POLO-like kinase 4 inhibitors

Abstract

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

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 187,049 filed on May 11, 2021, U.S. Provisional Application Serial No. 63 / 249,809 filed on September 29, 2021, U.S. Provisional Application Serial No. 63 / 317,174 filed on March 7, 2022, and U.S. Provisional Application Serial No. 63 / 337,445 filed on May 2, 2022, which are hereby incorporated by reference in their entireties. Background Art

[0003] Polo-like kinases (PLKs) are a family of serine / threonine kinases that play key roles in cell cycle regulation and cellular responses under stress (Helmke et al., 2016; Zitouni et al., 2014). Mammalian cells express five PLK family members (PLK1-5). All PLKs share a similar structure, with an N-terminal kinase catalytic domain and a C-terminal Polo-box domain (PBD) (Archambault et al., 2015). Polo-like kinase 4 (PLK4), also known as SAK, is a regulator of centriole duplication (Habedanck et al., 2005; Kleylein-Sohn et al., 2007). In proliferating tissues, PLK4 is expressed as a low-abundance enzyme under normal conditions and is essential for centriole biogenesis via phosphorylation and interaction with centriole 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). Therefore, strong evidence supports a key role for PLK4 in carcinogenesis and therapeutic inventions. Therefore, compounds that inhibit PLK4 in subjects with cancer are needed to treat these cancers. Summary of the invention

[0004] Provided herein are compounds of formula (I) or pharmaceutically acceptable salts, solvates or stereoisomers thereof:

[0005]

[0006] in:

[0007] Ring A is C 6 -C 10 Aryl, heteroaryl, C 3 -C10 Cycloalkyl or heterocycloalkyl;

[0008] Each R 1 are independently deuterium, halogen, -CN, oxo, -NO 2 、-OH、-OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d 、-P(O)(R a ) 2 、-P(O) 2 (R a ) 2 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OC 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3-C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl or heteroaryl; wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is optionally and independently substituted with one or more R 1a replace;

[0009] or two R on adjacent atoms 1 Put together to form C 3 -C 10 Cycloalkyl or heterocycloalkyl; each of which is optionally substituted by one or more R 1b replace;

[0010] Each R 1a are independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl or heteroaryl;

[0011] or two R on the same atom 1a together to form oxo;

[0012] Each R 1b are independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl or heteroaryl;

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

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

[0015] R 2 It is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 Deuterated alkyl;

[0016] R 3 It is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 Deuterated alkyl;

[0017] R 4a , R 4b and R 4c Each of which is independently hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-NR c R d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl;

[0018] R 5 It is hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl;

[0019] Each R 6 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl;

[0020] R 7 It is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 aminoalkyl;

[0021] R 8a , R 8b , R8c and R 8d Each of which is independently hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl or heteroaryl;

[0022] Each R a Independently C 1 -C 6 Alkyl, C1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl, heteroaryl, C 1 -C 6 Alkyl (C 3 -C 10 Cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (C 6 -C 10 Aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3, -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl substitution;

[0023] Each R b are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl, heteroaryl, C 1 -C 6 Alkyl (C 3 -C 10 Cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (C 6 -C 10 Aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10Each of the aryl and heteroaryl groups is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substituted; and

[0024] Each R c and R d are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Aminoalkyl, C 1 -C 6 Alkylamino, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C6 -C 10 Aryl, heteroaryl, C 1 -C 6 Alkyl (C 3 -C 10 Cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (C 6 -C 10 Aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl substitution;

[0025] or Rc and R d Together with the atoms to which they are attached to form a heterocycloalkyl group, the heterocycloalkyl group is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution.

[0026] In some embodiments of the compound of Formula (I), Ring A is C 6 -C 10 Aryl or heteroaryl.

[0027] In some embodiments of the compound of Formula (I), Ring A is C 6 -C 10 Aryl.

[0028] In some embodiments of the compound of Formula (I), Ring A is heteroaryl.

[0029] In some embodiments of the compound of Formula (I), Ring A is furanyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl.

[0030] In some embodiments of the compound of Formula (I), each R 1 are independently halogen, -CN, -OH, -ORa , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OC 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl or heteroaryl; wherein C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is optionally and independently substituted with one or more R 1a replace.

[0031] In some embodiments of the compound of Formula (I), n is 1, 2 or 3.

[0032] In some embodiments of the compound of Formula (I), R 2 It's hydrogen.

[0033] In some embodiments of the compound of Formula (I), R 3 It's hydrogen.

[0034] In some embodiments of the compound of Formula (I), R 4a , R 4b and R 4c It's hydrogen.

[0035] In some embodiments of the compound of Formula (I), R 5 It's hydrogen.

[0036] In some embodiments of the compound of Formula (I), each R 6 It's hydrogen.

[0037] In some embodiments of the compound of Formula (I), R 7 is hydrogen or C 1 -C 6 alkyl.

[0038] In some embodiments of the compound of Formula (I), R 8a , R 8b and R 8dEach of is hydrogen, and R 8c is hydrogen, halogen or -OR a .

[0039] In some embodiments of the compound of Formula (I), R 8c Is halogen or -OR a .

[0040] In some embodiments of the compound of Formula (I), R 8c Yes-OR a .

[0041] In some embodiments of the compound of Formula (I), R a It is C 1 -C 6 alkyl.

[0042] In some embodiments of the compound of Formula (I), R a Yes-CH 3 .

[0043] Also disclosed herein is a pharmaceutical composition comprising an amount of a compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and one or more pharmaceutically acceptable excipients.

[0044] Also disclosed herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0045] Incorporation by reference

[0046] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION

[0047] As used in the specification and appended claims, the following terms have the following indicated meanings unless specified to the contrary.

[0048] 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 cells) and equivalents known to those skilled in the art, and so forth. When ranges are used herein for physical properties (such as molecular weight) or chemical properties (such as chemical formula), all combinations and subcombinations of ranges and specific embodiments thereof are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus in some cases, the number or numerical range will vary between 1% and 15% of the number or numerical range. The term "comprising" (and related terms such as "having" or "including") is not intended to exclude "consisting of" or "consisting essentially of" the features in certain other embodiments (e.g., embodiments of any composition of matter, composition, method or process, etc. described herein).

[0049] "Administering" when used in conjunction with treatment means systemic or local administration of a therapeutic agent, such as direct administration 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 "administering" when used in conjunction with the compositions described herein may 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 cells. "Administering" a composition may be accomplished by injection, topical administration, and oral administration, or by other methods alone or in combination with other known techniques.

[0050] As used herein, the term "C 2 -C 6 "Alkenyl" means an alkyl moiety containing 2 to 6 carbon atoms having at least one carbon-carbon double bond. The carbon-carbon double bond in such groups may be in any position along the 2 to 6 carbon atom chain that will produce a stable compound. Examples of such groups include, but are not limited to, ethenyl, propenyl, butenyl, allyl, and pentenyl. Alkenyl groups may be in either the cis or trans configuration about the double bond and should be understood to include both isomers. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH 2 ), 1-propenyl (-CH 2 CH=CH 2 ), isopropenyl [-C(CH 3 )=CH 2 ], butenyl, 1,3-butadienyl, etc. Whenever a numerical range such as "C 2 -C 6The term "alkenyl" means that the alkenyl group can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the definition also encompasses occurrences of the term "alkenyl" without specifying a numerical range. In some embodiments, alkenyl is C 2 -C 10 Alkenyl, C 2 -C 9 Alkenyl, C 2 -C 8 Alkenyl, C 2 -C 7 Alkenyl, C 2 -C 6 Alkenyl, C 2 -C 5 Alkenyl, C 2 -C 4 Alkenyl, C 2 -C 3 Alkenyl or C 2 Alkenyl.

[0051] As used herein, the term "C 1 -C 6 "Alkyl" refers to a straight or branched hydrocarbon monovalent radical which may be fully saturated or unsaturated and has from one to about ten carbon atoms, or from one to six carbon atoms. Examples of saturated hydrocarbon monovalent radicals 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-2-propyl, 2-methyl-1-butyl, 3-methyl-2-pentyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-2-pentyl, 2-methyl-3 ...propyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl and hexyl, as well as longer alkyl groups such as heptyl, octyl, etc. Whenever numerical ranges such as “C” appear in this document, 1 -C 6 The term "alkyl" means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the definition also covers the occurrence of the term "alkyl" without specifying a numerical range.

[0052] As used herein, the term "C 2 -C 6"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 a group can be in any position along the 2 to 6 carbon chain that will produce a stable compound. Examples of such groups 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, and the like. Whenever a numerical range such as "C 2 -C 6 The term "alkynyl" means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the definition also covers the occurrence of the term "alkynyl" without specifying a numerical range.

[0053] As used herein, the term "C 6 -C 10 "Aryl" means a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 10 carbon atoms and at least one aromatic ring. The aryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a fused ring system (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl group is bonded through an aromatic ring atom) or a bridged ring system. In some embodiments, the aryl group is a 6- to 10-membered aryl group. In some embodiments, the aryl group is a 6-membered aryl group. Aryl groups include, but are not limited to, aryl groups derived from anthracene, naphthylene, phenanthrenyl, anthracene, azulene, benzene, In some embodiments, the aryl group is a phenyl group.

[0054] As used herein, the term "C 1 -C 6 "Aminoalkyl" refers to a C 1 -C 6 Alkyl groups. 1 -C 6 The amino group in the aminoalkyl group may be unsubstituted, monosubstituted or disubstituted. 1 -C 6 Examples of aminoalkyl groups include, but are not limited to, -CH 2 NH 2 、-CH 2 N(H)CH 3 、-CH 2 N(CH 3 ) 2 wait.

[0055] The term "C 3 -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. Representative cycloalkyl groups include. In some embodiments, the cycloalkyl group is a 3- to 6-membered cycloalkyl group. In some embodiments, the cycloalkyl group is a 5- to 6-membered cycloalkyl group. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups or carbocyclic rings include , for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane and bicyclo[3.3.2]decane and 7,7-dimethyl-bicyclo[2.2.1]heptyl. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.

[0056] As used herein, the term "C 1 -C 6 "Deuterated alkyl" means a C 1 -C 6 Alkyl groups, where C 1 -C 6 One or more hydrogen atoms in the alkyl group are replaced by a deuterium atom.

[0057] As used herein, the term "C 1 -C 6 "Haloalkyl" refers to a C alkyl group as defined above substituted by one or more halo groups as defined above. 1 -C 6 Alkyl groups, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl and the like.

[0058] As used herein, the term "C 1 -C 6 "Hydroxyalkyl" refers to a C 1 -C 6 Alkyl group.

[0059] The term "animal" as used herein includes, but is not limited to, humans 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 may occur. Examples include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats, and transgenic species thereof. In a preferred embodiment, the object is a primate. In certain embodiments, the primate or object is a human. In some cases, the human is an adult. In some cases, the human is a child. In other cases, the human is less than 12 years old. In some cases, the human is an elderly. In other cases, the human is 60 years old or older. Other examples of objects include experimental animals, such as mice, rats, dogs, cats, goats, sheep, pigs, and cows. The experimental animal can be an animal model of a disease, such as a transgenic mouse with hypertensive pathology.

[0060] As used herein, the term "Aurora kinase A" or "AurA" refers to the human protein known to those of ordinary skill in the art as Aurora kinase A and encoded by the AURKA gene.

[0061] As used herein, the term "Aurora kinase B" or "AurB" refers to the human protein known to those of ordinary skill in the art as Aurora kinase B and encoded by the AURKB gene.

[0062] "Cyano" refers to a -CN group.

[0063] As used herein, the term "halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0064] The term "heterocycloalkyl" as used herein refers to a 3 to 24-membered partially or fully saturated ring group containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from boron, nitrogen, oxygen, phosphorus and sulfur. Unless otherwise specifically stated in the specification, the heterocycloalkyl group can be a monocyclic, bicyclic, tricyclic or tetracyclic system, which can include a fused ring system (when fused with an aryl or heteroaryl ring, the heterocycloalkyl is bonded by 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, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidine, thiazolidinyl, tetrahydro Furanyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 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 heterocycloalkyl, the number of carbon atoms in heterocycloalkyl is different from the total number of atoms (including heteroatoms) constituting heterocycloalkyl (i.e., the backbone atoms of the heterocycloalkyl ring).

[0065] As used herein, the term "C 1 -C 6 "Heteroalkyl" means an alkyl group in which one or more backbone atoms of the alkyl group are selected from atoms other than carbon, such as boron, oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or a combination thereof. The heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. In one aspect, the heteroalkyl group is C 1 -C 6 Heteroalkyl, wherein 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 combinations thereof, wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.

[0066] The term "heteroaryl" as used herein refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from boron, nitrogen, oxygen, phosphorus and sulfur, and at least one aromatic ring. The heteroaryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring 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, aza yl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxane, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothiazolyl, phenyl (benzothienyl, benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolyl, isoindolyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepine 1-Oxiranyl, 1-Phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolyl, quinuclidine, isoquinolyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl and thiophenyl (i.e., thienyl).

[0067] As used herein, "pharmaceutically acceptable" means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0068] The term "pharmaceutical composition" means a composition comprising at least one active ingredient, whereby the composition is suitable for studying a specified effective outcome in a mammal (e.g., but not limited to a human). One of ordinary skill in the art will understand and appreciate the techniques suitable for determining whether an active ingredient has a desired effective outcome based on the needs of the skilled artisan.

[0069] As used herein, the term "pharmaceutically acceptable salts" refers to salts of the compounds of the invention that retain the biological effectiveness of the free acids and free bases of the specified derivatives and which are not biologically or otherwise undesirable.

[0070] The term "PLK4" as used herein refers to a human protein known to those of ordinary skill in the art as polo-like kinase 4 and encoded by the PLK4 gene.

[0071] As used herein, the term "oxo" refers to a carbonyl moiety, thus an alkyl group substituted with oxo refers to a keto group.

[0072] The term "solvate" as used herein means a molecular complex between a compound of the present invention and a solvent molecule. Examples of solvates include, but are not limited to, a combination of a compound of the present invention and water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or a mixture thereof. When the solvent is water, the term "hydrate" may be used. It is specifically contemplated that in the present invention, one solvent molecule may be associated with one molecule of the compound of the present invention, such as a hydrate. In addition, it is specifically contemplated that in the present invention, more than one solvent molecule may be associated with one molecule of the compound of the present invention, such as a dihydrate. In addition, it is specifically contemplated that in the present invention, less than one solvent molecule may be associated with one molecule of the compound of the present invention, such as a hemihydrate. In addition, the solvate of the present invention is considered to be a solvate of the compound of the present invention, which retains the biological effectiveness of the non-hydrate form of the compound.

[0073] In the case where the compounds of the present invention contain alkenyl groups, geometric cis / trans (or Z / E) isomers are possible. In the case where the compounds contain, for example, keto or oxime groups or aromatic moieties, tautomeric isomerism (tautomerism, tautomerism) may 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 present invention, including compounds exhibiting more than one type of isomerism, and mixtures thereof or more. Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art (e.g., chromatography and fractional crystallization).

[0074] The term "stereoisomer" refers to a compound having the same chemical structure, but with different arrangements of its atoms or groups in space. In particular, the term "enantiomer" refers to two stereoisomers of a compound, which are non-superimposable mirror images of each other. As used herein, the term "racemic" or "racemic mixture" refers to a 1:1 mixture of enantiomers of a particular compound. A mixture of racemates in which one racemate is present in an amount greater than the amount of another racemate in such a mixture can be described as "enriched in enantiomers". 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 specific asymmetric carbon atom of a compound disclosed herein, or a mixture thereof. For example, a single racemate or stereocenter of a compound can be described as a (+), (-), (R) configuration, or (S) configuration. A mixture of racemates can be described using the symbol (±).

[0075] The compounds of the present invention may have asymmetric carbon atoms. The carbon-carbon bonds of the compounds of the present invention may be represented herein by solid lines. or solid wedge or dashed wedges (......). The use of solid lines to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) at that carbon atom are included. The use of solid lines or dashed wedges to depict bonds to asymmetric carbon atoms is meant to indicate that only the stereoisomers shown are intended to be included. It is possible that the compounds of the present invention may contain more than one asymmetric carbon atom. In these compounds, the use of solid lines to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are intended to be included. For example, unless otherwise stated, it is intended that the compounds of the present invention may exist in the form of enantiomers and diastereomers or racemates and mixtures thereof. The use of solid lines to depict bonds to one or more asymmetric carbon atoms in the compounds of the present invention and the use of solid lines or dashed wedges to depict bonds to other asymmetric carbon atoms in the same compound is meant to indicate that a mixture of diastereomers exists.

[0076] Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors, or separation of racemates using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound, such as an alcohol, or, in the case of a compound containing an acidic or basic moiety, with an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization, and one or both diastereomers can be converted into the corresponding pure enantiomers by methods well known to those skilled in the art. The chiral compounds of the present invention (and chiral precursors thereof) can be obtained in the form of an enriched enantiomer on an asymmetric resin with a mobile phase using chromatography (usually HPLC), the mobile phase consisting of a hydrocarbon (usually heptane or hexane), containing 0 to 50% isopropanol (usually 2% to 20%), and 0 to 5% alkylamine (usually 0.1% diethylamine). Concentration of the eluent provides an enriched mixture. Stereoisomers can be separated by conventional techniques known to those skilled in the art. See, for example, "Stereochemistry of Organic Compounds" by EL Eliel (Wiley, New York, 1994), the disclosure of which is incorporated herein by reference in its entirety.

[0077] As used herein, the term "substituted" means that the specified group or moiety bears one or more substituents. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted with" means that the specified 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 fewer groups than would fill the valences of all the atoms in the compound, the remaining valences on such group are filled with hydrogen. For example, if C 6 If an aryl group, also referred to herein as a "phenyl group", is substituted with another substituent, then one of ordinary skill in the art will understand that such a group is 6 There are 4 open positions left on the carbon atoms of the aryl group (6 original positions, minus one position bonded to the remainder of the compound of the invention, minus additional substituents, to leave 4). In such cases, the remaining 4 carbon atoms are each bonded to a hydrogen atom to fill their valences. Similarly, if the C 6 When an aryl group is referred to as "disubstituted", those skilled in the art will understand that it means that C 6 The aryl group has the remaining 3 carbon atoms which are unsubstituted. Each of the three unsubstituted carbon atoms is bonded to a hydrogen atom to fill their valency.

[0078] According to the convention used in the art, the symbol

[0079]

[0080] In the structural formulae herein, it is used to depict the bond that serves as the point of attachment of a moiety or substituent to a core or backbone structure. According to another convention, in some of the structural formulae herein, carbon atoms and their bonded hydrogen atoms are not explicitly depicted, e.g.

[0081]

[0082] represents the methyl group,

[0083]

[0084] represents an ethyl group, and

[0085]

[0086] represents a cyclopentyl group, etc.

[0087] If a group, such as (R 1 ) n Depicted as a "floating" ring A in the formula:

[0088]

[0089] Then, unless otherwise defined, a substituent R 1 The ring system A may be located on any atom in the ring system, provided that a depicted, implied or explicitly defined hydrogen is replaced from one of the ring atoms, as long as a stable structure results. The ring system A may be, for example but not limited to, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, spirocyclyl or a fused ring system.

[0090] If the radical "R" is depicted as "floating" on a ring system A as shown above, and ring A contains a saturated carbon, then "n" may be greater than 1, assuming that each replaces a hydrogen on ring A as currently described, implied, or explicitly defined; then, unless otherwise defined, two R 1 The groups can be located on the same carbon. For example, when R 1 When the two R groups are methyl groups, a germinal dimethyl group may be present on the carbon of ring A. In another example, two R groups on the same carbon may be present on the same carbon. 1 , including the carbon, can form a ring, thereby generating a spirocycle (a "spirocyclyl group"). It should be understood that in the compounds of Formula (I), (Ia), (Ib), (II) and (III), 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.

[0091] As used herein, the term "therapeutic agent" means an agent used to treat, combat, alleviate, prevent or ameliorate an adverse condition or disease in a subject.

[0092] 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 medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) preventing disease; for example, preventing a disease, condition or disorder in an individual who may be susceptible to the disease, condition or disorder but does not yet experience or display the pathology or symptomology of the disease, (2) inhibiting disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptomology), and (3) alleviating disease; for example, alleviating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomology).

[0093] The term "treatment" as used herein refers to therapeutic treatment in some embodiments and to preventive measures or preventive measures in other embodiments, wherein the purpose is to prevent or slow down (mitigate) 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, mitigation of symptoms; mitigation of the extent of a condition, disorder or disease; stabilization of the state of a condition, disorder or disease (i.e., not worsening); delayed onset or slowed progression of a condition, disorder or disease; mitigation of a condition, disorder or disease state; and relief (partial or complete), whether detectable or undetectable, or improvement or improvement of a condition, disorder or disease. Treatment includes inducing a clinically significant response without excessive levels of side effects. Treatment also includes a prolonged survival period compared to the expected survival period if treatment is not received. The preventive 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" includes prevention in some embodiments.

[0094] As used herein, the term "TRIM37" refers to a 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.

[0095] The term "CFI-400495" refers to a compound having Chemical Abstract Service registration number 1338806-73-7, and the structure is shown below. The preparation of this compound is described in PCT Application Publication No. WO 2011 / 123946, and it is commercially available.

[0096]

[0097] PLK4 inhibitor compounds

[0098] Provided herein are compounds of formula (I) or pharmaceutically acceptable salts, solvates or stereoisomers thereof:

[0099]

[0100] in:

[0101] Ring A is C 6 -C 10 Aryl, heteroaryl, C 3 -C 10 Cycloalkyl or heterocycloalkyl;

[0102] Each R 1 are independently deuterium, halogen, -CN, oxo, -NO 2 、-OH、-OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NRc R d 、-P(O)(R a ) 2 、-P(O) 2 (R a ) 2 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OC 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl or heteroaryl; wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is optionally and independently substituted with one or more R 1a replace;

[0103] or two R on adjacent atoms 1 Put together to form C 3 -C 10 Cycloalkyl or heterocycloalkyl; each of which is optionally substituted by one or more R 1b replace;

[0104] Each R 1a are independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SRa 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl or heteroaryl;

[0105] or two R on the same atom 1a together to form oxo;

[0106] Each R 1b are independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)Ra 、-S(=O) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl or heteroaryl;

[0107] or two R on the same atom 1b together to form oxo;

[0108] n is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0109] R 2 It is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 Deuterated alkyl;

[0110] R3 It is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 Deuterated alkyl;

[0111] R 4a , R 4b and R 4c Each of which is independently hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-NR c R d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl;

[0112] R 5 It is hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl;

[0113] Each R 6 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl, C1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl;

[0114] R 7 It is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 aminoalkyl;

[0115] R 8a , R 8b , R 8c and R 8d Each of which is independently hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c Rd , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl or heteroaryl;

[0116] Each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl, heteroaryl, C 1 -C 6 Alkyl (C 3 -C 10 Cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (C 6 -C 10 Aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein C 1 -C 6 Alkyl, C 2 -C 6Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl substitution;

[0117] Each R b are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl, heteroaryl, C 1 -C 6 Alkyl (C 3 -C 10 Cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (C 6 -C 10 Aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substituted; and

[0118] Each R c and R d are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Aminoalkyl, C 1 -C 6 Alkylamino, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl, heteroaryl, C 1 -C 6 Alkyl (C 3 -C 10 Cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (C 6 -C 10 Aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O)2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl substitution;

[0119] or R c and R d Together with the atoms to which they are attached to form a heterocycloalkyl group, the heterocycloalkyl group is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6Aminoalkyl or C 1 -C 6 Heteroalkyl substitution.

[0120] Provided herein are compounds of formula (I) or pharmaceutically acceptable salts, solvates or stereoisomers thereof:

[0121]

[0122] in:

[0123] Ring A is C 6 -C 10 Aryl, heteroaryl, C 3 -C 10 Cycloalkyl or heterocycloalkyl;

[0124] Each R 1 are independently deuterium, halogen, -CN, oxo, -NO 2 、-OH、-OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OC 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl or heteroaryl; wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is optionally and independently substituted with one or more R 1a replace;

[0125] or two R on adjacent atoms 1 Put together to form C 3 -C 10 Cycloalkyl or heterocycloalkyl; each of which is optionally substituted by one or more R 1b replace;

[0126] Each R 1a are independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR bC(=O)OR a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl or heteroaryl;

[0127] or two R on the same atom 1a together to form oxo;

[0128] Each R 1b are independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR a、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl or heteroaryl;

[0129] or two R on the same atom 1b together to form oxo;

[0130] n is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0131] R 2 It is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 Deuterated alkyl;

[0132] R 3 It is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 Deuterated alkyl;

[0133] R 4a , R 4b and R 4c Each of which is independently hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-NR cR d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl;

[0134] R 5 It is hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl;

[0135] Each R 6 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl;

[0136] R 7 It is hydrogen, C 1 -C 6 Alkyl, C 1 -C6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 aminoalkyl;

[0137] R 8a , R 8b , R 8c and R 8d Each of which is independently hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl or heteroaryl;

[0138] Each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl, heteroaryl, C 1 -C 6 Alkyl (C 3 -C 10 Cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (C 6 -C 10 Aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O)2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl substitution;

[0139] Each R b are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl, heteroaryl, C 1 -C 6 Alkyl (C 3 -C 10 Cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (C 6 -C 10 Aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein C1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substituted; and

[0140] Each R c and R d are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2-C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl, heteroaryl, C 1 -C 6 Alkyl (C 3 -C 10 Cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (C 6 -C 10 Aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1-C 6 Aminoalkyl or C 1 -C 6 heteroalkyl substitution;

[0141] or R c and R d Together with the atoms to which they are attached to form a heterocycloalkyl group, the heterocycloalkyl group is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution.

[0142] In other embodiments, provided is a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0143]

[0144] in:

[0145] Ring A is C 6 -C 10 Aryl, heteroaryl, C 3 -C 10 Cycloalkyl or heterocycloalkyl;

[0146] Each R 1 are independently deuterium, halogen, -CN, oxo, -NO 2、-OH、-OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OC 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl or heteroaryl; wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is optionally and independently substituted with one or more R 1a replace;

[0147] or two R on adjacent atoms 1 Put together to form C 3 -C 10 Cycloalkyl or heterocycloalkyl; each of which is optionally substituted by one or more R 1b replace;

[0148] Each R 1a are independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl or heteroaryl;

[0149] or two R on the same atom 1a together to form oxo;

[0150] Each R 1b are independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl or heteroaryl;

[0151] or two R on the same atom 1b together to form oxo;

[0152] n is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0153] R 2 It is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 Deuterated alkyl;

[0154] R 3 It is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 Deuterated alkyl;

[0155] R 4a , R 4b and R 4c Each of which is independently hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-NR c R d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl;

[0156] R 5It is hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl;

[0157] Each R 6 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl;

[0158] R 7 It is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 aminoalkyl;

[0159] R 8a , R 8b , R 8c and R 8d Each of which is independently hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c Rd , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl or heteroaryl;

[0160] Each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl, heteroaryl, C 1 -C 6 Alkyl (C 3 -C 10 Cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (C 6 -C 10 Aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl substitution;

[0161] Each R b are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl, heteroaryl, C 1 -C 6 Alkyl (C 3 -C 10 Cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (C 6 -C 10 Aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substituted; and

[0162] Each R c and R d are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl, heteroaryl, C 1 -C 6 Alkyl (C 3 -C 10 Cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (C 6 -C 10 Aryl) or C 1 -C 6Alkyl(heteroaryl); wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl substitution;

[0163] or R c and R d Together with the atoms to which they are attached to form a heterocycloalkyl group, the heterocycloalkyl group is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O)2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution.

[0164] In other embodiments, provided is a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0165]

[0166] in:

[0167] Ring A is C 6 -C 10 Aryl, heteroaryl, C 3 -C 10 Cycloalkyl or heterocycloalkyl;

[0168] Each R 1 are independently deuterium, halogen, -CN, oxo, -NO 2 、-OH、-OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NRb C(=O)R a 、-NR b C(=O)OR a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OC 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl or heteroaryl; wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is optionally and independently substituted with one or more R 1a replace;

[0169] or two R on adjacent atoms 1 Put together to form C 3 -C 10 Cycloalkyl or heterocycloalkyl; each of which is optionally substituted by one or more R 1b replace;

[0170] Each R 1a are independently deuterium, halogen, -CN, -NO 2 、-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) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl or heteroaryl;

[0171] or two R on the same atom 1a together to form oxo;

[0172] Each R 1b are independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(=O)R a、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl or heteroaryl;

[0173] or two R on the same atom 1b together to form oxo;

[0174] n is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0175] R 2 It is hydrogen, C 1 -C 6 Alkyl, C 1-C 6 Haloalkyl or C 1 -C 6 Deuterated alkyl;

[0176] R 3 It is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 Deuterated alkyl;

[0177] R 4a , R 4b and R 4c Each of which is independently hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-NR c R d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl;

[0178] R 5 It is hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl;

[0179] Each R 6are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl;

[0180] R 7 It is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 aminoalkyl;

[0181] R 8a , R 8b , R 8c and R 8d Each of which is independently hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR a 、-NR bS(=O) 2 R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl or heteroaryl;

[0182] Each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl, heteroaryl, C 1 -C 6 Alkyl (C 3 -C 10 Cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (C 6 -C 10Aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl substitution;

[0183] Each R b are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl, heteroaryl, C 1 -C 6 Alkyl (C 3 -C 10 Cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (C 6 -C 10 Aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substituted; and

[0184] Each R c and R d are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl, heteroaryl, C 1 -C 6 Alkyl (C 3 -C 10 Cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (C 6 -C 10 Aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl substitution;

[0185] or R c and R d Together with the atoms to which they are attached to form a heterocycloalkyl group, the heterocycloalkyl group is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1-C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution.

[0186] Further provided herein are compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, wherein Ring A is C 6 -C 10 In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is C 6 -C 10In some embodiments, compounds of formula (I), formula (Ia) and formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein ring A is phenyl. In some embodiments, compounds of formula (I), formula (Ia) and formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein ring A is heteroaryl. In some embodiments, compounds of formula (I), formula (Ia) and formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein ring A is furanyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is pyrazolyl, pyridinyl, pyrazinyl or pyrimidinyl. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is pyrazolyl. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl or 5-pyrazolyl. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is 1-pyrazolyl. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is 3-pyrazolyl. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is 4-pyrazolyl. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is 5-pyrazolyl. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is pyridinyl. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl or 6-pyridyl.In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is 2-pyridyl. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is 3-pyridyl. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is 4-pyridyl. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is 5-pyridyl. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is 6-pyridyl. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is pyrazinyl. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl or 6-pyrazinyl. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is 2-pyrazinyl. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is 3-pyrazinyl. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is 5-pyrazinyl. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is 6-pyrazinyl. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is pyrimidinyl. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl or 6-pyrimidinyl. In some embodiments, provided are compounds of Formula (I), Formula (Ia), and Formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein Ring A is 2-pyrimidinyl.In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is 4-pyrimidinyl. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is 5-pyrimidinyl. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is 6-pyrimidinyl. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is pyridazinyl. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl or 6-pyridazinyl. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is 3-pyridazinyl. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is 4-pyridazinyl. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is 5-pyridazinyl. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is 6-pyridazinyl. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is C. 3 -C 10 In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein Ring A is C 3 -C 10 Cycloalkyl. In some embodiments, provided are compounds of Formula (I), Formula (Ia), and Formula (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein Ring A is a heterocycloalkyl.

[0187] Further provided herein are compounds of Formula (I), Formula (Ia) and Formula (Ib), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, wherein each R 1 are independently halogen, -CN, -OH, -OR a , C 1 -C6 Alkyl, C 1 -C 6 Haloalkyl, -OC 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl or heteroaryl; wherein C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is optionally and independently substituted with one or more R 1a In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein each R 1 are independently halogen, -CN, -OH, -OR a , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OC 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 3 -C 10 Cycloalkyl or heterocycloalkyl; wherein C 1 -C 6 Alkyl, C 3 -C 10 Each of the cycloalkyl and heterocycloalkyl groups is optionally and independently substituted with one or more R 1a In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein each R 1 are independently halogen, -CN, -OH, -OR a , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OC 1 -C 6 Haloalkyl, C 3-C 10 Cycloalkyl or heterocycloalkyl; wherein C 1 -C 6 Alkyl, C 3 -C 10 Each of the cycloalkyl and heterocycloalkyl groups is optionally and independently substituted with one or more R 1a In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein each R 1 are independently halogen, -CN, -OH, -OR a , C 1 -C 6 Alkyl, -OC 1 -C 6 Haloalkyl, -CF 3 , C 3 -C 10 Cycloalkyl or heterocycloalkyl; wherein C 1 -C 6 Alkyl, C 3 -C 10 Each of the cycloalkyl and heterocycloalkyl groups is optionally and independently substituted with one or more R 1a In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein each R 1 are independently fluorine, chlorine, bromine, iodine, -CN, -OH, -OR a , C 1 -C 6 Alkyl, -OC 1 -C 6 Haloalkyl, -CF 3 , C 3 -C 10 Cycloalkyl or heterocycloalkyl; wherein C 1 -C 6 Alkyl, C 3 -C 10 Each of the cycloalkyl and heterocycloalkyl groups is optionally and independently substituted with one or more R 1a In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein each R 1 are independently fluorine, chlorine, bromine, -CN, -OH, -OC 1 -C 6 Alkyl, -OC 1 -C 6 Haloalkyl, C 1 -C 6 Alkyl, -CF3 , C 3 -C 10 Cycloalkyl or heterocycloalkyl; wherein -OC 1 -C 6 Alkyl, C 1 -C 6 Alkyl, C 3 -C 10 Each of the cycloalkyl and heterocycloalkyl groups is optionally and independently substituted with one or more R 1a In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein each R 1 are independently fluorine, chlorine, -CN, -OH, -OCH 3 、-OCH 2 CH 3 , -C 1 -C 6 Alkyl (OR 1a ),-CH 3 、-CH 2 CH 3 , isopropyl, n-propyl, n-butyl, isobutyl, tert-butyl, -OCHF 2 、-OC 1 -C 6 Hydroxyalkyl, -CF 3 , cyclopropyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl, 1,4-oxazepanyl or thiazinyl; wherein each of azetidinyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl, thiazinyl and 1,4-oxazepanyl is optionally and independently replaced by one or more R 1a In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein each R 1 are independently chlorine, -CN, -OH, -OCH 3 、-OCH 2 CH 3 、-CH 3 , isopropyl, -OCHF 2 , -CF 3 , cyclopropyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl or 1,4-oxazepanyl; wherein each of azetidinyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl and 1,4-oxazepanyl is optionally and independently replaced by one or more R 1aIn some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein each R 1 are independently chlorine, -CN, -OCH 2 -CH 3 , isopropyl, -OCHF 2 , -CF 3 , cyclopropyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl; wherein each of azetidinyl, piperidinyl, piperazinyl and morpholinyl is optionally and independently replaced by one or more R 1a In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein each R 1 are independently chlorine, -CN, -OCH 2 -CH 3 , isopropyl, -OCHF 2 , -CF 3 , cyclopropyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl; wherein each of azetidinyl, piperidinyl, piperazinyl and morpholinyl is optionally and independently replaced by one or more R 1a In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein each R 1 are independently chlorine, -CN, -OCH 2 -CH 3 , isopropyl, -OCHF 2 , -CF 3 , cyclopropyl, piperidinyl, piperazinyl or morpholinyl; wherein piperidinyl, piperazinyl and morpholinyl are optionally substituted by one or more R 1a In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein each R 1 are independently chlorine, -CN, -OCH 2 -CH 3 , isopropyl, -OCHF 2 , -CF 3 , cyclopropyl, piperidinyl, piperazinyl or morpholinyl; wherein piperidinyl, piperazinyl and morpholinyl are optionally substituted by one or more -CH 3 、-CH 2 CH 3 、-CH 2 CH 2 CH 3 , -OH and -OCH 3In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein each R 1 are independently chlorine, -CN, -OCH 2 -CH 3 、-OCHF 2 , cyclopropyl, piperidinyl, piperazinyl or morpholinyl; wherein piperidinyl, piperazinyl and morpholinyl are optionally substituted by one or more -CH 3 、-CH 2 CH 3 、-CH 2 CH 2 CH 3 , -OH and -OCH 3 In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein each R 1 are independently chlorine, -CN, -OCH 2 -CH 3 、-OCHF 2 , cyclopropyl or morpholinyl; wherein the morpholinyl is optionally substituted by one or more -CH 3 、-CH 2 CH 3 、-CH 2 CH 2 CH 3 , -OH and -OCH 3 In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein each R 1 are independently chlorine, -OCH 2 -CH 3 、-OCHF 2 , cyclopropyl or morpholinyl; wherein the morpholinyl is optionally substituted by one or more -CH 3 replace.

[0188] Further provided herein are compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein n is 1, 2, or 3. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein n is 1 are provided. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein n is 2 are provided. In some embodiments, compounds of Formula (I), (Ia), and (Ib), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein n is 3 are provided.

[0189] Further provided herein are compounds of Formula (I), Formula (Ia) and Formula (Ib), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, wherein R 2 is hydrogen. Further provided herein are compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, wherein R 3 It's hydrogen.

[0190] Further provided herein are compounds of Formula (I), Formula (Ia) and Formula (Ib), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, wherein R 4a , R 4b and R 4c In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein R 4a is a halogen, and R 4b and R 4c In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein R 4a and R 4c is hydrogen, and R 4b In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein R 4a and R 4b is hydrogen, and R 4c In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein R 4a and R 4b is a halogen, and R 4cIn some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein R 4a and R 4c is a halogen, and R 4b In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein R 4a , R 4b and R 4c In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein R 4a , R 4b and R 4c In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein R 5 It's hydrogen.

[0191] Further provided herein are compounds of Formula (I), Formula (Ia) and Formula (Ib), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, wherein each R 6 It's hydrogen.

[0192] Further provided herein are compounds of Formula (I), Formula (Ia) and Formula (Ib), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, wherein R 7 is hydrogen or C 1 -C 6 In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein R 7 In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein R 7 It is C 1 -C 6 alkyl.

[0193] Further provided herein are compounds of Formula (I), Formula (Ia) and Formula (Ib), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, wherein R 8a , R 8b , R 8c and R 8d Each of is independently hydrogen, halogen or -OR aIn some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein R 8a , R 8b and R 8d Each of which is hydrogen and R 8c is hydrogen, halogen or -OR a In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein R 8c Is halogen or -OR a In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein R 8c In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein R 8c is fluorine, chlorine, bromine or iodine. In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein R 8c Yes-OR a .

[0194] Further provided herein are compounds of Formula (I), Formula (Ia) and Formula (Ib), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, wherein R a It is C 1 -C 6 In some embodiments, compounds of Formula (I), Formula (Ia) and Formula (Ib) or pharmaceutically acceptable salts, solvates or stereoisomers thereof are provided, wherein R a Yes-CH 3 .

[0195] Further provided herein are compounds of formula (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof:

[0196]

[0197] in:

[0198] Ring A is C 6 -C 10 Aryl or heteroaryl, C 3 -C 10 Cycloalkyl and heterocycloalkyl groups;

[0199] Each R 1 are independently halogen, -CN, -OH, -OR a, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OC 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl or heteroaryl; wherein C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is optionally and independently substituted with one or more R 1a replace;

[0200] Each R 1a are independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl or heteroaryl;

[0201] n is 1, 2, 3, 4, 5, 6, 7, or 8;

[0202] R 2 is hydrogen or C 1 -C 6 alkyl;

[0203] R 3 is hydrogen or C 1 -C 6 alkyl;

[0204] R 4a , R 4b and R 4c each independently is hydrogen, deuterium or halogen;

[0205] R 7 is hydrogen or C 1 -C 6 alkyl;

[0206] R 8a , R 8b , R 8c and R 8d Each of is independently hydrogen, deuterium, halogen or -OR a ;

[0207] Each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1-C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl, heteroaryl, C 1 -C 6 Alkyl (C 3 -C 10 Cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (C 6 -C 10 Aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1-C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl substitution;

[0208] Each R b are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl, heteroaryl, C 1 -C 6 Alkyl (C 3 -C 10 Cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (C 6 -C 10 Aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O)2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substituted; and

[0209] Each R c and R d are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl, heteroaryl, C 1 -C 6 Alkyl (C 3 -C 10 Cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (C 6 -C10 Aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl substitution;

[0210] or R c and R d Together with the atoms to which they are attached to form a heterocycloalkyl group, the heterocycloalkyl group is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution.

[0211] Further provided herein are compounds of formula (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, wherein Ring A is C 6 -C 10 In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein Ring A is C 6 -C 10Aryl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is phenyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is heteroaryl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is furanyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is pyrazolyl, pyridinyl, pyrazinyl or pyrimidinyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is pyrazolyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl or 5-pyrazolyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 1-pyrazolyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 3-pyrazolyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 4-pyrazolyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 5-pyrazolyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is pyridyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl or 6-pyridyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 2-pyridyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 3-pyridyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein Ring A is 4-pyridinyl.In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 5-pyridyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 6-pyridyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is pyrazinyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl or 6-pyrazinyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 2-pyrazinyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 3-pyrazinyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 5-pyrazinyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 6-pyrazinyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is pyrimidinyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl or 6-pyrimidinyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 2-pyrimidinyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 4-pyrimidinyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 5-pyrimidinyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 6-pyrimidinyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is pyridazinyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl or 6-pyridazinyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 3-pyridazinyl.In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 4-pyridazinyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 5-pyridazinyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 6-pyridazinyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is C. 3 -C 10 In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein Ring A is C 3 -C 10 Cycloalkyl. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is a heterocycloalkyl.

[0212] Further provided herein are compounds of formula (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, wherein each R 1 are independently halogen, -CN, -OH, -OR a , C 1 -C 6 Alkyl, C 1 -C 6 Halogenated alkyl, OC 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 3 -C 10 Cycloalkyl and heterocycloalkyl; wherein C 1 -C 6 Alkyl, C 3 -C 10 Each of the cycloalkyl and heterocycloalkyl groups is optionally and independently substituted with one or more R 1a In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein each R 1 are independently halogen, -CN, -OH, -OR a , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OC 1 -C 6 Haloalkyl, C 3 -C 10Cycloalkyl or heterocycloalkyl; wherein C 1 -C 6 Alkyl, C 3 -C 10 Each of the cycloalkyl and heterocycloalkyl groups is optionally and independently substituted with one or more R 1a In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein each R 1 are independently fluorine, chlorine, bromine, iodine, -CN, -OH, -OR a , C 1 -C 6 Alkyl, -CF 3 、-OC 1 -C 6 Haloalkyl, C 3 -C 10 Cycloalkyl or heterocycloalkyl; wherein C 1 -C 6 Alkyl, C 3 -C 10 Each of the cycloalkyl and heterocycloalkyl groups is optionally and independently substituted with one or more R 1a In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein each R 1 are independently fluorine, chlorine, bromine, -CN, -OH, -OR a , C 1 -C 6 Alkyl, -CF 3 、-OC 1 -C 6 Haloalkyl, C 3 -C 10 Cycloalkyl or heterocycloalkyl; wherein C 1 -C 6 Alkyl, C 3 -C 10 Each of the cycloalkyl and heterocycloalkyl groups is optionally and independently substituted with one or more R 1a In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein each R 1 are independently fluorine, chlorine, -CN, -OH, -OC 1 -C 6 Alkyl, C 1 -C 6 Alkyl, -CF 3 、-OC 1 -C 6 Haloalkyl, C 3 -C 10Cycloalkyl or heterocycloalkyl; wherein -OC 1 -C 6 Alkyl, C 1 -C 6 Alkyl, C 3 -C 10 Each of the cycloalkyl and heterocycloalkyl groups is optionally and independently substituted with one or more R 1a In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein each R 1 are independently fluorine, chlorine, -CN, -OH, -OCH 3 、-OCH 2 CH 3 , -C 1 -C 6 Alkyl (OR 1a ),-CH 3 、-CH 2 CH 3 , isopropyl, n-propyl, n-butyl, isobutyl, tert-butyl, -OC 1 -C 6 Hydroxyalkyl, -CF 3 、-OCHF 2 , cyclopropyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl, 1,4-oxazepanyl or thiazinyl; wherein each of azetidinyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl, thiazinyl and 1,4-oxazepanyl is optionally and independently replaced by one or more R 1a In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein each R 1 are independently chlorine, -CN, -OH, -OCH 3 、-OCH 2 CH 3 、-CH 3 , isopropyl, -CF 3 、-OCHF 2 , cyclopropyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl or 1,4-oxazepanyl; wherein each of azetidinyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl and 1,4-oxazepanyl is optionally and independently replaced by one or more R 1a In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein each R 1 are independently chlorine, -CN, -OCH 3 、-CH 3, isopropyl, -CF 3 、-OCHF 2 , cyclopropyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl; wherein each of azetidinyl, piperidinyl, piperazinyl and morpholinyl is optionally and independently replaced by one or more R 1a In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein each R 1 are independently chlorine, -CN, -OCH 3 、-CH 3 , isopropyl, -CF 3 、-OCHF 2 , cyclopropyl, piperidinyl, piperazinyl or morpholinyl; wherein each of cyclopropyl, piperidinyl, piperazinyl and morpholinyl is optionally and independently replaced by one or more R 1a In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein each R 1 are independently chlorine, -OCH 3 、-CH 3 , isopropyl, -CF 3 、-OCHF 2 , cyclopropyl, piperidinyl, piperazinyl or morpholinyl; wherein piperidinyl, piperazinyl and morpholinyl are optionally substituted by one or more R 1a In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein each R 1 are independently chlorine, -OCH 3 、-CH 3 , isopropyl, -CF 3 、-OCHF 2 , cyclopropyl, piperidinyl, piperazinyl or morpholinyl; wherein piperidinyl, piperazinyl and morpholinyl are optionally substituted by one or more -CH 3 、-CH 2 CH 3 、-CH 2 CH 2 CH 3 , -OH and -OCH 3 In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein each R 1 are independently chlorine, -OCH 3 、-CH 3 、-OCHF 2 , cyclopropyl, piperidinyl, piperazinyl or morpholinyl; wherein piperidinyl, piperazinyl and morpholinyl are optionally substituted by one or more -CH3 、-CH 2 CH 3 、-CH 2 CH 2 CH 3 , -OH and -OCH 3 In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein each R 1 are independently chlorine, -OCH 2 -CH 3 、-OCHF 2 , cyclopropyl or morpholinyl; wherein the morpholinyl is optionally substituted by one or more -CH 3 、-CH 2 CH 3 、-CH 2 CH 2 CH 3 , -OH and -OCH 3 In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein each R 1 are independently chlorine, -OCH 3 、-CH 3 , cyclopropyl or morpholinyl; wherein the morpholinyl is optionally substituted by one or more -CH 3 replace.

[0213] Further provided herein are compounds of formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein n is 1, 2, or 3. In some embodiments, compounds of formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein n is 1 are provided. In some embodiments, compounds of formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein n is 2 are provided. In some embodiments, compounds of formula (II), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein n is 3 are provided.

[0214] Further provided herein are compounds of formula (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, wherein R 2 It's hydrogen.

[0215] Further provided herein are compounds of formula (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, wherein R 3 It's hydrogen.

[0216] Further provided herein are compounds of formula (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, wherein R 4a , R4b and R 4c In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein R 4a is a halogen, and R 4b and R 4c In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein R 4a and R 4c is hydrogen, and R 4b In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein R 4a and R 4b is hydrogen, and R 4c In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein R 4a and R 4b is a halogen, and R 4c In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein R 4a and R 4c is a halogen, and R 4b In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein R 4a is a halogen, and R 4b and R 4c In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein R 4a , R 4b and R 4c In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein R 4a , R 4b and R 4c In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein R 4a , R 4b and R 4c It's fluorine.

[0217] Further provided herein are compounds of formula (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, wherein R 7 is hydrogen or C 1 -C6 In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein R 7 In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein R 7 It is C 1 -C 6 alkyl.

[0218] Further provided herein are compounds of formula (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, wherein R 8a , R 8b , R 8c and R 8d Each of is independently hydrogen, deuterium, halogen or -OR a In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein R 8a , R 8b and R 8d Each of is hydrogen, and R 8c is hydrogen, halogen or -OR a In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein R 8c Is halogen or -OR a In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein R 8c In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein R 8c is fluorine, chlorine, bromine or iodine. In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein R 8c Yes-OR a .

[0219] Further provided herein are compounds of formula (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, wherein R a It is C 1 -C 6 In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein R a Yes-CH 3 .

[0220] Further provided herein are compounds of formula (III) or pharmaceutically acceptable salts, solvates or stereoisomers thereof:

[0221]

[0222] in:

[0223] Ring A is a heteroaryl group;

[0224] Each R 1 are independently halogen, -CN, -OH, -OR a , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OC 1 -C 6 Haloalkyl, C 3 -C 10 Cycloalkyl or heterocycloalkyl; wherein C 1 -C 6 Alkyl, C 3 -C 10 Each of the cycloalkyl and heterocycloalkyl groups is optionally and independently substituted with one or more R 1a replace;

[0225] Each R 1a are independently deuterium, -OH, -OR a , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl or heteroaryl;

[0226] n is 1, 2, 3, 4, 5, 6, 7, or 8;

[0227] R 7 is hydrogen or C 1 -C 6 alkyl;

[0228] R 8c Is halogen or -OR a ;and

[0229] Each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl, heteroaryl, C 1 -C 6 Alkyl (C 3 -C 10 Cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (C 6 -C 10 Aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O)2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution.

[0230] Further provided herein is a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein ring A is pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl. In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is pyrazolyl. In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl or 5-pyrazolyl. In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 1-pyrazolyl. In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 3-pyrazolyl. In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 4-pyrazolyl. In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 5-pyrazolyl. In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is pyridyl. In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl or 6-pyridyl. In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 2-pyridyl. In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 3-pyridyl. In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 4-pyridyl. In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 5-pyridyl. In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 6-pyridyl. In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is pyrazinyl. In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl or 6-pyrazinyl. In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 2-pyrazinyl.In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 3-pyrazinyl. In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 5-pyrazinyl. In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 6-pyrazinyl. In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is pyrimidinyl. In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl or 6-pyrimidinyl. In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 2-pyrimidinyl. In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 4-pyrimidinyl. In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 5-pyrimidinyl. In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 6-pyrimidinyl. In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is pyridazinyl. In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl or 6-pyridazinyl. In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 3-pyridazinyl. In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 4-pyridazinyl. In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 5-pyridazinyl. In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is provided, wherein ring A is 6-pyridazinyl.

[0231] Further provided herein are compounds of formula (III) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, wherein:

[0232] Ring A is pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl;

[0233] Each R 1 are independently halogen, -CN, -OH, -OR a , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OC 1 -C 6 Haloalkyl, C 3 -C 10 Cycloalkyl or heterocycloalkyl; wherein C 1 -C 6 Alkyl, C 3 -C 10 Each of the cycloalkyl and heterocycloalkyl groups is optionally and independently substituted with one or more R 1a replace;

[0234] Each R 1a are independently -OH, -OR a , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 heteroalkyl;

[0235] n is 1, 2, or 3;

[0236] R 7 It is hydrogen;

[0237] R 8c Yes-OR a ;and

[0238] Each R a It is C 1 -C 6 In some embodiments, ring A is pyrimidinyl. In other embodiments, ring A is 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl or 6-pyrimidinyl. In still other embodiments, ring A is 2-pyrimidinyl. Additional embodiments provide that ring A is 4-pyrimidinyl. In other embodiments, ring A is 5-pyrimidinyl. In yet other embodiments, ring A is 6-pyrimidinyl.

[0239] Further provided herein are compounds of formula (III) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, wherein:

[0240] Ring A is pyridyl or pyrimidinyl;

[0241] Each R 1 are independently fluorine, chlorine, -CN, -OH, -ORa , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OC 1 -C 6 Haloalkyl, C 3 -C 10 Cycloalkyl or heterocycloalkyl; wherein C 1 -C 6 Alkyl, C 3 -C 10 Each of the cycloalkyl and heterocycloalkyl groups is optionally and independently substituted with one or more R 1a replace;

[0242] Each R 1a are independently -OH, -OR a , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 heteroalkyl;

[0243] n is 1, 2, or 3;

[0244] R 7 It is hydrogen;

[0245] R 8c Yes-OCH 3 ;and

[0246] Each R a It is C 1 -C 6 In some embodiments, ring A is pyridinyl. In other embodiments, ring A is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 5-pyridinyl or 6-pyridinyl. In still other embodiments, ring A is 2-pyridinyl. In some embodiments, ring A is 3-pyridinyl. In some embodiments, ring A is 4-pyridinyl. In some embodiments, ring A is 5-pyridinyl. In some embodiments, ring A is 6-pyridinyl. In some embodiments, ring A is pyrimidinyl. In some embodiments, ring A is 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl or 6-pyrimidinyl. In some embodiments, ring A is 2-pyrimidinyl. In some embodiments, ring A is 4-pyrimidinyl. In some embodiments, ring A is 5-pyrimidinyl. In some embodiments, ring A is 6-pyrimidinyl.

[0247] Further provided herein are compounds of formula (III) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, wherein:

[0248] Ring A is pyridyl or pyrimidinyl;

[0249] Each R 1 are independently chlorine, -CN, -OH, -OCH 3 ,-OCH 2 CH 3 、-CH 3 、-

[0250] CH 2 CH 3 、-CH(CH 3 ) 2 , -CF 3 、-OCHF 2 , cyclopropyl, morpholinyl, piperidinyl, piperazinyl, azetidinyl, 1,1-dioxidothiomorpholinyl or oxetanyl; wherein morpholinyl, piperidinyl, piperazinyl, azetidinyl, 1,1-dioxidothiomorpholinyl and oxetanyl are each optionally and independently replaced by one or more R 1a replace;

[0251] Each R 1a are independently -OH, -OR a , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 heteroalkyl;

[0252] n is 1, 2, or 3;

[0253] R 7 It is hydrogen;

[0254] R 8c Yes-OCH 3 ;and

[0255] Each R a It is C 1 -C 6 alkyl.

[0256] Further provided herein are compounds of formula (III) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, wherein:

[0257] Ring A is a heteroaryl group;

[0258] Each R 1are independently halogen, -CN, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OC 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl or heteroaryl; wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C6 -C 10 Each of the aryl and heteroaryl groups is optionally and independently substituted with one or more R 1a replace;

[0259] Each R 1a are independently deuterium, -OH, -OR a , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl or heteroaryl;

[0260] n is 1, 2, or 3;

[0261] R 7 is hydrogen or C 1 -C 6 alkyl;

[0262] R 8c Is halogen or -OR a ;

[0263] Each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C6 -C 10 Aryl, heteroaryl, C 1 -C 6 Alkyl (C 3 -C 10 Cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (C 6 -C 10 Aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl substitution;

[0264] Each Rb are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl, heteroaryl, C 1 -C 6 Alkyl (C 3 -C 10 Cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (C 6 -C 10 Aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substituted; and

[0265] Each R c and R d are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl, heteroaryl, C 1 -C 6 Alkyl (C 3 -C 10 Cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (C 6 -C 10 Aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substituted; or

[0266] R c and R d Together with the atoms to which they are attached to form a heterocycloalkyl group, the heterocycloalkyl group is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 In some embodiments, ring A is pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl. In some embodiments, ring A is pyrazolyl. In some embodiments, ring A is pyridinyl. In some embodiments, ring A is pyrazinyl. In some embodiments, ring A is pyrimidinyl. In some embodiments, ring A is pyridazinyl.

[0267] Further provided herein are compounds of formula (III) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, wherein:

[0268] Ring A is a heteroaryl group;

[0269] Each R 1 are independently halogen, -OR a 、-SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OC 1 -C 6 Haloalkyl, C 1 -C6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 3 -C 10 Cycloalkyl or heterocycloalkyl; wherein C 1 -C 6 Alkyl, C 3 -C 10 Each of the cycloalkyl and heterocycloalkyl groups is optionally and independently substituted with one or more R 1a replace;

[0270] Each R 1a are independently deuterium, -OH, -OR a , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl or heteroaryl;

[0271] n is 1, 2, or 3;

[0272] R 7 is hydrogen or C 1 -C 6 alkyl;

[0273] R 8c Is halogen or -OR a ;

[0274] Each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl, heteroaryl, C 1 -C 6 Alkyl (C 3 -C 10 Cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (C 6 -C 10 Aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl substitution;

[0275] Each R b are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl, heteroaryl, C 1 -C 6 Alkyl (C 3 -C 10 Cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (C 6 -C 10 Aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O)2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substituted; and

[0276] Each R c and R d are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl, heteroaryl, C 1 -C 6 Alkyl (C 3 -C 10 Cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (C 6 -C10 Aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 In some embodiments, ring A is pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl. In some embodiments, ring A is pyrazolyl. In some embodiments, ring A is pyridinyl. In some embodiments, ring A is pyrazinyl. In some embodiments, ring A is pyrimidinyl. In some embodiments, ring A is pyridazinyl.

[0277] Further provided herein are compounds of formula (III) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, wherein:

[0278] Ring A is a heteroaryl group;

[0279] Each R 1 are independently halogen, -OR a 、-SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OC 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 3 -C 10 Cycloalkyl or heterocycloalkyl; wherein C 1 -C 6 Alkyl, C 3 -C 10 Each of the cycloalkyl and heterocycloalkyl groups is optionally and independently substituted with one or more R 1a replace;

[0280] Each R 1a are independently deuterium, -OH, -OR a , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl or heteroaryl;

[0281] n is 1, 2, or 3;

[0282] R 7 is hydrogen or C 1 -C 6 alkyl;

[0283] R 8c Is halogen or -OR a ;

[0284] Each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl, heteroaryl, C 1 -C 6 Alkyl (C 3 -C 10 Cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (C 6 -C 10 Aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substituted; each R b are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C10 Aryl, heteroaryl, C 1 -C 6 Alkyl (C 3 -C 10 Cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (C 6 -C 10 Aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substituted; and

[0285] Each R c and Rd are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl, heteroaryl, C 1 -C 6 Alkyl (C 3 -C 10 Cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (C 6 -C 10 Aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 In some embodiments, ring A is pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl. In some embodiments, ring A is pyrazolyl. In some embodiments, ring A is pyridinyl. In some embodiments, ring A is pyrazinyl. In some embodiments, ring A is pyrimidinyl. In some embodiments, ring A is pyridazinyl.

[0286] Further provided herein are compounds of formula (III) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, wherein:

[0287] Ring A is phenyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl;

[0288] Each R 1 are independently halogen, -S(=O) 2 (C 1 -C 6 Alkyl), -S(=O) 2 N(C 1 -C 6 alkyl) 2 、-OC 1 -C 6 Alkyl, -C(=O)N(C 1 -C 6 alkyl) 2 、-C(=O)N(H)(C 1 -C 6 Alkyl), -OC 1 -C 6 Haloalkyl, C 1 -C 6 Alkyl, -S(C 1 -C 6 alkyl), heterocycloalkyl or -C(=O)(heterocycloalkyl); n is 1, 2 or 3;

[0289] R 7 is hydrogen; and

[0290] R 8c is hydrogen, halogen, CH 3 or -OCH 3 In some embodiments, Ring A is phenyl. In some embodiments, Ring A is pyrazolyl. In some embodiments, Ring A is pyridinyl. In some embodiments, Ring A is pyrazinyl. In some embodiments, Ring A is pyrimidinyl. In some embodiments, Ring A is pyridazinyl. In some embodiments, R 8c is hydrogen. In some embodiments, R 8c is halogen. In some embodiments, R 8c is fluorine, chlorine, bromine or iodine. 8c In some embodiments, R 8c Yes CH 3 In some embodiments, R 8c Yes or -OCH 3 .

[0291] Further provided herein are compounds of formula (III) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, wherein:

[0292] Ring A is phenyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl;

[0293] Each R 1 are independently halogen, -CF 3 、-CN、-S(=O) 2 (CH 3 )、-S(=O) 2 (CH 2 CH 3 )-S(=O) 2 N(CH 3 ) 2 、-OCH 3 、-CH 2 CHF 2 、-C(=O)N(CH 3 ) 2 、-C(=O)N(H)(CH 3 ),-OC 1 C 6 Haloalkyl, -CH 3 、-CH 2 CH 3 , isopropyl, n-propyl, -SCH 3, azetidinyl, pyrrolidinyl, fluoropyrrolidinyl, difluoropiperidinyl, difluoroazetidinyl, fluoroazetidinyl, morpholinyl, dioxythiomorpholinyl, -C(=O)(morpholinyl), -C(=O)(azetidinyl), -C(=O)(difluoroazetidinyl), or -C(=O)difluoropiperidinyl;

[0294] n is 1, 2, or 3;

[0295] R 7 is hydrogen; and

[0296] R 8c is hydrogen, halogen, CH 3 or -OCH 3 In some embodiments, Ring A is phenyl. In some embodiments, Ring A is pyrazolyl. In some embodiments, Ring A is pyridinyl. In some embodiments, Ring A is pyrazinyl. In some embodiments, Ring A is pyrimidinyl. In some embodiments, Ring A is pyridazinyl. In some embodiments, R 8c is hydrogen. In some embodiments, R 8c is halogen. In some embodiments, R 8c is fluorine, chlorine, bromine or iodine. 8c In some embodiments, R 8c Yes CH 3 In some embodiments, R 8c Yes or -OCH 3 .

[0297] Further provided herein are compounds of formula (III) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, wherein:

[0298] Ring A is phenyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl;

[0299] Each R 1 are independently halogen, -CF 3 、-CN、-S(=O) 2 (CH 3 )、-S(=O) 2 (CH 2 CH 3 )、-S(=O) 2 (i-Pr), -S(=O) 2 (cyclopropyl), -S(=O) 2 (C 1 -C 6 Haloalkyl), -S(=O) 2 N(CH 3 ) 2、-S(=O) 2 NH 2 、-S(=O) 2 N(CH 3 )(H),-OCH 3 、-OCH 3 、-OCH 2 CH 3 、-CH 2 CHF 2 、-C(=O)N(CH 3 ) 2 、-C(=O)N(H)(CH 3 ),-OC 1 -C 6 Haloalkyl, -CH 3 、-CH 2 CH 3 , isopropyl, n-propyl, -SCH 3 , azetidinyl, pyrrolidinyl, oxazolyl, fluoropyrrolidinyl, difluoropiperidinyl, difluoroazetidinyl, fluoroazetidinyl, morpholinyl, dioxythiomorpholinyl, -C(=O)(morpholinyl), -C(=O)(azetidinyl), -C(=O)(difluoroazetidinyl), or -C(=O)difluoropiperidinyl; n is 1, 2, or 3;

[0300] R 7 is hydrogen; and

[0301] R 8c is hydrogen, halogen, CH 3 or -OCH 3 In some embodiments, Ring A is phenyl. In some embodiments, Ring A is pyrazolyl. In some embodiments, Ring A is pyridinyl. In some embodiments, Ring A is pyrazinyl. In some embodiments, Ring A is pyrimidinyl. In some embodiments, Ring A is pyridazinyl. In some embodiments, R 8c is hydrogen. In some embodiments, R 8c is halogen. In some embodiments, R 8c is fluorine, chlorine, bromine or iodine. 8c In some embodiments, R 8c Yes CH 3 In some embodiments, R 8c Yes or -OCH 3 .

[0302] Further provided herein are compounds of formula (III) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, wherein:

[0303] Ring A is phenyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl;

[0304] Each R 1 are independently halogen, -CF 3 、-CN、-S(=O) 2 (C 1 -C 6 Alkyl), -S(=O) 2 (C 3 -C 10 Cycloalkyl), -S(=O) 2 N(C 1 -C 6 alkyl) 2 、-S(=O) 2 NH 2 、-S(=O) 2 N(C 1 -C 6 Alkyl)(H), -OC 1 -C 6 Alkyl, -CH 2 CHF 2 、-C(=O)N(C 1 -C 6 alkyl) 2 、-C(=O)N(H)(C 1 -C 6 Alkyl), -OC 1 C 6 Haloalkyl, -C 1 -C 6 Alkyl, -SC 1 -C 6 alkyl, azetidinyl, pyrrolidinyl, oxazolyl, fluoropyrrolidinyl, difluoropiperidinyl, difluoroazetidinyl, fluoroazetidinyl, morpholinyl, dioxythiomorpholinyl, -C(=O)(morpholinyl), -C(=O)(azetidinyl), -C(=O)(difluoroazetidinyl), or -C(=O)difluoropiperidinyl;

[0305] n is 1, 2, or 3;

[0306] R 7 is hydrogen; and

[0307] R 8c is hydrogen, halogen, CH 3 or -OCH 3In some embodiments, Ring A is phenyl. In some embodiments, Ring A is pyrazolyl. In some embodiments, Ring A is pyridinyl. In some embodiments, Ring A is pyrazinyl. In some embodiments, Ring A is pyrimidinyl. In some embodiments, Ring A is pyridazinyl. In some embodiments, R 8c is hydrogen. In some embodiments, R 8c is halogen. In some embodiments, R 8c is fluorine, chlorine, bromine or iodine. 8c In some embodiments, R 8c Yes CH 3 In some embodiments, R 8c Yes or -OCH 3 .

[0308] Further provided herein are compounds of formula (III) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, wherein:

[0309] Ring A is phenyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl;

[0310] Each R 1 are independently halogen, -CF 3 、-CN、-S(=O) 2 (C 1 -C 6 Alkyl), -S(=O) 2 (C 3 -C 10 Cycloalkyl), -S(=O) 2 N(C 1 -C 6 alkyl) 2 、-S(=O) 2 NH 2 、-S(=O) 2 N(C 1 -C 6 Alkyl)(H), -OC 1 -C 6 Alkyl, -CH 2 CHF 2 、-C(=O)N(C 1 -C 6 alkyl) 2 、-C(=O)N(H)(C 1 -C 6 Alkyl), -OC 1 C 6 Haloalkyl, -C 1 -C 6 Alkyl, -SC 1 -C6 alkyl, azetidinyl, pyrrolidinyl, oxazolyl, fluoropyrrolidinyl, difluoropiperidinyl, difluoroazetidinyl, fluoroazetidinyl, morpholinyl, dioxythiomorpholinyl, -C(=O)(morpholinyl), -C(=O)(azetidinyl), -C(=O)(difluoroazetidinyl), or -C(=O)difluoropiperidinyl, and wherein R 1 At least one of them is -S(=O) 2 (C 1 -C 6 Alkyl), -S(=O) 2 (C 3 -C 10 Cycloalkyl), -S(=O) 2 N(C 1 -C 6 alkyl) 2 、-S(=O) 2 NH 2 or -S(=O) 2 N(C 1 -C 6 Alkyl)(H);

[0311] n is 1, 2, or 3;

[0312] R 7 is hydrogen; and

[0313] R 8c is hydrogen, halogen, CH 3 or -OCH 3 In some embodiments, Ring A is phenyl. In some embodiments, Ring A is pyrazolyl. In some embodiments, Ring A is pyridinyl. In some embodiments, Ring A is pyrazinyl. In some embodiments, Ring A is pyrimidinyl. In some embodiments, Ring A is pyridazinyl. In some embodiments, R 8c is hydrogen. In some embodiments, R 8c is halogen. In some embodiments, R 8c is fluorine, chlorine, bromine or iodine. 8c In some embodiments, R 8c Yes CH 3 In some embodiments, R 8c Yes or -OCH 3 .

[0314] Further provided herein are compounds of formula (III) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, wherein:

[0315] Ring A is a heterocycloalkyl group;

[0316] Each R1 are independently halogen, -CF 3 、-CN、-S(=O) 2 (C 1 -C 6 Alkyl), -S(=O) 2 (C 3 -C 10 Cycloalkyl), -S(=O) 2 N(C 1 -C 6 alkyl) 2 、-S(=O) 2 NH 2 、-S(=O) 2 N(C 1 -C 6 Alkyl)(H), -OC 1 -C 6 Alkyl, -CH 2 CHF 2 、-C(=O)N(C 1 -C 6 alkyl) 2 、-C(=O)N(H)(C 1 -C 6 Alkyl), -OC 1 C 6 Haloalkyl, -C 1 -C 6 Alkyl, -SC 1 -C 6 alkyl, azetidinyl, pyrrolidinyl, oxazolyl, fluoropyrrolidinyl, difluoropiperidinyl, difluoroazetidinyl, fluoroazetidinyl, morpholinyl, dioxythiomorpholinyl, -C(=O)(morpholinyl), -C(=O)(azetidinyl), -C(=O)(difluoroazetidinyl), or -C(=O)difluoropiperidinyl;

[0317] n is 1, 2, or 3;

[0318] R 7 is hydrogen; and

[0319] R 8c is hydrogen, halogen, CH 3 or -OCH 3 In some embodiments, Ring A is dihydropyridazinyl. In some embodiments, Ring A is 1,6-dihydropyridazin-3-yl. In some embodiments, R 8c is hydrogen. In some embodiments, R 8c is halogen. In some embodiments, R 8c is fluorine, chlorine, bromine or iodine. 8cIn some embodiments, R 8c Yes CH 3 In some embodiments, R 8c Yes or -OCH 3 .

[0320] Further provided herein are compounds of formula (III) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, wherein:

[0321] Ring A is an aryl group;

[0322] Each R 1 are independently halogen, -CN, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-SR a 、-S(=O)R a 、-S(=O) 2 R a 、-S(=O) 2 NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR a 、-NR b S(=O) 2 R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OC 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl or heteroaryl; wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is optionally and independently substituted with one or more R 1a replace;

[0323] Each R 1a are independently deuterium, -OH, -OR a , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl or heteroaryl;

[0324] n is 1, 2, or 3;

[0325] R 7 is hydrogen or C 1 -C 6 alkyl;

[0326] R 8c It is hydrogen, C 1 -C 6 Alkyl, halogen or -OR a ;

[0327] Each R a Independently C 1 -C 6 Alkyl, C 1 -C6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl, heteroaryl, C 1 -C 6 Alkyl (C 3 -C 10 Cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (C 6 -C 10 Aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3, -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 heteroalkyl substitution;

[0328] Each R b are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl, heteroaryl, C 1 -C 6 Alkyl (C 3 -C 10 Cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (C 6 -C 10 Aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10Each of the aryl and heteroaryl groups is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substituted; and

[0329] Each R c and R d are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Aryl, heteroaryl, C 1 -C 6 Alkyl (C3 -C 10 Cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (C 6 -C 10 Aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, heterocycloalkyl, C 6 -C 10 Each of the aryl and heteroaryl groups is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substituted; or

[0330] R c and R dTogether with the atoms to which they are attached to form a heterocycloalkyl group, the heterocycloalkyl group is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(=O)CH 3 、-S(=O) 2 CH 3 、-S(=O) 2 NH 2 、-S(=O) 2 NHCH 3 、-S(=O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution.

[0331] Further provided herein is a compound of formula (I) selected from (1R,2S)-5'-methoxy-2-{3-[(5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-{3-[(5-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-{3-[(5-chloropyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; 2-{3-[(5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-{3-[(5-ethoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-{3-[(5-cyclopropylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-{3-[(5-chloropyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one Oxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1S,2R)-5'-methoxy-2-{3-[(5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-(3-{[5-chloro-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-{3-[(2-chloro-5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2 '(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[5-methoxy-6-(piperidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-{3-[(3-methoxypyrazin-2-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one;(1R,2S)-5'-methoxy-2-{3-[(6-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-{3-[(6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-{3-[(2,3-dihydro-1-benzofuran-7-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2' (1'H)-one; (1R,2S)-5'-methoxy-2-{3-[(3-methoxypyridin-2-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-{3-[(4-methoxypyridin-3-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-{3-[(3-methoxypyridin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-{3-[(3-methoxypyridin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-{3-[(1,3,5-trimethyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-{3-[(1,3,5-trimethyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[5-(trifluoromethyl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2 '(1'H)-one; (1R,2S)-2-{3-[(5-chloro-2-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-methoxypyridin-3-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-{3-[(1-benzofuran-7-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one;(1R,2S)-5'-methoxy-2-{3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-{3-[(3-hydroxy-2,3-dihydro-1-benzofuran-7-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[(3S)-3-hydroxy-2,3-dihydro-1-benzofuran-7-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one indol]-2'(1'H)-one; (1R,2S)-2-(3-{[(3R)-3-hydroxy-2,3-dihydro-1-benzofuran-7-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-{3-[(2,3-dihydropyrazolo[5,1-b][1,3]oxazol-7-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-{3-[(3-oxo-2,3-dihydro-1-benzofuran-7-yl)amino]-1 H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-{3-[(2,3-dihydrofuro[2,3-c]pyridin-7-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[(3S)-3-(hydroxymethyl)-2,3-dihydrofuro[2,3-c]pyridin-7-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[(3R)-3-(hydroxymethyl)-2,3-dihydrofuro[2,3-c]pyridin-7-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[6-(3-methoxyazetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-(3-{[6-(3-hydroxyazetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one;(1R,2S)-2-(3-((6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-methoxypyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one; (1R,2S)-2-(3-{[6-(2-hydroxyethoxy)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'(1'H)-one; (1R,2S)-2-(3-((6-(1,1-dioxythiomorpholino)pyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane -1,3'-indolin]-2'-one); (1R,2S)-5'-methoxy-2-(3-{[6-(1,4-oxazepan-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[5-methoxy-2-methyl-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-(3-{[6-(azetidin-1-yl)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one oxazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[6-(3-hydroxyazetidin-1-yl)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[5-methoxy-6-(1,4-oxazepan-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[6-(3-hydroxyazetidin-1-yl)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one [cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-(3-{[5-chloro-6-(3-hydroxyazetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-(3-{[5-chloro-6-(3-methoxyazetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one;(1R,2S)-2-(3-{[2-chloro-5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[4-chloro-5-methoxy-6-(morpholin-4-yl)pyrimidin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[1-(2-hydroxyethyl)-3-methoxy-1H-pyrazol-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one 1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[2-cyclopropyl-5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-[3-({6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-5-methoxypyrimidin-4-yl}amino)-1H-indazol-6-yl]-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-((5-chloro-6-(1,1-dithiomorpholin-4-yl)pyrimidin-4-yl)amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one (1R,2S)-2-(3-((6-(1,1-dioxythiomorpholino)-5-methoxypyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one; (1R,2S)-2-(3-{[5-(2-hydroxyethyl)-3-methoxypyrazin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'(1'H)-one; (1R,2S)-2-(3-{[6-(2-hydroxyethyl)-3-methoxypyrazin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'(1'H)-one; (1R,2S)-2-(3-((6-(1,1-dioxythiomorpholino)-5-methoxy-2-methylpyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'-one; (1R,2S)-2-(3-((6-(1,1-dioxythiomorpholino)-5-methoxy-2-methylpyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'-one; (1R,2S)-2-(3-((5-chloro-6-(1,1-dioxythiomorpholino)-2-methylpyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'-one;(1R,2S)-2-(3-((2-cyclopropyl-6-(1,1-dihydrothiomorpholino)pyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one; (1R,2S)-2-(3-((6-(1,1-dihydrothiomorpholino)-2-methylpyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one; 5-methoxy-4-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indolin]-2-yl]-1H-indazol-3-yl} pyrimidine-2-carbonitrile; (1R,2S)-2-{3-[(1,3-dimethyl-1H-pyrazol-4-yl)amino]-1H-indole]-6-(morpholin-4-yl)pyrimidine-2-carbonitrile; (1R,2S)-5'-methoxy-2-(3-{[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]amino}- 1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-{3-[(1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; 4-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-1-methyl-1H-pyrazole-3-carbonitrile; (1R,2S)-2-[3-({6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-5-methoxy -2-methylpyrimidin-4-yl}amino)-1H-indazol-6-yl]-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[2-(2-hydroxyethyl)-5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-((2-cyclopropyl-6-(1,1-dioxythiomorpholino)-5-methoxypyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolino]-2'-one;(1R,2S)-2-(3-((5-chloro-2-cyclopropyl-6-(1,1-dioxythiomorpholino)pyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one; (1R,2S)-5'-methoxy-2-{3-[(3-methoxy-6-methylpyrazin-2-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-(3-{[5-chloro-6-(3-hydroxyazetidin-1-yl)-2-methylpyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane -1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[6-(3-hydroxyazetidin-1-yl)-5-methoxy-2-methylpyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-{3-[(1,3-dimethyl-1H-pyrazol-5-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-{3-[(4-methoxy-1-methyl-1H-pyrazol-5-yl)amino]-1 H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[5-chloro-2-cyclopropyl-6-(3-hydroxyazetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-[3-({2-cyclopropyl-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-5-methoxypyrimidin-4-yl}amino)-1H-indazol-6-yl]-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)- 2-(3-((5-chloro-6-(1,1-dioxothiomorpholino)-2-isopropylpyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one; (1R,2S)-5'-methoxy-2-{3-[(4-methoxy-1-methyl-1H-pyrazol-3-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-{3-[(6-cyclopropyl-3-methoxypyrazin-2-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one;(1R,2S)-2-(3-{[2-cyclopropyl-6-(3-hydroxyazetidin-1-yl)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-{3-[(3,6-dimethylpyrazin-2-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-6-(propan-2-yl)pyrazin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2' (1'H)-one; (1R,2S)-2-(3-((6-(1,1-dioxythiomorpholino)-2-isopropyl-5-methoxypyrimidin-4-yl)amino)-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one; (1R,2S)-5'-methoxy-2-(3-{[5-methoxy-6-(morpholin-4-yl)-2-(propan-2-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-{3-[(5-methoxy-2-methylpyridin-4-yl)amino]-1H-indazol-6-yl}spiro [Cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-{3-[(3-methoxy-6-methylpyridin-2-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-{3-[(2-methoxy-5-methylpyridin-3-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole] -2'(1'H)-one; (1R,2S)-5'-methoxy-2-{3-[(4-methoxypyridazin-3-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-{3-[(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-{3-[(3-cyclopropyl-1-ethyl-1H-pyrazol-5-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one;(1R,2S)-2-(3-{[2-(2-hydroxy-2-methylpropyl)-5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-5-(morpholin-4-yl)pyrazin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-2-(morpholin-4-yl)pyridin-4-yl]amino} -1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-{3-[(5-chloro-2-methylpyridin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[5-methoxy-2-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-{3-[(5-chloro-2-methylpyrimidin-4-yl)amino]-1H -indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-6-(morpholin-4-yl)pyrazin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-6-(oxetane-3-yl)pyrazin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-6-(oxetane-3-yl)pyrazin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; [3-methoxy-6-(propan-2-yl)pyridazin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[6-(morpholin-4-yl)-2-(propan-2-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[5-chloro-2-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one;(1R,2S)-2-(3-{[5-(3-hydroxyazetidin-1-yl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[3-methyl-6-(propan-2-yl)pyrazin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-5' -methoxy-2-(3-{[6-(propan-2-yl)pyrazin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[5-chloro-6-(3-hydroxyazetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxy-1'-methylspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[5-chloro-6-(3-hydroxyazetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl) (3-hydroxyazetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-1'-ethyl-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[5-(difluoromethoxy)-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[6-(azacyclohexyl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; and (1R,2S)-2-(3-{[6-(3-hydroxyazetidin-1-yl)-2-(propan-2-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. ;

[0332] Further provided herein is a compound of formula (I) selected from (1R,2S)-2-(3-{[1-(2,2-difluoroethyl)-3-methyl-1H-pyrazol-5-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-1'-methylspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[2-(3-hydroxyazetidin-1-yl)-5-methoxypyrimidin-1-yl) pyrimidine-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[6-(oxetane-3-yl)pyrazin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[5-chloro-2-(propan-2-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[5-chloro-2-(propan-2-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[5-methoxy-2-(oxetan-3-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-(3-{[5-chloro-2-(3-hydroxyazetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-(3-{[5-chloro-2-(3-hydroxyazetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; R,2S)-2-(3-{[5-(difluoromethoxy)-2-methylpyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-1'-methylspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2R)-2-{7-fluoro-3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one;(1R,2S)-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[5-methoxy-2-(propan-2-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methylspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1S,2S) -2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methylspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-(3-{[5-(difluoromethoxy)-2-(propan-2-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-4'-fluoro-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1S,2 S)-4'-fluoro-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-6'-fluoro-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-(3-{[5-chloro-6-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1' H)-one; (1R,2S)-5'-fluoro-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-{3-[(5-ethoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[5-(difluoromethoxy)-2-methylpyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-fluorospiro[cyclopropane-1,3'-indol]-2'(1'H)-one;(1R,2S)-5'-methoxy-2-[3-({2-methyl-5-[(propan-2-yl)oxy]pyrimidin-4-yl}amino)-1H-indazol-6-yl]spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-(trifluoromethyl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-(trifluoromethyl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; 2S)-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1S,2S)-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-{3 -[(5-cyclopropyl-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[5-(difluoromethoxy)-2-(oxetane-3-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2R)-5'-fluoro-2- {7-fluoro-3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; and (1R,2R)-2-(3-{[5-(difluoromethoxy)-2-methylpyrimidin-4-yl]amino}-7-fluoro-1H-indazol-6-yl)-5'-fluorospiro[cyclopropane-1,3'-indol]-2'(1'H)-one or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. ;

[0333] Further provided herein is a compound of formula (I) selected from (1R,2R)-2-{5-fluoro-3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-{3-[(3-methoxy-6-methylpyridazin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-(3-{[5-(cyclopropylmethoxy)-2-methylpyrimidin-4-yl]amino}-1H-indazol-6-yl )-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[5-(2,2-difluoroethoxy)-2-methylpyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-[3-(2-methoxy-5-methylanilino)-1H-indazol-6-yl]spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[2-methyl-5-(2,2,2-trifluoroethoxy)- 1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-{3-[(2-methoxy-6-methylpyridin-3-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[2-methyl-6-(propan-2-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-{3-[(5-ethyl-2- 1H-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-{3-[(2-methyl-6,7-dihydrofuro[3,2-d]pyrimidin-4-yl)amino]-1H-indole-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[5-methoxy-2-(oxan-4-yl)pyrimidin-4-yl]amino}-1H-indole-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one;(1R,2S)-5'-methoxy-2-(3-{[5-methoxy-2-(methylsulfanyl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-{3-[(2,5-dimethoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-(3-{[2-(azetidin-1-yl)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one -one; (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-5-(trifluoromethyl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-{3-[(2-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-{3-[(2-ethyl-5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]- 2'(1'H)-one; (1R,2S)-5'-methoxy-2-{3-[(7-methoxyquinolin-6-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[2-methyl-5-(methylsulfanyl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-{3-[(3-methoxyquinolin-2-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-{3-[(3-methoxyquinolin-2-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (S)-2-{3-[(2,5-dimethoxypyridin-3-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-{3-[(2-chlorofuro[3,2-d]pyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; 6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyridine-2-carboxamide;(1R,2S)-5'-methoxy-2-(3-{[5-methoxy-2-(pyrrolidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[6-(methylsulfonyl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-[3-({2-[(3R)-3-fluoropyrrolidin-1-yl]-5-methoxypyrimidin-4-yl}amino)-1H-indazol-6-yl]-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one propane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[2-(3,3-difluoropyrrolidin-1-yl)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-{3-[(2-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; 5-methoxy-4-({6-[(1R,2S)-5'-methoxy-2'-oxo-1' ,2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)pyrimidine-2-carbonitrile; (1R,2S)-2-(3-{[2-(3,3-difluoroazetidin-1-yl)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[2-(3-fluoroazetidin-1-yl)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; -{3-[5-(ethylsulfonyl)-2-methoxyanilino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; 4-methoxy-3-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylbenzamide; 4-methoxy-3-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-N-methylbenzamide;(1R,2S)-5'-methoxy-2-{3-[2-methoxy-5-(propane-2-sulfonyl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; 4-methoxy-3-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylbenzene-1-sulfonamide; (1R,2S)-5'-methoxy-2-{3-[2-methoxy-5-(morpholine-4-carbonyl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2 '(1'H)-one; 6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyridine-3-carboxamide; (1R,2S)-2-(3-{[2-(dimethylamino)-5-methylpyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[2-methoxy-6-(morpholine-4-carbonyl)pyridin-3-yl]amino}-1H-indazol- 6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[6-(3,3-difluoroazetidine-1-carbonyl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[6-(4,4-difluoropiperidine-1-carbonyl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(4-fluoro-3-{[5-methoxy- (1R,2S)-5'-methoxy-2-{3-[(2-methoxy-5-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-{3-[(2-methoxy-5-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[2-methoxy-6-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)pyridin-3-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one;(1R,2S)-2-(3-{[2-(4,4-difluoropiperidin-1-yl)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; 4-[5-methoxy-4-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)pyrimidin-2-yl]-1λ6-thiomorpholine-1,1-dione; 6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)pyrimidin-2-yl]-1λ6-thiomorpholine-1,1-dione 1H-indazol-3-yl}amino)-N-methylpyridine-2-carboxamide; (1R,2S)-5'-methoxy-2-(3-{[5-methoxy-2-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[5-(methylsulfonyl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; 6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxa-6-azaspiro[3.3]hept-6-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one (1R,2S)-2-(3-{[5-ethoxy-2-(methylsulfanyl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[6-(methylsulfonyl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; 5-methoxy-6-({6-[(1 (1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyridine-3-carboxamide; 5-methoxy-4-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyridine-2-carboxamide; (1R,2S)-5'-methoxy-2-{3-[2-methoxy-4-(morpholine-4-carbonyl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one;Diastereomer 1: (1R, 2S)-5'-methoxy-2-(3-{[5-methoxy-2-(oxolan-3-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; Diastereomer 2: (1R, 2S)-5'-methoxy-2-(3-{[5-methoxy-2-(oxolan-3-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R, 2S)-2-(3 -{[2-ethoxy-6-(methylsulfonyl)pyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; 5-ethoxy-6-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyridine-3-carboxamide; 5-methoxy-6-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyridine-3-carboxamide (1R,2S)-2-(3-{[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; 2-fluoro-5-methoxy-4-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]- (1R,2S)-2-{3-[5-fluoro-2-methoxy-4-(morpholine-4-carbonyl)anilino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; and (1R,2S)-2-(3-{[3-ethoxy-5-(methylsulfonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one or a pharmaceutically acceptable salt thereof. ;

[0334] Further provided herein is a compound of formula (I) selected from (1R,2S)-2-(3-{[6-(ethylsulfonyl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; 5-methoxy-4-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-N,2-dimethylbenzene-1-sulfonamide; (1R,2S)-2-{3-[(2,5-dimethyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)amino]-1H-indazol -6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; 2,5-dimethoxy-4-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)benzene-1-sulfonamide; (1R,2S)-2-(3-{[2-(dimethylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; 6-ethoxy-5-({6-[(1R,2S)-5'-methoxy-2 (1R,2S)-5'-methoxy-2-(3-{[2-methoxy-6-(2-oxopyrrolidin-1-yl)pyridin-3-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-{3-[2-methoxy-5-(morpholine-4-sulfonyl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[2-methoxy-6-(2-oxopyrrolidin-1-yl)pyridin-3-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; {3-[(3-methoxy-1,5-naphthyridin-2-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; N,6-dimethoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-N-methylpyridine-2-carboxamide; 6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-N'-(propan-2-yl)pyridine-2-carboxylic acid hydrazide;(1R,2S)-5'-methoxy-2-(3-{[2-methoxy-5-(2-oxopyrrolidin-1-yl)pyridin-3-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[2-methoxy-5-(3-methyl-2-oxoimidazolidin-1-yl)pyridin-3-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; 6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2 -yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyridine-2-sulfonamide; 6-ethoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyridine-2-sulfonamide; (1R,2S)-5'-methoxy-2-{3-[2-methoxy-5-(oxacyclohexane-4-sulfonyl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[5-(dimethylphosphoryl)-3-methoxypyridine- 2-{[5-(2-hydroxypropan-2-yl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-(3-{[5-(2-hydroxypropan-2-yl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-(3-{[6-(methylsulfonyl)-2-methoxy-5-methylpyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-(3-{[5-( (1R,2S)-2-(3-{[5-(dimethylphosphoryl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; N-(cyclopropylmethyl)-6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)pyridine-2-carboxamide;6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-N-(propan-2-yl)pyridine-2-carboxamide; (1R,2S)-5'-methoxy-2-(3-{[2-methoxy-6-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)pyridin-3-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-{3-[(4-methoxy-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl) [amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[2-methoxy-5-(1,3-oxazol-2-yl)pyridin-3-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-5-(3-methoxyazetidine-1-carbonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; 6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2 6-ethoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyrazine-2-carboxamide; 6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyrazine-2-carboxamide ; (1R,2S)-2-(3-{[6-(methylsulfinyl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-(3-{[6-(methylsulfinyl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-(3-{[6-(methylsulfonyl)-4-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one;(1R,2S)-2-(3-{[5-(methylsulfonyl)-3-methoxypyrazin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; N,N-dicyclopropyl-6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)pyridine-2-carboxamide; N-(2,2-difluoroethyl)-6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl] -1H-indazol-3-yl}amino)pyridine-2-carboxamide; (1R,2S)-2-[3-({6-[(2R,6S)-2,6-dimethylpiperidine-1-carbonyl]-2-methoxypyridin-3-yl}amino)-1H-indazol-6-yl]-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[2-methoxy-6-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)pyridin-3-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[3-chloro-5-(methanesulfonyl)pyridin-3-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one [cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-5-(propane-2-sulfonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-(3-{[6-(dimethylphosphoryl)-4-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; N-(1,3-difluoropropan-2-yl)-6-methoxy-5 -({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)pyridine-2-carboxamide; 6-chloro-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyridine-2-carboxamide; (1R,2S)-2-{3-[(5-chloro-2-methyl-1,3-benzoxazol-6-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one;4-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyridine-2-carboxamide; 3-[6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)pyrazin-2-yl]-1λ6-thietane-1,1-dione; (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-5-(morpholine-4-sulfonyl)pyridin-2-yl]amino 1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-5-(8-oxa-3-azabicyclo[3.2.1]octane-3-sulfonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[6-(diethylphosphoryl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[5- (cyclopropanesulfonyl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-5-(oxacyclohexane-4-sulfonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; 6-methoxy-5-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)pyridine-2-carbonitrile; (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-5-(oxacyclohexane-4-sulfonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one (1R,2S)-2-{3-[5-(diethylphosphoryl)-2-methoxyanilino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[6-(ethylsulfonyl)-4-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[5-(azetidine-1-carbonyl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one;(1R,2S)-5'-methoxy-2-(3-{[3-methoxy-5-(morpholine-4-carbonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-{3-[(6-methoxy-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-{3-[(4-methoxy-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]-1H-indazol-6-yl 1,3'-indole]-2'(1'H)-one; (1R,2S)-5'-methoxy-2-(3-{[3-methoxy-5-(1,2-oxazolidin-2-sulfonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-(3-{[5-(azetidine-1-sulfonyl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; 5-methoxy-6-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydro Spiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-N-(3-methyloxetan-3-yl)pyridine-3-sulfonamide; 5-methoxy-6-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-N-methyl-N-(3-methyloxetan-3-yl)pyridine-3-sulfonamide; (1R,2S)-2-(3-{[5-(1-hydroxyethyl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)- ketone; (1R,2S)-2-{3-[2-ethoxy-4-(methylsulfonyl)anilino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-(3-{[3-ethoxy-5-(4-methylpiperazine-1-sulfonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one; (1R,2S)-2-(3-{[5-(ethylsulfonyl)-3-ethoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indole]-2'(1'H)-one;5-ethoxy-6-({6-[(1R,2S)-5'-methoxy-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]-2-yl]-1H-indazol-3-yl}amino)-N-methylpyridine-3-sulfonamide; (1R,2S)-5'-chloro-2-(3-{[3-ethoxy-5-(methylsulfonyl)pyridin-2-yl]amino (1R,2S)-2-{3-[(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-{3-[(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[6-(2-hydroxypropan-2-yl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; (1R,2S)-2-(3-{[4-ethoxy-6-(methylsulfonyl)pyridin-3-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one -yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one; and (1R,2S)-2-(3-{[5-(difluoromethanesulfonyl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one or a pharmaceutically acceptable salt thereof. ;

[0335] Further provided herein are compounds of formula (I) selected from those shown in Table 1A.

[0336] Table 1A

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406] Further provided herein are pharmaceutical compositions comprising an amount of a compound of Formula (I), (Ia), (Ib), (II) or (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and one or more pharmaceutically acceptable excipients.

[0407] Treatment

[0408] Further provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II) or (III), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition disclosed herein comprising a compound of Formula (I), (Ia), (Ib), (II) or (III), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. Such methods of treating cancer in a subject are provided herein, wherein the subject's cancer 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, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney cancer or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) tumor, primary CNS lymphoma, spinal tumor, brain stem glioma, or pituitary adenoma. In some embodiments, the subject's cancer expresses polo-like kinase 4 (PLK4). In some embodiments, prior to administering a compound of Formula (I), (Ia), (Ib), (II) or (III), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, to a subject, it has been determined that the subject's cancer expresses polo-like kinase 4 (PLK4). In some embodiments, the subject's cancer exhibits overexpression of an E3 ubiquitin-protein ligase (TRIM37) protein. In some embodiments, the subject's cancer exhibits overexpression of a gene encoding a protein containing a tripartite motif 37 (TRIM37). In some embodiments, the subject's cancer exhibits amplification of a gene encoding a protein containing a tripartite motif 37 (TRIM37).

[0409] Further provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II) or (III), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein prior to administering the compound to the subject, the subject's cancer has been determined to overexpress a gene encoding tripartite motif-containing protein 37 (TRIM37).

[0410] Further provided herein is a method of treating cancer in a subject in need thereof, wherein it has been determined that the subject's cancer overexpresses a gene encoding tripartite motif-containing protein 37 (TRIM37), the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II) or (III), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0411] Further provided herein are methods of treating cancer in a subject comprising:

[0412] a. obtaining a biological sample of cancer from a subject;

[0413] b. Determine whether a cancer biological sample overexpresses a protein encoding a tripartite motif37

[0414] (TRIM37) gene; and

[0415] c. If the cancerous biological sample is determined to overexpress a protein encoding a three-part motif 37

[0416] (TRIM37) gene, then administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II) or (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0417] Further provided herein are methods of treating cancer in a subject as described herein, wherein the cancer is neuroblastoma or breast cancer. Also provided herein are methods of treating cancer in a subject as described herein, wherein the cancer is neuroblastoma. Also provided herein are methods of treating cancer in a subject as described herein, wherein the cancer is breast cancer.

[0418] Further provided herein are methods of treating cancer in a subject as described herein, wherein a compound of Formula (I), (Ia), (Ib), (II) or (III), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, is administered to the subject together with one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are selected from one or more mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, antiangiogenic agents, topoisomerase I and II inhibitors, plant alkaloids, hormone agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors (such as inhibitors of protein tyrosine kinases and / or serine / threonine kinases), cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxic drugs and immuno-oncology agents.

[0419] Further provided herein is a method of inhibiting polo-like kinase 4 (PLK4) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II) or (III), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition comprising a compound of Formula (I), (Ia), (Ib), (II) or (III), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0420] Further provided herein is a method of inhibiting polo-like kinase 4 (PLK4) in a subject having cancer, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (II) or (III), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition comprising a compound of Formula (I), (Ia), (Ib), (II) or (III), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein prior to administering the compound or pharmaceutical composition to the subject, it has been determined that the subject's cancer expresses polo-like kinase 4 (PLK4).

[0421] Further provided herein is 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), (Ia), (Ib), (II) or (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the subject's cancer is acute myeloid leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, triple-negative breast cancer, advanced breast cancer, metastatic breast cancer or prostate cancer. In some embodiments, the subject's cancer is acute myeloid leukemia. In some embodiments, the subject's cancer is myelodysplastic syndrome. In some embodiments, the subject's cancer is chronic myelomonocytic leukemia. In some embodiments, the subject's cancer is triple-negative breast cancer. In some embodiments, the subject's cancer is advanced breast cancer. In some embodiments, the subject's cancer is metastatic breast cancer. In some embodiments, the subject's cancer is prostate cancer.

[0422] Further provided herein are compounds of Formula (I), (Ia), (Ib), (II) or (III), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, or pharmaceutical compositions comprising compounds of Formula (I), (Ia), (Ib), (II) or (III), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, for use in a method of treating cancer in a subject in need thereof. In some embodiments, such compounds or pharmaceutical compositions for such uses are provided, wherein the subject's cancer is a solid tumor. In some embodiments, such compounds or pharmaceutical compositions for such uses are provided, wherein the cancer is neuroblastoma, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) tumor, primary CNS lymphoma, spinal tumor, brain stem glioma or pituitary adenoma. In some embodiments, such compounds or pharmaceutical compositions for such uses are provided, wherein the subject's cancer expresses polo-like kinase 4 (PLK4). In some embodiments, such compounds or pharmaceutical compositions for such uses are provided, wherein before administering the compound or pharmaceutical composition to the subject, it has been determined that the subject's cancer expresses polo-like kinase 4 (PLK4). In some embodiments, such compounds or pharmaceutical compositions for such uses are provided, wherein the subject's cancer exhibits overexpression of E3 ubiquitin-protein ligase (TRIM37) protein. In some embodiments, such compounds or pharmaceutical compositions for such uses are provided, wherein the subject's cancer exhibits overexpression of a gene encoding a protein containing a three-part motif 37 (TRIM37). In some embodiments, such compounds or pharmaceutical compositions for such uses are provided, wherein the subject's cancer exhibits amplification of a gene encoding a protein containing a three-part motif 37 (TRIM37). In some embodiments, such compounds or pharmaceutical compositions for such uses are provided, wherein before administering the compound or pharmaceutical composition to the subject, it has been determined that the subject's cancer overexpresses a gene encoding a protein containing a three-part motif 37 (TRIM37). In some embodiments, such compounds or pharmaceutical compositions for such uses are provided, wherein the cancer is neuroblastoma or breast cancer. In some embodiments, such compounds or pharmaceutical compositions for such use are provided, wherein the cancer is neuroblastoma.In some embodiments, such compounds or pharmaceutical compositions for such use are provided, wherein the cancer is breast cancer.

[0423] Further provided herein are compounds of Formula (I), (Ia), (Ib), (II) or (III), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, or pharmaceutical compositions comprising compounds of Formula (I), (Ia), (Ib), (II) or (III), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, for use in a method of treating a cancer in a subject in need thereof, wherein the subject's cancer is acute myeloid leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, triple-negative breast cancer, advanced breast cancer, metastatic breast cancer or prostate cancer. In some embodiments, the subject's cancer is acute myeloid leukemia. In some embodiments, the subject's cancer is myelodysplastic syndrome. In some embodiments, the subject's cancer is chronic myelomonocytic leukemia. In some embodiments, the subject's cancer is triple-negative breast cancer. In some embodiments, the subject's cancer is advanced breast cancer. In some embodiments, the subject's cancer is metastatic breast cancer. In some embodiments, the subject's cancer is prostate cancer.

[0424] Further provided herein are compounds of Formula (I), (Ia), (Ib), (II) or (III), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, or pharmaceutical compositions comprising compounds of Formula (I), (Ia), (Ib), (II) or (III), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, for use in methods of inhibiting polo-like kinase 4 (PLK4) in subjects suffering from cancer.

[0425] Further provided herein is the use of a compound of Formula (I), (Ia), (Ib), (II) or (III), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, in the preparation of a medicament for treating cancer in a subject in need thereof. In some embodiments, such use is provided, wherein the cancer is neuroblastoma, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) tumor, primary CNS lymphoma, spinal tumor, brain stem glioma or pituitary adenoma. In some embodiments, the subject's cancer expresses polo-like kinase 4 (PLK4). In some embodiments, prior to administering the compound to the subject, it has been determined that the subject's cancer expresses polo-like kinase 4 (PLK4). In some embodiments, the cancer of the subject exhibits overexpression of an E3 ubiquitin-protein ligase (TRIM37) protein. In some embodiments, the cancer of the subject exhibits overexpression of a gene encoding a protein containing a three-part motif 37 (TRIM37). In some embodiments, the cancer of the subject exhibits amplification of a gene encoding a protein containing a three-part motif 37 (TRIM37). In some embodiments, prior to administering the compound to the subject, it has been determined that the cancer of the subject overexpresses a gene encoding a protein containing a three-part motif 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.

[0426] Further provided herein is the use of a compound of Formula (I), (Ia), (Ib), (II) or (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof in the preparation of a medicament for treating cancer in a subject in need thereof, wherein the subject's cancer is acute myeloid leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, triple-negative breast cancer, advanced breast cancer, metastatic breast cancer or prostate cancer. In some embodiments, the subject's cancer is acute myeloid leukemia. In some embodiments, the subject's cancer is myelodysplastic syndrome. In some embodiments, the subject's cancer is chronic myelomonocytic leukemia. In some embodiments, the subject's cancer is triple-negative breast cancer. In some embodiments, the subject's cancer is advanced breast cancer. In some embodiments, the subject's cancer is metastatic breast cancer. In some embodiments, the subject's cancer is prostate cancer.

[0427] In some embodiments, the compound of formula (I), (Ia), (Ib), (II) or (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is used in combination with one or more additional anticancer agents. In some embodiments, the anticancer agent is mitoxantrone, estramustine, etoposide, vinblastine, carboplatin, vinorelbine, paclitaxel, daunomycin, darubicin, epirubicin, docetaxel, cabazitaxel or doxorubicin. In some embodiments, the anticancer agent is paclitaxel, daunomycin, idarubicin, epirubicin, docetaxel, cabazitaxel or doxorubicin. In certain embodiments, the anticancer agent is docetaxel.

[0428] In some embodiments, one or more additional anticancer agents may include, but are not limited to, surgery, radiation, or chemotherapy. Chemotherapy may 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 (e.g., paclitaxel, docetaxel, paclitaxel, docetaxel, cabazitaxel, tesetaxel, or nab-paclitaxel).

[0429] or nanoalbumin paclitaxel) or vinca alkaloids (e.g., vinblastine, vincristine, vindesine, or vinorelbine). Examples of antimetabolites include, but are not limited to, 5-fluorouracil, 6-mercaptopurine, capecitabine, cytarabine, floxuridine, fludarabine, gemcitabine, hydroxyurea, methotrexate, pemetrexed, or phototrexate. Examples of platinum-based agents include, but are not limited to, cisplatin, carboplatin, dicycloplatin, eptaplatin, lobaplatin, miriplatin, nedaplatin, oxaliplatin, picoplatin, satraplatin, or triplatintetranitrate. Additional anticancer therapies may include anti-PDL1 agents, anti-PD1 agents, or anti-CTLA-4 agents. Anti-PD-L1 agents may include atezolizumab, avelumab, durvalumab, MPDL3280A (RG7446), MDX-1105 (BMS-936559) or BMS-935559, MSB0010718C, and MEDI4736. Anti-PD1 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.

[0430] Combining biomarker-based approaches

[0431] In some embodiments, disclosed herein is a method for detecting the presence, absence or level of a biomarker. Such biomarkers may include genetic changes in genes encoding certain proteins, such as protein 37 (TRIM37) containing a three-part motif. Such biomarkers may be measured in biological samples obtained from an object. The presence, absence or level of such biomarkers, such as samples of solid tumors (such as prostate cancer), or samples of related biological fluids, such as blood samples. In some cases, the detection methods disclosed herein are used to predict the therapeutic response to the therapy described herein (e.g., PLK4 inhibitors) in an object, monitor the treatment using the therapy, and treat the proliferative diseases or conditions described herein with the therapy. In some embodiments, by analyzing the genetic material in the sample, the presence, absence and / or expression level of one or more biomarkers are detected in a sample obtained from an object. In some embodiments, the genetic material is obtained from blood, serum, plasma, sweat, hair, tears, urine, and other techniques known to those skilled in the art. In some embodiments, the sample comprises circulating tumor RNA (ctRNA). In some embodiments, the sample comprises peripheral blood mononuclear cells (PBMC). In some cases, genetic material is obtained from a tumor biopsy or a liquid biopsy. In some embodiments, a tumor biopsy includes a formalin-fixed paraffin-embedded biopsy, a fresh frozen biopsy, a fresh biopsy, or a frozen biopsy. In some embodiments, a liquid biopsy includes PBMC, circulating tumor RNA, plasma cell-free RNA, or circulating tumor cells (CTC). A tumor biopsy can undergo additional analytical processing for sample dissociation, cell sorting, and enrichment of a cell population of interest.

[0432] In some embodiments, the method for detecting the presence, absence or level of a biomarker in a sample obtained from an object relates to detecting a nucleic acid sequence. In some cases, the nucleic acid sequence comprises deoxyribonucleic acid (DNA), such as in the case of detecting a 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 a DNA selected from genomic DNA, viral DNA, mitochondrial DNA, plasmid DNA, amplified DNA, circular DNA, circulating DNA, cell-free DNA or exosome DNA. In some cases, DNA is single-stranded DNA (ssDNA), double-stranded DNA, denatured double-stranded DNA, synthetic DNA and a combination thereof. Circular DNA can be cut or fragmented. In some cases, the nucleic acid sequence includes 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 fragmented RNA molecule (RNA fragment) selected from the group consisting of microRNA (miRNA), pre-miRNA, primary-miRNA, mRNA, pre-mRNA, viral RNA, viroid RNA, pseudoviral RNA, circular RNA (circRNA), ribosomal RNA (rRNA), transfer RNA (tRNA), pre-tRNA, long noncoding RNA (lncRNA), small nuclear RNA (snRNA), circulating RNA, cell-free RNA, exosomal RNA, vector-expressed RNA, RNA transcripts, synthetic RNA, and combinations thereof.

[0433] In some embodiments disclosed herein, biomarkers are detected by performing a nucleic acid-based detection assay on a sample obtained from a subject. In some cases, nucleic acid-based detection assays include quantitative polymerase chain reaction (qPCR), gel electrophoresis (including, for example, Northern or Southern blots), immunochemistry, in situ hybridization (such as fluorescent in situ hybridization (FISH)), cytochemistry, microarrays, or sequencing. In some embodiments, sequencing techniques include next generation sequencing. In some embodiments, the methods involve hybridization assays, such as fluorescent qPCR (e.g., TaqMan TM, SYBR green, SYBR greenI, SYBR green II, SYBR gold, ethidium bromide, methylene blue, Pyronin Y, DAPI, acridine orange, Blue View or phycoerythrin), which relates to a nucleic acid amplification reaction with a specific primer pair, and a hybridization of a nucleic acid probe comprising a detectable portion or amplification of a molecule specific to a target nucleic acid sequence. In some cases, the number of amplification cycles for detecting a target nucleic acid in a qPCR assay is about 5 to about 30 cycles. In some cases, the number of amplification cycles for detecting a target nucleic acid is at least about 5 cycles. In some cases, the number of amplification cycles for detecting a target nucleic acid is up to about 30 cycles. In some cases, the number of amplification cycles used to detect the target nucleic acid is about 5 to about 10, about 5 to about 15, about 5 to about 20, about 5 to about 25, about 5 to about 30, about 10 to about 15, about 10 to about 20, about 10 to about 25, about 10 to about 30, about 15 to about 20, about 15 to about 25, about 15 to about 30, about 20 to about 25, about 20 to about 30, or about 25 to about 30 cycles. For TaqMan TM Method, the probe can be a hydrolyzable probe comprising a fluorophore and a quencher, which is hydrolyzed by a DNA polymerase when hybridized with a target nucleic acid. In some cases, the presence of the target nucleic acid is determined when the number of amplification cycles reaching a threshold is less than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21 or 20 cycles. In some cases, hybridization can occur at a standard hybridization temperature, for example, between about 35°C and about 65°C in a standard PCR buffer.

[0434] Other exemplary nucleic acid-based detection assays include using conjugated or otherwise fixed on a nucleic acid probe on a bead, a multi-well plate or other substrate, wherein the nucleic acid probe is configured to hybridize with a target nucleic acid sequence. In some cases, the nucleic acid probe is specific to one or more gene products as described herein. In some cases, the nucleic acid probe having specificity for a biomarker comprises a nucleic acid probe sequence fully complementary to the polynucleotide sequence of a biomarker. In some cases, a biomarker includes a polynucleotide sequence (e.g., RNA, cDNA) of transcription. In some embodiments, the nucleic acid probe can be, for example, a full-length cDNA or a portion thereof, such as a length of at least about 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45 or 50 nucleotides and an oligonucleotide sufficient to specifically hybridize with a target nucleic acid sequence under standard hybridization conditions. In some embodiments, the target nucleic acid sequence is fixed on a solid surface and contacted with a probe, for example, by running a 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 probes are immobilized on a solid surface, such as in an Affymetrix gene chip array, and the probes are contacted with the target nucleic acid sequence.

[0435] In some embodiments, the term "probe" for nucleic acid refers to any nucleic acid molecule that can selectively bind to a specific expected 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 label, a colorimetric label, or other labels or labels 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 dye, 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 with amino groups at the α or β positions. For example, naphthylamino compounds include 1-dimethylaminonaphthalene-5-sulfonate, 1-anilino-8-naphthalenesulfonate and 2-p-toluidin-6-naphthalenesulfonate, 5-(2'-aminoethyl)aminonaphthalene-1-sulfonic acid (EDANS). Exemplary coumarins include, for example, 3-phenyl-7-isocyanatocoumarin; acridines, such as 9-isothiocyanatoacridine and acridine orange; N-(p-(2-benzoxazolyl)phenyl)maleimide; cyanines, such as, for example, indolylcarbocyanine 3 (Cy3), indolylcarbocyanine 5 (Cy5), indolylcarbocyanine 5.5 (Cy5.5), 3-(-carboxy-pentyl)-3'-ethyl-5,5'-dimethyloxacarbocyanine (CyA); 1 H,5H,11H,15H-xantheno[2,3,4-ij:5,6,7-i'j']biquinolizin-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-indole (TR or Texas Red); or BODIPYTM dye. In some cases, the probe comprises FAM as a dye label.

[0436] In some embodiments, detecting one or more biomarkers, such as gene products in a predicted response signature (PRS), comprises sequencing genetic material obtained from a sample of an object. Sequencing can be performed using 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, pyrophosphate sequencing, Maxam-Gilbert sequencing, chain termination (e.g., Sanger) sequencing, +S sequencing, or synthetic sequencing. 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. Other sequencing methods available to those skilled in the art can also be used.

[0437] 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 between about 1 to about 100,000 nucleotides, about 1 to about 10,000 nucleotides, about 1 to about 1,000 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 100,000 nucleotides, about 5 to about 10,000 nucleotides, about 5 to about 1,000 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 100,000 nucleotides, about 10 to about 10,000 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, In some embodiments, the present invention relates to a polypeptide having a plurality of nucleic acids and a plurality of nucleic acids. The polypeptide may be a polypeptide having a plurality of nucleic acids and a plurality of nucleic acids. The polypeptide may be a polypeptide having a plurality of nucleic acids and a plurality of nucleic acids.

[0438] The methods disclosed herein include: (a) providing a sample obtained from a subject with a proliferative disease or condition (e.g., cancer); (b) determining to detect the presence or absence of relevant biomarkers in the sample obtained from the subject; and (c) detecting the presence or absence of biomarkers in the sample using the methods described herein. In some cases, hybridization assays (such as hybridization assays described herein) are used to detect biomarkers in samples. Exemplary probe sequences that can be hybridized with target nucleic acid sequences (e.g., one or more genes in a biomarker, such as PRS) include at least 10 but no more than 100 consecutive nucleotides containing relevant sequences. In some cases, RNA sequencing (RNAseq) is used to detect one or more biomarkers.

[0439] In some cases, the detection of related biomarkers involves the nucleic acid of the object amplified by polymerase chain reaction (PCR). In some embodiments, PCR determination involves the use of a pair of primers capable of amplifying at least about 10 continuous nucleobases in a nucleic acid sequence, thereby amplifying one or more gene products in a biomarker. In fluorescent quantitative PCR, quantification is based on the amount of fluorescent signal (TaqMan and SYBR green). In some embodiments, nucleic acid probes are conjugated to detectable molecules. Detectable molecules can be fluorophores. Nucleic acid probes can also be conjugated to quenchers.

[0440] In some embodiments, the determination for detecting the presence or absence of related biomarkers includes reverse transcription of related mRNA molecules to produce corresponding complementary DNA (cDNA) molecules. In some embodiments, the determination further includes contacting the cDNA molecule with a nucleic acid probe, which includes a nucleic acid sequence complementary to the nucleic acid sequence of the cDNA molecule. In some embodiments, the determination includes detecting double-stranded hybridization products between nucleic acid probes and cDNA molecules. In some embodiments, a pair of primers is used to further amplify the hybridization product. In some embodiments, the primer includes a first primer with a nucleic acid sequence, which includes at least 10 but no more than 50 continuous nucleic acids in the related nucleic acid sequence of the top chain of the double-stranded hybridization product; and a second primer with a nucleic acid sequence, which is included in the nucleic acid sequence of the reverse complementary nucleic acid sequence of the bottom chain of the double-stranded hybridization product. At least 10 but no more than 50 continuous nucleic acids.

[0441] In some embodiments, disclosed herein are methods including preparing complementary DNA (cDNA) libraries. In some embodiments, the cDNA library is sequenced using a suitable sequencing method disclosed herein. In some embodiments, the cDNA library is labeled, a plurality of nucleic acid probes are produced, and fixed to a fixed surface (such as a microarray). In some embodiments, a plurality of nucleic acid probes can hybridize with at least about 10 continuous nucleotides of two or more genes in a sample obtained from an object. In some embodiments, detecting the presence or absence of a biomarker includes detecting the high or low expression level of two or more genes compared to a reference level.

[0442] In some embodiments disclosed herein, genetic material is extracted from a sample (e.g., blood or serum sample) obtained from an object. In certain embodiments of extracting nucleic acid, any technique that does not interfere with subsequent analysis is used to extract nucleic acid. In certain embodiments, the technology uses alcohol precipitation utilizing ethanol, methanol or isopropanol. In certain embodiments, the technology uses phenol, chloroform or any combination thereof. In certain embodiments, the technology uses cesium chloride. In certain embodiments, the technology uses sodium acetate, potassium acetate or ammonium acetate or any other salt commonly used for precipitating DNA. In certain embodiments, the technology utilizes nucleic acid purification schemes based on columns or resins, such as those commonly commercially available schemes, and a non-limiting example is the GenElute bacterial genomic DNA kit available from Sigma Aldrich. In certain embodiments, after extraction, before subsequent analysis, nucleic acid is stored in water, Tris buffer or Tris-EDTA buffer. In an exemplary embodiment, nucleic acid material is extracted in water. In some cases, extraction does not include nucleic acid purification. In certain embodiments, RNA can be extracted from cells using RNA extraction techniques, including, for example, acid phenol / guanidine isothiocyanate extraction (RNAzol B; Biogenesis), RNeasy RNA preparation kit (Qiagen), or PAXgene (PreAnalytix, Switzerland).

[0443] Circulating tumor DNA (ctDNA) and RNA (ctRNA)

[0444] 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 by tumors into the bloodstream.

[0445] In some embodiments, the detection of ctDNA or ctRNA is useful, for example, for detecting and diagnosing tumors. Because tumor DNA and RNA have acquired multiple gene mutations, leading to tumor development, ctDNA and ctRNA do not fully match the DNA and RNA of an individual, respectively. It is found that DNA and RNA with genetic differences are helpful for tumor detection. Using ctDNA or ctRNA to diagnose the type of tumor can reduce the need to obtain samples of tumor tissue (tumor biopsy), which may be challenging when the tumor is difficult to access, such as tumors in the brain or lungs.

[0446] In some embodiments, a decrease in the amount of ctDNA or ctRNA indicates that the solid tumor is shrinking and that treatment with a compound of Formula (I), (Ia), (Ib), (II) and (III) or a pharmaceutically acceptable salt thereof is effective. In some embodiments, the absence of ctDNA or ctRNA in the bloodstream indicates that the cancer has not recurred after treatment with a compound of Formula (I), (Ia), (Ib), (II) and (III) or a pharmaceutically acceptable salt thereof.

[0447] Methods for assessing genetic changes by ctDNA or ctRNA genomic profiling are described herein. In some embodiments, genomic profiling is performed after each treatment cycle with a compound of Formula (I), (Ia), (Ib), (II) and (III) or a pharmaceutically acceptable salt thereof. In some embodiments, the genetic mutation indicates that the cancer is resistant to treatment with a compound of Formula (I), (Ia), (Ib), (II) and (III) or a pharmaceutically acceptable salt thereof. In some embodiments, the lack of genetic mutation indicates that the cancer is not resistant to treatment with a compound of Formula (I), (Ia), (Ib), (II) and (III) or a pharmaceutically acceptable salt thereof.

[0448] Compounds of formula (I), (Ia), (Ib), (II) and (III) can be administered as prodrugs. Thus, when administered to a mammal, certain derivatives of a compound that may have little or no pharmacological activity itself can be converted into a compound having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as "prodrugs". For example, prodrugs can be produced by replacing appropriate functional groups present in compounds of formula (I), (Ia), (Ib), (II) and (III) with certain moieties known to those skilled in the art. See, for example, "Pro-drugs as Novel Delivery Systems", Vol. 14, ACSSymposium Series (T Higuchi and W Stella) and "Bioreversible Carriers in Drug Design", Pergamon Press, 1987 (E.B. Roche, American Pharmaceutical Association), the disclosures of which are incorporated herein by reference in their entirety. Some examples of such prodrugs include: ester moieties replacing carboxylic acid functional groups; ether moieties or amide moieties replacing alcohol functional groups; and amide moieties replacing primary or secondary amino functional groups. Examples of alternative groups are known to those skilled in the art. See, for example, "Design of Prodrugs" by H. Bundgaard (Elsevier, 1985), the disclosure of which is incorporated herein by reference in its entirety.

[0449] The salt 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, acetate, acrylate, benzenesulfonate, benzoate (such as chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate and methoxybenzoate), bicarbonate, bisulfate, bisulfite, hydrogen tartrate, borate, bromide, butyne-1,4-dioate, calcium edetate, camphorsulfonate, carbonate, chloride, hexanoate, octanoate, clavulanate, citrate, decanoate, dihydrochloride, dihydrogen phosphate, edetate, edisylate, etopoate, ethanesulfonate, ethyl succinate, formate, fumarate, glucoheptonate, gluconate, glutamate, glycolate, glycolyl para-aminophenylarsenate (glycollylarsanilate), enanthate, hexyne-1,6-dioate, hexylresorcinate (hexylresorcinate), hybamine The compounds described herein include, but are not limited to, hydrabamine, hydrobromide, hydrochloride, gamma-hydroxybutyrate, iodide, isobutyrate, isothiosulfate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate, metaphosphate, methanesulfonate, methylsulfate, monohydrogenphosphate, mucate, naphthalenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, nitrate, oleate, phenylpropionate, phthalate, phosphate / diphosphate, polygalacturonate, propanesulfonate, propionate, propiolate, pyrophosphate, pyrosulfate, salicylate, stearate, subacetate, suberate, oxalate, pamoate (pamoate), palmitate, pantothenate, phenylacetate, phenylbutyrate, succinate, sulfate, sulfonate, sulfite, tannate, tartrate, theoclorate, toluenesulfonate, triethiodode, and valerate.

[0450] Compounds of formula (I), (Ia), (Ib), (II) and (III) that are essentially alkaline can form various different salts with various inorganic acids and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is usually desirable in practice to first separate the compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt, then simply convert the latter back to the free base compound by treating with an alkaline agent, and subsequently convert the latter's free base into a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compound of the present invention can be prepared by treating the base compound with substantially equal amounts of selected inorganic or organic acids 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 free base solution in an organic solvent by adding a suitable inorganic or organic acid to the solution.

[0451] Compounds of formula (I), (Ia), (Ib), (II) and (III) that are acidic in nature can form basic salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal salts or alkaline earth metal salts, and particularly sodium and potassium salts. These salts are all prepared by conventional techniques. Chemical bases used as reagents for preparing 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 salts derived from such pharmacologically acceptable cations such as sodium, potassium, calcium and magnesium. These salts can be prepared by treating the corresponding acidic compound with an aqueous solution containing the desired pharmacologically acceptable cation, and then evaporating the resulting solution to dryness (preferably evaporating to dryness under reduced pressure). Alternatively, they can also be prepared by mixing a lower alkanol solution of the acidic compound with the desired alkali metal alkoxide, and then evaporating the resulting solution to dryness in the same manner as before. In either case, a stoichiometric amount of the reagent is preferably used to ensure the completeness of the reaction and the maximum yield of the desired final product.

[0452] If the compound of formula (I), (Ia), (Ib), (II) and (III) is a base, the desired salt can be prepared by any suitable method available in the art, for example, treating the free base with an inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.), or treating the free base 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, pyranosidic acid (such as glucuronic acid or galacturonic acid), α-hydroxy acid (such as citric acid or tartaric acid), amino acid (such as aspartic acid or glutamic acid), aromatic acid (such as benzoic acid or cinnamic acid), sulfonic acid (such as p-toluenesulfonic acid or ethanesulfonic acid), etc.

[0453] If the compound of formula (I), (Ia), (Ib), (II) and (III) is an acid, the desired salt may be prepared by any suitable method, for example, by treating the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide, etc. Illustrative examples of suitable salts include organic salts derived from amino acids (such as glycine and arginine), ammonia, primary, secondary and tertiary amines, and cyclic amines (such as piperidine, morpholine and piperazine), and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0454] If the compound of formula (I), (la), (lb), (II) and (III) is a solid, it will be appreciated by those skilled in the art 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 formula.

[0455] Also provided herein are isotopically labeled compounds of Formula (I), (Ia), (Ib), (II) and (III) wherein one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of suitable isotopes for inclusion in the compounds of the 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 invention (e.g., compounds incorporating a radioactive isotope) are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium ( 3 H) and carbon-14 ( 14 C) are particularly suitable for this purpose in view of their ease of incorporation and readily available means of detection. 2 H) substitution may offer certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. Substitution with positron-emitting isotopes such as 11 C. 18 F. 15 O and 13 N) Substitutions can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies.

[0456] Isotopically-labeled compounds of Formula (I), (Ia), (Ib), (II) and (III) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

[0457] In one aspect, the compositions of the compounds of Formula (I), (Ia), (Ib), (II) and (III) as described herein, or pharmaceutically acceptable salts, solvates or stereoisomers thereof, are used to treat cancer in a subject. In one embodiment, such compositions are in the form of a suitable dosage form. Suitable dosage forms include, for example, liquids, suspensions, powders for reconstitution, tablets, pills, sachets, or hard or soft gelatin capsules (see, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21st ed., Mack Pub. Co., Easton, PA (2005)).

[0458] The compounds of formula (I), (Ia), (Ib), (II) and (III) or their pharmaceutically acceptable salts, solvates or stereoisomers can be formulated into pharmaceutical compositions as described below in any pharmaceutical form deemed suitable by the skilled person. The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of at least one compound of the present invention and an inert pharmaceutically acceptable carrier or diluent.

[0459] The pharmaceutical carrier used 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 syrup, peanut oil, olive oil, water, etc. Similarly, the composition 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 wax, ethylcellulose, hydroxypropyl methylcellulose, methyl methacrylate, etc. Additional additives or excipients can be added to obtain the desired formulation properties. For example, a bioavailability enhancer such as Labrasol can be added. TM , Gelucire TM etc., or formulations such as CMC (carboxymethyl cellulose), PG (propylene glycol) or PEG (polyethylene glycol). For example, when preparing a capsule formulation, Gelucire TM , a semisolid vehicle that protects the active ingredient from light, moisture, and oxidation.

[0460] If a solid carrier is used, the preparation can be made into tablets, placed in a hard gelatin capsule in the form of a powder or pellet, or made into a lozenge or a lozenge. The amount of the solid carrier can vary, but is generally 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 injection solution, or a suspension or non-aqueous liquid suspension in an ampoule or a vial. If a semi-solid carrier is used, the preparation can be in the form of a hard gelatin capsule preparation and a soft gelatin capsule preparation. The composition of the present invention is prepared into a unit dosage form suitable for administration (e.g., parenteral or oral administration).

[0461] In order 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 0.3M solution of succinic acid or citric acid). If a soluble salt form is not available, the medicament can be dissolved in a suitable cosolvent or a combination of cosolvents. The example of a suitable cosolvent includes ethanol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerol, etc., with 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 a solution form of the salt form of the active ingredient in a suitable aqueous vehicle such as water or isotonic saline or glucose solution.

[0462] Suitable formulations depend on the chosen route of administration. For injection, the medicament of the compound of the invention can be formulated into an aqueous solution, preferably in a physiologically compatible buffer such as Hanks solution, Ringer solution or physiological saline buffer. For transmucosal administration, penetrants suitable for the permeation barrier are used in the formulation. Such penetrants are generally known in the art.

[0463] For oral administration, the compound can be formulated by combining the active compound with a pharmaceutically acceptable carrier known in the art. Such carriers enable the compounds of the present invention to be formulated 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 use solid excipients mixed with active ingredients (medicaments), optionally grinding the resulting mixture, and if necessary, processing the mixture of particles after adding suitable adjuvants 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, gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose or polyvinylpyrrolidone (PVP). If necessary, disintegrants such as cross-linked polyvinylpyrrolidone, agar or alginic acid or its salt (such as sodium alginate) can be added.

[0464] The dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, polyvinyl pyrrolidone, Carbopol gel, 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 identification or characterization of different combinations of active agents.

[0465] Pharmaceutical preparations that can be used orally include press-fit capsules made of gelatin, and sealed soft capsules made of gelatin and plasticizers (such as glycerol or sorbitol). Press-fit capsules can contain active ingredients mixed with fillers such as lactose, adhesives such as starch and / or lubricants such as talc or magnesium stearate and optionally stabilizers. In soft capsules, active agents can be dissolved or suspended in suitable liquids (such as fatty oils, liquid paraffin or liquid polyethylene glycol). In addition, stabilizers can be added. All preparations for oral administration should be dosages suitable for such administration. For buccal administration, compositions can be in the form of tablets or lozenges prepared in a conventional manner.

[0466] For intranasal administration or administration by inhalation, the compounds used according to the invention can conveniently be delivered in the form of an aerosol spray using a suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas from a pressurized bag or nebulizer. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of gelatin for use in inhalers or insufflators etc. can be formulated as a powder mixture containing the compound and a suitable powder base (such as lactose or starch).

[0467] The compound can be formulated for parenteral administration by injection (e.g., by bolus injection or continuous infusion). Formulations for injection can be in unit dosage form, for example in ampoules or in multidose containers, with the addition of preservatives. The composition can take the form of a suspension, solution or emulsion in an oily or aqueous vehicle, and can contain preparatons such as suspending agents, stabilizers and / or dispersants.

[0468] Pharmaceutical preparations for parenteral administration include aqueous solutions of active compounds in water-soluble form. In addition, suspensions of active agents can be prepared into 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 materials 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.

[0469] Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle (eg, sterile pyrogen-free water) before use.

[0470] In addition to the above-mentioned 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., subcutaneous or intramuscular) or by intramuscular injection. Therefore, for example, the compound 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, for example, as a sparingly soluble salt. The drug carrier for hydrophobic compounds is a co-solvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer and an aqueous phase. The co-solvent system can be a VPD co-solvent system. VPD is a solution of 3% w / v benzyl alcohol, 8% w / v of a non-polar surfactant polysorbate 80 and 65% w / v of polyethylene glycol 300 by volume in anhydrous ethanol. The VPD co-solvent system (VPD: 5W) contains VPD diluted 1:1 with a 5% aqueous glucose solution. This co-solvent system dissolves hydrophobic compounds well, and it itself produces low toxicity when administered systemically. The proportions of the cosolvent system can be varied appropriately without destroying its solubility and toxicity characteristics. In addition, the identity of the cosolvent components can be varied: for example, other low-toxicity nonpolar surfactants can be used instead of polysorbate 80; the fraction size of polyethylene glycol can be varied; other biocompatible polymers can replace polyethylene glycol, such as polyvinyl pyrrolidone; and other sugars or polysaccharides can replace glucose.

[0471] Alternatively, other delivery systems of hydrophobic drug compounds can be used. Liposomes and emulsions are known examples of delivery vehicles or carriers of hydrophobic drugs. Certain organic solvents, such as dimethyl sulfoxide (DMSO), can also be used, although due to the toxic properties of DMSO, usually at the expense of greater toxicity. In addition, sustained release systems can be used to deliver compounds, such as semipermeable matrices of solid hydrophobic polymers containing therapeutic agents. Various sustained release materials have been established and are well known to those skilled in the art. According to its chemical properties, sustained release capsules can release compounds in a few weeks to more than 100 days. According to the chemical properties and biostability of therapeutic agents, other strategies for protein stability can be adopted.

[0472] The pharmaceutical composition may also contain a suitable solid or gel phase carrier or excipient. 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 may be used. TM , Capryol TM 、Labrafil TM 、Labrasol TM 、Lauroglycol TM, Plurol TM , Peceol TM 、Transcutol TM wait.

[0473] Additionally, the pharmaceutical compositions may be incorporated into skin patches for delivering the drug directly to the skin.

[0474] It should be understood that the actual dosage of the medicament of the present invention will vary according to the specific medicament used, the specific composition prepared, the mode of administration, and the specific part, host and disease treated. In view of the experimental data of a given compound, the optimal dosage for a given set of conditions can be determined by those skilled in the art using conventional dose determination tests. For oral administration, the exemplary daily dosage generally used will be from about 0.001 mg / kg body weight to about 1000 mg / kg body weight, with the course of treatment repeated at appropriate intervals.

[0475] In addition, the pharmaceutically acceptable preparations of the present invention may contain a compound of the present invention or a salt or solvate thereof in an amount of about 10 mg to about 2000 mg, or about 10 mg to about 1500 mg, or about 10 mg to about 1000 mg, or about 10 mg to about 750 mg, or about 10 mg to about 500 mg, or about 25 mg to about 500 mg, or about 50 to about 500 mg, or about 100 mg to about 500 mg.

[0476] In addition, the pharmaceutically acceptable preparations of the present invention may contain a compound of the present invention or a salt or solvate thereof in an amount of about 0.5 w / w% to about 95 w / w%, about 1 w / w% to about 95 w / w%, about 1 w / w% to about 75 w / w%, about 5 w / w% to about 75 w / w%, about 10 w / w% to about 75 w / w%, or about 10 w / w% to about 50 w / w%.

[0477] The compounds of the present invention, or salts or solvates 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, such as a human, suffering from abnormal cell growth.

[0478] One of ordinary skill in the art will appreciate that the specific pharmaceutical formulation, dosage, and amount of dosage administered per day to a mammal in need of such treatment for a compound of Formula (I), (Ia), (Ib), (II) or (III), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, are all choices within the knowledge of one of ordinary skill in the art and can be determined without undue experimentation.

[0479] 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 the compound of formula (I), (Ia), (Ib), (II) or (III) or its pharmaceutically acceptable salt, solvate or stereoisomer can be determined via established animal and human experimental protocols and the embodiments described herein. For example, the toxicity and therapeutic efficacy of the compound of formula (I), (Ia), (Ib), (II) or (III) or its pharmaceutically acceptable salt, solvate or stereoisomer can be determined by standard pharmaceutical procedures in cell culture or experimental animals, including but not limited to determining LD50 (a dose lethal to 50% of the population) and ED50 (a dose effective for the treatment of 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 LD50 and ED50. The 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 the range of circulating concentrations including ED50 with minimal toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.Additional relative dosages, expressed as a percentage of the maximal response or maximum tolerated dose, can be readily obtained via the protocol.

[0480] In some embodiments, the amount of a compound of Formula (I), (Ia), (Ib), (II) or (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, including formulations corresponding to such amounts, varies depending on factors such as the particular 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 based on 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.

[0481] In some embodiments, the compound of formula (I), (Ia), (Ib), (II) or (III) or its pharmaceutically acceptable salt, solvate or stereoisomer is administered in an amount of about 10 mg to 500 mg per day. In some embodiments, the compound of formula (I), (Ia), (Ib), (II) or (III) or its pharmaceutically acceptable salt, solvate or stereoisomer is administered in an amount of about 100 mg to about 400 mg per day. In some embodiments, the compound of formula (I), (Ia), (Ib), (II) or (III) or its pharmaceutically acceptable salt, solvate or stereoisomer is administered in an amount of about 150 mg to about 350 mg per day. In some embodiments, the compound of formula (I), (Ia), (Ib), (II) or (III) or its pharmaceutically acceptable salt, solvate or stereoisomer is administered in an amount of about 150 mg to about 300 mg per day. In some embodiments, the compound of formula (I), (Ia), (Ib), (II) or (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is administered in an amount of about 160 mg to about 300 mg per day. In some embodiments, the compound of formula (I), (Ia), (Ib), (II) or (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is administered in an amount of about 160 mg per day. In some embodiments, the compound of formula (I), (Ia), (Ib), (II) or (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is administered in an amount of about 200 mg per day. In some embodiments, the compound of formula (I), (Ia), (Ib), (II) or (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is administered in an amount of about 240 mg per day. In some embodiments, the compound of Formula (I), (Ia), (Ib), (II) or (III), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, is administered in an amount of about 280 mg per day. In some embodiments, the compound of Formula (I), (Ia), (Ib), (II) or (III), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, is administered in an amount of about 320 mg per day.

[0482] Typically, appropriate dosage and treatment regimen provide a composition of the amount sufficient to provide a therapeutic benefit and / or a preventive benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remission, or longer disease-free and / or total survival, or mitigation of symptom severity). The optimal dose is typically determined using experimental models and / or clinical trials. The optimal dose depends on the body mass, body weight, or blood volume of the subject. Typically, appropriate dosage and treatment regimen provide a composition of the amount sufficient to provide a therapeutic benefit and / or a preventive benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remission, or longer disease-free and / or total survival, or mitigation of symptom severity). The optimal dose is typically determined using experimental models and / or clinical trials. The optimal dose depends on the body mass, body weight, or blood volume of the subject.

[0483] In certain embodiments where the subject's condition does not improve, at the discretion of the physician, administration of the compositions described herein is chronic, i.e., for a long period of time, including for the duration of the subject's lifetime, in order to alleviate or otherwise control or limit the symptoms of the subject's disease. In other embodiments, administration of the compositions continues until complete or partial response to the disease.

[0484] In some embodiments, a compound of Formula (I), (Ia), (Ib), (II) or (III), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, is administered to a subject in need thereof once a day. In some embodiments, a compound of Formula (I), (Ia), (Ib), (II) or (III), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, is administered to a subject in need thereof twice a day. In some embodiments, a compound of Formula (I), (Ia), (Ib), (II) or (III), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, is administered to a subject in need thereof three times a day.

[0485] In some cases, the methods described herein include administering to a subject or subject in need thereof a composition or formulation comprising a compound of Formula (I), (Ia), (Ib), (II), (III) in combination with one or more additional therapeutic agents in multiple cycles repeated on a regular schedule, with a rest period between each cycle. For example, in some cases, one week of treatment followed by three weeks of rest is one treatment cycle.

[0486] The length of the treatment cycle depends on the treatment given. In some embodiments, the length of the treatment cycle is in the range of two to six weeks. In some embodiments, the length of the treatment cycle is in the range of three to six weeks. In some embodiments, the length of the treatment cycle is in the range of 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 week, two weeks, three weeks or four weeks. In some embodiments, the treatment cycle lasts three weeks. In some embodiments, the treatment cycle lasts four weeks. The number of treatment doses planned in each cycle also varies according to the medicine given.

[0487] Kits and Products

[0488] In certain embodiments, kits and articles for use with one or more methods and compositions described herein are disclosed herein. Such kits include carriers, packages or containers that are separated to accommodate one or more containers, such as vials, tubes, etc., each container including one of the independent 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 of a variety of materials, such as glass or plastic.

[0489] The kit typically includes a label listing the contents and / or instructions for use, and a package insert with instructions for use. A set of instructions will also typically be included.

[0490] In one embodiment, the label is on or associated with the container. In one embodiment, the label is on the container when the letters, numbers or other characters forming the label are attached, molded or etched into the container itself. When the label is present in a receiver or carrier that also keeps the container, for example, as a package insert, the label is associated with the container. In one embodiment, the label is used to indicate that the content will be used for a specific treatment application. The label also indicates the instructions for use of the content, such as in the method described herein.

[0491] In certain embodiments, the pharmaceutical composition is present in a package or dispenser device, which is equipped with one or more unit dosage forms containing compounds provided herein. For example, the package contains metal or plastic foil, such as a blister package. In one embodiment, the package or dispenser device is accompanied by instructions for use. In one embodiment, the package or dispenser is also accompanied by a notice associated with the container, the form of which is specified by a government agency that manages the manufacture, use or sale of the drug, and the notice reflects the agency's approval of the drug form for human or veterinary administration. For example, such a notice is a drug label or approved product insert approved by the U.S. Food and Drug Administration. In one embodiment, a composition containing a compound provided herein formulated in a compatible pharmaceutical carrier is also prepared, placed in a suitable container, and labeled for treatment of a specified condition.

[0492] Preparation method

[0493] Compounds of formula (I), (Ia), (Ib), (II) or (III), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, can be prepared using the following reaction routes and synthetic schemes, using techniques available in the art, using readily available starting materials. The preparation of certain embodiments of the present invention is described in detail in the following examples, but one of ordinary skill in the art will recognize that the described preparations can be readily adapted to prepare other embodiments of the present invention. For example, the synthesis of non-exemplary compounds according to the present invention can be carried out by modifications apparent to one skilled in the art, such as by appropriately protecting interfering groups, by changing other suitable reagents known in the art, or by making conventional modifications to the reaction conditions. Alternatively, other reactions mentioned herein or known in the art will be considered to have adaptability for preparing other compounds of the present invention.

[0494] The compound of formula (I) can be prepared from the compound of formula (IV) by reacting the compound of formula (IV) with the compound of formula (V), wherein R 2 , R 3 , R 4a , R 4b , R 4c , R 5 , R 6 , R 7 , R 8a , R 8b , R 8c and R 8d As defined herein, wherein A, R 1and n are as defined herein, and wherein LG is a leaving group. LG that can be used includes halogens such as chlorine, bromine and iodine. The reaction of the compound of formula (IV) with the compound of formula (V) can be carried out using methods known to those of ordinary skill in the art. For example, the reaction of the compound of formula (IV) with the compound of formula (V) can be carried out in an aprotic solvent (such as acetonitrile, DMF, etc.), a protic solvent (such as water or alcohol), a mixture of a protic solvent and an aprotic solvent (e.g., 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 (V) can be prepared by the methods disclosed herein and / or by methods known to those of ordinary skill in the art.

[0495]

[0496] Alternatively, the compound of formula (VI) (wherein R 3 , R 4a , R 4b , R 4c , R 5 , R 6 , R 7 , R 8a , R 8b , R 8c and R 8d As defined herein, and Hal is a halogen, such as bromine or iodine) and a compound of formula (VII) wherein A, R 1 , R 2 and n as defined herein) to prepare compounds of formula (I). Such reactions 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 phosphate 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 an organic base, such as a tertiary amine, for example triethylamine, or an inorganic base, for example cesium carbonate. The aprotic solvent can be, for example, toluene. The reaction of the compound of formula (VI) with the compound of formula (VII) 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 in toluene at a temperature of 100°C. The compound of formula (VII) 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.

[0497]

[0498] Compounds of formula (VI) may be prepared by methods known to those of ordinary skill in the art. For example, compound (1R,2S)-2-(3-bromo-1H-indazole-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one of formula (IV) may be prepared according to the scheme described below. Other compounds of formula (VI) may be prepared by methods known to those skilled in the art, with modifications apparent to those skilled in the art, such as by using different starting materials, appropriately protecting interfering groups, by varying other suitable reagents known in the art, or by making conventional modifications to the reaction conditions.

[0499]

[0500] Similarly, (1R,2S)-2-(3-iodo-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolino]-2'-one can be prepared by reacting (1R,2S)-2-(1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolino]-2'-one with iodine in DMF and methanol in the presence of potassium carbonate as described below.

[0501]

[0502] Compounds of formula (IV) can be prepared from compounds of formula (VI) by methods known to those of ordinary skill in the art. For example, tert-butyl (1R, 2S)-2-(3-amino-1-(tert-butoxycarbonyl)-1H-indazole-6-yl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-carboxylate can be prepared from (1R, 2S)-2-(3-bromo-1H-indazole-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one as described below.

[0503]

[0504] Compounds such as (1R,2S)-tert-butyl 2-(3-amino-1-(tert-butoxycarbonyl)-1H-indazol-6-yl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-carboxylate can be reacted with a compound of formula (V) as described herein, followed by deprotection of the Boc group using an acid such as trifluoroacetic acid to provide compounds of formula (I). For example, tert-butyl (1R,2S)-2-(3-amino-1-(tert-butoxycarbonyl)-1H-indazol-6-yl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-carboxylate can be reacted with 4-chloro-5-methoxypyrimidine to give (1R,2S)-5'-methoxy-2-(3-((5-methoxypyrimidin-4-yl)amino)-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indoline]-2'-one.

[0505]

[0506] In the following preparations and examples, "Ac" means acetyl, "ACN" and "MeCN" mean acetonitrile, "Me" means methyl, "Et" means ethyl, "Ph" means phenyl, "BOC", "Boc" or "boc" means N-tert-butyloxycarbonyl, and "DCM" (CH 2 Cl 2 ) means dichloromethane, “DIPEA” or “DIEA” means diisopropylethylamine, “DMA” means N,N-dimethylacetamide, “DMF” means N--N-dimethylformamide, “DMSO” means dimethyl sulfoxide, “DPPP” means 1,3-bis(diphenylphosphino)propane, “HOAc” means acetic acid, “IPA” means isopropanol, “min” means minutes, “NMP” means 1-methyl 2-pyrrolidone, “TEA” means triethylamine, “TFA” means trifluoroacetic acid, “DCM” means dichloromethane, “EtOAc” and “EA” mean ethyl acetate, “MgSO 4 " means magnesium sulfate, "Na 2 SO 4 ” means sodium sulfate, “MeOH” means methanol, “Et 2 O" means ether, "EtOH" means ethanol, and "H 2 O" means water, "HCl" means hydrochloric acid, and "K 2 CO 3means potassium carbonate, “THF” means tetrahydrofuran, “DBU” means 1,8-diazabicyclo[5.4.0]undec-7-ene, “LiHMDS” or “LHMDS” means lithium hexamethyldisilazane, “TBME” or “MTBE” means 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 degrees Celsius, “Pa” means Pascal, “rt” or “RT” means room temperature, “h” means hour, “satd.” means saturated, “aq” means aqueous solution, “anhyd.” or “anh.” means anhydrous, “MBTE” means methyl tert-butyl ether, “PE” means petroleum ether, and “TBSCl” means tert-butyldimethylsilyl chloride.

[0507] Example

[0508] Intermediate 1. (1R,2S)-2-(3-amino-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one

[0509]

[0510] Step A. (E)-3-(3-Fluoro-4-isocyanobenzylidene)-5-methoxyindolin-2-one

[0511]

[0512] A round-bottom flask was charged with 5-methoxyoxindole (5.00 g, 30.6 mmol), 4-cyano-3-fluorobenzaldehyde (4.57 g, 30.6 mmol), piperidine (835 μL, 8.40 mmol) and ethanol (120 mL). The reaction was refluxed for 4 h and stirred at room temperature for 16 h. The reaction was cooled to 0 ° C and the resulting precipitate was collected by filtration and dried to give the title compound (5.10 g, 57%) as a dark red solid. m / z (ESI, positive ion) = 295.0 [M+H] + .

[0513] Step B. rac-2-fluoro-4-((1R,2S)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-2-yl)benzonitrile

[0514]

[0515] To a solution of trimethylsulfoxide iodide (4.20 g, 19.1 mmol) in anhydrous DMF (173 mL) was added sodium hydride (60% dispersion in oil) (81.5 mg, 2.04 mmol) at 0°C under nitrogen. The mixture was stirred for 15 minutes, after which (E)-3-(3-fluoro-4-isocyanobenzylidene)-5-methoxyindolin-2-one (5.10 g, 17.3 mmol) was added to the solution, and the reaction was stirred at room temperature for 1 h. The solution was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was then washed with brine and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under vacuum. The crude mixture was purified by column chromatography (10% to 65% EtOAc / heptane, gradient elution) to give the title compound (1.50 g, 28%) as an orange solid. NOESY NMR experiments confirmed the relative stereochemistry. m / z (ESI, positive ion) = 309.0 [M+H] + 1H NMR (400MHz, CDCl 3 )δ8.14(s,1H),7.63-7.54(m,1H),7.13-7.08(m,2H),6.85(d,J=8.5Hz,1H),6.67(dd,J=8.5,2.5Hz,1H),5.55(d,J=2.4Hz,1H),3.55(s,3H),3.29(t,J=8.5Hz,1H),2.26(dd,J=9.0,5.0Hz,1H),1.94(dd,J=8.0,5.0Hz,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 (400MHz, CDCl 3 )δ8.08(s,1H),7.52(dd,J=7.8,6.9Hz,1H),7.21(s,1H),7.19(s,1H),6.78(d,J=1.5Hz,2H),6.54( s, 1H), 3.81 (s, 3H), 3.07 (t, J = 8.7Hz, 1H), 2.34 (dd, J = 8.5, 5.3Hz, 1H), 2.12 (dd, J = 8.9, 5.3Hz, 1H).

[0516] Step C. (1R,2S)-2-(3-amino-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one

[0517]

[0518] In a 20mL vial, 2-fluoro-4-((1R,2S)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-2-yl)benzonitrile (20.0mg, 64.9μmol) was dissolved in tert-amyl alcohol (10.0mL), followed by addition of hydrazine hydrate solution (50.0μL, 1.58mmol). The reaction was refluxed for 16h. 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 (60.0mg, 58%) as a colorless oil. m / z (ESI, positive ion) = 321.1 [M+H] + .

[0519] Intermediate 2. (1R,2S)-2-(1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one

[0520]

[0521] Step A. 1-Benzyl-5-methoxyindoline-2,3-dione

[0522]

[0523] 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 and then dried (Na 2 O). 2 SO 4 ), 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 (400MHz, CDCl 3 )δ7.38-7.27(m,5H),7.15(d,J=2.7Hz,1H),7.02(dd,J=8.6,2.7Hz,1H),6.67(d,J=8.6Hz,1H),4.90(s,2H),3.77(s,3H).

[0524] Step B. 1-Benzyl-5-methoxyindolin-2-one

[0525]

[0526] 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 1M H 2 SO 4 , washed with brine (twice), then dried (Na 2 SO 4 ), 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 (400MHz, CDCl 3 )δ7.38-7.22(m,5H),6.90-6.86(m,1H),6.68(dd,J=8.5,2.6Hz,1H),6.60(d,J=8.5Hz,1H),4.89(s,2H),3.75(s,3H),3.61(s,2H).

[0527] Step C. 1-Benzyl-6-bromo-1H-indazole

[0528]

[0529] 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 slowly added at 0 ° C. The mixture was stirred at room temperature for 3 h, and then saturated NH 4 The mixture was diluted with aqueous Cl solution (400 mL) and extracted with MTBE (3×200 mL). The combined organic layers were washed twice with brine and then dried (Na 2 SO 4), filtered and concentrated to obtain a crude material as a mixture of 1-benzyl-6-bromo-1H-indazole and 2-benzyl-6-bromo-2H-indazole. Benzyl bromide (37.7mL, 311mmol) is added to a mixture of 1-benzyl-6-bromo-1H-indazole and 2-benzyl-6-bromo-2H-indazole (31g, 108mmol). The mixture is stirred evenly at 150°C. After 6h, benzyl bromide is removed by distillation at 130°C under high vacuum (vacuum pump). The residue is ground in heptane, then filtered and washed with heptane. The crude material is placed under high vacuum overnight to obtain the title compound (20.6g, 67%) as a solid. m / z (ESI, positive ion) = 287.0 [M + H] + .

[0530] Step D. 1-Benzyl-6-vinyl-1H-indazole

[0531]

[0532] 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 (nitrogen bubbling through) DME / water (3:1) (70.0 mL) was purged with nitrogen, and nitrogen was further bubbled through the reaction mixture. Vinylboronic acid pinacol ester (4.82 mL, 27.6 mmol) was added, followed by dichlorobis(triphenylphosphine)palladium(II) (774 mg, 1.10 mmol), and the mixture was heated to 80 ° C overnight. The mixture was diluted with heptane and washed with water (3×) and brine. With Na 2 SO 4 The organic phase was dried, filtered and concentrated. The crude product was purified by column chromatography (0 to 10% EtOAc / hexanes, gradient elution) to give the title compound 4D (3.80 g, 74%). m / z (ESI, positive ion) = 235.4 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.01 (d, J = 0.9Hz, 1H), 7.73-7.64 (m, 1H), 7.36-7.23 (m, 5H), 7.23-7.16 (m, 2H), 6 .80(dd,J=17.6,10.9Hz,1H),5.80(dd,J=17.5,0.7Hz,1H),5.60(s,2H),5.30(dd,J=10.9,0.6Hz,1H).

[0533] Step E. (S)-1-(1-Benzyl-1H-indazol-6-yl)ethane-1,2-diol

[0534]

[0535] AD-mixture-α (83.7 g, 59.8 mmol) and t-BuOH / water (1: 1) (598 mL) were added to a 500 mL flask to form a clear two-phase mixture under stirring. The reaction mixture was cooled to 0 ° C with an ice bath, and 1-benzyl-6-vinyl-1H-indazole (14.0 g, 59.8 mmol) was then added. The resulting mixture was vigorously stirred at 0 ° C, and heated to room temperature with an ice bath slowly warming up. The reaction mixture was stirred for 9 h. The reaction was quenched by adding 92 g of sodium sulfite in batches. The reaction mixture was stirred overnight. The reaction mixture was diluted with brine and DCM and filtered through a diatomaceous earth pad. The filtrate was extracted with DCM (4 ×), and the combined organic layer was filtered through MgSO 4 Dry, filter and concentrate. The crude product was recrystallized from toluene (80 mL) to give the title compound (12.2 g, 76%) as a white solid. m / z (ESI, positive ion) = 269.2 [M+H] + .99.1%ee.

[0536] Step F. (S)-1-(1-benzyl-1H-indazol-6-yl)ethane-1,2-diol methanesulfonate

[0537]

[0538] A solution of (S)-1-(1-benzyl-1H-indazole-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 slowly adding 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 monomesylated 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 with DCM (500 mL) and 1 M aqueous HCl solution (200 mL) at 0 °C. The layers were separated and the organic layer was washed with saturated NaHCO 3 The solution was washed with aqueous solution (2×200 mL), brine (200 mL), and then dried (Na 2 SO 4 ), filtered and concentrated. The crude material was passed through a small pad of celite and washed with DCM / Et 2 The solvent was removed to obtain a white solid. The solid was stirred in Et 2O (40 mL), and the precipitate was collected by filtration to give the title compound (17.5 g, 91%) as a white crystalline solid. m / z (ESI, positive ion) = 425.0 [M+H] + 1H NMR (400MHz, CDCl 3 )δ8.08(s,1H),7.81(d,J=8.3Hz,1H),7.41(s,1H),7.35-7.27(m,3H),7.18(dd,J=17.3,7.5Hz,3H),5.89(dd,J=8.6,3.2Hz,1H),5. 66(d,J=15.8Hz,1H),5.60(d,J=15.8Hz,1H),4.53(dd,J=11.9,8.6Hz,1H),4.40(dd,J=11.9,3.3Hz,1H),3.05(s,3H),2.75(s,3H).

[0539] Step G. (1R,2S)-1'-Benzyl-2-(1-benzyl-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one

[0540]

[0541] Under nitrogen, a solution of (S)-1-(1-benzyl-1H-indazole-6-yl)ethane-1,2-diester (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 with an addition funnel. The reaction mixture was stirred at 0 ° C for 3 h. Saturated NH 4 The reaction was quenched with Cl solution, diluted with water, and extracted with EtOAc (3×). 4 The organic layer was dried and concentrated to a crude product. The crude product was triturated with 3:1 hexanes / EtOAc to give the title compound as an orange solid (2.10 g, 54%). m / z (ESI, positive ion) = 486.2 [M+H] + .

[0542] Step H. (1R,2S)-2-(1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one

[0543]

[0544] 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'-indolin]-2'-one (4.00 g, 8.24 mmol) in THF (118 mL). The solution was cooled to 0°C and potassium tert-butoxide (23.0 mL, 165 mmol) was added 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 heated at 0°C with saturated NH 4 The mixture was quenched with aqueous Cl and diluted with EtOAc (50 mL). 4 The organic phase was washed with aqueous Cl solution (1×) and extracted with EtOAc (2×). 2 SO 4 Dry, filter, and concentrate under vacuum. The crude product is concentrated in Et 2 O and recrystallized from ethanol to give the title compound (2.56 g, 56%). m / z (ESI, positive ion) = 306.4 [M+H] + .

[0545] Intermediate 3: (1R,2S)-2-(3-bromo-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one

[0546]

[0547] In a flask, (1R,2S)-2-(1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one (4.49 g, 12.5 mmol) was dissolved in DMF (16.7 mL), and NBS (2.70 g, 15.0 mmol) dissolved in DMF (8.33 mL) was added dropwise at 0°C. The reaction was stirred at room temperature for 2 h. Na 2 S 2 O 3 The reaction was quenched with aqueous solution and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), 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] + .

[0548] Intermediate 4: tert-butyl 3-bromo-6-((1R,2S)-1'-(tert-butoxycarbonyl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indolin]-2-yl)-1H-indazole-1-carboxylate

[0549]

[0550] 4-dimethylaminopyridine (79.8mg, 640μmol) is added to triethylamine (3.61mL, 25.6mmol), di-tert-butyl dicarbonate (4.0mL, 17.3mmol) and (1R, 2S) -2- (3- bromo-1H- indazole -6- bases) -5'-methoxyspiro [cyclopropane -1,3'- indole ] -2'- ketone (2.46g, 6.40mmol) in a solution of DCM (24mL). The solution is stirred at room temperature for 16h. LCMS shows incomplete conversion. Di-tert-butyl dicarbonate (0.75mL, 3.2mmol, 0.5 equivalents) is added and the reaction is stirred for another hour. The crude product is purified by column chromatography (0 to 20% EtOAc / heptane, gradient elution) to obtain the title compound (3.06g, 82%) as a yellow foamy solid. m / z (ESI, positive ion) = 384.0, 386.0 [M+H-boc] + .

[0551] Intermediate 5: tert-butyl 3-amino-6-((1R,2S)-1'-(tert-butoxycarbonyl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indolin]-2-yl)-1H-indazole-1-carboxylate

[0552]

[0553] Step A. tert-Butyl 6-((1R,2S)-1'-(tert-butoxycarbonyl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indolin]-2-yl)-3-((diphenylmethylene)amino)-1H-indazole-1-carboxylate

[0554]

[0555] A microwave vial was charged with tert-butyl 3-bromo-6-((1R,2S)-1'-(tert-butoxycarbonyl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indolinoline]-2-yl)-1H-indazole-1-carboxylate (1.00 g, 1.71 mmol), cesium carbonate (1.14 g, 3.42 mmol), Pd 2 (dba) 3(157 mg, 171 μmol) and XantPhos (101 mg, 171 μmol). Anhydrous dioxane (17.1 mL) was added followed by benzophenone imine (310 μL, 1.83 mmol), and nitrogen was bubbled through the reaction mixture for 5 min. The vial was sealed and the reaction mixture was heated to 90 °C in an oil bath for 2 h. Saturated NaHCO 3 The reaction mixture was extracted with EtOAc (3×). The combined extracts were then washed with brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under vacuum. The crude product was purified by column chromatography (0 to 30% EtOAc / heptane, gradient elution) to give the title compound (1.03 g, 88%) as a yellow oil. m / z (ESI, positive ion) = 685.4 [M+H] + .

[0556] Step B. tert-Butyl 3-amino-6-((1R,2S)-1'-(tert-butoxycarbonyl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indolin]-2-yl)-1H-indazole-1-carboxylate

[0557]

[0558] 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 crude product was purified by column chromatography (0 to 60% EtOAc / heptane, gradient elution) to give the title compound (640 mg, 84%) as a yellow solid. m / z (ESI, positive ion) = 521.0 [M+H] +. 1H NMR (400MHz, CDCl3) δ8.06(s,1H),7.78(d,J=8.9Hz,1H),7.41(d,J=8.2Hz,1H),7.01(d,J=8.2Hz,1H),6.66(dd,J=8.9,2.6Hz,1H),5.55( d,J=2.3Hz,1H),4.44(s,2H),3.49(t,J=8.6Hz,1H),3.37(s,3H),2.34(dd,J=9.2,4.8Hz,1H),2.14-2.06(m,1H),1.67(d,J=2.4Hz,18H).

[0559] Example 1. Racemic-5'-methoxy-2-{3-[(5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one

[0560]

[0561] (1R, 2S) -2- (3-amino-1H-indazole-6-yl) -5'-methoxyspiro [cyclopropane-1,3'-indolin] -2'-one (54.0 mg, 169 μmol) and 4-chloro-5-methoxypyrimidine (29.8 mg, 202 μmol) were dissolved in acetic acid / water (1: 1) (1.00 mL) in a 4 mL vial. The reaction was heated to 100 ° C for 1 h. The reaction mixture was poured into 5 mL of NaOH 2M aqueous solution. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (0 to 10% MeOH / DCM, gradient elution) to give Example 1 (22.9 mg, 32%) as a white solid after lyophilization. m / z (ESI, positive ion) = 429.2 [M + H] + 1H NMR (400 MHz, DMSO) δ 12.68 (s, 1H), 10.42 (s, 1H), 9.12 (s, 1H), 8.04 (d, J = 3.0 Hz, 2H), 7.40 (d, J = 7.9 Hz, 2H), 6.89 (d, J = 9.4 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.58 (dd, J = 8.5, 2.6 Hz, 1H), 5.72 (d, J = 2.5 Hz, 1H), 3.94 (s, 3H), 3.33 (s, 3H underwater peak), 3.18 (t, J = 8.5 Hz, 1H), 2.33 (dd, J = 7.8, 4.7 Hz, 1H), 1.98 (dd, J = 9.0, 4.7 Hz, 1H).

[0562] Example 2. Racemic-5'-methoxy-2-{3-[(5-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one

[0563]

[0564] Example 2 was prepared from (1R,2S)-2-(3-amino-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolinoline]-2'-one (60.0 mg, 187 μmol) and 4-chloro-5-methylpyrimidine (27 mg, 206 μmol) using the procedure described in Example 1. The product was purified by column chromatography (0 to 10% MeOH / DCM, gradient elution), concentrated, and then lyophilized from MeCN and water to give Example 2 (7.7 mg, 10%) as a white solid. m / z (ESI, positive ion) = 413.2 [M+H] + . 1HNMR(400MHz,DMSO)δ12.69(s,1H),10.43(s,1H),9.02(s,1H),8.24(s,1H),8.13(s ,1H),7.41(s,1H),7.34(d,J=8.5Hz,1H),6.89(dd,J=8.5,1.0Hz,1H),6.74(d,J=8.4 Hz, 1H), 6.58 (dd, J = 8.5, 2.6 Hz, 1H), 5.71 (d, J = 2.6 Hz, 1H), 3.33 (s, 3H, underwater peak), 3.18 (t, J = 8.4 Hz, 1H), 2.33 (dd, J = 7.9, 4.7 Hz, 1H), 2.21 (s, 3H), 1.98 (dd, J = 9.0, 4.7 Hz, 1H).

[0565] Example 3. Racemic-2-{3-[(5-chloropyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one

[0566]

[0567] Example 3 was prepared from (1R,2S)-2-(3-amino-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one (60.0 mg, 187 μmol) and 4,5-dichloropyrimidine (31.3 mg, 206 μmol) using the procedure described in Example 1. The product was purified by C18 column chromatography (5% to 40% MeCN / aqueous ammonium formate buffer, gradient elution) to give Example 3 (4.8 mg, 6%) as a white solid after lyophilization. m / z (ESI, positive ion) = 433.1 [M+H] +. 1HNMR(400MHz,DMSO)δ12.85(s,1H),10.43(s,1H),9.58(s,1H),8.46(s,1H), 8.31(s,1H),7.44(s,1H),7.37(d,J=8.3Hz,1H),6.95-6.87(m,1H),6.74(d,J= 8.4Hz,1H),6.58(dd,J=8.5,2.6Hz,1H),5.70(d,J=2.5Hz,1H),3.33(s,3H),3 .19(t,J=8.4Hz,1H), 2.34(dd,J=8.0,4.7Hz,1H), 1.98(dd,J=9.0,4.6Hz,1H).

[0568] Example 4. (1R,2S)-5'-methoxy-2-{3-[(5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one

[0569]

[0570] This compound was prepared from tert-butyl 3-amino-6-((1R,2S)-1'-(tert-butoxycarbonyl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-2-yl)-1H-indazole-1-carboxylate (108 mg, 207 μmol) and 4-chloro-5-methoxypyrimidine (36.7 mg, 249 μmol) using the procedure described in Example 1. The Boc group was cleaved in situ during the reaction conditions. The product was purified by C18 column chromatography (10% to 30% MeCN / aqueous ammonium formate buffer, gradient elution) to give Example 4 (9.6 mg, 11%) as a white solid after lyophilization. m / z (ESI, positive ion) = 429.2 [M+H] + 1H NMR (400 MHz, DMSO) δ 12.68 (s, 1H), 10.43 (s, 1H), 9.12 (s, 1H), 8.04 (d, J = 3.1 Hz, 2H), 7.44-7.35 (m, 2H), 6.89 (d, J = 9.4 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.58 (dd, J = 8.5, 2.6 Hz, 1H), 5.72 (d, J = 2.5 Hz, 1H), 3.94 (s, 3H), 3.33 (s, 3H underwater peak), 3.18 (t, J = 8.6 Hz, 1H), 2.33 (dd, J = 7.9, 4.7 Hz, 1H), 1.98 (dd, J = 9.0, 4.6 Hz, 1H).

[0571] Example 5. (1R, 2S)-5'-methoxy-2-{3-[(5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3'-indol]-2'(1'H)-one

[0572]

[0573] Step A. (1R,2S)-2-(3-iodo-1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one

[0574]

[0575] To an oven-dried flask was added (1R,2S)-2-(1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolinoline]-2'-one (4.00 g, 13.1 mmol), followed by DMF (8 mL) and methanol (8 mL). 2 CO 3 (3.62 g, 26.2 mmol). Finally, molecular iodine (4.32 g, 17.0 mmol) dissolved in DMF (8 mL) was added dropwise and stirred at room temperature. After 4 h, the reaction was complete. 2 S 2 O 3 The mixture was quenched with aqueous solution 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).

[0576] Step B. (1R,2S)-tert-Butyl 2-(1-(tert-butoxycarbonyl)-3-iodo-1H-indazol-6-yl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-carboxylate

[0577]

[0578] 4-dimethylaminopyridine (9.0 mg, 0.07 mmol) was added to an oven-dried flask, followed by (1R, 2S)-2-(3-iodo-1H-indazole-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one (637 mg, 1.48 mmol), N-ethyl-N-isopropyl-propan-2-amine (1.0 mL, 5.9 mmol) and MeCN (5.0 mL). The mixture was stirred at room temperature, and di-tert-butyl dicarbonate (967 mg, 4.43 mmol) was added to give a 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 (5B) (822 mg, 88%) as a white foam.

[0579] Step C. (1R,2S)-2-[1-tert-Butyloxycarbonyl-3-[(5-ethoxypyrimidin-4-yl)amino]indazol-6-yl]-5'-methoxy-2'-oxo-spiro[cyclopropane-1,3'-indoline]-1'-carboxylic acid tert-butyl ester

[0580]

[0581] To a 50 ml round bottom flask were added cesium carbonate (41.3 mg, 0.130 mmol), 5-ethoxypyrimidin-4-amine (9.3 mg, 0.070 mmol), Pd 2 (dba) 3 (5.8 mg, 0.010 mmol), (1R, 2S)-2-(1-(tert-butoxycarbonyl)-3-iodo-1H-indazole-6-yl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-carboxylic acid tert-butyl ester (40.0 mg, 0.0600 mmol), XantPhos (3.7 mg, 0.010 mmol) and anhydrous toluene (4.2 mL). The reaction mixture was stirred and purged with argon (in a balloon) for 10 min to form a green suspension, then heated to 120 ° C to give a yellow suspension. The reaction was monitored by LCMS and TLC until the starting material was fully converted (approximately 70 min), cooled to room temperature, diluted with EtOAc, and washed with saturated NaHCO 3 The aqueous solution was washed and the 2 SO 4 The residue was purified by column chromatography (0% to 90% ethyl acetate / hexanes, gradient elution) to give the title compound (24.0 mg, 59%) as a yellow oil.

[0582] Step D. (1R,2S)-2-[3-[(5-ethoxypyrimidin-4-yl)amino]-1H-indazol-6-yl]-5'-methoxy-spiro[cyclopropane-1,3'-indolin]-2'-one

[0583]

[0584] Trifluoroacetic acid (0.15 mL, 1.9 mmol) was added to a 50 ml round bottom flask containing (1R, 2S) -2- [1- tert-butoxycarbonyl -3- [(5-ethoxypyrimidin-4-yl) amino] indazole -6-yl] -5'-methoxy -2'-oxo -spiro [cyclopropane -1,3'-indoline] -1'- tert-butyl carboxylate (24.0 mg, 0.0400 mmol) in DCM (1.9 mL). The reaction mixture was stirred and monitored by LCMS until the starting material was completely converted (about 3 h), diluted with acetonitrile. The resulting brown solution was purified by preparative HPLC (Gemini C18, 30% to 80% (0.1% TFA / water) / (0.1% TFA / acetonitrile)) to obtain the desired product Example 5 (12.4 mg, 75%) as a yellow film. m / z (ESI, positive ion) 443.2 (M+H) + . 1 H NMR (400 MHz, methanol-d 4 )δppm 1.58(t,J=6.94Hz,3H)2.10-2.32(m,2H)3.26-3.30(m,3H)3.32-3.39(m,1H)4.27-4.44(m,2H)5.50-5.61(m,1 H)6.55-6.67(m,1H)6.76-6.89(m,1H)6.91-7.04(m,1H)7.44-7.62(m,2H)8.03-8.18(m,1H)8.36-8.49(m,1H).

[0585] Example 6. (1R, 2S)-2-{3-[(5-cyclopropylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indol]-2'(1'H)-one

[0586]

[0587] Step A. (1R,2S)-2-[1-tert-Butyloxycarbonyl-3-[(5-cyclopropylpyrimidin-4-yl)amino]indazol-6-yl]-5'-methoxy-2'-oxo-spiro[cyclopropane-1,3'-indoline]-1'-carboxylic acid tert-butyl ester

[0588]

[0589] This compound was prepared from tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-iodo-1H-indazol-6-yl)-5'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-carboxylate (40.0 mg, 0.0600 mmol) and 5-cyclopropylpyrimidin-4-amine (9.0 mg, 0.070 mmol) using the procedure described in Example 5. The residue was purified by column chromatography (ethyl acetate / hexane=0-90%) to give the title compound (17.0 mg, 42%) as a yellow oil.

[0590] Step B. (1R,2S)-2-[3-[(5-cyclopropylpyrimidin-4-yl)amino]-1H-indazol-6-yl]-5'-methoxy-spiro[cyclopropane-1,3'-indolin]-2'-one

[0591]

[0592] This compound was prepared from (1R,2S)-2-[1-tert-butoxycarbonyl-3-[(5-cyclopropylpyrimidin-4-yl)amino]indazol-6-yl]-5'-methoxy-2'-oxo-spiro[cyclop...

Claims

1. A compound selected from the following or a pharmaceutically acceptable salt thereof: as well as 2. The compound according to claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

18. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

19. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising a certain amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

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