Polo-like kinase 4 inhibitors

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 incorporated herein by reference in their entireties. [Background technology]

[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 centriole 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 centriole biogenesis through phosphorylation and interaction with centriolar proteins (Habedanck et al., 2005; Maniswami et al., 2018). Overexpression of PLK4 leads to centriole amplification, as well as genomic instability and tumorigenesis (Holland et al., 2010). Abnormal PLK4 expression has been reported to be associated with several common human cancers (Marina and Saavedra, 2014; Shinmura et al., 2014). Thus, strong evidence supports the important role of PLK4 in carcinogenesis and therapeutic development. Therefore, there is a need for compounds that inhibit PLK4 in cancer-bearing subjects to treat such cancers. Summary of the Invention

[0003] As used herein, compounds of formula (I):

[0004] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, Ring A is C6-C 10 Aryl, heteroaryl, C3-C 10 cycloalkyl, or heterocycloalkyl; R 1 are each independently 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 , -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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C10 aryl, or heteroaryl, and C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 Each of the aryl and heteroaryl independently and optionally includes one or more R 1a is replaced by Alternatively, two R on adjacent atoms 1 By uniting, C3-C 10 form a cycloalkyl or heterocycloalkyl, each optionally containing one or more R 1b is replaced by R 1a are each 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 10aryl, or heteroaryl; Alternatively, two R on the same carbon atom 1a come together to form oxo, R 1b are each 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; Alternatively, two R on the same atom 1b come together to form oxo, n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; R 2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R 3is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R 4a , R 4b , and R 4c Each of the is independently 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 represents hydrogen, deuterium, halogens, -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 are each independently 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 , R 8b , R 8c , and R 8d Each of the 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; 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 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10each 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 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 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 each 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 c and R dare each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, 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), and is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 each 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; Or R c and R d taken together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, 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.

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

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

[0007] In some embodiments of the compounds 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 compounds of Formula (I), R 1 are each independently a halogen, -CN, -OH, or -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, C1-C6 alkyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 Each of the aryl and heteroaryl may optionally and independently be one or more R 1a is replaced by

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

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

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

[0013] In some embodiments of the compounds of Formula (I), R 4a , R 4b , and R 4c is hydrogen.

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

[0015] In some embodiments of the compounds of Formula (I), R 6 are hydrogen atoms.

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

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

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

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

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

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

[0022] Also disclosed herein are pharmaceutical compositions comprising an amount of a compound disclosed herein, 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, 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 in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION

[0025] As used in this specification and the appended claims, the following terms have the meanings indicated below, unless expressly stated to the contrary.

[0026] As used herein and in the appended claims, the singular forms "a," "an," and "the" include the plural unless the context clearly dictates otherwise. Thus, for example, a reference to "an agent" includes a plurality of such agents; a reference to "the cell" includes a reference to one or more cells (or cells), and equivalents thereof known to those of skill in the art, and so forth. When ranges relating to physical properties, such as molecular weight, or chemical properties, such as chemical formula, are used herein, all combinations and subcombinations of ranges and specific embodiments therein are intended to be encompassed. The term "about," when referring to a number or range, means that the referenced number or range is approximate within experimental variation (or within statistical experimental error), and thus, in some instances, varies by between 1% and 15% of the stated number or range. The term "comprising" (and related terms such as "comprise," "comprises," "having," or "including") is not intended to exclude that in other particular embodiments, embodiments such as, for example, any composition of matter, composition of matter, method, or process described herein "consist of" or "consist essentially of" the recited features.

[0027] "Administering," when used in conjunction with a therapeutic agent, means systemic or local administration of a therapeutic agent directly into or onto a target tissue, or administration of a therapeutic agent to a subject where the tissue targeted by the therapeutic agent will be positively affected. Thus, as used herein, the term "administering," when used in conjunction with the compositions disclosed herein, can include, but is not limited to, providing the composition into or onto a target tissue, for example, providing the composition systemically to a subject by oral administration where the therapeutic agent reaches the target tissue or tissues. "Administering" a composition may be accomplished by injection, topical administration, oral administration, or other methods alone or in combination with other known techniques.

[0028] The term "C2-C6 alkenyl," as used herein, refers to an alkyl moiety containing 2 to 6 carbon atoms with at least one carbon-carbon double bond. The carbon-carbon double bond in such groups 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. The 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. Whenever a numerical range such as "C2-C6 alkenyl" appears herein, it means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkenyl" where no numerical range is specified. In some embodiments, alkenyl is any of C2-C6 alkenyl. 10alkenyl, 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] The term "C1-C6 alkyl," as used herein, refers to a straight or branched chain hydrocarbon monoradical that may be fully saturated or unsaturated and has from 1 to about 10 carbon atoms, or from 1 to 6 carbon atoms. Examples of saturated hydrocarbon monoradicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl and octyl. Whenever a numerical range such as "C1-C6 alkyl" appears herein, it means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified.

[0030] The term "C2-C6 alkynyl," as used herein, refers to an alkyl moiety containing 2 to 6 carbon atoms with at least one carbon-carbon triple bond. The carbon-carbon triple bond in such groups 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, ethyne, propyne, 1-butyne, 2-butyne, 1-pentyne, 2-pentyne, 1-hexyne, 2-hexyne, and 3-hexyne, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever a numerical range such as "C2-C6 alkynyl" appears herein, it means that the alkynyl group can consist of 2, 3, 4, 5, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkynyl" where no numerical range is specified.

[0031] "C6-C 10 The term "aryl," as used herein, refers to a radical derived from a hydrocarbon ring system containing hydrogen, 6 to 10 carbon atoms, and at least one aromatic ring. Aryl radicals can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems and can include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is attached through an aromatic ring atom) or bridged ring systems. In some embodiments, an aryl is a 6-membered aryl. Aryl radicals include, but are not limited to, aryl radicals derived from anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene hydrocarbon ring systems. In some embodiments, an aryl is phenyl.

[0032] The term "C1-C6 aminoalkyl," as used herein, refers to a radical of C1-C6 alkyl as defined above, substituted with one or more amino groups. The amino groups in such a C1-C6 aminoalkyl group 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 The term "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 through a non-aromatic ring atom) or bridged ring systems. Representative cycloalkyls include: In some embodiments, a cycloalkyl is a 3- to 6-membered cycloalkyl; In some embodiments, a cycloalkyl is a 5- to 6-membered cycloalkyl; Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl or carbocycle include 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 cycloalkyl include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

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

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

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

[0037] The term "animal," as used herein, includes, but is not limited to, humans and non-human vertebrates, such as wild, domestic, and farm animals. As used herein, the terms "subject," "subject," and "individual" are intended to include organisms in which a particular disease described herein can occur. Examples include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats, and transgenic species. In preferred embodiments, the subject is a primate. In particular embodiments, the primate or subject is human. In particular examples, the subject is an adult. In particular examples, the human is a child. In further examples, the human is under 12 years of age. In particular examples, the human is an elderly person. In other examples, the human is 60 years of age or older. Other examples of subjects include laboratory animals, such as mice, rats, dogs, cats, goats, sheep, pigs, and cows. The laboratory animal can be an animal model for a disorder, e.g., a transgenic mouse with a hypertensive condition.

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

[0039] The term "Aurora kinase B" or "AurB," as used herein, refers to the human protein known to those skilled in the art as Aurora kinase B and encoded by the AURKB gene.

[0040] A "cyano" group refers to 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] The term "heterocycloalkyl," as used herein, 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 specifically stated otherwise in the specification, a heterocycloalkyl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and can include fused (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems. The nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized. In some embodiments, a heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. Examples of such heterocycloalkyl radicals include 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, and the like. Examples of heterocycloalkyl include, but are not limited to, lysinyl, 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 ring 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] The term "C1-C6 heteroalkyl," as used herein, refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from atoms other than carbon, e.g., 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, e.g., 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] The term "heteroaryl," as used herein, 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. Heteroaryl radicals can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems and can include fused (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems. The nitrogen, carbon, or sulfur atoms in a heteroaryl can be optionally oxidized, and the nitrogen atom can be optionally quaternized. In some embodiments, a heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, a heteroaryl is a 5- to 6-membered heteroaryl.Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl, benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, and indophenyl. linyl, 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] "Pharmaceutically acceptable," as used herein, means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0046] The term "pharmaceutical composition" means a composition comprising at least one active ingredient, whereby the composition is suitable for investigation for a particular efficacious outcome in a mammal (for example, but not limited to, a human). Those of skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based on the needs of the art.

[0047] The term "pharmaceutically acceptable salts," as used herein, means salts of the compounds of the present invention which retain the biological effectiveness of the free acids and free bases of the particular derivative, and which are not biologically or otherwise undesirable.

[0048] The term "PLK4," as used herein, refers to the human protein known to those skilled in the art as polo-like kinase 4 and encoded by the PLK4 gene.

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

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

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

[0052] The term "stereoisomers" refers to compounds that have identical chemical structure but differ in the arrangement of atoms or groups in space. Specifically, the term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. The terms "racemate" or "racemic mixture," as used herein, refer to a 1:1 mixture of the enantiomers of a particular compound. A racemic mixture in which one racemate is present in greater amount than the other may be described as "enantiomerically enriched." The term "diastereomer," on the other hand, refers to the relationship between a pair of stereoisomers that contain two or more asymmetric centers but are not mirror images of each other. Conventional nomenclature in the art may be used to describe the stereoisomers of a compound or the stereochemistry of a particular asymmetric carbon atom, compounds disclosed herein, or mixtures thereof. For example, a single racemate or stereocenter of a compound may be described as being of the (+), (-), (R), or (S) configuration. A racemic mixture may be described by using the (±) symbol.

[0053] The compounds of the present invention may have asymmetric carbon atoms. Carbon-carbon bonds in the compounds of the present invention may be represented herein using a solid line (_), a solid wedge (_), or a dotted wedge (.....). The use of a solid line to represent a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom (e.g., a specific enantiomer, a racemic mixture, etc.) are included. The use of a solid or dotted wedge to represent a bond to an asymmetric carbon atom is intended to indicate that only the depicted stereoisomer is included. It is possible that the compounds of the present invention may 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, it is intended that the compounds of the present invention can exist as enantiomers and diastereomers, or as racemates and mixtures thereof. The use of solid lines to represent bonds to one or more asymmetric carbon atoms in the compounds of the present invention, and the use of wedged solid or dotted lines to represent bonds to other asymmetric carbon atoms in the same compound, is intended to indicate the presence of a mixture of diastereomers.

[0054] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable, optically pure precursors or resolution of the racemate using, for example, chiral high-pressure liquid chromatography (HPLC). 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 base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and / or fractional crystallization, and one or both diastereomers may be converted to the corresponding pure enantiomer by means well known to those skilled in the art. The chiral compounds of the present invention (and their chiral precursors) may be obtained in enantiomerically enriched form using chromatography, typically HPLC, on an asymmetric resin, with a mobile phase consisting of 0-50%, typically 2-20% isopropanol, and a hydrocarbon, typically heptane or hexane, containing 0-5% alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture. Stereoisomeric conglomerates 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), incorporated herein by reference in its entirety.

[0055] The term "substituted," as used herein, 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 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 satisfy the valences of all atoms in the compound, it is understood that the remaining valences on such groups are satisfied with hydrogen. For example, if a C6 aryl group designated herein as "phenyl" is substituted with one additional substituent, one skilled in the art would understand that such a group leaves four open positions on the carbon atoms of the C6 aryl group (minus the six original positions to which the remainder of the compound of the present invention is attached and the additional substituents, leaving four). In such cases, the remaining four carbon atoms are each bonded to one hydrogen atom to satisfy their own valences. Similarly, when a C aryl group in a compound of the present invention is said to be "disubstituted," one of ordinary skill in the art will understand that the C aryl group is intended to have three carbon atoms remaining unsubstituted, each of which is bonded to one hydrogen atom to satisfy its valence.

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

[0057] [ka] is used in structural formulas herein to represent the bond that is the point at which the moiety or substituent is attached to the core or backbone structure. Following another convention, in some structural formulas herein, carbon atoms and their attached hydrogen atoms are not explicitly represented, e.g.,

[0058] [ka] represents a methyl group,

[0059] [ka] represents an ethyl group,

[0060] [ka] represents a cyclopentyl group.

[0061] Unless otherwise specified, groups such as (R 1 ) n But the expression:

[0062] [ka] When represented as a "floating" ring A in 1 may be present on any atom of the ring system, and substitution of a hydrogen atom, whether shown, implied, or explicitly defined, from one of the ring atoms is assumed so long as a stable structure is formed. For example, ring system A can be, but is not limited to, an aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, spirocyclyl, or a fused ring system.

[0063] When a group "R" is represented as "floating" on a ring system A as shown above, and ring A contains saturated carbons, "n" can be greater than 1, each assumed to replace a currently represented, implied, or explicitly defined hydrogen on ring A. Unless otherwise specified, two R 1 The group may remain on the same carbon. For example, R 1 is a methyl group, there can be a geminal dimethyl on a carbon of ring A. In another example, two R 1The groups may form rings to form spirocyclic rings ("spirocyclyl groups"). In compounds of formulas (I), (Ia), (Ib), (II), and (III), when n is less than the number of substitutable atoms on ring A, it is understood that 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, combat, alleviate, prevent, or ameliorate an unwanted disease or disorder in a subject.

[0065] A "therapeutically effective amount" or "effective amount," as used herein, refers to an amount of an active compound or pharmaceutical agent that elicits the biological or medical response in a tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, physician, or other clinician, where such response includes one or more of: (1) preventing a disease, e.g., preventing a disease, illness, or disorder in an individual who may be susceptible to the disease, illness, or disorder but who has not yet suffered or exhibited the pathology or symptomology of the disease; (2) inhibiting a disease, e.g., inhibiting a disease, illness, or disorder (i.e., preventing further progression of the pathology or symptomology) in an individual who is suffering or exhibiting the pathology or symptomology of the disease, illness, or disorder; and (3) ameliorating a disease, e.g., ameliorating a disease, illness, or disorder (i.e., reversing the pathology or symptomology) in an individual who is suffering or exhibiting the pathology or symptomology of the disease, illness, or disorder.

[0066] "Treat," "treated," "treatment," or "treating," as used herein, refers to both therapeutic treatment in some embodiments and prophylactic measures in other embodiments, the purpose of which is to prevent or slow (reduce) an undesired physiological condition or to obtain a beneficial or desired clinical result. For purposes herein, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; reduction in the extent of a disease, disorder, or condition; stabilization of the disease, disorder, or condition (i.e., prevention of worsening); delay in the onset or slowing of the progression of a disease, disorder, or condition; remission of the disease, disorder, or condition; and remission, improvement, or amelioration of a disease, disorder, or condition, whether detectable or undetectable. Treatment includes eliciting a clinically significant response without producing excessive levels of side effects. Treatment further includes prolonging survival beyond that expected in the absence of treatment. Prophylactic benefits of treatment include preventing disease, delaying disease progression, stabilizing disease, or reducing the likelihood of disease occurrence. As used herein, "treat," "treated," "treatment," or "treating" includes, in some embodiments, prophylaxis.

[0067] The term "TRIM37," as used herein, refers to the human protein known to those skilled 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" refers to the 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 is commercially available.

[0069] [ka]

[0070] PLK4 inhibitor compounds As used herein, compounds of formula (I):

[0071] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, Ring A is C6-C 10 Aryl, heteroaryl, C3-C 10 cycloalkyl, or heterocycloalkyl; R 1 are each independently 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 , -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 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 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 Each of the aryl and heteroaryl independently and optionally includes one or more R 1a is replaced by Alternatively, two R on adjacent atoms 1 By uniting, C3-C 10 form a cycloalkyl or heterocycloalkyl, each optionally containing one or more R 1b is replaced by R 1a are each 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; Alternatively, two R on the same carbon atom 1a come together to form oxo, R 1b are each 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; Alternatively, two R on the same atom 1b come together to form oxo, n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; 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 of the is independently 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 represents hydrogen, deuterium, halogens, -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 are each independently 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 the 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; 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-C10 aryl), or C1-C6 alkyl (heteroaryl), and is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 each 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 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 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10each 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 c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, 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), and is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 each 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; Or Rc and R d taken together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, 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.

[0072] As used herein, compounds of formula (I):

[0073] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, Ring A is C6-C 10 Aryl, heteroaryl, C3-C 10 cycloalkyl, or heterocycloalkyl; R 1 are each independently 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 , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NRb 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 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 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 Each of the aryl and heteroaryl independently and optionally includes one or more R 1a is replaced by Alternatively, two R on adjacent atoms 1 By uniting, C3-C 10 form a cycloalkyl or heterocycloalkyl, each optionally containing one or more R 1b is replaced by R 1a are each 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 , -NRb 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; Alternatively, two R on the same carbon atom 1a come together to form oxo, R 1b are each 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; Alternatively, two R on the same atom 1b come together to form oxo, n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; 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 of the is independently 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 represents hydrogen, deuterium, halogens, -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 are each independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR cR 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 , R 8b , R 8c , and R 8d Each of the 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; 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 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 each 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 10 Aryl, heteroaryl, C1-C6 alkyl (C3-C 10 Cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (C6-C 10aryl), or C1-C6 alkyl (heteroaryl), and is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 each 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 c and R d 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 10 aryl), or C1-C6 alkyl (heteroaryl), and is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10each 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; Or R c and R d taken together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, 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.

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

[0075] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, Ring A is C6-C 10 Aryl, heteroaryl, C3-C 10 cycloalkyl, or heterocycloalkyl; R 1are each independently 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 , -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 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 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 Each of the aryl and heteroaryl independently and optionally includes one or more R 1a is replaced by Alternatively, two R on adjacent atoms 1 By uniting, C3-C 10 form a cycloalkyl or heterocycloalkyl, each optionally containing one or more R 1b is replaced by R 1aare each 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; Alternatively, two R on the same carbon atom 1a come together to form oxo, R 1b are each 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 , -NRc 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; Alternatively, two R on the same atom 1b come together to form oxo, n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; 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 of the is independently 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 represents hydrogen, deuterium, halogens, -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 are each independently 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 , R 8b , R 8c , and R 8d Each of the 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; 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 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 each 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 bare 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 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 each 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 c and R d 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 10aryl), or C1-C6 alkyl (heteroaryl), and is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 each 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; Or R c and R d taken together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, 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.

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

[0077] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, Ring A is C6-C 10Aryl, heteroaryl, C3-C 10 cycloalkyl, or heterocycloalkyl; R 1 are each independently 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 , -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 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 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 Each of the aryl and heteroaryl independently and optionally includes one or more R 1a is replaced by Alternatively, two R on adjacent atoms 1 By uniting, C3-C 10form a cycloalkyl or heterocycloalkyl, each optionally containing one or more R 1b is replaced by R 1a are each 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; Alternatively, two R on the same carbon atom 1a come together to form oxo, R 1b are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SRa , -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; Alternatively, two R on the same atom 1b come together to form oxo, n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; 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 of the is independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c Rd , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R 5 represents hydrogen, deuterium, halogens, -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 are each independently 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 , R 8b , R 8c , and R 8d Each of the 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; 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 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 each 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 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 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 each 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 c and R d 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 10aryl), or C1-C6 alkyl (heteroaryl), and is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 each 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; Or R c and R d taken together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, 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.

[0078] Further herein, it is understood that ring A may be a C6-C 10 Compounds of Formula (I), Formula (Ia), and Formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is aryl or heteroaryl. In some embodiments, Ring A is C6-C 10Compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is aryl. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is phenyl. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is heteroaryl. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is furanyl, pyrrolyl, thiophenyl, oxazolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is pyrazolyl, pyridinyl, pyrazinyl, or pyrimidinyl. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is pyrazolyl. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, or 5-pyrazolyl. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is 1-pyrazolyl.In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is 3-pyrazolyl. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is 4-pyrazolyl. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is 5-pyrazolyl. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is pyridinyl. In some embodiments, compounds of Formula (I), (Ia), and (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), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is 2-pyridinyl. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is 3-pyridinyl. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is 4-pyridinyl. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is 5-pyridinyl. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is 6-pyridinyl. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is pyrazinyl.In some embodiments, compounds of Formula (I), (Ia), and (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), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is 2-pyrazinyl. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is 3-pyrazinyl. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is 5-pyrazinyl. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is 6-pyrazinyl. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is pyrimidinyl. In some embodiments, compounds of Formula (I), (Ia), and (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), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is 2-pyrimidinyl. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is 4-pyrimidinyl. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is 5-pyrimidinyl.In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is 6-pyrimidinyl. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is pyridazinyl. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, or 6-pyridazinyl. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is 3-pyridazinyl. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is 4-pyridanyl. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is 5-pyridanyl. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is 6-pyridanyl. In some embodiments, Ring A is C3-C6. 10 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 C3-C 10 Compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is cycloalkyl. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is heterocycloalkyl.

[0079] Further, in this specification, R 1 are each independently a halogen, -CN, -OH, or -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, C1-C6 alkyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 Each of the aryl and heteroaryl may optionally and independently be one or more R 1a In some embodiments, compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is substituted with 1 are each independently a halogen, -CN, -OH, or -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 selected from one or more R 1a In some embodiments, compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is substituted with 1 are each independently a halogen, -CN, -OH, or -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 selected from one or more R 1aIn some embodiments, compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is substituted with 1 are each independently a halogen, -CN, -OH, or -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 selected from one or more R 1a In some embodiments, compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is substituted with 1 are each independently 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 selected from one or more R 1a In some embodiments, compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is substituted with 1 are each independently fluoro, chloro, bromo, -CN, -OH, -OC1-C6 alkyl, -OC1-C6 haloalkyl, C1-C6 alkyl, -CF3, C3-C 10 cycloalkyl, or heterocycloalkyl, and is -OC1-C6 alkyl, C1-C6 alkyl, C3-C 10 Cycloalkyl, and heterocycloalkyl are optionally and independently selected from one or more R 1a In some embodiments, compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is substituted with 1are each independently 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, each of azetidinyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl, thiazinyl, and 1,4-oxazepanyl optionally and independently selected from one or more R 1a In some embodiments, compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is substituted with 1 are each independently chloro, -CN, -OH, -OCH3, -OCH2CH3, -CH3, isopropyl, -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 selected from one or more R 1a In some embodiments, compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is substituted with 1 are each independently chloro, —CN, —OCH—CH, isopropyl, —OCHF, —CF, cyclopropyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, or morpholinyl, and each of azetidinyl, piperidinyl, piperazinyl, and morpholinyl is optionally and independently selected from one or more R 1a In some embodiments, compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is substituted with 1are each independently chloro, —CN, —OCH—CH, isopropyl, —OCHF, —CF, cyclopropyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, or morpholinyl, and each of azetidinyl, piperidinyl, piperazinyl, and morpholinyl is optionally and independently selected from one or more R 1a In some embodiments, compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is substituted with 1 are each independently chloro, —CN, —OCH3—CH3, isopropyl, —OCHF2, —CF3, cyclopropyl, piperidinyl, piperazinyl, or morpholinyl, and piperidinyl, piperazinyl, and morpholinyl are optionally joined by one or more R 1a In some embodiments, compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is substituted with 1 are each independently chloro, -CN, -OCH3-CH3, isopropyl, -OCHF2, -CF3, cyclopropyl, piperidinyl, piperazinyl, or morpholinyl, and piperidinyl, piperazinyl, and morpholinyl are optionally substituted with one or more of -CH3, -CH2CH3, -CH2CH2CH3, -OH, and -OCH3. In some embodiments, R 1 are each independently chloro, -CN, -OCH-CH, -OCHF, cyclopropyl, piperidinyl, piperazinyl, or morpholinyl, and piperidinyl, piperazinyl, and morpholinyl are optionally substituted with one or more of -CH, -CHCH, -CHCHCH, -OH, and -OCH. In some embodiments, R 1are each independently chloro, -CN, -OCH-CH, -OCHF, cyclopropyl, or morpholinyl, wherein morpholinyl is optionally substituted with one or more of -CH, -CHCH, -CHCHCH, -OH, and -OCH. In some embodiments, R 1 are each independently chloro, —OCH—CH, —OCHF, cyclopropyl, or morpholinyl, wherein morpholinyl is optionally substituted with one or more —CHs, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

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

[0081] Further herein, R 2 Further provided herein are compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is hydrogen. 3 is hydrogen.

[0082] Further herein, R4a , R 4b , and R 4c In some embodiments, compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided wherein R is independently hydrogen or halogen. 4a is a halogen and R 4b and R 4c In some embodiments, compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is hydrogen. 4a and R 4c is hydrogen and R 4b In some embodiments, compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is halogen. 4a and R 4b is hydrogen and R 4c In some embodiments, compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is halogen. 4a and R 4b is a halogen and R 4c In some embodiments, compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is hydrogen. 4a and R 4c is a halogen and R 4b In some embodiments, compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is hydrogen. 4a , R 4b , and R 4c In some embodiments, compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided wherein R is halogen. 4a , R 4b , and R 4cIn some embodiments, compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided wherein R 5 is a halogen.

[0083] Further herein, R 6 and R are each hydrogen; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0084] Further herein, R 7 In some embodiments, compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is hydrogen or C1-C6 alkyl. 7 In some embodiments, compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is hydrogen. 7 is C1-C6 alkyl.

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

[0086] Further herein, R a In some embodiments, compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is C1-C6 alkyl. a is —CH 3 .

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

[0088] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, Ring A is C6-C 10 Aryl or heteroaryl, C3-C 10cycloalkyl, and heterocycloalkyl; R 1 are each independently a halogen, -CN, -OH, or -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, C1-C6 alkyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 Each of the aryl and heteroaryl may optionally and independently be one or more R 1a is replaced by R 1a are each 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; n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; R 2 is hydrogen or C1-C6 alkyl, R 3 is hydrogen or C1-C6 alkyl, R 4a , R 4b , and R 4c are each independently hydrogen, deuterium, or halogen; R 7 is hydrogen or C1-C6 alkyl, R 8a , R 8b , R 8c , and R 8d each of which is independently hydrogen, deuterium, a 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 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10each 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 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 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 each 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 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 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 each 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; Or R c and R d taken together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, 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.

[0089] Further herein, it is understood that ring A may be a C6-C 10 In some embodiments, compounds of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are provided, wherein ring A is C6-C 10

[0023] Provided are compounds of formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein ring A is aryl. In some embodiments, provided are compounds of formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein ring A is phenyl. In some embodiments, provided are compounds of formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein ring A is heteroaryl. In some embodiments, provided are compounds of formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein ring A is furanyl, pyrrolyl, thiophenyl, oxazolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments, compounds of Formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments, compounds of Formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is pyrazolyl, pyridinyl, pyrazinyl, or pyrimidinyl. In some embodiments, compounds of Formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is pyrazolyl. In some embodiments, compounds of Formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, or 5-pyrazolyl. In some embodiments, compounds of Formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is 1-pyrazolyl. In some embodiments, compounds of formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein ring A is 3-pyrazolyl. In some embodiments, compounds of formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein ring A is 4-pyrazolyl.In some embodiments, compounds of Formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is 5-pyrazolyl. In some embodiments, compounds of Formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is pyridinyl. In some embodiments, compounds of Formula (II), 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 (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is 2-pyridinyl. In some embodiments, compounds of Formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is 3-pyridinyl. In some embodiments, compounds of Formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is 4-pyridinyl. In some embodiments, compounds of Formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is 5-pyridinyl. In some embodiments, compounds of Formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is 6-pyridinyl. In some embodiments, compounds of Formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is pyrazinyl. In some embodiments, compounds of Formula (II), 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 (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein ring A is 2-pyrazinyl. In some embodiments, compounds of formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein ring A is 3-pyrazinyl.In some embodiments, compounds of Formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is 5-pyrazinyl. In some embodiments, compounds of Formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is 6-pyrazinyl. In some embodiments, compounds of Formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is pyrimidinyl. In some embodiments, compounds of Formula (II), 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 (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is 2-pyrimidinyl. In some embodiments, compounds of Formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is 4-pyrimidinyl. In some embodiments, compounds of Formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is 5-pyrimidinyl. In some embodiments, compounds of Formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is 6-pyrimidinyl. In some embodiments, compounds of Formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is pyridanyl. In some embodiments, compounds of Formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, or 6-pyridazinyl. In some embodiments, compounds of Formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is 3-pyridazinyl. In some embodiments, compounds of Formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is 4-pyridazinyl.In some embodiments, compounds of formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein ring A is 5-pyridazinyl. In some embodiments, compounds of formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein ring A is 6-pyridazinyl. In some embodiments, ring A is C3-C. 10 In some embodiments, compounds of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are provided, wherein ring A is C3-C 10 In some embodiments, compounds of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein ring A is cycloalkyl. In some embodiments, compounds of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein ring A is heterocycloalkyl.

[0090] Further, in this specification, R 1 are each independently a halogen, -CN, -OH, or -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 selected from one or more R 1a In some embodiments, compounds of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is substituted with 1 are each independently a halogen, -CN, -OH, or -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 selected from one or more R 1aIn some embodiments, compounds of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is substituted with 1 are each independently 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 selected from one or more R 1a In some embodiments, compounds of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is substituted with 1 are each independently 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 selected from one or more R 1a In some embodiments, compounds of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is substituted with 1 are each independently fluoro, chloro, -CN, -OH, -OC1-C6 alkyl, C1-C6 alkyl, -CF3, -OC1-C6 haloalkyl, C3-C 10 cycloalkyl, or heterocycloalkyl, and is -OC1-C6 alkyl, C1-C6 alkyl, C3-C 10 Cycloalkyl, and heterocycloalkyl are optionally and independently selected from one or more R 1a In some embodiments, compounds of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is substituted with 1 are each independently 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, each of azetidinyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl, thiazinyl, and 1,4-oxazepanyl optionally and independently selected from one or more R 1a In some embodiments, compounds of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is substituted with 1 are each independently chloro, -CN, -OH, -OCH3, -OCH2CH3, -CH3, isopropyl, -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 selected from one or more R 1a In some embodiments, compounds of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is substituted with 1 are each independently chloro, —CN, —OCH3, —CH3, isopropyl, —CF3, —OCHF2, cyclopropyl, azetidinyl, piperidinyl, piperazinyl, or morpholinyl, and each of azetidinyl, piperidinyl, piperazinyl, and morpholinyl is optionally and independently selected from one or more R 1a In some embodiments, compounds of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is substituted with 1are each independently chloro, —CN, —OCH3, —CH3, isopropyl, —CF3, —OCHF2, cyclopropyl, piperidinyl, piperazinyl, or morpholinyl, and each of cyclopropyl, piperidinyl, piperazinyl, and morpholinyl is optionally and independently selected from one or more R 1a In some embodiments, compounds of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is substituted with 1 are each independently chloro, -OCH3, -CH3, isopropyl, -CF3, -OCHF2, cyclopropyl, piperidinyl, piperazinyl, or morpholinyl, and piperidinyl, piperazinyl, and morpholinyl are optionally joined by one or more R 1a In some embodiments, compounds of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is substituted with 1 are each independently chloro, -OCH3, -CH3, isopropyl, -CF3, -OCHF2, cyclopropyl, piperidinyl, piperazinyl, or morpholinyl, and piperidinyl, piperazinyl, and morpholinyl are optionally substituted with one or more of -CH3, -CH2CH3, -CH2CH2CH3, -OH, and -OCH3. In some embodiments, compounds of Formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein R 1 is each independently chloro, -OCH, -CH, cyclopropyl, piperidinyl, piperazinyl, or morpholinyl, and piperidinyl, piperazinyl, and morpholinyl are optionally substituted with one or more of -CH, -CHCH, -CHCHCH, -OH, and -OCH. In some embodiments, R 1are each independently chloro, -OCH3, -CH3, -OCHF2, cyclopropyl, or morpholinyl, wherein morpholinyl is optionally substituted with one or more of -CH3, -CH2CH3, -CH2CH2CH3, -OH, and -OCH3. In some embodiments, compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided wherein R 1 is each independently chloro, —OCH3, —CH3, cyclopropyl, or morpholinyl, wherein morpholinyl is optionally substituted with one or more —CH3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

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

[0092] Further herein, R 2 is hydrogen, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0093] Further herein, R 3 is hydrogen, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0094] Further herein, R 4a , R 4b , and R 4cIn some embodiments, compounds of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is independently hydrogen or halogen. 4a is a halogen and R 4b and R 4c In some embodiments, compounds of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided wherein R 4a and R 4c is hydrogen and R 4b In some embodiments, compounds of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is halogen. 4a and R 4b is hydrogen and R 4c In some embodiments, compounds of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is halogen. 4a and R 4b is a halogen and R 4c In some embodiments, compounds of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided wherein R 4a and R 4c is a halogen and R 4b In some embodiments, compounds of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided wherein R 4a is a halogen and R 4b and R 4c In some embodiments, compounds of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided wherein R 4a , R 4b , and R 4c In some embodiments, compounds of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R 4a , R 4b , and R 4cIn some embodiments, compounds of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is halogen. 4a , R 4b , and R 4c is fluoro.

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

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

[0097] Further herein, R a In some embodiments, compounds of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are provided, wherein R is C1-C6 alkyl. a is —CH 3 alkyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

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

[0099] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, Ring A is heteroaryl; R 1 are each independently a halogen, -CN, -OH, or -OR a , C1-C6 alkyl, C1-C6 haloalkyl, -OC1-C6 haloalkyl, C3-C 10 cycloalkyl, or heterocycloalkyl, and C1-C6 alkyl, C3-C 10 Each of the cycloalkyl and heterocycloalkyl optionally and independently may be one or more R 1a is replaced by R 1a are each independently deuterium, -OH, or -OR a, 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; n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; R 7 is hydrogen or C1-C6 alkyl, R 8c is 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 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 each 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; A compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided.

[0100] Further provided herein are compounds of Formula (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein Ring A is pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments, compounds of Formula (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein Ring A is pyrazolyl. In some embodiments, compounds of Formula (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein Ring A is 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, or 5-pyrazolyl. In some embodiments, compounds of Formula (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein Ring A is 1-pyrazolyl. In some embodiments, compounds of Formula (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein Ring A is 3-pyrazolyl. In some embodiments, compounds of Formula (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is 4-pyrazolyl. In some embodiments, compounds of Formula (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is 5-pyrazolyl. In some embodiments, compounds of Formula (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is pyridinyl. In some embodiments, compounds of Formula (III), 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 (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is 2-pyridinyl. In some embodiments, compounds of formula (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein ring A is 3-pyridinyl. In some embodiments, compounds of formula (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein ring A is 4-pyridinyl.In some embodiments, compounds of Formula (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is 5-pyridinyl. In some embodiments, compounds of Formula (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is 6-pyridinyl. In some embodiments, compounds of Formula (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is pyrazinyl. In some embodiments, compounds of Formula (III), 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 (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is 2-pyrazinyl. In some embodiments, compounds of Formula (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is 3-pyrazinyl. In some embodiments, compounds of Formula (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is 5-pyrazinyl. In some embodiments, compounds of Formula (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is 6-pyrazinyl. In some embodiments, compounds of Formula (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein Ring A is pyrimidinyl. In some embodiments, compounds of Formula (III), 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 (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein ring A is 2-pyrimidinyl. In some embodiments, compounds of formula (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein ring A is 4-pyrimidinyl.In some embodiments, compounds of Formula (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is 5-pyrimidinyl. In some embodiments, compounds of Formula (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is 6-pyrimidinyl. In some embodiments, compounds of Formula (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is pyridanyl. In some embodiments, compounds of Formula (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, or 6-pyridazinyl. In some embodiments, compounds of Formula (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided, wherein Ring A is 3-pyridazinyl. In some embodiments, compounds of formula (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein ring A is 4-pyridazinyl. In some embodiments, compounds of formula (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided wherein ring A is 5-pyridazinyl. In some embodiments, compounds of formula (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are provided 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 are each independently a halogen, -CN, -OH, or -OR a , C1-C6 alkyl, C1-C6 haloalkyl, -OC1-C6 haloalkyl, C3-C 10 cycloalkyl, or heterocycloalkyl, and C1-C6 alkyl, C3-C 10Each of the cycloalkyl and heterocycloalkyl optionally and independently may be one or more R 1a is replaced by R 1a are 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 HA-OR a and R a are each C1-C6 alkyl; A compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided. 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 a further embodiment, 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 are each independently fluoro, chloro, -CN, -OH, or -OR a , C1-C6 alkyl, C1-C6 haloalkyl, -OC1-C6 haloalkyl, C3-C 10 cycloalkyl, or heterocycloalkyl, and C1-C6 alkyl, C3-C 10 Each of the cycloalkyl and heterocycloalkyl optionally and independently may be one or more R 1a is replaced by R 1a are each independently -OH, -ORa , 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 are each C1-C6 alkyl; A compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided. 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 1are each independently chloro, -CN, -OH, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -CH(CH3)2, -CF3, -OCHF2, cyclopropyl, morpholinyl, piperidinyl, piperazinyl, azetidinyl, 1,1-dioxidethiomorpholinyl, or oxetanyl, and morpholinyl, piperidinyl, piperazinyl, azetidinyl, 1,1-dioxidethiomorpholinyl, and oxetanyl are each optionally and independently selected from one or more R 1a is replaced by R 1a are 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 -OCH3, R a are each C1-C6 alkyl; A compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided.

[0104] 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 are each independently a halogen, -CN, or -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, and C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 Each of the aryl and heteroaryl independently and optionally includes one or more R 1a is replaced by R 1a are each independently deuterium, -OH, or -OR a , 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; 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 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 each 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 10 Aryl, heteroaryl, C1-C6 alkyl (C3-C 10 Cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (C6-C 10aryl), or C1-C6 alkyl (heteroaryl), and is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 each 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 c and R d 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 10 aryl), or C1-C6 alkyl (heteroaryl), and is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10each 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; Or R c and R d taken together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Provided is 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 are each independently a 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, and C1-C6 alkyl, C3-C 10 Each of the cycloalkyl and heterocycloalkyl optionally and independently may be one or more R 1a is replaced by R 1a are each independently deuterium, -OH, or -OR a , 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; 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 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 each 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 10 Aryl, heteroaryl, C1-C6 alkyl (C3-C 10 Cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (C6-C 10aryl), or C1-C6 alkyl (heteroaryl), and is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 each 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 c and R d 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 10 aryl), or C1-C6 alkyl (heteroaryl), and is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10each 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; Provided is 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 are each independently a 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, and C1-C6 alkyl, C3-C 10 Each of the cycloalkyl and heterocycloalkyl optionally and independently may be one or more R 1a is replaced by R 1a are each independently deuterium, -OH, or -OR a , 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; n is 1, 2, or 3; R 7 is hydrogen or C1-C6 alkyl, R 8c is 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 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10each 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 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 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 each 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 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 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 each 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; Provided is 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.

[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 are each independently halogen, —S(═O)2(C1-C6 alkyl), —S(═O)2N(C1-C6 alkyl)2, —O-C6 alkyl, —C(═O)N(C1-C6 alkyl)2, —C(═O)N(H)(C1-C6 alkyl), —O-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 1are each independently 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, dioxidedothiomorpholinyl, —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 are each independently 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, dioxidethiomorpholinyl, -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 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)N(C1-C6 alkyl)2, -S(=O)NH2, -S(=O)N(C1-C6 alkyl)(H), -O-C6 alkyl, -CH2CHF2, -C(=O)N(C1-C6 alkyl)2, -C(=O)N(H)(C1-C6 alkyl), -O-C6 haloalkyl, -C1-C6 alkyl, -SC1-C6 alkyl, azetidinyl, pyrrolidinyl, oxazolyl, fluoropyrrolidinyl, difluoropiperidinyl, difluoroazetidinyl, fluoroazetidinyl, morpholinyl, dioxidedothiomorpholinyl, -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 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 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(H), -C(=O)N(H)(C1-C6 alkyl)2, -OC1-C6 haloalkyl, -C1-C6 alkyl, -SC1-C6 alkoxy alkyl, azetidinyl, pyrrolidinyl, oxazolyl, fluoropyrrolidinyl, difluoropiperidinyl, difluoroazetidinyl, fluoroazetidinyl, morpholinyl, dioxidethiomorpholinyl, —C(═O)(morpholinyl), —C(═O)(azetidinyl), —C(═O)(difluoroazetidinyl), or —C(═O)difluoropiperidinyl; R 1 At least one of -S(=O)2(C1-C6 alkyl), -S(=O)2(C3-C 10 cycloalkyl), -S(=O)N(C1-C6 alkyl), -S(=O)NH, or -S(=O)N(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 are 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 alkoxy alkyl, azetidinyl, pyrrolidinyl, oxazolyl, fluoropyrrolidinyl, difluoropiperidinyl, difluoroazetidinyl, fluoroazetidinyl, morpholinyl, dioxidethiomorpholinyl, —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 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 are each independently a halogen, -CN, or -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, and C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 Each of the aryl and heteroaryl independently and optionally includes one or more R 1a is replaced by R 1a are each independently deuterium, -OH, or -OR a , 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; 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 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 each 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 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 each 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 c and R d 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 10 aryl), or C1-C6 alkyl (heteroaryl), and is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10each 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; Or R c and R d taken together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, 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.

[0114] Further provided herein are compounds including (1R,2S)-5'-methoxy-2-{3-[(5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[(5-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[(5-chloropyrimidin-4-yl)amino]-1H-indazol-6 -yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[(5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[(5-ethoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2 -{3-[(5-cyclopropylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[(5-chloropyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1S,2R)-5'-methoxy-2-{3-[(5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro [Cyclopropane-1,3'-indol]-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'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[(2-chloro-5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-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'-indol]-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'-indol]-2'(1'H)-one, (1R,2S)-5'-Methoxy-2-{3-[(3-methoxypyra (1R,2S)-5'-methoxy-2-{3-[(6-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[(6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3 '-indol]-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'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[(3-methoxypyridin-2-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[(4-methoxypyridin -3-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[(3-methoxypyridin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-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,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'-indol]-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'-indol]-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'-indol]-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'-indol]-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'-indol]-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'-indol]-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'-indol] [6-(2-hydroxyethoxy)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-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'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[6-(2-hydroxyethoxy)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one,2S)-2-(3-((6-(1,1-dioxidethiomorpholino)pyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-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'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[6-(3-hydroxyazetidin-1-yl)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl) amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-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'-methoxy 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'-methoxyspiro[cyclopropane-1,3'-indol]-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-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-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'-indol]-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'-indol]-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'-indol]-2'(1'H)-one, (1R,2S)-2-(3-((5-chloro-6-(1,1-dioxidethiomorpholino)pyrimidin-4-yl)amino)-1H-indazole -6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one, (1R,2S)-2-(3-((6-(1,1-dioxidethiomorpholino)-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'-indolin]-2'-one, indol]-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'-indol]-2'(1'H)-one, (1R,2S)-2-(3-((6-(1,1-dioxidethiomorpholino)-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-dioxidethiomorpholino)-2-methylpyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one, (1R,2S)-2-(3-((2-cyclopropyl-6-(1,1-dioxidethiomorpholino)pyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one, (1R,2S)-2-( 3-((6-(1,1-dioxidethiomorpholino)-2-methylpyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-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-dioxide Thiomorpholino)-5-methoxy-6-((6-((1R,2S)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indolin]-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- 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'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[2-(2-hydroxyethyl)-5-methoxy-6-(morpholin-4-yl)pyrazole 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-(1,1-dioxidethiomorpholino)-5-methoxypyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one, (1R,2S)-2-(3-((5-chloro-2-cyclopropyl-6-(1,1-dioxidethiomorpholino)pyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one (1R,2S)-2-(3-{[5-chloro-6-(3-hydroxyazetidin-1-yl)-2-methylpyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[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'-indol]-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'-methoxyspiro[cyclopropane-1,3'-indol]-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'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[(1,3-dimethyl-1H-pyrazol-5-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[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 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-dioxidethiomorpholino)-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'-indole]-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-dioxidethiomorpholino)-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-ine, (1R,2S)-2-{3-[(5-chloro-2-methylpyridin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[(5-chloro-2-methylpyridin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one )-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'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[(5-chloro-2-methylpyrimidin-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-6-(mo (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-6-(oxetan-3-yl)pyrazin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-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'-indol]-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'-indol]-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-chloro-2-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one3'-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,2 S)-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)-5'-methoxy-1'-methylspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, thiazetidin-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-methoxypyrazine

[0013] In one embodiment, the compound of formula (I) is selected from (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, (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, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0115] Further provided herein are (1R,2S)-2-(3-{[1-(2,2-difluoroethyl)-3-methyl-1H-pyrazol-5-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-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'-methyl ... S)-2-(3-{[2-(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)-5'-methoxy-2-(3-{[6-(oxetan-3-yl)pyrazin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-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'-indol]-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'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[5-methoxy-2-(oxetan-3-yl)pyrimidin-4-yl]amino}-1H-in (1R,2S)-2-(3-{[5-chloro-2-(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-{[5-(difluoromethoxy)-2-methylpyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one3'-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, spiro[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'-indol]-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'-indol]-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'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[(5-ethoxy-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-methylpyrimidin-4-yl]amino}-1H-indazol-6-yl (1R,2S)-5'-fluorospiro[cyclopropane-1,3'-indol]-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'-indol]-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'-indol]-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'-indol]-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'-indol]-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

[0010] Provided is a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from (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, (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.

[0116] Further provided herein are compounds such as (1R,2R)-2-{5-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)-5'-methoxy-2-{3-[(3-methoxy-6-methylpyridazin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[5-(cyclopropylmethoxy) -2-methylpyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-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'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-[3-(2-methoxy-5-methylanilino)-1H-indazol-6-yl]spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, spiro[cyclopropane-1,3'-indol]-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'-indol]-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'-indol]-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'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[(5-ethyl-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-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'-indol]-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'-indol]-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'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[(2,5-dimethoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[2-(azetidin-1-yl)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-meth 5'-Methoxy-2-(3-{[3-methoxy-5-(trifluoromethyl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-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'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[(2-ethyl-5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[(7-methoxyquinolin-6-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-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-indazo 6-Methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl)-2-(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)-2-(cyclopropane-1,3'-indol)-2'(1'H)-one}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'-indol]-2'(1'H)-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)pyrimidine-2-carbonitrile, (1R,2S)-2-(3-{[2-(3,3-difluorobenzoyl) (1R,2S)-2-(3-{[2-(3-fluoroazetidin-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-fluoroazetidin-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-[5-(ethanesulfonyl)-2-methoxyanilino]-1H-i Indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, 4-methoxy-3-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-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'-indol]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylbenzamide (1R,2S)-5'-methoxy-2-{3-[2-methoxy-5-(propane-2-sulfonyl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, 4-methoxy-3-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylbenzene-1-sulfonamide, (1R,2S)-5'-Methoxy-2-{3-[2-methoxy-5-(morpholine-4-carbonyl)anilino]-1H-indazol-6-yl}spiro[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-3-carboxamide, (1R,2S )-2-(3-{[2-(dimethylamino)-5-methylpyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-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'-indol]-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'-indol]-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'-indol]-2'(1'H)-one -one, (1R,2S)-2-(4-fluoro-3-{[5-methoxy-2-(methylsulfanyl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-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'-indol]-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'-indol]-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'-indol]-2'(1'H)-one, 4-[5-methoxy-4-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-, indazol-3-yl}amino)pyrimidin-2-yl]-1λ6-thiomorpholine-1,1-dione, 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-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-in (1R,2S)-2-(3-{[5-(methanesulfonyl)-3-methoxypyridin-2-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-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'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[6-(methanesulfonyl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one -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,N-dimethylpyridine-3-carboxamide, 5-methoxy-4-({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-[2-methoxy-4-(morpholine-4-carbonyl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-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'-indol]-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'-indol]-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'-indol]-2'(1'H)-one, 5-ethoxy-6-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[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,N-dimethylpyridine-3-carboxamide, 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,N-dimethylpyridine-3-sulfonamide, (1R,2S)-2-(3-{[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl) -5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, 2-fluoro-5-methoxy-4-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-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,

[0013] The compound of formula (I) is selected from (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, 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.

[0117] Further described herein are compounds such as (1R,2S)-2-(3-{[6-(ethanesulfonyl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-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)-N,2-dimethylbenzene-1-sulfonamide, (1 R,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'-indol]-2'(1'H)-one, 2,5-dimethoxy-4-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-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'-indol]-2'(1'H)-one, 6-ethoxy-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-{[2-methoxy-6-(2-oxopyrrolidin-1-yl)pyridin-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-(morpholine-4-sulfonyl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-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'-indol]-2'(1'H)-one, N,6-dimethoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-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'-indol]-2-yl]-1H-indazol-3-yl}amino)-N-methylpyridine-2-carboxamide 1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-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'-indol]-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'-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-sulfonamide, 6-Ethoxy-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-sulfonamide, (1R,2S)-5'-methoxy-2-{3-[2-methoxy-5-(oxane-4-sulfonyl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-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'-methoxyspiro[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'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[5-(ethanesulfonyl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[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'-indol]-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'-indol]-2'(1'H)-one, 6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[ 6-ethoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-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'-indol]-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'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[6-(methanesulfinyl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro [Cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[6-(methanesulfonyl)-4-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[5-(methanesulfonyl)-3-methoxypyrazin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, N,N-Dicyclopropyl-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, N-(2,2-difluoroethyl)-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 amide, (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'-indol]-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'-indol]-2'(1'H)-one indol]-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'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-5-(propane-2-sulfonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3 -{[6-(dimethylphosphoryl)-4-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-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'-indol]-2-yl]-1H-indazol-3-yl}amino)pyridine-2-carboxamide, 6-chloro-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)-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'-indol]-2-yl]-1H-indazol-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'-indol]-2-yl]-1H-indazol-3-yl}amino)pyrazin-2-yl]-1 λ6-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'-indol]-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'-indol]-2'(1'H)-one 1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[6-(diethylphosphoryl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[5-(cyclopropanesulfonyl)-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-(oxane-4-sulfonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[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)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-methoxy pyridin-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-i (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-[(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)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)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'-indol]-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-methoxypyridine 1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[2-ethoxy-4-(methanesulfonyl)anilino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-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'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[5-(ethanesulfonyl)-3-ethoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, 5-ethoxy-6-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-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'-indol]-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'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[6-(2-hydroxypropan-2-yl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[4-ethoxy-6-(methanesulfonyl)pyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one The compound of formula (I) is selected from (1R,2S)-2-(3-{[5-(difluoromethanesulfonyl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, and (1R,2S)-2-(3-{[5-(difluoromethanesulfonyl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, or a pharmaceutically acceptable salt thereof.

[0118] Further provided herein is a compound of Formula (I) selected from those set forth 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] Further provided herein are pharmaceutical compositions 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 are methods 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. Provided herein are methods of treating cancer in a subject, wherein the subject's cancer 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, stomach 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 gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) neoplasm, primary CNS lymphoma, spinal axis tumor, brainstem glioma, or pituitary adenoma. In some embodiments, the target cancer expresses polo-like kinase 4 (PLK4). In some embodiments, the subject's cancer is determined to express polo-like kinase 4 (PLK4) before administering a compound of Formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to the subject. In some embodiments, the subject's cancer exhibits overexpression of E3 ubiquitin protein ligase (TRIM37) protein. In some embodiments, the subject's cancer exhibits overexpression of the gene encoding tripartite motif-containing protein 37 (TRIM37). In some embodiments, the subject's cancer exhibits amplification of the gene encoding 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 subject's cancer has been determined to overexpress the gene encoding tripartite motif-containing protein 37 (TRIM37) prior to administering 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 subject's cancer has been determined to overexpress the 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 cancer biological sample from a subject; b. determining whether the cancer biological sample overexpresses the gene encoding tripartite motif-containing protein 37 (TRIM37); c. if the cancer biological sample 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 is provided that includes:

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

[0181] Further provided herein are methods of treating cancer in 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 along with one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are selected from one or more antimitotic agents, 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 kinase inhibitors, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxic agents, and tumor immunotherapeutics.

[0182] Further provided herein are methods for 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] Further provided herein is a method for 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 subject's cancer 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 are methods for 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 subject's cancer 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 subject's cancer is acute myeloid leukemia. In some embodiments, the subject's cancer is myelodysplastic syndrome. In some embodiments, the subject's cancer is chronic myelomonocytic leukemia. In some embodiments, the subject's cancer is triple-negative breast cancer. In some embodiments, the subject's cancer is advanced breast cancer. In some embodiments, the subject's cancer is metastatic breast cancer. In some embodiments, the subject's cancer is prostate cancer.

[0185] 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 a method of treating cancer in a subject in need thereof. In some embodiments, the compound or pharmaceutical composition for the above-mentioned use is provided, wherein the cancer is a solid tumor. In some embodiments, the compound or pharmaceutical composition for the above-mentioned use is provided, wherein the cancer is neuroblastoma, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin 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 gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) neoplasm, primary CNS lymphoma, spinal axis tumor, brainstem glioma or pituitary adenoma.In some embodiments, the compound or pharmaceutical composition for the above-mentioned use is provided, wherein the cancer of the subject expresses polo-like kinase 4 (PLK4). In some embodiments, a compound or pharmaceutical composition for the above-described use is provided, wherein the subject's cancer is determined to express polo-like kinase 4 (PLK4) before administering the compound or pharmaceutical composition to the subject. In some embodiments, a compound or pharmaceutical composition for the above-described use is provided, wherein the subject's cancer exhibits overexpression of E3 ubiquitin protein ligase (TRIM37) protein. In some embodiments, a compound or pharmaceutical composition for the above-described use is provided, wherein the subject's cancer exhibits overexpression of the gene encoding tripartite motif-containing protein 37 (TRIM37). In some embodiments, a compound or pharmaceutical composition for the above-described use is provided, wherein the subject's cancer exhibits amplification of the gene encoding tripartite motif-containing protein 37 (TRIM37).In some embodiments, a compound or pharmaceutical composition for the above-described use is provided, wherein the subject's cancer is determined to overexpress a gene encoding tripartite motif-containing protein 37 (TRIM37) prior to administering the compound or pharmaceutical composition to the subject. In some embodiments, a compound or pharmaceutical composition for the above-described use is provided, wherein the cancer is neuroblastoma or breast cancer. In some embodiments, a compound or pharmaceutical composition for the above-described use is provided, wherein the cancer is neuroblastoma. In some embodiments, a compound or pharmaceutical composition for the above-described use is provided, 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 a method of treating cancer in a subject in need thereof, wherein the subject's cancer 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 subject's cancer is acute myeloid leukemia. In some embodiments, the subject's cancer is myelodysplastic syndrome. In some embodiments, the subject's cancer is chronic myelomonocytic leukemia. In some embodiments, the subject's cancer is triple-negative breast cancer. In some embodiments, the subject's cancer is advanced breast cancer. In some embodiments, the subject's cancer is metastatic breast cancer. In some embodiments, the cancer of interest is prostate cancer.

[0187] 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 a method of inhibiting polo-like kinase 4 (PLK4) in a subject with cancer.

[0188] 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. In some embodiments, the cancer is provided as follows: neuroblastoma, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach 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 gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) neoplasm, primary CNS lymphoma, spinal 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 subject's cancer is determined to express polo-like kinase 4 (PLK4) prior to administering the compound to the subject. In some embodiments, the subject's cancer exhibits overexpression of E3 ubiquitin protein ligase (TRIM37) protein. In some embodiments, the subject's cancer exhibits overexpression of the gene encoding tripartite motif-containing protein 37 (TRIM37). In some embodiments, the subject's cancer exhibits amplification of the gene encoding tripartite motif-containing protein 37 (TRIM37). In some embodiments, the subject's cancer is determined to overexpress the gene encoding tripartite motif-containing protein 37 (TRIM37) prior to administering 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 subject's cancer 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 subject's cancer is acute myeloid leukemia. In some embodiments, the subject's cancer is myelodysplastic syndrome. In some embodiments, the subject's cancer is chronic myelomonocytic leukemia. In some embodiments, the subject's cancer is triple-negative breast cancer. In some embodiments, the subject's cancer is advanced breast cancer. In some embodiments, the subject's cancer is metastatic breast cancer. In some embodiments, the cancer of interest is prostate cancer.

[0190] In some embodiments, a 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 anticancer agents. In some embodiments, the anticancer agent is mitoxantrone, estramustine, etoposide, vinblastine, carboplatin, vinorelbine, paclitaxel, daunomycin, darubicin, epirubicin, docetaxel, cabazitaxel, or doxorubicin. In some embodiments, the anticancer agent is paclitaxel, daunomycin, darubicin, epirubicin, docetaxel, cabazitaxel, or doxorubicin. In certain embodiments, the anticancer agent is docetaxel.

[0191] In some embodiments, the one or more additional anticancer agents may include, but are not limited to, surgery, radiation, or chemotherapy. Chemotherapeutic agents may be androgen receptor antagonists, mitotic inhibitors, antimetabolites, or 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, 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 phototrexate. Examples of platinum-based drugs include, but are not limited to, cisplatin, carboplatin, dicycloplatin, eptaplatin, lobaplatin, miriplatin, nedaplatin, oxaliplatin, picoplatin, satraplatin, or triplatin tetranitrate. Additional anticancer therapeutic agents may include anti-PDL1 agents, anti-PD1 agents, or anti-CTLA-4 agents. Anti-PD-L1 agents may include atezolizumab, avelumab, durvalumab, MPDL3280A (RG7446), MDX-1105 (BMS-936559), or BMS-935559, MSB0010718C, and MEDI4736. Anti-PD1 drugs may include pembrolizumab, nivolumab, cemiplimab, partalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS001), dostallimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, or AMP-514 (MEDI0680). Anti-CTLA drugs may include ipilimumab or tremelimumab.

[0192] Treatment methods in conjunction with biomarkers In some embodiments, methods for detecting the presence, absence, or level of a biomarker are disclosed. Such biomarkers may include genetic alterations in genes encoding specific proteins, such as tripartite motif-containing protein 37 (TRIM37). The presence, absence, or level of such biomarkers can be measured in a biological sample obtained from a subject, such as a sample of a solid tumor such as prostate cancer, or from a sample of a relevant bodily fluid, such as a blood sample. In some examples, the detection methods disclosed herein are useful for predicting therapeutic response to a therapeutic agent described herein (e.g., a PLK4 inhibitor), monitoring treatment of a subject with a therapeutic agent for a proliferative disorder or disease described herein, and administering treatment with the therapeutic agent. In some embodiments, the presence, absence, and / or level of one or more biomarkers is detected in a sample obtained from a subject by analyzing genetic material in the sample. In some embodiments, the genetic material is obtained from blood, serum, plasma, sweat, hair, tears, urine, and other techniques known to those skilled in the art. In some embodiments, the sample contains circulating tumor RNA (ctRNA). In some embodiments, the sample comprises peripheral blood mononuclear cells (PBMCs). Optionally, the genetic material is obtained from a tumor biopsy or liquid biopsy. In some embodiments, the tumor biopsy comprises a formalin-fixed, paraffin-embedded biopsy, a fresh frozen biopsy, a fresh biopsy, or a frozen biopsy. In some embodiments, the liquid biopsy comprises PBMCs, circulating tumor RNA, plasma cell-free RNA, or circulating tumor cells (CTCs). The tumor biopsy may also undergo additional analytical processing for sample dissociation, cell sorting, and enrichment for cell populations of interest.

[0193] In some embodiments, a method for detecting the presence, absence, or level of a biomarker in a sample obtained from a subject includes 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 instances, the DNA is single-stranded DNA (ssDNA), double-stranded DNA, denatured double-stranded DNA, synthetic DNA, and combinations thereof. The circular DNA may 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 a microRNA or a portion thereof. In some instances, 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), circular 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, the nucleic acid-based detection assay includes quantitative polymerase chain reaction (qPCR), gel electrophoresis (including, for example, Northern blot or Southern blot), immunochemistry, in situ hybridization such as fluorescent in situ hybridization (FISH), cytochemistry, microarray, or sequencing. In some embodiments, the sequencing technique includes next-generation sequencing. In some embodiments, the method includes a hybridization assay, such as fluorogenic 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), which includes a nucleic acid amplification reaction with a specific primer pair, or hybridization to an amplified nucleic acid probe containing 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 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 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 comprising a fluorophore and a quencher that is hydrolyzed by a DNA polymerase when hybridized to a target nucleic acid. Optionally, the presence of the target nucleic acid is determined if the number of amplification cycles that reach the threshold is less than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, or 20 cycles.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 typical nucleic acid-based detection assays involve the use of nucleic acid probes conjugated or otherwise immobilized to beads, multiwell plates, or other substrates, where the nucleic acid probes are configured to hybridize with target nucleic acid sequences. In some examples, the nucleic acid probes are specific to one or more gene products described herein. In some examples, biomarker-specific nucleic acid probes comprise nucleic acid probe sequences sufficiently complementary to the biomarker polynucleotide sequence. In some examples, the biomarkers comprise transcribed polynucleotide sequences (e.g., RNA, cDNA). In some embodiments, the nucleic acid probes may be full-length cDNAs or portions thereof, such as oligonucleotides at least about 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides in length, 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 and contacted with a probe, for example, by running the isolated target nucleic acid sequence on an agarose gel and transferring the target nucleic acid sequence from the gel to a membrane such as nitrocellulose. In some embodiments, the probe is immobilized on a solid surface, for example, in an Affymetrix gene chip array, and the probe is contacted with the target nucleic acid sequence.

[0196] In some embodiments, the term "probe" in reference to nucleic acids refers to any nucleic acid molecule capable of selectively binding to a specific intended target nucleic acid sequence. In some instances, the probe is specifically designed to be labeled with, for example, a radiolabel, a fluorescent label, an enzyme, a chemiluminescent tag, a colorimetric tag, or other labels or tags known in the art. In some instances, the fluorescent label comprises a fluorophore. In some instances, the fluorophore is an aromatic or heteroaromatic compound. In some instances, the fluorophore is pyrene, anthracene, naphthalene, acridine, stilbene, benzoxazole, indole, benzindole, oxazole, thiazole, benzothiazole, cyanine, carbocyanine, salicylate, anthranilate, xanthene dye, or coumarin. Exemplary xanthene dyes include, for example, fluorescein and rhodamine dyes. 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), and 6-carboxy-X-rhodamine (ROX). Suitable fluorescent probes also include naphthylamine dyes with an amino group at the alpha or beta position. For example, naphthylamino 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-isocyanatocoumarin; acridines such as 9-isothiocyanatoacridine and acridine orange; N-(p-(2-benzoxazolyl)phenyl)maleimide; and compounds such as indodicarbocyanine 3 (Cy3), indodicarbocyanine 5 (Cy5), indodicarbocyanine 5.5 (Cy5.5), 3-(-carboxy-pentyl)-3'-ethyl-5,5'-diamine. Examples include methyloxacarbocyanine (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 BODIPY™ dye. Optionally, the probe contains FAM as a dye label.

[0197] In some embodiments, detecting 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 by 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 modern sequencing techniques such as next-generation sequencing, e.g., Illumina sequencing (e.g., Solexa), Roche454 sequencing, Ion Torrent sequencing, and SOLiD sequencing. In some cases, next-generation sequencing includes high-throughput sequencing methods. Additional sequencing methods available to those skilled in the art may also be employed.

[0198] In some examples, the number of nucleotides 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 from about 1 to about 100,000 nucleotides, from about 1 to about 10,000 nucleotides, from about 1 to about 1,000 nucleotides, from about 1 to about 500 nucleotides, from about 1 to about 300 nucleotides, from about 1 to about 200 nucleotides, from about 1 to about 100 nucleotides, from about 5 to about 100,000 nucleotides, from about 5 to about 10,000 nucleotides, from about 5 to about 1,000 nucleotides, from about 5 to about 500 nucleotides, from about 5 to about 300 nucleotides, from about 5 to about 200 nucleotides, from about 5 to about 100 nucleotides, from about 10 to about 100,000 nucleotides, from about 10 to about 10,000 nucleotides, from about 10 to about 1,000 nucleotides, from about 10 to about 500 nucleotides, from about 10 to about 300 nucleotides, from about 10 to about 200 nucleotides, or from about 10 to about 100 nucleotides. The length of the fragment is in the range of about 20 to about 100,000 nucleotides, about 20 to about 10,000 nucleotides, about 20 to about 1,000 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 100,000 nucleotides, about 30 to about 10,000 nucleotides, about 30 to about 1,000 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 100,000 nucleotides, about 50 to about 10,000 nucleotides, about 50 to about 1,000 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 are methods including (a) obtaining a sample from a subject with a proliferative disease or condition (e.g., cancer); (b) assaying the sample from the subject for the presence or absence of a relevant biomarker; and (c) detecting the presence or absence of the biomarker in the sample using a method described herein. Optionally, a hybridization assay, such as one described herein, is used to detect the biomarker in the sample. A typical probe sequence hybridizable to a target nucleic acid sequence (e.g., one or more genes in a biomarker, such as a PRS) comprises between 10 and 100 consecutive nucleotides that include the relevant sequence. Optionally, RNA sequencing (RNAseq) is used to detect one or more biomarkers.

[0200] Detection of related biomarkers optionally involves amplification of the nucleic acid of interest by polymerase chain reaction (PCR). In some embodiments, the PCR assay involves the use of a pair of primers capable of amplifying at least about 10 adjacent nucleic acid bases within a nucleic acid sequence, thereby amplifying one or more gene products in the biomarker. In fluorogenic quantitative PCR, quantification is based on the amount of fluorescent 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 related biomarker comprises reverse transcribing a related mRNA molecule to produce a corresponding complementary DNA (cDNA) molecule. In some embodiments, the assay further comprises contacting the cDNA molecule with a nucleic acid probe comprising a nucleic acid sequence complementary to a nucleic acid sequence of the cDNA molecule. In some embodiments, the assay comprises detecting a double-stranded hybridization product between the nucleic acid probe and the cDNA molecule. In some embodiments, the hybridization product is further amplified using a pair of primers. In some embodiments, the primers comprise a first primer having a nucleic acid sequence comprising 10 to 50 contiguous nucleic acids within the related amino acid sequence that binds to the top strand of the double-stranded hybridization product, and a second primer having a nucleic acid sequence comprising 10 to 50 contiguous nucleic acids within the related amino acid sequence that binds to the bottom strand of the double-stranded hybridization product.

[0202] In some embodiments, methods are disclosed herein that include 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 an immobile surface (such as a microarray). In some embodiments, the plurality of nucleic acid probes are hybridizable 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 biomarkers includes detecting high or low levels of expression of two or more genes compared to a reference level.

[0203] Some embodiments disclosed herein involve genetic material extracted from a sample obtained from a subject, such as a blood or serum sample. In certain embodiments in which 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 using 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 available commercially; 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 RNA extraction techniques including, for example, using acid phenol / guanidine isothiocyanate extraction (RNAzol B; Biogenesis), the RNeasy RNA preparation kit (Qiagen), or PAXgene (PreAnalytix, Switzerland).

[0204] Circulating tumor DNA (ctDNA) and RNA (ctRNA) In some embodiments, 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, detecting ctDNA or ctRNA is useful for, for example, detecting and diagnosing tumors.Because tumor DNA and RNA have acquired many genetic mutations, leading to tumor development, ctDNA and ctRNA do not exactly correspond to individual DNA and RNA, respectively.Finding DNA and RNA with genetic differences is useful for tumor detection.Using ctDNA or ctRNA to diagnose tumor type can reduce the need to obtain tumor tissue samples (tumor biopsy), which can be difficult when tumors, such as brain or lung tumors, are difficult to access.

[0206] In some embodiments, a decrease in the amount of ctDNA or ctRNA indicates that the solid tumor is shrinking and that treatment with a compound 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 a compound of Formula (I), (Ia), (Ib), (II), and (III), or a pharmaceutically acceptable salt thereof.

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

[0208] The compounds of formulas (I), (Ia), (Ib), (II), and (III) may be administered as prodrugs. Thus, derivatives of certain compounds, which may have little or no pharmacological activity themselves, can be converted, for example, by hydrolysis, into compounds with the desired activity when administered to a mammal. Such derivatives are referred to as "prodrugs." Prodrugs can be produced by replacing appropriate functionalities present in the compounds of formulas (I), (Ia), (Ib), (II), and (III) with specific moieties known to those skilled in the art. See, for example, "Prodrugs as Novel Delivery Systems," Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (ed. EB Roche, American Pharmaceutical Association), the disclosures of which are incorporated herein by reference in their entirety. Some examples of such prodrugs include ester moieties in place of carboxylic acid functional groups, ether or amide moieties in place of alcohol functional groups, and amide moieties in place of primary or secondary amino functional groups. Examples of substituents are known to those skilled 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 acetate, acrylate, benzenesulfonate, benzoate (such as chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, and methoxybenzoate), bicarbonate, bisulfate, bisulfite, bitartrate, borate, bromide, butyne-1,4-dioate, calcium edetate, camsylate, carbonate, chloride, caproate, caprylate, clavulanate, citrate, decahydrate, and the like. Noate, dihydrochloride, dihydrogen phosphate, edetate, edisylate, estolate, esylate, ethylsuccinate, formate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycollylarsanilate, heptanoate, hexyne-1,6-dioate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, gamma-hydroxybutyrate, iodide, isobutyrate Late, isothionate, lactate, lactobionate, laurate, maleate, maleate, malonate, mandelate, mesylate, metaphosphate, methanesulfonate, methylsulfate, monohydrogen phosphate, mucate, napsylate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phenylacetate, phenylbutyrate, phenyl These include, but are not limited to, propionate, phthalate, phosphate / diphosphate, polygalacturonate, propanesulfonate, propionate, propiolate, pyrophosphate, pyrosulfate, salicylate, stearate, subacetate, suberate, succinate, sulfate, sulfonate, sulfite, tannate, tartrate, theoclate, tosylate, triethiodode, and valerate.

[0210] The compounds of formulas (I), (Ia), (Ib), (II), and (III), which are normally basic, can form a wide variety of different salts with various inorganic and organic acids. While such salts must be pharmaceutically acceptable for administration to animals, it is often desirable to first isolate the compound of the present invention from the reaction mixture as a pharmaceutically acceptable salt, convert the latter back to the free base compound by treatment with an alkaline reagent, and then convert the latter free base to a pharmaceutically acceptable acid addition salt. Acid addition salts of the base compounds of the present invention can be prepared by treating the base 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 an organic solvent solution of the free base by adding the appropriate mineral or organic acid to the solution.

[0211] The compounds of formulas (I), (Ia), (Ib), (II), and (III), which are normally acidic, can form base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, specifically sodium and potassium salts. All of these salts are prepared by conventional techniques. The chemical bases used as reagents to prepare the pharmaceutically acceptable base salts of the present invention are those that form non-toxic base salts with the acidic compounds of the present invention. Such non-toxic base salts include those derived from pharmacologically acceptable cations such as sodium, potassium, calcium, and magnesium. These salts can be prepared by treating the corresponding acidic compound with an aqueous solution containing the desired pharmacologically acceptable cation, followed by evaporation of the resulting solution to dryness, preferably under reduced pressure. Alternatively, these salts can be prepared by mixing together lower alkanolic solutions of the acidic compound and the desired alkali metal alkoxide, followed by evaporation of the resulting solution to dryness in the same manner as described above. In either case, stoichiometric quantities of reagents are preferably employed to ensure completeness of reaction and maximum yields of the desired final product.

[0212] When the compounds of Formulae (I), (Ia), (Ib), (II), and (III) are bases, the desired salts may be prepared by any suitable method available in the art, for example, treatment of the free base with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; 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 Formulas (I), (Ia), (Ib), (II), and (III) are acids, the desired salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide, or an alkaline earth metal hydroxide. Illustrative 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 Formulas (I), (Ia), (Ib), (II), and (III) are solids, one of skill in the art will recognize that the compounds or salts thereof may exist in various crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formula.

[0215] Also provided herein are isotopically labeled compounds of formula (I), (Ia), (Ib), (II), and (III) in which one or more atoms are replaced with an atom having the same atomic number but an atomic mass or mass number different from that normally found in nature. Examples of isotopes suitable for inclusion in compounds of the invention include: 2 H and 3 hydrogen isotopes such as H, 11 C. 13 C, and 14 carbon isotopes such as C, 36 chlorine isotopes such as Cl, 18 fluorine isotopes such as F, 123 I and 125 Iodine isotopes such as I, 13 N and 15 Nitrogen isotopes such as N, 15 O. 17 O, and 18 Oxygen isotopes such as O 32 phosphorus isotopes such as P, and 35 Certain isotopically labeled compounds of the present invention, for example, compounds incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. 3 H) and carbon-14 ( 14 C) is particularly useful for this purpose in view of its ease of incorporation and ready means of detection. 2 Substitution with heavier isotopes, such as H), may afford certain therapeutic advantages due to greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and therefore may be preferable in some circumstances. 11 C. 18 F, 15 O, and 13 Substitution with positron emitting isotopes, such as N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0216] Isotopically labeled compounds of Formulas (I), (Ia), (Ib), (II), and (III) can generally be prepared by conventional techniques known to those skilled in the art or by processes similar to those described herein, substituting isotopically labeled reagents, as appropriate, for unlabeled reagents otherwise employed.

[0217] In one aspect, a composition of a compound of Formula (I), (Ia), (Ib), (II), and (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, described herein, is used to treat cancer in a subject. In one embodiment, such a composition is in a suitable dosage form. Suitable dosage forms include, for example, a liquid, a suspension, a powder for reconstitution, a tablet, a pill, a sachet, or a capsule 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 Formulas (I), (Ia), (Ib), (II), and (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, can be formulated into pharmaceutical compositions, as described below, in any pharmaceutical form that would be recognized as suitable by one of skill in the art. 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 carriers employed can 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 can include time-delay or sustained-release materials known in the art, such as glyceryl monostearate or glyceryl distearate, alone or in combination with waxes, ethylcellulose, hydroxypropylmethylcellulose, methyl methacrylate, and the like. Additional additives or excipients can be added to achieve desired formulation characteristics. For example, bioavailability enhancers such as Labrasol™ and Gelucire™, or formulating agents such as CMC (carboxymethylcellulose), PG (propylene glycol), or PEG (polyethylene glycol), can be added. For example, when preparing a capsule formulation, Gelucire™, a semi-solid vehicle that protects the active ingredient from light, moisture, and oxidation, can be added.

[0220] When a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or formed into a troche or lozenge. The amount of solid carrier can vary, but is generally about 25 mg to about 1 g. When a liquid carrier is used, the preparation can be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial, or a non-aqueous liquid suspension. When a semi-solid carrier is used, the preparation can be in the form of a hard gelatin or soft gelatin capsule formulation. The compositions of the present invention are prepared in a unit dosage form appropriate for the mode of administration, for example, parenteral or oral administration.

[0221] To obtain a stable, water-soluble dosage form, 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 cosolvent or a combination of cosolvents. Examples of suitable cosolvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin, and the like, at concentrations ranging from 0 to 60% of the total volume. In a typical embodiment, the compounds of the present invention are dissolved in DMSO and diluted with water. The composition may also be in the form of a solution of a salt form of the active ingredient in a suitable aqueous vehicle, such as water, isotonic saline, or dextrose solution.

[0222] Appropriate formulations depend on the selected route of administration. For injection, the compounds of the present invention may be formulated into aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0223] For oral administration, compounds can be formulated by combining the active compound with a pharmaceutically acceptable carrier known in the art. Such carriers allow 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 medicaments can be obtained by using a solid excipient mixed with the active ingredient (drug), optionally milling the resulting mixture, and processing the granular mixture after adding suitable additives as needed to obtain tablets or dragee cores. Suitable additives include excipients such as sugars, including lactose, sucrose, mannitol, or sorbitol, and cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0224] The dragee core is provided with a suitable coating.For this purpose, concentrated sugar solution may be used, which may optionally contain gum arabic, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solution, and suitable organic solvent or solvent mixture.Dyes or pigments may be added to tablets or dragee coatings for identifying or characterizing various combinations of active agents.

[0225] Orally available pharmaceuticals include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Push-fit capsules can contain the 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 soft capsules, the active agent may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration, the composition may be in the form of tablets or lozenges formulated in a conventional manner.

[0226] For intranasal or inhalation administration, the compounds for use according to the invention may conveniently be delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Gelatin capsules and cartridges for use in inhalers, insufflators, and the like may be formulated containing a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0227] The compound may be formulated for parenteral administration by injection, for example, bolus injection or continuous infusion.The preparation for injection may be provided in a unit dosage form, for example, in an ampule or a multi-dose container with added preservative.The composition may take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and may contain formulatory agents such as suspending agents, stabilizing agents, and / or dispersing agents.

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

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

[0230] In addition to the formulations described above, the compounds of the present invention can also be formulated as depot preparations. Such long-acting formulations can be administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, such as a sparingly soluble salt. A pharmaceutical carrier for hydrophobic compounds is a cosolvent system containing benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. The cosolvent system can be the VPD cosolvent system. VPD is a solution of 3% w / v benzyl alcohol, 8% w / v of the nonpolar surfactant polysorbate 80, and 65% w / v polyethylene glycol 300, made up to volume in absolute ethanol. The VPD cosolvent system (VPD:5W) contains VPD diluted 1:1 with 5% dextrose in water. This cosolvent system dissolves hydrophobic compounds well and, by itself, produces low toxicity upon systemic administration. The proportions of the cosolvent system may be varied as desired without destroying its solubility and toxicity characteristics. Furthermore, the identity of the cosolvent components may be varied; for example, other low-toxicity nonpolar surfactants may be substituted for polysorbate 80, the fraction of polyethylene glycol may be varied, other biocompatible polymers may be substituted for polyethylene glycol, such as polyvinylpyrrolidone, or other sugars or polysaccharides may be substituted for 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 many toxicities usually result from the toxic nature of DMSO. In addition, compounds may be delivered using sustained-release systems, such as semipermeable matrices of solid hydrophobic polymers containing therapeutic agents. Various sustained-release materials have been established and are known to those skilled in the art. Sustained-release capsules release compounds for several 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 suitable solid or gel-phase carriers or excipients. These carriers and excipients can significantly improve the bioavailability of poorly soluble drugs. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol. Additionally, additives or excipients such as Gelucire™, Capryol™, Labrafil™, Labrasol™, Lauroglycol™, Plurol™, Peceol™, and Transcutol™ may be used.

[0233] Additionally, the pharmaceutical composition may be incorporated into a skin patch for delivering the drug directly to the skin.

[0234] The actual dosage of the agent of the present invention may vary depending on the specific agent used, the specific composition formulated, the administration form, and the specific site, host, and disease being treated. Those skilled in the art can use conventional dosage determination tests in light of experimental data for a given compound to determine the optimal dosage for a given set of conditions. For oral administration, a typical daily dose typically employed is about 0.001 to about 1000 mg per kg of body weight, with the treatment regimen being 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, a pharmaceutically acceptable formulation of the present invention may contain a 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 compounds of the invention, or salts or solvates thereof, may be administered once daily, twice daily, three times daily, four times daily, or more frequently, alone or as part of a pharmaceutically acceptable formulation, to a mammal, such as a human, suffering from abnormal cell growth.

[0238] The particular pharmaceutical formulation, dosage, and number of doses given per day to a mammal in need of such treatment for a compound of Formula (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are all within the skill of the art and can be determined without undue experimentation.

[0239] The dosage of the compositions described herein can be determined by any suitable method. The maximum tolerated dose (MTD) and maximum response dose (MRD) of 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 in 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, determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, which can be expressed as the ratio of LD50 to ED50. Data obtained from cell culture assays and animal studies can be used to formulate a dosage range for human use.The dosage of such compounds is preferably within a circulating concentration range that includes the ED50 with minimal toxicity.Dosages may vary within this range depending on the dosage form employed and the route of administration utilized.Further relative dosages, expressed as a percentage of the maximum response or maximum tolerated dose, can be easily obtained through the present 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, including the formulation equivalent to such amount, will vary depending on factors such as the particular salt or form, the disease state and its severity, the identity (e.g., age, weight, sex) of the subject or host requiring treatment, but can still be determined depending on the particular circumstances surrounding the case, e.g., the particular agent being administered, the type of liquid formulation, the disease being treated, and the subject or host being treated.

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

[0242] Generally, an appropriate dose and treatment regimen provides the composition in an amount sufficient to provide therapeutic and / or preventive benefits (e.g., improved clinical outcomes), such as more frequent complete or partial remission, longer disease-free and / or overall survival, or reduced severity of symptoms. Optimal doses are generally determined using experimental models and / or clinical trials. Optimal doses depend on the subject's body type, weight, or blood volume. Generally, an appropriate dose and treatment regimen provides the composition in an amount sufficient to provide therapeutic and / or preventive benefits (e.g., improved clinical outcomes), such as more frequent complete or partial remission, longer disease-free and / or overall survival, or reduced severity of symptoms. Optimal doses are generally determined using experimental models and / or clinical trials. Optimal doses depend on the subject's body type, weight, or blood volume.

[0243] In certain embodiments in which the subject's condition does not improve, at the physician's discretion, administration of the compositions described herein is chronic, i.e., administered for an extended period of time, including the entire lifespan of the subject, to ameliorate or otherwise control or limit the symptoms of the subject's disease or disorder. In other embodiments, administration of the compositions continues until a complete or partial disease response 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 involve administering to a subject in need thereof compositions and formulations comprising a compound of Formula (I), (Ia), (Ib), (II), or (III) in combination with one or more additional therapeutic agents in multiple cycles repeated on a regular schedule with rest periods between each cycle. For example, in some examples, one treatment cycle consists of one week of treatment followed by three weeks of rest.

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

[0247] Kits and Manufactured Products In certain embodiments herein, kits and articles of manufacture are disclosed for use in one or more of the methods and compositions described herein. Such kits include carriers, packages, or containers compartmentalized to receive one or more containers, such as vials or tubes, each containing one of the individual components 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 includes a label and / or instructions listing the contents, as well as a package insert with the instructions. A set of instructions will also typically be included.

[0249] In one embodiment, the label is on or associated with the container. In one embodiment, the label is on the container when letters, numbers, or other characters forming the label are attached, molded, or engraved onto the container itself, or is associated with the container when present in a receptacle or carrier that holds the container, e.g., as a package insert. In one embodiment, the label is used to indicate that the contents are to be used for a particular therapeutic application. The label also provides instructions for using the contents, such as in the methods described herein.

[0250] In certain embodiments, the pharmaceutical compositions are provided in a pack or dispenser containing one or more unit dosage forms containing a compound provided herein. The pack comprises, for example, metal or plastic foil, such as 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 attached to the container in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the agency's approval of the drug form for human or veterinary administration. Such notice may be, for example, a label approved by the U.S. Food and Drug Administration for a drug, or an approved product insert. In one embodiment, compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are also prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0251] Preparation method Compounds of Formula (I), (Ia), (Ib), (II), or (III), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, can be prepared using the reaction routes and synthetic schemes described below and employing techniques available in the art using readily available starting materials. The preparation of specific embodiments of the present invention is detailed in the Examples below, but those skilled in the art will understand that the described preparations can be readily adapted to prepare other embodiments of the present invention. For example, the synthesis of unexemplified compounds according to the present invention can be carried out by modifications obvious to those skilled in the art, such as appropriate protection of interfering groups, substitution of other suitable reagents known in the art, or routine modification of reaction conditions. Alternatively, other reactions mentioned herein or known in the art will be recognized as suitable for preparing other compounds of the present invention.

[0252] The compounds of formula (I) are 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 is as defined herein, 1 The compound of formula (IV) can be prepared from the compound of formula (IV) by reacting it with a compound of formula (V), where n is as defined herein and LG is a leaving group. LG that can be used includes halogens such as chloro, bromo, and iodo. The reaction of the compound of formula (IV) with the compound of formula (V) can be carried out using methods known to those skilled in the art. For example, the reaction of the compound of formula (IV) with 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 an alcohol, or a mixture of a protic and aprotic solvent such as a mixture of acetonitrile and water, in the presence of an acid or base, at a temperature ranging from 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] [ka]

[0254] Alternatively, the compound of formula (I) may be R 3 , R 4a , R 4b , R 4c , R 5 , R 6 , R 7 , R 8a , R 8b , R 8c , and R 8d is as defined herein and Hal is a halogen such as bromo or iodo, 1 , R 2and n is as defined herein, by reacting a compound of formula (VII) with 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 organic bases such as tertiary amines, e.g., triethylamine, or inorganic bases, e.g., cesium carbonate. The aprotic solvent can be, for example, toluene. For example, the reaction of a compound of formula (VI) with a compound of formula (VII) can be carried out at a temperature ranging from 25°C to 200°C; for example, such a reaction can be carried out in toluene at a temperature of 100°C. Compounds of formula (VII) are commercially available or can be prepared by methods known to those skilled in the art or similar to those described herein.

[0255] [ka]

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

[0257] [ka]

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

[0259] [ka]

[0260] The compound of formula (IV) can be prepared from the compound of formula (VI) by a method 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'-indolin]-2'-one as described below.

[0261] [ka]

[0262] A compound 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 a compound of formula (V) described herein using an acid such as trifluoroacetic acid to provide a compound of formula (I), followed by 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 give (1R,2S)-5'-methoxy-2-(3-((5-methoxypyrimidin-4-yl)amino)-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-one.

[0263] [ka]

[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" means N-tert-butoxycarbonyl, "DCM" (CHCl) means methylene chloride, "DIPEA" or "DIEA" means diisopropylethylamine, "DMA" means N,N-dimethylacetamide, "DMF" means N-N-dimethylformamide, "DMSO" means dimethylsulfoxide, "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, and "MgSO" means magsulfate. "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" means lithium hexamethyldisilazide, "TBME" or " "MTBE" means 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 degrees Celsius, "Pa" means Pascal, "rt" or "RT" means room temperature, "h" means hours, "satd." means saturated, "aq" means aqueous, and "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'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one

[0266] [ka]

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

[0268] [ka]

[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 was refluxed for 4 hours and stirred at room temperature for 16 hours. The reaction 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] [ka]

[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) under nitrogen at 0°C. The mixture was stirred for 15 min, after which (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 h. 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 in vacuo. The crude mixture was purified by column chromatography (10% to 65% EtOAc / heptane, gradient elution) to afford the title compound (1.50 g, 28%) as an orange solid. NOESY NMR experiments confirmed the relative stereochemistry. 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 to elute first under the given conditions. m / z (ESI, +ve ion) = 309.0 [M+H]. + . 1H NMR(400MHz,CDCl3)δ 8.08(s,1H),7.52(dd,J=7.8,6.9Hz,1H),7.21(s,1H),7.19(s,1H),6.78(d,J=1.5Hz,2H),6.54(s ,1H),3.81(s,3H),3.07(t,J=8.7Hz,1H),2.34(dd,J=8.5,5.3Hz,1H),2.12(dd,J=8.9,5.3Hz,1H).

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

[0274] [ka]

[0275] In a 20 mL vial, 2-fluoro-4-((1R,2S)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-2-yl)benzonitrile (20.0 mg, 64.9 μmol) was dissolved in tert-amyl alcohol (10.0 mL), followed by the addition of hydrazine hydrate solution (50.0 μL, 1.58 mmol). The reaction was refluxed for 16 hours. The reaction was cooled to room temperature, and silica was added directly to the mixture, which was then concentrated. The product was purified by column chromatography (0-20% MeOH / DCM, gradient elution) to afford 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] [ka]

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

[0279] [ka]

[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. It was diluted with water (300 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine, 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 (400MHz, CDCl3)δ 7.38-7.27(m,5H),7.15(d,J=2.7Hz,1H),7.02(dd,J=8.6,2.7Hz,1H),6.67(d,J=8.6Hz,1H),4.90(s,2H),3.77(s,3H).

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

[0282] [ka]

[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 x 200 mL). The combined organic layers were washed with 1M H2SO4, brine (2 x 10), 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(400MHz,CDCl3)δ 7.38-7.22(m,5H),6.90-6.86(m,1H),6.68(dd,J=8.5,2.6Hz,1H),6.60(d,J=8.5Hz,1H),4.89(s,2H),3.75(s,3H),3.61(s,2H).

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

[0285] [ka]

[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, and 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 x 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 neat at 150° C. After 6 h, the benzyl bromide was removed by distillation under high vacuum (vacuum pump) at 130° C. 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] [ka]

[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 DME / water (3:1) (70.0 mL), previously degassed (by bubbling with nitrogen), was purged with nitrogen, and nitrogen was further bubbled 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(400MHz,CDCl3)δ 8.01(d,J=0.9Hz,1H),7.73-7.64(m,1H),7.36-7.23(m,5H),7.23-7.16(m,2H),6.80(dd,J= 17.6,10.9Hz,1H),5.80(dd,J=17.5,0.7Hz,1H),5.60(s,2H),5.30(dd,J=10.9,0.6Hz,1H).

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

[0291] [ka]

[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 after stirring, a clear biphasic mixture was formed. The reaction mixture was cooled to 0 °C in an ice bath, and then 1-benzyl-6-vinyl-1H-indazole (14.0 g, 59.8 mmol) was added. The resulting mixture was stirred vigorously at 0 °C and allowed to warm to room temperature while slowly warming in the ice bath. The reaction mixture was stirred for 9 h. The reaction was quenched by the portionwise addition of 92 g of sodium sulfate. 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] [ka]

[0295] A solution of (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) was cooled in an ice bath and treated with methanesulfonyl chloride (7.77 mL, 100 mmol) by slow addition over 15 minutes. The internal temperature was allowed to rise to a maximum of 11°C. The resulting mixture was stirred at 0°C. After 6 hours, 10% monomesylated product was observed by LCMS. Methanesulfonyl chloride (0.400 mL) and triethylamine (0.600 mL) were added. The mixture was stirred for 1 hour and, upon completion, diluted with DCM (500 mL) and 1 M aqueous HCl (200 mL) at 0°C. 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 pad of Celite 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(400MHz,CDCl3)δ 8.08(s,1H),7.81(d,J=8.3Hz,1H),7.41(s,1H),7.35-7.27(m,3H),7.18(dd,J=17.3,7.5Hz,3H),5.89(dd,J=8.6,3.2Hz,1H),5.6 6(d,J=15.8Hz,1H),5.60(d,J=15.8Hz,1H),4.53(dd,J=11.9,8.6Hz,1H),4.40(dd,J=11.9,3.3Hz,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'-indolin]-2'-one

[0297] [ka]

[0298] A solution of (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 minutes. A solution of 1-benzyl-5-methoxyindolin-2-one (3.40 g, 8.01 mmol) in dry THF (50 mL) was added dropwise via addition funnel. The reaction mixture was stirred at 0 °C for 3 hours. The reaction was quenched with saturated NH4Cl solution, diluted with water, and extracted with EtOAc (3 x). The organic layer was dried over anhydrous MgSO4 and concentrated to give the crude product. The crude product was triturated with 3:1 hexanes / EtOAc to give 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] [ka]

[0301] A round-bottom flask was equipped with a stir bar and (1R,2S)-1'-benzyl-2-(1-benzyl-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one (4.00 g, 8.24 mmol) in THF (118 mL) was added. The solution was cooled to 0 °C, and potassium tert-butoxide (23.0 mL, 165 mmol) was added in small portions over 20 min, followed by DMSO (10.7 mL). Oxygen was bubbled through the solution at 0 °C for 1 h. 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 (1 x) and extracted with EtOAc (2 x). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was triturated in Et2O and recrystallized from ethanol to give 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'-indolin]-2'-one

[0303] [ka]

[0304] In a flask, (1R,2S)-2-(1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-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 was stirred at room temperature for 2 h. The reaction was quenched with an aqueous solution of NaSO and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried (NaSO), filtered, and concentrated. The crude material was purified by column chromatography (40-100% EtOAc / hexane, gradient elution) to give 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'-indolin]-2-yl)-1H-indazole-1-carboxylate

[0306] [ka]

[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 was added tert-butyl 3-bromo-6-((1R,2S)-1'-(tert-butoxycarbonyl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indolin]-2-yl)-1H-indazole-1-carboxylate (1.00 g, 1.71 mmol), cesium carbonate (1.14 g, 3.42 mmol), Pd(dba) (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. A saturated aqueous solution of 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 in vacuo. The crude product was purified by column chromatography (0-30% EtOAc / heptane, gradient elution) to afford 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'-indolin]-2-yl)-1H-indazole-1-carboxylate

[0314] [ka]

[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'-indolin]-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(400MHz,CDCl3)δ8.06(s,1H),7.78(d,J=8.9Hz,1H),7.41(d,J=8.2Hz,1H),7.01(d,J=8.2Hz,1H),6.66(dd,J=8.9,2.6Hz,1H),5.55( d,J=2.3Hz,1H),4.44(s,2H),3.49(t,J=8.6Hz,1H),3.37(s,3H),2.34(dd,J=9.2,4.8Hz,1H),2.14-2.06(m,1H),1.67(d,J=2.4Hz,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] [ka]

[0318] In a 4 mL vial, (1R,2S)-2-(3-amino-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one (54.0 mg, 169 μmol) and 4-chloro-5-methoxypyrimidine (29.8 mg, 202 μmol) were dissolved in 1.00 mL of acetic acid / water (1:1). The reaction was heated to 100 °C for 1 h. 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(400MHz,DMSO)δ 12.68(s,1H),10.42(s,1H),9.12(s,1H),8.04(d,J=3.0Hz,2H),7.40(d,J =7.9Hz,2H),6.89(d,J=9.4Hz,1H),6.74(d,J=8.4Hz,1H),6.58(dd,J=8.5, 2.6Hz,1H), 5.72(d,J=2.5Hz,1H),3.94(s,3H),3.33(s,3H under water peak),3.18(t,J=8.5Hz,1H),2.33(dd,J=7.8,4.7Hz,1H),1.98(dd,J=9.0,4.7Hz,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] [ka]

[0321] Example 2 was prepared from (1R,2S)-2-(3-amino-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one (60.0 mg, 187 μmol) and 4-chloro-5-methylpyrimidine (27 mg, 206 μmol) using the procedure described in Example 1. 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 (400MHz, 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, 3H under water peak), 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] [ka]

[0324] Example 3 was prepared from (1R,2S)-2-(3-amino-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one (60.0 mg, 187 μmol) and 4,5-dichloropyrimidine (31.3 mg, 206 μmol) using the procedure described in Example 1. The product was purified by C18 column chromatography (5-40% MeCN / ammonium formate aqueous 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(400MHz,DMSO)δ 12.85(s,1H),10.43(s,1H),9.58(s,1H),8.46(s,1H),8.31(s,1H),7.4 4(s,1H),7.37(d,J=8.3Hz,1H),6.95-6.87(m,1H),6.74(d,J=8.4Hz,1H) ,6.58(dd,J=8.5,2.6Hz,1H),5.70(d,J=2.5Hz,1H),3.33(s,3H),3.19(t,J=8.4Hz,1H),2.34(dd,J=8.0,4.7Hz,1H),1.98(dd,J=9.0,4.6Hz,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] [ka]

[0327] This compound was prepared from tert-butyl 3-amino-6-((1R,2S)-1'-(tert-butoxycarbonyl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indolin]-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 during the reaction conditions. The product was purified by C18 column chromatography (10% to 30% MeCN / ammonium formate aqueous 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(400MHz,DMSO)δ 12.68(s,1H),10.43(s,1H),9.12(s,1H),8.04(d,J=3.1Hz,2H),7.44-7. 35(m,2H),6.89(d,J=9.4Hz,1H),6.74(d,J=8.4Hz,1H),6.58(dd,J=8.5,2 .6Hz,1H), 5.72(d,J=2.5Hz,1H),3.94(s,3H),3.33(s,3H under water peak),3.18(t,J=8.6Hz,1H),2.33(dd,J=7.9,4.7Hz,1H),1.98(dd,J=9.0,4.6Hz,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] [ka]

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

[0331] [ka]

[0332] To an oven-dried flask was added (1R,2S)-2-(1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one (4.00 g, 13.1 mmol), followed by DMF (8 mL) and methanol (8 mL). To this suspension was added K2CO3 (3.62 g, 26.2 mmol). Finally, molecular sieves (4.32 g, 17.0 mmol) dissolved in DMF (8 mL) were added dropwise and stirred at room temperature. After 4 h, the reaction was complete. The mixture was quenched with Na2SO3 in water and stirred for 2 h. 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] [ka]

[0335] To an oven-dried flask was added 4-dimethylaminopyridine (9.0 mg, 0.07 mmol), followed by (1R,2S)-2-(3-iodo-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-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 di-tert-butyl dicarbonate (967 mg, 4.43 mmol) was added to give a pale yellow homogeneous solution. After 2 h, the reaction mixture was concentrated, and the resulting residue was purified by column chromatography (0% to 25%, EtOAc / hexanes, gradient elution) to give the product (5B) (822 mg, 88%) as a white foam.

[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] [ka]

[0338] To a 50 mL round-bottom flask was added cesium carbonate (41.3 mg, 0.130 mmol), 5-ethoxypyrimidin-4-amine (9.3 mg, 0.070 mmol), Pd(dba) (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). 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 give a yellow suspension. The reaction was monitored by LCMS and TLC until complete conversion of the starting material (approximately 70 min), then cooled to room temperature, diluted with EtOAc, washed with saturated aqueous NaHCO3, and dried over Na2SO4. The residue was purified by column chromatography (0% to 90% ethyl acetate / hexane, gradient elution) to afford 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'-indolin]-2'-one

[0340] [ka]

[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'-oxo-spiro[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 complete conversion of the starting material (approximately 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(400MHz, methanol-d4)δ ppm 1.58(t,J=6.94Hz,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,1 H)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] [ka]

[0344] Step 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] [ka]

[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 to 90%) to give the title compound (17.0 mg, 42%) as a yellow oil.

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

[0348] [ka]

[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 give 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(400MHz, 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)6.58-6.6 9(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] [ka]

[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] [ka]

[0354] This compound was prepared from tert-butyl 3-bromo-6-((1R,2S)-1'-(tert-butoxycarbonyl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indolin]-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'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one

[0356] [ka]

[0357] This compound was prepared from tert-butyl 6-((1R,2S)-1'-(tert-butoxycarbonyl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indolin]-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] +H 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), 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) in water.

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

[0359] [ka]

[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] [ka]

[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, 5 μm; 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 toward the end of elution corresponds to the title product, while the first peak is the corresponding enantiomer (1R, 2S). The solution was concentrated and lyophilized from MeCN and water to give the title compound (15a) (6.7 mg, 39%) as a white solid. m / z (ESI, +ve ion) = 429.3 [M+H] + . 1H NMR(400MHz,DMSO)δ 12.67(s,1H),10.41(s,1H),9.10(s,1H),8.04(d,J=2.1Hz,2H),7.42-7.37(m,2H),6.89(d,J=9.5Hz,1H),6.74(d,J=8.4Hz,1H),6.58(d d,J=8.5,2.6Hz,1H),5.72(d,J=2.5Hz,1H),3.94(s,3H),3.18(t,J=8.5Hz,1H),2.32(dd,J=7.9,4.6Hz,1H),1.98(dd,J=9.0,4.7Hz,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] [ka]

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

[0366] [ka]

[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] A microwave vial was charged with tert-butyl 3-bromo-6-((1R,2S)-1'-(tert-butoxycarbonyl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indolin]-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), Pd(dba) (9.4 mg, 10.3 μmol), and XantPhos (6.0 mg, 10.3 μmol) and purged with nitrogen. Pre-degassed toluene (2.0 mL) was added, and nitrogen was bubbled through the reaction mixture for 2 min. The vial was sealed and the reaction mixture was heated to 100° C. in an oil bath for 2 h. The reaction mixture was filtered through a pad of Celite with EtOAc and concentrated. The crude product was purified by column chromatography (0% to 10% MeOH / DCM, gradient elution) to give the title compound (49.5 mg, 67%). m / z (ESI, +ve ion) = 718.0 [M+H] + .

[0371] Process C.

[0372] [ka]

[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 was stirred at room temperature for 5 minutes and then concentrated to dryness. The crude residue was directly purified by C18 column chromatography (10-40% MeCN / ammonium formate aqueous buffer, gradient elution). The desired fractions were combined and lyophilized to give Example 9 (12.3 mg, 39%) as a white solid. m / z (ESI, +ve ion)=518.2[M+H] + . 1H NMR (400MHz, 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'(1'H)-one

[0375] [ka]

[0376] A microwave vial was charged with tert-butyl 3-bromo-6-((1R,2S)-1'-(tert-butoxycarbonyl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indolin]-2-yl)-1H-indazole-1-carboxylate (75.0 mg, 128 μmol), 2-chloro-5-methoxypyrimidin-4-amine (22.6 mg, 137 μmol), cesium carbonate (85.3 mg, 257 μmol), Pd(dba) (11.8 mg, 12.8 μmol), and XantPhos (7.6 mg, 12.8 μmol) and purged with nitrogen. Pre-degassed toluene (2.6 mL) was added, and nitrogen was bubbled through the reaction mixture for 2 min. The vial was sealed, and the reaction mixture was heated to 100°C in an oil bath for 2 hours. The reaction mixture was then filtered through a pad of Celite with EtOAc, and the crude product was concentrated. The residue was dissolved in DCM (5.00 mL), and trifluoroacetic acid (1.00 mL, 13.0 mmol) was added. The reaction was stirred at room temperature for 1.5 hours. A saturated aqueous solution of sodium bicarbonate was slowly added, and the reaction mixture was transferred to a separatory funnel. The layers were separated, and the aqueous phase was extracted with DCM (3 x 10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The product was purified by C18 column chromatography (10%-40% MeCN / ammonium formate aqueous buffer, gradient elution). The desired fractions were combined and lyophilized to give Example 10 (4.8 mg, 8.0%) as a white solid. m / z (ESI, +ve ion) = 463.2 [M+H] + . 1H NMR(400MHz,DMSO)δ 12.80(s,1H),10.43(s,1H),9.61(br s,1H),7.94(s,1H),7.46-7.40(m,2H),6.97-6.91(m,1H),6.74(d,J=8.4Hz,1H),6.57(dd,J=8.5,2.6Hz,1H),5.70(d,J =2.5Hz,1H),3.94(s,3H),3.30(s,3H),3.19(t,J=8.3Hz,1H),2.33(dd,J=7.9,4.6Hz,1H),1.98(dd,J=9.1,4.7Hz,1H).

[0377] Example 11 (1R,2S)-5'-Methoxy-2-(3-{[5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one

[0378] [ka]

[0379] A microwave vial was charged with tert-butyl 3-bromo-6-((1R,2S)-1'-(tert-butoxycarbonyl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indolin]-2-yl)-1H-indazole-1-carboxylate (75.0 mg, 128 μmol), 5-chloro-6-morpholinopyrimidin-4-amine (29.7 mg, 141 μmol), cesium carbonate (85.3 mg, 257 μmol), Pd(dba) (11.8 mg, 12.8 μmol), and XantPhos (7.6 mg, 12.8 μmol) and purged with nitrogen. Pre-degassed toluene (2.57 mL) was added, and nitrogen was bubbled through the reaction mixture for 2 min. The vial was sealed, and the reaction mixture was heated to 100 °C in an oil bath for 2 h. The reaction mixture was filtered through a pad of Celite with EtOAc, and the crude product was concentrated. The residue was then dissolved in DCM (5.00 mL), and trifluoroacetic acid (1.00 mL, 13.0 mmol) was added. The reaction was stirred at room temperature for 1.5 h. A saturated aqueous solution of sodium bicarbonate was slowly added, and the reaction mixture was transferred to a separatory funnel. The layers were separated, and the aqueous phase was extracted with DCM (3 x 10 mL). The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by C18 column chromatography (10%-40% MeCN / ammonium formate aqueous buffer, gradient elution). The desired fractions were combined and lyophilized to give Example 11 (23.2 mg, 35%) as a white solid. m / z (ESI, +ve ion) = 514.3 [M+H]+. 1H NMR (400MHz, DMSO) δ 12.58(s,1H),10.42(s,1H),8.88(s,1H),7.80(s,1H),7.47-7.32(m,2H),6.8 7(d,J=8.4Hz,1H),6.74(d,J=8.4Hz,1H),6.58(dd,J=8.4,2.3Hz,1H),5.72(d, J=2.2Hz,1H),379-3.68(m,4H),3.67(s,3H),3.62-3.53(m,4H),3.33(s,3H),3 .18(t,J=8.4Hz,1H),2.32(dd,J=7.7,4.7Hz,1H),1.98(dd,J=8.9,4.6Hz,...

Claims

1. Formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, During the ceremony, Ring A is C ６ -C １０ Aryl, Heteroaryl, C ３ -C １０ cycloalkyl, or heterocycloalkyl; R １ each independently represents deuterium, halogen, -CN, oxo, or -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 N.R. 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, １ -C ６ Alkyl, the C ２ -C ６ Alkenyl, the above C ２ -C ６ Alkynyl, the above C ３ -C １０ cycloalkyl, the heterocycloalkyl, the C ６ -C １０ Aryl, and each of said heteroaryls may optionally and independently be selected from one or more R １ａ is replaced by Alternatively, two of the R on adjacent atoms １ By becoming one, ３ -C １０ cycloalkyl or heterocycloalkyl, each of which is optionally joined by one or more R １ｂ is replaced by The R １ａ are each independently deuterium, halogen, -CN, or -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 N.R. 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; Alternatively, two of the R １ａ come together to form oxo, The R １ｂ are each independently deuterium, halogen, -CN, or -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 N.R. 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; Alternatively, two of the R １ｂ come together to form oxo, 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 is a deuteroalkyl; R ３ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, or C １ -C ６ is a deuteroalkyl; R ４ａ , R ４ｂ , and R ４ｃ each independently represents hydrogen, deuterium, a 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 is heteroalkyl, 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 Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, or C １ -C ６ is heteroalkyl, R ６ are each independently hydrogen, deuterium, halogen, -CN, -OH, or -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 is heteroalkyl, R ７ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, or C １ -C ６ is an aminoalkyl; R ８ａ , R ８ｂ , R ８ｃ , and R ８ｄ each independently represents hydrogen, deuterium, a 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 N.R. 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; R ａ are each independently 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, 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), １ -C ６ Alkyl, the C ２ -C ６ Alkenyl, the above C ２ -C ６ Alkynyl, the above C ３ -C １０ cycloalkyl, the heterocycloalkyl, the C ６ -C １０ Aryl, and each of said heteroaryls, independently and optionally, may be one or more of oxo, deuterium, halogen, -CN, -OH, -OCH ３ , -S(=O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ N.H. ２ , -S(=O) ２ N.H.C.H. 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 substituted with heteroalkyl; R ｂ are each independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C 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), １ -C ６ Alkyl, the C ２ -C ６ Alkenyl, the above C ２ -C ６ Alkynyl, the above C ３ -C １０ cycloalkyl, the heterocycloalkyl, the C ６ -C １０ Aryl, and each of said heteroaryls, independently and optionally, may be one or more of oxo, deuterium, halogen, -CN, -OH, -OCH ３ , -S(=O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ N.H. ２ , -S(=O) ２ N.H.C.H. 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 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 Deuteroalkyl, 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), １ -C ６ Alkyl, the C ２ -C ６ Alkenyl, the above C ２ -C ６ Alkynyl, the above C ３ -C １０ cycloalkyl, the heterocycloalkyl, the C ６ -C １０ Aryl, and each of said heteroaryls, independently and optionally, may be one or more of oxo, deuterium, halogen, -CN, -OH, -OCH ３ , -S(=O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ N.H. ２ , -S(=O) ２ N.H.C.H. 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 substituted with heteroalkyl; Or the above R ｃ and the above R ｄ together with the atom to which they are attached, optionally include one or more of oxo, deuterium, halogen, —CN, —OH, —OCH ３ , -S(=O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ N.H. ２ , -S(=O) ２ N.H.C.H. 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 forming a heterocycloalkyl substituted with a heteroalkyl; The compound, or a pharma- ceutically acceptable salt thereof.

2. The ring A is C ６ -C １０ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, which is aryl or heteroaryl.

3. The ring A is C ６ -C １０ 3. The compound of claim 2, or a pharma- ceutically acceptable salt thereof, which is aryl.

4. 3. The compound of claim 2, or a pharma- ceutically acceptable salt thereof, wherein said ring A is heteroaryl.

5. 5. The compound of claim 4, wherein Ring A is furanyl, pyrrolyl, thiophenyl, oxazolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl, or a pharma- ceutically acceptable salt thereof.

6. The R １ each independently represents a halogen, —CN, —OH, or —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, １ -C ６ Alkyl, the C ３ -C １０ cycloalkyl, the heterocycloalkyl, the C ６ -C １０ aryl, and each of said heteroaryls may optionally and independently be one or more R １ａ 2. The compound of claim 1 , or a pharma- ceutically acceptable salt thereof, substituted with:

7. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein n is 1, 2, or 3.

8. The R ２ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

9. The R ３ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

10. The R ４ａ , the R ４ｂ and the R ４ｃ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein: is hydrogen.

11. The R ５ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

12. The R ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein each is hydrogen.

13. The R ７ is hydrogen or C １ -C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

14. The R ８ａ , the R ８ｂ and the R ８ｄ are each hydrogen; ８ｃ is hydrogen, halogen, or -OR ａ 2. The compound of claim 1, wherein:

15. The R ８ｃ is halogen or -OR ａ 15. The compound of claim 14, which is: or a pharma- ceutically acceptable salt thereof.

16. The R ８ｃ Ga-OR ａ 16. The compound of claim 15, wherein:

17. 17. The compound of claim 16, or a pharma- ceutically acceptable salt thereof, wherein R8c is -O(C1-C6 alkyl).

18. The R8c is —OCH ３ 18. The compound of claim 17, which is: or a pharma- ceutically acceptable salt thereof.

19. A pharmaceutical composition comprising an amount of a compound of claim 1, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients.

20. 13. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein the cancer in the subject is neuroblastoma or breast cancer.

21. The method of claim 20, wherein the cancer in the subject is neuroblastoma.

22. The method of claim 20, wherein the cancer in the subject is breast cancer. 【Request 23】 【Chemical 2-1】 【Chemistry 2-2】 【Chemistry 2-3】 1. A compound selected from the group consisting of:

24. The compound 【Chemistry 3】 24. The compound of claim 23, which is: or a pharma- ceutically acceptable salt thereof.

25. The compound comprising: 【Chemistry 4】 24. The compound of claim 23, which is: or a pharma- ceutically acceptable salt thereof.

26. The compound comprising: 【Chemistry 5】 24. The compound of claim 23, which is: or a pharma- ceutically acceptable salt thereof.

27. ​​The compound 【Chemistry 6】 24. The compound of claim 23, which is: or a pharma- ceutically acceptable salt thereof.

28. The compound comprising: 【Chemistry 7】 24. The compound of claim 23, which is: or a pharma- ceutically acceptable salt thereof.

29. The compound comprising: 【Chemistry 8】 24. The compound of claim 23, which is: or a pharma- ceutically acceptable salt thereof.

30. The compound 【Chemistry 9】 24. The compound of claim 23, which is: or a pharma- ceutically acceptable salt thereof.

31. The compound 【Chemistry 10】 24. The compound of claim 23, which is: or a pharma- ceutically acceptable salt thereof.

32. The compound 【Chemistry 11】 24. The compound of claim 23, which is: or a pharma- ceutically acceptable salt thereof.

33. The compound 【Chemistry 12】 24. The compound of claim 23, which is: or a pharma- ceutically acceptable salt thereof.

34. The compound 【Chemistry 13】 24. The compound of claim 23, which is: or a pharma- ceutically acceptable salt thereof.

35. The compound comprising: 【Chemistry 14】 24. The compound of claim 23, which is: or a pharma- ceutically acceptable salt thereof.

36. The compound 【Chemistry 15】 24. The compound of claim 23, which is: or a pharma- ceutically acceptable salt thereof.

37. The compound 【Chemistry 16】 24. The compound of claim 23, which is: or a pharma- ceutically acceptable salt thereof.

38. The compound 【Chemistry 17】 24. The compound of claim 23, which is: or a pharma- ceutically acceptable salt thereof.

39. The compound comprising: 【Chemistry 18】 24. The compound of claim 23, which is: or a pharma- ceutically acceptable salt thereof.

40. The compound 【Chemistry 19】 24. The compound of claim 23, which is: or a pharma- ceutically acceptable salt thereof.

41. The compound 【Chemistry 20】 24. The compound of claim 23, which is: or a pharma- ceutically acceptable salt thereof. Claim 42: The compound 【Chemistry 21】 24. The compound of claim 23, which is: or a pharma- ceutically acceptable salt thereof.

43. A pharmaceutical composition comprising an amount of a compound of claim 23, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients.

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