Heteroaromatic ring compound, pharmaceutical composition as well as preparation method and application of heteroaromatic ring compound

Abstract

The invention relates to a compound containing aromatic heterocycle, a pharmaceutical composition containing the compound, a preparation method and application of the compound. Specifically, the invention relates to a compound with a structure as shown in a formula (I) which can be used for preventing or treating tumors or cancers.

Description

Heteroaromatic ring compound, pharmaceutical composition, preparation method and use thereof

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefits of Chinese Patent Application No. 202310827477.6 filed with the State Intellectual Property Office of China on July 6, 2023 and Chinese Patent Application No. 202410417593.5 filed with the State Intellectual Property Office of China on April 8, 2024, the contents disclosed in which are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention 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 use 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 PKMYT1 Kinases, Molecules, 2017, 22(12): 2045; Wells NJ, et al., The C-terminal domain of the Cdc2 inhibitory kinase Myt1 interacts with Cdc2 complexes and is required for inhibition of G2 / M progression, Journal of Cell Science, 1999, 112(19): 3361-3371).

[0006] In tumor cells, in response to the replication pressure brought about by the need for high proliferation rates, PKMYT1 can be upregulated to ensure that tumor cells repair DNA damage, maintain replication pressure and the genomic stability of tumor cells, and thus play a tumor-promoting role. 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-suppressing effect. David Gallo et al., CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition, Nature, 2022, 604(7907): 749-756, confirmed that CCNE1 can activate the MMB-FOXM1 transcription complex, thereby upregulating CDK1 and CCNB1 gene expression. In CCNE1-overexpressing cells, CyclinB and CDK1 expression are increased, and these cells are more sensitive to PKMYT1 inhibition, leading to synthetic lethality.

[0007] PKMYT1 and FBXW7 are key genes 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.

[0010] Summary of the Invention

[0011] The object of the present invention is to provide a novel class of compounds containing heteroaromatic rings, which have excellent inhibitory activity against PKMYT1, can be used to prevent or treat diseases or conditions associated with PKMYT1 activity, and have good pharmacokinetic properties.

[0012] One aspect of the present invention provides a compound of formula (I) or a pharmaceutically acceptable form thereof:

[0013] in:

[0014] X is selected from N and CR 2 ; Z is selected from N and CH; Y is selected from N and CR 1 ;

[0015] 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 、-OR x 、-SR x 、-CHR 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(O)NH(5-10 membered heteroaryl), -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 and its connected atoms together form C 3-6 Cycloalkyl, partially saturated C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, partially saturated 3-6 membered heterocycloalkyl, C 5-6 Aryl or 5-6 membered heteroaryl; or R 1 With R 3 and its connected atoms together form C 3-6Cycloalkyl, partially saturated C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, partially saturated 3-6 membered heterocycloalkyl, C 5-6 Aryl or 5-6 membered heteroaryl; each of the alkyl, alkylene, 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 Halogenated alkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 Alkyl), -NR x R y 、-C 3-6 Cycloalkyl and optionally substituted by one or more R a The substituent of the substituted 4-6 membered heterocycloalkyl group is substituted;

[0016] R 4 、R 5 and R 6 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-4 Cycloalkyl or C 1-6 alkyl halide;

[0017] R 7 Selected from OH, C 1-6 Alkoxy and -OC(O)(C 1-6 alkyl);

[0018] R 8 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-4 Cycloalkyl or C 1-6 alkyl halide;

[0019] Or, R 4 and R 5 、R 5 and R 6 、R 6 and R 7 、R 7 and R 8 Any group of atoms and their connected atoms together form C 5-6 aryl or 5-6 membered heteroaryl, said aryl or heteroaryl being optionally substituted with one or more Ra;

[0020] 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 3-6Cycloalkyl), -C(O)(4-6 membered heterocycloalkyl), -C(O)O(C 1-6 alkyl), -C(O)O(C3-6 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, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2 and optionally replaced by one or more R a The substituent of the substituted 4-6 membered heterocycloalkyl group is substituted;

[0021] R a Each independently selected from hydrogen, halogen, hydroxy, -NH2, oxo, 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, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2 and 4-6 membered heterocycloalkyl substituents;

[0022] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled substances, metabolites, or prodrugs.

[0023] Another aspect of the present invention provides a pharmaceutical composition comprising a compound of Formula (I)-(IA)-(II)-(IIA)-(IIB)-(IIC)-(IID)-(IIE) or a pharmaceutically acceptable form 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, isotopically labeled, metabolite or prodrug.

[0024] Another aspect of the present invention provides a compound of Formula (I), (IA), (II), (IIA), (IIB), (IIC), (IID), or (IIE), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention, 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, isotopically labeled, metabolite, or prodrug.

[0025] Another aspect of the present invention provides a compound of Formula (I), (IA), (II), (IIA), (IIB), (IIC), (IID), or (IIE) or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention, for 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-labeled, metabolite, or prodrug.

[0026] Another aspect of the present invention 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 (A)-(C), (IA), (II), (IIA), (IIB), (IIC), (IID), or (IIE) or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention, wherein the pharmaceutically acceptable form is selected from a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-dioxide, isotope-labeled, metabolite, or prodrug.

[0027] Another aspect of the present invention provides methods of preparing the compounds of the present invention.

[0028] General Terms and Definitions

[0029] 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 invention.

[0030] 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 unrecited elements or method steps. Those skilled in the art will appreciate that the above terms, such as "comprising," encompass the meaning of "consisting of."

[0031] 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.

[0032] 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 1-5 etc., 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.

[0033] 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 1-6The 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).

[0034] 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.

[0035] 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.

[0036] 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, cyclohexyl, 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 or 10) ring carbon atoms. The term "C 3-8 "Cycloalkyl" refers to a cycloalkyl group having 3 to 8 ring carbon atoms, such as C 3-8 Cycloalkyl, which may be a monocyclic alkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, or a bicyclic alkyl, 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.

[0037] 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, or 9) 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. "Heterocyclyl" or "heterocycloalkyl" can be characterized by the number of ring atoms. For example, 3-12 yuan of heterocyclyl or heterocycloalkyl can contain 3-12 (such as 3,4,5,6,7,8,9,10,11 or 12) ring atoms, particularly containing 3,4,5,6,7,8,9,10 ring atoms.If the valence bond requirement is met, heterocycloalkyl can be connected to other groups (or fragments) by any one carbon atom or heteroatom in the ring.For example, 3-12 yuan, 3-8 yuan, 3-6 yuan, 3-5 yuan of heterocycloalkyl include but are not limited to oxirane, azetidinyl, oxetane, thietanyl, tetrahydrofuranyl, dioxolane, dioxane, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl etc.

[0038] 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, dihydrofuran, etc.

[0039] 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, dioxolanyl, dioxanyl, tetrahydrothiophenyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and the like.

[0040] 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 to 10 carbon atoms, such as phenyl or naphthyl.

[0041] 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 in which the heteroaryl group is optionally further fused to an aryl (e.g., benzene) or heteroaryl ring to form a fused ring system.

[0042] 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 5-10 membered nitrogen-containing heteroaryl, 5-10 membered oxygen-containing heteroaryl, 5-10 membered sulfur-containing heteroaryl, 5-6 membered nitrogen-containing heteroaryl, 5-6 membered oxygen-containing heteroaryl, 5-6 membered sulfur-containing heteroaryl, etc. The "nitrogen-containing heteroaryl", "oxygen-containing heteroaryl" and "sulfur-containing heteroaryl" each optionally contain one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur. Examples 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., as well as 5-10 membered cyclic groups containing these groups.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049]

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

[0050]

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

[0051]

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

[0052]

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

[0053] The term "amino," as used herein alone or in combination with other groups, refers to -NH2.

[0054] The term "oxo," as used herein, alone or in combination with other groups, refers to =0.

[0055] 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.

[0056] The term "substituted" and its other variant forms in this article refer to one or more (such as 1, 2, 3 or 4) atoms or atomic groups (such as hydrogen atoms) on the specified atom being 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.

[0057] 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 1-6 ) 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.

[0058] 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, and coordination bonds. Unless otherwise specified, the chemical bonds in the compounds of the present invention that exist in free form are mostly covalent bonds.

[0059] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention that are substantially non-toxic to living organisms. Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof, such as hexafluorophosphate salts and meglumine salts. For a review of suitable salts, see Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

[0060] The term "pharmaceutically acceptable ester" refers to an ester that is substantially non-toxic to organisms and is hydrolyzed in vivo to form the compound of the present invention or a salt thereof. In addition, the compound of the present invention itself may also be an ester.

[0061] 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.

[0062] 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, chiral axis, chiral plane, etc.), thereby being able to rotate plane-polarized light. Since the compounds of the present invention may have asymmetric centers and other chemical structures that may lead to stereoisomerism, the present invention also includes these stereoisomers and mixtures thereof. Since the compounds of the present invention (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 invention are within the scope of the present invention.

[0063] Solid lines are used in this paper Solid wedge or virtual wedge To depict the covalent chemical bonds of the compounds of the present invention. 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 invention may encompass specific enantiomers, diastereomers, racemates, or mixtures thereof in any proportion.

[0064] 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 invention are within the scope of the present invention.

[0065] The term "polymorph" (or "polymorphic form") refers to a solid crystalline form of a compound or complex. The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of multiple polymorphs in any proportion.

[0066] The term "solvate" refers to a compound of the present invention (or a pharmaceutically acceptable salt thereof) bound to at least one solvent molecule by non-covalent intermolecular forces. The compounds of the present invention 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.

[0067] The term "isotopically labeled" refers to a derivative compound formed by replacing a specific atom in a compound of the present invention with an isotope thereof. Unless otherwise indicated, the compounds of the present invention 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.

[0068] 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).

[0069] The term "metabolite" refers to a derivative compound formed by metabolism of a compound of the invention, such as by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, and the like. For further information on metabolism, see Goodman and Gilman's: The Pharmacological Basis of Therapeutics [M], McGraw-Hill International Editions, 1996. The present invention encompasses all possible metabolites of the compounds of the invention, i.e., substances formed in the body of a subject to administration of a compound of the invention. Metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized experimentally.

[0070] The term "prodrug" refers to a derivative compound that can directly or indirectly provide a compound of the present invention after administration to an individual. Particularly preferred derivative compounds or prodrugs are compounds that can increase 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., the lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of the present invention are within the scope of the present invention, 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 invention also covers 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 compound of the present invention. This can be achieved by conventional protecting groups, such as those described in TW Greene, PGM Wuts, Protective Groups in Organic Synthesis [M], John Wiley & Sons, 2006. These protecting groups may be removed at an appropriate subsequent stage using methods known in the art.

[0071] The present invention also encompasses methods for preparing the compounds described herein. It should be understood that the compounds of the present invention can be synthesized using the methods described below, as well as synthetic methods known in the art 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 that is appropriate for the reagents and materials used and suitable for the transformation to be achieved.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] As used herein, unless otherwise indicated, the terms "treat," ...

[0076] 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.

[0077] 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. "Non-human animals" herein 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.).

[0078] Compound

[0079] In an embodiment of the present invention, the present invention provides a compound of formula (I) or a pharmaceutically acceptable form thereof:

[0080] in:

[0081] X is selected from N and CR 2 ; Z is selected from N and CH; Y is selected from N and CR 1 ;

[0082] 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 、-OR x 、-SR x 、-CHR x R y 、-C(O)NH2、-C(O)(4-6 membered heterocycloalkyl),-C(O)NH(C 1-6 alkyl), -C(O)NH(C 3-6Cycloalkyl), -C(O)NH(4-6 membered heterocycloalkyl), -C(O)NH(5-10 membered heteroaryl), -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 and its connected atoms together form C 3-6 Cycloalkyl, partially saturated C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, partially saturated 3-6 membered heterocycloalkyl, C 5-6 Aryl or 5-6 membered heteroaryl; or R 1 With R 3 and its connected atoms together form C 3-6 Cycloalkyl, partially saturated C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, partially saturated 3-6 membered heterocycloalkyl, C 5-6 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 Hydroxyalkyl, -O(C 1-6 Alkyl), -NR x R y 、C 3-6 Cycloalkyl and optionally substituted by one or more R a The substituent of the substituted 4-6 membered heterocycloalkyl group is substituted;

[0083] R 4 、R 5 and R 6 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-4 Cycloalkyl and C 1-6 alkyl halide;

[0084] R 7 Selected from -OH, C 1-6 Alkoxy and -OC(O)(C 1-6 alkyl);

[0085] R 8 Selected from hydrogen, halogen, C 1-6 Alkyl, C3-4 cycloalkyl or C 1-6 alkyl halide;

[0086] or R 4 and R 5 、R 5 and R6 、R 6 and R 7 、R 7 and R 8 Any group of atoms and their connected atoms together form C 5-6 Aryl or 5-6 membered heteroaryl, said aryl or heteroaryl being optionally substituted by one or more R a replace;

[0087] 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, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2 and optionally replaced by one or more R a The substituent of the substituted 4-6 membered heterocycloalkyl group is substituted;

[0088] R a Each independently selected from hydrogen, halogen, hydroxy, -NH2, oxo, C 1-6 Alkyl, C 3-8 Cycloalkyl, -C(O)(C 1-6 alkyl), -C(O)(C 3-6 Cycloalkyl), -C(O)(4-6 membered heterocycloalkyl), -C(O)O(C 1-6 alkyl), -C(O)O(C 3-6 Cycloalkyl), -C(O)O(4-6 membered heterocycloalkyl), -S(O)2(C 1-6 Alkyl), -S(O)2(C 3-6Cycloalkyl), -S(O)2(4-6 membered heterocycloalkyl), 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 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 and 4-6 membered heterocycloalkyl substituents;

[0089] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled substances, metabolites, or prodrugs.

[0090] In certain embodiments, the present invention provides a compound of formula (I), wherein the compound of formula (I) is a compound as shown in formula (II):

[0091] Among them, X, Z, R 1 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 As defined in formula (I).

[0092] In certain embodiments, the present invention provides compounds of formula (I),

[0093] X is selected from N and CR 2 ; Z is selected from N and CH;

[0094] 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 、-OR x 、-SR x、-CHR 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(O)NH(5-10 membered heteroaryl), -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 and its connected atoms together form C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 5-6 Aryl or 5-6 membered heteroaryl; or R 1 With R 3 and its connected atoms together form C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 5-6 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 Hydroxyalkyl, -O(C 1-6 Alkyl), -NR x R y 、C 3-6 Substitution of cycloalkyl and 4-6 membered heterocycloalkyl substituents;

[0095] R 4 、R 5 and R 6 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-4 Cycloalkyl and C 1-6 alkyl halide;

[0096] R 7 Selected from -OH; R 8 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-4 Cycloalkyl or C 1-6 haloalkyl; or R 7 With R 8 Co-formed-CR 9 =N-NH-, and R 9 selected from hydrogen and halogen;

[0097] R x and Ry 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, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2 and 4-6 membered heterocycloalkyl substituents.

[0098] In certain embodiments, the present invention provides compounds of formula (I),

[0099] X is selected from N and CR 2 ; Z is selected from N and CH;

[0100] 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 1-6Alkyl), -S(O)2NR x R y 、C 6-10 Aryl and 5-10 membered heteroaryl; or R 1 With R 2 and its connected atoms together form C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 5-6 Aryl or 5-6 membered heteroaryl; or R 1 With R 3 and its connected atoms together form C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 5-6 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 Hydroxyalkyl, -O(C 1-6 Alkyl), -NR x R y 、C 3-6 Substitution of cycloalkyl and 4-6 membered heterocycloalkyl substituents;

[0101] R 4 、R 5 and R 6 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-4 Cycloalkyl and C 1-6 alkyl halide;

[0102] R 7 Selected from -OH; R 8 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-4 Cycloalkyl or C 1-6 haloalkyl; or R 7 With R 8 Co-formed-CR 9 =N-NH-, and R 9 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 3-6Cycloalkyl), -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, 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 and 4-6 membered heterocycloalkyl substituents.

[0104] In certain embodiments, the present invention provides compounds of formula (I), wherein X is selected from N.

[0105] In certain embodiments, the present invention provides compounds of formula (I), wherein X is selected from CR 2 .

[0106] In certain embodiments, the present invention provides compounds of formula (I), wherein Y is selected from N.

[0107] In certain embodiments, the present invention provides compounds of formula (I), wherein Y is selected from CR 1 .

[0108] In certain embodiments, the present invention provides compounds of formula (I), wherein Z is selected from N.

[0109] In certain embodiments, the present invention provides compounds of formula (I), wherein Z is selected from CH.

[0110] In certain embodiments, the present invention provides compounds of formula (I), wherein X is selected from CR 2 , Y is selected from CR 1 , Z is selected from N.

[0111] In certain embodiments, the present invention provides compounds of formula (I), wherein X is selected from CR 2 , Y is selected from CR 1 , Z is selected from CH.

[0112] In certain embodiments, the present invention provides compounds of formula (I), wherein X is selected from N, and Y is selected from CR 1 , Z is selected from N.

[0113] In certain embodiments, the present invention provides compounds of formula (I), wherein X is selected from N, and Y is selected from CR 1 , Z is selected from CH.

[0114] In certain embodiments, the present invention provides compounds of formula (I), wherein X is selected from CR 2 , Y is selected from N, and Z is selected from N.

[0115] In certain embodiments, the present invention provides compounds of formula (I), wherein R 1 Selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 alkyl), -O(C 3-6 Cycloalkyl) and -NR x R y 、-CHR x R y and 5-10 membered heteroaryl, wherein each of the alkyl, cycloalkyl, heterocycloalkyl and heteroaryl groups is optionally substituted by one or more independently selected from deuterium, halogen, -CN, oxo, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -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.

[0116] In certain embodiments, the present invention provides compounds of formula (I), wherein R 1 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, -C 1-4 Alkyl-O(C 1-4 Alkyl), C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-4 alkyl), -O(C 3-6 Cycloalkyl), -NR x R y 、-CHR x R y and 5-6 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl or heteroaryl is optionally substituted by one or more C 1-6 Alkyl substitution; R x and R y Each independently selected from H, C 1-6 Alkyl, C 3-8 cycloalkyl and 5-6 membered heteroaryl.

[0117] In certain embodiments, the present invention provides compounds of formula (I), wherein R 1is selected from hydrogen, methyl, ethyl, isopropyl, difluoromethyl, dimethylamino, cyclopropyl, cyclobutyl,

[0118] In certain embodiments, the present invention provides compounds of formula (I), wherein R 1 Selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl,

[0119] In certain embodiments, the present invention provides compounds of formula (I), wherein R 1 Selected from hydrogen, halogen, hydroxyl, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 alkyl), -O(C 3-6 Cycloalkyl) and -NR x R y , wherein the alkyl, cycloalkyl and heterocycloalkyl groups are each optionally substituted by one or more independently selected from deuterium, halogen, -CN, oxo, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -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.

[0120] In certain embodiments, the present invention provides compounds of formula (I), wherein R 1 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 alkyl), -O(C 3-6 Cycloalkyl) and -NR x R y , wherein the alkyl, cycloalkyl and heterocycloalkyl groups are each optionally substituted by one or more independently selected from deuterium, halogen, -CN, oxo, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -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.

[0121] In certain embodiments, the present invention provides compounds of formula (I), wherein R 1 Selected from hydrogen, C1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-4 alkyl), -O(C 3-6 Cycloalkyl) and -NR x R y , R x and R y Each independently selected from C 1-6 Alkyl and C 3-8 Cycloalkyl, said heterocycloalkyl is optionally replaced by one or more C 1-6 Alkyl substitution.

[0122] In certain embodiments, the present invention provides compounds of formula (I), wherein R 1 Selected from hydrogen, methyl, isopropyl, cyclopropyl, cyclobutyl, difluoromethyl, dimethylamino,

[0123] In certain embodiments, the present invention provides compounds of formula (I), wherein R 2 Selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 alkyl), -O(C 3-6 Cycloalkyl) and -NR x R y , wherein the alkyl, cycloalkyl, and heterocycloalkyl groups are each optionally substituted by one or more independently selected from deuterium, halogen, -CN, oxo, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 Alkyl), -NR x R y 、C 3-6 Substituents of cycloalkyl and 4-6 membered heterocycloalkyl; R x and R y are each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl and 4-10 membered heterocycloalkyl, said cycloalkyl or heterocycloalkyl each optionally substituted by one or more independently selected from halogen, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 alkyl) is substituted with a substituent.

[0124] In certain embodiments, the present invention provides compounds of formula (I), wherein R 2 Selected from hydrogen, halogen, C1-4 Alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene O(C 1-4 Alkyl), C 3-6 Cycloalkyl and -O(C 3-6 Cycloalkyl) and -NR x R y , the cycloalkyl group 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 Hydroxyalkyl and -O(C 1-6 alkyl) is substituted with a substituent; R x and R y are each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl and 4-6 membered heterocycloalkyl, said cycloalkyl or heterocycloalkyl being each optionally substituted by one or more independently selected from halogen, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 alkyl) is substituted with a substituent.

[0125] In certain embodiments, the present invention provides compounds of formula (I), wherein R 2 is selected from hydrogen, halogen, methyl, ethyl, isopropyl, cyclopropyl, fluoromethyl, -CH2OCH3, -OCH3, -NH-cyclopropyl and

[0126] In certain embodiments, the present invention provides compounds of formula (I), wherein R 2 Selected from hydrogen or

[0127] In certain embodiments, the present invention provides compounds of formula (I), wherein R 2 Selected from hydrogen.

[0128] In certain embodiments, the present invention provides compounds of formula (I), wherein R 2 Selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 alkyl), -O(C 3-6 Cycloalkyl) and -NR x R y , wherein the alkyl, cycloalkyl, and heterocycloalkyl groups are each optionally substituted by one or more independently selected from deuterium, halogen, -CN, oxo, hydroxy, C 1-6 Alkyl, C 1-6Halogenated alkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 Alkyl), -NR x R y 、C 3-6 Substituents of cycloalkyl and 4-6 membered heterocycloalkyl, R x and R y are each independently selected from hydrogen, C 1-6 Alkyl and C 3-8 Cycloalkyl.

[0129] In certain embodiments, the present invention provides compounds of formula (I), wherein 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 3-6 Cycloalkyl) and -NR x R y , R x and R y are each independently selected from hydrogen, C 1-6 Alkyl and C 3-8 Cycloalkyl.

[0130] In certain embodiments, the present invention provides compounds of formula (I), wherein R 2 is selected from hydrogen, halogen, methyl, isopropyl, cyclopropyl, fluoromethyl, -CH2OCH3, -OCH3 and -NH-cyclopropyl.

[0131] In certain embodiments, the present invention provides compounds of formula (I), wherein R 3 Selected from hydrogen, halogen, -CN, C 3-6 Cycloalkyl, C 1-6 Alkyl, -O(C 1-6 Alkyl), -NR x R y 、-C(O)NH2、-C(O)NH(C 1-6 alkyl), -C(O)NH(5-10 membered heteroaryl), -OR x and 5-10 membered heteroaryl, wherein the alkyl, cycloalkyl 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 Hydroxyalkyl, -O(C 1-6 Alkyl), -NR x R y 、C 3-6 Cycloalkyl and optionally substituted by one or more Ra The substituent of the substituted 4- to 6-membered heterocycloalkyl group is substituted.

[0132] In certain embodiments, the present invention provides compounds of formula (I), wherein R 3 Selected from hydrogen, halogen, -CN, C 3-6 Cycloalkyl, C 1-4 Alkyl, -O(C 1-6 Alkyl), C 1-4 Haloalkyl, -O(C 1-4 Hydroxyalkyl), -OC 1-4 Alkyl-O(C 1-4 alkyl), -O(C 1-4 haloalkyl), -NH(5-6 membered heteroaryl), -NH(C 6-10 Aryl), -NH(C 3-6 Cycloalkyl), -NH (4-7 membered heterocycloalkyl), -NH (C 1-6 Alkyl), -N(C 1-6 Alkyl)2、-C(O)NH2、-C(O)NH(C 1-4 alkyl), -C(O)NH(5-6 membered heteroaryl), -OR x and 5-9 membered heteroaryl; said aryl, 4-7 membered heterocycloalkyl, cycloalkyl or heteroaryl are optionally substituted by one or more independently selected from deuterium, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 Alkyl), -NR x R y 、C 3-6 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are optionally substituted by one or more independently selected from halogen, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 alkyl) is substituted with a substituent; said R x 、R y are each independently selected from hydrogen, C 1-6 Alkyl, C 6-10 Aryl and C 3-8 Cycloalkyl.

[0133] In certain embodiments, the present invention provides compounds of formula (I), wherein R 3 Selected from hydrogen, fluorine, chlorine, -CN, methyl, methoxy, ethoxy, methylamino, cyclopropyl, difluoromethyl, trifluoromethyl,

[0134] In certain embodiments, the present invention provides compounds of formula (I), wherein R 3 Selected from hydrogen, -CN, C 1-4 Alkyl, -O(C 1-6 alkyl), -O(C 1-4 Hydroxyalkyl), -O(C 1-4 Halogenated alkyl), -NH (5-6 membered heteroaryl), -C(O)NH2, -C(O)NH(C 1-4 alkyl), -C(O)NH(5-6 membered heteroaryl), 5-9 membered heteroaryl, -O(C 6-10 aryl), said heteroaryl being optionally substituted by one or more independently selected from deuterium, halogen, CN, C 1-6 Alkyl, -O(C 1-6 Alkyl), -N(C 1-6 alkyl) 2 and 4-6 membered heterocycloalkyl substituents, the 4-6 membered heterocycloalkyl optionally being substituted by one or more independently selected from C 1-6 The alkyl group is substituted with a substituent.

[0135] In certain embodiments, the present invention provides compounds of formula (I), wherein R 3 Selected from hydrogen, -CN, methyl, methoxy, ethoxy,

[0136] In certain embodiments, the present invention provides compounds of formula (I), wherein R 3 Selected from hydrogen, halogen, -CN, C 3-6 Cycloalkyl, C 1-6 Alkyl, -O(C 1-6 Alkyl), -NR x R y 、-C(O)NH2、-C(O)NH(C 1-6 alkyl), -C(O)NH(5-10 membered heteroaryl) and 5-10 membered heteroaryl, wherein each of the alkyl, cycloalkyl or heteroaryl groups is optionally substituted by one or more independently selected from deuterium, halogen, -CN, oxo, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 Alkyl), -NR x R y 、C 3-6 Cycloalkyl and optionally substituted by one or more R a The substituent of the substituted 4- to 6-membered heterocycloalkyl group is substituted.

[0137] In certain embodiments, the present invention provides compounds of formula (I), wherein R 3Selected from hydrogen, halogen, -CN, C 3-6 Cycloalkyl, C 1-4 Alkyl, -O(C 1-6 Alkyl), C 1-4 Haloalkyl, -O(C 1-4 Hydroxyalkyl), -OC 1-4 Alkyl-O(C 1-4 alkyl), -O(C 1-4 haloalkyl), -NH(5-6 membered heteroaryl), -NH(C 6-10 Aryl), -NH(C 3-6 Cycloalkyl), -NH (4-7 membered heterocycloalkyl), -NH (C 1-6 Alkyl), -N(C 1-6 Alkyl)2、-C(O)NH2、-C(O)NH(C 1-4 alkyl), -C(O)NH(5-6 membered heteroaryl) and 5-9 membered heteroaryl; said aryl, 4-7 membered heterocycloalkyl, cycloalkyl or heteroaryl are optionally substituted by one or more independently selected from deuterium, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 Alkyl), -NR x R y 、C 3-6 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are optionally substituted by one or more independently selected from halogen, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 alkyl) is substituted with a substituent; said R x 、R y are each independently selected from hydrogen, C 1-6 Alkyl and C 3-8 Cycloalkyl.

[0138] In certain embodiments, the present invention provides compounds of formula (I), wherein R 3 Selected from hydrogen, fluorine, chlorine, -CN, methyl, methoxy, ethoxy, methylamino, cyclopropyl, difluoromethyl, trifluoromethyl,

[0139] In certain embodiments, the present invention provides compounds of formula (I), wherein R 3 Selected from hydrogen, halogen, -CN, C 3-6 Cycloalkyl, C 1-6 Alkyl and -O(C 1-6alkyl), each of which is optionally substituted by one or more independently selected from deuterium, halogen, -CN, oxo, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -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.

[0140] In certain embodiments, the present invention provides compounds of formula (I), wherein R 3 Selected from hydrogen, halogen, -CN, C 3-6 Cycloalkyl, C 1-4 Alkyl, -O(C 1-6 alkyl) and C 1-4 Halogenated alkyl.

[0141] In certain embodiments, the present invention provides compounds of formula (I), wherein R 3 is selected from hydrogen, fluorine, chlorine, -CN, methyl, methoxy, cyclopropyl, difluoromethyl and trifluoromethyl.

[0142] In certain embodiments, the present invention provides compounds of formula (I), wherein X is selected from CR 2 , Y is selected from CR 1 , R 1 With R 2 and the atoms to which it is attached together form a dihydrofuranyl group.

[0143] In certain embodiments, the present invention provides compounds of formula (I), wherein Y is selected from CR 1 , R 1 With R 3 and the atoms to which it is attached together form a dihydrofuranyl group.

[0144] In certain embodiments, the present invention provides compounds of formula (I), wherein X is selected from CR 2 , Y is selected from CR 1 , R 1 With R 2 and the atoms to which it is attached together form a tetrahydrofuranyl group.

[0145] In certain embodiments, the present invention provides compounds of formula (I), wherein Y is selected from CR 1 , R 1 With R 3 and the atoms to which it is attached together form a tetrahydrofuranyl group.

[0146] In certain embodiments, the present invention provides compounds of formula (I), wherein R 4 Selected from hydrogen, halogen, C1-4 Alkyl and C 1-4 Halogenated alkyl.

[0147] In certain embodiments, the present invention provides compounds of formula (I), wherein R 4 Selected from C 1-4 alkyl.

[0148] In certain embodiments, the present invention provides compounds of formula (I), wherein R 4 is selected from the group consisting of methyl, chloro, fluoro and difluoromethyl.

[0149] In certain embodiments, the present invention provides compounds of formula (I), wherein R 4 Selected from methyl.

[0150] In certain embodiments, the present invention provides compounds of formula (I), wherein R 5 Selected from hydrogen, halogen, C 1-4 Alkyl and C 1-4 Halogenated alkyl.

[0151] In certain embodiments, the present invention provides compounds of formula (I), wherein R 5 is selected from hydrogen and halogen.

[0152] In certain embodiments, the present invention provides compounds of formula (I), wherein R 5 Selected from hydrogen and fluorine.

[0153] In certain embodiments, the present invention provides compounds of formula (I), wherein R 5 Selected from hydrogen.

[0154] In certain embodiments, the present invention provides compounds of formula (I), wherein R 6 Selected from hydrogen, halogen, C 1-4 Alkyl and C 1-4 Halogenated alkyl.

[0155] In certain embodiments, the present invention provides compounds of formula (I), wherein R 6 is selected from hydrogen and halogen.

[0156] In certain embodiments, the present invention provides compounds of formula (I), wherein R 6 Selected from hydrogen, chlorine and fluorine.

[0157] In certain embodiments, the present invention provides compounds of formula (I), wherein R 6 Selected from hydrogen.

[0158] In certain embodiments, the present invention provides compounds of formula (I), wherein R 7 Selected from OH.

[0159] In certain embodiments, the present invention provides compounds of formula (I), wherein R 8 Selected from hydrogen, halogen, C 1-4 Alkyl, C 3-4 Cycloalkyl and C 1-4 Halogenated alkyl.

[0160] In certain embodiments, the present invention provides compounds of formula (I), wherein R 8 Selected from halogen and C 1-4 alkyl.

[0161] In certain embodiments, the present invention provides compounds of formula (I), wherein R 8 is selected from hydrogen, methyl, chlorine, fluorine and difluoromethyl.

[0162] In certain embodiments, the present invention provides compounds of formula (I), wherein R 8 Selected from methyl and chlorine.

[0163] In certain embodiments, the present invention provides compounds of formula (I), wherein R 7 and R 8 and the atoms to which they are attached together form a 5-6 membered heteroaryl group, which is optionally substituted by one or more R a replace.

[0164] In certain embodiments, the present invention provides compounds of formula (I), wherein R 7 and R 8 and its connected atoms together form a 5-membered heteroaryl, which is optionally substituted by one or more R a replace.

[0165] In certain embodiments, the present invention provides compounds of formula (I), wherein R 7 and R 8 and the atoms to which they are attached together form pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl (e.g., 1,3,5-triazinyl), pyrrolyl, pyrazolyl, imidazolyl, furyl, and thienyl, wherein the heteroaryl group is optionally substituted by one or more R a replace.

[0166] In certain embodiments, the present invention provides compounds of formula (I), wherein R 7 and R 8 and the atoms to which they are attached together form pyrrolyl, pyrazolyl, imidazolyl, furyl and thienyl, wherein the heteroaryl is optionally substituted by one or more R a replace.

[0167] In certain embodiments, the present invention provides compounds of formula (I), wherein R 7 With R 8 Co-formed-CR 9=N-NR 10 -、-N=CR 9 -NR 10 -、-NR 10 -CR 9 =CR 11 -、-O-CR 9 =CR 11 -、-S-CR 9 =CR 11 -, and R 9 、R 10 and R 11 Each independently has R a Preferably, R 9 、R 10 and R 11 Each independently selected from hydrogen, halogen, hydroxy, amino, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl); preferably, R 10 For H.

[0168] In certain embodiments, the present invention provides compounds of formula (I), when R7 and R 8 Co-formed-CR 9 =N-NR 10 -When covering from R 7 to R 8 Direction, R 7 With R 8 Jointly formed Two situations, namely Covered Two situations.

[0169] Similarly, R 7 With R 8 Together they form -N=CR 9 -NR 10 -、-NR 10 -CR 9 =CR 11 -、-O-CR 9 =CR 11 -、-S-CR 9 =CR 11 -、-CR 9 =N-NH-, both cases are covered.

[0170] In certain embodiments, the present invention provides compounds of formula (I), wherein R 7 With R 8 Co-formed-CR9 =N-NH-, and R 9 selected from hydrogen and halogen;

[0171] In certain embodiments, the present invention provides compounds of formula (I), wherein R 7 With R 8 Jointly formed And R 9 is selected from hydrogen and halogen.

[0172] In certain embodiments, the present invention provides compounds of formula (I), wherein R 7 With R 8 Together they form -CH=N-NH-.

[0173] In certain embodiments, the present invention provides compounds of formula (I), wherein R 7 With R 8 Jointly formed

[0174] In certain embodiments, the present invention provides compounds of formula (I), Selected from

[0175] In certain embodiments, the present invention provides compounds of formula (I), Selected from

[0176] In certain embodiments, the compound represented by formula (I) is a compound represented by formula (IA):

[0177] Among them, X, Y, Z, R 3 、R 4 、R 5 、R 6 、R 7 and R 8 As defined in formula (I).

[0178] In certain embodiments, the compound represented by formula (I) or formula (II) is a compound represented by the following formula (IIA):

[0179] Among them, X, Z, R 1 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 As defined in formula (I).

[0180] In certain embodiments, the compound represented by formula (I) or formula (II) is a compound represented by the following formula (IIB):

[0181] Among them, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 As defined in formula (I).

[0182] In certain embodiments, the compound represented by formula (I) or formula (II) is a compound represented by the following formula (IIC):

[0183] Among them, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 As defined in formula (I).

[0184] In certain embodiments, the compound represented by formula (I) or formula (II) is a compound represented by the following formula (IID):

[0185] Among them, R 1 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 As defined in formula (I).

[0186] In certain embodiments, the compound represented by formula (I) or formula (II) is a compound represented by the following formula (IIE):

[0187] Among them, R 1 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 As defined in formula (I).

[0188] In certain embodiments, the present invention provides compounds of formula (I), formula (IA), formula (II), formula (IIA), formula (IIB), formula (IIC), formula (IID), or formula (IIE), wherein R1 If present, R 1 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, -C 1-4 Alkyl-O(C 1-4 Alkyl), C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-4 alkyl), -O(C 3-6 Cycloalkyl), -NR x R y 、-CHR x R y and 5-6 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl or heteroaryl is optionally substituted by one or more C 1-6 Alkyl substitution; R x and R y Each independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl and 5-6 membered heteroaryl;

[0189] R 2 If present, 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 and -O(C 3-6 Cycloalkyl) and -NR x R y , the cycloalkyl group 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 Hydroxyalkyl and -O(C 1-6 alkyl) is substituted with a substituent; R x and R y are each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl and 4-6 membered heterocycloalkyl, said cycloalkyl or heterocycloalkyl being each optionally substituted by one or more independently selected from halogen, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 alkyl) is substituted with a substituent;

[0190] R 3 Selected from hydrogen, halogen, -CN, C 3-6 Cycloalkyl, C 1-4Alkyl, -O(C 1-6 Alkyl), C 1-4 Haloalkyl, -O(C 1-4 Hydroxyalkyl), -OC 1-4 Alkyl-O(C 1-4 alkyl), -O(C 1-4 haloalkyl), -NH(5-6 membered heteroaryl), -NH(C 6-10 Aryl), -NH(C 3-6 Cycloalkyl), -NH (4-7 membered heterocycloalkyl), -NH (C 1-6 Alkyl), -N(C 1-6 Alkyl)2、-C(O)NH2、-C(O)NH(C 1-4 alkyl), -C(O)NH(5-6 membered heteroaryl), -OR x and 5-9 membered heteroaryl; said aryl, 4-7 membered heterocycloalkyl, cycloalkyl or heteroaryl are optionally substituted by one or more independently selected from deuterium, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 Alkyl), -NR x R y 、C 3-6 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are optionally substituted by one or more independently selected from halogen, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 alkyl) is substituted with a substituent; said R x 、R y are each independently selected from hydrogen, C 1-6 Alkyl, C 6-10 Aryl and C 3-8 Cycloalkyl;

[0191] R 4 Selected from C 1-4 alkyl;

[0192] R 5 is selected from hydrogen and halogen;

[0193] R 6 is selected from hydrogen and halogen;

[0194] R 7 Selected from OH;

[0195] R 8 Selected from halogen, C 1-4 alkyl;

[0196] or R7 and R 8 and the atoms to which they are connected together form a 5-6 membered heteroaryl group.

[0197] In certain embodiments, the present invention provides compounds of Formula (I), Formula (IA), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), or Formula (IIE), wherein R 1 If present, R 1 is selected from hydrogen, methyl, ethyl, isopropyl, difluoromethyl, dimethylamino, cyclopropyl, cyclobutyl, R 2 If present, R 2 is selected from hydrogen, halogen, methyl, ethyl, isopropyl, cyclopropyl, fluoromethyl, -CH2OCH3, -OCH3, -NH-cyclopropyl and

[0198] R 3 Selected from hydrogen, fluorine, chlorine, -CN, methyl, methoxy, ethoxy, methylamino, cyclopropyl, difluoromethyl, trifluoromethyl,

[0199] Selected from

[0200] In certain embodiments, the present invention provides compounds of Formula (I), Formula (IA), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), or Formula (IIE), wherein R 1 If present, R 1 Selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl,

[0201] R 2 If present, R 2 Selected from hydrogen or

[0202] R 3 Selected from hydrogen, -CN, methyl, methoxy, ethoxy,

[0203] Selected from

[0204] The present invention covers any combination of the above embodiments.

[0205] In some embodiments, the present invention provides the following compounds or pharmaceutically acceptable forms thereof, including but not limited to:

[0206] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled substances, metabolites, or prodrugs.

[0207] Preparation method

[0208] The compounds of the present invention 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, 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).

[0209] The present invention provides a method for preparing a compound represented by formula (I). In certain embodiments, the method comprises the following steps:

[0210] Step 1: Compound S-1 reacts with compound S-1-1 to produce compound S-2;

[0211] Step 2: Compound S-2 and compound S-2-1 undergo a ring-closure reaction to generate compound S-3;

[0212] Step 3: deprotection and hydrolysis of compound S-3 to generate compound of formula I;

[0213] in

[0214] X 1 is halogen (such as iodine, bromine or chlorine) or C optionally substituted by halogen 1-6 Alkyl sulfonate (such as trifluoromethanesulfonate), preferably halogen;

[0215] X, Y, Z, R3 、R 4 、R 5 、R 6 、R 7 and R 8 The groups are as defined above.

[0216] In some embodiments of the present invention, the first step reaction is carried out in the presence of a condensing agent, which can be selected from HATU, HBTU, EDCI, T3P, T4P, DCC or DIC, etc., preferably HATU. In some embodiments of the present invention, the first step reaction is carried out in the presence of a suitable base, which can be selected from DIPEA, TEA, DMAP, NMM, DBU, etc., and any combination thereof, preferably DIPEA. In some embodiments of the present invention, the first step reaction is carried out in a suitable solvent, which can be selected from DCM, 1,4-dioxane, THF, DCE or DMF, etc., preferably DMF. In some embodiments of the present invention, the first step reaction is carried out at a suitable temperature, for example, a reaction temperature of 0-100°C.

[0217] In some embodiments of the present invention, the second step reaction is carried out in the presence of a metal catalyst and a base. The catalyst can be selected from Xphos-Pd-G3, Pd(OAc)2, Pd2(dba)3, Pd(dba)2, PdCl2, Pd(PPh3)4, Pd(dppf)Cl2 or Pd(acac)2, etc., preferably Pd(dppf)Cl2; the base can be selected from t BuOK, t BuONa, LiHMDS, NaH, LiHMDS, K3PO4, KOAc, Cs2CO3, K2CO3, or Na2CO3, etc., preferably NaH. In some embodiments of the present invention, the second step reaction is carried out in a solvent, which can be selected from toluene, DME, 1,4-dioxane, THF, DCE, or DMF, etc., preferably DME. In some embodiments of the present invention, the second step reaction is carried out at a suitable temperature, for example, a reaction temperature of 20-120°C.

[0218] In some embodiments of the present invention, the second step reaction is carried out in the presence of a metal catalyst and a base, preferably in the presence of CuI and the inorganic base K2CO3. In some embodiments of the present invention, the second step reaction is carried out in a solvent, preferably DME, 1,4-dioxane, THF, DMSO, or DMF. In some embodiments of the present invention, the second step reaction is carried out at a suitable temperature, for example, a reaction temperature of 20-120°C.

[0219] In some embodiments of the present invention, the deprotection and hydrolysis reactions in the third step are carried out in the presence of an acid. The acid can be selected from concentrated hydrochloric acid, concentrated sulfuric acid, concentrated nitric acid, and the like, preferably concentrated sulfuric acid. In some embodiments of the present invention, the deprotection and hydrolysis reactions in the third step are carried out at a suitable temperature, preferably 20-80°C.

[0220] The present invention provides a method for preparing a compound represented by formula (II). In certain embodiments, the method comprises the following steps:

[0221] Step 1: Compound S-1 reacts with compound S-1-1 to produce compound S-2;

[0222] Step 2: Compound S-2 and compound S-2-1 undergo a ring-closure reaction to generate compound S-3;

[0223] Step 3: deprotection and hydrolysis of compound S-3 to generate compound II;

[0224] in

[0225] X 1 is halogen (such as iodine, bromine or chlorine) or C optionally substituted by halogen 1-6 Alkyl sulfonate (such as trifluoromethanesulfonate), preferably halogen;

[0226] X, Z, R 1 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 The groups are as defined above.

[0227] In some embodiments of the present invention, the first step reaction is carried out in the presence of a condensing agent, which can be selected from HATU, HBTU, EDCI, T3P, T4P, DCC or DIC, etc., preferably HATU. In some embodiments of the present invention, the first step reaction is carried out in the presence of a suitable base, which can be selected from DIPEA, TEA, DMAP, NMM, DBU, etc., and any combination thereof, preferably DIPEA. In some embodiments of the present invention, the first step reaction is carried out in a suitable solvent, which can be selected from DCM, 1,4-dioxane, THF, DCE or DMF, etc., preferably DMF. In some embodiments of the present invention, the first step reaction is carried out at a suitable temperature, for example, a reaction temperature of 0-100°C.

[0228] In some embodiments of the present invention, the second step reaction is carried out in the presence of a metal catalyst and a base. The catalyst can be selected from Xphos-Pd-G3, Pd(OAc)2, Pd2(dba)3, Pd(dba)2, PdCl2, Pd(PPh3)4, Pd(dppf)Cl2 or Pd(acac)2, etc., preferably Pd(dppf)Cl2; the base can be selected from t BuOK, t BuONa, LiHMDS, NaH, LiHMDS, K3PO4, KOAc, Cs2CO3, K2CO3, or Na2CO3, etc., preferably NaH. In some embodiments of the present invention, the second step reaction is carried out in a solvent, which can be selected from toluene, DME, 1,4-dioxane, THF, DCE, or DMF, etc., preferably DME. In some embodiments of the present invention, the second step reaction is carried out at a suitable temperature, for example, a reaction temperature of 20-120°C.

[0229] In some embodiments of the present invention, the second step reaction is carried out in the presence of a metal catalyst and a base, preferably in the presence of CuI and the inorganic base K2CO3. In some embodiments of the present invention, the second step reaction is carried out in a solvent, preferably DME, 1,4-dioxane, THF, DMSO, or DMF. In some embodiments of the present invention, the second step reaction is carried out at a suitable temperature, for example, a reaction temperature of 20-120°C.

[0230] In some embodiments of the present invention, the deprotection and hydrolysis reactions in the third step are carried out in the presence of an acid. The acid can be selected from concentrated hydrochloric acid, concentrated sulfuric acid, concentrated nitric acid, and the like, preferably concentrated sulfuric acid. In some embodiments of the present invention, the deprotection and hydrolysis reactions in the third step are carried out at a suitable temperature, preferably 20-80°C.

[0231] In some embodiments of the present invention, the condensing agent used in the first step reaction is HATU, HBTU, EDCI, T3P, T4P, DCC or DIC, etc., preferably HATU; the base that can be used is DIPEA, TEA, DMAP, NMM, DBU, etc. and any combination thereof, preferably DIPEA; the solvent that can be used is DCM, 1,4-dioxane, THF, DCE or DMF, etc., preferably DMF; the reaction temperature is 0-100°C.

[0232] In some embodiments of the present invention, the second step reaction is carried out in the presence of a metal catalyst and a base. The catalyst used is Xphos-Pd-G3, Pd(OAc)2, Pd2(dba)3, Pd(dba)2, PdCl2, Pd(PPh3)4, Pd(dppf)Cl2 or Pd(acac)2, preferably Pd(dppf)Cl2; the base that can be used is t BuOK, t BuONa, LiHMDS, NaH, LiHMDS, K3PO4, KOAc, Cs2CO3, K2CO3 or Na2CO3, etc., preferably NaH; the solvent is toluene, DME, 1,4-dioxane, THF, DCE or DMF, etc., preferably DME; the reaction temperature is 20-120°C.

[0233] In some embodiments of the present invention, the deprotection and hydrolysis reaction in the third step is carried out in the presence of an acid such as concentrated hydrochloric acid, concentrated sulfuric acid, concentrated nitric acid, etc., preferably concentrated sulfuric acid; and the reaction temperature is 20-80°C.

[0234] In some embodiments of the present invention, the present invention further provides that when R 7 When it is -OH, R 2 、R 3 A method (1) for preparing a compound of formula (IIB) when is H, comprising step (5), optionally further comprising step (4), optionally further comprising step (3), optionally further comprising step (2), optionally further comprising step (1):

[0235] in

[0236] R 1 、R 4 、R 5 、R 6 、R 7 、R 8 As defined above;

[0237] R m =CN or R m =

[0238] X 1 is halogen, such as bromine or chlorine, preferably chlorine;

[0239] X 2 is halogen, such as bromine or iodine, preferably bromine;

[0240] Pg 1represents a hydroxyl protecting group; preferably, the hydroxyl protecting group is, for example, 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; preferably, the hydroxyl protecting group is methoxymethyl ether (MOM), methyl or benzyl; more preferably, the hydroxyl protecting group is methyl and methoxymethyl ether (MOM);

[0241] L1 is a leaving group of the coupling reaction; preferably, the leaving group can be selected from wait;

[0242] in

[0243] Step (1) reacting compound IIB1-1 with IIB1-2 to obtain compound IIB1-3;

[0244] Step (2) subjecting compound IIB1-3 to a ring-closure reaction with IIB1-4-A or IIB1-4-B to obtain compound IIB1-5;

[0245] Step (3) subjecting compound IIB1-5 to a coupling reaction to obtain compound IIB1-6;

[0246] Step (4) subjecting compound IIB1-6 to hydrolysis or aminolysis to obtain compound IIB1-7;

[0247] Step (5) Compound IIB1-7 is subjected to a hydroxyl group deprotection reaction to obtain compound IIB1-8.

[0248] The addition reaction in step (1) is preferably carried out in the presence of a suitable organic base. The organic base can be selected from DIPEA, TEA, and N,N-dimethylaniline. The addition reaction in step (1) is preferably carried out in a suitable organic solvent. The organic solvent can be selected from DMF, 1,4-dioxane, THF, DCM, or NMP. The addition reaction in step (1) is preferably carried out at a suitable temperature. The reaction temperature is 0-100°C.

[0249] The reaction conditions of step (2) are the same as those described above for the ring-closure reaction of compound S-2 with compound S-2-1 to produce compound S-3.

[0250] The coupling reaction of step (3) is preferably a Suzuki and Stille coupling reaction. The coupling reaction of step (3) is preferably carried out in the presence of a catalyst. The catalyst can be selected from Pd(OAc)2, Pd(dppf)Cl2, Pd(PPh3)4, etc. The coupling reaction of step (3) is preferably carried out in the presence of a ligand. The ligand can be selected from PPh3, XPhos, SPhos, RuPhos, Dppf or PCy3, etc. The coupling reaction of step (3) is preferably carried out in the presence of a base. The base can be selected from t-BuOK, t-BuONa, K3PO4, KOAc, Cs2CO3, K2CO3 or Na2CO3, etc. The coupling reaction of step (3) is preferably carried out in a solvent. The solvent can be selected from DMF, 1,4-dioxane, THF, DCE or DMA, etc. The coupling reaction of step (3) is carried out at a suitable temperature. The reaction temperature is preferably 60-150°C. The coupling reaction of step (3) is carried out for a suitable time. The reaction time is preferably 2-24 hours. In some embodiments of the present invention, the Suzuki coupling reaction uses a catalyst, a ligand and a base and any combination thereof. In some embodiments of the present invention, the Stille coupling reaction uses only a catalyst without using a ligand and a base.

[0251] In some embodiments of the present invention, R m =CN, the cyano group in step (4) undergoes hydrolysis reaction. In some embodiments of the present invention, the hydrolysis reaction conditions are as described above for the deprotection and hydrolysis of compound S-3 to produce the compound of formula I. In some embodiments of the present invention, the hydrolysis reaction can be carried out in the presence of hydrogen peroxide and a base. The base can be selected from KOH, NaOH, K2CO3, etc. In some embodiments of the present invention, the hydrolysis reaction is carried out in a suitable solvent. The solvent can be selected from DMF, DMSO, THF or DMA, etc. In some embodiments of the present invention, the hydrolysis reaction is carried out at a suitable temperature. The reaction temperature is preferably 0-100°C. In some embodiments of the present invention, the hydrolysis reaction is carried out for a suitable time. The reaction time is preferably 2-24 hours.

[0252] In some embodiments of the present invention, R m = In step (4), an ammonolysis reaction occurs. In some embodiments of the present invention, the ammonia source for the ammonolysis reaction may be selected from aqueous ammonia and methanolic ammonia solution. In some embodiments of the present invention, the ammonolysis reaction is carried out in a suitable solvent. The solvent may be selected from MeOH, EtOH, tert-butanol, and the like. In some embodiments of the present invention, the ammonolysis reaction is carried out at a suitable temperature. The reaction temperature is preferably 60-150° C. In some embodiments of the present invention, the ammonolysis reaction is carried out for a suitable time. The reaction time is preferably 12-72 hours.

[0253] In some embodiments of the present invention, when Pg 1 = methoxymethyl ether (MOM), a deprotection reaction occurs in step (5). In some embodiments of the present invention, the deprotection reaction can be carried out in the presence of an acid. The acid can be selected from TFA, 1,4-dioxane hydrochloric acid solution, sulfuric acid, etc. In some embodiments of the present invention, the deprotection reaction is carried out in a suitable solvent. The solvent can be selected from 1,4-dioxane, MeOH, THF, etc. In some embodiments of the present invention, the deprotection reaction is carried out at a suitable temperature. The reaction temperature is preferably 0-100°C.

[0254] In some embodiments of the present invention, pg 1 = methyl, the above step (5) undergoes a deprotection reaction. In some embodiments of the present invention, the above deprotection reaction is carried out in the presence of a deprotection reagent. The deprotection reagent can be selected from BCl3, BBr3, etc. In some embodiments of the present invention, the above deprotection reaction is carried out in a suitable solvent. The solvent can be selected from 1,4-dioxane, DCM, THF, etc. In some embodiments of the present invention, the above deprotection reaction is carried out at a suitable temperature. The reaction temperature is preferably 0-100°C.

[0255] In some embodiments of the present invention, the present invention further provides that when R 7 When it is -OH, R 2 、R 3 H, R 1 -NR x R y A method (2) for preparing a compound of formula (IIB) comprising step (5), optionally further comprising step (4), optionally further comprising step (3), optionally further comprising step (2), optionally further comprising step (1):

[0256] in

[0257] R x 、R y 、R 4 、R5 、R 6 、R 7 、R 8 、Pg 1 、X 2 、R m As defined above;

[0258] in

[0259] Step (1) Boc protection is performed on compound IIB1-5 to obtain compound IIB2-1;

[0260] Step (2) subjecting compound IIB2-1 and IIB2-2 to a Buchwald coupling reaction to obtain compound IIB2-3;

[0261] Step (3) subjecting compound IIB2-3 to amino deprotection reaction to obtain compound IIB2-4;

[0262] Step (4) subjecting compound IIB2-4 to hydrolysis or aminolysis to obtain compound IIB2-5;

[0263] Step (5) Compound IIB2-5 is subjected to a hydroxyl group deprotection reaction to obtain compound IIB2-6.

[0264] In some embodiments of the present invention, the Boc protection reaction in step (1) is preferably carried out in the presence of DMAP in a suitable base and solvent. The organic base includes organic bases and inorganic bases. The organic base can be selected from DIPEA, TEA, N,N-dimethylaniline, DBU, etc. The solvent can be selected from DMF, 1,4-dioxane, THF, DCM, etc. In some embodiments of the present invention, the Boc protection reaction is preferably carried out at a suitable temperature. The reaction temperature is preferably 0-120°C.

[0265] In some embodiments of the present invention, the Buchwald coupling reaction of step (2) is carried out in the presence of a catalyst. The catalyst may be selected from Pd(OAc)2, Pd2(dba)3, t-BuXPhos-Pd-G3, etc. In some embodiments of the present invention, the Buchwald coupling reaction of step (2) is carried out in the presence of a ligand. The ligand may be selected from PPh3, XPhos, XantPhos, SPhos, RuPhos, Dppf, BINAP or PCy3, etc. In some embodiments of the present invention, the Buchwald coupling reaction of step (2) is carried out in the presence of a base. The base may be selected from t-BuOK, t-BuONa, LiHMDS, NaHMDS, KHMDS, K3PO4, KOAc, Cs2CO3, K2CO3 or Na2CO3, etc. In some embodiments of the present invention, the Buchwald coupling reaction of step (2) is carried out in a suitable solvent. The solvent may be selected from DMF, 1,4-dioxane, NMP, DCE, or DMA. In some embodiments of the present invention, the Buchwald coupling reaction in step (2) is carried out at a suitable temperature. The reaction temperature is preferably 60-150° C. In some embodiments of the present invention, the Buchwald coupling reaction in step (2) is carried out for a suitable time. The reaction time is preferably 2-24 hours.

[0266] In some embodiments of the present invention, the deprotection reaction in step (3) above can be carried out in the presence of an acid. The acid can be selected from TFA, 1,4-dioxane hydrochloric acid solution, sulfuric acid, etc. In some embodiments of the present invention, the deprotection reaction in step (3) above is carried out in a solvent. The solvent can be selected from 1,4-dioxane, MeOH, THF, etc. In some embodiments of the present invention, the deprotection reaction in step (3) above is carried out at a suitable reaction temperature. The reaction temperature is preferably 0-100°C.

[0267] In some embodiments of the present invention, the reaction conditions of step (4) are the same as those described above for the hydrolysis or aminolysis reaction of compound IIB1-6 to obtain compound IIB1-7.

[0268] In some embodiments of the present invention, the reaction conditions of step (5) are the same as those described above for the hydroxyl deprotection reaction of compound IIB1-7 to obtain compound IIB1-8.

[0269] In some embodiments of the present invention, the present invention further provides that when R 7 When it is -OH, R 2 、R 3 H, R 1 -NR xR y A method (3) for preparing a compound of formula (IIB) comprising step (4), optionally further comprising step (3), optionally further comprising step (2), optionally further comprising step (1):

[0270] in

[0271] R 1 、R 4 、R 5 、R 6 、R 7 、R 8 、Pg 1 、X 2 、R m As defined above;

[0272] in

[0273] Step (1) subjecting compound IIB1-5 to a coupling reaction to obtain compound IIB3-1;

[0274] Step (2) coupling reaction of compound IIB3-1 with IIB3-2-A or IIB3-2-B to obtain compound IIB3-3;

[0275] Step (3) subjecting compound IIB3-3 to hydrolysis or aminolysis to obtain compound IIB3-4;

[0276] Step (4) Compound IIB3-4 is subjected to a hydroxyl group deprotection reaction to obtain compound IIB3-5.

[0277] In some embodiments of the present invention, the coupling reaction of step (1) is carried out in the presence of a catalyst; the catalyst may be selected from Pd(OAc)2, Pd(dppf)Cl2, etc.; in some embodiments of the present invention, the coupling reaction of step (1) is carried out in the presence of a ligand; the ligand may be selected from PPh3, XPhos, SPhos, RuPhos, Dppf or PCy3, etc.; in some embodiments of the present invention, the coupling reaction of step (1) is carried out in the presence of a base; the base may be selected from K3PO4, KOAc, Cs2CO3, K2CO3 or Na2CO3, etc.; in some embodiments of the present invention, the coupling reaction of the above step (1) is carried out in a suitable solvent; the solvent can be selected from DMF, 1,4-dioxane, THF, DCE or DMA, etc.; in some embodiments of the present invention, the coupling reaction of the above step (1) is carried out at a suitable reaction temperature; the reaction temperature is preferably 60-150°C; in some embodiments of the present invention, the coupling reaction of the above step (1) is carried out for a suitable time; the reaction time is preferably 2-24 hours.

[0278] In some embodiments of the present invention, the Suzuki coupling reaction of IIB3-1 and IIB3-2-A in step (2) above is carried out under the conditions described above for the Suzuki coupling reaction.

[0279] In some embodiments of the present invention, the coupling reaction of IIB3-1 and IIB3-2-B in step (2) is preferably carried out in the presence of a base; the base is preferably K2CO3 or Cs2CO3; in some embodiments of the present invention, the coupling reaction of IIB3-1 and IIB3-2-B in step (2) is carried out in a suitable solvent; the solvent is preferably 1,4-dioxane; in some embodiments of the present invention, the coupling reaction of IIB3-1 and IIB3-2-B in step (2) is carried out at a suitable reaction temperature; the reaction temperature is preferably 60-150°C.

[0280] In some embodiments of the present invention, the reaction conditions of step (3) are the same as those described above for the hydrolysis or aminolysis reaction of compound IIB1-6 to obtain compound IIB1-7.

[0281] In some embodiments of the present invention, the reaction conditions of step (4) are the same as those described above for the hydroxyl deprotection reaction of compound IIB1-7 to obtain compound IIB1-8.

[0282] In some embodiments of the present invention, the present invention further provides that when R 7 When it is -OH, R 2 H, R 3 A method (1) for preparing a compound of formula (IIB) when is not H, comprising step (5), optionally further comprising step (4), optionally further comprising step (3), optionally further comprising step (2), optionally further comprising step (1):

[0283] in

[0284] R 1 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、Pg 1 、X 1 As defined above;

[0285] L2 is a reactive group, for example wait;

[0286] in

[0287] Step (1) condensing compound IIB1-1 with IIB4-1 to obtain compound IIB4-2;

[0288] Step (2) subjecting compound IIB4-2 to a ring-closure reaction with IIB1-4-A to obtain compound IIB4-3;

[0289] Step (3) subjecting compound IIB4-3 to a coupling or substitution reaction to obtain compound IIB4-4;

[0290] Step (4) subjecting compound IIB4-4 to an aminolysis reaction to obtain compound IIB4-5;

[0291] Step (5) Compound IIB4-5 is subjected to a hydroxyl group deprotection reaction to obtain compound IIB4-6.

[0292] In some embodiments of the present invention, the condensation reaction conditions of step (1) are the same as those described above for the reaction of compound S-1 with compound S-1-1 to produce compound S-2.

[0293] In some embodiments of the present invention, the ring-closure reaction conditions of step (2) are the same as those described above for the ring-closure reaction of compound S-2 and compound S-2-1 to produce compound S-3.

[0294] In some embodiments of the present invention, when R 3 =CN, in step (3), IIB4-3 undergoes a coupling reaction with zinc cyanide. 3 When it is not H or CN, the compound IIB4-3 in the above step (3) and R 3 -L2 undergoes a coupling or substitution reaction. In some embodiments of the present invention, the coupling reaction of step (3) above is carried out in the presence of a catalyst. The catalyst may be selected from Pd(OAc)2, Pd(dppf)Cl2, Pd(PPh3)4, etc. In some embodiments of the present invention, the coupling reaction of step (3) above is carried out in a suitable solvent. The solvent may be selected from DMF, 1,4-dioxane, NMP or DMSO, etc. In some embodiments of the present invention, the coupling reaction of step (3) above is carried out at a suitable reaction temperature. The reaction temperature is preferably 60-150°C; in some embodiments of the present invention, the coupling reaction of step (3) above is carried out for a suitable time. The reaction time is preferably 12-24 hours.

[0295] In some embodiments of the present invention, compound IIB4-3 undergoes a substitution reaction with IIB4-4-A in step (3). In some embodiments of the present invention, the substitution reaction in step (3) is carried out in a suitable solvent. The solvent may be selected from DMF, MeOH, EtOH, or DMSO. In some embodiments of the present invention, the substitution reaction in step (3) is carried out at a suitable reaction temperature. The reaction temperature is preferably 20-120°C. In some embodiments of the present invention, the substitution reaction in step (3) is carried out for a suitable time. The reaction time is preferably 2-24 hours.

[0296] In some embodiments of the present invention, in step (3), compound IIB4-3 and IIB4-4-A undergo a Stille coupling reaction. In some embodiments of the present invention, the reaction conditions are as described above for the Stille coupling reaction.

[0297] In some embodiments of the present invention, the reaction conditions of step (4) are the same as those described above for the aminolysis conditions.

[0298] In some embodiments of the present invention, the reaction conditions of step (5) are the same as those described above for the hydroxyl deprotection conditions.

[0299] In some embodiments of the present invention, the present invention further provides that when R 7 When it is -OH, R 2 H, R 3 Not for H(R 3 -NR x R y ) when preparing a compound of formula (IIB) (2), which comprises step (4), optionally further comprises step (3), optionally further comprises step (2), optionally further comprises step (1):

[0300] in

[0301] R x 、R y 、R 1 、R 4 、R 5 、R 6 、R 7 、R 8 、Pg 1 、X 1 As defined above;

[0302] in

[0303] Step (1) Boc protection is performed on compound IIB4-3 to obtain compound IIB5-1;

[0304] Step (2) subjecting compound IIB5-1 and IIB5-2 to a Buchwald coupling reaction to obtain compound IIB5-3;

[0305] Step (3) subjecting compound IIB5-3 to a hydroxyl deprotection reaction to obtain compound IIB5-4;

[0306] Step (4) Compound IIB5-4 is subjected to aminolysis reaction to obtain compound IIB5-5.

[0307] In some embodiments of the present invention, the reaction conditions of step (1) are the same as those described above for the Boc protection reaction.

[0308] In some embodiments of the present invention, the reaction conditions of step (2) are the same as those described above for the Buchwald coupling reaction.

[0309] In some embodiments of the present invention, the reaction conditions of step (3) are the same as those described above for the hydroxyl deprotection reaction conditions.

[0310] In some embodiments of the present invention, the reaction conditions of step (3) are the same as those described above for the aminolysis reaction conditions.

[0311] In some embodiments of the present invention, the present invention further provides that when R 7 When it is -OH, R 2 H, R 3 Not for H(R 3 is -OCHF2), comprising step (5), optionally further comprising step (4), optionally further comprising step (3), optionally further comprising step (2), optionally further comprising step (1):

[0312] in

[0313] R 1 、R 4 、R 5 、R 6 、R 7 、R 8 、pg 1 、X 1 As defined above;

[0314] in

[0315] Step (1) hydrolyzing compound IIB5-1 to obtain compound IIB6-1;

[0316] Step (2) subjecting compound IIB6-1 to a Boc removal reaction to obtain compound IIB6-2;

[0317] Step (3) subjecting compound IIB6-2 to an aminolysis reaction to obtain compound IIB6-3;

[0318] Step (4) reacting compound IIB6-3 with IIB6-4 to obtain compound IIB6-5;

[0319] Step (5) Compound IIB6-5 is subjected to a hydroxyl group deprotection reaction to obtain compound IIB6-6.

[0320] In some embodiments of the present invention, the hydrolysis reaction of step (1) is preferably carried out in the presence of a base. The base can be selected from t-BuOK. In some embodiments of the present invention, the hydrolysis reaction of step (1) is preferably carried out in a suitable solvent. The solvent can be selected from tert-butanol, MeOH, EtOH or THF and any combination thereof. In some embodiments of the present invention, the hydrolysis reaction of step (1) is preferably carried out at a suitable reaction temperature. The reaction temperature is 20-120°C. In some embodiments of the present invention, the hydrolysis reaction of step (1) is carried out for a suitable time. The reaction time is preferably 2-24 hours.

[0321] In some embodiments of the present invention, the de-Boc reaction in step (2) is preferably carried out in the presence of a de-Boc reagent. The de-Boc reagent is preferably zinc bromide. In some embodiments of the present invention, the de-Boc reaction in step (2) is carried out in a suitable solvent. The solvent may be selected from DCM, DCE, 1,4-dioxane or THF and any combination thereof. In some embodiments of the present invention, the de-Boc reaction in step (2) is carried out at a suitable reaction temperature. The reaction temperature is preferably 0-100° C.; in some embodiments of the present invention, the de-Boc reaction in step (2) is carried out for a suitable time. The reaction time is preferably 2-24 hours.

[0322] In some embodiments of the present invention, the reaction conditions of step (3) are the same as those described above for the aminolysis reaction conditions.

[0323] In some embodiments of the present invention, the above step (4) is preferably carried out in the presence of K2CO3 and sodium sulfate; in some embodiments of the present invention, the above step (4) is carried out in a suitable solvent; the solvent can be selected from DCM, ACN, 1,4-dioxane or THF and any combination thereof; in some embodiments of the present invention, the above step (4) is carried out at a suitable reaction temperature; the reaction temperature is preferably 0-100°C; in some embodiments of the present invention, the above step (4) is carried out for a suitable time; the reaction time is preferably 2-24 hours.

[0324] In some embodiments of the present invention, the reaction conditions of step (5) are the same as those described above for the hydroxyl deprotection reaction conditions.

[0325] In some embodiments of the present invention, the present invention further provides that when R 7 When it is -OH, R 1 、R 2 When is H, a method (1) for preparing a compound of formula (IIB), 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):

[0326] in

[0327] R 4 、R 5 、R 6 、R 7 、R 8 、Pg 1 、X 1 As defined above, R 3x H, C 1-6 Alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl or 5-10 membered heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl or heteroaryl are each optionally substituted by one or more independently selected from deuterium, halogen, -CN, oxo, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 Alkyl), -NR x R y 、C 3-6 Cycloalkyl and optionally substituted by one or more R a The substituent of the substituted 4-6 membered heterocycloalkyl is substituted; R x 、R y 、R a As defined above;

[0328] in

[0329] Step (1) reacting compound IIB1-1 with IIB7-1 to obtain compound IIB7-2;

[0330] Step (2) subjecting compound IIB7-2 to a ring-closure reaction with IIB1-4-B to obtain compound IIB7-3;

[0331] Step (3) subjecting compound IIB7-3 to a carbonyl insertion reaction to obtain compound IIB7-4;

[0332] Step (4) subjecting compound IIB7-4 to a hydrolysis reaction to obtain compound IIB7-5;

[0333] Step (5) condensing compound IIB7-5 and IIB7-6 to obtain compound IIB7-7;

[0334] Step (6) subjecting compound IIB7-7 to a hydrolysis reaction to obtain compound IIB7-8;

[0335] Step (7) Compound IIB7-8 is subjected to a hydroxyl group deprotection reaction to obtain compound IIB7-9.

[0336] In some embodiments of the present invention, the reaction conditions of step (1) are the same as those described above for the addition reaction of compound IIB1-1 and IIB1-2 to obtain compound IIB1-3.

[0337] In some embodiments of the present invention, the ring-closure reaction conditions of step (2) are the same as those described above for the ring-closure reaction of compound S-2 and compound S-2-1 to produce compound S-3.

[0338] In some embodiments of the present invention, the carbonyl insertion reaction of the above step (3) is preferably carried out in the presence of a catalyst; the catalyst can be selected from Pd(OAc)2, Pd(dppf)Cl2, Pd(PPh3)4, etc.; in some embodiments of the present invention, the carbonyl insertion reaction of the above step (3) is preferably carried out in a suitable solvent; the solvent can be selected from MeOH, EtOH, tert-butanol, etc.; in some embodiments of the present invention, the carbonyl insertion reaction of the above step (3) is preferably carried out at a suitable reaction temperature; the reaction temperature is 40-120°C; in some embodiments of the present invention, the carbonyl insertion reaction of the above step (3) is preferably carried out for a suitable time; the reaction time is 2-12 hours.

[0339] In some embodiments of the present invention, the hydrolysis reaction of step (4) is preferably carried out in the presence of a base. The base can be selected from KOH, NaOH, LiOH, etc. In some embodiments of the present invention, the hydrolysis reaction of step (4) is preferably carried out in a solvent. The solvent can be selected from MeOH, EtOH, THF and water and any combination thereof; in some embodiments of the present invention, the hydrolysis reaction of step (4) is carried out at a suitable reaction temperature. The reaction temperature is preferably 0-100°C. In some embodiments of the present invention, the hydrolysis reaction of step (4) is carried out for a suitable time. The reaction time is preferably 2-12 hours.

[0340] In some embodiments of the present invention, the condensation reaction conditions of step (5) are the same as those described above for the reaction of compound S-1 with compound S-1-1 to produce compound S-2.

[0341] In some embodiments of the present invention, the reaction conditions of step (6) are the same as those described above for the hydrolysis reaction of compound IIB1-6 to obtain compound IIB1-7.

[0342] In some embodiments of the present invention, the reaction conditions of step (7) are the same as those described above for the hydroxyl deprotection reaction conditions.

[0343] In some embodiments of the present invention, the present invention further provides that when R 7 When it is -OH, R 1 、R 3 H, R 2 -NR x R y A method for preparing a compound of formula (IIB) 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 x 、R y 、R 4 、R 5 、R 6 、R 7 、R 8 、Pg 1 、X 1 As defined above;

[0346] in

[0347] Step (1) condensing compound IIB1-1 with IIB8-1 to obtain compound IIB8-2;

[0348] Step (2) Compound IIB8-2 is subjected to a ring-closure reaction with IIB1-4-B to obtain compound IIB8-3;

[0349] Step (3) subjecting compound IIB8-3 to a substitution reaction with IIB8-4 to obtain compound IIB8-5;

[0350] Step (4) subjecting compound IIB8-5 to a hydrolysis reaction to obtain compound IIB8-6;

[0351] Step (5) Compound IIB8-6 is subjected to a hydroxyl group deprotection reaction to obtain compound IIB8-7.

[0352] In some embodiments of the present invention, the condensation reaction of step (1) is preferably carried out in the presence of 2-chloro-1-methylpyridinium iodide (CMPI) and a base; the base can be selected from DIPEA, TEA, K2CO3, etc.; the solvent can be selected from DCM, ACN, THF, etc.; in some embodiments of the present invention, the condensation reaction of step (1) is carried out at a suitable reaction temperature; the reaction temperature is preferably 0-100°C; in some embodiments of the present invention, the condensation reaction of step (1) is carried out for a suitable time; the reaction time is preferably 2-12 hours.

[0353] In some embodiments of the present invention, the ring-closure reaction conditions of step (2) are the same as those described above for the ring-closure reaction of compound S-2 and compound S-2-1 to produce compound S-3.

[0354] In some embodiments of the present invention, the substitution reaction in step (3) is preferably carried out in the presence of a base; the base can be selected from DIPEA, TEA, K2CO3, etc.; in some embodiments of the present invention, the substitution reaction in step (3) is preferably carried out in the presence of a solvent; the solvent can be selected from DMF, DMA, NMP, etc.; in some embodiments of the present invention, the substitution reaction in step (3) is carried out at a suitable reaction temperature; the reaction temperature is preferably 50-150°C; in some embodiments of the present invention, the substitution reaction in step (3) is carried out for a suitable time; the reaction time is preferably 2-12 hours.

[0355] In some embodiments of the present invention, the reaction conditions of step (4) are the same as those described above for the hydrolysis reaction of compound IIB1-6 to obtain compound IIB1-7.

[0356] In some embodiments of the present invention, the reaction conditions of step (5) are the same as those described above for the hydroxyl deprotection reaction conditions.

[0357] In some embodiments of the present invention, the present invention further provides that when R 7 With R 8 Together they form -CH=N-NH-, R 2 H, R 3 -NR x R y When , a method for preparing a compound of formula (IIB) comprises 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):

[0358] in

[0359] R x 、R y 、R 1 、R 4 、R 5 、R 6 、X 1 As defined above;

[0360] pg 2 represents an amino protecting group;

[0361] The amino protecting group is, for example, an alkoxycarbonyl amino protecting group, such as benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), fluorenylmethyloxycarbonyl (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, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, trichloroethoxy carbonyl, trimethylsilylethoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, tert-butyl, trifluoroacetyl, methoxycarbonyl, or ethoxycarbonyl; an alkyl amino protecting group, such as trityl (Trt), 2,4-dimethoxybenzyl (Dmb), 4-methoxybenzyl (PMB), benzyl (Bn), tetrahydropyranyl (THP); preferably, the amino protecting group is 2,4-dimethoxybenzyl, 4-methoxybenzyl or tetrahydropyranyl (THP); more preferably, the amino protecting group is tetrahydropyranyl (THP);

[0362] in

[0363] Step (1) reacting compound IIB9-1 with IIB4-1 to obtain compound IIB9-2;

[0364] Step (2) Compound IIB9-2 is subjected to a ring-closure reaction with IIB1-4-A to obtain compound IIB9-3;

[0365] Step (3) performing a Boc protection reaction on compound IIB9-3 to obtain compound IIB9-4;

[0366] Step (4) subjecting compound IIB9-4 and IIB9-5 to a Buchwald coupling reaction to obtain compound IIB9-6;

[0367] Step (5) subjecting compound IIB9-6 to amino deprotection reaction to obtain compound IIB9-7;

[0368] Step (6) subjecting compound IIB9-7 and IIB9-8 to an amine transesterification reaction to obtain compound IIB9-9;

[0369] Step (7) Compound IIB9-9 is subjected to amino deprotection reaction to obtain compound IIB9-10.

[0370] In some embodiments of the present invention, the reaction conditions of step (1) are the same as those described above for the addition reaction of compounds 1IB1-1 and 1IB1-2 to obtain compound IIB1-3.

[0371] In some embodiments of the present invention, the ring-closure reaction conditions of step (2) are the same as those described above for the ring-closure reaction of compound S-2 and compound S-2-1 to produce compound S-3.

[0372] In some embodiments of the present invention, the reaction conditions of step (3) are the same as those described above for the Boc protection reaction.

[0373] In some embodiments of the present invention, the reaction conditions of step (4) are the same as those described above for the Buchwald coupling reaction.

[0374] In some embodiments of the present invention, the deprotection reaction in step (5) is preferably carried out in the presence of a suitable acid. The acid can be selected from sulfuric acid, hydrochloric acid in dioxane solution, and trifluoroacetic acid, preferably hydrochloric acid in dioxane solution. In some embodiments of the present invention, the deprotection reaction in step (5) is preferably carried out at a suitable reaction temperature; the reaction temperature is 0-80°C. In some embodiments of the present invention, the deprotection reaction in step (5) is carried out for a suitable time; the reaction time is preferably 2-24 hours.

[0375] In some embodiments of the present invention, the reaction of step (6) is preferably carried out in the presence of a catalyst. The catalyst may be selected from 1,5,7-triazidebicyclo(4.4.0)dec-5-ene (TBD). In some embodiments of the present invention, the reaction of step (6) is preferably carried out in a suitable solvent; the solvent may be selected from 1,4-dioxane, toluene, ACN, THF, etc. In some embodiments of the present invention, the reaction of step (6) is carried out at a suitable reaction temperature; the reaction temperature is preferably 0-120°C; in some embodiments of the present invention, the reaction of step (6) is carried out for a suitable time; the reaction time is preferably 2-12 hours.

[0376] In some embodiments of the present invention, the deprotection reaction in step (7) is preferably carried out in the presence of a suitable acid. The acid can be selected from sulfuric acid, hydrochloric acid 1,4-dioxane solution and TFA, preferably TFA. In some embodiments of the present invention, the deprotection reaction in step (7) is carried out at a suitable reaction temperature; the reaction temperature is preferably 20-100° C. In some embodiments of the present invention, the deprotection reaction in step (7) is carried out for a suitable time; the reaction time is preferably 2-12 hours.

[0377] Those skilled in the art will appreciate that, depending on the desired product structure, one or more steps in the above-described preparation method may be omitted, and the order of the reaction steps may be appropriately adjusted, and protection / deprotection reaction steps may be added or omitted, as needed.

[0378] Pharmaceutical compositions, formulations, and kits

[0379] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of Formula (A)-(II), (IA)-(IIB), (IIC)-(IID), or (IIE)-(IIB) 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, isotopically labeled, metabolite, or prodrug.

[0380] A further object of the present invention is to provide a method for preparing the pharmaceutical composition of the present invention, which comprises combining a compound of the present invention 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, isotope labels, metabolites or prodrugs.

[0381] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention 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).

[0382] 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.

[0383] When administered orally, the pharmaceutical composition can be prepared into any orally acceptable preparation form.

[0384] 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.

[0385] The pharmaceutical composition can also be used in the form of injections, including injection solutions, sterile powders for injection, and concentrated solutions for injection.

[0386] Another aspect of the present invention also relates to a pharmaceutical formulation comprising a compound of Formula (I), (IA), (II), (IIA), (IIB), (IIC), (IID), or (IIE), a pharmaceutically acceptable form thereof, or a mixture thereof as an active ingredient, or a pharmaceutical composition of the present invention, wherein the pharmaceutically acceptable form is selected from a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled substance, metabolite, or prodrug. In some embodiments, the formulation is in the form of a solid formulation, a semisolid formulation, a liquid formulation, or a gaseous formulation.

[0387] A further object of the present invention 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, an article of manufacture of the present invention 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 invention 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, isotopically labeled, 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-related condition.

[0388] 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 U.S. Food and Drug Administration) that governs 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).

[0389] Treatment methods and uses

[0390] The present invention aims to provide a compound of Formula (I), (IA), (II), (IIA), (IIB), (IIC), (IID), or (IIE), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention, for preventing or treating diseases or conditions associated with PKMYT1 activity, wherein the pharmaceutically acceptable form is selected from a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite, or prodrug. The diseases or conditions include cancers that overexpress CCNE1 or have inactivating mutations in the FBXW7 gene.

[0391] Another object of the present invention is to provide 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), (IA), (II), (IIA), (IIB), (IIC), (IID), or (IIE) or a pharmaceutically acceptable form thereof, or a mixture thereof, or a pharmaceutical composition of the present invention, wherein the pharmaceutically acceptable form is selected from a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled, metabolite, or prodrug.

[0392] Another object of the present invention is to provide a compound of Formula (I), Formula (IA), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID) or Formula (IIE) or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention, for 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.

[0393] Another object of the present invention is to provide a compound of Formula (I), Formula (IA), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID) or Formula (IIE) or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention for use 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-labeled substance, metabolite or prodrug.

[0394] According to some embodiments of the present invention, the MYT1 inhibitor comprises a compound disclosed herein or a pharmaceutically acceptable form thereof.

[0395] According to some embodiments of the present invention, 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.

[0396] According to some embodiments of the present invention, 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.

[0397] According to some embodiments of the present invention, 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, a tumor or cancer disease or condition. 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.

[0398] 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.

[0399] In an embodiment of the present invention, the present invention 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.

[0400] The dosage regimen can be adjusted to provide the optimal desired response. For example, when administered as an injectable, 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. Generally, 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 composition or compound of the present invention 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 required dose may be administered in one or more doses to achieve the desired result.The pharmaceutical composition according to the present invention may also be provided in unit dosage form. Beneficial effects

[0401] The present invention provides a novel class of PKMYT1 inhibitors capable of achieving at least one of the following technical effects:

[0402] (1) High inhibitory activity against PKMYT1.

[0403] (2) Excellent physicochemical properties (e.g., solubility, physical and / or chemical stability).

[0404] (3) Excellent pharmacokinetic properties (e.g., good bioavailability, appropriate half-life and duration of action).

[0405] (4) Excellent safety (lower toxicity and / or fewer side effects, wider therapeutic window), etc. DETAILED DESCRIPTION

[0406] Example

[0407] The present invention will be described in detail below with reference to Examples and Test Examples. However, these examples are not intended to limit the scope of the present invention, and variations are possible without departing from the scope of the present invention.

[0408] Nuclear magnetic resonance (NMR) measurements were performed using a Bruker nuclear magnetic resonance spectrometer, manufactured by Bruker, model: AVANCE III HD-400.

[0409] Preparation method for preparative high performance liquid chromatography:

[0410] 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.

[0411] Thin layer chromatography purification was performed using GF 254 (0.4-0.5 nm) silica gel plates produced in Yantai.

[0412] 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.

[0413] 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.

[0414] Unless otherwise specified in the examples, the reaction temperature is room temperature (15°C to 30°C).

[0415] 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.

[0416] The abbreviations used in this document have the following meanings:

[0417] Example

[0418] Intermediate Preparation Example 1: Preparation of 3-(methoxymethoxy)-2,6-dimethylaniline

[0419] Step 1: Preparation of 1-methoxy-2,4-dimethyl-3-nitrobenzene

[0420] 1-Bromo-2,4-dimethyl-3-nitrobenzene (3.00 g, 13.0 mmol) was placed in a reaction flask and added to DMF (10 mL). Then, cuprous bromide (187 mg, 1.30 mmol) and sodium methoxide (5.4 M dissolved in MeOH, 7.24 mL) were added and reacted at 95°C for 6 h. After completion of the reaction, the system was added to water (100 mL) and extracted with EA (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the title compound (2.70 g). The crude product was used directly in the next reaction.

[0421] 1 H NMR (400MHz, CDCl3): δ7.07 (d, J=8.4Hz, 1H), 6.85 (d, J=8.4Hz, 1H), 3.85 (s, 3H), 2.24 (s, 3H), 2.14 (s, 3H).

[0422] Step 2: Preparation of 2,4-dimethyl-3-nitrophenol

[0423] 1-Methoxy-2,4-dimethyl-3-nitrobenzene (2.70 g, 14.9 mmol) was placed in a reaction flask, and DCM (20 mL) was added. The temperature was lowered to -40°C, followed by the addition of boron tribromide (5.60 g, 22.4 mmol, 2.15 mL). The temperature was slowly raised to 25°C and stirred for 2 hours. After the reaction, the system was added to a saturated aqueous solution of potassium dihydrogen phosphate (100 mL) and extracted with DCM (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the title compound (2.20 g). The crude product was used directly in the next reaction.

[0424] 1 H NMR (400MHz, CDCl3): δ6.97 (d, J=8.4Hz, 1H), 6.81 (d, J=8.4Hz, 1H), 5.36-5.66 (m, 1H), 2.22 (s, 3H), 2.17 (s, 3H).

[0425] Step 3: Preparation of 1-(methoxymethoxy)-2,4-dimethyl-3-nitrobenzene

[0426] 2,4-Dimethyl-3-nitrophenol (2.20 g, 13.2 mmol) was placed in a reaction flask, and DCM (20 mL) was added, followed by DIPEA (2.55 g, 19.7 mmol, 3.44 mL) and chloromethyl methyl ether (1.85 g, 23.0 mmol, 1.75 mL). The reaction was allowed to proceed at 25°C for 12 hours. After completion of the reaction, the system was added to saturated aqueous ammonium chloride (100 mL) and extracted with DCM (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the title compound (2.20 g). The crude product was used directly in the next reaction.

[0427] Step 4: Preparation of 3-(methoxymethoxy)-2,6-dimethylaniline

[0428] 1-(Methoxymethoxy)-2,4-dimethyl-3-nitrobenzene (2.20 g, 10.4 mmol) was placed in a reaction flask, and MeOH (20 mL) was added, followed by 10% palladium on carbon (200 mg). The hydrogen atmosphere was replaced three times, and the reaction was carried out at 25°C under a hydrogen balloon for 12 h. After the reaction, the palladium on carbon was filtered through a celite pad and washed with MeOH (50 mL x 3). The solvent was evaporated under reduced pressure, and the title compound (1.80 g) was isolated and purified by column chromatography (PE / EA = 5 / 1). MS m / z (ESI): 182.1 [M+H] + .

[0429] 1H NMR (400MHz, CDCl3): δ6.87 (d, J=8.4Hz, 1H), 6.49 (d, J=8.4Hz, 1H), 5.16 (s, 2H), 3.49 (s, 3H), 2.14 (s, 3H), 2.11 (s, 3H).

[0430] Intermediate Preparation Example 2: Preparation of 7-amino-3-bromo-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carbonitrile

[0431] Step 1: Preparation of 5-bromo-2-chloronicotinoyl chloride

[0432] To a 100 mL vial, add 5-bromo-2-chloropyridine-3-carboxylic acid (5.10 g, 21.15 mmol) and dissolve in DCM (65.0 mL). Slowly add oxalyl chloride (3.01 g, 23.26 mmol, 2.11 mL) in an ice bath, followed by DMF (157.71 mg, 2.11 mmol, 158.66 μL). Allow to warm to room temperature naturally and stir for 3 hours. After the reaction is complete, concentrate under reduced pressure to afford the title compound (5.30 g) as a pale yellow solid. The crude product is used directly in the next reaction.

[0433] Step 2: Preparation of 5-bromo-2-chloro-N-(3-methoxy-2,6-dimethylphenyl)nicotinamide

[0434] 5-Bromo-2-chloronicotinoyl chloride (5.58 g, 20.79 mmol) was dissolved in DCM (50.0 mL). 3-Methoxy-2,6-dimethylaniline (3.64 g, 22. mmol) and DIPEA (5.48 g, 41.6 mmol) were added sequentially. The reaction mixture turned from clear to turbid, and solid precipitated. After completion of the reaction, the reaction mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and slurried with ethyl acetate. The filter cake was collected to obtain the title compound (6 g, 14.61 mmol) as a white solid. MS m / z (ESI): 369.1 [M+H] + .

[0435] Step 3: Preparation of 7-amino-3-bromo-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carbonitrile

[0436] 5-Bromo-2-chloro-N-(3-methoxy-2,6-dimethylphenyl)nicotinamide (6.00 g, 14.6 mmol), malononitrile (2.95 g, 43.8 mmol), K2CO3 (4.12 g, 29.2 mmol), and CuI (567.81 mg, 2.92 mmol) were dissolved in DMSO (60 mL). The mixture was heated to 85°C and stirred for 2 hours under N2 protection. After the reaction, the reaction solution was directly added to silica gel, concentrated to dryness, and purified by column chromatography (DCM / EA = 90 / 10 elution) to yield the title compound (1.90 g, 4.52 mmol) as a yellow solid. MS m / z (ESI): 399.1 [M+H] + .

[0437] Intermediate Preparation Example 3: Preparation of 7-amino-3-bromo-6-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carbonitrile

[0438] The title compound was obtained by a similar synthetic route to that of Intermediate Preparation Example 2. MS m / z (ESI): 429.0 [M+H] + .

[0439] Intermediate Preparation Example 4: Preparation of ethyl 7-amino-3-bromo-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate

[0440] The title compound was obtained by a similar synthetic route to that of Intermediate Preparation Example 2. MS m / z (ESI): 446.1 [M+H] + .

[0441] Intermediate Preparation Example 5: Preparation of ethyl 7-(bis(tert-butoxycarbonyl)amino)-2-chloro-6-(3-(methoxymethoxy)-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate

[0442] Step 1: Preparation of 2-chloro-3-(methoxycarbonyl)-5-methylpyridine 1-oxide

[0443] Methyl 2-chloro-5-methylnicotinate (9.00 g, 48.5 mmol) was dissolved in CHCl₃ (130 mL) and placed in a reaction flask. The mixture was cooled to 0°C, and then m-CPBA (19.7 g, 96.9 mmol, 85% purity) was added portionwise. The mixture was stirred at 45°C for 12 hours. After the reaction, the reaction system was filtered, and the filtrate was slowly added to a saturated sodium sulfite solution (200 mL). The organic layer was tested with water-moistened starch potassium iodide paper. A negative result was required for subsequent operations. The mixture was then extracted with DCM (30.0 mL x 3). The organic phases were combined and dried over anhydrous NaSO₃. The solvent was removed by filtration and reduced pressure evaporation. The title compound (4.80 g) was obtained by column purification (PE / EA = 1 / 1 elution). MS m / z (ESI): 201.9 [M+H] + .

[0444] Step 2: Preparation of 2,6-dichloro-5-methylnicotinate

[0445] Dissolve 2-chloro-3-(methoxycarbonyl)-5-methylpyridine 1-oxide (4.50 g, 22.3 mmol) in DMF (50 mL) in a reaction flask, cool to 0°C, add POCl3 (4.11 g, 26.7 mmol), and react at 25°C for 2 hours. After completion of the reaction, add saturated NaHCO3 solution (100 mL), filter, and spin-dry the filter cake to obtain the title compound (3.60 g). MS m / z (ESI): 220.0 [M+H] + .

[0446] Step 3: Preparation of 2,6-dichloro-5-methylnicotinic acid

[0447] Methyl 2,6-dichloro-5-methylnicotinate (3.6 g, 16.4 mmol) was dissolved in THF (28.0 mL) and H₂O (14.0 mL) in a reaction flask. Lithium hydroxide (2.06 g, 49.1 mmol) was added at room temperature and allowed to react for 2 hours. After completion of the reaction, the pH of the reaction system was adjusted to 2-3 with 1M HCl, and then extracted with EA (20.0 mL x 3). The organic phases were combined, dried over anhydrous NaSO₄, filtered, and the solvent was evaporated under reduced pressure to obtain the title compound (3.3 g). MS m / z (ESI): 206.0 [M+H] + .

[0448] Step 4: Preparation of 2,6-dichloro-N-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5-methylnicotinamide

[0449] 2,6-Dichloro-5-methylnicotinic acid (1.90 g, 9.22 mmol) and 3-(methoxymethoxy)-2,6-dimethylaniline (1.67 g, 9.22 mmol) were dissolved in DCM (50.0 mL) and placed in a reaction flask. DIPEA (9.54 g, 73.7 mmol, 12.8 mL) and T4P (33.2 g, 46.1 mmol, 50% purity) were added sequentially and reacted at 25°C for 3 hours. After completion of the reaction, the reaction system was added to water (100 mL) and extracted with CHCl (30 × 3 mL). The organic phases were combined and dried over anhydrous Na2SO4. The solvent was evaporated from the filtrate under reduced pressure and purified by column chromatography (PE / EA = 3 / 1) to yield the title compound (2.40 g). MS m / z (ESI): 369.1 [M+H] + .

[0450] Step 5: Preparation of ethyl 7-amino-2-chloro-6-(3-(methoxymethoxy)-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate

[0451] 2,6-Dichloro-N-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5-methylnicotinamide (910 mg, 2.46 mmol) and ethyl cyanoacetate (473 mg, 4.19 mmol) were dissolved in DMSO (12.0 mL) and placed in a reaction flask. KCO (681 mg, 4.93 mmol) and CuI (93.8 mg, 492 μmol) were added sequentially. The mixture was reacted at 85°C under a nitrogen atmosphere for 1 hr. After completion of the reaction, the reaction system was added to saturated ammonium chloride solution (20.0 mL) and extracted with EA (20.0 × 3 mL). The organic phases were combined and dried over anhydrous NaSO. The solvent was evaporated from the filtrate under reduced pressure, and the title compound (900 mg) was obtained by column purification (PE / EA = 2 / 1). MS m / z (ESI): 446.1 [M+H]. + .

[0452] Step 6: Preparation of ethyl 7-(bis(tert-butoxycarbonyl)amino)-2-chloro-6-(3-(methoxymethoxy)-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate

[0453] Ethyl 7-amino-2-chloro-6-(3-(methoxymethoxy)-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate (900 mg, 2.02 mmol), di-tert-butyl dicarbonate (2.20 g, 10.09 mmol), and DIPEA (1.30 g, 10.09 mmol) were placed in a reaction flask. THF (20 mL) was added, followed by DMAP (123 mg, 1.01 mmol). The mixture was heated to 50°C and reacted for 10 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the title compound was purified by column chromatography (PE / EA = 3 / 2) to obtain the title compound (950 mg). MS m / z (ESI): 602.3 [M-44+1] + .

[0454] Intermediate Preparation Example 6: Preparation of ethyl 7-amino-8-cyano-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-2-carboxylate

[0455] Step 1: Preparation of 2,6-dichloronicotinyl chloride

[0456] Dissolve 2,6-dichloronicotinic acid (3 g, 15.5 mmol) in DCM (15 mL) and place in a reaction flask. Slowly add oxalyl chloride (2.18 g, 17.1 mmol) and DMF (114 mg, 1.55 mmol) dropwise under ice-cooling. Stir at 25°C for 2 hours. After TLC analysis, evaporate the solvent under reduced pressure to obtain the title compound (3.2 g).

[0457] Step 2: Preparation of 2,6-dichloro-N-(3-methoxy-2,6-dimethylphenyl)nicotinamide

[0458] 2,6-Dichloronicotinoyl chloride (3.2 g, 15.2 mmol) was dissolved in DCM (15 mL) and placed in a reaction flask. After stirring on ice for 5 min, DIPEA (3.92 g, 30.4 mmol) and 3-methoxy-2,6-dimethylaniline (2.2 g, 15.2 mmol) were added dropwise. After the addition, the temperature was naturally raised to 25°C and stirred for 1 hr. LCMS monitoring was used. After the reaction was completed, H2O was added to quench the reaction and the mixture was extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product. 20 mL of a mixed solvent (DCM / EA = 1 / 10) was added to the slurry. The solid was filtered and dried under vacuum to obtain the title compound (3.3 g). MS m / z (ESI): 325.0 [M+1] + .

[0459] Step 3: Preparation of 7-amino-2-chloro-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carbonitrile

[0460] 2,6-Dichloro-N-(3-methoxy-2,6-dimethylphenyl)nicotinamide (3 g, 9.2 mmol), malononitrile (1.82 g, 27.6 mmol), potassium carbonate (2.54 g, 18.4 mmol), and cuprous iodide (350 mg, 1.84 mmol) were dissolved in DMSO (15 mL) and placed in a reaction flask. After nitrogen replacement three times, the mixture was stirred at 85°C for 2 hours. LCMS monitoring was performed. After completion of the reaction, the mixture was cooled to room temperature and poured into ice water. The mixture was extracted with EA (20 mL x 3) and washed with saturated sodium chloride water. The organic phase was collected, dried over anhydrous sodium sulfate, and then purified by column chromatography on silica gel (PE / EA = 1 / 1) to obtain the title compound (1.8 g). MS m / z (ESI): 355.1 [M+1] + .

[0461] Step 4: Preparation of methyl 7-amino-8-cyano-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-2-carboxylate

[0462] 7-Amino-2-chloro-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carbonitrile (1.1 g, 3.1 mmol) and triethylamine (940 mg, 9.3 mmol) were dissolved in methanol (20 mL) and placed in an autoclave. The atmosphere was purged with nitrogen three times, and then [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (120 mg, 0.15 mmol) was added. CO was then introduced three times, and the temperature was raised to 100°C and stirred for 16 hours. After the reaction, the mixture was cooled to room temperature, poured into ice water, and extracted with EA (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and then purified by column chromatography on silica gel (PE / EA = 2 / 3) to give the title compound (1.2 g). MS m / z (ESI): 379.1 [M+1] + Step 5: Preparation of 7-amino-8-cyano-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-2-carboxylic acid

[0463] Methyl 7-amino-8-cyano-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-2-carboxylate (1.1 g, 2.9 mmol) was dissolved in MeOH (10 mL) and H₂O (4 mL) in a reaction flask. Sodium hydroxide (0.58 g, 14.5 mmol) was added and stirred at 25°C for 1 hour. After the reaction, the pH was adjusted to 6-7 with 1N dilute hydrochloric acid and extracted with EA (20 mL x 3). After washing with saturated sodium chloride water, the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain the title compound (1 g). MS m / z (ESI): 365.1 [M+1] + .

[0464] Example 1: Preparation of 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide (Compound 1)

[0465] Step 1: Preparation of 2-chloro-N-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5-methylnicotinamide

[0466] 2-Chloro-5-methylnicotinic acid (200 mg, 1.17 mmol) and 3-(methoxymethoxy)-2,6-dimethylaniline (211 mg, 1.17 mmol) were dissolved in DMF (10.0 mL) and placed in a reaction flask. HATU (886 mg, 2.33 mmol) and DIPEA (753 mg, 5.83 mmol, 1.02 mL) were then added sequentially and reacted at 25°C for 2 h. After completion of the reaction, the reaction system was added to water (20.0 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 title compound (185 mg) was purified by Prep-TLC (PE / EA = 1 / 1 development) to yield the title compound. MS m / z (ESI): 334.9 [M+H] + .

[0467] Step 2: Preparation of 7-amino-6-[3-(methoxymethoxy)-2,6-dimethylphenyl]-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carbonitrile

[0468] Sodium hydride (268 mg, 6.72 mmol, 60% purity) was placed in a reaction flask, and DME (10.0 mL) was added. Malononitrile (295 mg, 4.48 mmol) was added at room temperature and stirred for 30 minutes. 2-Chloro-N-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5-methylnicotinamide (150 mg, 448 μmol) and Pd(dppf)Cl2.CH2Cl2 (36.0 mg, 44.8 μmol) were then added sequentially. The reaction was allowed to proceed at 100°C under a nitrogen atmosphere for 12 hours. After completion of the reaction, the reaction system was added to NH4Cl solution (30.0 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 Prep-TLC (PE / EA = 1 / 1) to yield the title compound (150 mg). MS m / z(ESI):365.2[M+H] + .

[0469] Step 3: Preparation of 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide (Compound 1)

[0470] 7-Amino-6-[3-(methoxymethoxy)-2,6-dimethylphenyl]-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carbonitrile (80.0 mg, 219 μmol) was dissolved in concentrated H₂SO₄ (4.60 g, 46.9 mmol, 2.50 mL) in a reaction flask and allowed to react at 25°C for 6 hours. After completion of the reaction, the reaction system was added to aqueous ammonia (50.0 mL) in an ice-water bath and then 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. Prep-HPLC analysis yielded the title compound (1.50 mg). MS m / z (ESI): 339.0 [M+H] + .

[0471] 1 H NMR (400MHz, DMSO-d6): δ 10.68 (s, 1H), 9.57 (br, 2H), 8.67 (d, J = 2.4Hz, 1H), 8.24 (d, J = 1.6Hz, 1H), 7.32 (s, 2H) , 7.09 (d, J=8.4Hz, 1H), 6.90 (d, J=8.0Hz, 1H), 2.36 (s, 3H), 1.85 (s, 3H), 1.78 (s, 3H).

[0472] The following compounds were prepared by the method and general steps described in Reference Example 1. 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.

[0473] Example 2: Preparation of 7-amino-2-cyano-6-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide (Compound 2)

[0474] Step 1: Preparation of ethyl 7-amino-2-cyano-6-(3-(methoxymethoxy)-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate

[0475] Ethyl 7-amino-2-chloro-6-(3-(methoxymethoxy)-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate (100 mg, 0.22 mmol) was dissolved in DMF (6 mL) and placed in a reaction flask. Zinc cyanide (129 mg, 1.1 mmol) and Pd(PPh3)4 (26 mg, 22 μmol) were added, and the temperature was rapidly raised to 150°C. The reaction was allowed to proceed under a nitrogen atmosphere for 12 hours. The temperature was then lowered to room temperature, and zinc cyanide (129 mg, 1.1 mmol) and Pd(PPh3)4 (26 mg, 22 μmol) were added. The temperature was rapidly raised to 150°C, and the reaction was allowed to proceed under a nitrogen atmosphere for 12 hours. After the reaction, the reaction system was added to water (50.0 mL), followed by extraction with EA (20.0 × 3 mL). The organic phases were combined and dried over anhydrous NaSO4. The solvent was evaporated from the filtrate under reduced pressure, and the filtrate was purified by column chromatography (PE / EA = 2 / 1) to obtain the title compound (50 mg). MS m / z (ESI): 437.2 [M+H] + .

[0476] Step 2: Preparation of 7-amino-2-cyano-6-(3-(methoxymethoxy)-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide

[0477] The compound 7-amino-2-cyano-6-(3-(methoxymethoxy)-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylic acid ethyl ester (50 mg, 114 μmol) was dissolved in a 7 M ammonia methanol solution (4.00 mL) and placed in a sealed container. The reaction was allowed to react at 100°C for 24 hours. After completion of the reaction, the solvent was evaporated under reduced pressure and the product was purified by prep-TLC (PE / EA = 1 / 1) to obtain the title compound (20 mg). MS m / z (ESI): 408.2 [M+H] + .

[0478] Step 3: Preparation of 7-amino-2-cyano-6-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide

[0479] 7-Amino-2-cyano-6-(3-(methoxymethoxy)-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide (20 mg, 49 μmol) was dissolved in 1,4-dioxane hydrochloride solution (4 M, 2 mL) and placed in a reaction flask. The mixture was reacted at 25°C for 1 hour. After completion of the reaction, the solvent was evaporated under reduced pressure and the title compound was purified by prep-HPLC to obtain 3 mg. MS m / z (ESI): 364.1 [M+H] + .

[0480] 1 H NMR (400MHz, DMSO-d6): δ9.80 (d, J=3.6Hz, 1H), 9.64 (s, 1H), 8.50 (s, 1H), 7.49 (d, J=3.6 Hz, 1H), 7.10 (d, J=8.4Hz, 1H), 6.89-6.96 (m, 1H), 2.52 (s, 3H), 1.86 (s, 3H), 1.79 (s, 3H).

[0481] Example 3: Preparation of 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-3-(4-methylpiperazin-1-yl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide (Compound 6)

[0482] Step 1: Preparation of ethyl 7-[bis(tert-butoxycarbonyl)amino]-3-bromo-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-1,6-naphthyridine-8-carboxylate

[0483] Ethyl 7-amino-3-bromo-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate (1.0 g, 2.24 mmol), di-tert-butyl dicarbonate (2.22 g, 10.08 mmol), N,N-diisopropylethylamine (1.32 g, 10.08 mmol), and 4-dimethylaminopyridine (DMAP) (24.89 mg, 201.66 μmol) were dissolved in tetrahydrofuran (15 mL). After complete addition, the mixture was stirred at 60°C for 3 hours. After completion of the reaction, the mixture was cooled to room temperature, and the reaction solution was directly added to silica gel, concentrated to dryness, and purified by column chromatography on silica gel (PE / EA = 3 / 1) to obtain the title compound (1.1 g). MS m / z (ESI): 602.3 [M-44+1]. + .

[0484] Step 2: Preparation of ethyl 7-[bis(tert-butoxycarbonyl)amino]-6-(3-methoxy-2,6-dimethylphenyl)-3-(4-methylpiperazin-1-yl)-5-oxo-1,6-naphthyridine-8-carboxylate

[0485] Ethyl 7-[bis(tert-butoxycarbonyl)amino]-3-bromo-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-1,6-naphthyridine-8-carboxylate (300 mg, 464.01 μmol), 4-methylpiperazine (92.96 mg, 928.02 μmol), Pd2(dba)3 (77.26 mg, 83.52 μmol), 1,1′-binaphthyl-2,2′-bisdiphenylphosphine ligand (52.53 mg, 83.52 μmol), and sodium tert-butoxide (81.08 mg, 835.23 μmol) were dissolved in toluene (8 mL). The atmosphere was then replaced with nitrogen three times, the temperature was raised to 100°C, and the mixture was stirred for 12 hours. After completion of the reaction, the mixture was cooled to room temperature, the reaction solution was directly added to silica gel, concentrated to dryness, and purified by column chromatography on silica gel (DCM / MeOH = 10 / 1). The title compound (250 mg) was obtained. MS m / z(ESI):622.4[M-44+1] + .

[0486] Step 3: Preparation of ethyl 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-3-(4-methylpiperazin-1-yl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate

[0487] To ethyl 7-[bis(tert-butoxycarbonyl)amino]-6-(3-methoxy-2,6-dimethylphenyl)-3-(4-methylpiperazin-1-yl)-5-oxo-1,6-naphthyridine-8-carboxylate (250 mg, 375.49 μmol) was added a 1,4-dioxane hydrochloric acid solution (4 M, 4 mL) and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to afford the crude title compound (150 mg). MS m / z (ESI): 466.3 [M+H] + .

[0488] Step 4: Preparation of 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-3-(4-methylpiperazin-1-yl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide

[0489] Ethyl 7-diamino-6-(3-methoxy-2,6-dimethylphenyl)-3-(4-methylpiperazin-1-yl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate (200 mg, 429.60 μmol) was dissolved in ethanol (1 mL). Aqueous ammonia (3 mL, 30% concentration) was then added. The mixture was heated to 100°C and stirred in an autoclave for 12 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted with EA (20 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 (12 mg). MS m / z (ESI): 437.2 [M+H] + .

[0490] Step 5: Preparation of 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-3-(4-methylpiperazin-1-yl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide

[0491] 7-Amino-6-(3-methoxy-2,6-dimethylphenyl)-3-(4-methylpiperazin-1-yl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide (12 mg, 27.49 μmol) was dissolved in DCM (3 mL). Boron tribromide (0.2 mL, 1 M in DCM) was added dropwise and 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 mixture was then purified by Prep-HPLC to yield the title compound (4.0 mg). MS m / z (ESI): 423.2 [M+H] + .

[0492] 1H NMR (400MHz, DMSO-d6) δ10.60 (d, J=4.4Hz, 1H), 9.60 (s, 1H), 8.74 (d, J=3.2Hz, 1H), 8.15 (s, 1H), 7.79 (d, J=3.2Hz, 1H), 7.29 (d , J=4.8Hz, 1H), 7.09 (d, J=8.0Hz, 1H), 6.89 (d, J=8.4Hz, 1H), 3.21 (m, 4H), 2.52 (m, 4H), 2.25 (s, 3H), 1.85 (s, 3H), 1.77 (s, 3H).

[0493] The following compounds were prepared by the method and general steps described in Reference Example 3. 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.

[0494] Example 4: Preparation of 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-2-methoxy-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide (Compound 12)

[0495] Step 1: Preparation of methyl 7-amino-2-methoxy-6-(3-(methoxymethoxy)-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate

[0496] Ethyl 7-amino-2-chloro-6-(3-(methoxymethoxy)-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate (200 mg, 0.45 mmol) was dissolved in methanol (6 mL) and placed in a reaction flask. Sodium methoxide (122 mg, 2.25 mmol) was added, and the temperature was raised to 70°C. The reaction was allowed to react under a nitrogen atmosphere for 12 hours. The reaction system was added to saturated ammonium chloride (50.0 mL) and extracted with EA (20.0 × 3 mL). The organic phases were combined and dried over anhydrous NaSO₄. The solvent was evaporated from the filtrate under reduced pressure to obtain the crude title compound (150 mg). MS m / z (ESI): 428.2 [M+H] + .

[0497] Step 2 Preparation of 7-amino-2-methoxy-6-(3-(methoxymethoxy)-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide

[0498] Methyl 7-amino-2-methoxy-6-(3-(methoxymethoxy)-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate (150 mg, 0.35 mmol) was dissolved in a 7 M ammonia methanol solution (10 mL) in a sealed container and reacted at 100°C for 24 h. After completion of the reaction, the solvent was evaporated under reduced pressure and the product was purified by prep-TLC (PE / EA = 1 / 1) to yield the title compound (20 mg). MS m / z (ESI): 413.2 [M+H] + .

[0499] Step 3: Preparation of 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-2-methoxy-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide

[0500] 7-Amino-2-methoxy-6-(3-(methoxymethoxy)-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide (20 mg, 48 μmol) was dissolved in 1,4-dioxane hydrochloride (4 M, 3 mL) and placed in a reaction flask. The reaction was allowed to react at 25°C for 1 hour. After completion of the reaction, the solvent was evaporated under reduced pressure and the title compound was purified by prep-HPLC to obtain 5 mg. MS m / z (ESI): 369.1 [M+H] + .

[0501] 1 H NMR (400MHz, DMSO-d6) δ10.22 (d, J=4.8Hz, 1H), 9.58 (s, 1H), 8.09 (d, J=1.2Hz, 1H), 7.37 (d, J=4.4Hz, 1H), 7.08 (d, J=8.0Hz, 1H), 6.89 (d, J=8.0Hz, 1H), 3.98 (s, 3H), 2.18 (d, J=1.2Hz, 3H), 1.85 (s, 3H), 1.77 (s, 3H).

[0502] The following compounds were prepared by the method and general steps described in Reference Example 4. 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.

[0503] Example 5: 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-2-((5-methylpyrimidin-2-yl)amino)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide (Compound 46)

[0504] Step 1: Preparation of ethyl 7-[bis(tert-butoxycarbonyl)amino]-6-[3-(methoxymethoxy)-2,6-dimethylphenyl]-3-methyl-2-[(5-methylpyrimidin-2-yl)amino]-5-oxo-1,6-naphthyridine-8-carboxylate

[0505] 5-Methylpyrimidin-2-amine (19 mg, 176 μmol), ethyl 7-[bis(tert-butoxycarbonyl)amino]-2-chloro-6-[3-(methoxymethoxy)-2,6-dimethylphenyl]-3-methyl-5-oxo-1,6-naphthyridine-8-carboxylate (100 mg, 147.03 μmol), sodium tert-butoxide (36 mg, 368 μmol), BINAP (19 mg, 29 μmol), and tris(dibenzylideneacetone)dipalladium (14 mg, 15 μmol) were dissolved in anhydrous toluene (6 mL) and placed in a reaction flask. The atmosphere was purged with nitrogen three times, and the temperature was raised to 100°C and stirred for 6 hr. After completion of the reaction, the mixture was spin-dried and purified by column chromatography on silica gel (PE / EA = 1 / 4 elution) to give the title compound (67 mg). MS m / z (ESI): 675.1 [M-44+1]. + .

[0506] Step 2: Preparation of ethyl 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-2-((5-methylpyrimidin-2-yl)amino)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate

[0507] Ethyl 7-[bis(tert-butoxycarbonyl)amino]-6-[3-(methoxymethoxy)-2,6-dimethylphenyl]-3-methyl-2-[(5-methylpyrimidin-2-yl)amino]-5-oxo-1,6-naphthyridine-8-carboxylate (67 mg, 88 μmol) was dissolved in 1,4-dioxane (2 mL) and placed in a reaction flask. A 4 M hydrochloric acid-dioxane solution (4 mL) was slowly added dropwise. After the addition, the mixture was stirred at 25°C for 1 hour. LCMS monitoring was performed. After the reaction was completed, 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 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 (30 mg). MS m / z (ESI): 475.2 [M+1] + .

[0508] Step 3: Preparation of 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-2-((5-methylpyrimidin-2-yl)amino)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide

[0509] Ethyl 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-2-((5-methylpyridin-2-yl)amino)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate (30 mg, 57 μmol) and sodium methoxide (6.4 mg, 114 μmol) were dissolved in a 7 M ammonia methanol solution (2 mL) in an autoclave. The mixture was heated to 100°C and stirred for 12 hours. Following completion of the reaction, the mixture was concentrated under reduced pressure to remove excess solvent, and then purified by Prep-HPLC to obtain the title compound (1.2 mg). MS m / z (ESI): 446.2 [M+1] + .

[0510] 1 H NMR (400MHz, DMSO-d6) δ11.28 (d, J=3.6Hz, 1H), 9.56 (d, J=4.8Hz, 1H), 9.19 (s, 1H), 8.55 (d, J=0.8Hz, 2H), 8.05 (d, J=1.1Hz, 1H), 7.22 (d, J=3.6Hz, 1H), 7.08 (d, J=8.2Hz, 1H), 6.89 (d, J=8.2Hz, 1H), 2.36 (s, 3H), 2.24 (s, 3H), 1.86 (s, 3H), 1.78 (s, 3H).

[0511] The following compounds were prepared by the method and general steps described in Reference 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.

[0512] Example 6: 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-2-(2-methoxyethoxy)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide (Compound 50)

[0513] Step 1: Preparation of ethyl 7-amino-2-(2-methoxyethoxy)-6-(3-(methoxymethoxy)-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate

[0514] Sodium hydride (269 mg, 6.73 mmol, 60% purity) was dissolved in DMF (4.00 mL) and placed in a reaction flask. 2-Methoxyethanol-1-ol (477.83 mg, 6.28 mmol) was added and stirred at room temperature for 30 min. Then, ethyl 7-amino-2-chloro-6-(3-(methoxymethoxy)-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate (200 mg, 0.45 mmol) was added and reacted at 40°C for 1 hr. After completion of the reaction, the reaction system was added to NH4Cl solution (30.0 mL) and extracted with EA (20 × 3 mL). The organic phases were combined and dried over anhydrous NaSO4. The solvent was evaporated from the filtrate under reduced pressure and purified by column chromatography (PE / EA = 1 / 1) to obtain the title compound (102 mg). MS m / z (ESI): 486.2 [M+H] + .

[0515] Step 2: Preparation of 7-amino-2-(2-methoxyethoxy)-6-(3-(methoxymethoxy)-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide

[0516] Dissolve ethyl 7-diaminobis(2-(2-methoxyethoxy)-6-(3-(methoxymethoxy)-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate (100 mg, 0.21 mmol) in a 7M methanolic ammonia solution (6 mL) in a sealed container and react at 100°C for 72 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude title compound (120 mg). MS m / z (ESI): 457.2 [M+H] + .

[0517] Step 3: Preparation of 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-2-(2-methoxyethoxy)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide

[0518] 7-Amino-2-(2-methoxyethoxy)-6-(3-(methoxymethoxy)-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide (120 mg, 0.26 mmol) was dissolved in 1,4-dioxane hydrochloric acid solution (4 M, 6 mL) and placed in a reaction flask. The reaction was allowed to react at 25°C for 1 hour. After completion of the reaction, the solvent was evaporated from the reaction system under reduced pressure, and the title compound (10 mg) was purified by prep-HPLC. MS m / z (ESI): 413.2 [M+H] + .

[0519] 1 H NMR (400MHz, DMSO-d6): δ10.00-10.10 (m, 1H), 9.45-9.65 (m, 2H), 8.10 (s, 1H), 7.30 (d, J=4.4Hz, 1H), 7.08 (d, J=8.2Hz , 1H), 6.89 (d, J = 8.0Hz, 1H), 4.42-4.46 (m, 2H), 3.74-3.78 (m, 2H), 3.35 (s, 3H), 2.18 (s, 3H), 1.84 (s, 3H), 1.77 (s, 3H).

[0520] The following compounds were prepared by the method and general steps described in Reference Example 6. 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.

[0521] Example 7: Preparation of 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-3-(hydroxymethyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide (Compound 52)

[0522] Step 1: Preparation of 7-amino-3-(hydroxymethyl)-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carbonitrile

[0523] 7-Amino-3-bromo-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carbonitrile (0.8 g, 1.90 mmol), tributyltin carbinol (1.23 g, 3.81 mmol), and Pd(PPh3)4 (0.22 g, 190 μmol) were dissolved in 1,4-dioxane (10 mL) and heated to 80°C under N2 protection for 8 hours. After completion of the reaction, the reaction system was added to water (100 mL) and extracted with EA (30.0 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 (PE / EA = 40 / 60) to obtain the title compound (185 mg) as a yellow solid. MS m / z (ESI): 351.0 [M+H] + .

[0524] Step 2: Preparation of 7-amino-3-(hydroxymethyl)-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide

[0525] 7-Amino-3-(hydroxymethyl)-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carbonitrile (50 mg, 143 μmol) was dissolved in H₂SO₄ (2 mL) and stirred at 25°C for 1 hr. After completion of the reaction, the reaction solution was poured into water (30.0 mL), and the pH was adjusted to a weakly alkaline state with aqueous NaOH. The mixture was then extracted with ethyl acetate (20 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 (10 mg) was purified by Prep-TLC (PE / EA = 1 / 2 development) to yield the title compound. MS m / z (ESI): 369.1 [M+H] + .

[0526] Step 3: Preparation of 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-3-(hydroxymethyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide (Compound 43)

[0527] 7-Amino-3-(hydroxymethyl)-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carbonitrile (10 mg, 27.2 μmol) was dissolved in DCM (4 mL). BBr (0.2 mL, 1 M in DCM) was slowly added dropwise and stirred at room temperature for 2 hours. After the reaction was completed, methanol was slowly added to the reaction solution to quench the reaction. The solvent was evaporated under reduced pressure, and the title compound (0.88 mg) was obtained by Prep-HPLC. MS m / z (ESI): 355.1 [M+H] + .

[0528] 1 H NMR (400MHz, DMSO-d6): δ10.72 (d, J=4.8Hz, 1H), 9.64 (s, 1H), 8.75 (d, J=2.4Hz, 1H), 8.37 (d, J=2.4Hz, 1H), 7.36 ( d, J=4.4Hz, 1H), 7.10 (d, J=8.0Hz, 1H), 6.91 (d, J=8.4Hz, 1H), 5.37 (s, 1H), 4.57 (s, 3H), 1.86 (s, 3H), 1.78 (s, 3H).

[0529] Example 8: Preparation of 3-((1H-pyrazol-4-yl)methyl)-7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide (Compound 53)

[0530] Step 1: Preparation of tert-butyl 4-((2-toluenesulfonylhydrazide)methyl)-1H-pyrazole-1-carboxylate

[0531] Dissolve tert-butyl 4-formyl-1H-pyrazole-1-carboxylate (1.36 g, 6.59 mmol) in MeOH (15 mL), add p-toluenesulfonylhydrazide (1.25 g, 6.59 mmol), and stir at room temperature for 1 hour. After the reaction, a solid precipitated, which was filtered to obtain the title compound (1.65 g) as a white solid. MS m / z (ESI): 365.1 [M+H] + .

[0532] Step 2: Preparation of (7-amino-8-cyano-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridin-3-yl)boronic acid

[0533] 7-Amino-3-bromo-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carbonitrile (1 g, 2.50 mmol), pinacol diboron (1.85 g, 7.29 mmol), potassium acetate (714.89 mg, 7.28 mmol), and Pd(dppf)Cl2 (355.33 mg, 485.62 μmol) were dissolved in dioxane (20 mL). The mixture was heated to 80°C and stirred for 10 hours under N2 protection. After completion of the reaction, the reaction solution was poured into water (80.0 mL) and extracted with ethyl acetate (40.0 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 (PE / EA = 20 / 80) to obtain the title compound (950 mg) as a brown solid. MS m / z (ESI): 365.2 [M+H] + .

[0534] Step 3: Preparation of (7-amino-8-carbamoyl-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridin-3-yl)boronic acid

[0535] Dissolve (7-amino-8-cyano-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridin-3-yl)boronic acid (50 mg, 137.30 μmol) in H₂SO₄ (2 mL) and heat to 50°C with stirring for 2 hours. After the reaction, slowly pour the reaction solution into water and adjust the pH to approximately 7 with saturated aqueous NaOH. The mixture is then extracted with ethyl acetate (30.0 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure. Purification by pre-TLC (PE / EA = 1 / 2 development) affords the title compound (40 mg) as a yellow solid. MS m / z (ESI): 383.2 [M+H] + .

[0536] Step 4: Preparation of tert-butyl 4-((7-amino-8-carbamoyl-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridin-3-yl)methyl)-1H-pyrazole-1-carboxylate

[0537] (7-Aminobis(8-carbamoyl)-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridin-3-yl)boronic acid (110 mg, 287.82 μmol), tert-butyl 4-((2-toluenesulfonylhydrazino)methyl)-1H-pyrazole-1-carboxylate (209.78 mg, 575.65 μmol), and K2CO3 (115.68 mg, 836.99 μmol) were dissolved in dioxane (10 mL), heated to 100°C, and stirred for 12 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 phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The product was purified by pre-TLC (PE / EA = 1 / 2) to obtain the title compound (15 mg) as a yellow solid. MS m / z(ESI):519.3[M+H] + .

[0538] Step 5: Preparation of 3-((1H-pyrazol-4-yl)methyl)-7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide

[0539] Tert-butyl 4-((7-amino-8-carbamoyl-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridin-3-yl)methyl)-1H-pyrazole-1-carboxylate (15 mg, 28.93 μmol) was dissolved in DCM (1 mL). BBr (0.2 mL, 1 M in DCM) was added and stirred at 25°C for 1 hour. After completion of the reaction, methanol was added to quench the reaction. The solvent was evaporated under reduced pressure and purified by pre-HPLC to obtain the title compound (0.62 mg) as a pale yellow solid. MS m / z (ESI): 405.2 [M+H] + .

[0540] 1 H NMR (400MHz, DMSO-d6) δ10.74 (d, J=4.4Hz, 1H), 8.81 (dd, J=4.8, 1.8Hz, 1H), 8.41 (dd, J=8.0, 1.6Hz, 1H), 7.39 (d, J =4.4Hz, 1H), 7.28-7.21 (m, 2H), 7.18 (d, J = 8.4Hz, 1H), 5.27 (q, J = 6.8, 2H), 3.43 (s, 3H), 1.92 (s, 3H), 1.86 (s, 3H).

[0541] Example 9: 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-N 2 Preparation of 5-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-2,8-dicarboxamide (Compound 54)

[0542] Step 1: Preparation of 7-amino-8-cyano-6-(3-methoxy-2,6-dimethylphenyl)-N-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-2-carboxamide

[0543] 7-Amino-8-cyano-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-2-carboxylic acid (50 mg, 137.23 μmol) and methylamine hydrochloride (16.85 mg, 247.01 μmol) were dissolved in acetonitrile (3 mL). N-methylimidazole (40.97 mg, 494.02 μmol) was added and stirred for 10 minutes. Finally, N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (70.0 mg, 247.01 μmol) was added and stirred at room temperature for 2 hours. After completion of the reaction, the reaction was quenched with water 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 to obtain the crude title compound (40 mg). MS m / z (ESI): 378.2 [M+H]+ .

[0544] Step 2: 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-N 2 Preparation of methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-2,8-dicarboxamide

[0545] Concentrated sulfuric acid (1 mL) was added to 7-amino-8-cyano-6-(3-methoxy-2,6-dimethylphenyl)-N-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-2-carboxamide (40 mg, 105.99 μmol) in an ice bath. The mixture was stirred for 10 minutes and then stirred at room temperature for 2 hours. After completion of the reaction, water was added to quench the reaction, followed by the addition of aqueous ammonia. The solution was adjusted to alkalinity 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 to yield the crude title compound (30 mg). MS m / z (ESI): 396.1 [M+H] + .

[0546] Step 3: 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-N 2 Preparation of methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-2,8-dicarboxamide

[0547] 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-N 2 5-Methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-2,8-dicarboxamide (30 mg, 75.87 μmol) was dissolved in DCM (2 mL), and boron tribromide (1 mL, 1 M in DCM) was added dropwise. After the addition, the mixture was stirred at 25°C for 30 min. After the reaction was completed, 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 (5.97 mg) was isolated and purified by Prep-HPLC. MS m / z (ESI): 382.1 [M+H] + .

[0548] 1H NMR (400MHz, DMSO-d6) δ10.15 (d, J=4.0Hz, 1H), 9.63 (s, 1H), 8.61 (d, J=4.8Hz, 1H), 8.53 (d, J=8.0Hz, 1H), 7.62 (d, J=8.0Hz , 1H), 7.37 (d, J=4.0Hz, 1H), 7.11 (d, J=8.4Hz, 1H), 6.91 (d, J=8.4Hz, 1H), 2.85 (d, J=4.8Hz, 3H), 1.87 (s, 3H), 1.80 (s, 3H).

[0549] The following compounds were prepared by the method and general steps described in Reference Example 9. 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.

[0550] Example 10: Preparation of 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-3-isopropoxy-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide (Compound 58)

[0551] Step 1: Preparation of 2-chloro-5-isopropoxynicotinate

[0552] Dissolve methyl 2-chloro-5-hydroxynicotinate (500 mg, 2.67 mmol), 2-bromopropane (655.67 mg, 5.33 mmol), and K2CO3 (1.11 g, 7.96 mmol) in ACN (15 mL) and heat to 85°C with stirring for 1 hour. After the reaction, pour the reaction solution into water (80.0 mL) and extract with ethyl acetate (40.0 mL x 3). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the solvent evaporated under reduced pressure to obtain the title compound (620 mg) as a yellow solid. MS m / z (ESI): 230.1 [M+H] + .

[0553] Step 2: Preparation of 2-chloro-5-isopropoxynicotinic acid

[0554] Methyl 2-chloro-5-isopropoxynicotinate (620 mg, 2.70 mmol) was dissolved in EtOH (10 mL) and H₂O (5 mL). NaOH (209.36 mg, 5.23 mmol) was added and stirred at 25°C for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to remove the EtOH. The reaction solution was then added to 1N HCl (30 mL), resulting in the precipitation of a solid. The solid was filtered to obtain the title compound (500 mg) as a beige solid. MS m / z (ESI): 216.1 [M+H] + .

[0555] Step 3: Preparation of 2-chloro-5-isopropoxynicotinoyl chloride

[0556] To a 100 mL vial, add 2-chloro-5-isopropoxynicotinic acid (450 mg, 2.09 mmol) and dissolve in DCM (15 mL). Slowly add oxalyl chloride (291.37 mg, 2.30 mmol) in an ice bath, followed by DMF (15.25 mg, 208.65 μmol). Allow to warm to room temperature naturally and stir for 3 hours. After completion of the reaction, concentrate under reduced pressure to obtain the title compound (470 mg) as a white solid.

[0557] Step 4: Preparation of 2-chloro-5-isopropoxy-N-(3-(methoxymethoxy)-2,6-dimethylphenyl)nicotinamide

[0558] 2-Chloro-5-isopropoxynicotinoyl chloride (470 mg, 2.01 mmol) was dissolved in DCM (20 mL). 3-(methoxymethoxy)-2,6-dimethylaniline (400.28 mg, 2.21 mmol) and DIPEA (503.11 mg, 3.90 mmol) were added sequentially. The reaction mixture turned from clear to turbid, and solid precipitated. After completion of the reaction, the reaction mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and then slurried with ethyl acetate. The solid was filtered and collected to obtain the title compound (520 mg) as a white solid. MS m / z (ESI): 379.2 [M+H] + .

[0559] Step 5: Preparation of 7-amino-3-isopropoxy-6-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carbonitrile

[0560] 2-Chloro-5-isopropoxy-N-(3-(methoxymethoxy)-2,6-dimethylphenyl)nicotinamide (382 mg, 1.01 mmol), malononitrile (193.71 mg, 2.93 mmol), K2CO3 (270.18 mg, 1.95 mmol), and CuI (37.23 mg, 195.48 μmol) were dissolved in DMSO (15 mL). The mixture was heated to 85°C and stirred for 2 hours under N2 protection. After completion of the reaction, the reaction solution was poured into water (80.0 mL) and extracted with ethyl acetate (30.0 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 (360 mg) as a yellow solid. MS m / z (ESI): 409.1 [M+H] + .

[0561] Step 6: Preparation of 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-3-isopropoxy-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carbonitrile

[0562] Dissolve 7-amino-3-isopropoxy-6-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carbonitrile (100 mg, 232.59 μmol) in DCM (6 mL). Add 1,4-dioxane hydrochloride solution (2 mL) and stir at 25°C for 30 minutes. After completion of the reaction, evaporate the solvent under reduced pressure to obtain the title compound (85 mg) as a yellow solid. MS m / z (ESI): 365.1 [M+H] + .

[0563] Step 7: Preparation of 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-3-isopropoxy-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide

[0564] 7-Amino-6-(3-hydroxy-2,6-dimethylphenyl)-3-isopropoxy-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carbonitrile (85 mg, 233.2 μmol) and NaOH (18.6 mg, 466.5 μmol) were dissolved in DMSO (3 mL). Hydrogen peroxide (52.9 mg, 466.5 μmol, 30% purity) was slowly added at 0°C. The temperature was raised to 25°C and stirred for 16 hours. After completion of the reaction, the reaction mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was collected and the solvent was evaporated under reduced pressure. The product was purified by pre-HPLC to obtain the title compound (28 mg) as a yellow solid. MS m / z (ESI): 383.2 [M+H] + .

[0565] 1 H NMR (400MHz, DMSO-d6) δ10.51 (s, 1H), 9.61 (s, 1H), 8.59 (d, J = 3.2Hz, 1H), 7.88 (d, J = 3.2Hz, 1H), 7.32 (s, 1H) , 7.10 (d, J=8.4Hz, 1H), 6.91 (d, J=8.4Hz, 1H), 4.73 (m, 1H), 1.86 (s, 3H), 1.79 (s, 3H), 1.31 (d, J=6.0Hz, 6H).

[0566] Example 11: Preparation of 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-3-(methoxymethyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide (Compound 59)

[0567] Step 1: Preparation of 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-3-(methoxymethyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carbonitrile

[0568] 7-Amino-3-bromo-6-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carbonitrile (105.26 mg, 245.20 μmol), potassium methoxymethyltrifluoroborate (55.9 mg, 367.8 μmoL), Pd(dppf)Cl2 (34.09 mg, 46.63 μmol), and K2CO3 (96.59 mg, 698.86 μmoL) were dissolved in 1,4-dioxane (6 mL) and H2O (2 mL), and the temperature was raised to 90°C and stirred for 2 hrs under N2 protection. After the reaction, the reaction solution was poured into water (50.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed by filtration under reduced pressure and purified by pre-TLC (PE / EA = 1 / 1 development) to obtain the title compound (27 mg) as a yellow solid. MS m / z (ESI): 351.2 [M+H] + .

[0569] Step 2: Preparation of 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-3-(methoxymethyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide

[0570] 7-Amino-6-(3-hydroxy-2,6-dimethylphenyl)-3-(methoxymethyl)-5-oxo-1,6-naphthyridine-8-carbonitrile (20 mg, 57.08 μmol) was dissolved in MeOH (1 mL) and H₂O (0.25 mL). K₂CO₃ (15.7 mg, 114.2 μmol) and H₂O₂ (61.49 mg, 542.40 μmol, 30% purity) were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was removed by filtration and reduced pressure. Purification by pre-HPLC afforded the title compound (1.43 mg) as a pale yellow solid. MS m / z (ESI): 369.1 [M+H] + .

[0571] 1H NMR (400MHz, DMSO-d6) δ10.74 (d, J=4.4Hz, 1H), 8.81 (dd, J=4.8, 2.0Hz, 1H), 8.41 (dd, J=8.0, 2.0Hz, 1H), 7.39 (d, J =4.4Hz, 1H), 7.28-7.21 (m, 2H), 7.18 (d, J = 8.4Hz, 1H), 5.27 (q, J = 6.8, 2H), 3.43 (s, 3H), 1.92 (s, 3H), 1.86 (s, 3H).

[0572] Example 12: Preparation of 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-2-(4-methylpyridin-2-yl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide (Compound 60)

[0573] Step 1: Preparation of ethyl 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-2-(4-methylpyridin-2-yl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate

[0574] Ethyl 7-amino-2-chloro-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate (300 mg, 746.55 μmol), 4-methyl-2-(tributylstannyl)pyridine (290.81 mg, 821.21 μmol), and tetrakis(triphenylphosphine)palladium (156.85 mg, 134.38 μmol) were dissolved in DMF (8 mL). The atmosphere was then replaced with nitrogen three times, the temperature was raised to 110°C, and the mixture was stirred for 4 hours. After the reaction was completed, the mixture was cooled to room temperature, and the reaction solution was directly added to silica gel, concentrated to dryness, and purified by column chromatography on silica gel (PE / EA = 3 / 1 elution) to obtain the title compound (280 mg). MS m / z (ESI): 459.3 [M+H] + .

[0575] Step 2: Preparation of 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-2-(4-methylpyridin-2-yl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide

[0576] Ethyl 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-2-(4-methylpyridin-2-yl)-5-oxo-5,6-dihydro-1,6-naphthalene-8-carboxylate (280 mg, 610.66 μmol) was dissolved in ethanol (1 mL), followed by the addition of aqueous ammonia (3 mL). The mixture was heated to 100°C and stirred in an autoclave for 12 hours. After completion of the reaction, the mixture was cooled to room temperature 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 yield the title compound (90 mg). MS m / z (ESI): 430.2 [M+H] + .

[0577] Step 3: Preparation of 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-2-(4-methylpyridin-2-yl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide

[0578] 7-Amino-6-(3-methoxy-2,6-dimethylphenyl)-2-(4-methylpyridin-2-yl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide (90 mg, 209.56 μmol) was dissolved in DCM (2 mL). Boron tribromide (1 mL, 1 M in DCM) was added dropwise and 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 mixture was then separated and purified by Prep-HPLC to yield the title compound (11 mg). MS m / z (ESI): 416.1 [M+H] + .

[0579] 1 H NMR (400MHz, DMSO-d6) δ10.89 (d, J=4.8Hz, 1H), 9.67 (s, 1H), 8.65 (d, J=4.8Hz, 1H), 8.55 (d, J=8.4Hz, 1H), 8.11 (d, J=8.0Hz, 1H), 7.98 (s , 1H), 7.49 (d, J=4.8Hz, 1H), 7.42 (d, J=4.8Hz, 1H), 7.11 (d, J=8.4Hz, 1H), 6.92 (d, J=8.4Hz, 1H), 2.47 (s, 3H), 1.89 (s, 3H), 1.82 (s, 3H).

[0580] Example 13: Preparation of (R)-7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-4-((1-methylpyrrolidin-3-yl)amino)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide (Compound 61)

[0581] Step 1: Preparation of 2,4-dichloro-N-(3-methoxy-2,6-dimethylphenyl)pyridine-3-carboxamide

[0582] Dissolve 2,4-dichloropyridine-3-carboxylic acid (3.5 g, 18.23 mmol), 3-methoxy-2,6-dimethylaniline (3.04 g, 20.10 mmol), 2-chloro-1-methylpyridinium iodide (12.83 g, 50.22 mmol), and triethylamine (10.16 g, 100.41 mmol) in THF (10 mL). Heat the mixture to 60°C and stir for 10 hours under N₂ protection. After completion of the reaction, filter the reaction mixture, wash the filter cake with ethyl acetate, and collect the filtrate. Evaporate the solvent under reduced pressure and elute on a column (PE / DCM = 50 / 50) to obtain the title compound (2.5 g) as a pale yellow solid. MS m / z (ESI): 325.0 [M+H] + .

[0583] Step 2: Preparation of 7-amino-4-chloro-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carbonitrile

[0584] 2,4-Dichloro-N-(3-methoxy-2,6-dimethyl-phenyl)pyridine-3-carboxamide (3.42 g, 10.5 mmol), malononitrile (2.08 g, 31.5 mmol), K2CO3 (2.89 g, 21 mmol), and CuI (403 mg, 2.1 mmol) were dissolved in DMSO (40 mL) and stirred at 85°C for 2 hours under N2 protection. After completion of the reaction, the reaction solution was poured into water (200 mL) and extracted with ethyl acetate (80 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent evaporated under reduced pressure. Purification by column chromatography (PE / EA = 50 / 50, DCM / EA = 98 / 2) afforded the title compound (500 mg) as a pale yellow solid. MS m / z (ESI): 355.1 [M+H] + .

[0585] Step 3: Preparation of (R)-7-amino-6-(3-methoxy-2,6-dimethylphenyl)-4-((1-methylpyrrolidin-3-yl)amino)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carbonitrile

[0586] 7-Amino-4-chloro-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carbonitrile (50 mg, 141 μmol), (R)-1-methylpyrrolidin-3-amine (21 mg, 211 μmol), and DIPEA (36 mg, 282 μmol) were dissolved in NMP (2 mL) and stirred at 140°C in a microwave oven for 2 hours. After completion of the reaction, the reaction solution was poured into water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Purification by pre-TLC (DCM / MeOH = 10 / 1) afforded the title compound (40 mg) as a yellow solid. MS m / z (ESI): 419.2 [M+H] + .

[0587] Step 4: Preparation of (R)-7-amino-6-(3-methoxy-2,6-dimethylphenyl)-4-((1-methylpyrrolidin-3-yl)amino)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide

[0588] (R)-7-Amino-6-(3-methoxy-2,6-dimethylphenyl)-4-((1-methylpyrrolidin-3-yl)amino)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carbonitrile (35 mg, 79 μmol) was dissolved in H₂SO₄ (1 mL), heated to 60°C, and stirred for 2 hours. After the reaction, the reaction solution was poured into water, and the pH was adjusted to neutral by adding saturated aqueous NaOH. The mixture was then extracted with ethyl acetate (30 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 (18 mg) as a yellow solid. MS m / z (ESI): 437.2 [M+H] + .

[0589] Step 5: Preparation of (R)-7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-4-((1-methylpyrrolidin-3-yl)amino)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide

[0590] (R)-7-amino-6-(3-methoxy-2,6-dimethylphenyl)-4-((1-methylpyrrolidin-3-yl)amino)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide (15 mg, 35 μmoL) was dissolved in DCM (2 mL). BBr3 (0.5 mL, 1 M in DCM) was added and stirred at 25°C for 1 hr. After completion of the reaction, MeOH was slowly added to quench the reaction. The solvent was evaporated under reduced pressure and purified by pre-HPLC to obtain the title compound (0.72 mg) as a yellow solid. MS m / z (ESI): 423.1 [M+H] + .

[0591] 1 H NMR(400MHz, DMSO-d6)δ 9.57 (s, 1H), 9.24 (d, J = 6.8Hz, 1H), 7.87 (d, J = 6.0Hz, 1H), 7.51 (s, 2H), 7.06 (s, 1H), 6.88 (d, J = 8.4Hz, 1H), 6.74 (d, J = 6.0Hz, 1H), 6.52 (s, 2H), 4.48 (s, 1H), 2.61 (s, 2H), 2.40-2.35 (m, 1H), 2.25 (s, 2H), 2.21 (s, 3H), 1.86 (s, 3H), 1.78 (s, 3H), 1.51-1.48 (m, 1H).

[0592] Example 14: Preparation of 7-amino-2-(difluoromethoxy)-6-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide (Compound 62)

[0593] Step 1: Preparation of ethyl 7-((tert-butoxycarbonyl)amino)-2-hydroxy-6-(3-(methoxymethoxy)-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-8-naphthylidenecarboxylate

[0594] Ethyl 7-[bis(tert-butoxycarbonyl)amino]-2-chloro-6-[3-(methoxymethoxy)-2,6-dimethylphenyl]-3-methyl-5-oxo-1,6-naphthyridine-8-carboxylate (100 mg, 155 μmol) and potassium tert-butoxide (87 mg, 773 μmol) were dissolved in a mixed solvent of tert-butanol (4 mL) and THF (2 mL). The mixture was placed in a reaction flask, purged with nitrogen three times, and heated to 80°C with stirring for 6 hours. After completion of the reaction, saturated aqueous ammonium chloride was added, and the mixture was extracted with EA (20 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 m / z (ESI): 528.2 [M+1] + .

[0595] Step 2: Preparation of ethyl 7-amino-2-hydroxy-6-(3-(methoxymethoxy)-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate

[0596] Ethyl 7-((tert-butoxycarbonyl)amino)-2-hydroxy-6-(3-(methoxymethoxy)-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-8-naphthylic acid ester (80 mg, 151 μmol) and zinc bromide (341 mg, 1.51 mmol) were dissolved in anhydrous DCM (6 mL) in a reaction flask and stirred at room temperature for 5 hours. After completion of the reaction, saturated aqueous NaHCO₃ was added, and the mixture was extracted with DCM (20 mL × 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 (60 mg). MS m / z (ESI): 428.2 [M+1] + .

[0597] Step 3: Preparation of 7-amino-2-hydroxy-6-(3-(methoxymethoxy)-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide

[0598] Ethyl 7-amino-2-hydroxy-6-(3-(methoxymethoxy)-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate (60 mg, 140 μmol) and sodium methoxide (40 mg, 0.7 mmol) were dissolved in a 7 M ammonia methanol solution (5 mL) in an autoclave. The mixture was heated to 100°C and stirred for 12 hours. Following completion of the reaction, the mixture was concentrated under reduced pressure to remove excess solvent, and then purified by Prep-TLC (DCM / MeOH = 10 / 1) to yield the title compound (12 mg). MS m / z (ESI): 399.2 [M+1]+ .

[0599] Step 4: Preparation of 7-amino-2-(difluoromethoxy)-6-(3-(methoxymethoxy)-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide

[0600] 7-Amino-2-hydroxy-6-(3-(methoxymethoxy)-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide (12 mg, 30 μmol), 2,2-difluoro-2-(fluorosulfonyl)acetic acid (16 mg, 90 μmol), potassium carbonate (21 mg, 150 μmol), and anhydrous sodium sulfate (0.2 g) were dissolved in anhydrous ACN (4 mL) in a reaction flask and stirred at room temperature for 12 hours. After completion of the reaction, the reaction was monitored by LCMS. The solvent was removed by filtration and reduced pressure to obtain the crude title compound (12 mg). MS m / z (EsI): 449.2 [M+1] + .

[0601] Step 5: Preparation of 7-amino-2-(difluoromethoxy)-6-(3-hydroxyhydroxy-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide

[0602] 7-Amino-2-(difluoromethoxy)-6-(3-(methoxymethoxy)-2,6-dimethylphenyl)-3-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide (12 mg, 27 μmol) was dissolved in 1,4-dioxane (2 mL) and placed in a reaction flask. Hydrochloric acid-dioxane solution (4 M, 1 mL) was slowly added dropwise. After the addition, the mixture was stirred at 25°C for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure to remove excess solvent, and then purified by Prep-HPLC to obtain the title compound (2 mg). MS m / z (ESI): 405.2 [M+1] + .

[0603] 1 H NMR (400MHz, CD3OD): δ8.37 (d, J=1.2Hz, 1H), 7.49 (t, J=72.4Hz, 1H), 7.12 (d, J=8 .4Hz, 1H), 6.90 (d, J=8.4Hz, 1H), 2.31 (d, J=0.8Hz, 3H), 1.95 (s, 3H), 1.90 (s, 3H).

[0604] Example 15: Preparation of 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-5-oxo-3-(pyrimidin-2-yl)-5,6-dihydro-1,6-naphthyridine-8-carboxamide (Compound 63)

[0605] Step 1: Preparation of 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-3-(pyrimidin-2-yl)-5,6-dihydro-1,6-naphthyridine-8-carbonitrile

[0606] (7-Amino-8-cyano-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridin-3-yl)boronic acid (170 mg, 466.83 μmol), 2-bromopyrimidine (106.83 mg, 671.97 μmol), Pd(dppf)Cl2 (5.56 mg, 89.60 μmol), and K2CO3 (185.73 mg, 1.34 mmol) were dissolved in dioxane (15 mL) and H2O (5 mL). The mixture was heated to 100°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 phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The mixture was purified by column chromatography (PE / EA = 50 / 50) to obtain the title compound (100 mg) as a yellow solid. MS m / z (ESI): 399.2 [M+H] + .

[0607] Step 2: Preparation of 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-3-(pyrimidin-2-yl)-5,6-dihydro-1,6-naphthyridine-8-carboxamide

[0608] Dissolve 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-3-(pyrimidin-2-yl)-5,6-dihydro-1,6-naphthyridine-8-carbonitrile (110 mg, 276.09 μmol) in H₂SO₄ (3 mL) and stir at room temperature for 2 hours. After the reaction, slowly pour the reaction solution into water, adjust the pH to 5 with saturated aqueous NaOH, and extract with ethyl acetate (30.0 mL x 3). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure to yield the title compound (95 mg) as a yellow solid. MS m / z (ESI): 417.3 [M+H] + .

[0609] Step 3: Preparation of 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-5-oxo-3-(pyrimidin-2-yl)-5,6-dihydro-1,6-naphthyridine-8-carboxamide

[0610] Dissolve 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-3-(pyrimidin-2-yl)-5,6-dihydro-1,6-naphthyridine-8-carboxamide (90 mg, 216.12 μmol) in DCM (4 mL). Add BBr (1 mL, 1 M in DCM) and stir at room temperature for 1 hour. After completion of the reaction, slowly add MeOH to quench the reaction. The solvent is evaporated under reduced pressure and purified by pre-HPLC to obtain the title compound (35 mg) as a yellow solid. MS m / z (ESI): 403.2 [M+H] + .

[0611] 1 H NMR (400MHz, DMSO-d6) δ10.71 (s, 1H), 9.69 (d, J = 2.4Hz, 1H), 9.64 (s, 1H), 9.28 (d, J = 2.4Hz, 1H), 8.94 (d, J = 4.8Hz , 2H), 7.49 (t, J=4.8Hz, 2H), 7.12 (d, J=8.4Hz, 1H), 6.93 (d, J=8.0Hz, 1H), 3.17 (s, 1H), 1.90 (s, 3H), 1.82 (s, 3H).

[0612] Example 16: Preparation of 7-amino-3-methyl-6-(5-methyl-1H-indazol-4-yl)-2-[(5-methylpyrimidin-2-yl)amino]-5-oxo-1,6-naphthyridine-8-carboxamide (Compound 64)

[0613] Step 1: Preparation of 2-chloro-5-methylnicotinate

[0614] Dissolve 2-chloro-5-methylnicotinic acid (20 g, 115.40 mmol) in MeOH (200 mL) and add thionyl chloride (27.74 g, 230.80 mmol). After complete addition, stir and react at 60°C for 12 hours. Concentrate to dryness and adjust to alkalinity with saturated aqueous NaHCO3. Extract three times with DCM. The combined organic phases are washed with brine, dried, and concentrated to obtain the crude product. Purify by column chromatography (MeOH / DCM = 5 / 95) and concentrate to give the title compound (19 g). MS (ESI, m / z): 186.1 [M+H]. + .

[0615] Step 2: Preparation of 2-chloro-3-(methoxycarbonyl)-5-methylpyridine-1-oxide

[0616] Methyl 2-chloro-5-methylnicotinate (12 g, 64.65 mmol) was dissolved in chloroform (80 mL), and m-CPBA (33.47 g, 193.96 mmol) was added. After complete addition, the reaction mixture was stirred at 60°C for 12 hours. After cooling, a large amount of solid precipitated. After filtration, the filtrate was concentrated to dryness, adjusted to alkalinity with saturated aqueous NaHCO₃, and extracted three times with DCM. The combined organic phases were washed with brine, dried, and concentrated to give the crude product. Column chromatography (MeOH / DCM = 8 / 92) afforded the title compound (10 g). MS (ESI, m / z): 202.1 [M+H]. + .

[0617] Step 3: Preparation of 2,6-dichloro-5-methylnicotinate

[0618] Dissolve 2-chloro-3-(methoxycarbonyl)-5-methylpyridine 1-oxide (10 g, 49.11 mmol) in DMF (50 mL). Slowly add POCl3 (15.18 g, 98.21 mmol) in an ice bath. Stir and react at 0°C for 2 hours. Concentrate directly to dryness, dilute with water, extract with DCM, wash with aqueous NaHCO3 solution, and dry and concentrate the organic phase to obtain the title compound (7 g). MS (ESI, m / z): 220.1 [M+H]. + .

[0619] Step 4: Preparation of 2,6-dichloro-5-methylnicotinic acid

[0620] Methyl 2,6-dichloro-5-methylnicotinate (6 g, 26.99 mmol) was dissolved in THF (10 mL), MeOH (10 mL), and H2O (5 mL). LiOH (3.27 g, 80.98 mmol) was slowly added. After the addition was complete, the mixture was stirred at 30°C for 12 hours. The mixture was directly concentrated to dryness, diluted with water, extracted with DCM, and washed with aqueous NaHCO3. The organic phase was dried and concentrated to dryness to give the title compound (7 g). MS (ESI, m / z): 206.1 [M+H] + .

[0621] Step 5: Preparation of 2,6-dichloro-5-methyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)nicotinamide

[0622] 2,6-Dichloro-5-methylnicotinic acid (4.73 g, 19.42 mmol) was dissolved in THF (50 mL). DMF (141.90 mg, 1.94 mmol) was added. After stirring for 3 minutes, SOCl2 (11.55 g, 97.08 mmol) was slowly added dropwise and allowed to react at 25°C for 2 hours. The acid chloride was concentrated to dryness and then added to THF twice. The mixture was dissolved in THF again. 5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (5 g, 19.42 mmol) was dissolved in THF and added to the acid chloride. The mixture was allowed to react at 25°C for 1 hour. The reaction mixture was directly concentrated to obtain the crude product, which was then purified on a silica gel column (EA / PE = 35 / 65) to obtain the title compound (5.5 g). MS (ESI, m / z): 419.1 [M+H]. + .

[0623] Step 6: Preparation of ethyl 7-amino-2-chloro-3-methyl-6-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate

[0624] 2,6-Dichloro-5-methyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)nicotinamide (5.3 g, 10.11 mmol), ethyl cyanoacetate (2.31 g, 20.22 mmol), and K2CO3 (2.82 g, 20.22 mmol) were dissolved in DMSO (20 mL). CuI (389.06 mg, 2.02 mmol) was added. After nitrogen displacement, the reaction solution was heated to 85°C and stirred for 2 hours. The reaction solution was filtered through celite, and the filtrate was extracted three times with EA. The combined organic phases were washed with brine, dried, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (EA / PE = 35 / 65) to obtain the title compound (5 g). MS (ESI, m / z): 496.2 [M+H]. + .

[0625] Step 7: Preparation of ethyl 7-(bis(tert-butoxycarbonyl)amino)-2-chloro-3-methyl-6-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate

[0626] Ethyl 7-amino-2-chloro-3-methyl-6-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate (600 mg, 1.03 mmol) was dissolved in THF (10 mL). DIPEA (1.61 g, 12.34 mmol), DMAP (63.45 mg, 514.16 μmol), and Boc2O (1.36 g, 6.17 mmol) were added sequentially. The reaction mixture was stirred at 60°C for 3 hours. The reaction solution was concentrated to obtain a crude product, which was then purified by silica gel column chromatography (EA / PE = 35 / 65) to obtain the title compound (700 mg). MS (ESI, m / z): 696.2 [M+H]. + .

[0627] Step 8: Preparation of ethyl 7-(bis(tert-butoxycarbonyl)amino)-amino-3-methyl-6-(5-methyl-1H-indazol-4-yl)-2-((5-methylpyrimidin-2-yl)amino)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate

[0628] 7-(Bis(tert-butoxycarbonyl)amino)-2-chloro-3-methyl-6-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylic acid ethyl ester (700 mg, 1.01 mmol), 5-methylpyrimidin-2-amine (131.67 mg, 1.21 mmol), Cs2CO3 (982.81 mg, 3.02 mmol), Xantphos (116.36 mg, 201.10 μmol) and Pd2(dba)3 (92.07 mg, 100.55 μmol) were dissolved in 1,4-Dioxane (3 mL), added to the reaction bottle, and reacted at 100°C for 3 hours under nitrogen protection. The reaction mixture was concentrated to obtain a crude product, which was then passed through a silica gel column (EA / PE = 45 / 55) to obtain the title compound (550 mg). MS (ESI, m / z): 769.1 [M+H] + .

[0629] Step 9: Preparation of ethyl 7-amino-3-methyl-6-(5-methyl-1H-indazol-4-yl)-2-((5-methylpyrimidin-2-yl)amino)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate

[0630] Ethyl 7-(bis(tert-butoxycarbonyl)amino)-amino-3-methyl-6-(5-methyl-1H-indazol-4-yl)-2-((5-methylpyrimidin-2-yl)amino)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate (600 mg, 780.38 μmol) was dissolved in 4N HCl in 1,4-Dioxane (10 mL) and reacted at 25°C for 1 hour. The mixture was concentrated to dryness and then made alkaline with saturated aqueous NaHCO₃. Extraction was performed three times with DCM, and the combined organic phases were washed with brine. The organic phases were dried and concentrated to obtain the crude product. Column chromatography (MeOH / DCM = 10 / 90) afforded the title compound (300 mg). MS (ESI, m / z): 485.1 [M+H]. + .

[0631] Step 10: Preparation of 7-amino-N-(2,4-dimethoxybenzyl)-3-methyl-6-(5-methyl-1H-indazol-4-yl)-2-((5-methylpyrimidin-2-yl)amino)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide

[0632] Ethyl 7-amino-3-methyl-6-(5-methyl-1H-indazol-4-yl)-2-((5-methylpyrimidin-2-yl)amino)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate (320 mg, 660.46 μmol) was dissolved in 1,4-Dioxane (5 mL), and (2,4-dimethoxyphenyl)methanamine (1.10 g, 6.60 mmol) and TBD (55.22 mg, 330.23 μmol) were added sequentially. After the addition, the mixture was reacted at 100°C for 16 hours. The mixture was concentrated to dryness, and the crude product was extracted three times with DCM. The combined organic phases were washed with brine, dried, and concentrated to obtain the crude product. Column chromatography (MeOH / DCM = 8 / 92) gave the title compound (320 mg). MS (ESI, m / z): 606.1 [M+H]. + .

[0633] Step 11: Preparation of 7-amino-3-methyl-6-(5-methyl-1H-indazol-4-yl)-2-((5-methylpyrimidin-2-yl)amino)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide

[0634] 7-Amino-N-(2,4-dimethoxybenzyl)-3-methyl-6-(5-methyl-1H-indazol-4-yl)-2-((5-methylpyrimidine-2-diyl)amino)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide (320 mg, 528.36 μmol) was dissolved in TFA (1 mL) and reacted at 80°C for 2 hours. The mixture was concentrated to dryness, the pH was adjusted to 8 with aqueous NaHCO3 solution, and the mixture was extracted three times with EA. The combined organic phases were washed with brine, dried, and concentrated to obtain the crude product. The title compound (90 mg) was obtained by pre-HPLC. MS (ESI, m / z): 456.1 [M+H] + .

[0635] 1 H NMR (400MHz, DMSO-d6) δ13.28 (s, 1H), 11.33 (d, J = 3.4Hz, 1H), 11.08 (s, 1H), 9.22 (s, 1H), 8.56 (d, J = 0.8Hz, 2H), 8.05 (d, J = 1.2Hz, 1H), 7.75 (s, 1H), 7.71-7.61 (m, 1H), 7.44 (d, J=8.6Hz, 1H), 7.24 (d, J=3.4Hz, 1H), 5.83 (s, 1H), 2.40-2.35 (m, 3H), 2.24 (s, 3H), 2.10 (s, 3H).

[0636] Step 12: Resolution of 7-amino-3-methyl-6-(5-methyl-1H-indazol-4-yl)-2-((5-methylpyrimidin-2-yl)amino)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide

[0637] 7-Amino-3-methyl-6-(5-methyl-1H-indazol-4-yl)-2-((5-methylpyrimidin-2-yl)amino)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide (100 mg) was subjected to chiral separation (chiral column: DAICEL CHIRALCEL OD (250 mm×30 mm, 10 μm); mobile phase: [CO₂-EtOH (0.1% NH₃H₂O)]; B%: 40%) to give Peak 1 (31.23 mg, Rt=2.204 min, >99% ee) and Peak 2 (29.95 mg, Rt=2.473 min, >99% ee). MS (ESI, m / z): 456.1 [M+H] + .

[0638] Peak 1: 1H NMR (400MHz, DMSO-d6) δ 11.32 (s, 1H), 8.56 (s, 2H), 11.08 (s, 1H), 8.04 (s, 1H), 7.73 (s, 1H), 7.65 (d, J=7. 8Hz, 1H), 7.42 (d, J=8.4Hz, 1H), 7.21 (d, J=2.4Hz, 1H), 5.83 (s, 1H), 2.37 (s, 3H), 2.24 (s, 3H), 2.10 (s, 3H)

[0639] Peak 2: 1 H NMR (400MHz, DMSO-d6) δ11.32 (s, 1H), 11.08 (s, 1H), 8.56 (s, 2H), 8.04 (s, 1H), 7.73 (s, 1H), 7.65 (d, J =8.0Hz, 1H), 7.42 (d, J = 8.4Hz, 1H), 7.21 (s, 1H), 5.83 (s, 1H), 2.37 (s, 3H), 2.24 (s, 3H), 2.10 (s, 3H).

[0640] The following compounds were prepared by the method and general steps described in Reference Example 16. 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.

[0641] Example 17: Preparation of 7-amino-3-cyclopropyl-6-(3-hydroxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide (Compound 65)

[0642] Step 1: Preparation of ethyl 7-amino-3-cyclopropyl-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate

[0643] Ethyl 7-amino-3-bromo-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate (200 mg, 448.13 μmol), cyclopropylboronic acid (349.94 mg, 4.03 mmol), and potassium carbonate (168.92 mg, 1.21 mmol) were dissolved in 1,4-dioxane (10 mL). The nitrogen atmosphere was then replaced three times. Pd(dppf)Cl2 (59.62 mg, 80.66 μmol) was added, and the temperature was raised to 90°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, 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 (160 mg). MS m / z(ESI):408.5[M+H] + .

[0644] Step 2: Preparation of 7-amino-3-cyclopropyl-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide

[0645] Dissolve ethyl 7-amino-3-cyclopropyl-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate (160 mg, 392.67 μmol) in ethanol (1 mL) and add to an autoclave. Ammonia (3 mL) is then added, the temperature is raised to 100°C, and the mixture is stirred for 12 hours. After the reaction is complete, the mixture is cooled to room temperature and extracted with EA (20 mL x 3). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure to yield the crude title compound (37 mg). MS m / z (ESI): 379.4 [M+H] + .

[0646] Step 3: Preparation of 7-amino-3-cyclopropyl-6-(3-hydroxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide

[0647] 7-Amino-3-cyclopropyl-6-(3-methoxy-2,6-dimethylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide (37 mg, 97.77 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 was completed, 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 (10.86 mg) was isolated and purified by Prep-HPLC. MS m / z (ESI): 365.4 [M+H] + .

[0648] 1 H NMR (400MHz, DMSO-d6) δ10.67 (d, J=4.8Hz, 1H), 9.60 (s, 1H), 8.66 (d, J=2.4Hz, 1H), 8.03 (d, J=2.8Hz, 1H), 7.34 (d, J=4.8Hz, 1H), 7.09 (d, J=8.4Hz, 2H), 6.90 (d, J=8.4Hz, 1H), 2.12-1.99 (m, 1H), 1.85 (s, 3H), 1.78 (s, 3H), 1.09-0.94 (m, 2H), 0.85-0.70 (m, 2H).

[0649] The following compounds were prepared by the method and general steps described in Reference Example 17. 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.

[0650] Example 18: 7-amino-3-methyl-6-(5-methyl-1H-indazol-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide (Compound 77)

[0651] Step 1: Preparation of ethyl 7-amino-3-methyl-6-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate

[0652] 7-Amino-2-chloro-3-methyl-6-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylic acid ethyl ester (100 mg, 201.63 μmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (83.90 mg, 403.26 μmol) were dissolved in dioxane (2 mL), and K3PO4 (128.40 mg, 604.89 μmol), cataCXium A Pd G3 (14.68 mg, 20.16 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 reaction for 16 hours. The reaction mixture was concentrated to give a crude product, which was purified by column chromatography (MeOH / DCM = 5% / 95%) to give the title compound (96 mg). MS (ESI, m / z): 542.1 [M+H] + .

[0653] Step 2: Preparation of 7-amino-N-(2,4-dimethoxybenzyl)-3-methyl-6-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide

[0654] Ethyl 7-amino-3-methyl-6-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate (130 mg, 240.03 μmol) was dissolved in dioxane (5 mL). (2,4-Dimethoxyphenyl)methanamine (1 mL) and TBD (100.23 mg, 720.09 μmol) were added sequentially. After the addition was complete, the mixture was reacted at 100°C for 16 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography (MeCN / H2O (0.05% formic acid) = 38% / 61%) to obtain the title compound (120 mg). MS (ESI, m / z): 663.1 [M+H]. + .

[0655] Step 3: Preparation of 7-amino-3-methyl-6-(5-methyl-1H-indazol-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide

[0656] 7-Amino-N-(2,4-dimethoxybenzyl)-3-methyl-6-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide (50 mg, 73.66 μmol) was dissolved in TFA (1 mL) and reacted at 80°C for 2 hours. The mixture was concentrated to dryness, the pH was adjusted to 8 with aqueous NaHCO3 solution, and the mixture was extracted three times with EA. The combined organic phases were washed with brine, dried, and concentrated to obtain the crude product. The title compound (4 mg) was obtained by pre-HPLC. MS (ESI, m / z): 429.1 [M+H] +

[0657] 1 H NMR (400MHz, DMSO-d6) δ13.29 (s, 1H), 10.99 (d, J = 4.9Hz, 2H), 8.36 (s, 1H), 8.23 ​​(d, J = 0.8Hz, 1H), 7.96 (d, J = 0.8Hz, 1H ), 7.81 (s, 1H), 7.69-7.63 (m, 1H), 7.44 (d, J=8.6Hz, 1H), 7.29 (d, J=4.8Hz, 1H), 3.97 (s, 3H), 2.51 (s, 3H), 2.11 (s, 3H).

[0658] Example 19: 7-amino-6-(5-methyl-1H-indazol-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5,6-dihydro-1,6-8-naphthyridinecarboxamide (Compound 79)

[0659] Step 1: Preparation of 2,6-dichloro-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)nicotinamide

[0660] 2,6-Dichloronicotinic acid (1 g, 5.21 mmol), tetrahydrofuran (5 mL) and DMF (38.07 mg, 520.83 μmol) were added to a reaction flask and stirred for 3 min. Then, thionyl chloride (3.10 g, 26.04 mmol, 1.89 mL) was added and reacted at 25°C for 2 hours. The concentrated product was obtained by rotary evaporation under reduced pressure. Anhydrous tetrahydrofuran (2 mL) was then added to dissolve the product, and the mixture was added dropwise to a solution of 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (1.02 g, 4.43 mmol) in tetrahydrofuran (2 mL) and reacted at 25°C for 2 hours. After the reaction was completed, silica gel was added to stir the sample, and then purified by normal phase column chromatography (petroleum ether:ethyl acetate = 75%:25%-60%:40%) to obtain the title compound (1.3 g). MS (ESI, m / z): 405.0 [M+H] + .

[0661] Step 2: Preparation of ethyl 7-amino-2-chloro-6-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate

[0662] 2,6-Dichloro-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)nicotinamide (1.15 g, 2.84 mmol), ethyl 2-cyanoacetate (648.43 mg, 5.68 mmol) and potassium carbonate (1.19 g, 8.51 mmol) were added to dimethyl sulfoxide (2 mL), and then copper iodide (109.17 mg, 567.51 μmol) was added. After fully replacing nitrogen, the reaction was carried out at 85°C for 2 hours. After the reaction was completed, 200 mL of water was added to dilute the mixture, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, separated, and dried by rotation. The sample was dissolved in ethyl acetate, and silica gel was added to mix the sample. The sample was further purified using a normal phase column (petroleum ether:ethyl acetate = 70%:30%-60%:40%). After the solvent was dried by rotation, the title compound (1.25 g) was obtained. MS (ESI, m / z): 482.2 [M+H] + .

[0663] Step 3: Preparation of ethyl 7-amino-6-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylate

[0664] 7-Amino-2-chloro-6-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylic acid ethyl ester (80 mg, 166.00 μmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (51.81 mg, 249.00 μmol), potassium phosphate (105.71 mg, 498.00 μmol), cataCXium A Pd G3 (12.09 mg, 16.60 μmol), 1,4-dioxane (3 mL) and water (0.5 mL) were added to a reaction flask and reacted at 100° C. for 16 hours under nitrogen protection. After the reaction was completed, the solvent was dried and the sample was dissolved in dichloromethane and injected into a normal phase column for purification (petroleum ether:ethyl acetate = 20%:80%-5%:95%) to obtain the title compound (81 mg). MS (ESI, m / z): 528.1 [M+H] + .

[0665] Step 4: Preparation of 7-amino-N-(2,4-dimethoxybenzyl)-6-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide

[0666] 7-Amino-6-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxylic acid ethyl ester (40 mg, 75.82 μmol) was dissolved in 1,4-dioxane (3 mL), and (2,4-dimethoxyphenyl)methanamine (253.55 mg, 1.52 mmol) and TBD (31.66 mg, 227.46 μmol) were added sequentially, and the reaction was carried out at 100°C for 16 hours. After the reaction was completed, the reaction solution was filtered and the solvent was dried. The resulting solid was dissolved in a small amount of methanol and purified by reverse phase column (H2O (0.05% NH4HCO3): acetonitrile = 73%: 27% - 0%: 100%). After the solvent was dried, the title compound (56 mg) was obtained. MS (ESI, m / z): 649.1 [M+H] +

[0667] Step 5: Preparation of 7-amino-6-(5-methyl-1H-indazol-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5,6-dihydro-1,6-8-naphthyridinecarboxamide

[0668] 7-Amino-N-(2,4-dimethoxybenzyl)-6-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carboxamide (46 mg, 70.91 μmol) was dissolved in trifluoroacetic acid (2 mL) and the temperature was raised to 80°C for 2 hours. After the reaction was completed, the reaction solution was dried and ammonia methanol solution was added to adjust the pH to alkaline. The reaction solution was dried again and purified by preparative purification. After lyophilization, the title compound (11.5 mg) was obtained. MS (ESI, m / z): 415.2 [M+H] + .

[0669] 1 H NMR (400MHz, DMSO-d6) δ13.28 (s, 1H), 10.99 (d, J=4.6Hz, 1H), 8.44 (s, 1H), 8.35 (d, J=8.3Hz, 1H), 8.05 (s, 1H), 7.84 (s, 1 H), 7.65 (d, J=8.6Hz, 1H), 7.49 (d, J=8.3Hz, 1H), 7.44 (d, J=8.6Hz, 1H), 7.25 (d, J=4.6Hz, 1H), 3.95 (s, 3H), 2.11 (s, 3H).

[0670] Biological evaluation

[0671] Experimental example: Test of the inhibitory effect of compounds on PKMYTi enzyme activity

[0672] 1. Test system

[0673] Enzyme: PKMYT1 (purchased from Carna)

[0674] Substrate: Unactive CDK1 (purchased from Signalchem)

[0675] ATP, ADP-Glo ​​Reagent, Detection Solution: all from ADP-Glo ​​Kinase Assay Kit (Promega)

[0676] 2. Test steps

[0677] Prepare 4× compound working solution by serial dilution of DMSO with Enzyme assay buffer, and add 2.5 μL / well of 4× compound working solution to 384-well plate; dilute PKMYT1 enzyme to 4× enzyme working solution with Enzyme assay buffer, and add 2.5 μL / well of 4× enzyme working solution to 384-well plate, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 15 min; prepare 2× CDKI+ATP mixed working solution with Enzyme assay buffer, add 5 μL of 2× CDK1+ATP mixed working solution to 384-well plate, centrifuge at 1000 rpm for 1 min, and incubate at 30°C for 180 min; equilibrate 384-well plate and ADP-Glo ​​Reagent to room temperature, add 10 μL ADP-Glo ​​Reagent to each well, centrifuge at 1000 rpm for 1 min, and incubate in the dark at 25°C for 40 min; add 20 μL Detection Kit to each well of 384-well plate Reagent, centrifuge at 1000 rpm for 1 minute, incubate in the dark at 25°C for 40 minutes, and read the chemiluminescent signal using a BMG microplate reader. Using the vehicle group (DMSO) as the negative control and the buffer group (without PKMYT1 enzyme) as the blank control, calculate the relative inhibitory activity percentage (i.e., inhibition rate) of different concentrations of the compound according to the following formula:

[0678] Relative inhibitory activity percentage = (1-(different concentration compound groups-blank control) / (negative control-blank control))*100%

[0679] The relative inhibitory activity percentages of the compounds at different concentrations were plotted against the compound concentrations, and the curves were fitted according to the four-parameter model to calculate the IC 50 value:

[0680] y=min+(max-min) / (1+(x / IC 50 )^(-Hillslope))

[0681] Where y is the relative inhibitory activity percentage, max and min are the maximum and minimum values ​​of the fitted curve, respectively, x is the logarithmic concentration of the compound, and Hillslope is the slope of the curve. The inhibitory effects of the compounds on PKMYT1 enzyme were determined according to the above method, and the results are shown in Table 1.

[0682] Table 1. Inhibitory activity of the compounds of the present invention on PKMYT1

[0683] The experimental results show that the compound of the present invention has a strong inhibitory effect on PKMYT1 enzyme.

[0684] In summary, the compounds provided by the present invention are highly active KYMYT1 inhibitors with novel structures and have great potential to be developed into drugs for treating diseases or conditions related to KYMYT1 activity.

[0685] In addition to those embodiments described herein, various modifications of the present invention will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) is incorporated herein by reference in its entirety.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable form thereof: in: X is selected from N and CR 2 ; Z is selected from N and CH; Y is selected from N and CR 1 ; R 1 , R 2 and R 3 are 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 、-OR x 、-SR x 、-CHR 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(O)NH(5-10 membered heteroaryl), -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 and its connected atoms together form C 3-6 Cycloalkyl, partially saturated C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, partially saturated 3-6 membered heterocycloalkyl, C 5-6 Aryl or 5-6 membered heteroaryl; or R 1 With R 3 and its connected atoms together form C 3-6 Cycloalkyl, partially saturated C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, partially saturated 3-6 membered heterocycloalkyl, C 5-6 Aryl or 5-6 membered heteroaryl; the alkyl, alkenyl, alkynyl, 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 Hydroxyalkyl, -O(C 1-6 Alkyl), -NR x R y , C 3-6 Cycloalkyl and optionally substituted by one or more R a Substituents of the substituted 4-6 membered heterocycloalkyl; R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-4 Cycloalkyl and C 1-6 Haloalkyl; R 7 Selected from OH, C 1-6 Alkoxy and -OC(O)(C 1-6 alkyl); R 8 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-4 Cycloalkyl and C 1-6 Haloalkyl; Or, R 4 and R 5 , R 5 and R 6 , R 6 and R 7 , R 7 and R 8 Any group of atoms in the 5-6 Aryl or 5-6 membered heteroaryl, the aryl or heteroaryl is optionally substituted by one or more R a replace; 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; 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 Haloalkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 Alkyl), -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2 and optionally one or more R a Substituents of the substituted 4-6 membered heterocycloalkyl; R a are independently selected from hydrogen, halogen, hydroxy, -NH2, oxo, 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; 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 Haloalkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 Alkyl), -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2 and 4-6 membered heterocycloalkyl substituents; 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, wherein: The compound of formula (I) is a compound as shown in formula (II):

3. A compound according to claim 1 or 2, or a pharmaceutically acceptable form thereof, wherein: X is selected from N and CR 2 ; Z is selected from N and CH; R 1 , R 2 and R 3 are 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 、-OR x 、-SR x 、-CHR 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(O)NH(5-10 membered heteroaryl), -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 and its connected atoms together form C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 5-6 Aryl or 5-6 membered heteroaryl; or R 1 With R 3 and its connected atoms together form C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 5-6 Aryl or 5-6 membered heteroaryl; the alkyl, alkenyl, alkynyl, 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 Hydroxyalkyl, -O(C 1-6 Alkyl), -NR x R y , C 3-6 Substitution of cycloalkyl and 4-6 membered heterocycloalkyl; R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-4 Cycloalkyl and C 1-6 Haloalkyl; R 7 Selected from OH; R 8 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-4 Cycloalkyl and C 1-6 haloalkyl; or R 7 With R 8 Co-formed-CR 9 =N-NH-, and R 9 is 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; 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 Haloalkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 Alkyl), -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2 and 4-6 membered heterocycloalkyl substituents.

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable form thereof, wherein: X is selected from N and CR 2 ; Z is selected from N and CH; R 1 , R 2 and R 3 are 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 and its connected atoms together form C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 5-6 Aryl or 5-6 membered heteroaryl; or R 1 With R 3 and its connected atoms together form C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 5-6 Aryl or 5-6 membered heteroaryl; the alkyl, alkenyl, alkynyl, 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 Hydroxyalkyl, -O(C 1-6 Alkyl), -NR x R y , C 3-6 Substitution of cycloalkyl and 4-6 membered heterocycloalkyl; R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-4 Cycloalkyl and C 1-6 Haloalkyl; R 7 Selected from OH; R 8 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-4 Cycloalkyl and C 1-6 haloalkyl; or R 7 With R 8 Co-formed-CR 9 =N-NH-, and R 9 is 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) and -S(O)2(4-6 membered heterocycloalkyl); each of the alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by one or more independently selected from deuterium, halogen, hydroxyl, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 alkyl), -NH2、-NH(C 1-6 Alkyl), -NH(C 1-6 alkyl)2 and 4-6 membered heterocycloalkyl substituents.

5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable form thereof, wherein: X is selected from CR 2 ; or X is selected from N.

6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable form thereof, wherein: Z is selected from N; or Z is selected from CH.

7. A compound according to any one of claims 1 and 3-6, or a pharmaceutically acceptable form thereof, wherein: Y is selected from N; or Y is selected from CR 1 .

8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable form thereof, wherein: R 1 Selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C 3-6 Cycloalkyl) and -NR x R y 、-CHR x R y and 5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl and 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 Hydroxyalkyl, -O(C 1-6 Alkyl), -NR x R y , C 3-6 Substitution of cycloalkyl and 4-6 membered heterocycloalkyl; Preferably, R 1 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -C 1-4 Alkyl-O(C 1-4 Alkyl), C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-4 Alkyl), -O(C 3-6 Cycloalkyl), -NR x R y 、-CHR x R y and 5-6 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl or heteroaryl is optionally substituted by one or more C 1-6 Alkyl substitution; R x and R y Each independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl and 5-6 membered heteroaryl; More preferably, R 1 is selected from hydrogen, methyl, ethyl, isopropyl, difluoromethyl, dimethylamino, cyclopropyl, cyclobutyl, 9. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable form thereof, wherein: R 1 Selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C 3-6 Cycloalkyl) and -NR x R y , wherein the alkyl, cycloalkyl and heterocycloalkyl 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 Hydroxyalkyl, -O(C 1-6 Alkyl), -NR x R y , C 3-6 Substitution of cycloalkyl and 4-6 membered heterocycloalkyl; Preferably, R 1 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-4 Alkyl), -O(C 3-6 Cycloalkyl) and -NR x R y , R x and R y Each independently selected from C 1-6 Alkyl and C 3-8 Cycloalkyl, the heterocycloalkyl is optionally substituted by one or more C 1-6 Alkyl substitution; More preferably, R 1 is selected from hydrogen, methyl, isopropyl, difluoromethyl, dimethylamino, cyclopropyl, cyclobutyl, 10. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable form thereof, wherein: R 2 Selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C 3-6 Cycloalkyl) and -NR x R y , the alkyl, cycloalkyl, heterocycloalkyl 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 Hydroxyalkyl, -O(C 1-6 Alkyl), -NR x R y , C 3-6 Substituents of cycloalkyl and 4-6 membered heterocycloalkyl; R x and R y are each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl and 4-10 membered heterocycloalkyl, the cycloalkyl or The heterocycloalkyl groups are each optionally substituted by one or more independently selected from halogen, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 alkyl) is substituted with a substituent; 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 and -O(C 3-6 Cycloalkyl) and -NR x R y The cycloalkyl group 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 Hydroxyalkyl and -O(C 1-6 alkyl) is substituted by a substituent; R x and R y are each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl and 4-6 membered heterocycloalkyl, each of which is optionally substituted by one or more independently selected from halogen, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 alkyl) is substituted with a substituent; More preferably, R 2 is selected from hydrogen, halogen, methyl, ethyl, isopropyl, cyclopropyl, fluoromethyl, -CH2OCH3, -OCH3 and -NH-cyclopropyl and 11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable form thereof, wherein: R 2 Selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 Alkyl), -O(C 3-6 Cycloalkyl) and -NR x R y , the alkyl, cycloalkyl, heterocycloalkyl 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 Hydroxyalkyl, -O(C 1-6 Alkyl), -NR x R y , C 3-6 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are substituted, R x and R y are each independently selected from hydrogen, C 1-6 Alkyl and C 3-8 Cycloalkyl; 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 and -O(C 3-6 Cycloalkyl) and -NR x R y , R x and R y are each independently selected from hydrogen, C 1-6 Alkyl and C 3-8 Cycloalkyl; More preferably, R 2 is selected from the group consisting of hydrogen, halogen, methyl, isopropyl, cyclopropyl, fluoromethyl, -CH2OCH3, -OCH3 and -NH-cyclopropyl.

12. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable form thereof, wherein: R 3 Selected from hydrogen, halogen, -CN, C 3-6 Cycloalkyl, C 1-6 Alkyl, -O(C 1-6 Alkyl), -NR x R y 、-C(O)NH2、-C(O)NH(C 1-6 alkyl), -C(O)NH(5-10 membered heteroaryl), -OR x and 5-10 membered heteroaryl, wherein the alkyl, cycloalkyl 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 Hydroxyalkyl, -O(C 1-6 Alkyl), -NR x R y , C 3-6 Cycloalkyl and optionally substituted by one or more R a Substituents of the substituted 4-6 membered heterocycloalkyl; Preferably, R 3 Selected from hydrogen, halogen, -CN, C 3-6 Cycloalkyl, C 1-4 Alkyl, -O(C 1-6 Alkyl), C 1-4 Haloalkyl, -O(C 1-4 Hydroxyalkyl), -OC 1-4 Alkyl-O(C 1-4 Alkyl), -O(C 1-4 haloalkyl), -NH(5-6 membered heteroaryl), -NH(C 6-10 Aryl), -NH(C 3-6 Cycloalkyl), -NH(4-7 membered heterocycloalkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -C(O)NH2, -C(O)NH(C 1-4 alkyl), -C(O)NH(5-6 membered heteroaryl), -OR x and 5-9 membered heteroaryl, wherein the aryl, 4-7 membered heterocycloalkyl, cycloalkyl or heteroaryl is optionally substituted by one or more independently selected from deuterium, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 Alkyl), -NR x R y , C 3-6 The substituents of cycloalkyl and 4-6 membered heterocycloalkyl are optionally substituted by one or more independently selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -O(C 1-6 alkyl) is substituted by a substituent; said R x , R y are each independently selected from hydrogen, C 1-6 Alkyl, C 6-10 Aryl and C 3-8 Cycloalkyl; More preferably, R 3 is selected from hydrogen, fluorine, chlorine, -CN, methyl, methoxy, ethoxy, methylamino, cyclopropyl, difluoromethyl, trifluoromethyl, More preferably, R 3 is selected from hydrogen, fluorine, chlorine, -CN, methyl, methoxy, ethoxy, methylamino, cyclopropyl, difluoromethyl, trifluoromethyl, 13. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable form thereof, wherein: R 3 Selected from hydrogen, halogen, -CN, C 3-6 Cycloalkyl, C 1-6 Alkyl and -O(C 1-6 alkyl), each of which 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 Hydroxyalkyl, -O(C 1-6 Alkyl), -NR x R y , C 3-6 Substitution of cycloalkyl and 4-6 membered heterocycloalkyl; Preferably, R 3 Selected from hydrogen, halogen, -CN, C 3-6 Cycloalkyl, C 1-4 Alkyl, -O(C 1-6 Alkyl) and C 1-4 Haloalkyl; More preferably, R 3 is selected from the group consisting of hydrogen, fluorine, chlorine, -CN, methyl, methoxy, cyclopropyl, difluoromethyl and trifluoromethyl.

14. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable form thereof, wherein: R 1 With R 2 and the atoms to which it is attached together form a dihydrofuranyl group; or R 1 With R 3 and the atoms to which it is attached together form a dihydrofuranyl group.

15. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable form thereof, wherein: R 1 With R 2 and the atoms to which it is attached together form a tetrahydrofuranyl group; or R 1 With R 3 and the atoms to which it is attached together form a tetrahydrofuranyl group.

16. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable form thereof, wherein: R 4 Selected from hydrogen, halogen, C 1-4 Alkyl and C 1-4 Preferably, R 4 is selected from the group consisting of methyl, chloro, fluoro and difluoromethyl.

17. A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable form thereof, wherein: R 5 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-4 Cycloalkyl or C 1-6 Preferably, R 5 Selected from hydrogen, halogen, C 1-4 Alkyl and C 1-4 Preferably, R 5 Selected from hydrogen and fluorine.

18. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable form thereof, wherein: R 6 Selected from hydrogen, halogen, C 1-4 Alkyl and C 1-4 Preferably, R 6 Selected from hydrogen, chlorine and fluorine.

19. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable form thereof, wherein: R 7 Selected from OH.

20. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable form thereof, wherein: R 8 Selected from hydrogen, halogen, C 1-4 Alkyl, C 3-4 Cycloalkyl or C 1-4 Preferably, R 8 Selected from hydrogen, methyl, chlorine and fluorine and difluoromethyl.

21. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable form thereof, wherein: R 7 and R 8 and the atoms to which they are connected together form a 5-6 membered heteroaryl group, wherein the heteroaryl group is optionally substituted by one or more R a replace,; Preferably, R 7 and R 8 and the atoms to which they are connected together form a 5-membered heteroaryl group, which may be optionally substituted by one or more R a replace; Preferably, R 7 and R 8 and the atoms to which they are attached together form a pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl (e.g., 1,3,5-triazinyl), pyrrolyl, pyrazolyl, imidazolyl, furanyl, and thienyl group, wherein the heteroaryl group is optionally substituted by one or more R a replace; Preferably, R 7 and R 8 and the atoms to which they are attached together form pyrrolyl, pyrazolyl, imidazolyl, furyl and thienyl, wherein the heteroaryl is optionally substituted by one or more R a replace; Preferably, R 7 With R 8 Co-formed-CR 9 =N-NR 10 -、-N=CR 9 -NR 10 -、-NR 10 -CR 9 =CR 11 -、-O-CR 9 =CR 11 -or-S-CR 9 =CR 11 -, and R 9 , R 10 and R 11 Each independently has R a Definition of .

22. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable form thereof, wherein: R 7 With R 8 Co-formed-CR 9 =N-NR 10 -, and R 9 , R 10 Selected from hydrogen, halogen, hydroxyl, amino, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -O(C 1-6 Alkyl) and -O(C 3-6 Cycloalkyl); Preferably, R 7 With R 8 Co-formed-CR 9 =N-NH-, and R 9 is selected from hydrogen and halogen; Preferably, R 7 With R 8 Together And R 9 is selected from hydrogen and halogen; Preferably, R 7 With R 8 Together they form -CH=N-NH-; Preferably, R 7 With R 8 Together 23. A compound according to any one of claims 1 to 22, or a pharmaceutically acceptable form thereof, wherein: Selected from 24. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable form thereof, wherein: The compound represented by formula (I) is a compound represented by the following formula (IIA):

25. A compound according to any one of claims 1 to 24, or a pharmaceutically acceptable form thereof, wherein: The compound represented by formula (I) is a compound represented by formula (IIB), formula (IIC), formula (IID) or formula (IIE):

26. 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.

27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 26 or a pharmaceutically acceptable form thereof, or a mixture thereof, and one or more pharmaceutically acceptable carriers.

28. Use of a compound according to any one of claims 1 to 26 or a pharmaceutically acceptable form thereof, or a pharmaceutical composition according to claim 27, in the preparation of a medicament for preventing or treating 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 with 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.

29. A method for preventing or treating a disease or condition associated with PKMYT1 activity, the method comprising administering to an individual in need thereof an effective amount of a compound of any one of claims 1 to 26 or a pharmaceutically acceptable form thereof or a mixture thereof, or a pharmaceutical composition of claim 27, wherein the pharmaceutically acceptable form is selected from a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug; 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 with 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.

30. A compound according to any one of claims 1 to 26 or a pharmaceutically acceptable form thereof or a mixture thereof, or a pharmaceutical composition according to claim 27, 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; 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 with 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.

31. A method for preparing a compound according to any one of claims 1 to 26, comprising the following steps: Step 1: Compound S-1 reacts with compound S-1-1 to generate compound S-2; Step 2: Compound S-2 undergoes a ring-closing reaction with compound S-2-1 to generate compound S-3; Step 3: deprotection and hydrolysis of compound S-3 to generate compound I; in X 1 is halogen (such as iodine, bromine or chlorine) or C optionally substituted by halogen 1-6 Alkyl sulfonate (such as triflate), preferably halogen; X, Y, Z, R 3 , R 4 , R 5 , R 6 , R 7 and R 8 The group is as defined in any one of claims 1 to 26.

32. A process for the preparation of a compound according to any one of claims 2 to 6 and 8 to 26, comprising the following steps: Step 1: Compound S-1 reacts with compound S-1-1 to generate compound S-2; Step 2: Compound S-2 reacts with compound S-2-1 to generate compound S-3; Step 3: deprotection and hydrolysis of compound S-3 to generate compound II; in X 1 is halogen (such as iodine, bromine or chlorine) or C optionally substituted by halogen 1-6 Alkyl sulfonate (such as triflate), preferably halogen; X, Z, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 The group is as defined in any one of claims 2 to 6 and 8 to 26.

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