Heteroaromatic ring compounds, pharmaceutical compositions comprising the same and methods of preparation and use thereof

Abstract

The present application relates to heteroaromatic ring compounds, pharmaceutical compositions comprising the same, and methods of preparation and uses thereof. In particular, the present application relates to a compound of Formula I which has a good inhibitory effect on CCNE1 amplified tumor cells and can be used for preventing or treating diseases or conditions associated with PKMYT1 activity.

Description

Technical Field

[0001] This invention relates to heterocyclic aromatic compounds, pharmaceutical compositions comprising the same, methods for their preparation, and their use for the prevention or treatment of diseases or conditions associated with PKMYT1 activity. Background Technology

[0002] PKMYT1 (membrane-associated tyrosine / threonine protein kinase 1, also known as MYT1) is a protein kinase belonging to the WEE protein kinase family and is involved in cell cycle regulation. The WEE protein kinase family includes three members: WEE1, WEE2, and PKMYT1. Among them, WEE1 and PKMYT1 are involved in regulating somatic cell mitosis, while WEE2 is involved in regulating germ cell meiosis (GhelliLuserna di Rorà et al., AWEE1 family business: regulation of mitosis, cancer progression, and therapeutic target, Journal of hematology & oncology, (2020) 13: 126.).

[0003] In eukaryotic somatic cells, PKMYT1 plays a crucial role in cell cycle regulation, primarily involved in the control of mitotic processes. Studies show that PKMYT1 acts on the G2 / M checkpoint but is not essential for normal cell cycle progression, while WEE1 acts on multiple checkpoints (S, G2 / M, and M) and is crucial for normal cell cycle progression, suggesting that inhibiting PKMYT1 may be less toxic to normal cells than inhibiting WEE1. Mechanistically, PKMYT1 inactivates the Cdk1 / CycB complex through phosphorylation, thereby promoting G2 checkpoint function and arresting the G2 / M transition in the cell cycle. PKMYT1 negatively regulates the Cdk1 / CycB complex primarily through two independent mechanisms: 1) PKMYT1 phosphorylates Thr14 and Tyr15 on the substrate Cdk1, thereby inhibiting the activity of the Cdk1 / CycB complex and leading to G2 / M cell cycle arrest; 2) PKMYT1 binds to Cdk1 and isolates it in the cytoplasm, preventing the Cdk1 / CycB complex from entering the nucleus and thus halting cell cycle progression (Schmidt*M et al., Regulation of G2 / M Transition by Inhibition of WEE1 and PKMYT1 Kinases, Molecules, 2017, 22(12): 2045; Wells NJ, et al., The C-terminal domain of the Cdc2 inhibitory kinase Myt1 interacts with Cdc2 complexes and is required for inhibition of G2 / M progression, Journal of Cell Science,1999,112(19):3361-3371).

[0004] In tumor cells, to cope with the replication pressure brought about by the high proliferation rate, PKMYT1 can be upregulated to ensure the repair of DNA damage. Inhibiting PKMYT1 forces tumor cells that have not completed DNA damage repair to enter the next stage of the cell cycle, leading to the accumulation of DNA damage in tumor cells, increased genetic instability, and induction of apoptosis and mitotic catastrophe, thus achieving tumor suppression. David Gallo et al., CCNE1 amplification is syntheticlethal with PKMYT1 kinase inhibition, Nature, 2022, 604(7907):749-756, confirmed that CCNE1 can activate the MMB-FOXM1 transcriptional complex, thereby upregulating the expression of CDK1 and CCNB1 genes. In CCNE1 overexpressing cells, Cyclin B and CDK1 expression are increased, and these cells are more sensitive to PKMYT1 inhibition, leading to synthetic lethality.

[0005] In summary, inhibition of PKMYT1 exhibits synthetic lethality in the presence of CCNE1 gene amplification. Currently, there are no marketed inhibitors targeting PKMYT1. Therefore, there is a need to develop new, highly effective, and low-toxicity PKMYT1 inhibitors to meet clinical needs. Summary of the Invention

[0006] The purpose of this invention is to provide a new class of heterocyclic compounds containing, for example, indazole, which have excellent inhibitory activity against PKMYT1 and can be used to prevent or treat diseases or conditions related to PKMYT1 activity.

[0007] This invention provides compounds of formula I or their pharmaceutically acceptable forms:

[0008]

[0009] in:

[0010] R 1 R 2 and R 3 Each time it appears, it is independently selected from H, OH, halogen, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 1-4 Hydroxyalkyl or C 3-6 cycloalkyl; preferably, R 1 R 2 and R 3 Each time it appears, it is independently selected from H, OH, halogen, C. 1-4 Alkyl, C 1-4 Haloalkyl, C1-4 Hydroxyalkyl or C 3-6 cycloalkyl; or R 1 and R 3 Together with the atoms it is attached to, they form C 5-8 Cycloalkyl, 5-8 membered heterocyclic, or 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclic, or heteroaryl group is optionally selected independently from one or more halogens, OH, CN, -NH2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups;

[0011] R 4 Selected from H, -NR 9 R 10 -C(=O)NH(R) 11 -C(=O)R 12 -NHC(=O)R 12 C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 Cycloalkoxy, C 6-10 aryl or 5-10 heteroaryl, wherein the alkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclic, cycloalkoxy, aryl, or heteroaryl group is optionally selected independently from one or more halogens, D, OH, CN, -NR. 9 R 10 -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups;

[0012] X 1 Selected from CR 5 Or N;

[0013] X 2 Selected from CR 6 Or N;

[0014] X 3 Selected from CR 7 Or N;

[0015] X 4 Selected from CR 8Or N;

[0016] Y and Z are each independently selected from CR 13 Or N;

[0017] R 5 Selected from H, halogens, CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl or C 3-6 Cycloalkyl, wherein the alkyl, alkenyl, alkoxy, hydroxyalkyl or cycloalkyl group is optionally selected from one or more elements independently chosen from halogen, D, OH, CN, -NR. 9 R 10 -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups; or R 4 and R 5 Together with the atoms to which it is attached, it forms a 5-8 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the heterocyclic group or heteroaryl group is optionally composed of one or more elements independently selected from halogen, D, OH, CN, -NH2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups;

[0018] R 6 R 7 and R 8 Each occurrence is independently selected from H, halogen, CN, -NR. 9 R 10 -C(=O)NH(R) 11 -C(=O)R 12 -NHC(=O)R 12 -S(=O)2R 11 -S(=O)2NR 9 R 10 -OR 12 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 Cycloalkoxy, C 6-10 aryl or 5-10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclic, cycloalkoxy, aryl, or heteroaryl group is optionally surrounded by one or more R groups. 14 replace;

[0019] Or R 5 and R 6 Together with the atoms it is attached to, they form C 5-8 cycloalkyl, 5-8 membered heterocyclic, C 6-10 Aryl or 5-10-membered heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally selected from one or more elements independently chosen from halogen, D, OH, CN, -NH2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups;

[0020] Or R 6 and R 7 Together with the atoms it is attached to, they form C 5-8 cycloalkyl, 5-8 membered heterocyclic, C 6-10 Aryl or 5-10-membered heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally selected from one or more elements independently chosen from halogen, D, OH, CN, -NH2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups;

[0021] Or R 7 and R 8 Together with the atoms it is attached to, they form C 5-8 cycloalkyl, 5-8 membered heterocyclic, C 6-10 Aryl or 5-10-membered heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally selected from one or more elements independently chosen from halogen, D, OH, CN, -NH2, C. 1-6 Alkyl, C1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups;

[0022] R 9 and R 10 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, or -S(=O)2R 11 The alkyl, cycloalkyl, aryl, or heteroaryl group is optionally separated by one or more elements independently selected from D, halogen, OH, CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic groups, C 6-10 Substitution of aryl or 5-10 heteroaryl groups;

[0023] R 11 Each time it appears, it is independently selected from H and C. 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 cycloalkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, aryl or heteroaryl group is optionally separated from one or more elements independently selected from halogen, OH, CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 6-10 Substitution of aryl or 5-10 heteroaryl groups;

[0024] R 12 Each time it appears, it is independently selected from C. 1-4 Alkyl, C 3-8 cycloalkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein the alkyl, cycloalkyl, aryl or heteroaryl group is optionally separated from one or more elements independently selected from halogen, OH, CN, -C(=O)CH3, C 1-4 Alkyl or C 1-4 Substituents of haloalkyl groups;

[0025] R 13Each time it appears, it is independently selected from H, halogen, OH, CN, C. 1-4 Alkyl or C 1-4 Halogenated alkyl groups;

[0026] R 14 Each occurrence is independently selected from H, halogen, D, OH, CN, -NR. 9 R 10 -C(=O)R 12 -NHC(=O)R 12 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-6 cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic groups, C 6-10 Aryl or 5-10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, cycloalkoxy, heterocyclic, aryl, or heteroaryl group is optionally selected from one or more elements independently chosen from halogen, D, OH, CN, -NR. 9 R 10 -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups;

[0027] Where R 4 When selected from H, R 7 Selected from -NR 9 R 10 , where R 9 Selected from H, C 1-6 Alkyl or C 3-8 cycloalkyl, R 10 Selected from C 6-10 Aryl or 5-10 heteroaryl, wherein the alkyl, cycloalkyl, aryl or heteroaryl group is optionally separated by one or more elements independently selected from D, halogen, OH, CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8Cycloalkoxy, 3-6 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl substitutions;

[0028] Or, when R 4 When selected from H, R 7 and R 8 Together with the atoms it is attached to, they form C 5-8 cycloalkyl, 5-8 membered heterocyclic, C 6-10 Aryl or 5-10-membered heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally selected from one or more elements independently chosen from halogen, D, OH, CN, -NH2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with a cycloalkoxy or 3-6 membered heterocyclic group, wherein the heteroaryl group is not:

[0029] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled compounds, esters, polymorphs, solvates, N-oxides, metabolites, or prodrugs.

[0030] Another aspect of the invention provides a pharmaceutical composition comprising, for example, a preventive or therapeutically effective amount of the compound of the invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, ester, polymorph, solvate, N-oxide, metabolite or prodrug, and one or more pharmaceutically acceptable carriers.

[0031] Another aspect of the invention provides the use of the compounds of the invention or pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled compounds, esters, polymorphs, solvates, N-oxides, metabolites or prodrugs thereof, or the pharmaceutical compositions of the invention in the preparation of medicaments, particularly medicaments for modulating PKMYT1 activity.

[0032] Another aspect of the invention provides the use of the compounds of the invention or pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled compounds, esters, polymorphs, solvates, N-oxides, metabolites or prodrugs thereof, or pharmaceutical compositions of the invention in the preparation of medicaments, particularly medicaments for the prevention or treatment of diseases or conditions associated with PKMYT1 activity.

[0033] Another aspect of the invention provides compounds of the invention or pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled compounds, esters, polymorphs, solvates, N-oxides, metabolites or prodrugs thereof, or pharmaceutical compositions of the invention, for the prevention or treatment of diseases or conditions, particularly those related to PKMYT1 activity.

[0034] Another aspect of the invention provides a method for preventing or treating diseases or conditions associated with PKMYT1 activity, the method comprising administering to an individual in need an effective amount of a compound of the invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, ester, polymorph, solvate, N-oxide, metabolite or prodrug of the invention, or a pharmaceutical composition of the invention.

[0035] Another aspect of the present invention provides a method for preparing the compounds of the present invention.

[0036] definition

[0037] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0038] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps, although such other unlisted elements or method steps may not necessarily exist (i.e., these terms also cover the terms “consistently made up of” and “composed of”).

[0039] As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, for example, 1 to 6 carbon atoms. For example, as used herein, the term "C" is used to refer to... 1-6 "Alkyl" refers to a linear or branched group having 1-6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl), optionally substituted with one or more (such as 1 to 3) suitable substituents such as halogens (in which case the group is called "haloalkyl") (e.g., CH2F, CHF2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl, or -CH2CH2CF3, etc.). The term "C"1-4 "Alkyl" refers to a linear or branched aliphatic hydrocarbon chain having 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0040] As used herein, the term "heteroalkyl" refers to an alkyl group having one or more skeletal chain atoms in its main chain that are independently selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. A numerical range for the C atom can be given, for example, C0. 1-6 Heteroalkyl refers to a heteroalkyl chain with 1-6 carbon atoms. For example, the -CH2OCH2CH3 group is called a C3 heteroalkyl, and the -CH2OCH2CH2NHCH3 group is called a C4 heteroalkyl. In a heteroalkyl chain, the alkyl group is attached to the remaining molecules or groups.

[0041] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more (such as 1 to 3) identical or different halogen atoms. The term "C" 1-6 "Halogenated alkyl" and "C" 1-4 "Halogenated alkyl" refers to alkyl halogens having 1-6 carbon atoms and 1-4 carbon atoms, such as -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl or -CH2CH2CF3, etc.

[0042] As used herein, the term "hydroxyalkyl" refers to a group formed by replacing one or more hydrogen atoms in an alkyl group with hydroxyl groups, such as C 1-4 Hydroxyalkyl or C 1-6 Hydroxyalkyl groups, examples of which include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, -CH(OH)CH3, etc.

[0043] As used herein, the term "alkenyl" refers to a straight-chain or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds. For example, the term "C" as used herein... 2-6 "Alkenyl" refers to an alkenyl group (such as vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, etc.) having 2-6 carbon atoms and one, two, or three carbon-carbon double bonds, which is optionally substituted by one or more (e.g., 1-3) substituents described herein.

[0044] As used herein, the term "alkynyl" refers to a straight-chain or branched aliphatic hydrocarbon group having one or more carbon-carbon triple bonds. For example, the term "C" as used herein... 2-6"Alynyl" refers to an alkynyl group having 2-6 carbon atoms and one, two or three carbon-carbon triple bonds (such as ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc.), which is optionally substituted by one or more (e.g., 1-3) substituents described herein.

[0045] As used herein, the term "alkoxy" refers to an alkyl (as defined above) group that is connected to the rest of the molecule by an oxygen atom, for example, a C10 group. 1-8 Alkoxy, C 1-6 Alkoxy, C 1-4 Alkoxy or C 1-3 Alkyl group. C 1-6 Alkoxy groups (e.g., C) 1-4 Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy, etc., wherein the alkoxy group is optionally substituted by one or more (such as 1 to 3) identical or different substituents. The term "haloalkoxy" refers to an alkoxy group in which the hydrogen atom is substituted by one or more (such as 1 to 3) identical or different halogen atoms.

[0046] As used herein, the term “fused ring” or “dense ring” refers to a ring system formed by two or more ring structures sharing two adjacent atoms.

[0047] As used herein, the term "spiroring" refers to a ring system consisting of two or more ring structures that share a single ring atom.

[0048] As used in this article, the term "bridged ring" refers to a ring system formed by two or more ring structures sharing two atoms that are not directly connected to each other.

[0049] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon cycloalkyl group, including but not limited to monocyclic alkyl groups (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.) and bicyclic alkyl groups, including spirocyclic, fused-ring (fused-ring) or bridged-ring systems (i.e., spirocyclic alkyl, fused-ring (fused-ring) alkyl, and bridged-ring alkyl groups, such as bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, etc.). In this invention, the cycloalkyl group is optionally substituted with one or more (such as 1 to 3) identical or different substituents. The carbon atom on the cycloalkyl group is optionally substituted with an oxo group (i.e., forming C=O). The term "C 3-8 "Cycloalkyl" refers to a cycloalkyl group having 3 to 8 cyclic carbon atoms, such as C10. 3-6 cycloalkyl and C5-8 Cycloalkyl groups can be monocycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, or they can be bicycloalkyl, such as C10, C20, C30, C40, C50, C60, C7 ... 5-8 Spirocycloalkyl, C 5-8 Bridged cycloalkyl, C 5-8 Polycyclic alkyl, C 5-6 Spirocycloalkyl, C 5-6 Bridged cycloalkyl or C 5-6 Fused cycloalkyl groups.

[0050] As used herein, the term "cycloalkoxy" refers to -O-cycloalkyl, wherein the cycloalkyl group is as defined above, for example, C... 3-8 Cycloalkoxy group. C 3-8 Representative examples of cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexyloxy.

[0051] As used herein, the term "heterocyclic group" or "heterocycle" refers to an aliphatic, saturated or partially unsaturated monocyclic or polycyclic (e.g., fused, spirocyclic, or bridged) group having two or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms, said heteroatoms including, but not limited to, oxygen, nitrogen, and sulfur atoms, wherein the carbon atoms and heteroatoms on said heterocyclic group are optionally substituted with oxo groups (e.g., forming C=O, S(=O) or S(=O)2), or optionally with one or more (such as 1 to 3) independently selected from halogens and C. 1-3 Alkyl substituents.

[0052] As used herein, the term "3-8 membered heterocyclic group" means a heterocyclic group containing 3-8 ring atoms, including but not limited to 4-8 membered heterocyclic groups, 4-7 membered heterocyclic groups, 3-6 membered heterocyclic groups, 5-6 membered heterocyclic groups, 3-7 membered heterocyclic groups, 4-7 membered nitrogen-containing heterocyclic groups, 4-7 membered oxygen-containing heterocyclic groups, 4-7 membered sulfur-containing heterocyclic groups, 5-6 membered nitrogen-containing heterocyclic groups, 5-6 membered oxygen-containing heterocyclic groups, 5-6 membered sulfur-containing heterocyclic groups, etc., wherein each of the "nitrogen-containing heterocyclic group", "oxygen-containing heterocyclic group" and "sulfur-containing heterocyclic group" optionally also contains one or more (e.g., 1, 2, 3 or 4, or 1-3, or 1-4) other heteroatoms independently selected from oxygen, nitrogen and sulfur. Examples of 3-8 membered heterocyclic groups (e.g., 3-6 membered heterocyclic groups, 5-6 membered heterocyclic groups, 6 membered heterocyclic groups) include, but are not limited to, ethylene oxide, aziridinyl, aziridine, oxetane, tetrahydrofuranyl, pyrrolylyl, pyrrolidone (e.g.) ), imidazoalkyl, pyrazolalkyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl, dihydro-1,4-oxazinyl, tetrahydropyrazinyl,

[0053] In this invention, the heterocyclic group can form a fused ring structure with a heterocyclic group or a cycloalkyl group. The connection point of the fused ring structure with other groups can be on any heterocyclic group or on a cycloalkyl group. Therefore, the heterocyclic group of this invention also includes (but is not limited to) heterocyclic fused heterocyclic groups, heterocyclic fused cycloalkyl groups, monoheterocyclic fused monoheterocyclic groups, and monoheterocyclic fused monocycloalkyl groups, such as 3-7 membered (mono)heterocyclic fused 3-7 membered (mono)heterocyclic groups, 3-7 membered (mono)heterocyclic fused (mono)cycloalkyl groups, and 3-7 membered (mono)heterocyclic fused C 4-6 (Mono)cycloalkyl groups, examples of which include, but are not limited to, pyrrolidinylcyclopropyl, cyclopentylazirylpropyl, pyrrolidinylcyclobutyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl, pyrrolidinylpiperazinyl, and piperidinylmorpholinyl.

[0054] In this invention, the heterocyclic group also includes bridged heterocyclic groups and spiroheterocyclic groups.

[0055] As used herein, the term "bridged heterocycle" refers to a ring structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, nitrogen, and / or sulfur atoms) formed by two saturated rings sharing two non-directly connected ring atoms. This includes, but is not limited to, 7-10 membered bridged heterocycles, 8-10 membered bridged heterocycles, 7-10 membered nitrogen-containing bridged heterocycles, 7-10 membered oxygen-containing bridged heterocycles, and 7-10 membered sulfur-containing bridged heterocycles, etc. The "nitrogen-bridged heterocycle", "oxygen-bridged heterocycle", and "sulfur-bridged heterocycle" may optionally also contain one or more other heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0056] As used herein, the term "spiroheterocycle" refers to a ring structure containing one or more heteroatoms (e.g., oxygen, nitrogen, sulfur) formed by two or more saturated rings sharing a single ring atom. This includes, but is not limited to, 5-10 membered spiroheterocycles, 6-10 membered spiroheterocycles, 6-10 membered nitrogen-containing spiroheterocycles, 6-10 membered oxygen-containing spiroheterocycles, and 6-10 membered sulfur-containing spiroheterocycles. The "nitrogen-containing spiroheterocycle", "oxygen-containing spiroheterocycle", and "sulfur-containing spiroheterocycle" may optionally also contain one or more other heteroatoms independently selected from oxygen, nitrogen, and sulfur. The term "6-10-membered nitrogen-containing spiroheterocycle group" refers to a spiroheterocycle group containing a total of 6-10 ring atoms, of which at least one ring atom is a nitrogen atom.

[0057] Examples of groups obtained by fusion of heterocyclic groups and aryl groups include, but are not limited to:

[0058] As used herein, the term "aryl" or "aromatic ring" refers to a fully carbon monocyclic or fused polycyclic aromatic group having a conjugated π-electron system. As used herein, the term "C" refers to a carbon monocyclic or fused polycyclic aromatic group. 6-10 "Aryl" or "aromatic ring" refers to an aryl group or aromatic ring containing 6 to 10 carbon atoms, such as a phenyl or benzene ring, naphthyl or naphthyl ring. The aryl group may optionally be substituented by one or more (such as 1 to 3) identical or different substituents (e.g., halogen, OH, CN, NO2, C). 1-6 Alkyl groups, etc., are substituted.

[0059] As used herein, the term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic or polycyclic aromatic group containing one or more (e.g., 1, 2, 3, or 4, or 1-3, or 1-4) identical or different heteroatoms, including monocyclic heteroaryl groups and bicyclic or polycyclic ring systems containing at least one heteroaromatic ring (an aromatic ring system containing at least one heteroatom), which may have 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, for example, 5, 6, 7, 8, 9, or 10 ring atoms. The heteroatom may be oxygen, nitrogen, or sulfur. The carbon atom and heteroatom on the heteroaryl group are optionally substituted with oxo groups (e.g., forming C=O, S(=O) or S(=O)2).

[0060] As used herein, the terms "5-10-membered heteroaryl" or "5-10-membered heteroaryl ring" refer to a heteroaryl (heteroaryl ring) containing 5 to 10 (e.g., 5 to 6) 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. Each of the "nitrogen-containing heteroaryl," "oxygen-containing heteroaryl," and "sulfur-containing heteroaryl" may optionally contain one or more other heteroatoms independently selected from oxygen, nitrogen, and sulfur. Examples of 5-10 membered heteroaryl groups (e.g., 5-6 membered heteroaryl groups) include, but are not limited to, thiophene, furanyl, pyrrole, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, etc., or pyridinyl, pyridazinyl, pyrazinyl, triazinyl, pyridoneyl, pyrimidinoneyl, etc., as well as benzo[a] derivatives of these groups or 5-10 membered fused cyclic groups composed of these groups.

[0061] In this invention, a heteroaryl group (e.g., a monoheteroaryl group) can share two adjacent atoms with an aryl group (e.g., a monocyclic aryl group, such as a phenyl group), a heterocyclic group (e.g., a monoheterocyclic group), a cycloalkyl group (e.g., a monocycloalkyl group), or another heteroaryl group (e.g., another monoheteroaryl group) to form a fused ring structure. The connection point can be on any heteroaryl ring or other rings, including but not limited to (mono)heteroaryl fused (mono)heteroaryl, (mono)heteroaryl fused (monocyclic) aryl, (mono)heteroaryl fused (mono)heterocyclic, and (mono)heteroaryl fused (mono)cycloalkyl, such as 5-6 membered (mono)heteroaryl fused 5-6 membered (mono)heteroaryl, 5-6 membered (mono)heteroaryl fused phenyl, 5-6 membered (mono)heteroaryl fused 5-6 membered (mono)heterocyclic, or 5-6 membered (mono)heteroaryl fused C 4-6 (Mono)cycloalkyl groups (e.g., 5-6-membered heteroarylcyclobutyl, 5-6-membered heteroarylcyclopentyl, or 5-6-membered heteroarylcyclohexyl), examples of which include, but are not limited to, indole, isoindole, indazole, benzimidazole, quinolinyl, isoquinolinyl, wait.

[0062] As used herein, the term “halogenated” or “halogenated” is defined as including F, Cl, Br, or I.

[0063] The term "substitution" refers to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound.

[0064] If a substituent is described as “optionally substituted by one or more…”, then the substituent may be (1) unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted by one or more of the substituents in the list, then one or more hydrogens on the carbon (to the extent that any hydrogens are present) may be substituted individually and / or together by independently selected optional substituents. If the nitrogen of the substituent is described as being optionally substituted by one or more of the substituents in the list, then one or more hydrogens on the nitrogen (to the extent that any hydrogens are present) may each be substituted by independently selected optional substituents.

[0065] If a substituent is described as being “independently selected” from a group, then each substituent is selected independently of the others. Therefore, each substituent may be the same as or different from another (other) substituent.

[0066] As used herein, the term "one or more" means one or more under reasonable conditions, such as two, three, four, five, six, seven, eight, nine, or ten.

[0067] Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable location of the substituent.

[0068] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom in the substituted ring.

[0069] This invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of this invention, except that one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from the dominant atomic mass or mass number in nature. Examples of isotopes suitable for inclusion in the compounds of this invention include (but are not limited to) isotopes of hydrogen (e.g., deuterium). 2 H), tritium ( 3 H); carbon isotopes (e.g., H); 11 C 13 C and 14 C); isotopes of chlorine (e.g.) 36 Cl); isotopes of fluorine (e.g., Cl); 18 F); isotopes of iodine (e.g., F); 123 I and 125 I); nitrogen isotopes (e.g.) 13 N and 15 N); isotopes of oxygen (e.g., N); 15 O、 17 O and 18 O); isotopes of phosphorus (e.g., O); phosphorus isotopes (e.g., O); 32 P); and isotopes of sulfur (e.g., ... 35 S). Certain isotope-labeled compounds of the present invention (e.g., those doped with radioactive isotopes) can be used in drug and / or substrate tissue distribution studies (e.g., analysis). Radioactive isotope tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) It is particularly suitable for this purpose due to its ease of incorporation and detection. Using positron-emitting isotopes (e.g.) 11 C 18 F, 15 O and 13 Substitution of N) can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The isotopically labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations, by using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be isotopically substituted, for example, D2O, acetone-d6, or DMSO-d6.

[0070] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and single diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. For example, pyridones can also exist in their hydroxypyridine form, pyrimidinones can also exist in their hydroxypyrimididine form, and nitroso-oximes can exist in equilibrium in solution in the following tautomeric forms:

[0071]

[0072] It should be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0073] Solid lines may be used in this article. solid wedge Or virtual wedge The chemical bonds of the compounds of the present invention are depicted. Solid lines are used to depict bonds to asymmetric carbon atoms to indicate all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) at that carbon atom. Solid or dashed wedges are used to depict bonds to asymmetric carbon atoms to indicate the presence of the indicated stereoisomers. When present in racemic mixtures, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise specified, the compounds of the present invention are intended to exist as stereoisomers (including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, trans-blocking isomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[0074] This invention covers all possible crystalline forms or polymorphs of the compounds of this invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0075] Cocrystal refers to the combination of active pharmaceutical molecules and other physiologically acceptable acids, bases, salts, and nonionic compound molecules in the same crystal lattice via hydrogen bonds, π-π stacking interactions, van der Waals forces, and other non-covalent bonds.

[0076] It should also be understood that certain compounds of the present invention may exist in their free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, or prodrugs, which, upon administration to a patient in need, can directly or indirectly provide the compounds of the present invention or their metabolites or residues. Therefore, when referring to "compounds of the present invention" herein, it is also intended to encompass the various derivative forms of the compounds described above.

[0077] Pharmaceutically acceptable salts of the compounds of the present invention include their acid addition salts and base addition salts. For a review of suitable salts, see Stahl and Wermuth, “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (Wiley-VCH, 2002).

[0078] As used herein, the term "ester" refers to an ester derived from the various general formula compounds of this application, including physiologically hydrolyzable esters (the compounds of the invention that can be hydrolyzed under physiological conditions to release free acids or alcohols). The compounds of the invention may themselves be esters.

[0079] The compounds of the present invention can exist as solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, can be stoichiometric or non-stoichiometric.

[0080] Those skilled in the art will understand that not all nitrogen-containing heterocycles can form N-oxides because nitrogen requires available lone pairs of electrons to be oxidized to oxides. Those skilled in the art will identify nitrogen-containing heterocycles capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including but not limited to the oxidation of heterocycles and tertiary amines using peroxy acids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl peroxides such as tert-butyl peroxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see, for example: T.L. Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp. 748-750; A.R. Katritzky and A.J. Boulton, Eds., Academic Press; and G.W. H. Heeseman and E.S. G. Wierstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp. 390-392, A.R. Katritzky and A.J. Boulton, Eds., Academic Press.

[0081] The scope of this invention also includes metabolites of the compounds of this invention, i.e., substances formed in the body when the compounds of this invention are administered. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compound. Therefore, this invention includes metabolites of the compounds of this invention, including compounds obtained by methods that expose the compounds of this invention to mammals for a time sufficient to produce their metabolites.

[0082] This invention further includes, within its scope, prodrugs of the compounds of this invention, which are certain derivatives of the compounds of this invention that may themselves have little or no pharmacological activity, and which, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of this invention having the desired activity. Typically, such prodrugs are functional group derivatives of the compounds that are readily converted in vivo into the compounds with the desired therapeutic activity. Further information regarding the use of prodrugs can be found in “Pro-drugs as Novel Delivery Systems,” Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella). The prodrugs of this invention can be prepared, for example, by replacing suitable functional groups present in the compounds of this invention with certain portions known to those skilled in the art as “pro-moiety” (e.g., as described in “Design of Prodrugs,” H. Bundgaard (Elsevier, 1985)).

[0083] This invention also covers compounds of the invention containing protecting groups. In any process of preparing the compounds of the invention, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of the invention. This can be achieved by conventional protecting groups, for example, those described in T.W. Greene & P. ​​G. W. M. Uts, *Protective Groups in Organic Synthesis*, John Wiley & Sons, 1991, which are incorporated herein by reference. Protecting groups can be removed at appropriate subsequent stages using methods known in the art.

[0084] The term “about” means within ±10% of the stated value, preferably within ±5%, and more preferably within ±2%.

[0085] compound

[0086] In some embodiments, the present invention provides compounds of formula I or their pharmaceutically acceptable form:

[0087]

[0088] in:

[0089] R 1 R 2 and R 3 Each time it appears, it is independently selected from H, OH, halogen, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4Deuterated alkyl, C 1-4 Hydroxyalkyl or C 3-6 cycloalkyl; preferably, R 1 R 2 and R 3 Each time it appears, it is independently selected from H, OH, halogen, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl or C 3-6 cycloalkyl; or R 1 and R 3 Together with the atoms it is attached to, they form C 5-8 Cycloalkyl, 5-8 membered heterocyclic, or 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclic, or heteroaryl group is optionally selected independently from one or more halogens, OH, CN, -NH2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups;

[0090] R 4 Selected from H, -NR 9 R 10 -C(=O)NH(R) 11 -C(=O)R 12 -NHC(=O)R 12 C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 Cycloalkoxy, C 6-10 aryl or 5-10 heteroaryl, wherein the alkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclic, cycloalkoxy, aryl, or heteroaryl group is optionally selected independently from one or more halogens, D, OH, CN, -NR. 9 R 10 -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups;

[0091] X 1 Selected from CR 5 Or N;

[0092] X 2 Selected from CR 6 Or N;

[0093] X 3 Selected from CR 7 Or N;

[0094] X 4 Selected from CR 8 Or N;

[0095] Y and Z are each independently selected from CR 13 Or N;

[0096] R 5 Selected from H, halogens, CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl or C 3-6 Cycloalkyl, wherein the alkyl, alkenyl, alkoxy, hydroxyalkyl or cycloalkyl group is optionally selected from one or more elements independently chosen from halogen, D, OH, CN, -NR. 9 R 10 -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups; or R 4 and R 5 Together with the atoms to which it is attached, it forms a 5-8 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the heterocyclic group or heteroaryl group is optionally composed of one or more elements independently selected from halogen, D, OH, CN, -NH2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups;

[0097] R 6 R 7 and R 8 Each occurrence is independently selected from H, halogen, CN, -NR. 9 R 10 -C(=O)NH(R) 11 -C(=O)R 12 -NHC(=O)R 12 -S(=O)2R11 -S(=O)2NR 9 R 10 -OR 12 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 Cycloalkoxy, C 6-10 aryl or 5-10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclic, cycloalkoxy, aryl, or heteroaryl group is optionally surrounded by one or more R groups. 14 replace;

[0098] Or R 5 and R 6 Together with the atoms it is attached to, they form C 5-8 cycloalkyl, 5-8 membered heterocyclic, C 6-10 Aryl or 5-10-membered heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally selected from one or more elements independently chosen from halogen, D, OH, CN, -NH2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups;

[0099] Or R 6 and R 7 Together with the atoms it is attached to, they form C 5-8 cycloalkyl, 5-8 membered heterocyclic, C 6-10 Aryl or 5-10-membered heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally selected from one or more elements independently chosen from halogen, D, OH, CN, -NH2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups;

[0100] Or R 7and R 8 Together with the atoms it is attached to, they form C 5-8 cycloalkyl, 5-8 membered heterocyclic, C 6-10 Aryl or 5-10-membered heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally selected from one or more elements independently chosen from halogen, D, OH, CN, -NH2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups;

[0101] R 9 and R 10 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, or -S(=O)2R 11 The alkyl, cycloalkyl, aryl, or heteroaryl group is optionally separated by one or more elements independently selected from D, halogen, OH, CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic groups, C 6-10 Substitution of aryl or 5-10 heteroaryl groups;

[0102] R 11 Each time it appears, it is independently selected from H and C. 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 cycloalkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, aryl or heteroaryl group is optionally separated from one or more elements independently selected from halogen, OH, CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 6-10 Substitution of aryl or 5-10 heteroaryl groups;

[0103] R 12 Each time it appears, it is independently selected from C. 1-4 Alkyl, C 3-8 cycloalkyl, C 6-10Aryl or 5-10 heteroaryl, wherein the alkyl, cycloalkyl, aryl or heteroaryl group is optionally separated from one or more elements independently selected from halogen, OH, CN, -C(=O)CH3, C 1-4 Alkyl or C 1-4 Substituents of haloalkyl groups;

[0104] R 13 Each time it appears, it is independently selected from H, halogen, OH, CN, C. 1-4 Alkyl or C 1-4 Halogenated alkyl groups;

[0105] R 14 Each occurrence is independently selected from H, halogen, D, OH, CN, -NR. 9 R 10 -C(=O)R 12 -NHC(=O)R 12 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-6 cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic groups, C 6-10 Aryl or 5-10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, cycloalkoxy, heterocyclic, aryl, or heteroaryl group is optionally selected from one or more elements independently chosen from halogen, D, OH, CN, -NR. 9 R 10 -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups;

[0106] Where R 4 When selected from H, R 7 Selected from -NR 9 R 10 , where R 9 Selected from H, C 1-6 Alkyl or C 3-8 cycloalkyl, R 10 Selected from C 6-10Aryl or 5-10 heteroaryl, wherein the alkyl, cycloalkyl, aryl or heteroaryl group is optionally separated by one or more elements independently selected from D, halogen, OH, CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl substitutions;

[0107] Or, when R 4 When selected from H, R 7 and R 8 Together with the atoms it is attached to, they form C 5-8 cycloalkyl, 5-8 membered heterocyclic, C 6-10 Aryl or 5-10-membered heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally selected from one or more elements independently chosen from halogen, D, OH, CN, -NH2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with a cycloalkoxy or 3-6 membered heterocyclic group, wherein the heteroaryl group is not:

[0108] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled compounds, esters, polymorphs, solvates, N-oxides, metabolites, or prodrugs.

[0109] In some embodiments, the compound of formula I provided by the present invention,

[0110] R 1 R 2 and R 3 Each time it appears, it is independently selected from H, OH, halogen, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl or C 3-6 cycloalkyl; or R 1 and R 3 Together with the atoms it is attached to, they form C 5-8Cycloalkyl, 5-8 membered heterocyclic, or 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclic, or heteroaryl group is optionally surrounded by one or more elements selected from halogen, OH, CN, -NH2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups;

[0111] R 4 Selected from H, -NR 9 R 10 -C(=O)NH(R) 11 -C(=O)R 12 -NHC(=O)R 12 C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 Cycloalkoxy, C 6-10 Aryl or 5-10-membered heteroaryl, wherein the alkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclic, cycloalkoxy, aryl, or heteroaryl group is optionally surrounded by one or more elements selected from halogen, D, OH, CN, -NR. 9 R 10 -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups;

[0112] X 1 Selected from CR 5 Or N;

[0113] X 2 Selected from CR 6 Or N;

[0114] X 3 Selected from CR 7 Or N;

[0115] X 4 Selected from CR 8 Or N;

[0116] Y and Z are each independently selected from CR 13 Or N;

[0117] R5 Selected from H, halogens, CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl or C 3-6 Cycloalkyl, wherein the alkyl, alkenyl, alkoxy, hydroxyalkyl or cycloalkyl group is optionally surrounded by one or more elements selected from halogen, D, OH, CN, -NR. 9 R 10 -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups; or R 4 and R 5 Together with the atoms to which it is attached, it forms a 5-8 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the heterocyclic group or heteroaryl group is optionally bonded by one or more elements selected from halogen, D, OH, CN, -NH2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups;

[0118] R 6 R 7 and R 8 Each occurrence is independently selected from H, halogen, CN, -NR. 9 R 10 -C(=O)NH(R) 11 -C(=O)R 12 -NHC(=O)R 12 -S(=O)2R 11 -S(=O)2NR 9 R 10 -OR 12 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 Cycloalkoxy, C 6-10aryl or 5-10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclic, cycloalkoxy, aryl, or heteroaryl group is optionally surrounded by one or more R groups. 14 replace;

[0119] Or R 5 and R 6 Together with the atoms it is attached to, they form C 5-8 cycloalkyl, 5-8 membered heterocyclic, C 6-10 Aryl or 5-10-membered heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more elements selected from halogen, D, OH, CN, -NH2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups;

[0120] Or R 6 and R 7 Together with the atoms it is attached to, they form C 5-8 cycloalkyl, 5-8 membered heterocyclic, C 6-10 Aryl or 5-10-membered heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more elements selected from halogen, D, OH, CN, -NH2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups;

[0121] Or R 7 and R 8 Together with the atoms it is attached to, they form C 5-8 cycloalkyl, 5-8 membered heterocyclic, C 6-10 Aryl or 5-10-membered heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more elements selected from halogen, D, OH, CN, -NH2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups;

[0122] R 9 and R 10 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, or -S(=O)2R 11 The alkyl, cycloalkyl, aryl, or heteroaryl group is optionally surrounded by one or more elements selected from D, halogen, OH, CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic groups, C 6-10 Substitution of aryl or 5-10 heteroaryl groups;

[0123] R 11 Each time it appears, it is independently selected from H and C. 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 cycloalkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, aryl or heteroaryl group is optionally surrounded by one or more elements selected from halogen, OH, CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 6-10 Substitution of aryl or 5-10 heteroaryl groups;

[0124] R 12 Each time it appears, it is independently selected from C. 1-4 Alkyl, C 3-8 cycloalkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein the alkyl, cycloalkyl, aryl or heteroaryl group is optionally surrounded by one or more elements selected from halogen, OH, CN, -C(=O)CH3, C 1-4 Alkyl or C 1-4 Substituents of haloalkyl groups;

[0125] R 13 Each time it appears, it is independently selected from H, halogen, OH, CN, C. 1-4 Alkyl or C 1-4 Halogenated alkyl groups;

[0126] R 14Each occurrence is independently selected from H, halogen, D, OH, CN, -NR. 9 R 10 -C(=O)R 12 -NHC(=O)R 12 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-6 cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic groups, C 6-10 Aryl or 5-10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, cycloalkoxy, heterocyclic, aryl, or heteroaryl group is optionally selected from one or more elements chosen from halogen, D, OH, CN, -NR. 9 R 10 -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups;

[0127] Where R 4 When selected from H, R 7 Selected from -NR 9 R 10 , where R 9 Selected from H, C 1-6 Alkyl or C 3-8 cycloalkyl, R 10 Selected from C 6-10 Aryl or 5-10 heteroaryl, wherein the alkyl, cycloalkyl, aryl or heteroaryl group is optionally surrounded by one or more elements selected from D, halogen, OH, CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl substitutions.

[0128] In some embodiments, in the compound of formula I provided by the present invention, R 1 and R2 Each time it appears, it is independently selected from H, halogen, C. 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Deuterated alkyl groups.

[0129] In some embodiments, in the compound of formula I provided by the present invention, R 1 and R 2 Each time it appears, it is independently selected from H, halogen, C. 1-4 Alkyl or C 1-4 Halogenated alkyl groups.

[0130] In some embodiments, in the compound of formula I provided by the present invention, R 1 and R 2 Each time it appears, it is independently selected from H and C. 1-4 Alkyl or C 1-4 Deuterated alkyl groups.

[0131] In some embodiments, in the compound of formula I provided by the present invention, R 1 and R 2 Each time it appears, it is independently selected from H or C. 1-4 alkyl.

[0132] In some embodiments, in the compound of formula I provided by the present invention, R 1 and R 2 All are C 1-4 alkyl.

[0133] In some embodiments, in the compound of formula I provided by the present invention, R 1 and R 2 All are methyl groups.

[0134] In some embodiments, in the compound of formula I provided by the present invention, R 3 It is OH.

[0135] In some embodiments, in the compound of formula I provided by the present invention, R 1 and R 3 Together with the atoms they are attached to, they form a 5-10 membered heteroaryl group, wherein the heteroaryl group is optionally surrounded by one or more atoms independently selected from halogen, OH, CN, -NH2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups.

[0136] In some embodiments, in the compound of formula I provided by the present invention, R1 and R 3 Together with the atoms to which they are attached, a pyrazol group is formed, which is optionally formed by one or more atoms independently selected from halogens or C. 1-4 Alkyl substituents.

[0137] In some embodiments, in the compound of formula I provided by the present invention, R 1 and R 3 Together with the atoms they are attached to, they form a pyrazol group.

[0138] In some embodiments, in the compound of formula I provided by the present invention, R 1 and R 3 Together with the atoms to which they are attached, they form a 5-10 member heteroaryl group (e.g., a pyrazolyl group), which is optionally surrounded by one or more atoms independently selected from halogen, OH, CN, -NH2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution of cycloalkoxy or 3-6 membered heterocyclic groups; R 2 Selected from H, halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Deuterated alkyl groups.

[0139] In some embodiments, in the compound of formula I provided by the present invention, R 1 and R 2 Each time it appears, it is independently selected from H, halogen, C. 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Deuterated alkyl; R 3 It is OH.

[0140] In some embodiments, in the compound of formula I provided by the present invention, R 4 Selected from C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the alkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, and heterocyclic groups are optionally selected independently from one or more halogens, D, OH, CN, -NR. 9 R 10 -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups.

[0141] In some embodiments, in the compound of formula I provided by the present invention, R 4 Selected from C 1-6 Alkyl or C 3-8 Cycloalkyl groups, wherein the alkyl or cycloalkyl group is optionally composed of one or more elements independently selected from halogens, D, OH, CN, C. 1-4 Alkyl or C 1-4 Substitution of alkyl halogens.

[0142] In some embodiments, in the compound of formula I provided by the present invention, R 4 Selected from C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more substituents independently selected from halogens or D.

[0143] In some embodiments, in the compound of formula I provided by the present invention, R 4 Examples include methyl, ethyl, deuterated methyl, cyclopropyl, etc.

[0144] In some embodiments, in the compound of formula I provided by the present invention, X 1 Selected from CR 5 .

[0145] In some embodiments, in the compound of formula I provided by the present invention, R 5 Selected from H, halogens, C 1-6 Alkyl or C 3-6 Cycloalkyl groups, wherein the alkyl or cycloalkyl group is optionally composed of one or more elements independently selected from halogens, D, OH, CN, C. 1-4 Alkyl or C 1-4 Substitution of haloalkyl groups; or R 4 and R 5 Together with the atoms to which it is attached, it forms a 5-8 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the heterocyclic group or heteroaryl group is optionally composed of one or more elements independently selected from halogen, D, OH, CN, -NH2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups.

[0146] In some embodiments, in the compound of formula I provided by the present invention, R 5 Selected from H, halogens, C 1-4 Alkyl or C 3-6Cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more substituents independently selected from halogen or D; or R 4 and R 5 Together with the atoms to which they are attached, they form a 5-6 membered heterocyclic group, which is optionally composed of one or more elements independently selected from halogens, D, OH, CN, -NH2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups.

[0147] In some embodiments, in the compound of formula I provided by the present invention, R 5 Selected from H, halogen or C 1-4 Alkyl groups, optionally substituted with one or more substituents independently selected from halogens or D; or R 4 and R 5 Together with the atoms to which it is attached, it forms a 6-membered heterocyclic group, which is optionally composed of one or more atoms independently selected from halogens, D, OH, CN, -NH2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy or C 3-6 Substitution of cycloalkyl groups.

[0148] In some embodiments, in the compound of formula I provided by the present invention, R 5 Selected from H, halogens, C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more substituents independently selected from halogens or D.

[0149] In some embodiments, in the compound of formula I provided by the present invention, R 5 Selected from H, halogen or C 1-4 Alkyl group, which is optionally substituted with one or more substituents independently selected from halogens or D.

[0150] In some embodiments, in the compound of formula I provided by the present invention, R 5 It is H or a halogen (e.g., chlorine).

[0151] In some embodiments, in the compound of formula I provided by the present invention, R 4 and R 5Together with the atoms to which it is attached, it forms a 5-8 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the heterocyclic group or heteroaryl group is optionally composed of one or more elements independently selected from halogen, D, OH, CN, -NH2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups.

[0152] In some embodiments, in the compound of formula I provided by the present invention, R 4 and R 5 Together with the atoms to which they are attached, they form a 5-6 membered heterocyclic group, which is optionally composed of one or more elements independently selected from halogens, D, OH, CN, -NH2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups.

[0153] In some embodiments, in the compound of formula I provided by the present invention, R 4 and R 5 Together with the atoms to which it is attached, it forms a 6-membered heterocyclic group, which is optionally composed of one or more atoms independently selected from halogens, D, OH, CN, -NH2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy or C 3-6 Substitution of cycloalkyl groups.

[0154] In some embodiments, in the compound of formula I provided by the present invention, R 4 and R 5 Together with the atoms to which it is attached, it forms a heterocyclic group selected from the following: The heterocyclic group is optionally selected from one or more independently chosen from halogen, D, OH, CN, -NH2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy or C 3-6 Substitution of cycloalkyl groups.

[0155] In some embodiments, in the compound of formula I provided by the present invention, R 4 and R 5Together with the atoms they are attached to, they form heterocyclic group structures selected from the following:

[0156] In some embodiments, in the compound of formula I provided by the present invention, X 2 Selected from CR 6 .

[0157] In some embodiments, in the compound of formula I provided by the present invention, R 6 R 7 and R 8 Each is independently selected from H, halogens, CN, -C(=O)R 12 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 Cycloalkoxy, C 6-10 aryl or 5-10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclic, cycloalkoxy, aryl, or heteroaryl group is optionally surrounded by one or more R groups. 14 replace;

[0158] Or R 5 and R 6 Together with the atoms it is attached to, they form C 6-10 Aryl or 5-10 heteroaryl, wherein the aryl or heteroaryl group is optionally composed of one or more elements independently selected from halogen, D, OH, CN, -NH2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups.

[0159] In some embodiments, in the compound of formula I provided by the present invention, R 6 R 7 and R 8 Each is independently selected from H, halogens, CN, -C(=O)R 12 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 Cycloalkoxy, phenyl, or 5-6-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclic, cycloalkoxy, phenyl, or heteroaryl group is optionally surrounded by one or more R groups. 14 replace;

[0160] Or R 5 and R 6 Together with the atoms to which they are attached, they form an aryl or a 5-6 membered heteroaryl group, wherein the aryl or heteroaryl group is optionally separated from one or more elements independently selected from halogen, D, OH, CN, -NH2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups.

[0161] In some embodiments, in the compound of formula I provided by the present invention, R 6 R 7 and R 8 Each is independently selected from H, halogens, CN, -C(=O)R 12 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 Cycloalkoxy, C 6-10 aryl or 5-10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclic, cycloalkoxy, aryl, or heteroaryl group is optionally surrounded by one or more R groups. 14 replace.

[0162] In some embodiments, in the compound of formula I provided by the present invention, R 6 R 7 and R 8 Each is independently selected from H, halogens, CN, -C(=O)R 12 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-8Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 Cycloalkoxy, phenyl, or 5-6-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclic, cycloalkoxy, phenyl, or heteroaryl group is optionally surrounded by one or more R groups. 14 replace.

[0163] In some embodiments, in the compound of formula I provided by the present invention, R 6 Selected from H, halogens, C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group (e.g., piperidinyl, oxetyl), wherein the alkyl, cycloalkyl or heterocyclic group is optionally surrounded by one or more R 14 replace.

[0164] In some embodiments, in the compound of formula I provided by the present invention, R 5 and R 6 Together with the atoms it is attached to, they form C 6-10 Aryl or 5-10 heteroaryl, wherein the aryl or heteroaryl group is optionally composed of one or more elements independently selected from halogen, D, OH, CN, -NH2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups.

[0165] In some embodiments, in the compound of formula I provided by the present invention, R 5 and R 6 Together with the atoms they are attached to, they form aryl or 5-6 heteroaryl groups (e.g. The aryl or heteroaryl group is optionally composed of one or more elements independently selected from halogens, D, OH, CN, -NH2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups.

[0166] In some implementations, R 7 Selected from H, halogen, CN, -NR 9 R 10 -C(=O)R 12 C 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 Cycloalkoxy, C 6-10 aryl or 5-10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclic, cycloalkoxy, aryl, or heteroaryl group is optionally surrounded by one or more R groups. 14 replace.

[0167] In some embodiments, in the compound of formula I provided by the present invention, when R 4 When R is not H, 7 Preferably selected from H, halogens, CN, -C(=O)R 12 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 Cycloalkoxy, phenyl, or 5-6-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclic, cycloalkoxy, phenyl, or heteroaryl group is optionally surrounded by one or more R groups. 14 replace.

[0168] In some embodiments, in the compound of formula I provided by the present invention, when R 4 When R is not H, 7 Preferably selected from H, halogens, and -C(=O)R 12 C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic (e.g., piperidinyl, piperazine), 5-6 membered heteroaryl (e.g., oxazolyl), wherein the alkyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, or heteroaryl group is optionally surrounded by one or more R 14 replace.

[0169] In some embodiments, in the compound of formula I provided by the present invention, when R 4 When it is H, R 7 Selected from -NR 9 R 10 , where R 9 Selected from H, C 1-6 Alkyl or C 3-8cycloalkyl, R 10 Selected from C 6-10 Aryl or 5-10 heteroaryl (e.g., pyrazolyl, pyrazinyl, pyrimidinyl), wherein the alkyl, cycloalkyl, aryl, or heteroaryl group is optionally surrounded by one or more elements independently selected from D, halogen, OH, CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl substitutions.

[0170] In some embodiments, in the compound of formula I provided by the present invention, when R 4 When it is H, R 7 Selected from -NR 9 R 10 , where R 9 Selected from C 1-6 Alkyl or C 1-6 Deuterated alkyl, R 10 Selected from

[0171] In some embodiments, in the compound of formula I provided by the present invention, when R 4 When it is H, R 7 and R 8 Together with the atoms it is attached to, they form C 5-8 cycloalkyl, 5-8 membered heterocyclic, C 6-10 Aryl or 5-10-membered heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally selected from one or more elements independently chosen from halogen, D, OH, CN, -NH2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with a cycloalkoxy or 3-6 membered heterocyclic group, wherein the heteroaryl group is not:

[0172] In some embodiments, in the compound of formula I provided by the present invention, when R 4 When it is H, R 7 and R 8 Together with the atoms to which they are attached, they form a pyridone or pyrimidinone group, which is optionally composed of one or more atoms independently selected from halogens, D, OH, CN, -NH2, C.1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups.

[0173] In some embodiments, in the compound of formula I provided by the present invention, when R 4 When it is H, R 7 and R 8 Together with the atoms it is connected to form

[0174] In some embodiments, in the compound of formula I provided by the present invention, R 8 Selected from H or halogens.

[0175] In some embodiments, in the compound of formula I provided by the present invention, R 9 and R 10 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-8 cycloalkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein the alkyl, cycloalkyl, aryl or heteroaryl group is optionally separated by one or more elements independently selected from D, halogen, OH, CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic groups, C 6-10 Substitution with aryl or 5-10 heteroaryl groups.

[0176] In some embodiments, in the compound of formula I provided by the present invention, R 9 and R 10 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-8 cycloalkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein the alkyl, cycloalkyl, aryl or heteroaryl group is optionally separated by one or more elements independently selected from D, halogen, OH, CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups.

[0177] In some embodiments, in the compound of formula I provided by the present invention, R 9 and R 10 Each time it appears, it is independently selected from H or C. 1-4 Alkyl groups, optionally separated by one or more elements independently selected from D, halogens, OH, CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic groups, C 6-10 Substitution with aryl or 5-10 heteroaryl groups.

[0178] In some embodiments, in the compound of formula I provided by the present invention, R 9 Selected from H, C 1-6 Alkyl or C 3-8 cycloalkyl, R 10 Selected from C 6-10 Aryl or 5-10 heteroaryl, wherein the alkyl, cycloalkyl, aryl or heteroaryl group is optionally separated by one or more elements independently selected from D, halogen, OH, CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic groups, C 6-10 Substitution with aryl or 5-10 heteroaryl groups.

[0179] In some embodiments, in the compound of formula I provided by the present invention, R 11 Each time it appears, it is independently selected from H and C. 1-4 Alkyl, C 3-8 cycloalkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein the alkyl, cycloalkyl, aryl or heteroaryl group is optionally separated from one or more elements independently selected from halogen, OH, CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 6-10 Substitution with aryl or 5-10 heteroaryl groups.

[0180] In some embodiments, in the compound of formula I provided by the present invention, R 11 Each time it appears, it is independently selected from C.1-4 Alkyl or C 3-6 Cycloalkyl groups, wherein the alkyl or cycloalkyl group is optionally separated from one or more halogens, OH, CN or C. 1-4 Alkyl substituents.

[0181] In some embodiments, in the compound of formula I provided by the present invention, R 12 Each time it appears, it is independently selected from C. 1-4 Alkyl or C 3-8 Cycloalkyl groups, wherein the alkyl group or cycloalkyl group is optionally composed of one or more elements independently selected from halogens, OH, CN, -C(=O)CH3, C 1-4 Alkyl or C 1-4 Substitution of alkyl halogens.

[0182] In some embodiments, in the compound of formula I provided by the present invention, Y is selected from CR 13 .

[0183] In some embodiments, in the compound of formula I provided by the present invention, Z is selected from CR. 13 .

[0184] In some embodiments, in the compound of formula I provided by the present invention, Y and Z are both selected from CR. 13 .

[0185] In some embodiments, in the compound of formula I provided by the present invention, R 13 Each time it appears, it is independently selected from H, halogen, or C. 1-4 alkyl.

[0186] In some embodiments, in the compound of formula I provided by the present invention, R 13 Each time it appears, it is independently selected from H or halogen.

[0187] In some embodiments, in the compound of formula I provided by the present invention, R 14 Each time it appears, it is independently selected from H, halogen, D, OH, or C. 1-6 Alkyl groups, optionally composed of one or more elements independently selected from halogens, D, OH, CN, and -NR. 9 R 10 -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups.

[0188] In some embodiments, the compound represented by Formula I is the compound represented by Formula IA:

[0189]

[0190] Among them, R 2 R 13 X 2 X 3 and X 4 As defined in any of the implementation schemes in Equation I.

[0191] In some embodiments, the compound represented by Formula I is the compound represented by Formula IB:

[0192]

[0193] Among them, R 2 R 13 X 1 X 2 and X 4 As defined in any implementation scheme of Equation I, R 9 Selected from H, C 1-6 Alkyl or C 3-8 cycloalkyl, R 10 Selected from C 6-10 Aryl or 5-10 heteroaryl (e.g., pyrazolyl, pyrazinyl, pyrimidinyl), wherein the alkyl, cycloalkyl, aryl, or heteroaryl group is optionally surrounded by one or more elements independently selected from D, halogen, OH, CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic groups, C 6-10 Substitution with aryl or 5-10 heteroaryl groups.

[0194] In some embodiments, in the compound of formula IB provided by the present invention, R 9 Selected from C 1-6 Alkyl or C 1-6 Deuterated alkyl, R 10 Selected from

[0195] In some embodiments, in the compound of formula IB provided by the present invention, R 9 Selected from C 1-4 Alkyl or C 1-4 Deuterated alkyl, R 10 Selected from

[0196] In some embodiments, in the compound of formula IB provided by the present invention, R 9 Selected from methyl or deuterated methyl, R 10 Selected from

[0197] In some embodiments, in the compound of formula IB provided by the present invention, R 9 It is methyl, R 10 Selected from

[0198] In some embodiments, in the compound of formula IB provided by the present invention, X 1 For CR 5 ;R 5 Selected from H, halogens, C 1-6 Alkyl or C 3-6 Cycloalkyl groups, wherein the alkyl or cycloalkyl group is optionally composed of one or more elements independently selected from halogens, D, OH, CN, C. 1-4 Alkyl or C 1-4 Substitution of alkyl halogens.

[0199] In some embodiments, in the compound of formula IB provided by the present invention, X 1 For CR 5 ;R 5 Selected from H, halogen or C 1-6 alkyl.

[0200] In some embodiments, in the compound of formula IB provided by the present invention, X 1 For CH.

[0201] In some embodiments, in the compound of formula IB provided by the present invention, X 2 For CR 6 ;R 6 Selected from H, halogens, C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group is optionally surrounded by one or more R groups. 14 replace.

[0202] In some embodiments, in the compound of formula IB provided by the present invention, X 2 For CR 6 ;R 6 Selected from H, halogens, C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups.

[0203] In some embodiments, in the compound of formula IB provided by the present invention, X 2 For CH.

[0204] In some embodiments, in the compound of formula IB provided by the present invention, X 1 and X 2 All are CH.

[0205] In some embodiments, in the compound of formula IB provided by the present invention, X 4 Let N be the number of elements in the array.

[0206] In some embodiments, the compound represented by Formula I is a compound represented by Formulas I-B':

[0207]

[0208] Among them, R 2 and R 13 As defined in any implementation scheme of Equation I, R 9 Selected from H, C 1-6 Alkyl or C 3-8 cycloalkyl, R 10 Selected from C 6-10 Aryl or 5-10 heteroaryl (e.g., pyrazolyl, pyrazinyl, pyrimidinyl), wherein the alkyl, cycloalkyl, aryl, or heteroaryl group is optionally surrounded by one or more elements independently selected from D, halogen, OH, CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic groups, C 6-10 Substitution with aryl or 5-10 heteroaryl groups.

[0209] In some embodiments, in the compounds of formula I-B' provided by the present invention, R 9 Selected from C 1-6 Alkyl or C 1-6 Deuterated alkyl, R 10 Selected from

[0210] In some embodiments, in the compounds of formula I-B' provided by the present invention, R 9 Selected from C 1-4 Alkyl or C 1-4 Deuterated alkyl, R 10 Selected from

[0211] In some embodiments, in the compounds of formula I-B' provided by the present invention, R 9 Selected from methyl or deuterated methyl, R 10 Selected from

[0212] In some embodiments, in the compounds of formula I-B' provided by the present invention, R 9 It is methyl, R 10 Selected from

[0213] In some embodiments, in the compounds of formula I-B' provided by the present invention, R 2 Selected from H, halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Deuterated alkyl groups.

[0214] In some embodiments, in the compounds of formula I-B' provided by the present invention, R 2 Selected from H, halogens, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups.

[0215] In some embodiments, in the compounds of formula I-B' provided by the present invention, R 2 For H.

[0216] In some embodiments, in the compounds of formula I-B' provided by the present invention, R 13 Selected from H, halogen or C 1-4 alkyl.

[0217] In some embodiments, in the compounds of formula I-B' provided by the present invention, R 13 It is H or halogen.

[0218] In some embodiments, in the compounds of formula I-B' provided by the present invention, R 13 It is H, fluorine or chlorine, preferably H or fluorine.

[0219] In some embodiments, in the compounds of formula IB and / or formula I-B' provided by the present invention, for Preferably, for

[0220] In some embodiments, the compound represented by Formula I is the compound represented by Formula I:

[0221]

[0222] Among them, R 2 R 13 X 1 X 2 As defined in any implementation scheme of Equation I, R 7 and R 8Together with the atoms it is attached to, they form C 5-8 cycloalkyl, 5-8 membered heterocyclic, C 6-10 Aryl or 5-10-membered heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally selected from one or more elements independently chosen from halogen, D, OH, CN, -NH2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with a cycloalkoxy or 3-6 membered heterocyclic group, wherein the heteroaryl group is not:

[0223] In some embodiments, in the IC compound provided by the present invention, R 7 and R 8 Together with the atoms to which they are attached, they form a pyridone or pyrimidinone group, which is optionally composed of one or more atoms independently selected from halogens, D, OH, CN, -NH2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups.

[0224] In some embodiments, in the IC compound provided by the present invention, R 7 and R 8 Together with the atoms it is connected to form

[0225] In some embodiments, the compound represented by Formula I is the compound represented by Formula ID:

[0226]

[0227] in,

[0228] R 4 Selected from C 1-6 Alkyl or C 3-8 Cycloalkyl groups, wherein the alkyl or cycloalkyl group is optionally composed of one or more elements independently selected from halogens, D, OH, CN, C. 1-4 Alkyl or C 1-4 Substituents of haloalkyl groups;

[0229] R 5 Selected from H, halogens, C 1-6 Alkyl or C 3-6 Cycloalkyl groups, wherein the alkyl or cycloalkyl group is optionally composed of one or more elements independently selected from halogens, D, OH, CN, C. 1-4 Alkyl or C 1-4 Substituents of haloalkyl groups;

[0230] R 2 R 13 X 2 X 3 and X 4 As defined in any of the implementation schemes in Equation I.

[0231] In some embodiments, in the compound of formula ID provided by the present invention, R 4 Selected from C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more substituents independently selected from halogens or D.

[0232] In some embodiments, in the compound of formula ID provided by the present invention, R 4 Examples include methyl, ethyl, deuterated methyl, cyclopropyl, etc.

[0233] In some embodiments, the compound represented by Formula I is the compound represented by Formula IE:

[0234]

[0235] in,

[0236] R 4 Selected from C 1-6 Alkyl or C 3-8 Cycloalkyl groups, wherein the alkyl or cycloalkyl group is optionally composed of one or more elements independently selected from halogens, D, OH, CN, C. 1-4 Alkyl or C 1-4 Substituents of haloalkyl groups;

[0237] R 2 R 13 X 3 and X 4 As defined in any of the implementation schemes in Equation I.

[0238] In some embodiments, in the IE compound provided by the present invention, R 4 Selected from C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with one or more substituents independently selected from halogens or D.

[0239] In some embodiments, in the IE compound provided by the present invention, R 4 Examples include methyl, ethyl, deuterated methyl, cyclopropyl, etc.

[0240] In some embodiments, the compounds of this application may optionally be substituted at the positions where substitution is possible by suitable substituents selected from: deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl compounds.

[0241] This invention covers any combination of the above embodiments.

[0242] In some embodiments, the compounds of the present invention include, but are not limited to:

[0243]

[0244]

[0245]

[0246] Beneficial effects

[0247] The compounds disclosed herein can achieve at least one of the following technical effects:

[0248] (1) It has regulatory activity on PKMYT1 activity.

[0249] (2) Excellent physicochemical properties (e.g., solubility, physical and / or chemical stability).

[0250] (3) Excellent pharmacokinetic properties (e.g., good bioavailability, appropriate half-life and duration of action).

[0251] (4) Excellent safety (lower toxicity and / or fewer side effects, wider therapeutic window), etc.

[0252] Preparation method

[0253] 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 skilled in the art. Individual isomers, enantiomers and diastereomers can be separated or resolved at any convenient point in the synthesis by methods such as selective crystallization or chiral chromatography (see, for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions").

[0254] In some embodiments, the present invention provides a method for preparing a compound of formula IA, comprising one or more of the following steps:

[0255] Step 1: Compound IA-1 and compound IA-2 are subjected to a Suzuki or Stille cross-coupling reaction to obtain compound IA-3;

[0256]

[0257] Step 2: Compound IA-3 is reduced to obtain compound IA-4;

[0258]

[0259] Step 3: Compound IA-4 was deprotected to obtain compound IA;

[0260]

[0261] in

[0262] L 1 and L 2 One of them is a leaving group such as OTf, Br, I, etc., another is trimethyltin, tri-n-butyltin, borate, pinacol borate, etc., and the remaining groups are as defined above.

[0263] In some embodiments of the present invention, the Suzuki cross-coupling reaction in the first step is carried out in the presence of a base, preferably NaHCO3, Na2CO3, K2CO3, Cs2CO3, or K3PO4, etc. The catalysts that can be used are Pd(dppf)Cl2, Pd(dppf)Cl2·DCM, Pd(PPh3)4, or a combination of Pd2(dba)3 and XantPhos, X-phos Pd G3, or cataCXium APd G3. The solvents that can be used are, for example, a mixture of 1,4-dioxane and water. In the Stille cross-coupling reaction in the first step, the catalysts that can be used are Pd(dppf)Cl2, Pd(dppf)Cl2·CH2Cl2, Pd(PPh3)4, or Pd(PPh3)2Cl2. The solvents that can be used are, for example, 1,4-dioxane, toluene, etc.

[0264] In some embodiments of the present invention, the reduction reaction in the second step is preferably carried out in SnCl2·2H2O, Raney nickel or Pd / C or Pd(OH)2 or a combination of Pt and H2, iron powder or zinc powder and NH4Cl, etc., and the solvents that can be used are, for example, a mixture of methanol, ethanol, acetic acid, THF and water.

[0265] In some embodiments of the present invention, the deprotection reaction in the third step described above is preferably carried out under the action of an acid, such as a 4M HCl solution of 1,4-dioxane, a methanol solution, an ethanol solution, an aqueous solution, or trifluoroacetic acid.

[0266] In some embodiments, the present invention provides a method for preparing compounds of formula IB, comprising reacting a compound of formula IB-1 with NHR. 9 R 10 The reaction produces a compound of formula IB:

[0267]

[0268] Among them, L 3 Selected from halogens; X 1 X 2 X 4 R 2 R 9 R 10 and R 13 As defined in any of the aforementioned implementation schemes.

[0269] In some embodiments, the catalyst used in the above steps is preferably (SP-4-1)-(1,3-bis(2,6-bis(1-propylbutyl)phenyl)-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylene)dichloro(3-chloropyridine-KN)palladium. The base used is preferably sodium tert-butoxide, potassium tert-butoxide, etc.; the solvent that can be used is preferably 1,4-dioxane. The reaction is preferably carried out in a microwave reactor.

[0270] intermediate

[0271] In some embodiments, the present invention provides intermediate compounds or salts thereof, stereoisomers, tautomers, isotopically labeled compounds, esters, polymorphs, solvates, and N-oxides as shown below:

[0272]

[0273] Where L 1 L 2 L 3 X 1 X 2 X 3 X 4 R 2 R 13 As defined in any of the preceding items;

[0274] PG 1 The amino protecting group is, for example, an alkoxycarbonyl amino protecting group, such as benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl (or ethoxycarbonyl); an acyl amino protecting group, such as phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), o-(p-)nitrobenzenesulfonyl (Ns), tert-pentanoyl, benzoyl, tert-butoxycarbonyl, 9-fluorenemethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, trimethylsilylethoxycarbonyl, benzyloxycarbonyl, p-methylbenzenesulfonyl, p-nitrobenzenesulfonyl, trifluoroacetyl, methoxycarbonyl, or ethoxycarbonyl; an alkyl amino protecting group, such as triphenylmethyl (Trt), C 1-6 Alkyl-substituted triphenylmethyl, p-methoxytriphenylmethyl (MMT), dimethoxytriphenylmethyl (DMT), 2,4-dimethoxybenzyl (Dmb), 4-methoxybenzyl (PMB), benzyl (Bn); or tetrahydropyranyl (THP).

[0275] In some implementation schemes, PG 1 For THP.

[0276] In some embodiments, the intermediates of the present invention can be used to prepare compounds of the general formula herein or pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled compounds, esters, polymorphs, solvates, N-oxides, metabolites or prodrugs thereof.

[0277] Pharmaceutical compositions, formulations and treatments

[0278] In some embodiments, the present invention provides pharmaceutical compositions comprising a preventive or therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, ester, polymorph, solvate, N-oxide, metabolite or prodrug, and one or more pharmaceutically acceptable carriers.

[0279] In some embodiments, the present invention provides a pharmaceutical formulation of the aforementioned pharmaceutical composition, wherein the pharmaceutical formulation is preferably a solid formulation, a semi-solid formulation, a liquid formulation, or a gaseous formulation.

[0280] In some embodiments, the pharmaceutical composition or pharmaceutical formulation may also contain one or more other therapeutic agents.

[0281] In some embodiments, the pharmaceutical composition or pharmaceutical preparation is preferably administered orally, intravenously, intra-arterially, subcutaneously, intraperitoneally, intramuscularly, or transdermally.

[0282] In some embodiments, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled compounds, esters, polymorphs, solvates, N-oxides, metabolites or prodrugs thereof, or pharmaceutical compositions or pharmaceutical preparations of the present invention in the preparation of medicaments, particularly medicaments for the prevention or treatment of diseases or conditions associated with PKMYT1 activity.

[0283] In some embodiments, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled compounds, esters, polymorphs, solvates, N-oxides, metabolites or prodrugs thereof, or pharmaceutical compositions or pharmaceutical formulations of the present invention, for modulating (e.g., reducing or inhibiting) PKMYT1 activity, particularly in the preparation of medicaments for modulating (e.g., reducing or inhibiting) PKMYT1 activity.

[0284] In some embodiments, the present invention provides compounds of the present invention or pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled compounds, esters, polymorphs, solvates, N-oxides, metabolites or prodrugs thereof, or pharmaceutical compositions or pharmaceutical preparations of the present invention for the prevention or treatment of diseases or conditions, particularly those related to PKMYT1 activity.

[0285] In some embodiments, the present invention provides a method for preventing or treating diseases or conditions associated with PKMYT1 activity, the method comprising administering to an individual in need an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, ester, polymorph, solvate, N-oxide, metabolite or prodrug of the present invention, or a pharmaceutical composition or formulation of the present invention.

[0286] In some embodiments, the disease or condition associated with PKMYT1 activity is cancer or tumor, preferably a cancer or tumor with high CCNE1 expression / CCNE1 amplification.

[0287] In some implementations, the cancer or tumor is thyroid cancer, stomach cancer, lung cancer, breast cancer, or ovarian cancer.

[0288] In this invention, "pharmaceutically acceptable carrier" refers to a diluent, excipient, vehicle, or medium that is administered co-administered with a therapeutic agent and is suitable, to the extent of reasonable medical judgment, for contact with human and / or other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0289] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

[0290] The pharmaceutical compositions of the present invention can act systemically and / or locally. For this purpose, they can be administered via suitable routes.

[0291] For these routes of administration, the pharmaceutical compositions of the present invention can be administered in suitable dosage forms.

[0292] As used in this article, the term "effective amount" refers to the amount of a compound that, when administered, will alleviate one or more symptoms of the treated condition to some extent.

[0293] The dosing regimen can be adjusted to provide the optimal required response. For example, a single bolus injection can be administered, several fractions can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the treatment situation. It should be noted that dosage values ​​can vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. To further understand, for any given individual, the specific dosing regimen should be adjusted over time based on individual needs and the professional judgment of the person administering the composition or supervising its administration.

[0294] The amount of the compound of the present invention administered will depend on the individual being treated, the severity of the condition or illness, the rate of administration, the disposal of the compound, and the judgment of the prescribing physician. Generally, the effective dose is from about 0.0001 to about 50 mg per kg of body weight per day. In some cases, dose levels not exceeding the lower limit of the foregoing range may be sufficient, while in other cases, larger doses may still be used without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses for administration throughout the day.

[0295] The content or amount of the compound of the present invention in a pharmaceutical composition or pharmaceutical preparation may be from about 0.01 mg to about 1000 mg.

[0296] Unless otherwise stated, as used herein, the term "prevention" means the prior administration of a medication to avoid or prevent the occurrence of one or more symptoms of a disease or condition, or to prevent the cause, effect, symptoms, or progression of a disease or condition before it fully manifests. Those skilled in the art of medicine will recognize that the term "prevention" is not an absolute term. In the medical field, it should be understood as the preventive administration of a medication to substantially reduce the likelihood or severity of a condition or its symptoms, as is the intended meaning in this disclosure.

[0297] The term “treating” means to reverse, alleviate, or suppress the progression of one or more symptoms of a disease or condition to which such terms are applied.

[0298] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0299] In some embodiments, the pharmaceutical composition or pharmaceutical preparation of the present invention may further comprise one or more additional therapeutic or preventative agents (e.g., other drugs for treating cancer or tumor diseases). In some embodiments, the treatment methods of the present invention may further include administering one or more additional therapeutic or preventative agents (e.g., other drugs for treating cancer or tumor diseases). Detailed Implementation

[0300] Example

[0301] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the invention.

[0302] The abbreviations used in this article have the following meanings:

[0303]

[0304] The compounds of this invention are separated and purified by preparative TLC, silica gel column chromatography, Prep-HPLC and / or fast column chromatography (Flash column chromatography), and their structures are determined by... 1 Confirmation was performed using 1H NMR and / or MS. Reaction monitoring was performed using TLC or LC-MS.

[0305] 1 The H NMR spectroscopy method was performed using a Bruker superconducting nuclear magnetic resonance spectrometer (model AVACE III HD 400MHz).

[0306] LC / MS uses Aglient 1260Infinity / Aglient 6120Quadrupole.

[0307] TLC uses silica gel GF 254 as the stationary phase.

[0308] Column chromatography typically uses 200-300 mesh silica gel (Qingdao Ocean) as the stationary phase.

[0309] The rapid column chromatography method uses the Biotage rapid column chromatograph.

[0310] Prep-HPLC was performed using an Agilent 1260 and a Waters 2489.

[0311] The microwave reaction was carried out using the BiotageInitiator microwave reactor.

[0312] In the following examples, unless otherwise specified, the reaction temperature is room temperature (15-30°C).

[0313] The reagents used in this application were purchased from Acros Organics, Aldrich Chemical Company, or TEB Chemicals, etc.

[0314] Separation methods

[0315] Prep-HPLC purification of the compounds in the examples was performed using an Aglient 1260 or Waters 2489 HPLC system, with Waters SunFire Prep C columns. 18 OBD(19mm×150mm×5.0μm), WatersXbridge Prep C 18 OBD (19mm×150mm×5.0μm) or YMC Actus Triart C 18 (20mm×150mm×5.0μm), column temperature 25℃, detection wavelength 214nm, 254nm or 280nm, mobile phase A is acetonitrile, mobile phase B is 0.05% formic acid aqueous solution or 0.05% ammonium bicarbonate aqueous solution or 0.05% TFA aqueous solution, the volume ratio of the mobile phase is adjusted according to the polarity of the compound; the mobile phase flow rate is 28mL / min.

[0316] The following examples are merely illustrative, and those skilled in the art will understand that other compounds of this application can also be synthesized similarly with reference to the following examples.

[0317] Synthesis Example:

[0318] In the examples, intermediate Int A: 7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-indazole

[0319]

[0320] Step 1: Synthesis of 4-bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (compound Int A-2)

[0321] Compound Int A-1 (10 g, 45.58 mmol) and p-toluenesulfonic acid (784.84 mg, 4.56 mmol) were dissolved in DCM (200 mL). After stirring under nitrogen for 2 min, DHP (11.50 g, 136.73 mmol) was added, and the reaction mixture was reacted at 25 °C for 16 h. After the reaction was complete, the mixture was washed once with saturated sodium bicarbonate aqueous solution and once with saturated brine. The solution was then concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 90:10) to obtain compound Int A-2 (10.2 g).

[0322] Step 2: Synthesis of 7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indazole (compound Int A)

[0323] Compounds Int A-2 (2 g, 6.69 mmol), Int A-3 (3.40 g, 13.37 mmol), Pd(dppf)Cl2 (489.21 mg, 668.59 μmol), and potassium acetate (1.97 g, 20.06 mmol) were dissolved in 1,4-dioxane (25 mL). Under nitrogen protection, the mixture was heated to 90 °C and reacted for 6 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the mixture was purified by silica gel column chromatography (PE:EA = 92:8) to obtain compound Int A (2.04 g). MS m / z (ESI): 347.1 [M+H] + .

[0324] In the examples, the intermediate Int B: 7-bromo-10-chloro-6-nitro-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-5-one

[0325]

[0326] Step 1: Synthesis of ethyl 10-chloro-7-hydroxy-5-oxo-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-6-carboxylate (compound Int B-3) and 10-chloro-7-hydroxy-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-5-one (compound Int B-4).

[0327] Compound Int B-1 (2 g, 9.80 mmol) and triethyl methanetricarboxylate (6.82 g, 29.40 mmol) were placed in a 50 mL reaction flask and heated to 250 °C for 4 hours. After the reaction was complete, the mixture was filtered, and the filtrate was compound Int B-3 (1.4 g). MS (ESI, m / z): 308.1 [M+H] + The filter cake was compound Int B-4 (1.1 g). MS (ESI, m / z): 236.1 [M+H] + .

[0328] Step 2: Synthesis of 10-chloro-7-hydroxy-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-5-one (compound Int B-4)

[0329] Compound Int B-3 (1.4 g, 4.55 mmol) was dissolved in AcOH (10 mL), H₂SO₄ (2.5 mL), and H₂O (5 mL), and the mixture was heated to 90 °C and reacted for 8 hours. After the reaction was complete, the mixture was cooled to room temperature, poured into water, and a solid precipitated. The solid was filtered, and the filter cake was dried to give compound Int B-4 (0.8 g). MS m / z (ESI): 236.1 [M+H] + .

[0330] Step 3: Synthesis of 10-chloro-7-hydroxy-6-nitro-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-5-one (compound Int B-5)

[0331] Compound Int B-4 (1 g, 4.24 mmol) was dissolved in AcOH (5 mL). A solution of HNO3 (401.06 mg, 6.36 mmol) and Ac2O (563.16 mg, 5.52 mmol) in AcOH (5 mL) was slowly added dropwise. After the addition was complete, the mixture was reacted at 25 °C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, poured into water, and a solid precipitated. This solid was filtered, and the filter cake was dried to obtain compound Int B-5 (1.02 g). MS m / z (ESI): 281.1 [M+H] + .

[0332] Step 4: Synthesis of 7-bromo-10-chloro-6-nitro-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-5-one (compound Int B)

[0333] Compound Int B-5 (200 mg, 712.60 μmol) and POBr3 (1.02 g, 3.56 mmol) were dissolved in MeCN (20 mL). DIEA (276.29 mg, 2.14 mmol) was added with stirring, and the mixture was heated to 80 °C and reacted for 1 hour. After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the mixture was purified by silica gel column chromatography (PE:EA = 85:15) to obtain compound Int B (100 mg). MS m / z (ESI): 342.9 [M+H] + .

[0334] Example 1: 6-Amino-10-chloro-7-(7-fluoro-1H-indazol-4-yl)-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-5-one (Compound 21)

[0335]

[0336] Step 1: Synthesis of 10-chloro-7-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-6-nitro-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-5-one (compound 21-1)

[0337] Compounds Int A (90 mg, 261.96 μmol), Int B (108.83 mg, 314.36 μmol), Pd(dppf)Cl2·DCM (21.39 mg, 26.20 μmol), and NaHCO3 (66.02 mg, 785.89 μmol) were dissolved in 1,4-dioxane (5 mL) and H2O (0.5 mL). Under nitrogen protection, the mixture was heated to 100 °C and reacted for 4 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the mixture was purified by silica gel column chromatography (PE:EA = 70:30) to obtain compound 21-1 (87 mg). MS m / z (ESI): 483.1 [M+H] + .

[0338] Step 2: Synthesis of 6-amino-10-chloro-7-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-5-one (compound 21-2)

[0339] Compound 21-1 (80 mg, 165.67 μmol) was dissolved in EtOH (5 mL), Raney nickel was added with stirring, and the reaction was carried out under hydrogen protection at 20 °C for 2 hours. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure to give the title compound 21-2 (75 mg). MS m / z (ESI): 453.1 [M+H] + .

[0340] Step 3: Synthesis of 6-amino-10-chloro-7-(7-fluoro-1H-indazol-4-yl)-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-5-one (compound 21)

[0341] Compound 21-2 (20 mg, 44.16 μmol) was dissolved in DCM (2 mL), and a 1,4-dioxane solution of 4N HCl (2 mL) was added. The reaction mixture was then incubated at 20 °C for 1 hour. After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the solution was purified by preparative Prep-HPLC to obtain the title compound 21. MS m / z (ESI): 369.1 [M+H] + .

[0342] 1H NMR (400MHz, DMSO-d6) δ13.82(s,1H),7.68(d,J=3.2Hz,1H),7.36(dd,J=11.6,8.0Hz,1H),7.05(d,J=8.4Hz,1H),6.99( dd,J=7.6,4.0Hz,1H),6.61(d,J=8.8Hz,1H),5.02(s,2H),4.32–4.16(m,2H),2.99(t,J=6.0Hz,2H),2.17–2.08(m,2H).

[0343] Example 2: 6-amino-7-(7-fluoro-1H-indazol-4-yl)-10-methyl-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-5-one (compound 19)

[0344]

[0345] Step 1: Synthesis of 6-amino-7-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-10-methyl-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-5-one

[0346] Compound 21-2 (40 mg, 88.32 μmol), methylboric acid (15.86 mg, 264.95 μmol), Pd(dtbpf)Cl2 (5.70 mg, 8.83 μmol), and K2CO3 (36.62 mg, 264.95 μmol) were dissolved in 1,4-dioxane (5 mL). Under N2 protection, the mixture was heated to 120 °C and reacted for 3 hours. After the reaction was complete, the solution was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 82:18) to obtain compound 19-1 (36 mg). MS m / z (ESI): 433.3 [M+H] + .

[0347] Step 2: Synthesis of 6-amino-7-(7-fluoro-1H-indazol-4-yl)-10-methyl-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-5-one

[0348] Compound 19-1 (36 mg, 83.24 μmol) was dissolved in DCM (3 mL), and 1,4-dioxane solution (3 mL) of 4 M HCl was added. The reaction mixture was then incubated at 20 °C for 1 hour. After the reaction was complete, the solvent was removed by concentration under reduced pressure, and compound 19 (20 mg) was obtained by preparative Prep-HPLC purification. MS m / z (ESI): 349.1 [M+H] + .

[0349] 1 H NMR (400MHz, DMSO-d6) δ13.81(s,1H),7.65(d,J=3.2Hz,1H),7.35(dd,J=11.2,7.6Hz,1H),6.97(dd,J=8.0,4.4Hz,1H),6.82( d,J=8.4Hz,1H),6.53(d,J=8.4Hz,1H),4.77(s,2H),4.29–4.18(m,2H),2.85(t,J=6.4Hz,2H),2.26(s,3H),2.16–2.04(m,2H).

[0350] Example 3: 3-Amino-4-(7-fluoro-1H-indazol-4-yl)-6-(methyl(1-methyl-1H-pyrazol-4-yl)amino)-1,5-naphthidium-2(1H)-one (Compound 49)

[0351]

[0352] Step 1: Preparation of tert-butyl(6-chloro-2-((7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)(hydroxy)methyl)pyridin-3-yl)carbamate (compound 49-3)

[0353] Compound 49-2 (5.6 g, 18.22 mmol) and THF (50 mL) were added sequentially to a 250 mL reaction flask. After purging with nitrogen, the mixture was cooled to -70 to -78 °C and stirred for 20 min. A 2.0 M n-butyllithium solution in n-hexane (21.51 mL, 63.78 mmol) was added dropwise, maintaining the temperature below -60 °C. After the addition was complete, the reaction was maintained at this temperature for 30 min. Then, a THF solution (30 mL) of compound 49-1 (5.42 g, 21.87 mmol) was added dropwise. After the addition was complete, the reaction was maintained at this temperature for 2 hours. After the reaction was complete, a saturated ammonium chloride aqueous solution was added dropwise to quench the reaction. The mixture was extracted twice with ethyl acetate, concentrated, and stirred. Column chromatography (PE / EA = 4 / 1) was performed to obtain the title compound 49-3 (3.54 g). MS (ESI, m / z): 477.2 [M+H] + .

[0354] Step 2: Preparation of tert-butyl(6-chloro-2-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonyl)pyridin-3-yl)carbamate (compound 49-4)

[0355] Compound 49-3 (3.5 g, 7.34 mmol) was dissolved in DCM (40 mL), and Desmartin reagent (6.24 g, 14.68 mmol) was added. The mixture was stirred at 25 °C for 2 hours. After the reaction was complete, sodium bicarbonate aqueous solution and ethyl acetate were added, and the mixture was extracted twice. The organic phases were combined, washed twice with brine, concentrated, and directly mixed for silica gel column chromatography (PE / EA = 7 / 3). After concentration, the title compound 49-4 (2.6 g) was obtained. MS m / z (ESI): 475.1 [M+H] + .

[0356] Step 3: Preparation of (3-amino-6-chloropyridin-2-yl)(7-fluoro-1H-indazol-4-yl)methyl ketone (compound 49-5)

[0357] Compound 49-4 (2.6 g, 5.47 mmol) was dissolved in DCM (30 mL), and TFA (10 mL) was added. The reaction was carried out at 25 °C for 2 hours. After the reaction was completed, sodium bicarbonate aqueous solution and ethyl acetate were added to adjust the pH to 8-9. The mixture was extracted twice, and the organic phases were combined, washed twice with brine, concentrated, and then subjected to silica gel column chromatography (PE / EA = 3 / 2) to give the title compound 49-5 (0.78 g). MS m / z (ESI): 291.0 [M+H] + .

[0358] Step 4: Preparation of 2-chloro-N-(6-chloro-2-(7-fluoro-1H-indazole-4-carbonyl)pyridin-3-yl)acetamide (compound 49-6)

[0359] Compound 49-5 (2.07 g, 7.12 mmol), triethylamine (7.21 g, 71.21 mmol), and DMF (20 mL) were added to a 50 mL reaction flask. After purging with nitrogen, the mixture was cooled to 0–10 °C and stirred for 5 min. Chloroacetyl chloride (3.28 g, 28.48 mmol) was added dropwise. After the addition was complete, the reaction was allowed to proceed for 1 h. No further processing was required; proceed directly to the next step. MS (ESI, m / z): 367.0 [M+H] + .

[0360] Step 5: Preparation of 1-(6-chloro-4-(7-fluoro-1H-indazol-4-yl)-2-oxo-1,2-dihydro-1,5-naphthid-3-yl)pyridin-1-onium (compound 49-7)

[0361] Pyridine (20 mL) was added to the crude reaction solution of compound 49-6 (2.62 g, 7.12 mmol), and the mixture was heated to 80 °C and stirred for 2 hours. After the reaction was complete, the crude reaction solution of the title compound was obtained, which was directly used for the next step. MS m / z (ESI): 393.5 [M+H] + .

[0362] Step 6: Preparation of 3-amino-6-chloro-4-(7-fluoro-1H-indazol-4-yl)-1,5-naphthidium-2(1H)-one (compound 49-8)

[0363] Hydrazine hydrate (25 mL) was added to the crude reaction solution of compound 49-7, and the mixture was heated to 80 °C and stirred for 2 hours. After the reaction was complete, water and ethyl acetate were added, and the mixture was extracted twice. The organic phases were combined, washed twice with brine, concentrated, and then subjected to silica gel column chromatography (PE / EA = 5 / 95) to give the title compound 49-8 (1.53 g). MS m / z (ESI): 330.2 [M+H] + .

[0364] Step 7: Preparation of 3-amino-6-bromo-4-(7-fluoro-1H-indazol-4-yl)-1,5-naphthidium-2(1H)-one (compound 49-9)

[0365] Compound 49-8 (2.56 g, 7.75 mmol) was dissolved in HBr / H₂O (60 mL) and stirred at 120 °C for 48 h. After the reaction was complete, sodium bicarbonate aqueous solution and ethyl acetate were added to adjust the pH to 8–9. The mixture was extracted twice, and the organic phases were combined, washed twice with brine, concentrated, and then subjected to silica gel column chromatography (DCM / MeOH = 4 / 1) to give the title compound 49-9 (2.12 g). MS m / z (ESI): 374.0 [M+H] + .

[0366] Step 8: Preparation of 8-(pyrazin-2-yl)-2-((5-(trifluoromethyl)-1H-indazol-4-yl)oxy)quinoline-3-carboxamide (compound 49-3)

[0367] Compound 49-9 (40.0 mg, 106.95 μmol) was dissolved in Dioxane (2 mL), and N,1-dimethyl-1H-pyrazole-4-amine hydrochloride (24.0 mg, 213.90 μmol), (SP-4-1)-(1,3-bis(2,6-bis(1-propylbutyl)phenyl)-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylyl)dichloro(3-chloropyridine-KN)palladium (31.11 mg, 31.98 μmol), and sodium tert-butoxide (51.39 mg, 534.75 μmol) were added. After purging with nitrogen for 2 min, the mixture was microwaved at 115 °C for 3 h. After the reaction was complete, aqueous solution and ethyl acetate were added, and the mixture was extracted twice. The organic phases were combined, washed twice with brine, concentrated, and then the contents were prepared by HPLC to obtain the title compound 49 (1.2 mg). MS m / z (ESI): 405.0 [M+H] + .

[0368] 1 H NMR (400MHz, DMSO-d6) δ13.65(s,1H),11.92(s,1H),7.67(d,J=3.4Hz,1H),7.47(d,J=8.8Hz,1H),7.35(dd,J=11.6, 7.8Hz,1H),7.20(d,J=0.4Hz,1H),7.11–7.01(m,2H),6.71(d,J=9.0Hz,1H),5.19(s,2H),3.51(s,3H),3.04(s,3H).

[0369] The following compounds were prepared by referring to the method and general steps described in Example 3. Other required raw materials can be purchased commercially or obtained by experienced synthesizers from commercially available reagents using conventional reactions.

[0370]

[0371] Biological evaluation

[0372] Experimental Example 1: Test on the inhibitory effect of compounds on PKMYT1 enzyme activity

[0373] 1. Test System

[0374] Enzyme: PKMYT1 (purchased from Carna)

[0375] Substrate: Unactive CDK1 (purchased from Signalchem)

[0376] ATP, ADP-Glo ​​Reagent, and Detection Solution are all derived from the ADP-Glo ​​Kinase AssayKit (Promega).

[0377] 2. Experimental Procedure

[0378] Prepare 4× compound working solutions by serially diluting the compounds in DMSO using Enzyme Assay Buffer, and add 2.5 μL / well of 4× compound working solution to a 384-well plate. Dilute PKMYT1 enzyme to prepare 4× enzyme working solution using Enzyme Assay Buffer, and add 2.5 μL / well of 4× enzyme working solution to a 384-well plate. Centrifuge at 1000 rpm for 1 min and incubate at 25°C for 15 min. Prepare a 2× CDK1+ATP mixed working solution using Enzyme Assay Buffer, and add 5 μL of 2× CDK1+ATP mixed working solution to a 384-well plate. Centrifuge at 1000 rpm for 1 min and incubate at 30°C for 180 min. Equilibrate the 384-well plate and ADP-Glo ​​Reagent to room temperature, add 10 μL of ADP-Glo ​​Reagent to each well, centrifuge at 1000 rpm for 1 min, and incubate at 25°C in the dark for 40 min. Add 20 μL of Detection to each well of the 384-well plate. Reagent was centrifuged at 1000 rpm for 1 min and incubated at 25°C in the dark for 40 min. The chemiluminescent signal was read using a BMG microplate reader. The solvent group (DMSO) was used as a negative control, and the buffer group (without PKMYT1 enzyme) was used as a blank control. The relative percentage of inhibitory activity (i.e., inhibition rate) of different concentrations of the compound was calculated using the following formula:

[0379] Relative inhibition percentage = (1 - (different concentrations of compound group - blank control) / (negative control - blank control)) * 100%

[0380] The relative inhibitory activity percentage of different compound concentrations was plotted against the compound concentration. The curve was fitted using a four-parameter model, and the IC was calculated using the following formula. 50 value:

[0381] y = min + (max - min) / (1 + (x / IC) 50 )^(-Hillslope))

[0382] Where y represents 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 effect of the compounds on PKMYT1 enzyme was determined according to the above method. Experimental results show that the compounds of this invention have strong inhibitory effects on PKMYT1 enzyme.

[0383] Table 1. Inhibitory activity of the compounds of the present invention against PKMYT1

[0384] Compound numbering <![CDATA[PKMYT1(IC 50 ,nM)]]> 49 15.6 57 12.5

[0385] In addition to those described herein, various modifications of the invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. All references cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) are incorporated herein by reference in their entirety.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, isotopically labeled compound, ester, polymorph, solvate, N-oxide, metabolite, or prodrug. in: R 1 R 2 and R 3 Each time it appears, it is independently selected from H, OH, halogen, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 1-4 Hydroxyalkyl or C 3-6 cycloalkyl; preferably, R 1 R 2 and R 3 Each time it appears, it is independently selected from H, OH, halogen, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl or C 3-6 cycloalkyl; or R 1 and R 3 Together with the atoms it is attached to, they form C 5-8 Cycloalkyl, 5-8 membered heterocyclic, or 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclic, or heteroaryl group is optionally selected independently from one or more halogens, OH, CN, -NH2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups; R 4 Selected from H, -NR 9 R 10 -C(=O)NH(R) 11 -C(=O)R 12 -NHC(=O)R 12 C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 Cycloalkoxy, C 6-10 aryl or 5-10 heteroaryl, wherein the alkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclic, cycloalkoxy, aryl, or heteroaryl group is optionally selected independently from one or more halogens, D, OH, CN, -NR. 9 R 10 -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups; X 1 Selected from CR 5 Or N; X 2 Selected from CR 6 Or N; X 3 Selected from CR 7 Or N; X 4 Selected from CR 8 Or N; Y and Z are each independently selected from CR 13 Or N; R 5 Selected from H, halogens, CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl or C 3-6 Cycloalkyl, wherein the alkyl, alkenyl, alkoxy, hydroxyalkyl or cycloalkyl group is optionally selected from one or more elements independently chosen from halogen, D, OH, CN, -NR. 9 R 10 -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups; or R 4 and R 5 Together with the atoms to which it is attached, it forms a 5-8 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the heterocyclic group or heteroaryl group is optionally composed of one or more elements independently selected from halogen, D, OH, CN, -NH2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups; R 6 R 7 and R 8 Each occurrence is independently selected from H, halogen, CN, -NR. 9 R 10 -C(=O)NH(R) 11 -C(=O)R 12 -NHC(=O)R 12 -S(=O)2R 11 -S(=O)2NR 9 R 10 -OR 12 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 Cycloalkoxy, C 6-10 aryl or 5-10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclic, cycloalkoxy, aryl, or heteroaryl group is optionally surrounded by one or more R groups. 14 replace; Or R 5 and R 6 Together with the atoms it is attached to, they form C 5-8 cycloalkyl, 5-8 membered heterocyclic, C 6-10 Aryl or 5-10-membered heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally selected from one or more elements independently chosen from halogen, D, OH, CN, -NH2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups; Or R 6 and R 7 Together with the atoms it is attached to, they form C 5-8 cycloalkyl, 5-8 membered heterocyclic, C 6-10 Aryl or 5-10-membered heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally selected from one or more elements independently chosen from halogen, D, OH, CN, -NH2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups; Or R 7 and R 8 Together with the atoms it is attached to, they form C 5-8 cycloalkyl, 5-8 membered heterocyclic, C 6-10 Aryl or 5-10-membered heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally selected from one or more elements independently chosen from halogen, D, OH, CN, -NH2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups; R 9 and R 10 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-8 cycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, or -S(=O)2R 11 The alkyl, cycloalkyl, aryl, or heteroaryl group is optionally separated by one or more elements independently selected from D, halogen, OH, CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic groups, C 6-10 Substitution of aryl or 5-10 heteroaryl groups; R 11 Each time it appears, it is independently selected from H and C. 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 cycloalkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, aryl or heteroaryl group is optionally separated from one or more elements independently selected from halogen, OH, CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 6-10 Substitution of aryl or 5-10 heteroaryl groups; R 12 Each time it appears, it is independently selected from C. 1-4 Alkyl, C 3-8 cycloalkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein the alkyl, cycloalkyl, aryl or heteroaryl group is optionally separated from one or more elements independently selected from halogen, OH, CN, -C(=O)CH3, C 1-4 Alkyl or C 1-4 Substituents of haloalkyl groups; R 13 Each time it appears, it is independently selected from H, halogen, OH, CN, C. 1-4 Alkyl or C 1-4 Halogenated alkyl groups; R 14 Each occurrence is independently selected from H, halogen, D, OH, CN, -NR. 9 R 10 -C(=O)R 12 -NHC(=O)R 12 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-6 cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic groups, C 6-10 Aryl or 5-10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, cycloalkoxy, heterocyclic, aryl, or heteroaryl group is optionally selected from one or more elements independently chosen from halogen, D, OH, CN, -NR. 9 R 10 -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups; Where R 4 When selected from H, R 7 Selected from -NR 9 R 10 , where R 9 Selected from H, C 1-6 Alkyl or C 3-8 cycloalkyl, R 10 Selected from C 6-10 Aryl or 5-10 heteroaryl, wherein the alkyl, cycloalkyl, aryl or heteroaryl group is optionally separated by one or more elements independently selected from D, halogen, OH, CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl substitutions; Or, when R 4 When selected from H, R 7 and R 8 Together with the atoms it is attached to, they form C 5-8 cycloalkyl, 5-8 membered heterocyclic, C 6-10 Aryl or 5-10-membered heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally selected from one or more elements independently chosen from halogen, D, OH, CN, -NH2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with a cycloalkoxy or 3-6 membered heterocyclic group, wherein the heteroaryl group is not:

2. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, ester, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, satisfying one or more of the following: (1)R 1 Selected from H, halogens, C 1-4 Alkyl or C 1-4 Halogenated alkyl; preferably, R 1 C 1-4 alkyl; (2)R 2 Selected from H, halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Deuterated alkyl; preferably, R 2 Selected from H, halogens, C 1-4 Alkyl or C 1-4 Halogenated alkyl; more preferably, R 2 C 1-4 alkyl; (3)R 3 It is OH; (4)R 1 and R 3 Together with the atoms they are attached to, they form a 5-10 membered heteroaryl group, wherein the heteroaryl group is optionally surrounded by one or more atoms independently selected from halogen, OH, CN, -NH2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups; Preferably, R 1 and R 3 Together with the atoms to which they are attached, a pyrazol group is formed, which is optionally formed by one or more atoms independently selected from halogens or C. 1-4 Alkyl substituents; More preferably, R 1 and R 3 Together with the atoms they are attached to, they form a pyrazol group; (5)R 4 Selected from C 1-6 Alkyl or C 3-8 Cycloalkyl groups, wherein the alkyl or cycloalkyl group is optionally composed of one or more elements independently selected from halogens, D, OH, CN, C. 1-4 Alkyl or C 1-4 Substituents of haloalkyl groups; (6)X 1 Selected from CR 5 ;R 5 Selected from H, halogens, C 1-6 Alkyl or C 3-6 Cycloalkyl groups, wherein the alkyl or cycloalkyl group is optionally composed of one or more elements independently selected from halogens, D, OH, CN, C. 1-4 Alkyl or C 1-4 Substituents of haloalkyl groups; (7)R 4 and R 5 Together with the atoms to which they are attached, they form a 5-6 membered heterocyclic group, which is optionally composed of one or more elements independently selected from halogens, D, OH, CN, -NH2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups; Preferably, R 4 and R 5 Together with the atoms to which it is attached, it forms a heterocyclic group selected from the following: The heterocyclic group is optionally selected from one or more independently chosen from halogen, D, OH, CN, -NH2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy or C 3-6 Substituents of cycloalkyl groups; (8)R 6 Selected from H, halogens, CN, -C(=O)R 12 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 Cycloalkoxy, C 6-10 aryl or 5-10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclic, cycloalkoxy, aryl, or heteroaryl group is optionally surrounded by one or more R groups. 14 replace; Preferably, R 6 Selected from H, halogens, C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group is optionally surrounded by one or more R groups. 14 replace; (9)R 5 and R 6 Together with the atoms it is attached to, they form C 6-10 Aryl or 5-10 heteroaryl, wherein the aryl or heteroaryl group is optionally composed of one or more elements independently selected from halogen, D, OH, CN, -NH2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups; (10) When R 4 When R is not H, 7 Selected from H, halogens, CN, -C(=O)R 12 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 Cycloalkoxy, phenyl, or 5-6-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclic, cycloalkoxy, phenyl, or heteroaryl group is optionally surrounded by one or more R groups. 14 replace; Preferably, when R 4 When R is not H, 7 Selected from H, halogens, -C(=O)R 12 C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8-membered heterocyclic, or 5-6-membered heteroaryl, wherein the alkyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, or heteroaryl group is optionally surrounded by one or more R groups. 14 replace; (11)R 8 Selected from H, halogens, CN, -C(=O)R 12 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 Cycloalkoxy, C 6-10 aryl or 5-10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclic, cycloalkoxy, aryl, or heteroaryl group is optionally surrounded by one or more R groups. 14 replace; Preferably, R 8 Selected from H or halogen; (12)R 9 and R 10 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-8 cycloalkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein the alkyl, cycloalkyl, aryl or heteroaryl group is optionally separated by one or more elements independently selected from D, halogen, OH, CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups; (13)R 11 Each time it appears, it is independently selected from H and C. 1-4 Alkyl, C 3-8 cycloalkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein the alkyl, cycloalkyl, aryl or heteroaryl group is optionally separated from one or more elements independently selected from halogen, OH, CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 6-10 Substitution of aryl or 5-10 heteroaryl groups; Preferably, R 11 Each time it appears, it is independently selected from C. 1-4 Alkyl or C 3-6 Cycloalkyl groups, wherein the alkyl or cycloalkyl group is optionally separated from one or more halogens, OH, CN or C. 1-4 Alkyl substituents; (14)R 12 Each time it appears, it is independently selected from C. 1-4 Alkyl or C 3-8 Cycloalkyl groups, wherein the alkyl group or cycloalkyl group is optionally composed of one or more elements independently selected from halogens, OH, CN, -C(=O)CH3, C 1-4 Alkyl or C 1-4 Substituents of haloalkyl groups; (15) Y is selected from CR 13 ;R 13 Selected from H, halogen or C 1-4 Alkyl groups, preferably H or halogens; (16) Z is selected from CR 13 ;R 13 Selected from H, halogen or C 1-4 Alkyl groups, preferably H or halogens; (17)R 14 Each time it appears, it is independently selected from H, halogen, D, OH, or C. 1-6 Alkyl groups, optionally composed of one or more elements independently selected from halogens, D, OH, CN, and -NR. 9 R 10 -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy or 3-6 membered heterocyclic groups.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, ester, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein formula I is further formula IA, IB, IC, ID, or IE. in, X 1 X 2 X 3 X 4 R 2 R 4 R 5 R 7 R 8 R 9 R 10 R 13 As defined in claim 1 or 2.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, ester, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein formula I is further a formula I-B'. in, R 2 R 9 R 10 R 13 As defined in claim 1 or 2.

5. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, ester, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein the compound is selected from:

6. A pharmaceutical composition comprising a compound of any one of claims 1-5 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, ester, polymorph, solvate, N-oxide, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.

7. Use of the compound of any one of claims 1-5 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, ester, polymorph, solvate, N-oxide, metabolite or prodrug of the same or the pharmaceutical composition of claim 6 in the preparation of a medicament, particularly in the preparation of a medicament for modulating PKMYT1 activity.

8. The use of the compound of any one of claims 1-5 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, ester, polymorph, solvate, N-oxide, metabolite or prodrug, or the pharmaceutical composition of claim 6 in the preparation of a medicament, particularly in the preparation of a medicament for the prevention or treatment of diseases or conditions 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 expression / CCNE1 amplification; Preferably, the cancer or tumor is thyroid cancer, stomach cancer, lung cancer, breast cancer, or ovarian cancer.

9. A method for preparing the compound or a pharmaceutically acceptable form thereof according to any one of claims 1 to 5, wherein the compound is selected from the following methods: Method 1 includes one or more of the following steps: Step 1: Compound IA-1 and compound IA-2 are subjected to a Suzuki or Stille cross-coupling reaction to obtain compound IA-3; Step 2: Compound IA-3 is reduced to obtain compound IA-4; Step 3: Compound IA-4 was deprotected to obtain compound IA; in X 2 X 3 X 4 R 2 R 13 As defined in any one of claims 1-5; L 1 and L 2 One of them is a leaving group such as OTf, Br, or I, and the other is trimethyltinyl, tri-n-butyltinyl, borate, or pinacol boronic acid ester. Method 2 involves reacting a compound of formula IB-1 with NHR. 9 R 10 The reaction produces a compound of formula IB: in X 1 X 2 X 4 R 2 R 9 R 10 and R 13 As defined in any one of claims 1-5; L 3 Selected from halogens.

10. The following are compounds or their salts, stereoisomers, tautomers, isotopically labeled compounds, esters, polymorphs, solvates, and N-oxides: Where L 1 L 2 L 3 X 1 X 2 X 3 X 4 R 2 R 13 As defined in claim 9; PG 1 The amino protecting group is, for example, an alkoxycarbonyl amino protecting group, such as benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl (or ethoxycarbonyl); an acyl amino protecting group, such as phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), o-(p-)nitrobenzenesulfonyl (Ns), tert-pentanoyl, benzoyl, tert-butoxycarbonyl, 9-fluorenemethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, trimethylsilylethoxycarbonyl, benzyloxycarbonyl, p-methylbenzenesulfonyl, p-nitrobenzenesulfonyl, trifluoroacetyl, methoxycarbonyl, or ethoxycarbonyl; an alkyl amino protecting group, such as triphenylmethyl (Trt), C 1-6 Alkyl-substituted triphenylmethyl, p-methoxytriphenylmethyl (MMT), dimethoxytriphenylmethyl (DMT), 2,4-dimethoxybenzyl (Dmb), 4-methoxybenzyl (PMB), benzyl (Bn); or tetrahydropyranyl (THP); Preferably, PG 1 For THP.

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