POLO-like kinase 4 inhibitor

Abstract

Disclosed herein is a compound of formula (IV) or a pharmaceutically 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 (IV) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. Further disclosed herein is a method for treating cancer in a subject in need thereof, the method comprising administering to the subject an amount of a compound of formula (IV) or a pharmaceutically acceptable salt thereof. [Formula 1] JPEG2025534982000146.jpg6291

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Application No. 63 / 378,142, filed October 3, 2022, and U.S. Provisional Application No. 63 / 383,773, filed November 15, 2022, which are incorporated 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 cell responses under stress (Helmke et al. 2016; Zitouni et al. 2014). 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 centriole proteins (Habedanck et al. 2005; Maniswami et al. 2018). Overexpression of PLK4 leads to centriole amplification, further genomic instability, and tumorigenesis (Holland et al. 2010). Aberrant PLK4 expression has been reported to be involved in 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 invention. Therefore, compounds that inhibit PLK4 in cancer-bearing subjects are needed for the treatment of these cancers. Summary of the Invention

[0003] In one embodiment, formula (IV)

[0004] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, During the ceremony, Ring A is C6-C 10 is aryl or heteroaryl, Each R 1 are 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 10Each of the aryl and heteroaryl may optionally independently be one or more R 1a is replaced by Alternatively, two R on adjacent atoms 1 Together, C3-C 10 cycloalkyl or heterocycloalkyl, each of which optionally contains one or more R 1b is replaced by Each R 1a are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR 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 1a together to form oxo, Each R 1bare 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 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 4cEach 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; Each R 6 are 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 independently represents 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)2NRc 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 9 optionally, one or more R 1a heteroaryl substituted with, or one or more R 1a is an oxetanyl substituted with Each R a are 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 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; Each R b are 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 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; and Each R c and R dare 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 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; Alternatively, R c and R d taken together with the atoms 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; However, the compound of formula (IV)

[0005] [ka] isn't it.

[0006] In another embodiment, the compound of formula (IVa)

[0007] [ka] The compound of formula (I) is provided.

[0008] In another embodiment, the compound of formula (IVb)

[0009] [ka] The compound of formula (I) is provided.

[0010] In another embodiment, formula (V)

[0011] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, During the ceremony, Ring A is C6-C 10 is aryl or heteroaryl, Each R 1 are 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)NRc 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 may optionally independently be one or more R 1a is replaced by Alternatively, two R on adjacent atoms 1 Together, C3-C 10 cycloalkyl or heterocycloalkyl, each of which optionally contains one or more R 1b is replaced by Each R 1a are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c Rd , -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 1a together to form oxo, Each R 1b are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR a , -NR b S(=O)2R a , -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, 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 together to form oxo, n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; R 8c are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR 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 9 optionally, one or more R 1a heteroaryl substituted with, or one or more R 1a is an oxetanyl substituted with Each R a are 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 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; Each R bare 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 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; and Each R c and R d are 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 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 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; Alternatively, R c and R d taken together with the atoms 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; However, the compound of formula (V)

[0012] [ka] isn't it.

[0013] In another embodiment, formula (Va)

[0014] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0015] In another embodiment, formula (Vb)

[0016] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0017] In another embodiment, there is provided a pharmaceutical composition comprising a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and one or more pharmaceutically acceptable excipients.

[0018] Also provided herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In other embodiments, such methods of treating cancer are provided, wherein the cancer in the subject expresses polo-like kinase 4 (PLK4). In further embodiments, such methods of treatment are provided, wherein the cancer in the subject exhibits overexpression of E3 ubiquitin-protein ligase (TRIM37). In other embodiments, such methods of treating cancer are provided, wherein the cancer in the subject exhibits overexpression of the gene encoding tripartite motif-containing protein 37 (TRIM37). In other embodiments, such methods of treating cancer are provided, wherein the cancer in the subject is determined to overexpress a gene encoding tripartite motif-containing protein 37 (TRIM37) prior to administering a compound to the subject.

[0019] In other embodiments, a method of treating cancer in a subject is provided, the method 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); If the cancer biological sample is determined to overexpress the gene encoding tripartite motif-containing protein 37 (TRIM37), administering to the subject a therapeutically effective amount of a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0020] In other embodiments, there is provided a method of inhibiting polo-like kinase 4 (PLK4) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the subject has cancer.

[0021] In other embodiments, there is provided a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), 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 cancer in the subject expresses polo-like kinase 4 (PLK4). In some embodiments, the cancer in the subject was determined to express polo-like kinase 4 (PLK4) prior to administering the compound to the subject. In some embodiments, the cancer in the subject exhibits overexpression of the gene encoding tripartite motif-containing protein 37 (TRIM37).

[0022] Further provided herein is the use of a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), 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 in the subject expresses polo-like kinase 4 (PLK4). In some embodiments, the cancer in the subject exhibits overexpression of E3 ubiquitin-protein ligase (TRIM37) protein. In some embodiments, the cancer in the subject exhibits amplification of the gene encoding tripartite motif-containing protein 37 (TRIM37).

[0023] 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.

[0024] As used in this specification and the appended claims, unless otherwise stated, the following terms have the meanings indicated below.

[0025] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents 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 are used herein for physical properties such as molecular weight or chemical properties such as chemical formula, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. When referring to a number or numerical range, the term "about" means that the referenced number or numerical range is approximate within experimental variability (or statistical experimental error); therefore, the number or numerical range will, in some cases, vary by 1% to 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude certain other embodiments, such as embodiments of any composition, composition, method, or process described herein, that "consist of" or "consist essentially of" the described features.

[0026] When used in conjunction with a therapy, "administering" means administering the therapy systemically or locally, such as directly into or onto a target tissue, or administering the therapy to a subject, whereby the therapy positively affects the targeted tissue. Thus, as used herein, the term "administering," when used in conjunction with the compositions described herein, can include, but is not limited to, providing the composition into or onto the target tissue, for example, by oral administration, or providing the composition systemically to a subject, whereby the therapeutic agent reaches the target tissue or cell. "Administering" a composition can be achieved by injection, topical administration, and oral administration, or by other methods, alone or in combination with other known techniques.

[0027] As used herein, the term "C2-C6 alkenyl" refers to an alkyl moiety containing from 2 to 6 carbon atoms having at least one carbon-carbon double bond. The carbon-carbon double bond in such groups may be anywhere along the 2-6 carbon atom chain that results in a stable compound. Examples of such groups include, but are not limited to, ethenyl, propenyl, butenyl, allyl, and pentenyl. Alkenyl may be in either the cis or trans conformation about the double bond and will be understood to include both isomers. Examples of alkenyl include, but are not limited to, ethenyl (-CH=CH), 1-propenyl (-CHCH=CH), isopropenyl [-C(CH)=CH], butenyl, 1,3-butadienyl, and the like. Whenever appearing herein, a numerical range such as "C2-C6 alkenyl" means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but this definition also encompasses occurrences of the term "alkenyl" where no numerical range is specified. In some embodiments, alkenyl is C-C10 alkenyl, C2-C9 alkenyl, C2-C8 alkenyl, C2-C7 alkenyl, C2-C6 alkenyl, C2-C5 alkenyl, C2-C4 alkenyl, C2-C3 alkenyl, or C2 alkenyl.

[0028] The term "C-C alkyl," as used herein, refers to a straight- or branched-chain hydrocarbon monoradical having from 1 to 6 carbon atoms, which may be fully saturated or unsaturated. 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. Whenever a numerical range appears herein, such as "C1-C6 alkyl," means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified.

[0029] The term "C2-C6 alkynyl," as used herein, means an alkyl moiety containing from 2 to 6 carbon atoms and having at least one carbon-carbon triple bond. The carbon-carbon triple bond in such groups may be anywhere along the 2-6 carbon chain that results in a stable compound. Examples of such groups include, but are not limited to, ethyne, propyne, 1-butyne, 2-butyne, 1-pentyne, 2-pentyne, 1-hexyne, 2-hexyne, and 3-hexyne, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever appearing herein, a numerical range such as "C2-C6 alkynyl" means that the alkynyl 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 "alkynyl" where no numerical range is specified.

[0030] "C6-C 10 Aryl (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 ring systems (when fused to 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- to 10-membered aryl. In some embodiments, an aryl is a 6-membered aryl. Aryl groups include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indene, naphthalene, phenalene, phenanthrene, pleiodene, pyrene, and triphenylene. In some embodiments, an aryl is phenyl.

[0031] The term "C1-C6 aminoalkyl" as used herein refers to a C1-C6 alkyl group as defined above, substituted with one or more amino groups. The amino groups in such a C1-C6 aminoalkyl group can 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.

[0032] "C3-C 10 Cycloalkyl (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 ring systems (when fused to an aryl or heteroaryl ring, the cycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems. In some embodiments, a cycloalkyl is 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. Polycyclic cycloalkyl or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7 dimethylbicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0033] The term "C1-C6 deuteroalkyl," as used herein, means a C1-C6 alkyl group, as defined herein, in which one or more hydrogen atoms in the C1-C6 alkyl group are replaced with deuterium atoms.

[0034] The term "C1-C6 haloalkyl," as used herein, refers to a C1-C6 alkyl group as defined above substituted by 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.

[0035] The term "C1-C6 hydroxyalkyl," as used herein, refers to a C1-C6 alkyl radical, as defined above, that is substituted with one or more hydroxy groups.

[0036] The term "animal" as used herein includes, but is not limited to, humans and non-human vertebrates, such as wild, domestic, and domestic animals. As used herein, the terms "subject," "subject," and "individual" are intended to include organisms in which a particular condition as described herein can occur. Examples include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats, and transgenic species thereof. In preferred embodiments, the subject is a primate. In certain embodiments, the primate or subject is a human. In certain examples, the human is an adult. In certain examples, the human is a child. In a further example, the human is under 12 years of age. In certain examples, the human is an elderly person. In another example, 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 of a disorder, for example, a transgenic mouse with hypertensive pathology.

[0037] As used herein, the term "Aurora kinase A" or "AurA" refers to the human protein known to those skilled in the art as Aurora kinase A and encoded by the AURKA gene.

[0038] As used herein, the term "Aurora kinase B" or "AurB" refers to the human protein known to those skilled in the art as Aurora kinase B and encoded by the AURKB gene.

[0039] A "cyano" group refers to a -CN group.

[0040] 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.

[0041] As used herein, the term "heterocycloalkyl" refers to a 3- to 24-membered partially or fully saturated ring radical containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from boron, nitrogen, oxygen, phosphorus, and sulfur. Unless otherwise specified in the specification, a heterocycloalkyl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused ring systems (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems, and 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 groups 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 pyrazolidinyl. Examples of heterocycloalkyl include, but are not limited to, cyclohexyl ...When referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring).

[0042] The term "C1-C6 heteroalkyl," as used herein, refers to an alkyl group in which one or more skeletal atoms of the alkyl group 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, where the heteroalkyl consists 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 the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl.

[0043] 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. The heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused ring systems (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl is attached through an aromatic ring atom) or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl.Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, 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, isoindolyl, indolinyl, Examples of aryl groups include, but are not limited to, 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, tetraazolyl, triazinyl, and thiophenyl (i.e., thienyl).

[0044] As used herein, "pharmaceutically acceptable" means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0045] The term "pharmaceutical composition" means a composition comprising at least one active ingredient, wherein the composition is suitable for investigation of a particular efficacious outcome in a mammal (e.g., 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 artisan.

[0046] The term "pharmaceutically acceptable salt," as used herein, means a salt of a compound of the present invention that retains the biological effectiveness of the free acids and bases of the specified derivative and that is not biologically or otherwise undesirable.

[0047] As used herein, the term "PLK4" refers to the human protein known to those skilled in the art as polo-like kinase 4 and encoded by the PLK4 gene.

[0048] The term "oxo," as used herein, refers to a carbonyl moiety such that an alkyl substituted by oxo refers to a ketone group.

[0049] 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 in combination with water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or a mixture thereof. The term "hydrate" can be used when the solvent is water. It is specifically contemplated in the present invention that one solvent molecule may be associated with one molecule of a compound of the present invention, such as a hydrate. It is also specifically contemplated in the present invention that multiple solvent molecules may be associated with one molecule of a compound of the present invention, such as a dihydrate. It is also specifically contemplated in the present invention that fewer 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 the compounds of the present invention that retain the biological effectiveness of the non-hydrate form of the compound.

[0050] 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) can occur. Examples of tautomerism include keto and enol tautomers. A single compound may exhibit more than one type of isomerism. Included within the scope of the 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, and mixtures of one or more thereof. Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

[0051] The term "stereoisomers" refers to compounds that have identical chemical constitution but differ with respect to the arrangement of their atoms or groups in space. In particular, the term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. As used herein, the terms "racemic" or "racemic mixture" refer to a 1:1 mixture of enantiomers of a particular compound. A racemic mixture in which one racemate is present in greater amounts than the other may be described as "enantiomerically enriched." On the other hand, the term "diastereomers" refers to the relationship between a pair of stereoisomers that contain two or more asymmetric centers and are not mirror images of each other. Conventional nomenclature in the art may be used to describe stereoisomers of the compounds disclosed herein, or the stereochemistry of a particular asymmetric carbon atom, or mixtures thereof. For example, a single racemate or stereocenter in a compound may be described as being in the (+), (-), (R)-, or (S) configuration. Racemic mixtures may be described by use of the (±) symbol.

[0052] The compounds of the present invention may have asymmetric carbon atoms. The carbon-carbon bonds of the compounds of the present invention are

[0053] [ka] As used herein, the term "asymmetric carbon atom" can be used to denote a bond to an asymmetric carbon atom. The use of a solid line to denote a bond to an asymmetric carbon atom is meant 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 dashed wedge to denote a bond to an asymmetric carbon atom is meant to indicate that only the depicted stereoisomer is included. The compounds of the present invention may contain more than one asymmetric carbon atom. In these compounds, the use of a solid line to denote a bond to an asymmetric carbon atom is meant to indicate that all possible stereoisomers are included. For example, unless otherwise stated, it is intended that the compounds of the present invention can exist as enantiomers and diastereomers, or as racemates and mixtures thereof. The use of a solid line to denote a bond to one or more asymmetric carbon atoms in a compound of the present invention, and the use of a solid or dashed wedge to denote a bond to another asymmetric carbon atom in the same compound, is meant to indicate that a mixture of diastereomers is present.

[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) can 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 can be separated by chromatography and / or fractional crystallization, and one or both diastereoisomers can 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) can be obtained in enantiomerically enriched form by chromatography on an asymmetric resin, typically using HPLC, using a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing 0-50%, typically 2-20%, isopropanol, and 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), the disclosure of which is incorporated herein by reference in its entirety.

[0055] As used herein, the term "substituted" means that a particular group or moiety has one or more substituents. The term "unsubstituted" means that a particular group has no substituents. The term "optionally substituted" means that a particular group is unsubstituted or substituted with one or more substituents. In the compounds of the present invention, when a group is "unsubstituted" or "substituted" with fewer groups than satisfy the valences of all atoms in the compound, it is understood that the remaining valences in such a group are satisfied with hydrogen. For example, if a C6 aryl group, also referred to herein as "phenyl," is substituted with one additional substituent, one skilled in the art will understand that such a group has four open positions remaining on the carbon atoms of the C6 aryl group (six initial positions minus one to which the remainder of the compound of the present invention is attached and the additional substituent, leaving four). In such cases, each of the remaining four carbon atoms is bonded to one hydrogen atom to satisfy their valences. Similarly, when a C aryl group in the present compounds is said to be "disubstituted," one skilled in the art will understand that this means that the C aryl group has three remaining unsubstituted carbon atoms, each of which is bonded to one hydrogen atom to satisfy the valence.

[0056] According to the convention used in the art, in the structural formulae herein, the symbol

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

[0058] [ka] represents a methyl group,

[0059] [ka] represents an ethyl group,

[0060] [ka] represents a cyclopentyl group, etc.

[0061] Certain groups, such as (R 1 ) n But, the formula

[0062] [ka] When depicted as a "floating" ring A in (Illegible character), unless otherwise defined, the substituent R1 may be present on any atom of the ring system, assuming replacement of a depicted, implied, or explicitly defined hydrogen from one of the ring atoms, so long as a stable structure is formed. Ring system A can be, for example, but is not limited to, an aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, spirocyclyl, or a fused ring system.

[0063] When a group "R" is shown as "floating" on a ring system A, as shown above, and ring A contains saturated carbons, "n" can be greater than 1, assuming each replaces a hydrogen on ring A, currently shown, implied, or explicitly defined, and then, unless otherwise defined, the resulting structure is stable and two R 1 Groups may be present on the same carbon. For example, R 1 is a methyl group, there can be a germinal dimethyl on the carbon of ring A. In another example, two R1 The group (including its carbons) can form a ring, thus producing a spirocyclic ring ("spirocyclyl group"). In a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), when n is less than the number of substitutable atoms on Ring A, the other substitutable positions on Ring A are bonded to hydrogen atoms.

[0064] As used herein, the term "therapeutic" means an agent utilized to treat, combat, ameliorate, prevent, or ameliorate an unwanted disease or disorder in a subject.

[0065] As used herein, a "therapeutically effective amount" or "effective amount" refers to an amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual, or human that is desired by a researcher, veterinarian, physician, or other clinician, and includes one or more of the following: (1) preventing a disease, e.g., preventing a disease, illness, or disorder in an individual who may be predisposed to the disease, illness, or disorder but who has not yet experienced or exhibited the pathology or symptoms of the disease; (2) inhibiting a disease, e.g., inhibiting a disease, illness, or disorder (i.e., preventing further development of the pathology and / or symptoms) in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, illness, or disorder; and (3) ameliorating a disease, e.g., ameliorating a disease, illness, or disorder (i.e., reversing the pathology and / or symptoms) in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, illness, or disorder.

[0066] The terms "treat," "treated," "treatment," or "treating," as used herein, refer to both therapeutic treatment in some embodiments and prophylactic or preventative measures in other embodiments, where the purpose is to prevent or slow (alleviate) an undesirable physiological disease, disorder, or condition, or to obtain a beneficial or desired clinical result. For purposes described herein, beneficial or desired clinical result includes alleviation of symptoms, reduction in the extent of the disease, disorder, or condition, stabilization (i.e., not worsening) of the disease, disorder, or condition, delay in the onset or slowing of progression of the disease, disorder, or condition, improvement of the disease, disorder, or condition, and remission (whether partial or total), whether detectable or undetectable, or enhancement or amelioration of the disease, disorder, or condition. Treating includes eliciting a clinically significant response without excessive levels of side effects. Treating also includes prolonging survival as compared to expected survival if not receiving treatment. The prophylactic benefit of treatment includes prevention of a condition, delaying the progression of a disease, stabilizing a disease, or reducing the likelihood of developing a disease. As used herein, "treat," "treated," "treatment," or "treating" includes prevention in some embodiments.

[0067] As used herein, the term "TRIM37" refers to the human protein known to those skilled in the art as tripartite motif-containing protein 37, 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 structure shown below: The preparation of the compound is described in PCT Application Publication WO2011 / 123946 and is commercially available for purchase.

[0069] [ka]

[0070] PLK4 inhibitor compounds As used herein, the term "compounds of formula (I)" is used interchangeably with "compounds of formula (I)"

[0071] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, During the ceremony, Ring A is C6-C 10 Aryl, heteroaryl, C3-C 10 cycloalkyl, or heterocycloalkyl; Each R 1 are 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 may optionally independently be one or more R 1a is replaced by Alternatively, two R on adjacent atoms 1 Together, C3-C 10 cycloalkyl or heterocycloalkyl, each of which optionally contains one or more R 1b is replaced by Each R 1a are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR 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 1a together to form oxo, Each R 1b are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR 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 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; Each R 6 are 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 , R8c and R 8d Each independently represents 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; Each R a are 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 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 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; Each R b are 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 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; and Each R c and R d are 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 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; Alternatively, R cand R d together with the atoms 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.

[0072] As used herein, the formula (Ia)

[0073] [ka] Also provided is a compound of the formula: During the ceremony, Ring A is C6-C 10 Aryl, heteroaryl, C3-C 10 cycloalkyl, or heterocycloalkyl; Each R 1 are 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 , -NRb 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, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 Each of the aryl and heteroaryl may optionally independently be one or more R 1a is replaced by Alternatively, two R on adjacent atoms 1 Together, C3-C 10 cycloalkyl or heterocycloalkyl, each of which optionally contains one or more R 1b is replaced by Each R 1a are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR a , -NR bS(=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 1a together to form oxo, Each R 1b are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR 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-C10 aryl, or heteroaryl; Alternatively, two R on the same atom 1b 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; Each R 6 are 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 7is 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 independently represents 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; Each R a are 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 10Cycloalkyl, 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 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; Each R b are 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 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; and Each R c and R d are 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 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; Alternatively, R c and R dtogether with the atoms 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.

[0074] A compound of formula (Ib),

[0075] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is further provided herein: During the ceremony, Ring A is C6-C 10 Aryl, heteroaryl, C3-C 10 cycloalkyl, or heterocycloalkyl; Each R 1 are 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 bS(=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, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 Each of the aryl and heteroaryl may optionally independently be one or more R 1a is replaced by Alternatively, two R on adjacent atoms 1 Together, C3-C 10 cycloalkyl or heterocycloalkyl, each of which optionally contains one or more R 1b is replaced by Each R 1a are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR a , -NR b S(=O)2Ra , -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 1a together to form oxo, Each R 1b are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR 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 atom 1b 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; Each R 6 are 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 7is 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 independently represents 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; Each R a are 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 10Cycloalkyl, 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 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; Each R b are 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 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; and Each R c and R d are 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 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; Alternatively, R c and R dtogether with the atoms 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.

[0076] Also, the formula (II)

[0077] [ka] Also provided is a compound of the formula: During the ceremony, Ring A is C6-C 10 Aryl or heteroaryl, C3-C 10 is cycloalkyl and heterocycloalkyl; Each R 1 are independently halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, -OC1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 aryl, or heteroaryl, C1-C6 alkyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 Each of the aryl and heteroaryl may optionally independently be one or more R 1a is replaced by Each R 1a are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)ORb , -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 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 independently represents hydrogen, deuterium, a halogen, or -OR a and Each Ra are 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 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; Each R b are 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-C10 Cycloalkyl, heterocycloalkyl, C6-C 10 each aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; and Each R c and R d are 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 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; Alternatively, R c and R d together with the atoms 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.

[0078] In another embodiment, the compound of formula (III)

[0079] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided, During the ceremony, Ring A is heteroaryl; Each R 1 are independently halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, -OC1-C6 haloalkyl, C3-C 10 cycloalkyl, or heterocycloalkyl, and C1-C6 alkyl, C3-C 10 Each of the cycloalkyl and heterocycloalkyl optionally independently comprises one or more R 1a is replaced by Each R 1a are independently deuterium, -OH, -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 10aryl, or heteroaryl; n is 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 Each R a are 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 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.

[0080] As used herein, the formula (IV)

[0081] [ka] Further provided is a compound of the formula: During the ceremony Ring A is C6-C 10 is aryl or heteroaryl, Each R 1 are 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 may optionally independently be one or more R1a is replaced by Alternatively, two R on adjacent atoms 1 Together, C3-C 10 cycloalkyl or heterocycloalkyl, each of which optionally contains one or more R 1b is replaced by Each R 1a are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR 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 1a together to form oxo, Each R 1b are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a, -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR 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 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; Each R 6 are 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 independently represents 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)NRc 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 9 optionally, one or more R 1a heteroaryl substituted with, or one or more R 1a is an oxetanyl substituted with Each R a are 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 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; Each R b are 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 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; and Each R c and R dare 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 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; Alternatively, R c and R d taken together with the atoms 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; However, the compound of formula (IV)

[0082] [ka] isn't it.

[0083] In some embodiments, the compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is C6-C 10In some embodiments, the compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is aryl. In some embodiments, the compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is phenyl. In some embodiments, the compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is heteroaryl. In some embodiments, the compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is furanyl, pyrrolyl, thiophenyl, oxazolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments, the compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments, the compound is represented by Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is pyrazolyl, pyridinyl, pyrazinyl, or pyrimidinyl. In some embodiments, the compound is represented by Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is pyrazolyl. In some embodiments, the compound is represented by Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, or 5-pyrazolyl. In some embodiments, the compound is represented by Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 1-pyrazolyl. In some embodiments, the compound is represented by Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 3-pyrazolyl. In some embodiments, the compound has Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 4-pyrazolyl. In some embodiments, the compound has Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 5-pyrazolyl.In some embodiments, the compound is represented by Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is pyridinyl. In some embodiments, the compound is represented by Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 5-pyridinyl, or 6-pyridinyl. In some embodiments, the compound is represented by Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 2-pyridinyl. In some embodiments, the compound is represented by Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 3-pyridinyl. In some embodiments, the compound is represented by Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 4-pyridinyl. In some embodiments, the compound is represented by Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 5-pyridinyl. In some embodiments, the compound is represented by Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 6-pyridinyl. In some embodiments, the compound is represented by Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is pyrazinyl. In some embodiments, the compound is represented by Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, or 6-pyrazinyl. In some embodiments, the compound is represented by Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 2-pyrazinyl. In some embodiments, the compound has Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 3-pyrazinyl. In some embodiments, the compound has Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 5-pyrazinyl. In some embodiments, the compound has Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 6-pyrazinyl.In some embodiments, the compound is represented by Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is pyrimidinyl. In some embodiments, the compound is represented by Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl. In some embodiments, the compound is represented by Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 2-pyrimidinyl. In some embodiments, the compound is represented by Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 4-pyrimidinyl. In some embodiments, the compound is represented by Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 5-pyrimidinyl. In some embodiments, the compound is represented by Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 6-pyrimidinyl. In some embodiments, the compound is represented by Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is pyridazinyl. In some embodiments, the compound is represented by Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, or 6-pyridazinyl. In some embodiments, the compound is represented by Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 3-pyridazinyl. In some embodiments, the compound is represented by Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 4-pyridazinyl. In some embodiments, the compound is of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 5-pyridazinyl. In some embodiments, the compound is of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 6-pyridazinyl. In some embodiments, the compound is of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R. 1is independently methyl, ethyl, trifluoromethyl, methoxy, ethoxy, methanesulfonyl, ethanesulfonyl, acetyl, or dimethylamino. In some embodiments, a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 1, 2, or 3. In some embodiments, a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 1. In some embodiments, a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 2. In some embodiments, a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 3. In some embodiments, a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 2 is hydrogen. In some embodiments, the compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 3 is hydrogen. In some embodiments, the compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 4a , R 4b and R 4c is independently hydrogen or halogen. In some embodiments, the compound is of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 4a is a halogen and R 4b and R 4c is hydrogen. In some embodiments, the compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 4a and R 4c is hydrogen and R 4b is halogen. In some embodiments, the compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 4a and R 4b is hydrogen and R 4cis halogen. In some embodiments, the compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 4a and R 4b is a halogen and R 4c is hydrogen. In some embodiments, the compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 4a and R 4c is a halogen and R 4b is hydrogen. In some embodiments, the compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 4a , R 4b and R 4c In some embodiments, the compound is of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 4a , R 4b and R 4c is hydrogen. In some embodiments, the compound is of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 5 is hydrogen. In some embodiments, the compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 6 is hydrogen. In some embodiments, the compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 7 is hydrogen or C1-C6 alkyl. In some embodiments, the compound is of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 7 is hydrogen. In some embodiments, the compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 7 is C1-C6 alkyl. In some embodiments, the compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 8a , R 8b , R 8c and R 8deach independently represents hydrogen, halogen, or -OR a In some embodiments, the compound of formula (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 8a , R 8b and R 8d is hydrogen, and R 8c is hydrogen, halogen or -OR a In some embodiments, the compound of formula (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 8c is halogen or -OR a In some embodiments, the compound of formula (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 8c is halogen. In some embodiments, the compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 8c Fluoro, In some embodiments, the compound of formula (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 8c HA-OR a In some embodiments, the compound of formula (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R a is C1-C6 alkyl. In some embodiments, the compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R a In some embodiments, the compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 9 is furanyl, pyrrolyl, thiophenyl, oxazolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or tetrazolyl, each of which may be selected from the group consisting of one or more R 1aIn some embodiments, the compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 9 optionally, one or more R 1a In some embodiments, the compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 9 optionally, one or more R 1a In some embodiments, the compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 9 optionally, one or more R 1a In some embodiments, the compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 9 optionally, one or more R 1a In some embodiments, the compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 9 optionally, one or more R 1a In some embodiments, the compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 9 optionally, one or more R 1a In some embodiments, the compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 9 optionally, one or more R 1a In some embodiments, the compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 9 optionally, one or more R 1a In some embodiments, the compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 9 optionally, one or more R1a In some embodiments, the compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 9 optionally, one or more R 1a In some embodiments, the compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 9 optionally, one or more R 1a In some embodiments, the compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 9 optionally, one or more R 1a In some embodiments, the compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 9 optionally, one or more R 1a In some embodiments, the compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 9 optionally, one or more R 1a In some embodiments, the compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is pyridazinyl substituted with R 9 optionally, one or more R 1a In some embodiments, the compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 9 is one or more R 1a and oxetanyl substituted with

[0084] In some embodiments, the compound of formula (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound of formula (IV) is represented by formula (IVa):

[0085] [ka] It has the following structure.

[0086] In some embodiments, the compound of formula (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound of formula (IV) is represented by formula (IVb):

[0087] [ka] It has the following structure.

[0088] In another embodiment, a compound of formula (V):

[0089] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, Ring A is C6-C 10 is aryl or heteroaryl, Each R 1 are 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 may optionally independently be one or more R 1a is replaced by Alternatively, two R on adjacent atoms 1 Together, C3-C 10 cycloalkyl or heterocycloalkyl, each of which optionally contains one or more R 1b is replaced by Each R 1a are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR a , -NR b S(=O)2R a , -C(=O)Ra , -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 1a together to form oxo, Each R 1b are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR 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 together to form oxo, n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; R 8c are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR 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 9 optionally, one or more R 1a heteroaryl substituted with, or one or more R 1a is an oxetanyl substituted with Each R a are 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 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; Each R b are 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 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; and Each R c and R d are 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 10Each aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Alternatively, R c and R d taken together with the atoms 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; However, the compound of formula (V)

[0090] [ka] isn't it.

[0091] In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is C6-C 10In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is aryl. In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is phenyl. In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is heteroaryl. In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is pyrazolyl. In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, or 5-pyrazolyl. In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 1-pyrazolyl. In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 3-pyrazolyl. In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 4-pyrazolyl. In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 5-pyrazolyl. In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is -pyridinyl. In some embodiments, the compound has Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 5-pyridinyl, or 6-pyridinyl. In some embodiments, the compound has Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 2-pyridinyl. In some embodiments, the compound has Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 3-pyridinyl.In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 4-pyridinyl. In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 5-pyridinyl. In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 6-pyridinyl. In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is pyrazinyl. In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, or 6-pyrazinyl. In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 2-pyrazinyl. In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 3-pyrazinyl. In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 5-pyrazinyl. In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 6-pyrazinyl. In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is pyrimidinyl. In some embodiments, the compound has Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl. In some embodiments, the compound has Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 2-pyrimidinyl. In some embodiments, the compound has Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 4-pyrimidinyl.In some embodiments, the compound is represented by Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 5-pyrimidinyl. In some embodiments, the compound is represented by Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 6-pyrimidinyl. In some embodiments, the compound is represented by Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is pyridazinyl. In some embodiments, the compound is represented by Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, or 6-pyridazinyl. In some embodiments, the compound is represented by Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 3-pyridazinyl. In some embodiments, the compound is of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 4-pyridazinyl. In some embodiments, the compound is of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 5-pyridazinyl. In some embodiments, the compound is of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is 6-pyridazinyl. In some embodiments, the compound is of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R. 9 is furanyl, pyrrolyl, thiophenyl, oxazolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or tetrazolyl, each of which optionally contains one or more R 1a In some embodiments, the compound of formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is substituted with R 9 optionally, one or more R 1a In some embodiments, the compound of formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 9 optionally, one or more R1a In some embodiments, the compound of formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 9 optionally, one or more R 1a In some embodiments, the compound of formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 9 optionally, one or more R 1a In some embodiments, the compound of formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 9 optionally, one or more R 1a In some embodiments, the compound of formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 9 optionally, one or more R 1a In some embodiments, the compound of formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 9 optionally, one or more R 1a In some embodiments, the compound of formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 9 optionally, one or more R 1a In some embodiments, the compound of formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 9 optionally, one or more R 1a In some embodiments, the compound of formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 9 optionally, one or more R 1a In some embodiments, the compound of formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R9 optionally, one or more R 1a In some embodiments, the compound of formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 9 optionally, one or more R 1a In some embodiments, the compound of formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 9 optionally, one or more R 1a In some embodiments, the compound of formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 9 optionally, one or more R 1a In some embodiments, the compound of formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is pyridazinyl substituted with R 9 optionally, one or more R 1a In some embodiments, the compound of formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 9 is one or more R 1a In some embodiments, the compound of formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 7 is hydrogen. In some embodiments, the compound of formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 8c is halogen or -OR a In some embodiments, the compound of formula (V) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 8c is halogen. In some embodiments, the compound of formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 8cis fluoro, chloro, bromo, or iodo. In some embodiments, the compound of formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 8c HA-OR a In some embodiments, the compound of formula (V) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R a is C1-C6 alkyl. In some embodiments, the compound of formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R a is -CH3. In some embodiments, a compound of formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 0, 1, or 2. In some embodiments, a compound of formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof or a stereoisomer thereof, wherein n is 0. In some embodiments, the compound is of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 1. In some embodiments, the compound is of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 2. In some embodiments, the compound is of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 are independently methyl, ethyl, trifluoromethyl, methoxy, ethoxy, methanesulfonyl, ethanesulfonyl, acetyl, or dimethylamino.

[0092] In some embodiments, the compound of formula (V) is represented by the formula (Va):

[0093] [ka] It has the following structure.

[0094] In some embodiments, the compound of formula (V) is a compound of formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound of formula (V) is a compound of formula (Vb):

[0095] [ka] It has the following structure.

[0096] In addition, in the present specification, 6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-2,3-dihydro-1H-1-benzothiophene-1,1-dione, (1R,2S)-2-{3-[4-(methanesulfonyl)-2-methoxyanilino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-[3 -(4-acetyl-2-methoxyanilino)-1H-indazol-6-yl]-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-6-(1,3-oxazol-2-yl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[4-(ethanesulfonyl)-2-methoxyanilino]-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)-1H-1-benzothiophene-1,1-dione, (1R,2S)-2-{3-[2-ethoxy-4-(pyrazin-2-yl)anilino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole ]-2'(1'H)-one, (1R,2S)-2-{3-[(3-ethoxyquinolin-2-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{4-[3-(dimethylamino)oxetan-3-yl]-2-methoxyanilino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[2-ethoxy-4-(1H-1,2,4-triazol-1-yl)anilino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, 7-ethoxy-6-((6-((1R,2S)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indolin]-2-yl)-1H-indazol-3-yl)amino)quinoline 1-oxide, (1R,2S)-5'-methoxy-2-{3-[2-methoxy-5-(1,3-oxazol-2-yl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[2-methoxy-5-(1,3-thiazol-2-yl)anilino]-1H- indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[2-methoxy-5-(1,3-thiazol-4-yl)anilino]-1H-in ... -{3-[2-methoxy-5-(1,3-oxazol-4-yl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[2-methoxy-4-(2-methyl-2H-tetrazol-5-yl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[2-methoxy-5-(1,3-oxazol-5-yl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-6-(1,3-oxazol-2-yl)pyrazin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[2-(dimethylamino)-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-[2-methoxy-5-(2-methyl-2H-tetrahydrofuran-4-yl)amino}-1H-indazol-6-yl

[0013] Provided is a compound selected from the group consisting of (1R,2S)-2-(3-{5-[3-(dimethylamino)oxetan-3-yl]-2-methoxyanilino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{5-[3-(dimethylamino)oxetan-3-yl]-2-methoxyanilino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0097] In addition, in the present specification, 6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-2,3-dihydro-1H-1-benzothiophene-1,1-dione, (1R,2S)-2-{3-[4-(methanesulfonyl)-2-methoxyanilino]-1H-indazol-3-yl}amino)-2,3-dihydro-1H-1-benzothiophene-1,1-dione, Indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-[3-(4-acetyl-2-methoxyanilino)-1H-indazol-6-yl]-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[4-(ethanesulfonyl)-2-methoxyanilino] o]-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)-1H-1-benzothiophene-1,1-dione, ( 1R,2S)-2-{3-[(3-ethoxyquinolin-2-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, 7-ethoxy-6-((6-((1R,2S)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indolin]-2-yl)-1H-indazol-3-yl)amino)quinoline 1-oxide, (1R,2S)-2-(3-{[2-(dimethylamino)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, and (1R,2S)-5'-methoxy-2-{3-[2-methoxy-5-(2-methyl-2H-tetrazol-5-yl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,

[0013] 3'-indol]-2'(1'H)-one, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0098] In addition, in the present specification, (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-6-(1,3-oxazol-2-yl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[2-ethoxy-4-(pyrazin-2-yl)anilino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{4-[3- (Dimethylamino)oxetan-3-yl]-2-methoxyanilino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[2-ethoxy-4-(1H-1,2,4-triazol-1-yl)anilino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[2-methoxy-5-(1-methyl-1H-pi (1R,2S)-5'-methoxy-2-{3-[2-methoxy-5-(1,3-thiazol-2-yl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[2-methoxy-5-(1,3-thiazol-2-yl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[2-methoxy-5-(1,3-thiazol-2-yl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, Cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[2-methoxy-5-(1,3-thiazol-4-yl)anilino]-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-4-yl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-Methoxy-2-{3-[2-methoxy-4-(2-methyl-2H-tetrazol-5-yl)anilino]-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-5-yl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-Methoxy-2-(3-{[3-methoxy-6-(1,3-oxazol-5-yl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one Provided herein is a compound selected from the group consisting of (1R,2S)-2-(3-{5-[3-(dimethylamino)oxetan-3-yl]-2-methoxyanilino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, and (1R,2S)-2-(3-{5-[3-(dimethylamino)oxetan-3-yl]-2-methoxyanilino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0099] In addition, in the present specification, (1R,2S)-2-{3-[2-ethoxy-4-(methanesulfonyl)anilino]-1H-indazol-6-yl}-5'-methoxy-1'-methylspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy- 2-{3-[(5-methoxy[2,5'-bipyrimidin]-4-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-methyl-1H-pyrazol-4-yl)pyridin-3-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one (1R,2S)-2-(3-{[3-ethoxy-6-(1,3-thiazol-2-yl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[3-ethoxy-6-(1,3-thiazol-2-yl)pyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[2-ethoxy-4-(1-methyl-1H-imidazol-4-yl)anilino]-1H-indazole- 6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[2-methoxy-5-(1,2-thiazol-3-yl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[5-methoxy-2-(1-methyl-1H-pyrazol-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-[2-methoxy-5-(1,2-oxazol-3-yl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[2-ethoxy-5-(1,3-thiazol-2-yl)anilino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2 -(3-{[5-ethoxy-2-(1,3-thiazol-2-yl)pyridin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[3-ethoxy-6-(1,3-thiazol-2-yl)pyrazin-2-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-(3-methoxy-1-methyl-1H-pyrazol-4-yl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[2-ethoxy-5-(1-methyl-1H-pyrazol-4-yl)anilino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[3-ethoxy-5-(1H-1,2,4-thiazolinone riazol-1-yl)pyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{5-[1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]-2-methoxyanilino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[5-methoxy-2-(1,3-oxazol-5-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[2-ethoxy-5-(1,3-thiazol-2-yl)pyridin-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-5-(1,3- (1R,2S)-2-{3-[(5-ethoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-[(2H3)methyloxy]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'-[(2H3)methyloxy]spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[5-ethoxy-2-(1,3-thiazol-2-yl)pyrimidin 1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-((5-ethoxy-2-(3-hydroxy-3-methylbut-1-yn-1-yl)pyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one, (1R,2S)-2-(3-((5-(1-(2,2-difluoroethyl)-1H-pyrimidin-4-yl)amino)-1H-indazol-6-yl) (1R,2S)-2-(3-((6-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-3-methoxypyridin-2-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one, (1R,2S)-2-(3-((6-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-3-methoxypyridin-2-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one, (1R,2S)-2-(3-((6-(1-(2,2-Difluoroethyl)-1H-pyrazol-4-yl)-3-methoxypyrazin-2-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one, (1R)-2-(3-((2-ethoxy-5-(oxazol-4-yl)pyridin-3-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one, (1R,2S)-2-(3-((5-ethoxy-2-ethynylpyrimidin-4-yl)amino) (1R,2S)-2-(3-((2-ethoxy-5-(1H-imidazol-1-yl)pyridin-3-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one, (1R,2S)-5'-methoxy-2-(3-((1-methyl-1H-1,2,4-triazol-5-yl)amino)-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-one -1,3'-indolin]-2'-one, (1R,2S)-2-(3-{[6-(1H-imidazol-1-yl)-3-methoxypyrazin-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-(1H-pyrazol-1-yl)pyrazin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, 1 R,2S)-5'-methoxy-2-(3-{[5-methoxy-2-(1,3-oxazol-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, 2-[4-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-5-methyl-1H-pyrazol-1-yl]-2-methylpropanenitrile, (1R,2S)-5'-Methoxy-2-(3-{[3-methyl-1-(trifluoromethyl)-1H-pyrazol-5-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-Methoxy-2-(3-{[2-methoxy-5-(morpholin-4-yl)pyridin-3-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'

[0013] Provided herein is a compound selected from the group consisting of [(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), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0100] Further provided herein is a compound selected from those set forth in Table 1A.

[0101] [Table 1-1]

[0102] [Table 1-2]

[0103] [Table 1-3]

[0104] [Table 1-4]

[0105] [Table 1-5]

[0106] [Table 1-6]

[0107] [Table 1-7]

[0108] [Table 1-8]

[0109] [Table 1-9]

[0110] [Table 1-10]

[0111] [Table 1-11]

[0112] [Table 1-12]

[0113] [Table 1-13]

[0114] [Table 1-14]

[0115] [Table 1-15]

[0116] Further provided herein is a compound of formula

[0117] [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0118] Further provided herein are pharmaceutical compositions comprising an amount of a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and one or more pharmaceutically acceptable excipients.

[0119] Treatment method Further provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition disclosed herein comprising a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Such a method of treating cancer in a subject is provided herein, wherein the cancer in the subject is a solid tumor. In some embodiments, the cancer is neuroblastoma, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, 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 carcinoma, central nervous system (CNS) neoplasm, primary CNS lymphoma, spinal axis tumor, brainstem glioma, or pituitary adenoma. In some embodiments, the cancer in the subject expresses polo-like kinase 4 (PLK4). In some embodiments, the cancer in the subject is determined to express polo-like kinase 4 (PLK4) prior to administering a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the cancer in the subject exhibits overexpression of E3 ubiquitin-protein ligase (TRIM37) protein. In some embodiments, the cancer in the subject exhibits overexpression of the gene encoding tripartite motif-containing protein 37 (TRIM37).In some embodiments, the cancer in the subject exhibits amplification of the gene encoding tripartite motif-containing protein 37 (TRIM37).

[0120] Further provided herein is a method of treating cancer in a subject in need thereof, the method comprising the step of administering to the subject a therapeutically effective amount of a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the cancer in the subject has been determined to overexpress a gene encoding tripartite motif-containing protein 37 (TRIM37) prior to administration of the compound to the subject.

[0121] Further provided herein is a method of treating cancer in a subject in need thereof, wherein the cancer in the subject is determined to overexpress a gene encoding tripartite motif-containing protein 37 (TRIM37), the method comprising the step of administering to the subject a therapeutically effective amount of a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0122] Further provided herein is a method of treating cancer in a subject, the method 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), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; Includes.

[0123] Further provided herein are methods of treating cancer in a subject described herein, wherein the cancer is neuroblastoma or breast cancer. Also provided herein are methods of treating cancer in a subject described herein, wherein the cancer is neuroblastoma. Also provided herein are methods of treating cancer in a subject described herein, wherein the cancer is breast cancer.

[0124] Further provided herein are methods of treating cancer in a subject described herein, wherein a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), 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 inhibitors of protein tyrosine kinases and / or serine / threonine kinases, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxic agents, and immuno-oncology agents.

[0125] Further provided herein is a method of inhibiting polo-like kinase 4 (PLK4) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition comprising a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0126] Further provided herein is a method of inhibiting polo-like kinase 4 (PLK4) in a subject having cancer, the method comprising the step of administering to the subject a therapeutically effective amount of a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition comprising a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the cancer in the subject has been determined to express polo-like kinase 4 (PLK4) prior to administering the compound or pharmaceutical composition to the subject.

[0127] Further provided herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the cancer in the subject is acute myeloid leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, triple-negative breast cancer, advanced breast cancer, metastatic breast cancer, or prostate cancer. In some embodiments, the 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 in question is prostate cancer.

[0128] Further provided herein is a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition comprising a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), 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, such a compound or pharmaceutical composition is provided for such use, wherein the subject's cancer is a solid tumor. In some embodiments, such compounds or pharmaceutical compositions are provided for such uses, wherein the cancer is neuroblastoma, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, 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, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumor, brain stem glioma, or pituitary adenoma. In some embodiments, such compounds or pharmaceutical compositions are provided for such uses, wherein the cancer in the subject expresses polo-like kinase 4 (PLK4). In some embodiments, such compounds or pharmaceutical compositions are provided for such uses, wherein the cancer in the subject has been determined to express polo-like kinase 4 (PLK4) prior to administering the compound or pharmaceutical composition to the subject. In some embodiments, such compounds or pharmaceutical compositions are provided for such uses, wherein the cancer in the subject exhibits overexpression of E3 ubiquitin-protein ligase (TRIM37) protein.In some embodiments, such compounds or pharmaceutical compositions are provided for such uses, wherein the cancer in the subject exhibits overexpression of the gene encoding tripartite motif-containing protein 37 (TRIM37). In some embodiments, such compounds or pharmaceutical compositions are provided for such uses, wherein the cancer in the subject exhibits amplification of the gene encoding tripartite motif-containing protein 37 (TRIM37). In some embodiments, such compounds or pharmaceutical compositions are provided for such uses, wherein the cancer in the subject is determined to overexpress the gene encoding tripartite motif-containing protein 37 (TRIM37) prior to administering the compound or pharmaceutical composition to the subject. In some embodiments, such compounds or pharmaceutical compositions are provided for such uses, wherein the cancer is neuroblastoma or breast cancer. In some embodiments, such compounds or pharmaceutical compositions are provided for such uses, wherein the cancer is neuroblastoma. In some embodiments, such compounds or pharmaceutical compositions are provided for such uses, wherein the cancer is breast cancer.

[0129] Further provided herein is a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition comprising a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), 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 cancer in the subject is acute myeloid leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, triple-negative breast cancer, advanced breast cancer, metastatic breast cancer, or prostate cancer. In some embodiments, the 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.

[0130] Further provided herein is a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition comprising a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), 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.

[0131] Further provided herein is the use of a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in the manufacture of a medicament for the treatment of cancer in a subject in need thereof. In some embodiments, such uses are provided, wherein the cancer is neuroblastoma, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, 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 carcinoma, central nervous system (CNS) neoplasm, primary CNS lymphoma, spinal axis tumor, brainstem glioma, or pituitary adenoma. In some embodiments, the cancer in the subject expresses polo-like kinase 4 (PLK4). In some embodiments, the cancer in the subject is determined to express polo-like kinase 4 (PLK4) prior to administering the compound to the subject. In some embodiments, the cancer in the subject exhibits overexpression of E3 ubiquitin-protein ligase (TRIM37) protein. In some embodiments, the cancer in the subject exhibits overexpression of the gene encoding tripartite motif-containing protein 37 (TRIM37). In some embodiments, the cancer in the subject exhibits amplification of the gene encoding tripartite motif-containing protein 37 (TRIM37). In some embodiments, the cancer in the subject was 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.

[0132] Further provided herein is the use of a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in the manufacture of a medicament for treating cancer in a subject in need thereof, wherein the cancer in the subject is acute myeloid leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, triple-negative breast cancer, advanced breast cancer, metastatic breast cancer, or prostate cancer. In some embodiments, the 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 in question is prostate cancer.

[0133] In some embodiments, a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), 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.

[0134] In some embodiments, the one or more additional anticancer agents may include, but are not limited to, surgery, radiation, or chemotherapy. The chemotherapeutic agent may be an androgen receptor antagonist, a mitotic inhibitor, an antimetabolite, or a platinum-based agent. 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 therapy may include an anti-PDL1 agent, an anti-PD1 agent, or an anti-CTLA-4 agent. Anti-PD-L1 agents may include atezolizumab, avelumab, durvalumab, MPDL3280A (RG7446), MDX-1105 (BMS-936559) or BMS-935559, MSB0010718C, and MEDI4736. Anti-PD1 agents may include pembrolizumab, nivolumab, cemipimab, partalizumab (PDR001), camelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS001), dostarimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, or AMP-514 (MEDI0680). The anti-CTLA agent may include ipilimumab or tremelimumab.

[0135] Treatment methods combined with biomarkers Disclosed herein, in some embodiments, are methods for detecting the presence, absence, or level of a biomarker. 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 biological fluid, such as a blood sample. In some examples, the detection methods disclosed herein are useful for predicting, monitoring, and treating a subject with a therapy described herein (e.g., a PLK4 inhibitor) for a proliferative disorder or disease described herein. In some embodiments, the presence, absence, and / or level of expression 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). In some cases, 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 can undergo further analytic processing for sample dissociation, cell sorting, and enrichment of cell populations of interest.

[0136] 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. In some cases, the nucleic acid sequence comprises deoxyribonucleic acid (DNA), for example, when 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 the following: genomic DNA, viral DNA, mitochondrial DNA, plasmid DNA, amplified DNA, circular DNA, circulating DNA, cell-free DNA, or exosomal DNA. In some examples, the DNA is single-stranded DNA (ssDNA), double-stranded DNA, denatured double-stranded DNA, synthetic DNA, and combinations thereof. The circular DNA 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 examples, the nucleic acid sequence comprises an RNA molecule or a fragmented RNA molecule (RNA fragment) selected from microRNA (miRNA), pre-miRNA, pri-miRNA, mRNA, pre-mRNA, viral RNA, viroid RNA, virusoid RNA, circular RNA (circRNA), ribosomal RNA (rRNA), transfer RNA (tRNA), pre-tRNA, long non-coding RNA (lncRNA), small nuclear RNA (snRNA), circular RNA, cell-free RNA, exosomal RNA, vector-expressed RNA, RNA transcript, synthetic RNA, and combinations thereof.

[0137] In some embodiments, 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, SYBR Green I, SYBR Green II, SYBR Gold, ethidium bromide, methylene blue, pyronin Y, DAPI, acridine orange, Blue View, or phycoerythrin), which involves a nucleic acid amplification reaction with a specific primer pair and hybridization of the amplified nucleic acid probe containing a detectable moiety or molecule specific to 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, about 5 to about 15, about 5 to about 20, about 5 to about 25, about 5 to about 30, about 10 to about 15, about 10 to about 20, about 10 to about 25, about 10 to about 30, about 15 to about 20, about 15 to about 25, about 15 to about 30, about 20 to about 25, about 20 to about 30, or about 25 to about 30 cycles. For the TaqMan™ method, the probe may be a hydrolyzable probe containing a fluorophore and a quencher that is hydrolyzed by a DNA polymerase when hybridized to a target nucleic acid.In some cases, the presence of the target nucleic acid is determined when the number of amplification cycles to reach the threshold is less than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, or 20. In some examples, hybridization can occur in a standard PCR buffer at a standard hybridization temperature, for example, from about 35°C to about 65°C.

[0138] Further exemplary nucleic acid-based detection assays include the use of nucleic acid probes conjugated or otherwise immobilized on 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 polynucleotide sequence of the biomarker. In some examples, the biomarkers comprise transcribed polynucleotide sequences (e.g., RNA, cDNA). In some embodiments, the nucleic acid probes can be, for example, full-length cDNAs, or portions thereof, e.g., 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.

[0139] In some embodiments, the term "probe," with respect to nucleic acids, refers to any nucleic acid molecule capable of selectively binding to a specifically intended target nucleic acid sequence. In some cases, the probe is specifically designed to be labeled with, for example, a radioactive label, a fluorescent label, an enzyme, a chemiluminescent tag, a colorimetric tag, or other labels or tags known in the art. In some examples, the fluorescent label comprises a fluorophore. In some examples, the fluorophore is an aromatic or heteroaromatic compound. In some examples, the fluorophore is pyrene, anthracene, naphthalene, acridine, stilbene, benzoxazole, indole, benzoindole, oxazole, thiazole, benzothiazole, indole, 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 α or β 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).Exemplary coumarins include, for example, 3-phenyl-7-isocyanatocoumarin, acridines such as 9-isothiocyanatoacridine and acridine orange, N-(p-(2-benzoxazolyl)phenyl) Maleimides containing cyanines such as indodicarbocyanine 3 (Cy3), indodicarbocyanine 5 (Cy5), indodicarbocyanine 5.5 (Cy5.5), 3-(-carboxy-pentyl)-3'-ethyl-5,5'-dimethyloxacarbocyanine (CyA), 1H,5H,11H,15H-xantheno[2,3,4-ij:5,6,7-i'j']diquinolizin-18-ium,9-[2(or 4)-[[[6-[2,5-dioxo-1-pyrrolidinyl)oxy]-6-oxohexyl]amino]sulfonyl]-4(or 2)-sulfophenyl]-2,3,6,7,12,13,16,17-octahydro-inner salt (TR or Texas Red), or BODIPY™ dyes. In some cases, the probe includes FAM as a dye label.

[0140] 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 from a subject. Sequencing can be performed using any suitable sequencing technology, including, but not limited to, single-molecule real-time (SMRT) sequencing, polony sequencing, sequencing by ligation, reversible terminator sequencing, proton detection sequencing, ion semiconductor sequencing, nanopore sequencing, electronic sequencing, pyrosequencing, Maxam-Gilbert sequencing, chain termination (e.g., Sanger) sequencing, +S sequencing, or sequencing by synthesis. Sequencing methods also include modern sequencing technologies such as next-generation sequencing, e.g., Illumina sequencing (e.g., Solexa), Roche 454 sequencing, Ion torrent sequencing, and SOLiD sequencing. In some cases, next-generation sequencing includes high-throughput sequencing methods. Additional sequencing methods available to those of skill in the art can also be used.

[0141] 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.

[0142] Disclosed herein are methods including: (a) providing a sample obtained from a subject with a proliferative disease or condition (e.g., cancer); (b) assaying the sample obtained from the subject to detect 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. In some cases, hybridization assays such as those described herein are used to detect the biomarker in the sample. Exemplary probe sequences hybridizable to a target nucleic acid sequence (e.g., one or more genes in a biomarker, such as a PRS) include at least 10 and no more than 100 contiguous nucleotides that include the relevant sequence. In some cases, RNA sequencing (RNAseq) is used to detect one or more biomarkers.

[0143] Detection of related biomarkers in some cases involves amplification of the nucleic acid of interest by polymerase chain reaction (PCR). In some embodiments, the PCR assay involves the use of a primer pair capable of amplifying at least about 10 consecutive 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.

[0144] In some embodiments, assays for detecting the presence or absence of associated biomarkers involve reverse transcribing associated mRNA molecules to generate corresponding complementary DNA (cDNA) molecules. In some embodiments, the assay further involves contacting the cDNA molecules with a nucleic acid probe comprising a nucleic acid sequence complementary to the nucleic acid sequence of the cDNA molecules. In some embodiments, the assay involves detecting a double-stranded hybridization product between the nucleic acid probe and the cDNA molecules. In some embodiments, the hybridization product is further amplified using a primer pair. In some embodiments, the primers include a first primer having a nucleic acid sequence comprising at least 10 and no more than 50 contiguous nucleic acids within the associated nucleic acid sequence that binds to the top strand of the double-stranded hybridization product, and a second primer having a nucleic acid sequence comprising at least 10 and no more than 50 contiguous nucleic acids within the nucleic acid sequence that is reverse complementary to the associated nucleic acid sequence that binds to the bottom strand of the double-stranded hybridization product.

[0145] Disclosed herein, in some embodiments, is a method comprising preparing a complementary DNA (cDNA) library. In some embodiments, the cDNA library is sequenced using a suitable sequencing methodology 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 capable of hybridizing to at least about 10 consecutive nucleotides of two or more genes in a sample obtained from a subject. In some embodiments, detecting the presence or absence of a biomarker comprises detecting elevated or reduced levels of expression of two or more genes compared to a reference level.

[0146] In some embodiments, genetic material is extracted from a sample obtained from a subject, such as a blood or serum sample. In certain embodiments, 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 any other salt typically used to precipitate DNA. In certain embodiments, the technique utilizes a column- or resin-based nucleic acid purification scheme, such as those commonly available commercially; one non-limiting example would be 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 exemplary embodiments, nucleic acid material is extracted in water. In some cases, extraction does not include nucleic acid purification. In certain embodiments, RNA can be extracted from cells using RNA extraction techniques, including, for example, the use of acid phenol / guanidine isothiocyanate extraction (RNAzol B; Biogenesis), the RNeasy RNA preparation kit (Qiagen), or PAXgene (PreAnalytix, Switzerland).

[0147] 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 released into the bloodstream by tumors.

[0148] In some embodiments, detecting ctDNA or ctRNA is useful for detecting and diagnosing tumors, for example.Because tumor DNA and RNA acquire multiple gene mutations, which leads to tumor development, ctDNA and ctRNA are not perfectly identical to individual DNA and RNA, respectively.Discovering 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 are difficult to access, such as tumors in the brain or lung.

[0149] 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), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt thereof, is effective. In some embodiments, the absence of ctDNA or ctRNA in the bloodstream indicates that the cancer has not recurred after treatment with a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt thereof.

[0150] Described herein is a method for evaluating genetic alterations by ctDNA or ctRNA genomic profiling.In some embodiments, genomic profiling is performed after each treatment cycle with a compound of formula (I), formula (Ia), formula (Ib), formula (II), formula (III), formula (IV), formula (IVa), formula (IVb), formula (V), formula (Va), or formula (Vb), or a pharmaceutically acceptable salt thereof.In some embodiments, genetic mutation indicates that cancer will become resistant to treatment with a compound of formula (I), formula (Ia), formula (Ib), formula (II), formula (III), formula (IV), formula (IVa), formula (IVb), formula (V), formula (Va), or formula (Vb), or a pharmaceutically acceptable salt thereof. In some embodiments, the absence of a genetic mutation indicates that the cancer will not become resistant to treatment with a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt thereof.

[0151] A compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb) can be administered as a prodrug. Thus, certain derivatives of a compound that may have little or no pharmacological activity themselves can be converted, for example, by hydrolytic cleavage, when administered to a mammal into a compound with the desired activity. Such derivatives are referred to as "prodrugs." Prodrugs can be generated, for example, by replacing appropriate functional groups present in compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb) 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 entireties. Some examples of such prodrugs include an ester moiety in place of a carboxylic acid functional group, an ether or amide moiety in place of an alcohol functional group, and an amide moiety in place of a primary or secondary amino functional group. Examples of 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.

[0152] The salts of the present invention can be prepared according to 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, decanoate, dihydrogen phosphate, edetate, edisylate, estolate, esylate, ethylsuccinate, formate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycolylsanilate, heptanoate, hexyne-1,6-dioate, hexylresorcinol, hydrabamine, hydrobromide, hydrochloride, gamma-hydroxybutyrate, iodide, isobutyrate, Isothionate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, mesylate, metaphosphate, methanesulfonate, methylsulfate, monohydrogen phosphate, mucate, napsylate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phenyl Acetate, phenylbutyrate, phenylpropionate, phthalate, phosphate / diphosphate, polygalacturonate, propanesulfonate, propionate, propiolate, pyrophosphate, pyrosulfate, salicylate, stearate, subacetate, suberate, succinate, sulfate, sulfonate, sulfite, tannate, tartarate, thioclate, tosylate, triethoxycaprylate, and valerate.

[0153] The compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), which are basic in nature, 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, in practice it is often desirable to first isolate the compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt, then simply convert the latter back to the free base compound by treatment with an alkaline reagent, followed by converting 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 equal amount of a selected mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. The solvent is evaporated, yielding the desired solid salt. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding an appropriate mineral or organic acid to the solution.

[0154] Compounds of Formula (I), (Ia), (Ib), (II), (III), (IV), (IVa), (IVb), (V), (Va), or (Vb) that are acidic in nature can form base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly 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, they may be prepared by mixing lower alkanoic acid solutions of the acidic compounds with the desired alkali metal alkoxide, and then evaporating the resulting solution to dryness in the same manner as before. In either case, it is preferable to employ stoichiometric quantities of reagents to ensure completeness of reaction and maximum yields of the desired final product.

[0155] When the compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb) is a base, the desired salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidylic acid, e.g., glucuronic acid or galacturonic acid, an α-hydroxy acid, e.g., citric acid or tartaric acid, an amino acid, e.g., aspartic acid or glutamic acid, an aromatic acid, e.g., benzoic acid or cinnamic acid, a sulfonic acid, e.g., p-toluenesulfonic acid or ethanesulfonic acid.

[0156] When the compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb) is an acid, the desired salt can be prepared by any suitable method, for example, by 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. Examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, primary amines, secondary amines, and tertiary amines, and cyclic amines, such as piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0157] When a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb) is a solid, one of ordinary skill in the art will understand that the compound or a salt thereof may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and the particular formula.

[0158] Also provided herein are isotopically labeled compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), wherein one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in compounds of the invention include: 2 H and 3 Hydrogen such as H 11 C. 13 C and 14 Carbon, such as C, 36 chlorine such as Cl, 18 Fluorine such as F, 123 I and 125 Iodine, such as I 13 N and 15Nitrogen such as N 15 O. 17 O and 18 Oxygen, such as O 32 Phosphorus, such as P, 35 Certain isotopically labeled compounds of the present invention, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, 3 H, and carbon-14, 14 C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. 2 Substitution with heavier isotopes, such as H, may afford certain therapeutic advantages resulting from greater metabolic stability, such as 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.

[0159] Isotopically labeled compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb) can generally be prepared by conventional techniques known to those skilled in the art or by processes similar to those described herein, or by using a suitable isotopically labeled reagent in place of an otherwise used non-labeled reagent.

[0160] In one aspect, a composition of a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), 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 hard or soft gelatin capsule (see, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005))).

[0161] A compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, can be formulated into a pharmaceutical composition, as described below, in any pharmaceutical form recognizable as suitable by one of ordinary skill in the art. Pharmaceutical compositions of the present invention comprise a therapeutically effective amount of at least one compound of the present invention and an inert, pharmaceutically acceptable carrier or diluent.

[0162] The pharmaceutical carrier used can be either solid or liquid. Exemplary solid carriers include lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, etc. Exemplary liquid carriers are syrup, peanut oil, olive oil, water, etc. Similarly, the compositions of the present invention can contain time-delay or time-release materials known in the art, such as glyceryl monostearate or glyceryl distearate, alone or in combination with wax, ethylcellulose, hydroxypropylmethylcellulose, methyl methacrylate, etc. Additional additives or excipients can be added to achieve desired formulation properties. For example, bioavailability enhancers such as Labrasol™, Gelucire™, or compounding 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 ingredients from light, moisture and oxidation, can be added.

[0163] 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 or soft gelatin capsule. 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.

[0164] To obtain a stable water-soluble dosage form, a salt of a compound of the invention can 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 can be dissolved in a suitable cosolvent or 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 an exemplary embodiment, a compound of the invention is dissolved in DMSO and diluted with water. The composition can also be in the form of a solution of a salt form of the active ingredient in a suitable aqueous vehicle, such as water or isotonic saline or dextrose solution.

[0165] Appropriate formulation depends on the selected route of administration.For injection, the compound of the present invention can be formulated into aqueous solution, preferably in physiologically compatible buffer such as Hanks' solution, Ringer's solution or physiological saline buffer.For transmucosal administration, penetrants suitable for the barrier to be permeated are used in formulation.Such penetrants are generally known in the art.

[0166] For oral administration, compounds can be formulated by combining active compounds with pharmaceutically acceptable carriers known in the art. Such carriers allow the compounds of the present invention to be formulated as tablets, pills, sugar-coated tablets, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by the subject to be treated. Pharmaceutical preparations for oral use use solid excipients mixed with active ingredients (medicines), optionally milling the resulting mixture, and optionally adding suitable excipients, and then processing the granular mixture to obtain tablet cores or sugar-coated cores. Suitable excipients include fillers 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 crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0167] Sugar-coated cores are provided with suitable coatings.For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, polyvinylpyrrolidone, Carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.For identification or to characterize different combinations of active agents, dyes or pigments can be added to tablets or sugar-coated coatings.

[0168] Pharmaceutical preparations that can be used orally 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 in a mixture 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 ingredient can be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers can be added. All preparations for oral administration should be in dosages suitable for such administration. For buccal administration, the composition can be in the form of tablets or lozenges formulated in a conventional manner.

[0169] For intranasal administration or administration by inhalation, the compounds for use according to the present invention can be conveniently delivered in the form of aerosol spray presentation from a pressurized pack or nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of gelatin for use in inhalers or insufflators can be formulated to contain a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0170] The compound can be formulated for parenteral administration by injection, for example, bolus injection or continuous infusion.The preparation for injection can be provided in a unit-dosage form, for example, in ampoules or multi-dose containers, with preservatives added.The composition can take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and can contain formulating agents such as suspending agents, stabilizing agents, and / or dispersing agents.

[0171] Pharmaceutical preparations for parenteral administration include aqueous solutions of the active compound in water-soluble form. Additionally, suspensions of the active agent can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of the compound, allowing for the preparation of highly concentrated solutions.

[0172] Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.

[0173] 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, e.g., as sparingly soluble salts. Pharmaceutical carriers for hydrophobic compounds are co-solvent systems containing benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer, and an aqueous phase. The co-solvent system may be the VPD co-solvent 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 dissolved 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 itself produces low toxicity upon systemic administration. The proportions of the cosolvent system can be varied appropriately without compromising its solubility and toxicity characteristics. Furthermore, the identity of the cosolvent components can be varied; for example, other low-toxicity nonpolar surfactants can be substituted for polysorbate 80, the fraction size of polyethylene glycol can be varied, other biocompatible polymers can replace polyethylene glycol, e.g., polyvinylpyrrolidone, and other sugars or polysaccharides can be used in place of dextrose.

[0174] Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents, such as dimethyl sulfoxide (DMSO), can also be used, but are usually more toxic due to the toxicity of DMSO. In addition, compounds can 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. Depending on their chemical nature, sustained-release capsules can release compounds for several weeks to over 100 days. Depending on the chemical nature and biological stability of the therapeutic reagent, additional strategies for protein stabilization can be used.

[0175] The pharmaceutical composition may also contain suitable solid-phase 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. In addition, additives or excipients such as Gelucire™, Capryol™, Labrafil™, Labrasol™, Lauroglycol™, Plurol™, Peceol™, and Transcutol™ may also be used.

[0176] Additionally, the pharmaceutical composition may be incorporated into a skin patch for delivering the drug directly to the skin.

[0177] It will be understood that the actual dosage of the agent of the present invention will vary according to the specific agent used, the specific composition formulated, the mode of administration, and the specific site, host, and disease being treated. Those skilled in the art can determine the optimal dosage for a given set of conditions by considering the experimental data for a given compound and using conventional dosage-determining tests. For oral administration, an exemplary daily dosage generally employed is about 0.001 to about 1000 mg / kg body weight, with treatment courses being repeated at appropriate intervals.

[0178] 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, or about 10 mg to about 1500 mg, or about 10 mg to about 1000 mg, or about 10 mg to about 750 mg, or about 10 mg to about 500 mg, or about 25 mg to about 500 mg, or about 50 to about 500 mg, or about 100 mg to about 500 mg.

[0179] Additionally, 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%, or about 1 w / w% to about 95 w / w%, or about 1 w / w% to about 75 w / w%, or about 5 w / w% to about 75 w / w%, or about 10 w / w% to about 75 w / w%, or about 10 w / w% to about 50 w / w%.

[0180] The compounds of the invention, or salts or solvates thereof, may be administered alone or as part of a pharmaceutically acceptable formulation to a mammal, such as a human, suffering from abnormal cell proliferation once daily, twice daily, three times daily, or four times daily, or even more frequently.

[0181] Those skilled in the art will recognize that for a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a stereoisomer thereof, the particular pharmaceutical formulation, dosage, and number of doses given per day to a mammal in need of such treatment are all choices within the knowledge of one of ordinary skill in the art and can be determined without undue experimentation.

[0182] Dosages of the compositions described herein can be determined by any suitable method. The maximum tolerated doses (MTD) and maximum response doses (MRD) of a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, can be determined through established animal and human experimental protocols and in the Examples described herein. For example, the toxicity and therapeutic efficacy of a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, 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 between LD50 and ED50. Data obtained from cell culture assays and animal studies can be used in formulating a range of dosages for use in humans. The dosage of such compounds preferably lies within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage can vary within this range depending on the dosage form used and the route of administration utilized. Further relative doses, expressed as percent of maximum response or maximum tolerated dose, are readily obtained through the protocol.

[0183] In some embodiments, the amount of a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, including formulations corresponding to such amounts, 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 nevertheless be determined depending on the particular circumstances surrounding the case, including, for example, the particular agent being administered, the type of liquid formulation, the disease being treated, and the subject or host being treated.

[0184] In some embodiments, the compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in an amount of about 10 mg to 500 mg per day. In some embodiments, the compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 100 mg to about 400 mg per day. In some embodiments, the compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in an amount of about 150 mg to about 350 mg per day. In some embodiments, the compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in an amount of about 150 mg to about 300 mg per day. In some embodiments, the compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in an amount of about 160 mg to about 300 mg per day. In some embodiments, the compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in an amount of about 160 mg per day.In some embodiments, the compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in an amount of about 200 mg per day. In some embodiments, the compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in an amount of about 240 mg per day. In some embodiments, the compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in an amount of about 280 mg per day. In some embodiments, the compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in an amount of about 320 mg per day.

[0185] Generally, the 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 remissions, or increased 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 weight, weight, or blood volume. Generally, the 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 remissions, or increased 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 weight, weight, or blood volume.

[0186] In certain embodiments where the subject's condition does not improve, at the physician's discretion, administration of the compositions described herein is administered chronically, i.e., for an extended period of time, including for the duration of the subject's life, to improve or otherwise control or limit the symptoms of the subject's disease. In other embodiments, administration of the compositions continues until a complete or partial response of the disease.

[0187] In some embodiments, a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), 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), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), 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), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered three times daily to a subject in need thereof.

[0188] In some examples, the methods described herein include administering compositions and formulations comprising a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with one or more additional therapeutic agents to a subject or subjects in need thereof in multiple cycles repeated on a regular schedule with a rest period between each cycle. For example, in some examples, one treatment cycle is given for one week, followed by three weeks of rest.

[0189] The length of a treatment cycle depends on the treatment being given. In some embodiments, the length of a treatment cycle is 2-6 weeks. In some embodiments, the length of a treatment cycle is 3-6 weeks. In some embodiments, the length of a treatment cycle is 3-4 weeks. In some embodiments, the length of a treatment cycle is 3 weeks (or 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 week, 2 weeks, 3 weeks, 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 doses scheduled within each cycle also varies depending on the drug being administered.

[0190] Kits and Products In certain embodiments, the present specification discloses kits and products for use with one or more methods and compositions described herein.Such kits include a carrier, package, or container that is compartmentalized to receive one or more containers, such as vials, tubes, etc., and each of the containers contains one of the separate elements used in the methods described herein.Suitable containers include, for example, bottles, vials, syringes, and test tubes.In one embodiment, the container is made of various materials, such as glass or plastic.

[0191] Kits typically include a label listing the contents and / or instructions for use, as well as a package insert containing the instructions for use. A set of instructions is also typically included.

[0192] 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 etched into the container itself, and the label is associated with the container when it is present in a receptacle or carrier that holds the container, for example, 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 indicates instructions for using the contents, such as in the methods described herein.

[0193] In certain embodiments, the pharmaceutical compositions are provided in a pack or dispenser device containing one or more unit dosage forms containing a compound provided herein. The pack may, for example, comprise metal or plastic foil, such as a blister pack. In one embodiment, the pack or dispenser device is accompanied by instructions for administration. In one embodiment, the pack or dispenser also carries a notice associated with the container in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects approval by the agency of the drug form for human or veterinary administration. Such notice may, for example, be the labeling of a drug approved by the US Food and Drug Administration or an approved product insert. In one embodiment, compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated disease.

[0194] Preparation method Compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, can be prepared using readily available starting materials and techniques available in the art using the reaction routes and synthetic schemes described below. The preparation of specific embodiments of the present invention is described in detail in the Examples below, but those of skill in the art will recognize 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 by appropriately protecting interfering groups, by substituting other suitable reagents known in the art, or by routine modification of reaction conditions. Alternatively, other reactions mentioned herein or known in the art will be recognized as having suitability for preparing other compounds of the present invention.

[0195] A compound of formula (I), formula (Ia), formula (Ib), formula (II), formula (III), formula (IV), formula (IVa), formula (IVb), formula (V), formula (Va), or formula (Vb) can be prepared from a compound of formula (VI), wherein R 2 , R 3 , R 4a , R 4b , R 4c , R 5 , R 6 , R 7 , R 8a , R 8b , R 8c , R 8d , and R 9 by reacting a compound as described herein with a compound of formula (VII), wherein A, R 1 , R 9, and n are as defined herein, and LG is a leaving group. LG that can be used can include halogens such as chloro, bromo, and iodo. The reaction of a compound of formula (VI) with a compound of formula (VII) can be carried out using methods known to those skilled in the art. For example, the reaction of a compound of formula (VI) with a compound of formula (VII) can be carried out in an aprotic solvent such as acetonitrile, DMF, or a protic solvent such as water or an alcohol, or a mixture of a protic solvent and an aprotic solvent such as a mixture of acetonitrile and water, at a temperature ranging from 25°C to 200°C, in the presence of an acid or a base. The compound of formula (VI) can be prepared by the methods disclosed herein and / or methods known to those skilled in the art.

[0196] [ka]

[0197] Alternatively, a compound of formula (IV) can be prepared by reacting a compound of formula (VIII) with a compound of formula (IX), wherein R 3 , R 4 , R 4b is R 5 , R 6 , R 7 , R 8c , R 8b , R 8a , R 8d , R 9 is as defined herein, Hal is a halogen such as chlorine and bromine, A, R 1 , R 2 , R 9, and n are as defined herein. Such reactions can be carried out in the presence of a catalytic amount of a palladium-containing compound, such as palladium(0) bis(dibenzylideneacetone) (also known as Pd(dba)), 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. The reaction of a compound of formula (VIII) with a compound of formula (IX) 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 (IX) are commercially available or can be prepared by methods known to those skilled in the art or by methods similar to those described herein.

[0198] [ka]

[0199] The compound of formula (VIII) can be prepared by methods known to those skilled in the art. For example, the compound (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. Similarly, the compound tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-iodo-1H-indazol-6-yl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-carboxylate can be prepared according to the scheme described below. Other compounds of formula (VIII) can be prepared by methods known to those skilled in the art, or by modifications obvious to those skilled in the art, such as by using different starting materials, by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by routinely modifying the reaction conditions.

[0200] [ka]

[0201] 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 the presence of potassium carbonate in DMF and methanol, as described below.

[0202] [ka]

[0203] Compounds of formula (VI) may be prepared by methods known to those skilled in the art. For example, tert-butyl (1R,2S)-2-(3-amino-1-(tert-butoxycarbonyl)-1H-indazol-6-yl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-carboxylate can be prepared from (1R,2S)-2-(3-bromo-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one as described below.

[0204] [ka]

[0205] 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 (VI) as described herein, followed by deprotection of the Boc group using an acid such as trifluoroacetic acid, to provide a compound of the present disclosure. 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 provide (1R,2S)-5'-methoxy-2-(3-((5-methoxypyrimidin-4-yl)amino)-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-one.

[0206] [ka]

[0207] 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, "DMAP" means 4-(dimethylamino)pyridine, "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, and "NMP" means 1-methyl 2-pyrrolidinone, "TEA" means triethylamine, "TFA" means trifluoroacetic acid, "DCM" means dichloromethane, "EtOAc" and "EA" mean ethyl acetate, "MgSO4" means magnesium sulfate, "Na2SO4" means sodium sulfate, "MeOH" means methanol, "Et2O" means diethyl ether, "EtOH" means ethanol, "H2O" means water, "HCl" means hydrochloric acid, "K2CO3" means potassium carbonate, "THF" means tetrahydrofuran, "DBU" means methyl methacrylate ...MgSO4" means magnesium sulfate, "MgSO4" means magnesium sulfate, "MgSO4" means magnesium sulfate, "MgSO4" means magnesium sulfate, "MgSO4" means magnesium sulfate, "MgSO4" means magnesium sulfate, "MgSO4" means magnesium sulfate, "MgSO4" means magnesium sulfate, "MgSO4" means magnesium sulfate, "MgSO4" means magnesium sulfate, "MgSO4" means magnesium sulfate, "MgSO4" means magnesium sulfate, "MgSO4" means magnesium sulfate, "MgSO4" means magnesium sulfate, "MgSO4" means magnesium sulfate, 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 molar, "mL" means milliliter, "mmol" means millimoles, "μmol" means micromoles, and "eq." means equivalent, "°C" means degrees Celsius, "Pa" means pascals, "rt" or "RT" means room temperature, "h" means hours, "satd." means saturated, "aq." means aqueous, "anhyd." or "anh." means anhydrous, "MBTE" means methyl tert-butyl ether, "PE" means petroleum ether, and "TBSCl" means tert-butyldimethylsilyl chloride. [Example]

[0208] Intermediate 1. (1R,2S)-2-(3-amino-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one

[0209] [ka]

[0210] Step A. (E)-3-(3-Fluoro-4-isocyanobenzylidene)-5-methoxyindolin-2-one

[0211] [ka] 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]+ .

[0212] Step B. Racemic 2-fluoro-4-((1R,2S)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-2-yl)benzonitrile

[0213] [ka] To a solution of trimethylsulfoxonium iodide (4.20 g, 19.1 mmol) in anhydrous DMF (173 mL) under nitrogen was added sodium hydride (60% dispersion in oil) (81.5 mg, 2.04 mmol) at 0° C. After the mixture was stirred for 15 minutes, (£)-3-(3-fluoro-4-isocyanobenzylidene)-5-methoxyindolin-2-one (5.10 g, 17.3 mmol) was added to the solution and the reaction was stirred at room temperature for 1 hour. The solution was quenched with saturated aqueous ammonium chloride solution 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 experiment 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 eluted first under the given conditions. m / z (ESI, +ve ion) = 309.0 [M+H] +.1H NMR(400 MHz,CDCl3) δ 8.08(s,1H),7.52(dd,J=7.8,6.9 Hz,1H),7.21(s,1H),7.19(s,1H),6.78(d,J=1.5 Hz,2H),6.54 (s,1H),3.81(s,3H),3.07(t,J=8.7 Hz,1H),2.34(dd,J=8.5,5.3 Hz,1H),2.12(dd,J=8.9,5.3 Hz,1H).

[0214] Step C. (1R,2S)-2-(3-amino-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one

[0215] [ka] 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, followed by concentration. 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] + .

[0216] Intermediate 2. (1R,2S)-2-(1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one

[0217] [ka] Step A. 1-Benzyl-5-methoxyindoline-2,3-dione

[0218] [ka] 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 hours 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 (3×80 mL). The combined organic layers were washed with brine, then dried (NaSO), filtered, and concentrated. The resulting solid was triturated with heptane, filtered, and washed with heptane to give the title compound (18.2 g, quantitative yield) as a solid. m / z (ESI, +ve ion)=268.1 [M+H] + .1H NMR(400 MHz,CDCl3) δ 7.38-7.27(m,5H),7.15(d,J=2.7 Hz,1H),7.02(dd,J=8.6,2.7 Hz,1H),6.67(d,J=8.6 Hz,1H),4.90(s,2H),3.77(s,3H).

[0219] Step B. 1-Benzyl-5-methoxyindolin-2-one

[0220] [ka] 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 hours and then cooled to room temperature. The mixture was diluted with water (300 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with 1M H2SO4, brine (twice), then dried (Na2SO4), filtered, and concentrated to give the title compound (14.0 g, 81%) as a dark oil. m / z (ESI, +ve ion) = 254.1 [M+H] +.1H NMR(400 MHz,CDCl3) δ 7.38-7.22(m,5H),6.90-6.86(m,1H),6.68(dd,J=8.5,2.6 Hz,1H),6.60(d,J=8.5 Hz,1H),4.89(s,2H),3.75(s,3H),3.61(s,2H).

[0221] Step C. 1-Benzyl-6-bromo-1H-indazole

[0222] [ka] 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 (3×200 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 gently stirred at 150°C. After 6 hours, the benzyl bromide was removed by distillation at 130°C under high vacuum (vacuum pump). The residue was triturated in heptane, then filtered and washed with heptane. The crude material was placed under high vacuum overnight to give the compound (20.6 g, 67%) as a solid in the form of droplets. m / z (ESI, +ve ion) = 287.0 [M+H] + .

[0223] Step D. 1-Benzyl-6-vinyl-1H-indazole

[0224] [ka] 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 previously degassed (nitrogen-bubbled) DME / water (3:1) (70.0 mL) 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 (3x) 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 (3.80 g, 74%). m / z(ESI,+ve ion)=235.4[M+H] + . 1H NMR(400 MHz,CDCl3) δ 8.01(d,J=0.9 Hz,1H),7.73-7.64(m,1H),7.36-7.23(m,5H),7.23-7.16(m,2H),6.80(dd,J=17.6,10.9 Hz,1H),5.80(dd,J=17.5,0.7 Hz,1H),5.60(s,2H),5.30(dd,J=10.9,0.6 Hz,1H).

[0225] Step E. (S)-1-(1-benzyl-1H-indazol-6-yl)ethane-1,2-diol

[0226] [ka] To a 500 mL flask, AD-mix-α (83.7 g, 59.8 mmol) and t-BuOH / water (1:1) (598 mL) were added, and a clear biphasic mixture was formed with stirring. 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 vigorously stirred at 0 °C and allowed to warm to room temperature while the ice bath was slowly warmed. The reaction mixture was stirred for 9 hours. The reaction was quenched by the portionwise addition of 92 g of sodium sulfite. The reaction mixture was stirred overnight. The reaction mixture was diluted with brine and DCM and filtered through a pad of Celite. The filtrate was extracted with DCM (4x), 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.

[0227] Step F. (S)-1-(1-benzyl-1H-indazol-6-yl)ethane-1,2-diyl dimethanesulfonate

[0228] [ka] 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 rose to a maximum of 11° C. The resulting mixture was stirred at 0° C. After 6 hours, LCMS showed 10% monomesylated product. 0.400 mL of methanesulfonyl chloride and 0.600 mL of triethylamine 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). The solvent was removed to give a white solid. The solid was triturated in Et2O (40 mL), and the precipitate was collected by filtration to give the title compound (17.5 g, 91%) as a white crystalline solid. m / z (ESI, +ve ion) = 425.0 [M+H] + .1H NMR(400 MHz,CDCl3) δ 8.08(s,1H),7.81(d,J=8.3 Hz,1H),7.41(s,1H),7.35-7.27(m,3H),7.18(dd,J=17.3,7.5 Hz,3H),5.89(dd,J=8.6, 3.2 Hz,1H),5.66(d,J=15.8 Hz,1H),5.60(d,J=15.8 Hz,1H),4.53(dd,J=11.9,8.6 Hz,1H),4.40(dd,J=11.9,3.3 Hz,1H),3.05(s,3H),2.75(s,3H).

[0229] Step G. (1R,2S)-1'-benzyl-2-(1-benzyl-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one

[0230] [ka] Under nitrogen, 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. 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 HCl. The NH4Cl solution was diluted with water and extracted with EtOAc (3x). 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] + .

[0231] Step H. (1R,2S)-2-(1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one

[0232] [ka] To a round-bottom flask charged with a stir bar was added (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). The solution was cooled to 0 °C, and potassium tert-butoxide (23.0 mL, 165 mmol) was added portionwise 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 (1x) and extracted with EtOAc (2x). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product 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] + .

[0233] Intermediate 3a: (1R,2S)-2-(3-bromo-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one

[0234] [ka] 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 aqueous NaSO and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine, dried (NaSO), filtered, and concentrated. The crude product was purified by column chromatography (40–100% EtOAc / hexane, gradient elution) to afford the title compound (3.12 g, 65%). m / z(ESI,+ve ion)=384.0,386.0[M+H] + .

[0235] Intermediate 3b: (1R,2S)-2-(3-iodo-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one

[0236] [ka] 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 iodine (4.32 g, 17.0 mmol) dissolved in DMF (8 mL) was added dropwise and stirred at room temperature. After 4 hours, the reaction was complete. The mixture was quenched with Na2SO3 in water and stirred for 2 hours. The solid was collected by filtration and washed with water. The wet solid was frozen and lyophilized to give the title compound (4.4 g, 78% yield).

[0237] Intermediate 4a: Tert-butyl 3-bromo-6-((1R,2S)-1'-(tert-butoxycarbonyl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-2-yl)-1H-indazole-1-carboxylate

[0238] [ka] 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 hours. LCMS showed incomplete conversion. Di-tert-butyl dicarbonate (0.75 mL, 3.2 mmol, 0.5 equiv.) was added, and the reaction was stirred for an additional hour. 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] + .

[0239] Intermediate 4b: tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-iodo-1H-indazol-6-yl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-carboxylate

[0240] [ka] 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 / hexane, gradient elution) to give the product as a white foam (822 mg, 88%).

[0241] Intermediate 5: Tert-butyl 3-amino-6-((1R,2S)-1'-(tert-butoxycarbonyl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-2-yl)-1H-indazole-1-carboxylate

[0242] [ka]

[0243] 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

[0244] [ka] 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. Saturated aqueous NaHCO3 was added, and the reaction mixture was extracted with EtOAc (3 times). The combined extracts were then washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (0-30% EtOAc / heptane, gradient elution) to give the title compound (1.03 g, 88%) as a yellow oil. m / z (ESI, +ve ion) = 685.4 [M+H] + .

[0245] Step B. Tert-butyl 3-amino-6-((1R,2S)-1'-(tert-butoxycarbonyl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-2-yl)-1H-indazole-1-carboxylate

[0246] [ka] Hydroxylamine hydrochloride (101 mg, 1.46 mmol) and sodium acetate (120 mg, 1.46 mmol) were added to tert-butyl 6-((1R,2S)-1'-(tert-butoxycarbonyl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-2-yl)-3-((diphenylmethylene)amino)-1H-indazole-1-carboxylate (1.00 g, 1.46 mmol) in dry MeOH (14.6 mL) at room temperature, and the reaction was stirred for 16 hours. The solvent was removed under reduced pressure. The crude product was purified by column chromatography (0-60% EtOAc / heptane, gradient elution) to afford the title compound (640 mg, 84%) as a yellow solid. m / z (ESI, +ve ion) = 521.0 [M+H] + .1H NMR(400 MHz,CDCl3) δ8.06(s,1H),7.78(d,J=8.9 Hz,1H),7.41(d,J=8.2 Hz,1H),7.01(d,J=8.2 Hz,1H),6.66(dd,J=8.9,2.6 Hz,1H),5.55(d,J=2.3 Hz,1H),4.44(s,2H),3.49(t,J=8.6 Hz,1H),3.37(s,3H),2.34(dd,J=9.2,4.8 Hz,1H),2.14-2.06(m,1H),1.67(d,J=2.4 Hz,18H).

[0247] Example 2. (1R,2S)-2-{3-[4-(methanesulfonyl)-2-methoxyanilino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one

[0248] [ka]

[0249] Step A. Tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)-1H-indazol-6-yl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-carboxylate

[0250] [ka] To a 40 mL vial was added 4-methanesulfonyl-2-methoxyaniline (35.06 mg, 0.174 mmol, 1.1 equiv.), tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-iodo-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate (100 mg, 0.158 mmol, 1.00 equiv.), Pd(dba) (19 mg, 0.031 mmol, 0.2 equiv.), XantPhos (18 mg, 0.031 mmol, 0.2 equiv.), CsCO (103 mg, 0.316 mmol, 2 equiv.), and toluene (3 mL) at 25 °C. The resulting mixture was stirred at 90° C. under a nitrogen atmosphere for 2 hours. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1) to give the title compound (110 mg, 90%) as a light yellow solid. m / z (ESI, +ve ion)=705.30 [M+H] + .

[0251] Step B. (1R,2S)-2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]-1H-indazol-6-yl}-5'-methoxy-1'H-spiro[cyclopropane-1,3'-indol]-2'-one

[0252] [ka] To a 40 mL vial was added tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[(4-methanesulfonyl-2-methoxyphenyl)amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (110 mg, 0.156 mmol, 1 equiv.) and HFIP (10 mL) at 25° C. The resulting mixture was stirred at 60° C. for 12 hours. The mixture was concentrated, and the crude product was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 35% B to 45% B, 45% B in 10 min; wavelength: 254 nm; RT1 (min): 8.5 to give Example 2 (36.3 mg, 46.10%) as a white solid. m / z (ESI, +ve ion) = 505.15 [M+H] + . 1 H-NMR(400 MHz,DMSO-d6) δ 12.39(s,1H),10.43(s,1H),8.35(s,1H),8.09(d,J=8.5 Hz,1H),7.83(d,J=8.4 Hz,1H),7.50-7.34(m,3H),6.92(d,J=8.3 Hz,1H),6.76(d,J=8.4 Hz,1H),6.59(dd,J=8.4,2.6 Hz,1H),5.71(d,J=2.5 Hz,1H),4.01(s,3H),3.33(s,4H),3.16(s,3H), 2.39-2.29(m,1H),2.05-1.94(m,1H).

[0253] Example 4. (1R,2S)-5'-Methoxy-2-(3-{[3-methoxy-6-(1,3-oxazol-2-yl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one

[0254] [ka]

[0255] Step A. tert-Butyl N-(6-bromo-3-methoxypyridin-2-yl)-N-(tert-butoxycarbonyl)carbamate

[0256] [ka] To a solution of 6-bromo-3-methoxypyridin-2-amine (250 mg, 1.231 mmol, 1 equiv) in DCM (4 mL) was added TEA (1121.38 mg, 11.079 mmol, 9 equiv), DMAP (30.09 mg, 0.246 mmol, 0.2 equiv), and (Boc)2O (2015.46 mg, 9.232 mmol, 7.5 equiv). After stirring for 16 h at room temperature under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0–100% EtOAc in PE to afford the title compound (350 mg, 70.49%) as a yellow solid. m / z(ESI,+ve ion)=403.15,405.05[M+H] + .

[0257] Step B. tert-Butyl N-(tert-butoxycarbonyl)-N-[3-methoxy-6-(1,3-oxazol-2-yl)pyridin-2-yl]carbamate

[0258] [ka] To a solution of tert-butyl N-(6-bromo-3-methoxypyridin-2-yl)-N-(tert-butoxycarbonyl) carbamate (330 mg, 0.818 mmol, 1 equiv.) and oxazole (56.51 mg, 0.818 mmol, 1 equiv.) in toluene (5 mL) was added Pd(OAc) (18.37 mg, 0.082 mmol, 0.1 equiv.), PCy BF (60.27 mg, 0.164 mmol, 0.2 equiv.), CuI (171.43 mg, 0.900 mmol, 1.1 equiv.), pivalic acid (33.43 mg, 0.327 mmol, 0.4 equiv.), and KCO (339.28 mg, 2.454 mmol, 3 equiv.). After stirring at 110°C for 16 hours under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0-20% MeOH in DCM to give the title compound (240 mg, 59.94%) as a yellow solid. m / z (ESI, +ve ion) = 392.15 [M+H] + .

[0259] Step C. 3-Methoxy-6-(1,3-oxazol-2-yl)pyridin-2-amine

[0260] [ka] A solution of tert-butyl N-(tert-butoxycarbonyl)-N-[3-methoxy-6-(1,3-oxazol-2-yl)pyridin-2-yl]carbamate (230 mg, 0.588 mmol, 1 equiv.) in DCM (1.6 mL) and TFA (0.4 mL) was stirred at room temperature for 16 hours. The resulting mixture was concentrated under reduced pressure to give the title compound (85 mg, crude) as a yellow oil. m / z (ESI, +ve ion) = 192.10 [M+H] + .

[0261] Step D. tert-Butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[3-methoxy-6-(1,3-oxazol-2-yl)pyridin-2-yl]amino}indazol-6-yl]-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indole]-1'-carboxylate

[0262] [ka] To a solution of 3-methoxy-6-(1,3-oxazol-2-yl)pyridin-2-amine (54.50 mg, 0.285 mmol, 1.5 equiv.) and tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-iodo-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate (120 mg, 0.190 mmol, 1.00 equiv.) in toluene (1 mL) was added Pd(dba) (34.80 mg, 0.038 mmol, 0.2 equiv.), XantPhos (21.99 mg, 0.038 mmol, 0.2 equiv.), and CsCO (185.75 mg, 0.570 mmol, 3 equiv.). After stirring at 90° C. under nitrogen atmosphere for 1 hour, the resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with EtOAc / PE=2 / 1 to give the title compound (100 mg, 75.74%) as a yellow solid. m / z (ESI, +ve ion)=695.50 [M+H] + /

[0263] Step E. (1R,2S)-5'-Methoxy-2-(3-{[3-methoxy-6-(1,3-oxazol-2-yl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one

[0264] [ka] A solution of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[3-methoxy-6-(1,3-oxazol-2-yl)pyridin-2-yl]amino}indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate) (100 mg, 0.144 mmol, 1 equiv) in HFIP (1.5 mL) was stirred for 16 h at 60° C. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC under the following conditions: column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 31% B to 39% B, 39% B in 8 min; wavelength: 220 nm; RT1 (min): 7.92. The fractions were concentrated under reduced pressure and then lyophilized overnight to give Example 4 (30 mg, 42.15%) as a pale yellow solid. m / z (ESI, +ve ion) = 495.20 [M+H] + . 1 H-NMR(400 MHz,DMSO-d6) δ 12.46(s,1H),10.41(s,1H),8.45(s,1H),7.97(s,1H),7.81(d,J=8.4 Hz,1H),7.52(d,J=8.0 Hz,1H),7.39-7.32(m,2H),7.26(s,1H),6.87(d,J=8.5 Hz,1H),6.75(d,J=8.4 Hz,1H),6.59(dd,J=8.4,2.6 Hz,1H),5.74(d,J=2.5 Hz,1H),3.96(s,3H),3.30(s,3H),3.19(t,J=8.4 Hz,1H),2.32(dd,J=8.1,4.8 Hz,1H),1.99(dd,J=9.0,4.6 Hz,1H).

[0265] Example 5. (1R,2S)-2-{3-[4-(ethanesulfonyl)-2-methoxyanilino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one

[0266] [ka]

[0267] Step A. 4-(ethanesulfonyl)-2-methoxyaniline

[0268] [ka] To a stirred mixture of 4-bromo-2-methoxyaniline (200 mg, 0.990 mmol, 1 equiv.) and (2S,4R)-4-hydroxy-N-(2-methylnaphthalen-1-yl)pyrrolidine-2-carboxamide (25 mg, 0.092 mmol, 0.09 equiv.) in DMSO (5 mL), CuI (20 mg, 0.105 mmol, 0.11 equiv.), sodium ethanesulfinate (170 mg, 1.464 mmol, 1.48 equiv.), and KPO (210 mg, 0.989 mmol, 1.00 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 120° C. for 16 hours under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was diluted with water (10 mL). The mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (3×5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1) to give the title compound (140 mg, 65.70%) as a light yellow solid. m / z (ESI, +ve ion) = 216.05 [M+H] + .

[0269] Step B. tert-Butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[4-(ethanesulfonyl)-2-methoxyphenyl]amino}indazol-6-yl]-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indole]-1'-carboxylate

[0270] [ka] To a solution of 4-(ethanesulfonyl)-2-methoxyaniline (18 mg, 0.084 mmol, 1.06 equiv.) and tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-iodoindazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate) (50 mg, 0.079 mmol, 1.00 equiv.) in toluene (2 mL) was added CsCO (55 mg, 0.169 mmol, 2.13 equiv.), Pd(dba) (15 mg, 0.016 mmol, 0.21 equiv.), and XantPhos (10 mg, 0.017 mmol, 0.22 equiv.). After stirring at 90° C. for 2 hours under a nitrogen atmosphere, the mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1) to give the title compound (30 mg, 52.71%) as a light yellow solid. m / z (ESI, +ve ion)=719.25 [M+H] + .

[0271] Step C. (1R,2S)-2-{3-[4-(ethanesulfonyl)-2-methoxyanilino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one

[0272] [ka] To an 8 mL vial, tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[4-(ethanesulfonyl)-2-methoxyphenyl]amino}indazol-6-yl]-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indole]-1'-carboxylate (80 mg, 0.111 mmol, 1 equivalent) and HFIP (1 mL) were added at room temperature. The mixture was stirred at 60°C under a nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions: Column: XBridge Prep Phenyl OBD column, 19 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 32% B to 42% B, 42% B in 9 min; Wavelength: 254 nm; RT1 (min): 8) to give Example 5 (18.4 mg, 31.88%) as a white solid. m / z (ESI, +ve ion) = 519.20 [M+H] + . 1 H-NMR(400 MHz,Methanol-d4) δ 7.92(d,J=8.4 Hz,1H),7.67(d,J=8.3 Hz,1H),7.46-7.37(m,3H),6.95(d,J=8.4 Hz,1H),6.84(d,J=8.4 Hz,1H),6.63(dd,J=8.5,2.5 Hz,1H),5.62(d,J=2.6 Hz,1H),4.07(s,3H),3.38(d,J=8.6 Hz,1H),3.31(s,3H),3.20(q,J=7.4 Hz,2H),2.25-2.18(m,2H),1.25(t,J=7.4 Hz,3H).

[0273] Example 6. 6-Methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-1H-1-benzothiophene-1,1-dione

[0274] [ka]

[0275] Step A. Methyl 6-methoxy-5-nitro-1-benzothiophene-2-carboxylate

[0276] [ka] To a stirred mixture of 2-fluoro-4-methoxy-5-nitrobenzaldehyde (1200 mg, 6.026 mmol, 1 equiv.) and methylthioglycolate (767.52 mg, 7.231 mmol, 1.2 equiv.) in DMF (15 mL) was added K2CO3 (1665.65 mg, 12.052 mmol, 2 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (3 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (5 / 1) to give the title compound (850 mg, 52.78%) as a yellow solid. m / z(ESI,+ve ion)=268.10[M+H] + .

[0277] Step B. 6-Methoxy-5-nitro-1-benzothiophene-2-carboxylic acid

[0278] [ka] To a stirred mixture of methyl 6-methoxy-5-nitro-1-benzothiophene-2-carboxylate (800 mg, 2.993 mmol, 1 equiv.) in HO (5 mL) and MeOH (5 mL) was added NaOH (478.90 mg, 11.972 mmol, 4 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was basified to pH 7 with HCl (2 mol / L in water). The precipitated solid was collected by filtration and washed with water (3 × 10 mL). The residue was purified by silica gel column chromatography eluting with DCM / MeOH (10 / 1) to give the title compound (480 mg, 63.32%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.61(s,1H),8.59(s,1H),8.14(s,1H),8.06(s,1H),4.00(s,3H).

[0279] Step C. 6-Methoxy-5-nitro-1-benzothiophene

[0280] [ka] To a 40 mL vial, 6-methoxy-5-nitro-1-benzothiophene-2-carboxylic acid (300 mg, 1.185 mmol, 1 equiv.), Cu (75.28 mg, 1.185 mmol, 1 equiv.), and quinoline (5 mL) were added at room temperature. The resulting mixture was stirred at 170° C. under a nitrogen atmosphere for 2 hours. The mixture was cooled to room temperature. The mixture was acidified to pH 7 with HCl (2 mol / L). The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1) to give the title compound (210 mg, 84.72%) as a yellow solid. 1 H NMR(400 MHz,Chloroform-d) δ 8.32(s,1H),7.53(s,1H),7.45 (d,J=5.5 Hz,1H),7.35(d,J=5.5 Hz,1H),4.04(s,3H).

[0281] Step D. 6-Methoxy-5-nitrobenzo[b]thiophene 1,1-dioxide

[0282] [ka] A mixture of 6-methoxy-5-nitro-1-benzothiophene (280 mg, 1.338 mmol, 1 equiv.) and mCPBA (461.88 mg, 2.676 mmol, 2 equiv.) in DCM (8 mL) was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH 10 / 1) to give the title compound (290 mg, 89.83%) as a white solid. 1 H NMR(400 MHz,DMSO-d6) δ 8.14(s,1H),8.05(s,1H),7.63(dd,J=6.9,0.9 Hz,1H),7.45(d,J=6.9 Hz,1H),4.07(s,3H).

[0283] Step E. 5-Amino-6-methoxybenzo[b]thiophene 1,1-dioxide

[0284] [ka] To a stirred solution of 6-methoxy-5-nitrobenzo[b]thiophene 1,1-dioxide (100 mg, 0.415 mmol, 1 equiv.) and Fe (115.76 mg, 2.075 mmol, 5 equiv.) in EtOH (4 mL) and HO (1 mL), NH4Cl (110.87 mg, 2.075 mmol, 5 equiv.) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was filtered, and the filter cake was washed with EtOAc (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (10 / 1) to give the title compound (60 mg, 68%). m / z (ESI +ve ion) = 212.05 [M+H] + .

[0285] Step F. tert-Butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[(6-methoxy-1,1-dioxo)-1lambda 6-benzothiophen-5-yl)amino]indazol-6-yl]-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indole]-1'-carboxylate

[0286] [ka] 5-amino-6-methoxy-1lambda6-benzothiophene-1,1-dione (40.14 mg, 0.190 mmol, 1.2 equiv.) and tert-butyl 2-(2-amino-6-methoxy-1lambda6-benzothiophene-1,1-dione) in toluene (5 mL) To a stirred solution of (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-iodoindazol-6-yl]-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indole]-1'-carboxylate (100 mg, 0.16 mmol, 1.00 equiv.), Pd(dba) (29.00 mg, 0.032 mmol, 0.2 equiv.), XantPhos (18.33 mg, 0.032 mmol, 0.2 equiv.), and CsCO (103.19 mg, 0.316 mmol, 2 equiv.) was added under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The residue was purified by preparative TLC (PE / EtOAc=1 / 1) to give the title compound (95 mg, 83.93%) as a yellow solid. m / z (ESI, +ve ion)=715.25 [M+H] + .

[0287] Step G. 6-Methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-1H-1-benzothiophene-1,1-dione

[0288] [ka] To an 8 mL vial, tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[(6-methoxy-1,1-dioxo-1lambda6-benzothiophen-5-yl)amino]indazol-6-yl]-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indole]-1'-carboxylate (95 mg, 0.133 mmol, 1 equivalent) and HFIP (5 mL) were added at room temperature. The resulting mixture was stirred at 60°C under a nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD column, 19 × 250 mm, 10 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 35% B to 50% B, 50% B in 8 min; wavelength: 254 nm; RT1 (min): 7.8 to give Example 6 (30.5 mg, 44.38%) as a white solid. m / z (ESI, +ve ion) = 515.15 [M+H] + . 1 H-NMR(400 MHz,DMSO-d6) δ 12.38(s,1H),10.42(s,1H),8.34(s,1H),8.09(s,1H),7.84(d,J=8.4 Hz,1H),7.54-7.46(m,2H),7.37(s,1H),7.15(d,J=6.8Hz,1H),6.93(dd,J=8.4,1.4 Hz,1H),6.75(d,J=8.4 Hz,1H),6.59(dd,J=8.4,2.6 Hz,1H),5.70(d,J=2.6 Hz,1H),4.02(s,3H),3.30(s,3H),3.19(t,J=8.4 Hz,1H),2.33(dd,J=7.9,4.7 Hz,1H),1.99(dd,J=9.0,4.7 Hz,1H).

[0289] Example 14 (1R,2S)-5'-Methoxy-2-{3-[2-methoxy-5-(1,3-thiazol-2-yl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one

[0290] [ka] Step A. 5-Bromo-2-methoxyaniline

[0291] [ka] To a 50 mL round-bottom flask, 4-bromo-1-methoxy-2-nitrobenzene (2 g, 8.619 mmol, 1 equiv.), Fe (2.4 g, 42.976 mmol, 4.99 equiv.), NHCl (2.30 g, 43.009 mmol, 4.99 equiv.), EtOH (10 mL), and water (2.5 mL) were added at room temperature. The mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The resulting mixture was filtered, and the filter cake was washed with EtOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (10 / 1) to give the title compound (1.45 g, 83.26%) as a yellow solid. m / z (ESI, +ve ion) = 201.90, 203.90 [M+H] + .

[0292] Step B. 2-Methoxy-5-(1,3-thiazol-2-yl)aniline

[0293] [ka] To a stirred mixture of 5-bromo-2-methoxyaniline (200 mg, 0.990 mmol, 1.00 equiv.), Pd(dppf)Cl2·CHCl2 (81 mg, 0.099 mmol, 0.10 equiv.), CuI (100 mg, 0.525 mmol, 0.53 equiv.), and LiCl (90 mg, 2.123 mmol, 2.14 equiv.) in DMF (5 mL) was added 2-(tributylstannyl)-1,3-thiazole (380 mg, 1.016 mmol, 1.03 equiv.) at room temperature under a nitrogen atmosphere. The mixture was stirred at 100 °C for 2 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous NaSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1) to give the title compound (130 mg, 63.67%) as a light yellow solid. m / z (ESI, +ve ion) = 207.00 [M+H] + .

[0294] Step C. tert-Butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[2-methoxy-5-(1,3-thiazol-2-yl)phenyl]amino}indazol-6-yl]-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indole]-1'-carboxylate)

[0295] [ka] To a solution of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-iodoindazol-6-yl]-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indole]-1'-carboxylate) (100 mg, 0.158 mmol, 1 equiv.) and 2-methoxy-5-(1,3-thiazol-2-yl)aniline (40 mg, 0.194 mmol, 1.22 equiv.) in toluene (2.5 mL) was added CsCO (100 mg, 0.307 mmol, 1.94 equiv.), Pd(dba) (30 mg, 0.033 mmol, 0.21 equiv.), and XantPhos (20 mg, 0.035 mmol, 0.22 equiv.). The mixture was stirred at 90° C. under a nitrogen atmosphere for 2 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1) to give the title compound (80 mg, 71.17%) as a light yellow solid. m / z (ESI, +ve ion)=710.20 [M+H] + .

[0296] Step D. (1R,2S)-5'-Methoxy-2-{3-[2-methoxy-5-(1,3-thiazol-2-yl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one

[0297] [ka] To an 8 mL vial was added tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[2-methoxy-5-(1,3-thiazol-2-yl)phenyl]amino}indazol-6-yl]-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indole]-1'-carboxylate) (80 mg, 0.113 mmol, 1 equivalent) and HFIP (2 mL) at room temperature. The mixture was stirred at 60°C under a nitrogen atmosphere for 12 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: XSelect CSH Prep C18 OBD column, 19 × 250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeOH-HPLC; flow rate: 20 mL / min; gradient: 70% B to 75% B, 75% B in 8 min; wavelength: 254 nm; RT1 (min): 10) to give Example 14 (28.1 mg, 48.93%) as a white solid. m / z (ESI, +ve ion) = 510.15 [M+H] + . 1 H-NMR(300 MHz,DMSO-d6) δ 12.26(s,1H),10.44(s,1H), 8.82 (d,J=2.2 Hz,1H),7.95-7.81(m,3H),7.67(d,J=3.3 Hz,1H),7.43(dd,J=8.3,2.2 Hz,1H),7.35(s,1H),7.10(d,J=8.4 Hz,1H),6.94-6.85(m,1H),6.75(d,J=8.4 Hz,1H),6.59(dd,J=8.4,2.5 Hz,1H),5.71(d,J=2.5 Hz,1H),3.97(s,3H),3.32(s,3H),3.19(t,J=8.4 Hz,1H),2.35(dd,J=7.9,4.7 Hz,1H),1.98(dd,J=9.0,4.6 Hz,1H).

[0298] Example 15. (1R,2S)-5'-Methoxy-2-{3-[2-methoxy-5-(1,3-thiazol-4-yl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one

[0299] [ka] Step A. 2-Methoxy-5-(1,3-thiazol-4-yl)aniline

[0300] [ka] To a solution of 5-bromo-2-methoxyaniline (200 mg, 0.990 mmol, 1 equiv.) and 4-(tributylstannyl)-1,3-thiazole (400.00 mg, 1.069 mmol, 1.08 equiv.) in DMF (5 mL) was added LiCl (90 mg, 2.123 mmol, 2.14 equiv.), CuI (100 mg, 0.525 mmol, 0.53 equiv.), and Pd(PPh3)4 (125 mg, 0.108 mmol, 0.11 equiv.). The mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h. The mixture was cooled to room temperature. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (10 / 1) to give the title compound (90 mg, 44.08%) as a light brown solid. m / z (ESI, +ve ion) = 207.05 [M+H] + .

[0301] Step B. tert-Butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[2-methoxy-5-(1,3-thiazol-4-yl)phenyl]amino}indazol-6-yl]-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indole]-1'-carboxylate)

[0302] [ka] To a solution of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-iodoindazol-6-yl]-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indole]-1'-carboxylate) (100 mg, 0.16 mmol, 1 equiv.) and 2-methoxy-5-(1,3-thiazol-4-yl)aniline (50 mg, 0.242 mmol, 1.53 equiv.) in toluene (2.5 mL) was added CsCO (100 mg, 0.307 mmol, 1.94 equiv.), Pd(dba) (60 mg, 0.066 mmol, 0.41 equiv.), and XantPhos (40 mg, 0.069 mmol, 0.44 equiv.). The resulting mixture was stirred at 90° C. under a nitrogen atmosphere for 2 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1) to give the title compound (60 mg, 53.38%) as a light yellow solid. m / z (ESI, +ve ion)=710.35 [M+H] + .

[0303] Step C. (1R,2S)-5'-Methoxy-2-{3-[2-methoxy-5-(1,3-thiazol-4-yl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one

[0304] [ka] To an 8 mL vial was added tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[2-methoxy-5-(1,3-thiazol-4-yl)phenyl]amino}indazol-6-yl]-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indole]-1'-carboxylate (60 mg, 0.085 mmol, 1 equiv.), TFA (1 mL), and DCM (3 mL) at room temperature. The mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was azeotroped with toluene (3 x 5 mL). The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: XSelect CSH Prep C18 OBD column, 19 × 250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeOH-HPLC; flow rate: 20 mL / min; gradient: 70% B to 75% B, 75% B in 8 min; wavelength: 254 nm; RT1 (min): 8), to give Example 15 (21.1 mg, 48.99%) as a white solid. m / z (ESI, +ve ion) = 510.15 [M+H] + . 1 H-NMR(400 MHz,Methanol-d4) δ 9.00(d,J=2.0 Hz,1H),8.33(d,J=2.2 Hz,1H),7.66(d,J=8.2 Hz,1H),7.60(d,J=2.0 Hz,1H),7.47(dd,J=8.4,2.2 Hz,1H),7.39(s,1H),7.07(d,J=8.4 Hz,1H),6.91(d,J=8.5 Hz,1H),6.85(d,J=8.5 Hz,1H),6.64(dd,J=8.5,2.6 Hz,1H),5.63(d,J=2.5 Hz,1H),4.02(s,3H),3.38(d,J=8.5 Hz,1H),3.29(s,3H),2.28-2.16(m,2H).

[0305] Example 25: (1R,2S)-5'-Methoxy-2-{3-[(5-methoxy[2,5'-bipyrimidin]-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one

[0306] [ka] Step A: 5-Methoxy-2-pyrimidin-5-yl-pyrimidin-4-amine

[0307] [ka] To a mixture of 2-chloro-5-methoxy-4-pyrimidinamine (100 mg, 0.63 mmol), 5-pyrimidinylboronic acid (85 mg, 0.69 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)-phosphine)dichloropalladium (36 mg, 0.05 mmol), potassium acetate (123 mg, 1.25 mmol), and sodium carbonate (199 mg, 1.88 mmol), MeCN (3 mL) and water (1.5 mL) were added. Argon was bubbled through the reaction mixture, and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with DCM, filtered through Celite, eluting with DCM, and the filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography (0 to 100% acetone in hexanes) to give the product as a pale yellow solid (37.2 mg, 29%). m / z(ESI,+ve ion)=204.2[M+H] + .

[0308] Step B: Tert-butyl (1R,2S)-2-[1-tert-butoxycarbonyl-3-[(5-methoxy-2-pyrimidin-5-yl-pyrimidin-4-yl)amino]indazol-6-yl]-5'-methoxy-2'-oxo-spiro[cyclopropane-1,3'-indoline]-1'-carboxylate

[0309] [ka] To a vial was added tert-butyl (1R,2S)-2-(1-tert-butoxycarbonyl-3-iodo-indazol-6-yl)-5'-methoxy-2'-oxo-spiro[cyclopropane-1,3'-indoline]-1'-carboxylate (105 mg, 0.17 mmol), 5-methoxy-2-pyrimidin-5-yl-pyrimidin-4-amine (37 mg, 0.18 mmol), Xantphos Pd G4 (32 mg, 0.03 mmol), Xantphos (19 mg, 0.03 mmol), and cesium carbonate (217 mg, 0.67 mmol), followed by 1,4-dioxane (1.6 mL). Argon was bubbled through the solution for 3 min, and then the reaction mixture was heated to 100 °C for 2 h and then to 110 °C for an additional 2 h. The reaction mixture was diluted with DCM, filtered through Celite, eluted with DCM, and the filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography (0-100% acetone in hexanes) to give the product as a brown solid (7.2 mg, 6%) m / z (ESI, +ve ion) = 708.4 [M+H]. + .

[0310] Step C: (1R,2S)-5'-Methoxy-2-[3-[(5-methoxy-2-pyrimidin-5-yl-pyrimidin-4-yl)amino]-1H-indazol-6-yl]spiro[cyclopropane-1,3'-indolin]-2'-one

[0311] [ka] A solution of tert-butyl (1R,2S)-2-[1-tert-butoxycarbonyl-3-[(5-methoxy-2-pyrimidin-5-yl-pyrimidin-4-yl)amino]indazol-6-yl]-5'-methoxy-2'-oxo-spiro[cyclopropane-1,3'-indoline]-1'-carboxylate (7.2 mg, 0.01 mmol) in hexafluoroisopropanol (0.5 mL) was heated at 50 °C for 16 h. The reaction mixture was concentrated in vacuo, and the crude residue was purified by RP-HPLC using 10-90% ACN / water (10 mmol / L ammonium bicarbonate) to give the title compound as a beige lyophilized solid. m / z (ESI, +ve ion) = 507.2 [M+H] + .1H NMR(400 MHz,DMSO) δ 12.75(s,1H),10.42(s,1H),9.53(s,1H),9.20-9.09(m,3H),8.24(s,1H),7.52(d,J=8.4 Hz,1H),7.43(s,1H),6.94(d,J=8.4 Hz,1H),6.74(d,J=8.4 Hz,1H),6.58(dd,J=8.5,2.6 Hz,1H),5.68(d,J=2.6 Hz,1H),4.02(s,3H),3.28(s,3H),3.25-3.18(m,1H),2.34-2.27(m,1H),2.04-1.96(m,1H).

[0312] Example 28 (1R,2S)-2-(3-{[3-ethoxy-6-(1,3-thiazol-2-yl)pyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one

[0313] [ka] Step A. 6-Bromo-3-ethoxypyridin-2-amine

[0314] [ka] To a stirred mixture of 2-amino-6-bromopyridin-3-ol (300 mg, 1.59 mmol, 1.00 equiv.) and iodoethane (248 mg, 1.59 mmol, 1.00 equiv.) in acetone (5 mL), CsCO (1.03 g, 3.17 mmol, 2.00 equiv.) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 50° C. for 16 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1) to give the title compound (280 mg, 81.3%) as a white solid. m / z (ESI, +ve ion) = 217.15, 219.15 [M+H] + .

[0315] Step B. 3-Ethoxy-6-(thiazol-2-yl)pyridin-2-amine

[0316] [ka] To a stirred mixture of 6-bromo-3-ethoxypyridin-2-amine (250 mg, 1.15 mmol, 1.00 equiv.) and 2-(tributylstannyl)-1,3-thiazole (517 mg, 1.38 mmol, 1.20 equiv.) in DMF (5 mL), Pd(dppf)Cl·CHCl (93.8 mg, 0.115 mmol, 0.100 equiv.), CuI (110 mg, 0.576 mmol, 0.500 equiv.), and LiCl (97.6 mg, 2.30 mmol, 2.00 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1) to give the title compound (125 mg, 49.1%) as a white solid. m / z (ESI, +ve ion) = 222.05 [M+H] + .

[0317] Step C. Tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-((3-ethoxy-6-(thiazol-2-yl)pyridin-2-yl)amino)-1H-indazol-6-yl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-carboxylate

[0318] [ka] 3-Ethoxy-6-(1,3-thiazol-2-yl)pyridin-2-amine (42.1 mg, 0.190 mmol, 1.20 equiv) and tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-iodoindazol-6-yl]-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indole] in toluene (5 mL) To a stirred mixture of Pd(dba) (29.0 mg, 0.032 mmol, 0.20 equiv.), XantPhos (18.3 mg, 0.032 mmol, 0.200 equiv.), and CsCO (103 mg, 0.316 mmol, 2.00 equiv.) was added Pd(dba) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EtOAc 1 / 1) to give the title compound (79 mg, 69%) as a yellow solid. m / z (ESI, +ve ion) = 725.25 [M+H] + .

[0319] Step D. (1R,2S)-2-(3-((3-ethoxy-6-(thiazol-2-yl)pyridin-2-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one

[0320] [ka] To an 8 mL vial was added tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[3-ethoxy-6-(1,3-thiazol-2-yl)pyridin-2-yl]amino}indazol-6-yl]-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indole]-1'-carboxylate) (74 mg, 0.10 mmol, 1.0 equiv.) and HFIP (5 mL) at room temperature. The resulting mixture was stirred at 60°C under a nitrogen atmosphere for 16 hours. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 50% B, 50% B in 11 min; wavelength: 220 nm; RT1 (min): 9.20) to give Example 28 (14 mg, 25.8%) as a white solid. m / z (ESI, +ve ion) = 525.25 [M+H] + . 1 H-NMR(400 MHz,DMSO-d6) δ 12.50(s,1H),10.41(s,1H),8.49(s,1H),7.76(s,1H),7.53-7.47(m,2H),7.40(s,1H),7.33-7.32(m,2H),6.83-6.77(m,2H),6.66 -6.63(m,1H),5.74(s,1H),4.24-4.21(m,2H),3.30(s,3H),3.22-3.20(m,1H),2.32-2.31(m,1H),1.99-1.98(m,1H),1.45(t,J=7.2 Hz,3H).

[0321] Example 33 (1R,2S)-2-{3-[2-ethoxy-5-(1,3-thiazol-2-yl)anilino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one

[0322] [ka] Step A. 2-Ethoxy-5-(1,3-thiazol-2-yl)aniline

[0323] [ka] To a stirred solution of 5-bromo-2-ethoxyaniline (220 mg, 1.02 mmol, 1.00 equiv.), Pd(dppf)Cl2·CHCl2 (82.9 mg, 0.102 mmol, 0.100 equiv.), and 2-(tributylstannyl)-1,3-thiazole (571 mg, 1.53 mmol, 1.50 equiv.) in DMF (5 mL) was added CuI (97.0 mg, 0.509 mmol, 0.500 equiv.) and LiCl (86.3 mg, 2.04 mmol, 2.00 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched by the addition of water (5 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (3×30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1) to give the title compound (65 mg, 29%) as an off-white solid. m / z (ESI, +ve ion) = 221.10 [M+H] + .

[0324] Step B: Tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[2-ethoxy-5-(1,3-thiazol-2-yl)phenyl]amino}indazol-6-yl]-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indole]-1'-carboxylate

[0325] [ka] tert-Butyl in toluene (3 mL) To a stirred solution of (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-iodoindazol-6-yl]-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indole]-1'-carboxylate (100 mg, 0.158 mmol, 1.00 equiv.), CsCO (103 mg, 0.316 mmol, 2.00 equiv.), and 2-ethoxy-5-(1,3-thiazol-2-yl)aniline (52.3 mg, 0.237 mmol, 1.50 equiv.) under a nitrogen atmosphere at room temperature, XantPhos (18.3 mg, 0.032 mmol, 0.20 equiv.) and Pd(dba) (29.0 mg, 0.032 mmol, 0.20 equiv.) were added. The resulting mixture was stirred at 90° C. for 2 hours under a nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched at room temperature by the addition of water (5 mL). The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (2×20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1) to give the title compound (110 mg, 97%) as an off-white solid. m / z (ESI, +ve ion)=724.30 [M+H] + .

[0326] Step C. (1R,2S)-2-(3-{[2-ethoxy-5-(1,3-thiazol-2-yl)phenyl]amino}-1H-indazol-6-yl)-5'-methoxy-1'H-spiro[cyclopropane-1,3'-indol]-2'-one)

[0327] [ka] A solution of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[2-ethoxy-5-(1,3-thiazol-2-yl)phenyl]amino}indazol-6-yl]-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indole]-1'-carboxylate) (110 mg, 0.152 mmol, 1.00 equiv) in HFIP (3 mL) was stirred at 60° C. for 16 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (70 mg) was purified by preparative HPLC under the following conditions: (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 42% B to 52% B, 52% B in 11 min; Wavelength: 220 nm; RT1 (min): 10.23) to give Example 33 (22.2 mg, 27.5%) as an off-white solid. m / z (ESI, +ve ion) = 524.15 [M+H] + . 1 H-NMR(400 MHz,DMSO-d6) δ 12.27(s,1H),10.42(s,1H),8.75(d,J=2.0 Hz,1H),7.84(d,J=3.2 Hz,1H),7.80-7.71(m,2H),7.65(d,J=3.2 Hz,1H),7.49-7.41(m,1H),7.37(s,1H),7.09(d,J=8.4 Hz,1H),6.90(d,J=8.4 Hz,1H),6.76(d,J=8.4 Hz,1H),6.63-6.59(m,1H),5.70(d,J=2.4 Hz,1H),4.24(q,J=7.2 Hz,2H),3.32(s,3H),3.20(t,J=8.4 Hz,1H),2.39-2.33(m,1H),2.05-1.99(m,1H),1.47(t,J=6.8 Hz,3H).

[0328] Example 44 (1R,2S)-2-(3-{[5-ethoxy-2-(1,3-thiazol-2-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one

[0329] [ka] Step A. 4-Amino-2-chloropyrimidin-5-ol

[0330] [ka] To a 100 mL vial, 2-chloro-5-methoxypyrimidin-4-amine (500 mg, 3.13 mmol, 1.00 equiv.), BBr3 (7.8 mg, 31 mmol, 10 equiv.), and DCE (15 mL) were added at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The resulting mixture was concentrated under reduced pressure to give 4-amino-2-chloropyrimidin-5-ol (420 mg, 92%) as a yellow solid. The crude product was used directly in the next step without further purification. m / z (ESI, +ve ion) = 146.05 [M+H] + .

[0331] Step B. 2-Chloro-5-ethoxypyrimidin-4-amine

[0332] [ka] To an 8 mL vial, 4-amino-2-chloropyrimidin-5-ol (400 mg, 2.75 mmol, 1.00 equiv.), iodoethane (343 mg, 2.20 mmol, 0.800 equiv.), CsCO (2695 mg, 8.271 mmol, 3.01 equiv.), and acetone (10 mL) were added at room temperature. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 16 hours. The resulting mixture was extracted with EtOAc (5 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1) to give the title compound (230 mg, 48.2%) as a white solid.

[0333] Step C. 5-Ethoxy-2-(1,3-thiazol-2-yl)pyrimidin-4-amine

[0334] [ka] To a stirred mixture of 2-chloro-5-ethoxypyrimidin-4-amine (120 mg, 0.691 mmol, 1.00 equiv.) and 2-(tributylstannyl)-1,3-thiazole (388 mg, 1.04 mmol, 1.50 equiv.) in DMF (0.5 mL), Pd(dppf)Cl (101 mg, 0.138 mmol, 0.200 equiv.), CuI (66 mg, 0.35 mmol, 0.50 equiv.), and LiCl (58.60 mg, 1.382 mmol, 2 equiv.) were added at room temperature under an argon atmosphere. The resulting mixture was stirred at 110 °C for an additional 2 h. The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc) to give the title compound (65 mg, 42%) as a white solid. m / z (ESI, +ve ion) = 223.00 [M+H] + .

[0335] Step D. tert-Butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[5-ethoxy-2-(1,3-thiazol-2-yl)pyrimidin-4-yl]amino}indazol-6-yl]-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indole]-1'-carboxylate

[0336] [ka] 5-Ethoxy-2-(1,3-thiazol-2-yl)pyrimidin-4-amine (33.6 mg, 0.151 mmol, 1.20 equiv) and tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-iodoindazol-6-yl]-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indole] in toluene (4 mL) To a stirred mixture of ]-1'-carboxylate (79.5 mg, 0.126 mmol, 1.00 equiv.), Pd2(dba)3 (34.6 mg, 0.038 mmol, 0.30 equiv.), Xantphos (22.0 mg, 0.038 mmol, 0.300 equiv.), and Cs2CO3 (82.1 mg, 0.252 mmol, 2.00 equiv.) were added at room temperature under an argon atmosphere. The resulting mixture was stirred at 60 °C for an additional 2 h. The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl2 / MeOH 15 / 1) to afford the title compound (37 mg, 40%) as a white solid. m / z(ESI,+ve ion)=726.30[M+H] + .

[0337] Step E. (1R,2S)-2-(3-{[5-ethoxy-2-(1,3-thiazol-2-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxy-1'H-spiro[cyclopropane-1,3'-indol]-2'-one

[0338] [ka] To a stirred mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[5-ethoxy-2-(1,3-thiazol-2-yl)pyrimidin-4-yl]amino}indazol-6-yl]-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indole]-1'-carboxylate (35 mg, 0.048 mmol, 1.0 equiv.) in HFIP (2 mL) was added under an argon atmosphere at room temperature. The resulting mixture was stirred at 60°C for an additional 5 hours. The resulting mixture was concentrated under reduced pressure. The crude product (50 mg) was purified by preparative HPLC under the following conditions (Column: SunFire C18 OBD Prep Column 19 x 150 mm, 5 μm; Mobile phase A: Water (0.1% FA), Mobile phase B: ACN; Flow rate: 20 mL / min mL / min; Gradient: 30% B to 40% B in 9 min; Wavelength: 254 nm / 220 nm; RT1 (min): 4.92) to give Example 44 (16.2 mg, 62%) as a white solid. m / z (ESI, +ve ion) = 525.95 [M+H] + . 1 H NMR(300 MHz,Methanol-d4) δ 8.08(s,1H),7.81(dd,J=3.2,1.1 Hz,1H),7.64(d,J=8.5 Hz,1H),7.49(s,1H),7.36(dd,J=3.2,1.1 Hz,1H),6.88-6.84(m,2H),6.67-6.64(m,1H),5.70(d,J=2.5 Hz,1H),4.37-4.30(m,2H),3.38(d,J=8.5 Hz,1H),3.27(d,J=1.2 Hz,3H),2.29(dd,J=7.9,4.9 Hz,1H),2.18(dd,J=9.0,4.8 Hz,1H),1.55(t,J=9.2 Hz,3H).

[0339] The compounds in Table 1B were prepared using materials and methods similar to those disclosed herein, as well as methods known to those skilled in the art.

[0340] [Table 2-1]

[0341]

Table 2-2

[0342]

Table 2-3

[0343]

Table 2-4

[0344]

Table 2-5

[0345]

Table 2-6

[0346]

Table 2-7

[0347]

Table 2-8

[0348]

Table 2-9

[0349]

Table 2-10

[0350]

Table 2-11

[0351] [Table 2-12]

[0352] [Table 2-13]

[0353] Examples of biological activity Biological Activity Example 1: PLK4 Biochemical Assay The activity of human recombinant PLK4 (ThermoFisher, catalog no. PV6396) was measured by quantitation of adenosine diphosphate (ADP) using the ADP-Glo ​​Kinase Assay Kit (Promega, catalog no. V9102). Test compounds were solubilized in dimethyl sulfoxide (DMSO) and dispensed in duplicate into a 384-well white polystyrene non-binding plate (Greiner, catalog no. 781094) in an 11-point, 3-fold titration using an Echo acoustic dispenser (Labcyte Inc.). Five microliters of 1.0 nM PLK4 protein in assay buffer (50 mM HEPES, pH 7.5, 0.01% Brij-35, 0.01% BSA, 10 mM MgCl2, 1 mM EGTA, 1 mM DTT) was added to the plate. The test compound and PLK4 were incubated at room temperature (RT) for 15 minutes. Then, 5 μL of 16 μM adenosine triphosphate (ATP) (Promega, Catalog No. V915B) and 9.3 μM myelin basic protein (MBP) (SignalChem, Catalog No. M42-51N) substrate solution in assay buffer was added, and the reaction mixture was incubated at RT for 6 hours. The final concentrations of PLK4, ATP, and MBP in the reaction were 0.5 nM, 8.0 μM, and 4.7 μM, respectively. The reaction was stopped and the remaining ATP was depleted by adding 10 μL of ADP-Glo ​​reagent (Promega, Catalog No. V912B) and incubating at RT for 40 minutes. Concurrent conversion of remaining ADP to ATP and measurement of newly synthesized ATP was achieved by adding 20 μL of kinase detection reagent (Promega, catalog no. V914B), incubating at RT for 30 min, and luminescence detection using an EnVision plate reader (PerkinElmer). Reactions lacking PLK4 were used as a 100% inhibition control. Reactions containing only DMSO were used as a 0% inhibition control. IC reported in Table 2 50Values ​​were determined using a four parameter non-linear regression curve fit.

[0354] Biological Activity Example 2: CHP134 CellTiter-Glo (CTG) Assay CHP-134 cells (DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany) were cultured in RPMI 1640 supplemented with 10% fetal bovine serum, penicillin (100 U / ml), 1% L-glutamine, and streptomycin (100 mg / ml). Cells were seeded (200 cells / well) in 384-well plates for 16 h. On day 2, nine serial 1:3 compound dilutions were made in DMSO in 96-well plates. Compounds were then further diluted in growth medium using a BRAVO robot (Agilent, Santa Clara, CA). The diluted compounds were then added to quadruplicate wells of the 384-well cell plate and incubated at 37°C and 5% CO2. After 5 days, the relative number of viable cells was determined by luminescence using CellTiter-Glo® (Promega) according to the manufacturer's instructions and read on a SPARK Multimode Microplate Reader (Tecan, Mannedorf Switzerland). The IC values ​​are reported in Table 2. 50 Calculations were performed using Prism 6.0 software (GraphPad, San Diego).

[0355] Biological Activity Example 3: Aurora A Kinase Biochemical Assay The activity of human recombinant Aurora A (ThermoFisher, catalog no. PR5935A) was measured by quantification of adenosine diphosphate (ADP) using an ADP-Glo ​​Kinase Assay Kit (Promega, catalog no. V9102). Test compounds were solubilized in dimethyl sulfoxide (DMSO) and dispensed in duplicate in 11-point, 3-fold titrations into a 384-well white polystyrene non-binding plate (Greiner, catalog no. 781094) using an Echo acoustic dispenser (Labcyte Inc.). 5.0 nM Aurora A in 5 μL of assay buffer (50 mM HEPES, pH 7.5, 0.01% Brij-35, 0.01% BSA, 10 mM MgCl2, 1 mM EGTA, 1 mM DTT) was added to the plate. The test compounds and Aurora A were incubated at room temperature (RT) for 15 minutes. Five microliters of 40 μM adenosine triphosphate (ATP) (Promega, catalog number V915B) and 9.3 μM myelin basic protein (MBP) (SignalChem, catalog number M42-51N) substrate solution in assay buffer was then added, and the reaction mixture was incubated at room temperature for 2 hours. The final concentrations of Aurora A, ATP, and MBP in the reaction were 2.5 nM, 20 μM, and 4.7 μM, respectively. The reaction was stopped, and the remaining ATP was depleted by adding 10 μL of ADP-Glo ​​reagent (Promega, catalog number V912B) and incubating at room temperature for 40 minutes. Simultaneous conversion of the remaining ADP to ATP and measurement of newly synthesized ATP was achieved by adding 20 μL of kinase detection reagent (Promega, catalog number V914B), incubating at room temperature for 30 minutes, and detecting luminescence using an EnVision plate reader (PerkinElmer). Reactions lacking Aurora A were used as 100% inhibition controls. Reactions containing DMSO only were used as 0% inhibition controls. IC reported in Table 2 50 Values ​​were determined using four-parameter nonlinear regression curve fitting.

[0356] Biological Activity Example 4: Aurora B Kinase Biochemical Assay The activity of human recombinant Aurora B (ThermoFisher, catalog no. PR9210B) was measured by quantification of adenosine diphosphate (ADP) using an ADP-Glo ​​Kinase Assay Kit (Promega, catalog no. V9102). Test compounds were solubilized in dimethyl sulfoxide (DMSO) and dispensed in duplicate into a 384-well white polystyrene non-binding plate (Greiner, catalog no. 781094) in 11-point, 3-fold titrations using an Echo acoustic dispenser (Labcyte Inc.). 20 nM Aurora B in 5 μL of assay buffer (50 mM HEPES, pH 7.5, 0.01% Brij-35, 0.01% BSA, 10 mM MgCl2, 1 mM EGTA, 1 mM DTT) was added to the plate. The test compounds and Aurora B were incubated at room temperature (RT) for 15 minutes. 5 μL of 228 μM adenosine triphosphate (ATP) (Promega, catalog no. V915B) and 9.3 μM myelin basic protein (MBP) (SignalChem, catalog no. M42-51N) substrate solution in assay buffer was then added, and the reaction mixture was incubated at RT for 2 hours. The final concentrations of Aurora b, ATP, and MBP in the reaction were 10 nM, 114 μM, and 4.7 μM, respectively. The reaction was stopped, and the remaining ATP was depleted by adding 10 μL of ADP-Glo ​​reagent (Promega, catalog no. V912B) and incubating at RT for 40 minutes. Simultaneous conversion of remaining ADP to ATP and measurement of newly synthesized ATP was achieved by adding 20 μL of kinase detection reagent (Promega, catalog no. V914B), incubating at RT for 30 minutes, and detecting luminescence using an EnVision plate reader (PerkinElmer). Reactions lacking Aurora B were used as 100% inhibition controls. Reactions containing DMSO only were used as 0% inhibition controls. IC reported in Table 2 50 Values ​​were determined using four-parameter nonlinear regression curve fitting.

[0357] As shown in Table 2, many of the compounds of formulas (I), (Ia), (Ib), (II), and (III) exhibited potent inhibition of PLK4 and less potent inhibition of Aurora A kinase and Aurora B kinase. Thus, the compounds of formulas (I), (Ia), (Ib), (II), and (III) exhibited selective inhibition of PLK4. Also, as shown in Table 2, many of the compounds of formulas (I), (Ia), (Ib), (II), and (III) surprisingly and unexpectedly exhibited greater selectivity in inhibiting PLK4 relative to inhibiting Aurora A kinase and / or Aurora B kinase than the CFI-400495 compound. In Table 2, ND means not determined.

[0358] [Table 3-1]

[0359] [Table 3-2]

[0360] Embodiment Embodiment 1. Formula (IV)

[0361] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, Ring A is C6-C 10 is aryl or heteroaryl, Each R 1 are 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, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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 Alternatively, two R on adjacent atoms 1 Together, C3-C 10 cycloalkyl or heterocycloalkyl, each of which optionally contains one or more R 1b is replaced by Each R 1a are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NRc 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 1a together to form oxo, Each R 1b are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a, -NR b C(=O)OR 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 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; Each R 6 are 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 independently represents 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 9 optionally, one or more R 1a heteroaryl substituted with, or one or more R 1a is an oxetanyl substituted with Each R a are 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), where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 each aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R bare 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 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; and Each R c and R d are 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 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 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; Alternatively, R c and R d taken together with the atoms 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; However, the compound of formula (IV)

[0362] [ka] isn't it.

[0363] Embodiment 2. Ring A is C6-C 10 The compound of embodiment 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

[0364] Embodiment 3. The compound of embodiment 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is phenyl;

[0365] Embodiment 4. The compound of embodiment 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is heteroaryl.

[0366] Embodiment 5. The compound of embodiment 4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is furanyl, pyrrolyl, thiophenyl, oxazolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl.

[0367] Embodiment 6. The compound of embodiment 5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl.

[0368] Embodiment 7. The compound of embodiment 6, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is pyrazolyl, pyridinyl, pyrazinyl, or pyrimidinyl.

[0369] Embodiment 8. The compound of embodiment 7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is pyrazolyl.

[0370] Embodiment 9. The compound of embodiment 8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, or 5-pyrazolyl.

[0371] Embodiment 10. The compound of embodiment 9, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 1-pyrazolyl.

[0372] Embodiment 11. The compound of embodiment 9, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 3-pyrazolyl.

[0373] Embodiment 12. The compound of embodiment 9, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 4-pyrazolyl.

[0374] Embodiment 13. The compound of embodiment 9, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 5-pyrazolyl.

[0375] Embodiment 14. The compound of embodiment 7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is pyridinyl.

[0376] Embodiment 15. The compound of embodiment 14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 5-pyridinyl, or 6-pyridinyl.

[0377] Embodiment 16. The compound of embodiment 15, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 2-pyridinyl.

[0378] Embodiment 17. The compound of embodiment 15, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 3-pyridinyl.

[0379] Embodiment 18. The compound of embodiment 15, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 4-pyridinyl.

[0380] Embodiment 19. The compound of embodiment 15, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 5-pyridinyl.

[0381] Embodiment 20. The compound of embodiment 15, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 6-pyridinyl.

[0382] Embodiment 21. The compound of embodiment 7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is pyrazinyl.

[0383] Embodiment 22. The compound of embodiment 21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, or 6-pyrazinyl.

[0384] Embodiment 23. The compound of embodiment 22, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 2-pyrazinyl.

[0385] Embodiment 24. The compound of embodiment 22, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 3-pyrazinyl.

[0386] Embodiment 25. The compound of embodiment 22, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 5-pyrazinyl.

[0387] Embodiment 26. The compound of embodiment 22, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 6-pyrazinyl.

[0388] Embodiment 27. The compound of embodiment 7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is pyrimidinyl.

[0389] Embodiment 28. The compound of embodiment 27, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl.

[0390] Embodiment 29. The compound of embodiment 28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 2-pyrimidinyl.

[0391] Embodiment 30. The compound of embodiment 28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 4-pyrimidinyl.

[0392] Embodiment 31. The compound of embodiment 28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 5-pyrimidinyl.

[0393] Embodiment 32. The compound of embodiment 28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 6-pyrimidinyl.

[0394] Embodiment 33. The compound of embodiment 6, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is pyridazinyl.

[0395] Embodiment 34. The compound of embodiment 33, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, or 6-pyridazinyl.

[0396] Embodiment 35. The compound of embodiment 34, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 3-pyridazinyl.

[0397] Embodiment 36. The compound of embodiment 34, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 4-pyridazinyl.

[0398] Embodiment 37. The compound of embodiment 34, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 5-pyridazinyl.

[0399] Embodiment 38. The compound of embodiment 34, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 6-pyridazinyl.

[0400] Embodiment 39. The compound of any one of embodiments 1-38, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R1 is independently methyl, ethyl, trifluoromethyl, methoxy, ethoxy, methanesulfonyl, ethanesulfonyl, acetyl, or dimethylamino.

[0401] Embodiment 40. A compound according to any one of embodiments 1 to 39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 1, 2, or 3.

[0402] Embodiment 41. The compound of embodiment 40, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 1.

[0403] Embodiment 42. The compound of embodiment 40, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 2.

[0404] Embodiment 43. The compound of embodiment 40, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 3.

[0405] Embodiment 44.R 2 The compound of any one of embodiments 1-43, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen.

[0406] Embodiment 45.R 3 The compound of any one of embodiments 1-44, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen.

[0407] Embodiment 46.R 4a , R 4b and R 4cThe compound of any one of embodiments 1-45, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein is independently hydrogen or halogen.

[0408] Embodiment 47.R 4a is a halogen and R 4b and R 4c is hydrogen, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0409] Embodiment 48.R 4a and R 4c is hydrogen and R 4b The compound of embodiment 46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein is halogen.

[0410] Embodiment 49.R 4a and R 4b is hydrogen and R 4c The compound of embodiment 46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein is halogen.

[0411] Embodiment 50.R 4a and R 4b is a halogen and R 4c The compound of embodiment 46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: is hydrogen.

[0412] Embodiment 51.R 4a and R 4c is a halogen and R 4b The compound of embodiment 46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: is hydrogen.

[0413] Embodiment 52.R 4a , R 4b and R 4c The compound of embodiment 46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: is halogen.

[0414] Embodiment 53.R 4a , R 4b and R 4c is hydrogen, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0415] Embodiment 54.R 5 The compound of any one of embodiments 1-53, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen.

[0416] Embodiment 55. Each R 6 The compound of any one of embodiments 1-54, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen.

[0417] Embodiment 56.R 7 The compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen or C1-C6 alkyl.

[0418] Embodiment 57.R 7 The compound of embodiment 56, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: is hydrogen.

[0419] Embodiment 58.R 7 is C1-C6 alkyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0420] Embodiment 59.R 8a , R 8b , R 8c and R 8d each independently represents hydrogen, halogen, or -OR a 59. The compound of any one of embodiments 1-58, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

[0421] Embodiment 60.R 8a, R 8b , and R 8d is hydrogen, and R 8c is hydrogen, halogen, or -OR a 60. The compound of embodiment 59, wherein:

[0422] Embodiment 61.R 8c is halogen or -OR a 61. The compound of embodiment 60, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

[0423] Embodiment 62.R 8c The compound of embodiment 61, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein is halogen.

[0424] Embodiment 63.R 8c is fluoro, chloro, bromo, or iodo, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0425] Embodiment 64.R 8c HA-OR a 62. The compound of embodiment 61, wherein:

[0426] Embodiment 65.R a is C1-C6 alkyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0427] Embodiment 66.R a is —CH 3 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0428] Embodiment 67.R 9is furanyl, pyrrolyl, thiophenyl, oxazolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl or tetrazolyl, each of which may be selected from the group consisting of one or more R 1a 67. The compound of any one of embodiments 1-66, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, optionally substituted with:

[0429] Embodiment 68.R 9 optionally, one or more R 1a 68. The compound of embodiment 67, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is furanyl substituted with R.

[0430] Embodiment 69.R 9 optionally, one or more R 1a or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0431] Embodiment 70.R 9 optionally, one or more R 1a 68. The compound of embodiment 67, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is substituted with thiophenyl.

[0432] Embodiment 71.R 9 optionally, one or more R 1a 68. The compound of embodiment 67, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is 1 or 2; or R is 2 or 3; or R is 4 or 5;

[0433] Embodiment 72.R 9 optionally, one or more R 1a or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0434] Embodiment 73.R 9optionally, one or more R 1a 68. The compound of embodiment 67, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is substituted with thiazolyl;

[0435] Embodiment 74.R 9 optionally, one or more R 1a or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0436] Embodiment 75.R 9 optionally, one or more R 1a or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0437] Embodiment 76.R 9 optionally, one or more R 1a or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0438] Embodiment 77.R 9 optionally, one or more R 1a or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0439] Embodiment 78.R 9 optionally, one or more R 1a 68. The compound of embodiment 67, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is substituted pyridinyl with R 1 or R 2 .

[0440] Embodiment 79.R 9 optionally, one or more R 1a or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0441] Embodiment 80.R 9 optionally, one or more R 1a or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0442] Embodiment 81.R 9 optionally, one or more R 1a or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0443] Embodiment 82.R 9 optionally, one or more R 1a 68. The compound of embodiment 67, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is tetrazolyl substituted with R.

[0444] Embodiment 83.R 9 is one or more R 1a 67. The compound of any one of embodiments 1-66, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is oxetanyl substituted with

[0445] Embodiment 84. The compound of formula (IV) has the structure of formula (IVa):

[0446] [ka] 84. The compound of any one of embodiments 1-83, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having the formula:

[0447] Embodiment 85. The compound of formula (IV) has the formula (IVb)

[0448] [ka] 84. The compound of any one of embodiments 1-83, having the structure: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0449] Embodiment 86. Formula (V)

[0450] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, Ring A is C6-C 10 is aryl or heteroaryl, Each R 1 are 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...

Claims

1. Formula (IV) 【Chemical 1】 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, Ring A is C ６ -C １０ aryl, or heteroaryl; Each R １ are independently selected from deuterium, halogen, -CN, oxo, and -NO ２ , —OH, —OR ａ , —OC(═O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ａ , -NR ｂ S (= O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , -P(O)(R ａ ) ２ , -P(O) ２ (R ａ ) ２ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, —OC １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C １０ Cycloalkyl, heterocycloalkyl, C ６ -C １０ aryl, or heteroaryl; １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C １０ Cycloalkyl, heterocycloalkyl, C ６ -C １０ Each of the aryl and heteroaryl may optionally independently be one or more R １ａ is replaced by Alternatively, two R on adjacent atoms １ Together, C ３ -C １０ cycloalkyl or heterocycloalkyl, each of which optionally contains one or more R １ｂ is replaced by Each R １ａ are independently deuterium, halogen, -CN, -NO ２ , —OH, —OR ａ , —OC(═O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR 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 R on the same atom １ａ together to form oxo, Each R １ｂ are independently deuterium, halogen, -CN, -NO ２ , —OH, —OR ａ , —OC(═O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , N.R. 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 R on the same atom １ｂ together to form oxo, n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; R ２ But hydrogen, C １ -C ６ Alkyl, C １ -C ６ haloalkyl, or C １ -C ６ is a deuteroalkyl; R ３ But 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, Each R ６ are independently 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 ７ But 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 NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ａ , -NR ｂ S (= O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C １０ Cycloalkyl, heterocycloalkyl, C ６ -C １０ aryl, or heteroaryl; R ９ optionally, one or more R １ａ heteroaryl substituted with, or one or more R １ａ is an oxetanyl substituted with Each R ａ are independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C 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), C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C １０ Cycloalkyl, heterocycloalkyl, C ６ -C １０ Each aryl and heteroaryl independently optionally includes one or more of oxo, deuterium, halogen, —CN, —OH, —OCH ３ , —S(═O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ NH ２ , -S(=O) ２ NHCH ３ , -S(=O) ２ N (CH ３ ) ２ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , —C(═O)CH ３ , -C(=O)OH, -C(=O)OCH ３ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ aminoalkyl, or C １ -C ６ substituted with heteroalkyl; Each R ｂ are independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C 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), C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C １０ Cycloalkyl, heterocycloalkyl, C ６ -C １０ Each aryl and heteroaryl independently optionally includes one or more of oxo, deuterium, halogen, —CN, —OH, —OCH ３ , —S(═O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ NH ２ , -S(=O) ２ NHCH ３ , -S(=O) ２ N (CH ３ ) ２ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , —C(═O)CH ３ , -C(=O)OH, -C(=O)OCH ３ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ aminoalkyl, or C １ -C ６ substituted with heteroalkyl, and Each R ｃ and R ｄ are independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ 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), C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C １０ Cycloalkyl, heterocycloalkyl, C ６ -C １０ Each aryl and heteroaryl independently optionally includes one or more of oxo, deuterium, halogen, —CN, —OH, —OCH ３ , —S(═O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ NH ２ , -S(=O) ２ NHCH ３ , -S(=O) ２ N (CH ３ ) ２ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , —C(═O)CH ３ , -C(=O)OH, -C(=O)OCH ３ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ aminoalkyl, or C １ -C ６ substituted with heteroalkyl; Or, R ｃ and R ｄ together with the atoms to which they are attached, optionally one or more of oxo, deuterium, halogen, —CN, —OH, —OCH ３ , —S(═O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ NH ２ , -S(=O) ２ NHCH ３ , -S(=O) ２ N (CH ３ ) ２ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , —C(═O)CH ３ , -C(=O)OH, -C(=O)OCH ３ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ aminoalkyl, or C １ -C ６ Forming a heterocycloalkyl substituted with a heteroalkyl, provided that said compound of formula (IV) 【Chemistry 2】 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is not

2. Ring A is C ６ -C １０ 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

3. 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is heteroaryl.

4. 4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 1, 2, or 3.

5. R ２ is hydrogen, and R ３ The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen.

6. R ４ａ , R ４ｂ , and R ４ｃ 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen.

7. R ５ 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen.

8. Each R ６ 8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen.

9. R ７ 9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen.

10. R ８ａ , R ８ｂ , and R ８ｄ are hydrogen, and R ８ｃ is hydrogen, halogen, or -OR ａ 10. The compound of any one of claims 1 to 9, wherein:

11. R ８ｃ Ga-OR ａ and R ａ is C １ -C ６ 11. The compound of claim 10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R is alkyl.

12. or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, comprising 6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-2,3-dihydro-1H-1-benzothiophene-1,1-dione, (1R,2S)-2-{3-[4-(methanesulfonyl)-2-methoxyanilino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-yl]amino)-2,3-dihydro-1H-1-benzothiophene-1,1-dione, indol]-2'(1'H)-one, (1R,2S)-2-[3-(4-acetyl-2-methoxyanilino)-1H-indazol-6-yl]-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-6-(1,3-oxazol-2-yl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[4-(ethanesulfonyl -2-methoxyanilino]-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)-1H-1-benzothiophene-1,1-dione, (1R,2S)-2-{3-[2-ethoxy-4-(pyrazin-2-yl)anilino]-1H-indazol-6-yl}-5' -Methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[(3-ethoxyquinolin-2-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{4-[3-(dimethylamino)oxetan-3-yl]-2-methoxyanilino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[2-ethoxy-4-(1H-1,2,4-triazol-1-yl)anilino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, 7-ethoxy-6-((6-((1R,2S)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-2-yl)-1H-indazol-3-yl)amino)quinoline 1-oxide, (1R,2S)-5'-methoxy-2-{3-[2-methoxy-5-(1,3-oxazol-2-yl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[2-methoxy-5-(1,3-thiazol-2-yl)anilino]-1H- indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[2-methoxy-5-(1,3-thiazol-4-yl)anilino]-1H-in ... -{3-[2-methoxy-5-(1,3-oxazol-4-yl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[2-methoxy-4-(2-methyl-2H-tetrazol-5-yl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[2-methoxy-5-(1,3-oxazol-5-yl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-6-(1,3-oxazol-2-yl)pyrazin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[2-(dimethylamino)-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-[2-methoxy-5-(2-methyl-2H-tetrazol-5-yl)anilino]-1H- indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{5-[3-(dimethylamino)oxetan-3-yl]-2-methoxyanilino}-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'-methoxy-1'-methylspiro[cyclopropane-1,3'-indol] ]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[(5-methoxy[2,5'-bipyrimidin]-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[(5-methoxy[2,5'-bipyrimidin]-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy ci-2-(3-{[2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[3-ethoxy-6-(1,3-thiazol-2-yl)pyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[2-ethoxy-4-(1-methyl-1H-imidazol-4-yl)anilino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-{3-[2-methoxy-5-(1,2-thiazol-3-yl) anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[5-methoxy-2-(1-methyl-1H-pyrazol-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-[2-methoxy-5-(1,2-oxazol-3-yl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[2-ethoxy-5-(1,3-thiazol-2-yl)anilino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[5-ethoxy-2-(1,3-thiazol-2-yl)pyridin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]- 2'(1'H)-one, (1R,2S)-2-(3-{[3-ethoxy-6-(1,3-thiazol-2-yl)pyrazin-2-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-(3-methoxy-1-methyl-1H-pyrazol-4-yl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-{3-[2-ethoxy-5-(1-methyl-1H-pyrazol-4-yl)anilino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[3-ethoxy-5-(1H-1,2,4-triazol-1-yl)pyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2 S)-2-(3-{5-[1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]-2-methoxyanilino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[5-methoxy-2-(1,3-oxazol-5-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one , (1R,2S)-2-(3-{[2-ethoxy-5-(1,3-thiazol-2-yl)pyridin-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-5-(1,3-oxazol-4-yl)pyridin-3-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'-[(2H3)methyloxy]spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-2-(3-{[5-ethoxy-2-(1,3-thiazol-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-ethoxy-2-(3-hydroxy-3-methylbut-1-yn-1-yl)pyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one, (1R,2S)-2-(3-((5-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-2-methoxypyridin-3-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one, (1R,2S)-2-(3-((6-(1-(2,2-difluoroethyl)-1H-pyrazole, (1R)-2-(3-((2-ethoxy-5-(oxazol-4-yl)pyridin-3-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one, (1R,2S)-2-(3-((5-ethoxy-2-ethynylpyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one, (1R,2S)-2-(3-((5-ethoxy-2-ethynylpyrimidin-4-yl)amino)-1H-indazol-6-yl) (1R,2S)-2-(3-((2-ethoxy-5-(1H-imidazol-1-yl)pyridin-3-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one, (1R,2S)-2-(3-((2-ethoxy-5-(1H-imidazol-1-yl)pyridin-3-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one, (1R,2S)-5'-methoxy-2-(3-((1-methyl-1H-1,2,4-triazol-5-yl)amino)-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-one Indol]-2'-one, (1R,2S)-2-(3-{[6-(1H-imidazol-1-yl)-3-methoxypyrazin-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-(1H-pyrazol-1-yl)pyrazin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, 1R,2S) -5'-methoxy-2-(3-{[5-methoxy-2-(1,3-oxazol-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, 2-[4-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-5-methyl-1H-pyrazol-1-yl]-2-methylpropanenitrile, (1R,2S)-5'-methoxy-2-(3-{[3-methyl-1-(trifluoromethyl)-1H-pyrazol-5-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one, (1R,2S)-5'-methoxy-2-(3-{[2-methoxy-5-(morpholin-4-yl)pyridin-3-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one A compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of pan-1,3'-indol]-2'(1'H)-one, and 5-({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.

13. 13. A pharmaceutical composition comprising an amount of a compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and one or more pharmaceutically acceptable excipients.

14. 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 any one of claims 1 to 12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

15. 15. The method of claim 14, wherein the cancer is neuroblastoma, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, 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, carcinoma of the renal pelvis, central nervous system (CNS) neoplasm, primary CNS lymphoma, spinal axis tumor, brain stem glioma, or pituitary adenoma.

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