 3), or a pharmaceutically acceptable salt thereof.

[0094] In some embodiments of the methods disclosed herein, the inhibitor of polo-like kinase 4 (PLK4)(Compound 4), or a pharmaceutically acceptable salt thereof.

[0095] In some embodiments of the methods disclosed herein, the inhibitor of polo-like kinase 4 (PLK4)(Compound 5), or a pharmaceutically acceptable salt thereof.

[0096] In some embodiments of the methods disclosed herein, the inhibitor of polo-like kinase 4 (PLK4)(Compound 6), or a pharmaceutically acceptable salt thereof.

[0097] In some embodiments of the methods disclosed herein, the inhibitor of polo-like kinase 4 (PLK4)(Compound 7), or a pharmaceutically acceptable salt thereof.

[0098] In some embodiments of the methods disclosed herein, the inhibitor of polo-like kinase 4 (PLK4)(Compound 8), or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments of the methods disclosed herein, the inhibitor of polo-like kinase 4 (PLK4)(Compound 9), or a pharmaceutically acceptable salt thereof.

[0100] In some embodiments of the methods disclosed herein, the inhibitor of polo-like kinase 4 (PLK4)(Compound 10), or a pharmaceutically acceptable salt thereof.

[0101] In some embodiments of the methods disclosed herein, the inhibitor of polo-like kinase 4 (PLK4)(Compound 11), or a pharmaceutically acceptable salt thereof.

[0102] In some embodiments of the methods disclosed herein, the inhibitor of polo-like kinase 4 (PLK4)(Compound 12), or a pharmaceutically acceptable salt thereof.

[0103] In some embodiments of the methods disclosed herein, the inhibitor of polo-like kinase 4 (PLK4)(Compound 13), or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments of the methods disclosed herein, the inhibitor of polo-like kinase 4 (PLK4)(Compound 14), or a pharmaceutically acceptable salt thereof.

[0105] In some embodiments of the methods disclosed herein, the inhibitor of polo-like kinase 4 (PLK4)(Compound 15), or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments of the methods disclosed herein, the inhibitor of polo-like kinase 4 (PLK4)thereof.

[0107] In some embodiments of the methods disclosed herein, the inhibitor of polo-like kinase 4 (PLK4)(Compound 17), or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments of the methods disclosed herein, the inhibitor of polo-like kinase 4 (PLK4)(Compound 18), or a pharmaceutically acceptable salt thereof.

[0109] In some embodiments of the methods disclosed herein, the inhibitor of polo-like kinase 4 (PLK4)(Compound 19), or a pharmaceutically acceptable salt thereof.

[0110] In some embodiments of the methods disclosed herein, the inhibitor of polo-like kinase 4 (PLK4) is selected from a compound of Formula (II), or a pharmaceutically acceptable salt thereofwherein:Ring A is C6-10 aryl or heteroaryl; each R1is independently deuterium, halogen, -CN, oxo, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2R% -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -P(O)(Ra)2, - P(O)2(Ra)2, C1a-6lkyl, hCa1l-o6alkyl, -OCi-Cehaloalkyl, Ci -Cedeuteroalkyl, hydroxyalkyl, C1-6C1-6 aminoalkyl, Ch1-e6teroalkyl, C2-Cealkenyl, C2-Cealkynyl, C6-10 cycloalkyl, heterocycloalkyl,C6-10 aryl, or heteroaryl; wherein each of the alkyl, C2C-C1-e6alkenyl, C2-Cealkynyl, C3- Ciocycloalkyl, heterocycloalkyl, aryCl,6- a1n0d heteroaryl is optionally and independently substituted with one or more Rla; or two R1on adjacent atoms are taken together to form a C6-10 cycloalkyl or heterocycloalkyl; each optionally substituted with one or more Rlb; each Rlais independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl,C1-6 haloalkyl, Ci -Cedeuteroalkyl, hydrCox1-y6alkyl, aminoalkyCl1,-6 heteroalkyl, C2C-1-6 Cealkenyl, C2-Cealkynyl, C6-10 cycloalkyl, heterocycloalkyl, aryl, or heteCr6o-a10ryl; or two Rlaon the same atom are taken together to form an oxo; each Rlbis independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl,C1-6 haloalkyl, Ci -Cedeuteroalkyl, hydrCox1-y6alkyl, aminoalkyCl1,-6 heteroalkyl, C2C-1-6 Cealkenyl, C2-Cealkynyl, C6-10 cycloalkyl, heterocycloalkyl, aryl, or heteCr6o-a10ryl; or two Rlbon the same atom are taken together to form an oxo; n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;R2is hydrogen, Ca1-l6kyl, haCl1o-a6lkyl, or Ci -Cedeuteroalkyl;R3is hydrogen, Ca1-l6kyl, haCl1o-a6lkyl, or Ci -Cedeuteroalkyl;each of R4a, R4b, and R4cis independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, alkyCl,1-6 haloalkCy1l-,6 Ci -Cedeuteroalkyl, C1-6 hydroxyalkyl, Ca1m-6inoalkyl, or heterCo1a-6lkyl;R5is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, alkyl, Ch1a-l6oalkyl, C1-6 Ci -Cedeuteroalkyl, hCy1-d6roxyalkyl, aminoCa1l-k6yl, or heteroalkylC;1-6 each R6is independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, alkyl, C1-6C1-6 haloalkyl, Ci -Cedeuteroalkyl, hydrCox1-y6alkyl, aminoalkyCl1,-6 or heteroalkyl; C1-6R7is hydrogen, Ca1l-k6yl, haClo1a-6lkyl, Ci -Cedeuteroalkyl, hydroxyalkyl, oCr1-6 aminoalkyl; C1-6 each ofR8a, R8b, R8c, andR8dis independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, - OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1a-6lkyl, hCal1o-6alkyl, Ci -Cedeuteroalkyl, hydroxyalkylC, 1-6 aminoalkyl, C1-6C1-6 heteroalkyl, C2-Cealkenyl, C2-Cealkynyl, C6-10 cycloalkyl, heterocycloalkyl, aryl, or C6-10 heteroaryl;R9is heteroaryl optionally substituted with one or more Rla, or oxetanyl substituted with one or more Rla; each Rais independently hydrogen, alkyl,C1-6 haloalkylC, C1-6i -Cedeuteroalkyl, hydroxyalkyl, C1-6C1-6 aminoalkyl, Ch1-e6teroalkyl, C2-Cealkenyl, C2-Cealkynyl, C6-10 cycloalkyl, heterocycloalkyl, C6-10 aryl, heteroaryl, alCky1-l6(C3-Ciocycloalkyl), alkyl(heteCro1c-6ycloalkyl), alkyl(Ce- C1-6 Cioaryl), or C1-6alkyl(heteroaryl); wherein each of the alkyl, C2-CeaClk1e-6nyl, C2-Cealkynyl, C3- Ciocycloalkyl, heterocycloalkyl, aryCl,6- a1n0d heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-6 alkyl, C1-6haloalkyl, Ci -Cedeuteroalkyl, hydroxyCa1l-k6yl, aminoalkyl,C or1-6 C1-6 heteroalkyl; each Rbis independently hydrogen, alkyl, C1-6 haloalkyl,C C1i-6 -Cedeuteroalkyl, hydroxyalkyl, C1-6C1-6 aminoalkyl, Ch1-e6teroalkyl, C2-Cealkenyl, C2-Cealkynyl, C6-10 cycloalkyl, heterocycloalkyl, C6-10 aryl, heteroaryl, alCky1-l6(C3-Ciocycloalkyl), alkyl(heteCro1c-6ycloalkyl), alkyl(Ce- C1-6 Cioaryl), or C1-6alkyl(heteroaryl); wherein each of the alkyl, C2-CeaClk1e-6nyl, C2-Cealkynyl, C3- Ciocycloalkyl, heterocycloalkyl, aryCl,6- a1n0d heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-6 alkyl, C1-6haloalkyl, Ci -Cedeuteroalkyl, hydroxyCa1l-k6yl, aminoalkyl,C or1-6 C1-6 heteroalkyl; and each Rcand Rdare independently hydrogen, alkyl, C1-h6aloalkyl, CCi -1C-6edeuteroalkyl, C1-6 hydroxyalkyl, Ca1l-6koxy, amCin1-o6alkyl, alkylamCin1-o6, heteroalkyl,C C12-6- Cealkenyl, C2-Cealkynyl, C6-10 cycloalkyl, heterocycloalkyl, aryl, heteroarCyl6,-1 C0i-Cealkyl(C3- Ciocycloalkyl), C1a-6lkyl(heterocycloalkyl), alkyl(CCe1--6Cioaryl), or alkyl(heteroaCry1l-)6; wherein each of the alCk1y-6l, C2-Cealkenyl, C2-Cealkynyl, C6-10 cycloalkyl, heterocycloalkyl, Ce-Cioaryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, - S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-C6alkyl,C1-6 haloalkyl, Ci -Cedeuteroalkyl, hydrCox1-y6alkyl, aminoalkyCl1,-6 or heteroalkyl; C1-6 or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, - S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -€(=0)0^, - C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, hydroxyalkyCl,1-6C1-6 aminoalkyl, or Ch1e-6teroalkyl; provided the compound of Formula (II) is not[OOlllJIn some embodiments of the methods disclosed herein, the inhibitor of polo-like kinase 4 (PLK4) is selected from 6-methoxy-5-({6-[(lR,2S)-5'-methoxy-2'-oxo-r,2'-dihydrospiro[cyclopropane-l,3'- indol]-2-yl]-lH-indazol-3-yl}amino)-2,3-dihydro-lH-l-benzothiophene-l,l-dione; (lR,2S)-2-{3-[4- (m ethanesulfonyl) -2-methoxyanilino] - lH-indazol-6-yl } -5 '-methoxy spiro [cyclopropane- 1 , 3 -indol] - 2'(l'H)-one; (lR,2S)-2-[3-(4-acetyl-2-methoxyanilino)-lH-indazol-6-yl]-5'-methoxyspiro[cyclopropane- l,3'-indol]-2'(lH)-one; (lR,2S)-5'-methoxy-2-(3-{[3-methoxy-6-(l,3-oxazol-2-yl)pyridin-2-yl]amino}- lH-indazol-6-yl)spiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-2-{3-[4-(ethanesulfonyl)-2- methoxyanilino]-lH-indazol-6-yl}-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(rH)-one; 6-methoxy-5- ({6-[(lR,2S)-5'-methoxy-2'-oxo-r,2'-dihydrospiro[cyclopropane-l,3'-indol]-2-yl]-lH-indazol-3- yl}amino)- 1H-1 -benzothiophene- 1,1-dione; (lR,2S)-2-{3-[2-ethoxy-4-(pyrazin-2-yl)anilino]-lH- indazol-6-yl}-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(lH)-one; (lR,2S)-2-{3-[(3-ethoxyquinolin-2- yl)amino]-lH-indazol-6-yl}-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(lH)-one; (lR,2S)-2-(3-{4-[3- (dimethylamino)oxetan-3-yl]-2-methoxyanilino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'- indol] -2'(l'H)-one; (lR,2S)-2-{3-[2-ethoxy-4-(lH-l,2,4-triazol-l-yl)anilino]-lH-indazol-6-yl}-5'- methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-5'-methoxy-2-{3-[2-methoxy-5-(l-methyl- lH-pyrazol-4-yl)anilino]-lH-indazol-6-yl}spiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; 7-ethoxy-6-((6- ((lR,2S)-5'-methoxy-2'-oxospiro[cyclopropane-l,3'-indolin]-2-yl)-lH-indazol-3-yl)amino)quinoline 1- oxide; (lR,2S)-5'-methoxy-2-{3-[2-methoxy-5-(l,3-oxazol-2-yl)anilino]-lH-indazol-6- yl}spiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-5'-methoxy-2-{3-[2-methoxy-5-(l,3-thiazol-2- yl)anilino]-lH-indazol-6-yl}spiro[cyclopropane-l,3'-indol]-2'(lH)-one; (lR,2S)-5'-methoxy-2-{3-[2- methoxy-5-( l,3-thiazol-4-yl)anilino]-lH-indazol-6-yl}spiro[cyclopropane- 1,3 -indol] -2'(l'H)-one;(lR,2S)-5'-methoxy-2-{3-[2-methoxy-5-(l,3-oxazol-4-yl)anilino]-lH-indazol-6-yl}spiro[cyclopropane-1 , 3 -indol] -2'( 1 H)-one; ( lR,2S)-5'-methoxy-2- { 3-[2-methoxy-4-(2-methyl-2H-tetrazol-5-yl)anilino] -1H- indazol-6-yl}spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-5'-methoxy-2-{3-[2-methoxy-5-(l,3- oxazol-5-yl)anilino]-lH-indazol-6-yl}spiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-5'-methoxy-2- (3-{[3-methoxy-6-(l,3-oxazol-2-yl)pyrazin-2-yl]amino}-lH-indazol-6-yl)spiro[cyclopropane-l,3'-indol]- 2'(l'H)-one; (lR,2S)-2-(3-{[2-(dimethylamino)-5-methoxypyrimidin-4-yl]amino}-lH-indazol-6-yl)-5'- methoxyspiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-5'-methoxy-2-{3-[2-methoxy-5-(2-methyl- 2H-tetrazol-5-yl)anilino]-lH-indazol-6-yl}spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-(3-{5- [3-(dimethylamino)oxetan-3-yl]-2-methoxyanilino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane- l,3'-indol]-2'(l'H)-one; (lR,2S)-2-{3-[2-ethoxy-4-(methanesulfonyl)anilino]-lH-indazol-6-yl}-5'- methoxy- l'-m ethylspiro [ cyclopropane- 1, 3'-indol ]-2'( 1 H)-one; (lR,2S)-5'-methoxy-2-(3-{[3-methoxy-6- (l-methyl-lH-pyrazol-4-yl)pyrazin-2-yl]amino}-lH-indazol-6-yl)spiro[cyclopropane-l,3'-indol]-2'(rH)- one; (lR,2S)-5'-methoxy-2-{3-[(5-methoxy[2,5'-bipyrimidin]-4-yl)amino]-lH-indazol-6- yl}spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-5'-methoxy-2-(3-{[2-methoxy-5-(l-methyl-lH- pyrazol-4-yl)pyridin-3-yl]amino}-lH-indazol-6-yl)spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (1R,2S)- 5'-methoxy-2-(3- { [5-methoxy-2-( 1-methyl- lH-pyrazol-4-yl)pyridin-4-yl]amino} - lH-indazol-6- yl)spiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-2-(3-{[3-ethoxy-6-(l,3-thiazol-2-yl)pyridin-2- yl]amino} -lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-2-{3-[2- ethoxy-4-(l -methyl- lH-imidazol-4-yl)anilino]-lH-indazol-6-yl}-5'-methoxyspiro[cyclopropane- 1,3'- indol] -2'(l'H)-one; (lR,2S)-5'-methoxy-2-{3-[2-methoxy-5-(l,2-thiazol-3-yl)anilino]-lH-indazol-6- yl}spiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-5'-methoxy-2-(3-{[5-methoxy-2-(l-methyl-lH- pyrazol-4-yl)pyrimidin-4-yl]amino}-lH-indazol-6-yl)spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-5'-methoxy-2-{3-[2-methoxy-5-(l,2-oxazol-3-yl)anilino]-lH-indazol-6-yl}spiro[cyclopropane- l,3'-indol]-2'(l'H)-one; (lR,2S)-2-{3-[2-ethoxy-5-(l,3-thiazol-2-yl)anilino]-lH-indazol-6-yl}-5'- methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-(3-{[5-ethoxy-2-(l,3-thiazol-2-yl)pyridin- 4-yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-(3-{[3- ethoxy-6-(l,3-thiazol-2-yl)pyrazin-2-yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'- indol] -2'(l'H)-one; (lR,2S)-5'-methoxy-2-{ 3-[2-methoxy-5-(3-methoxy- 1-methyl- lH-pyrazol-4- yl)anilino]-lH-indazol-6-yl}spiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-{3-[2-ethoxy-5-(l- methyl-lH-pyrazol-4-yl)anilino]-lH-indazol-6-yl}-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(rH)- one; (lR,2S)-2-(3-{[3-ethoxy-5-(lH-l,2,4-triazol-l-yl)pyridin-2-yl]amino}-lH-indazol-6-yl)-5'- methoxyspiro[cyclopropane-l,3'-indol]-2'(rH)-one; (lR,2S)-2-(3-{5-[l-(2,2-difluoroethyl)-lH-pyrazol- 4-yl] -2-methoxyanilino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-5'-methoxy-2-(3-{[5-methoxy-2-(l,3-oxazol-5-yl)pyrimidin-4-yl]amino}-lH-indazol-6- yl)spiro[cyclopropane- 1,3 -indol] -2'(l'H)-one; (lR,2S)-2-(3-{[2-ethoxy-5-(l,3-thiazol-2-yl)pyridin-3- yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (1R, 2S)-5'-methoxy- 2-(3-{[2-methoxy-5-(l,3-oxazol-4-yl)pyridin-3-yl]amino}-lH-indazol-6-yl)spiro[cyclopropane-l,3'- indol]-2'(l'H)-one; (lR,2S)-2-{3-[(5-ethoxy-2-methylpyrimidin-4-yl)amino]-lH-indazol-6-yl}-5'-[(2H3)methyloxy] spiro [cyclopropane- l,3'-indol]-2'(rH)-one; (lR,2S)-2-(3-{[5-ethoxy-2-(l,3-thiazol-2-yl)pyrimidin-4-yl]amino}-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(l'H)-one; (lR,2S)-2-(3-((5-ethoxy-2-(3-hydroxy-3-methylbut-l-yn-l-yl)pyrimidin-4-yl)amino)-lH-indazol-6-yl)- 5'-methoxyspiro[cyclopropane-l,3'-indolin]-2'-one; (lR,2S)-2-(3-((5-(l-(2,2-difluoroethyl)-lH-pyrazol- 4-yl)-2-methoxypyridin-3-yl)amino)-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indolin]-2'- one; (lR,2S)-2-(3-((6-(l-(2,2-difluoroethyl)-lH-pyrazol-4-yl)-3-methoxypyrazin-2-yl)amino)-lH- indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indolin]-2'-one; (lR)-2-(3-((2-ethoxy-5-(oxazol-4- yl)pyridin-3-yl)amino)-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indolin]-2'-one; (lR,2S)-2- (3-((5-ethoxy-2-ethynylpyrimidin-4-yl)amino)-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'- indolin]-2'-one; (lR,2S)-2-(3-((2-ethoxy-5-(lH-imidazol-l-yl)pyridin-3-yl)amino)-lH-indazol-6-yl)-5'- methoxyspiro[cyclopropane-l,3'-indolin]-2'-one; (lR,2S)-5'-methoxy-2-(3-((l-methyl-lH-l,2,4-triazol-5- yl)amino)-lH-indazol-6-yl)spiro[cyclopropane-l,3'-indolin]-2'-one; (lR,2S)-2-(3-{[6-(lH-imidazol-l- yl)-3-methoxypyrazin-2-yl] amino} -lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indol]-2'(rH)- one; (lR,2S)-5'-methoxy-2-(3-{[3-methoxy-6-(lH-pyrazol-l-yl)pyrazin-2-yl]amino}-lH-indazol-6- yl)spiro[cyclopropane-l,3'-indol]-2'(rH)-one; lR,2S)-5'-methoxy-2-(3-{[5-methoxy-2-(l,3-oxazol-4- yl)pyrimidin-4-yl]amino}-IH-indazol-6-yl)spiro[cyclopropane-I,3'-indol]-2'(l'H)-one; 2-[4-({6- [(lR,2S)-5'-methoxy-2'-oxo-r,2'-dihydrospiro[cyclopropane-l,3'-indol]-2-yl]-lH-indazol-3-yl}amino)-5- methyl- lH-pyrazol-l-yl]-2-methylpropanenitrile; (lR,2S)-5'-methoxy-2-(3-{[3-methyl-l- (trifluoromethyl)-lH-pyrazol-5-yl]amino}-lH-indazol-6-yl)spiro[cyclopropane-l,3'-indol]-2'(rH)-one; (1R, 2S)-5'-methoxy-2-(3-{[2-methoxy-5-(morpholin-4-yl)pyridin-3-yl]amino}-lH-indazol-6- yl)spiro[cyclopropane-l,3'-indol]-2'(rH)-one; and 5-({6-[(lR,2S)-5'-methoxy-2'-oxo-r,2'- dihydrospiro [cyclopropane- 1 , 3 -indol] -2-yl] - lH-indazol-3 -yl } amino) - 1 -methyl- 1 H-pyrazole-3 - carbonitrile, or a pharmaceutically acceptable salt thereof.

[0112] In some embodiments of the methods disclosed herein, the inhibitor of polo-like kinase 4 (PLK4) is ocifisertib ((lR,2S)-2-[3-[(lE)-2-[4-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl]phenyl]ethenyl]- lH-indazol-6-yl]-5'-methoxy-spiro[cyclopropane-l,3'-[3H]indol]-2'(rH)-one), or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments of the methods disclosed herein, the inhibitor of polo-like kinase 4 (PLK4) is selected from a compound of formula (III):or a pharmaceutically acceptable salt thereof.wherein n is 0, 1, 2, 3, or 4; m is 0, 1, or 2;L is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl, or optionally substituted C3-8 cycloalkyl, wherein L is further optionally substituted by n occurrences of R3;R!ais hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted Ci-s heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or nitrile;R!bis hydrogen; orR!aand Rlb, together with the atoms to which they are attached, are a 3 -5-membered cycloalkyl, cycloalkylene, cycloalkylyne, heterocycloalkyl, aryl, or heteroaryl;A is O or S, and R2Aand R2Bare both absent; or A is N, R2Ais absent, and R2Bis hydrogen, optionally substitutedC1-6 alkyl, optionally substitutedC1-6 heteroalkyl, optionally substituted CA-10 aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or optionally substituted C1-6 alky isul fony 1, or R2Band L, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl or optionally substituted C2- 9 heteroaryl; or A is C, and each of R2Aand R2Bare independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C6-10 aryl Cl-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or optionally substituted C1-6 alkyl sulfonyl; each R3is independently halogen, cyano, optionally substituted C-..6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, -S(O)mR3A, -N(R3B)2, or - OR3B;R3Ais optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C 1-9 heteroaryl, - OR3Bor ~N(R3B)2,Each R3Bis independently hydrogen, optionally substituted Ci-s alkyl, optionally substituted C6-10 aryl Ci- 6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or optionally substituted C1-6 alkylsulfonyl; or two R3Bgroups, together with the atom to which both are attached, combine to form an optionally substituted C2-9 heterocyclyl;X is N, and R4is absent; or X is C, and R4is hydrogen, halogen, cyano, optionally substituted amino, optionally substituted acyl, optionally substituted alkyl, optionCa1ll-6y substituted heteroalkyl, C1-6 optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, or optionally substituted C1-9 heteroaryl;R5is optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, -C0NH2, or -Z-R5A;Z is optionally substituted amino, optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, optionally substituted C6-10 arylene, or optionally substituted C3-8 cycloalkylene;R5Ais hydrogen, halogen, cyano, optionally substituted C1-6 alkyl sulfonyl, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, or optionally substituted C1-9 heteroaryl;R6is hydrogen, halogen, cyano, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or -OR6A; andR6Ais hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, or optionally substituted C3-8 cycloalkyl.

[0114] In some embodiments of the methods disclosed herein, the inhibitor of polo-like kinase 4 (PLK4) is selected from any one of compounds 1 to 365, or a pharmaceutically acceptable salt thereof:

[0115] In some embodiments, the inhibitor of polo-like kinase 4 (PLK4) is used in combination with one or more additional anti-cancer agents. In some embodiments, the anti -cancer agent is mitoxantrone, estramustine, etoposide, vinblastine, carboplatin, vinorelbine, paclitaxel, daunomycin, darubicin, epirubicin, docetaxel, cabazitaxel, or doxorubicin. In some embodiments, the anti-cancer agent is paclitaxel, daunomycin, darubicin, epirubicin, docetaxel, cabazitaxel, or doxorubicin. In certain embodiments, the anti-cancer agent is docetaxel.

[0116] In some embodiments, one or more additional anti-cancer agents may include, without limitations, surgery, radiation, or chemotherapy. The chemotherapy may be an androgen receptor antagonist, amitotic inhibitor, an antimetabolite, a platinum -based agent. Examples of androgen receptor antagonist include, without limitations, apalutamide, flutamide, nilutamide, bicalutamide, or enzalutamide. Examples of mitotic inhibitors include, without limitations, a taxane (e.g. paclitaxel, docetaxel, paclitaxel, docetaxel, cabazitaxel, tesetaxel, or nab-paclitaxel) or a vinca alkaloid (e.g., vinblastine, vincristine, vindesine, or vinorelbine). Examples of antimetabolites include, without limitations, 5 -Fluorouracil, 6-mercaptopurine, capecitabine, cytarabine, floxuridine, fludarabine, gemcitabine, hydroxy carbamide, methotrexate, pemetrexed, or phototrexate. Examples of platinum -based agents include, without limitations, cisplatin, carboplatin, dicycloplatin, eptaplatin, lobaplatin, miriplatin, nedaplatin, oxaliplatin, picoplatin, satraplatin, or triplatin tetranitrate. The additional anti-cancer therapy may comprise an anti-PDLl agent, an anti-PDl agent or an anti CTLA-4 agent. The anti-PD-Ll agent may comprise atezolizumab, avelumab, durvalumab, MPDL3280A (RG7446), MDX-1105 (BMS- 936559) or BMS-935559, MSB0010718C, and MEDI4736. The anti-PDl agent may comprise pembrolizumab, nivolumab, cemiplimab, partalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, or AMP -514 (MEDI0680). The anti-CTLA agent may comprise ipilimumab, or tremelimumab.Methods of treatment in conjunction with biomarkers

[0117] Disclosed herein, in some embodiments, are methods of detecting the presence, absence, or level, of a biomarker. Such biomarkers may comprise genetic alterations in the gene encoding for certain proteins such as tripartite motif-containing protein 37 (TRIM37). The presence, absence, or level, of such biomarkers may be measured in a biological sample obtained from a subject, such as a sample of a solid tumor, such as a prostate cancer, or from a sample of a relevant biological fluid, such as a blood sample . In some instances, the methods of detection disclosed herein are useful for predicting a therapeutic response to atherapy described herein (e.g., a PLK4 inhibitor) in, monitorthe treatment using the therapy of, and treating with the therapy, a proliferative disease or condition described herein in a subject. In some embodiments, the presence, or an absence, and / or a level of expression of the one or more biomarkers is detected in the sample obtained from a subject by analyzing the genetic material in the sample. In some embodiments, the genetic material is obtained from blood, serum, plasma, sweat, hair, tears, urine, and other techniques known by one of skill in the art. In some embodiments the sample comprises circulating tumor RNA (ctRNA). In some embodiments the sample comprises peripheral blood mononuclear cells (PBMCs) . In some cases, the genetic material is obtained from a tumor biopsy or liquid biopsy. In some embodiments, a tumor biopsy comprises a formalin -fixed paraffin embedded biopsy, a fresh frozen biopsy, a fresh biopsy, or a frozen biopsy. In some embodiments, a liquid biopsy comprises PBMCs, circulating tumor RNA, plasma cell-free RNA, or circulating tumor cells (CTCs). Tumor biopsies can undergo additional analytic processing for sample dissociation, cell sorting, and enrichment of cell populations of interest.

[0118] In some embodiments, methods of detecting a presence, absence, or level of a biomarker in the sample obtained from the subject involve detecting a nucleic acid sequence. In some cases, the nucleic acid sequence comprises deoxyribonucleic acid (DNA), such as in the case of detecting complementary DNA (cDNA) of an mRNA transcript. In some instances, the nucleic acid sequence comprises a denatured DNA molecule or fragment thereof. In some instances, the nucleic acid sequence comprises DNA selected from: genomic DNA, viral DNA, mitochondrial DNA, plasmid DNA, amplified DNA, circular DNA, circulating DNA, cell-free DNA, or exosomal DNA. In some instances, the DNA is single-stranded DNA (ssDNA), double-stranded DNA, denaturing double-stranded DNA, synthetic DNA, and combinations thereof. The circular DNA may be cleaved or fragmented. In some instances, the nucleic acid sequence comprises ribonucleic acid (RNA) . In some instances, the nucleic acid sequence comprises fragmented RNA. In some instances, the nucleic acid sequence comprises partially degraded RNA. In some instances, the nucleic acid sequence comprises a microRNA or portion thereof. In some instances, the nucleic acid sequence comprises an RNA molecule or a fragmented RNA molecule (RNA fragments) selected from: a microRNA (miRNA), apre-miRNA, apri-miRNA, a mRNA, apre-mRNA, a viral RNA, a viroid RNA, a virusoid RNA, circular RNA (circRNA), a ribosomal RNA (rRNA), a transfer RNA (tRNA), a pre-tRNA, a long non-coding RNA (IncRNA), a small nuclear RNA (snRNA), a circulating RNA, a cell-free RNA, an exosomal RNA, a vector-expressed RNA, an RNA transcript, a synthetic RNA, and combinations thereof.

[0119] Disclosed herein, in some embodiments, the biomarker is detected by subjecting a sample obtained from the subject to a nucleic acid-based detection assay. In some instances, the nucleic acidbased detection assay comprises quantitative polymerase chain reaction (qPCR), gel electrophoresis (including for e.g., Northern or Southern blot), immunochemistry, in situ hybridization such as fluorescent in situ hybridization (FISH), cytochemistry, microarray, or sequencing. In some embodiments, the sequencing technique comprises next generation sequencing. In some embodiments, the methods involve a hybridization assay such as Anorogenic qPCR (e.g., TaqMan™, SYBR green, SYBR green I, SYBR green II, SYBR gold, ethidium bromide, methylene blue, Pyronin Y, DAPI, acridine orange, Blue View or phycoerythrin), which involves a nucleic acid amplification reaction with a specific primer pair, and hybridization of the amplified nucleic acid probes comprising a detectable moiety or molecule that is specific to a target nucleic acid sequence. In some instances, a number of amplification cycles for detecting a target nucleic acid in a qPCR assay is about 5 to about 30 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is at least about 5 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is at most about 30 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is about 5 to about 10, about 5 to about 15, about 5 to about 20, about 5 to about 25, about 5 to about 30, about 10 to about 15, about 10 to about 20, about 10 to about 25, about 10 to about 30, about 15 to about 20, about 15 to about 25, about 15 to about 30, about 20 to about 25, about 20 to about 30, or about 25 to about 30 cycles. For TaqMan™ methods, the probe may be a hydrolysable probe comprising a Auorophore and quencher that is hydrolyzed by DNA polymerase when hybridized to a target nucleic acid. In some cases, the presence of a target nucleic acid is determined when the number of amplification cycles to reach a threshold value is less than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, or 20 cycles. In some instances, hybridization may occur at standard hybridization temperatures, e.g., between about 35 °C and about 65 °C in a standard PCR buffer.

[0120] An additional exemplary nucleic acid-based detection assay comprises the use of nucleic acid probes conjugated or otherwise immobilized on a bead, multi -well plate, or other substrate, wherein the nucleic acid probes are configured to hybridize with a target nucleic acid sequence. In some instances, the nucleic acid probe is specific to one or more gene products described herein. In some instances, the nucleic acid probe specific to a biomarker comprises a nucleic acid probe sequence sufficiently complementary to the polynucleotide sequence of the biomarker. In some instances, the biomarker comprises a transcribed polynucleotide sequence (e.g., RNA, cDNA). In some embodiments, the nucleic acid probe can be, for example, a full-length cDNA, or a portion thereof, such as an oligonucleotide of at least about 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides in length and sufficient to specifically hybridize under standard hybridization conditions to the target nucleic acid sequence. In some embodiments, the target nucleic acid sequence is immobilized on a solid surface and contacted with a probe, for example by running the isolated target nucleic acid sequence on an agarose gel and transferring the target nucleic acid sequence from the gel to a membrane, such as nitrocellulose. In someembodiments, the probe(s) are immobilized on a solid surface, for example, in an Affymetrix gene chip array, and the probe(s) are contacted with the target nucleic acid sequence.

[0121] In some embodiments, the term “probe” with regards to nucleic acids, refers to any nucleic acid molecule that is capable of selectively binding to a specifically intended target nucleic acid sequence. In some instances, probes are specifically designed to be labeled, for example, with a radioactive label, a fluorescent label, an enzyme, a chemiluminescent tag, a colorimetric tag, or other labels or tags that are known in the art. In some instances, the fluorescent label comprises a fluoropho re. In some instances, the fluorophore is an aromatic or heteroaromatic compound. In some instances, the fluorophore is a pyrene, anthracene, naphthalene, acridine, stilbene, benzoxazole, indole, benzindole, oxazole, thiazole, benzothiazole, canine, carbocyanine, salicylate, anthranilate, xanthenes dye, coumarin. Exemplary xanthene dyes include, e.g., fluorescein and rhodamine dyes. Fluorescein and rhodamine dyes include, but are not limited to 6 -carboxy fluorescein (FAM), 2'7'-dimethoxy-4'5'-dichloro-6-carboxyfluorescein (JOE), tetrachlorofluorescein (TET), 6-carboxyrhodamine (R6G), N,N,N; N'-tetramethyl-6- carboxyrhodamine (TAMRA), 6-carboxy-X-rhodamine (ROX). Suitable fluorescent probes also include the naphthylamine dyes that have an amino group in the alpha or beta position. For example, naphthylamino compounds include l-dimethylaminonaphthyl-5-sulfonate, l-anilino-8-naphthalene sulfonate, and 2-p-toluidinyl-6-naphthalene sulfonate, 5 -(2'-aminoethyl)aminonaphthalene-l -sulfonic acid (EDANS). Exemplary coumarins include, e.g., 3 -phenyl -7-isocyanatocoumarin; acridines, such as 9- isothiocyanatoacridine and acridine orange; N-(p-(2-benzoxazolyl)phenyl) maleimide; cyanines, such as, e.g., indodicarbocyanine 3 (Cy3), indodicarbocyanine 5 (Cy5), indodicarbocyanine 5.5 (Cy5.5), 3-(- carboxy-pentyl)-3'-ethyl-5,5'-dimethyloxacarbocyanine (CyA); 1H, 5H, 11H, 15H-Xantheno[2,3, 4-ij: 5,6, 7-i'j']diquinolizin-18-ium, 9-[2 (or 4)-[[[6-[2,5-dioxo-l-pyrrolidinyl)oxy]-6- oxohexyl]amino]sulfonyl]-4 (or2)-sulfophenyl]-2,3, 6,7, 12,13, 16, 17 -octahydro -inner salt (TR or Texas Red); or BODIPYTM dyes. In some cases, the probe comprises FAM as the dye label.

[0122] In some embodiments, detecting the one or more biomarkers, such as gene products in a predictive response signature (PRS), comprises sequencing genetic material obtained from a sample from the subject. Sequencing can be performed with any appropriate sequencing technology, including but not limited to single-molecule real-time (SMRT) sequencing, Polony sequencing, sequencing by ligation, reversible terminator sequencing, proton detection sequencing, ion semiconductor sequencing, nanopore sequencing, electronic sequencing, pyrosequencing, Maxam -Gilbert sequencing, chain termination (e.g., Sanger) sequencing, +S sequencing, or sequencing by synthesis. Sequencing methods also include nextgeneration sequencing, e.g., modern sequencing technologies such as Illumina sequencing (e.g., Solexa), Roche 454 sequencing, Ion torrent sequencing, and SOLiD sequencing. In some cases, next-generation sequencing involves high-throughput sequencing methods. Additional sequencing methods available to one of skill in the art may also be employed.

[0123] In some instances, a number of nucleotides that are sequenced are at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 150, 200, 300, 400, 500, 2000, 4000, 6000, 8000, 10000, 20000, 50000, 100000, or more than 100000 nucleotides. In some instances, the number of nucleotides sequenced is in a range ofabout 1 to about 100000 nucleotides, about 1 to about 10000 nucleotides, about 1 to about 1000 nucleotides, about 1 to about 500 nucleotides, about 1 to about 300 nucleotides, about 1 to about 200 nucleotides, about 1 to about 100 nucleotides, about 5 to about 100000 nucleotides, about 5 to about 10000 nucleotides, about 5 to about 1000 nucleotides, about 5 to about 500 nucleotides, about 5 to about 300 nucleotides, about 5 to about 200 nucleotides, about 5 to about 100 nucleotides, about 10 to about 100000 nucleotides, about 10 to about 10000 nucleotides, about 10 to about 1000 nucleotides, about 10 to about 500 nucleotides, about 10 to about 300 nucleotides, about 10 to about 200 nucleotides, about 10 to about 100 nucleotides, about 20 to about 100000 nucleotides, about 20 to about 10000 nucleotides, about 20 to about 1000 nucleotides, about 20 to about 500 nucleotides, about 20 to about 300 nucleotides, about 20 to about 200 nucleotides, about 20 to about 100 nucleotides, about 30 to about 100000 nucleotides, about 30 to about 10000 nucleotides, about 30 to about 1000 nucleotides, about 30 to about 500 nucleotides, about 30 to about 300 nucleotides, about 30 to about 200 nucleotides, about 30 to about 100 nucleotides, about 50 to about 100000 nucleotides, about 50 to about 10000 nucleotides, about 50 to about 1000 nucleotides, about 50 to about 500 nucleotides, about 50 to about 300 nucleotides, about 50 to about 200 nucleotides, or about 50 to about 100 nucleotides.

[0124] Disclosed herein are methods comprising: (a) providing a sample obtained from a subject with a proliferative disease or condition (e.g., cancer); (b) assaying to detect in the sample obtained from the subject a presence or absence of the relevant biomarker; and (c) detecting the presence or absence of the biomarker in the sample using the methods described herein. In some cases, a hybridization assay, such as those described herein, is used to detect the biomarker in the sample. Exemplary probe sequences that are hybridizable to atarget nucleic acid sequence (e.g., one or more genes in the biomarker, such as the PRS) comprise at least 10, but no more than 100 contiguous nucleotides comprising the relevant sequence. In some cases, RNA sequencing (RNAseq) is used to detect the one or more biomarkers.

[0125] Detection of the relevant biomarker, in some cases, involves amplification of the subject’s nucleic acid by the polymerase chain reaction (PCR) . In some embodiments, the PCR assay involves use of a pair of primers capable of amplifying at least about 10 contiguous nucleobases within a nucleic acid sequence, thereby amplifying the one or more gene products in the biomarker. In Anorogenic quantitative PCR, quantitation is based on amount of fiuorescence signals (TaqMan and SYBR green). In some embodiments, the nucleic acid probe is conjugated to a detectable molecule. The detectable molecule may be a fiuorophore. The nucleic acid probe may also be conjugated to a quencher.

[0126] In some embodiments, the assay for detecting the presence or absence of a relevant biomarker comprises reverse-transcribing the relevant mRNA molecule to produce a corresponding complementary DNA (cDNA) molecule). In some embodiments, the assay further comprises contacting the cDNA molecule with a nucleic acid probe comprising a nucleic acid sequence that is complementary to a nucleic acid sequence of the cDNA molecule. In some embodiments, the assay comprises detecting a double-stranded hybridization product between the nucleic acid probe and the cDNA molecule. In some embodiments, the hybridization product is further amplified using a pair of primers. In some embodiments, the primers comprises a first primer with a nucleic acid sequence comprising at least 10but not more than 50 contiguous nucleic acids within a relevant nucleic acid sequence that binds to a top strand of the double-stranded hybridization product; and a second primer with a nucleic acid sequence comprising at least 10 but not more than 50 contiguous nucleic acids within a nucleic acid sequence that is reverse complement to the relevant nucleic acid sequence that binds to a bottom strand of the doublestranded hybridization product.

[0127] Disclosed herein, in some embodiments, are methods comprising preparing a complementary DNA (cDNA) library. In some embodiments, the cDNA library is sequenced using suitable sequence methodologies disclosed herein. In some embodiments, the cDNA library is labeled, a plurality of nucleic acid probes is generated, and fixed to an immobile surface (such as a microarray). In some embodiments, the plurality of nucleic acid probes is capable of hybridizing to at least about 10 contiguous nucleotides of the two or more genes in a sample obtained from the subject. In some embodiments, detecting the presence of or absence of a biomarker includes detecting a high or a low level of expression of the two or more genes as compared to a reference level.

[0128] Disclosed herein, in some embodiments, genetic material is extracted from a sample obtained from a subject, e.g., a sample of blood or serum. In certain embodiments where nucleic acids are extracted, the nucleic acids are extracted using any technique that does not interfere with subsequent analysis. In certain embodiments, this technique uses alcohol precipitation using ethanol, methanol, or isopropyl alcohol. In certain embodiments, this technique uses phenol, chloroform, or any combination thereof. In certain embodiments, this technique uses cesium chloride. In certain embodiments, this technique uses sodium, potassium or ammonium acetate or any other salt commonly used to precipitate DNA. In certain embodiments, this technique utilizes a column or resin based nucleic acid purification scheme such as those commonly sold commercially, one non-limiting example would be the GenElute Bacterial Genomic DNA Kit available from Sigma Aldrich. In certain embodiments, after extraction the nucleic acid is stored in water, Tris buffer, or Tris-EDTA buffer before subsequent analysis. In an exemplary embodiment, the nucleic acid material is extracted in water. In some cases, extraction does not comprise nucleic acid purification. In certain embodiments, RNA may be extracted from cells using RNA extraction techniques including, for example, using acid phenol / guanidine isothiocyanate extraction (RNAzol B; Biogenesis), RNeasy RNA preparation kits (Qiagen) or PAXgene (PreAnalytix, Switzerland) .Circulating Tumor DNA (ctDNA) and RNA (ctRNA)

[0129] In some aspects, circulating tumor DNA (ctDNA) is used to assess the presence of certain DNA molecules and circulating tumor RNA (ctRNA) is used to assess the expression levels of RNA molecules, shed by the tumor into the blood stream.

[0130] In some embodiments, detection of ctDNA or ctRNA is useful, for example, for detecting and diagnosing a tumor. Because tumor DNA and RNA has acquired multiple genetic mutations, leading to tumor development, ctDNA and ctRNA are not an exact match to the individual’s DNA and RNA, respectively. Finding DNA and RNA with genetic differences aids in tumor detection. Diagnosing the type of tumor using ctDNA or ctRNA can reduce the need for getting a sample of the tumor tissue (tumorbiopsy), which can be challenging when a tumor is difficult to access, such as a tumor in the brain or lung.

[0131] In some embodiments, a decrease in the quantity of ctDNA or ctRNA suggests the solid tumor is shrinking and treatment with an inhibitor of polo-like kinase 4 (PLK4) is effective. In some embodiments, a lack of ctDNA or ctRNA in the bloodstream indicates that the cancer has not returned after treatment with an inhibitor of polo-like kinase 4 (PLK4).

[0132] Described herein are methods of assessing genetic alterations by ctDNA or ctRNA genomic profiling. In some embodiments, the genomic profiling is performed after each treatment cycle with an inhibitor of polo-like kinase 4 (PLK4).

[0133] The inhibitors of polo-like kinase 4 (PLK4)may be administered as prodrugs. Thus certain derivatives of the compounds, which may have little or no pharmacological activity themselves can, when administered to a mammal, be converted into a compound having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as “prodrugs.” Prodrugs can, for example, be produced by replacing appropriate functionalities present in the inhibitor of polo-like kinase 4 (PLK4) with certain moieties known to those skilled in the art. See, e.g. “Pro-drugs as Novel Delivery Systems,” Vol. 14, ACS Symposium Series (THiguchi and W Stella) and “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association), the disclosures of which are incorporated herein by reference in their entireties. Some examples of such prodrugs include: an ester moiety in the place of a carboxylic acid functional group; an ether moiety or an amide moiety in place of an alcohol functional group; and an amide moiety in place of a primary or secondary amino functional group. Examples of replacement groups are known to those of skill in the art. See, e.g. “Design of Prodrugs” by H Bundgaard (Elsevier, 1985), the disclosure of which is incorporated herein by reference in its entirety.

[0134] Salts of the inhibitor of polo-like kinase 4 (PLK4) that may be used according to the presently disclosed methods can be prepared according to methods known to those of skill in the art. Examples of salts include, but are not limited to, acetate, acrylate, benzenesulfonate, benzoate (such as chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, and methoxybenzoate), bicarbonate, bisulfate, bisulfite, bitartrate, borate, bromide, butyne- 1,4-dioate, calcium edetate, camsylate, carbonate, chloride, caproate, caprylate, clavulanate, citrate, decanoate, dihydrochloride, dihydrogenphosphate, edetate, edisylate, estolate, esylate, ethylsuccinate, formate, fumarate, gluceptate, gluconate, glutamate, glycollate, glycollylarsanilate, heptanoate, hexyne- 1,6-dioate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, .gamma. -hydroxybutyrate, iodide, isobutyrate, isothionate, lactate, lactobionate, laurate, malate, maleate, mal onate, mandelate, mesylate, metaphosphate, methane - sulfonate, methylsulfate, monohydrogenphosphate, mucate, napsylate, naphthalene- 1-sulfonate, naphthalene-2-sulfonate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phenylacetates, phenylbutyrate, phenylpropionate, phthalate, phosphate / diphosphate, polygalacturonate, propanesulfonate, propionate, propiolate, pyrophosphate, pyrosulfate, salicylate, stearate, subacetate,suberate, succinate, sulfate, sulfonate, sulfite, tannate, tartrate, teoclate, tosylate, triethiodode, and valerate salts.

[0135] The inhibitors of polo-like kinase 4 (PLK4) that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention can be prepared by treating the base compound with a substantially equivalent amount of the selected mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon evaporation of the solvent, the desired solid salt is obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding an appropriate mineral or organic acid to the solution.

[0136] The inhibitors of polo-like kinase 4 (PLK4) that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of the present invention. Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium calcium and magnesium, etc. These salts can be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.

[0137] If the inhibitor of polo-like kinase 4 (PLK4) is a base, the desired salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

[0138] If the inhibitor of polo-like kinase 4 (PLK4) is an acid, the desired salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as anamine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0139] If the inhibitor of polo-like kinase 4 (PLK4) is a solid, it is understood by those skilled in the art that the compounds or salts thereof may exist in different crystal or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulas.

[0140] Also provided herein are isotopically-labeled inhibitors of polo-like kinase 4 (PLK4), wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as2H and3H, carbon, such as11C,13C and14C, chlorine, such as36C1, fluorine, such as18F, iodine, such as123I and125I, nitrogen, such as13N and15N, oxygen, such as15O,17O and18O, phosphorus, such as32P, and sulfur, such as35S. Certain isotopically-labeled compounds of the invention, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium,3H, and carbon-14,14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium,2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as " C.18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0141] Isotopically-labeled inhibitors of polo-like kinase 4 (PLK4) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

[0142] In one aspect, the inhibitors of polo-like kinase 4 (PLK4) described herein are used for the treatment of cancer in a subject. In one embodiment, such compositions are in the form of suitable dosage forms. Suitable dosage forms include, for example, liquids, suspensions, powders for reconstitution, tablets, pills, sachets, or capsules of hard or soft gelatin (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0143] The inhibitors of polo-like kinase 4 (PLK4) may be formulated into pharmaceutical compositions as described below in any pharmaceutical form recognizable to the skilled artisan as being suitable. Pharmaceutical compositions of the invention comprise a therapeutically effective amount of at least one compound of the present invention and an inert, pharmaceutically acceptable carrier or diluent.

[0144] The pharmaceutical carriers employed may be either solid or liquid. Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like.Exemplary liquid carriers are syrup, peanut oil, olive oil, water, and the like. Similarly, the inventivecompositions may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate or the like. Further additives or excipients may be added to achieve the desired formulation properties. For example, a bioavailability enhancer, such as Labrasol™, Gelucire™ or the like, or formulator, such as CMC (carboxy-methylcellulose), PG (propyleneglycol), or PEG (polyethyleneglycol), may be added. Gelucire™, a semi-solid vehicle that protects active ingredients from light, moisture, and oxidation, may be added, e.g., when preparing a capsule formulation.

[0145] If a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or formed into a troche or lozenge. The amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or non-aqueous liquid suspension. If a semi-solid carrier is used, the preparation may be in the form of hard and soft gelatin capsule formulations. The inventive compositions are prepared in unit-dosage form appropriate for the mode of administration, e.g. parenteral or oral administration.

[0146] To obtain a stable water-soluble dose form, a salt of a compound of the present invention may be dissolved in an aqueous solution of an organic or inorganic acid, such as a 0.3 M solution of succinic acid or citric acid. If a soluble salt form is not available, the agent may be dissolved in a suitable co -solvent or combinations of co-solvents. Examples of suitable co-solvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0 to 60% of the total volume. In an exemplary embodiment, a compound of the present invention is dissolved in DMSO and diluted with water. The composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution.

[0147] Proper formulation is dependent upon the route of administration selected. For injection, the agents of the compounds of the present invention may be formulated into aqueous solutions, preferably in physiologically compatible buffers such as Hanks solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants are generally known in the art.

[0148] For oral administration, the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (agent), optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodiumcarboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0149] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents.

[0150] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0151] For administration intranasally or by inhalation, the compounds for use according to the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of gelatin for use in an inhaler or insufflator and the like may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0152] The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit-dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents.

[0153] Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active agents may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0154] Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.

[0155] In addition to the formulations described above, the compounds of the present invention may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion-exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. A pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, anon-polar surfactant, a water-miscible organic polymer, and an aqueous phase. The co-solvent system may be a VPD co-solvent system. VPD is a solution of 3% w / v benzyl alcohol, 8% w / v of the non-polar surfactant polysorbate 80, and 65% w / v polyethylene glycol 300, made up to volume in absolute ethanol. The VPD co-solvent system (VPD: 5W) contains VPD diluted 1: 1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration. The proportions of a cosolvent system may be suitably varied without destroying its solubility and toxicity characteristics.Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity non-polar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may be substituted for dextrose.

[0156] Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide (DMSO) also may be employed, although usually at the cost of greater toxicity due to the toxic nature of DMSO. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.

[0157] The pharmaceutical compositions also may comprise suitable solid- or gel-phase carriers or excipients. These carriers and excipients may provide marked improvement in the bioavailability of poorly soluble drugs. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Furthermore, additives or excipients such as Gelucire™, Capryol™, Labrafil™, Labrasol™, Lauroglycol™, Plurol™, Peceol™, Transcutol™ and the like may be used.

[0158] Further, the pharmaceutical composition may be incorporated into a skin patch for delivery of the drug directly onto the skin.

[0159] It will be appreciated that the actual dosages of the agents of this invention will vary according to the particular agent being used, the particular composition formulated, the mode of administration, and the particular site, host, and disease being treated. Those skilled in the art using conventional dosage -determination tests in view of the experimental data for a given compound may ascertain optimal dosages for a given set of conditions. For oral administration, an exemplary daily dose generally employed will be from about 0.001 to about 1000 mg / kg of body weight, with courses of treatment repeated at appropriate intervals.

[0160] Furthermore, the pharmaceutically acceptable formulations useful in the presently disclosed methods may contain an inhibitor of polo-like kinase 4 (PLK4) in an amount of about 10 mg to about 2000 mg, or from about 10 mg to about 1500 mg, or from about 10 mg to about 1000 mg, or from about 10 mg to about 750 mg, or from about 10 mg to about 500 mg, or from about 25 mg to about 500 mg, or from about 50 to about 500 mg, or from about 100 mg to about 500 mg.

[0161] Additionally, the pharmaceutically acceptable formulations useful in the presently disclosed methods may contain an inhibitor of polo-like kinase 4 (PLK4) in an amount from about 0.5 w / w % to about 95 w / w %, or from about 1 w / w % to about 95 w / w %, or from about 1 w / w % to about 75 w / w %, or from about 5 w / w % to about 75 w / w %, or from about 10 w / w % to about 75 w / w %, or from about 10 w / w % to about 50 w / w %.

[0162] The inhibitor of polo-like kinase 4 (PLK4) may be administered to a mammal suffering from abnormal cell growth, such as a human, either alone or as part of a pharmaceutically acceptable formulation, once a day, twice a day, three times a day, or four times a day, or even more frequently.

[0163] Those of ordinary skill in the art will understand that with respect to the inhibitor of polo-like kinase 4 (PLK4), the particular pharmaceutical formulation, the dosage, and the number of doses given per day to a mammal requiring such treatment, are all choices within the knowledge of one of ordinary skill in the art and can be determined without undue experimentation.

[0164] Dosages of an inhibitor of polo-like kinase 4 (PLK4) described herein can be determined by any suitable method. Maximum tolerated doses (MTD) and maximum response doses (MRD) for the inhibitor of polo-like kinase 4 (PLK4) can be determined via established animal and human experimental protocols as well as in the examples described herein. For example, toxicity and therapeutic efficacy of an inhibitor of polo-like kinase 4 (PLK4) may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. Additional relative dosages, represented as a percent of maximal response or of maximum tolerated dose, are readily obtained via the protocols.

[0165] In some embodiments, the amount of an inhibitor of polo-like kinase 4 (PLK4) varies depending upon factors such as the particular salt or form, disease condition and its severity, the identity (e.g., age, weight, sex) of the subject or host in need of treatment, but can nevertheless be determined according tothe particular circumstances surrounding the case, including, e.g., the specific agent being administered, the liquid formulation type, the condition being treated, and the subject or host being treated.

[0166] In some embodiments, an inhibitor of polo-like kinase 4 (PLK4) is administered in an amount between about 10 mg to 500 mg per day. In some embodiments, an inhibitor of polo-like kinase 4 (PLK4) is administered in an amount between about between about 100 mg to about 400 mg per day. In some embodiments, an inhibitor of polo-like kinase 4 (PLK4) is administered in an amount between about 150 mg to about 350 mg per day. In some embodiments, an inhibitor of polo-like kinase 4 (PLK4) is administered in an amount between about 150 mg to about 300 mg per day. In some embodiments, an inhibitor of polo-like kinase 4 (PLK4) is administered in an amount between about 160 mg to about 300 mg per day. In some embodiments, an inhibitor of polo-like kinase 4 (PLK4) is administered in an amount between about of about 160 mg per day. In some embodiments, an inhibitor of polo-like kinase 4 (PLK4) is administered in an amount between about 200 mg per day. In some embodiments, an inhibitor of polo-like kinase 4 (PLK4) is administered in an amount between about 240 mg per day. In some embodiments, an inhibitor of polo-like kinase 4 (PLK4) is administered in an amount between about 280 mg per day. In some embodiments, an inhibitor of polo -like kinase 4 (PLK4) is administered in an amount between about administered in an amount of about 320 mg per day.

[0167] In some embodiments of the methods disclosed herein, the cyclin-dependent kinase inhibitor administered to the subject having cancer is abemaciclib, In some embodiments, abemaciclib may be administered to the subject in an amount that is 150 mg twice daily, with or without food, in combination with fulvestrant, tamoxifen, or an aromatase inhibitor. In some embodiments, abemaciclib may be administered to the subject in an amount that is 200 mg twice daily, with or without food. One of skill in the art will appreciate that the dosing of abemaciclib to a subject may be interrupted or reduced based on individual safety and tolerability.

[0168] In some embodiments of the methods disclosed herein, the cyclin-dependent kinase inhibitor administered to the subject having cancer is palbociclib. In some embodiments, palbociclib may be administered to the subject in an amount that is 125 mg once daily taken with food for 21days followed by 7 days off treatment, and optionally in combination with an aromatase inhibitor as an initial endocrine-based therapy, or in combination with fulvestrant in subjects with disease progression following endocrine therapy. One of skill in the art will appreciate that the dosing of palbociclib to a subject may be interrupted or reduced based on individual safety and tolerability

[0169] In some embodiments of the methods disclosed herein, the cyclin-dependent kinase inhibitor administered to the subject having cancer is riboci clib. In some embodiments, ribociclib may be administered to the subject in an amount that is 600 mg orally taken once daily with or without food for 21 consecutive days followed by 7 days off treatment, and optionally in combination with an aromatase inhibitor as initial endocrine -based therapy, or fulvestrant as initial endocrine -based therapy following disease progression on endocrine therapy in postmenopausal women or in men. One of skill in the art will appreciate that the dosing of ribociclib to a subject may be interrupted or reduced based on individual safety and tolerability

[0170] In some embodiments of the methods disclosed herein, the cyclin-dependent kinase inhibitor administered to the subject having cancer is trilaciclib. In some embodiments, trilaciclib may be administered to the subject in an amount that is 240 mg / m2as a 30-minute intravenous infusion. One of skill in the art will appreciate that the dosing of trilaciclib to a subject may be interrupted or reduced based on individual safety and tolerability

[0171] In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the subject. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the subject.

[0172] In certain embodiments wherein the subject’s condition does not improve, upon the doctor’s discretion the administration of a composition described herein are administered chronically, that is, for an extended period of time, including throughout the duration of the subject’s life in order to ameliorate or otherwise control or limit the symptoms of the subject’s disease. In other embodiments, administration of a composition continues until complete or partial response of a disease.

[0173] In some embodiments, an inhibitor of polo-like kinase 4 (PLK4) is administered to a subject in need thereof once a day. In some embodiments, an inhibitor of polo-like kinase 4 (PLK4) is administered to a subject in need thereof twice a day. In some embodiments, an inhibitor of polo-like kinase 4 (PLK4) is administered to a subject in need thereof three times a day.

[0174] In some instances, the methods described herein comprise administering an inhibitor of polo-like kinase 4 (PLK4) to the subject or subject in need thereof in multiple cycles repeated on a regular schedule with periods of rest in between each cycle. For example, in some instances, treatment given for one week followed by three weeks of rest is one treatment cycle.

[0175] The length of a treatment cycle depends on the treatment being given. In some embodiments, the length of a treatment cycle ranges from two to six weeks. In some embodiments, the length of a treatment cycle ranges from three to six weeks. In some embodiments, the length of a treatment cycle ranges from three to four weeks. In some embodiments, the length of a treatment cycle is three weeks (or 21 days). In some embodiments, the length of a treatment cycle is four weeks (28 days). In some embodiments, the length of a treatment cycle is 56 days. In some embodiments, a treatment cycle lasts one, two, three, or four weeks. In some embodiments, a treatment cycle lasts three weeks. In some embodiments, a treatment cycle lasts four weeks. The number of treatment doses scheduled within each cycle also varies depending on the drugs being given.Kits and articles of manufacture

[0176] Disclosed herein, in certain embodiments, are kits and articles of manufacture for use with one or more methods and compositions described herein. Such kits include a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In one embodiment, the containers are formed from a variety of materials such as glass or plastic.

[0177] A kit typically includes labels listing contents and / or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included.

[0178] In one embodiment, a label is on or associated with the container. In one embodiment, a label is on a container when letters, numbers or other characters forming the label are attached, molded, or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In one embodiment, a label is used to indicate that the contents are to be used for a specific therapeutic application. The label also indicates directions for use of the contents, such as in the methods described herein.

[0179] In certain embodiments, the pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. The pack, for example, contains metal or plastic foil, such as a blister pack. In one embodiment, the pack or dispenser device is accompanied by instructions for administration. In one embodiment, the pack or dispenser is also accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U. S . Food and Drug Administration for drugs, or the approved product insert. In one embodiment, compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are also prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.Methods of Preparation

[0180] Compounds of Formulae (I) and (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, may be prepared using the reaction routes and synthetic schemes described in WO 2022 / 240876 and United States Patent No. 11,858,915, as well as those methods described below, employing the techniques available in the art using starting materials that are readily available. The preparation of certain embodiments of the present invention is described in detail in the following examples, but those of ordinary skill in the art will recognize that the preparations described may be readily adapted to prepare other embodiments of the present invention. For example, the synthesis of non-exemplified compounds according to the invention may be performed by modifications apparent to those skilled in the art, e.g. by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions. Alternatively, otherreactions referred to herein or known in the art will be recognized as having adaptability for preparing other compounds of the invention.

[0181] The compounds of Formula (I) may be prepared from Compounds of Formula (IV), wherein R2, R3, R4a, R4b, R4c, R5, R6, R7, R8a, R8b, R8c, and R8dare as defined herein, by allowing the compounds to react with compounds of Formula (V), wherein A, R1, and n are as defined herein, and wherein LG is a leaving group. LG that may be used include halogens, such as chloro, bromo, and iodo. The reaction of the compounds of Formula (IV) with compounds of Formula (V) may be conducted using methods known to those of ordinary skill in the art. For example, the reaction of the compounds of Formula (IV) with compounds of Formula (V) may be conducted in aprotic solvents, such as acetonitrile, DMF, and the like, protic solvents, such as water or alcohols, mixtures of protic and aprotic solvents, such as mixtures of acetonitrile and water, at temperatures in the range from 25 °C to 200 °C, and in the presence of an acid or a base. Compounds of Formula (V) may be prepared by methods disclosed herein and / or by methods known to those of ordinary skill in the art.

[0182] Alternatively, compounds of Formula (I) may be prepared by allowing compounds of Formula (VI), wherein R3, R4a, R4b, R4c, R5, R6, R7, R8a, R8b, R8c, and R8dare as defined herein, and Hal is a halogen, such as bromo or iodo, by allowing the compounds to react with compounds of Formula (VII), wherein A, R1, R2, and n are as defined herein. Such reactions may be performed in the presence of a catalytic amount of a palladium -containing compound, such as palladium(O) bis(dibenzylideneacetone) (also known as Pd(dba)2), a phosphate ligand, such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (also known as Xantphos), a base, and in an aprotic solvent. The base may be selected from an organic base, such as a tertiary amine, for example triethyl amine, or an inorganic base, for example cesium carbonate. The aprotic solvent may be, for example, toluene. The reactions of the compounds of Formula (VI) with the compounds of Formula (VII) may be conducted at temperatures in the range from 25 °C to 200 °C, for example such reactions may be conducted in toluene at a temperature of 100 °C. The compounds of Formula (VII) are commercially available, or may be prepared by methods known to those having ordinary skill in the art, or by methods similar to those set forth herein.Formula (VI) Formula (I)

[0183] Compounds of Formula (II) may be prepared from Compounds of Formula (VIII), wherein R2, R3, R4a, R4b, R4c, R5, R6, R7, R8a, R8b, R8c, R8d, and R9are as defined herein, by allowing the compounds to react with compounds of Formula (IX), wherein A, R1, R9, and n are as defined herein, and wherein LG is a leaving group. LG that may be used include halogens, such as chloro, bromo, and iodo. The reaction of the compounds of Formula (VIII) with compounds of Formula (IX) may be conducted using methods known to those of ordinary skill in the art. For example, the reaction of the compounds of Formula (VIII) with compounds of Formula (IX) may be conducted in aprotic solvents, such as acetonitrile, DMF, and the like, protic solvents, such as water or alcohols, mixtures of protic and aprotic solvents, such as mixtures of acetonitrile and water, at temperatures in the range from 25 °C to 200 °C, and in the presence of an acid or a base. Compounds of Formula (IX) may be prepared by methods disclosed herein and / or by methods known to those of ordinary skill in the art.

[0184] Alternatively, compounds of Formula (II) may be prepared by allowing compounds of Formula (X), wherein R3, R4a, R4b, R4c, R5, R6, R7, R8a, R8b, R8c, R8d, and R9are as defined herein, and Hal is a halogen, such as bromo or iodo, by allowing the compounds to react with compounds of Formula (XI), wherein A, R1, R2, R9and n are as defined herein. Such reactions may be performed in the presence of a catalytic amount of a palladium -containing compound, such as palladium(O) bis(dibenzylideneacetone) (also known as Pd(dba)2), a phosphate ligand, such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (also known as Xantphos), a base, and in an aprotic solvent. The base may be selected from an organic base, such as a tertiary amine, for example triethyl amine, or an inorganic base, for example cesium carbonate. The aprotic solvent may be, for example, toluene. The reactions of the compounds of Formula (X) with the compounds of Formula (XI) may be conducted at temperatures in the range from 25 °C to 200 °C, for example such reactions may be conducted in toluene at a temperature of 100 °C. Thecompounds of Formula (XI) are commercially available, or may be prepared by methods known to those having ordinary skill in the art, or by methods similar to those set forth herein.Formula (X) Formula (II)

[0185] Compounds of Formula (VI) may be prepared by methods known to those having ordinary skill in the art. For example, the compound of Formula (IV) (lR,2S)-2-(3-bromo-lH-indazol-6-yl)-5'- methoxyspiro[cyclopropane-l,3'-indolin]-2'-one may be prepared according to the scheme set forth below. Other compounds of Formula (VI) may be prepared by methods known to those of skill in the art by modifications apparent to those skilled in the art, e.g. by using different starting materials, appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions.

[0186] Similarly, (lR,2S)-2-(3-Iodo-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'-indolin]-2'- one may be prepared by allowing (lR,2S)-2-(lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'- indolin]-2'-one to react with iodine in DMF and methanol in the presence of potassium carbonate as set forth below.

[0187] Compounds of Formula (IV) may be prepared from compounds of Formula (VI) by methods known to those having ordinary skill in the art. For example, tert-butyl (lR,2S)-2-(3-amino-l-(tert- butoxycarbonyl)-lH-indazol-6-yl)-5'-methoxy-2'-oxospiro[cyclopropane-l,3'-indoline]-r-carboxylate may be prepared from (lR,2S)-2-(3-bromo-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropane-l,3'- indolin]-2'-one as set forth below.

[0188] Compounds such as tert-butyl (lR,2S)-2-(3-amino-l-(tert-butoxycarbonyl)-lH-indazol-6-yl)-5'- methoxy-2'-oxospiro[cyclopropane-l,3'-indoline]-r-carboxylate may be allowed to react with compounds of Formula (V) as described herein, followed by deprotection of the Boc groups using an acid, such as trifluoroacetic acid, to provide compounds of Formula (I). For example, tert-butyl (1R,2S)- 2-(3-amino-l-(tert-butoxy carbonyl)- lH-indazol-6-yl)-5'-methoxy-2'-oxospiro[cyclopropane- 1,3'- indoline]-r-carboxylate may be allowed to react with 4-chloro-5-methoxypyrimidine to afford (1R,2S)- 5'-methoxy-2-(3-((5-methoxypyrimidin-4-yl)amino)-lH-indazol-6-yl)spiro[cyclopropane-l,3'-indolin]-2- one.

[0189] Compounds of Formula (III), or pharmaceutically acceptable salts thereof, may be prepared by methods known to those having ordinary skill in the art as well as those described in International Publication No. WO 2023 / 159307.Numbered Embodiments

[0190] Embodiment 1: A method of treating cancer in a subject, wherein the cancer in the subject has progressed following administration to the subject of a cyclin-dependent kinase inhibitor, comprising administering to the subject an inhibitor of polo -like kinase 4 (PLK4).

[0191] Embodiment 2: A method of treating cancer in a subject, wherein the cancer in the subject has been determined to be resistant to at least one cyclin-dependent kinase inhibitor, comprising administering to the subject an inhibitor of polo -like kinase 4 (PLK4).

[0192] Embodiment 3: A method of treating cancer in a subject, wherein the cancer in the subject has (a) progressed following administration to the subject of a cyclin-dependent kinase inhibitor, and (b) been determined to be resistant to at least one cyclin-dependent kinase inhibitor, comprising administering to the subject an inhibitor of polo-like kinase 4 (PLK4).

[0193] Embodiment 4: A method of treating cancer in a subject, comprising administering to the subject an inhibitor of polo-like kinase 4 (PLK4), wherein the cancer in the subject has progressed following administration to the subject of a cyclin-dependent kinase inhibitor prior to administration to the subject of the inhibitor of polo-like kinase 4 (PLK4).

[0194] Embodiment 5: A method of treating cancer in a subject, comprising administering to the subject an inhibitor of polo-like kinase 4 (PLK4), wherein the cancer in the subject has been determined to be resistant to at least one cyclin-dependent kinase inhibitor prior to administration to the subject of the inhibitor of polo-like kinase 4 (PLK4).

[0195] Embodiment 6: A method of treating cancer in a subject, comprising administering to the subject an inhibitor of polo-like kinase 4 (PLK4), wherein priorto administration to the subject of the inhibitor of polo-like kinase 4 (PLK4) the cancer in the subject has (a) progressed following administration to the subject of a cyclin-dependent kinase inhibitor, and (b) been determined to be resistant to at least one cyclin-dependent kinase inhibitor.

[0196] Embodiment 7: The method of any one of embodiments 1 to 6, wherein the cancer in the subject has been further determined to exhibit an overexpression of the gene that encodes the tripartite motif - containing protein 37 (TRIM37) priorto administration to the subject of the inhibitor of polo -like kinase 4 (PLK4).

[0197] Embodiment 8: The method of any one of embodiments 1 to 6, wherein the cancer in the subject has been further determined to exhibit an amplification of the gene that encodes the tripartite motif - containing protein 37 (TRIM37) prior to administration to the subject of the inhibitor of polo -like kinase 4 (PLK4).

[0198] Embodiment 9: The method of any one of embodiments 1 to 6, wherein the cancer in the subject has been further determined to overexpress the gene that encodes the tripartite motif-containing protein 37 (TRIM37) prior to administration to the subject of the inhibitor of polo -like kinase 4 (PLK4).

[0199] Embodiment 10: A method of treating cancer in a subject, comprising administering to the subject an inhibitor of polo-like kinase 4 (PLK4), wherein prior to administration to the subject of the inhibitor of polo-like kinase 4 (PLK4) the cancer in the subject has (a) progressed followingadministration to the subject of a cyclin -dependent kinase inhibitor, (b) been determined to be resistant to at least one cyclin-dependent kinase inhibitor, and (c) been determined to exhibit an overexpression of the gene that encodes the tripartite motif-containing protein 37 (TRIM37).

[0200] Embodiment 11 : A method of treating cancer in a subject, comprising administering to the subject an inhibitor of polo-like kinase 4 (PLK4), wherein prior to administration to the subject of the inhibitor of polo-like kinase 4 (PLK4) the cancer in the subject has (a) progressed following administration to the subject of a cyclin-dependent kinase inhibitor, (b) been determined to be resistant to at least one cyclin-dependent kinase inhibitor, and (c) been determined to exhibit an amplification of the gene that encodes the tripartite motif-containing protein 37 (TRIM37).

[0201] Embodiment 12: A method of treating cancer in a subject, comprising administering to the subject an inhibitor of polo-like kinase 4 (PLK4), wherein prior to administration to the subject of the inhibitor of polo-like kinase 4 (PLK4) the cancer in the subject has (a) progressed following administration to the subject of a cyclin-dependent kinase inhibitor, (b) been determined to be resistant to at least one cyclin-dependent kinase inhibitor, and (c) been determined to overexpress the gene that encodes the tripartite motif-containing protein 37 (TRIM37).

[0202] Embodiment 13: The method of any one of embodiments 1 to 12, wherein the cancer in the subject is selected from chordoma, small -cell lung cancer, large cell neuroendocrine lung carcinoma, extrapulmonary small cell carcinoma, glioblastoma, glioma, head and neck cancer, esophagus squamous cell carcinoma, oligodendroglioma, oligoastrocytoma, prostate cancer, colorectal cancer, endometrial cancer, melanoma, breast cancer, neuroblastoma, non-squamous cell lung carcinoma, bladder cancer, and liver cancer.

[0203] Embodiment 14: The method of embodiment 13, wherein the cancer in the subject is breast cancer.

[0204] Embodiment 15: The method of embodiment 14, wherein the breast cancer in the subject is selected from (a) hormone receptor (HR) -positive, human epidermal growth factor receptor 2 (HER2)- positive breast cancer (b) hormone receptor (HR) -positive, human epidermal growth factor receptor 2 (HER2) -negative breast cancer; (c) hormone receptor (HR)-positive breast cancer, (d) hormone receptor (HR) -negative breast cancer, (e) HE R2 -positive breast cancer, (f) human epidermal growth factor receptor 2 (HE R2) -negative advanced or metastatic breast cancer, (g) human epidermal growth factor receptor 2 (HE R2) -negative, node-positive, early breast cancer at high risk of recurrence, (h) hormone receptor (HR) -positive, human epidermal growth factor receptor 2 (HER2) -negative advanced or metastatic breast cancer with disease progression following endocrine therapy; (i) hormone receptor (HR) -positive, human epidermal growth factor receptor 2 (HE R2) -negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting; (j) hormone receptor (HR) -positive, human epidermal growth factor receptor 2 (HE R2) -negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine - based therapy; (k) fulvestrant as initial endocrine -based therapy or following disease progression onendocrine therapy in postmenopausal women or in men; (1) HER2-low breast cancer, (m) triple -negative breast cancer, (n) BRCA1 -mutated breast cancer, and (o) BRCA2-mutated breast cancer.

[0205] Embodiment 16: The method of any one of embodiments 1 to 15, wherein the cyclin -dependent kinase inhibitor is selected from an inhibitor of one or more of cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 4 (CDK4), and cyclin-dependent kinase 6 (CDK6).

[0206] Embodiment 17 : The method of embodiment 16, wherein the cyclin-dependent kinase inhibitor is an inhibitor of cyclin-dependent kinase 2 (CDK2) .

[0207] Embodiment 18: The method of embodiment 16, wherein the cyclin-dependent kinase inhibitor is an inhibitor of cyclin-dependent kinase 4 (CDK4) .

[0208] Embodiment 19: The method of embodiment 16, wherein the cyclin-dependent kinase inhibitor is an inhibitor of cyclin-dependent kinase 6 (CDK6) .

[0209] Embodiment 20: The method of any one of embodiments 1 to 15, wherein the cyclin-dependent kinase inhibitor is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, dinaciclib, PF-07104091, BLU-222, and PF-07220060.

[0210] Embodiment 21: The method of any one of embodiments 1 to 20, wherein the subject is administered one or more additional therapeutic agents.

[0211] Embodiment 22: The method of embodiment 21, wherein the one or more additional therapeutic agents is selected from: (a) an aromatase inhibitor: (b) fulvestrant; (c) luteinizing hormone -releasing hormone (LHRH) agonists.

[0212] Embodiment 23: The method of embodiment 22, wherein the one or more additional therapeutic agents is one or more aromatase inhibitors.

[0213] Embodiment 24: The method of embodiment 23, wherein the aromatase inhibitor is selected from anastrozole, exemestane, letrozole, vorozole, formestane, fadrozole, aminoglutethimide, testolactone, 1, 4, 6-androstatrien-3, 17-dione, and 4-androstene-3, 6, 17-trione.

[0214] Embodiment 25: The method of embodiment 22, wherein the one or more additional therapeutic agents is fulvestrant.

[0215] Embodiment 26: The method of embodiment 22, wherein the one or more additional therapeutic agents is one or more luteinizing hormone-releasing hormone (LHRH) agonists.

[0216] Embodiment 27: The method of embodiment 26, wherein the one or more luteinizing hormone- releasing hormone (LHRH) agonists is selected from leuprolide, goserelin, triptorelin, histrelin, buserelin, and triptorelin.

[0217] Embodiment 28: The method of any one of embodiments 1 to 27, wherein the inhibitor of pololike kinase 4 (PLK4) is selected from a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (I), wherein:Ring A is C6-10 aryl, heteroaryl, C6-10 cycloalkyl, or heterocycloalkyl; each R1is independently deuterium, halogen, -CN, oxo, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -P(O)(Ra)2, - P(O)2(Ra)2, C1a-6lkyl, hCa1l-o6alkyl, -OCi-Cehaloalkyl, Ci -Cedeuteroalkyl, hydroxyalkyl, C1-6C1-6 aminoalkyl, Ch1-e6teroalkyl, C2-Cealkenyl, C2-Cealkynyl, C6-10 cycloalkyl, heterocycloalkyl,C6-10 aryl, or heteroaryl; wherein each of the alkyl, C2C-C1-e6alkenyl, C2-Cealkynyl, C3- Ciocycloalkyl, heterocycloalkyl, aryCl,6- a1n0d heteroaryl is optionally and independently substituted with one or more Rla; or two R1on adjacent atoms are taken together to form a C6-10 cycloalkyl or heterocycloalkyl; each optionally substituted with one or more Rlb; each Rlais independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl,C1-6 haloalkyl, Ci -Cedeuteroalkyl, hydrCox1-y6alkyl, aminoalkyCl1,-6 heteroalkyl, C2C-1-6 Cealkenyl, C2-Cealkynyl, C6-10 cycloalkyl, heterocycloalkyl, aryl, or heteCr6o-a10ryl; or two Rlaon the same atom are taken together to form an oxo; each Rlbis independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl,C1-6 haloalkyl, Ci -Cedeuteroalkyl, hydrCox1-y6alkyl, aminoalkyCl1,-6 heteroalkyl, C2C-1-6 Cealkenyl, C2-Cealkynyl, C6-10 cycloalkyl, heterocycloalkyl, aryl, or heteCr6o-a10ryl; or two Rlbon the same atom are taken together to form an oxo; n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;R2is hydrogen, Ca1-l6kyl, haCl1o-a6lkyl, or Ci -Cedeuteroalkyl;R3is hydrogen, Ca1-l6kyl, haCl1o-a6lkyl, or Ci -Cedeuteroalkyl; each of R4a, R4b, and R4cis independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, alkyCl,1-6 haloalkCy1l-,6 Ci -Cedeuteroalkyl, C1-6 hydroxyalkyl, Ca1m-6 inoalkyl, or heterCo1a-6lkyl;R5is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, alkyl, Ch1a-l6oalkyl, C1-6 Ci -Cedeuteroalkyl, hCy1-d6roxyalkyl, aminoCa1l-k6yl, or heteroalkylC;1-6 each R6is independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, alkyl, C1-6C1-6 haloalkyl, Ci -Cedeuteroalkyl, hydrCox1-y6alkyl, aminoalkyCl1,-6 or heteroalkyl; C1-6R7is hydrogen, Ca1l-k6yl, haClo1a-6lkyl, Ci -Cedeuteroalkyl, hydroxyalkyl, oCr1-6 aminoalkyl; C1-6 each ofR8a, R8b, R8c, andR8dis independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, - OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1a-6lkyl, hCal1o-6alkyl, Ci -Cedeuteroalkyl, hydroxyalkylC, 1-6 aminoalkyl, C1-6C1-6 heteroalkyl, C2-Cealkenyl, C2-Cealkynyl, C3-Ciocycloalkyl, heterocycloalkyl, aryl, or C6-10 heteroaryl; each Rais independently alkCyl1,-6 haloalCk1y-6l, Ci -Cedeuteroalkyl, hydroxyalkyl, C1-6 C1-6 aminoalkyl, Ch1-e6teroalkyl, C2-Cealkenyl, C2-Cealkynyl, C3-Ciocycloalkyl, heterocycloalkyl, C6-10 aryl, heteroaryl, alCky1-l6(C3-Ciocycloalkyl), alkyl(heteCro1c-6ycloalkyl), alkyl(Ce- C1-6 Cioaryl), or C1-6alkyl(heteroaryl); wherein each of the alkyl, C2-CeaClk1e-6nyl, C2-Cealkynyl, C3- Ciocycloalkyl, heterocycloalkyl, aryCl,6- a1n0d heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-6 alkyl, C1-6haloalkyl, Ci -Cedeuteroalkyl, hydroxyCa1l-k6yl, aminoalkyl,C or1-6 C1-6 heteroalkyl; each Rbis independently hydrogen, alkyl, C1-6 haloalkyl,C C1i-6 -Cedeuteroalkyl, hydroxyalkyl, C1-6C1-6 aminoalkyl, Ch1-e6teroalkyl, C2-Cealkenyl, C2-Cealkynyl, C3-Ciocycloalkyl, heterocycloalkyl, C6-10 aryl, heteroaryl, alCky1-l6(C3-Ciocycloalkyl), alkyl(heteCro1c-6ycloalkyl), alkyl(Ce- C1-6 Cioaryl), or C1-6alkyl(heteroaryl); wherein each of the alkyl, C2-CeaClk1e-6nyl, C2-Cealkynyl, C3- Ciocycloalkyl, heterocycloalkyl, aryCl,6- a1n0d heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-6 alkyl, C1-6haloalkyl, Ci -Cedeuteroalkyl, hydroxyCa1l-k6yl, aminoalkyl,C or1-6 C1-6 heteroalkyl; and each Rcand Rdare independently hydrogen, alkyl, C1-h6aloalkyl, CCi -1C-6edeuteroalkyl, C1-6 hydroxyalkyl, Ca1l-6koxy, amCin1-o6alkyl, alkylamCin1-o6, heteroalkyl,C C12-6- Cealkenyl, C2-Cealkynyl, C3-Ciocycloalkyl, heterocycloalkyl, aryl, heteroarCyl6,-1 C0i-Cealkyl(C3- Ciocycloalkyl), C1a-6lkyl(heterocycloalkyl), alkyl(CCe1--6Cioaryl), or alkyl(heteroaCry1l-)6; wherein each of the alCk1y-6l, C2-Cealkenyl, C2-Cealkynyl, C3-Ciocycloalkyl, heterocycloalkyl, C’e- Cioaryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, alkyl, C1-6C1-6 haloalkyl, Ci -Cedeuteroalkyl, hydrCox1-y6alkyl, aminoalkyCl1,-6 or heteroalkyl; C1-6or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, - S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, hydroxyalkyCl,1-6C1-6 aminoalkyl, or Ch1e-6teroalkyl.

[0218] Embodiment 29: The method of any one of embodiments 1 to 27, wherein the inhibitor of pololike kinase 4 (PLK4) is selected from a compound disclosed in paragraph

[0086] , or a pharmaceutically acceptable salt thereof.

[0219] Embodiment 30: The method of any one of embodiments 1 to 27, wherein the inhibitor of polo like kinase 4 (PLK4) is selected from a compound disclosed in paragraph

[0087] , or a pharmaceutically acceptable salt thereof.

[0220] Embodiment 31: The method of any one of embodiments 1 to 27, wherein the inhibitor of polo like kinase 4 (PLK4) is selected from a compound disclosed in paragraph

[0088] , or a pharmaceutically acceptable salt thereof.

[0221] Embodiment 32: The method of any one of embodiments 1 to 27, wherein the inhibitor of polo like kinase 4 (PLK4) is selected from a compound disclosed in paragraph

[0089] , or a pharmaceutically acceptable salt thereof.

[0222] Embodiment 33: The method of any one of embodiments 1 to 27, wherein the inhibitor of polo- like kinase 4 (PLK4) is selected from a compound disclosed in paragraph

[0090] .

[0223] Embodiment 34: The method of embodiment 33, wherein the inhibitor of polo -like kinase 4(Compound 1), or a pharmaceutically acceptable salt thereof.

[0224] Embodiment 35: The method of embodiment 33, wherein the inhibitor of polo -like kinase 4(Compound 2), or a pharmaceutically acceptable salt thereof.

[0225] Embodiment 36: The method of embodiment 33, wherein the inhibitor of polo -like kinase 4(Compound 3), or a pharmaceutically acceptable salt thereof.

[0226] Embodiment 37: The method of embodiment 33, wherein the inhibitor of polo-like kinase 4(Compound 4), or a pharmaceutically acceptable salt thereof.

[0227] Embodiment 38: The method of embodiment 33, wherein the inhibitor of polo -like kinase 4(Compound 5), or a pharmaceutically acceptable salt thereof.

[0228] Embodiment 39: The method of embodiment 33, wherein the inhibitor of polo -like kinase 4(Compound 6), or a pharmaceutically acceptable salt thereof.

[0229] Embodiment 40: The method of embodiment 33, wherein the inhibitor of polo-like kinase 4(Compound 7), or a pharmaceutically acceptable salt thereof.

[0230] Embodiment 41: The method of embodiment 33, wherein the inhibitor of polo-like kinase 4(Compound 8), or a pharmaceutically acceptable salt thereof.

[0231] Embodiment 42: The method of embodiment 33, wherein the inhibitor of polo-like kinase 4(Compound 9), or a pharmaceutically acceptable salt thereof.

[0232] Embodiment 43: The method of embodiment 33, wherein the inhibitor of polo-like kinase 4(Compound 10), or a pharmaceutically acceptable salt thereof.

[0233] Embodiment 44: The method of embodiment 33, wherein the inhibitor of polo -like kinase 4(Compound 11), or a pharmaceutically acceptable salt thereof.

[0234] Embodiment 45: The method of embodiment 33, wherein the inhibitor of polo-like kinase 4(Compound 12), or a pharmaceutically acceptable salt thereof.

[0235] Embodiment 46: The method of embodiment 33, wherein the inhibitor of polo-like kinase 4(Compound 13), or a pharmaceutically acceptable salt thereof.

[0236] Embodiment 47: The method of embodiment 33, wherein the inhibitor of polo-like kinase 4(Compound 14), or a pharmaceutically acceptable salt thereof.

[0237] Embodiment 48: The method of embodiment 33, wherein the inhibitor of polo -like kinase 4(Compound 15), or a pharmaceutically acceptable salt thereof.

[0238] Embodiment 49: The method of embodiment 33, wherein the inhibitor of polo-like kinase 4(Compound 16), or a pharmaceutically acceptable salt thereof.

[0239] Embodiment 50: The method of embodiment 33, wherein the inhibitor of polo -like kinase 4(Compound 17), or a pharmaceutically acceptable salt thereof.

[0240] Embodiment 51: The method of embodiment 33, wherein the inhibitor of polo-like kinase 4(Compound 18), or a pharmaceutically acceptable salt thereof.

[0241] Embodiment 52: The method of embodiment 33, wherein the inhibitor of polo-like kinase 4(Compound 19), or a pharmaceutically acceptable salt thereof.

[0242] Embodiment 53: The method of any one of embodiments 1 to 27, wherein the inhibitor of pololike kinase 4 (PLK4) is selected from a compound of Formula (II), or a pharmaceutically acceptable salt thereofFormula (II), wherein:Ring A isC6-10 aryl or heteroaryl; each R1is independently deuterium, halogen, -CN, oxo, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2R% -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -P(O)(Ra)2, - P(O)2(Ra)2, C1-6 alkyl,C1-6 haloalkyl, -OCi-Cehaloalkyl, Ci -Cedeuteroalkyl,C1-6 hydroxyalkyl,C1-6 aminoalkylC, 1-6 heteroalkyl, C2-Cealkenyl, C2-Cealkynyl, C6-10 cycloalkyl, heterocycloalkyl, C6-10 aryl, or heteroaryl; wherein each of the C1-6 alkyl, C2-Cealkenyl, C2-Cealkynyl, C3- C10cycloalkyl, heterocycloalkylC, 6-10 aryl, and heteroaryl is optionally and independently substituted with one or more Rla; or two R1on adjacent atoms are taken together to form a C3-10 cycloalkyl or heterocycloalkyl; each optionally substituted with one or more Rlb; each Rlais independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-6 alkyl,C1-6 haloalkyl, Ci -Cedeuteroalkyl, C1-6 hydroxyalkylC, 1-6 aminoalkylC, 1-6 heteroalkyl, C2- Cealkenyl, C2-Cealkynyl, C6-10 cycloalkyl, heterocycloalkylC, 6-10 aryl, or heteroaryl; or two Rlaon the same atom are taken together to form an oxo;each Rlbis independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, C1-6 haloalkyl, Ci -Cedeuteroalkyl, hydrCox1-y6alkyl, aminoalkyCl1,-6 heteroalkyl, C2C-1-6 Cealkenyl, C2-Cealkynyl, C6-10 cycloalkyl, heterocycloalkyl, aryl, or heteCr6o-a10ryl; or two Rlbon the same atom are taken together to form an oxo; n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;R2is hydrogen, Ca1-l6kyl, haCl1o-a6lkyl, or Ci -Cedeuteroalkyl;R3is hydrogen, Ca1-l6kyl, haCl1o-a6lkyl, or Ci -Cedeuteroalkyl; each of R4a, R4b, and R4cis independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, alkyCl,1-6 haloalkCy1l-,6 Ci -Cedeuteroalkyl, C1-6 hydroxyalkyl, Ca1m-6inoalkyl, or heterCo1a-6lkyl;R5is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, alkyl, Ch1a-l6oalkyl, C1-6 Ci -Cedeuteroalkyl, Chy1-d6roxyalkyl, aminoCa1l-k6yl, or heteroalkylC;1-6 each R6is independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, alkyl, C1-6C1-6 haloalkyl, Ci -Cedeuteroalkyl, hydrCox1-y6alkyl, aminoalkyCl1,-6 or heteroalkyl; C1-6R7is hydrogen, Ca1l-k6yl, haClo1a-6lkyl, Ci -Cedeuteroalkyl, hydroxyalkyl, oCr1-6 aminoalkyl; C1-6 each ofR8a, R8b, R8c, andR8dis independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, - OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2a, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-a6lkyl, hCal1o-6alkyl, Ci -Cedeuteroalkyl, hydroxyalkylC, 1-6 aminoalkyl, C1-6C1-6 heteroalkyl, C2-Cealkenyl, C2-Cealkynyl, C6-10 cycloalkyl, heterocycloalkyl, aryl, or C6-10 heteroaryl;R9is heteroaryl optionally substituted with one or more Rlaor oxetanyl substituted with one or more Rla; each Rais independently hydrogen, alkyl,C1-6 haloalkylC, C1-6i -Cedeuteroalkyl, hydroxyalkyl, C1-6C1-6 aminoalkyl, Ch1-e6teroalkyl, C2-Cealkenyl, C2-Cealkynyl, C6-10 cycloalkyl, heterocycloalkyl, C6-10 aryl, heteroaryl, alCky1-l6(C3-Ciocycloalkyl), alkyl(heteCro1c-6ycloalkyl), alkyl(Ce- C1-6 Cioaryl), or C1-6alkyl(heteroaryl); wherein each of the alkyl, C2-CeaClk1-e6nyl, C2-Cealkynyl, C3- Ciocycloalkyl, heterocycloalkyl, aryCl,6- a1n0d heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-6 alkyl, C1-6haloalkyl, Ci -Cedeuteroalkyl, hydroxCya1l-6kyl, aminoalkyl,C or1-6 C1-6 heteroalkyl; each Rbis independently hydrogen, alkyl, C1-6 haloalkyl,C C1i-6 -Cedeuteroalkyl, hydroxyalkyl, C1-6C1-6 aminoalkyl, Ch1-e6teroalkyl, C2-Cealkenyl, C2-Cealkynyl, C6-10 cycloalkyl, heterocycloalkyl, C6-10 aryl, heteroaryl, alCky1-l6(C3-Ciocycloalkyl), alkyl(heteCro1c-6ycloalkyl), alkyl(Ce- C1-6 Cioaryl), or C1-6alkyl(heteroaryl); wherein each of the alkyl, C2-CeaClk1-e6nyl, C2-Cealkynyl, C3- Ciocycloalkyl, heterocycloalkyl, aryCl,6- a1n0d heteroaryl is independently optionally substitutedwith one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-6 alkyl, C1-6haloalkyl, Ci -Cedeuteroalkyl, hydroxCya1l-6kyl, aminoalkyl, C or1-6 C1-6 heteroalkyl; and each Rcand Rdare independently hydrogen, alkyl, C1-h6aloalkyl, CCi -1C-6edeuteroalkyl, C1-6 hydroxyalkyl, Ca1-l6koxy, amCin1-o6alkyl, alkylamCi1n-o6 , heteroalkyl,C C12-6- Cealkenyl, C2-Cealkynyl, C6-10 cycloalkyl, heterocycloalkyl, aryl, heteroarCyl6,-1 C0 i-Cealkyl(C3- Ciocycloalkyl), Ci-C6alkyl(heterocycloalkyl), alkyl(CCe1--6Cioaryl), or Ci-C6alkyl(heteroaryl); wherein each of the aClk1y-6l, C2-Cealkenyl, C2-Cealkynyl, C6-10 cycloalkyl, heterocycloalkyl, Ce- Cioaryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, - S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, alkyl, C1-6C1-6 haloalkyl, Ci -Cedeuteroalkyl, hydrCox1-y6alkyl, aminoalkyCl1,-6 or heteroalkyl; C1-6 or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, - S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, - C(=O)OH, -C(=O)OCH3, Ca1l-k6yl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-C6hydroxyalkyl, C1-6 aminoalkyl, or Ch1e-6teroalkyl; provided the compound of Formula (II) is not

[0243] Embodiment 54: The method of any one of embodiments 1 to 27, wherein the inhibitor of pololike kinase 4 (PLK4) is selected from a compound disclosed in paragraph

[0111] , or a pharmaceutically acceptable salt thereof.

[0244] Embodiment 55: The method of any one of embodiments 1 to 27, wherein the inhibitor of pololike kinase 4 (PLK4) is ocifisertib ((lR,2S)-2-[3-[(lE)-2-[4-[[(2R,6S)-2,6-dimethyl-4- morpholinyl]methyl]phenyl]ethenyl]-lH-indazol-6-yl]-5'-methoxy-spiro[cyclopropane-l,3'-[3H]indol]- 2'(l'H)-one), or a pharmaceutically acceptable salt thereof.

[0245] Embodiment 56: The method of any one of embodiments 1 to 27, wherein the inhibitor of pololike kinase 4 (PLK4) is selected from a compound of formula (III):or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, 3, or 4; m is 0, 1, or 2;L is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl, or optionally substituted C3-8 cycloalkyl, wherein L is further optionally substituted by n occurrences of R3;Rlais hydrogen, halogen, optionally substituted Ct-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2--. alkynyl, optionally substituted C3-8 cycloalkyl, or nitrile;Ribis hydrogen; orRlaand R!b, together with the atoms to which they are attached, are a 3-5-membered cycloal ky I, cycloalkylene, cycloalkylyne, heterocycloalkyl, aryl, or heteroaryl;A is O or S, and R2Aand R2Bare both absent; or A is N, R2Ais absent, and R2Bis hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl Ci-s alkyl, or optionally substituted C1-6 alkylsulfonyl, or R2Band L, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl or optionally substituted C2- 9 heteroaryl; or A is C, and each of R2Aand R2Bare independently hydrogen, optionally substitutedC1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C6-10 aryl Cl-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or optionally substitutedC1-6 alkyl sulfonyl; each R3is independently halogen, cyano, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionallysubstituted C1-9 heteroaryl, optionally substituted Cj -9 heteroaryl C1-6 alkyl, -S(O)mR3A, -N(R3B)2, or - OR3B;R3Ais optionally substituted C1-6 alkyl, optionally substituted Ci-s heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, - OR3Bor -N(R3B)2Each R3Bis independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl Ci- 6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or optionally substituted C1-6 alkylsulfonyl; or two R3Bgroups, together with the atom to which both are attached, combine to form an optionally substituted C2-9 heterocyclyl;X is N, and R4is absent; or X is C, and R4is hydrogen, halogen, cyano, optionally substituted amino, optionally substituted acyl, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, or optionally substituted C1-9 heteroaryl;R5is optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, -C0NH2, or -Z-R5A;Z is optionally substituted amino, optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, optionally substituted C6-10 arylene, or optionally substituted C3-8 cycloalkylene;R5Ais hydrogen, halogen, cyano, optionally substituted C1-6 alkyl sulfonyl, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, or optionally substituted C1-9 heteroaryl;R6is hydrogen, halogen, cyano, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or -OR6A; andR6Ais hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, or optionally substituted C3-8 cycloalkyl.

[0246] Embodiment 57: The method of any one of embodiments 1 to 27, wherein the inhibitor of polo- like kinase 4 (PLK4) is selected from any one of compounds 1 to 365 disclosed in paragraph

[0114] , or a pharmaceutically acceptable salt thereof.Example No. 1: Inhibition of PLK4 in palbociclib-resistant MCF7 cells by Compound 11

[0247] Palbociclib resistant cells were generated by dose gradual escalation beginning at 25nM palbociclib, and increased by 50% every 2-3 weeks until cell proliferation was sustained in >lpMpalbociclib (hereafter referred to as PalboR). Analysis of basal protein levels by western blot demonstrated amplification of Cyclin El in PalboR cells relative to parental lines (Figure 1). Cellular potency of MCF7 and PalboR cells was assessed by CellTiter-Glo 2.0 cell viability assay, after incubation with Compound 11 for 9 days. IC50s were calculated and plotted in GraphPad Prism (Figure 2).Example No. 2: Tumor growth inhibition study using Compound 11 in mice implanted with a palbociclib-resistant tumor.

[0248] Female Athymic Nude, Outbred Homozygous (Crl:NU(NCr)-Foxnlnu), Strain #490 mice were utilized from Charles River Laboratories. Mice were approximately 6-12 weeks of age, weighing an approximate minimum of 20 grams on Day 0, and were acclimated for a minimum of 24 hours. Mice were housed on irradiated corncob bedding (Teklad) in individual HEPA ventilated cages (Sealsafe® Plus, Techniplast USA) on a 12-hour light-dark cycle at 70-74°F (21-23°C) and 40-60% humidity. Animals were fed water ad libitum (reverse osmosis, 2 ppm C12) and an irradiated standard rodent diet (Teklad 2919) consisting of 19% protein, 9% fat, and 4% fiber. Animals were housed in individually ventilated cages under specific pathogen free (SPF) environment of a vivarium facility.

[0249] STI 799 is a patient-derived xenograft model that was established from an axillary lymph node FNA taken from a 66-year-old female pretreated with prior fulvestrant, erubilin, vinorelbine and doxorubicin / cyclophosphamide treatments. It was established from viable human tumor tissue and then serially passaged in mice a limited number of times to maintain tumor heterogeneity. The STI 799 model was challenged with chronic palbociclib treatment to produce drug resistance, defined as evidence of tumor growth rate similar to that of the parental model, and a new model was generated, ST1799 / PBR, used for this study. Pre-study tumor volumes were recorded for each experiment beginning approximately one week prior to its estimated start date. When tumors reached the appropriate Tumor Volume Initiation (TVI) range (150-300 mm3), mice were randomly divided into tumor-size equivalent groups for treatment with 10 mice in each group for treatment.

[0250] The treatment start day was denoted as treatment day 0. Mice were dosed by daily (QD) oral administration of vehicle solutions, Compound 11 at 250 mg / kg QD and Compound 11 at 150 mg / kg QD for 52 days. The dosing volume was 10 mL / kg for each formulation based on the most recent body weight. Vehicle group was dosed using 10% D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS), 1% polyvinyl alcohol (PVA). Compound 11 was formulated using 10% TPGS, 1% PVA at 250 mg / kg and 150 mg / kg and each was prepared once every 7 days. Compound 11 solids and formulated stocks, along with vehicles were stored 4°C throughout the 52-day administration in mice.

[0251] Subcutaneous tumor volumes were measured twice a week by caliper with the following formula: Tumor volume (TV) = (length x width2) / 2. Mouse body weights were measured daily for the first 5 days and then twice a week with a weighing scale. Conditions of animal health and clinical signs of side effects were monitored by daily observation of gross morphology and necropsy of euthanized animals at study endpoint. The study was terminated following 52 days of treatment. All procedures related to animal handling, care, and treatment in this study were performed according to the protocolsand guidelines approved by the Institutional Animal Care and Use Committee (IACUC) at XenoSTART. Animal facility and program are operated by the standard of Guide for the Care and Use of Uaboratory Animals (Eighth Edition, National Research Council 2011) and accredited by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). Specifically, all portions of this study performed at XenoSTART adhered to the study protocols reviewed and approved by IACUC and applicable standard operating procedures (SOPs).

[0252] As shown in FIG. 3, 52-day daily repeated oral administration of Compound 11 at 250 mg / kg and 150mg / kg exhibited robust tumor growth inhibition of 64% and 48% respectively when compared to the vehicle control. As shown in FIG. 4, 52-day daily repeated oral administration of Compound 11 was well tolerated, resulting in an average maximal body weight loss (BWL) of 3.6% for the vehicle group, 16.4% for the Compound 11 at 250 mg / kg group and 10.2% for the Compound 11 at 150 mg / kg group. As shown in FIG. 5, 52-day daily repeated oral administration of Compound 11 resulted in a statistically significant decrease in end of study tumor volumes for both the 250 mg / kg group (p=0.0003) and the 150 mg / kg group (p=0.0052) when compared to vehicle control.I l l

Claims

CLAIMSWhat is claimed is:

1. A method of treating cancer in a subject, comprising administering to the subject an inhibitor of polo-like kinase 4 (PLK4), wherein the cancer in the subject has been determined to be resistant to at least one cyclin-dependent kinase inhibitor prior to administration to the subject of the inhibitor of polo-like kinase 4 (PLK4).

2. The method of claim 1, wherein the cancer in the subject has been further determined to exhibit an overexpression of the gene that encodes the tripartite motif -containing protein 37 (TRIM37) prior to administration to the subject of the inhibitor of polo-like kinase 4 (PLK4).

3. The method of claim 1, wherein the cancer in the subject has been further determined to exhibit an amplification of the gene that encodes the tripartite motif -containing protein 37 (TRIM37) prior to administration to the subject of the inhibitor of polo-like kinase 4 (PLK4).

4. The method of any one of claims 1 to 3, wherein the cancer in the subject is selected from chordoma, small-cell lung cancer, large cell neuroendocrine lung carcinoma, extrapulmonary small cell carcinoma, glioblastoma, glioma, head and neck cancer, esophagus squamous cell carcinoma, oligodendroglioma, oligoastrocytoma, prostate cancer, colorectal cancer, endometrial cancer, melanoma, breast cancer, neuroblastoma, non-squamous cell lung carcinoma, bladder cancer, and liver cancer.

5. The method of claim 4, wherein the cancer in the subject is breast cancer.

6. The method of claim 5, wherein the breast cancer in the subject is selected from (a) hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)- positive breast cancer (b) hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer; (c) hormone receptor (E1R) -positive breast cancer, (d) hormone receptor (E1R) -negative breast cancer, (e) HER2 -positive breast cancer, (f) human epidermal growth factor receptor 2 (HER2) -negative advanced or metastatic breast cancer, (g) human epidermal growth factor receptor 2 (HER2)- negative, node-positive, early breast cancer at high risk of recurrence, (h) hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy; (i) hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting; (j) hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine-based therapy; (k) fulvestrant as initial endocrine-based therapy or following disease progression on endocrine therapy in postmenopausal women or in men; (1) HER2-low breast cancer, (m) triple-negative breast cancer, (n) BRCA1 -mutated breast cancer, and (o) BRCA2 -mutated breast cancer.

7. The method of any one of claims 1 to 6, wherein the cyclin-dependent kinase inhibitor is selected from an inhibitor of one or more of cyclin-dependent kinase 2 (CDK2), cyclin- dependent kinase 4 (CDK4), and cyclin-dependent kinase 6 (CDK6).

8. The method of any one of claims 1 to 7, wherein the cyclin-dependent kinase inhibitor is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, dinaciclib, PF-07104091, BLU-222, and PF-07220060.

9. The method of any one of claims 1 to 8, wherein the subject is administered one or more additional therapeutic agents, and wherein the one or more additional therapeutic agents is selected from: (a) an aromatase inhibitor: (b) fulvestrant; and (c) luteinizing hormone- releasing hormone (LHRH) agonists.

10. The method of any one of claims 1 to 9, wherein the inhibitor of polo-like kinase 4(PLK4) is selected from the group consisting of:

11. The method of any one of claims 1 to 9, wherein the inhibitor of polo-like kinase 4 (PLK4) is ocifisertib ((lR,2S)-2-[3-[(lE)-2-[4-[[(2R,6S)-2,6-dimethyl-4- morpholinyl]methyl]phenyl]ethenyl]-lH-indazol-6-yl]-5'-methoxy-spiro[cyclopropane- l,3'-[3H]indol]-2'(TH)-one), or a pharmaceutically acceptable salt thereof.

12. The method of any one of claims 1 to 9, wherein the inhibitor of polo-like kinase 4 (PLK4) is selected from a compound of formula (III):or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, 3, or 4;m is 0, 1, or 2;L is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl, or optionally substituted C3-8 cycloalkyl, wherein L is further optionally substituted by n occurrences of R3;Riais hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or nitrile;Ri&is hydrogen; orR!aand R!b, together with the atoms to which they are attached, are a 3-5-membered cycloalkyl, cycloalkylene, cycloalkylyne, heterocycloalkyl, aryl, or heteroaryl;A is O or S, and R2Aand R2Bare both absent; or A is N, R2Ais absent, and R2Bis hydrogen, optionally substitutedC1-6 alkyl, optionally substitutedC1-6 heteroalkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or optionally substituted Cj-e alkylsulfonyl, or R2Band L, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl or optionally substituted C2- 9 heteroaryl; or A is C, and each of R2Aand R2Bare independently hydrogen, optionally substitutedC1-6 alkyl, optionally substituted Ci-s heteroalkyl, optionally substituted C6-10 aryl Cl -6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or optionally substituted C1-6 alkyl sulfonyl; each R3is independently halogen, cyano, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1.9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, -S(0)mR3A, -N(R3B)2, or - OR3B;R3Ais optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C 1-9 heteroaryl, - OR3Bor -N(R3B)2Each R3Bis independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl Ci- e alkyl, optionally substituted C3-8 cy cloalkyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or optionally substituted C1-6 alkylsulfonyl; or two R3Bgroups, together with the atom to which both are attached, combine to form an optionally substituted C2-9 heterocyclyl;X is N, and R4is absent; or X is C, and R4is hydrogen, halogen, cyano, optionally substituted amino, optionally substituted acyl, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl.optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, or optionally substituted C1-9 heteroaryl;R5is optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, -C0NH2, or -Z-R5A;Z is optionally substituted amino, optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, optionally substituted C6-10 arylene, or optionally substituted C3-8 cycloalkylene;R5Ais hydrogen, halogen, cyano, optionally substituted C1-6 alkyl sulfonyl, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, or optionally substituted C1-9 heteroaryl;R6is hydrogen, halogen, cyano, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or -OR6A; andR6Ais hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, or optionally substituted C3-8 cycloalkyl.

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