Polo-like kinase 4 inhibitor

Abstract

Disclosed herein is a compound of formula (I), or a pharma- ceutically acceptable salt thereof, which is an inhibitor of polo-like kinase 4 (PLK4). Also disclosed herein is a pharmaceutical composition comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients. Also disclosed herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject an amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof. [Formula 1] JPEG2024521657000750.jpg4884

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 187,049, filed May 11, 2021; U.S. Provisional Patent Application No. 63 / 249,809, filed September 29, 2021; U.S. Provisional Patent Application No. 63 / 317,174, filed March 7, 2022; and U.S. Provisional Patent Application No. 63 / 337,445, filed May 2, 2022, which are hereby incorporated by reference in their entirety.

Background Art

[0002] Polo - like kinases (PLKs) are a family of serine / threonine kinases that play important roles in cell cycle regulation and cellular responses under stress. Mammalian cells express five PLK family members (PLK1 - 5). All PLKs share a similar structure with an N - terminal kinase catalytic domain and a C - terminal polo box domain (PBD) (Archambault et al., 2015). Polo - like kinase 4 (PLK4), also known as SAK, is a regulator of centrosome duplication (Habedanck et al., 2005; Kleylein - Sohn et al., 2007). In proliferating tissues, PLK4 is expressed as a low - abundance enzyme under normal conditions and is required for centrosome biogenesis through phosphorylation and interaction with centrosomal proteins (Habedanck et al., 2005; Maniswami et al., 2018). Overexpression of PLK4 leads to centrosome amplification, and further genomic instability and tumorigenesis (Holland et al., 2010). Aberrant PLK4 expression has been reported to be associated with several cancers commonly seen in humans (Marina and Saavedra 2014; Shinmura et al., 2014). Therefore, strong evidence supports the important role of PLK4 in carcinogenesis and therapeutic inventions. Thus, there is a need for compounds that inhibit PLK4 in a subject having cancer for treating such cancers.

Summary of the Invention

[0003] This specification discloses a compound of formula (I):

[0004]

Chemical Formula

[0005] In some embodiments of the compound of formula (I), ring A is C6-C 10 aryl or heteroaryl.

[0006] In some embodiments of the compound of formula (I), ring A is C6-C 10 aryl.

[0007] In some embodiments of the compound of formula (I), ring A is heteroaryl.

[0008] In some embodiments of the compound of formula (I), ring A is furanyl, pyrrolyl, thiophenyl, oxazolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl.

[0009] In some embodiments of the compound of formula (I), R 1 is each independently halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, -OC1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, or heteroaryl, and each of C1-C6 alkyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, and heteroaryl is optionally and independently substituted with one or more R 1a .

[0010] In some embodiments of the compound of formula (I), n is 1, 2, or 3.

[0011] In some embodiments of the compound of formula (I), R 2 is hydrogen.

[0012] In some embodiments of the compound of formula (I), R 3 is hydrogen.

[0013] In some embodiments of the compound of formula (I), R 4a , R 4b , and R 4c are hydrogen.

[0014] In some embodiments of the compound of formula (I), R 5 is hydrogen.

[0015] In some embodiments of the compound of formula (I), R 6 are each hydrogen.

[0016] In some embodiments of the compound of formula (I), R 7 is hydrogen or C1-C6 alkyl.

[0017] In some embodiments of the compound of formula (I), R 8a , R 8b , and R 8d are each hydrogen, and R 8c is hydrogen, halogen, or -OR a .

[0018] In some embodiments of the compound of formula (I), R 8c is halogen or -OR a .

[0019] In some embodiments of the compound of formula (I), R 8c is -OR a .

[0020] In some embodiments of the compound of formula (I), R a is C1-C6 alkyl.

[0021] In some embodiments of the compound of formula (I), R a is -CH3.

[0022] Also disclosed herein are pharmaceutical compositions comprising a disclosed amount of a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and one or more pharmaceutically acceptable excipients.

[0023] Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0024] Incorporation by reference All publications, patents, and patent applications mentioned herein are hereby 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.

Best Mode for Carrying Out the Invention

[0025] As used herein and in the appended claims, the following terms have the meanings set forth below unless the contrary meaning is expressly stated.

[0026] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include the plural unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, reference to "the cell" includes reference to one or more cells (or cell populations), and their equivalents known to those skilled in the art. When ranges are used herein with respect to physical properties such as molecular weight or chemical properties such as chemical formula, all combinations and sub-combinations of the range and specific embodiments therein are intended to be included. The term "about", when referring to a number or a range of numbers, means that the recited number or range of numbers is an approximation within the experimental variability (or within the statistical experimental error), and thus in some instances may vary between 1% and 15% of the recited number or range. The term "comprising" (and related terms such as "comprise", "comprises", "having", or "including") is intended not to exclude, in other specific embodiments, embodiments such as any substance composition, composition, method, or process described herein from consisting of or consisting essentially of the recited features.

[0027] "Administering" means, when used with a therapeutic agent, directly administering the therapeutic agent systemically or locally into or onto a target tissue, or administering the therapeutic agent to a subject in which the tissue targeted by the therapeutic agent is positively affected. Thus, as used herein, the term "administering", when used with a composition disclosed herein, includes, but is not limited to, providing the composition into or onto a target tissue, e.g., systemically providing the composition to a subject by oral administration such that the therapeutic agent reaches the target tissue or tissue. "Administering" a composition may be accomplished by injection, topical administration, and oral administration, or by other means alone or in combination with other known techniques.

[0028] The term "C2-C6 alkenyl", as used herein, means an alkyl moiety containing from 2 to 6 carbon atoms having at least one carbon-carbon double bond. The carbon-carbon double bond in such a group may be located anywhere along the 2 to 6 carbon atom chain, thereby stabilizing the compound. Examples of such groups include, but are not limited to, ethenyl, propenyl, butenyl, allyl, and pentenyl. Alkenyl may be in either the cis or trans configuration about the double bond and is understood to include both isomers. Examples of alkenyl include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, and the like. Numerical ranges such as "C2-C6 alkenyl", when they appear herein, always mean that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but this definition also encompasses the occurrence of the term "alkenyl" without a specified numerical range. In some embodiments, alkenyl is C2-C 10It is alkenyl, C2-C9 alkenyl, C2-C8 alkenyl, C2-C7 alkenyl, C2-C6 alkenyl, C2-C5 alkenyl, C2-C4 alkenyl, C2-C3 alkenyl, or C2 alkenyl.

[0029] As used herein, the term "C1-C6 alkyl" refers to a straight-chain or branched hydrocarbon monoradical having from 1 to about 10 carbon atoms, or from 1 to 6 carbon atoms, which may be fully saturated or may be unsaturated. Examples of saturated hydrocarbon monoradicals include methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups such as heptyl and octyl, but are not limited thereto. Numerical ranges such as "C1-C6 alkyl" always mean, when they appear herein, that the alkyl group consists of 1, 2, 3, 4, 5, or 6 carbon atoms, but this definition also encompasses the appearance of the term "alkyl" when no numerical range is specified.

[0030] As used herein, the term "C2-C6 alkynyl" means an alkyl moiety containing 2 to 6 carbon atoms having at least one carbon-carbon triple bond. The carbon-carbon triple bond in such a group may be present anywhere along the 2 to 6 carbon atom chain, thereby stabilizing the 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, etc. Numerical ranges such as "C2-C6 alkynyl", when they appear herein, always mean that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but this definition also encompasses the occurrence of the term "alkynyl" when no numerical range is specified.

[0031] 「C6-C 10 As used herein, the term "C6-C aryl" refers to a radical derived from a hydrocarbon ring system containing 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 and may include fused (when fused to 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, preiadene, pyrene, and triphenylene. In some embodiments, the aryl is phenyl.

[0032] As used herein, the term "C1-C6 aminoalkyl" refers to a radical of C1-C6 alkyl as defined above, substituted with one or more amino groups. The amino groups within such C1-C6 aminoalkyl groups may be unsubstituted, monosubstituted, or disubstituted. Examples of C1-C6 aminoalkyl groups include, but are not limited to, -CH2NH2, -CH2N(H)CH3, -CH2N(CH3)2, and the like.

[0033] 「C3-C 10 As used herein, the term "C3-C cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring containing 3 to 10 carbon atoms, which may include fused (when fused to an aryl or heteroaryl ring, the cycloalkyl is attached via a non-aromatic ring atom) or bridged ring systems. Representative cycloalkyls are listed. In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl. Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Examples of partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0034] As used herein, the term "C1-C6 dideuteroalkyl" means a C1-C6 alkyl group as defined herein, wherein one or more hydrogen atoms within the C1-C6 alkyl group are replaced by deuterium atoms.

[0035] As used herein, the term "C1-C6 haloalkyl" refers to a radical of C1-C6 alkyl as defined above, substituted with one or more of the above-defined halogen radicals such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0036] As used herein, the term "C1-C6 hydroxyalkyl" refers to a radical of C1-C6 alkyl as defined above, substituted with one or more hydroxy groups.

[0037] As used herein, the term "animal" includes, but is not limited to, humans and non-human vertebrates such as wild animals, livestock, and farm animals. As used herein, the terms "subject", "subject", and "individual" are intended to include organisms in which the specific diseases described herein can occur. Examples include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats, and genetically engineered species. In a preferred embodiment, the subject is a primate. In a specific embodiment, the primate or subject is a human. In a specific example, the subject is an adult. In a specific example, the human is a child. In a further example, the human is under 12 years old. In a specific example, the human is an elderly person. In another example, the human is 60 years 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, for example, a transgenic mouse having a hypertensive condition.

[0038] As used herein, the term "Aurora kinase A" or "AurA" means a human protein that is known to those skilled in the art as Aurora kinase A and is encoded by the AURKA gene.

[0039] The term "Aurora kinase B" or "AurB", as used herein, means a human protein that is known to those of skill in the art as Aurora kinase B and is encoded by the AURKB gene.

[0040] The "cyano" group represents a -CN group.

[0041] The term "halo" or "halogen", as used herein, refers to bromo, chloro, fluoro, or iodo. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the halogen is fluoro.

[0042] As used herein, the term "heterocycloalkyl" refers to a 3- to 24-membered partially or fully saturated ring radical containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from boron, nitrogen, oxygen, phosphorus, and sulfur. Unless otherwise specifically defined herein, a heterocycloalkyl radical may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, and may include fused (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached via a non-aromatic ring atom) or bridged ring systems. The nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may optionally be oxidized, and the nitrogen atoms may optionally be 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, octahydroindolyl, octahydroisoindolyl, 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-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides.When referring to the number of carbon atoms in a heterocycloalkyl, it is understood that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl, i.e., the skeletal atoms of the heterocycloalkyl ring.

[0043] As used herein, the term "C1-C6 heteroalkyl" means an alkyl group in which one or more of the skeletal atoms of the alkyl are atoms other than carbon, such as boron, oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl in which the heteroalkyl is composed of 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof, and is attached to the remainder of the molecule at a carbon atom of the heteroalkyl.

[0044] As used herein, the term "heteroaryl" refers to a 5- to 14-membered ring system radical containing a hydrogen atom, 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from boron, nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. The heteroaryl radical may be monocyclic, bicyclic, tricyclic, or tetracyclic, and may include fused (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl is attached through an aromatic ring atom) or bridged ring systems. The nitrogen, carbon, or sulfur atoms within the heteroaryl may optionally be oxidized, and the nitrogen atoms may optionally be quaternized. 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, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4 - benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl, benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2 - a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2 - oxoazepinyl, oxazolyl, oxiranyl, 1 - oxidopyridinyl, 1 - oxidopyrimidinyl, 1 - oxidopyrazinyl, 1 - oxidopyridazinyl, 1 - phenyl - 1H - pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl).

[0045] As used herein, "pharmaceutically acceptable" means that the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not be harmful to the recipient.

[0046] The term "pharmaceutical composition" means a composition containing at least one active ingredient, whereby the composition is suitable for investigation of a particular effective outcome in mammals (e.g., but not limited to, humans). One of ordinary skill in the art will understand and recognize appropriate techniques for determining whether an active ingredient has the desired effective outcome based on the needs of one of ordinary skill in the art.

[0047] The term "pharmaceutically acceptable salt", as used herein, means a salt of a compound of the invention that retains the biological effectiveness of the free acid and free base of the particular derivative and is not inappropriate in a biological or other respect.

[0048] The term "PLK4", as used herein, means a human protein that is known to one of ordinary skill in the art as polo-like kinase 4 and is encoded by the PLK4 gene.

[0049] The term "oxo", as used herein, refers to a carbonyl moiety such that an alkyl substituted with oxo refers to a ketone group.

[0050] The term "solvate", as used herein, means a molecular complex between a compound of the invention and a solvent molecule. Examples of solvates include, but are not limited to, compounds of the invention combined with water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. When the aforementioned solvent is water, the term "hydrate" can be used. In the present invention, it is specifically contemplated that one solvent molecule can be associated with one molecule of a compound of the invention, such as a hydrate. Furthermore, in the present invention, it is specifically contemplated that more than one solvent molecule can be associated with one molecule of a compound of the invention, such as a dihydrate. In addition, in the present invention, it is specifically contemplated that less than one solvent molecule can be associated with one molecule of a compound of the invention, such as a hemihydrate. Furthermore, the solvates of the present invention are contemplated as solvates of the compound that retain the biological effectiveness of the anhydrous form of the compound of the invention.

[0051] When the compounds of the present invention contain an alkenyl group, geometric cis / trans (or Z / E) isomers are possible. When the compound contains, for example, a keto or oxime group, or an aromatic moiety, tautomeric isomerism ("tautomerism") may occur. Examples of tautomerism include keto and enol tautomers. A single compound may exhibit more than one type of isomerism. Within the scope of the present invention, all stereoisomers, geometric isomers, and tautomeric forms of the compounds of the present invention, including compounds exhibiting more than one type of isomerism, as well as mixtures of one or more of them, are included. Cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, such as chromatography, fractional crystallization.

[0052] The term "stereoisomer" refers to compounds that have the same chemical structure but differ in the arrangement of atoms or groups in space. Specifically, the term "enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other. The term "racemate" or "racemic mixture" as used herein refers 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 may be described as "enantioisomerically enriched". On the other hand, the term "diastereomer" refers to the relationship between a pair of stereoisomers that contain two or more chiral centers but are not mirror images of each other. Conventional names in the art may be used to describe the stereoisomers of a compound, or the stereochemistry of a particular chiral carbon atom, the compounds disclosed herein, or mixtures thereof. For example, a single racemate or stereocenter of a compound may be described as having the configuration of (+), (-), (R), or (S). A mixture of racemates may be described by the use of the (±) symbol.

[0053] The compounds of the present invention may have asymmetric carbon atoms. The carbon-carbon bonds of the compounds of the present invention may be represented herein using solid lines (_), solid wedges (_), or dashed wedges (.....). The use of a solid line to represent a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) at that carbon atom are included. The use of a solid or dashed wedge to represent a bond to an asymmetric carbon atom is intended to indicate that only the indicated stereoisomer is included. It is possible for the compounds of the present invention to contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to represent a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers are included. For example, unless otherwise specified, the compounds of the present invention are intended to be present as enantiomers and diastereomers, or as racemates and mixtures thereof. The use of a solid line to represent a bond to one or more asymmetric carbon atoms within a compound of the present invention, and the use of a solid or dashed wedge to represent a bond to other asymmetric carbon atoms within the same compound, is intended to indicate the presence of a mixture of diastereomers.

[0054] As conventional techniques for the preparation / isolation of individual enantiomers, for example, chiral synthesis from a suitable and optically pure precursor using chiral high performance liquid chromatography (HPLC), or resolution of a racemate can be mentioned. Alternatively, the racemate (or racemic precursor) may be reacted with a suitable optically active compound, such as an alcohol, or, if the compound contains an acidic or basic moiety, an acid or a base such as tartaric acid or 1-phenylethylamine. The resulting mixture of diastereomers may be separated by chromatography and / or fractional crystallization, and one or both of the diastereomers are converted to the corresponding pure enantiomers by means well known to those skilled in the art. The chiral compounds (and their chiral precursors) of the present invention may be obtained in enantiomerically enriched form using chromatography on a chiral resin, typically HPLC, and the mobile phase consists of a hydrocarbon, typically heptane or hexane, containing 0 to 50%, typically 2 to 20% isopropanol, and 0 to 5% alkylamine, typically 0.1% diethylamine. By concentrating the eluate, an enriched mixture is obtained. The stereoisomeric aggregates can be separated by conventional techniques known to those skilled in the art. See, for example, "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New York, 1994), which is incorporated herein by reference in its entirety.

[0055] As used herein, the term "substituted" means that the specified group or moiety has one or more substituents. The term "unsubstituted" means that the specified group has no substituents. The term "optionally substituted" means that the specified group is either unsubstituted or substituted with one or more substituents. In the compounds of the present invention, when a group is said to be "unsubstituted" or "substituted" with fewer groups than would satisfy the valencies of all the atoms in the compound, it is to be understood that the remaining valencies on such group are satisfied by hydrogen. For example, when a C6 aryl group referred to herein as "phenyl" is substituted with one additional substituent, one of ordinary skill in the art would understand that such group leaves four open positions on the carbon atoms of the C6 aryl group (of the six initial positions, the position to which the remainder of the compound of the present invention is attached and the additional substituent is subtracted, leaving four). In such a case, each of the remaining four carbon atoms is bonded to one hydrogen atom to satisfy its valency. Similarly, when a C6 aryl group within a compound of the present invention is said to be "disubstituted", one of ordinary skill in the art would understand that it is intended to have three carbon atoms remaining on the C6 aryl group that are unsubstituted. Each of those three unsubstituted carbon atoms is bonded to one hydrogen atom to satisfy its valency.

[0056] In accordance with conventions used in the art, the symbol

[0057]

Chem.

[0058]

Chem.

[0059]

Chem.

[0060]

Chem.

[0061] Unless otherwise specified, a group, such as (R 1 ) n when represented as the "floating" ring A in the formula:

[0062]

Chem.

[0063] When the group "R" is represented as "floating" on the ring system A as shown above, and the ring A contains saturated carbon, "n" can be greater than 1, and it is assumed that each hydrogen that is currently represented, indicated, or clearly defined replaces a hydrogen of the ring A. Unless otherwise specified, if the resulting structure is stable, two R 1 groups can remain on the same carbon. For example, when R 1 is a methyl group, there may be geminal dimethyl on the carbon of the ring A. In another example, two R 1The base can form a spirocyclic ring (a "spirocyclic group") by forming a ring. In the compounds of formulas (I), (Ia), (Ib), (II), and (III), it should be understood that when n is less than the number of substitutable atoms on ring A, the other substitutable positions on ring A are bonded to hydrogen atoms.

[0064] As used herein, the term "therapeutic" means an agent utilized to treat, counteract, alleviate, prevent, or improve an undesirable disease or disorder in a subject.

[0065] "Therapeutically effective amount" or "effective amount", as used herein, refers to the amount of an active compound or pharmaceutical that elicits a biological or medical response in a tissue, system, animal, individual, or human as sought by a researcher, veterinarian, physician, or other clinician, and such response includes one or more of (1) preventing a disease, e.g., preventing a disease, disorder, or affliction in an individual who may be susceptible to the disease, disorder, or affliction but who has not yet presented with the disease state or overall symptoms thereof, (2) inhibiting a disease, e.g., inhibiting a disease, disorder, or affliction in an individual who is presenting with or has presented with the disease state or overall symptoms thereof (i.e., preventing further progression of the disease state or overall symptoms), and (3) alleviating a disease, e.g., alleviating a disease, disorder, or affliction in an individual who is presenting with or has presented with the disease state or overall symptoms thereof (i.e., reversing the disease state or overall symptoms).

[0066] As used herein, the terms "treat," "treated," "treatment," or "treating" refer to both therapeutic treatment in some embodiments and prophylactic measures in other embodiments, with the goal of preventing or alleviating (reducing) an undesired physiological condition or achieving a beneficial or desired clinical outcome. For the purposes described herein, beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms, diminishment of the degree of a disease, disorder, or affliction, stabilization of a disease, disorder, or affliction state (i.e., preventing worsening), delay in onset or slowing of progression of a disease, disorder, or affliction, amelioration of a disease, disorder, or affliction state, and remission, improvement, or amelioration of a disease, disorder, or affliction, whether detectable or undetectable. Treatment includes inducing a clinically significant response without causing excessive levels of side effects. Treatment further includes extending survival longer than expected survival in the absence of treatment. Preventive benefits of treatment include prevention of a disease, delay in progression of a disease, stabilization of a disease, or reduction in the likelihood of a disease occurring. As used herein, the terms "treat," "is treated," "treatment," or "treating" include prophylaxis in some embodiments.

[0067] As used herein, the term "TRIM37" refers to a human protein known to those of skill in the art as tripartite motif-containing protein 37, which is an E3 ubiquitin ligase encoded by the TRIM37 gene.

[0068] The term "CFI-400495" means a compound having Chemical Abstract Service Registry Number 1338806-73-7 and the following structure. The preparation of this compound is described in PCT Application Publication WO2011 / 123946 and it is commercially available.

[0069]

Chemical Structure

[0070] PLK4 inhibitor compound This specification discloses a compound of formula (I):

[0071] [Chemical formula] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein in the formula,[[]] ring A is C6-C 10 aryl, heteroaryl, C3-C 10 cycloalkyl, or heterocycloalkyl, R 1 each independently is deuterium, halogen, -CN, oxo, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a [[ID=ID=40]], -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR a , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(O)(R a )2, -P(O)2(R a)2. C1-C6 alkyl, C1-C6 haloalkyl, -OC1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, or heteroaryl, and C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 each of aryl and heteroaryl is independently and optionally substituted with one or more R 1a or two R's on adjacent atoms combine to form a C3-C cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R 1 R 10 is independently deuterium, halogen, -CN, -NO2, -OH, -OR 1b -OC(=O)R R 1a -OC(=O)OR a -OC(=O)NR a R b -SH, -SR c -S(=O)R d -S(=O)2R a -S(=O)2NR a R a -NR c R d -NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR a -NR b S(=O)2R a -C(=O)R a -C(=O)OR b -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, or heteroaryl, and alternatively, two Rs on the same carbon atom 1a combine to form an oxo group, R 1b is independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR a , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, or heteroaryl, and alternatively, two Rs on the same atom 1b combine to form an oxo group, n is 0, 1, 2, 3, 4, 5, 6, 7, or 8, and R 2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl, R 3 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl, R 4a 、R 4b 、and R 4c each independently is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a 、-NR c R d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d 、C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, R 5 is hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, R 6 each independently is hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl, R 8a 、R8b , R 8c , and R 8d Each of them is independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR a , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, or heteroaryl, and R a is independently, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, heteroaryl, C1-C6 alkyl(C3-C 10 cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(C6-C10 aryl), or C1-C6 alkyl(heteroaryl), where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 Each of aryl and heteroaryl is independently and 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-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, R b are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, heteroaryl, C1-C6 alkyl(C3-C 10 cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(C6-C 10 aryl), or C1-C6 alkyl(heteroaryl), where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10Each of aryl and heteroaryl is independently and 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-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, heteroaryl, C1-C6 alkyl(C3-C 10 cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(C6-C 10 aryl), or C1-C6 alkyl(heteroaryl), where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 Each of aryl and heteroaryl is independently and 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-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, or Rc and R d forms, by being integrated with the atoms to which they are attached, an optionally substituted heterocycloalkyl group which is 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-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided.

[0072] This specification discloses a compound of formula (I):

[0073]

Chemical formula

[0074] In other embodiments, formula (Ia):

[0075]

Chemical formula

[0076] In other embodiments, formula (Ib):

[0077]

Chemical formula

[0078] Further provided herein are compounds of formula (I), formula (Ia), and formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is C6-C 10 aryl or heteroaryl. In some embodiments, ring A is C6-C 10Compounds of formula (I), formula (Ia), and formula (Ib) which are aryl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided. In some embodiments, compounds of formula (I), formula (Ia), and formula (Ib) wherein ring A is phenyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided. In some embodiments, compounds of formula (I), formula (Ia), and formula (Ib) wherein ring A is heteroaryl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided. In some embodiments, compounds of formula (I), formula (Ia), and formula (Ib) wherein ring A is furanyl, pyrrolyl, thiophenyl, oxazolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided. In some embodiments, compounds of formula (I), formula (Ia), and formula (Ib) wherein ring A is pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided. In some embodiments, compounds of formula (I), formula (Ia), and formula (Ib) wherein ring A is pyrazolyl, pyridinyl, pyrazinyl, or pyrimidinyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided. In some embodiments, compounds of formula (I), formula (Ia), and formula (Ib) wherein ring A is pyrazolyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided. In some embodiments, compounds of formula (I), formula (Ia), and formula (Ib) wherein ring A is 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, or 5-pyrazolyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided. In some embodiments, compounds of formula (I), formula (Ia), and formula (Ib) wherein ring A is 1-pyrazolyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided.In some embodiments, compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein ring A is 3-pyrazolyl. In some embodiments, compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein ring A is 4-pyrazolyl. In some embodiments, compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein ring A is 5-pyrazolyl. In some embodiments, compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein ring A is pyridinyl. In some embodiments, compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein ring A is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 5-pyridinyl, or 6-pyridinyl. In some embodiments, compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein ring A is 2-pyridinyl. In some embodiments, compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein ring A is 3-pyridinyl. In some embodiments, compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein ring A is 4-pyridinyl. In some embodiments, compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein ring A is 5-pyridinyl. In some embodiments, compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein ring A is 6-pyridinyl. In some embodiments, compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein ring A is pyrazinyl.In some embodiments, compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein ring A is 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, or 6-pyrazinyl. In some embodiments, compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein ring A is 2-pyrazinyl. In some embodiments, compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein ring A is 3-pyrazinyl. In some embodiments, compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein ring A is 5-pyrazinyl. In some embodiments, compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein ring A is 6-pyrazinyl. In some embodiments, compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein ring A is pyrimidinyl. In some embodiments, compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein ring A is 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl. In some embodiments, compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein ring A is 2-pyrimidinyl. In some embodiments, compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein ring A is 4-pyrimidinyl. In some embodiments, compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein ring A is 5-pyrimidinyl.In some embodiments, there are provided compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein ring A is 6-pyrimidinyl. In some embodiments, there are provided compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein ring A is pyridazinyl. In some embodiments, there are provided compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein ring A is 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, or 6-pyridazinyl. In some embodiments, there are provided compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein ring A is 3-pyranyl. In some embodiments, there are provided compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein ring A is 4-pyranyl. In some embodiments, there are provided compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein ring A is 5-pyranyl. In some embodiments, there are provided compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein ring A is 6-pyranyl. In some embodiments, ring A is C3-C. 10 There are provided compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein ring A is C3-C cycloalkyl or heterocycloalkyl. In some embodiments, ring A is C3-C 10 There are provided compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein ring A is cycloalkyl. There are provided compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein ring A is heterocycloalkyl.

[0079] Furthermore, this specification also discloses that R 1 is, independently of each other, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, -OC1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, or heteroaryl, and that each of C1-C6 alkyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, and heteroaryl is optionally and independently substituted with one or more R 1a . Compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided. In some embodiments, R 1 is, independently of each other, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, -OC1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C 10 cycloalkyl, or heterocycloalkyl, and that each of C1-C6 alkyl, C3-C 10 cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 1a . Compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided. In some embodiments, R 1 is, independently of each other, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, -OC1-C6 haloalkyl, C3-C 10 cycloalkyl, or heterocycloalkyl, and that each of C1-C6 alkyl, C3-C 10 cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 1aCompounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, which are replaced by are provided. In some embodiments, R 1 is, independently of each other, halogen, -CN, -OH, -OR a , C1-C6 alkyl, -OC1-C6 haloalkyl, -CF3, C3-C 10 cycloalkyl, or heterocycloalkyl, and C1-C6 alkyl, C3-C 10 cycloalkyl, and heterocycloalkyl are optionally and independently substituted with one or more R 1a Compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, which are replaced by are provided. In some embodiments, R 1 is, independently of each other, fluoro, chloro, bromo, iodo, -CN, -OH, -OR a , C1-C6 alkyl, -OC1-C6 haloalkyl, -CF3, C3-C 10 cycloalkyl, or heterocycloalkyl, and C1-C6 alkyl, C3-C 10 cycloalkyl, and heterocycloalkyl are optionally and independently substituted with one or more R 1a Compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, which are replaced by are provided. In some embodiments, R 1 is, independently of each other, fluoro, chloro, bromo, -CN, -OH, -OC1-C6 alkyl, -OC1-C6 haloalkyl, C1-C6 alkyl, -CF3, C3-C 10 cycloalkyl, or heterocycloalkyl, and -OC1-C6 alkyl, C1-C6 alkyl, C3-C 10 cycloalkyl, and heterocycloalkyl are optionally and independently substituted with one or more R 1a Compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, which are replaced by are provided. In some embodiments, R 1is, independently of one another, fluoro, chloro, -CN, -OH, -OCH3, -OCH2CH3, -C1-C6 alkyl(OR 1a ), -CH3, -CH2CH3, iso-propyl, n-propyl, n-butyl, i-butyl, t-butyl, -OCHF2, -OC1-C6 hydroxyalkyl, -CF3, cyclopropyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl, 1,4-oxazepanyl, or thiazinyl, and each of azetidinyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl, thiazinyl, and 1,4-oxazepanyl is, optionally and independently, one or more R 1a substituted, compounds of formula (I), formula (Ia), and formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are provided. In some embodiments, R 1 is, independently of one another, chloro, -CN, -OH, -OCH3, -OCH2CH3, -CH3, iso-propyl, -OCHF2, -CF3, cyclopropyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl, or 1,4-oxazepanyl, and each of azetidinyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl, and 1,4-oxazepanyl is, optionally and independently, one or more R 1a substituted, compounds of formula (I), formula (Ia), and formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are provided. In some embodiments, R 1 is, independently of one another, chloro, -CN, -OCH3-CH3, iso-propyl, -OCHF2, -CF3, cyclopropyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, or morpholinyl, and each of azetidinyl, piperidinyl, piperazinyl, and morpholinyl is, optionally and independently, one or more R 1a substituted, compounds of formula (I), formula (Ia), and formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are provided. In some embodiments, R 1is, independently of each other, chloro, -CN, -OCH3-CH3, iso-propyl, -OCHF2, -CF3, cyclopropyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, or morpholinyl, and each of azetidinyl, piperidinyl, piperazinyl, and morpholinyl is optionally and independently substituted with one or more R 1a There are provided compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, which are substituted with. In some embodiments, R 1 is, independently of each other, chloro, -CN, -OCH3-CH3, iso-propyl, -OCHF2, -CF3, cyclopropyl, piperidinyl, piperazinyl, or morpholinyl, and piperidinyl, piperazinyl, and morpholinyl are optionally substituted with one or more R 1a There are provided compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, which are substituted with. In some embodiments, R 1 is, independently of each other, chloro, -CN, -OCH3-CH3, iso-propyl, -OCHF2, -CF3, cyclopropyl, piperidinyl, piperazinyl, or morpholinyl, and piperidinyl, piperazinyl, and morpholinyl are optionally substituted with one or more -CH3, -CH2CH3, -CH2CH2CH3, -OH, and -OCH3, and there are provided compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof. In some embodiments, R 1 is, independently of each other, chloro, -CN, -OCH3-CH3, -OCHF2, cyclopropyl, piperidinyl, piperazinyl, or morpholinyl, and piperidinyl, piperazinyl, and morpholinyl are optionally substituted with one or more -CH3, -CH2CH3, -CH2CH2CH3, -OH, and -OCH3, and there are provided compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof. In some embodiments, R 1is, independently of each other, chloro, -CN, -OCH3-CH3, -OCHF2, cyclopropyl, or morpholinyl, where morpholinyl is optionally substituted with one or more -CH3, -CH2CH3, -CH2CH2CH3, -OH, and -OCH3, compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof are provided. In some embodiments, R 1 is, independently of each other, chloro, -OCH3-CH3, -OCHF2, cyclopropyl, or morpholinyl, where morpholinyl is optionally substituted with one or more -CH3, compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof are provided.

[0080] Further provided herein are compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein n is 1, 2, or 3. In some embodiments, provided are compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein n is 1. In some embodiments, provided are compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein n is 2. In some embodiments, provided are compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein n is 3.

[0081] Further provided herein is R 2 is hydrogen, compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof are provided. Further provided herein is R 3 is hydrogen, compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof are provided.

[0082] Further provided herein is R4a , R 4b , and R 4c are each independently hydrogen or halogen, there are provided compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof. In some embodiments, R 4a is halogen, and R 4b and R 4c are hydrogen, there are provided compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof. In some embodiments, R 4a and R 4c are hydrogen, and R 4b is halogen, there are provided compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof. In some embodiments, R 4a and R 4b are hydrogen, and R 4c is halogen, there are provided compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof. In some embodiments, R 4a and R 4b are halogen, and R 4c is hydrogen, there are provided compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof. In some embodiments, R 4a and R 4c are halogen, and R 4b is hydrogen, there are provided compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof. In some embodiments, R 4a , R 4b , and R 4c are halogen, there are provided compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof. In some embodiments, R 4a , R 4b , and R 4cThere are provided compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein is hydrogen. In some embodiments, R 5 There are provided compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein is halogen.

[0083] Further provided herein are compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein each of R 6 is hydrogen.

[0084] Further provided herein are compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein R 7 is hydrogen or C1-C6 alkyl. In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is C1-C6 alkyl.

[0085] Further provided herein are compounds of formula (I), formula (Ia), and formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein each of R 8a , R 8b , R 8c and R 8d is independently hydrogen, halogen, or -OR a . In some embodiments, each of R 8a , R 8b and R 8d is hydrogen, and R 8c is hydrogen, halogen, or -OR aThere are provided compounds of formula (I), formula (Ia), and formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, R 8c is halogen or -OR a There are provided compounds of formula (I), formula (Ia), and formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, R 8c is halogen, there are provided compounds of formula (I), formula (Ia), and formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, R 8c is fluoro, chloro, bromo, or iodo, there are provided compounds of formula (I), formula (Ia), and formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, R 8c is -OR a There are provided compounds of formula (I), formula (Ia), and formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0086] Further provided herein are compounds of formula (I), formula (Ia), and formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R a is C1-C6 alkyl. In some embodiments, R a is -CH3, there are provided compounds of formula (I), formula (Ia), and formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0087] Further provided herein is a compound of formula (II):

[0088]

Chemical formula

[0089] Also provided herein is a compound of formula (II) wherein ring A is C6-C 10 There is provided an aryl or heteroaryl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, ring A is C6-C 10There is provided a compound of formula (II) which is aryl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (II) wherein ring A is phenyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (II) wherein ring A is heteroaryl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (II) wherein ring A is furanyl, pyrrolyl, thiophenyl, oxazolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (II) wherein ring A is pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (II) wherein ring A is pyrazolyl, pyridinyl, pyrazinyl, or pyrimidinyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (II) wherein ring A is pyrazolyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (II) wherein ring A is 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, or 5-pyrazolyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (II) wherein ring A is 1-pyrazolyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (II) wherein ring A is 3-pyrazolyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (II) wherein ring A is 4-pyrazolyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.In some embodiments, there is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 5-pyrazolyl. In some embodiments, there is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is pyridinyl. In some embodiments, there is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 5-pyridinyl, or 6-pyridinyl. In some embodiments, there is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 2-pyridinyl. In some embodiments, there is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 3-pyridinyl. In some embodiments, there is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 4-pyridinyl. In some embodiments, there is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 5-pyridinyl. In some embodiments, there is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 6-pyridinyl. In some embodiments, there is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is pyrazinyl. In some embodiments, there is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, or 6-pyrazinyl. In some embodiments, there is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 2-pyrazinyl. In some embodiments, there is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 3-pyrazinyl.In some embodiments, there is provided a compound of formula (II) wherein ring A is 5 - pyrazinyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (II) wherein ring A is 6 - pyrazinyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (II) wherein ring A is pyrimidinyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (II) wherein ring A is 2 - pyrimidinyl, 4 - pyrimidinyl, 5 - pyrimidinyl, or 6 - pyrimidinyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (II) wherein ring A is 2 - pyrimidinyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (II) wherein ring A is 4 - pyrimidinyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (II) wherein ring A is 5 - pyrimidinyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (II) wherein ring A is 6 - pyrimidinyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (II) wherein ring A is pyridazinyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (II) wherein ring A is 3 - pyridazinyl, 4 - pyridazinyl, 5 - pyridazinyl, or 6 - pyridazinyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (II) wherein ring A is 3 - pyridazinyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (II) wherein ring A is 4 - pyridazinyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.In some embodiments, there is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 5-pyridazinyl. In some embodiments, there is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 6-pyridazinyl. In some embodiments, ring A is C3-C. 10 There is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is C3-C cycloalkyl or heterocycloalkyl. In some embodiments, ring A is C3-C 10 There is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is C3-C cycloalkyl. In some embodiments, there is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is heterocycloalkyl.

[0090] Further provided herein, R 1 is, independently of each other, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, -OC1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C 10 cycloalkyl, or heterocycloalkyl, and C1-C6 alkyl, C3-C 10 cycloalkyl, and heterocycloalkyl are optionally and independently substituted with one or more R 1a There is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, R 1 is, independently of each other, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, -OC1-C6 haloalkyl, C3-C 10 cycloalkyl, or heterocycloalkyl, and C1-C6 alkyl, C3-C 10 cycloalkyl, and heterocycloalkyl are optionally and independently substituted with one or more R 1aThere is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is replaced by. In some embodiments, R 1 is, independently of each other, fluoro, chloro, bromo, iodo, -CN, -OH, -OR a , C1-C6 alkyl, -CF3, -OC1-C6 haloalkyl, C3-C 10 cycloalkyl, or heterocycloalkyl, and C1-C6 alkyl, C3-C 10 cycloalkyl, and heterocycloalkyl are optionally and independently substituted with one or more R 1a There is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is replaced by. In some embodiments, R 1 is, independently of each other, fluoro, chloro, bromo, -CN, -OH, -OR a , C1-C6 alkyl, -CF3, -OC1-C6 haloalkyl, C3-C 10 cycloalkyl, or heterocycloalkyl, and C1-C6 alkyl, C3-C 10 cycloalkyl, and heterocycloalkyl are optionally and independently substituted with one or more R 1a There is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is replaced by. In some embodiments, R 1 is, independently of each other, fluoro, chloro, -CN, -OH, -OC1-C6 alkyl, C1-C6 alkyl, -CF3, -OC1-C6 haloalkyl, C3-C 10 cycloalkyl, or heterocycloalkyl, and -OC1-C6 alkyl, C1-C6 alkyl, C3-C 10 cycloalkyl, and heterocycloalkyl are optionally and independently substituted with one or more R 1a There is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is replaced by. In some embodiments, R 1 is, independently of each other, fluoro, chloro, -CN, -OH, -OCH3, -OCH2CH3, -C1-C6 alkyl(OR1a ), -CH3, -CH2CH3, iso-propyl, n-propyl, n-butyl, i-butyl, t-butyl, -OC1-C6 hydroxyalkyl, -CF3, -OCHF2, cyclopropyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl, 1,4-oxazepanyl, or thiazinyl, and each of azetidinyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl, thiazinyl, and 1,4-oxazepanyl is optionally and independently one or more R 1a substituted compounds of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, R 1 is each independently chloro, -CN, -OH, -OCH3, -OCH2CH3, -CH3, iso-propyl, -CF3, -OCHF2, cyclopropyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl, or 1,4-oxazepanyl, and each of azetidinyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl, and 1,4-oxazepanyl is optionally and independently one or more R 1a substituted compounds of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, R 1 is each independently chloro, -CN, -OCH3, -CH3, iso-propyl, -CF3, -OCHF2, cyclopropyl, azetidinyl, piperidinyl, piperazinyl, or morpholinyl, and each of azetidinyl, piperidinyl, piperazinyl, and morpholinyl is optionally and independently one or more R 1a substituted compounds of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, R 1is, independently of each other, chloro, -CN, -OCH3, -CH3, iso-propyl, -CF3, -OCHF2, cyclopropyl, piperidinyl, piperazinyl, or morpholinyl, and each of cyclopropyl, piperidinyl, piperazinyl, and morpholinyl is optionally and independently one or more R 1a substituted with, a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided. In some embodiments, R 1 is, independently of each other, chloro, -OCH3, -CH3, iso-propyl, -CF3, -OCHF2, cyclopropyl, piperidinyl, piperazinyl, or morpholinyl, and piperidinyl, piperazinyl, and morpholinyl are optionally one or more R 1a substituted with, a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided. In some embodiments, R 1 is, independently of each other, chloro, -OCH3, -CH3, iso-propyl, -CF3, -OCHF2, cyclopropyl, piperidinyl, piperazinyl, or morpholinyl, and piperidinyl, piperazinyl, and morpholinyl are optionally substituted with one or more -CH3, -CH2CH3, -CH2CH2CH3, -OH, and -OCH3, a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided. In some embodiments, R 1 is, independently of each other, chloro, -OCH3, -CH3, cyclopropyl, piperidinyl, piperazinyl, or morpholinyl, and piperidinyl, piperazinyl, and morpholinyl are optionally substituted with one or more -CH3, -CH2CH3, -CH2CH2CH3, -OH, and -OCH3, a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided. In some embodiments, R 1is, independently of each other, chloro, -OCH3, -CH3, -OCHF2, cyclopropyl, or morpholinyl, where morpholinyl is optionally substituted with one or more -CH3, -CH2CH3, -CH2CH2CH3, -OH, and -OCH3, a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, R 1 is, independently of each other, chloro, -OCH3, -CH3, cyclopropyl, or morpholinyl, where morpholinyl is optionally substituted with one or more -CH3, a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0091] Also provided herein are compounds of formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein n is 1, 2, or 3. In some embodiments, provided are compounds of formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein n is 1. In some embodiments, provided are compounds of formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein n is 2. In some embodiments, provided are compounds of formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein n is 3.

[0092] Also provided herein is R 2 is hydrogen, a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0093] Also provided herein is R 3 is hydrogen, a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0094] Also provided herein is R 4a R 4b and R 4cThere is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is, independently, hydrogen or halogen. In some embodiments, R 4a is halogen and R 4b and R 4c are hydrogen. There is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, R 4a and R 4c are hydrogen and R 4b is halogen. There is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, R 4a and R 4b are hydrogen and R 4c is halogen. There is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, R 4a and R 4b are halogen and R 4c is hydrogen. There is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, R 4a and R 4c are halogen and R 4b is hydrogen. There is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, R 4a is halogen and R 4b and R 4c are hydrogen. There is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, R 4a , R 4b , and R 4c are hydrogen. There is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, R 4a , R 4b , and R 4cThere is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein is a halogen. In some embodiments, R 4a R 4b and R 4c are fluorine, and there is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0095] Further provided herein is a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 7 is hydrogen or C1-C6 alkyl. In some embodiments, R 7 is hydrogen, and there is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, R 7 is C1-C6 alkyl, and there is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0096] Further provided herein is a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each of R 8a R 8b R 8c and R 8d is independently hydrogen, deuterium, halogen, or -OR a . In some embodiments, each of R 8a R 8b and R 8d is hydrogen, and R 8c is hydrogen, halogen, or -OR a . In some embodiments, R 8c is halogen or -OR a , and there is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, R 8cThere is provided a compound of formula (II) wherein R is halogen, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, R 8c There is provided a compound of formula (II) wherein R is fluoro, chloro, bromo, or iodo, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, R 8c There is provided a compound of formula (II) wherein R is -OR a and a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0097] Also provided herein is a compound of formula (II) wherein R a is C1-C6 alkyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, R a There is provided a compound of formula (II) wherein R is -CH3 alkyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0098] Further provided herein is a compound of formula (III):

[0099]

Chemical formula

[0100] Furthermore, the present specification provides a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments, a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided wherein ring A is pyrazolyl. In some embodiments, a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided wherein ring A is 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, or 5-pyrazolyl. In some embodiments, a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided wherein ring A is 1-pyrazolyl. In some embodiments, a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided wherein ring A is 3-pyrazolyl. In some embodiments, a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided wherein ring A is 4-pyrazolyl. In some embodiments, a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided wherein ring A is 5-pyrazolyl. In some embodiments, a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided wherein ring A is pyridinyl. In some embodiments, a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided wherein ring A is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 5-pyridinyl, or 6-pyridinyl. In some embodiments, a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided wherein ring A is 2-pyridinyl. In some embodiments, a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided wherein ring A is 3-pyridinyl. In some embodiments, a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided wherein ring A is 4-pyridinyl.In some embodiments, there is provided a compound of formula (III) wherein ring A is 5-pyridinyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (III) wherein ring A is 6-pyridinyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (III) wherein ring A is pyrazinyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (III) wherein ring A is 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, or 6-pyrazinyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (III) wherein ring A is 2-pyrazinyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (III) wherein ring A is 3-pyrazinyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (III) wherein ring A is 5-pyrazinyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (III) wherein ring A is 6-pyrazinyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (III) wherein ring A is pyrimidinyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (III) wherein ring A is 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (III) wherein ring A is 2-pyrimidinyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, there is provided a compound of formula (III) wherein ring A is 4-pyrimidinyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.In some embodiments, there is provided a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 5-pyrimidinyl. In some embodiments, there is provided a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 6-pyrimidinyl. In some embodiments, there is provided a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is pyridinyl. In some embodiments, there is provided a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, or 6-pyridazinyl. In some embodiments, there is provided a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 3-pyridazinyl. In some embodiments, there is provided a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 4-pyridazinyl. In some embodiments, there is provided a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 5-pyridazinyl. In some embodiments, there is provided a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 6-pyridazinyl.

[0101] Further provided herein is a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl, R 1 is, independently of one another, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, -OC1-C6 haloalkyl, C3-C 10 cycloalkyl, or heterocycloalkyl, C1-C6 alkyl, C3-C 10Each of cycloalkyl and heterocycloalkyl is optionally and independently one or more R 1a substituted with R 1a is each independently -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 heteroalkyl, n is 1, 2, or 3, R 7 is hydrogen, R 8c is -OR a and R a is each C1-C6 alkyl, There is provided a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, ring A is pyrimidinyl. In other embodiments, ring A is 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl. In still further embodiments, ring A is 2-pyrimidinyl. In further embodiments, ring A is 4-pyrimidinyl. In other embodiments, ring A is 5-pyrimidinyl. In still other embodiments, ring A is 6-pyrimidinyl.

[0102] Further provided herein is a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is pyridinyl or pyrimidinyl, R 1 is each independently fluoro, chloro, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, -OC1-C6 haloalkyl, C3-C 10 cycloalkyl, or heterocycloalkyl, and each of C1-C6 alkyl, C3-C 10 cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 1a and R 1a is each independently -OH, -ORa is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 heteroalkyl, and n is 1, 2, or 3, and R 7 is hydrogen, R 8c is -OCH3, R a are each C1-C6 alkyl, There is provided a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, ring A is pyridinyl. In other embodiments, ring A is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 5-pyridinyl, or 6-pyridinyl. In still further embodiments, ring A is 2-pyridinyl. In some embodiments, ring A is 3-pyridinyl. In some embodiments, ring A is 4-pyridinyl. In some embodiments, ring A is 5-pyridinyl. In some embodiments, ring A is 6-pyrimidinyl. In some embodiments, ring A is pyrimidinyl. In some embodiments, ring A is 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl. In some embodiments, ring A is 2-pyrimidinyl. In some embodiments, ring A is 4-pyrimidinyl. In some embodiments, ring A is 5-pyrimidinyl. In some embodiments, ring A is 6-pyrimidinyl.

[0103] Further provided herein is a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is pyridinyl or pyrimidinyl, R 1is, independently of one another, chloro, -CN, -OH, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH(CH3)2, -CF3, -OCHF2, cyclopropyl, morpholinyl, piperidinyl, piperazinyl, azetidinyl, 1,1-dioxidothiomorpholinyl, or oxetanyl, and morpholinyl, piperidinyl, piperazinyl, azetidinyl, 1,1-dioxidothiomorpholinyl, and oxetanyl are each, optionally and independently of one another, substituted with one or more R 1a and R 1a is, independently of one another, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 heteroalkyl, n is 1, 2, or 3, R 7 is hydrogen, R 8c is -OCH3, R a is each C1-C6 alkyl, a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided.

[0104] Furthermore, provided herein is a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is heteroaryl, R 1 is, independently of one another, halogen, -CN, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c Rd 、 -NR b C(=O)R a 、 -NR b C(=O)OR a 、 -NR b S(=O)2R a 、 -C(=O)R a 、 -C(=O)OR b 、 -C(=O)NR c R d 、 C1-C6 alkyl, C1-C6 haloalkyl, -OC1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, or heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, and heteroaryl are each, independently and optionally, substituted with one or more R 1a s, R 1a is each independently deuterium, -OH, -OR a 、 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, or heteroaryl, n is 1, 2, or 3, R 7 is hydrogen or C1-C6 alkyl, R 8c is halogen or -OR a and R aare each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, heteroaryl, C1-C6 alkyl(C3-C 10 cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(C6-C 10 aryl), or C1-C6 alkyl(heteroaryl), and C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, and heteroaryl are each independently and 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-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, R b are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, heteroaryl, C1-C6 alkyl(C3-C 10 cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(C6-C 10is aryl), or C1-C6 alkyl(heteroaryl), and C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 Each of aryl and heteroaryl is, independently and 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-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, heteroaryl, C1-C6 alkyl(C3-C 10 cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(C6-C 10 aryl), or C1-C6 alkyl(heteroaryl), and C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10Each of aryl and heteroaryl is independently and 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-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, or R c and R d together with the atom to which they are attached, optionally form a heterocycloalkyl 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-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, There is provided a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, ring A is pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments, ring A is pyrazolyl. In some embodiments, ring A is pyridinyl. In some embodiments, ring A is pyrazinyl. In some embodiments, ring A is pyrimidinyl. In some embodiments, ring A is pyridazinyl.

[0105] Further provided herein is a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is heteroaryl, R 1 is each independently halogen, -OR a, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b , -NR c R d , -NR b , -NR a , -NR b , -S(=O)2R a , -C(=O)R a , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, -OC1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, or heterocycloalkyl, where each of C1-C6 alkyl, C3-C 10 cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 1a s, R 1a is independently deuterium, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, or heteroaryl, n is 1, 2, or 3, R 7 is hydrogen or C1-C6 alkyl, R 8c is halogen or -OR a , R ais, independently of each other, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, heteroaryl, C1-C6 alkyl(C3-C 10 cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(C6-C 10 aryl), or C1-C6 alkyl(heteroaryl), and C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, and heteroaryl each is, independently and 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-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, R b is, independently of each other, hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, heteroaryl, C1-C6 alkyl(C3-C 10 cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(C6-C 10is aryl), or C1-C6 alkyl(heteroaryl), and C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 Each of aryl and heteroaryl is independently and 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-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, heteroaryl, C1-C6 alkyl(C3-C 10 cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(C6-C 10 aryl), or C1-C6 alkyl(heteroaryl), and C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10Each of aryl and heteroaryl is independently and 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-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, There is provided a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, ring A is pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments, ring A is pyrazolyl. In some embodiments, ring A is pyridinyl. In some embodiments, ring A is pyrazinyl. In some embodiments, ring A is pyrimidinyl. In some embodiments, ring A is pyridazinyl.

[0106] Further provided herein is a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein, ring A is heteroaryl, R 1 is each independently halogen, -OR a , -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b S(=O)2R a , -C(=O)R a , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, -OC1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, or heterocycloalkyl, where each of C1-C6 alkyl, C3-C 10 cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 1a and R 1a is independently deuterium, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, or heteroaryl, n is 1, 2, or 3, R 7 is hydrogen or C1-C6 alkyl, R 8c is halogen or -OR a and R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, heteroaryl, C1-C6 alkyl(C3-C 10 cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(C6-C 10 aryl), or C1-C6 alkyl(heteroaryl), and C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10Each of aryl and heteroaryl is independently and 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-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, R b each independently is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, heteroaryl, C1-C6 alkyl(C3-C 10 cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(C6-C 10 aryl), or C1-C6 alkyl(heteroaryl), and C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 each of aryl and heteroaryl is independently and 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-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, R c and R dare each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, heteroaryl, C1-C6 alkyl(C3-C 10 cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(C6-C 10 aryl), or C1-C6 alkyl(heteroaryl), and C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, and heteroaryl are each independently and 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-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, A compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided. In some embodiments, ring A is pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments, ring A is pyrazolyl. In some embodiments, ring A is pyridinyl. In some embodiments, ring A is pyrazinyl. In some embodiments, ring A is pyrimidinyl. In some embodiments, ring A is pyridazinyl.

[0107] Further provided herein is a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein, Ring A is phenyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl, R 1 each independently is halogen, -S(=O)2(C1-C6 alkyl), -S(=O)2N(C1-C6 alkyl)2, -OC1-C6 alkyl, -C(=O)N(C1-C6 alkyl)2, -C(=O)N(H)(C1-C6 alkyl), -OC1-C6 haloalkyl, C1-C6 alkyl, -S(C1-C6 alkyl), heterocycloalkyl, or -C(=O)(heterocycloalkyl), n is 1, 2, or 3, R 7 is hydrogen, R 8c is hydrogen, halogen, CH3, or -OCH3, A compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided. In some embodiments, ring A is phenyl. In some embodiments, ring A is pyrazolyl. In some embodiments, ring A is pyridinyl. In some embodiments, ring A is pyrazinyl. In some embodiments, ring A is pyrimidinyl. In some embodiments, ring A is pyridazinyl. In some embodiments, R 8c is hydrogen. In some embodiments, R 8c is halogen. In some embodiments, R 8c is fluoro, chloro, bromo, or iodo. In some embodiments, R 8c is fluoro. In some embodiments, R 8c is CH3. In some embodiments, R 8c is, or -OCH3.

[0108] Further provided herein is a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is phenyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl, R 1is, independently of each other, halogen, -CF3, -CN, -S(=O)2(CH3), -S(=O)2(CH2CH3), -S(=O)2N(CH3)2, -OCH3, -CH2CHF2, -C(=O)N(CH3)2, -C(=O)N(H)(CH3), -OC1-C6 haloalkyl, -CH3, -CH2CH3, iso-propyl, n-propyl, -SCH3, azetidinyl, pyrrolidinyl, fluoropyrrolidinyl, difluoropiperidinyl, difluoroazetidinyl, fluoroazetidinyl, morpholinyl, dioxido thiomorpholinyl, -C(=O)(morpholinyl), -C(=O)(azetidinyl), -C(=O)(difluoroazetidinyl), or -C(=O)difluoropiperidinyl, n is 1, 2, or 3, R 7 is hydrogen, R 8c is hydrogen, halogen, CH3, or -OCH3, A compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided. In some embodiments, ring A is phenyl. In some embodiments, ring A is pyrazolyl. In some embodiments, ring A is pyridinyl. In some embodiments, ring A is pyrazinyl. In some embodiments, ring A is pyrimidinyl. In some embodiments, ring A is pyridazinyl. In some embodiments, R 8c is hydrogen. In some embodiments, R 8c is halogen. In some embodiments, R 8c is fluoro, chloro, bromo, or iodo. In some embodiments, R 8c is fluoro. In some embodiments, R 8c is CH3. In some embodiments, R 8c is, or -OCH3.

[0109] Further provided herein is a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein, Ring A is phenyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl, R 1 each independently is halogen, -CF3, -CN, -S(=O)2(CH3), -S(=O)2(CH2CH3), -S(=O)2(i-Pr), -S(=O)2(cyclopropyl), -S(=O)2(C1-C6 haloalkyl), -S(=O)2N(CH3)2, -S(=O)2NH2, -S(=O)2N(CH3)(H), -OCH3, -OCH3, -OCH2CH3, -CH2CHF2, -C(=O)N(CH3)2, -C(=O)N(H)(CH3), -OC1-C6 haloalkyl, -CH3, -CH2CH3, iso-propyl, n-propyl, -SCH3, azetidinyl, pyrrolidinyl, oxazolyl, fluoropyrrolidinyl, difluoropiperidinyl, difluoroazetidinyl, fluoroazetidinyl, morpholinyl, dioxidthiomorpholinyl, -C(=O)(morpholinyl), -C(=O)(azetidinyl), -C(=O)(difluoroazetidinyl), or -C(=O)difluoropiperidinyl, n is 1, 2, or 3, R 7 is hydrogen, R 8c is hydrogen, halogen, CH3, or -OCH3, A compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided. In some embodiments, ring A is phenyl. In some embodiments, ring A is pyrazolyl. In some embodiments, ring A is pyridinyl. In some embodiments, ring A is pyrazinyl. In some embodiments, ring A is pyrimidinyl. In some embodiments, ring A is pyridazinyl. In some embodiments, R 8c [[ID=**18**]]is hydrogen. In some embodiments, R 8c is halogen. In some embodiments, R 8c is fluoro, chloro, bromo, or iodo. In some embodiments, R 8c is fluoro. In some embodiments, R 8cis CH3. In some embodiments, R 8c is, or -OCH3.

[0110] Further provided herein is a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is phenyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl, R 1 are each independently halogen, -CF3, -CN, -S(=O)2(C1-C6 alkyl), -S(=O)2(C3-C 10 cycloalkyl), -S(=O)2N(C1-C6 alkyl)2, -S(=O)2NH2, -S(=O)2N(C1-C6 alkyl)(H), -OC1-C6 alkyl, -CH2CHF2, -C(=O)N(C1-C6 alkyl)2, -C(=O)N(H)(C1-C6 alkyl), -OC1-C6 haloalkyl, -C1-C6 alkyl, -SC1-C6 alkyl, azetidinyl, pyrrolidinyl, oxazolyl, fluoropyrrolidinyl, difluoropiperidinyl, difluoroazetidinyl, fluoroazetidinyl, morpholinyl, dioxidthiomorpholinyl, -C(=O)(morpholinyl), -C(=O)(azetidinyl), -C(=O)(difluoroazetidinyl), or -C(=O)difluoropiperidinyl, n is 1, 2, or 3, R 7 is hydrogen, R 8c is hydrogen, halogen, CH3, or -OCH3, A compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided. In some embodiments, ring A is phenyl. In some embodiments, ring A is pyrazolyl. In some embodiments, ring A is pyridinyl. In some embodiments, ring A is pyrazinyl. In some embodiments, ring A is pyrimidinyl. In some embodiments, ring A is pyridazinyl. In some embodiments, R 8c is hydrogen. In some embodiments, R 8cis a halogen. In some embodiments, R 8c is fluoro, chloro, bromo, or iodo. In some embodiments, R 8c is fluoro. In some embodiments, R 8c is CH3. In some embodiments, R 8c is, or -OCH3.

[0111] Further provided herein is a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is phenyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl, R 1 is each independently halogen, -CF3, -CN, -S(=O)2(C1-C6 alkyl), -S(=O)2(C3-C 10 cycloalkyl), -S(=O)2N(C1-C6 alkyl)2, -S(=O)2NH2, -S(=O)2N(C1-C6 alkyl)(H), -OC1-C6 alkyl, -CH2CHF2, -C(=O)N(C1-C6 alkyl)2(H), -C(=O)N(H)(C1-C6 alkyl)2, -OC1-C6 haloalkyl, -C1-C6 alkyl, -SC1-C6 alkyl, azetidinyl, pyrrolidinyl, oxazolyl, fluoropyrrolidinyl, difluoropiperidinyl, difluoroazetidinyl, fluoroazetidinyl, morpholinyl, dioxidthiomorpholinyl, -C(=O)(morpholinyl), -C(=O)(azetidinyl), -C(=O)(difluoroazetidinyl), or -C(=O)difluoropiperidinyl, and at least one of R 1 is -S(=O)2(C1-C6 alkyl), -S(=O)2(C3-C 10 cycloalkyl), -S(=O)2N(C1-C6 alkyl)2, -S(=O)2NH2, or -S(=O)2N(C1-C6 alkyl)(H), n is 1, 2, or 3, R 7 is hydrogen, R 8cis hydrogen, halogen, CH3, or -OCH3, A compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided. In some embodiments, ring A is phenyl. In some embodiments, ring A is pyrazolyl. In some embodiments, ring A is pyridinyl. In some embodiments, ring A is pyrazinyl. In some embodiments, ring A is pyrimidinyl. In some embodiments, ring A is pyridazinyl. In some embodiments, R 8c is hydrogen. In some embodiments, R 8c is halogen. In some embodiments, R 8c is fluoro, chloro, bromo, or iodo. In some embodiments, R 8c is fluoro. In some embodiments, R 8c is CH3. In some embodiments, R 8c is, or -OCH3.

[0112] Further provided herein is a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is heterocycloalkyl, R 1 is each independently halogen, -CF3, -CN, -S(=O)2(C1-C6 alkyl), -S(=O)2(C3-C 10cycloalkyl), -S(=O)2N(C1-C6 alkyl)2, -S(=O)2NH2, -S(=O)2N(C1-C6 alkyl)(H), -OC1-C6 alkyl, -CH2CHF2, -C(=O)N(C1-C6 alkyl)2(H), -C(=O)N(H)(C1-C6 alkyl)2, -OC1-C6 haloalkyl, -C1-C6 alkyl, -SC1-C6 alkyl, azetidinyl, pyrrolidinyl, oxazolyl, fluoropyrrolidinyl, difluoropiperidinyl, difluoroazetidinyl, fluoroazetidinyl, morpholinyl, dioxido thiomorpholinyl, -C(=O)(morpholinyl), -C(=O)(azetidinyl), -C(=O)(difluoroazetidinyl), or -C(=O) difluoropiperidinyl, and n is 1, 2, or 3, and R 7 is hydrogen, R 8c is hydrogen, halogen, CH3, or -OCH3, There is provided a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, ring A is dihydropyridazinyl. In some embodiments, ring A is 1,6-dihydropyridazin-3-yl. In some embodiments, R 8c is hydrogen. In some embodiments, R 8c is halogen. In some embodiments, R 8c is fluoro, chloro, bromo, or iodo. In some embodiments, R 8c is fluoro. In some embodiments, R 8c is CH3. In some embodiments, R 8c is, or -OCH3.

[0113] Further provided herein is a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is aryl, R 1 is each independently halogen, -CN, -OR a , -OC(=O)R a、 -OC(=O)OR b 、 -OC(=O)NR c R d 、 -SR a 、 -S(=O)R a 、 -S(=O)2R a 、 -S(=O)2NR c R d 、 -NR c R d 、 -NR b C(=O)NR c R d 、 -NR b C(=O)R a 、 -NR b C(=O)OR a 、 -NR b S(=O)2R a 、 -C(=O)R a 、 -C(=O)OR b 、 -C(=O)NR c R d 、 C1-C6 alkyl, C1-C6 haloalkyl, -OC1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, or heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, and heteroaryl each are, independently and optionally, substituted with one or more R 1a and, R 1a is, independently for each, deuterium, -OH, -OR a 、 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, or heteroaryl, and n is 1, 2, or 3, R 7 is hydrogen or C1-C6 alkyl, R 8c is hydrogen, C1-C6 alkyl, halogen, or -OR a and R a are each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, heteroaryl, C1-C6 alkyl(C3-C 10 cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(C6-C 10 aryl), or C1-C6 alkyl(heteroaryl), and each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, and heteroaryl is independently and 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-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, R b are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10Aryl, heteroaryl, C1-C6 alkyl(C3-C 10 cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(C6-C 10 aryl), or C1-C6 alkyl(heteroaryl), and each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, and heteroaryl is, independently and 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-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, heteroaryl, C1-C6 alkyl(C3-C 10 cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(C6-C 10 aryl), or C1-C6 alkyl(heteroaryl), and each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10Each of aryl and heteroaryl is independently and 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-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, or R c and R d together with the atom to which they are attached optionally form a heterocycloalkyl 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-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, There is provided a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0114] This specification further includes (1R,2S)-5'-methoxy-2-{3-[(5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[(5-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-{3-[(5-chloropyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[(5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-{3-[(5-ethoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-{3-[(5-cyclopropylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-{3-[(5-chloropyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1S,2R)-5'-methoxy-2-{3-[(5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-(3-{[5-chloro-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-{3-[(2-chloro-5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,(2S)-5'-Methoxy-2-(3-{[5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[5-methoxy-6-(piperidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[(3-methoxypyrazin-2-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[(6-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-{3-[(6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-{3-[(2,3-dihydro-1-benzofuran-7-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[(3-methoxypyridin-2-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[(4-methoxypyridin-3-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[(3-methoxypyridin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-(3-{[5-chloro-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-Indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[(1,3,5-trimethyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[5-(trifluoromethyl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[(5-chloro-2-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[(2-methoxypyridin-3-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[(1-benzofuran-7-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[(3-hydroxy-2,3-dihydro-1-benzofuran-7-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[(3S)-3-hydroxy-2,3-dihydro-1-benzofuran-7-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[(3R)-3-hydroxy-2,3-dihydro-1-benzofuran-7-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[(2,3-dihydropyrazolo[5,1-b][1,3]Oxazol-7-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[(3-oxo-2,3-dihydro-1-benzofuran-7-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-{3-[(2,3-dihydrofuro[2,3-c]pyridin-7-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-(3-{[(3S)-3-(hydroxymethyl)-2,3-dihydrofuro[2,3-c]pyridin-7-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-(3-{[(3R)-3-(hydroxymethyl)-2,3-dihydrofuro[2,3-c]pyridin-7-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[6-(3-methoxyazetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-(3-{[6-(3-hydroxyazetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-(3-((6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-methoxypyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one, (1R,2S)-2-(3-{[6-(2-hydroxyethoxy)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,(2S)-2-(3-((6-(1,1-Dioxidothiomorpholino)pyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one), (1R,2S)-5'-methoxy-2-(3-{[6-(1,4-oxazepan-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[5-methoxy-2-methyl-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[6-(azetidin-1-yl)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'(1'H)-one, (1R,2S)-2-(3-{[6-(3-hydroxyazetidin-1-yl)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[5-methoxy-6-(1,4-oxazepan-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[6-(azetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'(1'H)-one, (1R,2S)-2-(3-{[5-chloro-6-(3-hydroxyazetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'(1'H)-one, (1R,2S)-2-(3-{[5-chloro-6-(3-methoxyazetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3’-Indol]-2’(1’H)-one, (1R,2S)-2-(3-{[2-chloro-5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5’-methoxyspiro[cyclopropane-1,3’-indol]-2’(1’H)-one, (1R,2S)-2-(3-{[4-chloro-5-methoxy-6-(morpholin-4-yl)pyrimidin-, 2-Imino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-(3-{[1-(2-Hydroxyethyl)-3-methoxy-1H-pyrazol-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-(3-{[2-Cyclopropyl-5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-[3-({6-[(2R,6S)-2,6-Dimethylmorpholin-4-yl]-5-methoxypyrimidin-4-yl}amino)-1H-indazol-6-yl]-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-(3-((5-Chloro-6-(1,1-dioxidothiomorpholino)pyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one, (1R,2S)-2-(3-((6-(1,1-dioxidothiomorpholino)-5-methoxypyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one, (1R,2S)-2-(3-{[5-(2-Hydroxyethyl)-3-methoxypyrazin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-(3-{[6-(2-Hydroxyethyl)-3-methoxypyrazin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-(3-((6-(1,1-dioxidothiomorpholino)-5-methoxy-2-methylpyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one, (1R,(2S)-2-(3-((5-chloro-6-(1,1-dioxidothiomorpholino)-2-methylpyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one, (1R,2S)-2-(3-((2-cyclopropyl-6-(1,1-dioxidothiomorpholino)pyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one, (1R,2S)-2-(3-((6-(1,1-dioxidothiomorpholino)-2-methylpyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one, 5-methoxy-4-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-6-(morpholin-4-yl)pyrimidine-2-carbonitrile, 4-(1,1-dioxidothiomorpholino)-5-methoxy-6-((6-((1R,2S)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-2-yl)-1H-indazol-3-yl)amino)pyrimidine-2-carbonitrile, (1R,2S)-2-{3-[(1,3-dimethyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[(1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, 4-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,{3’-Indol]-2-yl]-1H-indazol-3-yl}amino)-1-methyl-1H-pyrazole-3-carbonitrile, (1R,2S)-2-[3-({6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-5-methoxy-2-methylpyrimidin-4-yl}amino)-1H-indazol-6-yl]-5’-methoxispiro[cyclopropane-1,3’-indole]-2’(1’H)-one, (1R,2S)-2-(3-{[2-(2-hydroxyethyl)-5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5’-methoxispiro[cyclopropane-1,3’-indole]-2’(1’H)-one, (1R,2S)-2-(3-((2-cyclopropyl-6-(1,1-dioxidothiomorpholino)-5-methoxypyrimidin-4-yl)amino)-1H-indazol-6-yl)-5’-methoxispiro[cyclopropane-1,3’-indolin]-2’-one, (1R,2S)-2-(3-((5-chloro-2-cyclopropyl-6-(1,1-dioxidothiomorpholino)pyrimidin-4-yl)amino)-1H-indazol-6-yl)-5’-methoxispiro[cyclopropane-1,3’-indolin]-2’-one, (1R,2S)-5’-methoxy-2-{3-[(3-methoxy-6-methylpyrazin-2-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3’-indole]-2’(1’H)-one, (1R,2S)-2-(3-{[5-chloro-6-(3-hydroxyazetidin-1-yl)-2-methylpyrimidin-4-yl]amino}-1H-indazol-6-yl)-5’-methoxispiro[cyclopropane-1,3’-indole]-2’(1’H)-one, (1R,2S)-2-(3-{[6-(3-hydroxyazetidin-1-yl)-5-methoxy-2-methylpyrimidin-4-yl]amino}-1H-indazol-6-yl)-5’-methoxispiro[cyclopropane-1,3’-indole]-2’(1’H)-one, (1R,2S)-2-{3-[(1,3-dimethyl-1H-pyrazol-5-yl)amino]-1H-indazol-6-yl}-5’-methoxispiro[cyclopropane-1,3'-Indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[(4-methoxy-1-methyl-1H-pyrazol-5-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[5-chloro-2-cyclopropyl-6-(3-hydroxyazetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-[3-({2-cyclopropyl-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-5-methoxypyrimidin-4-yl}amino)-1H-indazol-6-yl]-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-((5-chloro-6-(1,1-dioxidothiomorpholino)-2-isopropylpyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one, (1R,2S)-5'-methoxy-2-{3-[(4-methoxy-1-methyl-1H-pyrazol-3-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[(6-cyclopropyl-3-methoxypyrazin-2-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[2-cyclopropyl-6-(3-hydroxyazetidin-1-yl)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[(3,6-dimethylpyrazin-2-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,(2S)-5'-Methoxy-2-(3-{[3-methoxy-6-(propan-2-yl)pyrazin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-((6-(1,1-dioxidothiomorpholino)-2-isopropyl-5-methoxypyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one, (1R,2S)-5'-Methoxy-2-(3-{[5-methoxy-6-(morpholin-4-yl)-2-(propan-2-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-Methoxy-2-{3-[(5-methoxy-2-methylpyridin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-Methoxy-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-Methoxy-2-{3-[(3-methoxy-6-methylpyridin-2-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-Methoxy-2-{3-[(2-methoxy-5-methylpyridin-3-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-Methoxy-2-{3-[(4-methoxypyridazin-3-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,(2S)-2-{3-[(3-cyclopropyl-1-ethyl-1H-pyrazol-5-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[2-(2-hydroxy-2-methylpropyl)-5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-5-(morpholin-4-yl)pyrazin-2-yl]amino}-1H-ind, (1R,2S)-5'-Methoxy-2-(3-{[3-methoxy-2-(morpholin-4-yl)pyridin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-{3-[(5-chloro-2-methylpyridin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[5-methoxy-2-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-{3-[(5-chloro-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-6-(morpholin-4-yl)pyrazin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-6-(oxetan-3-yl)pyrazin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-6-(propan-2-yl)pyridazin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[6-(morpholin-4-yl)-2-(propan-2-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-(3-{[5-chloro-2-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-Indol]-2'(1'H)-one, (1R,2S)-2-(3-{[5-(3-hydroxyazetidin-1-yl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[3-methyl-6-(propan-2-yl)pyrazin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[6-(propan-2-yl)pyrazin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[5-chloro-6-(3-hydroxyazetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxy-1'-methylspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[5-chloro-6-(3-hydroxyazetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-1'-ethyl-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[5-(difluoromethoxy)-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[6-(azetidin-3-yl)-3-methoxypyrazin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, and (1R,2S)-2-(3-{[6-(3-hydroxyazetidin-1-yl)-2-(propan-2-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided.,

[0115] This specification further includes (1R,2S)-2-(3-{[1-(2,2-difluoroethyl)-3-methyl-1H-pyrazol-5-yl]amino}-1H-indazol-6-yl)-5’-methoxyspiro[cyclopropane-1,3’-indole]-2’(1’H)-one, (1R,2S)-5’-methoxy-2-(3-{[5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-1’-methylspiro[cyclopropane-1,3’-indole]-2’(1’H)-one, (1R,2S)-2-(3-{[2-(3-hydroxyazetidin-1-yl)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)-5’-methoxyspiro[cyclopropane-1,3’-indole]-2’(1’H)-one, (1R,2S)-5’-methoxy-2-(3-{[6-(oxetan-3-yl)pyrazin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3’-indole]-2’(1’H)-one, (1R,2S)-2-(3-{[5-chloro-2-(propan-2-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5’-methoxyspiro[cyclopropane-1,3’-indole]-2’(1’H)-one, (1R,2S)-2-(3-{[5-chloro-2-(oxetan-3-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5’-methoxyspiro[cyclopropane-1,3’-indole]-2’(1’H)-one, (1R,2S)-5’-methoxy-2-(3-{[5-methoxy-2-(oxetan-3-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3’-indole]-2’(1’H)-one, (1R,2S)-2-(3-{[5-chloro-2-(3-hydroxyazetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5’-methoxyspiro[cyclopropane-1,3’-indole]-2’(1’H)-one, (1R,2S)-2-(3-{[5-(difluoromethoxy)-2-methylpyrimidin-4-yl]amino}-1H-indazol-6-yl)-5’-methoxyspiro[cyclopropane-1,3'-Indol]-2'(1'H)-one, (1R,2S)-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-1'-methylspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2R)-2-{7-fluoro-3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[5-methoxy-2-(propan-2-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methylspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1S,2S)-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methylspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[5-(difluoromethoxy)-2-(propan-2-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-4'-fluoro-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1S,2S)-4'-fluoro-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,(2S)-6'-Fluoro-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-(3-{[5-chloro-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-fluoro-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-{3-[(5-ethoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-(3-{[5-(difluoromethoxy)-2-methylpyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-fluorospiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-[3-({2-methyl-5-[(propan-2-yl)oxy]pyrimidin-4-yl}amino)-1H-indazol-6-yl]spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-(trifluoromethyl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1S,2S)-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,(2S)-2-{3-[(5-cyclopropyl-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5’-methoxyspiro[cyclopropane-1,3’-indol]-2’(1’H)-one, (1R,2S)-2-(3-{[5-(difluoromethoxy)-2-(oxetan-3-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5’-methoxyspiro[cyclopropane-1,3’-indol]-2’(1’H)-one, (1R,2R)-5’-fluoro-2-{7-fluoro-3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3’-indol]-2’(1’H)-one, and (1R,2R)-2-(3-{[5-(difluoromethoxy)-2-methylpyrimidin-4-yl]amino}-7-fluoro-1H-indazol-6-yl)-5’-fluorospiro[cyclopropane-1,3’-indol]-2’(1’H)-one, a compound of formula (I) as selected therefrom, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided.,

[0116] This specification further includes (1R,2R)-2-{5-fluoro-3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[(3-methoxy-6-methylpyridazin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-(3-{[5-(cyclopropylmethoxy)-2-methylpyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-(3-{[5-(2,2-difluoroethoxy)-2-methylpyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-[3-(2-methoxy-5-methylanilino)-1H-indazol-6-yl]spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[2-methyl-5-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[(2-methoxy-6-methylpyridin-3-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[2-methyl-6-(propan-2-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-{3-[(5-ethyl-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[(2-methyl-6,7-dihydrofuro[3,2-d]pyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[5-methoxy-2-(oxan-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[5-methoxy-2-(methylsulfanyl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-{3-[(2,5-dimethoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-(3-{[2-(azetidin-1-yl)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-5-(trifluoromethyl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[(2-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-{3-[(2-ethyl-5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[(7-methoxyquinolin-6-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,(2S)-5'-Methoxy-2-(3-{[2-methyl-5-(methylsulfanyl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[(3-methoxyquinolin-2-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[(2,5-dimethoxypyridin-3-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[(2-chlorofuro[3,2-d]pyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, 6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyridine-2-carboxamide, (1R,2S)-5'-methoxy-2-(3-{[5-methoxy-2-(pyrrolidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[6-(methanesulfonyl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-[3-({2-[(3R)-3-fluoropyrrolidin-1-yl]-5-methoxypyrimidin-4-yl}amino)-1H-indazol-6-yl]-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[2-(3,3-difluoropyrrolidin-1-yl)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,(2S)-2-{3-[(2-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, 5-methoxy-4-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)pyrimidine-2-carbonitrile, (1R,2S)-2-(3-{[2-(3,3-difluoroazetidin-1-yl)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-(3-{[2-(3-fluoroazetidin-1-yl)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-{3-[5-(ethanesulfonyl)-2-methoxyanilino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, 4-methoxy-3-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylbenzamide, 4-methoxy-3-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)-N-methylbenzamide, (1R,2S)-5'-methoxy-2-{3-[2-methoxy-5-(propan-2-sulfonyl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, 4-methoxy-3-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylbenzenesulfonamide, (1R,(2S)-5’-Methoxy-2-{3-[2-methoxy-5-(morpholine-4-carbonyl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3’-indole]-2’(1’H)-one, 6-methoxy-5-({6-[(1R,2S)-5’-methoxy-2’-oxo-1’,2’-dihydrospiro[cyclopropane-1,3’-indole]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyridine-3-carboxamide, (1R,2S)-2-(3-{[2-(dimethylamino)-5-methylpyrimidin-4-yl]amino}-1H-indazol-6-yl)-5’-methoxyspiro[cyclopropane-1,3’-indole]-2’(1’H)-one, (1R,2S)-5’-methoxy-2-(3-{[2-methoxy-6-(morpholine-4-carbonyl)pyridin-3-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3’-indole]-2’(1’H)-one, (1R,2S)-2-(3-{[6-(3,3-difluoroazetidine-1-carbonyl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5’-methoxyspiro[cyclopropane-1,3’-indole]-2’(1’H)-one, (1R,2S)-2-(3-{[6-(4,4-difluoropiperidine-1-carbonyl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5’-methoxyspiro[cyclopropane-1,3’-indole]-2’(1’H)-one, (1R,2S)-2-(4-fluoro-3-{[5-methoxy-2-(methylsulfanyl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5’-methoxyspiro[cyclopropane-1,3’-indole]-2’(1’H)-one, (1R,2S)-5’-methoxy-2-{3-[(2-methoxy-5-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3’-indole]-2’(1’H)-one, (1R,(2S)-5’-Methoxy-2-(3-{[2-methoxy-6-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)pyridin-3-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3’-indole]-2’(1’H)-one, (1R,2S)-2-(3-{[2-(4,4-difluoropiperidin-1-yl)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)-5’-methoxyspiro[cyclopropane-1,3’-indole]-2’(1’H)-one, 4-[5-methoxy-4-({6-[(1R,2S)-5’-methoxy-2’-oxo-1’,2’-dihydrospiro[cyclopropane-1,3’-indole]-2-yl]-1H-, {Indazol-3-yl}amino)pyrimidin-2-yl]-1λ6-thiomorpholin-1,1-dione, 6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)-N-methylpyridine-2-carboxamide, (1R,2S)-5'-methoxy-2-(3-{[5-methoxy-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-(3-{[5-(methanesulfonyl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, 6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)-N-methyl-N-(propan-2-yl)pyridine-2-carboxamide, (1R,2S)-2-(3-{[5-ethoxy-2-(methylsulfanyl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-(3-{[6-(methanesulfonyl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, 5-methoxy-6-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyridine-3-carboxamide, 5-methoxy-4-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyridine-2-carboxamide, (1R,(2S)-5'-Methoxy-2-{3-[2-methoxy-4-(morpholine-4-carbonyl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, diastereomer 1: (1R,2S)-5'-Methoxy-2-(3-{[5-methoxy-2-(oxolan-3-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, diastereomer 2: (1R,2S)-5'-Methoxy-2-(3-{[5-methoxy-2-(oxolan-3-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-(3-{[2-ethoxy-6-(methanesulfonyl)pyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, 5-ethoxy-6-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyridine-3-carboxamide, 5-methoxy-6-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyridine-3-sulfonamide, (1R,2S)-2-(3-{[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, 2-fluoro-5-methoxy-4-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylbenzamide, (1R,2S)-2-{3-[5-fluoro-2-methoxy-4-(morpholine-4-carbonyl)anilino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,Compounds of formula (I) selected from 3'-indol]-2'(1'H)-one, and (1R,2S)-2-(3-{[3-ethoxy-5-(methanesulfonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, or a pharmaceutically acceptable salt thereof are provided.,

[0117] This specification further includes (1R,2S)-2-(3-{[6-(ethanesulfonyl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, 5-methoxy-4-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)-N,2-dimethylbenzene-1-sulfonamide, (1R,2S)-2-{3-[(2,5-dimethyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, 2,5-dimethoxy-4-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)benzene-1-sulfonamide, (1R,2S)-2-(3-{[2-(dimethylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, 6-ethoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyridine-2-carboxamide, (1R,2S)-5'-methoxy-2-(3-{[2-methoxy-6-(2-oxopyrrolidin-1-yl)pyridin-3-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[2-methoxy-5-(morpholine-4-sulfonyl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[(3-methoxy-1,{5-Naphthyridin-2-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, N,6-dimethoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)-N-methylpyridine-2-carboxamide, 6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)-N'-(propan-2-yl)pyridine-2-carbohydrazide, (1R,2S)-5'-methoxy-2-(3-{[2-methoxy-5-(2-oxopyrrolidin-1-yl)pyridin-3-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[2-methoxy-5-(3-methyl-2-oxoimidazolidin-1-yl)pyridin-3-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, 6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyridine-2-sulfonamide, 6-ethoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyridine-2-sulfonamide, (1R,2S)-5'-methoxy-2-{3-[2-methoxy-5-(oxane-4-sulfonyl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-(3-{[5-(dimethylphosphoryl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3’-Indol]-2’(1’H)-one, (1R,2S)-2-(3-{[5-(2-Hydroxypropan-2-yl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5’-methoxispiro[cyclopropane-1,3’-indol]-2’(1’H)-one, (1R,2S)-2-(3-{[6-(Methanesulfonyl)-2-methoxy-5-methylpyridin-3-yl]amino}-1H-indazol-6-yl)-5’-methoxispiro[cyclopropane-1,3’-indol]-2’(1’H)-one, (1R,2S)-2-(3-{[5-(Ethanesulfonyl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5’-methoxispiro[cyclopropane-1,3’-indol]-2’(1’H)-one, (1R,2S)-2-(3-{[5-(Dimethylphosphoryl)-3-methoxypyrazin-2-yl]amino}-1H-indazol-6-yl)-5’-methoxispiro[cyclopropane-1,3’-indol]-2’(1’H)-one, N-(Cyclopropylmethyl)-6-methoxy-5-({6-[(1R,2S)-5’-methoxy-2’-oxo-1’,2’-dihydrospiro[cyclopropane-1,3’-indol]-2-yl]-1H-indazol-3-yl}amino)pyridine-2-carboxamide, 6-methoxy-5-({6-[(1R,2S)-5’-methoxy-2’-oxo-1’,2’-dihydrospiro[cyclopropane-1,3’-indol]-2-yl]-1H-indazol-3-yl}amino)-N-(propan-2-yl)pyridine-2-carboxamide, (1R,2S)-5’-methoxy-2-(3-{[2-methoxy-6-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)pyridin-3-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3’-indol]-2’(1’H)-one, (1R,2S)-5’-methoxy-2-{3-[(4-methoxy-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3’-indol]-2’(1’H)-one, (1R,2S)-5’-methoxy-2-(3-{[2-methoxy-5-(1,(3-Oxazol-2-yl)pyridin-3-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-5-(3-methoxyazetidine-1-carbonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, 6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyrazine-2-carboxamide, 6-ethoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyrazine-2-carboxamide, 6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)-N,N,3-trimethylpyridine-2-carboxamide, (1R,2S)-2-(3-{[6-(methanesulfinyl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-(3-{[6-(methanesulfinyl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-(3-{[6-(methanesulfonyl)-4-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-(3-{[5-(methanesulfonyl)-3-methoxypyrazin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, N,N-dicyclopropyl-6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)pyridine-2-carboxamide, N-(2,2-difluoroethyl)-6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)pyridine-2-carboxamide, (1R,2S)-2-[3-({6-[(2R,6S)-2,6-dimethylpiperidine-1-carbonyl]-2-methoxypyridin-3-yl}amino)-1H-indazol-6-yl]-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[2-methoxy-6-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)pyridin-3-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-(3-{[3-chloro-5-(methanesulfonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-5-(propan-2-sulfonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-(3-{[6-(dimethylphosphoryl)-4-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, N-(1,3-difluoropropan-2-yl)-6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)pyridine-2-carboxamide, 6-chloro-5-({6-[(1R,((1R,2S)-5'-Methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl)-1H-indazol-3-yl}amino)-N,N-dimethylpyridine-2-carboxamide, (1R,2S)-2-{3-[(5-chloro-2-methyl-1,3-benzoxazol-6-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H), -One, 4-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazole-3-yl}amino)-N,N-dimethylpyridine-2-carboxamide, 3-[6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazole-3-yl}amino)pyrazin-2-yl]-1λ6-thietane-1,1-dione, (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-5-(morpholine-4-sulfonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-5-(8-oxa-3-azabicyclo[3.2.1]octane-3-sulfonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-(3-{[6-(diethylphosphoryl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-(3-{[5-(cyclopropanesulfonyl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-5-(oxane-4-sulfonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one, 6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazole-3-yl}amino)pyridine-2-carbonitrile, (1R,(2S)-2-{3-[5-(Diethylphosphoryl)-2-methoxyanilino]-1H-indazol-6-yl}-5’-methoxyspiro[cyclopropane-1,3’-indol]-2’(1’H)-one, (1R,2S)-2-(3-{[6-(Ethanesulfonyl)-4-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5’-methoxyspiro[cyclopropane-1,3’-indol]-2’(1’H)-one, (1R,2S)-2-(3-{[5-(Azetidine-1-carbonyl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5’-methoxyspiro[cyclopropane-1,3’-indol]-2’(1’H)-one, (1R,2S)-5’-Methoxy-2-(3-{[3-methoxy-5-(morpholine-4-carbonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3’-indol]-2’(1’H)-one, (1R,2S)-5’-Methoxy-2-{3-[(6-methoxy-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3’-indol]-2’(1’H)-one, (1R,2S)-5’-Methoxy-2-{3-[(4-methoxy-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3’-indol]-2’(1’H)-one, (1R,2S)-5’-Methoxy-2-(3-{[3-methoxy-5-(1,2-oxazolidine-2-sulfonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3’-indol]-2’(1’H)-one, (1R,2S)-2-(3-{[5-(Azetidine-1-sulfonyl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5’-methoxyspiro[cyclopropane-1,3’-indol]-2’(1’H)-one, 5-Methoxy-6-({6-[(1R,2S)-5’-methoxy-2’-oxo-1’,2’-dihydrospiro[cyclopropane-1,{3’-Indol]-2-yl]-1H-indazol-3-yl}amino)-N-(3-methyloxetan-3-yl)pyridine-3-sulfonamide, 5-methoxy-6-({6-[(1R,2S)-5’-methoxy-2’-oxo-1’,2’-dihydrospiro[cyclopropane-1,3’-indole]-2-yl]-1H-indazol-3-yl}amino)-N-methyl-N-(3-methyloxetan-3-yl)pyridine-3-sulfonamide, (1R,2S)-2-(3-{[5-(1-hydroxyethyl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5’-methoxyspiro[cyclopropane-1,3’-indole]-2’(1’H)-one, (1R,2S)-2-{3-[2-ethoxy-4-(methanesulfonyl)anilino]-1H-indazol-6-yl}-5’-methoxyspiro[cyclopropane-1,3’-indole]-2’(1’H)-one, (1R,2S)-2-(3-{[3-ethoxy-5-(4-methylpiperazine-1-sulfonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)-5’-methoxyspiro[cyclopropane-1,3’-indole]-2’(1’H)-one, (1R,2S)-2-(3-{[5-(ethanesulfonyl)-3-ethoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5’-methoxyspiro[cyclopropane-1,3’-indole]-2’(1’H)-one, 5-ethoxy-6-({6-[(1R,2S)-5’-methoxy-2’-oxo-1’,2’-dihydrospiro[cyclopropane-1,3’-indole]-2-yl]-1H-indazol-3-yl}amino)-N-methylpyridine-3-sulfonamide, (1R,2S)-5’-chloro-2-(3-{[3-ethoxy-5-(methanesulfonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3’-indole]-2’(1’H)-one, (1R,2S)-2-{3-[(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)amino]-1H-indazol-6-yl}-5’-methoxyspiro[cyclopropane-1,3’-indole]-2’(1’H)-one, (1R,The compound of formula (I) selected from (2S)-2-(3-{[6-(2-hydroxypropan-2-yl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxispiro[cyclopropane-1,3'-indole]-2'(1'H)-one, (1R,2S)-2-(3-{[4-ethoxy-6-(methanesulfonyl)pyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxispiro[cyclopropane-1,3'-indole]-2'(1'H)-one, and (1R,2S)-2-(3-{[5-(difluoromethanesulfonyl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxispiro[cyclopropane-1,3'-indole]-2'(1'H)-one, or a pharmaceutically acceptable salt thereof, is provided.,

[0118] Further provided herein are compounds of formula (I) selected from those described in Table 1A.,

[0119] [Table 1A-1]

[0120] [Table 1A-2]

[0121] [Table 1A-3]

[0122] [Table 1A-4]

[0123] [Table 1A-5]

[0124]

Table 1A-6

[0125]

Table 1A-7

[0126]

Table 1A-8

[0127]

Table 1A-9

[0128]

Table 1A-10

[0129]

Table 1A-11

[0130]

Table 1A-12

[0131]

Table 1A-13

[0132]

Table 1A-14

[0133]

Table 1A-15

[0134]

Table 1A-16

[0135]

Table 1A-17

[0136]

Table 1A-18

[0137]

Table 1A-19

[0138]

Table 1A-20

[0139]

Table 1A-21

[0140]

Table 1A-22

[0141]

Table 1A-23

[0142]

Table 1A-24

[0143]

Table 1A-25

[0144]

Table 1A-26

[0145]

Table 1A-27

[0146]

Table 1A-28

[0147]

Table 1A-29

[0148]

Table 1A-30

[0149]

Table 1A-31

[0150]

Table 1A-32

[0151]

Table 1A-33

[0152]

Table 1A-34

[0153]

Table 1A-35

[0154]

Table 1A-36

[0155]

Table 1A-37

[0156]

Table 1A-38

[0157]

Table 1A-39

[0158]

Table 1A-40

[0159]

Table 1A-41

[0160]

Table 1A-42

[0161]

Table 1A-43

[0162]

Table 1A-44

[0163]

Table 1A-45

[0164]

Table 1A-46

[0165]

Table 1A-47

[0166]

Table 1A-48

[0167]

Table 1A-49

[0168]

Table 1A-50

[0169]

Table 1A-51

[0170]

Table 1A-52

[0171]

Table 1A-53

[0172]

Table 1A-54

[0173]

Table 1A-55

[0174]

Table 1A-56

[0175] Furthermore, the present specification provides a pharmaceutical composition comprising an amount of a compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and one or more pharmaceutically acceptable excipients.

[0176] Treatment method Further provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition comprising a compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Also provided herein is a method of treating cancer in a subject, wherein the cancer of the subject is a solid tumor. In some embodiments, the cancer is neuroblastoma, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal cell carcinoma, renal pelvic cancer, central nervous system (CNS) neoplasm, primary CNS lymphoma, spinal cord axis tumor, brainstem glioma, or pituitary adenoma. In some embodiments, the cancer of the subject expresses polo-like kinase 4 (PLK4). In some embodiments, the cancer of the subject has been determined to express polo-like kinase 4 (PLK4) prior to administering to the subject a compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the cancer of the subject exhibits overexpression of the E3 ubiquitin-protein ligase (TRIM37) protein. In some embodiments, the cancer of the subject exhibits overexpression of the gene encoding the tripartite motif-containing protein 37 (TRIM37). In some embodiments, the cancer of the subject exhibits amplification of the gene encoding the tripartite motif-containing protein 37 (TRIM37).

[0177] Further provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the cancer of the subject has been determined to overexpress a gene encoding tripartite motif-containing protein 37 (TRIM37) prior to administration of the compound to the subject.

[0178] Further provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the cancer of the subject has been determined to overexpress a gene encoding tripartite motif-containing protein 37 (TRIM37).

[0179] Further provided herein is a method of treating cancer in a subject, comprising a. obtaining a biological sample of cancer from the subject; b. determining whether the biological sample of cancer overexpresses a gene encoding tripartite motif-containing protein 37 (TRIM37); and c. if the biological sample of cancer is determined to overexpress a gene encoding tripartite motif-containing protein 37 (TRIM37), administering to the subject a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. A method comprising the above steps is provided.

[0180] Further provided herein is a method of treating cancer in a subject as described herein, wherein the cancer is neuroblastoma or breast cancer. Further provided herein is a method of treating cancer in a subject as described herein, wherein the cancer is neuroblastoma. Further provided herein is a method of treating cancer in a subject as described herein, wherein the cancer is breast cancer.

[0181] Further provided herein is a method of treating a cancer of a subject described herein, wherein a compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is administered to the subject together with one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are selected from one or more mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, antiangiogenic agents, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors such as protein tyrosine kinase inhibitors and / or serine / threonine kinases, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxic agents, and tumor immunotherapeutic agents.

[0182] Also provided herein is a method of inhibiting polo-like kinase 4 (PLK4) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition comprising a compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0183] Also provided herein is a method of inhibiting polo-like kinase 4 (PLK4) in a subject having cancer, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition comprising a compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the cancer of the subject has been determined to express polo-like kinase 4 (PLK4) prior to administering the compound or pharmaceutical composition to the subject.

[0184] Further provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the cancer of the subject is acute myeloid leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, triple-negative breast cancer, advanced breast cancer, metastatic breast cancer, or prostate cancer. In some embodiments, the cancer of the subject is acute myeloid leukemia. In some embodiments, the cancer of the subject is myelodysplastic syndrome. In some embodiments, the cancer of the subject is chronic myelomonocytic leukemia. In some embodiments, the cancer of the subject is triple-negative breast cancer. In some embodiments, the cancer of the subject is advanced breast cancer. In some embodiments, the cancer of the subject is metastatic breast cancer. In some embodiments, the cancer of the subject is prostate cancer.

[0185] Further provided herein are compounds of formula (I), (Ia), (Ib), (II), or (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, for use in a method of treating cancer in a subject in need thereof, or a pharmaceutical composition comprising a compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, provided are the compounds or pharmaceutical compositions for use as described above, wherein the cancer is a solid tumor. In some embodiments, provided are the compounds or pharmaceutical compositions for use as described above, wherein the cancer is neuroblastoma, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal cell cancer, renal pelvis cancer, central nervous system (CNS) neoplasm, primary CNS lymphoma, spinal cord axis tumor, brainstem glioma, or pituitary adenoma. In some embodiments, provided are the compounds or pharmaceutical compositions for use as described above, wherein the cancer of the subject expresses polo-like kinase 4 (PLK4). In some embodiments, provided are the compounds or pharmaceutical compositions for use as described above, wherein the cancer of the subject has been determined to express polo-like kinase 4 (PLK4) prior to administration of the compound or pharmaceutical composition to the subject. In some embodiments, provided are the compounds or pharmaceutical compositions for use as described above, wherein the cancer of the subject exhibits overexpression of the E3 ubiquitin-protein ligase (TRIM37) protein. In some embodiments, provided are the compounds or pharmaceutical compositions for use as described above, wherein the cancer of the subject exhibits overexpression of the gene encoding tripartite motif-containing protein 37 (TRIM37). In some embodiments, provided are the compounds or pharmaceutical compositions for use as described above, wherein the cancer of the subject exhibits amplification of the gene encoding tripartite motif-containing protein 37 (TRIM37).In some embodiments, there is provided a compound or pharmaceutical composition for use as described above, wherein the cancer of interest has been determined to overexpress the gene encoding tripartite motif-containing protein 37 (TRIM37) prior to administration of the compound or pharmaceutical composition to the subject. In some embodiments, there is provided a compound or pharmaceutical composition for use as described above, wherein the cancer is neuroblastoma or breast cancer. In some embodiments, there is provided a compound or pharmaceutical composition for use as described above, wherein the cancer is neuroblastoma. In some embodiments, there is provided a compound or pharmaceutical composition for use as described above, wherein the cancer is breast cancer.

[0186] Further provided herein is a compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition comprising a compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in treating cancer in a subject in need thereof, wherein the cancer of the subject is acute myeloid leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, triple-negative breast cancer, advanced breast cancer, metastatic breast cancer, or prostate cancer. In some embodiments, the cancer of the subject is acute myeloid leukemia. In some embodiments, the cancer of the subject is myelodysplastic syndrome. In some embodiments, the cancer of the subject is chronic myelomonocytic leukemia. In some embodiments, the cancer of the subject is triple-negative breast cancer. In some embodiments, the cancer of the subject is advanced breast cancer. In some embodiments, the cancer of the subject is metastatic breast cancer. In some embodiments, the cancer of the subject is prostate cancer.

[0187] Furthermore, the present specification provides a compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in a method of inhibiting polo-like kinase 4 (PLK4) in a subject having cancer, or a pharmaceutical composition comprising a compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0188] Furthermore, the present specification provides the use of a compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition comprising a compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in the manufacture of a medicament for treating cancer in a subject in need of cancer treatment. In some embodiments, the cancer is neuroblastoma, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal cell cancer, renal pelvis cancer, central nervous system (CNS) neoplasm, primary CNS lymphoma, spinal cord axis tumor, brainstem glioma, or pituitary adenoma. In some embodiments, the cancer of the subject expresses polo-like kinase 4 (PLK4). In some embodiments, the cancer of the subject has been determined to express polo-like kinase 4 (PLK4) prior to administration of the compound to the subject. In some embodiments, the cancer of the subject exhibits overexpression of the E3 ubiquitin-protein ligase (TRIM37) protein. In some embodiments, the cancer of the subject exhibits overexpression of the gene encoding the tripartite motif-containing protein 37 (TRIM37). In some embodiments, the cancer of the subject exhibits amplification of the gene encoding the tripartite motif-containing protein 37 (TRIM37). In some embodiments, the cancer of the subject has been determined to overexpress the gene encoding the tripartite motif-containing protein 37 (TRIM37) prior to administration of the compound to the subject. 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.

[0189] Further provided herein is the use of a compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition comprising a compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in the manufacture of a medicament for treating cancer in a subject in need thereof, wherein the cancer of the subject is acute myeloid leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, triple negative breast cancer, advanced breast cancer, metastatic breast cancer, or prostate cancer. In some embodiments, the cancer of the subject is acute myeloid leukemia. In some embodiments, the cancer of the subject is myelodysplastic syndrome. In some embodiments, the cancer of the subject is chronic myelomonocytic leukemia. In some embodiments, the cancer of the subject is triple negative breast cancer. In some embodiments, the cancer of the subject is advanced breast cancer. In some embodiments, the cancer of the subject is metastatic breast cancer. In some embodiments, the cancer of the subject is prostate cancer.

[0190] In some embodiments, the compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof 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, darbicin, epirubicin, docetaxel, cabazitaxel, or doxorubicin. In some embodiments, the anti-cancer agent is paclitaxel, daunomycin, darbicin, epirubicin, docetaxel, cabazitaxel, or doxorubicin. In one embodiment, the anti-cancer agent is docetaxel.

[0191] In some embodiments, the one or more additional anti-cancer agents can include, but are not limited to, surgery, radiation, or chemotherapeutic agents. Chemotherapeutic agents can be androgen receptor antagonists, mitotic inhibitors, antimetabolites, platinum-based drugs. Examples of androgen receptor antagonists include, but are not limited to, apalutamide, flutamide, nilutamide, bicalutamide, or enzalutamide. Examples of mitotic inhibitors include, but are not limited to, taxanes (e.g., paclitaxel, docetaxel, paclitaxel, docetaxel, cabazitaxel, tesetaxel, or nab-paclitaxel), or vinca alkaloids (e.g., vinblastine, vincristine, vindesine, or vinorelbine). Examples of antimetabolites include, but are not limited to, 5-fluorouracil, 6-mercaptopurine, capecitabine, cytarabine, floxuridine, fludarabine, gemcitabine, hydroxycarbamide, methotrexate, pemetrexed, or fotemustine. Examples of platinum-based drugs include, but are not limited to, cisplatin, carboplatin, diclo-platin, eptaplatin, lobaplatin, miltiplatin, nedaplatin, oxaliplatin, picoplatin, satraplatin, or triplatin tetranitrate. The additional anti-cancer therapeutic agent can include an anti-PDL1 agent, an anti-PD1 agent, or an anti-CTLA-4 agent. Anti-PD-L1 agents can include atezolizumab, avelumab, durvalumab, MPDL3280A (RG7446), MDX-1105 (BMS-936559), or BMS-935559, MSB0010718C, and MEDI4736. Anti-PD1 agents can include pembrolizumab, nivolumab, semiprimab, partalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS001), dostarlimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, or AMP-514 (MEDI0680). Anti-CTLA agents can include ipilimumab or tremelimumab.

[0192] Treatment methods that collaborate with biomarkers In some embodiments herein, methods for detecting the presence, absence, or level of a biomarker are disclosed. Such biomarkers can include genetic changes in genes encoding specific proteins such as tripartite motif-containing protein 37 (TRIM37). The presence, absence, or level of such a biomarker can be measured in a biological sample obtained from a subject, such as a sample of a solid tumor like prostate cancer, or from a sample of a related body fluid such as a blood sample. In some examples, the detection methods disclosed herein are useful for predicting a therapeutic response to a therapeutic agent described herein (e.g., a PLK4 inhibitor), monitoring treatment with a therapeutic agent for a proliferative disease or disorder described herein in a subject, and treating the subject with the therapeutic agent. In some embodiments, the presence or absence, and / or level of one or more biomarkers is detected by analyzing genetic material in a sample obtained from a subject. In some embodiments, the genetic material is obtained from blood, serum, plasma, sweat, hair, tears, urine, and by other techniques known to those of skill in the art. In some embodiments, the sample includes circulating tumor RNA (ctRNA). In some embodiments, the sample includes peripheral blood mononuclear cells (PBMC). Optionally, the genetic material is obtained from a tumor biopsy or a liquid biopsy. In some embodiments, the tumor biopsy includes a formalin-fixed paraffin-embedded biopsy, a fresh frozen biopsy, a fresh biopsy, or a frozen biopsy. In some embodiments, the liquid biopsy includes PBMC, circulating tumor RNA, RNA without plasma cells, or circulating tumor cells (CTC). The tumor biopsy may also be subject to additional analytical processing for sample dissociation, cell sorting, and enrichment for the cell population of interest.

[0193] In some embodiments, a method of detecting the presence, absence, or level of a biomarker in a sample obtained from a subject comprises detecting a nucleic acid sequence. Optionally, the nucleic acid sequence comprises deoxyribonucleic acid (DNA), such as in the case of detecting complementary DNA (cDNA) of an mRNA transcript. In some examples, the nucleic acid sequence comprises a denatured DNA molecule or a fragment thereof. In some examples, 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 examples, the DNA is single-stranded DNA (ssDNA), double-stranded DNA, denatured double-stranded DNA, synthetic DNA, and combinations thereof. The circular DNA can be cleaved or fragmented. In some examples, the nucleic acid sequence comprises ribonucleic acid (RNA). In some examples, the nucleic acid sequence comprises fragmented RNA. In some examples, the nucleic acid sequence comprises partially degraded RNA. In some examples, the nucleic acid sequence comprises microRNA or a portion thereof. In some examples, the nucleic acid sequence comprises an RNA molecule or a fragmented RNA molecule (RNA fragment) selected from microRNA (miRNA), pre-miRNA, pri-miRNA, mRNA, pre-mRNA, viral RNA, viroid RNA, virusoid RNA, circular RNA (circRNA), ribosomal RNA (rRNA), transfer RNA (tRNA), pre-tRNA, long non-coding RNA (lncRNA), small nuclear RNA (SnRNA), circulating RNA, cell-free RNA, exosomal RNA, vector-expressed RNA, RNA transcript, synthetic RNA, and combinations thereof.

[0194] In some embodiments herein, biomarkers are detected by subjecting a sample obtained from a subject to a nucleic acid-based detection assay. In some examples, nucleic acid-based detection assays include quantitative polymerase chain reaction (qPCR), gel electrophoresis (including, e.g., Northern blot or Southern blot), immunochemistry, in situ hybridization such as fluorescence in situ hybridization (FISH), cytochemistry, microarrays, or sequencing. In some embodiments, sequencing techniques include next-generation sequencing. In some embodiments, the method includes fluorescence-generating qPCR (e.g., TaqMan™, SYBR green I, SYBR green II, SYBR gold, ethidium bromide, methylene blue, pyronin Y, DAPI, acridine orange, Blue View, or phycoerythrin) that includes a nucleic acid amplification reaction with a specific primer pair, and hybridization assays such as hybridization to an amplified nucleic acid probe that includes a detectable moiety or molecule specific for the target nucleic acid sequence. In some examples, the number of amplification cycles for detecting a target nucleic acid in a qPCR assay is from about 5 to about 30 cycles. In some examples, the number of amplification cycles for detecting a target nucleic acid is at least about 5 cycles. In some examples, the number of amplification cycles for detecting a target nucleic acid is at most about 30 cycles. In some examples, the number of amplification cycles for detecting a target nucleic acid is from about 5 to about 10, 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. In the TaqMan™ method, the probe can be a hydrolyzable probe that includes a fluorophore and a quencher that are hydrolyzed by DNA polymerase when hybridized to the target nucleic acid. Optionally, if the number of amplification cycles reaching the threshold is 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, or less than 20 cycles, the presence of the target nucleic acid is determined.In some examples, hybridization can occur at standard hybridization temperatures, for example, between about 35°C and about 65°C in a standard PCR buffer.

[0195] Additional exemplary nucleic acid-based detection assays include the use of nucleic acid probes that are conjugated or otherwise immobilized on beads, multiwell plates, or other substrates, and the nucleic acid probes are configured to hybridize to a target nucleic acid sequence. In some examples, the nucleic acid probe is specific for one or more gene products described herein. In some examples, a nucleic acid probe specific for a biomarker comprises a nucleic acid probe sequence that is sufficiently complementary to the polynucleotide sequence of the biomarker. In some examples, the biomarker comprises a transcribed polynucleotide sequence (e.g., RNA, cDNA). In some embodiments, the nucleic acid probe is a full-length cDNA or a portion thereof, such as an oligonucleotide having a length of at least about 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides, and may be sufficient to specifically hybridize to the target nucleic acid sequence under standard hybridization conditions. In some embodiments, the target nucleic acid sequence is immobilized on a solid surface, for example, by flowing an isolated target nucleic acid sequence onto an agarose gel and transferring the target nucleic acid sequence from the gel to a membrane such as nitrocellulose, and contacted with the probe. In some embodiments, the probe is immobilized on a solid surface, such as in an Affymetrix gene chip array, and the probe is contacted with the target nucleic acid sequence.

[0196] In some embodiments, the term "probe" with respect to a nucleic acid refers to any nucleic acid molecule that is capable of selectively binding to a specifically intended target nucleic acid sequence. In some examples, the probe is specifically designed to be labeled with, for example, a radiolabel, a fluorescent label, an enzyme, a chemiluminescent tag, a colorimetric quantification tag, or other labels or tags known in the art. In some examples, the fluorescent label includes a fluorophore. In some examples, the fluorophore is an aromatic or heteroaromatic compound. In some examples, the fluorophore is pyrene, anthracene, naphthalene, acridine, stilbene, benzoxazole, indole, benzindole, oxazole, thiazole, benzothiazole, cyanine, carbocyanine, salicylate, anthranilate, xanthene dye, coumarin. Typical xanthene dyes include, for example, fluorescein and rhodamine dyes. Examples of fluorescein and rhodamine dyes include, but are not limited to, 6-carboxyfluorescein (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 naphthylamine dyes having an amino group at the alpha or beta position. For example, naphthylamine compounds include 1-dimethylaminonaphthyl-5-sulfonate, 1-anilino-8-naphthalenesulfonate, and 2-p-toluidinyl-6-naphthalenesulfonate, 5-(2’-aminoethyl)aminonaphthalene-1-sulfonic acid (EDANS).Typical coumarins include, for example, 3-phenyl-7-isocyanate coumarin; acridines such as 9-isothiocyanate acridine and acridine orange; N-(p-(2-benzoxazolyl)phenyl) maleimide; for example, 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-1-pyrrolidinyl)oxy]-6-oxohexyl]amino]sulfonyl]-4(or 2)-sulfophenyl]-2,3,6,7,12,13,16,17-octahydro-inner salt (TR or Texas Red); or BODIPYTM dyes. Optionally, the probe contains FAM as a dye label.

[0197] In some embodiments, detection of one or more biomarkers, such as gene products in a predictive response signature (PRS), involves sequencing genetic material obtained from a sample derived from a subject. Sequencing can be performed with any suitable sequencing technique, 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 next generation sequencing, such as modern sequencing techniques like Illumina sequencing (e.g., Solexa), Roche 454 sequencing, Ion Torrent sequencing, and SOLiD sequencing. Optionally, next generation sequencing includes high throughput sequencing methods. Additional sequencing methods available to those of skill in the art may also be employed.

[0198] In some examples, the number of nucleotides to be sequenced is 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 examples, the number of nucleotides to be sequenced is in the range of about 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.

[0199] Disclosed herein is a method comprising: (a) obtaining a sample from a subject having a proliferative disorder or condition (e.g., cancer); (b) assaying for the presence or absence of a relevant biomarker in the sample obtained from the subject; and (c) detecting the presence or absence of the biomarker in the sample using the methods described herein. Optionally, a hybridization assay, such as those described herein, is used to detect the biomarker in the sample. A typical probe sequence that is capable of hybridizing to a target nucleic acid sequence (e.g., one or more genes in a biomarker such as a PRS) comprises from 10 to 100 contiguous nucleotides that include the relevant sequence. Optionally, RNA sequencing (RNAseq) is used to detect one or more biomarkers.

[0200] Detection of a relevant biomarker optionally includes amplification of the subject's nucleic acid by polymerase chain reaction (PCR). In some embodiments, the PCR assay includes the use of a pair of primers capable of amplifying at least about 10 adjacent nucleobases within the nucleic acid sequence, whereby one or more gene products in the biomarker are amplified. In quantitative PCR with fluorescence generation, quantification is based on the amount of the fluorescence signal (TaqMan and SYBR green). In some embodiments, the nucleic acid probe is conjugated to a detectable molecule. The detectable molecule can be a fluorophore. The nucleic acid probe can also be conjugated to a quencher.

[0201] In some embodiments, an assay for detecting the presence or absence of a relevant biomarker includes reverse transcribing a relevant mRNA molecule to produce a corresponding complementary DNA (cDNA) molecule. In some embodiments, the assay further includes contacting the cDNA molecule with a nucleic acid probe that includes a nucleic acid sequence complementary to the nucleic acid sequence of the cDNA molecule. In some embodiments, the assay includes 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 include a first primer having a nucleic acid sequence that includes 10 to 50 consecutive nucleic acids within a relevant amino acid sequence that binds to the upper strand of the double-stranded hybridization product, and a second primer having a nucleic acid sequence that includes 10 to 50 consecutive nucleic acids within a relevant amino acid sequence that binds to the lower strand of the double-stranded hybridization product.

[0202] In some embodiments herein, a method is disclosed that includes the step of preparing a complementary DNA (cDNA) library. In some embodiments, the cDNA library is sequenced using a suitable sequencing method disclosed herein. In some embodiments, the cDNA library is labeled and a plurality of nucleic acid probes are generated and immobilized on a solid surface (such as a microarray). In some embodiments, the plurality of nucleic acid probes are capable of hybridizing to at least about 10 adjacent nucleotides of two or more genes in a sample obtained from a subject. In some embodiments, detecting the presence or absence of a biomarker includes detecting high-level or low-level expression of two or more genes as compared to a reference level.

[0203] In some embodiments herein, samples obtained from a subject, such as genetic material extracted from a blood or serum sample, are disclosed. 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, the technique uses alcohol precipitation with ethanol, methanol, or isopropyl alcohol. In certain embodiments, the technique uses phenol, chloroform, or any combination thereof. In certain embodiments, the technique uses cesium chloride. In certain embodiments, the technique uses sodium, potassium, or ammonium acetate, or other salts commonly used to precipitate DNA. In certain embodiments, the technique utilizes a nucleic acid purification scheme using a column or resin, such as those commonly commercially available, and one non-limiting example is the GenElute Bacterial Genomic DNA Kit available from Sigma Aldrich. In certain embodiments, after extraction, the nucleic acids are stored in water, Tris buffer, or Tris-EDTA buffer prior to subsequent analysis. In typical embodiments, the nucleic acid sample is extracted in water. Optionally, the extraction does not include nucleic acid purification. In certain embodiments, RNA can be extracted from cells using, for example, acid phenol / guanidinium isothiocyanate extraction (RNAzol B; Biogenesis), RNeasy RNA preparation kit (Qiagen), or PAXgene (PreAnalytix, Switzerland) including RNA extraction techniques.

[0204] Circulating tumor DNA (ctDNA) and RNA (ctRNA) In some aspects, circulating tumor DNA (ctDNA) is used to assess the presence of specific DNA molecules, and circulating tumor RNA (ctRNA) is used to assess the expression levels of RNA molecules, which are shed into the bloodstream by tumors.

[0205] In some embodiments, the detection of ctDNA or ctRNA is useful, for example, for the detection and diagnosis of tumors. Since tumor DNA and RNA have acquired numerous genetic mutations and led to tumor development, ctDNA and ctRNA do not exactly match the individual DNA and RNA, respectively. Finding DNA and RNA with genetic differences is helpful for tumor detection. Diagnosing the type of tumor using ctDNA or ctRNA can reduce the need to obtain a sample of tumor tissue (tumor biopsy), which can be a problem when access to tumors such as brain or lung tumors is difficult.

[0206] In some embodiments, a decrease in the amount of ctDNA or ctRNA suggests that the solid tumor is shrinking and that treatment with the compounds of formula (I), (Ia), (Ib), (II), and (III), or a pharmaceutically acceptable salt thereof, is effective. In some embodiments, the absence of ctDNA or ctRNA in the bloodstream indicates that the cancer will not return after treatment with the compounds of formula (I), (Ia), (Ib), (II), and (III), or a pharmaceutically acceptable salt thereof.

[0207] Described herein are methods for assessing genetic changes by genomic profiling of ctDNA or ctRNA. In some embodiments, genomic profiling is performed for each treatment cycle with the compounds of formula (I), (Ia), (Ib), (II), and (III), or a pharmaceutically acceptable salt thereof. In some embodiments, the genetic mutations indicate that the cancer is becoming resistant to treatment with the compounds of formula (I), (Ia), (Ib), (II), and (III), or a pharmaceutically acceptable salt thereof. In some embodiments, the absence of genetic mutations indicates that the cancer is not becoming resistant to treatment with the compounds of formula (I), (Ia), (Ib), (II), and (III), or a pharmaceutically acceptable salt thereof.

[0208] The compounds of formula (I), (Ia), (Ib), (II), and (III) may be administered as prodrugs. Thus, derivatives of certain compounds, which may have little or no pharmacological activity per se, can be converted, upon administration to a mammal, into a compound having the desired activity, for example, by hydrolysis. Such derivatives are referred to as "prodrugs". Prodrugs can be produced by replacing appropriate functionalities present in the compounds of formula (I), (Ia), (Ib), (II), and (III) with certain moieties known to those of ordinary skill in the art. See, for example, "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T Higuchi 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 entirety. Some examples of such prodrugs include an ester moiety in place of a carboxylic acid functionality, an ether or amide moiety in place of an alcohol functionality, and an amide moiety in place of a primary or secondary amino functionality. Examples of substituents are known to those of ordinary skill in the art. See, for example, "Design of Prodrugs" by H Bundgaard (Elsevier, 1985), the disclosure of which is incorporated herein by reference in its entirety.

[0209] The salts of the present invention can be prepared by methods known to those skilled 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, clubranate, citrate, decanoate, dihydrochloride, dihydrogen phosphate, edetate, edisylicate, estolate, esylate, ethyl succinate, formate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycollylarsanilate, heptanoate, hexine-1,6-dioate, hexyl resorcinol, hydrabamine, hydrobromide, hydrochloride, γ-hydroxybutyrate, iodide, isobutyrate, isothionate, lactate, lactobionate, laurate, maleate, maleate, malonate, mandelate, mesylate, metaphosphate, methane-sulfonate, methyl sulfate, monohydrogen phosphate, mucate, napsylate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phenylacetate, phenylbutyrate, phenylpropionate, phthalate, phosphate / diphosphate, polygalacturonate, propanesulfonate, propionate, propionate, pyrophosphate, pyrosulfate, salicylate, stearate, subacetate, suberate, succinate, sulfate, sulfonate, sulfite, tannate, tartrate, theocrate, tosylate, triethiodode, and valerate.

[0210] The compounds of formulas (I), (Ia), (Ib), (II), and (III), which are usually basic, are capable of forming a wide variety of different salts with various inorganic and organic acids. Such salts must be pharmaceutically acceptable for administration to animals, but in many cases, it is desirable first to isolate the compounds of the invention as pharmaceutically acceptable salts from the reaction mixture and then to convert the latter back to the free base compound by treatment with an alkaline reagent and thereafter to convert the free base of the latter to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of the invention can be prepared by treating the basic compound with a substantially equivalent amount of a selected mineral or organic acid in an aqueous solvent or in a suitable organic solvent such as methanol or ethanol. After 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.

[0211] The compounds of formulas (I), (Ia), (Ib), (II), and (III), which are usually acidic, are capable of forming basic salts with various pharmaceutically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, specifically sodium salts and potassium salts. All of these salts are prepared by conventional techniques. The chemical bases used as reagents for preparing the pharmaceutically acceptable basic salts of the invention are those that form non-toxic basic salts with the acidic compounds of the invention. Examples of such non-toxic basic salts include those derived from pharmaceutically acceptable cations such as sodium, potassium, calcium, magnesium, etc. These salts can be prepared by treating the corresponding acidic compound with an aqueous solution containing the desired pharmaceutically acceptable cation and then, preferably under reduced pressure, evaporating the resulting solution to dryness. Alternatively, these salts can also be prepared by integrally mixing a lower alkanolic solution of the acidic compound with the desired alkali metal alkoxide and then evaporating the resulting solution to dryness in the same manner as described above. In either case, it is preferable to employ stoichiometric amounts of the reagents to ensure the completeness of the reaction and the maximum yield of the desired final product.

[0212] When the compounds of formula (I), (Ia), (Ib), (II), and (III) are bases, the desired salts may be prepared by treating the free base with any suitable method available in the art, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acids such as glucuronic acid and galacturonic acid, α-hydroxy acids such as citric acid and tartaric acid, amino acids such as aspartic acid and glutamic acid, aromatic acids such as benzoic acid and cinnamic acid, and sulfonic acids such as p-toluenesulfonic acid and ethanesulfonic acid.

[0213] When the compounds of formula (I), (Ia), (Ib), (II), and (III) are acids, the desired salts may be prepared by treating the free acid with any suitable method, for example, with inorganic or organic bases such as amines (primary, secondary, or tertiary), alkali metal hydroxides, or alkaline earth metal hydroxides. Exemplary examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, cyclic amines such as piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0214] When the compounds of formula (I), (Ia), (Ib), (II), and (III) are solids, those skilled in the art will understand that the compound or its salts may exist in various crystalline or polymorphic forms, and all of these forms are intended to be within the scope of the present invention and in the specified formula.

[0215] This specification also provides isotopically labeled compounds of formula (I), (Ia), (Ib), (II), and (III), wherein one or more atoms are replaced with atoms having the same number of atoms but a different atomic mass or mass number than the atomic mass or mass number typically found in nature. Examples of suitable isotopes for inclusion in the compounds of the invention include 2 H and 3 H and other hydrogen isotopes, 11 C, 13 C, and 14 C and other carbon isotopes, 36 Cl and other chlorine isotopes, 18 F and other fluorine isotopes, 123 I and 125 I and other iodine isotopes, 13 N and 15 N and other nitrogen isotopes, 15 O, 17 O, and 18 O and other oxygen isotopes, 32 P and other phosphorus isotopes, and 35 S and other sulfur isotopes. Certain isotopically labeled compounds of the invention, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. Tritium ([[]] 3 [[]] 14 [[]]H) and carbon-14 ([[]] 14 [[]] 2 [[]]C), which are radioactive isotopes, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with a heavier isotope such as deuterium ([[]] 2 [[]] 11 [[]]H) can result in certain therapeutic advantages due to greater metabolic stability, for example, an extended in vivo half-life or a reduced required dosage, and may thus be preferred in some situations. 11 C, 18 F, 15 O, and 13 N and other positron-emitting isotopes can be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy.

[0216] ​​​​​​The isotopically labeled compounds of formula (I), (Ia), (Ib), (II), and (III) can generally be prepared by conventional techniques known to those skilled in the art or, where appropriate, using isotopically labeled reagents in place of the unlabeled reagents employed, by processes similar to those described herein.

[0217] In one aspect, the compositions of the compounds of formula (I), (Ia), (Ib), (II), and (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, described herein are used for the treatment of cancer in a subject. In one embodiment, such compositions are in the form of a suitable dosage form. Suitable dosage forms include, for example, liquids, suspensions, powders for reconstitution, tablets, pills, sachets, or capsules made of hard or soft gelatin (see, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005))).

[0218] The compounds of formula (I), (Ia), (Ib), (II), and (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, can be formulated into pharmaceutical compositions in any pharmaceutical form recognized by those skilled in the art as suitable. The pharmaceutical compositions of the present invention comprise an effective amount of at least one compound of the present invention and an inert, pharmaceutically acceptable carrier or diluent.

[0219] The pharmaceutical carrier to be used may be either solid or liquid. Typical solid carriers include lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like. Typical liquid carriers include syrup, peanut oil, olive oil, water, and the like. Similarly, the compositions of the present invention may contain alone or in combination with waxes, ethyl cellulose, hydroxypropylmethyl cellulose, methyl methacrylate, and the like, time-delay or sustained-release materials known in the art such as glyceryl monostearate and glyceryl distearate. Additional additives or excipients may be added to achieve the desired formulation characteristics. For example, bioavailability enhancers such as Labrasol (trademark) and Gelucire (trademark), or formulating agents such as CMC (carboxy-methyl cellulose), PG (propylene glycol), or PEG (polyethylene glycol) may be added. For example, when preparing a capsule formulation, Gelucire (trademark), a semi-solid vehicle that protects the active ingredient from light, moisture, and oxidation, may be added.

[0220] When a solid carrier is used, the preparation can be tableted, placed in hard gelatin capsules in the form of powder or pellets, or formed into troches or lozenges. The amount of the solid carrier can vary, but generally ranges from about 25 mg to about 1 g. When a liquid carrier is used, the preparation may be in the form of syrup, emulsion, soft gelatin capsules, sterile injection solutions or suspensions in ampoules or vials, or non-aqueous liquid suspensions. When a semi-solid carrier is used, the preparation may be in the form of hard gelatin and soft gelatin capsule formulations. The compositions of the present invention are prepared in unit dosage forms suitable for the mode of administration, such as parenteral or oral administration.

[0221] To obtain a stable water-soluble dosage form, the salts of the compounds 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 drug may be dissolved in a suitable co-solvent or combination of co-solvents. Examples of suitable co-solvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin, etc. at a concentration ranging from 0 to 60% of the total volume. In a typical embodiment, the 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 the salt form of the active ingredient in a suitable aqueous vehicle such as water, isotonic saline, or a dextrose solution.

[0222] Suitable formulations depend on the selected route of administration. For injection, the drug of the compound of the present invention may preferably be formulated into an aqueous solution in a physiologically compatible buffer such as Hank's solution, Ringer's solution, or a physiological saline buffer. For transmucosal administration, a penetration enhancer appropriate for the barrier to be penetrated is used in the formulation. Such penetration enhancers are generally known in the art.

[0223] In the case of oral administration, the compounds can be formulated by combining the active compound with a pharmaceutically acceptable carrier known in the art. Such carriers enable the compounds of the present invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc. for administration by the subject to be treated. Oral pharmaceuticals can be obtained by using a solid excipient mixed with the active ingredient (drug), optionally grinding the resulting mixture, and treating the mixture of granules after optionally adding suitable auxiliaries to obtain a tablet or dragee core. Suitable additives include excipients such as saccharides including lactose, sucrose, mannitol, or sorbitol, and cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, gum, methylcellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). Optionally, disintegrants such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts such as sodium alginate may also be added.

[0224] The dragee cores are provided with a suitable coating. For this purpose, a concentrated sugar solution may be used, which may optionally contain gum arabic, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or pigments may be added to the tablet or dragee coating for the identification or characterization of various combinations of the active agent.

[0225] Pharmaceuticals that can be used orally include, in addition to gelatin push-fit capsules, soft-sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Push-fit capsules can contain an active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In the case of soft capsules, the active agent may be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, a stabilizer may be added. All formulations for oral administration must be in a dosage suitable for such administration. In the case of buccal administration, the composition may be formulated in the form of tablets or lozenges in a conventional manner.

[0226] For nasal or inhalation administration, the compounds for use according to the present invention may conveniently be delivered in the form of an aerosol spray from a pressurized pack or nebulizer, with the use of a suitable propellant such as 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 measured quantity. Gelatin capsules and cartridges used in inhalers and insufflators, etc. may be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch.

[0227] The compounds may be formulated for parenteral administration by injection, for example bolus injection or continuous infusion. Injectable formulations may be provided in unit dosage forms, for example in ampoules or multi-dose containers to which a preservative has been added. The composition may be in the form of a suspension, solution, or emulsion, etc. in an oily or aqueous vehicle, and may contain formulatory agents such as suspending agents, stabilizers, and / or dispersing agents.

[0228] Pharmaceutical preparations for parenteral administration contain an aqueous solution of the active compound in water-soluble form. Additionally, suspensions of the active agent may be prepared as suitable oily injection suspensions. Suitable lipidophilic solvents or vehicles include sesame oil, synthetic fatty acid esters such as ethyl oleate and triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound to enable the preparation of highly concentrated solutions.

[0229] Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, such as pyrogen-free distilled water, before use.

[0230] In addition to the above formulations, the compounds of the present invention can also be formulated as depot preparations. Such long-acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly), or by intramuscular injection. For this purpose, for example, the compound may be formulated with a suitable polymeric material or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion exchange resin, or as a slightly less soluble derivative, e.g., as a slightly less soluble salt. The pharmaceutical carrier for hydrophobic compounds is a co-solvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer, and an aqueous phase. The co-solvent system can be a VPD co-solvent system. VPD is a solution of 3% w / v benzyl alcohol, 8% w / v non-polar surfactant polysorbate 80, and 65% w / v polyethylene glycol 300, which is constituted at a maximum volume in absolute ethanol. The VPD co-solvent system (VPD:5W) contains VPD diluted 1:1 with 5% dextrose in an aqueous solution. This co-solvent system dissolves hydrophobic compounds sufficiently and has low toxicity on its own when administered systemically. The ratio of the co-solvent system may be suitably varied without destroying its solubility and toxicity characteristics. Further, the identity of the co-solvent components may be varied, for example, other low-toxic non-polar surfactants may be used instead of polysorbate 80, the number of segments of polyethylene glycol may be varied, other biocompatible polymers may be substituted for polyethylene glycol, e.g., polyvinylpyrrolidone, and other saccharides or polysaccharides may be used instead of dextrose.

[0231] Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be utilized. Known examples of delivery vehicles or carriers for hydrophobic drugs are liposomes and emulsions. Certain organic solvents such as dimethyl sulfoxide (DMSO) may also be employed, but usually many toxicities arise due to the toxic nature of DMSO. In addition, the compounds may be delivered using a sustained release system such as a semipermeable matrix of a solid hydrophobic polymer containing the therapeutic agent. Various sustained release materials have been established and are known to those skilled in the art. Sustained release capsules release the compound over a period of weeks to over 100 days depending on their chemical nature. Depending on the chemical nature and biostability of the therapeutic reagent, additional strategies for protein stabilization may be employed.

[0232] The pharmaceutical composition may also include a suitable solid or gel phase carrier or excipient. These carriers and excipients can bring about a significant improvement in the bioavailability of drugs with insufficient solubility. Examples of such carriers or additives include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol. Additionally, additives or excipients such as Gelucire™, Capryol™, Labrafil™, Labrasol™, Lauroglycol™, Plurol™, Peceol™, Transcutol™ may be used.

[0233] Furthermore, the pharmaceutical composition may be incorporated into a skin patch for direct delivery of the drug to the skin.

[0234] The actual dosage of the agent of the present invention may vary depending on the particular agent used, the particular composition formulated, the mode of administration, and the particular site, host, and disease being treated. One skilled in the art can use conventional dosage determination tests considering the experimental data for a given compound and confirm the optimal dosage for a given set of conditions. In the case of oral administration, a typical daily dosage commonly employed is about 0.001 to about 1000 mg per kg of body weight, and the treatment regimen is repeated at appropriate intervals.

[0235] Furthermore, the pharmaceutically acceptable formulation of the present invention may contain the compound of the present invention, or a salt or solvate thereof, in an amount of about 10 mg to about 2000 mg, about 10 mg to about 1500 mg, about 10 mg to about 1000 mg, about 10 mg to about 750 mg, about 10 mg to about 500 mg, about 25 mg to about 500 mg, about 50 to about 500 mg, or about 100 mg to about 500 mg.

[0236] Furthermore, the pharmaceutically acceptable formulation of the present invention may contain the compound of the present invention, or a salt or solvate thereof, in an amount of about 0.5 w / w% to about 95 w / w%, about 1 w / w% to about 95 w / w%, about 1 w / w% to about 75 w / w%, about 5 w / w% to about 75 w / w%, about 10 w / w% to about 75 w / w%, or about 10 w / w% to about 50 w / w%.

[0237] The compound of the present invention, or a salt or solvate thereof, can be administered once a day, twice a day, three times a day, four times a day, or more frequently, either alone or as part of a pharmaceutically acceptable formulation, to mammals such as humans suffering from abnormal cell growth.

[0238] For those skilled in the art, with respect to the compounds of formula (I), (Ia), (Ib), (II), or (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, the specific pharmaceutical formulation, dosage, and the number of administrations per day given to mammals in need of the above-described treatment can all be selected within the scope conceivable by those skilled in the art and determined without the need for undue experimentation.

[0239] The dosage of the compositions described herein can be determined by any suitable method. The maximum tolerated dose (MTD) and the maximum response dose (MRD) in a compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, can be determined by established experimental protocols for animals and humans, as well as in the examples described herein. For example, the toxicity and therapeutic efficacy of a compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, can be determined in cell cultures or experimental animals by standard pharmaceutical procedures including, but not limited to, determination of the LD50 (lethal dose for 50% of the population) and the ED50 (therapeutically effective dose for 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index, which can be expressed as the ratio of the LD50 to the ED50. Data obtained from cell culture assays and animal tests can be used to formulate a dosage range for use in humans. The dosage of such a compound preferably lies within a range of circulating concentrations that includes the ED50 with minimum toxicity. The dosage may vary within this range depending on the dosage form employed and the route of administration utilized. Further relative dosages are expressed as a percentage of the maximum response or maximum tolerated dose and can be readily obtained via this protocol.

[0240] In some embodiments, the amount of a compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, varies depending on factors such as the particular salt or form, the disease state and its severity, the identity of the subject or host in need of treatment (e.g., age, weight, gender), etc., but still can be determined according to the particular circumstances surrounding the case, e.g., the particular drug being administered, the type of liquid formulation, the disease being treated, and the subject or host being treated.

[0241] In some embodiments, the compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in an amount between about 10 mg and 500 mg per day. In some embodiments, the compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in an amount between about 100 mg and about 400 mg per day. In some embodiments, the compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in an amount between about 150 mg and about 350 mg per day. In some embodiments, the compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in an amount between about 150 mg and about 300 mg per day. In some embodiments, the compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in an amount between about 160 mg and about 350 mg per day. In some embodiments, the compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in an amount of about 160 mg per day. In some embodiments, the compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in an amount of about 200 mg per day. In some embodiments, the compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in an amount of about 240 mg per day. In some embodiments, the compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in an amount of about 280 mg per day.In some embodiments, the compounds of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are administered in an amount between about 320 mg per day.

[0242] Generally, appropriate dosages and treatment regimens provide the composition in an amount sufficient to provide a therapeutic and / or prophylactic benefit (e.g., improvement of a clinical outcome), such as more frequent complete or partial remission, longer disease-free survival and / or overall survival, or reduction in severity of symptoms. Optimal dosages are generally determined using experimental models and / or clinical trials. Optimal dosages depend on the body size, body weight, or blood volume of the subject. Generally, appropriate dosages and treatment regimens provide the composition in an amount sufficient to provide a therapeutic and / or prophylactic benefit (e.g., improvement of a clinical outcome), such as more frequent complete or partial remission, longer disease-free survival and / or overall survival, or reduction in severity of symptoms. Optimal dosages are generally determined using experimental models and / or clinical trials. Optimal dosages depend on the body size, body weight, or blood volume of the subject.

[0243] In certain embodiments where the condition of the subject does not improve, at the discretion of the physician, administration of the compositions described herein is carried out over a long term, i.e., over the entire lifespan of the subject to alleviate or otherwise control or limit the symptoms of the subject's disease or disorder. In other embodiments, administration of the composition continues until a complete or partial response to the disease occurs.

[0244] In some embodiments, a compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered once daily to a subject in need thereof. In some embodiments, a compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered twice daily to a subject in need thereof. In some embodiments, a compound of formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered three times daily to a subject in need thereof.

[0245] In some examples, the methods described herein are in a plurality of cycles repeated on a regular schedule with a rest period between each cycle, and comprise administering to a subject in need thereof a composition and formulation comprising a compound of formula (I), (Ia), (Ib), (II), (III) in combination with one or more additional therapeutic agents. For example, in some examples, a 3-week rest after a 1-week treatment is one treatment cycle.

[0246] The length of the treatment cycle depends on the treatment being performed. In some embodiments, the length of the treatment cycle ranges from 2 to 6 weeks. In some embodiments, the length of the treatment cycle ranges from 3 to 6 weeks. In some embodiments, the length of the treatment cycle ranges from 3 to 4 weeks. In some embodiments, the length of the treatment cycle is 3 weeks (i.e., 21 days). In some embodiments, the length of the treatment cycle is 4 weeks (28 days). In some embodiments, the length of the treatment cycle is 56 days. In some embodiments, the treatment cycle lasts 1, 2, 3, or 4 weeks. In some embodiments, the treatment cycle lasts 3 weeks. In some embodiments, the treatment cycle lasts 4 weeks. The number of treatment administrations scheduled within each cycle also varies depending on the drug given.

[0247] Kits and Manufactured Articles In certain embodiments herein, kits and articles of manufacture for use in one or more of the methods and compositions described herein are disclosed. Such kits comprise a carrier, package, or container that is compartmentalized to receive one or more containers, such as vials and tubes, each of the containers containing one of the distinct elements to be used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, and the like. The containers may be formed from a variety of materials, such as glass or plastic.

[0248] The kit typically comprises a label and / or instructions listing the contents, as well as an accompanying document with instructions. Typically, a set of instructions will also be included.

[0249] In one embodiment, the label is on or associated with the container. In one embodiment, the label is on the container if the letters, numbers, or other characters forming the label are attached to, molded onto, or engraved on the container itself, or is associated with the container as an accompanying document, for example, if it is present in a receptacle or carrier that holds the container. In one embodiment, the label is used to indicate that the contents are for use in a particular therapeutic application. The label also indicates instructions regarding the use of the contents in methods such as those described herein.

[0250] In certain embodiments, the pharmaceutical composition is provided in a pack or dispenser comprising one or more unit dosage forms containing the compounds provided herein. The pack includes a metal or plastic foil, such as, for example, a blister pack. In one embodiment, the pack or dispenser is accompanied by instructions for administration. In one embodiment, the pack or dispenser is also accompanied by a notice affixed to the container in a form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects approval by the agency of the form of the drug for human or veterinary administration. Such notice is, for example, a label approved by the U.S. Food and Drug Administration for the drug, or an approved product insert. In one embodiment, a composition containing a compound provided herein, formulated in a compatible pharmaceutical carrier, is also prepared, placed in an appropriate container, and labeled for the treatment of an indication.

[0251] Preparation Method The compounds of formula (I), (Ia), (Ib), (II), or (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, can be prepared by employing techniques available in the art using readily available starting materials and the reaction pathways and synthetic schemes described hereinafter. The preparation of specific embodiments of the invention is detailed in the following examples, but those skilled in the art will understand that the preparations described can be readily adopted to prepare other embodiments of the invention. For example, the synthesis of compounds not exemplified by the present invention can be effected by modifications apparent to those skilled in the art, such as, for example, appropriately protecting interfering groups, changing to other suitable reagents known in the art, or making conventional modifications to reaction conditions. Alternatively, other reactions referred to herein or known in the art will be recognized as having applicability for preparing other compounds of the invention.

[0252] The compound of formula (I) is R 2 , R 3 , R 4a, R 4b , R 4c , R 5 , R 6 , R 7 , R 8a , R 8b , R 8c , and R 8d reacting a compound of formula (IV) in which A, R 1 , and n are as defined herein and LG is a leaving group, with a compound of formula (V), whereby a compound of formula (IV) can be prepared. LG that can be used includes halogens such as chloro, bromo, and iodo. The reaction between the compound of formula (IV) and the compound of formula (V) may be carried out using methods known to those skilled in the art. For example, the reaction between the compound of formula (IV) and the compound of formula (V) can be carried out in an aprotic solvent such as acetonitrile or DMF, a protic solvent such as water or alcohol, or a mixture of a protic solvent and an aprotic solvent such as a mixture of acetonitrile and water, in the presence of an acid or a base, at a temperature in the range of 25 °C to 200 °C. The compound of formula (V) can be prepared by the methods disclosed herein and / or methods known to those skilled in the art.

[0253] [Chemical formula]

[0254] Alternatively, the compound of formula (I) is a compound of formula (VI) in which R 3 , R 4a , R 4b , R 4c , R 5 , R 6 , R 7 , R 8a , R 8b , R 8c , and R 8d are as defined herein and Hal is a halogen such as bromo or iodo, with A, R 1 , R 2It can be prepared by reacting with a compound of formula (VII) wherein n is as defined herein. Such a reaction can be carried out in the presence of a catalytic amount of a palladium-containing compound such as palladium(0) 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 an aprotic solvent. The base can be selected from a tertiary amine, an organic base such as triethylamine, or an inorganic base such as cesium carbonate. The aprotic solvent can be, for example, toluene. For example, the reaction between the compound of formula (VI) and the compound of formula (VII) may be carried out at a temperature in the range of 25 °C to 200 °C. For example, such a reaction can be carried out at a temperature of 100 °C in toluene. The compound of formula (VII) is commercially available or can be prepared by methods known to those skilled in the art or methods similar to those described herein.

[0255]

Chemical formula

[0256] The compound of formula (VI) can be prepared by methods known to those skilled in the art. For example, (1R,2S)-2-(3-bromo-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one, which is a compound of formula (IV), can be prepared by the scheme described below. Other compounds of formula (VI) can be prepared by methods known to those skilled in the art with obvious modifications by those skilled in the art, for example, by using various starting materials, appropriately protecting interfering groups, changing to other suitable reagents known in the art, or making conventional modifications to the reaction conditions.

[0257]

Chemical formula

[0258] Similarly, (1R,2S)-2-(3-iodo-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one can be prepared by reacting (1R,2S)-2-(1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one with iodine in DMF and methanol in the presence of potassium carbonate as described below.

[0259]

Chemical formula

[0260] The compound of formula (IV) can be prepared from the compound of formula (VI) by methods known to those skilled in the art. For example, tert-butyl (1R,2S)-2-(3-amino-1-(tert-butoxycarbonyl)-1H-indazol-6-yl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-carboxylate can be prepared from (1R,2S)-2-(3-bromo-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one as described below.

[0261]

Chemical formula

[0262] Compounds such as tert-butyl (1R,2S)-2-(3-amino-1-(tert-butoxycarbonyl)-1H-indazol-6-yl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-carboxylate can be reacted with the compounds of formula (V) described herein using an acid such as trifluoroacetic acid to provide the compounds of formula (I), and subsequently be subjected to deprotection of the Boc group. For example, tert-butyl (1R,2S)-2-(3-amino-1-(tert-butoxycarbonyl)-1H-indazol-6-yl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-carboxylate can be reacted with 4-chloro-5-methoxypyrimidine to obtain (1R,2S)-5'-methoxy-2-(3-((5-methoxypyrimidin-4-yl)amino)-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indoline]-2'-one.

[0263]

Chemical formula

[0264] In the following preparations and examples, "Ac" means acetyl, "ACN" and "MeCN" mean acetonitrile, "Me" means methyl, "Et" means ethyl, "Ph" means phenyl, "BOC", "Boc", or "boc" mean N-tert-butoxycarbonyl, "DCM" (CH2Cl2) means methylene chloride, "DIPEA" or "DIEA" mean diisopropylethylamine, "DMA" means N,N-dimethylacetamide, "DMF" means N,N-dimethylformamide, "DMSO" means dimethyl sulfoxide, "DPPP" means 1,3-bis(diphenylphosphino)propane, "HOAc" means acetic acid, "IPA" means isopropyl alcohol, "min" means minute, "NMP" means 1-methyl-2-pyrrolidinone, "TEA" means triethylamine, "TFA" means trifluoroacetic acid, "DCM" means dichloromethane, "EtOAc" and "EA" mean ethyl acetate, "MgSO4" means magnesium sulfate, "Na2SO4" means sodium sulfate, "MeOH" means methanol, "Et2O" means diethyl ether, "EtOH" means ethanol, "H2O" means water, "HCl" means hydrochloric acid, "K2CO3" means potassium carbonate, "THF" means tetrahydrofuran, "DBU" means 1,8-diazabicyclo[5.4.0]undec-7-ene, "LiHMDS" or "LHMDS" mean lithium hexamethyldisilazide, "TBME" or "MTBE" mean tert-butyl methyl ether, "LDA" means lithium diisopropylamide, "N" means normal, "M" means mole, "mL" means milliliter, "mmol" means millimole, "μmol" means micromole, "eq." means equivalent, "°C" means degree Celsius, "Pa" means pascal, "rt" or "RT" mean room temperature, "h" means hour, "satd." means saturated, "aq" means aqueous, "anhyd." or "anh." means anhydrous, "MBTE" means methyl tert-butyl ether, "PE" means petroleum ether, and "TBSCl" means tert-butyldimethylsilyl chloride.

Example

[0265] Intermediate 1. (1R,2S)-2-(3-Amino-1H-indazol-6-yl)-5'-methoxispiro[cyclopropane-1,3'-indoline]-2'-one

[0266]

Chem.

[0267] Step A. (E)-3-(3-Fluoro-4-isocyanobenzylidene)-5-methoxyindolin-2-one

[0268]

Chem.

[0269] A round-bottom flask was charged with 5-methoxyoxindole (5.00 g, 30.6 mmol), 4-cyano-3-fluorobenzaldehyde (4.57 g, 30.6 mmol), piperidine (835 μL, 8.40 mmol), and ethanol (120 mL). The reaction mixture was refluxed for 4 h and stirred at room temperature for 16 h. The reaction mixture was cooled to 0 °C, and the resulting precipitate was collected by filtration and dried to give the title compound (5.10 g, 57%) as a dark red solid. m / z (ESI, +ve ion) = 295.0 [M+H] + .

[0270] Step B. Racemic-2-fluoro-4-((1R,2S)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-2-yl)benzonitrile

[0271]

Chem.

[0272] To a solution of trimethylsulfoxonium iodide (4.20 g, 19.1 mmol) in anhydrous DMF (173 mL) was added sodium hydride (60% dispersion in oil) (81.5 mg, 2.04 mmol) at 0 °C under nitrogen. The mixture was stirred for 15 minutes, then (E)-3-(3-fluoro-4-isocyanobenzylidene)-5-methoxyindolin-2-one (5.10 g, 17.3 mmol) was added to the solution and the reaction was stirred at room temperature for 1 hour. The solution was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was then washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. Purification of the crude mixture by column chromatography (10% - 65% EtOAc / heptane, gradient elution) gave the title compound (1.50 g, 28%) as an orange solid. The relative stereochemistry was confirmed by NOESY NMR experiments. m / z (ESI, +ve ion) = 309.0 [M+H] + 。1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.63 - 7.54 (m, 1H), 7.13 - 7.08 (m, 2H), 6.85 (d, J = 8.5 Hz, 1H), 6.67 (dd, J = 8.5, 2.5 Hz, 1H), 5.55 (d, J = 2.4 Hz, 1H), 3.55 (s, 3H), 3.29 (t, J = 8.5 Hz, 1H), 2.26 (dd, J = 9.0, 5.0 Hz, 1H), 1.94 (dd, J = 8.0, 5.0 Hz, 1H). The corresponding diastereoisomer was found to be less polar and eluted first under the given conditions. m / z (ESI, +ve ion) = 309.0 [M+H] + 。1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.52 (dd, J = 7.8, 6.9 Hz, 1H), 7.21 (s, 1H), 7.19 (s, 1H), 6.78 (d, J = 1.5 Hz, 2H), 6.54 (s, 1H), 3.81 (s, 3H), 3.07 (t, J = 8.7 Hz, 1H), 2.34 (dd, J = 8.5, 5.3 Hz, 1H), 2.12 (dd, J = 8.9, 5.3 Hz, 1H).

[0273] Process C. (1R,2S)-2-(3-Amino-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one

[0274] [Chemical Structure]

[0275] In a 20 mL vial, 2-Fluoro-4-((1R,2S)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indolin]-2-yl)benzonitrile (20.0 mg, 64.9 μmol) was dissolved in tert-amyl alcohol (10.0 mL), and then hydrazine hydrate solution (50.0 μL, 1.58 mmol) was added. The reaction mixture was refluxed for 16 hours. The reaction mixture was cooled to room temperature, silica was added directly to the mixture, and the mixture was concentrated. The product was purified by column chromatography (0 - 20% MeOH / DCM, gradient elution) to obtain the title compound (60.0 mg, 58%) as a colorless oil. m / z (ESI, +ve ion) = 321.1 [M+H] + .

[0276] Intermediate 2. (1R,2S)-2-(1H-Indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one

[0277] [Chemical Structure]

[0278] Process A. 1-Benzyl-5-methoxyindoline-2,3-dione

[0279] [Chemical Structure]

[0280] Benzyl bromide (9.65 mL, 79.7 mmol) was added to a mixture of 5-methoxyisatin (12.0 g, 66.4 mmol) and potassium carbonate (27.5 g, 199 mmol) in acetonitrile (250 mL). The mixture was stirred at 80 °C for 15 h and then cooled to room temperature. The mixture was filtered and the filtrate was concentrated. This was diluted with water (300 mL) and extracted with EtOAc (3 times with 80 mL). The combined organic layers were washed with brine and then dried (Na2SO4), filtered, and concentrated. The resulting solid was triturated with heptane, filtered, and washed with heptane to give the title compound (18.2 g, quantitative yield as a solid). m / z (ESI, +ve ion) = 268.1 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 7.38 - 7.27 (m, 5H), 7.15 (d, J = 2.7 Hz, 1H), 7.02 (dd, J = 8.6, 2.7 Hz, 1H), 6.67 (d, J = 8.6 Hz, 1H), 4.90 (s, 2H), 3.77 (s, 3H).

[0281] Step B. 1-Benzyl-5-methoxyindolin-2-one

[0282]

Chemical Structure

[0283] Hydrazine monohydrate (8.64 mL, 107 mmol) was added to a mixture of 1-benzyl-5-methoxyindoline-2,3-dione (18.2 g, 68.1 mmol) in DMSO (44.1 mL). The mixture was stirred at 140 °C for 5 h and then cooled to room temperature. The mixture was diluted with water (300 mL) and extracted with EtOAc (3 times with 200 mL). The combined organic layers were washed with 1 M H2SO4, brine (2 times), then dried (Na2SO4), filtered, and concentrated to give the title compound (14.0 g, 81%) as a dark oil. m / z (ESI, +ve ion) = 254.1 [M+H] +。1H NMR (400 MHz, CDCl3) δ 7.38 - 7.22 (m, 5H), 6.90 - 6.86 (m, 1H), 6.68 (dd, J = 8.5, 2.6 Hz, 1H), 6.60 (d, J = 8.5 Hz, 1H), 4.89 (s, 2H), 3.75 (s, 3H), 3.61 (s, 2H).

[0284] Step C. 1-Benzyl-6-bromo-1H-indazole

[0285]

Chem.

[0286] Potassium tert-butoxide (20.5 g, 179 mmol) was added to a mixture of 6-bromo-1H-indazole (30.0 g, 152 mmol) in DMSO (149 mL). The mixture was stirred for 10 minutes, then benzyl chloride (20.8 mL, 179 mmol) was added slowly at 0 °C. The mixture was stirred at room temperature for 3 hours, then diluted with saturated aqueous NH4Cl (400 mL) and extracted with MTBE (3 times with 200 mL). The combined organic layers were washed twice with brine, then dried (Na2SO4), filtered, and concentrated to give the crude material as a mixture of 1-benzyl-6-bromo-1H-indazole and 2-benzyl-6-bromo-2H-indazole. Benzyl bromide (37.7 mL, 311 mmol) was added to a mixture of 1-benzyl-6-bromo-1H-indazole and 2-benzyl-6-bromo-2H-indazole (31 g, 108 mmol). The mixture was stirred at 150 °C, neat. After 6 hours, benzyl bromide was removed by distillation at 130 °C under high vacuum (vacuum pump). The residue was triturated in heptane, then filtered and washed with heptane. The crude material was subjected to high vacuum overnight to give the title compound (20.6 g, 67% as a solid. m / z (ESI, +ve ion) = 287.0 [M + H] + 。

[0287] Step D. 1-Benzyl-6-vinyl-1H-indazole

[0288] [Chem.]

[0289] A mixture of 1-benzyl-6-bromo-1H-indazole (6.33 g, 22.0 mmol) and potassium carbonate (9.14 g, 66.1 mmol) in degassed (by bubbling with nitrogen) DME / water (3:1) (70.0 mL) was purged with nitrogen and further bubbled with nitrogen through the reaction mixture. Vinylboronic acid pinacol ester (4.82 mL, 27.6 mmol) was added, followed by dichlorobis(triphenylphosphine)palladium(II) (774 mg, 1.10 mmol), and the mixture was heated to 80 °C overnight. The mixture was diluted with heptane and washed with water (3 times) and brine. The organic phase was dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (0 - 10% EtOAc / hexane, gradient elution) to give the title compound 4D (3.80 g, 74%). m / z (ESI, +ve ion) = 235.4 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 0.9 Hz, 1H), 7.73 - 7.64 (m, 1H), 7.36 - 7.23 (m, 5H), 7.23 - 7.16 (m, 2H), 6.80 (dd, J = 17.6, 10.9 Hz, 1H), 5.80 (dd, J = 17.5, 0.7 Hz, 1H), 5.60 (s, 2H), 5.30 (dd, J = 10.9, 0.6 Hz, 1H).

[0290] Step E. (S)-1-(1-Benzyl-1H-indazol-6-yl)ethane-1,2-diol

[0291] [Chem.]

[0292] To a 500 mL flask, AD-mix-alpha (83.7 g, 59.8 mmol) and t-BuOH / water (1:1) (598 mL) were added, and a clear two-phase mixture was formed after stirring. After cooling the reaction mixture to 0 °C in an ice bath, 1-benzyl-6-vinyl-1H-indazole (14.0 g, 59.8 mmol) was added. The resulting mixture was vigorously stirred at 0 °C and warmed to room temperature while slowly warming in the ice bath. The reaction mixture was stirred for 9 hours. The reaction was quenched by adding 92 g of sodium sulfate in small portions. The reaction mixture was stirred overnight. The reaction mixture was diluted with brine and DCM and filtered through a Celite pad. The filtrate was extracted with DCM (4 times), and the combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was recrystallized from toluene (80 mL) to give the title compound (12.2 g, 76%) as a white solid. m / z (ESI, +ve ion) = 269.2 [M+H] + 。99.1% ee。

[0293] Step F. (S)-1-(1-Benzyl-1H-indazol-6-yl)ethane-1,2-diyl dimethanesulfonate

[0294]

Chem.

[0295] (S)-1-(1-Benzyl-1H-indazol-6-yl)ethane-1,2-diol (12.2 g, 45.5 mmol) and triethylamine (16.0 mL, 114 mmol) in DCM (227 mL) were cooled in an ice bath and treated by slowly adding methanesulfonyl chloride (7.77 mL, 100 mmol) over 15 minutes. The internal temperature was raised to a maximum of 11 °C. The resulting mixture was stirred at 0 °C. After 6 hours, 10% monomesylated product was observed by LCMS. 0.400 mL of methanesulfonyl chloride and 0.600 mL of triethylamine were added. The mixture was stirred for 1 hour and after completion, diluted at 0 °C with DCM (500 mL) and 1 M aqueous HCl (200 mL). The layers were separated and the organic layer was washed with saturated aqueous NaHCO3 (2 x 200 mL), brine (200 mL), then dried (Na2SO4), filtered, and concentrated. The crude material was passed through a small celite pad and eluted with a mixture of DCM / Et2O (1:1). Removal of the solvent gave a white solid. The solid was triturated in Et2O (40 mL) and the precipitate was collected by filtration to give the title compound (17.5 g, 91%) as a white crystalline solid. m / z (ESI, +ve ion) = 425.0 [M+H] + 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.41 (s, 1H), 7.35 - 7.27 (m, 3H), 7.18 (dd, J = 17.3, 7.5 Hz, 3H), 5.89 (dd, J = 8.6, 3.2 Hz, 1H), 5.66 (d, J = 15.8 Hz, 1H), 5.60 (d, J = 15.8 Hz, 1H), 4.53 (dd, J = 11.9, 8.6 Hz, 1H), 4.40 (dd, J = 11.9, 3.3 Hz, 1H), 3.05 (s, 3H), 2.75 (s, 3H).

[0296] Step G. (1R,2S)-1'-Benzyl-2-(1-benzyl-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one

[0297]

Chemical Structure

[0298] (S)-1-(1-Benzyl-1H-indazol-6-yl)ethane-1,2-diyl dimethanesulfonate (2.03 g, 8.01 mmol) in dry THF (80 mL) was cooled in an ice bath under nitrogen. Sodium hydride (673 mg, 16.8 mmol) was added portionwise and the mixture was stirred at 0 °C for 15 min. A solution of 1-benzyl-5-methoxyindolin-2-one (3.40 g, 8.01 mmol) in dry THF (50 mL) was added dropwise via an addition funnel. The reaction mixture was stirred at 0 °C for 3 h. The reaction was quenched with saturated NH4Cl solution, diluted with water and extracted with EtOAc (3 times). The organic layer was dried over anhydrous MgSO4 and concentrated to give the crude product. Trituration of the crude product with hexane / EtOAc 3:1 gave the title compound (2.10 g, 54%) as an orange solid. m / z (ESI, +ve ion) = 486.2 [M+H] + 。

[0299] Step H. (1R,2S)-2-(1H-Indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one

[0300]

Chem.

[0301] A round-bottom flask was charged with a stirring bar and (1R,2S)-1'-benzyl-2-(1-benzyl-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one (4.00 g, 8.24 mmol) in THF (118 mL). The solution was cooled to 0 °C, potassium tert-butoxide (23.0 mL, 165 mmol) was added portionwise over 20 minutes, and then DMSO (10.7 mL) was added. Oxygen was bubbled through the solution at 0 °C for 1 hour. The reaction was quenched with saturated aqueous NH4Cl at 0 °C and diluted with EtOAc (50 mL). The mixture was washed with saturated aqueous NH4Cl (once) and extracted with EtOAc (twice). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was triturated in Et2O and recrystallized from ethanol to afford the title compound (2.56 g, 56%). m / z (ESI, +ve ion) = 306.4 [M+H] + .

[0302] Intermediate 3: (1R,2S)-2-(3-bromo-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one

[0303] [Chemical Structure]

[0304] In a flask, (1R,2S)-2-(1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one (4.49 g, 12.5 mmol) was dissolved in DMF (16.7 mL), and NBS (2.70 g, 15.0 mmol) dissolved in DMF (8.33 mL) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with an aqueous solution of Na2S2O3 and extracted with EtOAc (3 times with 100 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by column chromatography (40 - 100% EtOAc / hexane, gradient elution) to obtain the title compound (3.12 g, 65%). m / z (ESI, +ve ion) = 384.0, 386.0 [M+H] + .

[0305] Intermediate 4: Tert-butyl 3-bromo-6-((1R,2S)-1'-(tert-butoxycarbonyl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-2-yl)-1H-indazole-1-carboxylate

[0306] [Chemical formula]

[0307] 4-Dimethylaminopyridine (79.8 mg, 640 μmol) was added to a solution of triethylamine (3.61 mL, 25.6 mmol), di-tert-butyl dicarbonate (4.0 mL, 17.3 mmol), and (1R,2S)-2-(3-bromo-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one (2.46 g, 6.40 mmol) in DCM (24 mL). The solution was stirred at room temperature for 16 h. Incomplete conversion was observed by LCMS. Di-tert-butyl dicarbonate (0.75 mL, 3.2 mmol, 0.5 equiv) was added, and the reaction was stirred for an additional 1 h. The crude product was purified by column chromatography (0-20% EtOAc / heptane, gradient elution) to give the title compound (3.06 g, 82%) as a yellow foamy solid. m / z (ESI, +ve ion) = 384.0, 386.0 [M+H-boc] + .

[0308] Intermediate 5: Tert-butyl 3-amino-6-((1R,2S)-1'-(tert-butoxycarbonyl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indolin]-2-yl)-1H-indazole-1-carboxylate

[0309] [ka]

[0310] Step A. Tert-butyl 6-((1R,2S)-1'-(tert-butoxycarbonyl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-2-yl)-3-((diphenylmethylene)amino)-1H-indazole-1-carboxylate

[0311] [ka]

[0312] To a microwave vial were added tert-butyl 3-bromo-6-((1R,2S)-1'-(tert-butoxycarbonyl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-2-yl)-1H-indazole-1-carboxylate (1.00 g, 1.71 mmol), cesium carbonate (1.14 g, 3.42 mmol), Pd2(dba)3 (157 mg, 171 μmol), and XantPhos (101 mg, 171 μmol). Dry dioxane (17.1 mL) was added, followed by benzophenone imine (310 μL, 1.83 mmol), and nitrogen was bubbled through the reaction mixture for 5 minutes. The vial was sealed and the reaction mixture was heated to 90 °C in an oil bath for 2 hours. Saturated aqueous NaHCO3 was added and the reaction mixture was extracted with EtOAc (3 times). The combined extracts were then washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by column chromatography (0 - 30% EtOAc / heptane, gradient elution) to give the title compound (1.03 g, 88%) as a yellow oil. m / z (ESI, +ve ion) = 685.4 [M+H] + .

[0313] Step B. Tert-butyl 3-amino-6-((1R,2S)-1'-(tert-butoxycarbonyl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-2-yl)-1H-indazole-1-carboxylate

[0314] [Chemical formula]

[0315] Hydroxylamine hydrochloride (101 mg, 1.46 mmol) and sodium acetate (120 mg, 1.46 mmol) were added to tert-butyl 6-((1R,2S)-1'-(tert-butoxycarbonyl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-2-yl)-3-((diphenylmethylene)amino)-1H-indazole-1-carboxylate (1.00 g, 1.46 mmol) in dry MeOH (14.6 mL) at room temperature and the reaction was stirred for 16 h. The solvent was removed under reduced pressure. The crude product was purified by column chromatography (0 - 60% EtOAc / heptane, gradient elution) to afford the title compound (640 mg, 84%) as a yellow solid. m / z (ESI, +ve ion) = 521.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.78 (d, J = 8.9 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.66 (dd, J = 8.9, 2.6 Hz, 1H), 5.55 (d, J = 2.3 Hz, 1H), 4.44 (s, 2H), 3.49 (t, J = 8.6 Hz, 1H), 3.37 (s, 3H), 2.34 (dd, J = 9.2, 4.8 Hz, 1H), 2.14 - 2.06 (m, 1H), 1.67 (d, J = 2.4 Hz, 18H).

[0316] Example 1. Racemic-5'-methoxy-2-{3-[(5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one

[0317]

Chemical Structure

[0318] In a 4 mL vial, (1R,2S)-2-(3-amino-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one (54.0 mg, 169 μmol) and 4-chloro-5-methoxypyrimidine (29.8 mg, 202 μmol) were dissolved in acetic acid / water (1:1) (1.00 mL). The reaction mixture was heated to 100 °C over 1 hour. The reaction mixture was poured into 5 mL of 2 M aqueous NaOH. The aqueous phase was extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The product was purified by column chromatography (0 - 10% MeOH / DCM, gradient elution) to give Example 1 (22.9 mg, 32%) as a white solid after lyophilization. m / z (ESI, +ve ion) = 429.2 [M+H] + 1H NMR (400 MHz, DMSO) δ 12.68 (s, 1H), 10.42 (s, 1H), 9.12 (s, 1H), 8.04 (d, J = 3.0 Hz, 2H), 7.40 (d, J = 7.9 Hz, 2H), 6.89 (d, J = 9.4 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.58 (dd, J = 8.5, 2.6 Hz, 1H), 5.72 (d, J = 2.5 Hz, 1H), 3.94 (s, 3H), 3.33 (s under water peak, 3H), 3.18 (t, J = 8.5 Hz, 1H), 2.33 (dd, J = 7.8, 4.7 Hz, 1H), 1.98 (dd, J = 9.0, 4.7 Hz, 1H).

[0319] Example 2. Racemic-5'-methoxy-2-{3-[(5-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one

[0320]

Chem.

[0321] Example 2 was prepared using the procedure described in Example 1 from (1R,2S)-2-(3-amino-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one (60.0 mg, 187 μmol) and 4-chloro-5-methylpyrimidine (27 mg, 206 μmol). The product was purified by column chromatography (0 - 10% MeOH / DCM, gradient elution), concentrated, and then lyophilized from MeCN and water to give Example 2 (7.7 mg, 10%) as a white solid. m / z (ESI, +ve ion) = 413.2 [M+H] + 1H NMR (400 MHz, DMSO) δ 12.69 (s, 1H), 10.43 (s, 1H), 9.02 (s, 1H), 8.24 (s, 1H), 8.13 (s, 1H), 7.41 (s, 1H), 7.34 (d, J = 8.5 Hz, 1H), 6.89 (dd, J = 8.5, 1.0 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.58 (dd, J = 8.5, 2.6 Hz, 1H), 5.71 (d, J = 2.6 Hz, 1H), 3.33 (s under water peak, 3H), 3.18 (t, J = 8.4 Hz, 1H), 2.33 (dd, J = 7.9, 4.7 Hz, 1H), 2.21 (s, 3H), 1.98 (dd, J = 9.0, 4.7 Hz, 1H).

[0322] Example 3. Racemic-2-{3-[(5-chloropyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one

[0323]

Chemical Structure

[0324] Example 3 was prepared using the procedure described in Example 1 from (1R,2S)-2-(3-amino-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one (60.0 mg, 187 μmol) and 4,5-dichloropyrimidine (31.3 mg, 206 μmol). The product was purified by C18 column chromatography (5 - 40% MeCN / aqueous ammonium formate buffer, gradient elution) to give Example 3 (4.8 mg, 6%) as a white solid after lyophilization. m / z (ESI, +ve ion) = 433.1 [M+H] + 1H NMR (400 MHz, DMSO) δ 12.85 (s, 1H), 10.43 (s, 1H), 9.58 (s, 1H), 8.46 (s, 1H), 8.31 (s, 1H), 7.44 (s, 1H), 7.37 (d, J = 8.3 Hz, 1H), 6.95 - 6.87 (m, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.58 (dd, J = 8.5, 2.6 Hz, 1H), 5.70 (d, J = 2.5 Hz, 1H), 3.33 (s, 3H), 3.19 (t, J = 8.4 Hz, 1H), 2.34 (dd, J = 8.0, 4.7 Hz, 1H), 1.98 (dd, J = 9.0, 4.6 Hz, 1H).

[0325] Example 4. (1R,2S)-5'-Methoxy-2-{3-[(5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one

[0326]

Chemical Structure

[0327] This compound was prepared from tert-butyl 3-amino-6-((1R,2S)-1'-(tert-butoxycarbonyl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-2-yl)-1H-indazole-1-carboxylate (108 mg, 207 μmol) and 4-chloro-5-methoxypyrimidine (36.7 mg, 249 μmol) using the procedure described in Example 1. The Boc group was cleaved in situ under the reaction conditions. The product was purified by C18 column chromatography (10% - 30% MeCN / aqueous ammonium formate buffer, gradient elution) to give Example 4 (9.6 mg, 11%) as a white solid after lyophilization. m / z (ESI, +ve ion) = 429.2 [M+H] + 1H NMR (400 MHz, DMSO) δ 12.68 (s, 1H), 10.43 (s, 1H), 9.12 (s, 1H), 8.04 (d, J = 3.1 Hz, 2H), 7.44 - 7.35 (m, 2H), 6.89 (d, J = 9.4 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.58 (dd, J = 8.5, 2.6 Hz, 1H), 5.72 (d, J = 2.5 Hz, 1H), 3.94 (s, 3H), 3.33 (s under water peak, 3H), 3.18 (t, J = 8.6 Hz, 1H), 2.33 (dd, J = 7.9, 4.7 Hz, 1H), 1.98 (dd, J = 9.0, 4.6 Hz, 1H).

[0328] Example 5. (1R,2S)-5'-Methoxy-2-{3-[(5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one

[0329]

Chemical Structure

[0330] Step A. (1R,2S)-2-(3-Iodo-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one

[0331]

Chem.

[0332] To a furnace-dried flask, (1R,2S)-2-(1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one (4.00 g, 13.1 mmol) was added, followed by DMF (8 mL) and methanol (8 mL). K2CO3 (3.62 g, 26.2 mmol) was added to this suspension. Finally, molecular sieve (4.32 g, 17.0 mmol) was dissolved in DMF (8 mL), added dropwise, and stirred at room temperature. After 4 hours, the reaction was complete. The mixture was quenched with Na2S2O3 in water and stirred for 2 hours. The solid was collected by filtration and washed with water. The wet solid was frozen and lyophilized to give the title compound (4.4 g, 78% yield).

[0333] Step B. Tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-iodo-1H-indazol-6-yl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-carboxylate

[0334]

Chem.

[0335] To a furnace-dried flask, 4-dimethylaminopyridine (9.0 mg, 0.07 mmol) was added, followed by (1R,2S)-2-(3-iodo-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one (637 mg, 1.48 mmol), N-ethyl-N-isopropyl-propan-2-amine (1.0 mL, 5.9 mmol), and MeCN (5.0 mL). The mixture was stirred at room temperature and a pale yellow homogeneous solution was obtained by adding di-tert-butyl dicarbonate (967 mg, 4.43 mmol). After 2 hours, the reaction mixture was concentrated and the resulting residue was purified by column chromatography (0% - 25%, EtOAc / hexane, gradient elution) to give the product as a white foam (5B) (822 mg, 88%).

[0336] Step C. Tert-butyl (1R,2S)-2-[1-tert-butoxycarbonyl-3-[(5-ethoxypyrimidin-4-yl)amino]indazol-6-yl]-5'-methoxy-2'-oxo-spiro[cyclopropane-1,3'-indoline]-1'-carboxylate

[0337] [Chemical formula]

[0338] To a 50 mL round-bottom flask, cesium carbonate (41.3 mg, 0.130 mmol), 5-ethoxypyrimidin-4-amine (9.3 mg, 0.070 mmol), Pd2(dba)3 (5.8 mg, 0.010 mmol), tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-iodo-1H-indazol-6-yl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-carboxylate (40.0 mg, 0.0600 mmol), XantPhos (3.7 mg, 0.010 mmol), and dry toluene (4.2 mL) were added. The reaction mixture was stirred and purged with argon (in a balloon) for 10 minutes to give a green suspension, which was then heated to 120 °C to obtain a yellow suspension. The reaction was monitored by LCMS and TLC until the starting materials were completely converted (about 70 minutes), cooled to room temperature, diluted with EtOAc, washed with saturated aqueous NaHCO3, and dried over Na2SO4. The residue was purified by column chromatography (0% - 90% ethyl acetate / hexane, gradient elution) to give the title compound (24.0 mg, 59%) as a yellow oil.

[0339] Step D. (1R,2S)-2-[3-[(5-Ethoxypyrimidin-4-yl)amino]-1H-indazol-6-yl]-5'-methoxy-spiro[cyclopropane-1,3'-indoline]-2'-one

[0340] [Chemical formula]

[0341] To a 50 ml round bottom flask containing tert-butyl (1R,2S)-2-[1-tert-butoxycarbonyl-3-[(5-ethoxypyrimidin-4-yl)amino]indazol-6-yl]-5’-methoxy-2’-oxospiro[cyclopropane-1,3’-indoline]-1’-carboxylate (24.0 mg, 0.0400 mmol) in DCM (1.9 mL) was added trifluoroacetic acid (0.15 mL, 1.9 mmol). The reaction mixture was stirred and monitored by LCMS until the starting material was completely converted (about 3 h), and diluted with acetonitrile. The resulting brown solution was purified by preparative HPLC (Gemini C18, 30 - 80% (0.1% TFA in water) / (0.1% TFA in acetonitrile)) to give the desired product, Example 5 (12.4 mg, 75%) as a yellow film. m / z (ESI, +ve ion) 443.2 (M+H) + 。 1 H NMR (400 MHz, methanol-d4) δ ppm 1.58 (t, J = 6.94 Hz, 3H) 2.10 - 2.32 (m, 2H) 3.26 - 3.30 (m, 3H) 3.32 - 3.39 (m, 1H) 4.27 - 4.44 (m, 2H) 5.50 - 5.61 (m, 1H) 6.55 - 6.67 (m, 1H) 6.76 - 6.89 (m, 1H) 6.91 - 7.04 (m, 1H) 7.44 - 7.62 (m, 2H) 8.03 - 8.18 (m, 1H) 8.36 - 8.49 (m, 1H).

[0342] Example 6. (1R,2S)-2-{3-[(5-cyclopropylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5’-methoxyspiro[cyclopropane-1,3’-indol]-2’(1’H)-one

[0343]

Chemical Structure

[0344] Project A. Tert-butyl (1R,2S)-2-[1-tert-butoxycarbonyl-3-[(5-cyclopropylpyrimidin-4-yl)amino]indazol-6-yl]-5'-methoxy-2'-oxo-spiro[cyclopropane-1,3'-indoline]-1'-carboxylate

[0345]

Chem.

[0346] This compound was prepared from tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-iodo-1H-indazol-6-yl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-carboxylate (40.0 mg, 0.0600 mmol) and 5-cyclopropylpyrimidin-4-amine (9.0 mg, 0.070 mmol) using the procedure described in Example 5. The residue was purified by column chromatography (ethyl acetate / hexane = 0 - 90%) to give the title compound (17.0 mg, 42%) as a yellow oil.

[0347] Project B. (1R,2S)-2-[3-[(5-cyclopropylpyrimidin-4-yl)amino]-1H-indazol-6-yl]-5'-methoxy-spiro[cyclopropane-1,3'-indoline]-2'-one

[0348]

Chem.

[0349] This compound was prepared from tert-butyl (1R,2S)-2-[1-tert-butoxycarbonyl-3-[(5-cyclopropylpyrimidin-4-yl)amino]indazol-6-yl]-5'-methoxy-2'-oxo-spiro[cyclopropane-1,3'-indoline]-1'-carboxylate (17.0 mg, 0.0400 mmol) and trifluoroacetic acid (0.10 mL, 1.3 mmol) using the procedure described in Example 5. The resulting brown solution was purified by preparative HPLC (Gemini C18, 10 - 90% (0.1% TFA in water) / (0.1% TFA in acetonitrile)) to obtain the desired product, Example 6 (6.2 mg, 53%) as a colorless film. m / z (ESI, +ve ion) 439.2 (M + H)+. 1 H NMR (400 MHz, methanol-d4) δ ppm 0.85 - 0.97 (m, 2H) 1.16 - 1.31 (m, 2H) 1.87 - 2.04 (m, 1H) 2.16 - 2.32 (m, 2H) 5.53 - 5.63 (m, 1H) 6.58 - 6.69 (m, 1H) 6.79 - 6.90 (m, 1H) 6.96 - 7.06 (m, 1H) 7.48 - 7.63 (m, 2H) 8.15 - 8.30 (m, 1H) 8.52 - 8.63 (m, 1H).

[0350] Example 7. (1R,2S)-2-{3-[(5-Chloropyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one

[0351]

Chemical Structure

[0352] Step A. Tert-butyl 6-((1R,2S)-1'-(tert-butoxycarbonyl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-2-yl)-3-((5-chloropyrimidin-4-yl)amino)-1H-indazole-1-carboxylate

[0353] [Chem.]

[0354] This compound was prepared from tert-butyl 3-bromo-6-((1R,2S)-1'-(tert-butoxycarbonyl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-2-yl)-1H-indazole-1-carboxylate (110 mg, 188 μmol) and 4-amino-5-chloropyrimidine (29.3 mg, 215 μmol) using the procedure described in Example 5. The product was purified by column chromatography (20 - 100% EtOAc / heptane, gradient elution) to give the title compound (18.0 mg, 15%). m / z (ESI, +ve ion) = 633.3 [M+H] + 。

[0355] Step B. (1R,2S)-2-(3-((5-chloropyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxospiro[cyclopropane-1,3'-indoline]-2'-one

[0356] [Chem.]

[0357] This compound was prepared from tert-butyl 6-((1R,2S)-1'-(tert-butoxycarbonyl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-2-yl)-3-((5-chloropyrimidin-4-yl)amino)-1H-indazole-1-carboxylate (18 mg, 28.4 μmol) using the procedure described in Example 5. The product was purified by C18 column chromatography (10 - 40% MeCN in aqueous ammonium formate buffer) to give Example 7 (3.0 mg, 24%) as a white solid after lyophilization. m / z (ESI, +ve ion) = 433.1 [M+H] +. 1H NMR (400 MHz, DMSO) δ 12.85 (s, 1H), 10.43 (s, 1H), 9.58 (s, 1H), 8.46 (s, 1H), 8.31 (s, 1H), 7.44 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.58 (dd, J = 8.4, 2.4 Hz, 1H), 5.70 (d, J = 2.3 Hz, 1H), 3.33 (s, 3H) under water, 3.19 (t, J = 8.4 Hz, 1H), 2.34 (dd, J = 7.9, 4.6 Hz, 1H), 1.98 (dd, J = 9.0, 4.6 Hz, 1H).

[0358] Example 8. (1S,2R)-5'-Methoxy-2-{3-[(5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one

[0359]

Chem.

[0360] Step A. (1S,2R)-5'-Methoxy-2-(3-((5-methoxypyrimidin-4-yl)amino)-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-one (8A)

[0361]

Chem.

[0362] A vial containing Example 1 (17.0 mg, 39.7 μmol) was subjected to chiral HPLC separation. The separation conditions were: column: AS-H, 10×250 mm 5um, mode: isocratic, mobile phase: 60% MeOH - 0.1% ammonium hydroxide, 40% supercritical CO2, flow rate: 10 mL / min, back pressure: 120 bar, column temperature: 40 °C, run time (min): 16). The second peak until elution corresponded to the title product, and the first peak was the corresponding enantiomer (1R,2S). The solution was concentrated and lyophilized from MeCN and water to obtain the title compound (15a) (6.7 mg, 39%) as a white solid. m / z (ESI, +ve ion) = 429.3 [M+H] + 1H NMR (400 MHz, DMSO) δ 12.67 (s, 1H), 10.41 (s, 1H), 9.10 (s, 1H), 8.04 (d, J = 2.1 Hz, 2H), 7.42 - 7.37 (m, 2H), 6.89 (d, J = 9.5 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.58 (dd, J = 8.5, 2.6 Hz, 1H), 5.72 (d, J = 2.5 Hz, 1H), 3.94 (s, 3H), 3.18 (t, J = 8.5 Hz, 1H), 2.32 (dd, J = 7.9, 4.6 Hz, 1H), 1.98 (dd, J = 9.0, 4.7 Hz, 1H).

[0363] Example 9. (1R,2S)-2-(3-{[5-Chloro-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one

[0364] [Chemical formula]

[0365] Step A. 5-Chloro-6-morpholinopyrimidin-4-amine (9A)

[0366] [Chemical formula]

[0367] A reaction vial was charged with 4-amino-5,6-dichloropyrimidine (300 mg, 1.83 mmol) and morpholine (145 μL, 1.65 mmol) in DMSO (3.66 mL). The reaction mixture was heated to 60 °C for 16 h. The reaction mixture was partially concentrated and directly purified by column chromatography (40% to 100% EtOAc / heptane, gradient elution) to give the title compound (9A) (318 mg, 81%) as white crystals. m / z (ESI, +ve ion) = 215.0 [M+H] + .

[0368] Step B. tert-Butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-((5-chloro-6-morpholinopyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-carboxylate

[0369] [ka]

[0370] To a microwave vial were added tert-butyl 3-bromo-6-((1R,2S)-1’-(tert-butoxycarbonyl)-5’-methoxy-2’-oxospiro[cyclopropane-1,3’-indoline]-2-yl)-1H-indazole-1-carboxylate (60.0 mg, 103 μmol), 5-chloro-6-morpholinopyrimidin-4-amine (24.2 mg, 113 μmol), cesium carbonate (68.3 mg, 205 μmol), Pd2(dba)3 (9.4 mg, 10.3 μmol), and XantPhos (6.0 mg, 10.3 μmol), and the mixture was purged with nitrogen. Degassed toluene (2.0 mL) was added first, and nitrogen was bubbled through the reaction mixture for 2 minutes. The vial was sealed, and the reaction mixture was heated to 100 °C in an oil bath for 2 hours. The reaction mixture was filtered through a pad of celite using EtOAc and concentrated. The crude product was purified by column chromatography (0%–10% MeOH / DCM, gradient elution) to afford the title compound (49.5 mg, 67%). m / z (ESI, +ve ion) = 718.0 [M+H] + .

[0371] Step C.

[0372] [Chemical formula]

[0373] In a flask, tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-((5-chloro-6-morpholinopyrimidin-4-yl)amino)-1H-indazol-6-yl)-5’-methoxy-2’-oxospiro[cyclopropane-1,3’-indoline]-1’-carboxylate (49.5 mg, 60.7 μmol) was dissolved in DCM (4.40 mL), and trifluoroacetic acid (440 μL, 5.69 mmol) was added. The reaction mixture was stirred at room temperature for 5 minutes and then concentrated to dryness. The crude residue was purified directly by C18 column chromatography (10 - 40% MeCN / aqueous ammonium formate buffer, gradient elution). Combining the desired fractions and freeze-drying gave Example 9 (12.3 mg, 39%) as a white solid. m / z (ESI, +ve ion) = 518.2 [M+H] + 1H NMR (400 MHz, DMSO) δ 12.72 (s, 1H), 10.43 (s, 1H), 9.16 (s, 1H), 7.98 (s, 1H), 7.41 (s, 1H), 7.35 (d, J = 8.3 Hz, 1H), 6.94 - 6.83 (m, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.58 (dd, J = 8.5, 2.5 Hz, 1H), 5.71 (d, J = 2.6 Hz, 1H), 3.74 - 3.67 (m, 4H), 3.51 - 3.44 (m, 4H), 3.33 (with water peak) (s, 3H), 3.18 (t, J = 8.4 Hz, 1H), 2.33 (dd, J = 8.0, 4.8 Hz, 1H), 1.98 (dd, J = 9.0, 4.7 Hz, 1H).

[0374] Example 10. (1R,2S)-2-{3-[(2-chloro-5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}-5’-methoxyspiro[cyclopropane-1,3’-indol]-2’...

Claims

1. Compound of formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein in the formula,[[]] Ring A is C ６ -C １０ aryl, heteroaryl, C ３ -C １０ cycloalkyl, or heterocycloalkyl, and R １ is, independently of one another, deuterium, halogen, -CN, oxo, -NO ２ , -OH, -OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ａ , -NR ｂ S(=O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , -P(O)(R ａ ) ２ , -P(O) ２ (R ａ ) ２ , C １ -C ６ alkyl, C １ -C ６ haloalkyl, -OC １ -C ６ haloalkyl, C １ -C ６ deuteroalkyl, C １ -C ６ hydroxyalkyl, C １ -C ６ aminoalkyl, C １ -C ６ heteroalkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C １０ Cycloalkyl, heterocycloalkyl, C ６ -C １０ -aryl, or heteroaryl, wherein said C １ -C ６ -alkyl, said C ２ -C ６ -alkenyl, said C ２ -C ６ -alkynyl, said C ３ -C １０ -cycloalkyl, said heterocycloalkyl, said C ６ -C １０ -aryl, and each of said heteroaryl is optionally and independently substituted with one or more R １ａ and Alternatively, two of said Rs on adjacent atoms １ are joined together to form a C ３ -C １０ -cycloalkyl or heterocycloalkyl, each optionally substituted with one or more Rs １ｂ and The aforementioned R １ａ is, independently of one another, deuterium, halogen, -CN, -NO ２ , -OH, -OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ａ , -NR ｂ S(=O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ deuteroalkyl, C １ -C ６ hydroxyalkyl, C １ -C ６ aminoalkyl, C １ -C ６ heteroalkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C １０ cycloalkyl, heterocycloalkyl, C ６ -C １０ aryl, or heteroaryl, and Alternatively, the two R's on the same carbon atom １ａ form an oxo by combining together Said R １ｂ is, independently of one another, deuterium, halogen, -CN, -NO ２ , -OH, -OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ａ , -NR ｂ S(=O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ dideuteroalkyl, C １ -C ６ hydroxyalkyl, C １ -C ６ aminoalkyl, C １ -C ６ heteroalkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C １０ cycloalkyl, heterocycloalkyl, C ６ -C １０ aryl, or heteroaryl, and Alternatively, the two R's on the same atom １ｂ combine to form an oxo group, n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; R ２ is hydrogen, C １ -C ６ -alkyl, C １ -C ６ -haloalkyl, or C １ -C ６ -dideuteroalkyl, and R ３ is hydrogen, C １ -C ６ -alkyl, C １ -C ６ -haloalkyl, or C １ -C ６ -deuteroalkyl, and R ４ａ 、 R ４ｂ 、 and R ４ｃ each independently is hydrogen, deuterium, halogen, -CN, -NO ２ 、 -OH, -OR ａ 、 -NR ｃ R ｄ 、 -C(=O)R ａ 、 -C(=O)OR ｂ 、 -C(=O)NR ｃ R ｄ 、 C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ deuteroalkyl, C １ -C ６ hydroxyalkyl, C １ -C ６ aminoalkyl, or C １ -C ６ heteroalkyl, and R ５ is hydrogen, deuterium, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ duteroalkyl, C １ -C ６ hydroxyalkyl, C １ -C ６ aminoalkyl, or C １ -C ６ heteroalkyl, and R ６ is, independently of each other, hydrogen, deuterium, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ deuteroalkyl, C １ -C ６ hydroxyalkyl, C １ -C ６ aminoalkyl, or C １ -C ６ heteroalkyl, and R ７ is hydrogen, C １ -C ６ -alkyl, C １ -C ６ -haloalkyl, C １ -C ６ -dideuteroalkyl, C １ -C ６ -hydroxyalkyl, or C １ -C ６ -aminoalkyl, and R ８ａ 、R ８ｂ 、R ８ｃ 、and R ８ｄ each of which is independently hydrogen, deuterium, halogen, -CN, -NO ２ 、-OH, -OR ａ 、-OC(=O)R ａ 、-OC(=O)OR ｂ 、-OC(=O)NR ｃ R ｄ 、-SH, -SR ａ 、-S(=O)R ａ 、-S(=O) ２ R ａ 、-S(=O) ２ NR ｃ R ｄ 、-NR ｃ R ｄ 、-NR ｂ C(=O)NR ｃ R ｄ 、-NR ｂ C(=O)R ａ 、-NR ｂ C(=O)OR ａ 、-NR ｂ S(=O) ２ R ａ 、-C(=O)R ａ 、-C(=O)OR ｂ 、-C(=O)NR ｃ R ｄ 、C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ deuteroalkyl, C １ -C ６ hydroxyalkyl, C １ -C ６ aminoalkyl, C １ -C ６ heteroalkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C １０ cycloalkyl, heterocycloalkyl, C ６ -C １０ is aryl or heteroaryl, R ａ is, independently of each other, C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ dideuteroalkyl, C １ -C ６ hydroxyalkyl, C １ -C ６ aminoalkyl, C １ -C ６ heteroalkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C １０ cycloalkyl, heterocycloalkyl, C ６ -C １０ aryl, heteroaryl, C １ -C ６ alkyl(C ３ -C １０ cycloalkyl), C １ -C ６ alkyl(heterocycloalkyl), C １ -C ６ alkyl(C ６ -C １０ aryl), or C １ -C ６ alkyl(heteroaryl), and each of said C １ -C ６ alkyl, said C ２ -C ６ alkenyl, said C ２ -C ６ alkynyl, said C ３ -C １０ cycloalkyl, said heterocycloalkyl, said C ６ -C １０ aryl, and said heteroaryl is, independently of each other and optionally, one or more oxo, deuterium, halogen, -CN, -OH, -OCH ３ , -S(=O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ NH ２ 、 -S(=O) ２ NHCH ３ 、 -S(=O) ２ N(CH ３ ) ２ 、 -NH ２ 、 -NHCH ３ 、 -N(CH ３ ) ２ 、 -C(=O)CH ３ 、 -C(=O)OH, -C(=O)OCH ３ 、 C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ deuterioalkyl, C １ -C ６ hydroxyalkyl, C １ -C ６ aminoalkyl, or C １ -C ６ is substituted with heteroalkyl, R ｂ is, independently of each other, hydrogen, C １ -C ６ -alkyl, C １ -C ６ -haloalkyl, C １ -C ６ -dideuteroalkyl, C １ -C ６ -hydroxyalkyl, C １ -C ６ -aminoalkyl, C １ -C ６ -heteroalkyl, C ２ -C ６ -alkenyl, C ２ -C ６ -alkynyl, C ３ -C １０ -cycloalkyl, heterocycloalkyl, C ６ -C １０ -aryl, heteroaryl, C １ -C ６ -alkyl(C ３ -C １０ -cycloalkyl), C １ -C ６ -alkyl(heterocycloalkyl), C １ -C ６ -alkyl(C ６ -C １０ -aryl), or C １ -C ６ -alkyl(heteroaryl), and each of said C １ -C ６ -alkyl, said C ２ -C ６ -alkenyl, said C ２ -C ６ -alkynyl, said C ３ -C １０ -cycloalkyl, said heterocycloalkyl, said C ６ -C １０ -aryl, and said heteroaryl, each is, independently of each other and optionally, one or more oxo, deuterium, halogen, -CN, -OH, -OCH ３ -, -S(=O)CH ３ ( ２ CH ３ ( ２ NH ２ 、 -S(=O) ２ NHCH ３ 、 -S(=O) ２ N(CH ３ ) ２ 、 -NH ２ 、 -NHCH ３ 、 -N(CH ３ ) ２ 、 -C(=O)CH ３ 、 -C(=O)OH、 -C(=O)OCH ３ 、 C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ deuterioalkyl, C １ -C ６ hydroxyalkyl, C １ -C ６ aminoalkyl, or C １ -C ６ substituted with heteroalkyl, R ｃ and R ｄ are each independently hydrogen, C １ -C ６ -alkyl, C １ -C ６ -haloalkyl, C １ -C ６ -dideuteroalkyl, C １ -C ６ -hydroxyalkyl, C １ -C ６ -alkoxy, C １ -C ６ -aminoalkyl, C １ -C ６ -alkylamino, C １ -C ６ -heteroalkyl, C ２ -C ６ -alkenyl, C ２ -C ６ -alkynyl, C ３ -C １０ -cycloalkyl, heterocycloalkyl, C ６ -C １０ -aryl, heteroaryl, C １ -C ６ -alkyl(C ３ -C １０ -cycloalkyl), C １ -C ６ -alkyl(heterocycloalkyl), C １ -C ６ -alkyl(C ６ -C １０ -aryl), or C １ -C ６ -alkyl(heteroaryl), and each of said C １ -C ６ -alkyl, said C ２ -C ６ -alkenyl, said C ２ -C ６ -alkynyl, said C ３ -C １０ -cycloalkyl, said heterocycloalkyl, said C ６ -C １０ -aryl, and said heteroaryl are each independently and optionally one or more oxo, deuterium, halogen, -CN, -OH, -OCH ３ 、 -S(=O)CH ３ 、 -S(=O) ２ CH ３ 、 -S(=O) ２ NH ２ 、 -S(=O) ２ NHCH ３ 、 -S(=O) ２ N(CH ３ ) ２ 、 -NH ２ 、 -NHCH ３ 、 -N(CH ３ ) ２ 、 -C(=O)CH ３ 、 -C(=O)OH, -C(=O)OCH ３ 、 C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ deuterioalkyl, C １ -C ６ hydroxyalkyl, C １ -C ６ aminoalkyl, or C １ -C ６ heteroalkyl substituted, Alternatively, said R ｃ and said R ｄ are optionally one or more oxo, deuterium, halogen, -CN, -OH, -OCH ３ , -S(=O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ NH ２ , -S(=O) ２ NHCH ３ , -S(=O) ２ N(CH ３ ) ２ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -C(=O)CH ３ , -C(=O)OH, -C(=O)OCH ３ , C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ deuteroalkyl, C １ -C ６ hydroxyalkyl, C １ -C ６ aminoalkyl, or C １ -C ６ heteroalkyl-substituted heterocycloalkyl is formed, a compound or a pharmaceutically acceptable salt thereof.[[]]

2. The ring A is C ６ -C １０ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the ring A is aryl or heteroaryl.

3. The ring A is C ６ -C １０ The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein the ring A is aryl.

4. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein the ring A is heteroaryl.[[]]

5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein the ring A is furanyl, pyrrolyl, thiophenyl, oxazolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl.[[]]

6. said R １ is each independently halogen, -CN, -OH, -OR ａ , C １ -C ６ alkyl, C １ -C ６ haloalkyl, -OC １ -C ６ haloalkyl, C １ -C ６ hydroxyalkyl, C １ -C ６ aminoalkyl, C １ -C ６ heteroalkyl, C ３ -C １０ cycloalkyl, heterocycloalkyl, C ６ -C １０ aryl, or heteroaryl, and each of said C １ -C ６ alkyl, said C ３ -C １０ cycloalkyl, said heterocycloalkyl, said C ６ -C １０ aryl, and said heteroaryl is each optionally and independently substituted with one or more R １ａ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3.[[]]

8. said R ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen.

9. Said R ３ is hydrogen, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

10. said R ４ａ said R ４ｂ and said R ４ｃ is hydrogen, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

11. Said R ５ is hydrogen, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

12. said R ６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each of said R is hydrogen.

13. Said R ７ is hydrogen or C １ -C ６ alkyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

14. said R ８ａ said R ８ｂ and said R ８ｄ each is hydrogen, and said R ８ｃ is hydrogen, halogen, or -OR ａ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

15. said R ８ｃ is halogen or -OR ａ The compound according to claim 14, or a pharmaceutically acceptable salt thereof.

16. wherein R ８ｃ is —OR ａ The compound according to claim 15, or a pharmaceutically acceptable salt thereof.

17. said R ８ｃ is -O(C １ -C ６ -alkyl), the compound according to claim 16, or a pharmaceutically acceptable salt thereof.

18. said R ８ｃ is -OCH ３ The compound according to claim 17, or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising an amount of the compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.[[]]

20. Use of the compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19, in the manufacture of a medicament for treating cancer in a subject, wherein the cancer in the subject is neuroblastoma or breast cancer.[[]]

21. The use according to claim 20, wherein the cancer in the subject is neuroblastoma.[[]]

22. The use according to claim 20, wherein the cancer in the subject is breast cancer.[[]]

23. 【Fig. 2-1】 【Chemical 2-2】 【Chemical 2-3】 A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.[[]]

24. The compound is [Chemical Formula 3] The compound according to claim 23, or a pharmaceutically acceptable salt thereof, wherein the compound is

25. The compound is 【Chemical Formula 4】 The compound according to claim 23, or a pharmaceutically acceptable salt thereof, wherein the compound is

26. The compound is 【Chemical Formula 5】 The compound according to claim 23, or a pharmaceutically acceptable salt thereof, wherein the compound is

27. The compound is 【Chemical Formula 6】 The compound according to claim 23, or a pharmaceutically acceptable salt thereof, wherein the compound is

28. The compound is [Chemical Formula 7] The compound according to claim 23, or a pharmaceutically acceptable salt thereof, wherein the compound is

29. The compound is 【Chemical Formula 8】 The compound according to claim 23, or a pharmaceutically acceptable salt thereof.

30. wherein the compound is 【Chemical Formula 9】 The compound according to claim 23, or a pharmaceutically acceptable salt thereof.

31. wherein the compound is 【Chemical 10】 The compound according to claim 23, or a pharmaceutically acceptable salt thereof.

32. wherein the compound is 【Chemical 11】 The compound according to claim 23, or a pharmaceutically acceptable salt thereof.

33. wherein the compound is 【Chemical 12】 The compound according to claim 23, or a pharmaceutically acceptable salt thereof.

34. wherein the compound is 【Chemical 13】 The compound according to claim 23, or a pharmaceutically acceptable salt thereof.

35. wherein the compound is 【Chemical Formula 14】 The compound according to claim 23, or a pharmaceutically acceptable salt thereof.

36. wherein the compound is 【Chemical Formula 15】 The compound according to claim 23, or a pharmaceutically acceptable salt thereof.

37. wherein the compound is 【Chemical 16】 The compound according to claim 23, or a pharmaceutically acceptable salt thereof.

38. wherein the compound is 【Chemical 17】 The compound according to claim 23, or a pharmaceutically acceptable salt thereof.

39. wherein the compound is 【Chemical 18】 The compound according to claim 23, or a pharmaceutically acceptable salt thereof.

40. wherein the compound is 【Chemical Formula 19】 The compound according to claim 23, or a pharmaceutically acceptable salt thereof.

41. wherein the compound is 【Chemical 20】 The compound according to claim 23, or a pharmaceutically acceptable salt thereof.

42. wherein the compound is 【Chemical 21】 The compound according to claim 23, or a pharmaceutically acceptable salt thereof.

43. A pharmaceutical composition comprising an amount of the compound according to any one of claims 23 to 42, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

44. Use of the compound according to any one of claims 23 to 42, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 43, in the manufacture of a medicament for treating cancer in a subject, wherein the cancer in the subject is neuroblastoma or breast cancer.

45. The use according to claim 44, wherein the cancer in the subject is neuroblastoma.

46. The use according to claim 44, wherein the cancer in the subject is breast cancer.

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