Compound containing heteroaromatic ring, pharmaceutical composition comprising same, and preparation method therefor and use thereof

Abstract

The present disclosure relates to a compound containing a heteroaromatic ring, a pharmaceutical composition comprising same, and a preparation method therefor and a use thereof. Specifically, the present disclosure relates to a compound having a structure as shown in formula (I), which can be used for preventing or treating tumors or cancers.

Description

Compounds containing heteroaromatic rings, pharmaceutical compositions containing them, their preparation methods and uses

[0001] Citation of relevant applications

[0002] This disclosure claims three patent applications filed with the State Intellectual Property Office on December 4, 2024, application number 202411769934.1, entitled "Compounds Containing Heteroaromatic Rings, Pharmaceutical Compositions Containing the Same, and Preparation Methods and Uses Thereof"; on February 13, 2025, application number 202510159292.1, entitled "Compounds Containing Heteroaromatic Rings, Pharmaceutical Compositions Containing the Same, and Preparation Methods and Uses Thereof"; and on May 16, 2025, application number 202510630453.0, entitled "Compounds Containing Heteroaromatic Rings, Pharmaceutical Compositions Containing the Same, and Preparation Methods and Uses Thereof". The present disclosure hereof priority to the invention patent application entitled "Compounds containing heteroaromatic rings, pharmaceutical compositions containing the same, preparation methods thereof and uses thereof", filed on September 3, 2025 with application number 202511250072.6 and entitled "Compounds containing heteroaromatic rings, pharmaceutical compositions containing the same, preparation methods thereof and uses thereof", and the invention patent application entitled "Compounds containing heteroaromatic rings, pharmaceutical compositions containing the same, preparation methods thereof and uses thereof", filed on November 27, 2025 with application number 202511767246.6 and entitled "Compounds containing heteroaromatic rings, pharmaceutical compositions containing the same, preparation methods thereof and uses thereof", the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure belongs to the field of medicinal chemistry and relates to a heterocyclic compound used as an inhibitor of membrane-associated tyrosine / threonine protein kinase 1 (PKMYT1), a pharmaceutical composition comprising the same, a method for its preparation, and its pharmaceutical uses. Background Technology

[0004] PKMYT1 (membrane-associated tyrosine / threonine protein kinase 1, also known as MYT1) is a protein kinase belonging to the WEE protein kinase family and involved in cell cycle regulation. The WEE protein kinase family includes three members: WEE1, WEE2, and MYT1. Among them, WEE1 and MYT1 are involved in regulating somatic cell mitosis, while WEE2 is involved in regulating germ cell meiosis. (Ghelli Luserna di Rorà et al., A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target, Journal of hematology & oncology, (2020) 13: 126.)

[0005] In eukaryotic somatic cells, PKMYT1 plays a crucial role in cell cycle regulation, primarily involved in the control of mitotic processes. Studies show that PKMYT1 acts on the G2 / M checkpoint but is not essential for normal cell cycle progression, while WEE1 acts on multiple checkpoints (S, G2 / M, and M) and is crucial for normal cell cycle progression, suggesting that inhibiting PKMYT1 may be less toxic to normal cells than inhibiting WEE1. Mechanistically, PKMYT1 inactivates the Cdk1 / CycB complex through phosphorylation, thereby promoting G2 checkpoint function and arresting the G2 / M transition in the cell cycle. PKMYT1 negatively regulates the Cdk1 / CycB complex primarily through two independent mechanisms: 1) PKMYT1 phosphorylates Thr14 and Tyr15 on the substrate Cdk1, thereby inhibiting the activity of the Cdk1 / CycB complex and leading to G2 / M cell cycle arrest; 2) PKMYT1 binds to Cdk1 and isolates it in the cytoplasm, preventing the Cdk1 / CycB complex from entering the nucleus and thus halting cell cycle progression (Schmidt*M et al., Regulation of G2 / M Transition by Inhibition of WEE1 and PKMYT1 Kinases, Molecules, 2017, 22(12):2045; Wells NJ, et al., The C-terminal domain of the Cdc2 inhibitory kinase Myt1 interacts with Cdc2 complexes and is required for inhibition of G2 / M progression, Journal of Cell Science,1999,112(19):3361-3371).

[0006] In tumor cells, to cope with the replication pressure caused by the high proliferation rate, PKMYT1 can be upregulated to ensure the repair of DNA damage, maintain replication pressure and genomic stability of tumor cells, and thus exert a tumor-promoting function. Inhibiting PKMYT1 forces tumor cells that have not completed DNA damage repair to enter the next stage of the cell cycle, leading to the accumulation of DNA damage in tumor cells, increased genetic instability, and induction of apoptosis and mitotic catastrophe, thereby achieving a tumor-suppressive effect. David Gallo et al., CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition, Nature, 2022, 604(7907):749-756, confirmed that CCNE1 can activate the MMB-FOXM1 transcriptional complex, thereby upregulating the expression of CDK1 and CCNB1 genes. In CCNE1 overexpressing cells, Cyclin B and CDK1 expression are increased, and these cells are more sensitive to PKMYT1 inhibition, leading to synthetic lethality.

[0007] PKMYT1 and FBXW7 are key genes with synthetic lethal effects related to CCNE1, with PKMYT1 showing the strongest dependence on CCNE1 gene amplification in tumor cell lines. Furthermore, FBXW7 mutations exhibit high sensitivity to PKMYT1 inhibitors, suggesting that FBXW7 is one of the synthetic lethal gene pairs associated with MYT1.

[0008] The MYT1 gene (mRNA level) is highly expressed in a variety of human tumors, such as gastric cancer, NSCLC, esophageal cancer, clear cell renal cell carcinoma, glioma, CRC, breast cancer, endometrial cancer, prostate cancer, head and neck squamous cell carcinoma, liver cancer, thyroid cancer, pancreatic cancer, and bile duct cancer (Shao C, Wang Y, Pan M, et al. The DNA damage repair-related gene PKMYT1 is a potential biomarker in various malignancies[J]. Translational Lung Cancer Research, 2021, 10(12): 4600).

[0009] In summary, inhibition of PKMYT1 exhibits synthetic lethality in the presence of CCNE1 gene amplification. Currently, there are no marketed inhibitors targeting PKMYT1. Therefore, there is a need to develop new, highly effective, and low-toxicity PKMYT1 inhibitors to meet clinical needs. Summary of the Invention

[0010] The purpose of this disclosure is to provide a new class of compounds containing heteroaromatic rings that exhibit excellent inhibitory activity against PKMYT1 and can be used to prevent or treat diseases or symptoms related to PKMYT1 activity.

[0011] One aspect of this disclosure provides compounds of formula (I) or their pharmaceutically acceptable form:

[0012] in:

[0013] X is selected from N and CH; Y is selected from N and CR. 2 Z is selected from N and CR 3 W is selected from N and CR 4 ;

[0014] R 1 R 2 R 3 R 4 and R 5 Each is independently selected from hydrogen, halogen, hydroxyl, oxo group, -CN, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NR x R y -C(O)NH2, -C(O) (4-6 membered heterocyclic alkyl groups), -C(O)NH(C 1-6 Alkyl), -C(O)NH(C 3-6 cycloalkyl), -C(O)NH (4-6 membered heterocycloalkyl), -S(O)2 (C 1-6 Alkyl group), -S(O)2NR x R y -O(C 6-10 aryl), -O (5-10 heteroaryl), C 6-10 Aryl and 5-10 heteroaryl groups, wherein each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally substituted by one or more substituents independently selected from: deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NRx R y -C(O)NR x R y -SO2-C 1-6 Alkyl group, optionally selected independently from one or more of deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 3-6 Cycloalkyl, optionally selected independently from one or more of deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The 4-6 membered heterocyclic alkyl group substituted with a haloalkyl group, optionally with one or more groups independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 6-10 The aryl group is optionally selected independently from one or more deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 The 5-10 membered heteroaryl group substituted by the haloalkyl group is preferably each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl group, optionally selected independently from one or more of deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl, C 1-6 The C-substituent of the haloalkyl group 3-6 Cycloalkyl, optionally selected independently from one or more of deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 The 4-6 membered heterocyclic alkyl group substituted with a haloalkyl group, optionally with one or more groups independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 The C-substituent of the haloalkyl group 6-10 The aryl group is optionally selected independently from one or more deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl, C 1-6The 5-10 membered heteroaryl group substituted by the haloalkyl group, more preferably the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, is optionally each independently selected from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-10 Substitution of aryl and 5-10 heteroaryl groups;

[0015] Or R 1 and R 2 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl or 5-10-membered heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0016] Or R 2 and R 3 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl or 5-10-membered heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0017] Or R 3 and R 4 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl or 5-10-membered heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0018] Or R 4 and R 5 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl or 5-10-membered heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0019] R 6 R 7 and R 8 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Haloalkyl, wherein the alkyl, cycloalkyl or haloalkyl group is optionally each selected independently from one or more of deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6Substituents of haloalkyl groups; preferably, R 6 R 7 and R 8 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Halogenated alkyl groups;

[0020] R 9 For OH; R 10 Selected from hydrogen, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Halogenated alkyl groups;

[0021] Or R 9 With R 10 Co-formation -CR 11 =N-NH-, and R 11 Selected from hydrogen and halogens;

[0022] R x and R y Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-8 cycloalkyl, -C(O)(C 1-6 Alkyl), -C(O)(C 3-6 cycloalkyl), -C(O) (4-6 membered heterocycloalkyl), -C(O)O(C 1-6 Alkyl), -C(O)O(C 3-6 cycloalkyl), -C(O)O (4-6 membered heterocycloalkyl), -S(O)2 (C 1-6 Alkyl), -S(O)2(C 3-6 Cycloalkyl), -S(O)2 (4-6 membered heterocycloalkyl), 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 heteroaryl groups; each of the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently by one or more radicals selected from deuterium, halogen, hydroxyl, oxo group, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -O(C) 1-6 Alkyl groups, -NH2, -C(O)NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0023] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs.

[0024] Another aspect of this disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable form thereof, or a mixture thereof, and one or more pharmaceutically acceptable carriers, said pharmaceutically acceptable form being selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs.

[0025] Another aspect of this disclosure provides compounds of formula (I) or pharmaceutically acceptable forms thereof, or pharmaceutical compositions thereof, for the prevention or treatment of diseases or conditions, particularly those associated with PKMYT1 activity, wherein the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs.

[0026] Another aspect of this disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable form thereof, or the use of a pharmaceutical composition of this disclosure in the preparation of a medicament, particularly in the preparation of a medicament for the prevention or treatment of diseases or symptoms associated with PKMYT1 activity, wherein the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs.

[0027] Another aspect of this disclosure provides a method for preventing or treating diseases or symptoms associated with PKMYT1 activity, the method comprising administering to an individual in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of this disclosure, said pharmaceutically acceptable form being selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs.

[0028] Another aspect of this disclosure provides a method for preparing the compounds disclosed herein.

[0029] Another aspect of this disclosure provides intermediates for preparing the compounds of this disclosure. Detailed Implementation

[0030] General terms and definitions

[0031] Unless otherwise defined, the terms used herein have the same meaning as commonly understood by those skilled in the art. The technical intent used herein refers to technology as commonly understood in the art, including variations or equivalent substitutions of technology that are obvious to those skilled in the art. While the following terms are readily understood by those skilled in the art, they are set forth below to better interpret this disclosure.

[0032] The terms “comprising,” “including,” “having,” or “involving,” and their other variations herein, refer to inclusive or open-ended collection concepts and do not exclude other unlisted elements or method steps. Those skilled in the art will understand that the foregoing terms such as “comprising” encompass the meaning of “consisting of.”

[0033] The term "one or more species" or similar expression "at least one species" refers to, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more species.

[0034] When the lower and upper limits of a numerical range are disclosed, any value or subrange falling within that range is specifically disclosed. In particular, each numerical range of parameters disclosed herein (e.g., in the form of "about a to b", or equivalently "approximately a to b", or equivalently "about ab") should be understood to encompass every value and subrange therein. For example, "C..." 1-6 "This should be understood as encompassing any subrange and every point value, such as C." 2-5 C 3-4 C 1-2 C 1-3 C 1-4 C 1-5 And so on, as well as C1, C2, C3, C4, C5, C6, etc. For example, "4-14 yuan" should be understood as encompassing any sub-range and each point value, such as 4-5 yuan, 4-6 yuan, 4-7 yuan, 4-8 yuan, 4-9 yuan, 4-10 yuan, 4-11 yuan, 4-12 yuan, 4-13 yuan, etc., as well as 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 yuan, etc.

[0035] When used alone or in combination with other groups herein, the term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group. For example, the term "C" as used in this disclosure 1-6 "Alkyl" refers to a saturated straight-chain or branched hydrocarbon group having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms). For example, "C 1-6 "Alkyl" can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl, etc. The term "C" 1-4 "Alkyl" refers to a linear or branched aliphatic hydrocarbon chain having 1 to 4 carbon atoms (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0036] When used alone or in combination with other groups herein, the term "alkylene" refers to a saturated straight-chain or branched divalent hydrocarbon group. For example, the term "C" as used herein...1-6 "Alkylene" refers to a saturated straight-chain or branched divalent hydrocarbon group with 1-6 carbon atoms, such as methylene, ethylene, propylene, butylene, pentylene, hexylene, etc.

[0037] When used alone or in combination with other groups herein, the term "hydroxyalkyl" refers to an alkyl group substituted with one or more (such as 1 to 3) hydroxyl groups. For example, the term "C" as used in this disclosure 1-6 "Hydroxyalkyl" refers to hydroxyalkyl groups having 1 to 6 carbon atoms, for example... wait.

[0038] When used alone or in combination with other groups herein, the term "cycloalkyl" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic hydrocarbon group; for example, monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutene, cyclopentene, cyclohexene; or bicyclic, including spirocyclic, fused-ring, or bridged rings (such as bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, bicyclic [5.2.0]nonyl, or decahydronaphthyl, etc.). For example, the term "C 3-12 "Cycloalkyl" refers to a cycloalkyl group having 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) ring carbon atoms. The term "C"... 3-8 "Cycloalkyl" refers to a cycloalkyl group having 3 to 8 cyclic carbon atoms, such as C10. 3-6 cycloalkyl (e.g., C10) 3-4 cycloalkyl). C 3-8 cycloalkyl (e.g., C10) 3-6 cycloalkyl, C 3-4 Cycloalkyl groups can be monocycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, or they can be bicycloalkyl, such as C10, C20, C30, C40, C50, C60, C7 ...70, C70, C70, C70, C70, C70, C70, C70, C70, C70, C70, C70, C70, C70, C70, C 5-8 Spirocycloalkyl, C 5-8 Bridged cycloalkyl, C 5-8 fused cycloalkyl, C 5-6 Spirocycloalkyl, C 5-6 Bridged cycloalkyl or C 5-6 Fused cycloalkyl groups.

[0039] When used alone or in combination with other groups herein, the terms "heterocyclic" or "heterocyclic alkyl" are used interchangeably to refer to a saturated or partially saturated, monocyclic or polycyclic (e.g., bicyclic) non-aromatic group having one or more carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13) and one or more (e.g., 1, 2, 3, or 4) heteroatoms, each independently selected from N, O, P, and S. The term also covers cases where a C or P atom in the ring can be substituted with an oxo group (=O), an S atom in the ring can be substituted with one or two oxo groups (=O), or a N atom in the ring can form a nitride. The ring system in a heterocyclic alkyl group can be a fused ring, a bridged ring, or a spirocyclic system. If valence requirements are met, a heterocyclic alkyl group can be linked to other groups (or segments) through any carbon atom or heteroatom in the ring. For example, 3-12, 3-8, 3-6, and 4-14 heterocyclic alkyl groups (e.g., 4-10, 4-8, or 4-6 heterocyclic alkyl groups) include, but are not limited to, ethylene oxide, azacyclic butyl, oxacyclic butyl, thiocyclic butyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyranyl, dioxacyclic pentyl, dioxacyclic hexyl, tetrahydrothiophenyl, pyrrolyl, pyrrolidone, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, etc.

[0040] In this disclosure, the heterocyclic group can form a fused ring structure with a heterocyclic group, cycloalkyl group, aryl group, or heteroaryl group, and the connection point of the fused ring structure with other groups can be on any ring. Therefore, the heterocyclic groups of this disclosure (e.g., 4-14 membered heterocyclic groups or 4-10 membered heterocyclic groups) also include (but are not limited to) heterocyclic fused heterocyclic groups, heterocyclic fused cycloalkyl groups, monoheterocyclic fused monoheterocyclic groups, monoheterocyclic fused monocycloalkyl groups, monoheterocyclic fused (monocyclic) aryl groups, spiroheterocyclic fused (monocyclic) aryl groups, and monoheterocyclic fused (mono) heteroaryl groups, such as 3-7 membered (mono) heterocyclic fused 3-7 membered (mono) heterocyclic groups, 3-7 membered (mono) heterocyclic fused (monocyclic) alkyl groups, and 3-7 membered (mono) heterocyclic fused C 4-6 (Mono)cycloalkyl, 3-7 membered (mono)heterocyclic phenyl, 3-7 membered (mono)heterocyclic 5-6 membered (mono)heteroaryl, examples of which include, but are not limited to, pyrrolidinylcyclopropyl, cyclopentylaziroxypropyl, pyrrolidinylcyclobutyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl, pyrrolidinylpiperazinyl, piperidinylmorpholinyl, (For example ), (For example ),

[0041] In this disclosure, heterocyclic groups (e.g., 4-14 membered heterocyclic groups or 4-10 membered heterocyclic groups) also include bridged heterocyclic groups and spiroheterocyclic groups.

[0042] As used herein, the term "bridged heterocycle" refers to a ring structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, nitrogen, and / or sulfur atoms) formed by two saturated rings sharing two non-directly connected ring atoms. This includes, but is not limited to, 7-10 membered bridged heterocycles, 8-10 membered bridged heterocycles, 7-10 membered nitrogen-containing bridged heterocycles, 7-10 membered oxygen-containing bridged heterocycles, and 7-10 membered sulfur-containing bridged heterocycles, etc. The "nitrogen-bridged heterocycle," "oxygen-bridged heterocycle," and "sulfur-bridged heterocycle" optionally further contain one or more other heteroatoms independently selected from oxygen, nitrogen, and sulfur. The bridged heterocycle group is, for example, […]. wait.

[0043] As used herein, the term "spiroheterocycle" refers to a ring structure containing one or more heteroatoms (e.g., oxygen, nitrogen, sulfur) formed by two or more saturated rings sharing a single ring atom. This includes, but is not limited to, 5-10 membered spiroheterocycles, 6-10 membered spiroheterocycles, 6-10 membered nitrogen-containing spiroheterocycles, 6-10 membered oxygen-containing spiroheterocycles, and 6-10 membered sulfur-containing spiroheterocycles. The "nitrogen-containing spiroheterocycle," "oxygen-containing spiroheterocycle," and "sulfur-containing spiroheterocycle" optionally also contain one or more other heteroatoms independently selected from oxygen, nitrogen, and sulfur. The term "6-10-membered nitrogen-containing spiroheterocycle group" refers to a spiroheterocycle group containing a total of 6-10 ring atoms, with at least one ring atom being a nitrogen atom. The spiroheterocycle group is, for example, a... wait.

[0044] The term "saturated heterocycle" refers to a completely saturated heterocycle, such as the tetrahydrofuran ring, piperidine ring, tetrahydropyran ring, piperazine ring, etc. The term "partially saturated heterocycle" refers to a heterocycle that contains both saturated single bonds and unsaturated double bonds, such as 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 4,5-dihydroisoxazolyl, 4,5-dihydrooxazolyl, 2,5-dihydrooxazolyl, 2,3-dihydrooxazolyl, etc.

[0045] As used herein, the terms “3-8 membered heterocyclic group” or “3-8 membered heterocyclic alkyl group” mean a heterocyclic group containing 3-8 ring atoms, including but not limited to 4-8 membered heterocyclic groups, 4-7 membered heterocyclic groups, 4-6 membered heterocyclic groups, 5-6 membered heterocyclic groups, 3-7 membered heterocyclic groups, 4-6 membered nitrogen-containing heterocyclic groups, 4-6 membered oxygen-containing heterocyclic groups, 4-6 membered sulfur-containing heterocyclic groups, 5-6 membered nitrogen-containing heterocyclic groups, 5-6 membered oxygen-containing heterocyclic groups, 5-6 membered sulfur-containing heterocyclic groups, etc., wherein each of the “nitrogen-containing heterocyclic group”, “oxygen-containing heterocyclic group” and “sulfur-containing heterocyclic group” optionally also contains one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur. Examples of “4-6 membered heterocyclic group” or “4-6 membered heterocyclic alkyl group” include, but are not limited to, nitrogen heterocyclic butyl, oxocyclic butyl, thiocyclic butyl, tetrahydrofuranyl, tetrahydropyranyl, dioxacyclopentyl, dioxacyclohexyl, tetrahydrothiophenyl, pyrrolyl, pyrrolidone, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, etc.

[0046] When used alone or in combination with other groups herein, the term "aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (e.g., bicyclic) aromatic group having a conjugated π-electron system. As used herein, the term "C" refers to a carbon-based aromatic group. 6-10 "Aryl" refers to an aromatic group containing 6-10 carbon atoms, such as phenyl (i.e., C6 aryl) or naphthyl.

[0047] When used alone or in combination with other groups herein, the term "heteroaryl" or "heteroary ring" refers to an aromatic group having a monocyclic or fused ring with a conjugated π-electron system, containing one or more carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 9, or 10 carbon atoms) and one or more (e.g., 1, 2, 3, or 4) heteroatoms, each independently selected from N, O, P, and S. Heteroaryls can be characterized by the number of ring atoms. For example, 5-12 membered heteroaryls can contain 5-12 (e.g., 5, 6, 7, 8, 9, 10, 11, or 12) ring atoms, particularly 5, 6, 7, 8, 9, and 10 ring atoms. If valence requirements are met, a heteroaryl group can be attached to the parent molecule via any one of the ring atoms.

[0048] As used herein, the terms "5-10-membered heteroaryl" or "5-10-membered heteroaryl ring" refer to a heteroaryl (heteroaryl ring) containing 5 to 10 (e.g., 5, 6, 7, 8, 9, 10) ring atoms, including 5-10-membered nitrogen-containing heteroaryl, 5-10-membered oxygen-containing heteroaryl, and 5-10-membered sulfur-containing heteroaryl, for example, "5-6-membered heteroaryl" or "5-6-membered heteroaryl ring," including 5-6-membered nitrogen-containing heteroaryl, 5-6-membered oxygen-containing heteroaryl, and 5-6-membered sulfur-containing heteroaryl, etc. The "nitrogen-containing heteroaryl," "oxygen-containing heteroaryl," and "sulfur-containing heteroaryl" may each optionally contain one or more other heteroatoms independently selected from oxygen, nitrogen, and sulfur. Examples of 5-10 membered heteroaryl groups (e.g., 5-6 membered heteroaryl groups) include, but are not limited to, thiophene, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyridazinyl, triazinyl, pyrimidinoneyl, etc., and fused ring systems formed by the fusion of these heteroaryl groups with each other or with aryl groups (such as phenyl), for example... Etc. Those skilled in the art will understand that pyrimidinones and the corresponding hydroxylated pyrimidines are tautomers, and therefore, when referring to pyrimidinones, it also means the corresponding hydroxylated pyrimidines.

[0049] The term "fused ring system" refers to a polycyclic structure formed by two or more (e.g., 3, 4, or 5) carbon rings or heterocycles sharing a common ring edge, wherein the carbon rings include cycloalkyl and aryl groups, and the heterocycles include heteroaryl and heterocyclic alkyl groups. The fused ring system can be, for example, a fused ring system formed by cycloalkyl groups with cycloalkyl groups, a fused ring system formed by cycloalkyl groups with heterocyclic alkyl groups, a fused ring system formed by cycloalkyl groups with aryl groups, a fused ring system formed by cycloalkyl groups with heterocyclic aryl groups, a fused ring system formed by heterocyclic alkyl groups with aryl groups, a fused ring system formed by heterocyclic aryl groups with heterocyclic aryl groups, a fused ring system formed by heterocyclic aryl groups with heterocyclic aryl groups, or a fused ring system formed by heterocyclic aryl groups with aryl groups.

[0050] When used alone or in combination with other groups herein, the term "alkenyl" refers to a straight-chain or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds. For example, the term "C" as used herein... 2-6 "Alkenyl" refers to an alkenyl group (such as vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, etc.) having 2-6 carbon atoms and one, two, or three carbon-carbon double bonds, which is optionally substituted by one or more (e.g., 1-3) substituents described herein.

[0051] When used alone or in combination with other groups in this document, the term "alkenyl" refers to a straight-chain or branched divalent aliphatic hydrocarbon group having one or more carbon-carbon double bonds, to which the two groups (or segments) may be attached, either to the same carbon atom or to different carbon atoms. For example, the term "C" as used herein... 2-4 "Alkenyl" refers to an alkenyl group having 2-4 carbon atoms (e.g., alkenyl group). (etc.), which may be optionally substituted by one or more (e.g., 1-3) substituents described herein.

[0052] When used alone or in combination with other groups herein, the term "alkynyl" refers to a straight-chain or branched aliphatic hydrocarbon group having one or more carbon-carbon triple bonds. For example, the term "C" as used herein... 2-6 "Alynyl" refers to an alkynyl group having 2-6 carbon atoms and one, two or three carbon-carbon triple bonds (such as ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc.), which is optionally substituted by one or more (e.g., 1-3) substituents described herein.

[0053] When used alone or in combination with other groups herein, the term "acetylenic" refers to a straight-chain or branched divalent aliphatic hydrocarbon group having one or more carbon-carbon triple bonds, wherein the two groups (or segments) to which it is attached are respectively attached to different carbon atoms. For example, the term "C" as used herein... 2-4 "Imyynyl" refers to an ynyl group having 2-4 carbon atoms (such as...). (etc.), which may be optionally substituted by one or more (e.g., 1-3) substituents described herein.

[0054] When used alone or in combination with other groups herein, the term "halogenated alkyl" or "halogen-substituted alkyl" refers to the alkyl group described above, wherein one or more hydrogen atoms are replaced by a halogen. For example, the term "C 1-6 "Halogenated alkyl" or "halogenated C" 1-6 "Alkyl" refers to a C-aryl group that is optionally substituted with one or more (e.g., 1-3) halogens. 1-6 Alkyl group. The term "C" 1-4 "Halogenated alkyl" or "halogenated C" 1-4 "Alkyl" refers to a C-aryl group that is optionally substituted with one or more (e.g., 1-3) halogens. 1-4 Alkyl groups. Those skilled in the art will understand that when there is more than one halogen substituent, the halogens can be the same or different, and can be located on the same or different C atoms. C 1-6 Haloalkyl (e.g., C10) 1-4Examples of alkyl halogens include -CH2F, -CHF2, -CF3, -CCl3, -C2F5, -C2Cl5, -CH2CF3, -CH2Cl, or -CH2CH2CF3, etc.

[0055] When used alone or in combination with other groups in this document, the term "halogenated" or "halogenated" group means F, Cl, Br or I.

[0056] When used alone or in combination with other groups in this document, the term "hydroxyl" refers to -OH.

[0057] When used alone or in combination with other groups in this document, the term "cyano" refers to -CN.

[0058] When used alone or in combination with other groups in this document, the term "nitro" refers to -NO2.

[0059] When used alone or in combination with other groups in this document, the term "amino" refers to -NH2.

[0060] When used alone or in combination with other groups in this document, the term "oxo" refers to =O.

[0061] The term "hydroxyl protecting group" refers to a group introduced onto a hydroxyl group that is easily removed, used to block or protect the hydroxyl group so that reactions can occur on other functional groups of the compound. Non-limiting examples of hydroxyl protecting groups include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.

[0062] The term "amino protecting group" refers to a readily removable group introduced onto an amino group to block or protect the amino group from reacting with other functional groups in the compound. Non-limiting examples of amino protecting groups include: alkoxycarbonyl amino protecting groups, such as benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), and methoxycarbonyl (or ethoxycarbonyl); and acyl amino protecting groups, such as phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), o-(p-)nitrobenzenesulfonyl (Ns), tert-pentanoyl, and benzyl... Acyl, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, trimethylsilylethoxycarbonyl, benzyloxycarbonyl, p-methylbenzenesulfonyl, p-nitrobenzenesulfonyl, tert-butyl, trifluoroacetyl, methoxycarbonyl, or ethoxycarbonyl; alkyl amino protecting groups, such as triphenylmethyl (Trt), 2,4-dimethoxybenzyl (Dmb), 4-methoxybenzyl (PMB), benzyl (Bn); tetrahydropyranyl (THP); (trimethylsilyl)ethoxymethyl (SEM), etc.

[0063] As used herein, the terms "independently" or "independently" mean that at least two groups (or segments) in a structure with the same or similar value ranges can have the same or different meanings under specific circumstances. For example, if substituent X and substituent Y are each independently hydrogen, halogen, hydroxyl, -CN, alkyl, or aryl, then when substituent X is hydrogen, substituent Y can be hydrogen, halogen, hydroxyl, -CN, alkyl, or aryl; similarly, when substituent Y is hydrogen, substituent X can be hydrogen, halogen, hydroxyl, -CN, alkyl, or aryl.

[0064] The term "substitution" and its other variant forms herein refer to the replacement of one or more (e.g., 1, 2, 3, or 4) atoms or groups of atoms (e.g., hydrogen atoms) on a specified atom with other equivalents, provided that the replacement does not exceed the normal valence of the specified atom or group of atoms in the present case and results in the formation of a stable compound. If an atom or group of atoms is described as "optionally substituted," it may or may not be substituted. Unless otherwise stated, the linking site of a substituent herein may be any suitable position of the substituent. When the linking bond in a substituent is shown as a chemical bond passing through two atoms connected to each other in the ring system, it indicates that the substituent may be linked to any one of the cyclic atoms in the ring system.

[0065] Whenever the term "alkyl" or "aryl" or any of its prefixes appears in the name of a substituent, unless otherwise stated, it shall be interpreted, either on its own or as part of another substituent, to include the limitations of "alkyl" and "aryl" given above. The specified number of carbon atoms (e.g., C...) l-6The number of carbon atoms in the alkyl moiety should be indicated independently, or the number of carbon atoms in the alkyl moiety in which the alkyl moiety is a larger substituent of its prefix root.

[0066] The term "chemical bond" refers to the strong force that binds two or more adjacent atoms (or ions) together within a molecule or crystal of a pure substance. It mainly includes covalent bonds, ionic bonds, metallic bonds, and coordinate bonds. Unless otherwise stated, the chemical bonds in the compounds disclosed herein, which exist in free form, are mostly covalent bonds.

[0067] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this disclosure that is substantially non-toxic to organisms. Pharmaceutically acceptable salts of the compounds of this disclosure include their acid addition salts and base addition salts. For a review of suitable salts, see Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of this disclosure are known to those skilled in the art.

[0068] The term "pharmaceutically acceptable ester" refers to an ester that is substantially non-toxic to organisms and is hydrolyzed in vivo to the disclosed compound or its salts. Additionally, the compounds disclosed herein may themselves be esters.

[0069] The term "isomer" refers to compounds that have the same molecular weight due to having the same number and type of atoms, but different spatial arrangements or configurations of atoms.

[0070] The term "stereoisomer" (or "optical isomer") refers to a stable isomer that, due to having at least one chiral element (including a chiral center, chiral axis, chiral plane, etc.), has a perpendicular asymmetric plane, thereby enabling the rotation of plane-polarized light. Because the compounds of this disclosure contain asymmetric centers and other chemical structures that may lead to stereoisomerism, this disclosure also includes these stereoisomers and mixtures thereof. Since the compounds of this disclosure (or pharmaceutically acceptable salts thereof) include asymmetric carbon atoms, they can exist as single stereoisomers, racemates, or mixtures of enantiomers and diastereomers. Typically, these compounds can be prepared as racemates. However, if desired, such compounds can be prepared or isolated to obtain pure stereoisomers, i.e., single enantiomers or diastereomers, or mixtures enriched with single stereoisomers (purity ≥99%, ≥98%, ≥97%, ≥96%, ≥95%, ≥90%, ≥85%, ≥80%, ≥75%, ≥70%, ≥65%, or ≥60%). As described below, the single stereoisomers of the compounds are prepared from optically active starting materials containing the desired chiral center, or by preparing a mixture of enantiomeric products followed by separation or resolution, for example, by converting to a mixture of diastereomers followed by separation or recrystallization, chromatographic treatment, using chiral resolving reagents, or by direct separation of the enantiomers on a chiral chromatographic column. Starting compounds with specific stereochemistry are commercially available or can be prepared according to the methods described below and then resolved by methods well known in the art. The term "enantiomer" refers to a pair of stereoisomers that are mirror images of each other. The term "diastereomer" or "diastereomer" refers to optical isomers that are not mirror images of each other. The term "racemic mixture" or "racemate" refers to a mixture containing equal parts of a single enantiomer (i.e., an equimolar mixture of two R and S enantiomers). The term "non-racemic mixture" refers to a mixture containing unequal parts of a single enantiomer. Unless otherwise stated, all stereoisomers of the compounds disclosed herein are within the scope of this disclosure.

[0071] Solid lines are used in this article. solid wedge Or virtual wedge The covalent chemical bonds of the compounds of this disclosure are depicted. When solid lines are used to depict bonds to chiral atoms, it indicates that all possible stereoisomers at that chiral atom are included (e.g., specific enantiomers, racemic mixtures, etc.). When solid or dashed wedges are used to depict bonds to chiral atoms, it indicates the presence of the stereoisomers shown. Unless otherwise specified, the stereoisomers of the compounds of this disclosure may encompass specific enantiomers, diastereomers, racemates, or mixtures thereof in any proportion.

[0072] The term "tautomer" (or "tautomer form") refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (or proton transfer tautomers) include (but are not limited to) interconversions via proton transfer, such as keto-enol isomerization, imine-enamine isomerization, amide-imine alcohol isomerization, nitroso-oxime isomerization, etc. Unless otherwise stated, all tautomer forms of the compounds disclosed herein are within the scope of this disclosure.

[0073] The term "polymorph" (or "polymorphic form") refers to the solid crystalline form of a compound or complex. This disclosure covers all possible crystalline forms or polymorphs of the compounds disclosed herein, which may be a single polymorph or a mixture of multiple polymorphs in any proportion.

[0074] The term "solvent" refers to a substance formed by the combination of a compound of the present disclosure (or a pharmaceutically acceptable salt thereof) with at least one solvent molecule through non-covalent intermolecular forces. The compounds of the present disclosure may exist as solvates, containing a polar solvent as an element of the crystal structure. The amount of polar solvent may be in stoichiometric or non-stoichiometric form.

[0075] The term "isotope-labeled compound" refers to a derivative compound formed by replacing a specific atom in a compound of this disclosure with its isotopic atom. Unless otherwise indicated, the compounds of this disclosure include various isotopes of H, C, N, O, F, P, S, and Cl, such as... 2 H(D), 3 H(T), 13 C 14 C 13 N、 15 N、 17 O、 18 O、 18 F, 31 P, 32 P, 34 S, 35 S, 36 S, 37 Cl and 125 I. For example, 12 C can be 13 C or 14 C substitution; 1 H can be 2 H(D, deuterium) or 3 H(T, tritium) substitution; 16 O can be 18 O substitution, etc.

[0076] Those skilled in the art will understand that not all nitrogen-containing heterocycles can form N-oxides because nitrogen requires available lone pairs of electrons to be oxidized into oxides. Those skilled in the art will identify nitrogen-containing heterocycles capable of forming N-oxides. They will also recognize that tertiary amines can form N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic acid and m-chloroperoxybenzoic acid (mCPBA), hydrogen peroxide, alkyl peroxides such as tert-butyl peroxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see, for example: T.L. Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp. 748-750 (AR. Katritzky and A.J. Boulton, Eds., Academic Press); and G.W. H. Heeseman and E.S. G. Wierstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp. 390-392 (AR. Katritzky and A.J. Boulton, Eds., Academic Press).

[0077] The term "metabolite" refers to a derivative compound formed after the metabolism of the compounds of this disclosure, such as by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, or enzymatic hydrolysis. Further information on metabolism can be found in Goodman and Gilman's: The Pharmacological Basis of Therapeutics [M], McGraw-Hill International Editions, 1996. This disclosure covers all possible metabolite forms of the compounds of this disclosure, i.e., substances formed in the body of an individual administering the compounds of this disclosure. Metabolites of the compounds can be identified by techniques known in the art, and their activity can be characterized by assays.

[0078] The term "prodrug" refers to a derivative compound that, upon administration to an individual, can directly or indirectly provide the compounds of this disclosure. Particularly preferred derivative compounds or prodrugs are those that, upon administration to an individual, can improve the bioavailability of the compounds of this disclosure (e.g., facilitate absorption into the bloodstream) or promote the delivery of the parent compound to its site of action (e.g., the lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of this disclosure are within the scope of this disclosure, and various prodrug forms are known in the art, see, for example, T. Higuchi, V. Stella, Pro-drugs as Novel Drug Delivery Systems [J], American Chemical Society, Vol. 14, 1975. Furthermore, this disclosure also covers compounds of this disclosure containing a protecting group. In any process of preparing the compounds of this disclosure, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of this disclosure. This can be achieved using conventional protecting groups, such as those described in TWGreene, PGMWuts, Protective Groups in Organic Synthesis [M], John Wiley & Sons, 2006. These protecting groups can be removed at appropriate subsequent stages using methods known in the art.

[0079] This disclosure also covers methods for preparing the compounds described herein. It should be understood that the compounds of this disclosure can be synthesized using the methods described below, as well as synthetic methods known in the field of synthetic organic chemistry or variations thereof understood by those skilled in the art. Preferred methods include (but are not limited to) those described below. The reaction can be carried out in a solvent or solvent mixture suitable for the reagents and materials used and suitable for achieving the conversion.

[0080] The terms “active ingredient,” “therapeutic agent,” “active substance,” or “active agent” refer to a chemical entity that can effectively treat one or more symptoms of a target condition or disease.

[0081] The term "FBXW7" refers to a protein 7 gene, transcript, or protein containing an F-box / WD repeat sequence. Mutated FBXW7 genes (FBXW7 genes with inactivation mutations) are genes that cannot produce functional FBXW7 protein in cells.

[0082] As used herein, the term "effective amount" (e.g., "therapeutic effective amount" or "preventive effective amount") refers to the amount of active ingredient that, when administered, will achieve the desired effect to a certain extent, such as relieving one or more symptoms of the treated condition or preventing the occurrence of the condition or its symptoms.

[0083] Unless otherwise stated, as used herein, the term “treatment” means to reverse, alleviate, or improve the condition or illness to which such term applies, or the progression of one or more symptoms of such condition or illness.

[0084] As used in this article, the term "prevention" includes suppressing and delaying the onset of disease, and includes not only prevention before the development of disease, but also prevention of recurrence of disease after treatment.

[0085] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this disclosure, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0086] compound

[0087] In certain embodiments of this disclosure, compounds of formula (I) or their pharmaceutically acceptable forms are provided:

[0088] in:

[0089] X is selected from N and CH; Y is selected from N and CR. 2 Z is selected from N and CR 3 W is selected from N and CR 4 ;

[0090] R 1 R 2 R 3 R 4 and R 5 Each is independently selected from hydrogen, halogen, hydroxyl, oxo group, -CN, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NR x R y -C(O)NH2, -C(O) (4-6 membered heterocyclic alkyl groups), -C(O)NH(C 1-6 Alkyl), -C(O)NH(C 3-6 cycloalkyl), -C(O)NH (4-6 membered heterocycloalkyl), -S(O)2 (C 1-6Alkyl group), -S(O)2NR x R y -O(C 6-10 aryl), -O (5-10 heteroaryl), C 6-10 Aryl and 5-10 heteroaryl groups, wherein each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally substituted by one or more substituents independently selected from: deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl group, optionally selected independently from one or more of deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 3-6 Cycloalkyl, optionally selected independently from one or more of deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The 4-6 membered heterocyclic alkyl group substituted with a haloalkyl group, optionally with one or more groups independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 6-10 The aryl group is optionally selected independently from one or more deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 5-10 membered heteroaryl groups substituted with haloalkyl groups;

[0091] Or R 1 and R 2 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl or 5-10-membered heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x Ry -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0092] Or R 2 and R 3 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl or 5-10-membered heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0093] Or R 3 and R 4 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl or 5-10-membered heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0094] Or R 4 and R 5 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10Aryl or 5-10-membered heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0095] R 6 R 7 and R 8 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Haloalkyl, wherein the alkyl, cycloalkyl or haloalkyl group is optionally each selected independently from one or more of deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0096] R 9 Selected from OH;R 10 Selected from hydrogen, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Halogenated alkyl groups;

[0097] Or R 9 With R 10 Co-formation -CR 11 =N-NH-, and R 11 Selected from hydrogen and halogens;

[0098] R x and R y Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-8 cycloalkyl, -C(O)(C 1-6 Alkyl), -C(O)(C 3-6 cycloalkyl), -C(O) (4-6 membered heterocycloalkyl), -C(O)O(C 1-6 Alkyl), -C(O)O(C 3-6 cycloalkyl), -C(O)O (4-6 membered heterocycloalkyl), -S(O)2 (C 1-6 Alkyl), -S(O)2(C 3-6Cycloalkyl), -S(O)2 (4-6 membered heterocycloalkyl), 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 heteroaryl groups; each of the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently by one or more radicals selected from deuterium, halogen, hydroxyl, oxo group, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -O(C) 1-6 Alkyl groups, -NH2, -C(O)NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0099] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs.

[0100] In some embodiments, in the compound of formula (I) provided in this disclosure,

[0101] X is selected from N and CH; Y is selected from N and CR. 2 Z is selected from N and CR 3 W is selected from N and CR 4 ;

[0102] R 1 R 2 R 3 R 4 and R 5 Each is independently selected from hydrogen, halogen, hydroxyl, oxo group, -CN, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NR x R y -C(O)NH2, -C(O) (4-6 membered heterocyclic alkyl groups), -C(O)NH(C 1-6 Alkyl), -C(O)NH(C 3-6 cycloalkyl), -C(O)NH (4-6 membered heterocycloalkyl), -S(O)2 (C 1-6 Alkyl group), -S(O)2NR x R y -O(C6-10 aryl), -O (5-10 heteroaryl), C 6-10 Aryl and 5-10 heteroaryl groups, wherein each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally substituted by one or more substituents independently selected from: deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl group, optionally selected independently from one or more of deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 3-6 Cycloalkyl, optionally selected independently from one or more of deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The 4-6 membered heterocyclic alkyl group substituted with a haloalkyl group, optionally with one or more groups independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 6-10 The aryl group is optionally selected independently from one or more deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 5-10 membered heteroaryl groups substituted with haloalkyl groups;

[0103] Or R 1 and R 2 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl or 5-10-membered heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0104] Or R 2 and R 3 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl or 5-10-membered heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0105] Or R 3 and R 4 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl or 5-10-membered heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0106] Or R 4 and R 5 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl or 5-10-membered heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NRx R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0107] R 6 R 7 and R 8 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Haloalkyl, wherein the alkyl, cycloalkyl or haloalkyl group is optionally each selected independently from one or more of deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0108] R 9 For OH; R 10 Selected from hydrogen, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Halogenated alkyl groups;

[0109] Or R 9 With R 10 Co-formation -CR 11 =N-NH-, and R 11 Selected from hydrogen and halogens;

[0110] R x and R y Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-8 cycloalkyl, -C(O)(C 1-6 Alkyl), -C(O)(C 3-6 cycloalkyl), -C(O) (4-6 membered heterocycloalkyl), -C(O)O(C 1-6 Alkyl), -C(O)O(C 3-6 cycloalkyl), -C(O)O (4-6 membered heterocycloalkyl), -S(O)2 (C 1-6 Alkyl), -S(O)2(C 3-6 Cycloalkyl), -S(O)2 (4-6 membered heterocycloalkyl), 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 heteroaryl groups; each of the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently by one or more radicals selected from deuterium, halogen, hydroxyl, oxo group, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6Hydroxyalkyl, -O(C) 1-6 Alkyl groups, -NH2, -C(O)NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0111] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs.

[0112] In some embodiments, in the compound of formula (I) provided in this disclosure,

[0113] X is selected from N and CH; Y is selected from N and CR. 2 Z is selected from N and CR 3 W is selected from N and CR 4 ;

[0114] R 1 R 2 R 3 R 4 and R 5 Each is independently selected from hydrogen, halogen, hydroxyl, oxo group, -CN, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NR x R y -C(O)NH2, -C(O) (4-6 membered heterocyclic alkyl groups), -C(O)NH(C 1-6 Alkyl), -C(O)NH(C 3-6 cycloalkyl), -C(O)NH (4-6 membered heterocycloalkyl), -S(O)2 (C 1-6 Alkyl group), -S(O)2NR x R y -O(C 6-10 aryl), -O (5-10 heteroaryl), C 6-10 Aryl and 5-10 heteroaryl groups, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally selected by one or more independently from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-10 Substitution of aryl and 5-10 heteroaryl groups;

[0115] Or R 1 and R 2 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl or 5-10-membered heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0116] Or R 2 and R 3 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl or 5-10-membered heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0117] Or R 3 and R 4 Together with the atoms it is attached to, they form C 3-6Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl or 5-10-membered heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0118] Or R 4 and R 5 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl or 5-10-membered heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0119] R 6 R 7 and R 8 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Halogenated alkyl groups;

[0120] R 9 For OH; R 10 Selected from hydrogen, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Halogenated alkyl groups;

[0121] Or R 9 With R 10 Co-formation -CR 11 =N-NH-, and R11 Selected from hydrogen and halogens;

[0122] R x and R y Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-8 cycloalkyl, -C(O)(C 1-6 Alkyl), -C(O)(C 3-6 cycloalkyl), -C(O) (4-6 membered heterocycloalkyl), -C(O)O(C 1-6 Alkyl), -C(O)O(C 3-6 cycloalkyl), -C(O)O (4-6 membered heterocycloalkyl), -S(O)2 (C 1-6 Alkyl), -S(O)2(C 3-6 Cycloalkyl), -S(O)2 (4-6 membered heterocycloalkyl), 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 heteroaryl groups; each of the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently by one or more radicals selected from deuterium, halogen, hydroxyl, oxo group, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -O(C) 1-6 Alkyl groups, -NH2, -C(O)NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0123] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs.

[0124] In some embodiments, X is N in the compound of formula (I) provided in this disclosure.

[0125] In some embodiments, X is CH in the compound of formula (I) provided in this disclosure.

[0126] In some embodiments, Y is N in the compound of formula (I) provided in this disclosure.

[0127] In some embodiments, in the compound of formula (I) provided in this disclosure, Y is CR 2 .

[0128] In some embodiments, Z is N in the compound of formula (I) provided in this disclosure.

[0129] In some embodiments, in the compounds of formula (I) provided in this disclosure, Z is CR 3 .

[0130] In some embodiments, W is N in the compound of formula (I) provided in this disclosure.

[0131] In some embodiments, in the compounds of formula (I) provided in this disclosure, W is CR 4 .

[0132] In some embodiments, in the compound of formula (I) provided in this disclosure, R 1 Selected from hydrogen, cyano, oxo, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NR x R y -C(O) (4-6 membered heterocyclic alkyl groups), -C(O)NH(C 1-6 Alkyl), -C(O)NH(C 3-6 cycloalkyl), -C(O)NH (4-6 membered heterocycloalkyl), -O(C 6-10 aryl), -O (5-10 heteroaryl), C 6-10 Aryl and 5-10 heteroaryl groups; each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups.

[0133] In some embodiments, in the compound of formula (I) provided in this disclosure, R 1 Selected from hydrogen, cyano, oxo, -NO2, C 1-6 Alkyl, C 2-6alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NR x R y -C(O) (4-6 membered heterocyclic alkyl groups), -C(O)NH(C 1-6 Alkyl), -C(O)NH(C 3-6 cycloalkyl), -C(O)NH (4-6 membered heterocycloalkyl), -O(C 6-10 aryl), -O (5-10 heteroaryl), C 6-10 Aryl and 5-10 heteroaryl groups; each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups.

[0134] In some embodiments, in the compound of formula (I) provided in this disclosure, R 1 Selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NR x R y -C(O) (4-6 membered heterocyclic alkyl groups), -C(O)NH(C 1-6 Alkyl), -C(O)NH(C 3-6 cycloalkyl), -C(O)NH (4-6 membered heterocycloalkyl), -O(C 6-10 aryl), -O (5-10 heteroaryl), C 6-10 Aryl and 5-10 heteroaryl groups, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally each selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups.

[0135] In some embodiments, in the compound of formula (I) provided in this disclosure, R 1 Selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NR x R y -C(O) (4-6 membered heterocyclic alkyl groups), -C(O)NH(C 1-6 Alkyl), -C(O)NH(C 3-6 cycloalkyl), -C(O)NH (4-6 membered heterocycloalkyl), -O(C 6-10 aryl), -O (5-10 heteroaryl), C 6-10 Aryl and 5-10 heteroaryl groups, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally each selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups.

[0136] In some embodiments, in the compound of formula (I) provided in this disclosure, R 1 Selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C)3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl groups, -NH2, -NH(C) 1-6 alkyl), -NH(C) 3-8 cycloalkyl), -NH(C 6-10 aryl), -NH (4-6 membered heterocyclic alkyl), -NH (5-10 membered heteroaryl), -O (C 6-10 aryl), -O (5-10 heteroaryl), C 6-10 Aryl and 5-10 heteroaryl groups; each of the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups.

[0137] In some embodiments, in the compound of formula (I) provided in this disclosure, R 1 Selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl groups, -NH2, -NH(C) 1-6 alkyl), -NH(C) 3-8 cycloalkyl), -NH(C 6-10 aryl), -NH (4-6 membered heterocyclic alkyl), -NH (5-10 membered heteroaryl), -O (C 6-10 aryl), -O (5-10 heteroaryl), C 6-10 Aryl and 5-10 heteroaryl groups; each of the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NRx R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups.

[0138] In some embodiments, in the compound of formula (I) provided in this disclosure, R 1 Selected from hydrogen, cyano, -NH(C) 1-6 Alkyl groups (e.g., methylamino groups), -NH(C) 3-8 cycloalkyl), -NH(C 6-10 Aryl (e.g., phenylamino), -NH (5-10 membered heteroaryl) (e.g., pyrazoleamino), C 6-10 Aryl (e.g., phenyl), 5-10 heteroaryl (e.g., pyridine, pyrazole), C 1-6 Alkyl (e.g., methyl, isopropyl), C 3-6 Cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclohexyl), (For example ), (For example ), (For example ),

[0139] In some embodiments, in the compound of formula (I) provided in this disclosure, R 1 Selected from

[0140] In some embodiments, in the compound of formula (I) provided in this disclosure, R 1 Selected from

[0141] In some embodiments, in the compound of formula (I) provided in this disclosure, R 1 Selected from

[0142] In some embodiments, in the compound of formula (I) provided in this disclosure, R 1 Selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6Cycloalkyl, 4-14-membered heterocycloalkyl, -O (4-6-membered heterocycloalkyl), and 5-10-membered heteroaryl, wherein each of the alkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally selected independently by one or more of deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups, preferably wherein each of the alkyl, cycloalkyl, heterocyclic alkyl or heteroaryl groups is optionally replaced by one or more groups independently selected from halogen, oxo, hydroxyl and C. 1-6 Alkyl substituents.

[0143] In some embodiments, in the compound of formula (I) provided in this disclosure, R 1 Selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-14-membered heterocycloalkyl, -O (4-6-membered heterocycloalkyl), and 5-10-membered heteroaryl, wherein each of the alkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally selected independently by one or more of deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 The cycloalkyl and 4-6 membered heterocyclic alkyl groups are substituted, preferably each optionally by one or more groups independently selected from halogens, oxo groups, hydroxyl groups, and C. 1-6 Alkyl substituents.

[0144] In some embodiments, in the compound of formula (I) provided in this disclosure, R 1 Selected from hydrogen, cyano, C 1-6 Alkyl groups (e.g., methyl, isopropyl),

[0145] In some embodiments, in the compound of formula (I) provided in this disclosure, R 1 Selected from hydrogen, cyano, C 1-6 Alkyl groups (e.g., methyl, isopropyl),

[0146] In some embodiments, in the compound of formula (I) provided in this disclosure, R 1 Selected from hydrogen, cyano, C 1-6 Alkyl groups (e.g., methyl, isopropyl),

[0147] In some embodiments, in the compound of formula (I) provided in this disclosure, R 1 Selected from hydrogen, cyano, C 1-6 Alkyl groups (e.g., methyl, isopropyl),

[0148] In some embodiments, in the compound of formula (I) provided in this disclosure, R 2 Selected from hydrogen, halogen, hydroxyl, oxo group, -CN, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NR x R y -C(O)NH2, -C(O) (4-6 membered heterocyclic alkyl groups), -C(O)NH(C 1-6 Alkyl), -C(O)NH(C 3-6 cycloalkyl), -C(O)NH (4-6 membered heterocycloalkyl), -S(O)2 (C 1-6 Alkyl group), -S(O)2NR x R y C 6-10 Aryl and 5-10 heteroaryl groups; each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y C 3-6Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups.

[0149] In some embodiments, in the compound of formula (I) provided in this disclosure, R 2 Selected from hydrogen, halogen, hydroxyl, oxo group, -CN, -NO2, C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NR x R y -C(O)NH2, -C(O) (4-6 membered heterocyclic alkyl groups), -C(O)NH(C 1-6 Alkyl), -C(O)NH(C 3-6 Cycloalkyl), -C(O)NH (4-6 membered heterocycloalkyl), C 6-10 Aryl and 5-10 heteroaryl groups, preferably selected from hydrogen, halogen, oxo group, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NR x R y C6 aryl and 5-6 heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is each optionally selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups.

[0150] In some embodiments, in the compound of formula (I) provided in this disclosure, R 2 Selected from hydrogen, halogens, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NR x R y C6 aryl and 5-6 heteroaryl; the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are each optionally selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups.

[0151] In some embodiments, in the compound of formula (I) provided in this disclosure, R 2 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene O(C) 1-4 Alkyl), C 3-6 cycloalkyl, -O(C) 1-6 Alkyl), -O(C) 3-6 cycloalkyl) and -NR x R y .

[0152] In some embodiments, in the compound of formula (I) provided in this disclosure, R 2 Selected from hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, fluoromethyl, -CH2OCH3 and -OCH3.

[0153] In some embodiments, in the compound of formula (I) provided in this disclosure, R 2 Selected from hydrogen, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0154] In some embodiments, in the compound of formula (I) provided in this disclosure, R 2 Selected from hydrogen and halogens; preferably, R 2 Selected from hydrogen and fluorine, more preferably hydrogen.

[0155] In some embodiments, in the compound of formula (I) provided in this disclosure, R 1 With R 2 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, C6 aryl, or 5-6 heteroaryl groups, wherein each cycloalkyl, aryl, or heteroaryl group is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups.

[0156] In some embodiments, in the compound of formula (I) provided in this disclosure, R 3 Selected from hydrogen, halogen, hydroxyl, oxo group, -CN, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NR x R y -C(O)NH2, -C(O) (4-6 membered heterocyclic alkyl groups), -C(O)NH(C 1-6 Alkyl), -C(O)NH(C 3-6 cycloalkyl), -C(O)NH (4-6 membered heterocycloalkyl), -S(O)2 (C 1-6 Alkyl group), -S(O)2NR x R y C 6-10 Aryl and 5-10 heteroaryl groups; each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups.

[0157] In some embodiments, in the compound of formula (I) provided in this disclosure, R 3 Selected from hydrogen, halogen, hydroxyl, oxo group, -CN, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NR x R y -C(O)NH2, -C(O) (4-6 membered heterocyclic alkyl groups), -C(O)NH(C 1-6 Alkyl), -C(O)NH(C 3-6 Cycloalkyl), -C(O)NH (4-6 membered heterocycloalkyl), C 6-10 Aryl and 5-10 heteroaryl groups; each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups.

[0158] In some embodiments, in the compound of formula (I) provided in this disclosure, R 3 Selected from hydrogen, halogens, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NR x R y C6 aryl and 5-6 heteroaryl; the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are each optionally selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups.

[0159] In some embodiments, in the compound of formula (I) provided in this disclosure, R 3 Selected from hydrogen, halogen, oxo group, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 alkyl), -NH(C) 1-6 alkyl), -NH (5-6 membered heteroaryl), C 6-10 Aryl and 5-10 heteroaryl groups; each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups, preferably by substituents selected from deuterium, halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -O(C) 1-6 Alkyl), C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups.

[0160] In some embodiments, in the compound of formula (I) provided in this disclosure, R 3 Selected from hydrogen, halogens, -CN, -C 3-4 cycloalkyl, C 1-4 Alkyl, -O(C) 1-6 alkyl), -NH(C) 1-6 Alkyl), -NH (5-6 membered heteroaryl), 4-6 membered heterocyclic alkyl, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally selected independently by one or more elements selected from deuterium, halogen, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, -O(C) 1-6 Alkyl), C 3-6 Substitution with cycloalkyl groups and 4-6 membered heterocyclic groups.

[0161] In some embodiments, in the compound of formula (I) provided in this disclosure, R 3 Selected from hydrogen, halogens, -CN, -C 3-4 cycloalkyl, C 1-4 Alkyl, -O(C) 1-6 alkyl), -NH(C) 1-6 Alkyl groups, -NH (5-6 membered heteroaryl groups), and 4-6 membered heterocyclic alkyl groups, wherein each of the alkyl, cycloalkyl, heterocyclic alkyl, aryl, or heteroaryl groups is optionally selected independently by one or more elements selected from deuterium, halogen, -CN, C. 1-6 Alkyl, C1-6 Haloalkyl, -O(C) 1-6 alkyl) and C 3-6 Substitution of cycloalkyl groups.

[0162] In some embodiments, in the compound of formula (I) provided in this disclosure, R 3 Selected from hydrogen, halogens, -CN, -C 3-4 cycloalkyl, C 1-4 Alkyl, C 1-4 Haloalkyl, -O(C) 1-6 Alkyl), -O(C) 1-6 Halogenated alkyl), -NH(C) 1-6 Alkyl), -NH (5-6 membered heteroaryl), and 4-6 membered heterocyclic alkyl.

[0163] In some embodiments, in the compound of formula (I) provided in this disclosure, R 3 Selected from hydrogen, fluorine, chlorine, -CN, methyl, methoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, difluoromethyl, trifluoromethyl, and -NH (5-6 membered heteroaryl), wherein the heteroaryl group is optionally selected independently by one or more elements from deuterium, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -O(C) 1-6 Alkyl), C 3-6 Substituents of cycloalkyl and 4-6 membered heterocyclic groups, preferably optionally replaced by one or more groups independently selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Substitution with cycloalkyl groups and 4-6 membered heterocyclic groups.

[0164] In some embodiments, in the compound of formula (I) provided in this disclosure, R 3 Selected from hydrogen, halogens, -CN, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0165] In some embodiments, in the compound of formula (I) provided in this disclosure, R 3 Selected from hydrogen, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0166] In some embodiments, in the compound of formula (I) provided in this disclosure, R 3 Selected from hydrogen and halogens.

[0167] In some embodiments, in the compound of formula (I) provided in this disclosure, R 2 and R 3 Together with the atoms it is attached to, they form C 3-6Cycloalkyl, 4-8 membered heterocyclic alkyl, C 6-10 Aryl or 5-10-membered heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups.

[0168] In some embodiments, in the compound of formula (I) provided in this disclosure, R 2 With R 3 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, C6 aryl, or 5-6 heteroaryl groups, wherein each cycloalkyl, aryl, or heteroaryl group is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups.

[0169] In some embodiments, in the compound of formula (I) provided in this disclosure, R 4 Selected from hydrogen, halogen, hydroxyl, oxo group, -CN, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NR x R y -C(O)NH2, -C(O) (4-6 membered heterocyclic alkyl groups), -C(O)NH(C 1-6 Alkyl), -C(O)NH(C 3-6 Cycloalkyl), -C(O)NH (4-6 membered heterocycloalkyl), C 6-10Aryl and 5-10 heteroaryl groups, wherein each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally substituted by one or more substituents independently selected from: deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl group, optionally selected independently from one or more of deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 3-6 Cycloalkyl, optionally selected independently from one or more of deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The 4-6 membered heterocyclic alkyl group substituted with a haloalkyl group, optionally with one or more groups independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 6-10 The aryl group is optionally selected independently from one or more deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 5-10 membered heteroaryl groups substituted with haloalkyl groups.

[0170] In some embodiments, in the compound of formula (I) provided in this disclosure, R 4 Selected from hydrogen, halogen, hydroxyl, oxo group, -CN, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NR x R y -C(O)NH2, -C(O) (4-6 membered heterocyclic alkyl groups), -C(O)NH(C 1-6 Alkyl), -C(O)NH(C 3-6 Cycloalkyl), -C(O)NH (4-6 membered heterocycloalkyl), C 6-10Aryl and 5-10 heteroaryl groups, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally selected by one or more independently from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-10 Substitution of aryl and 5-10 heteroaryl groups.

[0171] In some embodiments, in the compound of formula (I) provided in this disclosure, R 4 Selected from hydrogen, halogen, hydroxyl, oxo group, -CN, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NHR x -C(O)NH2, -C(O) (4-6 membered heterocyclic alkyl groups), -C(O)NH(C 1-6 Alkyl), -C(O)NH(C 3-6 Cycloalkyl), -C(O)NH (4-6 membered heterocycloalkyl), C 6-10 Aryl and 5-10 heteroaryl groups, wherein each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally substituted by one or more substituents independently selected from: deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl group, optionally selected independently from one or more of deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl, C 1-6 The C-substituent of the haloalkyl group 3-6Cycloalkyl, optionally selected independently from one or more of deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The 4-6 membered heterocyclic alkyl group substituted with a haloalkyl group, optionally with one or more groups independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 6-10 The aryl group is optionally selected independently from one or more deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 5-10 membered heteroaryl groups substituted with haloalkyl groups.

[0172] In some embodiments, in the compound of formula (I) provided in this disclosure, R 4 Selected from hydrogen, halogen, hydroxyl, oxo group, -CN, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NHR x -C(O)NH2, -C(O) (4-6 membered heterocyclic alkyl groups), -C(O)NH(C 1-6 Alkyl), -C(O)NH(C 3-6 Cycloalkyl), -C(O)NH (4-6 membered heterocycloalkyl), C 6-10 Aryl and 5-10 heteroaryl groups, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally selected by one or more independently from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-10 Substitution of aryl and 5-10 heteroaryl groups.

[0173] In some embodiments, in the compound of formula (I) provided in this disclosure, R 4 Selected from hydrogen, halogens, -CN, C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NHR x C 6-10 Aryl and 5-6-membered heteroaryl; each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more substituents independently selected from: deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y Optionally selected by one or more independently chosen from deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 3-6 Cycloalkyl, optionally selected independently from one or more of deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The 4-6 membered heterocyclic alkyl group substituted with a haloalkyl group, optionally with one or more groups independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 6-10 The aryl group is optionally selected independently from one or more deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 5-10 membered heteroaryl groups substituted with haloalkyl groups.

[0174] In some embodiments, in the compound of formula (I) provided in this disclosure, R 4 Selected from hydrogen, halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NHR x C 6-10Aryl and 5-6-membered heteroaryl; each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-10 Substitution of aryl and 5-10 heteroaryl groups.

[0175] In some implementations, R 4 Selected from hydrogen, halogens, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group and C 3-6 Cycloalkyl; the alkyl, alkenyl, ynyl and cycloalkyl groups are each optionally substituted by one or more substituents independently selected from: deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 The alkyl halide and optionally one or more independently selected from deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 5-10 membered heteroaryl groups substituted with haloalkyl groups.

[0176] In some embodiments, in the compound of formula (I) provided in this disclosure, R 4 Selected from hydrogen, halogens, -CN, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group, wherein the alkyl, alkenyl, or alkynyl group is optionally substituted by one or more substituents independently selected from: deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y Optionally selected by one or more independently chosen from deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 3-6 Cycloalkyl, optionally selected independently from one or more of deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6The 4-6 membered heterocyclic alkyl group substituted with a haloalkyl group, optionally with one or more groups independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 6-10 The aryl group is optionally selected independently from one or more deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 5-10 membered heteroaryl groups substituted with haloalkyl groups.

[0177] In some embodiments, in the compound of formula (I) provided in this disclosure, R 4 Selected from hydrogen, halogens, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group, wherein the alkyl, alkenyl, or alkynyl group is each optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-10 Substitution of aryl and 5-10 heteroaryl groups.

[0178] In some embodiments, in the compound of formula (I) provided in this disclosure, R 4 Selected from hydrogen, halogens, -CN, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0179] In some embodiments, in the compound of formula (I) provided in this disclosure, R 4 Selected from hydrogen, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0180] In some embodiments, in the compound of formula (I) provided in this disclosure, R 4 Selected from hydrogen and halogens.

[0181] In some embodiments, in the compound of formula (I) provided in this disclosure, R 4 C 2-6 Alkynyl group, wherein the alkynyl group is optionally C 6-10 The aryl or 5-10 heteroaryl group is substituted, wherein the aryl or heteroaryl group is optionally substituted by one or more groups independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6Substituents of haloalkyl groups.

[0182] In some embodiments, in the compound of formula (I) provided in this disclosure, R 4 C 2-6 Alkynyl group, wherein the alkynyl group is optionally C 6-10 Aryl or 5-10 heteroaryl substitutions.

[0183] In some embodiments, in the compound of formula (I) provided in this disclosure, R 3 and R 4 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, 4-8 membered heterocyclic alkyl, C 6-10 Aryl or 5-10-membered heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups.

[0184] In some embodiments, in the compound of formula (I) provided in this disclosure, R 3 With R 4 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, C6 aryl, or 5-6 heteroaryl groups, wherein each cycloalkyl, aryl, or heteroaryl group is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups.

[0185] In some embodiments, in the compound of formula (I) provided in this disclosure, R 5 Selected from hydrogen, halogen, hydroxyl, oxo group, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 alkyl) and -NHR x The alkyl, alkenyl, ynyl, cycloalkyl, or heterocycloalkyl groups are each optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups.

[0186] In some embodiments, in the compound of formula (I) provided in this disclosure, R 5 Selected from hydrogen, halogen, hydroxyl, oxo group, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl) and -NHR x The alkyl, alkenyl, ynyl, cycloalkyl, or heterocycloalkyl groups are each optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-10 Substitution of aryl and 5-10 heteroaryl groups.

[0187] In some embodiments, in the compound of formula (I) provided in this disclosure, R 5 Selected from hydrogen, halogen, hydroxyl, oxo group, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -NH2, -NH(C 1-6 alkyl), -NH(C) 3-6 cycloalkyl), -NH (4-6 membered heterocycloalkyl), -NH (C 6-10 Aryl) and -NH (5-10 heteroaryl); the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is each optionally selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-10 Substitution of aryl and 5-10 heteroaryl groups, preferably by substituents selected from halogens and C 1-6 Alkyl substituents.

[0188] In some embodiments, in the compound of formula (I) provided in this disclosure, R 5 Selected from hydrogen, hydroxyl, -NH2, -NH(C) 1-6 alkyl), -NH(C) 3-6 Cycloalkyl) and NH (4-6 membered heterocyclic alkyl); each of the alkyl, cycloalkyl, or heterocyclic alkyl groups is optionally selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-10 Substitution of aryl and 5-10 heteroaryl groups, preferably by substituents selected from halogens and C 1-6 Alkyl substituents.

[0189] In some embodiments, in the compound of formula (I) provided in this disclosure, R 5 Selected from hydrogen, halogens, C 1-6 Alkyl, C 1-6Halogenated alkyl groups, -NH(C) 1-6 alkyl), -NH(C) 3-6 cycloalkyl), -NH (4-6 membered heterocycloalkyl), -NH (C 6-10 Aryl) and -NH (5-10 heteroaryl).

[0190] In some embodiments, in the compound of formula (I) provided in this disclosure, R 5 It is hydrogen.

[0191] In some embodiments, in the compound of formula (I) provided in this disclosure, R 4 and R 5 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl or 5-10-membered heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups.

[0192] In some embodiments, in the compound of formula (I) provided in this disclosure, R 4 and R 5 Together with the atoms to which they are attached, they form 4-14 membered heterocyclic alkyl groups, wherein the heterocyclic alkyl group is optionally composed of one or more elements independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C. 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups.

[0193] In some embodiments, in the compound of formula (I) provided in this disclosure, R 4 and R 5 Together with the atoms it is attached to, they form

[0194] In some embodiments, in the compound of formula (I) provided in this disclosure, R 1 For H, R 4 and R 5 Together with the atoms it is attached to, they form a ring structure as described above.

[0195] In some embodiments, in the compound of formula (I) provided in this disclosure, R 6 Selected from hydrogen, halogens, C 1-4 Alkyl, C 3-4 cycloalkyl and C 1-4 Halogenated alkyl group, wherein the alkyl, cycloalkyl or haloalkyl group is optionally selected independently from one or more deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups.

[0196] In some embodiments, in the compound of formula (I) provided in this disclosure, R 6 Selected from hydrogen, halogens, C 1-4 Alkyl, C 3-4 cycloalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Deuterated alkyl groups.

[0197] In some embodiments, in the compound of formula (I) provided in this disclosure, R 6 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and C 1-4 Deuterated alkyl groups.

[0198] In some embodiments, in the compound of formula (I) provided in this disclosure, R 6 Selected from hydrogen, halogens, C 1-4 Alkyl, C 3-4 cycloalkyl and C 1-4 Deuterated alkyl groups.

[0199] In some embodiments, in the compound of formula (I) provided in this disclosure, R 6 Selected from hydrogen, halogens, C 1-4 Alkyl, C 3-4 cycloalkyl and C 1-4 Halogenated alkyl groups.

[0200] In some embodiments, in the compound of formula (I) provided in this disclosure, R 6 Selected from hydrogen, halogens and C 1-4 alkyl.

[0201] In some embodiments, in the compound of formula (I) provided in this disclosure, R 6Selected from halogens and C 1-4 alkyl.

[0202] In some embodiments, in the compound of formula (I) provided in this disclosure, R 6 It is selected from hydrogen, fluorine, chlorine, methyl, trifluoromethyl and deuterated methyl.

[0203] In some embodiments, in the compound of formula (I) provided in this disclosure, R 6 Selected from hydrogen, fluorine, chlorine and methyl.

[0204] In some embodiments, in the compound of formula (I) provided in this disclosure, R 6 Selected from methyl.

[0205] In some embodiments, in the compound of formula (I) provided in this disclosure, R 7 Selected from hydrogen, halogens, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups.

[0206] In some embodiments, in the compound of formula (I) provided in this disclosure, R 7 Selected from hydrogen and halogens.

[0207] In some embodiments, in the compound of formula (I) provided in this disclosure, R 7 Selected from hydrogen and fluorine.

[0208] In some embodiments, in the compound of formula (I) provided in this disclosure, R 7 It is hydrogen.

[0209] In some embodiments, in the compound of formula (I) provided in this disclosure, R 8 Selected from hydrogen, halogens, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups.

[0210] In some embodiments, in the compound of formula (I) provided in this disclosure, R 8 Selected from hydrogen and halogens.

[0211] In some embodiments, in the compound of formula (I) provided in this disclosure, R 8 Selected from hydrogen and fluorine.

[0212] In some embodiments, in the compound of formula (I) provided in this disclosure, R 8 It is hydrogen.

[0213] In some embodiments, in the compound of formula (I) provided in this disclosure, R 10 Selected from hydrogen, halogens, C 1-4 Alkyl, C 3-4 cycloalkyl and C 1-4Halogenated alkyl groups.

[0214] In some embodiments, in the compound of formula (I) provided in this disclosure, R 10 Selected from hydrogen, halogens, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups.

[0215] In some embodiments, in the compound of formula (I) provided in this disclosure, R 10 C 1-4 alkyl.

[0216] In some embodiments, in the compound of formula (I) provided in this disclosure, R 10 It is selected from hydrogen, fluorine, chlorine, methyl and difluoromethyl.

[0217] In some embodiments, in the compound of formula (I) provided in this disclosure, R 10 It is a methyl group.

[0218] In some embodiments, in the compound of formula (I) provided in this disclosure, R 9 With R 10 Together they form -CH=N-NH-.

[0219] In some embodiments, in the compound of formula (I) provided in this disclosure, R 11 It is hydrogen.

[0220] In some implementations, R x and R y Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 Aryl and 5-10 heteroaryl groups, for example selected from hydrogen, C 1-6 Alkyl, C 3-8 cycloalkyl, C 6-10 Aryl and 5-10 heteroaryl groups, for example, selected from hydrogen, C 1-6 Alkyl and C 3-8 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally each selected independently from one or more deuterium, halogen, hydroxyl, oxo group, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -O(C) 1-6 Alkyl groups, -NH2, -C(O)NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups.

[0221] In some embodiments, in the compound of formula (I) provided in this disclosure, R x and R y Each is independently selected from hydrogen and C. 1-6 Alkyl and C 3-8 Cycloalkyl.

[0222] In some implementations, equation (I) is further expressed as equation (I'), for example, equation (IA'):

[0223] Among them, Y, Z, W, R 1 R 2 R 3 R 4 R 6 R 7 R 8 R 9 and R 10 The group is as defined in any of the preceding implementation schemes.

[0224] In some implementations, equation (I) is further expressed as equation (I-1'):

[0225] Among them, X, Y, Z, W, R 1 R 5 R 6 R 7 R 8 R 11 The functional group is as defined in any of the preceding embodiments.

[0226] In some implementations, formula (I) is further expressed as formula (IA), formula (IB), formula (IC), formula (ID), or formula (IE):

[0227] Among them, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 and R 10 The functional group is as defined in any of the preceding embodiments.

[0228] In some embodiments, formula (I) is further defined as formula (I-1A), formula (I-1B), formula (I-1C), formula (I-1D), or formula (I-1E):

[0229] Among them, R 1 R 2 R3 R 4 R 6 R 7 R 8 and R 11 The functional group is as defined in any of the preceding embodiments.

[0230] In some embodiments, in formulas (I-1A), (I-1B), (I-1C), (I-1D), or (I-1E) provided in this disclosure, R 11 It is hydrogen.

[0231] In some embodiments, in formula (I-1A) provided in this disclosure, R 7 Selected from hydrogen, halogens, C 1-4 Alkyl and C 1-4 Halogenated alkyl; preferably, R 7 Selected from hydrogen and fluorine; more preferably, R 7 It is hydrogen.

[0232] In some embodiments, in formula (I-1A) provided in this disclosure, R 8 Selected from hydrogen, halogens, C 1-4 Alkyl and C 1-4 Halogenated alkyl; preferably, R 8 Selected from hydrogen and fluorine; more preferably, R 8 It is hydrogen.

[0233] In some embodiments, in formula (I-1A) provided in this disclosure, R 7 and R 8 Both are hydrogen.

[0234] In some embodiments, in formula (I-1A) provided in this disclosure, R 2 It is hydrogen.

[0235] In some implementations, equation (I) is further expressed as equation (I-2A):

[0236] Among them, R 1 R 3 R 4 and R 6 The functional group is as defined in any of the preceding embodiments.

[0237] In some embodiments, in formula (I-2A) provided in this disclosure, R 3 Selected from hydrogen, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably, R 3 Selected from hydrogen and fluorine; more preferably, R 3 It is hydrogen.

[0238] In some embodiments, in formula (I-2A) provided in this disclosure, R 4 Selected from hydrogen, halogens, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group and C 3-6 Cycloalkyl; the alkyl, alkenyl, ynyl and cycloalkyl groups are each optionally substituted by one or more substituents independently selected from: deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 The alkyl halide and optionally one or more independently selected from deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 5-10 membered heteroaryl groups substituted with haloalkyl groups.

[0239] In some embodiments, in formula (I-2A) provided in this disclosure, R 4 Selected from hydrogen, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl and

[0240] In some embodiments, in formula (I-2A) provided in this disclosure, R 4 Selected from hydrogen, methyl, cyclopropane and

[0241] In some embodiments, in formula (I-2A) provided in this disclosure, R 4 It is hydrogen.

[0242] In some implementations, equation (I) is further expressed as equation (I-3A):

[0243] Among them, R 1 and R 6 The functional group is as defined in any of the preceding embodiments.

[0244] In some embodiments, in formula (I-3A) provided in this disclosure, R 6 Selected from hydrogen, halogens, C 1-4 Alkyl, C 3-4 cycloalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Deuterated alkyl groups.

[0245] In some embodiments, in formula (I-3A) provided in this disclosure, R 6 Selected from hydrogen, halogens, C 1-4 Alkyl and C 1-4 Deuterated alkyl groups.

[0246] In some embodiments, in formula (I-3A) provided in this disclosure, R 6 It is selected from hydrogen, fluorine, chlorine, methyl and deuterated methyl.

[0247] In some embodiments, in formula (I-3A) provided in this disclosure, R 1 Selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NR x R y -C(O) (4-6 membered heterocyclic alkyl groups), -C(O)NH(C 1-6 Alkyl), -C(O)NH(C 3-6 cycloalkyl), -C(O)NH (4-6 membered heterocycloalkyl), -O(C 6-10 aryl), -O (5-10 heteroaryl), C 6-10 Aryl and 5-10 heteroaryl groups, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally each selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups.

[0248] In some embodiments, in formula (I-3A) provided in this disclosure, R 1 Selected from 4-14-membered heterocyclic alkyl groups and 5-10-membered heteroaryl groups, wherein each heterocyclic alkyl group or heteroaryl group is optionally selected independently by one or more groups selected from deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NRx R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups.

[0249] In some embodiments, in formula (I-3A) provided in this disclosure, R 1 Selected from

[0250] In some implementations, equation (I) is further expressed as equation (I-4A):

[0251] in,

[0252] n is selected from 0, 1, 2, and 3;

[0253] If it exists, each R 12 Each is independently selected from deuterium, halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, -O(C) 1-6 Alkyl groups and -NH2; or, any two R groups attached to adjacent carbon atoms. 12 They interconnect to form 5-10 membered heteroaryl rings;

[0254] R 6 The functional group is as defined in any of the preceding embodiments.

[0255] In some embodiments, in formula (I-4A) provided in this disclosure, if present, each R 12 Each of the following is independently selected from deuterium, fluorine, chlorine, methyl, deuterated methyl, trifluoromethyl, methoxy, and -NH2; or, any two R atoms attached to adjacent carbon atoms. 12 They connect to form pyrazole rings or pyrrole rings.

[0256] In some embodiments of formulas (IA), (IB), (IC), (ID), (IE), (I-1'), (I'), (IA'), (I-1A), (I-1B), (I-1C), (I-1D), (I-1E), (I-2A), (I-3A), and (I-4A), R 1 Selected from 5-10-membered heteroaryl groups, wherein the heteroaryl group is optionally substituted by one or more substituents independently selected from: deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl group, optionally selected independently from one or more of deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 3-6 Cycloalkyl, optionally selected independently from one or more of deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The 4-6 membered heterocyclic alkyl group substituted with a haloalkyl group, optionally with one or more groups independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 6-10 The aryl group is optionally selected independently from one or more deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 5-10 membered heteroaryl groups substituted with haloalkyl groups.

[0257] In some embodiments, the compounds of this disclosure may optionally be substituted at the positions where substitution is possible with suitable substituents, such suitable substituents being selected, for example, from: deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl compounds.

[0258] This disclosure covers any combination of the above implementation schemes.

[0259] In some embodiments, this disclosure provides compounds or pharmaceutically acceptable forms thereof, including, but not limited to:

[0260] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs.

[0261] Preparation method

[0262] The compounds disclosed herein can be prepared by any method known in the art. Reagents and starting materials are readily available to those skilled in the art. Individual isomers, enantiomers and diastereomers can be separated or resolved at any convenient point in the synthesis by methods such as selective crystallization techniques or chiral chromatography (see, for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981, and E.L. Leel and S.H. Wilen).

[0263] Another object of this disclosure is to provide a method for preparing the compounds of this disclosure. For example,

[0264] In some embodiments, this disclosure provides a method for preparing a compound of formula (I), comprising one or more steps of steps (1) to (5) of the following route:

[0265] The route is, for example, the following route:

[0266] in,

[0267] Y, Z, W, R 1 R 2 R 3 R 4 R 6 R 7 R 8 R 9 R 10 As defined in any of the above implementation schemes;

[0268] X 1 It is a halogen, such as chlorine, bromine or iodine, preferably bromine;

[0269] X 2 It is a halogen, such as chlorine, bromine or iodine, preferably chlorine;

[0270] in:

[0271] Step (1) involves reacting compound I-1 (e.g., compound IA-1) with compound IA-2 to obtain compound I-3 (e.g., compound IA-3);

[0272] Step (2) involves halogenating compound I-3 to obtain compound I-4 (e.g., compound IA-4);

[0273] Step (3) involves reacting compound I-4 with compound IA-5 to give compound I-6 (e.g., compound IA-6);

[0274] Step (4) involves coupling compound I-6 to obtain compound I-7 (e.g., compound IA-7);

[0275] Step (5) involves hydrolyzing compound I-7 to obtain compound I' (e.g., compound IA').

[0276] In some implementations, R in compound IA-5 9 and / or R 10 It is protected by a protecting group, and the protecting group is removed in subsequent steps such as hydrolysis.

[0277] In some embodiments, compound IA-5 has the following structure: Among them, R 6 R 7 R 8 As defined in any of the above implementation schemes; PG 1 The protecting group is a hydrogen or amino group, such as an alkoxycarbonyl amino group, for example, benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), fluorenemethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl (or ethoxycarbonyl); acyl amino groups, such as phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), o-(p-)nitrobenzenesulfonyl (Ns), tert-pentanoyl, benzoyl, tert-butoxycarbonyl, 9-fluorenemethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, trimethylsilylethoxycarbonyl, benzyloxycarbonyl, p-methylbenzenesulfonyl, p-nitrobenzenesulfonyl, trifluoroacetyl, methoxycarbonyl, or ethoxycarbonyl; alkyl amino groups, such as triphenylmethyl (Trt), C 1-6 Alkyl-substituted triphenylmethyl, p-methoxytriphenylmethyl (MMT), dimethoxytriphenylmethyl (DMT), 2,4-dimethoxybenzyl (Dmb), 4-methoxybenzyl (PMB), benzyl (Bn); tetrahydropyranyl (THP); or (trimethylsilyl)ethoxymethyl (SEM).

[0278] In some embodiments, the amino protecting group is a tetrahydropyranyl (THP).

[0279] In some embodiments, the amino protecting group is (trimethylsilyl)ethoxymethyl (SEM).

[0280] In some embodiments, R in compounds IA-5, I-6, and I-7 9 With R 10 Co-formation -CR 11 =NN(PG) 1 The structure of )-, after hydrolysis, yields compound I' with R 9 With R 10 Co-formation -CR 11 =N-NH-, where R 11 and PG 1 As defined in any of the preceding implementation schemes.

[0281] In some embodiments, compound IA-5 has the following structure: Among them PG 2 The protecting group is a hydrogen or hydroxyl group, such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), (trimethylsilyl)ethoxymethyl (SEM), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, or p-nitrobenzoyl.

[0282] In some embodiments, the hydroxyl protecting group is (trimethylsilyl)ethoxymethyl (SEM).

[0283] In some embodiments, R in compounds IA-5, I-6, and I-7 9 For -OPG 2 After the hydrolysis step, compound I' is formed, containing R. 9 For OH, where PG 2 As defined in any of the preceding implementation schemes.

[0284] The reaction in step (1) above is preferably carried out in the presence of ammonium acetate in a suitable organic solvent. The organic solvent may be selected from N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, and any combination thereof, preferably 1,4-dioxane. The reaction is preferably carried out at a temperature of 0-120°C for 2-24 hours.

[0285] The halogenation reaction in step (2) above is preferably carried out in the presence of a suitable halogenating agent. The halogenating agent may be selected from phosphorus oxychloride and phosphorus tribromooxychloride, preferably phosphorus oxychloride. The reaction is preferably carried out at a temperature of 0-120°C for 0.5-24 hours.

[0286] The substitution reaction in step (3) above is preferably carried out in the presence of cuprous bromide or iodine ketone, in a suitable organic solvent, and in the presence of a suitable base. The organic solvent may be selected from N,N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, 1,4-dioxane, and any combination thereof, preferably N-methylpyrrolidone. The base may be an organic or inorganic base, for example selected from N,N-diisopropylethylamine, triethylamine, sodium tert-butoxide, potassium carbonate, cesium carbonate, and sodium carbonate, preferably cesium carbonate. The reaction is preferably carried out at a temperature of 0-120°C for 2-24 hours.

[0287] The coupling reaction in step (4) above is preferably carried out in a suitable organic solvent. The organic solvent may be selected from N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, water, toluene, and any combination thereof, preferably a combination of 1,4-dioxane and water. The coupling reaction is preferably carried out in the presence of a metal catalyst. Preferably, the metal catalyst is a palladium metal catalyst, such as tris(dibenzylacetone)dipalladium, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride, tetra(triphenylphosphine)palladium, palladium acetate, Pd(dtbpf)Cl2, BINAP, BrettPhos Pd G3, cataCXium A Pd G3, or any combination thereof, preferably cataCXium A Pd G3. Alternatively, a copper catalyst may be used, such as copper acetate, cuprous chloride, cuprous bromide, cuprous iodide, cuprous oxide, etc. The reaction is preferably carried out in the presence of a suitable base, which may be selected from N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, potassium phosphate, sodium tert-butoxide, and cesium carbonate, with potassium phosphate being preferred. The reaction is preferably carried out at a suitable temperature, preferably 0-150°C. The reaction is preferably carried out for a suitable time, for example, 2-24 hours.

[0288] The hydrolysis reaction in step (5) above is preferably carried out in the presence of a suitable acid. The acid can be concentrated sulfuric acid, concentrated hydrochloric acid, or concentrated nitric acid, preferably concentrated sulfuric acid. The reaction is preferably carried out at a temperature of 0-80°C for 0.5-24 hours.

[0289] In some embodiments, compound I-3 reacts directly with compound IA-5 to generate compound I-6:

[0290] This reaction step is preferably carried out in a suitable organic solvent. The organic solvent may be selected from N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, NMP, and any combination thereof, with N,N-dimethylformamide being preferred. The reaction is preferably carried out in the presence of a suitable condensing agent, such as PyBOP and HATU, with PyBOP being preferred. The reaction is preferably carried out in the presence of a suitable organic base, such as N,N-diisopropylethylamine, triethylamine, N,N-dimethylaniline, or DBU, with N,N-diisopropylethylamine being preferred. The reaction is preferably carried out at a suitable temperature, preferably 0-100°C. The reaction is preferably carried out for a suitable time, for example, 2-24 hours.

[0291] In some embodiments, R in compound I-7 9 With R 10 Co-formation -CR 11 =NN(PG) 1 )-structure or R 9 For -OPG 2 In this process, compound I-7 first undergoes a hydrolysis reaction to convert the cyano group to a carbamoyl group, and then undergoes a deprotection reaction to remove the PG. 1 or PG 2 Compound I' is formed, or PG is removed first through a deprotection reaction. 1 or PG 2 The cyano group is then hydrolyzed to form a carbamoyl group, thus generating compound I'. In some embodiments, the hydrolysis reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, NMP, DMSO, DCM, methanol, and any combination thereof, with DMSO being preferred. The reaction is preferably carried out in the presence of a suitable oxidant, such as H2O2 and mCPBA, with H2O2 being preferred. The reaction is preferably carried out in the presence of a suitable base, such as Na2CO3, K2CO3, Cs2CO3, NaOH, KOH, with K2CO3 being preferred. The reaction is preferably carried out at a suitable temperature, preferably 0-100°C. The reaction is preferably carried out for a suitable time, for example, 0.5-24 hours. The deprotection is carried out under acidic conditions, with the acid preferably selected from 1,4-dioxane solution of HCl, aqueous solution of HCl, alcoholic solution of HCl, trifluoroacetic acid, etc., with trifluoroacetic acid being preferred.

[0292] In some implementations, for example when R 1 When the molecule is -CN, compound IA-5 first undergoes the hydrolysis reaction in step (5) above, and then undergoes the coupling reaction in step (4).

[0293] For example, in some implementations, such as when R1 When -CN, this disclosure provides a method for preparing a compound of formula (I), comprising one or more steps of steps (1) to (2) of the following route:

[0294] The route is, for example, the following route.

[0295] in

[0296] Y, Z, W, R 1 R 2 R 3 R 4 R 6 R 7 R 8 R 9 R 10 X 1 As defined in any of the above implementation schemes;

[0297] Step (1) hydrolyzes compound I-6 (e.g., compound IA-6) to obtain compound I-6-2 (e.g., compound IA-6-2);

[0298] Step (2) involves coupling compound I-6-2 to obtain compound I'.

[0299] In some implementations, when R 1 When it is -CN, R in compound I-6 9 With R 10 Co-formation -CR 11 =NN(PG) 1 The structure of )-, the compound I-6-2 formed after hydrolysis, and the compound I' formed after subsequent coupling reaction, R 9 With R 10 Co-formation -CR 11 =N-NH-, where R 11 and PG 1 As defined in any of the aforementioned implementation schemes.

[0300] The hydrolysis reaction in step (1) above is preferably carried out in the presence of a suitable acid. The acid can be concentrated sulfuric acid, concentrated hydrochloric acid, or concentrated nitric acid, preferably concentrated sulfuric acid. The reaction is preferably carried out at a temperature of 0-80°C for 0.5-24 hours.

[0301] The coupling reaction in step (2) above is preferably carried out in the presence of zinc cyanide, in a suitable organic solvent, and in the presence of a suitable catalyst. The organic solvent may be selected from N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, toluene, and any combination thereof, with N,N-dimethylformamide being preferred. The coupling reaction is preferably carried out in the presence of a metal catalyst. Preferably, the metal catalyst is a palladium metal catalyst, such as XPhos Pd G3, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride, tetra(triphenylphosphine) palladium, palladium acetate, Pd(dtbpf)Cl2, BINAP, BrettPhos Pd G3, t-Bu-Xphos-Pd-G3, cataCXium APd G3, or any combination thereof, with XPhos Pd G3 being preferred. The reaction is preferably carried out at a suitable temperature, preferably 0-150°C. The reaction is preferably carried out for a suitable time, for example, 2-24 hours.

[0302] In some embodiments, R in compound I-6 9 With R 10 Co-formation -CR 11 =NN(PG) 1 )-structure or R 9 For -OPG 2 In this process, compound I-6 first undergoes a hydrolysis reaction to convert the cyano group to a carbamoyl group, and then undergoes a deprotection reaction to remove the PG. 1 or PG 2 Compound I-6-2 is generated. In some embodiments, the hydrolysis reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, NMP, DMSO, DCM, and any combination thereof, with DMSO being preferred. The reaction is preferably carried out in the presence of a suitable oxidant, such as H2O2 and mCPBA, with H2O2 being preferred. The reaction is preferably carried out in the presence of a suitable base, such as Na2CO3, K2CO3, Cs2CO3, NaOH, KOH, etc., with K2CO3 being preferred. The reaction is preferably carried out at a suitable temperature, preferably 0-100°C. The reaction is preferably carried out for a suitable time, for example, 0.5-24 hours. The deprotection is carried out under acidic conditions, with the acid selected from 1,4-dioxane solution of HCl, aqueous solution of HCl, alcoholic solution of HCl, trifluoroacetic acid, etc., with trifluoroacetic acid being preferred.

[0303] In some embodiments, this disclosure also provides a method for preparing a compound of formula (I), comprising one or more steps of steps (1) to (3) of the following route:

[0304] The route is, for example, the following route:

[0305] in,

[0306] Y, Z, W, X 1 R 1 R 2 R 3 R 4 R 6 R 7 R 8 R 9 R 10 As defined in any of the above implementation schemes;

[0307] in:

[0308] Step (1) involves coupling compound I-6 with pinacol diboronic acid ester to generate compound I-6-1 (e.g., compound IA-6-1);

[0309] Step (2) involves coupling compound I-6-1 to obtain compound I-7;

[0310] Step (3) involves hydrolyzing compound I-7 to obtain compound I'.

[0311] In some embodiments, R in compounds I-6, I-6-1, and I-7 9 With R 10 Co-formation -CR 11 =NN(PG) 1 The structure of )-, after hydrolysis, produces compound I' with R 9 With R 10 Co-formation -CR 11 =N-NH-, where R 11 and PG 1 As defined in any of the aforementioned implementation schemes.

[0312] The coupling reaction in step (1) is preferably carried out in a suitable organic solvent. The organic solvent may be selected from N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, toluene, and any combination thereof, with 1,4-dioxane being preferred. The coupling reaction is preferably carried out in the presence of a metal catalyst. Preferably, the metal catalyst is a palladium metal catalyst, such as tris(dibenzylacetone)dipalladium, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride, tetra(triphenylphosphine)palladium, palladium acetate, Pd(dtbpf)Cl2, or any combination thereof, with 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride being preferred. The reaction is preferably carried out in the presence of a suitable base, which may be selected from potassium acetate, potassium carbonate, potassium phosphate, and cesium carbonate, with potassium acetate being preferred. The reaction is preferably carried out at a suitable temperature, preferably 20-120°C. The reaction is preferably carried out for a suitable time, for example, 2-24 hours.

[0313] The reaction conditions for step (2) above are as described above regarding the reaction conditions for the coupling reaction of compound I-6 to generate I-7.

[0314] The reaction conditions for step (3) above are as described above regarding the reaction conditions for the hydrolysis of compound I-7 to obtain compound I'.

[0315] In some embodiments, this disclosure also provides a method for preparing a compound of formula (I), comprising one or more steps from (1) to (3):

[0316] Step (1) involves coupling compound I-4 with pinacol diboronic acid ester to generate compound I-4-1;

[0317] Step (2) involves coupling compound I-4-1 to obtain compound I-4-2;

[0318] Step (3) involves a substitution reaction between compound I-4 and compound IA-5 to obtain compound I-7.

[0319] The coupling reaction in step (1) is preferably carried out in a suitable organic solvent. The organic solvent may be selected from N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, toluene, and any combination thereof, with 1,4-dioxane being preferred. The coupling reaction is preferably carried out in the presence of a metal catalyst. Preferably, the metal catalyst is a palladium metal catalyst, such as tris(dibenzylacetone)dipalladium, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride, tetra(triphenylphosphine)palladium, palladium acetate, Pd(dtbpf)Cl2, or any combination thereof, with 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride being preferred. The reaction is preferably carried out in the presence of a suitable base, which may be selected from potassium acetate, potassium carbonate, potassium phosphate, and cesium carbonate, with potassium acetate being preferred. The reaction is preferably carried out at a suitable temperature, preferably 20-120°C. The reaction is preferably carried out for a suitable time, for example, 2-24 hours.

[0320] The reaction conditions for step (2) above are as described above regarding the reaction conditions for the coupling reaction of compound I-6 to generate I-7.

[0321] The substitution reaction in step (3) above is preferably carried out in the presence of cuprous bromide, in a suitable organic solvent, and in the presence of a suitable base. The organic solvent may be selected from N,N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, 1,4-dioxane, and any combination thereof, preferably N-methylpyrrolidone. The base may be an organic or inorganic base, for example selected from N,N-diisopropylethylamine, triethylamine, sodium tert-butoxide, potassium carbonate, cesium carbonate, and sodium carbonate, preferably cesium carbonate. The reaction is preferably carried out at a temperature of 0-120°C for 0.5-24 hours, for example, 2-24 hours.

[0322] intermediate

[0323] In some embodiments, this disclosure provides compounds, or salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, or isotope labels thereof, as shown below:

[0324] in,

[0325] R 9 R 10 As defined in any of the preceding implementation schemes, or R 9 For -OPG 2 , or R 9 With R 10 Co-formation -CR 11 =NN(PG) 1 )-, Y, Z, W, R 1 R 2 R 3 R 4 R6 R 7 R 8 R 11 X 1 X 2 As defined in any of the preceding implementation schemes;

[0326] The PG 1 The protecting group is a hydrogen or amino group, such as an alkoxycarbonyl amino group, for example, benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), fluorenemethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl (or ethoxycarbonyl); acyl amino groups, such as phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), o-(p-)nitrobenzenesulfonyl (Ns), tert-pentanoyl, benzoyl, tert-butoxycarbonyl, 9-fluorenemethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, trimethylsilylethoxycarbonyl, benzyloxycarbonyl, p-methylbenzenesulfonyl, p-nitrobenzenesulfonyl, trifluoroacetyl, methoxycarbonyl, or ethoxycarbonyl; alkyl amino groups, such as triphenylmethyl (Trt), C 1-6 Alkyl-substituted triphenylmethyl, p-methoxytriphenylmethyl (MMT), dimethoxytriphenylmethyl (DMT), 2,4-dimethoxybenzyl (Dmb), 4-methoxybenzyl (PMB), benzyl (Bn); tetrahydropyranyl (THP); or (trimethylsilyl)ethoxymethyl (SEM); preferably, the amino protecting group is tetrahydropyranyl (THP) or (trimethylsilyl)ethoxymethyl (SEM);

[0327] The PG 2 The protecting group is a hydrogen or hydroxyl group, such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), (trimethylsilyl)ethoxymethyl (SEM), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl or p-nitrobenzoyl, preferably (trimethylsilyl)ethoxymethyl (SEM).

[0328] The above-mentioned intermediate compounds or their salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, and isotope labels can be used to prepare the compounds represented by the general formula herein or their pharmaceutically acceptable forms.

[0329] Pharmaceutical compositions, formulations and packaging

[0330] In some embodiments, this disclosure provides a pharmaceutical composition comprising a compound of the disclosure or a pharmaceutically acceptable form thereof, or a mixture thereof, and one or more pharmaceutically acceptable carriers, said pharmaceutically acceptable form being selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs.

[0331] A further object of this disclosure is to provide a method for preparing a pharmaceutical composition of the present disclosure, the method comprising combining a compound of the present disclosure or a pharmaceutically acceptable form thereof or a mixture thereof with one or more pharmaceutically acceptable carriers, the pharmaceutically acceptable form being selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites or prodrugs.

[0332] Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions disclosed herein include, but are not limited to, sterile liquids. Pharmaceutically acceptable carriers include pharmaceutical excipients. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (2005).

[0333] Pharmaceutical compositions can be administered in any form, provided they achieve the purpose of preventing, alleviating, preventing, or curing symptoms in human or animal patients. For example, they can be formulated into various suitable dosage forms depending on the route of administration.

[0334] When taken orally, the pharmaceutical composition may be formulated into any orally acceptable dosage form.

[0335] When applied transdermally or topically, the pharmaceutical composition may be formulated as a suitable ointment, lotion, or liniment, wherein the active ingredient may be suspended or dissolved in one or more carriers.

[0336] The pharmaceutical composition can also be administered in injectable form, including injectable solutions, sterile powders for injection, and concentrated solutions for injection.

[0337] Another aspect of this disclosure relates to a pharmaceutical formulation comprising, as an active ingredient, a compound of the present disclosure, a pharmaceutically acceptable form thereof, or a mixture thereof, or a pharmaceutical composition thereof, wherein the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope-labeled substances, metabolites, or prodrugs. In some embodiments, the formulation is in the form of a solid dosage form, a semi-solid dosage form, a liquid dosage form, or a gaseous dosage form.

[0338] The amount or dosage of the compounds disclosed herein in a pharmaceutical composition or pharmaceutical formulation may be from about 0.01 mg to about 1000 mg. A further object of this disclosure is to provide an article of manufacture, for example, provided in a cassette form. The articles of manufacture as used herein are intended to include, but are not limited to, pharmaceutical compositions and packaging. For example, an article of manufacture of this disclosure comprises: (a) a first container; (b) a pharmaceutical composition located in the first container, wherein the composition comprises: a first therapeutic agent comprising: a compound of this disclosure or a pharmaceutically acceptable form thereof, or a mixture thereof, wherein the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs; and (c) optionally present packaging instructions stating that the pharmaceutical composition may be used to treat diseases or conditions for which MYT1 inhibitors are applicable, such as oncological conditions.

[0339] The packaging instructions, such as trademarks, labels, or markings, list information relating to the pharmaceutical composition located within the first container. The listed information is typically determined by the regulatory authority (e.g., the Food and Drug Administration) governing the region where the product is to be sold. Preferably, the packaging instructions specifically list the approved indications for which the pharmaceutical composition is used. The packaging instructions can be made of any material from which information contained therein or on the material can be read. Preferably, the packaging instructions are made of a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper, or plastic, on which the desired information can be formed (e.g., printed or coated).

[0340] Treatment methods and uses

[0341] The purpose of this disclosure is to provide compounds of the general formula or pharmaceutically acceptable forms thereof, or pharmaceutical compositions thereof, for the prevention or treatment of diseases or conditions, particularly those related to PKMYT1 activity, wherein the pharmaceutically acceptable forms are selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs. The diseases or conditions include cancers with high CCNE1 gene expression / CCNE1 gene extension or with FBXW7 gene inactivation mutations.

[0342] Another object of this disclosure is to provide a method for preventing or treating diseases or symptoms associated with PKMYT1 activity, the method comprising administering to an individual in need an effective amount of a compound of the present disclosure or a pharmaceutically acceptable form thereof, or a mixture thereof, or a pharmaceutical composition of the present disclosure, wherein the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs.

[0343] Another object of this disclosure is to provide the use of the compounds of this disclosure or pharmaceutically acceptable forms thereof, or pharmaceutical compositions thereof, in the preparation of medicaments, particularly in the preparation of medicaments for the prevention or treatment of diseases or symptoms associated with PKMYT1 activity, wherein the pharmaceutically acceptable forms are selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs.

[0344] Another object of this disclosure is to provide the use of the compounds of the disclosed herein or pharmaceutically acceptable forms thereof, or pharmaceutical compositions thereof, in the preparation of PKMYT1 inhibitors, wherein the pharmaceutically acceptable forms are selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs.

[0345] In some embodiments, this disclosure provides a method for inhibiting PKMYT1 in cells, comprising contacting the cells with a compound of this disclosure or a pharmaceutically acceptable form thereof or a pharmaceutical composition of this disclosure, wherein the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs.

[0346] According to some embodiments of this disclosure, the PKMYT1 inhibitor comprises the compounds disclosed in this disclosure or in a pharmaceutically acceptable form thereof.

[0347] According to some embodiments of this disclosure, the diseases or conditions associated with PKMYT1 activity are diseases or conditions dependent on PKMYT1 activity, including (but not limited to) tumor-related or cancer-related diseases or conditions.

[0348] According to some embodiments of this disclosure, the diseases or conditions associated with PKMYT1 activity are diseases that are sensitive to or responsive to PKMYT1 inhibitors, including (but not limited to) tumor-related or cancer-related diseases or conditions.

[0349] According to some embodiments of this disclosure, the disease or symptom includes a disease or symptom of excessive cell proliferation. Further, the disease or symptom of excessive cell proliferation includes (but is not limited to) tumor-related or cancer-related diseases or symptom. Even further, the tumor or cancer is a tumor or cancer with high expression / extension of the CCNE1 gene or with an FBXW7 gene inactivation mutation.

[0350] In some implementations, the cancers with high CCNE1 gene expression or CCNE1 gene expansion are uterine cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, liver cancer, or endometrial cancer.

[0351] In embodiments of this disclosure, a method for treating cancer is provided, the method comprising administering an effective amount of a PKMYT1 inhibitor to a subject, wherein the cancer has an inactivating mutation in the FBXW7 gene.

[0352] Dosing regimens can be adjusted to provide the optimal required response. For example, when administered as an injection, a single bolus, bolus, and / or continuous infusion can be given, etc. For example, several fractions can be administered over time, or the dose can be reduced or increased proportionally as indicated by the urgency of the treatment situation. It should be noted that dose values ​​can vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. Generally, the dosage of treatment is variable, depending on considerations such as: the age, sex, and general health of the patient to be treated; the frequency of treatment and the nature of the desired effect; the extent of tissue damage; the duration of symptoms; and other variables that can be adjusted by individual physicians. To further understand, for any particular individual, the specific dosing regimen should be adjusted over time based on individual needs and the professional judgment of the person administering the composition or supervising the administration of the composition. The dosage and administration regimen of the pharmaceutical composition can be determined by a person skilled in the clinical field. For example, the compositions or compounds of this disclosure can be administered in fractions from four times daily to once every three days, with dosages ranging from, for example, 0.01 to 1000 mg per dose. The required dose can be administered once or multiple times to achieve the desired results. The pharmaceutical compositions according to this disclosure can also be provided in unit dose form. Beneficial effects

[0353] This disclosure provides a novel class of PKMYT1 inhibitors that can achieve at least one of the following technical effects:

[0354] (1) High inhibitory activity against PKMYT1.

[0355] (2) Excellent physicochemical properties (e.g., solubility, physical and / or chemical stability).

[0356] (3) Excellent pharmacokinetic properties (e.g., good bioavailability, appropriate half-life and duration of action).

[0357] (4) Excellent safety profile (lower toxicity and / or fewer side effects, wider therapeutic window), etc.

[0358] (5) Excellent anti-tumor effect. In some embodiments, the compounds of this disclosure have a tumor growth inhibition rate (TGI) of more than 60%, such as more than 70%, more than 80%, more than 90%, and more than 100% in animal models (e.g., OVCAR3 cell CDX mouse model and HCC1569 cell CDX mouse model).

[0359] This disclosure includes the following implementation schemes:

[0360] Implementation Scheme 1. A compound of formula (I) or a pharmaceutically acceptable form thereof:

[0361] in:

[0362] X is selected from N and CH; Y is selected from N and CR. 2 Z is selected from N and CR 3 W is selected from N and CR 4 ;

[0363] R 1 R 2 R 3 R 4 and R 5 Each is independently selected from hydrogen, halogen, hydroxyl, oxo group, -CN, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NR x R y -C(O)NH2, -C(O) (4-6 membered heterocyclic alkyl groups), -C(O)NH(C 1-6 Alkyl), -C(O)NH(C 3-6 cycloalkyl), -C(O)NH (4-6 membered heterocycloalkyl), -S(O)2 (C 1-6 Alkyl group), -S(O)2NR x R y -O(C 6-10 aryl), -O (5-10 heteroaryl), C 6-10 Aryl and 5-10 heteroaryl groups, wherein each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally substituted by one or more substituents independently selected from: deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C1-6 Deuterated alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl group, optionally selected independently from one or more of deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 3-6 Cycloalkyl, optionally selected independently from one or more of deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The 4-6 membered heterocyclic alkyl group substituted with a haloalkyl group, optionally with one or more groups independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 6-10 The aryl group is optionally selected independently from one or more deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 The 5-10 membered heteroaryl group substituted by the haloalkyl group is preferably each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl group, optionally selected independently from one or more of deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 3-6 Cycloalkyl, optionally selected independently from one or more of deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The 4-6 membered heterocyclic alkyl group substituted with a haloalkyl group, optionally with one or more groups independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 6-10The aryl group is optionally selected independently from one or more deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 The 5-10 membered heteroaryl group substituted by the haloalkyl group, more preferably the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, is optionally each independently selected from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-10 Substitution of aryl and 5-10 heteroaryl groups;

[0364] Or R 1 and R 2 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl or 5-10-membered heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0365] Or R 2 and R 3 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl or 5-10-membered heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NRx R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0366] Or R 3 and R 4 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl or 5-10-membered heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0367] Or R 4 and R 5 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl or 5-10-membered heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0368] R 6 R 7 and R 8 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6Haloalkyl, wherein the alkyl, cycloalkyl or haloalkyl group is optionally each selected independently from one or more of deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups; preferably, R 6 R 7 and R 8 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Halogenated alkyl groups;

[0369] R 9 For OH; R 10 Selected from hydrogen, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Halogenated alkyl groups;

[0370] Or R 9 With R 10 Co-formation -CR 11 =N-NH-, and R 11 Selected from hydrogen and halogens;

[0371] R x and R y Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-8 cycloalkyl, -C(O)(C 1-6 Alkyl), -C(O)(C 3-6 cycloalkyl), -C(O) (4-6 membered heterocycloalkyl), -C(O)O(C 1-6 Alkyl), -C(O)O(C 3-6 cycloalkyl), -C(O)O (4-6 membered heterocycloalkyl), -S(O)2 (C 1-6 Alkyl), -S(O)2(C 3-6 Cycloalkyl), -S(O)2 (4-6 membered heterocycloalkyl), 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 heteroaryl groups; each of the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently by one or more radicals selected from deuterium, halogen, hydroxyl, oxo group, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -O(C) 1-6 Alkyl groups, -NH2, -C(O)NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0372] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs.

[0373] Implementation Scheme 2. The compound according to Implementation Scheme 1, or its pharmaceutically acceptable form, satisfies one or more of the following conditions:

[0374] (1) X is CH; or X is N;

[0375] (2) Y is N; or Y is CR 2 ;

[0376] (3) Z is N; or Z is CR 3 ;

[0377] (4) W is N; or W is CR 4 ;

[0378] (5)R 1 Selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NR x R y -C(O) (4-6 membered heterocyclic alkyl groups), -C(O)NH(C 1-6 Alkyl), -C(O)NH(C 3-6 cycloalkyl), -C(O)NH (4-6 membered heterocycloalkyl), -O(C 6-10 aryl), -O (5-10 heteroaryl), C 6-10 Aryl and 5-10 heteroaryl groups, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally each selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups, preferably wherein each of the alkyl, cycloalkyl, heterocyclic alkyl, aryl or heteroaryl groups is optionally replaced by one or more groups independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0379] Furthermore, R 1 Selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl groups, -NH2, -NH(C) 1-6 alkyl), -NH(C) 3-8 cycloalkyl), -NH(C 6-10 aryl), -NH (4-6 membered heterocyclic alkyl), -NH (5-10 membered heteroaryl), -O (C 6-10 aryl), -O (5-10 heteroaryl), C 6-10 Aryl and 5-10 heteroaryl groups, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally each selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups, preferably wherein each of the alkyl, cycloalkyl, heterocyclic alkyl, aryl or heteroaryl groups is optionally replaced by one or more groups independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0380] Preferably, R 1 Selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-14-membered heterocycloalkyl, -O (4-6-membered heterocycloalkyl), and 5-10-membered heteroaryl, wherein each of the alkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally selected independently by one or more of deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups, preferably wherein each of the alkyl, cycloalkyl, heterocyclic alkyl or heteroaryl groups is optionally replaced by one or more groups independently selected from halogen, oxo, hydroxyl and C. 1-6 Alkyl substituents;

[0381] Furthermore, R 1 Selected from hydrogen, cyano, -NH(C) 1-6 Alkyl groups (e.g., methylamino groups), -NH(C) 3-8 cycloalkyl), -NH(C 6-10 Aryl (e.g., phenylamino), -NH (5-10 membered heteroaryl) (e.g., pyrazoleamino), C 6-10 Aryl (e.g., phenyl), 5-10 heteroaryl (e.g., pyridine, pyrazole), C 1-6 Alkyl (e.g., methyl, isopropyl), C 3-6 Cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclohexyl), (For example ), (For example ), (For example ),

[0382] Or R 1 Selected from

[0383] Or R 1 Selected from

[0384] Or R 1 Selected from

[0385] (6)R x and R y Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally selected independently by one or more groups selected from deuterium, halogen, hydroxyl, oxo group, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -O(C) 1-6 Alkyl groups, -NH2, -C(O)NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0386] (7)R 2 Selected from hydrogen, halogen, hydroxyl, oxo group, -CN, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NR x R y -C(O)NH2, -C(O) (4-6 membered heterocyclic alkyl groups), -C(O)NH(C 1-6 Alkyl), -C(O)NH(C 3-6Cycloalkyl), -C(O)NH (4-6 membered heterocycloalkyl), C 6-10 Aryl and 5-10 heteroaryl groups; each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0387] Preferably, R 2 Selected from hydrogen, halogens, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NR x R y C6 aryl and 5-6 heteroaryl; the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are each optionally selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0388] More preferably, R 2 Selected from hydrogen, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0389] (8)R 1 With R 2 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, C6 aryl, or 5-6 heteroaryl groups, wherein each cycloalkyl, aryl, or heteroaryl group is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R yC 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0390] (9)R 3 Selected from hydrogen, halogen, hydroxyl, oxo group, -CN, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NR x R y -C(O)NH2, -C(O) (4-6 membered heterocyclic alkyl groups), -C(O)NH(C 1-6 Alkyl), -C(O)NH(C 3-6 Cycloalkyl), -C(O)NH (4-6 membered heterocycloalkyl), C 6-10 Aryl and 5-10 heteroaryl groups; each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0391] Preferably, R 3 Selected from hydrogen, halogen, oxo group, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 alkyl), -NH(C) 1-6 alkyl), -NH (5-6 membered heteroaryl), C 6-10 Aryl and 5-10 heteroaryl groups; each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0392] More preferably, R 3 Selected from hydrogen, halogens, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NR x R y C6 aryl and 5-6 heteroaryl; the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are each optionally selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0393] More preferably, R 3 Selected from hydrogen, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0394] (10)R 2 With R 3 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, C6 aryl, or 5-6 heteroaryl groups, wherein each cycloalkyl, aryl, or heteroaryl group is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0395] (11)R 4 Selected from hydrogen, halogen, hydroxyl, oxo group, -CN, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NR x R y -C(O)NH2, -C(O) (4-6 membered heterocyclic alkyl groups), -C(O)NH(C 1-6 Alkyl), -C(O)NH(C 3-6 Cycloalkyl), -C(O)NH (4-6 membered heterocycloalkyl), C 6-10 Aryl and 5-10 heteroaryl groups; each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally substituted by one or more substituents independently selected from: deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl group, optionally selected independently from one or more of deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 3-6 Cycloalkyl, optionally selected independently from one or more of deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The 4-6 membered heterocyclic alkyl group substituted with a haloalkyl group, optionally with one or more groups independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 6-10 The aryl group is optionally selected independently from one or more deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 The 5-10 membered heteroaryl group substituted by the haloalkyl group is preferably a alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, each optionally being selected independently by one or more elements selected from deuterium, halogen, -CN, oxo, hydroxyl, C. 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NRx R y -SO2-C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-10 Substitution of aryl and 5-10 heteroaryl groups;

[0396] Furthermore, R 4 Selected from hydrogen, halogens, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NHR x C 6-10 Aryl and 5-6-membered heteroaryl; each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more substituents independently selected from: deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y Optionally selected by one or more independently chosen from deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 3-6 Cycloalkyl, optionally selected independently from one or more of deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The 4-6 membered heterocyclic alkyl group substituted with a haloalkyl group, optionally with one or more groups independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 6-10 The aryl group is optionally selected independently from one or more deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 5-10 membered heteroaryl groups substituted with haloalkyl groups;

[0397] Preferably, R 4 Selected from hydrogen, halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6Cycloalkyl, 4-14 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NHR x C 6-10 Aryl and 5-6-membered heteroaryl; each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-10 Substitution of aryl and 5-10 heteroaryl groups;

[0398] Furthermore, R 4 Selected from hydrogen, halogens, -CN, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group, wherein the alkyl, alkenyl, or alkynyl group is optionally substituted by one or more substituents independently selected from: deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y Optionally selected by one or more independently chosen from deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 3-6 Cycloalkyl, optionally selected independently from one or more of deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The 4-6 membered heterocyclic alkyl group substituted with a haloalkyl group, optionally with one or more groups independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 6-10 The aryl group is optionally selected independently from one or more deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 5-10 membered heteroaryl groups substituted with haloalkyl groups;

[0399] Preferably, R4 Selected from hydrogen, halogens, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group, wherein the alkyl, alkenyl, or alkynyl group is each optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-10 Substitution of aryl and 5-10 heteroaryl groups;

[0400] (12)R 3 With R 4 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, C6 aryl, or 5-6 heteroaryl groups, wherein each cycloalkyl, aryl, or heteroaryl group is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0401] (13)R 5 Selected from hydrogen, halogen, hydroxyl, oxo group, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -NH2, -NH(C 1-6 alkyl), -NH(C) 3-6 cycloalkyl), -NH (4-6 membered heterocycloalkyl), -NH (C 6-10 Aryl) and -NH (5-10 heteroaryl); the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is each optionally selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x Ry -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-10 Substitution of aryl and 5-10 heteroaryl groups;

[0402] Preferably, R 5 Selected from hydrogen, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -NH(C) 1-6 alkyl), -NH(C) 3-6 cycloalkyl), -NH (4-6 membered heterocycloalkyl), -NH (C 6-10 aryl) and -NH (5-10 heteroaryl);

[0403] (14)R 4 With R 5 Together with the atoms to which they are attached, they form 4-14 membered heterocyclic alkyl groups, wherein the heterocyclic alkyl group is optionally composed of one or more elements independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C. 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups;

[0404] (15)R 6 Selected from hydrogen, halogens, C 1-4 Alkyl, C 3-4 cycloalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Deuterated alkyl; preferably, R 6 Selected from hydrogen, halogens, C 1-4 Alkyl, C 3-4 cycloalkyl and C 1-4 Deuterated alkyl; more preferably, R 6 Selected from hydrogen, halogens, C 1-4 Alkyl, C 3-4 cycloalkyl and C 1-4 Halogenated alkyl; more preferably, R 6 Selected from hydrogen, fluorine, chlorine, and methyl;

[0405] (16)R 7 Selected from hydrogen, halogens, C 1-4 Alkyl and C 1-4 Halogenated alkyl; preferably, R 7 Selected from hydrogen and fluorine;

[0406] (17)R 8 Selected from hydrogen, halogens, C 1-4 Alkyl and C 1-4 Halogenated alkyl; preferably, R 8 Selected from hydrogen and fluorine;

[0407] (18)R 10 Selected from hydrogen, halogens, C 1-4 Alkyl, C 3-4 cycloalkyl and C 1-4 Halogenated alkyl; preferably, R 10 Selected from hydrogen, methyl, chlorine, fluorine, and difluoromethyl;

[0408] (19)R 9 With R 10 Together they form -CH=N-NH-;

[0409] (20)R 11 It is hydrogen.

[0410] Implementation Scheme 3. The compound according to Implementation Scheme 1 or 2, or a pharmaceutically acceptable form thereof, wherein formula (I) is further formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), formula (I-1'), formula (I'), formula (IA'), formula (I-1A), formula (I-1B), formula (I-1C), formula (I-1D), or formula (I-1E):

[0411] Implementation Scheme 4. A compound or a pharmaceutically acceptable form thereof, wherein the compound is selected from compounds 1 to 113;

[0412] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs.

[0413] Implementation Scheme 5. A pharmaceutical composition comprising any one of the compounds of embodiments 1 to 4 or a pharmaceutically acceptable form thereof, or a mixture thereof, and one or more pharmaceutically acceptable carriers.

[0414] Implementation Scheme 6. Use of the compound of any one of Implementation Schemes 1 to 4 or a pharmaceutically acceptable form thereof, or the pharmaceutical composition of Implementation Scheme 5, in the preparation of a PKMYT1 inhibitor.

[0415] Implementation Scheme 7. Use of the compound of any one of Implementation Schemes 1 to 4 or a pharmaceutically acceptable form thereof or the pharmaceutical composition of Implementation Scheme 5 in the preparation of a medicament, particularly in the preparation of a medicament for the prevention or treatment of diseases or symptoms associated with PKMYT1 activity;

[0416] Preferably, the disease or symptom associated with PKMYT1 activity is a tumor or cancer;

[0417] Preferably, the tumor or cancer is a tumor or cancer with high expression of the CCNE1 gene / CCNE1 gene expansion or with an FBXW7 gene inactivation mutation;

[0418] Preferably, the cancers with high CCNE1 gene expression / CCNE1 gene expansion are uterine cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, liver cancer, or endometrial cancer.

[0419] Implementation Scheme 8. A method for preparing the compound or a pharmaceutically acceptable form thereof according to any one of Implementation Schemes 1 to 4, wherein the compound is selected from the following methods:

[0420] Method 1 includes one or more steps from steps (1) to (5) of the following route:

[0421] The route is, for example, the following route:

[0422] in:

[0423] Step (1) involves reacting compound I-1 (e.g., compound IA-1) with compound IA-2 to obtain compound I-3 (e.g., compound IA-3);

[0424] Step (2) involves halogenating compound I-3 to obtain compound I-4 (e.g., compound IA-4);

[0425] Step (3) involves reacting compound I-4 with compound IA-5 to give compound I-6 (e.g., compound IA-6);

[0426] Step (4) involves coupling compound I-6 to obtain compound I-7 (e.g., compound IA-7);

[0427] Step (5) involves hydrolyzing compound I-7 to obtain compound I' (e.g., compound IA');

[0428] Method 2 includes the following steps:

[0429] Among them, compound I-3 is reacted with compound IA-5 to generate compound I-6;

[0430] Method 3 includes one or more steps from steps (1) to (2) of the following route:

[0431] The route is, for example, the following route:

[0432] in:

[0433] Step (1) hydrolyzes compound I-6 (e.g., compound IA-6) to obtain compound I-6-2 (e.g., compound IA-6-2);

[0434] Step (2) involves coupling compound I-6-2 to obtain compound I';

[0435] Method four includes one or more steps from steps (1) to (3) of the following route:

[0436] The route is, for example, the following route:

[0437] in:

[0438] Step (1) involves coupling compound I-6 with pinacol diboronic acid ester to generate compound I-6-1 (e.g., compound IA-6-1);

[0439] Step (2) involves coupling compound I-6-1 to obtain compound I-7;

[0440] Step (3) involves hydrolyzing compound I-7 to obtain compound I';

[0441] Method 5 includes one or more steps from steps (1) to (3) of the following route:

[0442] in:

[0443] Step (1) involves coupling compound I-4 with pinacol diboronic acid ester to generate compound I-4-1;

[0444] Step (2) involves coupling compound I-4-1 to obtain compound I-4-2;

[0445] Step (3) involves a substitution reaction between compound I-4 and compound IA-5 to yield compound I-7.

[0446] in,

[0447] X 1 It is a halogen, such as chlorine, bromine or iodine, preferably bromine;

[0448] X 2 It is a halogen, such as chlorine, bromine or iodine, preferably chlorine;

[0449] R 9 and R 10 As defined in any of Implementation Schemes 1-4, or R 9 For -OPG 2 , or R 9 With R 10 Co-formation -CR 11 =NN(PG) 1 )-,

[0450] PG 1 The protecting group is a hydrogen or amino group, such as an alkoxycarbonyl amino group, for example, benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), fluorenemethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl (or ethoxycarbonyl); acyl amino groups, such as phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), o-(p-)nitrobenzenesulfonyl (Ns), tert-pentanoyl, benzoyl, tert-butoxycarbonyl, 9-fluorenemethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, trimethylsilylethoxycarbonyl, benzyloxycarbonyl, p-methylbenzenesulfonyl, p-nitrobenzenesulfonyl, trifluoroacetyl, methoxycarbonyl, or ethoxycarbonyl; alkyl amino groups, such as triphenylmethyl (Trt), C 1-6 Alkyl-substituted triphenylmethyl, p-methoxytriphenylmethyl (MMT), dimethoxytriphenylmethyl (DMT), 2,4-dimethoxybenzyl (Dmb), 4-methoxybenzyl (PMB), benzyl (Bn); tetrahydropyranyl (THP); or (trimethylsilyl)ethoxymethyl (SEM); preferably, the amino protecting group is tetrahydropyranyl (THP) or (trimethylsilyl)ethoxymethyl (SEM);

[0451] The PG 2 The protecting group is a hydrogen or hydroxyl group, such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), (trimethylsilyl)ethoxymethyl (SEM), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl or p-nitrobenzoyl, preferably (trimethylsilyl)ethoxymethyl (SEM);

[0452] Y, Z, W, R 1 R 2 R 3 R4 R 6 R 7 R 8 R 11 As defined in any of Implementation Schemes 1 to 4;

[0453] Among them, in R 9 For -OPG 2 , or R 9 With R 10 Co-formation -CR 11 =NN(PG) 1 When )-, the method further includes a deprotection reaction step.

[0454] Implementation Scheme 9. Compounds or their salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, or isotope labels having the following structures:

[0455] Among them, Y, Z, W, R 1 R 2 R 3 R 4 R 6 R 7 R 8 R 9 R 10 X 1 X 2 As defined in Implementation Scheme 8.

[0456] Implementation Scheme 10. A method for preventing or treating a disease or symptom associated with PKMYT1 activity, the method comprising administering to an individual in need an effective amount of any one of Implementation Schemes 1 to 4 or a pharmaceutically acceptable form thereof, or a pharmaceutical composition as described in Implementation Scheme 5;

[0457] Preferably, the disease or symptom associated with PKMYT1 activity is a tumor or cancer;

[0458] Preferably, the tumor or cancer is a tumor or cancer with high expression of the CCNE1 gene / CCNE1 gene expansion or with an FBXW7 gene inactivation mutation;

[0459] Preferably, the cancers with high CCNE1 gene expression / CCNE1 gene expansion are uterine cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, liver cancer, or endometrial cancer.

[0460] Example

[0461] The following examples and test cases are provided to illustrate this disclosure in detail, but they do not limit the scope of this disclosure, and variations can be made without departing from the scope of this disclosure. Those skilled in the art will understand that the following examples are merely exemplary, and other compounds of this application can be synthesized similarly with reference to the following examples.

[0462] Nuclear magnetic resonance (NMR) measurements were performed using a Bruker NMR spectrometer, manufacturer: Bruker, model: AVANCE III HD-400.

[0463] Preparation method of high performance liquid chromatograph:

[0464] Instrument model: Agilent 1260; Column: Waters SunFire Prep C18 OBD (19mm×150mm×5.0μm); Column temperature: 25℃; Flow rate: 20.0mL / min; Detection wavelength: 214nm; Elution gradient: (0min: 10%A, 90%B; 16.0min: 90%A, 10%B); Mobile phase A: Acetonitrile; Mobile phase B: 0.05% formic acid aqueous solution or 0.05% ammonium bicarbonate aqueous solution.

[0465] Thin-layer chromatography purification was performed using GF 254 (0.4–0.5 nm) silica gel plates produced in Yantai.

[0466] The reaction was monitored using thin-layer chromatography (TLC) or liquid chromatography-mass spectrometry (SHIMADZU, LCMS-2020). The developing solvent systems used included, but were not limited to, dichloromethane and methanol systems, n-hexane and ethyl acetate systems, and petroleum ether and ethyl acetate systems. The volume ratio of the solvent was adjusted according to the polarity of the compound, or by adding triethylamine, etc.

[0467] Column chromatography typically uses 200-300 mesh silica gel from Qingdao Ocean as the stationary phase. Eluent systems include, but are not limited to, dichloromethane and methanol systems and n-hexane and ethyl acetate systems. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added for adjustment.

[0468] Unless otherwise specified in the examples, the reaction temperature is room temperature (15℃~30℃).

[0469] Unless otherwise specified, the reagents used in the examples were purchased from Acros Organics, Aldrich Chemical Company, Nanjing Yaoshi Technology, or Shanghai Shuya Pharmaceutical Technology, etc.

[0470] The abbreviations used in this article have the following meanings:

[0471] Compound Examples:

[0472] Intermediate Example 1: Preparation of 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-ol

[0473] Step 1: Preparation of 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0474] 4-Bromo-5-methyl-1H-indazole (31 g, 146.88 mmol) and p-toluenesulfonic acid (4.94 g, 28.39 mmol) were added to DCM (100 mL). 3,4-Dihydro-2H-pyran (36.23 g, 426.42 mmol) was slowly added dropwise at 0 °C, and the mixture was then heated to 25 °C and reacted for 0.5 hr. After the reaction was complete, water was added and stirred, followed by extraction with EA and concentration to give the title compound (42 g). MS (ESI, m / z): 295.1 [M+H] + .

[0475] Step 2: Preparation of 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-ol

[0476] 4-Bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (42 g, 142.29 mmol), Pd2(dba)3 (5.21 mg, 5.69 mmol), t-Bu-XPhos (4.83 g, 11.38 mmol), and KOH (15.97 g, 584.58 mmol) were dissolved in 1,4-dioxane (150 mL) and H2O (70 mL). The mixture was reacted at 100 °C for 16 h under nitrogen protection. After the reaction was complete, most of the 1,4-dioxane was removed by rotary evaporation. The aqueous layer was adjusted to pH 5 with formic acid, and after adding water, it was extracted with EA, concentrated, and the crude product was purified by reversed-phase HPLC to obtain the title compound (19 g). MS (ESI, m / z): 233.2 [M+H] + .

[0477] Intermediate Example 2: Preparation of 8-bromo-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-nitrile

[0478] Step 1: Preparation of 8-bromo-2-oxo-1,2-dihydroquinoline-3-onitrile

[0479] 2-Amino-3-bromobenzaldehyde (740 mg, 3.70 mmol), ethyl cyanoacetate (803.10 mg, 7.10 mmol), and NH4OAc (1.37 g, 17.77 mmol) were dissolved in 1,4-dioxane (15 mL), and the mixture was heated to 90 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was poured into water (50.0 mL) and extracted with ethyl acetate (30.0 mL * 3). The organic phase was collected and concentrated under reduced pressure to give the title compound (800 mg). MS (ESI, m / z): 249.0 [M + H] + .

[0480] Step 2: Preparation of 8-bromo-2-chloroquinoline-3-onitrile

[0481] 1.1 g (4.42 mmol) of 8-bromo-2-oxo-1,2-dihydroquinoline-3-onitrile was dissolved in 8 mL of POCl3, and the mixture was heated to 110 °C and stirred for 1 hour. After the reaction was complete, the reaction solution was slowly added to room temperature water to quench the reaction, and the pH was adjusted to neutral with NaHCO3. The mixture was then extracted with ethyl acetate (30.0 mL * 3), and the organic phase was collected and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 70:30, v / v) to obtain the title compound (900 mg). MS (ESI, m / z): 267 [M+H] + .

[0482] Step 3: Preparation of 8-bromo-2-(5-methyl-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-nitrile

[0483] 8-Bromo-2-chloroquinoline-3-onitrile (500 mg, 1.87 mmol), 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-ol (458.27 mg, 1.97 mmol), Cs₂CO₃ (876.57 mg, 2.70 mmol), and CuBr (25.73 mg, 179.36 μmol) were dissolved in NMP (10 mL), and the mixture was heated to 120 °C and stirred for 2 hours. The reaction mixture was poured into water (50.0 mL) and extracted with ethyl acetate (30.0 mL x 3). The organic phase was collected and concentrated under reduced pressure to give the title compound (800 mg). MS (ESI, m / z): 463.0 [M+H] + .

[0484] Intermediate Example 3: Preparation of 7-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-ol

[0485] Step 1: Preparation of 2-bromo-5,6-difluoro-3-methylbenzaldehyde

[0486] Under nitrogen protection, 1-bromo-4,5-difluoro-2-methylbenzene (5 g, 24.15 mmol) was added to dry THF (50 mL). A 2 M LDA THF solution (6.47 g, 60.38 mmol) was slowly added dropwise at -78 °C. After stirring for 30 min at this temperature, dry DMF (5.30 g, 72.46 mmol) was added dropwise, and the reaction was continued at this temperature for 2 h. After the reaction was complete, a saturated ammonium chloride aqueous solution was added to quench the reaction. The mixture was extracted with EA and concentrated to obtain a crude product. The crude product was purified by column chromatography (PE / EA = 75 / 25, v / v) to give the title compound (5.3 g).

[0487] Step 2: Preparation of 4-bromo-7-fluoro-5-methyl-1H-indazole

[0488] 2-Bromo-5,6-difluoro-3-methylbenzaldehyde (5.3 g, 22.55 mmol) and 80% hydrazine hydrate (7.06 g, 112.75 mmol) were dissolved in DMSO (20 mL) and reacted at 120 °C for 3 hours. After the reaction was complete, water was added, and the mixture was extracted with EA. The organic layer was washed twice with saturated brine and concentrated to give the title compound (5 g). MS (ESI, m / z): 229.0 [M+H] + .

[0489] Step 3: Preparation of 4-bromo-7-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0490] 4-Bromo-7-fluoro-5-methyl-1H-indazole (5 g, 21.83 mmol) and p-toluenesulfonic acid (758.52 mg, 4.36 mmol) were added to DCM (20 mL), and DHP (3.71 g, 43.66 mmol) was slowly added dropwise at 0 °C, with stirring for 30 min at this temperature. After the reaction was complete, the reaction solution was extracted with water and then concentrated to obtain the crude product. The crude product was purified by column chromatography (PE / EA = 90 / 10, v / v) to give the title compound (6.6 g), MS (ESI, m / z): 313.0 [M+H]. + .

[0491] Step 4: Preparation of 7-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indazole

[0492] 4-Bromo-7-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.2 g, 3.83 mmol), Pd(dppf)Cl2 (280.38 mg, 383.18 μmol), and KOAc (752.13 mg, 7.66 mmol) were dissolved in 1,4-dioxane (10 mL) and reacted at 100 °C for 16 h. After the reaction was complete, the reaction solution was concentrated, and the crude product was purified by column chromatography (PE / EA = 80 / 20, v / v) to give the title compound (1.2 g). MS (ESI, m / z): 361.2 [M+H] + .

[0493] Step 5: Preparation of 7-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-ol

[0494] 7-Fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indazole (1.2 g, 3.33 mmol) and K₂CO₃ (920.78 mg, 6.66 mmol) were dissolved in EtOH (8 mL), and 35% hydrogen peroxide solution (3.24 g, 33.31 mmol) was added dropwise at 0 °C for 1 hour. After the reaction was complete, the reaction solution was filtered, and the filtrate was directly purified by reverse-phase HPLC (ACN / H₂O = 60 / 40, v / v) to give the title compound (400 mg). MS (ESI, m / z): 251.2 [M+H] + .

[0495] Intermediate Example 4: Preparation of 5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine-4-ol

[0496] Step 1: Preparation of 4-bromo-5-methyl-1H-pyrazolo[3,4-c]pyridine

[0497] 3.1 g (15.42 mmol) of 5-bromo-4,6-dimethylpyridin-3-amine was added to 10 mL of acetic acid. Sodium nitrite (2.13 g, 30.84 mmol) was added at 25 °C, and the reaction was continued at 60 °C for 3 hours. After the reaction was complete, the reaction mixture was evaporated to dryness, reconstituted with methanol, and adjusted to alkalinity with triethylamine. The mixture was stirred with silica gel, and the crude product was purified by column chromatography (DCM / MeOH = 90 / 10, v / v) to give the title compound (2 g). MS (ESI, m / z): 211.9 [M+H] + .

[0498] Step 2: Preparation of 4-bromo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine

[0499] 4-Bromo-5-methyl-1H-pyrazolo[3,4-c]pyridine (800 mg, 3.77 mmol) was dissolved in dry THF (10 mL). NaH (452.73 mg, 11.32 mmol) was added under ice bath conditions. After stirring for 20 min, SEMCl (1.89 g, 11.32 mmol) was added in portions, and the reaction was carried out at 60 °C for 3 h. After the reaction was complete, the reaction was quenched with methanol, and the sample was mixed with silica gel. The crude product was purified by column chromatography (DCM / MeOH = 95 / 5, v / v) to give the title compound (800 mg). MS (ESI, m / z): 342.0 [M+H] + .

[0500] Step 3: Preparation of 5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine-4-ol

[0501] 4-Bromo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (800 mg, 2.34 mmol), Pd2(dba)3 (107.01 mg, 116.85 μmol), t-BuXPhos (99.24 mg, 233.71 μmol), and powdered NaOH (934.84 mg, 23.37 mmol) were added to 1,4-dioxane (10 mL), and the mixture was reacted at 120 °C for 5 h under nitrogen protection. After the reaction was complete, the mixture was evaporated to dryness, reconstituted with methanol, filtered through diatomaceous earth, and the filtrate was purified by reversed-phase HPLC and lyophilized to give the title compound (160 mg). MS (ESI, m / z): 280.1 [M+H] + .

[0502] Intermediate Example 5: Preparation of 6-bromo-N-methylpyrazine-2-amine

[0503] 2,6-Dibromopyrazine (1 g, 4.20 mmol) was added to a sealed container, followed by 10 mL of 30% methylamine methanol solution. The reaction was carried out at 100 °C for 16 h. After the reaction was complete, the solution was directly concentrated to obtain the title compound (790 mg). The crude product was used directly in the next step without purification. MS (ESI, m / z): 187.9, 189.9 [M+H] + .

[0504] Intermediate Example 6: Preparation of 5-(methyl-d3)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-ol

[0505] Step 1: Synthesis of 5-bromo-4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0506] 5-Bromo-4-chloro-1H-indazole (2 g, 8.64 mmol) was dissolved in DCM (30 mL), and p-toluenesulfonic acid (297.57 mg, 1.73 mmol) and DHP (799.65 mg, 21.60 mmol) were added sequentially. The reaction mixture was incubated at 20 °C for 16 h. After the reaction was complete, a saturated NaHCO3 aqueous solution was slowly added. The layers were separated; the organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE:EA = 85:15, v / v) to obtain the target compound (2.26 g). MS (ESI, m / z): 315.0 [M+H] + .

[0507] Step 2: Synthesis of 4-chloro-5-(methyl-d3)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0508] ZnCl2 (0.5M, 32.51mL) was placed in a two-necked flask, and deuterated methyl magnesium iodide (1M, 32.51mL) was slowly added dropwise. After the addition was complete, the reaction system was reacted at 20℃ for 40 min, and the supernatant was used for the next step. 5-bromo-4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.71g, 5.42mmol), tri-tert-butylphosphine tetrafluoroborate (314.40mg, 1.08mmol), and Pd2(dba)3 (496.17mg, 541.84μmol) were placed in a three-necked flask. Under N2 protection, the supernatant was slowly added, and after the addition was complete, the temperature was raised to 70℃ and the reaction was carried out for 3 hours. After the reaction was complete, the mixture was cooled to room temperature and diluted with saturated NH4Cl aqueous solution (100 mL) and EtOAc (150 mL). The mixture was filtered, separated into layers, extracted with EA, and the organic layer was dried and concentrated. The resulting product was purified by silica gel column chromatography (PE:EA = 88:12, v / v) to give the title compound (1.3 g). MS (ESI, m / z): 254.1 [M+H] + .

[0509] Step 3: Synthesis of 5-(methyl-d3)-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indazole

[0510] 4-Chloro-5-(methyl-d3)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (880 mg, 3.47 mmol), pinacol diboronate (1.06 g, 4.16 mmol), X-Phos (165.33 mg, 346.81 μmol), and potassium isooctanoate (1.59 g, 8.67 mmol) were dissolved in isopropyl acetate (20 mL). Under N2 protection, the mixture was heated to 50 °C and reacted for 5 min. XPhos Pd(allyl)Cl (228.08 mg, 346.81 μmol) was added, and the reaction was continued at 50 °C for 18 h. After the reaction was complete, the mixture was diluted with 100 mL of EtOAc and 50 mL of water. The aqueous layer was separated, the organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 72:28, v / v) to give the title compound (1 g). MS (ESI, m / z): 346.1 [M+H] + .

[0511] Step 4: Synthesis of 5-(methyl-d3)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-ol

[0512] 5-(methyl-d3)-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indazole (1 g, 2.90 mmol) was dissolved in EtOH (5 mL), and K2CO3 (400.30 mg, 2.90 mmol) and H2O2 (2.81 g, 28.96 mmol, 3 mL, 35% purity) were added. The reaction was carried out at 25 °C for 2 hours. After the reaction was complete, the mixture was filtered, purified by reversed-phase column chromatography (H2O (0.05% ammonium bicarbonate): MeCN = 58:42, v / v), and then lyophilized to give the title compound (480 mg). MS (ESI, m / z): 236.2 [M+H] + .

[0513] Intermediate Example 7: Preparation of 3-bromo-2-chloro-5-iodopyrazine

[0514] 3-Bromo-5-iodopyrazin-2-amine (1 g, 3.33 mmol) and cuprous chloride (660.23 mg, 6.67 mmol) were added to ACN (10 mL), and tert-butyl nitrite (687.70 mg, 6.67 mmol) was added dropwise at room temperature. After the addition was complete, the reaction mixture was reacted at 80 °C for 16 hours. After the reaction was complete, the mixture was concentrated and purified by silica gel chromatography (PE / EA = 90 / 10, v / v) to obtain the title compound (270 mg).

[0515] Intermediate Example 8: Preparation of (2-((5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-3-cyanoquinoline-8-yl)boronic acid)

[0516] Step 1: Preparation of 4-bromo-5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0517] 4-Bromo-5-chloro-1H-indazole (50.0 g, 216.0 mmol) was dissolved in DMF (400 mL). After purging with nitrogen three times, TsOH (9.30 g, 54.0 mmol) and 3,4-dihydro-2H-pyran (55.98 g, 1.51 mol) were added at 25 °C. After the addition was complete, nitrogen was purged once, and the mixture was stirred for 5 min. The temperature was then raised to 90 °C and reacted for 16 h. After the reaction was complete, a saturated sodium bicarbonate solution and ethyl acetate were added. The mixture was extracted twice, and the organic phases were combined, washed twice with brine, concentrated, and then subjected to silica gel column chromatography (PE:EA = 86:14, v / v) to give the title compound (47.0 g). MS (ESI, m / z): 317.0 [M+H] + .

[0518] Step 2: Preparation of 5-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indazole

[0519] 4-Bromo-5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (20.0 g, 63.37 mmol), pinacol diboronate (32.19 g, 126.75 mmol), potassium acetate (18.66 g, 190.12 mmol), Pd(dppf)Cl2 (2.32 g, 3.17 mmol), and 1,4-dioxane (300 mL) were sequentially added to a 500 mL reaction flask. After purging with nitrogen, the mixture was heated to 100 °C and stirred for 4 hours. After the reaction was complete, the mixture was concentrated and directly mixed with silica gel column chromatography (PE:EA = 4:1, v / v) to give the title compound (15.10 g). MS (ESI, m / z): 362.2 [M+H] +

[0520] Step 3: Preparation of 5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-ol

[0521] 5-Chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)-1H-indazole (5.46 g, 15.06 mmol) was dissolved in EtOH (60 mL) and DMSO (5 mL), followed by the addition of potassium carbonate (2.08 g, 15.06 mmol). After the addition was complete, the mixture was cooled to 0 °C, and 35% H₂O₂ (14.63 g, 150.60 mmol) was added dropwise. After the addition was complete, the mixture was slowly warmed to 10–20 °C and stirred for 2 hours. After the reaction was complete, water and ethyl acetate were added, and the mixture was extracted twice. The organic phases were combined, washed twice with brine, and tested with potassium iodide reagent to find no H₂O₂ residue. The mixture was concentrated and then subjected to silica gel column chromatography (PE:EA = 6:4, v / v) to give the title compound (2.60 g). MS(ESI,m / z):253.0[M+H] + .

[0522] Step 4: Preparation of 8-bromo-2-((5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-nitrile

[0523] 5-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-ol (8.75 g, 34.63 mmol) and 8-bromo-2-chloroquinoline-3-onitrile (9.26 g, 34.63 mmol) were dissolved in NMP (100 mL), and cuprous iodide (993.44 mg, 6.93 mmol) and cesium carbonate (16.92 g, 51.94 mmol) were added. The mixture was stirred at 60 °C for 6 hours. After the reaction was completed, the mixture was filtered through diatomaceous earth, and water and ethyl acetate were added. The mixture was extracted twice, and the organic phases were combined, washed twice with brine, concentrated, and then subjected to silica gel column chromatography (PE:EA = 55:45, v / v) to give the title compound (12.38 g). MS (ESI, m / z): 483.0 [M+H] + .

[0524] Step 5: Preparation of (2-((5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-3-cyanoquinoline-8-yl)boronic acid

[0525] 8-Bromo-2-((5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-onitrile (7.2 g, 14.88 mmol), pinacol diboronate (6.61 g, 26.05 mmol), potassium acetate (18.66 g, 44.65 mmol), Pd(dppf)Cl2 (544.53 mg, 0.74 mmol), and 1,4-dioxane (150 mL) were sequentially added to a 500 mL reaction flask. After purging with nitrogen, the mixture was heated to 100 °C and stirred for 4 hours. After the reaction was complete, the temperature was lowered to 15 °C, filtered through a diatomaceous earth liner, and the filter cake was washed with EA. The mother liquor was concentrated to obtain the title compound (16.0 g). MS (ESI, m / z): 449.2 [M+H] +

[0526] Example 1: 8-Methyl-2-((5-methyl-1H-indazol-4-yl)oxy)quinoline-3-carboxamide (Compound 1)

[0527] Step 1: Preparation of 8-methyl-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-nitrile

[0528] 8-Bromo-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-onitrile (40 mg, 86.33 μmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxaborane (11.82 mg, 94.16 μmol), Pd(dppf)Cl2 (5.74 mg, 7.84 μmol), and K2CO3 (21.69 mg, 156.69 μmol) were dissolved in 1,4-dioxane (4 mL) and H2O (1 mL). The mixture was heated to 100 °C and stirred for 3 hours under N2 protection. After the reaction was complete, the reaction solution was poured into water (50.0 mL) and extracted with ethyl acetate (30.0 mL * 3). The organic phase was collected and concentrated under reduced pressure to give the title compound (30 mg). MS(ESI, m / z): 399.2 [M+H] + .

[0529] Step 2: Preparation of 8-methyl-2-((5-methyl-1H-indazol-4-yl)oxy)quinoline-3-carboxamide

[0530] 31.67 mg (79.48 μmol) of 8-methyl-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-onitrile was dissolved in H₂SO₄ and the mixture was heated to 60 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was slowly added to water, and the pH was adjusted to weakly basic with NaHCO₃. The solution was then extracted with ethyl acetate (30.0 mL * 3), and the organic phase was collected. After purification by prep-HPLC, the solution was lyophilized to give the title compound (10 mg). MS (ESI, m / z): 333.1 [M + H] + .

[0531] 1 H NMR (400MHz, DMSO-d6) δ13.08(s,1H),8.76(s,1H),8.08(s,1H),7.89(d,J=8.4Hz,2H),7.75(s, 1H),7.51(d,J=6.8Hz,1H),7.41-7.38(m,2H),7.33(d,J=8.4Hz,1H),2.24(s,3H),2.04(s,3H).

[0532] Example 2: 8-Cyano-2-((5-methyl-1H-indazol-4-yl)oxy)quinoline-3-carboxamide (Compound 2)

[0533] Step 1: Preparation of 8-bromo-2-((5-methyl-1H-indazol-4-yl)oxy)quinoline-3-carboxamide

[0534] 200 mg (431.66 μmol) of 8-bromo-2-(5-methyl-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-onitrile was dissolved in 5 mL of H₂SO₄ and the mixture was heated to 60 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was slowly added to water, and the pH was adjusted to weakly basic with NaHCO₃. The solution was then extracted with ethyl acetate (30.0 mL x 3), and the organic phase was collected. The solution was purified by column chromatography (PE:EA = 70:30, v / v) to give the title compound (120 mg). MS (ESI, m / z): 397.1 [M+H] + .

[0535] Step 2: Preparation of 8-cyano-2-((5-methyl-1H-indazol-4-yl)oxy)quinoline-3-carboxamide

[0536] 8-Bromo-2-((5-methyl-1H-indazol-4-yl)oxy)quinoline-3-carboxamide (30 mg, 75.52 μmol), Zn(CN)₂ (14.19 mg, 122.04 μmol), and XPos Pd G₃ (5.11 mg, 6.11 μmol) were dissolved in DMF (6 mL), and the mixture was heated to 110 °C and stirred overnight under N₂ protection. After the reaction was complete, the mixture was extracted with ethyl acetate (30.0 mL * 3), and the organic phase was collected, purified by prep-HPLC, and lyophilized to give the title compound (20 mg). MS (ESI, m / z): 344.1 [M+H] + .

[0537] 1 H NMR (400MHz, DMSO-d6) δ13.11(s,1H),8.88(s,1H),8.40(dd,J=8.0,1.2Hz,1H),8.21(dd,J=7.2,1.6Hz,1H),8.17(s, 1H),7.98(s,1H),7.79(s,1H),7.64(dd,J=8.0,7.2Hz,1H),7.41(d,J=8.4Hz,1H),7.33(d,J=8.4Hz,1H),2.25(s,3H).

[0538] Example 3: 2-((5-methyl-1H-indazol-4-yl)oxy)-8-(1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)quinoline-3-carboxamide (Compound 3)

[0539] Step 1: Preparation of (3-cyano-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-8-yl)boronic acid

[0540] 8-Bromo-2-(5-methyl-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-onitrile (200 mg, 431.66 μmol), pinacol diboronate (132.87 mg, 523.23 μmol), Pd(dppf)Cl2 (25.52 mg, 34.88 μmol), and AcOK (102.70 mg, 1.05 mmol) were dissolved in 1,4-dioxane (10 mL). The mixture was heated to 100 °C and stirred for 2 hours under N2 protection. After the reaction was completed, the reaction solution was poured into water (50.0 mL) and extracted with ethyl acetate (30.0 mL * 3). The organic phase was collected, concentrated under reduced pressure to obtain the crude product, and purified by silica gel column chromatography (DCM:MeOH = 90:10, v / v) to obtain the title compound (120 mg). MS(ESI, m / z): 429.2 [M+H] + .

[0541] Step 2: Preparation of 2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)quinoline-3-nitrile)

[0542] (3-cyano-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-8-yl)boronic acid (40 mg, 93.40 μmol), 6-chloro-3-methylpyrimidin-4(3H)-one (25.91 mg, 179.23 μmol), cataCXium A Pd G3 (13.05 mg, 17.92 μmol), and K3PO4 (57.08 mg, 268.90 μmol) were dissolved in 1,4-dioxane (6 mL) and H2O (2 mL). The mixture was heated to 120 °C and stirred for 3 hours under N2 protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and silica gel powder was added. The mixture was then purified by silica gel column chromatography (DCM:MeOH = 93:7, v / v) to obtain the title compound (40 mg). MS(ESI, m / z): 493.2 [M+H] + .

[0543] Step 3: Preparation of 2-((5-methyl-1H-indazol-4-yl)oxy)-8-(1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)quinoline-3-carboxamide

[0544] 2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)quinoline-3-onitrile (40 mg, 81.21 μmol) was dissolved in H₂SO₄ and the mixture was heated to 60 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was slowly added to water, and the pH was adjusted to weakly basic with NaHCO₃. The solution was then extracted with ethyl acetate (30.0 mL * 3), and the organic phase was collected. After purification by prep-HPLC, the solution was lyophilized to give the title compound (2 mg). MS (ESI, m / z): 427.1 [M+H] + .

[0545] 1 H NMR (400MHz, DMSO-d6) δ13.05(s,1H),8.87(s,1H),8.41(d,J=7.2Hz,1H),8.31(s,1H),8.19(d,J=7.6Hz,1H),8.11(s,1H),7.95 (s,1H),7.71(s,1H),7.62(t,J=7.6Hz,1H),7.36(d,J=8.4Hz,1H),7.28(d,J=8.4Hz,1H),6.62(s,1H),3.30(s,3H),2.24(s,3H).

[0546] The following compounds were prepared by referring to the method and general steps described in Example 3. Other required raw materials can be purchased commercially or obtained by experienced synthesizers from commercially available reagents using conventional reactions.

[0547] Example 6: 2-(3-hydroxy-2,6-dimethylphenoxy)-12H-pyrido[2',3':2,3][1,4]oxaza[5,6,7-de]quinoline-1-carboxamide (Compound 6)

[0548] Step 1: Preparation of 5-methoxy-2H-benzo[d][1,3]oxazine-2,4(1H)-dione

[0549] 2-Amino-6-methoxybenzoic acid (90.0 g, 538 mmol) and pyridine (106 g, 1.35 mol) were dissolved in MeCN (1.00 L). Then, bis(trichloromethyl) carbonate (65.9 g, 222 mmol) was slowly added dropwise under a nitrogen atmosphere, controlling the temperature to not exceed 10 °C. After the addition was complete, the temperature was raised to 25 °C and the reaction continued for 2 hours. LC-MS analysis confirmed the reaction was complete. The reaction was quenched by adding H₂O (1.50 L) in an ice bath, and the mixture was stirred continuously for 1 hour. The mixture was then filtered, and the filter cake was dried to give the title compound (62.0 g). MS (ESI, m / z): 194.0 [M+H] + .

[0550] 1 H NMR (400MHz, DMSO-d6) δ11.57(s,1H),7.63(t,J=8.0Hz,1H),6.82(d,J=8.4Hz,1H),6.68(d,J=8.0Hz,1H),3.87(s,3H).

[0551] Step 2: Preparation of 5-hydroxy-2H-benzo[d][1,3]oxazine-2,4(1H)-dione

[0552] 5-Methoxy-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (58.0 g, 300 mmol) was dissolved in CH2Cl2 (650 mL), purged with nitrogen, and then AlCl3 (160 g, 1.20 mol) was slowly added under ice bath conditions. The mixture was then heated to room temperature and stirred for 6 hours. After the reaction was complete as detected by LCMS, saturated brine (1.50 L) was slowly added dropwise under ice bath conditions to quench the reaction. The mixture was then stirred for 1 hour, filtered, and the filter cake was dried to give the title compound (71.6 g). MS (ESI, m / z): 178.0 [MH] + .

[0553] Step 3: Preparation of methyl 2-amino-6-hydroxybenzoate

[0554] The compound 5-hydroxy-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (66.5 g, 371 mmol) was dissolved in MeOH (500 mL), purged with nitrogen, and then heated to 70 °C and stirred for 3 hours. The reaction was confirmed by LC-MS. After direct concentration, the mixture was extracted with H₂O (500 mL) and CH₂Cl₂ (500 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (40.0 g). MS (ESI, m / z): 166.1 [MH] + .

[0555] 1H NMR (400MHz, DMSO-d6) δ 10.89 (s, 1H), 7.05 (t, J = 8.0 Hz, 1H), 6.22 (dd, J = 8.4, 0.8 Hz, 1H), 6.00 (dd, J = 8.0, 0.8 Hz, 1H), 3.88 (s, 3H).

[0556] Step 4: Preparation of methyl 2-amino-6-((3-nitropyridin-2-yl)oxy)benzoate

[0557] 2-Amino-6-hydroxybenzoate (20.0 g, 120 mmol), 2-fluoro-3-nitropyridine (42.5 g, 299 mmol), and K₂CO₃ (49.6 g, 359 mmol) were dissolved in DMF (200 mL), purged with nitrogen, and reacted at 25 °C for 2 hours. The reaction was detected by LCMS and TLC (PE / DCM = 1 / 1, Rf = 0.2). The reaction was quenched with H₂O (600 mL), extracted with EtOAc (600 mL), and the organic phases were combined, washed with saturated brine (600 mL), dried over anhydrous sodium sulfate, concentrated by filtration, and purified by silica gel column chromatography (PE / DCM = 100 / 0 to 30 / 70, v / v). The concentrated solution yielded the title compound (29.1 g). MS (ESI, m / z): 290.0 [M+H] + .

[0558] 1 H NMR (400MHz, DMSO-d6) δ8.54(dd,J=8.0,1.6Hz,1H),8.35(dd,J=4.8,1.6Hz,1H),7.31(dd,J=7.6,4.8Hz,1H ), 7.26 (t, J = 8.4Hz, 1H), 6.72 (dd, J = 8.4, 0.8Hz, 1H), 6.47 (s, 2H), 6.40 (dd, J = 8.0, 0.8Hz, 1H), 3.40 (s, 3H).

[0559] Step 5: Preparation of methyl 2-(3-methoxy-3-oxopropamido)-6-((3-nitropyridin-2-yl)oxy)benzoate

[0560] Methyl 2-amino-6-((3-nitropyridin-2-yl)oxy)benzoate (29.0 g, 100 mmol) was dissolved in CH₂Cl₂ (200 mL). Then, TEA (30.4 g, 301 mmol) and methyl 3-chloro-3-oxopropionate (20.5 g, 150 mmol) were added at 0 °C, and the reaction was heated to 25 °C for 2 hours. The reaction was confirmed to be complete by LC-MS. Direct concentration yielded the title compound (40.0 g), MS (ESI, m / z): 390.0 [M+H]. + .

[0561] Step 6: Preparation of methyl 2,4-dihydroxy-5-((3-nitropyridin-2-yl)oxy)quinoline-3-carboxylate

[0562] 40.0 g (103 mmol) of methyl 2-(3-methoxy-3-oxopropamido)-6-((3-nitropyridin-2-yl)oxy)benzoate and 16.7 g (308 mmol) of NaOMe were dissolved in 300 mL of MeOH. After purging with nitrogen, the mixture was heated to 80 °C and stirred for 16 hours. The reaction was confirmed by LCMS. The filter cake was collected, dried, and the title compound (35.4 g) was obtained. MS (ESI, m / z): 358.0 [M+H] + .

[0563] 1 H NMR (400MHz, DMSO-d6) δ9.94(s,1H),8.48(dd,J=8.0,2.0Hz,1H),8.21(dd,J=4.8,1.6Hz,1H),7.29(t,J=8. 0Hz, 1H), 7.18 (dd, J=8.0, 4.8Hz, 1H), 7.00 (dd, J=8.0, 0.8Hz, 1H), 6.62 (dd, J=7.6, 0.8Hz, 1H), 3.45 (s, 3H).

[0564] Step 7: Preparation of methyl 2,4-dichloro-5-((3-nitropyridin-2-yl)oxy)quinoline-3-carboxylate

[0565] 15.0 g (42.0 mmol) of methyl 2,4-dihydroxy-5-((3-nitropyridin-2-yl)oxy)quinoline-3-carboxylate was dissolved in DCE (300 mL). POCl3 (25.8 g, 168 mmol) and DMF (3.07 g, 42.0 mmol) were added under a nitrogen atmosphere, and the reaction was heated to 70 °C and stirred for 10 hours. The reaction was confirmed by LC-MS. After cooling to room temperature, the reaction was quenched by slow dropwise addition of NaHCO3 (600 mL). The pH was adjusted to approximately 8 with potassium carbonate, followed by extraction with CH2Cl2 (600 mL). The organic phases were combined, washed with saturated brine (600 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (17.2 g). MS (ESI, m / z): 393.9 [M+H] + .

[0566] Step 8: Preparation of methyl 4-chloro-2-(2,6-dimethyl-3-((2-(trimethylsilyl)ethoxy)methoxy)phenoxy)-5-((3-nitropyridin-2-yl)oxy)quinoline-3-carboxylic acid

[0567] Methyl 2,4-dichloro-5-((3-nitropyridin-2-yl)oxy)quinoline-3-carboxylate (7.50 g, 19.0 mmol) and 2,6-dimethyl-3-((2-(trimethylsilyl)ethoxy)methoxy)phenol (5.11 g, 19.0 mmol) were dissolved in MeCN (80.0 mL), and then Cs₂CO₃ (15.5 g, 47.6 mmol) was added. The reaction was heated to 60 °C and stirred for 4 hours. The reaction was detected by LCMS and TLC (PE / EA = 3 / 1, Rf = 0.6) to indicate its completion. After cooling to room temperature, the compound was extracted with H₂O (200 mL) and EtOAc (300 mL). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE / EA = 100 / 0 to 92 / 8, v / v). The final concentration yielded the title compound (1.05 g). MS (ESI, m / z): 626.3 [M+H] + .

[0568] 1H NMR(400MHz,DMSO-d6)δ8.66(dd,J=8.0,1.6Hz,1H),8.37(dd,J=4.8,1.6Hz,1H),7 .78-7.85(m,1H),7.62(d,J=8.4Hz,1H),7.47(d,J=8.0Hz,1H),7.41(dd,J=8.0,4.8 Hz,1H),7.12(d,J=8.4Hz,1H),6.98(d,J=8.4Hz,1H),5.27(s,2H),3.95(s,3H),3. 73(t,J=8.0Hz,2H),2.00(s,3H),1.94(s,3H),0.90(t,J=8.0Hz,2H),-0.02(s,9H).

[0569] Step 9: Preparation of methyl 5-((3-aminopyridin-2-yl)oxy)-4-chloro-2-(2,6-dimethyl-3-((2-(trimethylsilyl)ethoxy)methoxy)phenoxy)quinoline-3-carboxylic acid

[0570] 4-Chloro-2-(2,6-dimethyl-3-((2-(trimethylsilyl)ethoxy)methoxy)phenoxy)-5-((3-nitropyridin-2-yl)oxy)quinoline-3-carboxylate (800 mg, 1.28 mmol) was dissolved in THF (15 mL), and then SnCl2·2H2O (721 mg, 3.19 mmol) was added. The reaction was heated to 55 °C and stirred for 3 hours. The reaction was detected by LCMS and TLC (PE / EA = 3 / 1, Rf = 0.4). The mixture was then extracted with H2O (40 mL) and EtOAc (40 mL). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE / EA = 100 / 0 to 80 / 20, v / v). The concentration yielded the title compound (360 mg). MS(ESI, m / z): 596.3 [M+H] + .

[0571] Step 10: Preparation of methyl 2-(2,6-dimethyl-3-((2-(trimethylsilyl)ethoxy)methoxy)phenoxy)-12H-pyrido[2',3':2,3][1,4]oxaza[5,6,7-de]quinoline-1-carboxylate

[0572] Methyl 5-((3-aminopyridin-2-yl)oxy)-4-chloro-2-(2,6-dimethyl-3-((2-(trimethylsilyl)ethoxy)methoxy)phenoxy)quinoline-3-carboxylate (450 mg, 755 μmol), Cs₂CO₃ (738 mg, 2.26 mmol), and CataCXiumA Pd G₃ (110 mg, 151 μmol) were dissolved in 1,4-dioxane (10 mL), and the mixture was heated to 100 °C for 2 hours after purging with nitrogen. LCMS and TLC (PE / EA = 3 / 1, R f =0.4) The reaction was detected as complete, and the mixture was directly concentrated and purified by silica gel column chromatography (PE / EA = 100 / 0 to 80 / 20, v / v). After concentration, the title compound (201 mg) was obtained. MS (ESI, m / z): 560.4 [M+H] + .

[0573] 1 H NMR(400MHz, DMSO-d6)δ9.79(s,1H),8.09(dd,J=4.8,1.2Hz,1H),7.78(dd,J=8 .0,1.6Hz,1H),7.60(t,J=8.0Hz,1H),7.35(dd,J=8.0,4.8Hz,1H),7.25(dd,J= 16.8,7.6Hz,2H),7.06(d,J=8.4Hz,1H),6.92(d,J=8.4Hz,1H),5.25(s,2H),4. 01(s,3H),3.72(t,J=8.0Hz,2H),1.98(s,6H),0.88-0.92(m,2H),-0.02(s,9H).

[0574] Step 11: Preparation of 2-(2,6-dimethyl-3-((2-(trimethylsilyl)ethoxy)methoxy)phenoxy)-N-(2,4-dimethoxybenzyl)-12H-pyrido[2',3':2,3][1,4]oxaza[5,6,7-de]quinoline-1-carboxamide

[0575] The compound methyl 2-(2,6-dimethyl-3-((2-(trimethylsilyl)ethoxy)methoxy)phenoxy)-12H-pyrido[2',3':2,3][1,4]oxaza[5,6,7-de]quinoline-1-carboxylic acid ester (200 mg, 357 μmol), DMBNH2 (597 mg, 3.57 mmol), and TBD (249 mg, 1.79 mmol) were dissolved in 1,4-dioxane (7.5 mL), and the mixture was heated to 80 °C for 2 hours after purging with nitrogen. The reaction was monitored by LC-MS until completion. After cooling to room temperature, the mixture was extracted with H2O (60 mL) and EtOAc (60 mL). The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (250 mg, crude). MS (ESI, m / z): 695.4 [M+H] + .

[0576] Step 12: Preparation of 2-(3-hydroxy-2,6-dimethylphenoxy)-12H-pyrido[2',3':2,3][1,4]oxaza[5,6,7-de]quinoline-1-carboxamide

[0577] Compound 2-(2,6-dimethyl-3-((2-(trimethylsilyl)ethoxy)methoxy)phenoxy)-N-(2,4-dimethylbenzyl)-12H-pyrido[2',3':2,3][1,4]oxaza[5,6,7-de]quinoline-1-carboxamide (250 mg, 360 μmol) was dissolved in TFA (10 mL), purged with nitrogen three times, and heated to 80 °C with stirring for 3 hours. LCMS and TLC (DCM / MeOH = 20 / 1, v / v, R) f =0.4) The reaction was detected as complete. H2O (100 mL) was added in an ice bath to quench the reaction. The pH was then adjusted to 8 with NaHCO3, followed by extraction with EtOAc (60 mL). The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (DCM / MeOH = 100 / 0 to 98 / 2, v / v). The concentration yielded the title compound (43.83 mg). MS (ESI, m / z): 415.2 [M+H] + .

[0578] 1H NMR(400MHz,DMSO-d6)δ12.29(s,1H),9.30(s,1H),8.19(s,1H),8.10(s,1H ),8.06(dd,J=4.8,1.6Hz,1H),7.69(dd,J=8.0,1.6Hz,1H),7.58(t,J=8.0Hz ,1H),7.32(dd,J=8.0,4.8Hz,1H),7.24(d,J=6.8Hz,1H),7.20(d,J=8.0Hz, 1H), 6.91 (d, J = 8.0Hz, 1H), 6.67 (d, J = 8.0Hz, 1H), 1.96 (s, 3H), 1.89 (s, 3H).

[0579] Example 7: 2-((5-methyl-1H-indazol-4-yl)oxy)-8-(1-methyl-1H-pyrazol-4-yl)-1,7-naphthidine-3-carboxamide (Compound 28)

[0580] Step 1: Preparation of 8-chloro-2-oxo-1,2-dihydro-1,7-naphthidine-3-onitrile

[0581] 3-Amino-2-chloroisononaldehyde (366 mg, 2.34 mmol), ammonium acetate (540.57 mg, 7.01 mmol), 1,4-dioxane (10 mL), and ethyl 2-cyanoacetate (396.63 mg, 3.51 mmol) were added to a flask and reacted at 90 °C for 2 hours. A yellow product precipitated, which was stirred with a small amount of EA, and filtered to obtain the title compound (360 mg). MS (ESI, m / z): 206.1, 208.1 [M+H] + .

[0582] Step 2: Preparation of 8-chloro-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-1,7-naphthidium-3-nitrile

[0583] 8-Chloro-2-oxo-1,2-dihydro-1,7-naphthidium-3-onitrile (310 mg, 1.51 mmol), 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-ol (420.27 mg, 1.81 mmol), DMF (10 mL), and DBU (459.08 mg, 3.02 mmol) were added to the reaction flask. After stirring and dissolving, PyBOP (1.18 g, 2.26 mmol) was added. The reaction was carried out under nitrogen protection at 45 °C for 2 hours. The reaction solution was diluted with water, extracted with EA, washed with organic phase brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (PE / EA = 67 / 33, v / v) to give the title compound (487 mg). MS (ESI, m / z): 420.1, 422.1 [M+H] + .

[0584] Step 3: Preparation of 2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(1-methyl-1H-pyrazol-4-yl)-1,7-naphthidine-3-nitrile)

[0585] 8-chloro-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-1,7-naphthidium-3-onitrile (100 mg, 238.17 μmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-pyrazole (74.33 mg, 357.26 μmol), cataCXium A Pd G3 (17.35 mg, 23.82 μmol), K3PO4 (101.11 mg, 476.35 μmol), 1,4-dioxane (4 mL), and water (0.4 mL) were added to the reaction flask. After nitrogen protection, the reaction was carried out at 100 °C for 2 hours. The reaction solution was first concentrated, and the crude product was purified by column chromatography (DCM / MeOH = 95 / 5, v / v) to obtain the title compound (87 mg). MS (ESI, m / z): 466.2 [M+H] + .

[0586] Step 4: Preparation of 2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(1-methyl-1H-pyrazol-4-yl)-1,7-naphthidine-3-carboxamide)

[0587] 2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(1-methyl-1H-pyrazol-4-yl)-1,7-naphthidium-3-onitrile (42 mg, 90.22 μmol), DMSO (1 mL), K₂CO₃ (12.47 mg, 90.22 μmol), and H₂O₂ (0.2 mL) were added to a reaction flask, and the reaction was carried out at 20 °C for 1 hour. The reaction solution was diluted with water, extracted with EA, and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (43 mg). MS (ESI, m / z): 484.2 [M+H] + .

[0588] Step 5: Preparation of 2-((5-methyl-1H-indazol-4-yl)oxy)-8-(1-methyl-1H-pyrazol-4-yl)-1,7-naphthidine-3-carboxamide

[0589] 2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(1-methyl-1H-pyrazol-4-yl)-1,7-naphthidine-3-carboxamide (43 mg, 88.93 μmol) was added to a reaction flask, followed by 2 mL of TFA. The reaction was carried out at 60 °C for 1 hour. The solution was first concentrated, then dissolved in MeOH, and the pH was adjusted to 8-9 with NaHCO3. Extraction was performed using EA, and the organic phase was dried and concentrated to obtain the crude product. The crude product was purified to obtain the title compound (6 mg). MS (ESI, m / z): 400.1 [M+H] + .

[0590] 1 H NMR (400MHz, DMSO-d6) δ13.30(s,1H),8.75(s,1H),8.46(d,J=5.4Hz,1H),8.24(s,1H),8.04(s,1H),7.90(s,1H),7.7 9(s,1H),7.76(d,J=5.4Hz,1H),7.59(d,J=8.5Hz,1H),7.48(d,J=8.5Hz,1H),7.14(s,1H),3.53(s,3H),2.21(s,3H).

[0591] The following compounds were prepared by the method and general steps described in Example 7. Other required raw materials can be purchased commercially or obtained by experienced synthesizers from commercially available reagents using conventional reactions.

[0592] Example 9: 8-(1-methyl-1H-1,2,3-triazol-5-yl)-2-((5-methyl-1H-indazol-4-yl)oxy)-1,7-naphthidine-3-carboxamide (Compound 7)

[0593] Step 1: Preparation of 2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(1-methyl-1H-1,2,3-triazol-5-yl)-1,7-naphthidium-3-nitrile)

[0594] 8-Chloro-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-1,7-naphthidium-3-onitrile (100 mg, 238.17 μmol), 1,4-dioxane (2 mL), 1-methyl-5-(tributyltinyl)-1H-1,2,3-triazole (177.27 mg, 476.35 μmol), and tetraphenylphosphine-palladium (27.52 mg, 23.82 μmol) were added to a flask, and the reaction was carried out at 120 °C for 6 hours under nitrogen protection. The reaction solution was concentrated and subjected to column chromatography (PE / EA = 20 / 80, v / v) to give the title compound (100 mg). MS (ESI, m / z): 467.2 [M+H] + .

[0595] Step 2: Preparation of 2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(1-methyl-1H-1,2,3-triazol-5-yl)-1,7-naphthidine-3-carboxamide)

[0596] 2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(1-methyl-1H-1,2,3-triazol-5-yl)-1,7-naphthidium-3-onitrile (100 mg, 214.37 μmol), K₂CO₃ (29.63 mg, 214.37 μmol), DMSO (2 mL), and H₂O₂ (0.2 mL) were added to a reaction flask, and the reaction was carried out at 20 °C for 1 hour. The reaction solution was diluted with water, extracted with EA, and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (103 mg). MS (ESI, m / z): 485.2 [M+H] + .

[0597] Step 3: Preparation of 8-(1-methyl-1H-1,2,3-triazol-5-yl)-2-((5-methyl-1H-indazol-4-yl)oxy)-1,7-naphthidine-3-carboxamide

[0598] 2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(1-methyl-1H-1,2,3-triazol-5-yl)-1,7-naphthidine-3-carboxamide (103 mg, 157.31 μmol) and TFA (2 mL) were added to a reaction flask, and the reaction was carried out at 60 °C for 1 hour. The mixture was first concentrated, then dissolved in MeOH, and the pH was adjusted to 8-9 with NaHCO3. Extraction was performed using EA, and the organic phase was dried and concentrated. The crude product was purified to obtain the title compound (5 mg). MS (ESI, m / z): 401.2 [M+H] + .

[0599] 1 H NMR (400MHz, DMSO-d6) δ13.23(s,1H),8.86(s,1H),8.69(d,J=5.3Hz,1H),8.27(s,1H),8.07(s,1H),8.05(d,J =5.4Hz,1H),7.84(s,1H),7.52(d,J=8.5Hz,1H),7.39(d,J=8.5Hz,1H),7.06(s,1H),4.22(s,3H),2.19(s,3H).

[0600] The following compounds were prepared by referring to the method and general steps described in Example 9. Other required raw materials can be purchased commercially or obtained by experienced synthesizers from commercially available reagents using conventional reactions.

[0601] Example 10: 2-((6-fluoro-5-methyl-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide (Compound 34)

[0602] Step 1: Preparation of (2-chloro-3-cyanoquinoline-8-yl)boronic acid

[0603] 8-Bromo-2-chloroquinoline-3-onitrile (500 mg, 1.87 mmol), pinacol diboronate (569.56 mg, 2.24 mmol), PdCl₂dppf (68.38 mg, 93.45 μmol), potassium acetate (550.31 mg, 5.61 mmol), and 1,4-dioxane (10 mL) were added to a flask, and the mixture was heated to 100 °C under nitrogen protection for 5 hours. The reaction solution was concentrated and then subjected to column chromatography (DCM / MeOH, 3-10% MeOH, v / v) to give the title compound (300 mg). MS (ESI, m / z): 233.2, 235.2 [M+H] + .

[0604] Step 2: Preparation of 2-chloro-8-(pyrazin-2-yl)quinoline-3-onitrile

[0605] (2-chloro-3-cyanoquinoline-8-yl)boric acid (250 mg, 1.08 mmol), 2-bromopyrazine (205.20 mg, 1.29 mmol), cataCXium A Pd G3 (39.17 mg, 53.78 μmol), K3PO4 (456.62 mg, 2.15 mmol), water (1 mL), and 1,4-dioxane (10 mL) were added to a reaction flask. Under nitrogen protection, the mixture was heated to 90 °C and reacted for 3 hours. The reaction solution was diluted with water, extracted with EA, and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Subsequent column chromatography (PE / EA = 50 / 50, v / v) yielded the title compound (131 mg). MS (ESI, m / z): 267.1, 269.1 [M+H] + .

[0606] Step 3: Preparation of 2-((6-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-onitrile

[0607] 2-Chloro-8-(pyrazin-2-yl)quinoline-3-onitrile (50 mg, 187.49 μmol), 6-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol (56.31 mg, 224.98 μmol), CuBr (2.69 mg, 18.75 μmol), Cs₂CO₃ (91.63 mg, 281.23 μmol), and NMP (2 mL) were added to a reaction flask. Under nitrogen protection, the mixture was heated to 60 °C and reacted for 2 hours. The reaction solution was diluted with water, and EA was added. After filtration through a diatomaceous earth layer, the mixture was extracted with EA from the aqueous phase. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (90 mg). MS (ESI, m / z): 481.1 [M+H] + .

[0608] Step 4: Preparation of 2-((6-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide

[0609] 2-((6-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-onitrile (90 mg, 187.31 μmol), K₂CO₃ (25.89 mg, 187.31 μmol), DMSO (1 mL), and H₂O₂ (0.2 mL) were added to a reaction flask, and the reaction was carried out at 20 °C for 0.5 hr. The reaction solution was diluted with water, and the aqueous phase was extracted with EA. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (93 mg). MS (ESI, m / z): 499.1 [M+H] + .

[0610] Step 5: Preparation of 2-((6-fluoro-5-methyl-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide

[0611] 2-((6-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide (73 mg, 146.44 μmol) and TFA (3 mL) were added to a reaction flask, and the reaction was carried out at 40 °C for 1 hour. The solution was first concentrated, then dissolved in MeOH, and then the pH was adjusted to 8-9 with methanol solution of NH3. The mixture was filtered, and the filtrate was concentrated and purified to obtain the title compound (20 mg). MS (ESI, m / z): 415.1 [M+H] + .

[0612] 1 H NMR (400MHz, DMSO-d6) δ13.19(s,1H),8.93(s,1H),8.57(dd,J=2.5,1.6Hz,1H),8.42(d,J=1.6Hz,1H),8.37(d,J=2.5Hz,1H), 8.29-8.22(m,2H),8.17(s,1H),7.98(s,1H),7.78(s,1H),7.70(t,J=7.7Hz,1H),7.31(d,J=9.0Hz,1H),2.08(d,J=2.0Hz,3H).

[0613] 19 F NMR(376MHz,DMSO-d6)δ-116.26(s,1F).

[0614] The following compounds were prepared by the method and general steps described in Example 10. Other required raw materials can be purchased commercially or obtained by experienced synthesizers from commercially available reagents using conventional reactions.

[0615] Example 11: 8-(3-methyl-1H-1,2,4-triazol-1-yl)-2-((5-methyl-1H-indazol-4-yl)oxy)quinoline-3-carboxamide (Compound 35)

[0616] Step 1: Preparation of 2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(3-methyl-1H-1,2,4-triazol-1-yl)quinoline-3-nitrile)

[0617] (3-cyano-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-8-yl)boronic acid (310 mg, 723.88 μmol), 3-methyl-1H-1,2,4-triazole (180.47 mg, 2.172 mmol), copper acetate (262.96 mg, 1.478 mmol), DIPEA (374.22 mg, 2.896 mmol), and DMF (6 mL) were added sequentially to a 50 mL reaction flask. After oxygen purging, the mixture was heated to 110 °C and stirred for 21 hours. After the reaction was complete, water and ethyl acetate were added, and the mixture was extracted twice. The organic phases were combined, washed twice with brine, concentrated, and directly mixed for silica gel column chromatography (PE:EA = 6:35, v / v) to give the title compound (65.0 mg). MS (ESI, m / z): 466.2 [M+H] + .

[0618] Step 2: Preparation of 2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(3-methyl-1H-1,2,4-triazol-1-yl)quinoline-3-carboxamide

[0619] 2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(3-methyl-1H-1,2,4-triazol-1-yl)quinoline-3-onitrile (65.0 mg, 139.63 μmol) was dissolved in DMSO (2 mL), potassium carbonate (19.27 mg, 139.63 μmol) was added, followed by dropwise addition of H₂O₂ (135.03 mg, 1.39 mmol), and the mixture was stirred at 25 °C for 1 hr. After the reaction was complete, water and ethyl acetate were added, and the mixture was extracted twice. The organic phases were combined, washed twice with brine, concentrated, and directly mixed for silica gel column chromatography (PE:EA = 45:55, v / v). After concentration, the title compound (20.0 mg) was obtained. MS (ESI, m / z): 484.2 [M+H] + .

[0620] Step 3: Preparation of 8-(3-methyl-1H-1,2,4-triazol-1-yl)-2-((5-methyl-1H-indazol-4-yl)oxy)quinoline-3-carboxamide

[0621] 2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(3-methyl-1H-1,2,4-triazol-1-yl)quinoline-3-carboxamide (20.0 mg, 41.36 μmol) was dissolved in 1,4-dioxane (2 mL), followed by the addition of 2 mL of 4M HCl solution of 1,4-dioxane. The mixture was stirred at 25 °C for 1 hr. After the reaction was complete, sodium bicarbonate aqueous solution and ethyl acetate were added, followed by extraction twice. The organic phases were combined, washed twice with brine, concentrated, and then HPLC was used to prepare the title compound (4.0 mg). MS (ESI, m / z): 400.2 [M+H] + .

[0622] 1 H NMR (400MHz, DMSO-d6) δ13.23(s,1H),8.94(s,1H),8.20(dd,J=7.8Hz,1.4Hz,1H),8.18(s,1H),8.10(dd,J=8.2Hz,1.4Hz,1H),8.02( s,1H),7.96(s,1H),7.84(s,1H),7.64(t,J=7.6Hz,1H),7.50(dd,J=8.4,1.0Hz,1H),7.38(d,J=8.4Hz,1H),2.22(s,3H),2.20(s,3H).

[0623] Example 12: 2-((7-fluoro-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide (Compound 36)

[0624] Step 1: Preparation of 7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indazole

[0625] 4-Bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2.0 g, 6.69 mmol), pinacol diboronate (2.55 g, 10.04 mmol), potassium acetate (1.97 g, 20.07 mmol), Pd(dppf)Cl2 (490.24 mg, 0.67 mmol), and 1,4-dioxane (30 mL) were added sequentially to a 50 mL reaction flask. After purging with nitrogen, the mixture was heated to 100 °C and stirred for 2 hours. After the reaction was complete, the mixture was concentrated and directly mixed with silica gel column chromatography (PE:EA = 80:20, v / v) to give the title compound (2.25 g). MS (ESI, m / z): 347.2 [M+H] + .

[0626] Step 2: Preparation of 7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-ol

[0627] 1.5 g (4.33 mmol) of 7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indazole was dissolved in EtOH (30 mL) and H₂O (10 mL), and m-CPBA (1.12 g, 6.50 mmol) was added. The mixture was stirred at 25 °C for 16 h. After the reaction was complete, water and ethyl acetate were added, and the mixture was extracted twice. The organic phases were combined, washed twice with brine, concentrated, and directly mixed for silica gel column chromatography (PE:EA = 70:30, v / v). After concentration, the title compound (750.0 mg) was obtained. MS (ESI, m / z): 237.1 [M+H] + .

[0628] Step 3: Preparation of 2-((7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-onitrile

[0629] 2-Chloro-8-(pyrazin-2-yl)quinoline-3-onitrile (70.0 mg, 262.48 μmol), 7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol (74.41 mg, 314.98 μmol), cuprous iodide (10.0 mg, 52.50 μmol), and cesium carbonate (128.28 mg, 393.72 μmol) were dissolved in NMP (3 mL) and stirred at 65 °C for 2 hours. After the reaction was complete, water and ethyl acetate were added, and the mixture was extracted twice. The organic phases were combined, washed twice with brine, concentrated, and then subjected to silica gel column chromatography (PE:EA = 50:50, v / v) to give the title compound (60.0 mg). MS (ESI, m / z): 467.2 [M+H] + .

[0630] Step 4: Preparation of 2-((7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide)

[0631] 2-((7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-onitrile (60.0 mg, 128.62 μmol) was dissolved in DMSO (2 mL), and potassium carbonate (17.75 mg, 128.62 μmol) was added. After the addition was complete, H₂O₂ (118.76 mg, 1286.2 μmol) was added dropwise, and the mixture was stirred at 25 °C for 1 hr. After the reaction was complete, water and ethyl acetate were added, and the mixture was extracted twice. The organic phases were combined, washed twice with brine, concentrated, and then purified by silica gel column chromatography (PE:EA = 50:50, v / v) to give the title compound (40.0 mg). MS (ESI, m / z): 485.2 [M+H] + .

[0632] Step 5: Preparation of 2-((7-fluoro-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide

[0633] 2-((7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide (40.0 mg, 82.56 μmol) was dissolved in DCM (2 mL), and TFA (2 mL) was added. After the addition was complete, the mixture was stirred at 25 °C for 2 hours. After the reaction was complete, sodium bicarbonate aqueous solution and ethyl acetate were added, and the mixture was extracted twice. The organic phases were combined, washed twice with brine, concentrated, and then the title compound (6.0 mg) was obtained by HPLC. MS (ESI, m / z): 401.2 [M+H] + .

[0634] 1 H NMR (400MHz, DMSO-d6) δ13.77(s,1H),8.91(s,1H),8.58(dd,J=2.6,1.6Hz,1H),8.38(dd,J=15.2,2.0Hz,2H),8.24(d,J=7. 6Hz,2H),8.11(s,1H),8.01-7.88(m,2H),7.69(t,J=7.6Hz,1H),7.20(dd,J=10.8,8.2Hz,1H),7.00(dd,J=8.2,3.2Hz,1H).

[0635] Example 13: 8-(pyrazin-2-yl)-2-((5-(trifluoromethyl)-1H-indazol-4-yl)oxy)quinoline-3-carboxamide (Compound 37)

[0636] Step 1: Preparation of 2-bromo-6-fluoro-3-(trifluoromethyl)benzaldehyde

[0637] 2-Bromo-4-fluoro-1-(trifluoromethyl)benzene (10.0 g, 41.15 mmol) and THF (50 mL) were added sequentially to a 250 mL reaction flask. After purging with nitrogen, the mixture was cooled to -70 to -78 °C and stirred for 20 min. LDA (61.73 mmol, 30.86 mL, 2.0 M) was added dropwise, maintaining the temperature below -60 °C. After the addition was complete, the reaction was maintained at this temperature for 30 min. DMF (9.02 g, 123.45 mmol) was then added dropwise. After the addition was complete, the reaction was maintained at this temperature for 2 hours. After the reaction was complete, a saturated ammonium chloride aqueous solution was added dropwise to quench the reaction. The mixture was extracted twice with ethyl acetate, concentrated, and stirred. Column chromatography (PE:EA = 70:30, v / v) was performed to obtain the title compound (8.50 g). MS (ESI, m / z): 272.1 [M+H] + .

[0638] Step 2: Preparation of 4-bromo-5-(trifluoromethyl)-1H-indazole

[0639] 2-Bromo-6-fluoro-3-(trifluoromethyl)benzaldehyde (3.5 g, 12.91 mmol) was dissolved in THF (20 mL), and hydrazine hydrate (2.42 g, 38.73 mmol) was added. The mixture was stirred at 55 °C for 16 h. After the reaction was complete, water and ethyl acetate were added, and the mixture was extracted twice. The organic phases were combined, washed twice with brine, concentrated, and directly mixed for silica gel column chromatography (PE:EA = 70:30, v / v). After concentration, the title compound (3.0 g) was obtained. MS (ESI, m / z): 266.0 [M+H] + .

[0640] Step 3: Preparation of 4-bromo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

[0641] 4-Bromo-5-(trifluoromethyl)-1H-indazole (3.0 g, 11.32 mmol) was dissolved in THF (30 mL). After purging with nitrogen three times, NaH (1.36 g, 33.96 mmol) was added in portions at 0 °C. After purging with nitrogen once, the mixture was stirred for 30 min, and then SEMCl (3.77 g, 22.64 mmol) was added dropwise. The mixture was allowed to cool naturally for 2 hours. After the reaction was complete, water and ethyl acetate were added, and the mixture was extracted twice. The organic phases were combined, washed twice with brine, concentrated, and then subjected to silica gel column chromatography (PE:EA = 80:20, v / v) to give the title compound (4.0 g). MS (ESI, m / z): 396.1 [M+H] + .

[0642] Step 4: Preparation of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

[0643] 4-Bromo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (2.0 g, 5.06 mmol), pinacol diboronate (1.93 g, 7.59 mmol), potassium acetate (1.42 g, 15.18 mmol), Pd(dppf)Cl2 (373.17 mg, 0.51 mmol), and 1,4-dioxane (30 mL) were added sequentially to a 100 mL reaction flask. After purging with nitrogen, the mixture was heated to 100 °C and stirred for 2 hours. After the reaction was complete, the mixture was concentrated and directly mixed with silica gel column chromatography (PE:EA = 80:20, v / v) to give the title compound (1.05 g). MS (ESI, m / z): 443.2 [M+H] + .

[0644] Step 5: Preparation of 5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-4-ol

[0645] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (715.0 mg, 1.62 mmol) was dissolved in DMSO (5 mL), and potassium carbonate (212.52 mg, 1.54 mmol) was added. After the addition was complete, H₂O₂ (1.57 g, 16.20 mmol) was added dropwise, and the mixture was stirred at 25 °C for 2 hours. After the reaction was complete, water and ethyl acetate were added, and the mixture was extracted twice. The organic phases were combined, washed twice with brine, concentrated, and then purified by silica gel column chromatography (PE:EA = 60:40, v / v) to give the title compound (160 mg). MS (ESI, m / z): 333.1 [M+H] + .

[0646] Step 6: Preparation of 8-(pyrazin-2-yl)-2-((5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)oxy)quinoline-3-nitrile

[0647] 5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-4-ol (150.0 mg, 449.97 μmol) and 2-chloro-8-(pyrazin-2-yl)quinoline-3-onitrile (100.0 mg, 374.97 μmol) were dissolved in NMP (4 mL), and cuprous iodide (14.28 mg, 74.99 μmol) and cesium carbonate (183.26 mg, 562.46 μmol) were added. The mixture was stirred at 80 °C for 6 hours. After the reaction was complete, water and ethyl acetate were added, and the mixture was extracted twice. The organic phases were combined, washed twice with brine, concentrated, and then subjected to silica gel column chromatography (PE:EA = 50:50, v / v) to give the title compound (100.0 mg). MS (ESI, m / z): 563.2 [M+H] + .

[0648] Step 7: Preparation of 8-(pyrazin-2-yl)-2-((5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)oxy)quinoline-3-carboxamide

[0649] 8-(pyrazin-2-yl)-2-((5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)oxy)quinoline-3-onitrile (100.0 mg, 177.74 μmol) was dissolved in DMSO (4 mL), and potassium carbonate (24.53 mg, 177.74 μmol) was added. After the addition was complete, H2O2 (172.91 mg, 1.78 mmol) was added dropwise, and the mixture was stirred at 25 °C for 1 hr. After the reaction was complete, water and ethyl acetate were added, and the mixture was extracted twice. The organic phases were combined, washed twice with brine, concentrated, and then purified by silica gel column chromatography (PE:EA = 35:65, v / v) to give the title compound (50.0 mg). MS (ESI, m / z): 581.2 [M+H] + .

[0650] Step 8: Preparation of 8-(pyrazin-2-yl)-2-((5-(trifluoromethyl)-1H-indazol-4-yl)oxy)quinoline-3-carboxamide

[0651] 8-(pyrazin-2-yl)-2-((5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)oxy)quinoline-3-carboxamide (50.0 mg, 86.11 μmol) was dissolved in 1,4-dioxane (2 mL), followed by the addition of 2 mL of 4M HCl solution of 1,4-dioxane. The mixture was stirred at 25 °C for 16 h. After the reaction was complete, sodium bicarbonate aqueous solution and ethyl acetate were added, followed by extraction twice. The organic phases were combined, washed twice with brine, concentrated, and then HPLC was used to prepare the title compound (7.0 mg). MS (ESI, m / z): 451.1 [M+H] + .

[0652] 1 H NMR (400MHz, DMSO-d6) δ13.58(s,1H),8.99(s,1H),8.56-8.51(m,1H),8.30(d,J=2.4Hz,1H),8.29-8.2 1(m,2H),8.18(d,J=1.6Hz,1H),8.02(d,J=4.8Hz,2H),7.96(s,1H),7.72(t,J=7.6Hz,1H),7.65(s,2H).

[0653] Example 14: 2-((5-methyl-1H-indazol-4-yl)oxy)-8-(1,2,4-triazin-6-yl)quinoline-3-carboxamide (Compound 8)

[0654] Step 1: Preparation of 8-(3-amino-1,2,4-triazin-6-yl)-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-nitrile

[0655] (3-cyano-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-8-yl)boronic acid (100.00 mg, 233.51 μmol), 3-amino-6-bromo-1,2,4-triazine (61.29 mg, 350.26 μmol), cataCXium A Pd G3 (17.01 mg, 23.35 μmol), and K3PO4 (99.13 mg, 467.02 μmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL). The mixture was heated to 120 °C for 2 hours under nitrogen protection. After the reaction was complete, the solution was concentrated under reduced pressure and separated by silica gel column chromatography (DCM / MeOH = 85 / 15, v / v) to give the title compound (82 mg). MS (ESI, m / z): 479.3 [M+H] + .

[0656] Step 2: Preparation of 2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(1,2,4-triazin-6-yl)quinoline-3-nitrile)

[0657] 8-(3-amino-1,2,4-triazin-6-yl)-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-onitrile (82 mg, 171.37 μmol) and isoamyl nitrite (60.22 mg, 514.10 μmol) were dissolved in THF (4 mL) and reacted in a microwave oven at 70 °C for 2 hours. After the reaction was complete, the solution was concentrated under reduced pressure and separated by silica gel column chromatography (DCM / MeOH = 85 / 15, v / v) to give the title compound (75 mg). MS (ESI, m / z): 464.3 [M+H] + .

[0658] Step 3: Preparation of 2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(1,2,4-triazin-6-yl)quinoline-3-carboxamide

[0659] 2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(1,2,4-triazin-6-yl)quinoline-3-onitrile (25.00 mg, 13.46 μmol), K₂CO₃ (1.86 mg, 13.46 μmol), and H₂O₂ (2.29 mg, 67.28 μmol) were dissolved in DMSO (3 mL) and reacted at 25 °C for 1 hour. After the reaction was complete, the mixture was diluted with water, extracted with EA, and the organic layer was collected. The organic layer was dried over anhydrous sodium sulfate and collected to give the crude product (12 mg). MS (ESI, m / z): 482.1 [M+H] + .

[0660] Step 4: Preparation of 2-((5-methyl-1H-indazol-4-yl)oxy)-8-(1,2,4-triazin-6-yl)quinoline-3-carboxamide

[0661] 2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(1,2,4-triazin-6-yl)quinoline-3-carboxamide (22.95 mg, 47.67 μmol) was dissolved in 2 mL of 4 M HCl solution of 1,4-dioxane. After addition, the mixture was reacted at 25 °C for 1 hr. After the reaction was complete, the solution was concentrated under reduced pressure, the pH was adjusted to neutral with ammonia-methanol solution, concentrated, and purified by Prep-HPLC to obtain the title compound (0.90 mg). MS (ESI, m / z): 398.1 [M+H] + .

[0662] 1 H NMR(400MHz,DMSO-d6)δ13.12(s,1H),9.45(s,1H),8.96(s,1H),8.38-8.29(m,3H),8.15(s,1H) ,8.00(s,1H),7.73(t,J=4.0Hz,2H),7.40(d,J=8.4Hz,1H),7.27(d,J=8.4Hz,1H),2.16(s,3H).

[0663] Example 15: 5-Fluoro-2-((5-methyl-1H-indazol-4-yl)oxy)-8-(1-methyl-1H-pyrazol-4-yl)quinoline-3-carboxamide (Compound 27)

[0664] Step 1: Preparation of 3-bromo-6-fluoro-2-nitrobenzaldehyde

[0665] 5-Bromo-2-fluorobenzaldehyde (2 g, 9.85 mmol) was dissolved in H2SO4 (6.00 mL), and HNO3 (931.19 mg, 14.78 mmol, 665.13 μL) was added dropwise at 0 °C. After the addition was complete, the reaction was carried out at 25 °C for 2 hours. After the reaction was completed by TLC monitoring, the reaction solution was poured into ice water, extracted with EA, and the organic layer was collected. The pH of the aqueous layer was adjusted to neutral and discarded. The organic layer was collected and separated by silica gel column chromatography (PE / EA = 80 / 20, v / v) to give the title compound (692 mg).

[0666] 1 H NMR (400MHz, DMSO-d6) δ10.10-10.02(m,1H),8.28(dd,J=9.2,5.2Hz,1H),7.75(dd,J=9.6,9.2Hz,1H).

[0667] Step 2: Preparation of 2-amino-3-bromo-6-fluorobenzaldehyde

[0668] 3-Bromo-6-fluoro-2-nitrobenzaldehyde (692 mg, 2.79 mmol) was dissolved in AcOH (3 mL) and EtOH (3 mL), and Fe (467.51 mg, 8.37 mmol) was added with stirring. After the addition was complete, the reaction was carried out at 80 °C for 2 hours under nitrogen protection. After the reaction was completed by TLC monitoring, the mixture was filtered while hot, and the filtrate was collected and separated by silica gel column chromatography (PE / EA = 85 / 15, v / v) to give the title compound (524 mg).

[0669] Step 3: Preparation of 8-bromo-5-fluoro-2-oxo-1,2-dihydroquinoline-3-onitrile

[0670] 2-Amino-3-bromo-6-fluorobenzaldehyde (492 mg, 2.26 mmol), ethyl cyanoacetate (382.89 mg, 3.38 mmol), and ammonium acetate (521.84 mg, 6.77 mmol) were dissolved in 1,4-dioxane (6 mL). The reaction was carried out at 100 °C for 2 hours under nitrogen protection. After the reaction was completed, the solution was concentrated under reduced pressure and separated by silica gel column chromatography (PE / EA = 85 / 15, v / v) to give the title compound (348 mg). MS (ESI, m / z): 284.0 [M+NH4] + .

[0671] Step 4: Preparation of 8-bromo-5-fluoro-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-nitrile

[0672] 8-Bromo-5-fluoro-2-oxo-1,2-dihydroquinoline-3-onitrile (348 mg, 1.30 mmol), 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-ol (382.34 mg, 1.56 mmol), and DBU (396.76 mg, 2.61 mmol, 357.76 μL) were added to a reaction flask, followed by 3 mL of DMF. After stirring to dissolve, PyBOP (1.02 g, 1.95 mmol) was added. The reaction was carried out at 60 °C for 3 hours under nitrogen protection. After the reaction was complete, the mixture was diluted with water, extracted with EA, and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was then separated by silica gel column chromatography (DCM: MeOH = 85 / 15, v / v) to give the title compound (556 mg). MS (ESI, m / z): 481.1 [M+H] + .

[0673] Step 5: Preparation of 5-fluoro-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(1-methyl-1H-pyrazol-4-yl)quinoline-3-nitrile)

[0674] Add 8-bromo-5-fluoro-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-onitrile (200 mg, 415.53 μmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrazole (103.75 mg, 498.63 μmol), and cataCXium A Pd to the reaction flask. G3 (30.26 mg, 41.55 μmol) and K3PO4 (176.40 mg, 831.05 μmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL). The reaction was carried out under nitrogen protection at 120 °C for 2 hours. After the reaction was complete, the solution was concentrated under reduced pressure and separated by silica gel column chromatography (DCM: MeOH = 85 / 15, v / v) to give the title compound (107 mg). MS (ESI, m / z): 483.3 [M+H] + .

[0675] Step 6: Preparation of 5-fluoro-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(1-methyl-1H-pyrazol-4-yl)quinoline-3-carboxamide

[0676] 5-Fluoro-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(1-methyl-1H-pyrazol-4-yl)quinoline-3-onitrile (97 mg, 201.03 μmol) and K₂CO₃ (27.78 mg, 201.03 μmol) were dissolved in DMSO (3 mL), and H₂O₂ (1 mL) was added. After the addition was complete, the mixture was reacted at 25 °C for 2 hours. After the reaction was complete, water and EA were added for extraction, and the organic layer was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (107 mg). MS (ESI, m / z): 501.2 [M+H] + .

[0677] Step 7: Preparation of 5-fluoro-2-((5-methyl-1H-indazol-4-yl)oxy)-8-(1-methyl-1H-pyrazol-4-yl)quinoline-3-carboxamide

[0678] 127 mg (253.73 μmol) of 5-fluoro-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(1-methyl-1H-pyrazol-4-yl)quinoline-3-carboxamide was dissolved in 4 mL of 4 M HCl in a solution of 1,4-dioxane. The reaction was carried out at 25 °C for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure, the pH was adjusted to neutral with ammonia-methanol solution, and the solution was concentrated under reduced pressure. The title compound (18.5 mg) was obtained by Prep-HPLC purification. MS (ESI, m / z): 417.2 [M+H] + .

[0679] 1 H NMR(400MHz,DMSO-d6)δ13.28(s,1H),8.84(s,1H),8.19(s,1H),8.07-7.96(m,2H),7.88(s,1H),7.73(s,1 H),7.57(d,J=8.4Hz,1H),7.46(d,J=8.4Hz,1H),7.40-7.29(m,1H),6.90(s,1H),3.47(s,3H),2.20(s,3H).

[0680] The following compounds were prepared by referring to the method and general steps described in Example 15. Other required raw materials can be purchased commercially or obtained by experienced synthesizers from commercially available reagents using conventional reactions.

[0681] Example 16: 6-Chloro-2-((5-methyl-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide (Compound 38)

[0682] Step 1: Preparation of methyl 2-amino-3-bromo-5-chlorobenzoate

[0683] Methyl 2-amino-5-chlorobenzoate (100 mg, 538.77 μmol) and NBS (95.89 mg, 538.77 μmol) were dissolved in AcOH (4 mL). After addition, the mixture was reacted at 120 °C for 1.5 hr. After the reaction was complete, the pH was adjusted to neutral by adding saturated sodium bicarbonate aqueous solution. The mixture was extracted with EA, and the organic layer was collected, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA = 85 / 15, v / v) to give the title compound (25 mg). MS (ESI, m / z): 264.1 [M+H] + .

[0684] Step 2: Preparation of (2-amino-3-bromo-5-chlorophenyl)methanol

[0685] Methyl 2-amino-3-bromo-5-chlorobenzoate (1 g, 3.78 mmol) was dissolved in THF (6 mL), and LiBH4 (6.43 mmol, 3.78 mL) was added dropwise. After the addition was complete, the mixture was reacted at 50 °C for 1 hour. After the reaction was complete, water was added and stirred for 30 min, followed by extraction with EA / water. The organic layer was collected and separated by silica gel column chromatography (PE:EA = 75 / 25, v / v) to give the title compound (576 mg). MS (ESI, m / z): 236.1 [M+H] + .

[0686] Step 3: Preparation of 2-amino-3-bromo-5-chlorobenzaldehyde

[0687] (2-Amino-3-bromo-5-chlorophenyl)methanol (1 g, 4.23 mmol) and PCC (885.90 mg, 4.23 mmol) were dissolved in DCM (8 mL) and reacted at 25 °C for 2 hours. After the reaction was completed by TLC monitoring, the mixture was filtered with diatomaceous earth, the filtrate was collected, concentrated, and separated by silica gel column chromatography (PE:EA = 85 / 15, v / v) to give the title compound (750 mg).

[0688] Step 4: Preparation of 8-bromo-6-chloro-2-oxo-1,2-dihydroquinoline-3-onitrile

[0689] 2-Amino-3-bromo-5-chlorobenzaldehyde (650 mg, 1.52 mmol), ammonium acetate (352.57 mg, 4.57 mmol), and ethyl cyanoacetate (258.69 mg, 2.29 mmol) were dissolved in 1,4-dioxane (8 mL). The reaction was carried out at 100 °C for 5 hours under nitrogen protection. After the reaction was completed, the solution was concentrated under reduced pressure and separated by silica gel column chromatography (DCM: MeOH = 85 / 15, v / v) to give the title compound (304 mg). MS (ESI, m / z): 300.1 [M + NH4] + .

[0690] Step 5: Preparation of 8-bromo-6-chloro-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-nitrile

[0691] 8-Bromo-6-chloro-2-oxo-1,2-dihydroquinoline-3-onitrile (284 mg, 1.00 mmol), 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-ol (279.22 mg, 1.20 mmol), PyBOP (700.48 mg, 1.50 mmol), and DBU (504.59 mg, 2.00 mmol) were dissolved in DMF (4 mL) and reacted at 60 °C for 3 hours. After the reaction was complete, EA and water were added for extraction. The organic layer was collected, concentrated under reduced pressure, and separated by silica gel column chromatography (DCM: MeOH = 85 / 15, v / v) to give the title compound (750 mg). MS (ESI, m / z): 497.3 [M+H] + .

[0692] Step 6: Preparation of (6-chloro-3-cyano-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-8-yl)boronic acid

[0693] 8-Bromo-6-chloro-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-onitrile (404 mg, 811.62 μmol), pinacol diboronate (309.15 mg, 1.22 mmol), Pd(dppf)Cl2 (118.77 mg, 162.32 μmol), and potassium acetate (238.96 mg, 2.43 mmol) were dissolved in 1,4-dioxane (3 mL). The reaction was carried out at 80 °C for 4 hours under nitrogen protection. After the reaction was completed, the next step was directly performed. MS (ESI, m / z): 463.2 [M+H] + .

[0694] Step 7: Preparation of 6-chloro-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-onitrile

[0695] (6-chloro-3-cyano-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-8-yl)boronic acid (375 mg, 810.47 μmol), 2-chloropyrazine (111.39 mg, 972.57 μmol), cataCXium A Pd G3 (59.02 mg, 81.05 μmol), and K3PO4 (344.07 mg, 1.62 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL). The reaction was carried out at 120 °C for 3 hours under nitrogen protection. After the reaction was completed, the solution was concentrated under reduced pressure and separated by silica gel column chromatography (DCM: MeOH = 85 / 15, v / v) to give the title compound (750 mg). MS (ESI, m / z): 497.2 [M+H] + .

[0696] Step 8: Preparation of 6-chloro-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide

[0697] 6-Chloro-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-onitrile (150 mg, 301.84 μmol), H₂O₂ (301.84 μmol, 2 mL), and K₂CO₃ (125.15 mg, 905.53 μmol) were dissolved in DMSO (4 mL). The reaction was carried out at 25 °C for 1 hour. After the reaction was completed, water and EA were added for extraction. The organic layer was collected, concentrated under reduced pressure, and directly added to the next step. MS (ESI, m / z): 515.1 [M+H] + .

[0698] Step 9: Preparation of 6-chloro-2-((5-methyl-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide

[0699] 6-Chloro-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide (67 mg, 130.11 μmol) was dissolved in 5 mL of 4 M HCl solution of 1,4-dioxane and reacted at 25 °C for 1 hr. After the reaction was complete, the solution was concentrated under reduced pressure, diluted with methanol, and the pH was adjusted to neutral with saturated sodium bicarbonate aqueous solution. Extraction was performed with EA and water, and the organic layer was collected, concentrated under reduced pressure, and purified by Prep-HPLC to obtain the title compound (18.5 mg). MS (ESI, m / z): 431.1 [M+H] + .

[0700] 1 H NMR (400MHz, DMSO-d6) δ13.14(s,1H),8.89(s,1H),8.57(s,1H),8.41(m,3H),8.22(m,2H),8.02(s,1H),7.76(s,1H),7.34(m,2H),2.17(s,3H).

[0701] Example 19: 2-((5-methyl-1H-indazol-4-yl)oxy)-8-(4-methylpiperazin-1-yl)quinoline-3-carboxamide (Compound 33)

[0702] Step 1: Preparation of 2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(4-methylpiperazin-1-yl)quinoline-3-nitrile)

[0703] 8-Bromo-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-onitrile (50 mg, 107.92 μmol), 1-methylpiperazine (21.62 mg, 215.83 μmol), Pd2(dba)3 (9.88 mg, 10.79 μmol), RuPhos (10.07 mg, 21.58 μmol), Cs2CO3 (105.48 mg, 323.75 μmol), and 1,4-dioxane (2 mL) were added to a reaction flask. After purging with nitrogen, the mixture was heated to 120 °C and stirred for 2 hours. After the reaction was complete, water and ethyl acetate were added, and the mixture was extracted twice. The organic phases were combined, washed twice with brine, concentrated, and directly mixed. The mixture was then subjected to silica gel column chromatography (DCM:MeOH = 92 / 8, v / v) to give the title compound (37 mg). MS(ESI, m / z): 483.2 [M+H] + .

[0704] Step 2: Preparation of 2-((5-methyl-1H-indazol-4-yl)oxy)-8-(4-methylpiperazin-1-yl)quinoline-3-carboxamide

[0705] 2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(4-methylpiperazin-1-yl)quinoline-3-onitrile (37 mg, 76.67 μmol) was dissolved in 5 mL of H₂SO₄ and heated to 80 °C with stirring for 1 hr. After the reaction was complete, the mixture was cooled to room temperature, and water was added. The mixture was then extracted twice with EA. The combined organic phases were washed twice with brine, concentrated, and purified to obtain the title compound (4.3 mg). MS (ESI, m / z): 417.2 [M+H] + .

[0706] 1 H NMR (400MHz, DMSO-d6) δ13.09(s,1H),8.73(s,1H),8.05(s,1H),7.91(s,1H),7.77(s,1H),7.56(dd,J=8.4,1.2Hz,1 H),7.44-7.27(m,3H),6.96(dd,J=8.0,1.2Hz,1H),2.92-2.71(m,4H),2.19(s,3H),2.01(s,3H),1.86-1.60(m,4H).

[0707] Example 20: 2-((5-methyl-1H-indazol-4-yl)oxy)-8-(tetrahydrofuran-3-yl)quinoline-3-carboxamide (Compound 29)

[0708] Step 1: Preparation of 8-bromo-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-carboxamide

[0709] 8-Bromo-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-onitrile (80 mg, 172.66 μmol) and potassium carbonate (71.59 mg, 517.99 μmol) were dissolved in DMSO (5 mL). 0.5 mL of 35% hydrogen peroxide solution was added dropwise under ice bath conditions, and the reaction was continued at this temperature for 1 h. After the reaction was complete, the reaction solution was poured into water and extracted with EA. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (54 mg). MS (ESI, m / z): 481.1 [M+H] + .

[0710] Step 2: Preparation of 8-bromo-2-((5-methyl-1H-indazol-4-yl)oxy)quinoline-3-carboxamide

[0711] 8-Bromo-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-carboxamide (54 mg, 112.19 μmol) was dissolved in dichloromethane (8 mL), and dioxane hydrochloride solution (2 mL) was added dropwise. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was evaporated under reduced pressure to give the title compound (40 mg). MS (ESI, m / z): 397.1 [M+H] + .

[0712] Step 3: Preparation of 8-(2,5-dihydrofuran-3-yl)-2-((5-methyl-1H-indazol-4-yl)oxy)quinoline-3-carboxamide

[0713] 8-Bromo-2-((5-methyl-1H-indazol-4-yl)oxy)quinoline-3-carboxamide (40 mg, 100.70 μmol), 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (39.48 mg, 201.40 μmol), potassium phosphate (42.75 mg, 201.40 μmol), and cataCXium A Pd G3 (7.33 mg, 10.07 μmol) were added to a mixed solvent of 1,4-dioxane (2 mL) and H2O (0.5 mL). The mixture was stirred at 100 °C for 2 h under nitrogen protection. After the reaction was complete, the reaction solution was directly purified by silica gel stirring (DCM / MeOH = 93 / 7, v / v) to obtain the title compound (14 mg). MS (ESI, m / z): 387.1 [M+H] + .

[0714] Step 4: Preparation of 2-((5-methyl-1H-indazol-4-yl)oxy)-8-(tetrahydrofuran-3-yl)quinoline-3-carboxamide

[0715] 8-(2,5-dihydrofuran-3-yl)-2-((5-methyl-1H-indazol-4-yl)oxy)quinoline-3-carboxamide (14 mg, 36.23 μmol) was added to MeOH (5 mL), followed by the addition of palladium on carbon (2 mg). After hydrogen purging, the mixture was reacted at room temperature for 1 h. After 1 h, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated and purified by reversed-phase HPLC to obtain the title compound (3.88 mg). MS (ESI, m / z): 389.2 [M+H] + .

[0716] 1H NMR (400MHz, DMSO-d6) δ13.09(s,1H),8.79(s,1H),8.07(s,1H),7.98-7.88(m,2H),7.74(s,1H),7.55(d,J=6.8Hz,1 H),7.47-7.38(m,2H),7.33(d,J=8.4Hz,1H),3.52-3.36(m,4H),3.26-3.14(m,1H),2.21(s,3H),1.81-1.64(m,2H).

[0717] Example 21: 6-Methyl-2-((5-methyl-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide (Compound 39)

[0718] Step 1: Preparation of 6-methyl-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-onitrile

[0719] 6-Chloro-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-onitrile (80 mg, 160.98 μmol), methylboronic acid (28.91 mg, 482.95 μmol), Pd(dtbpf)Cl2 (10.39 mg, 16.10 μmol), and K2CO3 (66.75 mg, 482.95 μmol) were dissolved in 1,4-dioxane (4 mL). The reaction was carried out at 120 °C for 3 hours under nitrogen protection. After the reaction was completed, the solution was concentrated under reduced pressure and separated by silica gel column chromatography (DCM:MeOH=85 / 15, v / v) to give the title compound (65 mg). MS (ESI, m / z): 477.1 [M+H] + .

[0720] Step 2: Preparation of 6-methyl-2-((5-methyl-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide

[0721] 6-Methyl-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-onitrile (65 mg, 136.40 μmol) was dissolved in 3 mL of H₂SO₄ and reacted at 60 °C for 2 hours. After the reaction was complete, the reaction solution was added dropwise to a saturated sodium bicarbonate aqueous solution to adjust the pH to neutral. Extraction was performed with EA, the organic layer was collected, concentrated, and purified by Prep-HPLC to obtain the title compound (1.08 mg). MS (ESI, m / z): 411.1 [M+H]+ .

[0722] 1 H NMR (400MHz, DMSO-d6) δ13.09(s,1H),8.81(s,1H),8.55(s,1H),8.43(s,1H),8.33(d,J=2.4Hz,1H),8.12(d,J=6.4Hz ,2H),8.00(s,1H),7.96(s,1H),7.74(s,1H),7.38(d,J=8.4Hz,1H),7.27(d,J=8.4Hz,1H),2.52(s,3H),2.17(s,3H).

[0723] Example 22: 6-cyano-2-((5-methyl-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide (Compound 40)

[0724] Step 1: Preparation of 6-chloro-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide

[0725] 6-Chloro-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-onitrile (150 mg, 301.84 μmol), H₂O₂ (2 mL), and K₂CO₃ (125.15 mg, 905.53 μmol) were dissolved in DMSO (4 mL). The reaction was carried out at 25 °C for 1 hour. After the reaction was completed, EA / water was added for extraction, the organic layer was collected, concentrated, and the crude product (57 mg) was directly added to the next step. MS (ESI, m / z): 515.1 [M+H] + .

[0726] Step 2: Preparation of 6-cyano-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide

[0727] 6-Chloro-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide (57 mg, 49.81 μmol), t-Bu-xphos Pd G3 (1.98 mg, 2.49 μmol), and Zn(CN)2 (17.55 mg, 149.43 μmol) were dissolved in DMF (3 mL) and reacted at 110 °C for 4 hours under nitrogen protection. After the reaction was complete, EA / water was added for extraction, the organic layer was collected, concentrated, and separated by silica gel column chromatography (DCM: MeOH = 85 / 15, v / v) to give the title compound (15 mg). MS (ESI, m / z): 506.2 [M+H] + .

[0728] Step 3: Preparation of 6-cyano-2-((5-methyl-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide

[0729] 15 mg (29.67 μmol) of 6-cyano-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide and 0.5 mL of TFA were dissolved in 2 mL of DCM and reacted at 25 °C for 1 hour. After the reaction was complete, the reaction solution was added dropwise to a saturated sodium bicarbonate aqueous solution to adjust the pH to neutral. The solution was then extracted with EA, and the organic layer was collected, concentrated, and purified by Prep-HPLC to obtain the title compound (1.03 mg). MS (ESI, m / z): 422.2 [M+H] + .

[0730] 1 H NMR (400MHz, DMSO-d6) δ13.13(s,1H),8.99(s,1H),8.85(d,J=2.0Hz,1H),8.63-8.55(m,1H),8.46(d,J=2.0Hz,1H),8. 40(d,J=2.0Hz,2H),8.22(s,1H),8.07(s,1H),7.78(s,1H),7.41(d,J=8.4Hz,1H),7.28(d,J=8.4Hz,1H),2.17(s,3H).

[0731] The following compounds were prepared by referring to the method and general steps described in Example 22. Other required raw materials can be purchased commercially or obtained by experienced synthesizers from commercially available reagents using conventional reactions.

[0732] Example 23: 2-((7-fluoro-5-methyl-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide (Compound 43)

[0733] Step 1: Preparation of 2-((7-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-onitrile

[0734] 2-Chloro-8-(pyrazin-2-yl)quinoline-3-onitrile (40 mg, 149.99 μmol), 7-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol (37.54 mg, 149.99 μmol), cuprous bromide (2.15 mg, 15.00 μmol), and Cs₂CO₃ (73.30 mg, 224.98 μmol) were dissolved in NMP (5 mL), and the mixture was heated to 80 °C and reacted for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, and water was added and stirred. The mixture was then extracted and concentrated using EA. The crude product was purified by silica gel column chromatography (DCM / MeOH = 95 / 5, v / v) to give the title compound (50 mg). MS (ESI, m / z): 481.1 [M+H] + .

[0735] Step 2: Preparation of 2-((7-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide

[0736] 2-((7-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-onitrile (50 mg, 104.06 μmol) and potassium carbonate (43.14 mg, 312.18 μmol) were added to DMSO (2 mL), and a 35% hydrogen peroxide solution was added dropwise at 0 °C for 1 hour. After the reaction was complete, water was added, and the mixture was extracted with EA and concentrated to give the title compound (34 mg). MS (ESI, m / z): 499.2 [M+H] + .

[0737] Step 3: Preparation of 2-((7-fluoro-5-methyl-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide

[0738] 2-((7-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide (34 mg, 68.20 μmol) was dissolved in DCM (3 mL), and a 1,4-dioxane solution of 4M HCl (2 mL) was added dropwise under ice bath conditions. The reaction was carried out at 25 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated, and the crude product was purified by reversed-phase HPLC to obtain the title compound (16.88 mg). MS (ESI, m / z): 415.1 [M+H] + .

[0739] 1 H NMR (400MHz, DMSO-d6) δ13.64(s,1H),8.93(s,1H),8.57(dd,J=2.4,1.6Hz,1H),8.40-8.33(m,2H),8.31-8.18(m, 2H),8.13(s,1H),7.98(s,1H),7.87(d,J=2.8Hz,1H),7.68(t,J=7.6Hz,1H),7.16(d,J=11.6Hz,1H),2.15(s,3H).

[0740] Example 24: 5-Chloro-2-((5-methyl-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide (Compound 41)

[0741] Step 1: Preparation of 3-bromo-6-chloro-2-nitrobenzaldehyde

[0742] At 0°C, 10 g (48.30 mmol) of 5-bromo-2-chlorobenzaldehyde was added to 10 mL of concentrated sulfuric acid, and fuming nitric acid (4.30 g, 68.34 mmol) was slowly added dropwise while maintaining the temperature at 0°C for 4 hours. After the reaction was complete, water was added to the reaction solution while maintaining the temperature at 0°C and stirring continuously. After the solid precipitated, it was filtered, and the filter cake was washed with water and dried to obtain the title compound (8 g).

[0743] Step 2: Preparation of 2-amino-3-bromo-6-chlorobenzaldehyde

[0744] 8 g (15.13 mmol) of 3-bromo-6-chloro-2-nitrobenzaldehyde was added to a mixed solvent of acetic acid (20 mL) and ethanol (20 mL). Iron powder (5.06 g, 90.76 mmol) was added while stirring, and the mixture was reacted at 80 °C for 2 hours. After the reaction was complete, water was added, and the mixture was extracted and concentrated using EA. The crude product was purified by silica gel column chromatography (PE / EA = 85 / 15, v / v) to give the title compound (6 g). MS (ESI, m / z): 233.9 [M+H]+ .

[0745] Step 3: Preparation of 8-bromo-5-chloro-2-oxo-1,2-dihydroquinoline-3-onitrile

[0746] 2-Amino-3-bromo-6-chlorobenzaldehyde (6 g, 25.59 mmol), ethyl cyanoacetate (5.79 g, 51.18 mmol), and ammonium acetate (5.92 g, 76.77 mmol) were added to 1,4-dioxane (10 mL), and the mixture was reacted at 100 °C for 16 h s. After the reaction was complete, the mixture was cooled to room temperature, and a solid precipitated. The solid was then filtered to give the title compound (4.6 g). MS (ESI, m / z): 299.9 [M+NH4] + .

[0747] Step 4: Preparation of 8-bromo-5-chloro-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-nitrile

[0748] 8-Bromo-5-chloro-2-oxo-1,2-dihydroquinoline-3-onitrile (1.0 g, 3.53 mmol), 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-ol (983.16 mg, 4.23 mmol), PyBOP (2.20 g, 4.23 mmol), and DBU (1.07 g, 7.05 mmol) were dissolved in NMP (10 mL) and reacted at 60 °C for 1 hour. After the reaction, water was added and the mixture was extracted and concentrated with EA to obtain the crude product. The crude product was purified by column chromatography (PE / EA = 70 / 30, v / v) to give the title compound (700 mg). MS (ESI, m / z): 497.1 [M+H] + .

[0749] Step 5: Preparation of (5-chloro-3-cyano-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-8-yl)boronic acid

[0750] 8-Bromo-5-chloro-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-onitrile (570 mg, 1.15 mmol), pinacol diboronate (348.94 mg, 1.37 mmol), Pd(dppf)Cl2 (83.79 mg, 114.51 μmol), and AcOK (337.14 mg, 3.44 mmol) were dissolved in 1,4-dioxane (10 mL) and reacted at 100 °C for 5 hrs under nitrogen protection. The crude liquid (proceed to the next step) was a brown title compound (529 mg). MS (ESI, m / z): 463.1 [M+H] +.

[0751] Step 6: Preparation of 5-chloro-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-onitrile

[0752] (5-chloro-3-cyano-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-8-yl)boronic acid (529 mg, 628.82 μmol), 2-bromopyrazine (149.96 mg, 943.23 μmol), cataCXium A Pd G3 (45.80 mg, 62.88 μmol), and K3PO4 (266.95 mg, 1.26 mmol) were dissolved in 1,4-dioxane (10 mL) and H2O (2 mL), and reacted at 100 °C for 3 hours under nitrogen protection. The solution was first concentrated and then subjected to column chromatography (PE / EA, 55% EA, v / v) to give the title compound (180 mg). MS (ESI, m / z): 497.1 [M+H] + .

[0753] Step 7: Preparation of 5-chloro-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide

[0754] 5-Chloro-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-onitrile (90 mg, 152.13 μmol), DMSO (2 mL), K₂CO₃ (21.03 mg, 152.13 μmol), and H₂O₂ (0.5 mL, 35% purity) were added to a reaction flask, and the reaction was carried out at 20 °C for 1 hour. The reaction solution was diluted with water, extracted with EA, and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (78 mg). MS (ESI, m / z): 515.1 [M+H] + .

[0755] Step 8: Preparation of 5-chloro-2-((5-methyl-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide

[0756] 5-Chloro-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide (118 mg, 229.14 μmol) and TFA (2 mL) were added to a reaction flask, and the reaction was carried out at 60 °C for 1 hour. The mixture was first concentrated, then dissolved in MeOH, and the pH was adjusted to 8-9 with NaHCO3. Extraction was performed using EA, and the organic phase was dried and concentrated to obtain the title compound (10 mg). MS (ESI, m / z): 431.1 [M+H) + .

[0757] 1 H NMR (400MHz, DMSO-d6) δ13.11(s,1H),9.02(s,1H),8.55(dd,J=2.5,1.6Hz,1H),8.38-8.32(m,2H),8.27-8.20(m, 2H),8.10(s,1H),7.87(d,J=8.1Hz,1H),7.76(s,1H),7.40(d,J=8.5,Hz,1H),7.27(d,J=8.5Hz,1H),2.18(s,3H).

[0758] Example 25: 5-Methyl-2-((5-methyl-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide (Compound 42)

[0759] 5-Chloro-2-((5-methyl-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide (50 mg, 116.05 μmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxorborane (291.37 mg, 1.16 mmol), cataCXium A Pd G3 (8.45 mg, 11.61 μmol), K3PO4 (49.27 mg, 232.10 μmol), 1,4-dioxane (2 mL), and water (0.2 mL) were added to a reaction flask. The reaction mixture was placed under nitrogen protection and reacted at 100 °C for 5 hours. The reaction solution was diluted with water, extracted with EA, and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered to obtain the title compound (6 mg). MS (ESI, m / z): 411.3 [M+H] + .

[0760] 1H NMR (400MHz, DMSO-d6) δ13.09(s,1H),8.95(s,1H),8.52(dd,J=2.5,1.6Hz,1H),8.37(d,J=1.6Hz,1H),8.30(d,J=2.5Hz,1H),8.19-8.10 (m,2H),8.00(s,1H),7.73(s,1H),7.52(dd,J=7.5,1.1Hz,1H),7.39(d,J=8.5,Hz,1H),7.27(d,J=8.5Hz,1H),2.78(s,3H),2.17(s,3H).

[0761] Example 26: 2-((5-methyl-1H-indazol-4-yl)oxy)-8-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)quinoline-3-carboxamide (Compound 55)

[0762] Step 1: Preparation of 8-cyano-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-carboxamide

[0763] 8-Bromo-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-carboxamide (130 mg, 270.08 μmol), tBuxphos Pd G3 (42.91 mg, 54.02 μmol), Zn(CN)2 (63.43 mg, 540.16 μmol), and Cs2CO3 (263.99 mg, 810.24 μmol) were dissolved in DMF (2 mL), and after purging with nitrogen, the reaction was carried out at 120 °C for 16 hours. The reaction solution was diluted with saturated brine, extracted with ethyl acetate, and purified by normal phase after concentration. The concentration was PE / EA = 0 / 1 (v / v) to give the title compound (45 mg). MS (ESI, m / z): 428.0 [M+H] + .

[0764] Step 2: Preparation of (Z)-8-(N'-hydroxymethamidinyl)-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-carboxamide

[0765] 8-Cyano-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-carboxamide (30 mg, 70.18 μmol), triethylamine (14.20 mg, 140.37 μmol), and hydroxylamine hydrochloride (9.75 mg, 140.37 μmol) were dissolved in ethanol (1 mL), and the mixture was purged with nitrogen and reacted at 60 °C for 5 hours. The reaction solution was diluted with saturated brine, extracted with ethyl acetate, and the organic phase was concentrated and purified in normal phase. The concentration was then adjusted to PE / EA = 0 / 1 (v / v) to give the title compound (20 mg). MS (ESI, m / z): 461.0 [M+H] + .

[0766] Step 3: Preparation of 2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)quinoline-3-carboxamide

[0767] (Z)-8-(N'-hydroxyformamidinyl)-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-carboxamide (25 mg, 54.29 μmol), CDI (17.61 mg, 108.58 μmol), and triethylamine (10.99 mg, 108.58 5 mol) were dissolved in tetrahydrofuran (2 mL), and the mixture was purged with nitrogen and reacted at 70 °C for 3 hours. The reaction solution was diluted with saturated brine, extracted with ethyl acetate, and the organic phase was concentrated to give the title compound (20 mg). MS (ESI, m / z): 487.3 [M+H] + .

[0768] Step 4: Preparation of 2-((5-methyl-1H-indazol-4-yl)oxy)-8-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)quinoline-3-carboxamide

[0769] 2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)quinoline-3-carboxamide (20 mg, 41.11 μmol) was dissolved in dichloromethane (1 mL), and TFA (4.69 mg, 41.11 μmol, 3.15 μL) was added. The reaction solution was reacted at 20 °C for 1 hour. The solvent was concentrated to prepare the product. After lyophilization, the title compound (1.3 mg) was obtained. MS (ESI, m / z): 403.3 [M+H] + .

[0770] 1H NMR (400MHz, DMSO-d6) δ13.12(s,1H),8.87(s,1H),8.28(d,J=7.6Hz,1H),8.15(s,2H),8.03(s,1H),7 .95(s,1H),7.74(s,1H),7.65-7.59(m,1H),7.38(d,J=8.8Hz,1H),7.28(d,J=8.4Hz,1H),2.23(s,3H).

[0771] Example 27: 6-Fluoro-2-((5-methyl-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide (Compound 56)

[0772] Step 1: Preparation of (2-amino-3-bromo-5-fluorophenyl)methanol

[0773] 2-Amino-3-bromo-5-fluorobenzoic acid (1.03 g, 4.27 mmol) and THF (5.00 mL) were added to a flask under nitrogen protection. After cooling the system to 0 °C, lithium aluminum hydride (486.54 mg, 12.82 mmol) was added, and the reaction was carried out at 20 °C for 12 hours. At 0 °C, 0.5 mL of water was added dropwise, followed by 0.5 mL of 15% NaOH aqueous solution, and finally 1.5 mL of water. The mixture was stirred at room temperature for 15 min. Then, some anhydrous Na₂SO₄ was added, and the mixture was stirred for another 15 min before filtration through a diatomaceous earth filter. The filtrate was dried and concentrated to give the title compound (945 mg). MS (ESI, m / z): 220.1, 222.1 [M+H] + .

[0774] Step 2: Preparation of 2-amino-3-bromo-5-fluorobenzaldehyde

[0775] (2-Amino-3-bromo-5-fluorophenyl)methanol (500 mg, 2.27 mmol), DCM (10 mL), and PCC (476.08 mg, 2.27 mmol) were added to the flask, and the reaction was carried out at 20 °C for 1 hour. After the reaction was completed, the mixture was filtered through diatomaceous earth, concentrated, and the crude product was purified by silica gel column chromatography (PE / EA, 10% EA, v / v) to give the title compound (138 mg).

[0776] Step 3: Preparation of 8-bromo-6-fluoro-2-oxo-1,2-dihydroquinoline-3-onitrile

[0777] 2-Amino-3-bromo-5-fluorobenzaldehyde (138 mg, 632.96 μmol), 1,4-dioxane (5.02 mL), ammonium acetate (146.37 mg, 1.90 mmol), and ethyl cyanoacetate (107.40 mg, 949.44 μmol) were added to a flask and reacted at 100 °C for 2 hours. The mixture was first concentrated, then EA and PE were added and stirred. The mixture was filtered to obtain the title compound (144 mg). MS (ESI, m / z): 267.1, 269.1 [M+H] + .

[0778] Step 4: Preparation of 8-bromo-6-fluoro-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-nitrile

[0779] 8-Bromo-6-fluoro-2-oxo-1,2-dihydroquinoline-3-onitrile (122 mg, 456.84 μmol), 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-ol (116.72 mg, 502.52 μmol), DMF (5 mL), and DBU (139.09 mg, 913.67 μmol) were added to a reaction flask and stirred until dissolved. Then, PyBOP (285.28 mg, 548.20 μmol) was added, and the reaction was carried out at 25 °C for 1 hour. The reaction solution was diluted with water, extracted with EA, washed with organic phase brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (PE / EA, 28% EA, v / v) to give the title compound (160 mg). MS (ESI, m / z): 481.1, 483.1 [M+H] + .

[0780] Step 5: Preparation of 6-fluoro-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-onitrile

[0781] The following compounds were added to a reaction flask: 8-bromo-6-fluoro-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-onitrile (140 mg, 290.87 μmol), pyrazine-2-boronic acid (75.87 mg, 581.74 μmol), cataCXium A Pd G3 (21.18 mg, 29.09 μmol), K3PO4 (123.48 mg, 581.74 μmol), 1,4-dioxane (5 mL), and water (1 mL). The reaction was carried out under nitrogen protection at 100 °C for 2 hours. The reaction solution was concentrated, and the crude product was purified by column chromatography (PE / EA, 55% EA, v / v) to give the title compound (70 mg). MS (ESI, m / z): 481.1 [M+H]+ .

[0782] Step 6: Preparation of 6-fluoro-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide

[0783] 6-Fluoro-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-onitrile (70 mg, 145.68 μmol), K₂CO₃ (20.13 mg, 145.68 μmol), DMSO (2 mL), MeOH (1 mL), and H₂O₂ (141.58 mg, 1.46 mmol, 1 mL, 35% purity) were added to a reaction flask, and the reaction was carried out at 20 °C for 1 hour. The reaction solution was diluted with water, extracted with EA, and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (70 mg). MS (ESI, m / z): 499.1 [M+H] + .

[0784] Step 7: Preparation of 6-fluoro-2-((5-methyl-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide

[0785] 6-Fluoro-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide (70 mg, 140.42 μmol) and TFA (2 mL) were added to a reaction flask, and the reaction was carried out at 40 °C for 1 hour. The mixture was first concentrated, then dissolved in MeOH, and the pH was adjusted to 8-9 with NaHCO3. Extraction was performed using EA, and the organic phase was dried and concentrated to obtain the title compound (15 mg). MS (ESI, m / z): 415.1 [M+H] + .

[0786] 1 H NMR (400MHz, DMSO-d6) δ13.11(s,1H),8.91(s,1H),8.58(dd,J=2.5,1.6Hz,1H),8.47(d,J=1.6Hz,1H),8.39(d,J=2.5Hz,1 H),8.17(s,1H),8.15-8.08(m,2H),8.02(s,1H),7.77(s,1H),7.41(d,J=8.4,Hz,1H),7.28(d,J=8.4Hz,1H),2.18(s,3H).

[0787] 19F NMR(376MHz,DMSO-d6)δ-115.14(s,1F).

[0788] Example 28: 2-((5-chloro-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide (Compound 57)

[0789] Step 1: Preparation of 2-bromo-3-chloro-6-fluorobenzaldehyde

[0790] 2-Bromo-1-chloro-4-fluorobenzene (5.0 g, 23.87 mmol) and THF (50 mL) were added sequentially to a 250 mL reaction flask. After purging with nitrogen, the mixture was cooled to -70 to -78 °C and stirred for 20 min. LDA (2.0 M, 17.91 mL, 35.81 mmol) was added dropwise, with the temperature controlled below -60 °C. After the addition was complete, the mixture was kept at this temperature for 30 min. DMF (3.49 g, 47.74 mmol) was then added dropwise. After the addition was complete, the mixture was kept at this temperature for 2 hours. After the reaction was complete, a saturated ammonium chloride aqueous solution was added dropwise to quench the reaction. The mixture was extracted twice with ethyl acetate, concentrated, and stirred. Column chromatography (PE:EA = 0–30%, v / v) was then performed to obtain the title compound (1.5 g).

[0791] Step 2: Preparation of 4-bromo-5-chloro-1H-indazole

[0792] 2-Bromo-3-chloro-6-fluorobenzaldehyde (1.5 g, 6.32 mmol) was dissolved in DMSO (15 mL), and hydrazine hydrate (3.95 g, 63.20 mmol) and K₂CO₃ (1.74 g, 12.64 mmol) were added. The mixture was stirred at 110 °C for 6 hours. After the reaction was complete, water and ethyl acetate were added, and the mixture was extracted twice. The organic phases were combined, washed twice with brine, concentrated, and directly mixed for silica gel column chromatography (PE:EA = 0–30%, v / v). After concentration, the title compound (1.45 g) was obtained. MS (ESI, m / z): 231.0 [M+H] + .

[0793] Step 3: Preparation of 4-bromo-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

[0794] 4-Bromo-5-chloro-1H-indazole (3.45 g, 14.90 mmol) was dissolved in THF (30 mL). After purging with nitrogen three times, NaH (1.79 g, 44.70 mmol) was added in portions at 0 °C. After purging with nitrogen once, the mixture was stirred for 30 min, and then SEMCl (4.97 g, 29.80 mmol) was added dropwise. The mixture was allowed to cool naturally for 2 hours. After the reaction was complete, water and ethyl acetate were added, and the mixture was extracted twice. The organic phases were combined, washed twice with brine, concentrated, and then subjected to silica gel column chromatography (PE:EA = 0–20%, v / v) to give the title compound (4.95 g). MS (ESI, m / z): 360.9 [M+H] + .

[0795] Step 4: Preparation of 5-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

[0796] 4-Bromo-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (4.95 g, 13.75 mmol), pinacol diboronate (3.84 g, 15.12 mmol), potassium acetate (4.05 g, 41.25 mmol), Pd(dppf)Cl2 (1.0 g, 1.37 mmol), and 1,4-dioxane (50 mL) were sequentially added to a 100 mL reaction flask. After purging with nitrogen, the mixture was heated to 100 °C and stirred for 2 hours. After the reaction was complete, the mixture was concentrated and directly mixed with silica gel column chromatography (PE:EA = 0–20%, v / v) to give the title compound (2.0 g). MS (ESI, m / z): 409.3 [M+H] + .

[0797] Step 5: Preparation of 5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-4-ol

[0798] 5-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (2.0 g, 4.89 mmol) was dissolved in DMSO (10 mL), and potassium carbonate (674.82 mg, 4.89 mmol) was added. After the addition was complete, H₂O₂ (2.08 g, 48.90 mmol) was added dropwise, and the mixture was stirred at 25 °C for 2 hours. After the reaction was complete, water and ethyl acetate were added, and the mixture was extracted twice. The organic phases were combined, washed twice with brine, concentrated, and then purified by silica gel column chromatography (PE:EA = 0–40%, v / v) to give the title compound (160 mg). MS (ESI, m / z): 299.1 [M+H] + .

[0799] Step 6: Preparation of 2-((5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-onitrile

[0800] 5-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-4-ol (150.0 mg, 449.97 μmol) and 2-chloro-8-(pyrazin-2-yl)quinoline-3-onitrile (100.0 mg, 374.97 μmol) were dissolved in NMP (4 mL), and cuprous iodide (14.28 mg, 74.99 μmol) and cesium carbonate (183.26 mg, 562.46 μmol) were added. The mixture was stirred at 60 °C for 2 hours. After the reaction was complete, water and ethyl acetate were added, and the mixture was extracted twice. The organic phases were combined, washed twice with brine, concentrated, and then subjected to silica gel column chromatography (PE:EA = 0–50%, v / v) to give the title compound (70.0 mg). MS (ESI, m / z): 529.2 [M+H] + .

[0801] Step 7: Preparation of 2-((5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide

[0802] 2-((5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-onitrile (70.0 mg, 132.33 μmol) was dissolved in DMSO (4 mL), and potassium carbonate (18.26 mg, 132.33 μmol) was added. After the addition was complete, H₂O₂ (56.1 mg, 1.32 mmol) was added dropwise, and the mixture was stirred at 25 °C for 1 hr. After the reaction was complete, water and ethyl acetate were added, and the mixture was extracted twice. The organic phases were combined, washed twice with brine, concentrated, and then purified by silica gel column chromatography (PE:EA = 0–65%, v / v) to give the title compound (50.0 mg). MS (ESI, m / z): 547.3 [M+H] + .

[0803] Step 8: Preparation of 2-((5-chloro-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide

[0804] 2-((5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)oxy)-8-(pyrazin-2-yl)quinoline-3-carboxamide (50.0 mg, 91.36 μmol) was dissolved in DCM (2 mL), and TFA (2 mL) was added. After the addition was complete, the mixture was stirred at 25 °C for 2 hours. After the reaction was complete, sodium bicarbonate aqueous solution and ethyl acetate were added, and the mixture was extracted twice. The organic phases were combined, washed twice with brine, concentrated, and then the title compound (12.0 mg) was obtained by HPLC. MS (ESI, m / z): 417.0 [M+H] + .

[0805] 1 H NMR (400MHz, DMSO-d6) δ13.41(s,1H),8.97(s,1H),8.56(dd,J=2.6,1.6Hz,1H),8.45(d,J=1.6Hz,1H),8.34(d,J=2.6Hz,1H),8.27(s ,1H),8.25(s,1H),8.10(s,1H),8.02(s,1H),7.98(s,1H),7.71(t,J=7.6Hz,1H),7.53(dd,J=8.8,1.0Hz,1H),7.48(d,J=8.8Hz,1H).

[0806] Example 29: 8-(5-chloropyrazin-2-yl)-2-((5-methyl-1H-indazol-4-yl)oxy)quinoline-3-carboxamide (Compound 58)

[0807] Step 1: Synthesis of (3-cyano-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-8-yl)boronic acid

[0808] 8-Bromo-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-onitrile (100.00 mg, 215.83 μmol), pinacol diboronate (82.21 mg, 323.75 μmol), Pd(dppf)Cl2 (15.79 mg, 21.58 μmol), and AcOK (63.55 mg, 647.79 μmol) were dissolved in 1,4-dioxane (4 mL). The mixture was heated to 100 °C and stirred for 2 hours under N2 protection. After the reaction was complete, the mixture was cooled and placed under nitrogen protection. The crude product was directly proceeded to the next step. MS (ESI, m / z): 429.2 [M+H] + .

[0809] Step 2: Synthesis of 8-(5-chloropyrazin-2-yl)-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-nitrile

[0810] (3-cyano-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-8-yl)boronic acid (70.0 mg, 163.33 μmol), 2-bromo-5-chloropyrazine (63.06 mg, 326.72 μmol), cataCXium A Pd G3 (11.89 mg, 16.33 μmol), and K3PO4 (104.01 mg, 489.99 μmol) were dissolved in 1,4-dioxane (6 mL) and H2O (2 mL). The mixture was heated to 120 °C and stirred for 3 hours under N2 protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and silica gel powder was added. The mixture was then purified by silica gel column chromatography (DCM:MeOH = 93:7, v / v) to obtain the title compound (60 mg). MS(ESI,m / z):497.0[M+H] + .

[0811] Step 3: Synthesis of 8-(5-chloropyrazin-2-yl)-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-carboxamide

[0812] 8-(5-chloropyrazin-2-yl)-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-onitrile (60.0 mg, 120.85 μmol) was dissolved in DMSO (3 mL), followed by the addition of K₂CO₃ (166.77 mg, 120.85 μmol) and dropwise addition of H₂O₂ (104.01 mg, 1.21 mmol) with stirring for 2 hours. After the reaction was complete, the reaction solution was slowly added to water, followed by extraction with ethyl acetate (30.0 mL * 3), collection of the organic phase, concentration, and direct administration of the crude product to the next step (50 mg). MS (ESI, m / z): 515.1 [M+H] + .

[0813] Step 4: Synthesis of 8-(5-chloropyrazin-2-yl)-2-((5-methyl-1H-indazol-4-yl)oxy)quinoline-3-carboxamide

[0814] 8-(5-chloropyrazin-2-yl)-2-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-carboxamide (50.0 mg, 97.08 μmol) was dissolved in DCM (2 mL), and TFA (2 mL) was added. The mixture was stirred at 25 °C for 2 hours after the addition was complete. After the reaction was complete, the reaction solution was slowly added to water, and the pH was adjusted to weakly alkaline with NaHCO3. The solution was then extracted with ethyl acetate (30.0 mL * 3), and the organic phase was collected. After purification by prep-HPLC, the solution was lyophilized to give the title compound (25.0 mg). MS (ESI, m / z): 431.0 [M+H] + .

[0815] 1 H NMR (400MHz, DMSO-d6) δ13.14(s,1H),8.94(s,1H),8.68(d,J=1.4Hz,1H),8.33-8.19(m,3H),8.14(s,1H), 7.99(s,1H),7.75(s,1H),7.68(t,J=8.0Hz,1H),7.43(d,J=8.8Hz,1H),7.31(d,J=8.4Hz,1H),2.18(s,3H).

[0816] Example 30: 8-(6-chloropyrazin-2-yl)-2-((5-methyl-1H-indazol-4-yl)oxy)quinoline-3-carboxamide (Compound 59)

[0817] Step 1: Synt...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable form thereof: in: X is selected from N and CH; Y is selected from N and CR. 2 Z is selected from N and CR 3 W is selected from N and CR 4 ; R 1 R 2 R 3 R 4 and R 5 Each is independently selected from hydrogen, halogen, hydroxyl, oxo group, -CN, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NR x R y -C(O)NH2, -C(O) (4-6 membered heterocyclic alkyl groups), -C(O)NH(C 1-6 Alkyl), -C(O)NH(C 3-6 cycloalkyl), -C(O)NH (4-6 membered heterocycloalkyl), -S(O)2 (C 1-6 Alkyl group), -S(O)2NR x R y -O(C 6-10 aryl), -O (5-10 heteroaryl), C 6-10 Aryl and 5-10 heteroaryl groups, wherein each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally substituted by one or more substituents independently selected from: deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl group, optionally selected independently from one or more of deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 3-6 Cycloalkyl, optionally selected independently from one or more of deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The 4-6 membered heterocyclic alkyl group substituted with a haloalkyl group, optionally with one or more groups independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 6-10 The aryl group is optionally selected independently from one or more deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 The 5-10 membered heteroaryl group substituted by the haloalkyl group is preferably each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl group, optionally selected independently from one or more of deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 3-6 Cycloalkyl, optionally selected independently from one or more of deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The 4-6 membered heterocyclic alkyl group substituted with a haloalkyl group, optionally with one or more groups independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 6-10 The aryl group is optionally selected independently from one or more deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 The 5-10 membered heteroaryl group substituted by the haloalkyl group, more preferably the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, is optionally each independently selected from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-10 Substitution of aryl and 5-10 heteroaryl groups; Or R 1 and R 2 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl or 5-10-membered heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups; Or R 2 and R 3 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, 4-14 membered heterocyclic alkyl, C 6-10 Aryl or 5-10-membered heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups; Or R 3 and R 4 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, 4-14 membered heterocyclic alkyl, C 6-10 Aryl or 5-10-membered heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups; Or R 4 and R 5 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl or 5-10-membered heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups; R 6 R 7 and R 8 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Haloalkyl, wherein the alkyl, cycloalkyl or haloalkyl group is optionally each selected independently from one or more of deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups; preferably, R 6 R 7 and R 8 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Halogenated alkyl groups; R 9 For OH; R 10 Selected from hydrogen, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Halogenated alkyl groups; or R 9 with R 10 together form -CR 11 = N-NH-, and R 11 is selected from hydrogen and halogen; R x and R y Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-8 cycloalkyl, -C(O)(C 1-6 Alkyl), -C(O)(C 3-6 cycloalkyl), -C(O) (4-6 membered heterocycloalkyl), -C(O)O(C 1-6 Alkyl), -C(O)O(C 3-6 cycloalkyl), -C(O)O (4-6 membered heterocycloalkyl), -S(O)2 (C 1-6 Alkyl), -S(O)2(C 3-6 Cycloalkyl), -S(O)2 (4-6 membered heterocycloalkyl), 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 heteroaryl groups; each of the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently by one or more radicals selected from deuterium, halogen, hydroxyl, oxo group, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -O(C) 1-6 Alkyl groups, -NH2, -C(O)NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups; The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs.

2. The compound according to claim 1 or a pharmaceutically acceptable form thereof, satisfying one or more of the following conditions: (1) X is CH; or X is N; (2) Y is N; or Y is CR 2 ; (3) Z is N; or Z is CR 3 ; (4) W is N; or W is CR 4 ; (5)R 1 Selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 alkyl), -NR x R y -C(O) (4-6 membered heterocyclic alkyl groups), -C(O)NH(C 1-6 Alkyl), -C(O)NH(C 3-6 cycloalkyl), -C(O)NH (4-6 membered heterocycloalkyl), -O(C 6-10 aryl), -O (5-10 heteroaryl), C 6-10 Aryl and 5-10 heteroaryl groups, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally each selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups, preferably wherein each of the alkyl, cycloalkyl, heterocyclic alkyl, aryl or heteroaryl groups is optionally replaced by one or more groups independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups; Furthermore, R 1 Selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl groups, -NH2, -NH(C) 1-6 alkyl), -NH(C) 3-8 cycloalkyl), -NH(C 6-10 aryl), -NH (4-6 membered heterocyclic alkyl), -NH (5-10 membered heteroaryl), -O (C 6-10 aryl), -O (5-10 heteroaryl), C 6-10 Aryl and 5-10 heteroaryl groups, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally each selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups, preferably wherein each of the alkyl, cycloalkyl, heterocyclic alkyl, aryl or heteroaryl groups is optionally replaced by one or more groups independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups; Preferably, R 1 Selected from hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-14-membered heterocycloalkyl, -O (4-6-membered heterocycloalkyl), and 5-10-membered heteroaryl, wherein each of the alkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally selected independently by one or more of deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups, preferably wherein each of the alkyl, cycloalkyl, heterocyclic alkyl or heteroaryl groups is optionally replaced by one or more groups independently selected from halogen, oxo, hydroxyl and C. 1-6 Alkyl substituents; Furthermore, R 1 Selected from hydrogen, cyano, -NH(C) 1-6 Alkyl groups (e.g., methylamino groups), -NH(C) 3-8 cycloalkyl), -NH(C 6-10 Aryl (e.g., phenylamino), -NH (5-10 membered heteroaryl) (e.g., pyrazoleamino), C 6-10 Aryl (e.g., phenyl), 5-10 heteroaryl (e.g., pyridine, pyrazole), C 1-6 Alkyl (e.g., methyl, isopropyl), C 3-6 Cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclohexyl), (For example )、 (For example )、 (For example )、 Or R 1 Selected from Or R 1 Selected from Or R 1 Selected from (6)R x and R y Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally selected independently by one or more groups selected from deuterium, halogen, hydroxyl, oxo group, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -O(C) 1-6 Alkyl groups, -NH2, -C(O)NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups; (7)R 2 Selected from hydrogen, halogen, hydroxyl, oxo group, -CN, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 alkyl), -NR x R y -C(O)NH2, -C(O) (4-6 membered heterocyclic alkyl groups), -C(O)NH(C 1-6 Alkyl), -C(O)NH(C 3-6 Cycloalkyl), -C(O)NH (4-6 membered heterocycloalkyl), C 6-10 Aryl and 5-10 heteroaryl groups; each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 alkyl), -NR x R y C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups; Preferably, R 2 Selected from hydrogen, halogens, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NR x R y C6 aryl and 5-6 heteroaryl; the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are each optionally selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups; More preferably, R 2 Selected from hydrogen, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; (8)R 1 With R 2 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, C6 aryl, or 5-6 heteroaryl groups, wherein each cycloalkyl, aryl, or heteroaryl group is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups; (9)R 3 Selected from hydrogen, halogen, hydroxyl, oxo group, -CN, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NR x R y -C(O)NH2, -C(O) (4-6 membered heterocyclic alkyl groups), -C(O)NH(C 1-6 Alkyl), -C(O)NH(C 3-6 Cycloalkyl), -C(O)NH (4-6 membered heterocycloalkyl), C 6-10 Aryl and 5-10 heteroaryl groups; each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups; Preferably, R 3 Selected from hydrogen, halogen, oxo group, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 alkyl), -NH(C) 1-6 alkyl), -NH (5-6 membered heteroaryl), C 6-10 Aryl and 5-10 heteroaryl groups; each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups; More preferably, R 3 Selected from hydrogen, halogens, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NR x R y C6 aryl and 5-6 heteroaryl; the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are each optionally selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups; More preferably, R 3 Selected from hydrogen, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; (10)R 2 With R 3 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, C6 aryl, or 5-6 heteroaryl groups, wherein each cycloalkyl, aryl, or heteroaryl group is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 alkyl), -NR x R y C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups; (11)R 4 Selected from hydrogen, halogen, hydroxyl, oxo group, -CN, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NR x R y -C(O)NH2, -C(O) (4-6 membered heterocyclic alkyl groups), -C(O)NH(C 1-6 Alkyl), -C(O)NH(C 3-6 Cycloalkyl), -C(O)NH (4-6 membered heterocycloalkyl), C 6-10 Aryl and 5-10 heteroaryl groups; each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally substituted by one or more substituents independently selected from: deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl group, optionally selected independently from one or more of deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 3-6 Cycloalkyl, optionally selected independently from one or more of deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The 4-6 membered heterocyclic alkyl group substituted with a haloalkyl group, optionally with one or more groups independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 6-10 The aryl group is optionally selected independently from one or more deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 The 5-10 membered heteroaryl group substituted by the haloalkyl group is preferably a alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, each optionally being selected independently by one or more elements selected from deuterium, halogen, -CN, oxo, hydroxyl, C. 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-10 Substitution of aryl and 5-10 heteroaryl groups; Furthermore, R 4 Selected from hydrogen, halogens, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NHR x C 6-10 Aryl and 5-6-membered heteroaryl; each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more substituents independently selected from: deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y Optionally selected by one or more independently chosen from deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 3-6 Cycloalkyl, optionally selected independently from one or more of deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The 4-6 membered heterocyclic alkyl group substituted with a haloalkyl group, optionally with one or more groups independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 6-10 The aryl group is optionally selected independently from one or more deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 5-10 membered heteroaryl groups substituted with haloalkyl groups; Preferably, R 4 Selected from hydrogen, halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -O (4-6 membered heterocycloalkyl), -S (C 1-6 Alkyl), -NHR x C 6-10 Aryl and 5-6-membered heteroaryl; each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-10 Substitution of aryl and 5-10 heteroaryl groups; Furthermore, R 4 Selected from hydrogen, halogens, -CN, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group, wherein the alkyl, alkenyl, or alkynyl group is optionally substituted by one or more substituents independently selected from: deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y Optionally selected by one or more independently chosen from deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 3-6 Cycloalkyl, optionally selected independently from one or more of deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The 4-6 membered heterocyclic alkyl group substituted with a haloalkyl group, optionally with one or more groups independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl and C 1-6 The C-substituent of the haloalkyl group 6-10 The aryl group is optionally selected independently from one or more deuterium, halogen, -CN, oxo group, hydroxyl group, C 1-6 Alkyl and C 1-6 5-10 membered heteroaryl groups substituted with haloalkyl groups; Preferably, R 4 Selected from hydrogen, halogens, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group, wherein the alkyl, alkenyl, or alkynyl group is each optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-10 Substitution of aryl and 5-10 heteroaryl groups; (12)R 3 With R 4 Together with the atoms it is attached to, they form C 3-6 Cycloalkyl, C6 aryl, or 5-6 heteroaryl groups, wherein each cycloalkyl, aryl, or heteroaryl group is optionally selected independently from one or more deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups; (13)R 5 Selected from hydrogen, halogen, hydroxyl, oxo group, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C) 3-6 cycloalkyl), -NH2, -NH(C 1-6 alkyl), -NH(C) 3-6 cycloalkyl), -NH (4-6 membered heterocycloalkyl), -NH (C 6-10 Aryl) and -NH (5-10 heteroaryl); the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is each optionally selected independently by one or more groups selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y -C(O)NR x R y -SO2-C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-10 Substitution of aryl and 5-10 heteroaryl groups; Preferably, R 5 Selected from hydrogen, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -NH(C) 1-6 alkyl), -NH(C) 3-6 cycloalkyl), -NH (4-6 membered heterocycloalkyl), -NH (C 6-10 aryl) and -NH (5-10 heteroaryl); (14)R 4 With R 5 Together with the atoms to which they are attached, they form 4-14 membered heterocyclic alkyl groups, wherein the heterocyclic alkyl group is optionally composed of one or more elements independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C. 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C) 1-6 Alkyl), -NR x R y C 3-6 Substitution of cycloalkyl and 4-6 membered heterocyclic alkyl groups; (15)R 6 Selected from hydrogen, halogens, C 1-4 Alkyl, C 3-4 cycloalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Deuterated alkyl; preferably, R 6 Selected from hydrogen, halogens, C 1-4 Alkyl, C 3-4 cycloalkyl and C 1-4 Deuterated alkyl; more preferably, R 6 Selected from hydrogen, halogens, C 1-4 Alkyl, C 3-4 cycloalkyl and C 1-4 Halogenated alkyl; more preferably, R 6 Selected from hydrogen, fluorine, chlorine, and methyl; (16)R 7 Selected from hydrogen, halogens, C 1-4 Alkyl and C 1-4 Halogenated alkyl; preferably, R 7 Selected from hydrogen and fluorine; (17)R 8 Selected from hydrogen, halogens, C 1-4 Alkyl and C 1-4 Halogenated alkyl; preferably, R 8 Selected from hydrogen and fluorine; (18)R 10 Selected from hydrogen, halogens, C 1-4 Alkyl, C 3-4 cycloalkyl and C 1-4 Halogenated alkyl; preferably, R 10 Selected from hydrogen, methyl, chlorine, fluorine, and difluoromethyl; (19)R 9 With R 10 Together they form -CH=N-NH-; (20)R 11 It is hydrogen.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable form thereof, wherein formula (I) is further formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), formula (I-1'), formula (I'), formula (IA'), formula (I-1A), formula (I-1B), formula (I-1C), formula (I-1D), or formula (I-1E):

4. A compound or a pharmaceutically acceptable form thereof, wherein the compound is selected from: The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs.

5. A pharmaceutical composition comprising the compound of any one of claims 1 to 4 or a pharmaceutically acceptable form thereof, or a mixture thereof, and one or more pharmaceutically acceptable carriers.

6. Use of the compound of any one of claims 1 to 4 or a pharmaceutically acceptable form thereof, or the pharmaceutical composition of claim 5, in the preparation of a PKMYT1 inhibitor.

7. Use of the compound of any one of claims 1 to 4 or a pharmaceutically acceptable form thereof or the pharmaceutical composition of claim 5 in the preparation of a medicament, particularly in the preparation of a medicament for the prevention or treatment of diseases or symptoms associated with PKMYT1 activity; Preferably, the disease or symptom associated with PKMYT1 activity is a tumor or cancer; Preferably, the tumor or cancer is a tumor or cancer with high expression of the CCNE1 gene / CCNE1 gene expansion or with an FBXW7 gene inactivation mutation; Preferably, the cancers with high CCNE1 gene expression / CCNE1 gene expansion are uterine cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, liver cancer, or endometrial cancer.

8. A method for preparing the compound or a pharmaceutically acceptable form thereof according to any one of claims 1 to 4, wherein the method is selected from the following: Method 1 includes one or more steps from steps (1) to (5) of the following route: The route is, for example, the following route: in: Step (1) involves reacting compound I-1 (e.g., compound IA-1) with compound IA-2 to obtain compound I-3 (e.g., compound IA-3); Step (2) involves halogenating compound I-3 to obtain compound I-4 (e.g., compound IA-4); Step (3) involves reacting compound I-4 with compound IA-5 to give compound I-6 (e.g., compound IA-6); Step (4) involves coupling compound I-6 to obtain compound I-7 (e.g., compound IA-7); Step (5) involves hydrolyzing compound I-7 to obtain compound I' (e.g., compound IA'); Method 2 includes the following steps: Among them, compound I-3 is reacted with compound IA-5 to generate compound I-6; Method 3 includes one or more steps from steps (1) to (2) of the following route: The route is, for example, the following route: in: Step (1) hydrolyzes compound I-6 (e.g., compound IA-6) to obtain compound I-6-2 (e.g., compound IA-6-2); Step (2) involves coupling compound I-6-2 to obtain compound I'; Method four includes one or more steps from steps (1) to (3) of the following route: The route is, for example, the following route: in: Step (1) involves coupling compound I-6 with pinacol diboronic acid ester to generate compound I-6-1 (e.g., compound IA-6-1); Step (2) involves coupling compound I-6-1 to obtain compound I-7; Step (3) involves hydrolyzing compound I-7 to obtain compound I'; Method 5 includes one or more steps from steps (1) to (3) of the following route: in: Step (1) involves coupling compound I-4 with pinacol diboronic acid ester to generate compound I-4-1; Step (2) involves coupling compound I-4-1 to obtain compound I-4-2; Step (3) involves a substitution reaction between compound I-4 and compound IA-5 to yield compound I-7. in, X 1 It is a halogen, such as chlorine, bromine or iodine, preferably bromine; X 2 It is a halogen, such as chlorine, bromine or iodine, preferably chlorine; R 9 and R 10 As defined in any one of claims 1-4, or R 9 For -OPG 2 , or R 9 With R 10 Co-formation -CR 11 =NN(PG) 1 )-, PG 1 The protecting group is a hydrogen or amino group, such as an alkoxycarbonyl amino group, for example, benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), fluorenemethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl (or ethoxycarbonyl); acyl amino groups, such as phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), o-(p-)nitrobenzenesulfonyl (Ns), tert-pentanoyl, benzoyl, tert-butoxycarbonyl, 9-fluorenemethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, trimethylsilylethoxycarbonyl, benzyloxycarbonyl, p-methylbenzenesulfonyl, p-nitrobenzenesulfonyl, trifluoroacetyl, methoxycarbonyl, or ethoxycarbonyl; alkyl amino groups, such as triphenylmethyl (Trt), C 1-6 Alkyl-substituted triphenylmethyl, p-methoxytriphenylmethyl (MMT), dimethoxytriphenylmethyl (DMT), 2,4-dimethoxybenzyl (Dmb), 4-methoxybenzyl (PMB), benzyl (Bn); tetrahydropyranyl (THP); or (trimethylsilyl)ethoxymethyl (SEM); preferably, the amino protecting group is tetrahydropyranyl (THP) or (trimethylsilyl)ethoxymethyl (SEM); The PG 2 The protecting group is a hydrogen or hydroxyl group, such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), (trimethylsilyl)ethoxymethyl (SEM), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl or p-nitrobenzoyl, preferably (trimethylsilyl)ethoxymethyl (SEM); Y, Z, W, R 1 R 2 R 3 R 4 R 6 R 7 R 8 R 11 As defined in any one of claims 1 to 4; Among them, in R 9 For -OPG 2 , or R 9 With R 10 Co-formation -CR 11 =NN(PG) 1 When )-, the method further includes a deprotection reaction step.

9. Compounds or their salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, or isotope labels having the following structures: in, Y, Z, W, R 1 R 2 R 3 R 4 R 6 R 7 R 8 R 9 R 10 X 1 X 2 As defined in claim 8.

10. A method for preventing or treating a disease or condition associated with PKMYT1 activity, the method comprising administering to an individual in need an effective amount of any one of claims 1 to 4, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition as described in claim 5; Preferably, the disease or symptom associated with PKMYT1 activity is a tumor or cancer; Preferably, the tumor or cancer is a tumor or cancer with high expression of the CCNE1 gene / CCNE1 gene expansion or with an FBXW7 gene inactivation mutation; Preferably, the cancers with high CCNE1 gene expression / CCNE1 gene expansion are uterine cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, liver cancer, or endometrial cancer.

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