Heteroaromatic ring-containing compound, pharmaceutical composition comprising same, and preparation method therefor and use thereof

Abstract

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

Description

Compounds containing heteroaromatic rings, pharmaceutical compositions containing the same, and preparation methods and uses thereof

[0001] Citation of Related Applications

[0002] The present disclosure claims priority to invention patent applications filed on January 31, 2024, March 27, 2024, May 31, 2024 and September 3, 2024 with the State Intellectual Property Office of China, with application numbers 202410142067.2, 202410358393.7, 202410696578.9 and 202411232976.1, all titled “Compounds containing heteroaromatic rings, pharmaceutical compositions containing the same, and methods for preparing the same and uses thereof”, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present disclosure belongs to the field of medicinal chemistry and relates to a compound containing a heteroaromatic ring used as a membrane-associated tyrosine / threonine protein kinase 1 (PKMYT1) inhibitor, a pharmaceutical composition containing the compound, a preparation method thereof, and medical uses thereof. Background Art

[0004] PKMYT1 (membrane-associated tyrosine / threonine protein kinase 1, also known as MYT1) is a protein kinase that belongs to the WEE protein kinase family and is involved in cell cycle regulation. The WEE protein kinase family includes three members: WEE1, WEE2, and MYT1. 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 cells, PKMYT1 plays a key role in cell cycle regulation, primarily involved in controlling mitotic progression. Studies have shown that PKMYT1 acts at the G2 / M checkpoint and is dispensable for normal cell cycle progression, whereas WEE1 acts at multiple checkpoints, including S, G2 / M, and M, and is essential for normal cell cycle progression. This suggests that inhibition of PKMYT1 may be less toxic to normal cells than inhibition of 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 mainly through two independent mechanisms: 1) PKMYT1 can phosphorylate Thr14 and Tyr15 on the substrate Cdk1, thereby inhibiting the activity of the Cdk1 / CycB complex and causing G2 / M arrest in the cell cycle; 2) PKMYT1 binds to Cdk1 and sequesters it in the cytoplasm, preventing the Cdk1 / CycB complex from entering the nucleus, thereby preventing the cell cycle from progressing (Schmidt*M et al., Regulation of G2 / M Transition by Inhibition of WEE1 and PKMYT1Kinases, 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, in response to the replication pressure brought about by the high proliferation rate demand, PKMYT1 can ensure that tumor cells repair DNA damage by upregulating expression, maintaining replication pressure and genomic stability of tumor cells, and thus exerting a tumor-promoting function. Inhibiting PKMYT1 forces the cell cycle of tumor cells that have not completed DNA damage repair to enter the next stage, leading to the accumulation of DNA damage in tumor cells, increased genetic instability, inducing cell apoptosis and mitotic catastrophe, and achieving a tumor suppressive effect. Studies by David Gallo et al. have confirmed that CCNE1 can activate the MMB-FOXM1 transcription complex, thereby upregulating CDK1 and CCNB1 gene expression. In CCNE1 overexpressing cells, CyclinB and CDK1 expression are increased, and such cells are more sensitive to PKMYT1 inhibition, leading to synthetic lethality (David Gallo et al., CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition, Nature, 2022, 604(7907):749-756).

[0007] PKMYT1 and FBXW7 are key genes that exhibit synthetic lethality with CCNE1, with PKMYT1 being the most highly dependent on CCNE1-amplified tumor cell lines. Furthermore, FBXW7 mutations are highly sensitive to PKMYT1 inhibitors, suggesting that FBXW7 is part of a synthetic lethal pair with MYT1.

[0008] The MYT1 gene (mRNA level) is highly expressed in a variety of human tumors, such as gastric cancer, NSCLC, esophageal cancer, renal clear cell carcinoma, glioma, CRC, breast cancer, endometrial cancer, prostate cancer, head and neck squamous cell carcinoma, liver cancer, thyroid cancer, pancreatic cancer, bile duct cancer, etc. (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 setting of CCNE1 gene amplification. Currently, no PKMYT1 inhibitors are available. Therefore, the development of new, highly effective, and low-toxic PKMYT1 inhibitors is needed to meet clinical needs. Summary of the Invention

[0010] The present disclosure aims to provide a novel class of compounds containing heteroaromatic rings, which have excellent inhibitory activity against PKMYT1 and can be used to prevent or treat diseases or conditions associated with PKMYT1 activity.

[0011] One aspect of the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable form thereof:

[0012] in:

[0013] X is selected from N and CH; Z is selected from N and CR 3 ;

[0014] R 1 、R 2 and R 3 Each independently selected from hydrogen, halogen, hydroxyl, oxo, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 heterocycloalkyl),-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), -S(O)2NR x R y 、-O(C 6-10 aryl), -O(5-10 membered heteroaryl), C 6-10 Aryl and 5-10 membered heteroaryl; or R 1 With R 2 Together with the atoms it is connected to form C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C6 aryl or 5-6 membered heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more 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 Ry 、-SO2-C 1-6 Alkyl, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocycloalkyl;

[0015] R 4 Selected from hydrogen, halogen, R 5 and NHR 5 ;

[0016] R 5 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are each optionally substituted by one or more 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 heterocycloalkyl;

[0017] R 6 、R 7 and R 8 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 alkyl halide;

[0018] R 9 Selected from OH; R 10 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 haloalkyl; or R 9 With R 10 Co-formed-CR 11 =N-NH-, and R 11 selected from hydrogen and halogen;

[0019] R x and R y are each independently selected from hydrogen, 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 3-6Cycloalkyl), -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 membered heteroaryl; each of the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more independently selected from deuterium, halogen, hydroxyl, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 alkyl), -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 heterocycloalkyl;

[0020] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled substances, metabolites, or prodrugs.

[0021] Another aspect of the present 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, wherein the pharmaceutically acceptable form is selected from a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug.

[0022] Another aspect of the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present disclosure, for use in preventing or treating a disease or condition associated with PKMYT1 activity, wherein the pharmaceutically acceptable form is selected from a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug.

[0023] Another aspect of the present disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present disclosure in the preparation of a medicament, in particular in the preparation of a medicament for preventing or treating a disease or condition associated with PKMYT1 activity, wherein the pharmaceutically acceptable form is selected from a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug.

[0024] Another aspect of the present disclosure provides a method for preventing or treating a disease or condition associated with PKMYT1 activity, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present disclosure, wherein the pharmaceutically acceptable form is selected from a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug.

[0025] Another aspect of the present disclosure provides methods of preparing the compounds of the present disclosure.

[0026] Another aspect of the present disclosure provides intermediates for preparing the compounds of the present disclosure. DETAILED DESCRIPTION

[0027] General Terms and Definitions

[0028] Unless otherwise defined, the meanings of the terms used herein are the same as those generally understood by those skilled in the art. The technical intent used herein refers to the technology generally understood in the art, including variations or equivalent substitutions of the technology that are obvious to those skilled in the art. Although the following terms are readily understood by those skilled in the art, they are still set forth below to better explain the present disclosure.

[0029] The terms "include," "comprising," "having," or "involving," and their variations herein, are intended to be inclusive or open-ended collective concepts and do not exclude other unlisted elements or method steps. Those skilled in the art will appreciate that the above terms, such as "comprising," encompass the meaning of "consisting of."

[0030] The term "one or more" or the similar expression "at least one" means, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.

[0031] When the lower and upper limits of a numerical range are disclosed, any value or sub-range falling within the range is specifically disclosed. In particular, each numerical range of a parameter disclosed herein (e.g., in the form of "about a to b," or equivalently "approximately a to b," or equivalently "about a b") should be understood to encompass every value and sub-range therein. For example, "C 1-6 " should be understood to include any sub-ranges and every point value therein, such as C 2-5 、C 3-4 、C 1-2 、C 1-3 、C 1-4 、C 1-5etc., as well as C1, C2, C3, C4, C5, C6, etc. For another example, "3-10 yuan" should be understood to cover any sub-range and every point value therein, such as 3-4 yuan, 3-5 yuan, 3-6 yuan, 3-7 yuan, 3-8 yuan, 3-9 yuan, 4-5 yuan, 4-6 yuan, 4-7 yuan, 4-8 yuan, 5-7 yuan, 5-8 yuan, 6-7 yuan, etc., as well as 3, 4, 5, 6, 7, 8, 9, 10 yuan, etc.

[0032] When used herein alone or in combination with other groups, the term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group. For example, the term "C 1-6 "Alkyl" refers to a saturated straight 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 The term "alkyl" may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl. 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).

[0033] When used herein alone or in combination with other groups, the term "alkylene" refers to a saturated straight or branched chain divalent hydrocarbon group. For example, the term "C 1-6 The term "alkylene" refers to a saturated straight-chain or branched divalent hydrocarbon group having 1 to 6 carbon atoms, such as methylene, ethylene, propylene, butylene, pentylene, hexylene, and the like.

[0034] When used herein alone or in combination with other groups, the term "hydroxyalkyl" refers to an alkyl group substituted with one or more (such as 1 to 3) hydroxy groups. For example, the term "C 1-6 "Hydroxyalkyl" refers to a hydroxyalkyl group having 1 to 6 carbon atoms, for example wait.

[0035] As used herein, alone or in combination with other groups, the term "cycloalkyl" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic hydrocarbon group; for example, a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutene, cyclopentene, cyclohexene; or a bicyclic ring including a spirocyclic ring, a fused ring or a bridged ring (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[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 ring carbon atoms, such as C 3-6 Cycloalkyl (e.g. C 3-4 Cycloalkyl), which may be a monocyclic alkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, or a bicyclic alkyl group, such as C 5-8 Spiroalkyl, C 5-8 Bridged cycloalkyl, C 5-8 Condensed cycloalkyl, C 5-6 Spiroalkyl, C 5-6 Bridged cycloalkyl or C 5-6 Fused cycloalkyl.

[0036] As used herein, alone or in combination with other groups, the term "heterocyclyl" or "heterocycloalkyl" refers 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 independently selected from N, O, P, and S. The term also encompasses situations where a C atom or P atom in the ring can be substituted with an oxo group (=O), a S atom in the ring can be substituted with one or two oxo groups (=O), or a N atom on the ring can form a nitrogen oxide. The ring system in a heterocycloalkyl group can be a fused ring, a bridged ring, or a spiro ring system. If the valence requirements are met, a heterocycloalkyl group can be connected to other groups (or fragments) through any one carbon atom or heteroatom in the ring. For example, 3-12 membered, 3-8 membered, 3-6 membered, 4-14 membered heterocycloalkyl (e.g., 4-10 membered heterocycloalkyl or 4-6 membered heterocycloalkyl) includes but is not limited to oxirane, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxolanyl, dioxane, tetrahydrothiophenyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, wait.

[0037] In the present disclosure, the heterocyclic group can form a parallel ring structure with a heterocyclic group, a cycloalkyl group, an aryl group or a heteroaryl group, and the connection point of the parallel ring structure with the other groups can be on any ring. Therefore, the heterocyclic group (such as a 4-14 membered heterocyclic group or a 4-10 membered heterocyclic group) disclosed in the present disclosure also includes (but is not limited to) heterocyclic groups and heterocyclic groups, heterocyclic groups and cycloalkyl groups, monoheterocyclic groups and monoheterocyclic groups, monoheterocyclic groups and monocycloalkyl groups, monoheterocyclic groups and (monocyclic) aryl groups, spiroheterocyclic groups and (monocyclic) aryl groups, monoheterocyclic groups and (monocyclic) heteroaryl groups, such as 3-7 membered (mono) heterocyclic groups and 3-7 membered (mono) heterocyclic groups, 3-7 membered (mono) heterocyclic groups and (mono) cycloalkyl groups, 3-7 membered (mono) heterocyclic groups and C 4-6 (mono)cycloalkyl, 3-7 membered (mono)heterocyclylphenyl, 3-7 membered (mono)heterocyclyl and 5-6 membered (mono)heteroaryl, examples of which include but are not limited to pyrrolidinyl and cyclopropyl, cyclopentyl and aziridine, pyrrolidinyl and cyclobutyl, pyrrolidinyl and pyrrolidinyl, pyrrolidinyl and piperidinyl, pyrrolidinyl and piperazinyl, piperidinyl and morpholinyl, (For example ), (For example ),

[0038] In the present disclosure, the heterocyclic group (eg, a 4- to 14-membered heterocyclic group or a 4- to 10-membered heterocyclic group) also includes a bridged heterocyclic group and a spiro heterocyclic group.

[0039] As used herein, the term "bridged heterocycle" refers to a cyclic structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen atoms, nitrogen atoms, and / or sulfur atoms) formed by two saturated rings sharing two ring atoms that are not directly connected, including but 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, 7-10 membered sulfur-containing bridged heterocycles, etc., for example The "nitrogen-containing bridged heterocycle", "oxygen-containing bridged heterocycle" and "sulfur-containing bridged heterocycle" optionally further contain one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur. The bridged heterocyclic group is, for example, wait.

[0040] As used herein, the term "spiroheterocycle" refers to a cyclic structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen atoms, nitrogen atoms, sulfur atoms) formed by two or more saturated rings sharing a ring atom, including but not limited to 5-10 membered spiroheterocycles, 6-10 membered spiroheterocycles, 6-10 membered nitrogen-containing spiroheterocycles, 6-10 membered oxygen-containing spiroheterocycles, 6-10 membered sulfur-containing spiroheterocycles, etc., for example The "nitrogen-containing spiro heterocycle", "oxygen-containing spiro heterocycle" and "sulfur-containing spiro heterocycle" optionally further contain one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur. The term "6-10 membered nitrogen-containing spiro heterocyclic group" refers to a spiro heterocyclic group containing a total of 6-10 ring atoms and at least one of which is a nitrogen atom. The spiro heterocyclic group is, for example, wait

[0041] The term "saturated heterocycle" refers to a fully saturated heterocycle, such as a tetrahydrofuran ring, a piperidine ring, a tetrahydropyran ring, a piperazine ring, etc. The term "partially saturated heterocycle" refers to a heterocycle containing 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.

[0042] As used herein, the term “3-8 membered heterocyclyl” or “3-8 membered heterocycloalkyl” means a heterocyclyl group containing 3-8 ring atoms, including but not limited to a 4-8 membered heterocyclyl group, a 4-7 membered heterocyclyl group, a 4-6 membered heterocyclyl group, a 5-6 membered heterocyclyl group, a 3-7 membered heterocyclyl group, a 4-6 membered nitrogen-containing heterocyclyl group, a 4-6 membered oxygen-containing heterocyclyl group, a 4-6 membered sulfur-containing heterocyclyl group, a 5-6 membered nitrogen-containing heterocyclyl group, a 5-6 membered oxygen-containing heterocyclyl group, a 5-6 membered sulfur-containing heterocyclyl group, and the like, wherein each of the “nitrogen-containing heterocyclyl group”, “oxygen-containing heterocyclyl group” and “sulfur-containing heterocyclyl group” optionally further contains one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur. Examples of “4- to 6-membered heterocyclyl” or “4- to 6-membered heterocycloalkyl” include, but are not limited to, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxolanyl, dioxanyl, tetrahydrothiophenyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and the like.

[0043] As used herein, the term "aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (such as bicyclic) aromatic group having a conjugated π electron system. 6-10 "Aryl" refers to an aromatic group containing 6-10 carbon atoms, such as phenyl (i.e., C6 aryl) or naphthyl.

[0044] As used herein, alone or in combination with other groups, the term "heteroaryl" or "heteroaromatic ring" refers to an aromatic group having a conjugated π electron system, a monocyclic or fused ring, and 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 independently selected from N, O, P, and S. A heteroaryl group can be characterized by the number of ring atoms. For example, a 5-12 membered heteroaryl group can contain 5-12 (e.g., 5, 6, 7, 8, 9, 10, 11, or 12) ring atoms, particularly 5, 6, 7, 8, 9, or 10 ring atoms. A heteroaryl group can be attached to the parent molecular moiety via any one of the ring atoms if valence requirements are met. For example, examples of heteroaryl groups include thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridine, pyrimidine, pyrazine, pyridazine, etc. The term also encompasses situations where the heteroaryl group is optionally further fused to an aryl (e.g., phenyl) or heteroaryl ring to form a fused ring system, for example wait.

[0045] As used herein, the term "5-10 membered heteroaryl" or "5-10 membered heteroaromatic ring" means a heteroaryl group (heteroaromatic ring) containing 5 to 10 (e.g., 5, 6, 7, 8, 9, 10) ring atoms, including a 5-10 membered nitrogen-containing heteroaryl group, a 5-10 membered oxygen-containing heteroaryl group, and a 5-10 membered sulfur-containing heteroaryl group. For example, "5-6 membered heteroaryl" or "5-6 membered heteroaromatic ring" includes a 5-6 membered nitrogen-containing heteroaryl group, a 5-6 membered oxygen-containing heteroaryl group, a 5-6 membered sulfur-containing heteroaryl group, etc. The "nitrogen-containing heteroaryl group," "oxygen-containing heteroaryl group," and "sulfur-containing heteroaryl group" 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, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, etc., or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and 5-10 membered paracyclic groups containing these groups, such as benzo derivatives of these groups or paracyclic groups formed by condensing these groups, such as wait.

[0046] The term "fused ring system (fused ring)" refers to a polycyclic structure formed by two or more (e.g., 3, 4, or 5) carbocyclic or heterocyclic rings with a common ring edge, wherein the carbocyclic ring includes a cycloalkyl group and an aryl group, and the heterocyclic ring includes a heteroaryl group and a heterocycloalkyl group. The fused ring system is, for example, a fused ring system formed by a cycloalkyl group and a cycloalkyl group, a fused ring system formed by a cycloalkyl group and a heterocycloalkyl group, a fused ring system formed by a cycloalkyl group and an aryl group, a fused ring system formed by a cycloalkyl group and a heteroaryl group, a fused ring system formed by a heterocycloalkyl group and a heteroaryl group, a fused ring system formed by a heterocycloalkyl group and an aryl group, a fused ring system formed by a heteroaryl group and a heteroaryl group, a fused ring system formed by a heteroaryl group and an aryl group, and the like.

[0047] As used herein, the term "alkenyl" alone or in combination with other groups refers to a straight-chain or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds. For example, the term "C 2-6 The term "alkenyl" refers to an alkenyl group having 2 to 6 carbon atoms and one, two or three carbon-carbon double bonds (e.g., ethenyl, 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.), which is optionally substituted with one or more (e.g., 1 to 3) substituents described herein.

[0048] When used herein alone or in combination with other groups, the term "alkenylene" refers to a straight or branched divalent aliphatic hydrocarbon group having one or more carbon-carbon double bonds, and the two groups (or fragments) connected thereto may be connected to the same carbon atom or to different carbon atoms. For example, the term "C 2-4 "Alkenylene" refers to an alkenylene group having 2 to 4 carbon atoms (e.g. , etc.), which are optionally substituted with one or more (e.g., 1-3) substituents described herein.

[0049] As used herein, the term "alkynyl" alone or in combination with other groups refers to a straight-chain or branched aliphatic hydrocarbon group having one or more carbon-carbon triple bonds. 2-6 The term "alkynyl" refers to an alkynyl group having 2 to 6 carbon atoms and one, two or three carbon-carbon triple bonds (e.g., 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 with one or more (e.g., 1 to 3) substituents described herein.

[0050] As used herein, the term "alkynylene" refers to a straight or branched divalent aliphatic hydrocarbon group having one or more carbon-carbon triple bonds, wherein the two groups (or fragments) connected thereto are each connected to a different carbon atom. For example, as used herein, the term "C 2-4 "Alkyne" refers to an alkynyl group having 2 to 4 carbon atoms (e.g. , etc.), which are optionally substituted with one or more (e.g., 1-3) substituents described herein.

[0051] The term "haloalkyl" or "halogen-substituted alkyl" as used herein, alone or in combination with other groups, refers to an alkyl group as described above in which one or more hydrogen atoms are replaced by a halogen. For example, the term "C 1-6 "Haloalkyl" or "halogen-substituted C 1-6 "Alkyl" refers to a C 1-6 The term "C 1-4 "Haloalkyl" or "halogen-substituted C 1-4 "Alkyl" refers to a C 1-4 Alkyl. It will be understood by those skilled in the art that when there are more than one halogen substituent, the halogens may be the same or different and may be located on the same or different C atoms. Examples of haloalkyl groups include -CH2F, -CHF2, -CF3, -CCl3, -C2F5, -C2Cl5, -CH2CF3, -CH2Cl or -CH2CH2CF3.

[0052] The term "deuterated alkyl" as used herein, alone or in combination with other groups, refers to an alkyl group as described above in which one or more hydrogen atoms are replaced by a deuterium atom. For example, the term "C 1-6 "Deuterated alkyl" refers to a C group optionally substituted by one or more (e.g., 1-3) deuterium atoms. 1-6 Alkyl. It will be understood by those skilled in the art that when there are more than one deuterium atom substituent, the deuterium atoms may be located on the same or different C atoms. Examples of deuterated alkyl groups include -CH2D, -CHD2, -CD3, -CHDCH3, -CD2CH3, -CH2CH2D, -CH2CHD2, -CH2CD3, or -CD2CD3.

[0053]

[0046] The term "halo" or "halogen" group, as used herein, alone or in combination with other groups, refers to F, Cl, Br, or I.

[0054]

[0046] The term "hydroxy," as used herein, alone or in combination with other groups, refers to -OH.

[0055]

[0046] The term "cyano," as used herein, alone or in combination with other groups, refers to -CN.

[0056]

[0046] The term "nitro," as used herein, alone or in combination with other groups, refers to -NO2.

[0057] The term "amino," as used herein alone or in combination with other groups, refers to -NH2.

[0058] The term "oxo," as used herein alone or in combination with other groups, refers to =0.

[0059] The term "hydroxy protecting group" refers to a group that is easily removed and is introduced on a hydroxy group to block or protect the hydroxy group while reacting on other functional groups of the compound. Non-limiting examples of hydroxy 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, and the like.

[0060] The term "amino protecting group" refers to an easily removable group introduced on an amino group, which is used to block or protect the amino group while reacting on other functional groups of the compound. Non-limiting examples of amino protecting groups include: alkoxycarbonyl amino protecting groups, such as benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), methyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methyl (or ethyl)oxycarbonyl; acyl amino protecting groups, such as phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), o-(p)nitrobenzenesulfonyl (NTS), thiazolinyl (TFA ... Acyl (Ns), pivaloyl, benzoyl, tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, trimethylsilylethoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, tert-butyl, trifluoroacetyl, methoxycarbonyl, or ethoxycarbonyl; alkyl amino protecting groups, such as trityl (Trt), 2,4-dimethoxybenzyl (Dmb), 4-methoxybenzyl (PMB), benzyl (Bn), etc.

[0061] As used herein, the term "each independently" or "independently" means that at least two groups (or fragments) present in a structure with the same or similar value ranges may have the same or different meanings in 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 may be either hydrogen, or halogen, hydroxyl, -CN, alkyl, or aryl; similarly, when substituent Y is hydrogen, substituent X may be either hydrogen, or halogen, hydroxyl, -CN, alkyl, or aryl.

[0062] The term "substituted" and its other variant forms in this article refer to that one or more (such as 1, 2, 3 or 4) atoms or atomic groups (such as hydrogen atoms) on the specified atom are replaced by other equivalents, provided that the normal valence of the specified atom or atomic group in the current situation is not exceeded and a stable compound can be formed. If an atom or atomic group is described as "optionally substituted by...", it can be substituted or unsubstituted. Unless otherwise indicated, the attachment site of a substituent herein can be from any suitable position of the substituent. When the connecting bond in a substituent is shown as a chemical bond between two atoms connected to each other in a ring system, it means that the substituent can be connected to any ring-forming atom in the ring system.

[0063] Whenever the term "alkyl" or "aryl" or any of its prefix roots appears in the name of a substituent, by itself or as part of another substituent, unless otherwise indicated, it should be interpreted as including the limitations given above for "alkyl" and "aryl". The number of carbon atoms specified (e.g., C l-6 ) shall independently refer to the number of carbon atoms in an alkyl portion or the number of carbon atoms in the alkyl portion of a larger substituent of which alkyl is the root prefix.

[0064] The term "chemical bond" refers to the strong force that binds two or more adjacent atoms (or ions) together within a pure molecule or crystal, and primarily includes covalent bonds, ionic bonds, metallic bonds, coordination bonds, and the like. Unless otherwise specified, the chemical bonds in the compounds of the present disclosure that exist in free form are mostly covalent bonds.

[0065] The term "pharmaceutically acceptable salt" refers to salts of the disclosed compounds that are substantially non-toxic to living organisms. Pharmaceutically acceptable salts of the disclosed compounds include acid addition salts and base addition salts thereof. Examples include hexafluorophosphate salts and meglumine salts. Suitable salts are reviewed in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the disclosed compounds are known to those skilled in the art.

[0066] The term "pharmaceutically acceptable ester" refers to an ester that is substantially non-toxic to organisms and is hydrolyzed in vivo to form a compound disclosed herein or a salt thereof. In addition, the compound disclosed herein itself may also be an ester.

[0067] The term "isomers" refers to compounds that have the same number and types of atoms and therefore the same molecular weight, but differ in the arrangement or configuration of the atoms in space.

[0068] The term "stereoisomer" (or "optical isomer") refers to a stable isomer that has a perpendicular asymmetric plane due to at least one chiral factor (including a chiral center, a chiral axis, a chiral plane, etc.), thereby being able to rotate plane-polarized light. Since the compounds of the present disclosure have asymmetric centers and other chemical structures that may lead to stereoisomerism, the present disclosure also includes these stereoisomers and mixtures thereof. Since the compounds of the present disclosure (or pharmaceutically acceptable salts thereof) include asymmetric carbon atoms, they can exist in the form of single stereoisomers, racemates, enantiomers, and mixtures of diastereomers. Generally, these compounds can be prepared in the form of racemates. However, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., single enantiomers or diastereomers, or mixtures enriched in a single stereoisomer (purity ≥99%, ≥98%, ≥97%, ≥96%, ≥95%, ≥90%, ≥85%, ≥80%, ≥75%, ≥70%, ≥65%, or ≥60%). As described below, single stereoisomers of a compound can be synthesized 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 conversion to a mixture of diastereomers followed by separation or recrystallization, chromatography, use of a chiral resolving agent, or direct separation of the enantiomers on a chiral chromatographic column. Starting compounds of a particular stereochemistry are either commercially available or prepared as described below and resolved by methods well known in the art. The term "enantiomers" refers to a pair of stereoisomers that are non-superimposable mirror images of each other. The term "diastereomers" or "diastereomers" 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 indicated, all stereoisomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0069] Solid lines are used in this paper Solid wedge or virtual wedge To depict the covalent chemical bonds of the compounds of the present disclosure. When a solid line is used to depict a bond to a chiral atom, all possible stereoisomers at that chiral atom (e.g., a specific enantiomer, a racemic mixture, etc.) are included. When a solid or dashed wedge is used to depict a bond to a chiral atom, the presence of the indicated stereoisomer is indicated. Unless otherwise indicated, stereoisomers of the compounds of the present disclosure may encompass specific enantiomers, diastereomers, racemates, or mixtures thereof in any proportion.

[0070] The term "tautomer" (or "tautomeric form") refers to structural isomers with different energies that can be interconverted via a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (or prototropic tautomers) include, but are not limited to, interconversions via proton migration, such as keto-enol isomerization, imine-enamine isomerization, amide-iminoalcohol isomerization, nitroso-oxime isomerization, and the like. Unless otherwise indicated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0071] The term "polymorph" (or "polymorphic form") refers to a solid crystalline form of a compound or complex. The present disclosure encompasses all possible crystalline forms or polymorphs of the compounds of the present disclosure, which may be a single polymorph or a mixture of multiple polymorphs in any proportion.

[0072] The term "solvate" refers to a substance formed by the compounds of the present disclosure (or pharmaceutically acceptable salts thereof) and at least one solvent molecule bound by non-covalent intermolecular forces. The compounds of the present disclosure may exist as solvates that contain a polar solvent as a structural element of the crystal lattice. The amount of polar solvent may be present in a stoichiometric or non-stoichiometric ratio.

[0073] The term "isotopically labeled" refers to a derivative compound formed by replacing a specific atom in a compound of the present disclosure with an isotope thereof. Unless otherwise indicated, the compounds of the present 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 replacement, etc.

[0074] Those skilled in the art will appreciate that, since nitrogen requires an available lone pair of electrons to be oxidized to an oxide, not all nitrogen-containing heterocycles are capable of forming N-oxides. Those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidizing heterocycles and tertiary amines with peroxyacids such as Peracetic Acid and Metachloroperbenzoic Acid (mCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see for example: TL Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750 (AR Katritzky and AJ Boulton, Eds., Academic Press); and GWH Cheeseman and ESGWerstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392 (AR Katritzky and AJ Boulton, Eds., Academic Press).

[0075] The term "metabolite" refers to a derivative compound formed after metabolism of a compound of the present invention, for example, through reactions such as oxidation, reduction, hydrolysis, amidation, deamidation, esterification, and enzymatic hydrolysis. For further information on metabolism, see Goodman and Gilman's: The Pharmacological Basis of Therapeutics [M], McGraw-Hill International Editions, 1996. This disclosure encompasses all possible metabolite forms of the compounds of the present invention, i.e., substances formed in the body of a subject to administration of a compound of the present invention. Metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized experimentally.

[0076] The term "prodrug" refers to a derivative compound that can directly or indirectly provide a compound of the present invention after being administered to an individual. Particularly preferred derivative compounds or prodrugs are compounds that can improve the bioavailability of the compound of the present invention when administered to an individual (e.g., more easily absorbed into the blood), or compounds that promote the delivery of the parent compound to the site of action (e.g., lymphatic system). Unless otherwise noted, all prodrug forms of the compounds of the present invention are within the scope of the present disclosure, and various prodrug forms are known in the art, for example, see T. Higuchi, V. Stella, Pro-drugs as Novel Drug Delivery Systems [J], American Chemical Society, Vol. 14, 1975. In addition, the present disclosure also encompasses compounds of the present invention containing protecting groups. In any process for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive groups or reactive groups on any related molecules, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example as described in TW Greene, PGM Wuts, Protective Groups in Organic Synthesis [M], John Wiley & Sons, 2006. These protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

[0077] The present disclosure also encompasses methods for preparing the compounds described herein. It should be understood that the compounds of the present 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 known to 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 transformation.

[0078] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating one or more symptoms of a target disorder or condition.

[0079] The term "FBXW7" refers to the F-box / WD repeat-containing protein 7 gene, transcript, or protein. A mutated FBXW7 gene (an FBXW7 gene with an inactivating mutation) is a gene that cannot produce functional FBXW7 protein in a cell.

[0080] As used herein, the term "effective amount" (e.g., "therapeutically effective amount" or "prophylactically effective amount") refers to an amount of active ingredient that, after administration, will achieve the desired effect to some extent, such as alleviating one or more symptoms of the condition being treated or preventing the appearance of the condition or its symptoms.

[0081] As used herein, unless otherwise indicated, the terms "treat," ...

[0082] The term "prevention" as used herein includes inhibition and delay of the onset of a disease, and includes not only prevention before the development of a disease but also prevention of recurrence of a disease after treatment.

[0083] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from a disease (e.g., a disease described herein) (referred to as a patient) or normal individuals. In the present disclosure, "non-human animals" include 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.).

[0084] Compound

[0085] In certain embodiments of the present disclosure, the present disclosure provides a compound of formula (I') or a pharmaceutically acceptable form thereof:

[0086] in:

[0087] X is selected from N and CH; Y is selected from N and CR 2 ; Z is selected from N and CR 3 ;

[0088] R 1 、R 2 and R 3 Each independently selected from hydrogen, halogen, hydroxyl, oxo, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 heterocycloalkyl),-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), -S(O)2NR x R y 、-O(C6-10 aryl), -O(5-10 membered heteroaryl), C 6-10 Aryl and 5-10 membered heteroaryl; or R 1 With R 2 Together with the atoms it is connected to form C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C6 aryl or 5-6 membered heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated 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 Cycloalkyl and optionally C 1-6 The substituents of the alkyl-substituted 4-6 membered heterocycloalkyl are preferably each optionally substituted by one or more independently selected from deuterium, halogen, -CN, oxo, hydroxy, 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 substituents of the cycloalkyl and 4-6 membered heterocycloalkyl groups are substituted.

[0089] R 4 Selected from hydrogen, halogen, R 5 and NR 5 R 5 ';

[0090] R 5 and R 5 ' are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are each optionally substituted by one or more independently 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 heterocycloalkyl;

[0091] R 6 、R 7 and R 8 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 alkyl halide;

[0092] R 9 Selected from OH; R 10 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 haloalkyl; or R 9 With R 10 Co-formed-CR 11 =N-NH-, and R 11 selected from hydrogen and halogen;

[0093] R x and R y are each independently selected from hydrogen, 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 membered heteroaryl; each of the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more independently selected from deuterium, halogen, hydroxyl, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 alkyl), -NH2, -C(O)NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 3-6The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are preferably each optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 alkyl), -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 heterocycloalkyl;

[0094] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled substances, metabolites, or prodrugs.

[0095] In certain embodiments of the present disclosure, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable form thereof:

[0096] in:

[0097] X is selected from N and CH; Z is selected from N and CR 3 ;

[0098] R 1 、R 2 and R 3 Each independently selected from hydrogen, halogen, hydroxyl, oxo, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 heterocycloalkyl),-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), -S(O)2NR x R y 、-O(C 6-10 aryl), -O(5-10 membered heteroaryl), C 6-10 Aryl and 5-10 membered heteroaryl; or R 1 With R2 Together with the atoms it is connected to form C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C6 aryl or 5-6 membered heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated 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 Cycloalkyl and optionally C 1-6 Substituents of the alkyl-substituted 4-6 membered heterocycloalkyl group;

[0099] R 4 Selected from hydrogen, halogen, R 5 and NHR 5 ;

[0100] R 5 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are each optionally substituted by one or more 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 heterocycloalkyl;

[0101] R 6 、R 7 and R 8 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 alkyl halide;

[0102] R 9 Selected from OH; R 10 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6haloalkyl; or R 9 With R 10 Co-formed-CR 11 =N-NH-, and R 11 selected from hydrogen and halogen;

[0103] R x and R y are each independently selected from hydrogen, 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 membered heteroaryl; each of the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more independently selected from deuterium, halogen, hydroxyl, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 alkyl), -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 heterocycloalkyl;

[0104] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled substances, metabolites, or prodrugs.

[0105] In certain embodiments, the present disclosure provides compounds of formula (I) wherein:

[0106] X is selected from N and CH; Z is selected from N and CR 3 ;

[0107] R 1 、R 2 and R 3 Each independently selected from hydrogen, halogen, hydroxyl, oxo, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, 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 heterocycloalkyl),-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), -S(O)2NR x R y 、-O(C 6-10 aryl), -O(5-10 membered heteroaryl), C 6-10 Aryl and 5-10 membered heteroaryl; or R 1 With R 2 Together with the atoms it is connected to form C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C6 aryl or 5-6 membered heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more 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 heterocycloalkyl;

[0108] R 4 Selected from hydrogen, halogen, R 5 and NHR 5 ;

[0109] R 5 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are each optionally substituted by one or more independently 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 heterocycloalkyl;

[0110] R 6 、R 7 and R 8 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 alkyl halide;

[0111] R 9 Selected from OH; R 10 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 haloalkyl; or R 9 With R 10 Co-formed-CR 11 =N-NH-, and R 11 selected from hydrogen and halogen;

[0112] R x and R y are each independently selected from hydrogen, 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 membered heteroaryl; each of the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more independently selected from deuterium, halogen, hydroxyl, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 alkyl), -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 heterocycloalkyl;

[0113] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled substances, metabolites, or prodrugs.

[0114] In certain embodiments, the present disclosure provides compounds of formula (I) wherein:

[0115] X is selected from N and CH; Z is selected from N and CR 3 ;

[0116] R 1 、R 2 and R 3 Each independently selected from hydrogen, halogen, hydroxyl, oxo, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-10 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 heterocycloalkyl),-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), -S(O)2NR x R y 、C 6-10 Aryl and 5-10 membered heteroaryl; or R 1 With R 2 Together with the atoms it is connected to form C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C6 aryl or 5-6 membered heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more 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 heterocycloalkyl;

[0117] R 4 Selected from hydrogen, halogen, R 5 and NHR5 ;

[0118] R 5 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are each optionally substituted by one or more 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 heterocycloalkyl;

[0119] R 6 、R 7 and R 8 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 alkyl halide;

[0120] R 9 Selected from OH; R 10 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 haloalkyl; or R 9 With R 10 Co-formed-CR 11 =N-NH-, and R 11 selected from hydrogen and halogen;

[0121] R x and R y are each independently selected from hydrogen, 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 6-10Aryl and 5-10 membered heteroaryl; each of the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more independently selected from deuterium, halogen, hydroxyl, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 alkyl), -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocycloalkyl;

[0122] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled substances, metabolites, or prodrugs.

[0123] In certain embodiments, the present disclosure provides compounds of formula (I) wherein:

[0124] X is selected from N and CH; Z is selected from N and CR 3 ;

[0125] R 1 、R 2 and R 3 Each independently selected from hydrogen, halogen, hydroxyl, oxo, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 heterocycloalkyl),-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), -S(O)2NR x R y 、C 6-10 Aryl and 5-10 membered heteroaryl; or R 1 With R 2 Together with the atoms it is connected to form C 3-6cycloalkyl, 4-6 membered heterocycloalkyl, C6 aryl or 5-6 membered heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more 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 heterocycloalkyl;

[0126] R 4 Selected from hydrogen and NHR 5 ;

[0127] R 5 Selected from hydrogen, C 1-6 Alkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the alkyl, aryl or heteroaryl groups are each optionally substituted by one or more 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 heterocycloalkyl;

[0128] R 6 、R 7 and R 8 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 alkyl halide;

[0129] R 9 Selected from OH; R 10 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 haloalkyl; or R 9 With R 10 Co-formed-CR 11 =N-NH-, and R 11 selected from hydrogen and halogen;

[0130] R x and R y are each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, -C(O)(C1-6 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) and -S(O)2(4-6 membered heterocycloalkyl); each of the alkyl, cycloalkyl or heterocycloalkyl groups is optionally substituted by one or more independently selected from deuterium, halogen, hydroxyl, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 alkyl), -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocycloalkyl;

[0131] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled substances, metabolites, or prodrugs.

[0132] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), wherein X is selected from N.

[0133] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), wherein X is selected from CH.

[0134] In certain embodiments, the present disclosure provides compounds of formula (I') wherein Y is selected from N.

[0135] In certain embodiments, the present disclosure provides compounds of formula (I'), wherein Y is selected from CR 2 .

[0136] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), wherein Z is selected from N.

[0137] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), wherein Z is selected from CR 3 .

[0138] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 1 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-14 membered heterocycloalkyl, -O(C1-6 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 heterocycloalkyl), -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 membered heteroaryl), C 6-10 Aryl and 5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are each optionally substituted by one or more independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated 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 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are preferably each optionally substituted with one or more substituents independently selected from deuterium, halogen, -CN, oxo, hydroxy, 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 substituents of cycloalkyl and 4-6 membered heterocycloalkyl are substituted, more preferably selected from halogen, C 1-6 Alkyl and C 3-6 The cycloalkyl group is substituted with a substituent.

[0139] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 1 Selected from hydrogen, 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 1-6alkyl), -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -N(C 1-6 alkyl)(C6 aryl), -N(C 1-6 alkyl)(4-6 membered heterocycloalkyl), -NH(4-6 membered heterocycloalkyl), -N(C 1-6 Alkyl)(C 3-6 Cycloalkyl), -N(4-6 membered heterocycloalkyl)(C 3-6 Cycloalkyl), -N(5-6 membered heteroaryl)(C 3-6 Cycloalkyl), -N(C 1-6 alkyl) (5-6 membered heteroaryl), -NH (5-6 membered heteroaryl), -C(O) (4-6 membered heterocycloalkyl), -O (C6 aryl), C6 aryl and 5-10 membered heteroaryl; each of the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated 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 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are preferably selected from halogen, oxo, hydroxy, C 1-6 Alkyl, -C 1-6 Alkyl-OH, -O(C 1-6 Alkyl), -NR x R y and C 3-6 The cycloalkyl group is substituted with a substituent.

[0140] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 1 Selected from hydrogen, 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), -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -N(C 1-6 alkyl)(C6 aryl), -N(C 1-6alkyl)(4-6 membered heterocycloalkyl), -N(C 1-6 alkyl) (5-6 membered heteroaryl), -O(C6 aryl), C6 aryl and 5-10 membered heteroaryl; each of the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more 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 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are preferably selected from halogen, oxo, hydroxy, C 1-6 Alkyl, -C 1-6 Alkyl-OH, -O(C 1-6 Alkyl), -NR x R y and C 3-6 The cycloalkyl group is substituted with a substituent.

[0141] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 1 Selected from hydrogen, halogen, hydroxyl, oxo, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-10 membered heterocycloalkyl (e.g., 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 heterocycloalkyl),-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), -S(O)2NR x R y 、C 6-10 Aryl and 5-10 membered heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C 1-6 Alkyl), -NR x R y 、C 3-6 The substituents of the cycloalkyl and 4-6 membered heterocycloalkyl groups are substituted.

[0142] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 1 Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-10 membered heterocycloalkyl (e.g., 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)(4-6 membered heterocycloalkyl), -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 membered heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more 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 The substituents of the cycloalkyl and 4-6 membered heterocycloalkyl groups are substituted.

[0143] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 1 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-10 membered heterocycloalkyl (e.g., 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)(4-6 membered heterocycloalkyl), -C(O)NH(C 1-6 alkyl), -C(O)NH(C3-6 Cycloalkyl), -C(O)NH(4-6 membered heterocycloalkyl), C 6-10 Aryl and 5-10 membered heteroaryl; each of the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more 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 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are preferably selected from halogen, C 1-6 Alkyl and C 3-6 The cycloalkyl group is substituted with a substituent.

[0144] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 1 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-10 membered heterocycloalkyl, -O(C 1-6 alkyl), -O(C 3-6 Cycloalkyl), -O(4-6 membered heterocycloalkyl), -S(C 1-6 alkyl), -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -N(C 1-6 alkyl)(C6 aryl), -N(C 1-6 alkyl) (5-6 membered heteroaryl), C6 aryl and 5-6 membered heteroaryl; each of the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more 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 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are preferably selected from halogen, oxo, hydroxy, C 1-6 Alkyl, -C 1-6 Alkyl-OH, -O(C 1-6 Alkyl), -NR x R y and C 3-6 The cycloalkyl group is substituted with a substituent.

[0145] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R1 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-10 membered heterocycloalkyl (e.g., 4-6 membered heterocycloalkyl), -O(C 1-6 alkyl), -O(C 3-6 Cycloalkyl), -O(4-6 membered heterocycloalkyl), -S(C 1-6 alkyl), -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl) 2, C6 aryl and 5-6 membered heteroaryl; each of the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more 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 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are preferably selected from halogen, C 1-6 Alkyl and C 3-6 The cycloalkyl group is substituted with a substituent.

[0146] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 1 Selected from hydrogen, -N(C 1-6 alkyl)2 (e.g. dimethylamino), C 6-10 Aryl (e.g. phenyl), C 1-6 Alkyl (e.g. isopropyl), C 3-6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl), (For example ), (For example ), (For example ), (For example ),

[0147] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 1 Selected from hydrogen, -N(C 1-6 Alkyl) 2 (e.g. dimethylamino), C 6-10Aryl (e.g. phenyl), C 1-6 Alkyl (e.g. isopropyl), C 3-6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl), (For example ), (For example ), (For example ), (For example ),

[0148] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 1 Selected from hydrogen, dimethylamino, phenyl, isopropyl, cyclopropyl, cyclobutyl, (For example ), (For example ), (For example ),

[0149] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 1 Selected from hydrogen, dimethylamino, phenyl, isopropyl, cyclopropyl, cyclobutyl, (For example ), (For example ), (For example ),

[0150] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 1 Selected from hydrogen, isopropyl, cyclopropyl, cyclobutyl, dimethylamino,

[0151] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 2 Selected from hydrogen, halogen, hydroxyl, oxo, -CN, -NO2, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, 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 heterocycloalkyl),-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), -S(O)2NR x R y 、C 6-10 Aryl and 5-10 membered heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more 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 The substituents of the cycloalkyl and 4-6 membered heterocycloalkyl groups are substituted.

[0152] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 2 Selected from hydrogen, halogen, hydroxyl, oxo, -CN, -NO2, C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 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 heterocycloalkyl),-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 membered heteroaryl, preferably selected from hydrogen, halogen, oxo, -CN, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, 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 membered heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more 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 The substituents of the cycloalkyl and 4-6 membered heterocycloalkyl groups are substituted.

[0153] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 2 Selected from hydrogen, halogen, 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 membered heteroaryl; each of the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more 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 The substituents of the cycloalkyl and 4-6 membered heterocycloalkyl groups are substituted.

[0154] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 2 Selected from hydrogen, halogen, 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(C3-6 Cycloalkyl) and -NR x R y .

[0155] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 2 is selected from hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, fluoromethyl, -CH2OCH3 and -OCH3.

[0156] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 2 is selected from hydrogen and halogen; preferably, R 2 Selected from hydrogen and fluorine, preferably hydrogen.

[0157] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 3 Selected from hydrogen, halogen, hydroxyl, oxo, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 heterocycloalkyl),-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), -S(O)2NR x R y 、C 6-10 Aryl and 5-10 membered heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more 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 Cycloalkyl and optionally C 1-6 The substituents of the alkyl-substituted 4-6 membered heterocycloalkyl are preferably each optionally substituted by one or more independently selected from deuterium, halogen, -CN, C 1-6 Alkyl, C1-6 Haloalkyl, -O(C 1-6 Alkyl), C 3-6 The substituents of the cycloalkyl and 4-6 membered heterocycloalkyl groups are substituted.

[0158] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 3 Selected from hydrogen, halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 or 5-10 membered heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more 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 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are preferably selected from deuterium, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -O(C 1-6 Alkyl), C 3-6 The substituents of the cycloalkyl and 4-6 membered heterocycloalkyl groups are substituted.

[0159] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 3 Selected from hydrogen, halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 6-10Aryl or 5-10 membered heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more independently selected from deuterium, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -O(C 1-6 Alkyl), C 3-6 Cycloalkyl and optionally C 1-6 The substituents of the alkyl-substituted 4-6 membered heterocycloalkyl are preferably each optionally substituted by one or more independently selected from deuterium, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -O(C 1-6 Alkyl), C 3-6 In certain embodiments, R 3 Selected from hydrogen, halogen, -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 heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are each optionally substituted by one or more independently selected from deuterium, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -O(C 1-6 Alkyl), C 3-6 The cycloalkyl group or the 4- to 6-membered heterocyclic group is substituted by a substituent.

[0160] In certain embodiments, R 3 Selected from hydrogen, halogen, -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 heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are each optionally substituted by one or more independently selected from deuterium, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -O(C 1-6 Alkyl), C 3-6 The cycloalkyl group is substituted with a substituent.

[0161] In certain embodiments, R 3 Selected from hydrogen, halogen, -CN, -C 3-4 Cycloalkyl, C 1-4 Alkyl, C1-4 Haloalkyl, -O(C 1-6 alkyl), -O(C 1-6 Haloalkyl), -NH(C 1-6 alkyl), -NH (5-6 membered heteroaryl), 4-6 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl.

[0162] In certain embodiments, R 3 selected from hydrogen, fluorine, chlorine, -CN, methyl, methoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, difluoromethyl, trifluoromethyl, -NH (5-6 membered heteroaryl) and 5-6 membered heteroaryl, the heteroaryl being optionally substituted by one or more independently selected from deuterium, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -O(C 1-6 Alkyl), C 3-6 The substituents of cycloalkyl, 4-6 membered heterocyclyl are preferably optionally substituted by one or more independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 The cycloalkyl group or the 4- to 6-membered heterocyclic group is substituted by a substituent.

[0163] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 3 selected from hydrogen, fluorine, chlorine, -CN, methyl, methoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, difluoromethyl, trifluoromethyl, -NH (5-6 membered heteroaryl) and 5-6 membered heteroaryl, the heteroaryl being optionally substituted by one or more independently selected from deuterium, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -O(C 1-6 Alkyl), C 3-6 The cycloalkyl substituents are preferably optionally substituted with one or more independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 The cycloalkyl group is substituted with a substituent.

[0164] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 3 selected from hydrogen, fluorine, chlorine, -CN, methyl, cyclopropyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy and -NH (5-6 membered heteroaryl), the heteroaryl being optionally substituted by one or more independently selected from deuterium, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -O(C 1-6 Alkyl), C 3-6The cycloalkyl substituents are preferably optionally substituted with one or more independently selected from halogen, C 1-6 Alkyl, C 1-6 The substituents of the haloalkyl group are substituted.

[0165] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 3 is selected from hydrogen, fluorine, chlorine, -CN, methyl, cyclopropyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy and -NH (5-6 membered heteroaryl). In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 3 -NH(5-6 membered heteroaryl), optionally substituted by one or more independently selected from deuterium, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -O(C 1-6 Alkyl), C 3-6 The cycloalkyl substituents are preferably optionally substituted with one or more independently selected from halogen, C 1-6 Alkyl, C 1-6 The substituents of the haloalkyl group are substituted.

[0166] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 3 Selected from -NH(5-6 membered heteroaryl).

[0167] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 3 is selected from hydrogen and halogen; preferably, R 3 Selected from hydrogen and fluorine, preferably hydrogen.

[0168] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 3 Selected from hydrogen, halogen (such as fluorine, chlorine), -CN, C 1-6 Alkyl (such as methyl),

[0169] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 1 With R 2 Together with the atoms it is connected to form C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C6 aryl or 5-6 membered heteroaryl, preferably forming C 3-6 Cycloalkyl, C6 aryl or 5-6 membered heteroaryl; each of the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C1-6 Haloalkyl, -C 1-6 Alkyl-OH, -O(C 1-6 Alkyl), -NR x R y 、C 3-6 In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), wherein R 4 Selected from hydrogen, halogen, R 5 and NR 5 R 5 ', for example, is selected from hydrogen and NR 5 R 5 ', where R 5 and R 5 ' are each independently selected from hydrogen, C 1-6 Alkyl, C 6-10 Aryl and 5-10 membered heteroaryl, preferably selected from hydrogen, C 1-6 Alkyl, C6 aryl and 5-6 membered heteroaryl; each of the alkyl, aryl or heteroaryl groups is optionally substituted by one or more 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 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are preferably selected from C 1-6 The alkyl group is substituted with a substituent.

[0170] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 5 and R 5 ' are each independently selected from C 1-6 alkyl.

[0171] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 5 and R 5 ' are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C6 aryl and 5-6 membered heteroaryl, preferably selected from hydrogen and 5-6 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are each optionally substituted by one or more 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), -NRx R y 、C 3-6 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are preferably selected from C 1-6 The alkyl group is substituted with a substituent.

[0172] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 4 Selected from hydrogen, halogen, R 5 and -NHR 5 , for example selected from hydrogen and -NHR 5 , where R 5 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, preferably selected from hydrogen, C 1-6 Alkyl, C 6-10 Aryl and 5-10 membered heteroaryl, preferably selected from hydrogen, C 1-6 Alkyl, C6 aryl and 5-6 membered heteroaryl; each of the alkyl, aryl or heteroaryl groups is optionally substituted by one or more 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 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are preferably selected from C 1-6 The alkyl group is substituted with a substituent.

[0173] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 4 Selected from hydrogen, halogen, R 5 and -NHR 5 , for example selected from hydrogen and -NHR 5 , where R 5 is selected from hydrogen and 5-6 membered heteroaryl, the heteroaryl being optionally substituted by one or more 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 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are preferably selected from C 1-6 The alkyl group is substituted with a substituent.

[0174] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 4 Selected from hydrogen, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl) 2, -NH (C6 aryl), -NH (5-6 membered heteroaryl), preferably selected from hydrogen, -NH2, -NH (C 1-6 alkyl), -NH(C6 aryl) and -NH(5-6 membered heteroaryl), preferably selected from hydrogen and -NH(5-6 membered heteroaryl), wherein the alkyl, aryl or heteroaryl are each optionally substituted by one or more 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 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are preferably selected from deuterium, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -O(C 1-6 Alkyl), C 3-6 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are preferably selected from C 1-6 The alkyl group is substituted with a substituent.

[0175] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 4 Selected from hydrogen, halogen, R 5 and -NHR 5 , for example selected from hydrogen and -NHR 5 , where R 5 Selected from hydrogen,

[0176] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 6 Selected from hydrogen, halogen, C 1-4 Alkyl, C 3-4 Cycloalkyl and C 1-4 preferably, R 6 Selected from hydrogen, halogen and C 1-4 Alkyl; More preferably, R 6 Selected from C 1-4 alkyl.

[0177] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 6 is selected from the group consisting of hydrogen, fluorine, chlorine and methyl.

[0178] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 6 Selected from methyl.

[0179] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 7 Selected from hydrogen, halogen, C 1-4 Alkyl and C 1-4 preferably, R 7 is selected from hydrogen and halogen.

[0180] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 7 Selected from hydrogen and fluorine.

[0181] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 7 Selected from hydrogen.

[0182] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 8 Selected from hydrogen, halogen, C 1-4 Alkyl and C 1-4 preferably, R 8 Selected from hydrogen and halogen.

[0183] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 8 Selected from hydrogen and fluorine.

[0184] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 8 Selected from hydrogen.

[0185] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 9 Selected from OH.

[0186] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 10 Selected from hydrogen, halogen, C 1-4 Alkyl, C 3-4 Cycloalkyl and C 1-4 preferably, R 10 Selected from hydrogen, halogen, C 1-4 Alkyl and C 1-4 More preferably, R 10 Selected from C 1-4 alkyl.

[0187] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R10 is selected from hydrogen, fluorine, chlorine, methyl and difluoromethyl. In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 10 Selected from methyl.

[0188] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R 9 With R 10 Together they form -CH=N-NH-.

[0189] In certain embodiments, R x and R y are each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, for example, selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, for example, is selected from hydrogen, C 1-6 Alkyl and C 3-8 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are each optionally substituted by one or more independently selected from deuterium, halogen, hydroxyl, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 alkyl), -NH2, -C(O)NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 3-6 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are preferably each optionally substituted by one or more independently selected from halogen, hydroxyl, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 alkyl), -NH2, -C(O)NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 3-6 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are substituted, for example, each of which is optionally substituted by one or more independently selected from halogen, hydroxy, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 alkyl), -NH2, -NH(C 1-6 Alkyl), -N(C1-6 Alkyl)2, C 3-6 The cycloalkyl group is substituted with a substituent.

[0190] In certain embodiments, the present disclosure provides compounds of formula (I') or formula (I), R x and R y are each independently selected from hydrogen, C 1-6 Alkyl and C 3-8 Cycloalkyl.

[0191] In certain embodiments, Formula (I') is further Formula (IA), Formula (IB), Formula (IC), or Formula (ID), preferably Formula (IA), Formula (IB), or Formula (ID):

[0192] Among them, R 1 、R 2 、R 3 、R 4 、R 6 、R 7 、R 8 、R 9 and R 10 The groups are as defined above.

[0193] In certain embodiments, Formula (I) is further Formula (IA), Formula (IB), or Formula (ID):

[0194] Among them, R 1 、R 2 、R 3 、R 4 、R 6 、R 7 、R 8 、R 9 and R 10 The groups are as defined above.

[0195] In certain embodiments, Formula (I') is further Formula (I'-1) or Formula (I'-2):

[0196] Among them, R 1 、R 2 、R 3 、R 4 、R 6 、R 7 、R 8 and R 10 The groups are as defined above.

[0197] In certain embodiments, Formula (I) is further Formula (I-1) or Formula (I-2):

[0198] Among them, R 1 、R 2 、R 3 、R 4 、R 6 、R 7 、R 8 and R 10 The groups are as defined above.

[0199] In certain embodiments, Formula (I) is further Formula (IA'), Formula (IA"), Formula (IB'), Formula (IB"), Formula (ID') or Formula (ID"):

[0200] Among them, R 1 、R 3 、R 4 、R 6 、R 7 、R 8 and R 10 The group is as defined in any of the above items.

[0201] The present disclosure covers any combination of the above embodiments.

[0202] In some embodiments, the present disclosure provides the following compounds or pharmaceutically acceptable forms thereof, including, but not limited to:

[0203] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled substances, metabolites, or prodrugs.

[0204] Preparation method

[0205] The compounds of the present disclosure can be prepared by any method known in the art. Reagents and starting materials are readily available to those of ordinary skill in the art. Individual isomers, enantiomers, and diastereomers can be separated or split 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. Elel and S. H. Wilen).

[0206] Another object of the present disclosure is to provide a method for preparing the compounds of the present disclosure. For example, in some embodiments, the present disclosure provides when X=CH, Z=N and R 9 When is -OH, a method for preparing a compound of formula (IA), comprising one or more steps of the following steps (1) to (10); preferably comprising step (10), optionally further comprising step (9), optionally further comprising step (8), optionally further comprising step (7), optionally further comprising step (6), optionally further comprising step (5), optionally further comprising step (4), optionally further comprising step (3), optionally further comprising step (2), optionally further comprising step (1):

[0207] in

[0208] R 1 、R 2 、R 4 、R 6 、R 7 、R 8 、R 9 、R 10 As defined above;

[0209] X1 is halogen, such as bromine or chlorine, preferably chlorine;

[0210] Pg 1represents a hydroxyl-protecting group, such as 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 or p-nitrobenzoyl, such as methoxymethyl ether (MOM), methyl or benzyl, preferably methyl;

[0211] in:

[0212] Step (1) reacting compound IA-1 with compound IA-2 to obtain compound IA-3;

[0213] Step (2) reducing compound IA-3 to obtain compound IA-4;

[0214] Step (3) subjecting compound IA-4 to an amino protection reaction to obtain compound IA-5;

[0215] Step (4) subjecting compound IA-5 to a hydrolysis reaction to obtain compound IA-6;

[0216] Step (5) subjecting compound IA-6 to a deprotection reaction to obtain compound IA-7;

[0217] Step (6) subjecting compound IA-7 to a ring-closure reaction to obtain compound IA-8;

[0218] Step (7) subjecting compound IA-8 to a halogenation reaction to obtain compound IA-9;

[0219] Step (8) subjecting compound IA-9 to a substitution reaction to obtain compound IA-10;

[0220] Step (9) subjecting compound IA-10 to a substitution or dehalogenation reaction to obtain compound IA-11;

[0221] Step (10) Compound IA-11 is subjected to a deprotection reaction to obtain compound IA.

[0222] The reaction in step (1) is preferably carried out in a suitable organic solvent and in the presence of a suitable base. The organic solvent may be selected from N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, and any combination thereof, preferably N,N-dimethylformamide. The base may be an organic base or an inorganic base, for example, selected from N,N-diisopropylethylamine, triethylamine, sodium tert-butoxide, potassium carbonate, cesium carbonate, and sodium carbonate, preferably potassium carbonate. The reaction is preferably carried out at a temperature of 0-120° C. for 2-24 hours.

[0223] The reaction in step (2) is preferably carried out in the presence of a suitable reducing system. The reducing system comprises: palladium on carbon and hydrogen, iron powder and ammonium chloride, tetrahydroxydiboron and 4,4'-bipyridine, preferably tetrahydroxydiboron and 4,4'-bipyridine. The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from N,N-dimethylformamide, dichloromethane, chloroform, tetrahydrofuran, and any combination thereof, preferably N,N-dimethylformamide. The reaction is preferably carried out at a temperature of 0-80°C for 5 minutes to 1 hour.

[0224] The amino protection reaction in step (3) is preferably carried out in a suitable organic solvent and in the presence of a suitable base. The organic solvent may be selected from N,N-dimethylformamide, dichloromethane, tetrahydrofuran, 1,4-dioxane, and any combination thereof, preferably tetrahydrofuran. The base may be an organic base or an inorganic base, for example, selected from N,N-diisopropylethylamine, triethylamine, sodium tert-butoxide, potassium carbonate, cesium carbonate, and sodium carbonate, preferably N,N-diisopropylethylamine. The reaction is preferably carried out at a temperature of 0-80°C for 2-24 hours.

[0225] The reaction in step (4) is preferably carried out in the presence of a suitable hydrolysis system. The hydrolysis system includes concentrated sulfuric acid, concentrated hydrochloric acid, sodium hydroxide, potassium hydroxide, and a potassium carbonate and hydrogen peroxide system, preferably potassium carbonate and hydrogen peroxide. The reaction is preferably carried out in a suitable organic solvent. The organic solvent can be selected from N,N-dimethylformamide, dichloromethane, dimethyl sulfoxide, tetrahydrofuran, and any combination thereof, preferably dimethyl sulfoxide. The reaction is preferably carried out in a suitable solvent at a temperature of 0-80°C for 2-24 hours.

[0226] The deprotection reaction in step (5) is preferably carried out in the presence of a suitable acid. The acid may be sulfuric acid, dioxane hydrochloride solution, or trifluoroacetic acid, preferably dioxane hydrochloride solution. The reaction is preferably carried out at a temperature of 0-80° C. for 2-24 hours.

[0227] The ring-closure reaction in step (6) is preferably carried out under suitable conditions. The conditions include: trimethyl orthoformate, triethyl orthoformate, and a system of di-tert-butyl dicarbonate and 4-dimethylaminopyridine, preferably a system of di-tert-butyl dicarbonate and 4-dimethylaminopyridine. The reaction is preferably carried out in a suitable organic solvent. The organic solvent can be selected from N,N-dimethylformamide, dichloromethane, acetonitrile, tetrahydrofuran, and any combination thereof, preferably acetonitrile. The reaction is preferably carried out at a temperature of 0-80°C for 2-24 hours.

[0228] The halogenation reaction in step (7) is preferably carried out in the presence of a suitable halogenating agent and a base. The halogenating agent includes phosphorus oxychloride and phosphorus oxybromide, preferably phosphorus oxychloride. The reaction is preferably carried out in the presence of a suitable base, for example, selected from N,N-diisopropylethylamine, triethylamine, N,N-dimethylaniline, potassium carbonate, and sodium carbonate, preferably N,N-dimethylaniline. The reaction is preferably carried out at a temperature of 0-100° C. for 2-24 hours.

[0229] The substitution reaction in step (8) is preferably carried out in a suitable solvent. The solvent may be selected from N,N-dimethylformamide, dichloromethane, chloroform, tetrahydrofuran, ethanol, methanol, and any combination thereof, preferably tetrahydrofuran. The reaction is preferably carried out in the presence of an ammonia methanol solution. The reaction is preferably carried out at a suitable temperature, preferably 0-80° C. The reaction is preferably carried out for a suitable time, for example, 2-24 hours.

[0230] When R 4 When it is not hydrogen, the substitution reaction in step (9) is preferably carried out in a suitable organic solvent. The organic solvent can be selected from N,N-dimethylformamide, N-methylpyrrolidone, tert-butanol, tetrahydrofuran, and any combination thereof, preferably tert-butanol. The reaction is preferably carried out in the presence of p-toluenesulfonic acid. The reaction is preferably carried out at a suitable temperature, preferably 0-120°C. The reaction is preferably carried out for a suitable time, for example, 2-24 hours.

[0231] When R 4 When hydrogen is present, the dehalogenation reaction in step (9) is preferably carried out in a suitable organic solvent. The organic solvent may be selected from N,N-dimethylformamide, N,N-dimethylacetamide, methanol, tetrahydrofuran and any combination thereof, preferably methanol. The reaction is preferably carried out in the presence of a suitable reaction reagent, which may be selected from palladium carbon and palladium hydroxide carbon, preferably palladium carbon. The reaction is preferably carried out under a hydrogen atmosphere. The reaction is preferably carried out at a suitable temperature, preferably 0-120°C. The reaction is preferably carried out for a suitable time, for example 2-24 hours.

[0232] The deprotection reaction in step (10) is preferably carried out in a suitable organic solvent. The organic solvent may be selected from N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, tetrahydrofuran, and any combination thereof, preferably dichloromethane. The reaction is preferably carried out in the presence of a suitable reaction reagent, which may be selected from boron tribromide and boron trichloride, preferably boron tribromide. The reaction is preferably carried out at a suitable temperature, preferably 0-120° C. The reaction is preferably carried out for a suitable time, for example, 10 minutes to 24 hours.

[0233] In some embodiments, the present disclosure also provides a method for preparing a compound of formula (IA), comprising one or more steps of steps (1) to (7):

[0234] in:

[0235] Step (1) reacting compound IA1-2 with compound IB1-1 to obtain compound IA1-3;

[0236] Step (2) reacting compound IA1-3 to obtain compound IA1-4;

[0237] Step (3) reacting compound IA1-4 to obtain compound IA1-5;

[0238] Step (4) reacting compound IA1-5 with pinacol diboronate to produce compound IA1-6;

[0239] Step (5) subjecting compound IA1-6 to a coupling reaction to obtain compound IA1-7;

[0240] Step (6) Compound IA1-7 is subjected to a deprotection reaction to obtain compound IA1.

[0241] The reaction of step (1) is preferably carried out in a suitable organic solvent and in the presence of a suitable base and a cuprous catalyst. The organic solvent may be selected from N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, N-methylpyrrolidone and any combination thereof, preferably N-methylpyrrolidone. The base may be an organic base or an inorganic base, for example, selected from N,N-diisopropylethylamine, triethylamine, sodium tert-butoxide, potassium carbonate, cesium carbonate and sodium carbonate, preferably cesium carbonate. The cuprous catalyst may be cuprous iodide, cuprous bromide, cuprous chloride or cuprous dimethyl sulfide, etc., preferably cuprous bromide. The reaction is preferably carried out at a temperature of 0-120°C for 2-24 hours.

[0242] The reaction in step (2) is preferably carried out in a suitable organic solvent in the presence of ammonia. The organic solvent may be selected from methanol, ethanol, isopropanol, and any combination thereof, preferably isopropanol. The ammonia may be selected from aqueous ammonia, ammonia methanol solution, and the like, preferably aqueous ammonia. The reaction is preferably carried out at a temperature of 0-120° C. for 2-24 hours.

[0243] The ring-closure reaction in step (3) is preferably carried out in a suitable organic solvent. The organic solvent may be selected from methanol, ethanol, isopropanol, and any combination thereof, preferably ethanol. The ring-closure reaction may be carried out under conditions selected from the following: a combination of ammonium acetate with methyl orthoformate or ethyl orthoformate, preferably a combination of ammonium acetate and ethyl orthoformate. The reaction is preferably carried out at a temperature of 0-120° C. for 2-24 hours.

[0244] The coupling reaction in step (4) is preferably carried out in a suitable organic solvent. The organic solvent may be selected from N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, N-methylpyrrolidone, and any combination thereof, preferably 1,4-dioxane. The coupling reaction conditions may be selected from a combination of Pd(dppf)Cl2 and potassium acetate. The reaction is preferably carried out at a temperature of 0-120°C for 2-24 hours.

[0245] The coupling reaction in step (5) 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 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(dibenzylideneacetone)dipalladium, 1,1'-bis(diphenylphosphinodiphenylphosphine)dichloropalladium, tetrakis(triphenylphosphine)palladium, palladium acetate, Pd(dtbpf)Cl2, BINAP, BrettPhos Pd G3, cataCXium A Pd G3 or any combination thereof, preferably cataCXium A Pd G3. The reaction is preferably carried out in the presence of a suitable base, which may be selected from sodium carbonate, potassium carbonate, potassium phosphate, sodium tert-butoxide and cesium carbonate, preferably potassium phosphate. 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 to 24 hours.

[0246] The reaction in step (6) is preferably carried out in a suitable acid. The acid may be selected from trifluoroacetic acid, trifluoromethanesulfonic acid, hydrochloric acid, and any combination thereof, preferably trifluoroacetic acid. 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.

[0247] In some embodiments, compound IA-5 is directly converted to compound IA1-7 via substitution or coupling reaction:

[0248] The coupling reaction in this step is preferably carried out in a suitable organic solvent and under suitable base and metal catalyst conditions. The organic solvent can be selected from N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, toluene and any combination thereof, preferably 1,4-dioxane. The base can be an organic base or an inorganic base, for example, selected from N,N-diisopropylethylamine, triethylamine, sodium tert-butoxide, potassium carbonate, cesium carbonate and sodium carbonate, preferably cesium carbonate. The metal catalyst can be a combination of Pd2(dba)3 and a ligand RuPhos, BrettPhos, BINAP, etc., preferably a combination of Pd2(dba)3 and RuPhos. The reaction is preferably carried out at a temperature of 0-120°C for 2-24 hours.

[0249] The present disclosure also provides that when X=N, Z=N, and R 9 When is -OH, a method for preparing a compound of formula (IB), comprising one or more steps of the following steps (1) to (6); preferably comprising step (6), optionally further comprising step (5), optionally further comprising step (4), optionally further comprising step (3), optionally further comprising step (2), optionally further comprising step (1):

[0250] in

[0251] R 1a R 1 or R protected by an amino protecting group 1 ;

[0252] R 1 、R 2 、R 4 、R 6 、R 7 、R 8 、R 9 、R 10 As defined above;

[0253] X2 is halogen, such as bromine or chlorine, preferably chlorine;

[0254] Pg 1 represents a hydroxyl-protecting group, such as 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 or p-nitrobenzoyl, such as methoxymethyl ether (MOM), methyl or benzyl, preferably methyl;

[0255] Lg 1represents an amino protecting group, such as an alkoxycarbonyl amino protecting group, such as benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), methyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methyl (or ethyl)oxycarbonyl; an acyl amino protecting group, such as phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), o-(p)nitrobenzenesulfonyl (Ns), pivaloyl, benzoyl, tert-butyloxycarbonyl (Boc), methyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methyl (or ethyl)oxycarbonyl; oxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, trimethylsilylethoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, tert-butyl, trifluoroacetyl, methoxycarbonyl, or ethoxycarbonyl; alkyl amino protecting groups such as trityl (Trt), 2,4-dimethoxybenzyl (Dmb), 4-methoxybenzyl (PMB), benzyl (Bn), specifically 2,4-dimethoxybenzyl, 4-methoxybenzyl or benzyl, preferably 2,4-dimethoxybenzyl;

[0256] in:

[0257] Step (1) subjecting compound IB-1 to a ring-closure reaction to obtain compound IB-2;

[0258] Step (2) subjecting compound IB-2 to a substitution reaction with IA-1 to obtain compound IB-3;

[0259] Step (3) condensing compound IB-3 and IB-4 to obtain compound IB-5;

[0260] Step (4) subjecting compound IB-5 to a substitution or coupling reaction to obtain compound IB-6;

[0261] Step (5) subjecting compound IB-6 to a deamination protection reaction to obtain compound IB-7;

[0262] Step (6) Compound IB-7 is subjected to a dehydroxylation protection reaction to obtain Compound IB.

[0263] The ring-closing reaction in step (1) is preferably carried out in the presence of a suitable reagent. 4 When hydrogen is present, the reagent may be selected from trimethyl orthoformate and triethyl orthoformate, preferably triethyl orthoformate. The reaction is preferably carried out at a suitable temperature, preferably 80-150° C. The reaction is preferably carried out for a suitable time, for example 2-24 hours.

[0264] The substitution reaction in step (2) is preferably carried out in a suitable organic solvent. The organic solvent may be selected from N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, acetonitrile, NMP and any combination thereof, preferably N,N-dimethylformamide. The reaction is preferably carried out in the presence of a suitable metal organic base, which may be selected from sodium hydride, potassium tert-butoxide, sodium tert-butoxide, cesium carbonate and n-butyl lithium, preferably sodium hydride. The reaction is preferably carried out at a suitable temperature, preferably 0-120° C. The reaction is preferably carried out for a suitable time, for example 2-24 hours.

[0265] The condensation reaction in step (3) 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, preferably N,N-dimethylformamide. The reaction is preferably carried out in the presence of a suitable condensing agent, which may be selected from PyBOP and HATU, etc., preferably PyBOP. The reaction is preferably carried out in the presence of a suitable organic base, which may be selected from N,N-diisopropylethylamine, triethylamine, N,N-dimethylaniline, DBU, preferably N,N-diisopropylethylamine. 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.

[0266] The substitution reaction in step (4) is preferably carried out in a suitable organic solvent. The organic solvent may be selected from N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, N-methylpyrrolidone, toluene, NMP and any combination thereof, preferably N,N-dimethylformamide. The reaction is preferably carried out in the presence of a suitable base, which may be selected from sodium hydride, potassium tert-butoxide, potassium carbonate and cesium carbonate, preferably potassium carbonate. 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 0.5-24 hours.

[0267] The coupling reaction in step (4) 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 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(dibenzylideneacetone)dipalladium, 1,1'-bis(diphenylphosphinodiphenylphosphine)palladium dichloride, tetrakis(triphenylphosphine)palladium, palladium acetate, Pd(dtbpf)Cl2, BINAP, BrettPhos Pd G3, cataCXium A Pd G3 or any combination thereof, preferably 1,1'-bis(diphenylphosphinodiphenylphosphine)palladium dichloride. The reaction is preferably carried out in the presence of a suitable base, which may be selected from sodium carbonate, potassium carbonate, potassium phosphate, sodium tert-butoxide and cesium carbonate, preferably potassium carbonate. 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 to 24 hours.

[0268] The deprotection reaction in step (5) is preferably carried out in the presence of a suitable acid. The acid may be sulfuric acid, hydrochloric acid, or trifluoroacetic acid, preferably trifluoroacetic acid. The reaction is preferably carried out at a temperature of 0-100° C. for 0.5-72 hours.

[0269] The deprotection reaction in step (6) above is as described in step (10) of the route to compound IA.

[0270] In some embodiments, R in IB-6 1a R is protected by an amino protecting group 1 In some embodiments, step (5) of the method simultaneously removes Lg in a one-step reaction. 1 and R 1a In some embodiments, step (5) of the method is to remove Lg in two steps. 1 and R 1a The amino protecting group in .

[0271] In some embodiments, R in IB-6 1a It is R 1 .

[0272] In some embodiments, the order of certain steps in the preparation methods of the present disclosure may be changed.

[0273] In some embodiments, the present disclosure also provides that when X=N, Z=N, and R 9 When is -OH, another method for preparing a compound of formula (IB) comprises one or more steps of the following steps (1) to (3); preferably comprises step (3), optionally further comprises step (2), and optionally further comprises step (1):

[0274] in

[0275] R 1 、R 2 、R 4 、R 6 、R 7 、R 8 、R 9 、R 10 、Pg 1 , Lg 1 , X2 is as defined above;

[0276] Step (1) subjecting compound IB-5 to a deamination protection reaction to obtain compound IB-5-2;

[0277] Step (2) subjecting compound IB-5-2 to a dehydroxylation reaction to obtain compound IB-5-3;

[0278] Step (3) subjecting compound IB-5-3 to a substitution or coupling reaction to obtain compound IB.

[0279] The reaction conditions of step (1) can be the same as those described above for the deamination protection reaction. The reaction conditions of step (2) can be the same as those described above for the dehydroxylation protection reaction. The reaction conditions of step (3) can be the same as those described above for subjecting compound IB-5 to a substitution or coupling reaction to obtain compound IB-6.

[0280] In some embodiments, the present disclosure provides that when X=N, Z=N, and R 9 When is -OH, a method for preparing a compound of formula (IB) comprises one or more steps from the following steps (1) to (2):

[0281] in:

[0282] R 1a 、R 2 、R 4 、R 6 、R 7 、R 8 , X2, Pg 1 , Lg 1 As defined above;

[0283] Step (1) reacting compound IB-5 with pinacol diboronate to produce compound IB-5-4;

[0284] Step (2) Compound IB-5-4 is subjected to a coupling reaction to obtain compound IB-6.

[0285] The reaction conditions of step (1) are the same as those described above for the reaction of compound ID2-1-1 with diboronic acid pinacol ester to produce ID2-1-1-1.

[0286] The reaction conditions of step (2) are the same as those described above for the coupling reaction of compound ID-7 to obtain compound ID-8.

[0287] The present disclosure also provides that when R 9 With R 10 When -CH=N-NH- is formed together, a method for preparing a compound of formula (IB) comprising one or more steps from step (1) to step (4); preferably comprising step (4), optionally further comprising step (3), optionally further comprising step (2), optionally further comprising step (1):

[0288] in

[0289] R 1a 、R 1 、R 2 、R 4 、R 6 、R 7 、R 8 As defined above;

[0290] X2 is halogen, such as bromine or chlorine, preferably chlorine;

[0291] Pg 2 represents an aromatic amino protecting group, such as tetrahydropyranyl (THP);

[0292] Lg 1 represents an amino protecting group, such as an alkoxycarbonyl amino protecting group, such as benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), methyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methyl (or ethyl)oxycarbonyl; an acyl amino protecting group, such as phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), o-(p)nitrobenzenesulfonyl (Ns), pivaloyl, benzoyl, tert-butyloxycarbonyl (Boc), methyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methyl (or ethyl)oxycarbonyl; oxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, trimethylsilylethoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, tert-butyl, trifluoroacetyl, methoxycarbonyl, or ethoxycarbonyl; alkyl amino protecting groups such as trityl (Trt), 2,4-dimethoxybenzyl (Dmb), 4-methoxybenzyl (PMB), benzyl (Bn), specifically 2,4-dimethoxybenzyl, 4-methoxybenzyl or benzyl, preferably 2,4-dimethoxybenzyl;

[0293] in:

[0294] Step (1) subjecting compound IB1-1 to a substitution reaction with IB-2 to obtain compound IB1-2;

[0295] Step (2) subjecting compound IB1-2 to a condensation reaction to obtain compound IB1-3;

[0296] Step (3) subjecting compound IB1-3 to a substitution or coupling reaction to obtain compound IB1-4;

[0297] Step (4) subjecting compound IB1-4 to a deprotection reaction to obtain compound IB1.

[0298] In some embodiments, R 1a It is R 1 .

[0299] The reaction conditions of step (1) are the same as those described above for the substitution reaction of compound IB-2 with IA-1 to obtain compound IB-3.

[0300] The reaction conditions of step (2) are the same as those described above for the condensation reaction of compounds IB-3 and IB-4 to obtain compound IB-5.

[0301] The reaction conditions of step (3) are the same as those described above for the substitution or coupling reaction of compound IB-5 to obtain compound IB-6.

[0302] The reaction conditions of step (4) are the same as those described above for the deprotection reaction of compound IB-6 to obtain compound IB-7.

[0303] In some embodiments, the reaction of IB1-3 to form IB1-4 comprises reacting IB1-3 with hexamethylditin to form IB1-3-1, and then subjecting IB1-3-1 to a substitution or coupling reaction to obtain compound IB1-4.

[0304] Therefore, in some embodiments, the present disclosure provides that when R 9 With R 10 When -CH=N-NH- is formed together, a method for preparing a compound of formula (IB) comprises one or more steps from the following steps (1) to (2):

[0305] in

[0306] R 1a 、R 2 、R 4 、R 6 、R 7 、R 8 , X2, Pg2 , Lg 1 As defined above;

[0307] Step (1) reacting IB1-3 with hexamethyltin disulfide to produce IB1-3-1;

[0308] Step (2) subjecting IB1-3-1 to a substitution or coupling reaction to obtain compound IB1-4.

[0309] The reaction conditions of step (1) are preferably carried out in the presence of a catalyst, such as PPd(dtbpf)Cl2; the coupling reaction is preferably carried out in a suitable solvent, such as 1,4-dioxane, THF, etc.; the reaction temperature is 60-120°C; and the reaction time is preferably 2-24 hours in a microwave reactor.

[0310] The reaction conditions of step (2) are preferably carried out in the presence of a catalyst, such as a combination of PPd(dtbpf)Cl2 and CuBr or CuI; the reaction is preferably carried out in the presence of a suitable base, such as lithium chloride. The coupling reaction is preferably carried out in a suitable solvent, such as 1,4-dioxane, THF, etc.; the reaction temperature is 60-120°C; and the reaction time is preferably 2-24 hours in a microwave reactor.

[0311] In some embodiments, compound IB1-3 is first subjected to a deprotection reaction to generate compound IB1-3-2, and then subjected to a substitution or coupling reaction to obtain compound IB1.

[0312] Therefore, in some embodiments, the present disclosure provides that when R 9 With R 10 When -CH=N-NH- is formed together, a method for preparing a compound of formula (IB) comprises one or more steps from the following steps (1) to (2):

[0313] in

[0314] R 1 、R 2 、R 4 、R 6 、R 7 、R 8 , X2, Pg 2 , Lg 1 As defined above;

[0315] Step (1) subjecting IB1-3 to a deprotection reaction to generate IB1-3-2;

[0316] Step (2) subjecting IB1-3-2 to a substitution or coupling reaction to obtain compound IB1.

[0317] The reaction conditions of step (1) are the same as those described above for the deprotection reaction of compound IB1-4 to obtain compound IB1.

[0318] The reaction conditions of step (1) are the same as those described above for the substitution or coupling reaction of compound IB1-3 to obtain compound IB1-4.

[0319] The present disclosure also provides that when R 9 With R 10 When they form -CH=N-NH-, and R 4 A method for preparing a compound of formula (IB) when is not H, comprising one or more steps of the following steps (1) to (7); preferably comprising step (7), optionally further comprising step (6), optionally further comprising step (5), optionally further comprising step (4), optionally further comprising step (3), optionally further comprising step (2), optionally further comprising step (1):

[0320] in

[0321] R 1a 、R 1 、R 2 、R 5 、R 6 、R 7 、R 8 As defined above;

[0322] X1 and X2 are halogen, such as bromine or chlorine, preferably chlorine;

[0323] Pg 2 represents an aromatic amino protecting group, such as tetrahydropyranyl (THP);

[0324] in:

[0325] Step (1) reacting compound IB2-1 with IB2-2 to form a urea to obtain compound IB2-3;

[0326] Step (2) subjecting compound IB2-3 to a ring-closure reaction to obtain compound IB2-4;

[0327] Step (3) subjecting compound IB2-4 to a substitution reaction with IB1-1 to obtain compound IB2-5;

[0328] Step (4) subjecting compound IB2-5 to a halogenation reaction to obtain compound IB2-6;

[0329] Step (5) subjecting compound IB2-6 to a substitution reaction with IB2-7 to obtain compound IB2-8;

[0330] Step (6) subjecting compound IB2-8 to a substitution reaction with IB2-9 to obtain compound IB2-10;

[0331] Step (7) subjecting compound IB2-10 to a substitution reaction to obtain compound IB2-11;

[0332] Optionally, if necessary (e.g., R in IB2-11 1a The group is R protected by a protecting group 1 ), the method further comprises step (8) subjecting compound IB2-11 to a deprotection substitution reaction to obtain compound IB2.

[0333] In some embodiments, R 1a It is R 1 .

[0334] The reaction conditions of the above step (1) are preferably carried out in a suitable solvent, such as 1,4-dioxane, DCM or THF; the reaction temperature is -20-60°C.

[0335] The reaction conditions of the above step (2) are preferably carried out in an ammonia methanol solution; the reaction temperature is 0-60°C.

[0336] The reaction conditions of step (3) are the same as those described above for the substitution reaction of compound IB-2 with IA-1 to obtain compound IB-3.

[0337] The halogenation reaction in step (4) is preferably carried out in the presence of POCl3 in the presence of N,N-dimethylaniline; the reaction temperature is 20-140°C; and the reaction time is 2-24 hours.

[0338] The reaction conditions of the above step (5) are preferably carried out in an ammonia methanol solution; the reaction temperature is 0-60°C.

[0339] The reaction conditions of the above step (6) are preferably carried out in an acid such as TFA, benzenesulfonic acid, p-toluenesulfonic acid, etc.; the reaction solvents include methanol, ethanol, tert-butanol, etc.; the reaction temperature is 40-140°C.

[0340] The reaction conditions of step (7) are the same as those described above for the substitution or coupling reaction of compound IB-5 to obtain compound IB-6.

[0341] The deprotection reaction conditions in step (8) are the same as those described above for the deprotection reaction of compound IB-6 to obtain compound IB-7.

[0342] In some embodiments, Formula (IB) is further Formula (IB1) or Formula (IB2).

[0343] The present disclosure also provides that when R 9 When it is -OH, R 4 A method for preparing a compound of formula (ID) when is H, comprising one or more steps of the following steps (1) to (9); preferably comprising step (9), optionally further comprising step (8), optionally further comprising step (7), optionally further comprising step (6), optionally further comprising step (5), optionally further comprising step (4), optionally further comprising step (3), optionally further comprising step (2), optionally further comprising step (1):

[0344] in

[0345] R 1a 、R 1 、R 2 、R 3 、R 6 、R 7 、R 8 、R 9 、R 10 、Pg 1 , Lg 1 As defined above;

[0346] X2 is halogen, such as bromine or chlorine, preferably chlorine;

[0347] X3 is halogen, such as bromine, iodine or chlorine, preferably bromine;

[0348] in:

[0349] Step (1) reacting compound ID-1 with DMF-DMA to obtain compound ID-2;

[0350] Step (2) subjecting compound ID-2 to a ring-closure reaction to obtain compound ID-3;

[0351] Step (3) subjecting compound ID-3 to a halogenation reaction to obtain compound ID-4;

[0352] Step (4) reacting compound ID-4 with IA-1 to obtain compound ID-5;

[0353] Step (5) subjecting compound ID-5 to a substitution reaction to obtain compound ID-6;

[0354] Step (6) reacting compound ID-6 with IB-4 to obtain compound ID-7;

[0355] Step (7) subjecting compound ID-7 to a coupling reaction to obtain compound ID-8;

[0356] Step (8) deaminoprotecting compound ID-8 to obtain compound ID-9;

[0357] Step (9) Compound ID-9 is dehydroxylated to obtain compound ID-10.

[0358] In some embodiments, R 1a It is R 1 .

[0359] The reaction conditions of the above step (1) are preferably at a temperature of 20-120° C. for 2-24 hours.

[0360] The reaction conditions of the above step (2) are preferably in the presence of concentrated hydrochloric acid at a temperature of 20-120° C. for 2-24 hours.

[0361] In the above step (3), the halogenating agent is preferably NBS or NCS; the solvent is acetonitrile, DMF or DCM; and the reaction temperature is 0-80°C.

[0362] The reaction conditions of step (4) are the same as those described above for the substitution reaction of compound IB-2 with IA-1 to obtain compound IB-3.

[0363] The reaction conditions of step (5) are the same as those described above for the substitution or coupling reaction of compound IB-5 to obtain compound IB-6.

[0364] The reaction conditions of step (6) are the same as those described above for the condensation reaction of compounds IB-3 and IB-4 to obtain compound IB-5.

[0365] The coupling reaction in step (7) is preferably carried out in the presence of a catalyst, such as Pd(OAc)2, Pd2(dba)3, Pd(dppf)Cl2, Pd(PPh3)4, t-BuXPhos-Pd-G3, cataCXium A Pd G3, etc. The coupling reaction is preferably carried out in the presence of a ligand, such as PPh3, XPhos, XantPhos, SPhos, RuPhos, BrettPhos, Dppf, BINAP or PCy3. The coupling reaction is preferably carried out in the presence of a base, such as t-BuOK, t-BuONa, LiHMDS, NaHMDS, KHMDS, K3PO4, KOAc, Cs2CO3, K2CO3 or Na2CO3, etc. The coupling reaction is preferably carried out in a suitable solvent, such as DMF, 1,4-dioxane, THF, DCE, toluene or DMA, or a mixed solvent thereof with water; the reaction temperature is 60-150° C.; and the reaction time is 2-24 hours.

[0366] The reaction conditions of step (8) are the same as those described above for the deamination protection reaction.

[0367] The reaction conditions of step (9) are the same as those described above for the dehydroxylation protection reaction.

[0368] In some embodiments, R 3 If it is X3, then ID-7 in the above route is ID-8, and step (7) is no longer necessary.

[0369] In some embodiments, the reaction of ID-7 to produce ID-8 comprises reacting ID-7 with ID2-3-1 ( ) reaction to generate ID-7-1, and then coupling reaction of ID-7-1 with ID2-3-3 to obtain compound ID-8.

[0370] Therefore, in some embodiments, the present disclosure also provides a method for preparing a compound of formula (ID), comprising one or more steps of the following steps (1) to (2):

[0371] in:

[0372] R 1a 、R 2 、R 3 、R 6 、R 7 、R 8 、Pg 1 , Lg 1 , X3 is as defined above;

[0373] Step (1) Compound ID-7 and ID2-3-1 ( ) reaction to generate ID-7-1;

[0374] Step (2) Compound ID-7-1 is subjected to coupling reaction with ID2-3-3 to obtain compound ID-8.

[0375] The reaction conditions of step (1) are preferably carried out in the presence of a catalyst, such as PPd(dppf)Cl2, etc. The reaction is preferably carried out in the presence of a base, such as TEA, DIPEA, etc. The coupling reaction is preferably carried out in a suitable solvent, such as 1,4-dioxane, THF, acetonitrile, etc. The reaction temperature is 60-120°C and the reaction time is 2-24 hours.

[0376] The reaction conditions of step (2) are preferably carried out in the presence of a catalyst, such as Pd(dtbpf)Cl2, Pd(dppf)Cl2, Pd(dppf)Cl2·DCM, Pd(PPh3)4, cataCXium A Pd G3, BrettPhos Pd G3, etc.; the reaction is preferably carried out in the presence of a suitable base, which can be selected from K3PO4, Cs2CO3, K2CO3, Na2CO3, NaHCO3, etc. The coupling reaction is preferably carried out in a suitable solvent, such as 1,4-dioxane or a combination of THF and water; the reaction temperature is 60-120°C; and the reaction time is preferably 2-24 hours.

[0377] The present disclosure also provides that when R 9 With R 10 When they form -CH=N-NH-, and R 4 A method (1) for preparing a compound of formula (ID) when is H, comprising one or more of the following steps (1) to (5); preferably comprising step (5), optionally further comprising step (4), optionally further comprising step (3), optionally further comprising step (2), optionally further comprising step (1):

[0378] in

[0379] R 1a 、R 1 、R 2 、R 3 、R 6 、R 7 、R 8 、Pg 2 , Lg 1 As defined above;

[0380] X2 is halogen, such as bromine or chlorine, preferably chlorine;

[0381] X3 is halogen, such as bromine, iodine or chlorine, preferably bromine;

[0382] in:

[0383] Step (1) reacting compound ID-4 with IB1-1 to obtain compound ID2-1;

[0384] Step (2) subjecting compound ID2-1 to a substitution reaction to obtain compound ID2-2;

[0385] Step (3) reacting compound ID2-2 with IB-4 to obtain compound ID2-3;

[0386] Step (4) Compound ID2-3 is reacted with, for example, ID2-4 ( ) or ID2-5( ) to undergo coupling reaction to obtain compound ID2-6;

[0387] Step (5) deaminoprotects compound ID2-6 to obtain compound ID2-7.

[0388] The reaction conditions of step (1) are the same as those described above for the substitution reaction of compound IB-2 with IA-1 to obtain compound IB-3.

[0389] The reaction conditions of step (2) are the same as those described above for the substitution or coupling reaction of compound IB-5 to obtain compound IB-6.

[0390] The reaction conditions of step (3) are the same as those described above for the condensation reaction of compounds IB-3 and IB-4 to obtain compound IB-5.

[0391] The reaction conditions of step (4) are the same as those described above for the coupling reaction of compound ID-7 to obtain compound ID-8.

[0392] The reaction conditions of step (5) are the same as those described above for the deamination protection reaction.

[0393] The present disclosure also provides that when R 9 With R 10 When they form -CH=N-NH-, and R 4 A method (2) for preparing a compound of formula (ID) when is H, comprising one or more steps from the following steps (1) to (3); preferably comprising step (3), optionally further comprising step (2), optionally further comprising step (1):

[0394] in

[0395] R 1a 、R 1 、R 2 、R 3 、R 6 、R 7 、R 8 、Pg 2 , Lg 1 As defined above;

[0396] X3 is halogen, such as bromine, iodine or chlorine, preferably bromine;

[0397] in:

[0398] Step (1) reacting compound ID2-3 with ID2-3-1 to obtain compound ID2-3-2;

[0399] Step (2) coupling reaction of compound ID2-3-2 and ID2-3-3 to obtain compound ID2-6;

[0400] Step (3) deamino-protecting compound ID2-6 to obtain compound ID2-7;

[0401] The reaction conditions in step (1) are preferably carried out in the presence of a catalyst, such as Pd(OAc)2, Pd(dppf)Cl2, Pd(PPh3)4, etc. The coupling reaction is preferably carried out in the presence of a base, such as KOAc, TEA, DIPEA, etc. The coupling reaction is preferably carried out in a suitable solvent, such as DMF, 1,4-dioxane, ACN, DCE, or DMA, etc. The reaction temperature is 60-150°C, and the reaction time is 2-24 hours.

[0402] The reaction conditions of step (2) are the same as those described above for the coupling reaction of compound ID-7 to obtain compound ID-8.

[0403] The reaction conditions of step (3) are the same as those described above for the deamination protection reaction.

[0404] In some embodiments, compound ID2-3 can also be directly combined with ID2-4 ( ) reaction produces ID2-6:

[0405] The reaction conditions of step (1) are the same as those described above for coupling reaction of compound ID-7 to obtain compound ID-8.

[0406] In some embodiments, the order of certain reaction steps in the aforementioned methods can be adjusted.

[0407] For example, in some embodiments, in the process of generating ID2-3 from ID2-1, R can be first introduced into ID2-1. 1a The group is generated to ID2-2, and then the Lg is introduced into ID2-2. 1 In other embodiments, in the process of generating ID2-3 from ID2-1, a protected amino group can be introduced into ID2-1. 1 The protected amino group was used to generate ID2-1-1, and then R was introduced into ID2-1-1. 1a group to generate ID2-3.

[0408] For example, in some embodiments, in the process of generating ID2-6 from ID2-1-1, R 1a The group is then used to generate ID2-3, and then ID2-6 is generated from ID2-3 by the corresponding steps in any of the above methods. In other embodiments, R can be introduced into ID2-1-1 first. 3 The group is used to generate ID2-1-2, and then R is introduced into ID2-1-2. 1a groups to generate ID2-6.

[0409] In some embodiments, the present disclosure also provides that when R 9 With R 10 A method for preparing a compound of formula (ID) when -CH=N-NH- is jointly formed, comprising one or more steps from the following steps (1) to (2); preferably comprising step (2), and optionally further comprising step (1):

[0410] in:

[0411] R 1a 、R 2 、R 6 、R 7 、R 8 、Pg 2 , Lg 1 , X2, X3 are as defined above;

[0412] Step (1) reacting compound ID2-1 with IB-4 to obtain compound ID2-1-1;

[0413] Step (2) Compound ID2-1-1 is subjected to a substitution reaction to obtain compound ID2-3.

[0414] The reaction conditions of step (1) are the same as those described above for the condensation reaction of compounds IB-3 and IB-4 to obtain compound IB-5.

[0415] The reaction conditions of step (2) are the same as those described above for the substitution reaction of compound IB-5 to obtain compound IB-6.

[0416] In some embodiments, the present disclosure also provides that when R 9 With R 10 A method for preparing a compound of formula (ID) when -CH=N-NH- is jointly formed, comprising one or more steps from the following steps (1) to (2); preferably comprising step (2), and optionally further comprising step (1):

[0417] in:

[0418] R 1a 、R 2 、R 3 、R 6 、R 7 、R 8 、Pg 2 , Lg 1 , X2, X3 are as defined above;

[0419] Step (1) subjecting compound ID2-1-1 to a coupling reaction to obtain compound ID2-1-2;

[0420] Step (2) Compound ID2-1-2 is subjected to a coupling reaction to obtain compound ID2-6.

[0421] The reaction conditions of step (1) are the same as those described above for the coupling reaction of compound ID-7 to obtain compound ID-8.

[0422] The reaction conditions of step (2) are the same as those described above for the coupling reaction of compound ID-7 to obtain compound ID-8.

[0423] In some embodiments, the reaction of ID2-1-1 to generate ID2-1-2 comprises reacting ID2-1-1 with diboronic acid pinacol ester to generate ID2-1-1-1, and then coupling ID2-1-1-1 with ID2-3-3 to obtain compound ID2-1-2.

[0424] Therefore, in some embodiments, the present disclosure also provides when R 9 With R 10 A method for preparing a compound of formula (ID) when -CH=N-NH- is formed together, comprising one or more steps from the following steps (1) to (2):

[0425] in:

[0426] R 2 、R3 、R 6 、R 7 、R 8 、Pg 2 , Lg 1 , X2, X3 are as defined above;

[0427] Step (1) reacting compound ID2-1-1 with diboronic acid pinacol ester to produce ID2-1-1-1;

[0428] Step (2): Compound ID2-1-1-1 is subjected to coupling reaction with ID2-3-3 to obtain compound ID2-1-2.

[0429] The reaction conditions of step (1) are preferably carried out in the presence of a catalyst, such as Pd(dppf)Cl2; the reaction is preferably carried out in the presence of a base, such as KOAc, TEA, DIPEA, etc.; the coupling reaction is preferably carried out in a suitable solvent, such as DMF, 1,4-dioxane, ACN, DCE or DMA, etc.; the reaction temperature is 60-120°C; and the reaction time is 2-24 hours.

[0430] The reaction conditions of step (2) are the same as those described above for the coupling reaction of compound ID-7 to obtain compound ID-8.

[0431] In some embodiments, the reaction of ID2-1-2 to form ID2-6 comprises reacting ID2-1-2 with diboronic acid pinacol ester to form ID2-1-2-1, and then coupling ID2-1-2-1 with ID2-3-3 to obtain compound ID2-6.

[0432] Therefore, in some embodiments, the present disclosure also provides when R 9 With R 10 A method for preparing a compound of formula (ID) when -CH=N-NH- is formed together, comprising one or more steps from the following steps (1) to (2):

[0433] in:

[0434] R 2 、R 3 、R 6 、R 7 、R 8 、Pg 2 , Lg 1 , X2, X3 are as defined above;

[0435] Step (1) reacting compound ID2-1-2 with diboronic acid pinacol ester to produce ID2-1-2-1;

[0436] Step (2) Compound ID2-1-2-1 is subjected to coupling reaction with ID2-3-3 to obtain compound ID2-6.

[0437] The reaction conditions of step (1) are the same as those described above for the reaction of compound ID2-1-1 with diboronic acid pinacol ester to produce ID2-1-1-1.

[0438] The reaction conditions of step (2) are the same as those described above for the coupling reaction of compound ID-7 to obtain compound ID-8.

[0439] In some embodiments, compound ID-5 can be reacted with IB-4 to first generate ID-5-1, which is then subjected to a substitution reaction to generate ID-7.

[0440] Therefore, the present disclosure also provides when R 9 When it is -OH, R 4 A method for preparing a compound of formula (ID) when is H, comprising one or more steps of the following steps (1) to (2):

[0441] in

[0442] R 1a 、R 2 、R 6 、R 7 、R 8 、R 10 、Pg 1 , Lg 1 , X2, X3 are as defined above;

[0443] Step (1) reacting compound ID-5 with IB-4 to generate ID-5-1,

[0444] Step (2) is to subject compound ID-5-1 to a substitution reaction to generate ID-7.

[0445] The reaction conditions of step (1) are the same as those described above for the reaction of compound ID-6 with IB-4 to obtain compound ID-7.

[0446] The reaction conditions of step (2) are the same as those described above for the substitution reaction of compound ID-5 to obtain compound ID-6.

[0447] In some embodiments, the present disclosure also provides that when R 9 When it is -OH, R 4 A method for preparing a compound of formula (ID) when is H, comprising one or more steps of the following steps (1) to (3):

[0448] in:

[0449] R 1a 、R 2 、R 3 、R 6 、R 7 、R 8 、Pg 1 , Lg 1 , X2, X3 are as defined above;

[0450] Step (1) reacting compound ID-5-1 with diboronic acid pinacol ester to produce ID-5-2;

[0451] Step (2) coupling reaction of compound ID-5-2 with ID2-3-3 to obtain compound ID-5-3;

[0452] Step (3) Compound ID-5-3 is subjected to a coupling reaction to obtain compound ID-8.

[0453] The reaction conditions of step (1) are the same as those described above for the reaction of compound ID2-1-1 with diboronic acid pinacol ester to produce ID2-1-1-1.

[0454] The reaction conditions of step (2) are the same as those described above for the coupling reaction of compound ID-7 to obtain compound ID-8.

[0455] The reaction conditions of step (3) are the same as those described above for the coupling reaction of compound ID-7 to obtain compound ID-8.

[0456] In some embodiments, compound ID-5-3 is first subjected to a deprotection reaction to generate compound ID-5-3-2, which is then reacted with A coupling reaction occurred to give compound ID-10.

[0457] Therefore, in some embodiments, the present disclosure also provides that when R 9 When it is -OH, R 4 A method for preparing a compound of formula (ID) when is H, comprising one or more steps of the following steps (1) to (3):

[0458] in:

[0459] R 1 、R 2 、R 3 、R 6 、R 7 、R 8 、Pg 1 , Lg 1, X2 is as defined above;

[0460] Step (1) subjecting compound ID-5-3 to a deamination protection reaction to generate compound ID-5-3-1;

[0461] Step (2) subjecting compound ID-5-3-1 to a dehydroxylation reaction to generate compound ID-5-3-2;

[0462] Step (3) Compound ID-5-3-2 and The compound with the same structure undergoes a coupling reaction to generate the compound ID.

[0463] The reaction conditions of step (1) are the same as those described above for the deamination protection reaction;

[0464] The reaction conditions of step (2) are the same as those described above for the dehydroxylation protection reaction;

[0465] The reaction conditions of step (3) are the same as those described above for the coupling reaction of compound ID-7 to obtain compound ID-8.

[0466] intermediates

[0467] In some embodiments, the present disclosure provides a compound of Formula IA-3, IA-4, IA-5, IA-6, IA-7, IA-8, IA-9, IA-10, or IA-11, or a salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled thereof:

[0468] where R 1 、R 2 、R 4 、R 6 、R 7 、R 8 、R 10 , X1, Pg 1 As defined above.

[0469] In some embodiments, the present disclosure provides compounds as shown below, or salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled versions thereof:

[0470] Among them, R 1a R 1 or R protected by an amino protecting group 1 ;

[0471] R 1 、R 2 、R3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 10 , X1, X2, X3, Pg 1 、Pg 2 , Lg 1 As defined above.

[0472] In some embodiments, in the above intermediate structures, R 1a It is R 1 .

[0473] The above-mentioned intermediate compounds or their salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope-labeled products can be used to prepare the compounds represented by the general formula herein or their pharmaceutically acceptable forms.

[0474] Pharmaceutical compositions, formulations, and kits

[0475] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable form thereof, or a mixture thereof, and one or more pharmaceutically acceptable carriers, wherein the pharmaceutically acceptable form is selected from a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug.

[0476] A further object of the present disclosure is to provide a method for preparing the pharmaceutical composition of the present disclosure, which comprises combining the compound of the present disclosure or a pharmaceutically acceptable form thereof, or a mixture thereof, with one or more pharmaceutically acceptable carriers, wherein the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled substances, metabolites, or prodrugs.

[0477] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present disclosure 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).

[0478] The pharmaceutical composition can be administered in any form, as long as it prevents, alleviates, prevents or cures the symptoms of a human or animal patient. For example, it can be prepared into various suitable dosage forms according to the administration route.

[0479] When administered orally, the pharmaceutical composition can be prepared into any orally acceptable preparation form.

[0480] For percutaneous or topical administration, the pharmaceutical compositions may be formulated in a suitable ointment, lotion or liniment, wherein the active ingredient is suspended or dissolved in one or more carriers.

[0481] The pharmaceutical composition can also be used in the form of injections, including injection solutions, sterile powders for injection, and concentrated solutions for injection.

[0482] Another aspect of the present disclosure is also directed to a pharmaceutical preparation comprising a compound of the present disclosure, a pharmaceutically acceptable form thereof, or a mixture thereof as an active ingredient, or a pharmaceutical composition of the present disclosure, wherein the pharmaceutically acceptable form is selected from a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug. In some embodiments, the preparation is in the form of a solid preparation, a semisolid preparation, a liquid preparation, or a gaseous preparation.

[0483] A further object of the present disclosure is to provide an article of manufacture, for example, provided in the form of a kit. Articles of manufacture as used herein are intended to include, but are not limited to, pharmaceutical compositions and packaging. For example, the article of manufacture of the present 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 the present disclosure or a pharmaceutically acceptable form thereof, or a mixture thereof, wherein the pharmaceutically acceptable form is selected from a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug; and (c) an optional package insert indicating that the pharmaceutical composition can be used to treat a disease or condition for which a MYT1 inhibitor is indicated, such as a tumor-like condition.

[0484] The package insert is a trademark, label, or indicia that lists information about the pharmaceutical composition within the first container. The information listed is typically determined by the regulatory agency (e.g., the Food and Drug Administration) that has jurisdiction over the region in which the product is to be sold. Preferably, the package insert specifically lists the indications for which the pharmaceutical composition is approved. The package insert can be made of any material from which the information contained therein or thereon can be read. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper, or plastic, etc.) onto which the desired information can be formed (e.g., printed or applied).

[0485] Treatment methods and uses

[0486] The present disclosure provides compounds of the general formula or pharmaceutically acceptable forms thereof, or pharmaceutical compositions of the present disclosure, for use in preventing or treating diseases or conditions associated with PKMYT1 activity, wherein the pharmaceutically acceptable forms are selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites, or prodrugs. Such diseases or conditions include cancers with overexpression or expansion of the CCNE1 gene or cancers harboring inactivating mutations in the FBXW7 gene.

[0487] Another object of the present disclosure is to provide a method for preventing or treating diseases or conditions associated with PKMYT1 activity, comprising administering to an individual in need thereof 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 a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug.

[0488] Another object of the present disclosure is to provide the use of the compound of the present disclosure or its pharmaceutically acceptable form or the pharmaceutical composition of the present disclosure in the preparation of a medicament, in particular, in the preparation of a medicament for preventing or treating a disease or condition associated with PKMYT1 activity, wherein the pharmaceutically acceptable form is selected from a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug.

[0489] Another object of the present disclosure is to provide the use of the compound of the present disclosure or its pharmaceutically acceptable form or the pharmaceutical composition of the present disclosure in the preparation of a PKMYT1 inhibitor, wherein the pharmaceutically acceptable form is selected from a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug.

[0490] According to some embodiments of the present disclosure, the PKMYT1 inhibitor comprises a compound disclosed herein or a pharmaceutically acceptable form thereof.

[0491] According to some embodiments of the present disclosure, the disease or condition associated with PKMYT1 activity is a disease or condition that is dependent on PKMYT1 activity, including but not limited to tumor or cancer diseases or conditions.

[0492] According to some embodiments of the present disclosure, the disease or condition associated with PKMYT1 activity is a disease that is sensitive or responsive to a PKMYT1 inhibitor, including but not limited to tumor or cancer diseases or conditions.

[0493] According to some embodiments of the present disclosure, the disease or condition includes a disease or condition characterized by excessive cell proliferation. Furthermore, the disease or condition characterized by excessive cell proliferation includes (but is not limited to) tumor or cancer diseases or conditions. Furthermore, the tumor or cancer is a tumor or cancer characterized by overexpression / expansion of the CCNE1 gene or an inactivating mutation in the FBXW7 gene.

[0494] In some embodiments, the cancer with high CCNE1 gene expression or CCNE1 gene expansion is uterine cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, liver cancer, or endometrial cancer.

[0495] In an embodiment of the present disclosure, the present disclosure provides a method of treating cancer, the method comprising administering to a subject an effective amount of a PKMYT1 inhibitor, wherein the cancer has an inactivating mutation in the FBXW7 gene.

[0496] The dosage regimen can be adjusted to provide the optimal desired response. For example, when administered as an injection, a single bolus, bolus, and / or continuous infusion can be administered, among others. For example, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the therapeutic situation. It should be noted that dosage values ​​can vary depending on the type and severity of the condition to be alleviated and can include single or multiple doses. In general, the dosage for treatment varies, 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 the individual physician. It will be further understood that for any particular individual, the specific dosage regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition. The dosage and administration regimen of the pharmaceutical composition can be determined by one of ordinary skill in the clinical field. For example, the compositions or compounds of the present disclosure can be administered in divided doses from 4 times a day to once every 3 days, with the dosage amount being, for example, 0.01 to 1000 mg / dose. The desired dose may be administered in one or more doses to achieve the desired result.The pharmaceutical compositions according to the present disclosure may also be provided in unit dosage form. Beneficial effects

[0497] The present disclosure provides a novel class of PKMYT1 inhibitors capable of achieving at least one of the following technical effects:

[0498] (1) High inhibitory activity against PKMYT1.

[0499] (2) Excellent physicochemical properties (e.g., solubility, physical and / or chemical stability).

[0500] (3) Excellent pharmacokinetic properties (e.g., good liver microsomal stability, good bioavailability, appropriate half-life and duration of action).

[0501] (4) Excellent safety (lower toxicity and / or fewer side effects, wider therapeutic window), etc.

[0502] Example

[0503] The present disclosure will be described in detail below with reference to Examples and Test Examples. However, these examples do not limit the scope of the present disclosure and variations can be made without departing from the scope of the present disclosure.

[0504] Nuclear magnetic resonance (NMR) measurements were performed using a Bruker nuclear magnetic resonance spectrometer, manufactured by Bruker, model: AVANCE III HD-400.

[0505] Preparation method for preparative high performance liquid chromatography:

[0506] Instrument model: Agilent 1260, chromatographic column: Waters SunFire Prep C18 OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25°C; flow rate: 20.0 mL / min; detection wavelength: 214 nm; elution gradient: (0 min: 10% A, 90% B; 16.0 min: 90% A, 10% B); mobile phase A: acetonitrile; mobile phase B: 0.05% formic acid aqueous solution or 0.05% ammonium bicarbonate aqueous solution.

[0507] Thin layer chromatography purification was performed using GF 254 (0.4-0.5 nm) silica gel plates produced in Yantai.

[0508] The reaction was monitored by thin layer chromatography (TLC) or liquid chromatography-mass spectrometry (SHIMADZU, LCMS-2020 model). 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 solvents was adjusted according to the polarity of the compounds or by adding triethylamine.

[0509] Column chromatography generally uses Qingdao Ocean 200-300 mesh silica gel 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 solvents is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added for adjustment.

[0510] Unless otherwise specified in the examples, the reaction temperature is room temperature (15°C to 30°C).

[0511] 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.

[0512] The abbreviations used in this document have the following meanings:

[0513] Compound Examples:

[0514] Intermediate Example 1: Preparation of 2-chloro-5-(3-methoxy-2,6-dimethylphenoxy)quinazolin-4-amine

[0515] Step 1: Preparation of 2-(3-methoxy-2,6-dimethylphenoxy)-6-nitrobenzonitrile

[0516] Dissolve 3-methoxy-2,6-dimethylphenol (1.3 g, 5.98 mmol), 2-fluoro-6-nitrobenzonitrile (836.05 mg, 4.98 mmol), and potassium carbonate (1.74 g, 12.46 mmol) in DMF (10 mL) in a reaction flask, heat to 100°C, and stir for 2 hours. After the reaction, cool to room temperature, pour into ice water (20 mL), and extract with EA (20.0 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure. Purify by column chromatography on silica gel (PE / EA = 4 / 1) to obtain the title compound (1.5 g). MS (ESI, m / z): 316.1 [M+18] + .

[0517] Step 2: Preparation of 2-amino-6-(3-methoxy-2,6-dimethylphenoxy)benzonitrile

[0518] The raw materials 2-(3-methoxy-2,6-dimethylphenoxy)-6-nitrobenzonitrile (1.5 g, 4.53 mmol) and tetrahydroxydiboron (1.64 g, 18.10 mmol) were dissolved in DMF (10 mL) and placed in a reaction flask. 4,4'-bipyridine (71.40 mg, 452.58 μmol) was added with stirring at 0°C. After the addition, the mixture was warmed to 25°C and stirred for 10 minutes. After the reaction, the mixture was poured into ice water (20 mL) and extracted with EA (20.0 mL x 3). The mixture was washed with saturated sodium bicarbonate (10.0 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the title compound (1.1 g). MS (ESI, m / z): 269.1 [M+H] + .

[0519] Step 3: Preparation of tert-butyl (2-cyano-3-(3-methoxy-2,6-dimethylphenoxy)phenyl)carbamate

[0520] 2-Amino-6-(3-methoxy-2,6-dimethylphenoxy)benzonitrile (900 mg, 2.68 mmol), N,N-diisopropylethylamine (1.05 g, 8.05 mmol), and di-tert-butyl dicarbonate (885 mg, 4.02 mmol) were dissolved in THF (15 mL) and placed in a reaction flask. The mixture was stirred at 25°C for 12 hours. After the reaction, the mixture was poured into ice water (20 mL) and extracted with EA (20.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The mixture was purified by column chromatography on silica gel (PE / EA = 7 / 3) to yield the title compound (1.1 g). MS (ESI, m / z): 313.2 [M-56] + .

[0521] Step 4: Preparation of tert-butyl (2-carbamoyl-3-(3-methoxy-2,6-dimethylphenoxy)phenyl)carbamate

[0522] Dissolve tert-butyl (2-cyano-3-(3-methoxy-2,6-dimethylphenoxy)phenyl)carbamate (1.1 g, 2.23 mmol) and potassium carbonate (932.68 mg, 6.69 mmol) in DMSO (10 mL) and place in a reaction flask. Add 30% hydrogen peroxide (1.52 g, 13.38 mmol) in portions with stirring. Stir at 25°C for 16 hours. After completion of the reaction, pour into ice water (20 mL) and extract with EA (20.0 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure. Purify by column chromatography on silica gel (PE / EA = 3 / 2) to obtain the title compound (1.0 g). MS (ESI, m / z): 387.2 [M+H] + .

[0523] Step 5: Preparation of 2-amino-6-(3-methoxy-2,6-dimethylphenoxy)benzamide

[0524] Dissolve tert-butyl (2-carbamoyl-3-(3-methoxy-2,6-dimethylphenoxy)phenyl)carbamate (1 g, 1.95 mmol) in a 4 M hydrochloric acid-1,4-dioxane solution (8 mL) and stir at 25°C for 2 hours. After the reaction, concentrate under reduced pressure to remove excess solvent. Add saturated aqueous sodium bicarbonate to adjust the pH to 8-9 and extract with EA (20.0 mL x 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and evaporate the solvent under reduced pressure to obtain the title compound (600 mg). MS (ESI, m / z): 287.1 [M+H]+ .

[0525] Step 6: Preparation of 5-(3-methoxy-2,6-dimethylphenoxy)quinazoline-2,4(1H,3H)-dione

[0526] 2-Amino-6-(3-methoxy-2,6-dimethylphenoxy)benzamide (600 mg, 1.89 mmol), di-tert-butyl dicarbonate (415.29 mg, 1.89 mmol), and 4-dimethylaminopyridine (15.52 mg, 125.73 μmol) were dissolved in ACN (10 mL) in a reaction flask and stirred at 25°C for 12 hours. After completion of the reaction, the mixture was poured into ice water (20 mL) and extracted with EA (20.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The mixture was purified by column chromatography on silica gel (PE / EA = 2 / 1) to yield the title compound (300 mg). MS (ESI, m / z): 313.2 [M+H] + .

[0527] Step 7: Preparation of 2,4-dichloro-5-(3-methoxy-2,6-dimethylphenoxy)quinazoline

[0528] 5-(3-Methoxy-2,6-dimethylphenoxy)quinazoline-2,4(1H,3H)-dione (300 mg, 912.53 μmol) was dissolved in phosphorus oxychloride (8 mL) and placed in a reaction flask. N,N-dimethylaniline (11.18 mg, 91.26 μmol) was added and the mixture was heated to 90°C and stirred for 3 hours. After completion of the reaction, the excess solvent was removed by concentration under reduced pressure, then poured into ice water (10.0 mL) and extracted with EA (10.0 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The product was purified by column chromatography on silica gel (PE / EA = 3 / 1) to yield the title compound (250 mg). MS (ESI, m / z): 349 / 351 [M+H] + .

[0529] Step 8: Preparation of 2-chloro-5-(3-methoxy-2,6-dimethylphenoxy)quinazolin-4-amine

[0530] Dissolve 2,4-dichloro-5-(3-methoxy-2,6-dimethylphenoxy)quinazoline (250 mg, 544.31 μmol) and a 7 M amine methanol solution (5 mL) in THF (4 mL) in a reaction flask and stir at 25°C for 4 hours. After completion of the reaction, pour into ice water (20 mL) and extract with EA (20.0 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure. Purification by Prep-TLC (DCM / EA = 9 / 1) affords the title compound (220 mg). MS (ESI, m / z): 330.1 [M+H] + .

[0531] Intermediate Example 2: Preparation of 7-chloro-N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine

[0532] Step 1: Preparation of 5,7-dichloropyrido[4,3-d]pyrimidin-4-ol

[0533] Place 4-amino-2,6-dichloronicotinamide (1.3 g, 6.3 mmol) and triethyl orthoformate (6 mL) in a reaction flask, heat to 150°C, and stir for 2 hours. After the reaction is complete, cool to room temperature, pour into ice water (20 mL), and extract with EA (20.0 mL x 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Purify by column chromatography on silica gel (PE / EA = 1 / 2) to obtain the title compound (1.2 g). MS (ESI, m / z): 216.2 [M+H] + .

[0534] Step 2: Preparation of 7-chloro-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-ol

[0535] Dissolve 3-methoxy-2,6-dimethylphenol (1.1 g, 7.3 mmol) in DMF (10 mL). Slowly add sodium hydride (333 mg, 8.3 mmol) while cooling in a water bath. Stir for 20 min, then add 5,7-dichloropyrido[4,3-d]pyrimidin-4-ol (1.2 g, 5.6 mmol). Raise the temperature to 60°C and stir for 6 hr. After the reaction, cool to room temperature, pour into saturated ammonium chloride (20 mL), and extract with EA (20.0 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure. Purify by column chromatography on silica gel (PE / EA = 1 / 1) to yield the title compound (1.3 g). MS (ESI, m / z): 332.1 [M+H] + .

[0536] Step 3: Preparation of 7-chloro-N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine

[0537] 7-Chloro-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-ol (1.3 g, 3.9 mmol), 2,4-dimethoxybenzylamine (0.98 g, 5.9 mmol), and DIPEA (1.0 g, 7.8 mmol) were dissolved in DMF (15 mL). PyBOP (2.2 g, 4.3 mmol) was added at room temperature, and the mixture was heated to 60°C and stirred for 12 hours. After the reaction, the mixture was cooled to room temperature, poured into ice water (20 mL), and extracted with EA (20.0 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The mixture was purified by column chromatography on silica gel (PE / EA = 1 / 1) to give the title compound (1.1 g). MS (ESI, m / z): 481.2 [M+H] + .

[0538] Intermediate Example 3: tert-Butyl (R)-(1-(5-bromo-8-((2,4-dimethoxybenzyl)amino)-1-(3-methoxy-2,6-dimethylphenoxy)-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate

[0539] Step 1: Preparation of 2,6-dichloro-4-(2-(dimethylamino)vinyl)nicotinonitrile

[0540] Dissolve 2,6-dichloro-4-methylpyridine-3-carbonitrile (14 g, 74.86 mmol) in DMF (30 mL), then add N,N-dimethylformamide dimethyl acetal (10.44 g, 89.83 mmol). Heat to 100°C and stir for 12 hours. After the reaction, cool to room temperature and extract with EA (40.0 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure. Purify by column chromatography on silica gel (PE:DCM = 3 / 7 eluent) to yield the title compound (6.0 g). MS (ESI, m / z): 242.1 [M+H] + .

[0541] Step 2: Preparation of 6,8-dichloro-2,7-naphthyridin-1(2H)-one

[0542] Dissolve 2,6-dichloro-4-(2-(dimethylamino)vinyl)nicotinonitrile (2 g, 8.26 mmol) in concentrated hydrochloric acid (5 mL), heat to 100°C, and stir for 12 hours. After the reaction is complete, cool to room temperature, add ice water, filter, and dry the filter cake under reduced pressure to obtain the title product (1.3 g). MS (ESI, m / z): 215.1 [M+H] + .

[0543] Step 3: Preparation of 4-bromo-6,8-dichloro-2,7-naphthyridin-1(2H)-one

[0544] Dissolve 6,8-dichloro-2,7-naphthyridin-1(2H)-one (1.3 g, 6.04 mmol) and N-bromosuccinimide (1.07 g, 6.04 mmol) in DMF (8 mL) and stir at room temperature for 1 hour. After the reaction is complete, quench the reaction with water and extract with EA (20.0 mL x 3). The organic phases are combined and dried over anhydrous sodium sulfate to directly obtain the crude title product (1.3 g). MS (ESI, m / z): 292.9 [M+H] + .

[0545] Step 4: Preparation of 4-bromo-6-chloro-8-(3-methoxy-2,6-dimethylphenoxy)-2,7-naphthyridin-1(2H)-one

[0546] Dissolve 4-bromo-6,8-dichloro-2,7-naphthyridin-1(2H)-one (1.3 g, 4.42 mmol) and 3-methoxy-2,6-dimethylphenol (0.81 g, 5.30 mmol) in DMF (10 mL). Add NaH (353.6 mg, 8.84 mmol, 60% purity) in an ice bath. Then raise the temperature to 60°C and stir for 2 hours. After the reaction, cool to room temperature and extract with EA (20.0 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure. Purify by column chromatography on silica gel (PE:EA = 10 / 1) to obtain the title compound (900 mg). MS (ESI, m / z): 409.0 [M+H]. + .

[0547] Step 5: Preparation of tert-butyl (R)-(1-(5-bromo-1-(3-methoxy-2,6-dimethylphenoxy)-8-oxo-7,8-dihydro-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate

[0548] Dissolve 4-bromo-6-chloro-8-(3-methoxy-2,6-dimethylphenoxy)-2,7-naphthyridin-1(2H)-one (800 mg, 1.95 mmol), (R)-methyl(pyrrolidin-3-yl)carbamic acid tert-butyl ester (782.22 mg, 3.91 mmol), and potassium carbonate (808.5 mg, 5.85 mmol) in DMF (6 mL), warm to 100°C, and stir for 12 hours. After completion of the reaction, cool to room temperature, quench with water, and extract with EA (20.0 mL x 3). The organic phases are combined, dried over anhydrous sodium sulfate, and purified by column chromatography on silica gel (PE:EA = 1 / 1) to yield the title compound (400 mg). MS (ESI, m / z): 573.2 M+H. + .

[0549] Step 6: Preparation of tert-butyl (R)-(1-(5-bromo-8-((2,4-dimethoxybenzyl)amino)-1-(3-methoxy-2,6-dimethylphenoxy)-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate

[0550] Tert-butyl (R)-(1-(5-bromo-1-(3-methoxy-2,6-dimethylphenoxy)-8-oxo-7,8-dihydro-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate (400 mg, 697 μmol), (2,4-dimethoxyphenyl)methanamine (175.57 mg, 1.05 mmol), and diazabicyclopentane (DBU) (319.7 mg, 2.1 mmol) were dissolved in DMF (6 mL), and 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (362.7 mg, 697 μmol) was added. The temperature was raised to 60°C and stirred for 2 hr. After the reaction, the mixture was cooled to room temperature, quenched with water, and extracted with EA (20.0 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was purified by column chromatography on silica gel (PE:EA = 10 / 3) to obtain the title compound (300 mg). MS (ESI, m / z): 722.2 M+H + .

[0551] Intermediate Example 4: Preparation of tert-butyl ((3R)-1-(5-bromo-8-((2,4-dimethoxybenzyl)amino)-1-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-)1H-indazol-4-yl)oxy)-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate

[0552] Step 1: Preparation of 4-bromo-6-chloro-8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2,7-naphthyridin-1(2H)-one

[0553] Dissolve 4-bromo-6,8-dichloro-2,7-naphthyridin-1(2H)-one (1.3 g, 3.54 mmol) and 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol (1.23 g, 5.31 mmol) in THF (10 mL). Add NaH (424.32 mg, 17.68 mmol) in an ice bath, then raise the temperature to 60°C and stir for 4 hours. After the reaction, cool to room temperature and extract with EA (20.0 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure. Purify by column chromatography on silica gel (PE:EA = 1 / 1) to yield the title compound (1.20 g). MS (ESI, m / z): 489.0 [M+H]. + .

[0554] Step 2: Preparation of 4-bromo-6-chloro-N-(2,4-dimethoxybenzyl)-8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2,7-naphthyridin-1-amine

[0555] 4-Bromo-6-chloro-8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2,7-naphthyridin-1(2H)-one (1.20 g, 2.45 mmol), (2,4-dimethoxyphenyl)methanamine (491.63 mg, 2.94 mmol), and diazabicyclopentadiene (DBU) (745.98 mg, 4.90 mmol) were dissolved in DMF (15 mL). 1H-Benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (1.40 g, 2.70 mmol) was then added. The mixture was heated to 60°C and stirred for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, quenched with water, and extracted with EA (20.0 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography on silica gel (PE:EA = 1 / 1) to give the title compound (920 mg). MS (ESI, m / z): 639.1 [M+H] + .

[0556] Step 3: Preparation of tert-butyl ((3R)-1-(5-bromo-8-((2,4-dimethoxybenzyl)amino)-1-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-)1H-indazol-4-yl)oxy)-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate

[0557] 4-Bromo-6-chloro-N-(2,4-dimethoxybenzyl)-8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2,7-naphthyridin-1-amine (920 mg, 1.44 mmol), (R)-methyl(pyrrolidin-3-yl)carbamic acid tert-butyl ester (865.14 mg, 4.32 mmol), and potassium carbonate (597.07 mg, 4.32 mmol) were dissolved in DMF (15 mL), heated to 100°C, and stirred for 12 hours. After completion of the reaction, the mixture was cooled to room temperature, quenched with water, and extracted with EA (20.0 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography on silica gel (PE:EA = 10 / 1) to give the title compound (500 mg). MS (ESI, m / z): 802.4 [M+H] + .

[0558] Intermediate Example 5: 4-Bromo-6-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-N-(2,4-dimethoxybenzyl)-8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2,7-naphthyridin-1-amine

[0559] 4-Bromo-6-chloro-N-(2,4-dimethoxybenzyl)-8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2,7-naphthyridin-1-amine (200 mg, 297.37 μmol) and 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine (186.45 mg, 1.49 mmol) were dissolved in DMAc (2 mL), and DIPEA (1.16 g, 8.92 mmol) and K2CO3 (205.49 mg, 1.49 mmol) were added. The mixture was stirred in a microwave at 120°C for 10 hrs. The reaction mixture was added with a large amount of water and extracted with EA. The organic phase was dried and concentrated, and the title compound (130 mg) was obtained by column chromatography (DCM / MeOH = 96 / 4). MS (ESI, m / z): 726.3, 728.3 [M+H] + .

[0560] The following compounds were prepared by the method and general steps described in Reference Intermediate Example 5. The other required raw materials can be purchased commercially or synthesized by experienced synthesizers in the field of organic synthesis using conventional reactions from commercially purchased reagents.

[0561] Intermediate Example 7: Preparation of 6-chloro-N-(2,4-dimethoxybenzyl)-4-(5-methyl-1,3,4-thiadiazol-2-yl)-8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2,7-naphthyridin-1-amine

[0562] Step 1: Preparation of 6-chloro-N-(2,4-dimethoxybenzyl)-8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridin-1-amine

[0563] 4-Bromo-6-chloro-N-(2,4-dimethoxybenzyl)-8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2,7-naphthyridin-1-amine (1.80 g, 2.82 mmol), pinacol diboron (1.43 g, 5.64 mmol), potassium acetate (829.43 mg, 8.46 mmol), and Pd(dppf)Cl2 (206.13 mg, 282.0 μmol) were added to 1,4-dioxane (35 mL) and reacted at 120°C for 3 hours under nitrogen. After completion of the reaction, the mixture was cooled to room temperature and concentrated to obtain the crude product, which was purified by silica gel column chromatography (PE / EA = 0-45%) to afford the title compound (1.25 g). MS (ESI, m / z): 686.4 [M+H] + .

[0564] Step 2: Preparation of 6-chloro-N-(2,4-dimethoxybenzyl)-4-(5-methyl-1,3,4-thiadiazol-2-yl)-8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2,7-naphthyridin-1-amine

[0565] 6-Chloro-N-(2,4-dimethoxybenzyl)-8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridin-1-amine (1.20 g, 1.05 mmol), 2-bromo-5-methyl-1,3,4-thiadiazole (395.6 mg, 2.10 mmol) 1), potassium carbonate (290.11 mg, 2.10 mmol), and Pd(dppf)Cl2 (115.19 mg, 157.43 μmol) were added to 1,4-dioxane (40 mL) and H2O (4 mL). The temperature was raised to 120°C and the reaction was allowed to proceed for 6 hours. After completion of the reaction, the mixture was cooled to room temperature and directly concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 0-70%) to obtain the title compound (460 mg). MS (ESI, m / z): 658.2 [M+H] + .

[0566] The following compounds were prepared by the method and general steps described in Reference Intermediate Example 7. The other required raw materials can be purchased commercially or synthesized by experienced synthesizers in the field of organic synthesis using conventional reactions from commercially purchased reagents.

[0567] Intermediate Example 8: Preparation of 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol

[0568] Step 1: Preparation of 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0569] 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. The mixture was then heated to 25°C and allowed to react for 0.5 hr. After the reaction, water was added, stirred, and extracted with EA. The mixture was concentrated to afford the title compound (42 g). MS (ESI, m / z): 295.1 [M+H] + .

[0570] Step 2: Preparation of 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol

[0571] 4-Bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (42 g, 142.29 mmol), Pd(dba) (5.21 mg, 5.69 mmol), tert-butyl 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 hours under a nitrogen atmosphere. After the reaction, most of the 1,4-dioxane was removed by evaporation. The aqueous layer was adjusted to pH 5 with formic acid, water was added, extracted with EA, and concentrated. The crude product was purified by reverse-phase HPLC to yield the title compound (19 g). MS (ESI, m / z): 233.2 [M+H] + .

[0572] Intermediate Example 9: Preparation of 7-chloro-N-(2,4-dimethoxybenzyl)-5-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)pyrido[4,3-d]pyrimidin-4-amine

[0573] Step 1: Preparation of 7-chloro-5-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)pyrido[4,3-d]pyrimidin-4-ol

[0574] Dissolve 5,7-dichloropyrido[4,3-d]pyrimidin-4-ol (3.6 g, 16.66 mmol), 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol (4.65 g, 20.00 mmol), cuprous bromide (239.06 mg, 1.67 mmol), and Cs2CO3 (8.14 g, 25.00 mmol) in NMP (20 mL). Under nitrogen, heat to 120°C and react for 2 hours. After the reaction, cool to room temperature, add water, stir, and extract with EA, concentrate to give the title compound (3.5 g). MS (ESI, m / z): 412.1 [M+H] + .

[0575] Step 2: Preparation of 7-chloro-N-(2,4-dimethoxybenzyl)-5-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)pyrido[4,3-d]pyrimidin-4-amine

[0576] 7-Chloro-5-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)pyrido[4,3-d]pyrimidin-4-ol (3.5 g, 8.50 mmol), 2,4-dimethoxybenzylamine (2.84 mg, 17 mmol), PyBOP (6.63 g, 12.75 mmol), and DIPEA (2.20 g, 17.00 mmol) were dissolved in NMP (10 mL) and reacted at 60°C for 5 hours. After the reaction, the mixture was cooled to room temperature, extracted with EA, and concentrated. The crude product was purified on a silica gel column (PE / EA = 48 / 52) to give the title compound (2.5 g). MS (ESI, m / z): 561.3 [M+H] + .

[0577] Intermediate Example 12: (4-((2,4-dimethoxybenzyl)amino)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-7-yl)boronic acid

[0578] 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (396.00 mg, 1.56 mmol), 7-chloro-N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine (500 mg, 1.04 mmol), potassium acetate (306.09 mg, 3.12 mmol) The product was dissolved in 1,4-dioxane (10 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (152.14 mg, 207.93 μmol) was added. The nitrogen atmosphere was fully replaced, and the temperature was raised to 120°C, replaced with nitrogen, and stirred for 16 hours. The product was directly filtered, and the filter cake was washed with methanol. The filtrate was concentrated, dissolved in a small amount of methanol, and the solution was added dropwise to water and filtered to obtain the title compound (270 mg). MS (ESI, m / z): 491.3 [M+H]. + .

[0579] Intermediate Example 13: 4-(5-Bromo-1,3,4-thiadiazol-2-yl)morpholine

[0580] Dissolve 2,5-dibromo-1,3,4-thiadiazole (2 g, 8.20 mmol) and morpholine (714.37 mg, 8.20 mmol) in 1,4-dioxane (10 mL). Then add DIPEA (1.59 g, 12.30 mmol). Heat to 100°C and allow to react for 8 hours. After the reaction is complete, cool to room temperature and extract three times with H2O and ethyl acetate (60 mL x 3). Combine the organic phases, wash once with brine, and concentrate to obtain the crude product. Purify by silica gel column chromatography (DCM / MeOH = 98 / 2) to obtain the title compound (1.8 g). MS m / z (ESI): 250.0 [M+H] + .

[0581] The following compounds were prepared by the method and general steps described in Reference Intermediate Example 13. The other required raw materials can be purchased commercially or synthesized by experienced synthesizers in the field of organic synthesis using conventional reactions from commercially purchased reagents.

[0582] Intermediate Example 17: 7-Bromo-5-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinazolin-4-amine

[0583] Step 1: Synthesis of 4-bromo-2-fluoro-6-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)benzonitrile

[0584] 5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol (586.03 mg, 2.52 mmol), 4-bromo-2,6-difluorobenzonitrile (500 mg, 2.29 mmol), Cs2CO3 (1.12 g, 3.43 mmol), and CuBr (32.90 mg, 223.70 μmol) were dissolved in NMP (10.0 mL). The mixture was heated to 60°C and stirred for 2 hours under N2 protection. After completion of the reaction, the reaction solution 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 obtain the crude product, which was then isolated and purified by silica gel column chromatography (PE:EA = 80:20) to obtain the title compound (970 mg). MS m / z (ESI): 431.1 [M+H] + .

[0585] Step 2: Synthesis of 2-amino-4-bromo-6-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)benzonitrile

[0586] 4-Bromo-2-fluoro-6-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)benzonitrile (200 mg, 464.82 μmol) was dissolved in aqueous ammonia (2 mL) and IPA (1 mL). The mixture was heated to 80°C and stirred in a microwave reactor for 4 hours. After completion of the reaction, the reaction solution 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 obtain the crude product, which was then isolated and purified by silica gel column chromatography (PE:EA = 75:25) to obtain the title compound (157 mg). MS m / z (ESI): 429.1 [M+H] + .

[0587] Step 3: Synthesis of 7-bromo-5-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinazolin-4-amine

[0588] 2-Amino-4-bromo-6-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)benzonitrile (157 mg, 367.43 μmol) and ammonium acetate (407.67 mg, 5.29 mmol) were dissolved in triethyl orthoformate (6 mL) and EtOH (6 mL). The mixture was heated to 110°C and stirred for 10 hours. After completion of the reaction, the reaction solution 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 obtain the crude product, which was then isolated and purified by silica gel column chromatography (PE:EA = 75:25) to obtain the title compound (150 mg). MS m / z (ESI): 455.1 [M+H] + .

[0589] Example 1: Preparation of 3-((4-aminoquinazolin-5-yl)oxy)-2,4-dimethylphenol (Compound 1)

[0590] Step 1: Preparation of 5-(3-methoxy-2,6-dimethylphenoxy)quinazolin-4-amine

[0591] Dissolve 2-chloro-5-(3-methoxy-2,6-dimethylphenoxy)quinazolin-4-amine (10 mg, 27.29 μmol) in MeOH (2 mL), add 10% palladium on carbon (5 mg), replace the atmosphere with hydrogen three times, and stir at 25°C for 2 hours. After the reaction, filter through Celite, collect the filtrate, and evaporate the solvent under reduced pressure to obtain the title compound (8.0 mg). MS (ESI, m / z): 296.3 [M+H] + .

[0592] Step 2: Preparation of 3-((4-aminoquinazolin-5-yl)oxy)-2,4-dimethylphenol

[0593] 5-(3-Methoxy-2,6-dimethylphenoxy)quinazolin-4-amine (8 mg, 24.38 μmol) was dissolved in DCM (3 mL) and boron tribromide (2.6 g, 10.30 mmol) was added dropwise. The mixture was stirred at 25°C for 30 min. After the reaction, the excess solvent was removed by concentration under reduced pressure. Saturated aqueous sodium bicarbonate was added to adjust the pH to 8-9, and the mixture was extracted with EA (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The title compound (0.6 mg) was isolated and purified by Prep-HPLC. MS (ESI, m / z): 282.2 [M+H] + .

[0594] 1 H NMR (400MHz, DMSO-d6) δ9.52(s,1H),8.35(s,1H),7.89(s,1H),7.78(s,1H),7.51(t,J=8.2Hz,1H),7.25(d, J=9.2Hz,1H),7.01(d,J=8.2Hz,1H),6.74(d,J=8.2Hz,1H),6.23(d,J=8.0Hz,1H),1.97(s,3H),1.90(s,3H).

[0595] Example 2: Preparation of 3-((4-amino-2-((1-methyl-1H-pyrazol-4-yl)amino)quinazolin-5-yl)oxy)-2,4-dimethylphenol (Compound 2)

[0596] Step 1: Preparation of 5-(3-methoxy-2,6-dimethylphenoxy)-N2-(1-methyl-1H-pyrazol-4-yl)quinazoline-2,4-diamine

[0597] Dissolve 2-chloro-5-(3-methoxy-2,6-dimethylphenoxy)quinazolin-4-amine (70 mg, 191.03 μmol), p-toluenesulfonic acid (16.63 mg, 95.51 μmol), and 1-methyl-1H-pyrazol-4-amine (22.51 mg, 229.25 μmol) in tert-butanol (5 mL), warm to 120°C, and stir for 3 hours. After the reaction, pour into ice water (20 mL) and extract with EA (20.0 mL x 3). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the solvent evaporated under reduced pressure to yield the title compound (58 mg). MS (ESI, m / z): 391.3 [M+H] + .

[0598] Step 2: Preparation of 3-((4-amino-2-((1-methyl-1H-pyrazol-4-yl)amino)quinazolin-5-yl)oxy)-2,4-dimethylphenol

[0599] 5-(3-Methoxy-2,6-dimethylphenoxy)-N2-(1-methyl-1H-pyrazol-4-yl)quinazoline-2,4-diamine (58 mg, 133.69 μmol) was dissolved in DCM (3 mL) and boron tribromide (2.6 g, 10.30 mmol) was added dropwise. The mixture was stirred at 25°C for 30 min. After the reaction, the excess solvent was removed by concentration under reduced pressure. Saturated aqueous sodium bicarbonate was added to adjust the pH to 8-9, and the mixture was extracted with EA (20.0 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The title compound (21.33 mg) was isolated and purified by Prep-HPLC. MS (ESI, m / z): 377.2 [M+H] + .

[0600] 1 H NMR (400MHz, DMSO-d6) δ9.50(s,1H),8.91(s,1H),8.11(s,1H),7.60(s,1H),7.51(s,1H),7.29(t,J=8.0Hz,1H ),6.99(d,J=8.4Hz,2H),6.73(d,J=8.2Hz,1H),5.88(d,J=7.6Hz,1H),3.80(s,3H),1.99(s,3H),1.92(s,3H).

[0601] Example 3: Preparation of 3-((4-amino-7-(4-methylpiperazin-1-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol (Compound 3)

[0602] Step 1: Preparation of N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)-7-(4-methylpiperazin-1-yl)pyrido[4,3-d]pyrimidin-4-amine

[0603] 7-Chloro-N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine (30 mg, 62 μmol), N-methylpiperazine (10 mg, 93 μmol), and K2CO3 (17 mg, 124 μmol) were dissolved in DMF (4 mL), then heated to 100°C and stirred for 12 hours. After the reaction, the mixture was cooled to room temperature, poured into ice water (20 mL), and extracted with EA (20.0 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude title compound (30 mg). MS (ESI, m / z): 545.3 [M+H] + .

[0604] Step 2: Preparation of 5-(3-methoxy-2,6-dimethylphenoxy)-7-(4-methylpiperazin-1-yl)pyrido[4,3-d]pyrimidin-4-amine

[0605] Dissolve N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)-7-(4-methylpiperazin-1-yl)pyrido[4,3-d]pyrimidin-4-amine (30 mg, 55 μmol) in trifluoroacetic acid (6 mL), then heat to 90°C and stir for 12 hours. After the reaction, remove the solvent under reduced pressure to obtain the crude title compound (20 mg). MS (ESI, m / z): 532.2 [M+H] + .

[0606] Step 3: Preparation of 3-((4-amino-7-(4-methylpiperazin-1-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol

[0607] The synthetic route of Example 2 was used to prepare the second step reaction raw material 5-(3-methoxy-2,6-dimethylphenoxy)-N 2 -(1-methyl-1H-pyrazol-4-yl)quinazoline-2,4-diamine was replaced with 5-(3-methoxy-2,6-dimethylphenoxy)-7-(4-methylpiperazin-1-yl)pyrido[4,3-d]pyrimidin-4-amine to obtain the title compound (5 mg). MS (ESI, m / z): 381.1 [M+H] + .

[0608] 1H NMR (400MHz, DMSO-d6) δ9.31(s,1H),8.22(s,1H),7.87(s,1H),7.48(s,1H),6.92(d,J=8.4Hz,1H),6.66(d ,J=8.4Hz,1H),6.26(s,1H),3.30-3.21(m,4H),2.26-2.17(m,4H),2.13(s,3H),1.96(s,3H),1.89(s,3H).

[0609] Example 4: Preparation of 3-((4-amino-7-morpholinopyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol (Compound 4)

[0610] The synthetic route of Example 3 was adopted, and the starting material of the first step, N-methylpiperazine, was replaced with morpholine to obtain the title compound (2.73 mg). MS (ESI, m / z): 368.2 [M+H] + .

[0611] 1 H NMR(400MHz,DMSO-d6)δ9.31(s,1H),8.23(s,1H),7.89(s,1H),7.51(s,1H),6.92(d,J=8.4Hz,1H), 6.65(d,J=8.2Hz,1H),6.27(s,1H),3.57-3.51(m,4H),3.24-3.18(m,4H),1.96(s,3H),1.88(s,3H).

[0612] Example 5: Preparation of 3-((4-amino-7-phenylpyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol (Compound 5)

[0613] Step 1: Preparation of N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)-7-phenylpyrido[4,3-d]pyrimidin-4-amine

[0614] 7-Chloro-N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine (80 mg, 166 μmol), phenylboronic acid (41 mg, 333 μmol), and KCO (69 mg, 498 μmol) were dissolved in 1,4-dioxane (6 mL) and water (1 mL). The atmosphere was then replaced with nitrogen three times. Pd(dppf)Cl.CHCl (14 mg, 16.6 μmol) was added, and the temperature was raised to 110°C and stirred for 12 hours. After completion of the reaction, the mixture was cooled to room temperature, poured into ice water (20 mL), and extracted with EA (20.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The mixture was purified by column chromatography on silica gel (PE / EA = 1 / 1) to give the title compound (60 mg). MS (ESI, m / z): 523.2 [M+H] + .

[0615] Step 2: Preparation of 5-(3-methoxy-2,6-dimethylphenoxy)-7-phenylpyrido[4,3-d]pyrimidin-4-amine

[0616] The synthetic route of Example 3 was used to obtain the title compound (40 mg). The starting material of the second step, N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)-7-(4-methylpiperazin-1-yl)pyrido[4,3-d]pyrimidin-4-amine, was replaced with N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)-7-phenylpyrido[4,3-d]pyrimidin-4-amine. MS (ESI, m / z): 373.2 [M+H] + .

[0617] Step 3: Preparation of 3-((4-amino-7-phenylpyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol

[0618] The synthetic route of Example 2 was used to obtain the title compound (10 mg). The starting material of the second step, 5-(3-methoxy-2,6-dimethylphenoxy)-N2-(1-methyl-1H-pyrazol-4-yl)quinazoline-2,4-diamine, was replaced with 5-(3-methoxy-2,6-dimethylphenoxy)-7-phenylpyrido[4,3-d]pyrimidin-4-amine. MS (ESI, m / z): 359.1 [M+H] + .

[0619] 1H NMR(400MHz,DMSO-d6)δ9.37(s,1H),8.52(s,1H),8.34(s,1H),7.91(s,1H),7.84-7.79(m,2H),7.7 1(s,1H),7.43-7.35(m,3H),6.99(d,J=8.4Hz,1H),6.73(d,J=8.4Hz,1H),2.00(s,3H),1.93(s,3H).

[0620] Example 6: Preparation of 3-((4-amino-7-(1-cyclopropyl-1H-pyrazol-4-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol (Compound 6)

[0621] The synthetic route of Example 5 was used, but the starting material in the first step, phenylboronic acid, was replaced with 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to obtain the title compound (3 mg). MS (ESI, m / z): 389.2 [M+H] + .

[0622] 1 H NMR(400MHz,DMSO-d6)δ9.36(s,1H),8.45(s,1H),8.22(s,1H),8.09(s,1H),7.81(s,1H),7.58-7.55(m,1H),7.39(s,1H),6.97(d ,J=8.4Hz,1H),6.72(d,J=8.4Hz,1H),3.75-3.69(m,4.0Hz,1H),1.98(s,3H),1.90(s,3H),1.02-0.98(m,2H),0.97-0.92(m,2H).

[0623] Example 7: Preparation of 3-((2,4-diaminoquinazolin-5-yl)oxy)-2,4-dimethylphenol (Compound 7)

[0624] Step 1: Preparation of 5-(3-methoxy-2,6-dimethylphenoxy)quinazoline-2,4-diamine

[0625] The synthetic route of Example 2 was used to replace the starting material of the first step, 1-methyl-1H-pyrazol-4-amine, with amine methanol solution to obtain the title compound (12 mg). MS (ESI, m / z): 311.2 [M+H] + .

[0626] Step 2: Preparation of 3-((2,4-diaminoquinazolin-5-yl)oxy)-2,4-dimethylphenol

[0627] The synthetic route of Example 2 was used to obtain the title compound (2.73 mg) by replacing the starting material of the second step, 5-(3-methoxy-2,6-dimethylphenoxy)-N2-(1-methyl-1H-pyrazol-4-yl)quinazoline-2,4-diamine, with 5-(3-methoxy-2,6-dimethylphenoxy)quinazoline-2,4-diamine. MS (ESI, m / z): 297.1 [M+H] + .

[0628] 1 H NMR (400MHz, DMSO-d6) δ9.48(s,1H),7.38(s,1H),7.27(s,1H),7.21(t,J=8.2Hz,1H),6.98(d,J=8.4Hz,1H) ,6.80(d,J=8.4Hz,1H),6.71(d,J=8.2Hz,1H),6.04(s,2H),5.78(d,J=8.0Hz,1H),1.97(s,3H),1.90(s,3H).

[0629] Example 8: Preparation of 3-((4-amino-2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)quinazolin-5-yl)oxy)-2,4-dimethylphenol (Compound 8)

[0630] Step 1: Preparation of N2-(1,5-dimethyl-1H-pyrazol-4-yl)-5-(3-methoxy-2,6-dimethylphenoxy)quinazoline-2,4-diamine

[0631] The synthetic route of Example 2 was used to replace the starting material of the first step, 1-methyl-1H-pyrazol-4-amine, with 1,5-dimethyl-1H-pyrazol-4-amine to obtain the title compound (35 mg). MS (ESI, m / z): 405.3 [M+H] + .

[0632] Step 2: Preparation of 3-((4-amino-2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)quinazolin-5-yl)oxy)-2,4-dimethylphenol

[0633] The synthetic route of Example 2 was used, but the starting material of the second step, 5-(3-methoxy-2,6-dimethylphenoxy)-N2-(1-methyl-1H-pyrazol-4-yl)quinazoline-2,4-diamine, was replaced with N2-(1,5-dimethyl-1H-pyrazol-4-yl)-5-(3-methoxy-2,6-dimethylphenoxy)quinazoline-2,4-diamine to obtain the title compound (13.89 mg). MS (ESI, m / z): 391.1 [M+H]+.

[0634] 1 H NMR (400MHz, DMSO-d6) δ9.49(s,1H),8.05(s,1H),7.59(s,1H),7.47(s,2H),7.25(t,J=8.2Hz,1H),6.99(d,J=8.4Hz,1H) ,6.85(d,J=7.6Hz,1H),6.72(d,J=8.2Hz,1H),5.83(d,J=7.6Hz,1H),3.71(s,3H),2.18(s,3H),1.98(s,3H),1.91(s,3H).

[0635] Example 9: Preparation of 3-((4-amino-2-((6-methylpyridin-3-yl)amino)quinazolin-5-yl)oxy)-2,4-dimethylphenol (Compound 9)

[0636] Step 1: Preparation of 5-(3-methoxy-2,6-dimethylphenoxy)-N2-(6-methylpyridin-3-yl)quinazoline-2,4-diamine

[0637] The synthetic route of Example 2 was used, and the starting material in the first step, 1-methyl-1H-pyrazol-4-amine, was replaced with 6-methylpyridin-3-amine to obtain the title compound (35 mg). MS (ESI, m / z): 402.3 [M+H]+.

[0638] Step 2: Preparation of 3-((4-amino-2-((6-methylpyridin-3-yl)amino)quinazolin-5-yl)oxy)-2,4-dimethylphenol

[0639] The synthetic route of Example 2 was followed, replacing the starting material of the second step, 5-(3-methoxy-2,6-dimethylphenoxy)-N2-(1-methyl-1H-pyrazol-4-yl)quinazoline-2,4-diamine, with 5-(3-methoxy-2,6-dimethylphenoxy)-N2-(6-methylpyridin-3-yl)quinazoline-2,4-diamine to obtain the title compound (9.78 mg). MS (ESI, m / z): 388.2 [M+H]+.

[0640] 1 H NMR (400MHz, DMSO-d6) δ10.50(s,1H),9.60(s,1H),8.98(s,2H),8.30(s,1H),7.68-7.49(m,2H),7.14(d,J=8.2Hz ,1H),7.03(d,J=8.2Hz,1H),6.76(d,J=8.2Hz,1H),6.23(d,J=8.2Hz,1H),2.57(s,3H),1.98(s,3H),1.91(s,3H).

[0641] Example 10: Preparation of 3-((4-amino-2-((5-methylpyridin-3-yl)amino)quinazolin-5-yl)oxy)-2,4-dimethylphenol (Compound 10)

[0642] Step 1: Preparation of 5-(3-methoxy-2,6-dimethylphenoxy)-N2-(5-methylpyridin-3-yl)quinazoline-2,4-diamine

[0643] The synthetic route of Example 2 was used to replace the starting material of the first step, 1-methyl-1H-pyrazol-4-amine, with 5-methylpyridin-3-amine to obtain the title compound (30 mg). MS (ESI, m / z): 402.3 [M+H] + .

[0644] Step 2: Preparation of 3-((4-amino-2-((5-methylpyridin-3-yl)amino)quinazolin-5-yl)oxy)-2,4-dimethylphenol

[0645] The synthetic route of Example 2 was used to obtain the title compound (8.30 mg), replacing the starting material of the second step, 5-(3-methoxy-2,6-dimethylphenoxy)-N2-(1-methyl-1H-pyrazol-4-yl)quinazoline-2,4-diamine, with 5-(3-methoxy-2,6-dimethylphenoxy)-N2-(5-methylpyridin-3-yl)quinazoline-2,4-diamine. MS (ESI, m / z): 388.2 [M+H] + .

[0646] 1H NMR (400MHz, DMSO-d6) δ9.11(s,1H),8.97(d,J=9.8Hz,2H),8.66(s,1H),7.70(dd,J=16.5,8.4Hz,2H),7.43(d,J=7.6Hz,1H), 7.03(d,J=8.4Hz,1H),6.89(s,2H),6.80(d,J=8.4Hz,1H),6.43(dd,J=8.0,0.8Hz,1H),2.48(s,3H),1.99(s,3H),1.92(s,3H).

[0647] Example 11: (R)-3-((4-amino-7-(3-(methylamino)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol (Compound 11)

[0648] Step 1: Preparation of tert-butyl (R)-(1-(4-((2,4-dimethoxybenzyl)amino)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-7-yl)pyrrolidin-3-yl)(methyl)carbamate

[0649] 7-Chloro-N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine (60 mg, 118.5 μmol), (R)-methyl(pyrrolidin-3-yl)carbamic acid tert-butyl ester (48 mg, 237 μmol), and K2CO3 (33 mg, 237 μmol) were dissolved in DMF (4 mL), then heated to 100°C and stirred for 16 hours. After the reaction, the mixture was cooled to room temperature, poured into ice water (20 mL), and extracted with EA (20.0 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the title compound (80 mg). MS (ESI, m / z): 645.5 [M+H] + .

[0650] Step 2: Preparation of (R)-5-(3-methoxy-2,6-dimethylphenoxy)-7-(3-(methylamino)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-4-amine

[0651] Tert-butyl (R)-(1-(4-((2,4-dimethoxybenzyl)amino)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-7-yl)pyrrolidin-3-yl)(methyl)carbamate (80 mg, 101.7 μmol) was dissolved in trifluoroacetic acid (6 mL), then heated to 90°C and stirred for 16 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the title compound (40 mg). MS (ESI, m / z): 395.2 [M+H] + .

[0652] Step 3: Preparation of (R)-3-((4-amino-7-(3-(methylamino)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol

[0653] (R)-5-(3-methoxy-2,6-dimethylphenoxy)-7-(3-(methylamino)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-4-amine (40 mg, 101.6 μmol) was dissolved in dichloromethane (2 mL), and BBr3 solution (4 mL) was added. The mixture was stirred at 25°C for 2 hours. After the reaction was completed, a small amount of methanol was added dropwise to quench the reaction. The solvent was evaporated under reduced pressure to obtain the crude product. Liquid phase preparation was used to obtain the title compound (15.0 mg). MS (ESI, m / z): 381.2 [M+H] + .

[0654] 1 H NMR (400MHz, DMSO-d6) δ9.27(s,1H),8.16(s,1H),7.75(s,1H),7.41(s,1H),6.90(d,J=8.2Hz,1H),6.65(d,J=8.2Hz,1H),5.8 7(s,1H),3.24-3.07(m,4H),2.95-2.89(m,1H),2.21(s,3H),1.96(s,3H),1.95-1.90(m,1H),1.89(s,3H),1.73-1.62(m,1H).

[0655] Example 12: (S)-3-((4-amino-7-(3-(methylamino)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol (Compound 12)

[0656] Step 1: Preparation of tert-butyl (S)-(1-(4-((2,4-dimethoxybenzyl)amino)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-7-yl)pyrrolidin-3-yl)(methyl)carbamate

[0657] 7-Chloro-N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine (70 mg, 138.3 μmol), (S)-methyl(pyrrolidin-3-yl)carbamic acid tert-butyl ester (111.9 mg, 553.1 μmol), and K2CO3 (58 mg, 414.8 μmol) were dissolved in DMF (4 mL), then heated to 100°C and stirred for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, poured into ice water (20 mL), and extracted with EA (20.0 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the title compound (85 mg). MS (ESI, m / z): 645.5 [M+H] + .

[0658] Step 2: Preparation of (S)-5-(3-methoxy-2,6-dimethylphenoxy)-7-(3-(methylamino)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-4-amine

[0659] Tert-butyl (S)-(1-(4-((2,4-dimethoxybenzyl)amino)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-7-yl)pyrrolidin-3-yl)(methyl)carbamate (85 mg, 106.8 μmol) was dissolved in trifluoroacetic acid (8 mL), then heated to 90°C and stirred for 16 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the title compound (50 mg). MS (ESI, m / z): 395.2 [M+H] + .

[0660] Step 3: Preparation of (S)-3-((4-amino-7-(3-(methylamino)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol

[0661] (S)-5-(3-methoxy-2,6-dimethylphenoxy)-7-(3-(methylamino)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-4-amine (50 mg, 101.4 μmol) was dissolved in dichloromethane (2 mL), and BBr3 solution (4 mL) was added. The mixture was stirred at 25°C for 2 hours. After completion of the reaction, a small amount of methanol was added dropwise to quench the reaction. The solvent was evaporated under reduced pressure to obtain a crude product (48 mg). Liquid phase preparation was used to obtain the title compound (20.0 mg). MS (ESI, m / z): 381.2 [M+H] + .

[0662] 1H NMR (400MHz, DMSO-d6) δ9.27(s,1H),8.17(s,1H),7.75(s,1H),7.42(s,1H),6.91(d,J=8.2Hz,1H),6.65(d,J=8.2Hz,1H),5.8 7(s,1H),3.26-3.03(m,4H),2.95-2.88(m,1H),2.20(s,3H),1.96(s,3H),1.95-1.90(m,1H),1.89(s,3H),1.73-1.61(m,1H).

[0663] Example 13: 3-((4-amino-7-((tetrahydro-2H-pyran-4-yl)oxy)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol (Compound 13)

[0664] Step 1: Preparation of N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)-7-((tetrahydro-2H-pyran-4-yl)oxy)pyrido[4,3-d]pyrimidin-4-amine

[0665] 7-Chloro-N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine (50 mg, 103.96 μmol), tetrahydro-2H-pyran-4-ol (101.89 mg, 987.64 μmol), and DMF (1 mL) were added to the bottle, followed by Cs2CO3 (64.36 mg, 197.53 μmol), Pd2dba3 (9.04 mg, 9.88 μmol), and Xantphos (11.43 mg, 19.75 μmol). The temperature was raised to 100°C under nitrogen protection for reaction. After adding a large amount of water, the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The title compound (12 mg) was obtained after column chromatography (PE / EA, 100% EA). MS (ESI, m / z): 547.3 [M+H] + .

[0666] Step 2: Preparation of 5-(3-methoxy-2,6-dimethylphenoxy)-7-((tetrahydro-2H-pyran-4-yl)oxy)pyrido[4,3-d]pyrimidin-4-amine

[0667] N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)-7-((tetrahydro-2H-pyran-4-yl)oxy)pyrido[4,3-d]pyrimidin-4-amine (12 mg, 21.95 μmol) was added to the vial. TFA (2 mL) was added and the temperature was raised to 85°C for 12 hours. The solvent was removed by concentration to obtain the title compound (11 mg). MS (ESI, m / z): 397.3 [M+H] + .

[0668] Step 3: Preparation of 3-((4-amino-7-((tetrahydro-2H-pyran-4-yl)oxy)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol

[0669] 5-(3-methoxy-2,6-dimethylphenoxy)-7-((tetrahydro-2H-pyran-4-yl)oxy)pyrido[4,3-d]pyrimidin-4-amine (11.2 mg, 21.94 μmol) and DCM (2 mL) were added to a vial, followed by BBr3 (1 M, 0.5 mL) and allowed to react at 25°C for 1 hour. The reaction was quenched with MeOH, the pH was adjusted to 8-9 with NaHCO3, and the title compound (3 mg) was obtained after concentration. MS (ESI, m / z): 383.1 [M+H] + .

[0670] 1 H NMR (400MHz, DMSO-d6) δ9.37(s,1H),8.33(s,1H),8.19(s,1H),7.76(s,1H),6.94(d,J=8.2Hz,1H),6.70(d,J=8.2Hz,1H),6.39(s,1H ),4.39(tt,J=9.4,4.1Hz,1H),3.78-3.68(m,2H),3.16-3.04(m,2H),1.95(s,3H),1.88(s,3H),1.78-1.66(m,2H),1.50-1.36(m,2H).

[0671] Example 14: (S)-3-((4-amino-7-(hexahydropyrazinyl[2,1-c][1,4]oxazin-8(1H)-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol (Compound 14)

[0672] Step 1: Preparation of (S)-N-(2,4-dimethoxybenzyl)-7-(hexahydropyrazinyl[2,1-c][1,4]oxazin-8(1H)-yl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine

[0673] 7-Chloro-N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine (40 mg, 79.01 μmol), (S)-octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride (33.99 mg, 158.02 μmol), and K2CO3 (21.8 mg, 158.02 μmol) were dissolved in NMP (5 mL), then heated to 120°C and stirred for 24 hours. After the reaction, the mixture was cooled to room temperature, poured into ice water (20 mL), and extracted with EA (20.0 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield the title compound (30 mg). MS (ESI, m / z): 587.3 [M+H] + .

[0674] Step 2: Preparation of (S)-7-(hexahydropyrazinyl[2,1-c][1,4]oxazin-8(1H)-yl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine

[0675] (S)-N-(2,4-Dimethoxybenzyl)-7-(hexahydropyrazinyl[2,1-c][1,4]oxazin-8(1H)-yl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine (30 mg, 51.14 μmol) was dissolved in trifluoroacetic acid (8 mL), then heated to 90°C and stirred for 5 hours. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the title compound (20 mg). MS (ESI, m / z): 437.2 [M+H] + .

[0676] Step 3: Preparation of (S)-3-((4-amino-7-(hexahydropyrazinyl[2,1-c][1,4]oxazin-8(1H)-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol

[0677] (S)-7-(Hexahydropyrazinyl[2,1-c][1,4]oxazin-8(1H)-yl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine (20 mg, 55.82 μmol) was added to DCM (5 mL). 2 mL of a 1 M solution of boron tribromide in dichloromethane was added dropwise under an ice-water bath and stirring was continued for 1 hour. After completion, methanol was added to quench the reaction. The crude product was concentrated to afford the title compound, which was purified by reverse-phase HPLC to afford the title compound (8.7 mg). MS (ESI, m / z): 423.2 [M+H]. + .

[0678] 1 H NMR(400MHz,DMSO-d6)δ9.31(s,1H),8.21(s,1H),7.86(s,1H),7.48(s,1H),6.92( d,J=8.0Hz,1H),6.66(d,J=8.4Hz,1H),6.29(s,1H),3.96-3.61(m,3H),3.56-3.39( m,2H),3.04(t,J=10.8Hz,1H),2.87-2.76(m,1H),2.59(t,J=11.6Hz,2H),2.38-2.2 5(m,1H),2.16-2.05(m,1H),2.03-1.99(m,2H),1.95(s,3H),1.88(d,J=3.6Hz,3H).

[0679] Example 15: 3-((4-amino-7-(1,7-diazaspiro[4.4]nonan-7-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol (Compound 15)

[0680] Step 1: Preparation of tert-butyl 7-(4-((2,4-dimethoxybenzyl)amino)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-7-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate

[0681] 7-Chloro-N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine (60 mg, 118.52 μmol), tert-butyl 1,7-diazaspiro[4.4]nonane-1-carboxylate (135.47 mg, 592.59 μmol), and K2CO3 (115.82 mg, 829.62 μmol) were added to a reaction flask, dissolved in DMF (2 mL), and heated to 100°C for 18 hours. After the reaction, the reaction solution was dried by rotary evaporation, dissolved in EA, filtered, and the organic phase was dried by rotary evaporation. The title compound (80 mg) was obtained. MS (ESI, m / z): 671.3 [M+H] + .

[0682] Step 2: Preparation of 5-(3-methoxy-2,6-dimethylphenoxy)-7-(1,7-diazaspiro[4.4]nonan-7-yl)pyrido[4,3-d]pyrimidin-4-amine

[0683] Tert-butyl 7-(4-((2,4-dimethoxybenzyl)amino)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-7-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate (80 mg, 119.26 μmol) was added to a reaction flask, followed by TFA (2 mL) and the reaction was carried out at 90°C for 1 hour. After completion of the reaction, the solvent was evaporated to give the title compound (80 mg). MS (ESI, m / z): 421.2 [M+H] + .

[0684] Step 3: Preparation of 3-((4-amino-7-(1,7-diazaspiro[4.4]nonan-7-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol

[0685] 5-(3-Methoxy-2,6-dimethylphenoxy)-7-(1,7-diazaspiro[4.4]nonan-7-yl)pyrido[4,3-d]pyrimidin-4-amine (80 mg, 149.66 μmol) was added to a reaction flask and dissolved in dichloromethane (2 mL). BBr3 (1 M, 2.24 mL) was then added and stirred at 25°C for 1 hour. After completion of the reaction, the reaction mixture was spin-dried and sent for preparative purification. After lyophilization, the title compound (22 mg) was obtained. MS (ESI, m / z): 407.2 [M+H] + .

[0686] 1 H NMR (400MHz, DMSO-d6) δ9.28(s,1H),8.16(s,1H),7.74(s,1H),7.41(s,1H),6.90(d,J=8.2Hz,1H),6.65(d,J=8.2Hz,1H),5.83(s,1H),3 .16(s,2H),3.03(s,2H),2.85-2.72(m,2H),1.96(s,3H),1.89(d,J=1.5Hz,3H),1.79-1.71(m,2H),1.71-1.63(m,2H),1.62-1.53(m,2H).

[0687] Example 16: (S)-3-((4-amino-7-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol (Compound 16)

[0688] Step 1: Preparation of (S)-N-(2,4-dimethoxybenzyl)-7-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine

[0689] To the reaction flask were added 7-chloro-N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine (55 mg, 114.36 μmol), (S)-octahydropyrrolo[1,2-a]pyrazine (46 mg, 228.72 μmol), K2CO3 (55 mg, 400.26 μmol), and NMP (1.5 mL). The reaction was carried out at 100°C for 24 hours under nitrogen atmosphere. After completion of the reaction, the reaction mixture was diluted with water and extracted with EA (30 ml x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield the title compound (70 mg). MS (ESI, m / z): 571.3 [M+H] + .

[0690] Step 2: Preparation of (S)-7-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine

[0691] To the reaction flask, (S)-N-(2,4-dimethoxybenzyl)-7-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine (60 mg, 105.14 μmol) and TFA (3 mL) were added. The mixture was reacted at 90°C for 5 hours under nitrogen atmosphere. After completion of the reaction, the reaction solution was directly concentrated under reduced pressure, dissolved in THF, and then spin-dried to remove residual TFA to obtain the title compound (40 mg). MS (ESI, m / z): 421.2 [M+H] + .

[0692] Step 3: Preparation of (S)-3-((4-amino-7-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol

[0693] To the reaction flask, (S)-7-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine (40 mg, 95.12 μmol), DCM (2.5 mL), and a 1M BBr3 solution in DCM (1.5 mL) were added. The mixture was incubated at 25°C for 1 hour under nitrogen atmosphere. After completion of the reaction, methanol was added to quench the reaction mixture, and the pH was adjusted to a weakly alkaline state by adding a methanolic ammonia solution. A solid precipitated and was filtered. The filter cake was washed with DCM, and the combined filtrates were concentrated under reduced pressure to obtain the crude product. The crude product was purified by Pre-HPLC to yield the title compound. MS (ESI, m / z): 407.3 [M+H] + .

[0694] 1 H NMR (400MHz, DMSO-d6) δ9.29(s,1H),8.21(s,1H),7.84(s,1H),7.46(s,1H),6.92(d,J=8.0Hz,1H),6.66(d,J=8.0Hz,1H),6.26(s,1H) ,4.05-3.84(m,2H),2.96-2.82(m,2H),2.78-2.70(m,1H),2.43-2.35(m,1H),1.98-1.85(m,8H),1.76-1.56(m,4H),1.27-1.15(m,1H).

[0695] Example 17: 3-((4-amino-7-(6-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol (Compound 17)

[0696] Step 1: Preparation of N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)-7-(6-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-4-amine

[0697] 7-Chloro-N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine (100 mg, 207.93 μmol), 2-methylpyridine-5-boronic acid pinacol ester (91.11 mg, 415.85 μmol), Pd(dppf)Cl2 (30.43 mg, 41.59 μmol), and K2CO3 (86.21 mg, 623.78 μmol) were dissolved in a solvent. After nitrogen substitution, the temperature was raised to 100°C and the reaction was allowed to proceed for 2 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (PE:EA = 10%:90%) to obtain the title compound (99 mg). MS (ESI, m / z): 538.2 [M+H] + .

[0698] Step 2: Preparation of 5-(3-methoxy-2,6-dimethylphenoxy)-7-(6-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-4-amine

[0699] Dissolve N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)-7-(6-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (89 mg, 165.55 μmol) in TFA (2 mL). After addition, heat to 90°C and react for 36 hours. After completion of the reaction, concentrate under reduced pressure to obtain the title compound (40 mg). MS (ESI, m / z): 388.2 [M+H] + .

[0700] Step 3: Preparation of 3-((4-amino-7-(6-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol

[0701] Dissolve 5-(3-methoxy-2,6-dimethylphenoxy)-7-(6-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-4-amine (40 mg, 103.24 μmol) in DCM (3 mL). Add 1M BBr3 in DCM (0.3 mL). After addition, react at 25°C for 30 min. After completion, quench the reaction with methanolic ammonia solution. Concentrate under reduced pressure. The crude product is separated and purified by Prep-HPLC to obtain the title compound (7.0 mg). MS (ESI, m / z): 374.2 [M+H] + .

[0702] 1H NMR (400MHz, DMSO-d6) δ9.43(s,1H),8.80(s,1H),8.53(s,1H),8.38(s,1H),8.09(d,J=8.0Hz,1H),7.95(s,1H),7.7 7(s,1H),7.29(d,J=8.0Hz,1H),6.99(d,J=8.2Hz,1H),6.73(d,J=8.2Hz,1H),2.46(s,3H),1.99(s,3H),1.92(s,3H).

[0703] Example 18: 3-((4-amino-7-(pyridin-2-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol (Compound 18)

[0704] Step 1: Preparation of N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)-7-(pyridin-2-yl)pyrido[4,3-d]pyrimidin-4-amine

[0705] 7-Chloro-N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine (100 mg, 207.93 μmol), tri-n-butyl 2-pyridyltin (306.19 mg, 831.70 μmol), Pd(PPh3)4 (12.01 mg, 10.40 μmol), and LiCl (24.68 mg, 582.19 μmol) were dissolved in Tol (3 mL). The mixture was added and reacted at 100°C for 20 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure. The crude product was separated and purified by silica gel column chromatography (PE:EA = 55%:45%) to obtain the title compound (148 mg). MS (ESI, m / z): 524.3 [M+H] + .

[0706] Step 2: Preparation of 5-(3-methoxy-2,6-dimethylphenoxy)-7-(pyridin-2-yl)pyrido[4,3-d]pyrimidin-4-amine

[0707] Dissolve N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)-7-(pyridin-2-yl)pyrido[4,3-d]pyrimidin-4-amine (40 mg, 76.40 μmol) in TFA (2 mL) and react at 90°C for 48 hours. After completion of the reaction, concentrate under reduced pressure to obtain the title compound. MS (ESI, m / z): 374.3 [M+H] + .

[0708] Step 3: Preparation of 3-[4-amino-7-(2-pyridyl)pyrido[4,3-d]pyrimidin-5-yl]oxy-2,4-dimethylphenol

[0709] 3-((4-amino-7-(pyridin-2-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol (40 mg, 107.12 μmol) was dissolved in DCM (1 mL) and a 1M BBr3 solution in DCM (0.5 mL) was added dropwise. The mixture was allowed to react at 25°C for 1 hour. After completion of the reaction, a methanolic ammonia solution was added to quench the reaction. The reaction was concentrated under reduced pressure and the crude product was separated and purified by Prep-HPLC to obtain the title compound (14.0 mg). MS (ESI, m / z): 360.1 [M+H] + .

[0710] 1 H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.71-8.62(m,1H),8.54(s,1H),8.40(s,1H),8.07(s,1H),7.97(s,1H),7.84(td,J=7.6,1.6Hz, 1H),7.63(d,J=8.0Hz,1H),7.41(ddd,J=7.6,4.8,1.2Hz,1H),7.00(d,J=8.2Hz,1H),6.74(d,J=8.2Hz,1H),2.00(s,3H),1.93(s,3H).

[0711] Example 19: (R)-5-((5-fluoro-1H-indazol-4-yl)oxy)-7-(3-(methylamino)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-4-amine (Compound 19)

[0712] Step 1: Preparation of 4-bromo-5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0713] Dissolve 4-bromo-5-fluoro-1H-indazole (500 mg, 2.30 mmol) and p-toluenesulfonic acid (79.99 mg, 460.42 μmol) in 10 mL of DCM. Slowly add DHP (586.82 mg, 6.91 mmol). Incubate the reaction at 25°C for 30 min. After completion, dilute with water, extract with DCM, wash with saturated brine, dry over anhydrous sodium sulfate, and filter. The crude product is purified by silica gel column chromatography (PE:EA = 85:15) to obtain the title compound (650 mg). MS (ESI, m / z): 299.1 [M+H] + .

[0714] Step 2: Preparation of 5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol

[0715] 4-Bromo-5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (200 mg, 635.16 μmol), t-Bu Xphos (54.49 mg, 127.03 μmol), Pd2(dba)3 (58.75 mg, 63.52 μmol), and NaOH (38.49 mg, 952.74 μmol) were dissolved in 4 mL of 1,4-dioxane and 2 mL of H2O. The mixture was heated to 95°C under N2 protection for 16 hours. After completion of the reaction, the reaction solution was poured into water (50.0 mL) and extracted with ethyl acetate (30.0 mL x 3). The organic phase was collected, dried, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to obtain the title compound (100 mg). MS (ESI, m / z): 237.1 [M+H] + .

[0716] Step 3: Preparation of 7-chloro-5-((5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)pyrido[4,3-d]pyrimidin-4-ol

[0717] Dissolve 5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol (164.04 mg, 659.65 μmol), Cs2CO3 (434.19 mg, 1.32 mmol), and 5,7-dichloropyrido[4,3-d]pyrimidin-4-ol (100 mg, 439.77 μmol) in 4 mL of acetonitrile and microwave-heat at 120°C for 2 hours. After completion of the reaction, pour the reaction solution into water (50.0 mL) and extract with ethyl acetate (30.0 mL*3). The organic phase is collected, dried, and concentrated to obtain the title compound (100 mg). MS (ESI, m / z): 416.2 [M+H] + .

[0718] Step 4: Preparation of 7-chloro-N-(2,4-dimethoxybenzyl)-5-((5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)pyrido[4,3-d]pyrimidin-4-amine

[0719] 7-Chloro-5-((5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)pyrido[4,3-d]pyrimidin-4-ol (92 mg, 199.13 μmol), 2,4-dimethoxybenzylamine (50.45 mg, 298.70 μmol), PyBOP (125.61 mg, 238.96 μmol), and DIEA (51.99 mg, 398.26 μmol) were dissolved in 6 mL of DMF and heated to 60°C for 10 hours. After completion of the reaction, the reaction solution was poured into water (50.0 mL) and extracted with ethyl acetate (30.0 mL x 3). The organic phase was collected, dried, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to obtain the title compound (100 mg). MS (ESI, m / z): 565.3 [M+H] + .

[0720] Step 5: Preparation of tert-butyl ((3R)-1-(4-((2,4-dimethoxybenzyl)amino)-5-((5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)pyrido[4,3-d]pyrimidin-7-yl)pyrrolidin-3-yl)(methyl)carbamate

[0721] 7-Chloro-N-(2,4-dimethoxybenzyl)-5-((5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)pyrido[4,3-d]pyrimidin-4-amine (40 mg, 67.26 μmol), (S)-methyl(pyrrolidin-3-yl)carbamic acid tert-butyl ester (20.41 mg, 100.89 μmol), Pd2(dba)3 (6.16 mg, 6.73 μmol), BINAP (4.19 mg, 6.73 μmol), and t-BuONa (19.39 mg, 201.77 μmol) were dissolved in 5 mL of toluene. After N2 protection, the temperature was raised to 120°C and the reaction was reacted for 16 hr. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM:MeOH=93:7) to obtain the title compound (20 mg). MS (ESI, m / z): 729.4 [M+H] + .

[0722] Step 6: Preparation of (R)-5-((5-fluoro-1H-indazol-4-yl)oxy)-7-(3-(methylamino)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-4-amine

[0723] Tert-butyl ((3R)-1-(4-((2,4-dimethoxybenzyl)amino)-5-((5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)pyrido[4,3-d]pyrimidin-7-yl)pyrrolidin-3-yl)(methyl)carbamate (15 mg, 20.58 μmol) was dissolved in trifluoroacetic acid (5 mL) and then heated to 90°C for 12 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the crude product was purified by reverse-phase HPLC to obtain the title compound (4 mg). MS (ESI, m / z): 395.1 [M+H] + .

[0724] 1 H NMR(400MHz,DMSO-d6)δ13.21(s,1H),11.31(s,1H),8.20(s,1H),8.01(s,1H),7.45-7.40(m,1H),7.38 -7.31(m,1H),5.44(s,1H),3.69-3.61(m,1H),3.61-3.52(m,2H),3.50-3.43(m,2H),2.46(s,3H),2.24-2.14(m,1H),2.06-1.89(m,2H).

[0725] Example 20: (R)-3-((4-amino-7-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol (Compound 20)

[0726] Step 1: Preparation of (R)-N-(2,4-dimethoxybenzyl)-7-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine

[0727] 7-Chloro-N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine (50 mg, 103.96 μmol), (R)-octahydropyrrolo[1,2-a]pyrazine dihydrochloride (41.40 mg, 207.93 μmol), and K2CO3 (50.29 mg, 363.87 μmol) were dissolved in NMP (3 mL), then heated to 120°C and stirred for 24 hours. After the reaction, the mixture was cooled to room temperature, poured into ice water (20 mL), and extracted with EA (20.0 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield the title compound (25 mg). MS (ESI, m / z): 571.4 [M+H]+ .

[0728] Step 2: Preparation of (R)-7-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine

[0729] (R)-N-(2,4-dimethoxybenzyl)-7-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine (25 mg, 43.81 μmol) was dissolved in trifluoroacetic acid (5 mL), then heated to 90°C and stirred for 3 hours. After the reaction, the solvent was evaporated under reduced pressure to obtain the title compound (18 mg). MS (ESI, m / z): 421.3 [M+H] + .

[0730] Step 3: Preparation of (R)-3-((4-amino-7-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol

[0731] (R)-7-(Hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine (18 mg, 42.81 μmol) was added to DCM (3 mL). 1 mL of a 1 M solution of boron tribromide in dichloromethane was added dropwise under an ice-water bath and stirring was continued for 1 hour. After completion, methanol was added to quench the reaction. The crude product was concentrated to afford the title compound, which was purified by reverse-phase HPLC to afford the title compound (6 mg). MS (ESI, m / z): 407.3 [M+H]. + .

[0732] 1 H NMR(400MHz,DMSO-d6)δ9.30(s,1H),8.21(s,1H),7.84(s,1H),7.46(s,1H),6.9 2(d,J=8.0Hz,1H),6.66(d,J=8.2Hz,1H),6.26(s,1H),4.01(d,J=11.6Hz,1H),3 .88(d,J=12.8Hz,1H),2.98-2.89(m,1H),2.85(d,J=10.8Hz,1H),2.80-2.70(m, 1H),2.43-2.35(m,1H),2.06-1.85(m,8H),1.79-1.53(m,4H),1.23-1.15(m,1H).

[0733] Example 21: Preparation of 3-((4-amino-7-(1-methyl-1H-pyrazol-4-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol (Compound 21)

[0734] The synthetic route of Example 5 was used, but the starting material in the first step, phenylboronic acid, was replaced with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to obtain the title compound (13.55 mg). MS (ESI, m / z): 363.1 [M+H] + .

[0735] 1 H NMR (400MHz, DMSO-d6) δ9.34(s,1H),8.44(s,1H),8.22(s,1H),7.89(s,1H),7.81(s,1H),7.67(d,J=0.8H z,1H),7.37(s,1H),6.97(d,J=8.0Hz,1H),6.72(d,J=8.4Hz,1H),3.81(s,3H),1.98(s,3H),1.90(s,3H).

[0736] Example 22: Preparation of 3-((4-amino-7-(4-(2-hydroxyethyl)piperazin-1-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol (Compound 22)

[0737] The synthetic route of Example 3 was used to replace the starting material N-methylpiperazine in the first step with N-hydroxyethylpiperazine to obtain the title compound (3.07 mg). MS (ESI, m / z): 411.2 [M+H] + .

[0738] 1 H NMR (400MHz, DMSO-d6) δ9.30(s,1H),8.22(s,1H),7.86(s,1H),7.48(s,1H),6.92(d,J=8.4Hz,1H),6.66(d,J=8.4 Hz,1H),6.25(s,1H),4.42(s,1H),3.48(q,J=5.6,5.7Hz,2H),3.25(s,4H),2.35(m,6H),1.96(s,3H),1.88(s,3H).

[0739] Example 23: Preparation of (R)-1-amino-8-(3-hydroxy-2,6-dimethylphenoxy)-6-(3-(methylamino)pyrrolidin-1-yl)-2,7-naphthyridine-4-carbonitrile (Compound 23)

[0740] Step 1: Preparation of tert-butyl (R)-(1-(5-cyano-8-((2,4-dimethoxybenzyl)amino)-1-(3-methoxy-2,6-dimethylphenoxy)-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate

[0741] Tert-butyl (R)-(1-(5-bromo-8-((2,4-dimethoxybenzyl)amino)-1-(3-methoxy-2,6-dimethylphenoxy)-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate (60 mg, 83.02 μmol), zinc cyanide (19.49 mg, 166.04 μmol), and tetrakistriphenylphosphine palladium (9.59 mg, 8.30 μmol) were dissolved in N,N-dimethylacetamide (5 mL). After addition, the atmosphere was replaced with nitrogen three times, and the temperature was raised to 125°C and stirred for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, quenched with water, and extracted with EA (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography on silica gel (PE:EA = 10 / 3) to give the title compound (30 mg). MS (ESI, m / z): 669.8 [M+H] + .

[0742] Step 2: Preparation of (R)-1-amino-8-(3-methoxy-2,6-dimethylphenoxy)-6-(3-(methylamino)pyrrolidin-1-yl)-2,7-naphthyridine-4-carbonitrile

[0743] Tert-butyl (R)-(1-(5-cyano-8-((2,4-dimethoxybenzyl)amino)-1-(3-methoxy-2,6-dimethylphenoxy)-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate (30 mg, 44.85 μmol) was dissolved in trifluoroacetic acid (5 mL), heated to 90°C, and stirred for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, quenched with water, and extracted with EA (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude title compound (8.0 mg). MS (ESI, m / z): 419.2 [M+H] + .

[0744] Step 3: Preparation of (R)-1-amino-8-(3-hydroxy-2,6-dimethylphenoxy)-6-(3-(methylamino)pyrrolidin-1-yl)-2,7-naphthyridine-4-carbonitrile

[0745] Boron tribromide (3 mL, 1 M in DCM) was added to (R)-1-amino-8-(3-methoxy-2,6-dimethylphenoxy)-6-(3-(methylamino)pyrrolidin-1-yl)-2,7-naphthyridine-4-carbonitrile (8.0 mg, 19.11 μmol) and stirred at room temperature for 2 hours. After completion of the reaction, the reaction was quenched with ammonia methanol and concentrated under reduced pressure. The title compound (0.5 mg) was isolated and purified by Prep-HPLC. MS (ESI, m / z): 405.5 [M+H] + .

[0746] 1 H NMR(400MHz,DMSO-d6)δ9.31(s,1H),8.21(s,1H),7.96(s,1H),7.81-7.74(m,1H),7.71(s,1H),6.92(d,J=8.4Hz,1H),6 .66(d,J=8.0Hz,1H),5.84(s,1H),3.15(m,3H),2.95(m,1H),2.20(s,3H),1.96(s,3H),1.89(s,3H),1.75-1.60(m,2H).

[0747] Example 24: Preparation of 3-((4-amino-7-(4-(methylamino)piperidin-1-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol (Compound 24)

[0748] The synthetic route of Example 3 was used to replace the starting material N-methylpiperazine in the first step with 4-N-tert-butyloxycarbonyl-4-N-methylaminopiperidine to obtain the title compound (14.12 mg). MS (ESI, m / z): 395.2 [M+H] + .

[0749] 1 H NMR (400MHz, DMSO-d6) δ9.30(s,1H),8.19(s,1H),7.81(s,1H),7.44(s,1H),6.92(d,J=8.4Hz,1H),6.66(d,J=8.0Hz,1H),6.24(s,1H),3 .78(d,J=13.2Hz,2H),2.79(t,J=11.2Hz,2H),2.42(m,1H),2.22(s,3H),1.96(s,3H),1.88(s,3H),1.66(dd,J=12.4Hz,2H),1.03(m,2H).

[0750] Example 25: Preparation of 3-((4-amino-7-(6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol (Compound 25)

[0751] Step 1: Preparation of 7-(6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine

[0752] 7-Chloro-N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine (50 mg, 103.97 μmol), 4,5,6,7-tetrahydropyrazolo[1,5-A]pyrazine dihydrochloride (40.8 mg, 207.94 μmol), Pd2(dba)3 (9.5 mg, 10.39 μmol), and BINAP (12.9 mg, 20.78 μmol) were dissolved in toluene (8 mL), heated to 120°C, and stirred for 10 hours. After the reaction, the reaction solution was poured into water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was collected and concentrated under reduced pressure to obtain the crude product. The crude product was analyzed by pre-TLC (PE:EA=0:1, R f =0.04) to obtain the title compound (45 mg). MS (ESI, m / z): 568.4 [M+H] + .

[0753] Step 2 & Step 3: Preparation of 3-[4-amino-7-(6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)pyrido[4,3-d]pyrimidin-5-yl]oxy-2,4-dimethylphenol

[0754] The synthetic route of Example 3 was used to replace the second step starting material, N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)-7-(4-methylpiperazin-1-yl)pyrido[4,3-d]pyrimidin-4-amine, with 7-(6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine, to obtain the title compound (19.55 mg). MS (ESI, m / z): 404.2 [M+H] + .

[0755] 1H NMR (400MHz, DMSO-d6) δ9.35(s,1H),8.26(s,1H),7.95(s,1H),7.55(s,1H),7.38(d,J=1.6Hz,1H),6.97(d,J=8.0Hz,1H),6.71(d,J= 8.4Hz,1H),6.46(s,1H),6.00(d,J=1.6Hz,1H),4.56(s,2H),3.99(t,J=5.6Hz,2H),3.82(t,J=5.6Hz,2H),1.95(s,3H),1.87(s,3H).

[0756] Example 26: Preparation of (R)-3-((8-amino-3-(3-(methylamino)pyrrolidin-1-yl)-5-((5-methylpyrimidin-2-yl)amino)-2,7-naphthyridin-1-yl)oxy)-2,4-dimethylphenol (Compound 26)

[0757] Step 1: Preparation of tert-butyl (R)-(1-(8-((2,4-dimethoxybenzyl)amino)-1-(3-methoxy-2,6-dimethylphenoxy)-5-((5-methylpyrimidin-2-yl)amino)-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate

[0758] Tert-butyl (R)-(1-(5-bromo-8-((2,4-dimethoxybenzyl)amino)-1-(3-methoxy-2,6-dimethylphenoxy)-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate (90 mg, 124.53 μmol), 5-methylpyrimidin-2-amine (31.18 mg, 249.06 μmol), tris(dibenzylideneacetone)dipalladium (11.40 mg, 12.45 μmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (7.20 mg, 12.45 μmol), and cesium carbonate (121.72 mg, 373.59 μmol) were dissolved in DMF (5 mL). After the addition, the atmosphere was replaced with nitrogen three times, and the temperature was raised to 120°C and stirred for 12 hr. After the reaction, the mixture was cooled to room temperature, quenched with water, and extracted with EA (10 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was purified by column chromatography on silica gel (DCM:MeOH = 10 / 1) to give the title compound (30 mg). MS (ESI, m / z): 751.8 [M+H] + .

[0759] Step 2: (R)-8-(3-methoxy-2,6-dimethylphenoxy)-6-(3-(methylamino)pyrrolidin-1-yl)-N 4Preparation of -(5-methylpyrimidin-2-yl)-2,7-naphthyridine-1,4-diamine

[0760] Tert-butyl (R)-(1-(8-((2,4-dimethoxybenzyl)amino)-1-(3-methoxy-2,6-dimethylphenoxy)-5-((5-methylpyrimidin-2-yl)amino)-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate (30 mg, 39.95 μmol) was dissolved in trifluoroacetic acid (4 mL), heated to 90°C and stirred for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, quenched with water, and extracted with EA (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude title compound (10 mg). MS (ESI, m / z): 501.6 [M+H] + .

[0761] Step 3: Preparation of (R)-3-((8-amino-3-(3-(methylamino)pyrrolidin-1-yl)-5-((5-methylpyrimidin-2-yl)amino)-2,7-naphthyridin-1-yl)oxy)-2,4-dimethylphenol

[0762] (R)-8-(3-methoxy-2,6-dimethylphenoxy)-6-(3-(methylamino)pyrrolidin-1-yl)-N 4 1-(5-Methylpyrimidin-2-yl)-2,7-naphthyridine-1,4-diamine (10 mg, 19.97 μmol) was added to boron tribromide (3 mL, 1 M in DCM) and stirred at room temperature for 2 hours. After completion of the reaction, the reaction was quenched with ammonia methanol and concentrated under reduced pressure. The title compound (5.0 mg) was isolated and purified by Prep-HPLC. MS (ESI, m / z): 487.3 [M+H] + .

[0763] 1 H NMR (400MHz, DMSO-d6) δ9.29(s,1H),8.62(m,J=2.5,1H),8.49(d,J=2.4Hz,1H),7.11(s,2H),6.93(d,J=8.4Hz,1H),6.67(d,J=8 .0Hz,1H),6.61(s,1H),3.17(m,3H),3.02(m,2H),2.37(s,3H),2.23(s,3H),2.00(s,3H),1.93(s,3H),1.73(s,2H),1.23(s,2H).

[0764] Example 27: (R)-5-((5-methyl-1H-indazol-4-yl)oxy)-N 2-(1-methyl-1H-pyrazol-4-yl)-7-(3-(methylamino)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidine-2,4-diamine (Compound 27)

[0765] Step 1: Preparation of tert-butyl 2,6-dichloro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate

[0766] Dissolve tert-butyl 4-amino-2,6-dichloronicotinate (1 g, 3.80 mmol) in THF (10 mL) in a reaction flask. Add 2,2,2-trichloroacetyl isocyanate (1.03 g, 5.42 mmol) dropwise under ice-cooling and stir at room temperature for 1 hr. Monitor by TLC. After the reaction is complete, spin dry the residue, purify it by slurrying with petroleum ether, filter the solid, and dry it in vacuo to give the title compound (1.6 g). MS (ESI, m / z): 452.0 [M+1]. + .

[0767] Step 2: Preparation of 5,7-dichloropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione

[0768] Dissolve tert-butyl 2,6-dichloro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate (1.6 g, 3.37 mmol) in MeOH (20 mL). Add 7M NH3-MeOH (5 mL) dropwise and stir at room temperature for 1 hour. Monitor by TLC. After the reaction is complete, spin dry the residue and purify it by slurrying with methyl tert-butyl ether. Filter the solid and dry it in vacuo to give the title compound (850 mg). MS (ESI, m / z): 232.0 [M+1]. + .

[0769] Step 3: Preparation of 7-chloro-5-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)pyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione

[0770] 5,7-Dichloropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (300 mg, 1.29 mmol), 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol (380 mg, 1.63 mmol), and cesium carbonate (1.21 g, 3.68 mmol) were dissolved in MeCN (8 mL) and placed in a microwave vial. The mixture was heated to 120°C and stirred for 8 hours under microwave conditions. LCMS monitoring was used. After the reaction was complete, the mixture was cooled to room temperature, dried by rotary evaporation, diluted with ice water, and adjusted to pH 6-7 by dropwise addition of 2N dilute hydrochloric acid. The mixture was filtered, the solid was washed with MeOH, and the filtrate was collected and dried by rotary evaporation to give the title compound (300 mg). MS (ESI, m / z): 428.2 [M+1]. + .

[0771] Step 4: Preparation of 2,4,7-trichloro-5-((5-methyl-1H-indazol-4-yl)oxy)pyrido[4,3-d]pyrimidine

[0772] 7-Chloro-5-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)pyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (300 mg, 701.26 μmol) was dissolved in POCl3 (10 mL) and placed in a reaction flask. N,N-dimethylaniline (7.99 mg, 65.25 μmol) was added dropwise, and the mixture was heated to 110°C and stirred for 16 hours. LCMS monitoring was used. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure to remove excess solvent. The mixture was then diluted with ice water and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The aqueous phase was extracted with EA (20.0 mL x 3) and washed with saturated sodium chloride water. The organic phase was collected, dried over anhydrous sodium sulfate, and then spin-dried to dryness. The mixture was purified by column chromatography on silica gel (PE / EA = 3 / 2) to give the title compound (120 mg). MS (ESI, m / z): 380.0 [M+1] + .

[0773] Step 5: Preparation of 2,7-dichloro-5-((5-methyl-1H-indazol-4-yl)oxy)pyrido[4,3-d]pyrimidin-4-amine

[0774] Dissolve 2,4,7-trichloro-5-((5-methyl-1H-indazol-4-yl)oxy)pyrido[4,3-d]pyrimidine (120 mg, 315.29 μmol) in THF (5 mL) and place in a reaction flask. Add NH3-MeOH (7 M, 5.33 mL) dropwise under ice-cooling and stir at room temperature for 2 hours. Monitor by LCMS. After completion of the reaction, spin dry and purify by silica gel column chromatography (PE / EA = 1 / 4 elution) to obtain the title compound (30 mg). MS (ESI, m / z): 361.0 [M+1] +.

[0775] Step 6: 7-chloro-5-((5-methyl-1H-indazol-4-yl)oxy)-N 2 Preparation of -(1-methyl-1H-pyrazol-4-yl)pyrido[4,3-d]pyrimidine-2,4-diamine

[0776] 2,7-Dichloro-5-((5-methyl-1H-indazol-4-yl)oxy)pyrido[4,3-d]pyrimidin-4-amine (30 mg, 83.06 μmol), 1-methyl-1H-pyrazol-4-amine (11.00 mg, 112.13 μmol), and p-toluenesulfonic acid (1.30 mg, 7.48 μmol) were dissolved in tert-butanol (3 mL) and placed in a reaction flask. The mixture was heated to 110°C and stirred for 2 hours. LCMS monitoring was performed. After completion of the reaction, the mixture was spin-dried, diluted with DCM, and filtered. After washing with MeOH, the solid was filtered and dried under vacuum to give the title compound (30 mg). MS (ESI, m / z): 422.1.[M+1] + .

[0777] Step 7: Preparation of tert-butyl (R)-(1-(4-amino-5-((5-methyl-1H-indazol-4-yl)oxy)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrido[4,3-d]pyrimidin-7-yl)pyrrolidin-3-yl)(methyl)carbamate

[0778] 7-Chloro-5-((5-methyl-1H-indazol-4-yl)oxy)-N2-(1-methyl-1H-pyrazol-4-yl)pyrido[4,3-d]pyrimidine-2,4-diamine (15 mg, 35.56 μmol), (R)-methyl(pyrrolidin-3-yl)carbamic acid tert-butyl ester (9.71 mg, 48.00 μmol), and potassium carbonate (8.92 mg, 64.00 μmol) were dissolved in DMF (1 mL) and placed in a microwave vial. The mixture was heated to 120°C and stirred for 3 hours under microwave conditions. LCMS monitoring was used. After completion of the reaction, the mixture was poured into ice water (3 mL) and extracted with EA (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield the title compound (10 mg, 17.09 μmol). MS (ESI, m / z): 586.1 [M+1]. + .

[0779] Step 8: (R)-5-((5-methyl-1H-indazol-4-yl)oxy)-N 2 Preparation of 7-(1-methyl-1H-pyrazol-4-yl)-7-(3-(methylamino)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidine-2,4-diamine

[0780] Tert-butyl (R)-(1-(4-amino-5-((5-methyl-1H-indazol-4-yl)oxy)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrido[4,3-d]pyrimidin-7-yl)pyrrolidin-3-yl)(methyl)carbamate (10 mg, 17.09 μmol) was dissolved in a 4 M hydrochloric acid-dioxane solution in a reaction flask and stirred at 25°C for 30 min. LCMS monitoring was used. After the reaction was completed, the excess solvent was removed by concentration under reduced pressure, and saturated aqueous sodium bicarbonate was added to adjust the pH to 8-9. The mixture was extracted with EA (3 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The title compound (0.71 mg) was isolated and purified by Prep-HPLC. MS (ESI, m / z): 486.1 [M+1]. +

[0781] 1 H NMR (400MHz, DMSO-d6) δ13.05(s,1H),8.26(s,2H),8.08(s,1H),7.73(s,1H),7.50(s,1H),7.36(d,J=8.2Hz,1H),7.29(d,J=8.2Hz ,1H),7.21(s,1H),3.80(s,3H),3.16-3.12(m,3H),2.84-2.80(m,1H),2.22(d,J=8.4Hz,6H),2.05-1.83(m,3H),1.71-1.58(m,1H).

[0782] Example 28: Preparation of (R)-3-((8-amino-5-chloro-3-(3-(methylamino)pyrrolidin-1-yl)-2,7-naphthyridin-1-yl)oxy)-2,4-dimethylphenol (Compound 28)

[0783] Step 1: Preparation of 4,6,8-trichloro-2,7-naphthyridin-1(2H)-one

[0784] Dissolve 6,8-dichloro-2,7-naphthyridin-1(2H)-one (260 mg, 1.21 mmol) and N-chlorosuccinimide (177.60 mg, 1.33 mmol) in DMF (4 mL) and stir at room temperature for 1 hour. After completion of the reaction, quench the reaction with water and extract with EA (20 mL x 3). The organic phases are combined and dried over anhydrous sodium sulfate to directly obtain the crude title product (250 mg). MS (ESI, m / z): 250.5 [M+H] + .

[0785] Step 2: Preparation of 4,6-dichloro-8-(3-methoxy-2,6-dimethylphenoxy)-2,7-naphthyridin-1(2H)-one

[0786] Dissolve 4,6,8-trichloro-2,7-naphthyridin-1(2H)-one (250 mg, 1 mmol) and 3-methoxy-2,6-dimethylphenol (228.28 mg, 1.5 mmol) in DMF (5 mL). Add NaH (76.16 mg, 1.90 mmol, 60% purity) in an ice bath, then raise the temperature to 60°C and stir for 2 hours. After the reaction, cool to room temperature and extract with EA (20.0 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure. Purify by column chromatography on silica gel (PE:EA = 10 / 1) to yield the title compound (300 mg). MS (ESI, m / z): 366.2 [M+H] + .

[0787] Step 3: Preparation of tert-butyl (R)-(1-(5-chloro-1-(3-methoxy-2,6-dimethylphenoxy)-8-oxo-7,8-dihydro-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate

[0788] Dissolve 4,6-dichloro-8-(3-methoxy-2,6-dimethylphenoxy)-2,7-naphthyridin-1(2H)-one (300 mg, 0.82 mmol), (R)-methyl(pyrrolidin-3-yl)carbamic acid tert-butyl ester (493.55 mg, 2.46 mmol), and potassium carbonate (409.10 mg, 2.96 mmol) in DMF (6 mL), heat to 100°C, and stir for 12 hours. After completion of the reaction, cool to room temperature, quench with water, and extract with EA (20.0 mL x 3). The organic phases are combined, dried over anhydrous sodium sulfate, and purified by column chromatography on silica gel (PE:EA = 1 / 1) to obtain the title compound (130 mg). MS (ESI, m / z): 529.2 [M+H] + .

[0789] Step 4: Preparation of tert-butyl (R)-(1-(5-chloro-8-((2,4-dimethoxybenzyl)amino)-1-(3-methoxy-2,6-dimethylphenoxy)-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate

[0790] Tert-butyl (R)-(1-(5-chloro-1-(3-methoxy-2,6-dimethylphenoxy)-8-oxo-7,8-dihydro-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate (130 mg, 245.73 μmol), (2,4-dimethoxyphenyl)methanamine (45.19 mg, 270.30 μmol), and diazabicyclopentane (DBU) (74.81 mg, 491.46 μmol) were dissolved in DMF (5 mL), and 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (153.48 mg, 294.94 μmol) was added, and the temperature was raised to 60°C and stirred for 2 hr. After the reaction, the mixture was cooled to room temperature, quenched with water, and extracted with EA (20.0 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was purified by column chromatography on silica gel (PE:EA = 10 / 3) to obtain the title compound (90 mg). MS (ESI, m / z): 679.2 [M+H] + .

[0791] Step 5: Preparation of (R)-4-chloro-8-(3-methoxy-2,6-dimethylphenoxy)-6-(3-(methylamino)pyrrolidin-1-yl)-2,7-naphthyridin-1-amine

[0792] Tert-butyl (R)-(1-(5-chloro-8-((2,4-dimethoxybenzyl)amino)-1-(3-methoxy-2,6-dimethylphenoxy)-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate (90 mg, 132.69 μmol) was dissolved in trifluoroacetic acid (3 mL), heated to 90°C, and stirred for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, quenched with water, and extracted with EA (10.0 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude title compound (25 mg). MS (ESI, m / z): 428.9 [M+H] + .

[0793] Step 6: Preparation of (R)-3-((8-amino-5-chloro-3-(3-(methylamino)pyrrolidin-1-yl)-2,7-naphthyridin-1-yl)oxy)-2,4-dimethylphenol

[0794] (R)-4-chloro-8-(3-methoxy-2,6-dimethylphenoxy)-6-(3-(methylamino)pyrrolidin-1-yl)-2,7-naphthyridin-1-amine (25 mg, 58.52 μmol) was added to boron tribromide (3 mL, 1 M in DCM) and stirred at room temperature for 2 hours. After completion of the reaction, the reaction was quenched with ammonia methanol and concentrated under reduced pressure. The title compound (10 mg) was isolated and purified by Prep-HPLC. MS (ESI, m / z): 414.3 [M+H] + .

[0795] 1 H NMR (400MHz, DMSO-d6) δ9.29(s,1H),7.79(s,1H),7.05(s,2H),6.92(d,J=8.0Hz,1H),6.66(d,J=8.0Hz,1H),5.94(s,1H ),3.25-3.07(m,4H),2.94(m,1H),2.21(s,3H),1.96(s,3H),1.93(m,1H),1.89(s,3H),1.84-1.77(m,1H),1.71(m,1H).

[0796] Example 29: 3-((4-amino-7-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol (Compound 29)

[0797] Step 1: Preparation of 8-methyl-3,8-diazabicyclo[3.2.1]octane

[0798] To the reaction flask, tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 2.36 mmol), THF (20 mL), and LiAlH4 (179 mg, 4.71 mmol) were added. The mixture was reacted at 70°C for 48 hours under nitrogen atmosphere. After completion of the reaction, the reaction solution was cooled to room temperature, quenched with sodium sulfate decahydrate, filtered, and the filter cake was washed with DCM. The filtrates were combined and concentrated under reduced pressure to yield the title compound (120 mg). MS (ESI, m / z): 127.2 [M+H] + .

[0799] Step 2: Preparation of N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)-7-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-4-amine

[0800] 7-Chloro-N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine (50 mg, 103.96 μmol), 8-methyl-3,8-diazabicyclo[3.2.1]octane (26 mg, 207.93 μmol), K2CO3 (36 mg, 259.91 μmol), and NMP (1.5 mL) were added to a microwave tube under nitrogen protection and microwaved at 105°C for 5 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with EA (30 mL x 3). 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 (40 mg). MS (ESI, m / z): 571.3 [M+H] + .

[0801] Step 3: Preparation of 5-(3-methoxy-2,6-dimethylphenoxy)-7-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-4-amine

[0802] N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)-7-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-4-amine (40 mg, 70.09 μmol) and TFA (3 mL) were added to the reaction flask under nitrogen protection and reacted at 90°C for 16 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, dissolved in THF, and then spin-dried to remove residual TFA to obtain the title compound. MS (ESI, m / z): 421.2 [M+H] + .

[0803] Step 4: Preparation of 3-((4-amino-7-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol

[0804] To a reaction flask, 5-(3-methoxy-2,6-dimethylphenoxy)-7-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-4-amine (20 mg, 47.56 μmol), DCM (2 mL), and a 1M BBr3 solution in DCM (1 mL) were added. The mixture was incubated at 25°C for 1 hour under nitrogen atmosphere. After completion of the reaction, methanol was added to quench the reaction mixture. A methanolic ammonia solution was then added to adjust the pH to a weakly alkaline state. Solids precipitated and were filtered. The filter cake was washed with DCM, and the combined filtrates were concentrated under reduced pressure to yield the crude product. The crude product was purified by Pre-HPLC to yield the title compound. MS (ESI, m / z): 407.3 [M+H].+ .

[0805] 1 H NMR (400MHz, DMSO-d6) δ9.27(s,1H),8.20(s,1H),7.82(s,1H),7.46(s,1H),6.91(d,J=8.0Hz,1H),6.65(d,J=8.0Hz,1H),6.20( s,1H),4.12-4.05(m,2H),2.41-2.37(m,2H),2.06-2.01(m,5H),1.96(s,3H),1.89(s,3H),1.81-1.76(m,2H),1.74-1.67(m,2H).

[0806] Example 30: Preparation of (R)-5-((5-methyl-1H-indazol-4-yl)oxy)-7-(3-(methylamino)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-4-amine (Compound 30)

[0807] Step 1: Preparation of 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol

[0808] 5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-indazole (4 g, 10.52 mmol) and m-CPBA (2.74 g, 15.78 mmol) were dissolved in ethanol (20 mL) and water (10 mL) and stirred at 25°C for 16 hours. After completion of the reaction, the reaction solution was poured into water and extracted with EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified on a silica gel column (PE / EA = 60 / 40) to afford the title compound (2.25 g). MS (ESI, m / z): 233.1 [M+H] + .

[0809] Step 2: Preparation of 7-chloro-5-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)pyrido[4,3-d]pyrimidin-4-ol

[0810] 5,7-Dichloropyrido[4,3-d]pyrimidin-4-ol (200 mg, 879.53 μmol), 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol (272.39 mg, 1.06 mmol), and Cs2CO3 (859.71 mg, 2.64 mmol) were dissolved in ACN (5 mL) and then heated to 120°C under microwave conditions for 8 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated to obtain a crude product, which was purified by silica gel column chromatography (DCM / MeOH = 93 / 7) to afford the title compound (118 mg). MS (ESI, m / z): 412.1 [M+H] + .

[0811] Step 3: Preparation of 7-chloro-N-(2,4-dimethoxybenzyl)-5-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)pyrido[4,3-d]pyrimidin-4-amine

[0812] 7-Chloro-5-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)pyrido[4,3-d]pyrimidin-4-ol (118 mg, 286.52 μmol), 2,4-dimethoxybenzylamine (57.49 mg, 343.82 μmol), PyBOP (223.65 mg, 429.78 μmol), and DIPEA (74.06 mg, 573.04 mmol) were dissolved in DMF (5 mL) and reacted at 60°C for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, extracted with EA, and concentrated to give the title compound (110 mg). MS (ESI, m / z): 561.3 [M+H] + .

[0813] Step 4: Preparation of tert-butyl ((3R)-1-(4-((2,4-dimethoxybenzyl)amino)-5-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)pyrido[4,3-d]pyrimidin-7-yl)pyrrolidin-3-yl)(methyl)carbamate

[0814] 7-Chloro-N-(2,4-dimethoxybenzyl)-5-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)pyrido[4,3-d]pyrimidin-4-amine (110 mg, 186.26 μmol), Pd2(dba)3 (17.06 mg, 18.63 μmol), BINAP (11.60 mg, 18.63 μmol), tert-butyl (R)-methyl(pyrrolidin-3-yl)carbamate (56.52 mg, 279.40 μmol), and sodium tert-butoxide (53.70 mg, 558.79 μmol) were added to toluene (5 mL) and reacted at 120°C for 16 hours under nitrogen. After completion, the reaction was cooled to room temperature, extracted with water, and concentrated with EA to obtain the crude product, which was purified by reverse-phase HPLC to give the title compound (34 mg). MS (ESI, m / z): 725.4 [M+H] + .

[0815] Step 5: Preparation of (R)-5-((5-methyl-1H-indazol-4-yl)oxy)-7-(3-(methylamino)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-4-amine

[0816] Tert-butyl ((3R)-1-(4-((2,4-dimethoxybenzyl)amino)-5-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)pyrido[4,3-d]pyrimidin-7-yl)pyrrolidin-3-yl)(methyl)carbamate (34 mg, 46.91 μmol) was added to TFA (5 mL) and reacted at 90°C for 2 hours. After completion of the reaction, the TFA was evaporated, and an amine methanol solution was added to adjust the base. The crude product was evaporated again to obtain the crude product, which was purified by reverse phase HPLC to obtain the title compound (6 mg). MS (ESI, m / z): 391.2 [M+H] + .

[0817] 1 H NMR (400MHz, DMSO-d6) δ13.07(s,1H),8.20(s,1H),7.82(s,1H),7.74(s,1H),7.47(s,1H),7.37(d,J=8.4H z,1H),7.30(d,J=8.4Hz,1H),5.90(s,1H),3.27-2.63(m,5H),2.21(s,3H),2.13(s,3H),1.96-1.44(m,3H).

[0818] The following compounds were prepared by the method and general steps described in Reference Example 30. The other required raw materials can be purchased commercially or synthesized by experienced synthesizers in the field of organic synthesis using conventional reactions from commercially purchased reagents.

[0819] Example 31: (R)-3-((8-amino-5-methyl-3-(3-(methylamino)pyrrolidin-1-yl)-2,7-naphthyridin-1-yl)oxy)-2,4-dimethylphenol (Compound 31)

[0820] Step 1: Preparation of tert-butyl (R)-(1-(8-((2,4-dimethoxybenzyl)amino)-1-(3-methoxy-2,6-dimethylphenoxy)-5-methyl-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate

[0821] To the reaction flask were added tert-butyl (R)-(1-(5-bromo-8-((2,4-dimethoxybenzyl)amino)-1-(3-methoxy-2,6-dimethylphenoxy)-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate (50 mg, 69.19 μmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxetriborane (26 mg, 207.56 μmol), K2CO3 (29 mg, 207.56 μmol), and dioxane (2 mL). After nitrogen replacement, Pd(PPh3)4 (8 mg, 6.92 μmol) was added, and the mixture was protected by nitrogen and reacted at 100°C for 16 hr. After the reaction was complete, the reaction mixture was diluted with water and extracted with EA (30 ml x 3). 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. The crude product was purified by silica gel column chromatography with a mobile phase of DCM:MeOH = 98:2 to obtain the title compound (40 mg). MS (ESI, m / z): 658.5 [M+H] + .

[0822] Step 2: Preparation of (R)-8-(3-methoxy-2,6-dimethylphenoxy)-4-methyl-6-(3-(methylamino)pyrrolidin-1-yl)-2,7-naphthyridin-1-amine

[0823] To the reaction flask, tert-butyl (R)-(1-(8-((2,4-dimethoxybenzyl)amino)-1-(3-methoxy-2,6-dimethylphenoxy)-5-methyl-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate (70 mg, 106.42 μmol) and TFA (3 mL) were added. The mixture was reacted at 90°C for 2 hours under nitrogen atmosphere. After completion of the reaction, the reaction solution was directly concentrated under reduced pressure, dissolved in THF, and then spin-dried to remove residual TFA to obtain the title compound. MS (ESI, m / z): 408.3 [M+H] + .

[0824] Step 3: Preparation of (R)-3-((8-amino-5-methyl-3-(3-(methylamino)pyrrolidin-1-yl)-2,7-naphthyridin-1-yl)oxy)-2,4-dimethylphenol

[0825] To the reaction flask, (R)-8-(3-methoxy-2,6-dimethylphenoxy)-4-methyl-6-(3-(methylamino)pyrrolidin-1-yl)-2,7-naphthyridin-1-amine (35 mg, 85.89 μmol), DCM (3 mL), and a 1M BBr3 solution in DCM (1 mL) were added. The mixture was incubated at 25°C for 1 hour under nitrogen atmosphere. After completion of the reaction, methanol was added to quench the reaction mixture. A methanolic ammonia solution was then added to adjust the pH to a weakly alkaline state. Solids precipitated and were filtered. The filter cake was washed with DCM, and the combined filtrates were concentrated under reduced pressure to yield the crude product. The crude product was purified by Pre-HPLC to yield the title compound. MS (ESI, m / z): 394.2 [M+H] + .

[0826] 1 H NMR (400MHz, DMSO-d6) δ9.04(s,1H),7.73(s,2H),7.49(s,1H),6.93(d,J=8.0Hz,1H),6.70(d,J=8.0Hz,1H),6.04(s,1H),3.78-3.72(m ,1H),3.56-3.48(m,1H),3.45-3.26(m,4H),2.53(s,3H),2.29-2.23(m,1H),2.20(s,3H),2.10-2.03(m,1H),1.98(s,3H),1.92(s,3H).

[0827] Example 32: Preparation of (R)-3-((4-amino-7-(3-((2-hydroxyethyl)amino)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol (Compound 32)

[0828] Step 1: Preparation of tert-butyl (R)-(1-(4-((2,4-dimethoxybenzyl)amino)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-7-yl)pyrrolidin-3-yl)carbamate

[0829] 7-Chloro-N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine (200 mg, 415.85 μmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate (154.9 mg, 831.7 μmol), and K2CO3 (114.95 mg, 831.70 μmol) were dissolved in NMP (8 mL), then heated to 120°C and stirred for 24 hours. After the reaction, the mixture was cooled to room temperature, poured into ice water (20 mL), and extracted with EA (20.0 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield the title compound (30 mg). MS (ESI, m / z): 631.3 [M+H] + .

[0830] Step 2: Preparation of (R)-7-(3-aminopyrrolidin-1-yl)-N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine

[0831] Dissolve tert-butyl (R)-(1-(4-((2,4-dimethoxybenzyl)amino)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-7-yl)pyrrolidin-3-yl)carbamate (260 mg, 412.22 μmol) in DCM (8 mL). Add 4 M hydrochloric acid in dioxane (2 mL) dropwise and stir at 25°C for 1 hr. After completion of the reaction, remove the solvent under reduced pressure to obtain the title compound (200 mg). MS (ESI, m / z): 531.3 [M+H] + .

[0832] Step 3: Preparation of (R)-N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)-7-(3-((2-methoxyethyl)amino)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-4-amine

[0833] (R)-7-(3-aminopyrrolidin-1-yl)-N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine (100 mg, 176.34 μmol), cesium carbonate (114.91 mg, 352.69 μmol), and 2-bromoethyl methyl ether (49.02 mg, 352.69 μmol) were added to NMP (5 mL) and reacted at 120°C for 16 hours. After completion of the reaction, water was added and the mixture was extracted three times with EA. The crude product was concentrated to obtain the title compound, which was purified by reverse-phase HPLC to yield the title compound (15 mg). MS (ESI, m / z): 589.3 [M+H]. + .

[0834] Step 4: Preparation of (R)-5-(3-methoxy-2,6-dimethylphenoxy)-7-(3-((2-methoxyethyl)amino)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-4-amine

[0835] (R)-N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)-7-(3-((2-methoxyethyl)amino)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-4-amine (15 mg, 25.48 μmol) was added to TFA (3 mL) and reacted at 90°C for 2 hours. After completion of the reaction, the TFA was evaporated to give the title compound (7 mg). MS (ESI, m / z): 439.2 [M+H] + .

[0836] Step 5: Preparation of (R)-3-((4-amino-7-(3-((2-hydroxyethyl)amino)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol

[0837] (R)-5-(3-methoxy-2,6-dimethylphenoxy)-7-(3-((2-methoxyethyl)amino)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-4-amine (7 mg, 15.96 μmol) was added to DCM (3 mL). A 1 M solution of boron tribromide in dichloromethane (1 mL) was added dropwise under an ice-water bath and stirring was continued for 1 h. After completion, methanol was added to quench the reaction. The crude product was concentrated to afford the title compound, which was purified by reverse-phase HPLC to afford the title compound (1.35 mg). MS (ESI, m / z): 411.2 [M+H]. + .

[0838] 1H NMR(400MHz,DMSO-d6)δ9.26(s,1H),8.16(s,1H),7.74(s,1H),7.41(s,1H),6.9 1(d,J=8.4Hz,1H),6.65(d,J=8.4Hz,1H),5.87(s,1H),5.32(t,J=4.6Hz,1H),4. 46(t,J=4.8Hz,1H),3.48-3.36(m,2H),3.30-3.20(m,3H),3.20-3.05(m,2H),2. 97-2.79(m,1H),2.64-2.53(m,1H),1.96(s,3H),1.89(s,3H),1.78-1.57(m,2H).

[0839] Examples 33 and 34: 3-((4-amino-7-(3,3-dimethylpiperazin-1-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol (Compound 33) and 3-((4-amino-7-(3,3,4-trimethylpiperazin-1-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol (Compound 34)

[0840] Step 1: Preparation of 1,2,2-trimethylpiperazine

[0841] To the reaction flask, tert-butyl 2,2-dimethylpiperazine-1-carboxylate (500 mg, 2.33 mmol), THF (20 mL), and LiAlH4 (177 mg, 4.67 mmol) were added. The mixture was stirred at 70°C for 48 hours under nitrogen atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature and quenched with sodium sulfate decahydrate. The mixture was filtered, the filter cake was washed with DCM, and the filtrates were combined and concentrated under reduced pressure to yield the title compound (175 mg). MS (ESI, m / z): 129.2 [M+H] + .

[0842] Step 2: Preparation of N-(2,4-dimethoxybenzyl)-7-(3,3-dimethylpiperazin-1-yl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine and N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)-7-(3,3,4-trimethylpiperazin-1-yl)pyrido[4,3-d]pyrimidin-4-amine

[0843] 7-Chloro-N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine (50 mg, 103.96 μmol), 1,2,2-trimethylpiperazine (42 mg, 207.93 μmol), K2CO3 (57 mg, 415.85 μmol), and NMP (1.5 mL) were added to a microwave tube under nitrogen protection and microwaved at 120°C for 8 hours. After completion of the reaction, the reaction solution was diluted with water and extracted with EA (30 ml x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a mixture of the title compounds (35 mg). MS (ESI, m / z): 559.4 [M+H]. + 、MS(ESI,m / z):573.4[M+H] + .

[0844] Step 3: Preparation of 7-(3,3-dimethylpiperazin-1-yl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine and 5-(3-methoxy-2,6-dimethylphenoxy)-7-(3,3,4-trimethylpiperazin-1-yl)pyrido[4,3-d]pyrimidin-4-amine

[0845] A mixture of N-(2,4-dimethoxybenzyl)-7-(3,3-dimethylpiperazin-1-yl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine and N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)-7-(3,3,4-trimethylpiperazin-1-yl)pyrido[4,3-d]pyrimidin-4-amine (35 mg) and TFA (3 mL) were added to the reaction flask under nitrogen protection and reacted at 80°C for 3 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, dissolved in THF, and then spin-dried to remove residual TFA to obtain a mixture of the title compounds. MS (ESI, m / z): 409.3 [M+H] + 、MS(ESI,m / z):423.3[M+H] + .

[0846] Step 4: Preparation of 3-((4-amino-7-(3,3,4-trimethylpiperazin-1-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol and 3-((4-amino-7-(3,3-dimethylpiperazin-1-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol

[0847] A mixture of 7-(3,3-dimethylpiperazin-1-yl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine and 5-(3-methoxy-2,6-dimethylphenoxy)-7-(3,3,4-trimethylpiperazin-1-yl)pyrido[4,3-d]pyrimidin-4-amine (25 mg), DCM (2.5 mL), and a 1M BBr3 solution in DCM (1 mL) were added to a reaction flask. The mixture was incubated at 25°C for 1 hour under nitrogen atmosphere. After completion of the reaction, methanol was added to quench the reaction mixture, and the pH was adjusted to a weakly alkaline state by adding a methanolic ammonia solution. Solids precipitated and were filtered. The filter cake was washed with DCM, and the combined filtrates were concentrated under reduced pressure to obtain the crude product. The crude product was purified by Pre-HPLC to yield the title compound. MS (ESI, m / z): 395.3 [M+H] + 、MS(ESI,m / z):409.3[M+H] + .

[0848] Compound 33: 1 H NMR (400MHz, DMSO-d6) δ9.28(s,1H),8.17(s,1H),7.76(s,1H),7.39(s,1H),6.92(d,J=8.0Hz,1H),6.67(d,J =8.0Hz,1H),6.17(s,1H),3.24-3.19(m,2H),3.02(s,2H),2.65-2.61(m,2H),2.04-1.79(m,7H),0.79(s,6H).

[0849] Compound 34: 1 H NMR (400MHz, DMSO-d6) δ9.28(s,1H),8.17(s,1H),7.78(s,1H),7.40(s,1H),6.92(d,J=8.0Hz,1H),6.67(d,J=8.0Hz,1H ),6.21(s,1H),3.38-3.34(m,2H),3.03(s,2H),2.35-2.30(m,2H),2.05(s,3H),1.94(s,3H),1.87(s,3H),0.71(s,6H).

[0850] Example 35: (R)-3-((4-amino-7-(hexahydropyrazinyl[2,1-c][1,4]oxazin-8(1H)-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol (Compound 35)

[0851] Step 1: Preparation of (R)-N-(2,4-dimethoxybenzyl)-7-(hexahydropyrazinyl[2,1-c][1,4]oxazin-8(1H)-yl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine

[0852] 7-Chloro-N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine (50 mg, 103.96 μmol), (R)-octahydropyrazino[2,1-c][1,4]oxazine (45 mg, 207.93 μmol), K2CO3 (50 mg, 363.87 μmol), and NMP (2 mL) were added to a microwave tube under nitrogen protection and microwaved at 120°C for 5 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with EA (30 ml x 3). 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 (55 mg). MS (ESI, m / z): 587.4 [M+H] + .

[0853] Step 2: Preparation of (R)-7-(hexahydropyrazinyl[2,1-c][1,4]oxazin-8(1H)-yl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine

[0854] To the reaction flask, (R)-N-(2,4-dimethoxybenzyl)-7-(hexahydropyrazinyl[2,1-c][1,4]oxazin-8(1H)-yl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine (55 mg, 93.75 μmol) and TFA (3 mL) were added. The mixture was reacted at 80°C for 3 hours under nitrogen atmosphere. After completion of the reaction, the reaction solution was directly concentrated under reduced pressure, dissolved in THF, and then spin-dried to remove residual TFA to obtain the title compound. MS (ESI, m / z): 437.3 [M+H] + .

[0855] Step 3: Preparation of (R)-3-((4-amino-7-(hexahydropyrazinyl[2,1-c][1,4]oxazin-8(1H)-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol

[0856] To a reaction flask, (R)-7-(hexahydropyrazinyl[2,1-c][1,4]oxazin-8(1H)-yl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine (35 mg, 80.18 μmol), DCM (2.5 mL), and a 1M BBr3 solution in DCM (1 mL) were added. The mixture was incubated at 25°C for 1 hour under nitrogen atmosphere. After completion of the reaction, methanol was added to quench the reaction mixture. A methanolic ammonia solution was then added to adjust the pH to a weakly alkaline state. A solid precipitated and was filtered. The filter cake was washed with DCM, and the combined filtrates were concentrated under reduced pressure to yield the crude product. The crude product was purified by Pre-HPLC to yield the title compound. MS (ESI, m / z): 423.3 [M+H] + .

[0857] 1 H NMR (400MHz, DMSO-d6) δ9.30 (d, J = 4.4Hz, 1H), 8.22 (s, 1H), 7.85 (s, 1H), 7.4 7(s,1H),6.92(dd,J=8.0,2.0Hz,1H),6.66(d,J=8.0Hz,1H),6.29(s,1H),3.9 2-3.85(m,1H),3.75-3.67(m,2H),3.51-3.43(m,2H),3.08-3.01(m,1H),2.8 7-2.77(m,1H),2.63-2.55(m,2H),2.36-2.29(m,1H),2.15-2.08(m,1H),2.03 -1.97(m,1H),1.97-1.90(m,4H),1.88(d,J=3.6Hz,3H).

[0858] Example 38: (R)-8-((5-methyl-1H-indazol-4-yl)oxy)-N 4 -(1-methyl-1H-pyrazol-3-yl)-6-(3-(methylamino)pyrrolidin-1-yl)-2,7-naphthyridine-1,4-diamine (Compound 38)

[0859] Step 1: Preparation of tert-butyl ((3R)-1-(8-((2,4-dimethoxybenzyl)amino)-1-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-5-((1-methyl-1H-pyrazol-3-yl)amino)-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate

[0860] Tert-butyl ((3R)-1-(5-bromo-8-((2,4-dimethoxybenzyl)amino)-1-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate (50 mg, 62.28 μmol), 1-methyl-1H-pyrazol-3-amine (9.07 mg, 93.43 μmol), were dissolved in 1,4-dimethoxybenzyl. To the mixture was added oxadiazole (3 mL), followed by the addition of Pd2(dba)3 (5.19 mg, 5.61 μmol), sodium tert-butoxide (13.60 mg, 140.14 μmol), and dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine (BrettPhos) (6.08 mg, 11.21 μmol). After the addition, the atmosphere was purged with nitrogen three times, and the temperature was raised to 120°C and stirred for 2 hours. After the reaction, the mixture was cooled to room temperature, quenched with water, and extracted with EA (10.0 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography on silica gel (DCM:MeOH = 10 / 1) to afford the title compound (40.0 mg). MS (ESI, m / z): 819.5 [M+H] + .

[0861] Step 2: (R)-8-((5-methyl-1H-indazol-4-yl)oxy)-N 4 Preparation of -(1-methyl-1H-pyrazol-3-yl)-6-(3-(methylamino)pyrrolidin-1-yl)-2,7-naphthyridine-1,4-diamine

[0862] Tert-butyl ((3R)-1-(8-((2,4-dimethoxybenzyl)amino)-1-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-5-((1-methyl-1H-pyrazol-3-yl)amino)-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate (40 mg, 48.84 μmol) was dissolved in trifluoroacetic acid (3 mL), heated to 90°C and stirred for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, quenched with water, and extracted with EA (10.0 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and separated and purified by Prep-HPLC to give the title compound (1.70 mg). MS (ESI, m / z): 485.3 [M+H] + .

[0863] 1H NMR (400MHz, DMSO-d6) δ13.08(s,1H),8.28(s,1H),7.93(s,1H),7.71(s,1H),7.41-7.35(m,2H),7.30(m,1H),7.19(s,1H),6.63(s, 2H), 6.16 (s, 1H), 5.57 (d, J = 2.4Hz, 1H), 3.67 (s, 3H), 3.07 (m, 4H), 2.79 (m, 1H), 2.23 (s, 3H), 2.16 (s, 3H), 1.87 (m, 1H), 1.59 (m, 1H).

[0864] Example 39: 4-(4-amino-5-(3-hydroxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-methylpiperazin-2-one (Compound 39)

[0865] Step 1: Preparation of 4-(4-((2,4-dimethoxybenzyl)amino)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-methylpiperazin-2-one

[0866] 7-Chloro-N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine (50.0 mg, 104.0 3H), 1-methylpiperazin-2-one (35.60 mg, 312.0 μmol), and K2CO3 (43.05 mg, 312.0 μmol) were dissolved in DMF (4 mL) and microwave-heated at 120°C for 9 hr. After completion of the reaction, the mixture was cooled to room temperature, poured into ice-water (20 mL), and extracted with EA (20.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The title compound (35 mg) was obtained by column chromatography (DCM:MeOH = 0-70%). MS (ESI, m / z): 559.3 [M+H]. + .

[0867] Step 2: Preparation of 4-(4-amino-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-methylpiperazin-2-one

[0868] 4-(4-((2,4-dimethoxybenzyl)amino)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-methylpiperazin-2-one (35 mg, 62.6 μmol) was dried and dissolved in trifluoroacetic acid (6 mL). The mixture was heated to 80°C and stirred for 16 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and ammonia methanol was added to adjust the pH to 8-9. The mixture was concentrated and purified by column chromatography (DCM:MeOH = 0-70%) to afford the title compound (12 mg). MS (ESI, m / z): 409.2 [M+H] + .

[0869] Step 3: Preparation of 4-(4-amino-5-(3-hydroxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-methylpiperazin-2-one

[0870] 4-(4-Amino-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-methylpiperazin-2-one (10 mg, 24.5 μmol) was dissolved in dichloromethane (2 mL). A 1M solution of BBr in dichloromethane (4 mL) was added, and the mixture was stirred at 25°C for 2 hours. After completion of the reaction, a small amount of methanol was added dropwise to quench the reaction. The solvent was evaporated under reduced pressure to obtain a crude product (25 mg). Liquid phase preparation yielded the title compound (3.1 mg). MS (ESI, m / z): 395.1 [M+H] + .

[0871] 1 H NMR (400MHz, DMSO-d6) δ9.33(s,1H),8.24(s,1H),7.92(s,1H),7.54(s,1H),6.93(d,J=8.4Hz,1H),6.68(d,J=8.0Hz ,1H),6.27(s,1H),3.80(s,2H),3.53(t,J=5.2Hz,2H),3.28(t,J=5.2Hz,2H),2.81(s,3H),1.95(s,3H),1.88(s,3H).

[0872] The following compounds were prepared by the method and general steps described in Reference Example 39. The other required raw materials can be purchased commercially or synthesized by experienced synthesizers in the field of organic synthesis using conventional reactions from commercially purchased reagents.

[0873] Example 42: 3-((4-amino-7-(4-methoxypiperidin-1-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol (Compound 42)

[0874] Step 1: Preparation of 7-chloro-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine

[0875] Dissolve 7-chloro-N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine (20 mg, 41.59 μmol) in TFA (2 mL). After addition, heat to 90°C and react for 21 hours. After completion of the reaction, concentrate under reduced pressure to remove the solvent to obtain the title compound (13.76 mg). MS (ESI, m / z): 331.2 [M+H] + .

[0876] Step 2: Preparation of 3-((4-amino-7-chloropyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol

[0877] Dissolve 7-chloro-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine (13.76 mg, 41.59 μmol) in DCM (2 mL) and add a 1M BBr3 solution in dichloromethane (1 mL). After addition, warm to 25°C and react for 18 hours. After completion of the reaction, concentrate under reduced pressure, purify by TLC (DCM:MeOH=20:1), and filter to obtain the title compound (13.5 mg). MS (ESI, m / z): 317.1 [M+H] + .

[0878] Step 3: Preparation of 3-((4-amino-7-(4-methoxypiperidin-1-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol

[0879] 3-((4-amino-7-chloropyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol (13.5 mg, 42.62 μmol), 4-methoxypiperidine (14.73 mg, 127.86 μmol), and K2CO3 (23.56 mg, 170.49 μmol) were dissolved in DMF (2 mL). After addition, the mixture was reacted at 100°C for 5 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The crude product was separated and purified by Prep-HPLC to obtain the title compound (14.0 mg). MS (ESI, m / z): 396.2 [M+H] + .

[0880] 1H NMR (400MHz, DMSO-d6) δ9.32(s,1H),8.20(s,1H),7.83(s,1H),7.46(s,1H),6.92(d,J=8.0Hz,1H),6.66(d,J=8.0Hz,1H),6.27(s, 1H),3.65-3.56(m,3H),3.21(s,3H),3.02-2.94(m,2H),1.95(s,3H),1.88(s,3H),1.76-1.66(m,2H),1.24(dt,J=12.0,9.0Hz,2H).

[0881] Example 43: 3-(4-amino-7-(1H-pyrazol-3-yl)-pyrido[4,3-d]pyrimidin-5-yloxy)-2,4-dimethyl-phenol (Compound 43)

[0882] Step 1: Preparation of (2,4-dimethoxybenzyl)-(5-(3-methoxy-2,6-dimethylphenoxy)-7-(1H-pyrazol-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-amine

[0883] 7-Chloro-N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine (200 mg, 415.85 μmol), 1H-pyrazole-3-boronic acid pinacol ester (242.07 mg, 1.25 mmol), cataCXium A Pd G3 (15.14 mg, 20.79 μmol), and K3PO4 (264.81 mg, 1.25 mmol) were dissolved in 1,4-dioxane (3 mL) / H2O (1 mL). The mixture was reacted at 100°C for 2 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (PE:EA = 70:30) to obtain the title compound (141 mg). MS (ESI, m / z): 513.1 [M+H] + .

[0884] Step 2: Preparation of 5-(3-methoxy-2,6-dimethylphenoxy)-7-(1H-pyrazol-3-yl)pyrido[4,3-d]pyrimidin-4-amine

[0885] (2,4-Dimethoxybenzyl)-(5-(3-methoxy-2,6-dimethylphenoxy)-7-(1H-pyrazol-3-yl)-pyrido[4,3-d]pyrimidin-4-yl)-amine (141 mg, 275.09 μmol) was dissolved in TFA (3 mL) and reacted at 90°C for 48 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, diluted with methanol, and the pH was adjusted to a weakly acidic state with aqueous ammonia to obtain the title compound (90 mg). MS (ESI, m / z): 363.2 [M+H] + .

[0886] Step 3: Preparation of 3-(4-amino-7-(1H-pyrazol-3-yl)-pyrido[4,3-d]pyrimidin-5-yloxy)-2,4-dimethylphenol

[0887] Dissolve 5-(3-methoxy-2,6-dimethylphenoxy)-7-(1H-pyrazol-3-yl)pyrido[4,3-d]pyrimidin-4-amine (95 mg, 262.15 μmol) in DCM (2 mL) and add 1M BBr3 in dichloromethane (1.5 mL). After addition, react at 25°C for 2 hours. After completion of the reaction, concentrate under reduced pressure. The crude product is separated and purified by Prep-HPLC to obtain the title compound (34.0 mg). MS (ESI, m / z): 349.2 [M+H] + .

[0888] 1 H NMR(400MHz,DMSO-d6)δ13.08(s,1H),9.33(s,1H),8.48(s,1H),8.29(s,1H),7.88(s,1H),7.70(s,1 H),7.60(s,1H),6.96(d,J=8.0Hz,1H),6.71(d,J=8.0Hz,1H),6.22(s,1H),1.99(s,3H),1.91(s,3H). The following compounds were prepared by the method and general steps described in Reference Example 43, or by replacing 7-chloro-N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine with (4-((2,4-dimethoxybenzyl)amino)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-7-yl)boronic acid and the corresponding heteroaromatic halide by the method and general steps described in Reference Example 43. Other required raw materials can be purchased commercially or obtained by synthesizers experienced in the field of organic synthesis using conventional reactions from commercially purchased reagents.

[0889] Example 44: (R)-3-((8-amino-3-(3-(methylamino)pyrrolidin-1-yl)-5-((4-methylpyrimidin-2-yl)amino)-2,7-naphthyridin-1-yl)oxy)-2,4-dimethylphenol (Compound 44)

[0890] Step 1: Preparation of tert-butyl (R)-(1-(8-((2,4-dimethoxybenzyl)amino)-1-(3-methoxy-2,6-dimethylphenoxy)-5-((4-methylpyrimidin-2-yl)amino)-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate

[0891] Tert-butyl (R)-(1-(5-bromo-8-((2,4-dimethoxybenzyl)amino)-1-(3-methoxy-2,6-dimethylphenoxy)-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate (37 mg, 51.20 μmol), 2-amino-4-methylpyrimidine (11.17 mg, 120.98 μmol), t-BuONa (12.30 mg, 128.00 μmol), BrettPhos (5.50 mg, 10.24 μmol), and Pd2(dba)3 (4.69 mg, 5.12 μmol) were dissolved in 1,4-dioxane (5 mL) and added to the reaction flask. The mixture was reacted at 120°C for 16 hours under nitrogen protection. The reaction mixture was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (DCM / MeOH=93 / 7) to obtain the title compound (35 mg). MS (ESI, m / z): 751.4 [M+H] + .

[0892] Step 2: (R)-8-(3-methoxy-2,6-dimethylphenoxy)-6-(3-(methylamino)pyrrolidin-1-yl)-N 4 Preparation of -(4-methylpyrimidin-2-yl)-2,7-naphthyridine-1,4-diamine

[0893] Tert-butyl (R)-(1-(8-((2,4-dimethoxybenzyl)amino)-1-(3-methoxy-2,6-dimethylphenoxy)-5-((4-methylpyrimidin-2-yl)amino)-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate (35 mg, 46.61 μmol) was dissolved in TFA (2 mL) and the temperature was raised to 90°C for 2 hours. The mixture was concentrated under reduced pressure to obtain the title compound (20 mg). MS (ESI, m / z): 501.3 [M+H] + .

[0894] Step 3: Preparation of (R)-3-((8-amino-3-(3-(methylamino)pyrrolidin-1-yl)-5-((4-methylpyrimidin-2-yl)amino)-2,7-naphthyridin-1-yl)oxy)-2,4-dimethylphenol

[0895] (R)-8-(3-methoxy-2,6-dimethylphenoxy)-6-(3-(methylamino)pyrrolidin-1-yl)-N 4 4-(4-Methylpyrimidin-2-yl)-2,7-naphthyridine-1,4-diamine (15 mg, 39.95 μmol) was dissolved in DCM (3 mL) and a 1M solution of BBr in dichloromethane (2 mL) was added. The reaction system was allowed to react at 25°C for 1 hour. After completion, the reaction was quenched with methanol, concentrated under reduced pressure, and purified by reverse-phase column chromatography (H2O (0.05% ammonium bicarbonate):MeCN = 65:35). The title compound (13 mg) was obtained by lyophilization. MS (ESI, m / z): 487.3 [M+H] + .

[0896] 1 H NMR (400MHz, DMSO-d6) δ9.26(s,1H),8.51(s,1H),8.10(d,J=5.2Hz,1H),7.70(s,1H),6.91(d,J=8.4Hz,1H),6.80(s,2H),6.65(d,J=8.0Hz,1H ),6.55(d,J=4.8Hz,1H),5.80(s,1H),3.20-2.95(m,5H),2.88-2.79(m ,1H),2.26(s,3H),2.17(s,3H),1.98(s,3H),1.91(s,3H),1.62(s,1H).

[0897] Example 45: 3-((4-amino-7-(5-(methylamino)-1H-pyrazol-3-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol (Compound 45)

[0898] Step 1: Preparation of tert-butyl 3-bromo-5-((tert-butoxycarbonyl)amino)-1H-pyrazole-1-carboxylate

[0899] Dissolve 5-bromo-1H-pyrazol-3-amine (3000 mg, 18.52 mmol) in THF (20 mL), then add TEA (9.37 g, 92.60 mmol), (Boc)2O (10.10 g, 46.30 mmol), and DMAP (226.26 mg, 1.85 mmol). After addition, react at 60°C for 8 hours. The reaction mixture is concentrated under reduced pressure to obtain a crude product, which is then separated and purified by column chromatography (EA / PE = 10 / 90) to obtain the title compound (1.3 g).

[0900] 1 H NMR (400MHz, DMSO-d6) δ9.29(s,1H),6.48(s,1H),1.57(s,9H),1.47(s,9H).

[0901] Step 2: Preparation of tert-butyl 3-bromo-5-((tert-butoxycarbonyl)(methyl)amino)-1H-pyrazole-1-carboxylate

[0902] tert-Butyl 3-bromo-5-((tert-butoxycarbonyl)amino)-1H-pyrazole-1-carboxylate (1100 mg, 3.04 mmol) was dissolved in DMF (2 mL), and NaH (145.77 mg, 6.07 mmol) was added dropwise. Methyl iodide (517.25 mg, 3.64 mmol) was added, and the mixture was reacted at 25°C for 2 hours. The reaction solution was extracted three times with EA, and the combined organic phases were washed with brine. The organic phases were dried and concentrated to obtain the crude product, which was separated and purified by column chromatography (EA / PE = 8 / 92) to obtain the title compound (1 g).

[0903] 1 H NMR (400MHz, DMSO-d6) δ6.71(s,1H),3.06(s,3H),1.55(s,9H),1.45(s,9H).

[0904] Step 3: Preparation of tert-butyl 5-((tert-butoxycarbonyl)(methyl)amino)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate

[0905] Dissolve tert-butyl 3-bromo-5-((tert-butoxycarbonyl)(methyl)amino)-1H-pyrazole-1-carboxylate (100 mg, 265.78 μmol) in 1,4-dioxane (3 mL). Add Pd(dppf)Cl2 (28.93 mg, 39.87 μmol), potassium acetate (78.25 mg, 797.35 μmol), and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (134.99 mg, 531.57 μmol). Stir the mixture at 100°C under nitrogen for 3 hours to obtain the title compound.

[0906] Step 4: Preparation of tert-butyl 5-((tert-butoxycarbonyl)(methyl)amino)-3-(4-((2,4-dimethoxybenzyl)amino)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-7-yl)-1H-pyrazole-1-carboxylate

[0907] 7-Chloro-N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-4-amine (50 mg, 103.96 μmol) and tert-butyl 5-((tert-butoxycarbonyl)(methyl)amino)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole-1-carboxylate (88.02 mg, 207.93 μmol) were dissolved in 1,4-dioxane (2 mL), and K3PO4 (66.20 mg, 311.89 μmol), cataCXium A Pd G3 (7.57 mg, 10.40 μmol), and H2O (0.5 mL) were added. The atmosphere was replaced with nitrogen three times, and the temperature was raised to 100°C for 16 hours. The reaction mixture was concentrated to give the title compound (49 mg), MS (ESI, m / z): 742.1 [M+H] + .

[0908] Step 5: Preparation of N-(2,4-dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)-7-(5-(methylamino)-1H-pyrazol-3-yl)pyrido[4,3-d]pyrimidin-4-amine

[0909] Tert-butyl 5-((tert-butoxycarbonyl)(methyl)amino)-3-(4-((2,4-dimethoxybenzyl)amino)-5-(3-methoxy-2,6-dimethylphenoxy)pyrido[4,3-d]pyrimidin-7-yl)-1H-pyrazole-1-carboxylate (50 mg, 67.40 μmol) was dissolved in 4 M HCl in 1,4-dioxane (2 mL). The mixture was reacted at 25°C for 30 min. The pH was adjusted to alkaline with saturated sodium bicarbonate solution, and the mixture was extracted three times with DCM. The organic phase was dried over anhydrous sodium sulfate and concentrated. The organic phase was purified by column chromatography (MeOH / DCM = 5 / 95) to obtain the title compound (32 mg). MS (ESI, m / z): 542.2 [M+H]. + .

[0910] Step 6: Preparation of 5-(3-methoxy-2,6-dimethylphenoxy)-7-(5-(methylamino)-1H-pyrazol-3-yl)pyrido[4,3-d]pyrimidin-4-amine

[0911] N-(2,4-Dimethoxybenzyl)-5-(3-methoxy-2,6-dimethylphenoxy)-7-(5-(methylamino)-1H-pyrazol-3-yl)pyrido[4,3-d]pyrimidin-4-amine (32 mg, 59.08 μmol) was dissolved in TFA (1 mL), heated to 80°C and stirred for 20 hours. After dilution with water, the mixture was adjusted to alkalinity with saturated aqueous sodium bicarbonate solution and extracted three times with DCM. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to give the title compound (20 mg). MS (ESI, m / z): 392.1 [M+H]. + .

[0912] Step 7: Preparation of 3-((4-amino-7-(5-(methylamino)-1H-pyrazol-3-yl)pyrido[4,3-d]pyrimidin-5-yl)oxy)-2,4-dimethylphenol

[0913] 5-(3-Methoxy-2,6-dimethylphenoxy)-7-(5-(methylamino)-1H-pyrazol-3-yl)pyrido[4,3-d]pyrimidin-4-amine (10 mg, 25.55 μmol) was dissolved in DCM (1 mL) and a 1 M BBr3 solution in dichloromethane (0.5 mL) was added. The mixture was reacted at 25°C for 3 hours. The pH of the reaction solution was adjusted to alkaline with saturated sodium bicarbonate solution, extracted three times with DCM, and concentrated to give the title compound (3 mg). MS (ESI, m / z): 378.2 [M+H] + .

[0914] 1H NMR (400MHz, DMSO-d6) δ12.02(d,J=64.0Hz,1H),9.32(s,1H),8.47(s,1H),8.27(s,1H),7.84(s,1H),7.54(s,1H),6.95( d,J=8.2Hz,1H),6.70(d,J=8.2Hz,1H),5.55(s,1H),5.44-5.02(m,1H),2.61(d,J=5.2Hz,3H),1.97(s,3H),1.90(s,3H).

[0915] Example 46: (R)-8-((5-methyl-1H-indazol-4-yl)oxy)-4-(1-methyl-1H-pyrazol-4-yl)-6-(3-(methylamino)pyrrolidin-1-yl)-2,7-naphthyridin-1-amine (Compound 46)

[0916] Step 1: Preparation of tert-butyl ((3R)-1-(8-((2,4-dimethoxybenzyl)amino)-1-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-5-(1-methyl-1H-pyrazol-4-yl)-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate

[0917] The reaction flask was added with tert-butyl ((3R)-1-(5-bromo-8-((2,4-dimethoxybenzyl)amino)-1-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-)1H-indazol-4-yl)oxy)-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate (30 mg, 37.37 μmol), 1-methyl-4-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (23.33 mg, 112.11 μmol), K2CO3 (15.49 mg, 112.11 μmol), and 1,4-dioxane (5 mL) were added after nitrogen replacement, followed by the addition of Pd(PPh3)4 (4.32 mg, 3.74 μmol). The mixture was reacted at 100°C for 16 hours under nitrogen protection. The solvent was removed by distillation under reduced pressure, and the mixture was purified by column chromatography (DCM:MeOH = 10:1) to dryness to obtain the title compound (30 mg). MS (ESI, m / z): 804.4 [M+H] + .

[0918] Step 2: Preparation of (R)-8-((5-methyl-1H-indazol-4-yl)oxy)-4-(1-methyl-1H-pyrazol-4-yl)-6-(3-(methylamino)pyrrolidin-1-yl)-2,7-naphthyridin-1-amine

[0919] Tert-butyl ((3R)-1-(8-((2,4-dimethoxybenzyl)amino)-1-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-5-(1-methyl-1H-pyrazol-4-yl)-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate (30 mg, 37.37 μmol) was dissolved in DCM (1 mL), TFA (2 ml) was added dropwise, and the mixture was reacted at room temperature for 1.5 hours. The solvent was removed by concentration under reduced pressure, the mixture was dissolved in methanol, the pH was adjusted to 8 with ammonia-methanol solution, and the solvent was removed by distillation under reduced pressure. The title compound (5 mg) was prepared and lyophilized. MS (ESI, m / z): 470.2 [M+H] + .

[0920] 1 H NMR(400MHz,DMSO-d6)δ13.07(br,1H),7.91-7.90(s,1H),7.72(s,1H),7.7 0(s,1H),7.63(d,J=0.8Hz,1H),7.38(dd,J=8.4,1.0Hz,1H),7.31(d,J=8.5 Hz,1H),6.93(br,2H),6.06(s,1H),3.90(s,3H),3.05-2.96(m,3H),2.74-2 .68(m,1H),2.23(s,3H),2.12(s,3H),1.86-1.80(m,1H),1.59-1.53(m,1H).

[0921] The following compounds were prepared by the method and general steps described in Reference Example 46. The other required raw materials can be purchased commercially or synthesized by experienced synthesizers in the field of organic synthesis using conventional reactions from commercially purchased reagents.

[0922] Example 47: (R)-3-((8-amino-5-((5-cyclopropylpyrimidin-2-yl)amino)-3-(3-(methylamino)pyrrolidin-1-yl)-2,7-naphthyridin-1-yl)oxy)-2,4-dimethylphenol (Compound 47)

[0923] Step 1: Preparation of tert-butyl (R)-(1-(5-((5-cyclopropylpyrimidin-2-yl)amino)-8-((2,4-dimethoxybenzyl)amino)-1-(3-methoxy-2,6-dimethylphenoxy)-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate

[0924] To a reaction flask were added tert-butyl (R)-(1-(5-bromo-8-((2,4-dimethoxybenzyl)amino)-1-(3-methoxy-2,6-dimethylphenoxy)-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate (35 mg, 48.43 μmol), 5-cyclopropylpyrimidin-2-amine (8 mg, 58.12 μmol), Pd2(dba)3 (5 mg, 4.84 μmol), XantPhos (6 mg, 9.69 μmol), Cs2CO3 (40 mg, 121.08 μmol), and 1,4-dioxane (1.5 mL). The reaction was carried out at 100°C for 16 hours under nitrogen atmosphere. After completion of the reaction, the reaction solution was diluted with water and extracted with EA (30 ml x 3). 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. The crude product was purified by silica gel column chromatography (mobile phase DCM:MeOH=97:3) to obtain the title compound (30 mg). MS (ESI, m / z): 777.5 [M+H] + .

[0925] Step 2: (R)-N 4 Preparation of 5-cyclopropylpyrimidin-2-yl)-8-(3-methoxy-2,6-dimethylphenoxy)-6-(3-(methylamino)pyrrolidin-1-yl)-2,7-naphthyridine-1,4-diamine

[0926] To the reaction flask, tert-butyl (R)-(1-(5-((5-cyclopropylpyrimidin-2-yl)amino)-8-((2,4-dimethoxybenzyl)amino)-1-(3-methoxy-2,6-dimethylphenoxy)-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate (30 mg, 38.61 μmol) and TFA (3 mL) were added. The mixture was reacted at 80°C for 2 hours under nitrogen protection. After completion of the reaction, the reaction solution was directly concentrated under reduced pressure to obtain the title compound. MS (ESI, m / z): 527.3 [M+H] + .

[0927] Step 3: Preparation of (R)-3-((8-amino-5-((5-cyclopropylpyrimidin-2-yl)amino)-3-(3-(methylamino)pyrrolidin-1-yl)-2,7-naphthyridin-1-yl)oxy)-2,4-dimethylphenol

[0928] Add (R)-N 4-(5-cyclopropylpyrimidin-2-yl)-8-(3-methoxy-2,6-dimethylphenoxy)-6-(3-(methylamino)pyrrolidin-1-yl)-2,7-naphthyridine-1,4-diamine (40 mg, 75.95 μmol), DCM (2.5 mL), and a 1M BBr3 solution in dichloromethane (1.5 mL) were reacted at 25°C for 1 hour under nitrogen. The reaction mixture was quenched with methanol and the pH was adjusted to a weakly alkaline state by adding ammonia in methanol. A solid precipitated and was filtered. The filter cake was washed with DCM, and the combined filtrates were concentrated under reduced pressure to obtain the crude product. The crude product was purified by Pre-HPLC to obtain the title compound (19.11 mg). MS (ESI, m / z): 513.2 [M+H] + .

[0929] 1 H NMR(400MHz,DMSO-d6)δ9.30(br,1H),8.49(s,1H),8.21(s,1H),8.09(s,2H),7.70( s,1H),6.94-6.86(m,3H),6.66(d,J=8.0Hz,1H),5.83(s,1H),3.28-3.21(m,2H),3.1 7-3.12(m,1H),3.08-3.01(m,2H),2.36(s,3H),2.09-2.02(m,1H),1.98(s,3H),1.91 (s,3H),1.88-1.82(m,1H),1.78-1.72(m,1H),0.88-0.83(m,2H),0.64-0.60(m,2H).

[0930] Example 48: (R)-3-((8-amino-5-(1-methyl-1H-pyrazol-4-yl)-3-(3-(methylamino)pyrrolidin-1-yl)-2,7-naphthyridin-1-yl)oxy)-2,4-dimethylphenol (Compound 48)

[0931] Step 1: Preparation of tert-butyl (R)-(1-(8-((2,4-dimethoxybenzyl)amino)-1-(3-methoxy-2,6-dimethylphenoxy)-5-(1-methyl-1H-pyrazol-4)-yl)-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate

[0932] To the reaction flask were added tert-butyl (R)-(1-(5-bromo-8-((2,4-dimethoxybenzyl)amino)-1-(3-methoxy-2,6-dimethylphenoxy)-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate (50 mg, 69.19 μmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (43 mg, 207.56 μmol), K2CO3 (29 mg, 207.56 μmol), 1,4-dioxane (2 mL) and water (0.5 mL). After nitrogen replacement, Pd(PPh3)4 (8 mg, 6.92 μmol) was added, and the reaction was carried out at 100°C for 16 hr under nitrogen protection. After the reaction was complete, the reaction solution was diluted with water and extracted with EA (30 mL x 3). 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. The crude product was purified by silica gel column chromatography (mobile phase DCM:MeOH = 98:2) to obtain the title compound (45 mg). MS (ESI, m / z): 724.5 [M+H] + .

[0933] Step 2: Preparation of (R)-8-(3-methoxy-2,6-dimethylphenoxy)-4-(1-methyl-1H-pyrazol-4-yl)-6-(3-(methylamino)pyrrolidin-1-yl)-2,7-naphthyridin-1-amine

[0934] To the reaction flask, tert-butyl (R)-(1-(8-((2,4-dimethoxybenzyl)amino)-1-(3-methoxy-2,6-dimethylphenoxy)-5-(1-methyl-1H-pyrazol-4-yl)-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate (45 mg, 62.17 μmol) and TFA (3 mL) were added. The mixture was reacted at 80°C for 3 hours under nitrogen protection. After completion of the reaction, the reaction solution was directly concentrated under reduced pressure to obtain the title compound. MS (ESI, m / z): 474.3 [M+H] + .

[0935] Step 3: Preparation of (R)-3-((8-amino-5-(1-methyl-1H-pyrazol-4-yl)-3-(3-(methylamino)pyrrolidin-1-yl)-2,7-naphthyridin-1-yl)oxy)-2,4-dimethylphenol

[0936] To the reaction flask, (R)-8-(3-methoxy-2,6-dimethylphenoxy)-4-(1-methyl-1H-pyrazol-4-yl)-6-(3-(methylamino)pyrrolidin-1-yl)-2,7-naphthyridin-1-amine (25 mg, 52.79 μmol), DCM (2 mL), and a 1M BBr3 solution in dichloromethane (1 mL) were added. The mixture was stirred at 25°C for 1 hour under nitrogen atmosphere. After completion of the reaction, methanol was added to quench the reaction solution. A methanolic ammonia solution was then added to adjust the pH to a weakly alkaline state. A solid precipitated and was filtered. The filter cake was washed with DCM, and the combined filtrates were concentrated under reduced pressure to obtain the crude product. The crude product was purified by Pre-HPLC to obtain the title compound (7 mg). MS (ESI, m / z): 460.2 [M+H] + .

[0937] 1 H NMR(400MHz,DMSO-d6)δ9.19(br,1H),8.27(s,1H),7.90(s,1H),7.68(s,1 H),7.63(s,1H),6.99-6.89(m,3H),6.66(d,J=8.0Hz,1H),6.06(s,1H),3.9 0(s,3H),3.29-3.23(m,2H),3.21-3.14(m,1H),3.13-3.06(m,1H),3.02-2. 96(m,1H),2.28(s,3H),2.04-1.96(m,4H),1.91(s,3H),1.80-1.72(m,1H).

[0938] Example 50: (R)-4-(1-methyl-1H-imidazol-4-yl)-8-((5-methyl-1H-indazol-4-yl)oxy)-6-(3-(methylamino)pyrrolidin-1-yl)-2,7-naphthyridin-1-amine (Compound 50)

[0939] Step 1: Preparation of tert-butyl ((3R)-1-(8-((2,4-dimethoxybenzyl)amino)-1-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-5-(1-methyl-1H-imidazol-4-yl)-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate

[0940] To a reaction flask, tert-butyl (R)-(1-(5-bromo-8-((2,4-dimethoxybenzyl)amino)-1-(3-methoxy-2,6-dimethylphenoxy)-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate (35 mg, 43.60 μmol), 1-methyl-4-(tributylmethylstannyl)-1H-imidazole (65 mg, 174.40 μmol), LiCl (5 mg, 122.08 μmol), and toluene (2 mL) were added. After nitrogen purging, Pd(PPh3)4 (5 mg, 4.36 μmol) was added. The atmosphere was purged with nitrogen three times and the reaction was continued at 100°C for 16 hr. After completion of the reaction, the reaction solution was diluted with water and extracted with EA (30 mL x 3). 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. The crude product was purified by silica gel column chromatography (mobile phase: DCM:MeOH = 98:2) to obtain the title compound (20 mg). MS (ESI, m / z): 804.5 [M+H] + .

[0941] Step 2: Preparation of (R)-4-(1-methyl-1H-imidazol-4-yl)-8-((5-methyl-1H-indazol-4-yl)oxy)-6-(3-(methylamino)pyrrolidin-1-yl)-2,7-naphthyridin-1-amine

[0942] To the reaction flask, tert-butyl ((3R)-1-(8-((2,4-dimethoxybenzyl)amino)-1-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-5-(1-methyl-1H-imidazol-4-yl)-2,7-naphthyridin-3-yl)pyrrolidin-3-yl)(methyl)carbamate (20 mg, 24.88 μmol) and TFA (2 mL) were added. The mixture was stirred at 25°C for 3 hours ...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable form thereof: in: X is selected from N and CH; Z is selected from N and CR 3 ; R 1 、R 2 and R 3 Each independently selected from hydrogen, halogen, hydroxyl, oxo, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 heterocycloalkyl),-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), -S(O)2NR x R y 、-O(C 6-10 aryl), -O(5-10 membered heteroaryl), C 6-10 Aryl and 5-10 membered heteroaryl; or R 1 With R 2 Together with the atoms it is connected to form C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C6 aryl or 5-6 membered heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated 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 Cycloalkyl and optionally C 1-6 The substituents of the alkyl-substituted 4-6 membered heterocycloalkyl are preferably each optionally substituted by one or more independently selected from deuterium, halogen, -CN, oxo, hydroxy, 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 heterocycloalkyl; Preferably, R 1 、R 2 and R 3 Each independently selected from hydrogen, halogen, hydroxyl, oxo, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-10 membered heterocycloalkyl (preferably 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 heterocycloalkyl),-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), -S(O)2NR x R y 、C 6-10 Aryl and 5-10 membered heteroaryl; or R 1 With R 2 Together with the atoms it is connected to form C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C6 aryl or 5-6 membered heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more 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 heterocycloalkyl; R 4 Selected from hydrogen, halogen, R 5 and NHR 5 ; Preferably, R 4 Selected from hydrogen and NHR 5 ; R 5 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are each optionally substituted by one or more 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 heterocycloalkyl; Preferably, R 5 Selected from hydrogen, C 1-6 Alkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the alkyl, aryl or heteroaryl groups are each optionally substituted by one or more 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 heterocycloalkyl; R 6 、R 7 and R 8 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 alkyl halide; R 9 Selected from OH; R 10 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 haloalkyl; or R 9 With R 10 Co-formed-CR 11 =N-NH-, and R 11 selected from hydrogen and halogen; R x and R y are each independently selected from hydrogen, 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 membered heteroaryl; each of the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more independently selected from deuterium, halogen, hydroxyl, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 alkyl), -NH2, -C(O)NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 3-6 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are preferably each optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 alkyl), -NH2, -C(O)NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 3-6 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are more preferably each optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 alkyl), -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocycloalkyl; Preferably, R x and R y are each independently selected from hydrogen, 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) and -S(O)2(4-6 membered heterocycloalkyl); each of the alkyl, cycloalkyl or heterocycloalkyl groups is optionally substituted by one or more independently selected from deuterium, halogen, hydroxyl, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 alkyl), -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 3-6 Substitution of cycloalkyl and 4-6 membered heterocycloalkyl; The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled substances, metabolites, or prodrugs.

2. The compound according to claim 1 or a pharmaceutically acceptable form thereof, which satisfies one or more of the following conditions: (1) X is selected from CH; or X is selected from N; (2) Z is selected from N; or Z is selected from CR 3 ; (3)R 1 Selected from hydrogen, 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 heterocycloalkyl), -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 membered heteroaryl), C 6-10 Aryl and 5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are each optionally substituted by one or more independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated 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 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are preferably each optionally substituted with one or more substituents independently selected from deuterium, halogen, -CN, oxo, hydroxy, 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 substituents of cycloalkyl and 4-6 membered heterocycloalkyl are substituted, more preferably selected from halogen, C 1-6 Alkyl and C 3-6 Substitution of cycloalkyl groups; Preferably, R 1 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-10 membered heterocycloalkyl (preferably 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)(4-6 membered heterocycloalkyl), -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 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are each optionally substituted by one or more 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 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are preferably selected from halogen, C 1-6 Alkyl and C 3-6 Substitution of cycloalkyl groups; Furthermore, R 1 Selected from hydrogen, 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), -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -N(C 1-6 alkyl)(C6 aryl), -N(C 1-6 alkyl)(4-6 membered heterocycloalkyl), -NH(4-6 membered heterocycloalkyl), -N(C 1-6 Alkyl)(C 3-6 Cycloalkyl), -N(4-6 membered heterocycloalkyl)(C 3-6 Cycloalkyl), -N(5-6 membered heteroaryl)(C 3-6 Cycloalkyl), -N(C 1-6 alkyl) (5-6 membered heteroaryl), -NH (5-6 membered heteroaryl), -C(O) (4-6 membered heterocycloalkyl), -O (C6 aryl), C6 aryl and 5-10 membered heteroaryl; each of the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more independently selected from deuterium, halogen, -CN, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated 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 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are preferably selected from halogen, oxo, hydroxy, C 1-6 Alkyl, -C 1-6 Alkyl-OH, -O(C 1-6 Alkyl), -NR x R y and C 3-6 Substitution of cycloalkyl groups; Preferably, R 1 Selected from hydrogen, 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), -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -N(C 1-6 alkyl)(C6 aryl), -N(C 1-6 alkyl)(4-6 membered heterocycloalkyl), -N(C 1-6 alkyl) (5-6 membered heteroaryl), -O(C6 aryl), C6 aryl and 5-10 membered heteroaryl; each of the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more 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 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are preferably selected from halogen, oxo, hydroxy, C 1-6 Alkyl, -C 1-6 Alkyl-OH, -O(C 1-6 Alkyl), -NR x R y and C 3-6 Substitution of cycloalkyl groups; More preferably, R 1 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-10 membered heterocycloalkyl, -O(C 1-6 alkyl), -O(C 3-6 Cycloalkyl), -O(4-6 membered heterocycloalkyl), -S(C 1-6 alkyl), -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -N(C 1-6 alkyl)(C6 aryl), -N(C 1-6 alkyl) (5-6 membered heteroaryl), C6 aryl and 5-6 membered heteroaryl; each of the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more 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 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are preferably selected from halogen, oxo, hydroxy, C 1-6 Alkyl, -C 1-6 Alkyl-OH, -O(C 1-6 Alkyl), -NR x R y and C 3-6 Substitution of cycloalkyl groups; More preferably, R 1 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-10 membered heterocycloalkyl (preferably 4-6 membered heterocycloalkyl), -O(C 1-6 alkyl), -O(C 3-6 Cycloalkyl), -O(4-6 membered heterocycloalkyl), -S(C 1-6 alkyl), -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl) 2, C6 aryl and 5-6 membered heteroaryl; each of the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more 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 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are preferably selected from halogen, C 1-6 Alkyl and C 3-6 Substitution of cycloalkyl groups; Furthermore, R 1 Selected from hydrogen, -N(C 1-6 alkyl)2 (e.g. dimethylamino), C 6-10 Aryl (e.g. phenyl), C 1-6 Alkyl (e.g. isopropyl), C 3-6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl), (For example )、 (For example )、 (For example )、 (For example )、 Preferably, R 1 Selected from hydrogen, -N(C 1-6 alkyl)2 (e.g. dimethylamino), C 6-10 Aryl (e.g. phenyl), C 1-6 Alkyl (e.g. isopropyl), C 3-6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl), (For example )、 (For example )、 (For example )、 (For example )、 More preferably, R 1 Selected from hydrogen, dimethylamino, phenyl, isopropyl, cyclopropyl, cyclobutyl, (For example )、 (For example )、 (For example )、 More preferably, R 1 Selected from hydrogen, dimethylamino, phenyl, isopropyl, cyclopropyl, cyclobutyl, (For example )、 (For example )、 (For example )、 More preferably, R 1 Selected from hydrogen, dimethylamino, phenyl, isopropyl, cyclopropyl, cyclobutyl, (4)R x and R y are each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, preferably selected from hydrogen, C 1-6 Alkyl and C 3-8 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are each optionally substituted by one or more independently selected from deuterium, halogen, hydroxyl, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 alkyl), -NH2, -C(O)NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 3-6 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are preferably each optionally substituted by one or more independently selected from halogen, hydroxyl, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 alkyl), -NH2, -C(O)NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 3-6 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are more preferably each optionally substituted by one or more independently selected from halogen, hydroxyl, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 alkyl), -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 3-6 Substitution of cycloalkyl groups; (5)R 2 Selected from hydrogen, halogen, hydroxyl, oxo, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 heterocycloalkyl),-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 membered heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more 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 heterocycloalkyl; Preferably, R 2 Selected from hydrogen, halogen, 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 membered heteroaryl; each of the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionally substituted by one or more 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 heterocycloalkyl; More preferably, R 2 Selected from hydrogen, halogen, 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 ; More preferably, R 2 is selected from hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, fluoromethyl, -CH2OCH3 and -OCH3; (6)R 3 Selected from hydrogen, halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 or 5-10 membered heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more independently selected from deuterium, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -O(C 1-6 Alkyl), C 3-6 Cycloalkyl and optionally C 1-6 The substituents of the alkyl-substituted 4-6 membered heterocycloalkyl are preferably each optionally substituted by one or more independently selected from deuterium, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -O(C 1-6 Alkyl), C 3-6 substituted by cycloalkyl and 4-6 membered heterocycloalkyl; further, R 3 Selected from hydrogen, halogen, -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 heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are each optionally substituted by one or more independently selected from deuterium, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -O(C 1-6 Alkyl), C 3-6 The substituents of cycloalkyl and 4-6 membered heterocyclic groups are preferably each optionally substituted by one or more independently selected from deuterium, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -O(C 1-6 Alkyl), C 3-6 Substitution of cycloalkyl groups; Preferably, R 3 Selected from hydrogen, halogen, -CN, -C 3-4 Cycloalkyl, C 1-4 Alkyl, C 1-4 Haloalkyl, -O(C 1-6 alkyl), -O(C 1-6 Haloalkyl), -NH(C 1-6 alkyl), -NH (5-6 membered heteroaryl), 4-6 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl; further, R 3 selected from hydrogen, fluorine, chlorine, -CN, methyl, methoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, difluoromethyl, trifluoromethyl, -NH (5-6 membered heteroaryl) and 5-6 membered heteroaryl, the heteroaryl being optionally substituted by one or more independently selected from deuterium, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -O(C 1-6 Alkyl), C 3-6 The substituents of cycloalkyl, 4-6 membered heterocyclyl are preferably optionally substituted by one or more independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Substitution of cycloalkyl or 4-6 membered heterocyclic group; Preferably, R 3 selected from hydrogen, fluorine, chlorine, -CN, methyl, methoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, difluoromethyl, trifluoromethyl, -NH (5-6 membered heteroaryl) and 5-6 membered heteroaryl, the heteroaryl being optionally substituted by one or more independently selected from deuterium, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -O(C 1-6 Alkyl), C 3-6 The cycloalkyl substituents are preferably optionally substituted with one or more independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Substitution of cycloalkyl groups; More preferably, R 3 selected from hydrogen, fluorine, chlorine, -CN, methyl, methoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, difluoromethyl, trifluoromethyl and -NH (5-6 membered heteroaryl), the heteroaryl being optionally substituted by one or more independently selected from deuterium, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -O(C 1-6 Alkyl), C 3-6 The cycloalkyl substituents are preferably optionally substituted with one or more independently selected from halogen, C 1-6 Alkyl, C 1-6 Substitution of haloalkyl groups; More preferably, R 3 is selected from hydrogen, fluorine, chlorine, -CN, methyl, methoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, difluoromethyl, trifluoromethyl, and -NH(5-6 membered heteroaryl); Furthermore, R 3 Selected from hydrogen, halogen (such as fluorine, chlorine), -CN, C 1-6 Alkyl (such as methyl), (7)R 1 With R 2 Together with the atoms it is connected to form C 3-6 Cycloalkyl, C6 aryl or 5-6 membered heteroaryl, wherein the cycloalkyl, aryl or heteroaryl are each optionally substituted by one or more 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 heterocycloalkyl; (8)R 4 Selected from hydrogen, halogen, R 5 and -NHR 5 , preferably selected from hydrogen and -NHR 5 , more preferably selected from hydrogen, -NH2, -NH(C 1-6 alkyl), -NH(C6 aryl) and -NH(5-6 membered heteroaryl), further preferably selected from hydrogen and -NH(5-6 membered heteroaryl), wherein the alkyl, aryl or heteroaryl are each optionally substituted by one or more 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 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are preferably selected from C 1-6 Substitution of alkyl groups; Furthermore, R 4 Selected from hydrogen, halogen, R 5 and -NHR 5 , preferably selected from hydrogen and -NHR 5 , where R 5 Selected from hydrogen, (9)R 5 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C6 aryl and 5-6 membered heteroaryl, preferably selected from hydrogen, C 1-6 alkyl, C6 aryl and 5-6 membered heteroaryl, preferably selected from hydrogen and 5-6 membered heteroaryl; each of the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more 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 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are preferably selected from C 1-6 Substitution of alkyl groups; (10)R 6 Selected from hydrogen, halogen, C 1-4 Alkyl, C 3-4 Cycloalkyl and C 1-4 preferably, R 6 is selected from the group consisting of hydrogen, fluorine, chlorine and methyl; (11)R 7 Selected from hydrogen, halogen, C 1-4 Alkyl and C 1-4 preferably, R 7 selected from hydrogen and fluorine; (12)R 8 Selected from hydrogen, halogen, C 1-4 Alkyl and C 1-4 preferably, R 8 selected from hydrogen and fluorine; (13)R 9 Selected from OH; R 10 Selected from hydrogen, halogen, C 1-4 Alkyl, C 3-4 Cycloalkyl and C 1-4 preferably, R 10 is selected from hydrogen, methyl, chlorine, fluorine and difluoromethyl; (14)R 9 With R 10 Together they form -CH=N-NH-.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable form thereof, wherein Formula (I) is further Formula (IA), Formula (IB) or Formula (ID):

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable form thereof, wherein Formula (I) is further Formula (I-1) or Formula (I-2), further Formula (IA'), Formula (IA"), Formula (IB'), Formula (IB"), Formula (ID') or Formula (ID"): R 1 、R 3 、R 4 、R 6 、R 7 、R 8 and R 10 The group is as defined in claim 1 or 2.

5. 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, isotopically labeled substances, metabolites, or prodrugs.

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

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

8. Use of the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable form thereof, or the pharmaceutical composition according to claim 6, in the preparation of a medicament, in particular for the preparation of a medicament for the prevention or treatment of a disease or condition associated with PKMYT1 activity; Preferably, the disease or condition associated with PKMYT1 activity is a tumor or cancer; Preferably, the tumor or cancer is a tumor or cancer with high CCNE1 gene expression / CCNE1 gene expansion or a tumor or cancer with an FBXW7 gene inactivation mutation; Preferably, the cancer with high CCNE1 gene expression / CCNE1 gene expansion is uterine cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, liver cancer or endometrial cancer.

9. A method for preparing a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable form thereof, which is selected from the following methods: Method 1, which comprises one or more steps from step (1) to step (10); preferably comprises step (10), optionally further comprises step (9), optionally further comprises step (8), optionally further comprises step (7), optionally further comprises step (6), optionally further comprises step (5), optionally further comprises step (4), optionally further comprises step (3), optionally further comprises step (2), optionally further comprises step (1): in Step (1) reacting compound IA-1 with compound IA-2 to obtain compound IA-3; Step (2) reducing compound IA-3 to obtain compound IA-4; Step (3) subjecting compound IA-4 to an amino protection reaction to obtain compound IA-5; Step (4) subjecting compound IA-5 to a hydrolysis reaction to obtain compound IA-6; Step (5) subjecting compound IA-6 to a deprotection reaction to obtain compound IA-7; Step (6) subjecting compound IA-7 to a ring-closure reaction to obtain compound IA-8; Step (7) subjecting compound IA-8 to a halogenation reaction to obtain compound IA-9; Step (8) subjecting compound IA-9 to a substitution reaction to obtain compound IA-10; Step (9) subjecting compound IA-10 to a substitution or dehalogenation reaction to obtain compound IA-11; Step (10) subjecting compound IA-11 to a deprotection reaction to obtain compound IA; Method 2, which comprises one or more steps from step (1) to step (6); preferably comprises step (6), optionally further comprises step (5), optionally further comprises step (4), optionally further comprises step (3), optionally further comprises step (2), optionally further comprises step (1): in: Step (1) subjecting compound IB-1 to a ring-closure reaction to obtain compound IB-2; Step (2) subjecting compound IB-2 to a substitution reaction with IA-1 to obtain compound IB-3; Step (3) condensing compound IB-3 and IB-4 to obtain compound IB-5; Step (4) subjecting compound IB-5 to a substitution or coupling reaction to obtain compound IB-6; Step (5) subjecting compound IB-6 to a deprotection reaction to obtain compound IB-7; Step (6) subjecting compound IB-7 to a deprotection reaction to obtain compound IB; Method 3, which includes one or more steps from step (1) to step (7): in: Step (1) reacting compound IA1-2 with compound IB1-1 to obtain compound IA1-3; Step (2) reacting compound IA1-3 to obtain compound IA1-4; Step (3) reacting compound IA1-4 to obtain compound IA1-5; Step (4) reacting compound IA1-5 with pinacol diboronate to produce compound IA1-6; Step (5) subjecting compound IA1-6 to a coupling reaction to obtain compound IA1-7; Step (6) subjecting compound IA1-7 to a deprotection reaction to obtain compound IA1; Method 4 comprises the following steps (1): in: Step (1) subjecting compound IA1-5 to a substitution or coupling reaction to obtain compound IA1-7; Method 5, which comprises one or more steps from step (1) to step (3); preferably comprises step (3), optionally further comprises step (2), optionally further comprises step (1): in: Step (1) subjecting compound IB-5 to a deamination protection reaction to obtain compound IB-5-2; Step (2) subjecting compound IB-5-2 to a dehydroxylation reaction to obtain compound IB-5-3; Step (3) subjecting compound IB-5-3 to a substitution or coupling reaction to obtain compound IB; Method 6, comprising one or more steps from step (1) to step (2): in: Step (1) reacting compound IB-5 with pinacol diboronate to produce compound IB-5-4; Step (2) subjecting compound IB-5-4 to a coupling reaction to obtain compound IB-6; Method seven, comprising one or more steps from step (1) to step (4); preferably comprising step (4), optionally further comprising step (3), optionally further comprising step (2), optionally further comprising step (1): in: Step (1) subjecting compound IB1-1 to a substitution reaction with IB-2 to obtain compound IB1-2; Step (2) subjecting compound IB1-2 to a condensation reaction to obtain compound IB1-3; Step (3) subjecting compound IB1-3 to a substitution or coupling reaction to obtain compound IB1-4; Step (4) subjecting compound IB1-4 to a deprotection reaction to obtain compound IB1; Method eight, comprising one or more of the following steps (1) to (2): in: Step (1) reacting IB1-3 with hexamethyltin disulfide to produce IB1-3-1; Step (2) subjecting IB1-3-1 to a substitution or coupling reaction to obtain compound IB1-4; Method nine, comprising one or more of the following steps (1) to (2): in: Step (1) subjecting IB1-3 to a deprotection reaction to generate IB1-3-2; Step (2) subjecting IB1-3-2 to a substitution or coupling reaction to obtain compound IB1; Method 10, comprising one or more steps from step (1) to step (8); preferably comprising step (7), optionally further comprising step (6), optionally further comprising step (5), optionally further comprising step (4), optionally further comprising step (3), optionally further comprising step (2), optionally further comprising step (1): in: Step (1) reacting compound IB2-1 with IB2-2 to form a urea to obtain compound IB2-3; Step (2) subjecting compound IB2-3 to a ring-closure reaction to obtain compound IB2-4; Step (3) subjecting compound IB2-4 to a substitution reaction with IB1-1 to obtain compound IB2-5; Step (4) subjecting compound IB2-5 to a halogenation reaction to obtain compound IB2-6; Step (5) subjecting compound IB2-6 to a substitution reaction with IB2-7 to obtain compound IB2-8; Step (6) subjecting compound IB2-8 to a substitution reaction with IB2-9 to obtain compound IB2-10; Step (7) subjecting compound IB2-10 to a substitution reaction to obtain compound IB2-11; Optionally, if necessary (e.g., R in IB2-11 1a The group is R protected by a protecting group 1 ), the method further comprises step (8) subjecting compound IB2-11 to a deprotection substitution reaction to obtain compound IB2; Method 11, comprising one or more steps from step (1) to step (9); preferably comprising step (9), optionally further comprising step (8), optionally further comprising step (7), optionally further comprising step (6), optionally further comprising step (5), optionally further comprising step (4), optionally further comprising step (3), optionally further comprising step (2), optionally further comprising step (1): in: Step (1) reacting compound ID-1 with DMF-DMA to obtain compound ID-2; Step (2) subjecting compound ID-2 to a ring-closure reaction to obtain compound ID-3; Step (3) subjecting compound ID-3 to a halogenation reaction to obtain compound ID-4; Step (4) reacting compound ID-4 with IA-1 to obtain compound ID-5; Step (5) subjecting compound ID-5 to a substitution reaction to obtain compound ID-6; Step (6) reacting compound ID-6 with IB-4 to obtain compound ID-7; Step (7) subjecting compound ID-7 to a coupling reaction to obtain compound ID-8; Step (8) deaminoprotecting compound ID-8 to obtain compound ID-9; Step (9) dehydroxylation of compound ID-9 to obtain compound ID-10; Method 12, comprising one or more steps from step (1) to step (2): in: Step (1) Compound ID-7 and ID2-3-1 The reaction produces ID-7-1; Step (2) coupling reaction of compound ID-7-1 with ID2-3-3 to obtain compound ID-8; Method 13, which comprises one or more steps from step (1) to step (5); preferably comprises step (5), optionally further comprises step (4), optionally further comprises step (3), optionally further comprises step (2), optionally further comprises step (1): in: Step (1) reacting compound ID-4 with IB1-1 to obtain compound ID2-1; Step (2) subjecting compound ID2-1 to a substitution reaction to obtain compound ID2-2; Step (3) reacting compound ID2-2 with IB-4 to obtain compound ID2-3; Step (4) coupling reaction of compound ID2-3 with ID2-4 or ID2-5 to obtain compound ID2-6; Step (5) deaminoprotecting compound ID2-6 to obtain compound ID2-7; Method 14, comprising one or more steps from step (1) to step (3); preferably comprising step (3), optionally further comprising step (2), optionally further comprising step (1): in: Step (1) reacting compound ID2-3 with ID2-3-1 to obtain compound ID2-3-2; Step (2) coupling reaction of compound ID2-3-2 and ID2-3-3 to obtain compound ID2-6; Step (3) deamino-protecting compound ID2-6 to obtain compound ID2-7; Method 15, comprising the following steps (1): wherein step (1) reacts compound ID2-3 with ID2-4 to produce ID2-6; Method 16, comprising one or more steps from step (1) to step (2); preferably comprising step (2), and optionally further comprising step (1): in: Step (1) reacting compound ID2-1 with IB-4 to obtain compound ID2-1-1; Step (2) subjecting compound ID2-1-1 to a substitution reaction to obtain compound ID2-3; Method 17, which comprises one or more steps from step (1) to step (2); preferably comprises step (2), and optionally further comprises step (1): in: Step (1) subjecting compound ID2-1-1 to a coupling reaction to obtain compound ID2-1-2; Step (2) subjecting compound ID2-1-2 to a coupling reaction to obtain compound ID2-6; Method 18, comprising one or more steps from step (1) to step (2): in: Step (1) reacting compound ID2-1-1 with diboronic acid pinacol ester to produce ID2-1-1-1; Step (2) coupling reaction of compound ID2-1-1-1 with ID2-3-3 to obtain compound ID2-1-2; Method 19, comprising one or more steps from step (1) to step (2): in: Step (1) reacting compound ID2-1-2 with diboronic acid pinacol ester to produce ID2-1-2-1; Step (2) coupling reaction of compound ID2-1-2-1 with ID2-3-3 to obtain compound ID2-6; Method 20, comprising one or more steps of the following steps (1) to (2): in: Step (1) reacting compound ID-5 with IB-4 to produce ID-5-1; Step (2) subjecting compound ID-5-1 to a substitution reaction to generate ID-7; Method 21, comprising one or more of the following steps (1) to (3): in: Step (1) reacting compound ID-5-1 with diboronic acid pinacol ester to produce ID-5-2; Step (2) coupling reaction of compound ID-5-2 with ID2-3-3 to obtain compound ID-5-3; Step (3) subjecting compound ID-5-3 to a coupling reaction to obtain compound ID-8; Method 22, comprising one or more of the following steps (1) to (3): in: Step (1) subjecting compound ID-5-3 to a deamination protection reaction to generate compound ID-5-3-1; Step (2) subjecting compound ID-5-3-1 to a dehydroxylation reaction to generate compound ID-5-3-2; Step (3) Compound ID-5-3-2 and The compound with the structure undergoes coupling reaction to generate compound ID-10; in: R 1a R 1 or R protected by an amino protecting group 1 , preferably R 1 ; R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 As defined in any one of claims 1 to 5; X1 is halogen, such as bromine or chlorine, preferably chlorine; X2 is halogen, such as bromine or chlorine, preferably chlorine; X3 is halogen, such as bromine, iodine or chlorine, preferably bromine; Pg 1 represents a hydroxyl-protecting group, such as 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 or p-nitrobenzoyl, such as methoxymethyl ether (MOM), methyl or benzyl, preferably methyl; Lg 1 represents an amino protecting group, such as an alkoxycarbonyl amino protecting group, such as benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), methyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methyl (or ethyl)oxycarbonyl; an acyl amino protecting group, such as phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), o-(p)nitrobenzenesulfonyl (Ns), pivaloyl, benzoyl, tert-butyloxycarbonyl (Boc), methyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methyl (or ethyl)oxycarbonyl; oxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, trimethylsilylethoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, tert-butyl, trifluoroacetyl, methoxycarbonyl, or ethoxycarbonyl; alkyl amino protecting groups such as trityl (Trt), 2,4-dimethoxybenzyl (Dmb), 4-methoxybenzyl (PMB), benzyl (Bn), specifically 2,4-dimethoxybenzyl, 4-methoxybenzyl or benzyl, preferably 2,4-dimethoxybenzyl; Pg 2 represents an aromatic amino protecting group, such as tetrahydropyranyl (THP).

10. A compound having the following structure or a salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, or isotope-labeled form thereof: in, R 1a 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 10 , X1, X2, X3, Pg 1 、Pg 2 , Lg 1 As defined in claim 9.

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