Polo-likinase 4 inhibitors

Abstract

Disclosed herein are compounds of Formula (IV) or pharmaceutically acceptable salts thereof that are Polo-like kinase 4 (PLK4) inhibitors. Also disclosed herein are pharmaceutical compositions comprising a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Further disclosed herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject an amount of a compound of Formula (IV) or a pharmaceutically acceptable salt thereof. # imgabs0 #

Description

[0001] Cross-reference

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 378,142, filed Oct. 3, 2022, and U.S. Provisional Application Serial No. 63 / 383,773, filed Nov. 15, 2022; they are hereby incorporated by reference in their entirety. BACKGROUND OF THE INVENTION

[0003] Polo-like kinases (PLKs) are a family of serine / threonine kinases that play key roles in cell cycle regulation and cellular responses to 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 via phosphorylation and interaction with centriolar proteins (Habedanck et al., 2005; Maniswami et al., 2018). Overexpression of PLK4 leads to centriole amplification and additional genomic instability and tumorigenesis (Holland et al., 2010). Aberrant PLK4 expression has been reported to be associated with several common human cancers (Marina and Saavedra, 2014; Shinmura et al., 2014). Thus, strong evidence supports a key role for PLK4 in carcinogenesis and therapeutic invention. Accordingly, there is a need for compounds that inhibit PLK4 in subjects with cancer to treat those cancers. SUMMARY OF THE INVENTION

[0004] In one embodiment, there is provided a compound of formula (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

[0005]

[0006] Wherein:

[0007] Ring A is C6-C 10 aryl or heteroaryl;

[0008] Each R 1 is independently deuterium, halogen, -CN, oxo, -NO2, -OH, -OR a 、-OC(=O)Ra 、 -OC(=O)OR b 、 -OC(=O)NR c R d 、 -SH, -SR a 、 -S(=O)R a 、 -S(=O)₂R a 、 -S(=O)₂NR c R d 、 -NR c R d 、 -NR b C(=O)NR c R d 、 -NR b C(=O)R a 、 -NR b C(=O)OR 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 deuterated alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ aminoalkyl, C₁-C₆ heteroalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C 10 cycloalkyl, heteroalkyl, C₆-C 10 aryl or heteroaryl; wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C 10 cycloalkyl, heteroalkyl, C₆-C 10 aryl and heteroaryl is optionally and independently substituted by one or more R 1a ;

[0009] Or two R on adjacent atoms are joined together to form a C₃-C 1 cycloalkyl or heteroalkyl; which is optionally substituted by one or more R 10 ; 1b ;

[0010] Each R 1a is independently deuterium, halogen, -CN, -NO₂, -OH, -OR a 、 -OC(=O)R a 、 -OC(=O)OR b 、 -OC(=O)NR c Rd 、 -SH, -SR a 、 -S(=O)R a 、 -S(=O)₂R a 、 -S(=O)₂NR c R d 、 -NR c R d 、 -NR b 、 -NR C(=O)NR c R d 、 -NR b 、 -NR C(=O)R a 、 -NR b 、 -NR C(=O)OR a 、 -NR b 、 -NR 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 deuterated alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ aminoalkyl, C₁-C₆ heteroalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C 10 cycloalkyl, heteroalkyl, C₆-C 10 aryl or heteroaryl;

[0011] Or two Rs on the same atom 1a combine together to form oxo;

[0012] Each R 1b independently is 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 、 -NR C(=O)NR c R d 、 -NR b 、 -NR C(=O)R a 、 -NR b 、 -NR 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl or heteroaryl;

[0013] or two Rs on the same atom 1b together form oxo;

[0014] n is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0015] R 2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl;

[0016] R 3 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl;

[0017] R 4a 、 R 4b and R 4c each of which 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0018] R 5 is hydrogen, deuterium, halogen, -CN, -OH, -OR a 、 -NR c R d 、 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0019] Each R 6 is independently hydrogen, deuterium, halogen, -CN, -OH, -OR a 、 -NRc R d is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0020] R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl or C1-C6 aminoalkyl;

[0021] R 8a , R 8b , R 8c and R 8d each independently is 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl or heteroaryl;

[0022] R 9 is a heteroaryl optionally substituted with one or more R 1a or an oxetanyl substituted with one or more R 1a ;

[0023] Each R a is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, 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); wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl and heteroaryl is independently optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0024] Each R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, 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); wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10Each of the aryl and heteroaryl is independently optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; and

[0025] each R c and R d is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, 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); wherein each of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl and heteroaryl is independently optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0026] or R c and R dTogether with the atoms to which they are attached to form a heterocycloalkyl group, which heterocycloalkyl group is optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0027] Provided that the compound of formula (IV) is not

[0028] In another embodiment, there is provided a compound of formula (IVa):

[0029]

[0030] In another embodiment, there is provided a compound of formula (IVB):

[0031]

[0032] In another embodiment, there is provided a compound of formula (V), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0033]

[0034] Wherein:

[0035] Ring A is a C6-C 10 aryl or heteroaryl;

[0036] Each R 1 is independently deuterium, halogen, -CN, oxo, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NRb C(=O)R a 、 -NR b C(=O)OR a 、 -NR b S(=O)₂R a 、 -C(=O)R a 、 -C(=O)OR b 、 -C(=O)NR c R d 、 -P(O)(R a )₂、 -P(O)₂(R a )₂、 C₁ - C₆ alkyl, C₁ - C₆ haloalkyl, -OC₁ - C₆ haloalkyl, C₁ - C₆ deuterated alkyl, C₁ - C₆ hydroxyalkyl, C₁ - C₆ aminoalkyl, C₁ - C₆ heteroalkyl, C₂ - C₆ alkenyl, C₂ - C₆ alkynyl, C₃ - C 10 cycloalkyl, heteroalkyl, C₆ - C 10 aryl or heteroaryl; wherein each of C₁ - C₆ alkyl, C₂ - C₆ alkenyl, C₂ - C₆ alkynyl, C₃ - C 10 cycloalkyl, heteroalkyl, C₆ - C 10 aryl and heteroaryl is optionally and independently substituted by one or more R 1a substituted;

[0037] Or two R on adjacent atoms are joined together to form a C₃ - C 1 cycloalkyl or heteroalkyl; which is optionally substituted by one or more R 10 substituted; 1b substituted;

[0038] Each R 1a is independently deuterium, halogen, -CN, -NO₂, -OH, -OR a 、 -OC(=O)R a 、 -OC(=O)OR b 、 -OC(=O)NR c R d 、 -SH, -SR a 、 -S(=O)R a 、 -S(=O)₂R a 、 -S(=O)₂NR c R d 、 -NR c R d 、 -NR b C(=O)NR c R d 、 -NR b C(=O)R a 、 -NR b C(=O)ORa 、 -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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl or heteroaryl;

[0039] Or two Rs on the same atom 1a together form oxo;

[0040] Each R 1b is independently deuterium, halogen, -CN, -NO2, -OH, -OR a 、 -OC(=O)R a 、 -OC(=O)OR b 、 -OC(=O)NR c R d 、 -SH, -SR a 、 -S(=O)R a 、 -S(=O)2R a 、 -S(=O)2NR c R d 、 -NR c R d 、 -NR b C(=O)NR c R d 、 -NR b C(=O)R a 、 -NR b C(=O)OR a 、 -NR b S(=O)2R a 、 -C(=O)R a 、 -C(=O)OR b 、 -C(=O)NR c R d 、 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl or heteroaryl;

[0041] or two Rs on the same atom 1b combine together to form oxo;

[0042] n is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0043] R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl or C1-C6 aminoalkyl;

[0044] R 8c is 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl or heteroaryl;

[0045] R 9 is optionally substituted by one or more Rs 1a substituted heteroaryl, or oxetanyl substituted by one or more Rs 1a ;

[0046] Each R aIndependently is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, 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); wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl and heteroaryl is independently optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0047] Each R b independently is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, 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); wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10Each of the aryl and heteroaryl is independently optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; and

[0048] each R c and R d is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, 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); wherein each of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl and heteroaryl is independently optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0049] or R c and R dTogether with the atoms to which they are attached to form a heterocycloalkyl group, which heterocycloalkyl group is optionally substituted by one or more of the following groups: 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0050] Provided that the compound of formula (V) is not

[0051] In another embodiment, there is provided a compound of formula (Va), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0052]

[0053] In another embodiment, there is provided a compound of formula (Vb), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0054]

[0055] 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.

[0056] The present invention also provides methods for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), 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, there are provided such methods for treating cancer, wherein the cancer of the subject expresses polo-like kinase 4 (PLK4). In further embodiments, there are provided such methods of treatment, wherein the cancer of the subject exhibits overexpression of E3 ubiquitin-protein ligase (TRIM37). In other embodiments, there are provided such methods for treating cancer, wherein the cancer of the subject exhibits overexpression of the gene encoding tripartite motif-containing protein 37 (TRIM37). In other embodiments, there are provided such methods for treating cancer, wherein prior to administering the compound to the subject, it has been determined that the cancer of the subject overexpresses the gene encoding tripartite motif-containing protein 37 (TRIM37).

[0057] In other embodiments, there are provided methods for treating cancer in a subject, comprising:

[0058] a. obtaining a biological sample of the cancer from the subject;

[0059] b. determining whether the biological sample of the cancer overexpresses the gene encoding tripartite motif-containing protein 37 (TRIM37); and

[0060] if it is determined that the biological sample of the cancer overexpresses the gene encoding tripartite motif-containing protein 37 (TRIM37), then 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.

[0061] In other embodiments, there are provided methods for inhibiting polo-like kinase 4 (PLK4) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), 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.

[0062] In other embodiments, there are provided 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, for use in a method of treating cancer in a subject in need thereof. In some embodiments, the cancer of the subject expresses polo-like kinase 4 (PLK4). In some embodiments, prior to administering the compound to the subject, it has been determined that the cancer of the subject expresses polo-like kinase 4 (PLK4). In some embodiments, the cancer of the subject exhibits overexpression of the gene encoding tripartite motif-containing protein 37 (TRIM37).

[0063] 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 of the subject expresses polo-like kinase 4 (PLK4). In some embodiments, the cancer of the subject exhibits overexpression of the E3 ubiquitin-protein ligase (TRIM37) protein. In some embodiments, the cancer of the subject exhibits amplification of the gene encoding tripartite motif-containing protein 37 (TRIM37).

[0064] Incorporated by reference

[0065] All publications, patents and patent applications mentioned in this specification are hereby incorporated by reference herein to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference. Detailed Description

[0066] As used in the specification and the appended claims, unless the context dictates otherwise, the following terms have the meanings indicated below.

[0067] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "a cell" includes reference to one or more cells (or a plurality of cells) and equivalents known to those of ordinary 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 the range, and specific embodiments therein, are intended to be included. The term "about," when referring to a number or numerical range, means that the number or numerical range so recited is an approximation within experimental variability (or within statistical experimental error), and thus in some instances the number or numerical range may vary between 1% and 15% of the recited number or numerical range. The term "comprising" (and related terms such as "having" or "including") is not intended to exclude the presence of other elements in other certain embodiments (e.g., embodiments of any substance composition, composition, method, or process described herein, etc.), "consisting of the recited features" or "consisting essentially of the recited features."

[0068] As used herein, the term "administer," when used in connection with a therapeutic means, means systemic or local administration of a therapeutic agent, such as directly into or onto a target tissue, or administration of a therapeutic agent to a subject, whereby the therapeutic agent has a positive effect on the tissue to which it is targeted. Thus, as used herein, the term "administer," when used in connection with the compositions described herein, can include, but is not limited to, providing the composition into or onto a target tissue; providing the composition systemically to a subject, such as by oral administration, whereby the therapeutic agent reaches the target tissue or cell. Administration of the composition can be accomplished by injection, topical application, and oral administration, or by other methods alone or in combination with other known techniques.

[0069] As used herein, the term "C2-C6 alkenyl" means an alkyl moiety containing from 2 to 6 carbon atoms and having at least one carbon-carbon double bond. The carbon-carbon double bond in such groups can be at any position along the 2- to 6-carbon atom chain that will result in a stable compound. Examples of such groups include, but are not limited to, vinyl, propenyl, butenyl, allyl, and pentenyl. The alkenyl can be in the cis or trans conformation with respect to the double bond and should be understood to include both isomers. Examples of alkenyl include, but are not limited to, vinyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, and the like. Whenever used herein, numerical ranges such as "C2-C6 alkenyl" mean that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkenyl" without a specified numerical range. In some embodiments, the alkenyl is C2-C 10Alkenyl, C2-C9 alkenyl, C2-C8 alkenyl, C2-C7 alkenyl, C2-C6 alkenyl, C2-C5 alkenyl, C2-C4 alkenyl, C2-C3 alkenyl or C2 alkenyl.

[0070] As used herein, the term "C1-C6 alkyl" refers to a straight or branched chain hydrocarbon monovalent group, which may be fully saturated or unsaturated and has one to six carbon atoms. Examples of saturated hydrocarbon monovalent groups 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, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl and hexyl. Whenever it appears herein, numerical ranges such as "C1-C6 alkyl" mean that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although this definition also covers the occurrence of the term "alkyl" without a specified numerical range.

[0071] As used herein, the term "C2-C6 alkynyl" means an alkyl moiety containing 2 to 6 carbon atoms and having at least one carbon-carbon triple bond. The carbon-carbon triple bond in such groups can be at any position along the 2 to 6 carbon chain that will result in a stable compound. Examples of such groups include, but are not limited to, acetylene, propyne, 1-butyne, 2-butyne, 1-pentyne, 2-pentyne, 1-hexyne, 2-hexyne and 3-hexyne, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. Whenever it appears herein, numerical ranges such as "C2-C6 alkynyl" mean 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 covers the occurrence of the term "alkynyl" without a specified numerical range.

[0072] As used herein, the term "C6-C 10 aryl" means a group derived from a hydrocarbon ring system containing hydrogen, 6 to 10 carbon atoms and at least one aromatic ring. The aryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic system, which can include a fused ring system (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or a bridged ring system. In some embodiments, the aryl is a 6 to 10 membered aryl. In some embodiments, the aryl is a 6 membered aryl. Aryl groups include, but are not limited to, those derived from anthracenylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, aryl groups of the hydrocarbon ring systems of fluoranthene, fluorene, asymmetric indacene, symmetric indacene, indane, indene, naphthalene, phenalene, phenanthrene, heptacene, pyrene, and 9,10-benzophenanthrene. In some embodiments, the aryl is phenyl.

[0073] As used herein, the term "C1-C6 aminoalkyl" refers to a C1-C6 alkyl group as defined above substituted with one or more amino groups. The amino groups in such C1-C6 aminoalkyl groups 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.

[0074] The term "C3-C 10 cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring containing 3 to 10 carbon atoms, which may include a fused ring system (when fused to an aryl or heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or a bridged ring system. In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decahydronaphthyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthalene, trans-decahydronaphthalene, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0075] As used herein, the term "C1-C6 deuterated alkyl" means a C1-C6 alkyl group as defined herein, wherein one or more hydrogen atoms in the C1-C6 alkyl group are replaced by deuterium atoms.

[0076] As used herein, the term "C1-C6 haloalkyl" refers to a C1-C6 alkyl as defined above substituted with one or more halo groups 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.

[0077] As used herein, the term "C1-C6 hydroxyalkyl" refers to a C1-C6 alkyl group as defined above substituted with one or more hydroxy groups.

[0078] As used herein, the term "animal" includes, but is not limited to, human and non-human vertebrates such as wild animals, domestic animals, and farm animals. As used herein, the terms "subject", "subject", and "individual" are intended to include living organisms in which certain conditions as described herein can occur. Examples include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats, and their transgenic species. In a preferred embodiment, the subject is a primate. In certain embodiments, the primate or subject is a human. In certain cases, the human is an adult. In certain cases, the human is a child. In other cases, the human is less than 12 years old. In certain cases, the human is an elderly person. In other cases, the human is 60 years old 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 disease, such as a transgenic mouse with a hypertension pathology.

[0079] As used herein, the term "Aurora kinase A" or "AurA" refers to the human protein that is known to those of ordinary skill in the art as Aurora kinase A and is encoded by the AURKA gene.

[0080] As used herein, the term "Aurora kinase B" or "AurB" refers to the human protein that is known to those of ordinary skill in the art as Aurora kinase B and is encoded by the AURKB gene.

[0081] "Cyano" refers to the -CN group.

[0082] As used herein, the term "halo" or "halogen" refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine.

[0083] As used herein, the term "heterocycloalkyl" refers to a 3- to 24-membered partially or fully saturated cyclic group containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from boron, nitrogen, oxygen, phosphorus, and sulfur. Unless specifically stated otherwise in the specification, a heterocycloalkyl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic system, which can include a fused ring system (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or a bridged ring system; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl group can be optionally oxidized; the nitrogen atom can be optionally quaternized. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. Examples of such heterocycloalkyl groups include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thieno[1,3]dithiolanyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidoneyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithiolanyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. It should be understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is different from the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the backbone atoms of the heterocycloalkyl ring).

[0084] As used herein, the term "C1-C6 heteroalkyl" means an alkyl group in which one or more of the backbone atoms of the alkyl are selected from atoms other than carbon, such as boron, oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or a combination 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, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or a combination thereof, and the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl.

[0085] As used herein, the term "heteroaryl" refers to a 5- to 14-membered ring system group that contains a hydrogen atom, one to thirteen carbon atoms, one to six heteroatoms selected from boron, nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. The heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic system, which can include a fused ring system (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or a bridged ring system; and the nitrogen, carbon, or sulfur atoms in the heteroaryl group can be optionally oxidized; 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 but are not limited to azido group, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxadienyl, chromenyl, chromenone, benzofuranyl, benzofuranone, benzothienyl (benzothienyl, benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanone, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazido group, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (thiophenyl, i.e., thienyl).

[0086] As used herein, "pharmaceutically acceptable" means that the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not harmful to its recipient.

[0087] The term "pharmaceutical composition" means a composition that contains at least one active ingredient, whereby the composition is adapted to study a specified effective result in a mammal (such as but not limited to a human). One of ordinary skill in the art will understand and recognize the techniques suitable for determining whether the active ingredient has the desired effective result based on the needs of the person skilled in the art.

[0088] As used herein, the term "pharmaceutically acceptable salt" means a salt of a compound of the invention that retains the biological effectiveness of the free acid and free base of the designated derivative and is not biologically or otherwise undesirable.

[0089] As used herein, the term "PLK4" means the human protein known to those of ordinary skill in the art as polo-like kinase 4 and encoded by the PLK4 gene.

[0090] As used herein, the term "oxo" refers to a carbonyl moiety, and thus an alkyl group substituted with oxo refers to a ketone group.

[0091] As used herein, the term "solvate" means a molecular complex between a compound of the invention and a solvent molecule. Examples of solvates include, but are not limited to, combinations of a compound of the invention with water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. When the solvent is water, the term "hydrate" may be used. It is specifically contemplated in the present invention that one solvent molecule may associate with one molecule of a compound of the invention, such as a hydrate. Additionally, it is specifically contemplated in the present invention that more than one solvent molecule may associate with one molecule of a compound of the invention, such as a dihydrate. Additionally, it is specifically contemplated in the present invention that less than one solvent molecule may associate with one molecule of a compound of the invention, such as a hemihydrate. Further, solvates of the compounds of the present invention are considered to be solvates of the compounds of the invention that retain the biological effectiveness of the non-solvated form of the compound.

[0092] In the case where a compound of the invention contains an alkenyl group, geometric cis / trans (or Z / E) isomers are possible. In the case where a compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism (tautomericisomerism, tautomerism) can occur. Examples of tautomeric isomerism include keto tautomers and enol tautomers. A single compound may exhibit more than one type of isomerism. Included within the scope of the present invention are all stereoisomers, geometric isomers, and tautomeric forms of the compounds of the invention, including compounds that exhibit 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 (e.g., chromatography and fractional crystallization).

[0093] The term "stereoisomer" refers to compounds that have the same chemical structure but differ in the arrangement of their atoms or groups in space. In particular, the term "enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other. As used herein, the term "racemic" or "racemic mixture" refers to a 1:1 mixture of the enantiomers of a particular compound. A racemic mixture in which the amount of one enantiomer present is greater than the amount of the other enantiomer in such a mixture can be described as "enantiomerically enriched". On the other hand, the term "diastereomer" 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 names in the art can be used to describe the stereoisomers of a compound, or the stereochemistry of a particular asymmetric carbon atom of a compound disclosed herein, or mixtures thereof. For example, an individual enantiomer or stereocenter of a compound can be described as having a (+), (-), (R) configuration or (S) configuration. A mixture of enantiomers can be described by using the symbol (±).

[0094] The compounds of the present invention may have asymmetric carbon atoms. The carbon-carbon bonds of the compounds of the present invention may be depicted herein by a solid line ( ) or a solid wedge ( ) or a dashed wedge ( ). The use of a solid line to depict a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers (e.g., a particular enantiomer, a racemic mixture, etc.) at that carbon atom are included. The use of a solid or dashed wedge to depict a bond to an asymmetric carbon atom is intended to indicate that only the depicted stereoisomer is intended to be included. It is possible that the compounds of the present invention may contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to depict a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers are intended to be included. For example, unless otherwise indicated, it is intended that the compounds of the present invention can exist in the form of enantiomers and diastereomers or racemates and mixtures thereof. The use of a solid line to depict 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 depict a bond to other asymmetric carbon atoms in the same compound is intended to indicate the presence of a mixture of diastereomers.

[0095] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of a racemate using, for example, chiral high performance liquid chromatography (HPLC). Alternatively, a racemate (or a racemic precursor) can be reacted with a suitable optically active compound such as an alcohol or, in the case where the compound contains an acidic or basic moiety, with an acid or a base such as tartaric acid or 1-phenylethylamine. The resulting mixture of diastereoisomers can be separated by chromatography and / or fractional crystallization, and one or both of the diastereoisomers can be converted to the corresponding pure enantiomers by methods well known to those skilled in the art. The chiral compounds (and their chiral precursors) of the present invention can be obtained in enantiomer-enriched form using chromatography (usually HPLC) on an asymmetric resin with a mobile phase consisting of a hydrocarbon (usually heptane or hexane) containing from 0 to 50% isopropanol (usually from 2% to 20%) and from 0 to 5% alkylamine (usually 0.1% diethylamine). Concentration of the eluate provides an enriched mixture. Stereoisomeric aggregates can be separated by conventional techniques known to those skilled in the art. See, for example, “Stereochemistry of Organic Compounds” by E L Eliel (Wiley, New York, 1994), the disclosure of which is incorporated herein by reference in its entirety.

[0096] As used herein, the term “substituted” means that the designated group or moiety bears one or more substituents. The term “unsubstituted” means that the designated group bears no substituents. The term “optionally substituted with...” means that the designated group is unsubstituted or substituted with one or more substituents. It should be understood that in the compounds of the present invention, when a group is referred to as “unsubstituted” or “substituted” with a group having fewer valences than would fill all the atoms of the compound, the remaining valences on such group are filled with hydrogen. For example, if a C6 aryl group, also referred to herein as “phenyl”, is substituted with an additional substituent, one of ordinary skill in the art will understand that such group leaves 4 open positions on the carbon atoms of the C6 aryl group (6 initial positions, minus one position bonded to the remainder of the compound of the present invention, minus the additional substituent, leaving 4). In such cases, each of the remaining 4 carbon atoms is bonded to a hydrogen atom to fill their valences. Similarly, if a C6 aryl group in a compound of the present invention is referred to as “disubstituted”, one of ordinary skill in the art will understand this to mean that the C6 aryl group has 3 remaining carbon atoms that are unsubstituted. Each of these three unsubstituted carbon atoms is bonded to a hydrogen atom to fill their valences.

[0097] According to the convention used in the art, the symbol

[0098]

[0099] In the structural formulas herein, bonds are used to depict points of attachment of moieties or substituents to a core or backbone structure. According to another convention, in some of the structural formulas herein, carbon atoms and the hydrogen atoms bonded to them are not explicitly depicted, for example

[0100]

[0101] represents a methyl group,

[0102]

[0103] represents an ethyl group, and

[0104]

[0105] represents a cyclopentyl group, etc.

[0106] If a moiety, such as for example (R 1 ) n is depicted as a "floating" ring A in the formula below:

[0107]

[0108] then, unless otherwise defined, the substituent R 1 can be located on any atom of the ring system, provided that the described, implied or explicitly defined hydrogen is replaced from one of the ring atoms, so long as a stable structure is formed. The ring system A can be, for example but not limited to, an aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, spiro or fused ring system.

[0109] If the moiety "R" is depicted as "floating" on the ring system A as shown above and ring A contains saturated carbons, then "n" can be greater than 1, provided that each replaces a currently described, implied or explicitly defined hydrogen on ring A; then, unless otherwise defined, two R 1 moieties can be located on the same carbon, in the case where a stable structure results. For example, when R 1 is a methyl group, geminal dimethyl can be present on a carbon of ring A. In another example, two R 1 , including the carbon, on the same carbon can form a ring, thereby giving rise to a spiro ring ("spiro moiety"). It should be understood that in 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), if n is less than the number of substitutable atoms on ring A, the other substitutable positions on ring A are bonded to hydrogen atoms.

[0110] As used herein, the term "therapeutic agent" means an agent used to treat, combat, alleviate, prevent, or improve an adverse condition or disease in a subject.

[0111] As used herein, "therapeutically effective amount" or "effective amount" refers to the amount of an active compound or pharmaceutical agent that elicits a biological or pharmaceutical response in a tissue, system, animal, individual, or human, which is sought by a researcher, veterinarian, physician, or other clinician, and which includes one or more of the following: (1) preventing a disease; e.g., preventing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder but has not yet experienced or displayed the pathology or symptomatology of the disease, (2) inhibiting a disease; e.g., inhibiting a disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition, or disorder (i.e., preventing further development of the pathology and / or symptomatology), and (3) alleviating a disease; e.g., alleviating a disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition, or disorder (i.e., reversing the pathology and / or symptomatology).

[0112] As used herein, the term "treatment" in some embodiments refers to therapeutic treatment and in other embodiments refers to prophylactic or preventive measures, where the aim is to prevent or slow down (alleviate) an adverse physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical outcome. For the purposes described herein, beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms; reduction in the degree of a condition, disorder, or disease; stabilization (i.e., non-worsening) of the state of a condition, disorder, or disease; delay in the onset or slowing of the progression of a condition, disorder, or disease; reduction in the state of a condition, disorder, or disease; and remission (partial or complete), whether detectable or not, or improvement or amelioration of a condition, disorder, or disease. Treatment includes eliciting a clinically significant response without an excessive level of side effects. Treatment also includes an extended survival period compared to the expected survival period if treatment is not received. The prophylactic benefits of treatment include preventing a condition, delaying the progression of a condition, stabilizing a condition, or reducing the likelihood of a condition occurring. As used herein, "treatment" in some embodiments includes prevention.

[0113] As used herein, the term "TRIM37" means the human protein known to those of ordinary skill in the art as tripartite motif-containing protein 37 (an E3 ubiquitin ligase encoded by the TRIM37 gene).

[0114] The term "CFI-400495" means the compound having Chemical Abstracts Service Registry Number 1338806-73-7 and having the structure shown below. The preparation of this compound is described in PCT Application Publication No. WO 2011 / 123946 and is commercially available.

[0115]

[0116] PLK4 inhibitor compounds

[0117] The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0118]

[0119] wherein:

[0120] Ring A is C6-C 10 aryl, heteroaryl, C3-C 10 cycloalkyl or heterocycloalkyl;

[0121] Each R 1 independently is deuterium, halogen, -CN, oxo, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b , -NR c R d , -NR b , -NR a , -NR b , -NR a , -NR b , -NR 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10An aryl or heteroaryl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 Each of the aryl and heteroaryl is optionally and independently substituted by one or more R 1a substituents;

[0122] Or two R on adjacent atoms 1 together form a C3-C 10 cycloalkyl or heterocycloalkyl; each of which is optionally substituted by one or more R 1b substituents;

[0123] Each R 1a independently is 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 deuterated alkyl, 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;

[0124] Or two R on the same atom 1a together form an oxo;

[0125] Each R 1bIndependently is 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 , -NR c C(=O)NR d , -NR b , -NR a , -NR b , -NR a , -NR b , -NR a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl or heteroaryl;

[0126] Or two Rs on the same atom 1b together form oxo;

[0127] n is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0128] R 2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl;

[0129] R 3 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl;

[0130] R 4a , R 4b and R 4c each of which independently is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -NR c Rd 、 -C(=O)R a 、 -C(=O)OR b 、 -C(=O)NR c R d 、 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0131] R 5 is hydrogen, deuterium, halogen, -CN, -OH, -OR a 、 -NR c R d 、 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0132] Each R 6 independently is hydrogen, deuterium, halogen, -CN, -OH, -OR a 、 -NR c R d 、 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0133] R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl or C1-C6 aminoalkyl;

[0134] R 8a 、 R 8b 、 R 8c and R 8d each of which independently is 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 、 -NRb 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl or heteroaryl;

[0135] Each R a independently is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl, heteroaryl, C1-C6 alkyl(C3-C 10 cycloalkyl), C1-C6 alkyl(heteroalkyl), C1-C6 alkyl(C6-C 10 aryl) or C1-C6 alkyl(heteroaryl); wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl and heteroaryl is independently optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0136] Each R b independently is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl, heteroaryl, C1-C6 alkyl(C3-C 10cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(C6-C 10 aryl) or C1-C6 alkyl(heteroaryl); wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl and heteroaryl is independently optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; and

[0137] each R c and R d is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, 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); wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl and heteroaryl is independently optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0138] or R c and R dTogether with the atoms to which they are attached to form a heterocycloalkyl group, which is optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl.

[0139] The present invention also provides a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0140]

[0141] Wherein:

[0142] Ring A is a C6-C 10 aryl, heteroaryl, C3-C 10 cycloalkyl or heterocycloalkyl;

[0143] Each R 1 independently is deuterium, halogen, -CN, oxo, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b , -NR c C(=O)NR d , -NR b C(=O)R a , -NR b , -NR a , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, -OC1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl or heteroaryl; wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl and heteroaryl is optionally and independently substituted with one or more R 1a substituents;

[0144] or two R on adjacent atoms are joined together to form a C3-C 1 cycloalkyl or heteroalkyl; each of which is optionally substituted with one or more R 10 substituents; 1b

[0145] Each R 1a is independently deuterium, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a -OC(=O)OR b -OC(=O)NR c R d -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR a -NR b S(=O)2R a -C(=O)R a -C(=O)OR b -C(=O)NR c R d -C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C​10 aryl or heteroaryl;

[0146] or two Rs on the same atom 1a taken together to form oxo;

[0147] each R 1b is independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR a , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, 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;

[0148] or two Rs on the same atom 1b taken together to form oxo;

[0149] n is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0150] R 2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl;

[0151] R 3 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl;

[0152] R 4a , R 4b and R 4c Each of which 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0153] R 5 It is hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0154] Each R 6 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0155] R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl or C1-C6 aminoalkyl;

[0156] R 8a , R 8b , R 8c and R 8d Each of which is independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NRc R d 、 -NR b C(=O)NR c R d 、 -NR b C(=O)R a 、 -NR b C(=O)OR a 、 -NR b S(=O)2R a 、 -C(=O)R a 、 -C(=O)OR b 、 -C(=O)NR c R d 、 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl or heteroaryl;

[0157] Each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl, heteroaryl, C1-C6 alkyl(C3-C 10 cycloalkyl), C1-C6 alkyl(heteroalkyl), C1-C6 alkyl(C6-C 10 aryl) or C1-C6 alkyl(heteroaryl); wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl and heteroaryl is independently optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0158] Each R bindependently is hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 deuterated alkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 aminoalkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C 10 cycloalkyl group, a heterocycloalkyl group, a C6-C 10 aryl group, a heteroaryl group, a C1-C6 alkyl group (C3-C 10 cycloalkyl group), a C1-C6 alkyl group (heterocycloalkyl group), a C1-C6 alkyl group (C6-C 10 aryl group) or a C1-C6 alkyl group (heteroaryl group); wherein each of the C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C3-C 10 cycloalkyl group, heterocycloalkyl group, C6-C 10 aryl group and heteroaryl group is independently optionally substituted by 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, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 deuterated alkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 aminoalkyl group or a C1-C6 heteroalkyl group; and

[0159] each R c and R d independently is hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 deuterated alkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 aminoalkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C 10 cycloalkyl group, heterocycloalkyl group, C6-C 10 aryl group, heteroaryl group, a C1-C6 alkyl group (C3-C 10 cycloalkyl group), a C1-C6 alkyl group (heterocycloalkyl group), a C1-C6 alkyl group (C6-C 10 aryl group) or a C1-C6 alkyl group (heteroaryl group); wherein each of the C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C3-C 10 cycloalkyl group, heterocycloalkyl group, C6-C 10Each of aryl and heteroaryl is independently optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0160] Or R c and R d together with the atom to which they are attached form a heterocycloalkyl, which is optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl.

[0161] The present invention further provides a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0162]

[0163] Wherein:

[0164] Ring A is C6-C 10 aryl, heteroaryl, C3-C 10 cycloalkyl or heterocycloalkyl;

[0165] Each R 1 independently is deuterium, halogen, -CN, oxo, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -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, -OC1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl or heteroaryl; wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl and heteroaryl is optionally and independently substituted by one or more R 1a ;

[0166] Or two R on adjacent atoms 1 combine together to form C3-C 10 cycloalkyl or heteroalkyl; each of which is optionally substituted by one or more R 1b ;

[0167] Each R 1a is independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NRb 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl or heteroaryl;

[0168] Or two Rs on the same atom 1a combine together to form oxo;

[0169] Each R 1b is independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR a , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl or heteroaryl;

[0170] or two Rs on the same atom 1b combine together to form an oxo group;

[0171] n is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0172] R 2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl;

[0173] R 3 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl;

[0174] R 4a , R 4b and R 4c each 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0175] R 5 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0176] each R 6 is independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0177] R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl or C1-C6 aminoalkyl;

[0178] R 8a , R 8b , R 8cand R 8d each of which is independently hydrogen, deuterium, a 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl or heteroaryl;

[0179] each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl, heteroaryl, C1-C6 alkyl(C3-C 10 cycloalkyl), C1-C6 alkyl(heteroalkyl), C1-C6 alkyl(C6-C 10 aryl) or C1-C6 alkyl(heteroaryl); wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10Each of the aryl and heteroaryl is independently optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0180] Each R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, 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); wherein each of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl and heteroaryl is independently optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; and

[0181] Each R c and R d are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, heteroaryl, C1-C6 alkyl(C3-C 10 cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(C6-C10 (aryl) or C1-C6 alkyl (heteroaryl); wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 Each of aryl and heteroaryl is independently optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0182] Or R c and R d together with the atom to which they are attached form a heterocycloalkyl, which heterocycloalkyl is optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl.

[0183] The present invention also provides a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0184]

[0185] Wherein:

[0186] Ring A is C6-C 10 aryl or heteroaryl, C3-C 10 cycloalkyl and heterocycloalkyl;

[0187] Each R 1 is 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; wherein C1-C6 alkyl, C3-C10 Each of cycloalkyl, heterocycloalkyl, C6-C 10 aryl, and heteroaryl is optionally and independently substituted with one or more R 1a substituents;

[0188] Each R 1a is independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b , -NR c C(=O)NR 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 deuterated alkyl, 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;

[0189] n is 1, 2, 3, 4, 5, 6, 7, or 8;

[0190] R 2 is hydrogen or C1-C6 alkyl;

[0191] R 3 is hydrogen or C1-C6 alkyl;

[0192] R 4a , R 4b , and R 4c are each independently hydrogen, deuterium, or halogen;

[0193] R7 is hydrogen or a C1-C6 alkyl group;

[0194] R 8a 、R 8b 、R 8c and R 8d each independently is hydrogen, deuterium, a halogen, or -OR a ;

[0195] Each R a independently is a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 deuterated alkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 aminoalkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C 10 cycloalkyl group, a heterocycloalkyl group, a C6-C 10 aryl group, a heteroaryl group, a C1-C6 alkyl group(C3-C 10 cycloalkyl group), a C1-C6 alkyl group(heterocycloalkyl group), a C1-C6 alkyl group(C6-C 10 aryl group) or a C1-C6 alkyl group(heteroaryl group); wherein each of the C1-C6 alkyl group, the C2-C6 alkenyl group, the C2-C6 alkynyl group, the C3-C 10 cycloalkyl group, the heterocycloalkyl group, the C6-C 10 aryl group and the heteroaryl group is independently optionally substituted by 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, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 deuterated alkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 aminoalkyl group or a C1-C6 heteroalkyl group;

[0196] Each R b independently is hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 deuterated alkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 aminoalkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C 10 cycloalkyl group, the heterocycloalkyl group, a C6-C 10 aryl group, a heteroaryl group, a C1-C6 alkyl group(C3-C 10 cycloalkyl group), a C1-C6 alkyl group(heterocycloalkyl group), a C1-C6 alkyl group(C6-C 10 aryl group) or a C1-C6 alkyl group(heteroaryl group); wherein each of the C1-C6 alkyl group, the C2-C6 alkenyl group, the C2-C6 alkynyl group, the C3-C 10 cycloalkyl group, the heterocycloalkyl group, a C6-C 10Each of the aryl and heteroaryl is independently optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; and

[0197] Each R c and R d is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, 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); wherein each of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl and heteroaryl is independently optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0198] Or R c and R dTogether with the atoms to which they are attached to form a heterocycloalkyl group, which is optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl.

[0199] In another embodiment, there is provided a compound of formula (III), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0200]

[0201] Wherein:

[0202] Ring A is a heteroaryl;

[0203] Each R 1 Independently is halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, -OC1-C6 haloalkyl, C3-C 10 Cycloalkyl or heterocycloalkyl; wherein each of C1-C6 alkyl, C3-C 10 Cycloalkyl and heterocycloalkyl is optionally and independently substituted by one or more R 1a Substituted;

[0204] Each R 1a Independently is deuterium, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, 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;

[0205] n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0206] R 7 Is hydrogen or C1-C6 alkyl;

[0207] R 8c Is halogen or -OR a ; And

[0208] Each R aIndependently is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl, heteroaryl, C1-C6 alkyl(C3-C 10 cycloalkyl), C1-C6 alkyl(heteroalkyl), C1-C6 alkyl(C6-C 10 aryl) or C1-C6 alkyl(heteroaryl); wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl and heteroaryl is independently optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl.

[0209] The present invention further provides a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0210]

[0211] Wherein:

[0212] Ring A is C6-C 10 aryl or heteroaryl;

[0213] Each R 1 independently is deuterium, halogen, -CN, oxo, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR bC(=O)NR c R d 、 -NR b C(=O)R a 、 -NR b C(=O)OR 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 deuterated alkyl, C1 - C6 hydroxyalkyl, C1 - C6 aminoalkyl, C1 - C6 heteroalkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C3 - C 10 cycloalkyl, heteroalkyl, C6 - C 10 aryl or heteroaryl; wherein each of C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C3 - C 10 cycloalkyl, heteroalkyl, C6 - C 10 aryl and heteroaryl is optionally and independently substituted by one or more R 1a substituents;

[0214] Or two R on adjacent atoms are joined together to form a C3 - C 1 cycloalkyl or heteroalkyl; which is optionally substituted by one or more R 10 substituents; 1b substituents;

[0215] Each R 1a is independently deuterium, halogen, -CN, -NO2, -OH, -OR a 、 -OC(=O)R a 、 -OC(=O)OR b 、 -OC(=O)NR c R d 、 -SH, -SR a 、 -S(=O)R a 、 -S(=O)2R a 、 -S(=O)2NR c R d 、 -NR c R d 、 -NR b C(=O)NR c R d 、 -NR b C(=O)Ra 、 -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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl or heteroaryl;

[0216] Or two Rs on the same atom 1a taken together to form oxo;

[0217] Each R 1b is independently deuterium, halogen, -CN, -NO2, -OH, -OR a 、 -OC(=O)R a 、 -OC(=O)OR b 、 -OC(=O)NR c R d 、 -SH, -SR a 、 -S(=O)R a 、 -S(=O)2R a 、 -S(=O)2NR c R d 、 -NR c R d 、 -NR b C(=O)NR c R d 、 -NR b C(=O)R a 、 -NR b C(=O)OR a 、 -NR b S(=O)2R a 、 -C(=O)R a 、 -C(=O)OR b 、 -C(=O)NR c R d 、 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10Aryl or heteroaryl;

[0218] Or two Rs on the same atom 1b Together form oxo;

[0219] n is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0220] R 2 Is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl;

[0221] R 3 Is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl;

[0222] R 4a 、R 4b And R 4c Each of them 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0223] R 5 Is hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0224] Each R 6 Independently is hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0225] R 7 Is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl or C1-C6 aminoalkyl;

[0226] R 8a 、R8b , R 8c and R 8d Each of which is independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR a , -NR b S(=O)R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl or heteroaryl;

[0227] R 9 is optionally a heteroaryl substituted by one or more R 1a or an oxetanyl substituted by one or more R 1a ;

[0228] Each R a is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl, heteroaryl, C1-C6 alkyl(C3-C 10 cycloalkyl), C1-C6 alkyl(heteroalkyl), C1-C6 alkyl(C6-C 10(aryl) or C1-C6 alkyl (heteroaryl); wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 Each of aryl and heteroaryl is independently optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0229] Each R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, 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); wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 Each of aryl and heteroaryl is independently optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; and

[0230] Each R c and R d are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 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); wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocycloalkyl, C6-C 10 Each of aryl and heteroaryl is independently optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0231] Or R c And R d Together with the atoms to which they are attached form a heterocycloalkyl which is optionally substituted by one or more of the following groups: 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0232] Provided that the compound of formula (IV) is not

[0233] In some embodiments, a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is C6-C 10Aryl. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is phenyl. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is heteroaryl. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is furyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is pyrazolyl, pyridyl, pyrazinyl or pyrimidinyl. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is pyrazolyl. In some embodiments, it is a compound of 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, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 1-pyrazolyl. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 3-pyrazolyl. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 4-pyrazolyl. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 5-pyrazolyl. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is pyridyl. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl or 6-pyridyl. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 2-pyridyl. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 3-pyridyl. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 4-pyridyl. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 5-pyridyl.In some embodiments, a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 6-pyridyl. In some embodiments, a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is pyrazinyl. In some embodiments, a compound of 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, a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 2-pyrazinyl. In some embodiments, a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 3-pyrazinyl. In some embodiments, a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 5-pyrazinyl. In some embodiments, a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 6-pyrazinyl. In some embodiments, a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is pyrimidinyl. In some embodiments, a compound of 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, a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 2-pyrimidinyl. In some embodiments, a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 4-pyrimidinyl. In some embodiments, a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 5-pyrimidinyl. In some embodiments, a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 6-pyrimidinyl. In some embodiments, a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is pyridazinyl. In some embodiments, a compound of 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, a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 3-pyridazinyl. In some embodiments, a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 4-pyridazinyl. In some embodiments, a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 5-pyridazinyl.In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 6-pyridazinyl. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R. 1 is independently methyl, ethyl, trifluoromethyl, methoxy, ethoxy, mesyl, ethylsulfonyl, acetyl or dimethylamino. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein n is 1, 2 or 3. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein n is 1. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein n is 2. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein n is 3. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 2 is hydrogen. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 3 is hydrogen. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 4a , R 4b and R 4c are independently hydrogen or halogen. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 4a is halogen, and R 4b and R 4c are hydrogen. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 4a and R 4c are hydrogen, and R 4b is halogen. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 4a and R 4b are hydrogen, and R 4c is halogen. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 4a and R 4b are halogen, and R 4c is hydrogen. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 4a and R 4cis a halogen, and R 4b is hydrogen. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 4a , R 4b and R 4c are halogens. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 4a , R 4b and R 4c are hydrogen. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 5 is hydrogen. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 6 is hydrogen. In some embodiments, it is a 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, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 7 is hydrogen. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 7 is C1-C6 alkyl. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 8a , R 8b , R 8c and R 8d each independently is hydrogen, halogen or -OR a . In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 8a , R 8b and R 8d each is hydrogen, and R 8c is hydrogen, halogen or -OR a . In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 8c is halogen or -OR a . In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 8c is halogen. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 8cis fluorine, chlorine, bromine or iodine. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 8c is -OR a In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R a is C1-C6 alkyl. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R a is -CH3. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is furyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl or tetrazolyl, each of which is optionally substituted by one or more R 1a In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is furyl optionally substituted by one or more R 1a In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is pyrrolyl optionally substituted by one or more R 1a In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is thienyl optionally substituted by one or more R 1a In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is oxazolyl optionally substituted by one or more R 1a In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is imidazolyl optionally substituted by one or more R 1a In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is thiazolyl optionally substituted by one or more R 1a In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is pyrazolyl optionally substituted by one or more R 1aSubstituted pyrazolyl. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is an isoxazolyl optionally substituted with one or more R 1a Substituted isoxazolyl. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is optionally substituted with one or more R 1a Substituted isothiazolyl. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is optionally substituted with one or more R 1a Substituted triazolyl. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is optionally substituted with one or more R 1a Substituted pyridyl. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is optionally substituted with one or more R 1a Substituted pyrazinyl. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is optionally substituted with one or more R 1a Substituted pyrimidinyl. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is optionally substituted with one or more R 1a Substituted pyridazinyl. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is optionally substituted with one or more R 1a Substituted tetrazolyl. In some embodiments, it is a compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is substituted with one or more R 1a Substituted oxetanyl.

[0234] In some embodiments, it is a compound of formula (IV), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound of formula (IV) has the structure of formula (IVa):

[0235]

[0236] In some embodiments, it is a compound of formula (IV), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound of formula (IV) has the structure of formula (IVb):

[0237]

[0238] In another embodiment, a compound of formula (V), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, is provided,

[0239]

[0240] wherein:

[0241] Ring A is a C6-C 10 aryl or heteroaryl;

[0242] Each R 1 is 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C10 An aryl or heteroaryl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 Each of the aryl and heteroaryl is optionally and independently substituted by one or more R 1a substituents;

[0243] Or two R on adjacent atoms 1 combine together to form a C3-C 10 cycloalkyl or heterocycloalkyl; each of which is optionally substituted by one or more R 1b substituents;

[0244] Each R 1a independently is 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 deuterated alkyl, 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;

[0245] Or two R on the same atom 1a combine together to form an oxo;

[0246] Each R 1bIndependently is 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 , -NR c C(=O)NR d , -NR b , -NR a , -NR b , -NR a , -NR b , -NR a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl or heteroaryl;

[0247] Or two Rs on the same atom 1b combine together to form oxo;

[0248] n is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0249] R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl or C1-C6 aminoalkyl;

[0250] R 8c is 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)Ra 、 -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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl or heteroaryl;

[0251] R 9 is optionally a heteroaryl substituted by one or more R 1a or an oxetanyl substituted by one or more R 1a ;

[0252] Each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl, heteroaryl, C1-C6 alkyl(C3-C 10 cycloalkyl), C1-C6 alkyl(heteroalkyl), C1-C6 alkyl(C6-C 10 aryl) or C1-C6 alkyl(heteroaryl); wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10Each of the aryl and heteroaryl is independently optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0253] Each R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, 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); wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl and heteroaryl is independently optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; and

[0254] Each R c and R d are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, 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 10cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(C6-C 10 aryl) or C1-C6 alkyl(heteroaryl); wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl and each of heteroaryl is independently optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0255] or R c and R d together with the atoms to which they are attached form a heterocycloalkyl which is optionally substituted by one or more of the following groups: 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0256] provided that the compound of formula (V) is not

[0257] In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is C6-C 10Aryl. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is phenyl. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is heteroaryl. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is pyrazolyl. In some embodiments, it is a 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, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 1-pyrazolyl. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 3-pyrazolyl. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 4-pyrazolyl. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 5-pyrazolyl. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is pyridyl. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl or 6-pyridyl. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 2-pyridyl. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 3-pyridyl. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 4-pyridyl. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 5-pyridyl. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 6-pyridyl. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is pyrazinyl. In some embodiments, it is a 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, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 2-pyrazinyl. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 3-pyrazinyl. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 5-pyrazinyl. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 6-pyrazinyl. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is pyrimidinyl. In some embodiments, it is a compound of 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, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 2-pyrimidinyl. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 4-pyrimidinyl. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 5-pyrimidinyl. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 6-pyrimidinyl. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is pyridazinyl. In some embodiments, it is a compound of 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, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 3-pyridazinyl. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 4-pyridazinyl. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 5-pyridazinyl. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is 6-pyridazinyl. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R. 9 is furyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl or tetrazolyl, each of which is optionally substituted by one or more R 1aSubstituted. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is a furyl group optionally substituted by one or more R 1a Substituted. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is a pyrrolyl group optionally substituted by one or more R 1a Substituted. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is a thienyl group optionally substituted by one or more R 1a Substituted. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is an oxazolyl group optionally substituted by one or more R 1a Substituted. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is an imidazolyl group optionally substituted by one or more R 1a Substituted. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is a thiazolyl group optionally substituted by one or more R 1a Substituted. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is a pyrazolyl group optionally substituted by one or more R 1a Substituted. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is an isoxazolyl group optionally substituted by one or more R 1a Substituted. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is an isothiazolyl group optionally substituted by one or more R 1a Substituted. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is a triazolyl group optionally substituted by one or more R 1a Substituted. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is a pyridyl group optionally substituted by one or more R 1a Substituted. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R9 is a pyrazinyl group optionally substituted by one or more R 1a In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is a pyrimidinyl group optionally substituted by one or more R 1a In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is a pyridazinyl group optionally substituted by one or more R 1a In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is a tetrazolyl group optionally substituted by one or more R 1a In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is an oxetanyl group substituted by one or more R 1a In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 7 is hydrogen. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 8c is halogen or -OR a In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 8c is halogen. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 8c is fluorine, chlorine, bromine or iodine. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 8c is -OR a In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R a is C1-C6 alkyl. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R ais -CH3. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein n is 0, 1 or 2. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein n is 0. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein n is 1. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein n is 2. In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 1 is independently methyl, ethyl, trifluoromethyl, methoxy, ethoxy, mesyl, ethylsulfonyl, acetyl or dimethylamino.

[0258] In some embodiments, it is a compound of formula (V) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound of formula (V) has the structure of formula (Va):

[0259]

[0260] In some embodiments, it is a compound of formula (V), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound of formula (V) has the structure of formula (Vb):

[0261]

[0262] The present invention also provides a compound selected from the following, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof: 6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)-2,3-dihydro-1H-1-benzothiophene-1,1-dione; (1R,2S)-2-{3-[4-(methylsulfonyl)-2-methoxyanilino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-[3-(4-acetyl-2-methoxyanilino)-1H-indazol-6-yl]-5'-methoxyspiro[cyclopropane-1,3'-indole]-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'-indole]-2'(1'H)-one; (1R,2S)-2-{3-[4-(ethylsulfonyl)-2-methoxyanilino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; 6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-2'(1'H)-one; (1R,2S)-2-(3-{[2-(dimethylamino)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-{3-[2-methoxy-5-(2-methyl-2H-tetrazol-5-yl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-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'-indole]-2'(1'H)-one.;

[0263] The present invention also provides a compound selected from the following, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof: 6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)-2,3-dihydro-1H-1-benzothiophene-1,1-dione; (1R,2S)-2-{3-[4-(methylsulfonyl)-2-methoxyanilino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-[3-(4-acetyl-2-methoxyanilino)-1H-indazol-6-yl]-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-{3-[4-(ethylsulfonyl)-2-methoxyanilino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; 6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)-1H-1-benzothiophene-1,1-dione; (1R,2S)-2-{3-[(3-ethoxyquinolin-2-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-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'-indole]-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-1,3'-indole]-2'(1'H)-one.

[0264] The present invention also provides a compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, which is selected from: (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'-indole]-2'(1'H)-one; (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-{4-[3-(dimethylamino)oxetan-3-yl]-2-methoxyanilino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-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'-indole]-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'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-{3-[2-methoxy-5-(1,3-oxazol-2-yl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-2'(1'H)-one;

[0265] The present invention also provides a compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, which is selected from: (1R,2S)-2-{3-[2-ethoxy-4-(methylsulfonyl)anilino]-1H-indazol-6-yl}-5'-methoxy-1'-methylspiro[cyclopropane-1,3'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-2'(1'H)-one; (1R,2S)-2-{3-[(5-Ethoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-[(2H3)methoxy]spiro[cyclopropane-1,3'-indole]-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'-indole]-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'-indoline]-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'-indoline]-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'-indoline]-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'-indoline]-2'-one; (1R)-2-(3-((2-ethoxy-5-(oxazol-4-yl)pyridin-3-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one; (1R,2S)-2-(3-((5-ethoxy-2-ethynylpyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-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'-indoline]-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'-indoline]-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’-indole]-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’-indole]-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’-indole]-2’(1’H)-one; and 5-({6-[(1R,2S)-5’-Methoxy-2’-oxo-1’,2’-dihydrospiro[cyclopropane-1,3’-indole]-2-yl]-1H-indazol-3-yl}amino)-1-methyl-1H-pyrazole-3-carbonitrile.;

[0266] The present invention further provides compounds selected from those shown in Table 1A.

[0267] Table 1A

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280] The present invention further provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0281]

[0282] The present invention further provides a pharmaceutical composition, which comprises a certain 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.

[0283] Therapeutic method

[0284] The present disclosure further provides methods for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), 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, as disclosed herein. Such methods for treating cancer in a subject are provided herein, wherein the cancer of the subject is a solid tumor. In some embodiments, the cancer is neuroblastoma, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, gastric cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney cancer or ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system (CNS) tumors, primary CNS lymphoma, spinal axis tumors, brainstem glioma or pituitary adenoma. In some embodiments, the cancer of the subject expresses polo-like kinase 4 (PLK4). In some embodiments, it has been determined that the cancer of the subject expresses polo-like kinase 4 (PLK4) prior to administering to the subject 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 of the subject exhibits overexpression of the E3 ubiquitin-protein ligase (TRIM37) protein. In some embodiments, the cancer of the subject exhibits overexpression of the gene encoding tripartite motif-containing protein 37 (TRIM37). In some embodiments, the cancer of the subject exhibits amplification of the gene encoding tripartite motif-containing protein 37 (TRIM37).

[0285] The present invention further provides a method for treating cancer 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, wherein prior to administering the compound to the subject, it has been determined that the cancer of the subject overexpresses a gene encoding tripartite motif-containing protein 37 (TRIM37).

[0286] The present invention further provides a method for treating cancer in a subject in need thereof (wherein it has been determined that the cancer of the subject overexpresses a gene encoding tripartite motif-containing protein 37 (TRIM37)), 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.

[0287] The present invention further provides a method for treating cancer in a subject, comprising:

[0288] a. obtaining a biological sample of the cancer from the subject;

[0289] b. determining whether the biological sample of the cancer overexpresses a gene encoding tripartite motif-containing protein 37 (TRIM37); and

[0290] c. if it is determined that the biological sample of the cancer overexpresses 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.

[0291] The present invention further provides a method for treating cancer in a subject as described herein, wherein the cancer is neuroblastoma or breast cancer. The present invention also provides a method for treating cancer in a subject as described herein, wherein the cancer is neuroblastoma. The present invention also provides a method for treating cancer in a subject as described herein, wherein the cancer is breast cancer.

[0292] The present invention further provides methods for treating cancer in the subjects 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 together with one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are selected from one or more mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, antiangiogenic agents, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors (such as inhibitors of protein tyrosine kinases and / or serine / threonine kinases), cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxins and immuno-oncology agents.

[0293] The present invention further provides methods for inhibiting polo-like kinase 4 (PLK4) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), 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.

[0294] The present invention further provides methods for inhibiting polo-like kinase 4 (PLK4) in a subject having cancer, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), 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 it has been determined that the cancer of the subject expresses polo-like kinase 4 (PLK4) prior to administering the compound or pharmaceutical composition to the subject.

[0295] The present invention further provides a method for treating cancer 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, wherein the cancer of the subject is acute myeloid leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, triple negative breast cancer, advanced breast cancer, metastatic breast cancer or prostate cancer. In some embodiments, the cancer of the subject is acute myeloid leukemia. In some embodiments, the cancer of the subject is myelodysplastic syndrome. In some embodiments, the cancer of the subject is chronic myelomonocytic leukemia. In some embodiments, the cancer of the subject is triple negative breast cancer. In some embodiments, the cancer of the subject is advanced breast cancer. In some embodiments, the cancer of the subject is metastatic breast cancer. In some embodiments, the cancer of the subject is prostate cancer.

[0296] The present invention further provides 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 compounds or pharmaceutical compositions for such use are provided, wherein the cancer of the subject is a solid tumor. In some embodiments, such compounds or pharmaceutical compositions for such use are provided, wherein the cancer is neuroblastoma, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, gastric cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney cancer or ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system (CNS) tumors, primary CNS lymphoma, spinal cord axis tumors, brainstem glioma or pituitary adenoma. In some embodiments, such compounds or pharmaceutical compositions for such use are provided, wherein the cancer of the subject expresses polo-like kinase 4 (PLK4). In some embodiments, such compounds or pharmaceutical compositions for such use are provided, wherein it has been determined that the cancer of the subject expresses polo-like kinase 4 (PLK4) prior to administering the compound or pharmaceutical composition to the subject. In some embodiments, such compounds or pharmaceutical compositions for such use are provided, wherein the cancer of the subject exhibits overexpression of the E3 ubiquitin-protein ligase (TRIM37) protein. In some embodiments, such compounds or pharmaceutical compositions for such use are provided, wherein the cancer of the subject exhibits overexpression of the gene encoding tripartite motif-containing protein 37 (TRIM37). In some embodiments, such compounds or pharmaceutical compositions for such use are provided, wherein the cancer of the subject exhibits amplification of the gene encoding tripartite motif-containing protein 37 (TRIM37). In some embodiments, such compounds or pharmaceutical compositions for such use are provided, wherein it has been determined that the cancer of the subject overexpresses the gene encoding tripartite motif-containing protein 37 (TRIM37) prior to administering the compound or pharmaceutical composition to the subject.In some embodiments, there are provided such compounds or pharmaceutical compositions for such uses, wherein the cancer is neuroblastoma or breast cancer. In some embodiments, there are provided such compounds or pharmaceutical compositions for such uses, wherein the cancer is neuroblastoma. In some embodiments, there are provided such compounds or pharmaceutical compositions for such uses, wherein the cancer is breast cancer.

[0297] Further provided herein are 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, or pharmaceutical compositions 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 pharmaceutically acceptable salts, solvates or stereoisomers thereof, for use in a method of treating cancer in a subject in need thereof, wherein the cancer of the subject is acute myeloid leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, triple-negative breast cancer, advanced breast cancer, metastatic breast cancer or prostate cancer. In some embodiments, the cancer of the subject is acute myeloid leukemia. In some embodiments, the cancer of the subject is myelodysplastic syndrome. In some embodiments, the cancer of the subject is chronic myelomonocytic leukemia. In some embodiments, the cancer of the subject is triple-negative breast cancer. In some embodiments, the cancer of the subject is advanced breast cancer. In some embodiments, the cancer of the subject is metastatic breast cancer. In some embodiments, the cancer of the subject is prostate cancer.

[0298] Further provided herein are 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, or pharmaceutical compositions 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 pharmaceutically acceptable salts, solvates or stereoisomers thereof, for use in a method of inhibiting polo-like kinase 4 (PLK4) in a subject having cancer.

[0299] The present invention further provides 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, there is provided such use, wherein the cancer is neuroblastoma, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, gastric cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney cancer or ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system (CNS) tumors, primary CNS lymphoma, spinal cord axis tumors, brainstem glioma or pituitary adenoma. In some embodiments, the cancer of the subject expresses polo-like kinase 4 (PLK4). In some embodiments, prior to administering the compound to the subject, it has been determined that the cancer of the subject expresses polo-like kinase 4 (PLK4). In some embodiments, the cancer of the subject exhibits overexpression of the E3 ubiquitin-protein ligase (TRIM37) protein. In some embodiments, the cancer of the subject exhibits overexpression of the gene encoding tripartite motif-containing protein 37 (TRIM37). In some embodiments, the cancer of the subject exhibits amplification of the gene encoding tripartite motif-containing protein 37 (TRIM37). In some embodiments, prior to administering the compound to the subject, it has been determined that the cancer of the subject overexpresses the gene encoding tripartite motif-containing protein 37 (TRIM37). 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.

[0300] The present invention further provides the use of a compound of formula (I), (Ia), (Ib), (II), (III), (IV), (IVa), (IVb), (V), (Va) or (Vb) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof in the preparation of a medicament for treating cancer in a subject in need thereof, wherein the cancer of the subject is acute myeloid leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, triple negative breast cancer, advanced breast cancer, metastatic breast cancer or prostate cancer. In some embodiments, the cancer of the subject is acute myeloid leukemia. In some embodiments, the cancer of the subject is myelodysplastic syndrome. In some embodiments, the cancer of the subject is chronic myelomonocytic leukemia. In some embodiments, the cancer of the subject is triple negative breast cancer. In some embodiments, the cancer of the subject is advanced breast cancer. In some embodiments, the cancer of the subject is metastatic breast cancer. In some embodiments, the cancer of the subject is prostate cancer.

[0301] In some embodiments, the compound of formula (I), (Ia), (Ib), (II), (III), (IV), (IVa), (IVb), (V), (Va) or (Vb) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is used in combination with one or more additional anti-cancer agents. In some embodiments, the anti-cancer agent is mitoxantrone, estramustine, etoposide, vinblastine, carboplatin, vinorelbine, paclitaxel, daunomycin, idarubicin, epirubicin, docetaxel, cabazitaxel or doxorubicin. In some embodiments, the anti-cancer agent is paclitaxel, daunomycin, idarubicin, epirubicin, docetaxel, cabazitaxel or doxorubicin. In certain embodiments, the anti-cancer agent is docetaxel.

[0302] In some embodiments, one or more additional anti-cancer agents can include, but are not limited to, surgery, radiation, or chemotherapy. Chemotherapy can be an androgen receptor antagonist, a mitotic inhibitor, an antimetabolite, 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 (such as paclitaxel, docetaxel, paclitaxel, docetaxel, cabazitaxel, tesetaxel, or nab-paclitaxel) or vinca alkaloids (such as vinblastine, vincristine, vindesine, or vinorelbine). Examples of antimetabolites include, but are not limited to, 5-fluorouracil, 6-mercaptopurine, capecitabine, cytarabine, floxuridine, fludarabine, gemcitabine, hydroxyurea, methotrexate, pemetrexed, or phototrexate. Examples of platinum-based agents include, but are not limited to, cisplatin, carboplatin, bicycloplatin, eptaplatin, lobaplatin, miriplatin, nedaplatin, oxaliplatin, picoplatin, satraplatin, or triplatintetranitrate. Additional anti-cancer therapies can include anti-PDL1 agents, anti-PD1 agents, or anti-CTLA-4 agents. Anti-PD-L1 agents can include atezolizumab, avelumab, durvalumab, MPDL3280A (RG7446), MDX-1105 (BMS-936559), or BMS-935559, MSB0010718C, and MEDI4736.Anti-PD1 agents may include pembrolizumab, nivolumab, cemiplimab, partalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224 or AMP-514 (MEDI0680). Anti-CTLA agents may include ipilimumab or tremelimumab.

[0303] Therapeutic methods that bind to biomarkers

[0304] In some embodiments, methods for detecting the presence, absence or level of a biomarker are disclosed herein. Such biomarkers may include genetic alterations in genes encoding certain 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 a sample of a related biological fluid, such as a blood sample. In some cases, the detection methods disclosed herein are used to predict a treatment response to a therapy described herein (e.g., a PLK4 inhibitor) in a subject, monitor treatment using the therapy, and treat a proliferative disease or condition described herein with the therapy. In some embodiments, the presence, absence and / or expression level of one or more biomarkers is detected in a sample obtained from a subject by analyzing the genetic material in the sample. In some embodiments, the genetic material is obtained from blood, serum, plasma, sweat, hair, tears, urine and other techniques known to those of skill in the art. In some embodiments, the sample contains circulating tumor RNA (ctRNA). In some embodiments, the sample contains peripheral blood mononuclear cells (PBMC). In some cases, the genetic material is obtained from a tumor biopsy or a liquid biopsy. In some embodiments, the tumor biopsy includes a formalin-fixed paraffin-embedded biopsy, a fresh frozen biopsy, a fresh biopsy or a frozen biopsy. In some embodiments, the liquid biopsy includes PBMC, circulating tumor RNA, cell-free plasma RNA or circulating tumor cells (CTC). The tumor biopsy may undergo additional analytical processing for sample dissociation, cell sorting and enrichment of the cell population of interest.

[0305] In some embodiments, methods of detecting the presence, absence, or level of a biomarker in a sample obtained from a subject involve detecting a nucleic acid sequence. In some cases, the nucleic acid sequence comprises deoxyribonucleic acid (DNA), such as in the case of detecting complementary DNA (cDNA) of an mRNA transcript. In some cases, the nucleic acid sequence comprises a denatured DNA molecule or a fragment thereof. In some cases, the nucleic acid sequence comprises DNA selected from genomic DNA, viral DNA, mitochondrial DNA, plasmid DNA, amplified DNA, circular DNA, circulating DNA, cell-free DNA, or exosomal DNA. In some cases, the DNA is single-stranded DNA (ssDNA), double-stranded DNA, denatured double-stranded DNA, synthetic DNA, and combinations thereof. Circular DNA may be cleaved or fragmented. In some cases, the nucleic acid sequence comprises ribonucleic acid (RNA). In some cases, the nucleic acid sequence comprises fragmented RNA. In some cases, the nucleic acid sequence comprises partially degraded RNA. In some cases, the nucleic acid sequence comprises microRNA or a portion thereof. In some cases, the nucleic acid sequence comprises an RNA molecule or a fragmented RNA molecule (RNA fragment) selected from the group consisting of: microRNA (miRNA), pre-miRNA, primary miRNA, mRNA, pre-mRNA, viral RNA, viroid RNA, satellite RNA, circular RNA (circRNA), ribosomal RNA (rRNA), transfer RNA (tRNA), pre-tRNA, long non-coding RNA (lncRNA), small nuclear RNA (snRNA), circulating RNA, cell-free RNA, exosomal RNA, vector-expressed RNA, RNA transcript, synthetic RNA, and combinations thereof.

[0306] In some embodiments disclosed herein, a biomarker is detected by performing a nucleic acid-based assay on a sample obtained from a subject. In some cases, the nucleic acid-based assay comprises quantitative polymerase chain reaction (qPCR), gel electrophoresis (including, for example, Northern or Southern blotting), immunochemistry, in situ hybridization (such as fluorescence in situ hybridization (FISH)), cytochemistry, microarray, or sequencing. In some embodiments, the sequencing technique comprises next-generation sequencing. In some embodiments, the method involves a hybridization assay, such as fluorescence qPCR (e.g., TaqMan TM, 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 nucleic acid amplification reactions with specific primer pairs and hybridization of nucleic acid probes containing detectable moieties or molecules specific for the target nucleic acid sequence. In some cases, the number of amplification cycles used to detect the target nucleic acid in a qPCR assay is from about 5 to about 30 cycles. In some cases, the number of amplification cycles used to detect the target nucleic acid is at least about 5 cycles. In some cases, the number of amplification cycles used to detect the target nucleic acid is at most about 30 cycles. In some cases, the number of amplification cycles used to detect the target nucleic acid is from about 5 to about 10, about 5 to about 15, about 5 to about 20, about 5 to about 25, about 5 to about 30, about 10 to about 15, about 10 to about 20, about 10 to about 25, about 10 to about 30, about 15 to about 20, about 15 to about 25, about 15 to about 30, about 20 to about 25, about 20 to about 30, or about 25 to about 30 cycles. For TaqMan TM method, the probe can be a hydrolyzable probe containing a fluorophore and a quencher, which is hydrolyzed by DNA polymerase when hybridized to the target nucleic acid. In some cases, the presence of the target nucleic acid is determined when the number of amplification cycles reaching the threshold is less than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, or 20 cycles. In some cases, hybridization can occur in a standard PCR buffer at a standard hybridization temperature, for example, between about 35°C and about 65°C.

[0307] Additional exemplary nucleic acid-based assays include the use of nucleic acid probes conjugated or otherwise immobilized on beads, microtiter plates, or other substrates, where the nucleic acid probes are configured to hybridize to a target nucleic acid sequence. In some cases, the nucleic acid probes are specific for one or more of the gene products described herein. In some cases, a nucleic acid probe specific for a biomarker comprises a nucleic acid probe sequence that is sufficiently complementary to the polynucleotide sequence of the biomarker. In some cases, the biomarker comprises a transcribed polynucleotide sequence (e.g., RNA, cDNA). In some embodiments, the nucleic acid probe can be, for example, a full-length cDNA or a portion thereof, such as an oligonucleotide that is at least about 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides in length and is sufficient to specifically hybridize to a 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 the probe, for example, by running the separated 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, such as in an Affymetrix gene chip array, and the probe is contacted with the target nucleic acid sequence.

[0308] In some embodiments, the term "probe" with respect to nucleic acids refers to any nucleic acid molecule capable of selectively binding to a specific 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 cases, the fluorescent label includes a fluorophore. In some cases, the fluorophore is an aromatic or heteroaromatic compound. In some cases, the fluorophore is pyrene, anthracene, naphthalene, acridine, stilbene, benzoxazole, indole, benzindole, oxazole, thiazole, benzothiazole, cyanine, carbocyanine, salicylate, anthranilate, xanthene dyes, 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), 6-carboxy-X-rhodamine (ROX). Suitable fluorescent probes also include naphthylamine dyes having an amino group at the α or β position. For example, naphthylamino compounds include 1-dimethylaminonaphthalene-5-sulfonate or ester, 1-anilinonaphthalene-8-sulfonate or ester, and 2-p-toluidino-6-naphthalenesulfonate or ester, 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)maleimide; cyanines, such as, for example, indodicarbocyanine 3 (Cy3), indodicarbocyanine 5 (Cy5), indodicarbocyanine 5.5 (Cy5.5), 3-(-carboxy-pentyl)-3’-ethyl-5,5’-dimethyloxacarbocyanine (CyA); 1H,5H,11H,15H-xantheno[2,3,4-ij:5,6,7-i’j’]diquinoxalin-18-ium, 9-[2(or 4)-[[6-[2,5-dioxo-1-pyrrolidinyl]oxy]-6-oxohexyl]amino]sulfonyl]-4(or 2)-sulfophenyl]-2,3,6,7,12,13,16,17-octahydro-inner salt (TR or Texas Red); or BODIPYTM dyes. In some cases, the probe contains FAM as a dye label.

[0309] In some embodiments, one or more biomarkers are detected, such as gene products in a predictive response signature (PRS), including sequencing genetic material obtained from a sample of a subject. Sequencing can be performed with any suitable sequencing technology, including but not limited to single molecule real-time (SMRT) sequencing, Polony sequencing, ligation sequencing, reversible terminator sequencing, proton detection sequencing, ion semiconductor sequencing, nanopore sequencing, electronic sequencing, pyrosequencing, Maxam-Gilbert sequencing, chain termination (e.g., Sanger) sequencing, +S sequencing, or sequencing by synthesis. Sequencing methods also include next-generation sequencing, such as modern sequencing technologies, such as Illumina sequencing (e.g., Solexa), Roche 454 sequencing, Ion torrent sequencing, and SOLiD sequencing. In some cases, next-generation sequencing involves high-throughput sequencing methods. Additional sequencing methods available to those of skill in the art can also be used.

[0310] In some cases, 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 cases, the number of nucleotides sequenced is in the range of about 1 to about 100000 nucleotides, about 1 to about 10000 nucleotides, about 1 to about 1000 nucleotides, about 1 to about 500 nucleotides, about 1 to about 300 nucleotides, about 1 to about 200 nucleotides, about 1 to about 100 nucleotides, about 5 to about 100000 nucleotides, about 5 to about 10000 nucleotides, about 5 to about 1000 nucleotides, about 5 to about 500 nucleotides, about 5 to about 300 nucleotides, about 5 to about 200 nucleotides, about 5 to about 100 nucleotides, about 10 to about 100000 nucleotides, about 10 to about 10000 nucleotides, about 10 to about 1000 nucleotides, about 10 to about 500 nucleotides, about 10 to about 300 nucleotides, about 10 to about 200 nucleotides, about 10 to about 100 nucleotides, about 20 to about 100000 nucleotides, about 20 to about 10000 nucleotides, about 20 to about 1000 nucleotides, about 20 to about 500 nucleotides, about 20 to about 300 nucleotides, about 20 to about 200 nucleotides, about 20 to about 100 nucleotides, about 30 to about 100000 nucleotides, about 30 to about 10000 nucleotides, about 30 to about 1000 nucleotides, about 30 to about 500 nucleotides, about 30 to about 300 nucleotides, about 30 to about 200 nucleotides, about 30 to about 100 nucleotides, about 50 to about 100000 nucleotides, about 50 to about 10000 nucleotides, about 50 to about 1000 nucleotides, about 50 to about 500 nucleotides, about 50 to about 300 nucleotides, about 50 to about 200 nucleotides, or about 50 to about 100 nucleotides.

[0311] The methods disclosed herein include: (a) providing a sample obtained from a subject having a proliferative disease or condition (e.g., cancer); (b) assaying to detect the presence or absence of a relevant biomarker in the sample obtained from the subject; and (c) detecting the presence or absence of the biomarker in the sample using the methods described herein. In some cases, a hybridization assay (such as the hybridization assays described herein) is used to detect the biomarker in the sample. Exemplary probe sequences that can hybridize to a target nucleic acid sequence (e.g., one or more genes in the biomarker, such as PRS) contain at least 10 but no more than 100 contiguous nucleotides that comprise the relevant sequence. In some cases, RNA sequencing (RNAseq) is used to detect one or more biomarkers.

[0312] In some cases, the detection of relevant biomarkers involves amplifying the nucleic acids of the subject by polymerase chain reaction (PCR). In some embodiments, the PCR assay involves using a pair of primers capable of amplifying at least about 10 consecutive nucleobases in a nucleic acid sequence, thereby amplifying one or more gene products in the biomarker. In quantitative real-time PCR, the quantification is based on the amount of fluorescence signal (TaqMan and SYBR green). In some embodiments, the nucleic acid probe is conjugated to a detectable molecule. The detectable molecule can be a fluorophore. The nucleic acid probe can also be conjugated to a quencher.

[0313] In some embodiments, the assay for detecting the presence or absence of a relevant biomarker includes reverse transcribing a relevant mRNA molecule to produce a corresponding complementary DNA (cDNA) molecule. In some embodiments, the assay further includes contacting the cDNA molecule with a nucleic acid probe that comprises a nucleic acid sequence complementary to the nucleic acid sequence of the cDNA molecule. In some embodiments, the assay includes detecting a double-stranded hybridization product between the nucleic acid probe and the cDNA molecule. In some embodiments, the hybridization product is further amplified using a pair of primers. In some embodiments, the primers comprise a first primer having a nucleic acid sequence that comprises at least 10 but no more than 50 consecutive nucleic acids within the relevant nucleic acid sequence that binds to the top strand of the double-stranded hybridization product; and a second primer having a nucleic acid sequence that comprises at least 10 but no more than 50 consecutive nucleic acids within the nucleic acid sequence that is reverse complementary to the relevant nucleic acid sequence that binds to the bottom strand of the double-stranded hybridization product.

[0314] In some embodiments, methods are disclosed herein that include preparing a complementary DNA (cDNA) library. In some embodiments, the cDNA library is sequenced using a suitable sequencing method disclosed herein. In some embodiments, the cDNA library is labeled, generating a plurality of nucleic acid probes, and immobilized to a solid surface (such as a microarray). In some embodiments, the plurality of nucleic acid probes are capable of hybridizing to at least about 10 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 includes detecting a high or low expression level of two or more genes compared to a reference level.

[0315] In some embodiments disclosed herein, genetic material is extracted from a sample obtained from a subject (e.g., a blood or serum sample). In certain embodiments of nucleic acid extraction, any technique that does not interfere with subsequent analysis is used to extract nucleic acids. In certain embodiments, the technique uses alcohol precipitation utilizing ethanol, methanol, or isopropanol. 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 acetate, potassium acetate, or ammonium acetate or any other salt commonly used for DNA precipitation. In certain embodiments, the technique utilizes a column- or resin-based nucleic acid purification protocol, such as those commonly commercially available, a non-limiting example being the GenElute Bacterial Genomic DNA Kit available from Sigma Aldrich. In certain embodiments, after extraction and prior to subsequent analysis, the nucleic acids are stored in water, Tris buffer, or Tris-EDTA buffer. In an exemplary embodiment, nucleic acid material is extracted in water. In some cases, the extraction does not include nucleic acid purification. In certain embodiments, RNA extraction techniques can be used to extract RNA from cells, including, for example, using acid phenol / isothiocyanate guanidine extraction (RNAzol B; Biogenesis), RNeasy RNA Preparation Kit (Qiagen), or PAXgene (PreAnalytix, Switzerland).

[0316] Circulating tumor DNA (ctDNA) and RNA (ctRNA)

[0317] In some aspects, circulating tumor DNA (ctDNA) is used to assess the presence of certain DNA molecules, and circulating tumor RNA (ctRNA) is used to assess the expression levels of RNA molecules released from tumors into the bloodstream.

[0318] In some embodiments, the detection of ctDNA or ctRNA is useful, for example, for detecting and diagnosing tumors. Since tumor DNA and RNA have acquired multiple gene mutations that lead to tumor development, ctDNA and ctRNA do not exactly match the individual's DNA and RNA, respectively. Detecting DNA and RNA with genetic differences aids in tumor detection. Diagnosing the type of tumor using ctDNA or ctRNA can reduce the need to obtain a sample of tumor tissue (tumor biopsy), which can be challenging when the tumor is difficult to access, such as tumors in the brain or lung.

[0319] 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.

[0320] Methods for assessing genetic alterations by ctDNA or ctRNA genomic profiling are described herein. In some embodiments, the 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, a gene mutation indicates that the cancer is 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 gene mutation indicates that the cancer is not 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.

[0321] Compounds of formula (I), (Ia), (Ib), (II), (III), (IV), (IVa), (IVb), (V), (Va) or (Vb) may be administered as prodrugs. Thus, certain derivatives of compounds that may have little or no pharmacological activity per se can be converted, for example, by hydrolytic cleavage into compounds having the desired activity when administered to a mammal. Such derivatives are referred to as "prodrugs". For example, prodrugs can be produced by replacing appropriate functional groups present in the compounds of formula (I), (Ia), (Ib), (II), (III), (IV), (IVa), (IVb), (V), (Va) or (Vb) with certain moieties known to those skilled in the art. See, for example, "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T Higuchi and W Stella) and "Bioreversible Carriers in Drug Design", Pergamon Press, 1987 (edited by E B Roche, American Pharmaceutical Association), the disclosures of which are incorporated herein by reference in their entirety. Some examples of such prodrugs include: an ester moiety in place of a carboxylic acid functional group; an ether moiety or an amide moiety in place of an alcohol functional group; and an amide moiety in place of a primary or secondary amino functional group. Examples of the substituting groups are known to those skilled in the art. See, for example, "Design of Prodrugs" by H Bundgaard

[0322] (Elsevier, 1985), the disclosure of which is incorporated herein by reference in its entirety.

[0323] The salts of the present invention can be prepared according to methods known to those skilled in the art. Examples of salts include, but are not limited to, acetates, acrylates, benzenesulfonates, benzoates (such as chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, and methoxybenzoates), bicarbonates, bisulfates, bisulfites, bitartrates, borates, bromides, butyne-1,4-dioates, calcium edetate, camphorsulfonates, carbonates, chlorides, caproates, caprylates, clavulanates, citrates, caprates, dihydrochlorides, dihydrogen phosphates, edetates, ethanedisulfonates, etidronates, esulfonates, ethylsuccinates, formates, fumarates, glucoheptonates, glucuronates, glutamates, glycolates, glycollylarsanilate, heptanoates, hexyne-1,6-dioates, hexylresorcinate, hydrabamine, hydrobromides, hydrochlorides, γ-hydroxybutyrates, iodides, isobutyrates, isothionates, lactates, lactobionates, laurates, malates, maleates, malonates, mandelates, mesylates, metaphosphates, methanesulfonates, methylsulfates, monohydrogen phosphates, mucates, naphthalenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, nitrates, oleates, phenylpropionates, phthalates, phosphates / diphosphates, polygalacturonates, propanesulfonates, propionates, propiolates, pyrophosphates, pyrosulfates, salicylates, stearates, subacetates, suberates, oxalates, embonates (pamoates), palmitates, pantothenates, phenylacetates, phenylbutyrates, succinates, sulfates, sulfonates, sulfites, tannates, tartrates, theophyllinates, toluenesulfonates, triethiodode, and valerates.

[0324] 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) that are essentially basic are capable of forming various different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, in practice it is usually desirable to first isolate the compounds of the present invention from the reaction mixture as pharmaceutically unacceptable salts and then simply convert the latter back to the free base compound by treatment with a basic reagent, and subsequently convert the free base of the latter into a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of the present invention can be prepared by treating the basic compound with substantially an equivalent amount of the selected inorganic or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. After evaporation of the solvent, the desired solid salt is obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding an appropriate inorganic or organic acid to the solution.

[0325] 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) that are acidic in nature are capable of forming basic salts with various pharmaceutically acceptable cations. Examples of such salts include alkali metal salts or alkaline earth metal salts, and especially sodium salts and potassium salts. These salts are all prepared by conventional techniques. The chemical bases used as reagents for preparing the pharmaceutically acceptable basic salts of the present invention are those that form non-toxic basic salts with the acidic compounds of the present invention. Such non-toxic basic salts include those derived from such pharmaceutically acceptable cations as sodium, potassium, calcium, and magnesium, etc. These salts can be prepared by treating the corresponding acidic compound with an aqueous solution containing the desired pharmaceutically acceptable cation and then evaporating the resulting solution to dryness (preferably under reduced pressure). Alternatively, they can also be prepared by mixing a lower alkanol solution of the acidic compound and the desired alkali metal alkoxide and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric amounts of the reagents are preferably used to ensure the completeness of the reaction and the maximum yield of the desired final product.

[0326] If 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) are bases, the desired salts can be prepared by any suitable method available in the art, for example, by treating the free base with an inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranoside acids (such as glucuronic acid or galacturonic acid), α-hydroxy acids (such as citric acid or tartaric acid), amino acids (such as aspartic acid or glutamic acid), aromatic acids (such as benzoic acid or cinnamic acid), sulfonic acids (such as p-toluenesulfonic acid or ethanesulfonic acid), etc.

[0327] If 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) are acids, the desired salts can be prepared by any suitable method, for example, by treating the free acid with an inorganic base or an organic base, such as an amine (primary, secondary or tertiary amine), an alkali metal hydroxide or an alkaline earth metal hydroxide, etc. Illustrative 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.

[0328] If the compound of formula (I), (Ia), (Ib), (II), (III), (IV), (IVa), (IVb), (V), (Va) or (Vb) is a solid, those skilled in the art will understand that the compound or its salt may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and the specified formulae.

[0329] Also provided herein are isotopically labeled compounds of formula (I), (Ia), (Ib), (II), (III), (IV), (IVa), (IVb), (V), (Va) or (Vb), wherein one or more atoms are replaced with atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include isotopes of hydrogen such as 2 H and 3 H, isotopes of carbon such as 11 C, 13 C and 14 C, isotopes of chlorine such as 36 Cl, isotopes of fluorine such as 18 F, isotopes of iodine such as 123 I and 125 I, isotopes of nitrogen such as 13 N and 15 N, isotopes of oxygen such as 15 O, 17 O and 18 O, isotopes of phosphorus such as 32 P, and isotopes of sulfur such as 35 S. Certain isotopically labeled compounds of the present invention (e.g., compounds incorporating radioactive isotopes) are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium ( 3 H) and carbon-14 ( 14 C) are particularly suitable for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium ( 2 H) can provide certain therapeutic advantages due to greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in some instances. Substitution with positron-emitting isotopes (such as 11 C, 18 F, 15 O and 13 N) can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy.

[0330] 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, using appropriate isotopically labeled reagents in place of the unlabeled reagents otherwise employed.

[0331] 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 is used for treating cancer in a subject. In one embodiment, such a composition is in a suitable dosage form. Suitable dosage forms include, for example, liquids, suspensions, powders for reconstitution, tablets, pills, sachets or hard or soft gelatin capsules (see, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21st ed., Mack Pub. Co., Easton, PA (2005))).

[0332] 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 considered suitable by a person skilled in the art. The pharmaceutical composition of the present invention comprises a therapeutically effective amount of at least one compound of the present invention and an inert pharmaceutically acceptable carrier or diluent.

[0333] The pharmaceutical carrier employed can be solid or liquid. Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid, etc. Exemplary liquid carriers are syrups, peanut oil, olive oil, water, etc. Similarly, the compositions of the present invention can include time-delay or sustained-release materials known in the art, such as glyceryl monostearate or glyceryl distearate alone, or together with waxes, ethyl cellulose, hydroxypropyl methylcellulose, methyl methacrylate, etc. Additional additives or excipients can be added to obtain the desired formulation properties. For example, bioavailability enhancers such as Labrasol TM , Gelucire TM , etc., or formulations such as CMC (carboxymethyl cellulose), PG (propylene glycol) or PEG (polyethylene glycol) can be added. For example, when preparing a capsule formulation, Gelucire TM, a semi-solid vehicle that protects the active ingredient from light, moisture, and oxidation.

[0334] If a solid carrier is used, the preparation can be made into tablets, placed in hard gelatin capsules in the form of powder or pellets, or made into lozenges or troches. The amount of the solid carrier can vary, but is usually from about 25 mg to about 1 g. If a liquid carrier is used, the preparation can be in the form of a syrup, an emulsion, a soft gelatin capsule, a sterile injectable solution, or a suspension or non-aqueous liquid suspension in an ampoule or vial. If a semi-solid carrier is used, the preparation can be in the form of hard gelatin capsule preparations and soft gelatin capsule preparations. The compositions of the present invention are prepared in unit dosage forms suitable for the mode of administration (e.g., parenteral or oral administration).

[0335] To obtain a stable water-soluble dosage form, the salt of the compound of the present invention can be dissolved in an aqueous solution of an organic acid or an inorganic acid (such as a 0.3 M solution of succinic acid or citric acid). If a soluble salt form is not obtainable, the medicament can be dissolved in a suitable co-solvent or a combination of co-solvents. Examples of suitable co-solvents include ethanol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerol, etc., in a concentration range of 0 to 60% of the total volume. In an exemplary embodiment, the compound of the present invention is dissolved in DMSO and diluted with water. The composition can also be in the form of a solution of the salt form of the active ingredient in a suitable aqueous vehicle such as water or isotonic saline or glucose solution.

[0336] The suitable preparation depends on the selected route of administration. For injection, the medicament of the compound of the present invention can be formulated as an aqueous solution, preferably in a physiologically compatible buffer such as Hanks solution, Ringer solution, or physiological saline buffer. For transmucosal administration, a penetrant suitable for the permeation barrier is used in the preparation. Such penetrants are generally known in the art.

[0337] For oral administration, the compounds can be formulated by combining the active compound with pharmaceutically acceptable carriers known in the art. Such carriers enable the compounds of the present invention to be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc. for oral ingestion by the subject to be treated. Pharmaceutical preparations for oral use can be obtained by using solid excipients, which are mixed with the active ingredient (drug substance), optionally grinding the resulting mixture, and, if necessary, processing the mixture of granules with the addition of suitable auxiliaries to obtain tablets or dragee 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, gums, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose or polyvinylpyrrolidone (PVP). If necessary, disintegrating agents can be added, such as cross-linked polyvinylpyrrolidone, agar or alginic acid or its salts (such as sodium alginate).

[0338] The dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, polyvinylpyrrolidone, Carbopol gels, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to the tablet or dragee coatings for identifying or characterizing different combinations of the active drug substances.

[0339] Pharmaceutical preparations for oral use include push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer (such as glycerol or sorbitol). The push-fit capsules can contain the active ingredient mixed with fillers such as lactose, binders such as starch and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In the soft capsules, the active drug substance can be dissolved or suspended in a suitable liquid (such as fatty oils, liquid paraffin or liquid polyethylene glycol). In addition, stabilizers can be added. All preparations for oral administration should be in doses suitable for such administration. For buccal administration, the compositions can take the form of tablets or lozenges formulated in a conventional manner.

[0340] For nasal administration or administration by inhalation, the compounds used according to the present invention can be conveniently delivered from a pressurized pack or a nebulizer in the form of an aerosol spray using a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Gelatin capsules and cartridges for inhalers or insufflators etc. can be formulated to contain a powder mixture of the compound and a suitable powder base (such as lactose or starch).

[0341] The compounds can be formulated for parenteral administration by injection (e.g., by bolus injection or continuous infusion). Preparations for injection can be presented in unit dosage form, for example in ampoules or in multi-dose containers, with an added preservative. The composition can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulating agents such as suspending, stabilizing and / or dispersing agents.

[0342] Pharmaceutical preparations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active agents can be prepared as suitable 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 to allow the preparation of highly concentrated solutions.

[0343] Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle (e.g., sterile pyrogen-free water) before use.

[0344] In addition to the above preparations, the compounds of the present invention can also be formulated into long-acting preparations. Such long-acting preparations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated with a suitable polymeric material or a hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion exchange resin, or as a sparingly soluble derivative, e.g., as a sparingly soluble salt. A pharmaceutical carrier for a hydrophobic compound is a co-solvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer and an aqueous phase. The co-solvent system can be the VPD co-solvent system. VPD is a solution of 3% w / v benzyl alcohol, 8% w / v non-polar surfactant polysorbate 80 and 65% w / v polyethylene glycol 300 in absolute ethanol by volume. The VPD co-solvent system (VPD: 5W) contains VPD diluted 1:1 with 5% glucose aqueous solution. This co-solvent system dissolves hydrophobic compounds well and produces low toxicity itself upon systemic administration. The ratio of the co-solvent system can be varied appropriately without destroying its solubility and toxicity characteristics. Additionally, the characteristics of the co-solvent components can be varied: for example, other low-toxic non-polar surfactants can be used instead of polysorbate 80; the fraction size of polyethylene glycol can be varied; other biocompatible polymers can be used instead of polyethylene glycol, such as polyvinylpyrrolidone; and other sugars or polysaccharides can be used instead of glucose.

[0345] Alternatively, other delivery systems for hydrophobic pharmaceutical compounds can be used. 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, although typically at the cost of greater toxicity due to the toxic nature of DMSO. In addition, sustained release systems can be used to deliver the compounds, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. A variety of 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 the compound over a period of weeks to over 100 days. Additional strategies for protein stabilization can be employed depending on the chemical nature and biological stability of the therapeutic agent.

[0346] The pharmaceutical composition can also contain suitable solid or gel phase carriers or excipients. These carriers and excipients can provide a significant increase in the bioavailability of poorly soluble drugs. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol. In addition, additives or excipients such as Gelucire TM , Capryol TM , Labrafil TM , Labrasol TM , Lauroglycol TM , Plurol TM , Peceol TM , Transcutol TM etc.

[0347] In addition, the pharmaceutical composition can be incorporated into a skin patch for direct delivery of the drug to the skin.

[0348] It should be understood that the actual dosage of the medicament of the present invention will vary depending on the particular medicament used, the particular composition formulated, the mode of administration, and the particular site, host, and disease being treated. Given the experimental data for a given compound, one of ordinary skill in the art using routine dosage determination tests can determine the optimal dosage for a given set of conditions. For oral administration, an exemplary daily dosage typically employed will be from about 0.001 mg / kg body weight to about 1000 mg / kg body weight, with the course of treatment being repeated at appropriate intervals.

[0349] In addition, the pharmaceutically acceptable formulation of the present invention can contain the compound of the present invention or its salt or solvate in an amount of from about 10 mg to about 2000 mg, or from about 10 mg to about 1500 mg, or from about 10 mg to about 1000 mg, or from about 10 mg to about 750 mg, or from about 10 mg to about 500 mg, or from about 25 mg to about 500 mg, or from about 50 to about 500 mg, or from about 100 mg to about 500 mg.

[0350] In addition, the pharmaceutically acceptable formulations of the present invention may contain the compound of the present invention or a salt or solvate thereof in an amount of from about 0.5 w / w% to about 95 w / w%, from about 1 w / w% to about 95 w / w%, from about 1 w / w% to about 75 w / w%, from about 5 w / w% to about 75 w / w%, from about 10 w / w% to about 75 w / w% or from about 10 w / w% to about 50 w / w%.

[0351] The compound of the present invention or a salt or solvate thereof may be administered, alone or as part of a pharmaceutically acceptable formulation, once, twice, three times or four times a day or even more frequently to a mammal having abnormal cell growth, such as a human being.

[0352] Those of ordinary skill in the art will understand that for 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) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, the specific pharmaceutical formulations, dosages and number of dosages to be administered daily to a mammal in need of such treatment are choices within the knowledge of those of ordinary skill in the art and can be determined without undue experimentation.

[0353] The dosage of the compositions described herein can be determined by any suitable method. The maximum tolerated dose (MTD) and the maximum response dose (MRD) 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 via established animal and human experimental protocols and 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 toxicity and therapeutic effect is the therapeutic index, and it can be expressed as the ratio between the LD50 and the ED50. Data obtained from cell culture assays and animal studies can be used to formulate a dosage range for humans. The dosage of such compounds is preferably within a range that includes the circulating concentration of the ED50 with minimal toxicity. The dosage can vary within this range depending on the dosage form employed and the route of administration utilized. Additional relative dosages, expressed as a percentage of the maximum response or maximum tolerated dose, can be readily obtained via the protocol.

[0354] 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 the formulation corresponding to this amount, varies depending on factors such as the specific salt or form, the disease condition and its severity, the characteristics of the subject or host to be treated (e.g., age, weight, sex), but can still be determined according to the specific circumstances surrounding the case, including, for example, the specific agent administered, the type of liquid formulation, the condition being treated, and the subject or host being treated.

[0355] 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 in an amount of about 10 mg to 500 mg per day. 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 or a pharmaceutically acceptable salt thereof is administered in an amount of about 100 mg to about 400 mg per day. 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 in an amount of about 150 mg to about 350 mg per day. 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 in an amount of about 150 mg to about 300 mg per day. 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 in an amount of about 160 mg to about 300 mg per day. 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 in an amount of about 160 mg per day. 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 in an amount of about 200 mg per day. 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 in an amount of about 240 mg per day.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 in an amount of about 280 mg per day. 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 in an amount of about 320 mg per day.

[0356] Generally, appropriate dosages and treatment regimens provide an amount of the composition sufficient to provide a therapeutic and / or prophylactic benefit (e.g., improved clinical outcomes such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or reduced symptom severity). Optimal dosages are typically determined using experimental models and / or clinical trials. The optimal dosage depends on the body mass, weight or blood volume of the subject. Generally, appropriate dosages and treatment regimens provide an amount of the composition sufficient to provide a therapeutic and / or prophylactic benefit (e.g., improved clinical outcomes such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or reduced symptom severity). Optimal dosages are typically determined using experimental models and / or clinical trials. The optimal dosage depends on the body mass, weight or blood volume of the subject.

[0357] In certain embodiments where the condition of the subject does not improve, the administration of the composition described herein is for long-term administration, i.e., for a prolonged period of time, including for the duration of the subject's life, in order to alleviate or otherwise control or limit the symptoms of the subject's disease. In other embodiments, the administration of the composition continues until a complete or partial response to the disease.

[0358] In some embodiments, a compound of formula (I), (Ia), (Ib), (II), (III), (IV), (IVa), (IVb), (V), (Va) or (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), (Ia), (Ib), (II), (III), (IV), (IVa), (IVb), (V), (Va) or (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), (Ia), (Ib), (II), (III), (IV), (IVa), (IVb), (V), (Va) or (Vb) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is administered three times daily to a subject in need thereof.

[0359] In some cases, the methods described herein include administering to a subject or a subject in need thereof, in a plurality of cycles repeated on a regular schedule, a composition and formulation comprising a compound of formula (I), (Ia), (Ib), (II), (III), (IV), (IVa), (IVb), (V), (Va) or (Vb) in combination with one or more additional therapeutic agents, wherein there is a rest period between each cycle. For example, in some cases, a treatment cycle is one week of treatment followed by three weeks of rest.

[0360] The length of the treatment cycle depends on the treatment being administered. In some embodiments, the length of the treatment cycle ranges from two to six weeks. In some embodiments, the length of the treatment cycle ranges from three to six weeks. In some embodiments, the length of the treatment cycle ranges from three to four weeks. In some embodiments, the length of the treatment cycle is three weeks (or 21 days). In some embodiments, the length of the treatment cycle is four weeks (28 days). In some embodiments, the length of the treatment cycle is 56 days. In some embodiments, the treatment cycle lasts one, two, three or four weeks. In some embodiments, the treatment cycle lasts three weeks. In some embodiments, the treatment cycle lasts four weeks. The number of planned treatment doses within each cycle also varies depending on the drug being administered.

[0361] Kits and articles

[0362] In certain embodiments, kits and articles for use with one or more of the methods and compositions described herein are disclosed. Such kits include a carrier, package, or container that is compartmentalized to receive one or more containers, such as vials, tubes, etc., each containing one of the separate elements to be used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In one embodiment, the container is formed from a variety of materials, such as glass or plastic.

[0363] The kit generally includes a label listing the contents and / or instructions for use, as well as a package insert with instructions for use. A set of instructions will generally also be included.

[0364] 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. The label is associated with the container when the label is present in a receptacle or carrier that also holds the container, such 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 use of the contents, such as in the methods described herein.

[0365] In certain embodiments, the pharmaceutical composition is present in a package or dispenser device that contains one or more unit dosage forms containing the compounds provided herein. For example, the package contains a metal or plastic foil, such as a blister pack. In one embodiment, the package or dispenser device is attached with instructions for administration. In one embodiment, the package or dispenser is also attached with a notice associated with the container, in a form prescribed by a government agency that regulates the manufacture, use, or sale of drugs, which notice reflects approval by the agency of the form of the drug for human or veterinary administration. For example, such notice is the drug label approved by the U.S. Food and Drug Administration (U.S.Food and Drug AdministR a tion) or an approved product insert. In one embodiment, a composition containing the compounds provided herein formulated in a compatible pharmaceutical carrier is also prepared, placed in a suitable container, and labeled for treatment of a designated condition.

[0366] Preparation Methods

[0367] Compounds of formula (I), (Ia), (Ib), (II), (III), (IV), (IVa), (IVb), (V), (Va) or (Vb), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, can be prepared using the following reaction routes and synthetic schemes, employing techniques available in the art and using readily available starting materials. The preparation of certain embodiments of the present invention is described in detail in the following examples, but those of ordinary skill in the art will recognize that the described preparation can be readily adapted to prepare other embodiments of the present invention. For example, the synthesis of non-exemplary 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 changing other suitable reagents known in the art, or by making routine modifications to the reaction conditions. Alternatively, other reactions mentioned herein or known in the art will be considered to have applicability for preparing other compounds of the present invention.

[0368] By reacting a compound of formula (VI) with a compound of formula (VII) (wherein A, R 1 、R 9 and n are as defined herein, and wherein LG is a leaving group), a compound of formula (I), (Ia), (Ib), (II), (III), (IV), (IVa), (IVb), (V), (Va) or (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 are as defined herein). LGs that can be used include halogens such as chlorine, bromine and iodine. The reaction of the compound of formula (VI) with the compound of formula (VII) can be carried out using methods known to those of ordinary skill in the art. For example, the reaction of the compound of formula (VI) with the compound of formula (VII) can be carried out in an aprotic solvent (such as acetonitrile, DMF, etc.), a protic solvent (such as water or alcohol), a mixture of a protic solvent and an aprotic solvent (such as a mixture of acetonitrile and water), at a temperature in the range of 25 °C to 200 °C, and in the presence of an acid or a base. The compound of formula (VI) can be prepared by the methods disclosed herein and / or by methods known to those of ordinary skill in the art.

[0369]

[0370] Alternatively, the compound of formula (VIII) (wherein 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 are as defined herein and Hal is a halogen such as bromine or iodine) is reacted with a compound of formula (IX) (wherein A, R 1 , R 2 , R 9 and n are as defined herein) to prepare the compound of formula (IV). Such a reaction can be carried out in the presence of a catalytic amount of a palladium-containing compound such as bis(dibenzylideneacetone)palladium(0) (also known as Pd(dba)2), a phosphine ligand such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (also known as Xantphos), a base, and in an aprotic solvent. The base can be selected from organic bases such as tertiary amines, for example triethylamine, or inorganic bases such as cesium carbonate. The aprotic solvent can be, for example, toluene. The reaction of the compound of formula (VIII) with the compound of formula (IX) can be carried out at a temperature in the range of 25 °C to 200 °C, for example, such a reaction can be carried out at 100 °C in toluene. The compound of formula (IX) is commercially available or can be prepared by methods known to those of ordinary skill in the art or by methods similar to those described herein.

[0371]

[0372] The compound of formula (VIII) can be prepared by methods known to those of ordinary skill in the art. For example, the compound (1R,2S)-2-(3-bromo-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one can be prepared according to the scheme described below. Similarly, the compound (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-iodo-1H-indazol-6-yl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-carboxylic acid tert-butyl ester 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, by modifications obvious to those skilled in the art, for example by using different starting materials, appropriately protecting interfering groups, by changing other suitable reagents known in the art, or by making conventional modifications to the reaction conditions.

[0373]

[0374] Similarly, (1R,2S)-2-(3-iodo-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one can be prepared by reacting (1R,2S)-2-(1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one with iodine in DMF and methanol in the presence of potassium carbonate as described below.

[0375]

[0376] The compounds of formula (VI) can be prepared by methods known to those of ordinary skill in the art. For example, (1R,2S)-2-(3-amino-1-(tert-butoxycarbonyl)-1H-indazol-6-yl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-carboxylic acid tert-butyl ester can be prepared from (1R,2S)-2-(3-bromo-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one as described below.

[0377]

[0378] Compounds such as (1R,2S)-2-(3-amino-1-(tert-butoxycarbonyl)-1H-indazol-6-yl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-carboxylic acid tert-butyl ester 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 the compounds of the present disclosure. For example, (1R,2S)-2-(3-amino-1-(tert-butoxycarbonyl)-1H-indazol-6-yl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-carboxylic acid tert-butyl ester can be reacted with 4-chloro-5-methoxypyrimidine to give (1R,2S)-5'-methoxy-2-(3-((5-methoxypyrimidin-4-yl)amino)-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indoline]-2'-one.

[0379]

[0380] In the following preparations and examples, "Ac" means acetyl, "ACN" and "MeCN" mean acetonitrile, "Me" means methyl, "Et" means ethyl, "Ph" means phenyl, "BOC", "Boc" or "boc" mean N-tert-butoxycarbonyl, "DCM" (CH2Cl2) means dichloromethane, "DIPEA" or "DIEA" mean diisopropylethylamine, "DMA" means N,N-dimethylacetamide, "DMAP" means 4-(dimethylamino)pyridine, "DMF" means N,N-dimethylformamide, "DMSO" means dimethyl sulfoxide, "DPPP" means 1,3-bis(diphenylphosphino)propane, "HOAc" means acetic acid, "IPA" means isopropyl alcohol, "min" means minute, "NMP" means 1-methyl-2-pyrrolidone, "TEA" means triethylamine, "TFA" means trifluoroacetic acid, "DCM" means dichloromethane, "EtOAc" and "EA" mean ethyl acetate, "MgSO4" means magnesium sulfate, "Na2SO4" means sodium sulfate, "MeOH" means methanol, "Et2O" means diethyl ether, "EtOH" means ethanol, "H2O" means water, "HCl" means hydrochloric acid, "K2CO3" means potassium carbonate, "THF" means tetrahydrofuran, "DBU" means 1,8-diazabicyclo[5.4.0]undec-7-ene, "LiHMDS" or "LHMDS" mean lithium hexamethyldisilazide, "TBME" or "MTBE" mean tert-butyl methyl ether, "LDA" means lithium diisopropylamide, "N" means normal, "M" means molar, "mL" means milliliter, "mmol" means millimole, "μmol" means micromole, "eq." means equivalent, "°C" means degree Celsius, "Pa" means pascal, "rt" or "RT" mean room temperature, "h" means hour, "satd." means saturated, "aq" means aqueous solution, "anhyd." or "anh." mean anhydrous, "MBTE" means methyl tert-butyl ether, "PE" means petroleum ether, and "TBSCl" means tert-butyldimethylsilyl chloride.

[0381] Example Intermediate 1. (1R,2S)-2-(3-amino-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one

[0382]

[0383] Step A. (E)-3-(3-fluoro-4-isocyanobenzylidene)-5-methoxyindolin-2-one

[0384]

[0385] Charge a round-bottom flask 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). Reflux the reaction for 4 h and stir at room temperature for 16 h. Cool the reaction to 0 °C and collect the resulting precipitate by filtration and dry to give the title compound as a dark red solid (5.10 g, 57%). m / z (ESI, positive ion) = 295.0 [M+H] + .

[0386] Step B. (±)-2-Fluoro-4-((1R,2S)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indolin]-2-yl)benzonitrile

[0387]

[0388] At 0 °C and under nitrogen, add sodium hydride (60% dispersion in oil) (81.5 mg, 2.04 mmol) to a solution of trimethylsulfoxonium iodide (4.20 g, 19.1 mmol) in anhydrous DMF (173 mL). Stir the mixture for 15 min, then add (E)-3-(3-fluoro-4-isocyano-benzylidene)-5-methoxyindolin-2-one (5.10 g, 17.3 mmol) to the solution and stir the reaction at room temperature for 1 h. Quench the solution with saturated aqueous ammonium chloride and extract with EtOAc. Then wash the organic layer with brine, dry over anhydrous Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by column chromatography (10% to 65% EtOAc / heptane, gradient elution) to give the title compound as an orange solid (1.50 g, 28%). The NOESY NMR experiment confirmed the relative stereochemistry. m / z (ESI, positive 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 diastereomer was found to be less polar and eluted first under the given conditions. m / z (ESI, positive 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)。

[0389] Step C. (1R,2S)-2-(3-Amino-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one

[0390]

[0391] 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), and then hydrazine hydrate solution (50.0 μL, 1.58 mmol) was added. The reaction was refluxed for 16 h. The reaction was cooled to room temperature, and silica was added directly to the mixture and concentrated. The product was purified by column chromatography (0 to 20% MeOH / DCM, gradient elution) to give the title compound as a colorless oil (60.0 mg, 58%). m / z (ESI, positive ion) = 321.1 [M+H] + 。

[0392] Intermediate 2. (1R,2S)-2-(1H-Indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one

[0393]

[0394] Step A. 1-Benzyl-5-methoxyindoline-2,3-dione

[0395]

[0396] Benzyl bromide (9.65 mL, 79.7 mmol) was added to a mixture of 5-methoxyisatin (12.0 g, 66.4 mmol) and potassium carbonate (27.5 g, 199 mmol) in acetonitrile (250 mL). The mixture was stirred at 80 °C for 15 h and then cooled to room temperature. The mixture was filtered and the filtrate was concentrated. It was diluted with water (300 mL) and extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine, then dried (Na2SO4), filtered and concentrated. The resulting solid was triturated with heptane, filtered and washed with heptane to give the title compound as a solid (18.2 g, quantitative yield). m / z (ESI, positive 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).

[0397] Step B. 1-Benzyl-5-methoxyindolin-2-one

[0398]

[0399] Hydrazine monohydrate (8.64 mL, 107 mmol) was added to a mixture of 1-benzyl-5-methoxyindoline-2,3-dione (18.2 g, 68.1 mmol) in DMSO (44.1 mL). The mixture was stirred at 140 °C for 5 h and then cooled to room temperature. The mixture was diluted with water (300 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with 1 M H2SO4, brine (twice), then dried (Na2SO4), filtered and concentrated to give the title compound as a dark oil (14.0 g, 81%). m / z (ESI, positive 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).

[0400] Step C. 1-Benzyl-6-bromo-1H-indazole

[0401] 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 min and then benzyl chloride (20.8 mL, 179 mmol) was added slowly at 0 °C. The mixture was stirred at room temperature for 3 h, 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 stirred homogeneously at 150 °C. After 6 h, 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 title compound as a solid (20.6 g, 67%). m / z (ESI, positive ion) = 287.0 [M+H] + 。

[0402] Step D. 1-Benzyl-6-vinyl-1H-indazole

[0403]

[0404] 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 pre-degassed (bubbled with nitrogen) 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, then dichlorobis(triphenylphosphine)palladium(II) (774 mg, 1.10 mmol) and the mixture was heated at 80 °C overnight. The mixture was diluted with heptane and washed with water (3×) and brine. The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (0 to 10% EtOAc / hexane, gradient elution) to give the title compound (3.80 g, 74%). m / z (ESI, positive 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).

[0405] Step E. (S)-1-(1-Benzyl-1H-indazol-6-yl)ethane-1,2-diol

[0406]

[0407] Add AD-mixture-α (83.7 g, 59.8 mmol) and t-BuOH / water (1:1) (598 mL) to a 500 mL flask to form a clear two-phase mixture with stirring. Cool the reaction mixture to 0 °C using an ice bath, then add 1-benzyl-6-vinyl-1H-indazole (14.0 g, 59.8 mmol). Stir the resulting mixture vigorously at 0 °C and heat it to room temperature as the ice bath warms up slowly. Stir the reaction mixture for 9 h. Quench the reaction by adding 92 g of sodium sulfite in portions. Stir the reaction mixture overnight. Dilute the reaction mixture with brine and DCM and filter it through a pad of diatomaceous earth. Extract the filtrate with DCM (4×) and dry the combined organic layers over MgSO4, filter, and concentrate. Recrystallize the crude product from toluene (80 mL) to obtain the title compound as a white solid (12.2 g, 76%). m / z (ESI, positive ion) = 269.2 [M + H] + 。99.1% ee.

[0408] Step F. (S)-1-(1-Benzyl-1H-indazol-6-yl)ethane-1,2-diyl dimethanesulfonate

[0409]

[0410] 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 by slow addition of methanesulfonyl chloride (7.77 mL, 100 mmol) over 15 minutes. The internal temperature increased to a maximum of 11 °C. The resulting mixture was stirred at 0 °C. After 6 h, LCMS showed 10% of the monomethanesulfonylated product. 0.400 mL of methanesulfonyl chloride and 0.600 mL of triethylamine were added. The mixture was stirred for 1 h and, after completion, diluted at 0 °C with DCM (500 mL) and 1 M aqueous HCl (200 mL). The layers were separated and the organic layer was washed with saturated aqueous NaHCO3 (2 × 200 mL), brine (200 mL), then dried (Na2SO4), filtered and concentrated. The crude material was passed through a small pad of Celite, eluting 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 as a white crystalline solid (17.5 g, 91%). m / z (ESI, positive 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).

[0411] Step G. (1R,2S)-1'-benzyl-2-(1-benzyl-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one

[0412]

[0413] 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 anhydrous THF (80 mL) was cooled in an ice bath. Sodium hydride (673 mg, 16.8 mmol) was added in portions, and the mixture was stirred at 0 °C for 15 min. A solution of 1-benzyl-5-methoxyindolin-2-one (3.40 g, 8.01 mmol) in anhydrous THF (50 mL) was added dropwise via an addition funnel. The reaction mixture was stirred at 0 °C for 3 h. The reaction was quenched with saturated NH4Cl solution, diluted with water, and extracted with EtOAc (3×). The organic layer was dried over anhydrous MgSO4 and concentrated to a crude product. The crude product was triturated with 3:1 hexane / EtOAc to afford the title compound as an orange solid (2.10 g, 54%). m / z (ESI, positive ion) = 486.2 [M+H] + 。

[0414] Step H. (1R,2S)-2-(1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one

[0415]

[0416] To a round-bottom flask equipped with a stir bar was added (1R,2S)-1'-benzyl-2-(1-benzyl-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one (4.00 g, 8.24 mmol) in THF (118 mL). The solution was cooled to 0 °C, and potassium tert-butoxide (23.0 mL, 165 mmol) was added in portions over 20 min, followed by DMSO (10.7 mL). Oxygen was bubbled through the solution at 0 °C for 1 h. The reaction was quenched at 0 °C with saturated aqueous NH4Cl and diluted with EtOAc (50 mL). The mixture was washed with saturated aqueous NH4Cl (1×) and extracted with EtOAc (2×). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was triturated in Et2O and recrystallized from ethanol to afford the title compound (2.56 g, 56%). m / z (ESI, positive ion) = 306.4 [M+H] + 。

[0417] Intermediate 3a: (1R,2S)-2-(3-bromo-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one

[0418]

[0419] In a flask, (1R,2S)-2-(1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one (4.49 g, 12.5 mmol) was dissolved in DMF (16.7 mL), and NBS (2.70 g, 15.0 mmol) dissolved in DMF (8.33 mL) was added dropwise at 0 °C. The reaction was stirred at room temperature for 2 h. The reaction was quenched with an aqueous solution of Na2S2O3 and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by column chromatography (40% to 100% EtOAc / hexane, gradient elution) to give the title compound (3.12 g, 65%). m / z (ESI, positive ion) = 384.0, 386.0 [M+H] + 。

[0420] Intermediate 3b: (1R,2S)-2-(3-iodo-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one

[0421]

[0422] (1R,2S)-2-(1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one (4.00 g, 13.1 mmol) was added to an oven-dried flask, followed by DMF (8 mL) and methanol (8 mL). K2CO3 (3.62 g, 26.2 mmol) was added to this suspension. Finally, molecular iodine (4.32 g, 17.0 mmol) was dissolved in DMF (8 mL), added dropwise and allowed to stir at room temperature. After 4 h, the reaction was complete. The mixture was quenched with an aqueous solution of Na2S2O3 and stirred for 2 h. The solid was collected by filtration and washed with water. The wet solid was frozen and lyophilized to give the title compound (4.4 g, 78% yield).

[0423] 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

[0424]

[0425] 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'-indoline]-2'-one (2.46 g, 6.40 mmol) in DCM (24 mL). The solution was stirred at room temperature for 16 h. LCMS showed incomplete conversion. Di-tert-butyl dicarbonate (0.75 mL, 3.2 mmol, 0.5 eq) was added and the reaction was stirred for an additional hour. The crude product was purified by column chromatography (0 to 20% EtOAc / heptane, gradient elution) to give the title compound as a yellow foamy solid (3.06 g, 82%). m / z (ESI, positive ion) = 384.0, 386.0 [M+H-Boc] + 。

[0426] Intermediate 4b: (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-iodo-1H-indazol-6-yl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-carboxylic acid tert-butyl ester

[0427]

[0428] 4-Dimethylaminopyridine (9.0 mg, 0.07 mmol) was added to an oven-dried flask, followed by (1R,2S)-2-(3-iodo-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one (637 mg, 1.48 mmol), N-ethyl-N-isopropylpropan-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 light 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%).

[0429] 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

[0430]

[0431] 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

[0432]

[0433] Charge a microwave vial with tert-butyl 3-bromo-6-((1R,2S)-1'-(tert-butoxycarbonyl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-2-yl)-1H-indazole-1-carboxylate (1.00 g, 1.71 mmol), cesium carbonate (1.14 g, 3.42 mmol), Pd2(dba)3 (157 mg, 171 μmol), and XantPhos (101 mg, 171 μmol). Add anhydrous dioxane (17.1 mL), then add diphenylketimine (310 μL, 1.83 mmol), and bubble nitrogen through the reaction mixture for 5 min. Seal the vial and heat the reaction mixture in an oil bath at 90 °C for 2 h. Add saturated aqueous NaHCO3 and extract the reaction mixture with EtOAc (3×). Then wash the combined extracts with brine, dry over anhydrous Na2SO4, filter, and concentrate in vacuo. Purify the crude product by column chromatography (0 to 30% EtOAc / heptane, gradient elution) to afford the title compound as a yellow oil (1.03 g, 88%). m / z (ESI, positive ion) = 685.4 [M+H] + 。

[0434] 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

[0435]

[0436] At room temperature, 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 anhydrous MeOH (1.46 mmol) and the reaction was stirred for 16 h. The solvent was removed under reduced pressure. The crude product was purified by column chromatography (0 to 60% EtOAc / heptane, gradient elution) to give the title compound as a yellow solid (640 mg, 84%). m / z (ESI, positive ion) = 521.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.78 (d, J = 8.9 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.66 (dd, J = 8.9, 2.6 Hz, 1H), 5.55 (d, J = 2.3 Hz, 1H), 4.44 (s, 2H), 3.49 (t, J = 8.6 Hz, 1H), 3.37 (s, 3H), 2.34 (dd, J = 9.2, 4.8 Hz, 1H), 2.14 - 2.06 (m, 1H), 1.67 (d, J = 2.4 Hz, 18H).

[0437] Example 2. (1R,2S)-2-{3-[4-(Methylsulfonyl)-2-methoxyanilino]-1H-indazol-6-yl}-5’-methoxyspiro[cyclopropane-1,3’-indol]-2’(1’H)-one

[0438]

[0439] Step A. (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’-carboxylic acid tert-butyl ester

[0440]

[0441] 4-Methylsulfonyl-2-methoxyaniline (35.06 mg, 0.174 mmol, 1.1 eq), (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-iodo-1H-indazol-6-yl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-carboxylic acid tert-butyl ester (100 mg, 0.158 mmol, 1.00 eq), Pd2(dba)3 (19 mg, 0.031 mmol, 0.2 eq), XantPhos (18 mg, 0.031 mmol, 0.2 eq), Cs2CO3 (103 mg, 0.316 mmol, 2 eq) and toluene (3 mL) were added to a 40 mL vial at 25 °C. The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with EtOAc (3 x 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 as a pale yellow solid (110 mg, 90%). m / z (ESI, positive ion) = 705.30 [M+H] + 。

[0442] Step B. (1R,2S)-2-{3-[(4-Methylsulfonyl-2-methoxyphenyl)amino]-1H-indazol-6-yl}-5'-methoxy-1'H-spiro[cyclopropane-1,3'-indole]-2'-one

[0443]

[0444] (1R,2S)-2-[1-(tert-Butoxycarbonyl)-3-[(4-methylsulfonyl-2-methoxyphenyl)amino]indazol-6-yl]-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indole]-1'-carboxylic acid tert-butyl ester (110 mg, 0.156 mmol, 1 eq) and HFIP (10 mL) were added to a 40 mL vial at 25 °C. The resulting mixture was stirred at 60 °C for 12 h. The mixture was concentrated and the crude product was purified by preparative HPLC using the following conditions: column: XBridge Shield RP18 OBD column, 30 x 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 in 10 min, 45% B; wavelength: 254 nm; RT1 (min): 8.5 to give Example 2 as a white solid (36.3 mg, 46.10%). m / z (ESI, positive ion) = 505.15 [M+H] + 。 1H-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).

[0445] 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'-indole]-2'(1'H)-one

[0446]

[0447] Step A. N-(6-Bromo-3-methoxypyridin-2-yl)-N-(tert-butoxycarbonyl)carbamic acid tert-butyl ester

[0448]

[0449] 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 / PE to give the title compound as a yellow solid (350 mg, 70.49%). m / z (ESI, positive ion) = 403.15, 405.05 [M+H] + .

[0450] Step B. N-(tert-Butoxycarbonyl)-N-[3-methoxy-6-(1,3-oxazol-2-yl)pyridin-2-yl]carbamic acid tert-butyl ester

[0451]

[0452] To a solution of N-(6-bromo-3-methoxypyridin-2-yl)-N-(tert-butoxycarbonyl)carbamic acid tert-butyl ester (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)2 (18.37 mg, 0.082 mmol, 0.1 equiv), PCy3·BF4 (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 K2CO3 (339.28 mg, 2.454 mmol, 3 equiv). Under a nitrogen atmosphere, the resulting mixture was stirred at 110 °C for 16 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 0 - 20% MeOH / DCM, to give the title compound as a yellow solid (240 mg, 59.94%). m / z (ESI, positive ion) = 392.15 [M+H] + 。

[0453] Step C. 3-Methoxy-6-(1,3-oxazol-2-yl)pyridin-2-amine

[0454]

[0455] A solution of N-(tert-butoxycarbonyl)-N-[3-methoxy-6-(1,3-oxazol-2-yl)pyridin-2-yl]carbamic acid tert-butyl ester (230 mg, 0.588 mmol, 1 equiv) in DCM (1.6 mL) and TFA (0.4 mL) was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure to give the title compound as a yellow oil (85 mg, crude). m / z (ESI, positive ion) = 192.10 [M+H] + 。

[0456] Step D. (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'-carboxylic acid tert-butyl ester

[0457]

[0458] 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 Pd2(dba)3 (34.80 mg, 0.038 mmol, 0.2 equiv), XantPhos (21.99 mg, 0.038 mmol, 0.2 equiv) and Cs2CO3 (185.75 mg, 0.570 mmol, 3 equiv). After stirring at 90 °C for 1 h under a nitrogen atmosphere, 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 as a yellow solid (100 mg, 75.74%). m / z (ESI, positive ion) = 695.50 [M+H] + /

[0459] 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

[0460]

[0461] 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'-indoline]-1'-carboxylate (100 mg, 0.144 mmol, 1 equiv) in HFIP (1.5 mL) was stirred at 60 °C for 16 h. 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 in 8 min, 39% B; wavelength: 220 nm; RT1 (min): 7.92; The fractions were concentrated under reduced pressure and then lyophilized overnight to give Example 4 as a pale yellow solid (30 mg, 42.15%). m / z (ESI, positive ion) = 495.20 [M+H] + 。 1H-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).

[0462] Example 5. (1R,2S)-2-{3-[4-(Ethanesulfonyl)-2-methoxyanilino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one

[0463]

[0464] Step A. 4-(Ethanesulfonyl)-2-methoxyaniline

[0465]

[0466] At room temperature, under a nitrogen atmosphere, CuI (20 mg, 0.105 mmol, 0.11 equiv), sodium ethanesulfinate (170 mg, 1.464 mmol, 1.48 equiv) and K3PO4 (210 mg, 0.989 mmol, 1.00 equiv) were added 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). The resulting mixture was stirred at 120 °C for 16 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (10 mL). The mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 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 as a pale yellow solid (140 mg, 65.70%). m / z (ESI, positive ion) = 216.05 [M+H] + 。

[0467] Step B. (1R,2S)-2-[1-(tert-Butoxycarbonyl)-3-{[4-(ethylsulfonyl)-2-methoxyphenyl]amino}indazole-6-yl]-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indole]-1'-carboxylic acid tert-butyl ester

[0468]

[0469] To a solution of 4-(ethylsulfonyl)-2-methoxyaniline (18 mg, 0.084 mmol, 1.06 equiv) and (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-iodoindazole-6-yl]-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indole]-1'-carboxylic acid tert-butyl ester (50 mg, 0.079 mmol, 1.00 equiv) in toluene (2 mL) was added Cs2CO3( 55 mg, 0.169 mmol, 2.13 equiv), Pd2(dba)3 (15 mg, 0.016 mmol, 0.21 equiv) and XantPhos (10 mg, 0.017 mmol, 0.22 equiv). The mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere and then 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 as a pale yellow solid (30 mg, 52.71%). m / z (ESI, positive ion) = 719.25 [M+H] + .

[0470] Step C. (1R,2S)-2-{3-[4-(ethylsulfonyl)-2-methoxyanilinyl]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one

[0471]

[0472] Add (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[4-(ethylsulfonyl)-2-methoxyphenyl]amino}indazole-6-yl]-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indole]-1'-carboxylic acid tert-butyl ester (80 mg, 0.111 mmol, 1 equiv) and HFIP (1 mL) to an 8 mL vial at room temperature. Stir the mixture at 60 °C for 16 h under a nitrogen atmosphere. Let the mixture cool to room temperature. Concentrate the resulting mixture under reduced pressure. Purify the crude product by preparative HPLC using the following conditions (column: XBridge Prep Phenyl OBD column, 19 x 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 32% B to 42% B in 9 min, 42% B; wavelength: 254 nm; RT1 (min): 8) to give Example 5 as a white solid (18.4 mg, 31.88%). m / z (ESI, positive ion) = 519.20 [M+H] + 。 1 1H-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).

[0473] Example 6. 6-Methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)-1H-1-benzothiophene-1,1-dione

[0474]

[0475] Step A. Methyl 6-methoxy-5-nitro-1-benzothiophene-2-carboxylate

[0476]

[0477] At room temperature under a nitrogen atmosphere, K2CO3 (1665.65 mg, 12.052 mmol, 2 equiv) was added to a stirred mixture of 2-fluoro-4-methoxy-5-nitrobenzaldehyde (1200 mg, 6.026 mmol, 1 equiv) and methyl mercaptoacetate (767.52 mg, 7.231 mmol, 1.2 equiv) in DMF (15 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 h. 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 as a yellow solid (850 mg, 52.78%). m / z (ESI, positive ion) = 268.10 [M+H] + Step B. 6-Methoxy-5-nitro-1-benzothiophene-2-carboxylic acid

[0478]

[0479] Under a nitrogen atmosphere, at room temperature, NaOH (478.90 mg, 11.972 mmol, 4 equiv) was added to a stirred mixture of methyl 6-methoxy-5-nitro-1-benzothiophene-2-carboxylate (800 mg, 2.993 mmol, 1 equiv) in H2O (5 mL) and MeOH (5 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The mixture was basified to pH 7 with HCl (2 mol / L aqueous solution). The precipitated solid was collected by filtration and washed with water (3 x 10 mL). The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10 / 1), to give the title compound as a white solid (480 mg, 63.32%). 1 H 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).

[0480] Step C. 6-Methoxy-5-nitro-1-benzothiophene

[0481]

[0482] At room temperature, 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 to a 40 mL vial. The resulting mixture was stirred at 170 °C for 2 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The mixture was acidified to pH 7 with HCl (2 mol / L). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were 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 as a yellow solid (210 mg, 84.72%). 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).

[0483] Step D. 6-Methoxy-5-nitrobenzo[b]thiophene 1,1-dioxide

[0484]

[0485] A compound 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 for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH 10 / 1) to give the title compound as a white solid (290 mg, 89.83%). 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).

[0486] Step E. 5-Amino-6-methoxybenzo[b]thiophene 1,1-dioxide

[0487]

[0488] At room temperature, under a nitrogen atmosphere, NH4Cl (110.87 mg, 2.075 mmol, 5 eq) was added to a stirred solution of 6-methoxy-5-nitrobenzo[b]thiophene 1,1-dioxide (100 mg, 0.415 mmol, 1 eq) and Fe (115.76 mg, 2.075 mmol, 5 eq) in EtOH (4 mL) and H2O (1 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The mixture was filtered and the filter cake was washed with EtOAc (3 x 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 positive ion) = 212.05 [M+H] + 。

[0489] Step F. (1R,2S)-2-[1-(tert-Butoxycarbonyl)-3-[(6-methoxy-1,1-dioxido-1λ6-benzo[b]thiophen-5-yl)amino]indazol-6-yl]-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indole]-1'-carboxylic acid tert-butyl ester

[0490]

[0491] At room temperature under a nitrogen atmosphere, Pd2(dba)3 (29.00 mg, 0.032 mmol, 0.2 eq), XantPhos (18.33 mg, 0.032 mmol, 0.2 eq) and Cs2CO3 (103.19 mg, 0.316 mmol, 2 eq) were added to a stirred solution of 5-amino-6-methoxy-1λ6-benzo[b]thiophene-1,1-dione (40.14 mg, 0.190 mmol, 1.2 eq) and (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-iodoindazol-6-yl]-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indole]-1'-carboxylic acid tert-butyl ester (100 mg, 0.16 mmol, 1.00 eq) in toluene (5 mL). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 2 h. The residue was purified by preparative TLC (PE / EtOAc = 1 / 1) to give the title compound as a yellow solid (95 mg, 83.93%). m / z (ESI, positive ion) = 715.25 [M+H] + 。

[0492] Step G. 6-Methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)-1H-1-benzo[b]thiophene-1,1-dione

[0493]

[0494] (1R,2S)-2-[1-(tert-Butoxycarbonyl)-3-[(6-methoxy-1,1-dioxido-1λ6-benzo[b]thiophen-5-yl)amino]indazol-6-yl]-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indole]-1'-carboxylic acid tert-butyl ester (95 mg, 0.133 mmol, 1 equiv) and HFIP (5 mL) were added to an 8 mL vial at room temperature. The resulting mixture was stirred at 60 °C for 16 h under a nitrogen atmosphere. The mixture was allowed to cool 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 x 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 in 8 min, 50% B; wavelength: 254 nm; RT1 (min): 7.8, to give Example 6 as a white solid (30.5 mg, 44.38%). m / z (ESI, positive ion) = 515.15 [M+H] + 。 1 1H-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 = 6.8 Hz, 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).

[0495] 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'-indole]-2'(1'H)-one

[0496]

[0497] Step A. 5-Bromo-2-methoxyaniline

[0498]

[0499] At room temperature, 4-bromo-1-methoxy-2-nitrobenzene (2 g, 8.619 mmol, 1 equiv), Fe (2.4 g, 42.976 mmol, 4.99 equiv), NH4Cl (2.30 g, 43.009 mmol, 4.99 equiv), EtOH (10 mL) and water (2.5 mL) were added to a 50 mL round-bottom flask. The mixture was stirred at room temperature for 3 h under a nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with EtOH (3 x 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 as a yellow solid (1.45 g, 83.26%). m / z (ESI, positive ion) = 201.90, 203.90 [M+H] + 。

[0500] Step B. 2-Methoxy-5-(1,3-thiazol-2-yl)aniline

[0501]

[0502] Under a nitrogen atmosphere at room temperature, 2-(tributylstannyl)-1,3-thiazole (380 mg, 1.016 mmol, 1.03 equiv) was added to a stirred mixture of 5-bromo-2-methoxyaniline (200 mg, 0.990 mmol, 1.00 equiv), Pd(dppf)Cl2·CH2Cl2 (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). Under a nitrogen atmosphere, the mixture was stirred at 100 °C for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (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 (1 / 1) to give the title compound as a pale yellow solid (130 mg, 63.67%). m / z (ESI, positive ion) = 207.00 [M+H] + 。

[0503] Step C. (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'-carboxylic acid tert-butyl ester

[0504]

[0505] 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 Cs2CO3 (100 mg, 0.307 mmol, 1.94 equiv), Pd2(dba)3 (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 for 2 h 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 as a pale yellow solid (80 mg, 71.17%). m / z (ESI, positive ion) = 710.20 [M+H] + 。

[0506] 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'-indole]-2'(1'H)-one

[0507]

[0508] At room temperature, 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 equiv) and HFIP (2 mL) were added to an 8 mL vial. The mixture was stirred at 60 °C for 12 h under a nitrogen atmosphere. 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, 19x250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeOH--HPLC; flow rate: 20 mL / min; gradient: from 70% B to 75% B in 8 min, 75% B; wavelength: 254 nm; RT1 (min): 10), to give Example 14 as a white solid (28.1 mg, 48.93%). m / z (ESI, positive 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). 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'-indole]-2'(1'H)-one

[0509]

[0510] Step A. 2-Methoxy-5-(1,3-thiazol-4-yl)aniline

[0511]

[0512] 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 for 2 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (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 DCM / MeOH (10 / 1) to give the title compound as a light brown solid (90 mg, 44.08%). m / z (ESI, positive ion) = 207.05 [M + H] + 。

[0513] Step B. (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’-carboxylic acid tert-butyl ester

[0514]

[0515] To a solution of (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-iodoindazol-6-yl]-5’-methoxy-2’-oxospiro[cyclopropane-1,3’-indole]-1’-carboxylic acid tert-butyl ester (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 Cs2CO3 (100 mg, 0.307 mmol, 1.94 equiv), Pd2(dba)3 (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 for 2 h 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 as a pale yellow solid (60 mg, 53.38%). m / z (ESI, positive ion) = 710.35 [M+H] + 。

[0516] 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’-indole]-2’(1’H)-one

[0517]

[0518] At room temperature, (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[2-methoxy-5-(1,3-thiazol-4-yl)phenyl]amino}indazole-6-yl]-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indole]-1'-carboxylic acid tert-butyl ester (60 mg, 0.085 mmol, 1 equiv), TFA (1 mL), and DCM (3 mL) were added to an 8 mL vial. The mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. 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 x 250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeOH--HPLC; flow rate: 20 mL / min; gradient: from 70% B to 75% B in 8 min, 75% B; wavelength: 254 nm; RT1 (min): 8), to give Example 15 as a white solid (21.1 mg, 48.99%). m / z (ESI, positive ion) = 510.15 [M+H] + 。 1 1H-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).

[0519] Example 25: (1R,2S)-5'-Methoxy-2-{3-[(5-methoxy[2,5'-bipyrimidine]-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one

[0520]

[0521] Step A: 5-Methoxy-2-pyrimidin-5-yl-pyrimidin-4-amine

[0522]

[0523] To a mixture of 2-chloro-5-methoxypyrimidin-4-amine (100 mg, 0.63 mmol), 5-pyrimidylboronic 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) was added MeCN (3 mL) and water (1.5 mL). 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, eluted with DCM and the filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography (0 - 100% acetone / hexane) to give the product as a pale yellow solid (37.2 mg, 29%). m / z (ESI, positive ion) = 204.2 [M+H]+.

[0524] Step B: (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'-carboxylic acid tert-butyl ester

[0525]

[0526] To a vial was added (1R,2S)-2-(1-tert-butoxycarbonyl-3-iodo-indazol-6-yl)-5'-methoxy-2'-oxo-spiro[cyclopropane-1,3'-indoline]-1'-carboxylic acid tert-butyl ester (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), then 1,4-dioxane (1.6 mL) was added. Argon was bubbled through the solution for 3 min, then the reaction mixture was heated to 100 °C and maintained for 2 h, then heated to 110 °C and maintained for another 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 / hexane) to give the product as a brown solid (7.2 mg, 6%). m / z (ESI, positive ion) = 708.4 [M+H]+.

[0527] 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'-indoline]-2'-one

[0528]

[0529] The solution of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[(5-methoxy-2-pyrimidin-5-ylpyrimidin-4-yl)amino]indazol-6-yl]-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-carboxylate (7.2 mg, 0.01 mmol) in hexafluoroisopropanol (0.5 mL) was heated to 50 °C and maintained 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 (2.2 mg, 43%). m / z (ESI, positive 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).

[0530] 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

[0531]

[0532] Step A. 6-Bromo-3-ethoxypyridin-2-amine

[0533]

[0534] At room temperature under a nitrogen atmosphere, Cs2CO3 (1.03 g, 3.17 mmol, 2.00 equiv) was added 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). The resulting mixture was stirred at 50 °C for 16 h 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 as a white solid (280 mg, 81.3%). m / z (ESI, positive ion) = 217.15, 219.15 [M+H] + 。

[0535] Step B. 3-Ethoxy-6-(thiazol-2-yl)pyridin-2-amine

[0536]

[0537] At room temperature under a nitrogen atmosphere, Pd(dppf)Cl2·CH2Cl2 (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 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). The resulting mixture was stirred at 90 °C for 3 h 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 as a white solid (125 mg, 49.1%). m / z (ESI, positive ion) = 222.05 [M+H] + 。

[0538] Step C. (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'-carboxylic acid tert-butyl ester

[0539]

[0540] At room temperature under a nitrogen atmosphere, Pd2(dba)3 (29.0 mg, 0.032 mmol, 0.20 equiv), XantPhos (18.3 mg, 0.032 mmol, 0.200 equiv), and Cs2CO3 (103 mg, 0.316 mmol, 2.00 equiv) were added to a stirred mixture of 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]-1'-carboxylate (100 mg, 0.158 mmol, 1.00 equiv) in toluene (5 mL). The resulting mixture was stirred at 90 °C for 1 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EtOAc 1 / 1) to give the title compound as a yellow solid (79 mg, 69%). m / z (ESI, positive ion) = 725.25 [M+H] + .

[0541] 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

[0542]

[0543] At room temperature, 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) were added to an 8 mL vial. The resulting mixture was stirred at 60 °C for 16 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30 x 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 in 11 min, 50% B; wavelength: 220 nm; RT1 (min): 9.20 to give Example 28 as a white solid (14 mg, 25.8%). m / z (ESI, positive ion) = 525.25 [M+H] + . 1H-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).

[0544] Example 33. (1R,2S)-2-{3-[2-Ethoxy-5-(1,3-thiazol-2-yl)anilino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one

[0545]

[0546] Step A. 2-Ethoxy-5-(1,3-thiazol-2-yl)aniline

[0547]

[0548] Under a nitrogen atmosphere at room temperature, CuI (97.0 mg, 0.509 mmol, 0.500 eq) and LiCl (86.3 mg, 2.04 mmol, 2.00 eq) were added to a stirred solution of 5-bromo-2-ethoxyaniline (220 mg, 1.02 mmol, 1.00 eq), Pd(dppf)Cl2·CH2Cl2 (82.9 mg, 0.102 mmol, 0.100 eq) and 2-(tributylstannyl)-1,3-thiazole (571 mg, 1.53 mmol, 1.50 eq) in DMF (5 mL). The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The mixture was allowed to cool 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 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), 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 as an off-white solid (65 mg, 29%). m / z (ESI, positive ion) = 221.10 [M + H] + .

[0549] Step B. (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'-carboxylic acid tert-butyl ester

[0550]

[0551] At room temperature under a nitrogen atmosphere, XantPhos (18.3 mg, 0.032 mmol, 0.20 equiv) and Pd2(dba)3 (29.0 mg, 0.032 mmol, 0.20 equiv) were added to a stirred solution of (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-iodoindazol-6-yl]-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indole]-1'-carboxylic acid tert-butyl ester (100 mg, 0.158 mmol, 1.00 equiv), Cs2CO3 (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) in toluene (3 mL). Under a nitrogen atmosphere, the resulting mixture was stirred at 90 °C for 2 h. The mixture was allowed to cool 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 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), 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 as an off-white solid (110 mg, 97%). m / z (ESI, positive ion) = 724.30 [M+H] + 。

[0552] 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'-indole]-2'-one

[0553]

[0554] 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 h. 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 x 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 in 11 min, 52% B; wavelength: 220 nm; RT1 (min): 10.23, to give Example 33 as an off-white solid (22.2 mg, 27.5%). m / z (ESI, positive ion) = 524.15 [M+H] + 。 1 1H-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).

[0555] 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'-indole]-2'(1'H)-one

[0556]

[0557] Step A. 4-Amino-2-chloropyrimidin-5-ol

[0558]

[0559] At room temperature, 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 to a 100 mL vial. The resulting mixture was stirred at room temperature for 16 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. 4-Amino-2-chloropyrimidin-5-ol as a yellow solid was obtained (420 mg, 92%). The crude product was used directly in the next step without further purification. m / z (ESI, positive ion) = 146.05 [M+H] + 。

[0560] Step B. 2-Chloro-5-ethoxypyrimidin-4-amine

[0561]

[0562] At room temperature, 4-amino-2-chloropyrimidin-5-ol (400 mg, 2.75 mmol, 1.00 equiv), iodoethane (343 mg, 2.20 mmol, 0.800 equiv), Cs2CO3 (2695 mg, 8.271 mmol, 3.01 equiv) and acetone (10 mL) were added to an 8 mL vial. The resulting mixture was stirred at 60 °C for 16 h under a nitrogen atmosphere. The resulting mixture was extracted with EtOAc (5 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), 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 as a white solid (230 mg, 48.2%). m / z (ESI, positive ion) = 174.05 [M+H] + 。

[0563] Step C. 5-Ethoxy-2-(1,3-thiazol-2-yl)pyrimidin-4-amine

[0564]

[0565] Under an argon atmosphere, Pd(dppf)Cl2 (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 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) at room temperature. The resulting mixture was stirred for an additional 2 h at 110 °C. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc) to give the title compound as a white solid (65 mg, 42%). m / z (ESI, positive ion) = 223.00 [M+H] + 。

[0566] Step D. (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'-carboxylic acid tert-butyl ester

[0567]

[0568] At room temperature under an argon atmosphere, 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 to a stirred mixture of 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]-1'-carboxylate (79.5 mg, 0.126 mmol, 1.00 equiv) in toluene (4 mL). The resulting mixture was stirred at 60 °C for an additional 2 h. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2 / MeOH 15 / 1) to afford the title compound as a white solid (37 mg, 40%). m / z (ESI, positive ion) = 726.30 [M+H] + .

[0569] 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'-indole]-2'-one

[0570]

[0571] Under an argon atmosphere, at room temperature, 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}indazole-6-yl]-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indole]-1'-carboxylate (35 mg, 0.048 mmol, 1.0 equiv) in HFIP (2 mL). The resulting mixture was stirred at 60 °C for an additional 5 h. The resulting mixture was concentrated under reduced pressure. The crude product (50 mg) was purified by preparative HPLC using 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 as a white solid (16.2 mg, 62%). m / z (ESI, positive 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).

[0572] The compounds in Table 1B were prepared using materials and methods similar to those disclosed herein and methods known to those of ordinary skill in the art.

[0573] Table 1B

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603] Biological Activity Examples

[0604] Biological Activity Example 1: PLK4 Biochemical Assay

[0605] The activity of human recombinant PLK4 (ThermoFisher, catalog number PV6396) was measured by quantifying adenosine diphosphate (ADP) using the ADP-Glo Kinase Assay Kit (Promega, catalog number V9102). Test compounds were dissolved in dimethyl sulfoxide (DMSO) and dispensed in duplicate into 384-well white polystyrene non-binding plates (Greiner, catalog number 781094) in an 11-point 3-fold titration using an Echo acoustic dispenser (Labcyte Inc.). 5 μL 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 plates. The test compounds and PLK4 were incubated at room temperature (RT) for 15 minutes. Then 5 μL of 16 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 were added, and the reaction mixture was incubated at room temperature 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 number V912B) and incubating at room temperature for 40 minutes. The conversion of the remaining ADP to ATP and the measurement of newly synthesized ATP were achieved simultaneously by adding 20 μL of kinase detection reagent (Promega, catalog number V914B), incubating at room temperature for 30 min, and performing luminescence detection using an EnVision microplate reader (PerkinElmer). A reaction lacking PLK4 was used as a 100% inhibition control. A reaction containing only DMSO was used as a 0% inhibition control. Four-parameter nonlinear regression curve fitting was used to determine the IC 50 values reported in Table 2.

[0606] Biological Activity Example 2: CHP134 CellTiter-Glo (CTG) Assay

[0607] 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 hours. On the next day, in 96-well plates, nine consecutive 1:3 compound dilutions were prepared in DMSO. The compounds were then further diluted into the growth medium using a BRAVO robot (Agilent, Santa Clara, CA). The diluted compounds were then added to four replicate wells of the 384-well cell plates and incubated at 37 °C and 5% CO2. After 5 days, according to the manufacturer's instructions, the relative number of live cells was measured by luminescence using CellTiter-Glo (Promega), and read on a SPARK multimode microplate reader (Tecan, Mannedorf Switzerland). The values reported in Table 2 were used to perform IC 50 calculations using Prism 6.0 software (GraphPad, San Diego).

[0608] Biological Activity Example 3: Aurora A Kinase Biochemical Assay

[0609] The activity of human recombinant Aurora A (ThermoFisher, catalog number PR5935A) was measured by quantifying adenosine diphosphate (ADP) using the ADP-Glo Kinase Assay Kit (Promega, catalog number V9102). The test compound was dissolved in dimethyl sulfoxide (DMSO) and dispensed in duplicate into a 384-well white polystyrene non-binding plate (Greiner, catalog number 781094) in an 11-point 3-fold titration using an Echo acoustic dispenser (Labcyte Inc.). 5 μL of 5.0 nM Aurora A 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 Aurora A were incubated at room temperature (RT) for 15 minutes. Then 5 μL 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 were 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. The conversion of the remaining ADP to ATP and the measurement of newly synthesized ATP were achieved simultaneously by adding 20 μL of kinase detection reagent (Promega, catalog number V914B), incubating at room temperature for 30 min, and performing luminescence detection using an EnVision microplate reader (PerkinElmer). A reaction lacking Aurora A was used as a 100% inhibition control. A reaction containing only DMSO was used as a 0% inhibition control. Four-parameter nonlinear regression curve fitting was used to determine the IC 50 values.

[0610] Biological Activity Example 4: Aurora B Kinase Biochemical Assay

[0611] The activity of recombinant human Aurora B (ThermoFisher, catalog number PR9210B) was measured by quantifying adenosine diphosphate (ADP) using the ADP-Glo Kinase Assay Kit (Promega, catalog number V9102). The test compound was dissolved in dimethyl sulfoxide (DMSO) and dispensed in duplicate into a 384-well white polystyrene non-binding plate (Greiner, catalog number 781094) in an 11-point 3-fold titration using an Echo acoustic dispenser (Labcyte Inc.). 5 μL of 20 nM Aurora B 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 Aurora B were incubated at room temperature (RT) for 15 minutes. Then 5 μL of 228 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 were added, and the reaction mixture was incubated at room temperature 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 number V912B) and incubating at room temperature for 40 minutes. The conversion of the remaining ADP to ATP and the measurement of the newly synthesized ATP were achieved simultaneously by adding 20 μL of kinase detection reagent (Promega, catalog number V914B), incubating at room temperature for 30 min, and performing luminescence detection using an EnVision microplate reader (PerkinElmer). A reaction lacking Aurora B was used as a 100% inhibition control. A reaction containing only DMSO was used as a 0% inhibition control. Four-parameter nonlinear regression curve fitting was used to determine the IC 50 values.

[0612] As shown in Table 2, many compounds of formula (I), (Ia), (Ib), (II) and (III) show effective inhibition of PLK4 and weaker inhibition of Aurora A kinase and Aurora B kinase. Thus, the compounds of formula (I), (Ia), (Ib), (II) and (III) show selective inhibition of PLK4. Also as shown in Table 2, many compounds of formula (I), (Ia), (Ib), (II) and (III) surprisingly and unexpectedly demonstrate higher selectivity in inhibiting PLK4 relative to inhibiting Aurora A kinase and / or Aurora B kinase compared to the CFI-400495 compound. In Table 2, ND means not determined.

[0613] Table 2

[0614]

[0615] Embodiment

[0616] Embodiment 1. A compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0617]

[0618] Wherein:

[0619] Ring A is a C6-C 10 aryl or heteroaryl;

[0620] Each R 1 is 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl or heteroaryl; wherein each of said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl and heteroaryl is optionally and independently substituted by one or more R 1a substituents;

[0621] Or two R on adjacent atoms are joined together to form a C3-C 1 cycloalkyl or heteroalkyl; each of which is optionally substituted by one or more R 10 substituents; 1b

[0622] Each R 1a is independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b , -NRC(=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)NRc R d 、 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl or heteroaryl;

[0623] or two Rs on the same atom 1a together form oxo;

[0624] each R 1b is independently deuterium, halogen, -CN, -NO2, -OH, -OR a 、 -OC(=O)R a 、 -OC(=O)OR b 、 -OC(=O)NR c R d 、 -SH, -SR a 、 -S(=O)R a 、 -S(=O)2R a 、 -S(=O)2NR c R d 、 -NR c R d 、 -NR b C(=O)NR c R d 、 -NR b C(=O)R a 、 -NR b C(=O)OR a 、 -NR b S(=O)2R a 、 -C(=O)R a 、 -C(=O)OR b 、 -C(=O)NR c R d 、 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl or heteroaryl;

[0625] or two Rs on the same atom 1b together form oxo;

[0626] n is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0627] R2 is hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, or a C1-C6 deuterated alkyl group;

[0628] R 3 is hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, or a C1-C6 deuterated alkyl group;

[0629] R 4a 、R 4b and R 4c each independently is hydrogen, deuterium, a halogen, -CN, -NO2, -OH, -OR a 、-NR c R d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d 、a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 deuterated alkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 aminoalkyl group, or a C1-C6 heteroalkyl group;

[0630] R 5 is hydrogen, deuterium, a halogen, -CN, -OH, -OR a 、-NR c R d 、a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 deuterated alkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 aminoalkyl group, or a C1-C6 heteroalkyl group;

[0631] Each R 6 independently is hydrogen, deuterium, a halogen, -CN, -OH, -OR a 、-NR c R d 、a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 deuterated alkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 aminoalkyl group, or a C1-C6 heteroalkyl group;

[0632] R 7 is hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 deuterated alkyl group, a C1-C6 hydroxyalkyl group, or a C1-C6 aminoalkyl group;

[0633] R 8a 、R 8b 、R 8c and R 8d each independently is hydrogen, deuterium, a 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 、 -NR-C(=O)NR c R d 、 -NR b 、 -NR-C(=O)R a 、 -NR b 、 -NR-C(=O)OR a 、 -NR b 、 -NR-S(=O)R a 、 -C(=O)R a 、 -C(=O)OR b 、 -C(=O)NR c R d 、 C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ deuterated alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ aminoalkyl, C₁-C₆ heteroalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C 10 cycloalkyl, heteroalkyl, C₆-C 10 aryl or heteroaryl;

[0634] R 9 is optionally a heteroaryl substituted by one or more R 1a or an oxetanyl substituted by one or more R 1a ;

[0635] Each R a is independently hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ deuterated alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ aminoalkyl, C₁-C₆ heteroalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C 10 cycloalkyl, heteroalkyl, C₆-C 10 aryl, heteroaryl, C₁-C₆ alkyl(C₃-C 10 cycloalkyl), C₁-C₆ alkyl(heteroalkyl), C₁-C₆ alkyl(C₆-C 10 aryl) or C₁-C₆ alkyl(heteroaryl); wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C 10 cycloalkyl, heteroalkyl, C₆-C 10Each of the aryl and heteroaryl is independently optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0636] Each R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, 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); wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl and heteroaryl are each independently optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; and

[0637] Each R c and R d are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, 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 10cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(C6-C 10 aryl) or C1-C6 alkyl(heteroaryl); wherein said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl and heteroaryl are each independently optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0638] or R c and R d together with the atoms to which they are attached form a heterocycloalkyl, which heterocycloalkyl is optionally substituted by one or more of the following groups: 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0639] provided that the compound of formula (IV) is not

[0640] Embodiment 2. The compound according to Embodiment 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is C6-C 10 aryl.

[0641] Embodiment 3. The compound according to Embodiment 2, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is phenyl.

[0642] Embodiment 4. The compound according to Embodiment 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is heteroaryl.

[0643] Embodiment 5. The compound according to Embodiment 4, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is furyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl.

[0644] Embodiment 6. The compound according to Embodiment 5, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl.

[0645] Embodiment 7. The compound according to Embodiment 6, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is pyrazolyl, pyridyl, pyrazinyl or pyrimidinyl.

[0646] Embodiment 8. The compound according to Embodiment 7, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is pyrazolyl.

[0647] Embodiment 9. The compound according to Embodiment 8, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl or 5-pyrazolyl.

[0648] Embodiment 10. The compound according to Embodiment 9, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is 1-pyrazolyl.

[0649] Embodiment 11. The compound according to Embodiment 9, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is 3-pyrazolyl.

[0650] Embodiment 12. The compound according to Embodiment 9, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is 4-pyrazolyl.

[0651] Embodiment 13. The compound according to Embodiment 9, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is 5-pyrazolyl.

[0652] Embodiment 14. The compound according to Embodiment 7, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is pyridyl.

[0653] Embodiment 15. The compound according to Embodiment 14, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl or 6-pyridyl.

[0654] Embodiment 16. The compound according to Embodiment 15, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is 2-pyridyl.

[0655] Embodiment 17. The compound according to Embodiment 15, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is 3-pyridyl.

[0656] Embodiment 18. The compound according to Embodiment 15, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is 4-pyridyl.

[0657] Embodiment 19. The compound according to Embodiment 15, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is 5-pyridyl.

[0658] Embodiment 20. The compound according to Embodiment 15, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is 6-pyridyl.

[0659] Embodiment 21. The compound according to Embodiment 7, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is pyrazinyl.

[0660] Embodiment 22. The compound according to Embodiment 21, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl or 6-pyrazinyl.

[0661] Embodiment 23. The compound according to Embodiment 22, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is 2-pyrazinyl.

[0662] Embodiment 24. The compound according to Embodiment 22, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is 3-pyrazinyl.

[0663] Embodiment 25. The compound according to Embodiment 22, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is 5-pyrazinyl.

[0664] Embodiment 26. The compound according to Embodiment 22, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is 6-pyrazinyl.

[0665] Embodiment 27. The compound according to Embodiment 7, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is pyrimidinyl.

[0666] Embodiment 28. The compound according to Embodiment 27, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl or 6-pyrimidinyl.

[0667] Embodiment 29. The compound according to Embodiment 28, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is 2-pyrimidinyl.

[0668] Embodiment 30. The compound according to Embodiment 28, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is 4-pyrimidinyl.

[0669] Embodiment 31. The compound according to Embodiment 28, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is 5-pyrimidinyl.

[0670] Embodiment 32. The compound according to Embodiment 28, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is 6-pyrimidinyl.

[0671] Embodiment 33. The compound according to Embodiment 6, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is pyridazinyl.

[0672] Embodiment 34. The compound according to Embodiment 33, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl or 6-pyridazinyl.

[0673] Embodiment 35. The compound according to Embodiment 34, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is 3-pyridazinyl.

[0674] Embodiment 36. The compound according to Embodiment 34, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is 4-pyridazinyl.

[0675] Embodiment 37. The compound according to Embodiment 34, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is 5-pyridazinyl.

[0676] Embodiment 38. The compound according to Embodiment 34, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ring A is 6-pyridazinyl.

[0677] Embodiment 39. The compound according to any one of Embodiments 1 to 38, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 1Independently is methyl, ethyl, trifluoromethyl, methoxy, ethoxy, mesyl, ethylsulfonyl, acetyl or dimethylamino.

[0678] 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.

[0679] Embodiment 41. A compound according to Embodiment 40, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein n is 1.

[0680] Embodiment 42. A compound according to Embodiment 40, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein n is 2.

[0681] Embodiment 43. A compound according to Embodiment 40, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein n is 3.

[0682] Embodiment 44. A compound according to any one of Embodiments 1 to 43, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 2 is hydrogen.

[0683] Embodiment 45. A compound according to any one of Embodiments 1 to 44, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 3 is hydrogen.

[0684] Embodiment 46. A compound according to any one of Embodiments 1 to 45, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 4a , R 4b and R 4c are independently hydrogen or halogen.

[0685] Embodiment 47. A compound according to Embodiment 46, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 4a is halogen, and R 4b and R 4c are hydrogen.

[0686] Embodiment 48. A compound according to Embodiment 46, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 4a and R 4c are hydrogen, and R 4b is halogen.

[0687] Embodiment 49. A compound according to Embodiment 46, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R4a and R 4b is hydrogen and R 4c is a halogen.

[0688] Embodiment 50. The compound according to Embodiment 46, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 4a and R 4b are halogens and R 4c is hydrogen.

[0689] Embodiment 51. The compound according to Embodiment 46, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 4a and R 4c are halogens and R 4b is hydrogen.

[0690] Embodiment 52. The compound according to Embodiment 46, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 4a , R 4b and R 4c are halogens.

[0691] Embodiment 53. The compound according to Embodiment 46, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 4a , R 4b and R 4c are hydrogen.

[0692] Embodiment 54. The compound according to any one of Embodiments 1 to 53, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 5 is hydrogen.

[0693] Embodiment 55. The compound according to any one of Embodiments 1 to 54, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 6 is hydrogen.

[0694] Embodiment 56. The compound according to any one of Embodiments 1 to 55, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 7 is hydrogen or C1-C6 alkyl.

[0695] Embodiment 57. The compound according to Embodiment 56, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 7 is hydrogen.

[0696] Embodiment 58. The compound according to Embodiment 56, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 7is a C1-C6 alkyl group.

[0697] Embodiment 59. A compound according to any one of Embodiments 1 to 58, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 8a , R 8b , R 8c and R 8d each independently is hydrogen, halogen or -OR a .

[0698] Embodiment 60. A compound according to Embodiment 59, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 8a , R 8b and R 8d each is hydrogen, and R 8c is hydrogen, halogen or -OR a .

[0699] Embodiment 61. A compound according to Embodiment 60, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 8c is halogen or -OR a .

[0700] Embodiment 62. A compound according to Embodiment 61, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 8c is halogen.

[0701] Embodiment 63. A compound according to Embodiment 62, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 8c is fluorine, chlorine, bromine or iodine.

[0702] Embodiment 64. A compound according to Embodiment 61, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 8c is -OR a .

[0703] Embodiment 65. A compound according to Embodiment 64, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R a is a C1-C6 alkyl group.

[0704] Embodiment 66. A compound according to Embodiment 65, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R a is -CH3.

[0705] Embodiment 67. A compound according to any one of Embodiments 1 to 66, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R9 is furyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl or tetrazolyl, each of which is optionally substituted with one or more R 1a substituents.

[0706] Embodiment 68. The compound according to Embodiment 67, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is furyl optionally substituted with one or more R 1a substituents.

[0707] Embodiment 69. The compound according to Embodiment 67, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is pyrrolyl optionally substituted with one or more R 1a substituents.

[0708] Embodiment 70. The compound according to Embodiment 67, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is thienyl optionally substituted with one or more R 1a substituents.

[0709] Embodiment 71. The compound according to Embodiment 67, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is oxazolyl optionally substituted with one or more R 1a substituents.

[0710] Embodiment 72. The compound according to Embodiment 67, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is imidazolyl optionally substituted with one or more R 1a substituents.

[0711] ...

Claims

1. A compound of formula (IV) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof: Wherein: Ring A is C6-C 10 aryl or heteroaryl; Each R 1 is independently deuterium, a 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 , -NR c C(=O)NR d , -NR b , -NR 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl or heteroaryl; wherein each of said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl and heteroaryl is optionally and independently substituted by one or more R 1a substituents; or two Rs on adjacent atoms 1 combine to form a C3-C 10 cycloalkyl or heterocycloalkyl; each of which is optionally substituted with one or more Rs 1b substituted; Each R 1a is independently deuterium, a 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl or heteroaryl; or two Rs on the same atom 1a combine to form an oxo; Each R 1b is independently deuterium, a 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl or heteroaryl; or two Rs on the same atom 1b combine to form an oxo; n is 0, 1, 2, 3, 4, 5, 6, 7 or 8; R 2 is hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group or a C1-C6 deuterated alkyl group; R 3 is hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group or a C1-C6 deuterated alkyl group; R 4a , R 4b and R 4c Each of which 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; R 5 is hydrogen, deuterium, a halogen, -CN, -OH, -OR a , -NR c R d , a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 deuterated alkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 aminoalkyl group or a C1-C6 heteroalkyl group; Each R 6 is independently hydrogen, deuterium, a halogen, -CN, -OH, -OR a , -NR c R d , a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 deuterated alkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 aminoalkyl group or a C1-C6 heteroalkyl group; R 7 is hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 deuterated alkyl group, a C1-C6 hydroxyalkyl group or a C1-C6 aminoalkyl group; R 8a , R 8b , R 8c and R 8d Each of which is independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR a 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, 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 is an optionally one or more R 1a substituted heteroaryl, or an oxetanyl group substituted by one or more R 1a groups; Each R a is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl, heteroaryl, C1-C6 alkyl(C3-C 10 cycloalkyl), C1-C6 alkyl(heteroalkyl), C1-C6 alkyl(C6-C 10 aryl) or C1-C6 alkyl(heteroaryl); wherein each of said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; Each R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, 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); wherein each of said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocycloalkyl, C6-C 10 aryl and heteroaryl is independently optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; and Each R c and R d is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, 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, heteroalkyl, C6-C 10 aryl, heteroaryl, C1-C6 alkyl(C3-C 10 cycloalkyl), C1-C6 alkyl(heteroalkyl), C1-C6 alkyl(C6-C 10 aryl) or C1-C6 alkyl(heteroaryl); wherein each of said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heteroalkyl, C6-C 10 aryl and heteroaryl is independently optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; or R c and R d together with the atoms to which they are attached to form a heterocycloalkyl group, which heterocycloalkyl group is optionally substituted by 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; provided that the compound of formula (IV) is not 2. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is a C6-C 10 aryl group.

3. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is a heteroaryl.

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

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

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

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

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

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

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 8a , R 8b and R 8d each is hydrogen, and R 8c is hydrogen, halogen or -OR a .

11. The compound according to claim 10, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 8c is -OR a , and R a is C1-C6 alkyl.

12. A compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, which is selected from 6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)-2,3-dihydro-1H-1-benzothiophene-1,1-dione; (1R,2S)-2-{3-[4-(methylsulfonyl)-2-methoxyanilino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-[3-(4-acetyl-2-methoxyanilino)-1H-indazol-6-yl]-5'-methoxyspiro[cyclopropane-1,3'-indole]-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'-indole]-2'(1'H)-one; (1R,2S)-2-{3-[4-(ethylsulfonyl)-2-methoxyanilino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; 6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-2'(1'H)-one; (1R,2S)-2-(3-{[2-(dimethylamino)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-{3-[2-methoxy-5-(2-methyl-2H-tetrazol-5-yl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-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'-indole]-2'(1'H)-one; (1R,2S)-2-{3-[2-ethoxy-4-(methylsulfonyl)anilino]-1H-indazol-6-yl}-5'-methoxy-1'-methylspiro[cyclopropane-1,3'-indole]-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’-indole]-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’-indole]-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’-indole]-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’-indole]-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’-indole]-2’(1’H)-one; (1R,2S)-2-{3-[2-ethoxy-4-(1-methyl-1H-imidazol-4-yl)phenylamino]-1H-indazol-6-yl}-5’-methoxyspiro[cyclopropane-1,3’-indole]-2’(1’H)-one; (1R,2S)-5’-Methoxy-2-{3-[2-methoxy-5-(1,2-thiazol-3-yl)phenylamino]-1H-indazol-6-yl}spiro[cyclopropane-1,3’-indole]-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’-indole]-2’(1’H)-one; (1R,2S)-5’-Methoxy-2-{3-[2-methoxy-5-(1,2-oxazol-3-yl)phenylamino]-1H-indazol-6-yl}spiro[cyclopropane-1,3’-indole]-2’(1’H)-one; (1R,2S)-2-{3-[2-ethoxy-5-(1,3-thiazol-2-yl)phenylamino]-1H-indazol-6-yl}-5’-methoxyspiro[cyclopropane-1,3’-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-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'-indole]-2'(1'H)-one; (1R,2S)-2-{3-[(5-Ethoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-[(2H3)methoxy]spiro[cyclopropane-1,3'-indole]-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'-indole]-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'-indoline]-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'-indoline]-2'-one; (1R)-2-(3-((2-ethoxy-5-(oxazol-4-yl)pyridin-3-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one; (1R,2S)-2-(3-((5-ethoxy-2-ethynylpyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indoline]-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'-indoline]-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'-indoline]-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'-indole]-2'(1'H)-one; and 5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-yl]-1H-indazol-3-yl}amino)-1-methyl-1H-pyrazole-3-carbonitrile.; 13. A pharmaceutical composition comprising an amount of the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and one or more pharmaceutically acceptable excipients.

14. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

15. The method according to claim 14, wherein the cancer is neuroblastoma, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, gastric cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney cancer or ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system (CNS) tumors, primary CNS lymphoma, spinal cord axis tumors, brainstem glioma or pituitary adenoma.

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