Cyano-substituted heteroaromatic ring derivative, pharmaceutical composition containing cyano-substituted heteroaromatic ring derivative as well as preparation method and application of cyano-substituted heteroaromatic ring derivative

Abstract

The invention belongs to the field of medicines, and relates to a cyano-substituted heteroaromatic ring derivative, a pharmaceutical composition containing the cyano-substituted heteroaromatic ring derivative, and a preparation method and application of the cyano-substituted heteroaromatic ring derivative. Specifically, the invention relates to a compound as shown in a formula I. The compound has a good inhibition effect on CCNE1 amplified tumor cells and can be used for preventing or treating diseases or conditions related to PKMYT1 activity. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicine and relates to a cyano-substituted heteroaromatic ring compound, a pharmaceutical composition containing the same, a preparation method thereof and use thereof for preventing or treating diseases or conditions associated with PKMYT1 activity. Background Art

[0002] PKMYT1 (membrane-associated tyrosine / threonine protein kinase 1, also known as MYT1) is a class of protein kinases that belongs to the WEE protein kinase family and is involved in cell cycle regulation. The WEE protein kinase family includes three members: WEE1, WEE2, and 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., A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target, Journal of hematology & oncology, (2020) 13: 126).

[0003] In eukaryotic cells, PKMYT1 plays a key role in cell cycle regulation, mainly involved in the regulation of mitotic processes. Studies have shown that PKMYT1 acts on the G2 / M checkpoint and is not essential for normal cell cycle progression, while WEE1 acts on multiple checkpoints, including S, G2 / M, and M, and is essential 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 blocking the G2 / M transition of the cell cycle. PKMYT1 negatively regulates the Cdk1 / CycB complex mainly through two independent mechanisms: 1) PKMYT1 can phosphorylate Thr14 and Tyr15 on the substrate Cdk1, thereby inhibiting the activity of the Cdk1 / CycB complex and causing G2 / M arrest in the cell cycle; 2) PKMYT1 binds to Cdk1 and isolates it in the cytoplasm, preventing the Cdk1 / CycB complex from entering the nucleus, thereby preventing the cell cycle from progressing (Schmidt M, et al., Regulation of G2 / M Transition by Inhibition of WEE1 and PKMYT1 Kinases, Molecules, 2017, 22(12): 2045; Wells NJ, et al., The C-terminal domain of the Cdc2inhibitory 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, in order to cope with the replication pressure brought by the high proliferation rate demand, PKMYT1 can ensure that tumor cells repair DNA damage by upregulating expression. Inhibiting PKMYT1 forces the cell cycle of tumor cells that have not completed DNA damage repair to enter the next stage, resulting in the accumulation of DNA damage in tumor cells, increased genetic instability, inducing cell apoptosis and mitotic catastrophe, and achieving tumor suppression. Studies have confirmed that CCNE1 can activate the MMB-FOXM1 transcription complex, thereby upregulating CDK1 and CCNB1 gene expression. In CCNE1 overexpressing cells, CyclinB and CDK1 expression are increased, and these cells are more sensitive to PKMYT1 inhibition, leading to synthetic lethality (David Gallo et al., CCNE1 amplification is syntheticlethal with PKMYT1 kinase inhibition, Nature, 2022, 604(7907): 749-756).

[0005] In summary, in the case of CCNE1 gene amplification, inhibition of PKMYT1 showed synthetic lethality. Currently, there are no inhibitors targeting PKMYT1 on the market. Therefore, it is necessary to develop new, highly effective and low-toxic PKMYT1 inhibitors to meet clinical needs. Summary of the invention

[0006] The present invention provides a novel cyano-substituted heteroaromatic ring compound, which has a good inhibitory effect on CCNE1-amplified tumor cells, is relatively stable in human / mouse liver microsomes, and has good pharmacokinetic properties and the like.

[0007] The present invention provides a compound of formula I or a pharmaceutically acceptable form thereof:

[0008]

[0009] in:

[0010] X 1 , X 2 and X 3 Each independently selected from CR 5 or N;

[0011] Y and Z are each independently selected from CR 13 or N;

[0012] R 1 , R 2 and R 6 are each independently selected from H, -OH, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4Hydroxyalkyl or C 3-6 Cycloalkyl; or R 1 and R 6 Together with the atoms to which it is attached, it forms C 5-8 aliphatic ring, 5-8 membered heterocyclic ring or 5-10 membered heteroaromatic ring, wherein the aliphatic ring, heterocyclic ring or heteroaromatic ring is optionally substituted by one or more halogen, -OH, -CN, -NH2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Substituted with cycloalkoxy or 3-6 membered heterocyclic group;

[0013] R 3 Selected from H or -NR 8 R 9 ;

[0014] R 4 Selected from -C(=O)NH(R 10 ), -C(=O)R 11 、-SO2R 11 or -S(=O)2N(R 10 )2;

[0015] R 5 is independently selected at each occurrence from H, halogen, -CN, -NR 8 R 9 、-C(=O)R 11 、-C(=O)NH(R 10 )、-NHC(=O)R 11 、-SO2R 11 、-OR 12 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 3-8 Cycloalkoxy, C 6-10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl or heteroaryl optionally substituted by one or more R 7 Replacement; or two adjacent R 5 Together with the atoms to which it is attached, it forms C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0016] R 7 is independently selected at each occurrence from H, halogen, -OH, -CN, -NR 8 R 9 、-C(=O)R 11 、-NHC(=O)R 11 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic group, C 6-10 The alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl or heteroaryl radicals are optionally substituted with one or more halogen, -OH, -CN, -NR 8 R 9 , -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Substituted with cycloalkoxy or 3-6 membered heterocyclic group;

[0017] R 8 and R 9 Each occurrence is independently selected from H, C 1-4 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl or -SO2R 11 The alkyl, cycloalkyl, aryl or heteroaryl groups are optionally substituted with one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl substituted;

[0018] R 10 Each occurrence is independently selected from H, C 1-4 Alkyl, C1-4 Alkoxy, C 3-8 Cycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, the alkyl, alkoxy, cycloalkyl, aryl or heteroaryl group is optionally substituted by one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl substituted;

[0019] R 11 Each occurrence is independently selected from C 1-4 Alkyl, C 3-8 Cycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, the alkyl, cycloalkyl, aryl or heteroaryl being optionally substituted with one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl or C 1-4 Haloalkyl substitution;

[0020] R 12 Each occurrence is independently selected from H, C 6-10 aryl or 5-10 membered heteroaryl, the aryl or heteroaryl is optionally substituted by one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Substituted with cycloalkoxy or 3-6 membered heterocyclic group;

[0021] R 13 is independently selected at each occurrence from H, halogen, -OH, -CN, C 1-4 Alkyl or C 1-4 Haloalkyl;

[0022] The pharmaceutically acceptable form is selected from a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, ester, polymorph, solvate, N-oxide, metabolite or prodrug.

[0023] Another aspect of the present invention provides a pharmaceutical composition comprising (e.g., a prophylactically or therapeutically 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 thereof, and optionally one or more pharmaceutically acceptable carriers.

[0024] Another aspect of the present invention provides use 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 thereof, or a pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating a disease or condition associated with PKMYT1 activity.

[0025] Another aspect of the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, ester, polymorph, solvate, N-oxide, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, for use in preventing or treating a disease or condition associated with PKMYT1 activity.

[0026] Another aspect of the present invention provides a method for preventing or treating a disease or condition associated with PKMYT1 activity, the method comprising administering to a subject in need thereof 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 thereof, or a pharmaceutical composition of the present invention.

[0027] Another aspect of the present invention provides a process for preparing a compound of the present invention.

[0028] definition

[0029] Unless otherwise defined below, the meanings of all technical terms and scientific terms used herein are intended to be the same as those generally understood by those skilled in the art. Reference to the technology used herein is intended to refer to the technology generally understood in the art, including those changes in technology or replacement of equivalent technology that are obvious to those skilled in the art. Although it is believed that the following terms are well understood by those skilled in the art, the following definitions are still set forth to better explain the present invention.

[0030] The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude other unrecited elements or method steps, even though the other unrecited elements or method steps are not necessarily present (i.e., these terms also encompass the terms "consisting essentially of" and "consisting of.").

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

[0032] As used herein, the term "alkyl" refers to a linear (or straight chain) or branched (or branched chain) saturated aliphatic hydrocarbon group. In some embodiments, the alkyl group has 1 to 12, such as 1 to 6 carbon atoms. For example, as used herein, the term "C 1-6 "Alkyl" refers to a linear or branched saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), which is optionally substituted with one or more (e.g., 1 to 3) suitable substituents (e.g., halogen) (in this case, the group is referred to as "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 saturated aliphatic hydrocarbon group having 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

[0033] As used herein, the term "heteroalkyl" refers to an alkyl group in which the main chain carbon atoms are separated by one or more backbone chain atoms each independently selected from atoms other than carbon (e.g., oxygen, nitrogen, sulfur, phosphorus, or a combination thereof), such as C 1-6 Heteroalkyl refers to an alkyl group with 1 to 6 carbon atoms in the chain. 2-6 Heteroalkyl refers to the number of carbons in the heteroalkyl chain being 2 to 6. Specifically, the -CH2OCH2CH3 group is referred to as a C3 heteroalkyl, and the -CH2OCH2CH2NHCH3 group is referred to as a C4 heteroalkyl. The alkyl portion of the heteroalkyl chain is connected to the remaining molecular fragments or groups.

[0034] As used herein, the term "haloalkyl" refers to an alkyl group substituted by one or more (such as 1 to 3) the same or different halogen atoms. 1-4The term "haloalkyl" refers to a halogenated alkyl group having 1 to 4 carbon atoms, for example, -CF3, -CHF2, -CH2F, -C2F5, -CH2CF3, -CH2Cl or -CH2CH2CF3.

[0035] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with one or more (such as 1 to 3) hydroxy groups, for example, C 1-4 Hydroxyalkyl or C 1-6 Examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, hydroxyethyl (eg, 2-hydroxyethyl), hydroxypropyl (eg, 3-hydroxypropyl), hydroxybutyl (eg, 4-hydroxybutyl), -CH(OH)CH3 (ie, 1-hydroxyethyl), and the like.

[0036] As used herein, the term "alkenyl" refers to a straight or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds. 2-6 The term "alkenyl" refers to an alkenyl group having 2 to 6 carbon atoms and one, two or three carbon-carbon double bonds (such as ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, etc.), which is optionally substituted by one or more (such as 1 to 3) substituents described herein.

[0037] As used herein, the term "alkynyl" refers to a straight or branched aliphatic hydrocarbon group having one or more carbon-carbon triple bonds. 2-6 The term "alkynyl" refers to an alkynyl group having 2 to 6 carbon atoms and one, two or three carbon-carbon triple bonds (e.g., ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc.), which is optionally substituted with one or more (e.g., 1 to 3) substituents described herein.

[0038] As used herein, the term "alkoxy" refers to a group in which an alkyl group (as defined above) is attached to the remainder of the molecule via an oxygen atom, e.g., C 1-8 Alkoxy, C 1-6 Alkoxy, C 1-4 Alkoxy or C 1-3 Alkoxy. C 1-6Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, and the like, wherein the alkoxy is optionally substituted with one or more (such as 1 to 3) identical or different substituents. For example, the term "haloalkoxy" means that the hydrogen atoms of the alkoxy are substituted with one or more (such as 1 to 3) identical or different halogen atoms, and the term "C 1-4 The term "haloalkoxy" refers to a haloalkoxy group having 1 to 4 carbon atoms.

[0039] As used herein, the term "paracyclic ring" or "fused ring" refers to a ring system formed by two or more cyclic structures sharing two adjacent ring atoms.

[0040] As used herein, the term "spirocycle" refers to a ring system formed by two or more cyclic structures that share one ring atom with each other.

[0041] As used herein, the term "bridged ring" refers to a ring system formed by two or more cyclic structures sharing two ring atoms that are not directly connected to each other.

[0042] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon group, including but not limited to monocyclic alkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.) and bicyclic alkyl, including spirocyclic, paracyclic (condensed) or bridged ring systems (i.e., spirocyclic alkyl, paracyclic (condensed) alkyl and bridged cycloalkyl, such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, etc.). In the present invention, the cycloalkyl is optionally substituted with one or more (such as 1 to 3) identical or different substituents. The carbon atoms on the cycloalkyl are optionally substituted with oxo (i.e., forming C=O). The term "C 3-8 "Cycloalkyl" refers to a cycloalkyl group having 3 to 8 ring carbon atoms, such as C 3-6 Cycloalkyl, which may be a monocyclic alkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, or a bicyclic alkyl, such as C 5-8 Spirocycloalkyl, C 5-8 Bridged cycloalkyl, C 5-8 Fused cycloalkyl, C 5-6 Spirocycloalkyl, C 5-6 Bridged cycloalkyl or C 5-6 Fused cycloalkyl.

[0043] As used herein, the term "aliphatic ring" refers to a saturated or unsaturated carbon ring containing 3 or more carbon atoms connected in the molecule. 5-8"Aliphatic ring" refers to a saturated or unsaturated carbon ring containing 5 to 8 carbon atoms in the molecule. Common aliphatic rings include cyclopropane, cyclobutane, cyclopentane, cyclohexane, etc.

[0044] As used herein, the term "cycloalkoxy" refers to an -O-cycloalkyl group, wherein the cycloalkyl group is as defined above, for example, C 3-8 Cycloalkoxy. Representative examples of cycloalkoxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0045] As used herein, the term "heterocyclyl" or "heterocycle" refers to an aliphatic, saturated or partially unsaturated monocyclic or polycyclic (e.g., fused ring, spirocyclic or bridged ring) group having 2 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, wherein the heteroatoms include, but are not limited to, oxygen atoms, nitrogen atoms and sulfur atoms, and the carbon atoms and heteroatoms on the heterocyclyl are optionally substituted with oxo groups (e.g., forming C=O, S(=O) or S(=O)2), or are optionally substituted with one or more (e.g., 1 to 3) independently selected from halogen and C 1-3 The alkyl group is substituted with a substituent.

[0046] As used herein, the term "3-8 membered heterocyclyl" refers to a heterocyclyl containing 3-8 ring atoms, including but not limited to 4-8 membered heterocyclyl, 4-7 membered heterocyclyl, 5-6 membered heterocyclyl, 3-7 membered heterocyclyl, especially 4-7 membered nitrogen-containing heterocyclyl, 4-7 membered oxygen-containing heterocyclyl, 4-7 membered sulfur-containing heterocyclyl, 5-6 membered nitrogen-containing heterocyclyl, 5-6 membered oxygen-containing heterocyclyl, 5-6 membered sulfur-containing heterocyclyl, etc., wherein the "nitrogen-containing heterocyclyl", "oxygen-containing heterocyclyl" and "sulfur-containing heterocyclyl" each optionally further contain one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur. Examples of 3-8 membered heterocyclyls include but are not limited to oxiranyl (or oxirane), aziridine (or aziridine, aziridine), azetidinyl, oxirane, tetrahydrofuranyl, pyrrolidinyl, pyrrolidonyl (such as ), imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, and the like.

[0047] In the present invention, the heterocyclic group can form a parallel ring structure with a heterocyclic group or a cycloalkyl group, and the connection point of the parallel ring structure with the other group can be on any heterocyclic group or cycloalkyl group. Therefore, the heterocyclic group of the present invention also includes but is not limited to heterocyclic groups and heterocyclic groups, heterocyclic groups and cycloalkyl groups, especially monoheterocyclic groups and monoheterocyclic groups, monoheterocyclic groups and monocycloalkyl groups, such as 3-7 membered (mono) heterocyclic groups and 3-7 membered (mono) heterocyclic groups, 3-7 membered (mono) heterocyclic groups and C 3-7 (mono)cycloalkyl, 3-7 membered (mono)heterocyclic group and C 4-6 (Mono)cycloalkyl, examples of which are not limited to pyrrolidinyl-cyclopropyl, cyclopentyl-aziridine, pyrrolidinyl-cyclobutyl, pyrrolidinyl-pyrrolidinyl, pyrrolidinyl-piperidinyl, pyrrolidinyl-piperazinyl, piperidinyl-morpholinyl,

[0048] In the present invention, the heterocyclic group also includes a bridged heterocyclic group and a spiro heterocyclic group.

[0049] As used herein, the term "bridged heterocycle" refers to a cyclic structure containing one or more (e.g., 1, 2, 3 or 4) heteroatoms (e.g., oxygen atoms, nitrogen atoms and / or sulfur atoms) formed by two saturated rings sharing two ring atoms that are not directly connected, including but not limited to 7-10 membered bridged heterocycles, 8-10 membered bridged heterocycles, especially 7-10 membered nitrogen-containing bridged heterocycles, 7-10 membered oxygen-containing bridged heterocycles, 7-10 membered sulfur-containing bridged heterocycles, etc., for example The "nitrogen-containing bridged heterocycle", "oxygen-containing bridged heterocycle" and "sulfur-containing bridged heterocycle" optionally further contain one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0050] As used herein, the term "spiroheterocycle" refers to a cyclic structure containing one or more (e.g., 1, 2, 3 or 4) heteroatoms (e.g., oxygen atoms, nitrogen atoms and / or sulfur atoms) formed by two or more saturated rings sharing one ring atom, including but not limited to 5-10 membered spiroheterocycles, 6-10 membered spiroheterocycles, especially 6-10 membered nitrogen-containing spiroheterocycles, 6-10 membered oxygen-containing spiroheterocycles, 6-10 membered sulfur-containing spiroheterocycles, etc., for example

[0051] The "nitrogen-containing spiro heterocycle", "oxygen-containing spiro heterocycle" and "sulfur-containing spiro heterocycle" optionally further contain one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur. The term "6-10 membered nitrogen-containing spiro heterocyclic group" refers to a spiro heterocyclic group containing a total of 6-10 ring atoms and at least one of the ring atoms being a nitrogen atom.

[0052] Examples of the group obtained by condensing a heterocyclic group with an aryl group include, but are not limited to:

[0053] As used herein, the term "aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic aromatic group having a conjugated π electron system. 6-10 "Aryl" or "aromatic ring" refers to an aromatic group or aromatic ring containing 6 to 10 carbon atoms, for example, phenyl or benzene ring, naphthyl or naphthalene ring. The aryl group is optionally substituted by one or more (such as 1 to 3) identical or different substituents (for example, halogen, OH, CN, NO2, C 1-6 alkyl, etc.) substituted.

[0054] As used herein, the term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic or polycyclic aromatic group containing one or more 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, such as 5, 6, 7, 8, 9 or 10 ring atoms. The heteroatom may be oxygen, nitrogen or sulfur, and the "heteroaryl" or "heteroaromatic ring" may contain one or more heteroatoms independently selected from oxygen, nitrogen or sulfur. The carbon atoms and heteroatoms on the heteroaryl are optionally substituted with oxo groups (e.g., forming C=O, S(=O) or S(=O)2).

[0055] As used herein, the term "5-10 membered heteroaryl" or "5-10 membered heteroaromatic ring" refers to a heteroaryl group (heteroaromatic 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. The “nitrogen-containing heteroaryl”, “oxygen-containing heteroaryl” and “sulfur-containing heteroaryl” each optionally contain one or more heteroatoms independently selected from oxygen, nitrogen and sulfur, examples of which include but are not limited to thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl and the like, or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and 5-10 membered cyclic groups containing these groups.

[0056] In the present 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 monocyclic alkyl group) or another heteroaryl group (e.g., another monoheteroaryl group) to form a parallel ring structure, and the connection point can be on any heteroaryl ring or on other rings, including but not limited to (mono)heteroaryl and (mono)heteroaryl, (mono)heteroaryl and (monocyclic) aryl, (mono)heteroaryl and (mono)heterocyclic group and (mono)heteroaryl and (mono)cycloalkyl, such as a 5-6-membered (mono)heteroaryl and 5-6-membered (mono)heteroaryl, a 5-6-membered (mono)heteroaryl and phenyl group, a 5-6-membered (mono)heteroaryl and 5-6-membered (mono)heterocyclic group or a 5-6-membered (mono)heteroaryl and C 4-6 (Mono)cycloalkyl (e.g., 5-6 membered heteroarylcyclobutyl, 5-6 membered heteroarylcyclopentyl or 5-6 membered heteroarylcyclohexyl), examples of which are not limited to indolyl, isoindolyl, indazolyl, benzimidazole, quinolyl, isoquinolyl, wait.

[0057] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0058] As used herein, the term "hydroxy" refers to an -OH group.

[0059] As used herein, the term "amino" refers to a -NH2 group.

[0060] As used herein, the term "cyano" refers to a -CN group.

[0061] As used herein, the term "nitro" refers to a -NO2 group.

[0062] The term "substituted" means that one or more (e.g., 1, 2, 3, or 4) hydrogen atoms on the designated atom are replaced by the indicated radical, provided that the normal valence of the designated atom in the present context is not exceeded and the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form stable compounds.

[0063] If a substituent is described as being "optionally substituted with one or more," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the listed substituents, one or more hydrogen atoms on the carbon may each be replaced with an independently selected optional substituent. If a nitrogen of a substituent is described as being optionally substituted with one or more of the listed substituents, one or more hydrogen atoms on the nitrogen may each be replaced with an independently selected optional substituent.

[0064] If substituents are described as being "each independently selected" or "independently selected" from a group, each substituent is selected independently of another that is equivalent. Thus, each substituent may be the same as or different from another (other) substituent.

[0065] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10, where reasonable.

[0066] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any convenient position of the substituent. When a bond to a substituent is shown as passing through a bond connecting two atoms in a ring, then such a substituent may be bonded to any ring-forming atom in the substitutable ring.

[0067] It should also be understood that the compounds of the present invention may exist in free form, or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable forms include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs, which, after being administered to an individual (e.g., a patient) in need thereof, 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 cover the above-mentioned various derivative forms of the compounds.

[0068] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof, such as hexafluorophosphate, meglumine salt, etc. For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002).

[0069] As used herein, the term "ester" refers to esters derived from compounds of the present invention, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the free acid or alcohol / phenol form of the compounds of the present invention). In addition, the compounds of the present invention themselves may also be esters.

[0070] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol. The amount of polar solvents, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0071] Those skilled in the art will appreciate that, since nitrogen requires available lone pairs of electrons to be oxidized to oxides, not all nitrogen-containing heterocycles can form N-oxides. Those skilled in the art will recognize nitrogen-containing heterocycles that can form N-oxides. Those skilled in the art will also recognize that tertiary amines can form N-oxides. The 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 oxidizing heterocycles and tertiary amines with peroxyacids such as peracetic acid and metachloroperbenzoic acid (mCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate and dioxirane (such as dimethyl dioxirane). These methods for preparing N-oxides have been extensively described and reviewed in the literature, see for example: TL Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750, AR Katritzky and AJ Boulton, Eds., Academic Press; and GWH Cheeseman and ES G Werstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, AR Katritzky and AJ Boulton, Eds., Academic Press.

[0072] Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo after administration of the compounds of the present invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Thus, the present invention includes metabolites of the compounds of the present invention, including compounds prepared by contacting the compounds of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0073] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may have less pharmacological activity or no pharmacological activity themselves, and can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered to the body or thereon. Typically, such prodrugs will be functional group derivatives of the compounds that are easily converted into the desired therapeutically active compounds in vivo. Additional information on 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 the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moiety" (e.g., "Design of Prodrugs", H. Bundgaard (Elsevier, 1985)).

[0074] The present invention also encompasses compounds of the present invention containing protecting groups. In any process of preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive groups or reactive groups on any related molecules, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example, those described in TW Greene & P.GMWuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which are incorporated herein by reference. Using methods known in the art, the protecting groups can be removed at an appropriate subsequent stage.

[0075] The present invention also includes all pharmaceutically acceptable isotope-labeled compounds, which are identical to the compounds of the present invention, except that one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number that predominates in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2 H), tritium ( 3 H)); isotopes of carbon (e.g. 11 C. 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (e.g. 123 I and 125 I); isotopes of nitrogen (e.g. 13 N and 15N); isotopes of oxygen (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (e.g. 32 P); and sulfur isotopes (e.g. 35 S). Certain isotopically-labeled compounds of the invention (e.g., those incorporating a radioactive isotope) are useful in drug and / or substrate tissue distribution studies (e.g., assays). 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because of their ease of incorporation and ease of detection. 11 C. 18 F. 15 O and 13 N) can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotope-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 appropriate isotope-labeled reagents instead of the non-labeled reagents previously employed. 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.

[0076] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds with one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers may occur.

[0077] In the compounds of the present invention, individual molecules can also exist in the form of geometric isomers (cis / trans). For example, the compounds of the present invention can exist in a mixture of two or more different structural forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. For example, nitroso-oxime can exist in the following tautomeric form equilibrium in solution:

[0078]

[0079] It is to be understood that the scope of the present invention encompasses all such isomers in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) or mixtures thereof.

[0080] In this article, solid lines can be used Solid wedge Virtual wedge Depicting chemical bonds of the compounds of the invention. The use of solid lines to depict bonds to asymmetric carbon atoms has the following implication: all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) arising from that carbon atom are present. The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms has the following implication: the stereoisomer shown is present. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the invention are intended to exist as stereoisomers, which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0081] The present invention also encompasses all possible crystalline forms or polymorphs of the compounds, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0082] The term "cocrystal" refers to a pharmaceutically active molecule and other physiologically acceptable acid, base, salt, non-ionic compound molecules that are combined in the same crystal lattice by hydrogen bonds, π-π stacking, van der Waals forces and other non-covalent bonds.

[0083] The term "about" means within ±10% of the stated numerical value, preferably within ±5%, more preferably within ±2%.

[0084] Compound

[0085] In some embodiments, the present invention provides a compound of Formula I or a pharmaceutically acceptable form thereof:

[0086]

[0087] in:

[0088] X 1 , X 2 and X 3 Each independently selected from CR 5 or N;

[0089] Y and Z are each independently selected from CR 13 or N;

[0090] R 1 , R 2 and R 6 are each 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 6 Together with the atoms to which it is attached, it forms C 5-8 aliphatic ring, 5-8 membered heterocyclic ring or 5-10 membered heteroaromatic ring, wherein the aliphatic ring, heterocyclic ring or heteroaromatic ring is optionally substituted by one or more halogen, -OH, -CN, -NH2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Substituted with cycloalkoxy or 3-6 membered heterocyclic group;

[0091] R 3 Selected from H or -NR 8 R 9 ;

[0092] R 4 Selected from -C(=O)NH(R 10 ), -C(=O)R 11 、-SO2R 11 or -S(=O)2N(R 10 )2;

[0093] R 5 is independently selected at each occurrence from H, halogen, -CN, -NR 8 R 9 、-C(=O)R 11 、-C(=O)NH(R 10 )、-NHC(=O)R 11 、-SO2R 11 、-OR 12 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 3-8 Cycloalkoxy, C 6-10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl or heteroaryl optionally substituted by one or more R 7 Replacement; or two adjacent R 5 Together with the atoms to which it is attached, it forms C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10Aryl or 5-10 membered heteroaryl;

[0094] R 7 is independently selected at each occurrence from H, halogen, -OH, -CN, -NR 8 R 9 、-C(=O)R 11 、-NHC(=O)R 11 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic group, C 6-10 The alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl or heteroaryl radicals are optionally substituted with one or more halogen, -OH, -CN, -NR 8 R 9 , -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Substituted with cycloalkoxy or 3-6 membered heterocyclic group;

[0095] R 8 and R 9 Each occurrence is independently selected from H, C 1-4 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl or -SO2R 11 The alkyl, cycloalkyl, aryl or heteroaryl groups are optionally substituted with one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl substituted;

[0096] R 10 Each occurrence is independently selected from H, C 1-4Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, the alkyl, alkoxy, cycloalkyl, aryl or heteroaryl group is optionally substituted by one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl substituted;

[0097] R 11 Each occurrence is independently selected from C 1-4 Alkyl, C 3-8 Cycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, the alkyl, cycloalkyl, aryl or heteroaryl being optionally substituted with one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl or C 1-4 Haloalkyl substitution;

[0098] R 12 Each occurrence is independently selected from H, C 6-10 aryl or 5-10 membered heteroaryl, the aryl or heteroaryl is optionally substituted by one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Substituted with cycloalkoxy or 3-6 membered heterocyclic group;

[0099] R 13 is independently selected at each occurrence from H, halogen, -OH, -CN, C 1-4 Alkyl or C 1-4 Haloalkyl;

[0100] The pharmaceutically acceptable form is selected from a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, ester, polymorph, solvate, N-oxide, metabolite or prodrug.

[0101] In certain embodiments, in the compound of formula I of the present invention:

[0102] X 1 , X 2 and X 3 Each independently selected from CR 5 or N;

[0103] Y and Z are each independently selected from CR13 or N;

[0104] R 1 , R 2 and R 6 are each 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 6 Together with the atoms to which it is attached, it forms C 5-8 aliphatic ring, 5-8 membered heterocyclic ring or 5-10 membered heteroaromatic ring, wherein the aliphatic ring, heterocyclic ring or heteroaromatic ring is optionally substituted by one or more halogen, -OH, -CN, -NH2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Substituted with cycloalkoxy or 3-6 membered heterocyclic group;

[0105] R 3 Selected from H or -NR 8 R 9 ;

[0106] R 4 Selected from -C(=O)NH(R 10 ), -C(=O)R 11 or-SO2R 11 ;

[0107] R 5 is independently selected at each occurrence from H, halogen, -CN, -NR 8 R 9 、-C(=O)R 11 、-C(=O)NH(R 10 )、-NHC(=O)R 11 、-SO2R 11 、-OR 12 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 3-8 Cycloalkoxy, C 6-10aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl or heteroaryl optionally substituted by one or more R 7 Replacement; or two adjacent R 5 Together with the atoms to which it is attached, it forms C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0108] R 7 is independently selected at each occurrence from H, halogen, -OH, -CN, -NR 8 R 9 、-C(=O)R 11 、-NHC(=O)R 11 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic group, C 6-10 The alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl or heteroaryl radicals are optionally substituted with one or more halogen, -OH, -CN, -NR 8 R 9 , -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Substituted with cycloalkoxy or 3-6 membered heterocyclic group;

[0109] R 8 and R 9 Each occurrence is independently selected from H, C 1-4 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl or -SO2R 11 The alkyl, cycloalkyl, aryl or heteroaryl groups are optionally substituted with one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl substituted;

[0110] R 10 Each occurrence is independently selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, the alkyl, alkoxy, cycloalkyl, aryl or heteroaryl group is optionally substituted by one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl substituted;

[0111] R 11 Each occurrence is independently selected from C 1-4 Alkyl, C 3-8 Cycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, the alkyl, cycloalkyl, aryl or heteroaryl being optionally substituted with one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl or C 1-4 Haloalkyl substitution;

[0112] R 12 Each occurrence is independently selected from H, C 6-10 aryl or 5-10 membered heteroaryl, the aryl or heteroaryl is optionally substituted by one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Substituted with cycloalkoxy or 3-6 membered heterocyclic group;

[0113] R 13 is independently selected at each occurrence from H, halogen, -OH, -CN, C 1-4 Alkyl or C 1-4 Haloalkyl;

[0114] The pharmaceutically acceptable form is selected from a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, ester, polymorph, solvate, N-oxide, metabolite or prodrug.

[0115] In certain embodiments, in the compound of formula I of the present invention,

[0116] X 1 and X 2 Each independently selected from CR 5 , X 3 Selected from CR 5 or N; R 5 Each occurrence is independently selected from H, C 1-6 Alkyl or C 1-6 Alkoxy, the alkyl or alkoxy group is optionally substituted by one or more R 7 Replacement; R 7 are independently selected at each occurrence from halogen;

[0117] Y and Z are each independently selected from CR 13 ; R 13 is independently selected at each occurrence from H or halogen;

[0118] R 1 and R 2 Each independently selected from C 1-4 Alkyl, R 6 Selected from -OH; or R 1 and R 6 Together with the atoms to which they are attached, they form a 5-10 membered heteroaromatic ring;

[0119] R 3 Selected from -NR 8 R 9 ; R 8 and R 9 Each independently selected from H or C 1-4 alkyl;

[0120] R 4 Selected from -C(=O)NH(R 10 );R 10 Select from H or C 1-4 alkyl.

[0121] In certain embodiments, the present invention provides compounds of formula I, wherein X 1 and X 2 Each independently selected from CR 5 , X 3 Selected from CR 5 or N.

[0122] In certain embodiments, the present invention provides compounds of formula I, wherein X 1 and X 2 Each independently selected from CR 5 , X 3 Selected from N.

[0123] In certain embodiments, the present invention provides compounds of formula I, wherein X 1 Selected from CH, X 2 Selected from CR 5 , X 3 Selected from N.

[0124] In certain embodiments, the present invention provides compounds of formula I, wherein Y and Z are each independently selected from CR 13 or N, where R 13 is selected from H, halogen, -OH, -CN, methyl, ethyl, propyl, halomethyl, haloethyl or halopropyl.

[0125] In certain embodiments, the present invention provides compounds of formula I, wherein Y and Z are each independently selected from CR 13 or N, where R 13 Selected from H or halogen.

[0126] In certain embodiments, the present invention provides compounds of formula I, wherein Y and Z are both CR 13 , where R 13 Selected from H or halogen.

[0127] In certain embodiments, the present invention provides compounds of formula I wherein Y and Z are both CH.

[0128] In certain embodiments, the present invention provides compounds of formula I wherein Y is CH, and Z is CF or CCl.

[0129] In certain embodiments, the present invention provides compounds of formula I in which R 1 and R 2 are each independently selected from H, halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl.

[0130] In certain embodiments, the present invention provides compounds of formula I in which R 1 and R 2 are each independently selected from halogen or C 1-4 alkyl.

[0131] In certain embodiments, the present invention provides compounds of formula I in which R 1 and R 2 Both C 1-4 alkyl.

[0132] In certain embodiments, the present invention provides compounds of formula I in which R 1 and R 2 Each is independently selected from methyl, ethyl, propyl (eg, n-propyl, isopropyl) and butyl (eg, n-butyl, isobutyl, sec-butyl, tert-butyl).

[0133] In certain embodiments, the present invention provides compounds of formula I in which R 1 and R 2 All are methyl.

[0134] In certain embodiments, the present invention provides compounds of formula I in which R 6 It is -OH.

[0135] In certain embodiments, the present invention provides compounds of formula I in which R 1 and R 6 Together with the atoms to which they are attached, they form a 5-10 membered heteroaromatic ring, which is optionally substituted by one or more halogen, -OH, -CN, -NH2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 The cycloalkyloxy group or the 3-6-membered heterocyclic group is substituted.

[0136] In certain embodiments, the present invention provides compounds of formula I in which R 1 and R 6 Together with the atoms to which it is attached, it forms a 5-10 membered nitrogen-containing heteroaromatic ring, wherein the 5-10 membered nitrogen-containing heteroaromatic ring contains 1-3 ring nitrogen atoms and is optionally substituted by one or more halogens or C 1-4 Alkyl substitution.

[0137] In certain embodiments, the present invention provides compounds of formula I in which R 1 and R 6 Together with the atoms to which it is attached, it forms a 5-6-membered nitrogen-containing heteroaromatic ring, wherein the 5-6-membered nitrogen-containing heteroaromatic ring contains 1-2 ring nitrogen atoms and is optionally substituted by one or more halogens or C 1-4 Alkyl substitution.

[0138] In certain embodiments, the present invention provides compounds of formula I in which R 1 and R 6 Together with the atoms to which it is attached, it forms a pyrazole ring, which is optionally substituted with one or more halogens or C 1-4 Alkyl substitution.

[0139] In certain embodiments, the present invention provides compounds of formula I in which R 1 and R 6 Together with the atoms to which it is attached, it forms a pyrazole ring.

[0140] In certain embodiments, the present invention provides compounds of formula I in which R 3 For-NR 8 R9 , where R 8 and R 9 Each independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl or -SO2R 11 The alkyl, cycloalkyl, aryl or heteroaryl groups are optionally substituted with one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl.

[0141] In certain embodiments, the present invention provides compounds of formula I in which R 3 For-NR 8 R 9 , where R 8 and R 9 Each independently selected from H or C 1-4 Alkyl, the alkyl group is optionally substituted by one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl.

[0142] In certain embodiments, the present invention provides compounds of formula I in which R 3 For-NR 8 R 9 , where R 8 and R 9 Each is independently selected from H, methyl, ethyl, propyl (eg, n-propyl, isopropyl) and butyl (eg, n-butyl, isobutyl, sec-butyl, tert-butyl).

[0143] In certain embodiments, the present invention provides compounds of formula I in which R 3 is -NH2.

[0144] In certain embodiments, the present invention provides compounds of formula I in which R 4 Selected from -C(=O)NH(R 10 ), -C(=O)R11 、-SO2R 11 or -S(=O)2N(R 10 )2, where R 10 Selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 6-10 Aryl or 5-6 membered heteroaryl, the alkyl, alkoxy, cycloalkyl, aryl or heteroaryl is optionally substituted by one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 6-10 Aryl or 5-6 membered heteroaryl substituted; R 11 Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl or 5-6 membered heteroaryl, the alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted by one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl or C 1-4 Haloalkyl substitution.

[0145] In certain embodiments, the present invention provides compounds of formula I in which R 4 Selected from -C(=O)NH(R 10 ), -C(=O)R 11 or-SO2R 11 , where R 10 Selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 6-10 Aryl or 5-6 membered heteroaryl, the alkyl, alkoxy, cycloalkyl, aryl or heteroaryl is optionally substituted by one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 6-10 Aryl or 5-6 membered heteroaryl substituted; R 11 Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl or 5-6 membered heteroaryl, the alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted by one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl or C 1-4 Haloalkyl substitution.

[0146] In certain embodiments, the present invention provides compounds of formula I in which R 4 Selected from -S(=O)2R11 , where R 11 Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl or 5-6 membered heteroaryl, the alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted by one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl or C 1-4 Haloalkyl substitution.

[0147] In certain embodiments, the present invention provides compounds of formula I in which R 4 -C(=O)NH(R 10 ), where R 10 Select from H or C 1-4 alkyl.

[0148] In certain embodiments, the present invention provides compounds of formula I in which R 4 -C(=O)NH(R 10 ), where R 10 is selected from H, methyl, ethyl, propyl (eg, n-propyl, isopropyl) and butyl (eg, n-butyl, isobutyl, sec-butyl, tert-butyl).

[0149] In certain embodiments, the present invention provides compounds of formula I in which R 4 It is -C(=O)NH2.

[0150] In certain embodiments, the present invention provides compounds of formula I in which R 5 is independently selected at each occurrence from H, halogen, -CN, -NR 8 R 9 、-C(=O)R 11 、-C(=O)NH(R 10 )、-NHC(=O)R 11 、-SO2R 11 、-OR 12 , C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 2-4 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 3-6 Cycloalkoxy, C 6-10 aryl or 5-6 membered heteroaryl, the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl or heteroaryl optionally substituted by one or more R 7 Replacement; or two adjacent R5 Together with the atoms to which it is attached, it forms C 3-6 Cycloalkyl or 3-6 membered heterocyclic group.

[0151] In certain embodiments, the present invention provides compounds of formula I in which R 5 is independently selected at each occurrence from H, halogen, -CN, -NR 8 R 9 , hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 aryl or 5-6 membered heteroaryl, the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R 7 replace.

[0152] In certain embodiments, the present invention provides compounds of formula I in which R 5 is independently selected at each occurrence from H, halogen, -CN, -NR 8 R 9 , hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally substituted by one or more halogen or C 1-4 Alkyl substitution.

[0153] In certain embodiments, the present invention provides compounds of formula I in which R 5 is independently selected at each occurrence from halogen, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Cycloalkyl, the alkyl, alkoxy or cycloalkyl is optionally substituted by one or more halogens.

[0154] In certain embodiments, the present invention provides compounds of formula I in which R 5 Each occurrence is independently selected from H, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Cycloalkyl, the alkyl, alkoxy or cycloalkyl is optionally substituted by one or more halogens.

[0155] In certain embodiments, the present invention provides compounds of formula I in which R 5 Each occurrence is independently selected from H, C 1-4 Alkyl or C 1-4 Alkoxy, the alkyl or alkoxy is optionally substituted by one or more halogens.

[0156] In certain embodiments, the present invention provides compounds of formula I in which R 5 Each occurrence is independently selected from H, C 1-4 Alkyl or C 1-4 Alkoxy, the alkyl group is optionally substituted by one or more halogens.

[0157] In certain embodiments, the present invention provides compounds of formula I in which R 5 is selected at each occurrence from H, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0158] In certain embodiments, the present invention provides compounds of formula I in which R 8 and R 9 Each occurrence is independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl or -SO2R 11 The alkyl, cycloalkyl, aryl or heteroaryl groups are optionally substituted with one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic group, C 6-10 aryl or 5-6 membered heteroaryl.

[0159] In certain embodiments, the present invention provides compounds of formula I in which R 8 and R 9 Each occurrence is independently selected from H, C 1-4 Alkyl, C 6-10 Aryl or 5-6 membered heteroaryl, the alkyl, aryl or heteroaryl is optionally substituted by one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 The cycloalkyloxy group or the 3-6-membered heterocyclic group is substituted.

[0160] In certain embodiments, the present invention provides compounds of formula I in which R 8 and R 9 Each occurrence is independently selected from H or C 1-4Alkyl, the alkyl group is optionally substituted by one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 The cycloalkyloxy group or the 3-6-membered heterocyclic group is substituted.

[0161] In certain embodiments, the present invention provides compounds of formula I in which R 8 and R 9 Each occurrence is independently selected from H or C 1-4 alkyl.

[0162] In certain embodiments, the present invention provides compounds of formula I in which R 8 and R 9 Both are H.

[0163] In certain embodiments, the present invention provides compounds of formula I in which R 10 Each occurrence is independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl or 5-6 membered heteroaryl, the alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted by one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 6-10 aryl or 5-6 membered heteroaryl.

[0164] In certain embodiments, the present invention provides compounds of formula I in which R 10 Each occurrence is independently selected from H or C 1-4 Alkyl, said alkyl being optionally substituted by one or more halogens.

[0165] In certain embodiments, the present invention provides compounds of formula I in which R 10 For H.

[0166] In certain embodiments, the present invention provides compounds of formula I in which R 11 Each occurrence is independently selected from C 1-4 Alkyl or C 3-8 Cycloalkyl, the alkyl or cycloalkyl is optionally substituted by one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl or C 1-4 Haloalkyl substitution.

[0167] In certain embodiments, the present invention provides compounds of formula I in which R 11 C 1-4 Alkyl, said alkyl being optionally substituted by one or more halogens.

[0168] In certain embodiments, the present invention provides compounds of formula I in which R 12 Each occurrence is independently selected from H, C 6-10 Aryl or 5-6 membered heteroaryl, the aryl or heteroaryl is optionally substituted by one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl group or the 3-6-membered heterocyclic group is substituted.

[0169] In certain embodiments, the present invention provides compounds of formula I in which R 12 For H.

[0170] In certain embodiments, the present invention provides compounds of formula I in which R 13 Each occurrence is independently selected from H, halogen, -OH, -CN.

[0171] In certain embodiments, the present invention provides compounds of formula I in which R 13 is independently selected at each occurrence from H, F, Cl, Br, -OH or -CN.

[0172] In certain embodiments, the present invention provides compounds of formula I in which R 13 is independently selected at each occurrence from H, F or Cl.

[0173] In certain embodiments, the present invention provides compounds of formula I in which R 13 is independently selected from H or F at each occurrence.

[0174] In certain embodiments, the compound of formula I provided by the present invention is a compound represented by the following formula I-1 or I-2:

[0175]

[0176] Among them, R 1 , R 2 , R 3 , R 4 , R 5 and R 13 As defined in Formula I.

[0177] In certain embodiments, the present invention provides compounds of formula I-1, wherein R 13 It is H or F, preferably F.

[0178] In certain embodiments, the present invention provides compounds of formula I-1, wherein R 5 It is selected from methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy or cyclopropyl, more preferably methyl, trifluoromethyl, methoxy or cyclopropyl.

[0179] In certain embodiments, the present invention provides compounds of formula I-2, wherein R 13 It is H or F, preferably H.

[0180] In certain embodiments, the present invention provides compounds of formula I-2, wherein R 5 It is selected from methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably methyl or ethyl.

[0181] In certain embodiments, the compound of formula I provided by the present invention is a compound represented by the following formula I-1-A or I-2-A:

[0182]

[0183] Among them, R 5 , R 13 As defined in Formula I.

[0184] In certain embodiments, the present invention provides compounds of formula I-1-A, wherein R 13 It is H or F, preferably F.

[0185] In certain embodiments, the present invention provides compounds of formula I-1-A, wherein R 5 It is selected from methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy or cyclopropyl, more preferably methyl, trifluoromethyl, methoxy or cyclopropyl.

[0186] In certain embodiments, the present invention provides compounds of formula I-2-A, wherein R 13 It is H or F, preferably H.

[0187] In certain embodiments, the present invention provides compounds of formula I-2-A, wherein R 5 It is selected from methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably methyl or ethyl.

[0188] In certain embodiments, the present invention provides compounds of formula I in which R 4and / or R 5 and / or R 8 and / or R 9 -SO2R in definition 11 Selected from -S(=O)2R 11 .

[0189] The present invention covers any combination of the above embodiments.

[0190] In some embodiments, compounds of the invention include, but are not limited to:

[0191]

[0192]

[0193]

[0194]

[0195] Preparation method

[0196] The compounds of the present invention can be prepared by any method known in the art. Reagents and starting materials are readily available to those of ordinary skill in the art. Individual isomers, enantiomers, and diastereomers can be separated or split at any convenient point in the synthesis by methods such as selective crystallization techniques or chiral chromatography (See for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981, and EL Elel and SH Wilen)).

[0197] In certain embodiments, the present invention provides a method for preparing a compound of formula I (especially formula I-1-A) or a pharmaceutically acceptable form thereof, comprising a seventh step, optionally further comprising a sixth step, optionally further comprising a fifth step, optionally further comprising a fourth step, optionally further comprising a third step, optionally further comprising a second step, and optionally further comprising a first step:

[0198] Step 1: Compound Int-1-1 undergoes halogenation reaction to generate compound Int-1-2;

[0199]

[0200] Step 2: Compound Int-1-2 reacts with amine via Buchwald cross-coupling reaction to generate compound Int-1-3;

[0201]

[0202] Step 3: Compound Int-1-3 reacts with a cyanation reagent to generate compound Int-1-4;

[0203]

[0204] Step 4: Compound Int-1-4 and tert-butyl cyanoacetate are reacted via Buchwald cross-coupling ring-closing tandem reaction to generate compound Int-1-5;

[0205]

[0206] Step 5: Compound Int-1-5 is hydrolyzed to generate compound Int-1-6;

[0207]

[0208] Step 6: Compound Int-1-6 undergoes condensation reaction to generate compound Int-1-7;

[0209]

[0210] Step 7: Compound Int-1-7 is subjected to a deprotection reaction to generate a compound of formula I-1-A;

[0211]

[0212] in:

[0213] The groups are as defined above.

[0214] In certain embodiments, the method for preparing the compound of formula I-1-A or a pharmaceutically acceptable form thereof provided by the present invention comprises the first to seventh reaction steps.

[0215] In some embodiments of the present invention, the halogenation reaction in the first step is carried out in the presence of a halogenation reagent. The halogenation reagent is preferably concentrated hydrochloric acid or the like. Preferably, in the first step, compound Int-1-1 is halogenated with concentrated hydrochloric acid to produce compound Int-1-2. The halogenation reaction in the first step is preferably carried out in a solvent. The solvent is, for example, 1,4-dioxane or the like.

[0216] In some embodiments of the present invention, the Buchwald cross-coupling reaction in the second step is preferably carried out in the presence of a base. The base is preferably Na2CO3, K2CO3, Cs2CO3 or K3PO4. The Buchwald cross-coupling reaction in the second step is preferably carried out in the presence of a catalyst. The catalyst is preferably a combination of Pd2(dba)3 and XantPhos. The Buchwald cross-coupling reaction in the second step is preferably carried out in a solvent. The solvent is, for example, 1,4-dioxane.

[0217] In some embodiments of the present invention, the cyanation reaction in the third step is preferably carried out in the presence of a base. The base is preferably TEA or DIPEA. The cyanation reaction in the third step is preferably carried out in a solvent. The solvent is, for example, DMF.

[0218] In some embodiments of the present invention, the Buchwald cross-coupling ring-closing tandem reaction in the fourth step is preferably carried out in the presence of a base. The base is preferably potassium tert-butoxide, sodium tert-butoxide or sodium hydride. The Buchwald cross-coupling ring-closing tandem reaction in the fourth step is preferably carried out in the presence of a catalyst. The catalyst is preferably Xantphos Pd G3. The Buchwald cross-coupling ring-closing tandem reaction in the fourth step is preferably carried out in the presence of a solvent. The solvent is, for example, 1,4-dioxane.

[0219] In some embodiments of the present invention, the hydrolysis reaction in the fifth step is preferably carried out in the presence of a catalyst. The catalyst is preferably trifluoroacetic acid or hydrochloric acid. The hydrolysis reaction in the fifth step is preferably carried out in a solvent. The solvent is, for example, dichloromethane.

[0220] In some embodiments of the present invention, the condensation reaction in the sixth step is preferably carried out in the presence of a condensation agent. The condensation agent is preferably HATU or the like. The condensation reaction in the sixth step is preferably carried out in the presence of a base. The base is preferably TEA or DIPEA or the like. The condensation reaction in the sixth step is preferably carried out in a solvent. The solvent is, for example, DMF or the like.

[0221] In some embodiments of the present invention, the deprotection reaction in the seventh step is preferably carried out in the presence of a deprotection reagent. The deprotection reagent is preferably BBr3 or hydrochloric acid. The deprotection reaction in the seventh step is preferably carried out in a solvent. The solvent is, for example, dichloromethane.

[0222] In certain embodiments, the present invention provides a method for preparing a compound of formula I (especially I-2-A) or a pharmaceutically acceptable form thereof, comprising a sixth step, optionally further comprising a fifth step, optionally further comprising a fourth step, optionally further comprising a third step, optionally further comprising a second step, and optionally further comprising a first step:

[0223] Step 1: Compound Int-1-1 undergoes halogenation reaction to generate compound Int-1-2;

[0224]

[0225] Step 2: Compound Int-1-2 reacts with amine via Buchwald cross-coupling reaction to generate compound Int-2-1;

[0226]

[0227] Step 3: Compound Int-2-1 reacts with a cyanation reagent to generate compound Int-2-2;

[0228]

[0229] Step 4: Compound Int-2-2 and tert-butyl cyanoacetate are reacted via Buchwald cross-coupling ring-closing tandem reaction to generate compound Int-2-3;

[0230]

[0231] Step 5: Compound Int-2-3 is hydrolyzed to generate compound Int-2-4;

[0232]

[0233] Step 6: Compound Int-2-4 undergoes condensation reaction to generate a compound of formula I-2-A;

[0234]

[0235] in:

[0236] THP stands for tetrahydro-2H-pyran-2-yl;

[0237] The remaining groups are as defined above.

[0238] In certain embodiments, the method for preparing the compound of formula I-2-A or a pharmaceutically acceptable form thereof provided by the present invention comprises the first to sixth reaction steps.

[0239] In some embodiments of the present invention, except for the different reactants, the reaction conditions of the first to sixth steps in the above method are substantially the same as the first to sixth steps in the method for preparing the compound of formula I-1-A, preferably the same.

[0240] Those skilled in the art will appreciate that, depending on the desired product structure, one or more steps in the above-described preparation method may be omitted, and the order of the reaction steps may be appropriately adjusted as well as protection / deprotection reaction steps may be added or omitted as needed.

[0241] Pharmaceutical compositions, preparations and methods of treatment

[0242] The present invention provides a pharmaceutical composition comprising (e.g., a prophylactic or therapeutically effective amount of) a compound of the present invention (e.g., a compound of Formula I, Formula I-1, Formula I-1-A, Formula I-2 or Formula I-2-A, etc., or Compound 1-13, etc.) or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled compound, ester, polymorph, solvate, N-oxide, metabolite or prodrug thereof, and optionally one or more pharmaceutically acceptable carriers.

[0243] In some embodiments, the pharmaceutical compositions of the present invention comprise a prophylactically or therapeutically 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 thereof and one or more pharmaceutically acceptable carriers.

[0244] Unless otherwise indicated, as used herein, the term "prevention" refers to the pre-administration of a drug to avoid or prevent the appearance of one or more symptoms of a disease or condition, avoiding the cause, effect, symptom or progression of a disease or condition before the disease or condition fully manifests itself. One of ordinary skill in the medical arts recognizes that the term "prevention" is not an absolute term. In the medical arts, it is understood that the prophylactic administration of a drug is to substantially reduce the likelihood or severity of a condition or the symptoms of a condition, which is the meaning intended in the disclosure of the present invention.

[0245] As used herein, unless otherwise indicated, the term "treat," ...

[0246] As used herein, the term "effective amount" refers to that amount of a compound which, when administered, will relieve to some extent one or more of the symptoms of the condition being treated.

[0247] As used herein, the term "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle with which a therapeutic agent is administered and which is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0248] 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).

[0249] The pharmaceutical compositions of the invention can act systemically and / or locally. For this purpose, they can be administered by a suitable route.

[0250] For these administration routes, the pharmaceutical composition of the present invention can be administered in a suitable dosage form, that is, in the form of a pharmaceutical preparation.

[0251] The present invention provides a pharmaceutical preparation, which is prepared from the compound or pharmaceutical composition of the present invention, and the pharmaceutical preparation is preferably a solid preparation, a semisolid preparation, a liquid preparation or a gaseous preparation.

[0252] In some embodiments, the pharmaceutical compositions or formulations of the present invention may further comprise one or more other therapeutic agents.

[0253] In some embodiments, the pharmaceutical composition or pharmaceutical formulation of the present invention may also contain one or more additional therapeutic or prophylactic agents (eg, other drugs for treating cancer or tumor diseases).

[0254] In some embodiments, the pharmaceutical composition or pharmaceutical formulation of the present invention is preferably administered by oral, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal routes.

[0255] The present invention provides a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled compound, ester, polymorph, solvate, N-oxide, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, or use of a pharmaceutical preparation of the present invention in the preparation of a medicament for preventing or treating a disease or condition associated with PKMYT1 activity.

[0256] The present invention provides a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled compound, ester, polymorph, solvate, N-oxide, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, or use of a pharmaceutical preparation of the present invention in the preparation of a drug for regulating (e.g., reducing or inhibiting) PKMYT1 activity.

[0257] The present invention provides a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled compound, ester, polymorph, solvate, N-oxide, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, or a pharmaceutical preparation of the present invention, for use in preventing or treating a disease or condition associated with PKMYT1 activity.

[0258] The present invention provides a method for preventing or treating a disease or condition associated with PKMYT1 activity, the method comprising administering to a subject in need thereof 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 thereof, or a pharmaceutical composition of the present invention, or a pharmaceutical preparation of the present invention.

[0259] In some embodiments, the disease or condition associated with PKMYT1 activity is preferably a CCNE1 amplified cancer or tumor.

[0260] In some embodiments, the cancer or tumor is preferably thyroid cancer, gastric cancer, lung cancer, breast cancer or ovarian cancer.

[0261] The dosage regimen may be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dosage may be proportionally reduced or increased as indicated by the urgency of the therapeutic situation. It is to be noted that dosage values ​​may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosage regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering the composition or supervising the administration of the composition.

[0262] The amount of the compound of the present invention administered will depend on the severity of the individual, disease or condition treated, the rate of administration, the disposal of the compound and the judgment of the prescribing physician. Generally speaking, the effective dose is about 0.0001 to about 50 mg per kg body weight per day. In some cases, the dosage level not higher than the lower limit of the aforementioned range may be sufficient, and in other cases, a larger dose may still be used without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses to be administered throughout the day.

[0263] The content or dosage of the compound of the present invention in the pharmaceutical composition or pharmaceutical preparation may be about 0.01 mg to about 1000 mg.

[0264] As used herein, "individual" includes humans or non-human animals. Exemplary human individuals include human individuals (referred to as patients) suffering from diseases (e.g., diseases described herein) or normal individuals. Exemplary non-human animal individuals include, but are not limited to, all vertebrates, such as non-mammals and mammals, the former such as birds, amphibians and / or reptiles, the latter such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.). DETAILED DESCRIPTION

[0265] The present invention is further described below in conjunction with examples, but these examples are not intended to limit the scope of the present invention.

[0266] The abbreviations used herein have the following meanings:

[0267]

[0268] The compounds of the present invention are separated and purified by preparative TLC, silica gel column chromatography, Prep-HPLC and / or flash column chromatography (Flash column chromatography), supercritical fluid chromatography (SFC), and their structures are shown in Table 1. 1 The reaction was confirmed by H NMR and / or MS. The reaction was monitored by TLC or LC-MS.

[0269] 1 H NMR was performed using a Bruker superconducting nuclear magnetic resonance spectrometer (model AVANCE III HD 400 MHz).

[0270] LC-MS uses Aglient 1260Infinity / Aglient 6120Quadrupole.

[0271] TLC used silica gel GF 254 as the stationary phase.

[0272] Column chromatography generally uses 200-300 mesh silica gel (Qingdao Ocean) as the stationary phase.

[0273] Flash column chromatography was performed using a Biotage flash column chromatograph.

[0274] Agilent 1260 and Waters 2489 were used for Prep-HPLC.

[0275] Supercritical fluid chromatography was performed using a DAICEL CHIRALCEL OX (250 mm*30 mm, 10 μm) chiral column.

[0276] Microwave reactions were performed using a BiotageInitiator microwave reactor.

[0277] In the following examples, unless otherwise specified, the reaction temperature is room temperature (15-30°C).

[0278] The reagents used in the present invention are purchased from Acros Organics, Aldrich Chemical Company, or Teber Chemical Company.

[0279] Compound preparation

[0280] Intermediate Int A:3-methoxy-2,6-dimethylaniline

[0281]

[0282] Step 1: Synthesis of 1-methoxy-2,4-dimethyl-3-nitrobenzene (Int A-2)

[0283] Int A-1 (4 g, 17.39 mmol) was dissolved in DMF (10 mL), nitrogen was replaced, and then a solution of CuBr (249.42 mg, 1.74 mmol) and NaOMe (2.82 g, 52.16 mmol) in MeOH (10 mL) was added at room temperature. After the addition was completed, nitrogen was replaced, and the reaction temperature was raised to 95 ° C and stirred for 6 h. TLC detected that the raw material disappeared and new spots were generated. Water was added to quench the reaction, and the methanol was removed by concentration under reduced pressure. Then, the mixture was extracted with ethyl acetate three times, the organic phases were combined, washed with saturated brine three times, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (PE: EA = 0% EA ~ 5% EA, v / v) was performed to obtain Int A-2 (3.3 g).

[0284] Step 2: Synthesis of 3-methoxy-2,6-dimethylaniline (Int A)

[0285] Int A-2 (3.3 g, 18.21 mmol) was dissolved in EtOH (80 mL), and Fe (6.10 g, 109.28 mmol) was added in batches, and a solution of NH4Cl (5.85 g, 109.28 mmol) in water (24 mL) was added, and the temperature was raised to 85°C for 4 h. The mixture was filtered, and the solvent was removed by distillation under reduced pressure, and column chromatography (PE:EA=10% EA, v / v) was performed to obtain Int A (2.4 g).

[0286] MS (ESI, m / z): 152.1 [M+H] + .

[0287] Intermediate Int B:3-Fluoro-5-methoxy-2,6-dimethylaniline

[0288]

[0289] Step 1: Synthesis of 2,4-dibromo-1-fluoro-5-methoxy-3-nitrobenzene (Int B-2)

[0290] Int B-1 (4.26 g, 13.44 mmol) and MeONa (726.26 mg, 13.44 mmol) were added to a single-necked flask, followed by MeOH (40 mL) and reacted at 50°C for 4 h. TLC (PE:EA=100:1, v / v, Rf=0.1) showed that the raw materials had reacted completely and a white solid was precipitated. After treatment, the mixture was concentrated first, then water was added, extracted with ethyl acetate, and the organic phase was dried over sodium sulfate. The solvent was removed by distillation under reduced pressure, and column chromatography (PE / EA, 10-25% EA, v / v) was performed to obtain Int B-2 (3.62 g).

[0291] Step 2: Synthesis of 1-fluoro-5-methoxy-2,4-dimethyl-3-nitrobenzene (Int B-4)

[0292] Int B-2 (1.95 g, 5.93 mmol), Int B-3 (5.21 g, 20.75 mmol, 6 mL), K3PO4 (3.78 g, 17.79 mmol), XPhos (282.62 mg, 592.85 μmol), XPhos Pd G3 (250.91 mg, 296.43 μmol), 1,4-dioxane (20 mL), and H2O (4 mL) were added to a single-necked flask in sequence, and the temperature was raised to 75 ° C for 5 h under nitrogen protection. LC-MS detected the appearance of a new peak, and TLC (PE:EA = 100: 0, v / v, Rf = 0.33) showed the appearance of a new point. After post-treatment, the reaction solution was cooled and concentrated, water was added, and EA was extracted. The organic phases were combined, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Column chromatography (PE / EA=5% EA, v / v) was performed to obtain Int B-4 (1.10 g).

[0293] Step 3: Synthesis of 3-fluoro-5-methoxy-2,6-dimethylaniline (Int B)

[0294] Int B-4 (1 g, 5.02 mmol), Int B-5 (1.80 g, 20.08 mmol), 4,4'-bipyridine (39.21 mg, 251.03 μmol) were added to the reaction bottle, DMF (5 mL) was added under ice bath, and then the temperature was raised to 25°C for reaction for 10 min. LC-MS monitored the reaction of the raw materials, and the reaction solution was post-treated by TLC (PE:EA=8:1, v / v, Rf=0.34), concentrated, and column chromatography (PE / EA=5% EA, v / v) to obtain Int B (468 mg).

[0295] MS (ESI, m / z): 170.1 [M+H] + .

[0296] 1 H NMR (400MHz, CDCl3): δ6.13 (d, J = 11.7 Hz, 1H), 3.86 (s, 2H), 3.76 (s, 3H), 2.04 (d, J = 1.6 Hz, 3H), 2.01 (d, J = 1.0 Hz, 3H).

[0297] Example 1: Synthesis of 2-amino-7-cyano-1-(3-hydroxy-2,6-dimethylphenyl)-5-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxamide

[0298]

[0299] Step 1: Synthesis of 5-bromo-4-chloro-2-methylpyridine 1-oxide (Compound 1-2)

[0300] Compound 1-1 (2000 mg, 8.41 mmol) and concentrated hydrochloric acid (22.4 mL, 296.16 mmol) were added to 1,4-dioxane (10 mL), and the reaction system was heated to 100 °C for 16 h. LC-MS confirmed that the reaction was complete. After cooling to room temperature, part of HCl and dioxane were concentrated and added to 50 ml of ice water. 4M NaOH was used to adjust Ph to 8-9. After stirring for 2 min, Ph was measured again and Ph = 8. 30 mL * 2 ethyl acetate was added for extraction. The organic phases were combined, washed once with brine, dried with sodium sulfate, concentrated and mixed, and subjected to silica gel column chromatography (PE / EA = 1 / 1, v / v) to obtain compound 1-2 (1.55 g).

[0301] MS (ESI, m / z): 223.4 [M+H] + .

[0302] Step 2: Synthesis of 4-chloro-5-((3-methoxy-2,6-dimethylphenyl)amino)-2-methylpyridine 1-oxide (Compound 1-3)

[0303] Compound 1-2 (500 mg, 2.14 mmol), Int A (476 mg, 2.99 mmol), Pd2(dba)3 (197.5 mg, 0.021 mmol), Xantphos (247.3 mg, 0.042 mmol), Cs2CO3 (2.09 g, 6.42 mmol) and 1,4-dioxane (12 mL) were added to a 50 mL reaction bottle in sequence, and after nitrogen replacement, the temperature was raised to 100 ° C and stirred for 16 h. After the reaction was completed, the sample was directly mixed and silica gel column chromatography (PE / EA=1 / 1, v / v) was performed to obtain compound 1-3 (465 mg).

[0304] MS (ESI, m / z): 293.7 [M+H] + .

[0305] Step 3: Synthesis of 4-chloro-3-((3-methoxy-2,6-dimethylphenyl)amino)-6-methylpyridinecarbonitrile (Compound 1-4)

[0306] Compound 1-3 (350 mg, 1.16 mmol), TEA (938.7 mg, 9.28 mmol) and TMSCN (1.15 g, 11.6 mmol) were added to DMF (10 mL). After the addition, the temperature was raised to 125°C and stirred for 2 h. TEA (938.7 mg, 9.28 mmol) and TMSCN (1.15 g, 11.6 mmol) were added and the reaction was continued at 125°C for 2 h. After the reaction was completed, aqueous solution was added to quench, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by silica gel flash column chromatography (PE / EA=9 / 1, v / v) to obtain compound 1-4 (280 mg).

[0307] MS (ESI, m / z): 302.7 [M+H] + .

[0308] Step 4: Synthesis of tert-butyl 2-amino-7-cyano-1-(3-methoxy-2,6-dimethylphenyl)-5-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (Compound 1-5)

[0309] Compound 1-4 (250 mg, 0.83 mmol), tert-butyl cyanoacetate (352 mg, 2.49 mmol), XantphosPd G3 (355 mg, 0.42 mmol), t-BuOK (280 mg, 2.49 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted at 110 °C in a microwave reactor for 2 h. After the reaction was completed, the sample was stirred and subjected to silica gel column chromatography (PE / EA=2 / 1, v / v) to obtain compound 1-5 (50 mg).

[0310] MS (ESI, m / z): 407.5 [M+H] + .

[0311] Step 5: Synthesis of 2-amino-7-cyano-1-(3-methoxy-2,6-dimethylphenyl)-5-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid (Compound 1-6)

[0312] Compound 1-5 (50 mg, 0.12 mmol) was added to DCM (4 mL), TFA (1 mL) was added dropwise, and the mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction system was directly concentrated to dryness to obtain compound 1-6 (50 mg).

[0313] MS (ESI, m / z): 351 [M+H] + .

[0314] Step 6: Synthesis of 2-amino-7-cyano-1-(3-methoxy-2,6-dimethylphenyl)-5-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (Compound 1-7)

[0315] Compound 1-6 (50 mg, 0.14 mmol), HATU (80 mg, 0.21 mmol), and DIEA (73 mg, 0.56 mmol) were added to DMF (5 mL), and the mixture was reacted at 25 °C for 10 min under nitrogen protection. NH4Cl (30 mg, 0.56 mmol) was added and stirred for 16 h. After the reaction was completed, the mixture was directly concentrated to dryness, methanol was added and concentrated again, and the crude product was purified by silica gel column chromatography (PE / EA=1 / 1, v / v) to obtain compound 1-7 (20 mg).

[0316] MS (ESI, m / z): 350.2 [M+H] + .

[0317] Step 7: Synthesis of 2-amino-7-cyano-1-(3-hydroxy-2,6-dimethylphenyl)-5-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (Compound 1)

[0318] Compound 1-7 (20 mg, 0.05 mmol) was added to DCM (3 mL), cooled to 0-5°C under nitrogen protection, and 1M BBr3 dichloromethane solution (0.3 mL) was added, and the mixture was reacted at 25°C for 2 h. After the reaction was completed, methanol (1 ml) solution was added to the reaction solution to quench, and then ammonia water (2 mL) was added until the system Ph was alkaline, and the mixture was concentrated to obtain a crude product (30 mg), which was purified by preparative liquid phase and freeze-dried to obtain compound 1 (5 mg).

[0319] MS (ESI, m / z): 336.1 [M+H] + .

[0320] 1 H NMR (400MHz, DMSO-d6): δ9.62(s,1H),7.85(s,1H),7.37(s,2H),7.09(d,J=8.4Hz,1 H),7.06-6.98(m,2H),6.96(d,J=8.4Hz,1H),2.47(s,3H),1.78(s,3H),1.70(s,3H).

[0321] Step 8: Separation of compound 1

[0322] Compound 1 (75 mg) was separated by SFC (chiral column: DAICEL CHIRALCEL OX (250 mm*30 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% v / v NH3H2O)]; B%: 50% v / v) to obtain compound 1-peak 1 (RT=2.012 min) (26.97 mg) and compound 1-peak 2 (RT=2.384 min) (27.09 mg).

[0323] Compound 1-Peak 1: 1 H NMR (400MHz, DMSO-d6): δ9.64(s,1H),7.83(s,1H),7.34(s,2H),7.07(d,J=8.4Hz ,1H),6.98(s,2H),6.94(d,J=8.4Hz,1H),2.46(s,3H),1.78(s,3H),1.69(s,3H).

[0324] Compound 1-Peak 2: 1H NMR (400MHz, DMSO-d6): δ9.63(s,1H),7.81(s,1H),7.35(s,2H),7.06(d,J=8.0Hz ,1H),6.98(s,2H),6.94(d,J=8.0Hz,1H),2.46(s,3H),1.77(s,3H),1.69(s,3H).

[0325] The following compounds were prepared by the methods and general procedures described in Reference Example 1. Other required raw materials can be purchased commercially or synthesized by experienced synthesizers in the field of organic synthesis using conventional reactions from commercially purchased reagents.

[0326]

[0327] Example 2: Synthesis of 2-amino-7-cyano-1-(3-fluoro-5-hydroxy-2,6-dimethylphenyl)-5-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxamide

[0328]

[0329] Step 1: Synthesis of 4-chloro-5-((3-fluoro-5-methoxy-2,6-dimethylphenyl)amino)-2-methylpyridine 1-oxide (Compound 2-1)

[0330] Compound 1-2 (330 mg, 1.41 mmol), Int B (301 mg, 1.69 mmol), Pd2(dba)3 (130.5 mg, 0.014 mmol), Xantphos (163.2 mg, 0.028 mmol), Cs2CO3 (1.38 g, 4.23 mmol) and 1,4-dioxane (20 mL) were added to a 50 mL reaction bottle in sequence, and after nitrogen replacement, the temperature was raised to 100 ° C and stirred for 16 h. After the reaction was completed, the sample was directly separated and purified by silica gel column chromatography (PE / EA=1 / 1, v / v) and concentrated to obtain compound 2-1 (275 mg).

[0331] MS (ESI, m / z): 311.1 [M+H] + .

[0332] Step 2: Synthesis of 4-chloro-3-((3-fluoro-5-methoxy-2,6-dimethylphenyl)amino)-6-methylpyridinecarbonitrile (Compound 2-2)

[0333] Compound 2-1 (250 mg, 0.78 mmol), TEA (631.7 mg, 6.24 mmol) and TMSCN (774.1 mg, 7.8 mmol) were added to DMF (5 mL). After the addition, the temperature was raised to 125 ° C. and stirred for 2 h. TEA (631.7 mg, 6.24 mmol) and TMSCN (774.1 g, 7.8 mmol) were added. The reaction was continued at 125 ° C for 2 h. After the reaction was completed, aqueous solution was added to quench, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by silica gel flash column chromatography (PE / EA=7 / 1, v / v) to obtain compound 2-2 (202 mg).

[0334] MS (ESI, m / z): 320.1 [M+H] + .

[0335] Step 3: Synthesis of tert-butyl 2-amino-7-cyano-1-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-5-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (Compound 2-3)

[0336] Compound 2-2 (180 mg, 0.53 mmol), tert-butyl cyanoacetate (226.7 mg, 1.59 mmol), XantphosPd G3 (226.3 mg, 0.27 mmol), and t-BuOK (181.8 mg, 1.59 mmol) were dissolved in 1,4-dioxane (3 mL) and reacted at 110 °C in a microwave reactor for 2 h. After the reaction, the sample was stirred and subjected to silica gel column chromatography (PE / EA=4 / 1, v / v) to obtain compound 2-3 (65 mg).

[0337] MS (ESI, m / z): 425.3 [M+H] + .

[0338] Step 4: Synthesis of 2-amino-7-cyano-1-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-5-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid (Compound 2-4)

[0339] Compound 2-3 (65 mg, 0.14 mmol) was added to DCM (4 mL), TFA (2 mL) was added dropwise, and the mixture was stirred at room temperature for 12 h. After the reaction was completed, the reaction system was directly concentrated to dryness to obtain compound 2-4 (65 mg).

[0340] MS (ESI, m / z): 369.2 [M+H] + .

[0341] Step 5: Synthesis of 2-amino-7-cyano-1-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-5-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (Compound 2-5)

[0342] Compound 2-4 (53 mg, 0.13 mmol), HATU (74.6 mg, 0.19 mmol), and DIEA (169 mg, 1.29 mmol) were added to DMF (5 mL), and the mixture was reacted at 25 °C for 10 min under nitrogen protection. NH4Cl (70 mg, 1.29 mmol) was added and stirred for 16 h. After the reaction was completed, the mixture was directly concentrated to dryness, methanol was added and concentrated again, and the crude product was purified by silica gel column chromatography (PE / EA=1 / 1, v / v) to obtain compound 2-5 (32 mg).

[0343] MS (ESI, m / z): 368.2 [M+H] + .

[0344] Step 6: Synthesis of 2-amino-7-cyano-1-(3-fluoro-5-hydroxy-2,6-dimethylphenyl)-5-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (Compound 2)

[0345] Compound 2-5 (32 mg, 0.07 mmol) was added to DCM (3 mL), cooled to 0-5°C under nitrogen protection, and 1M BBr3 dichloromethane solution (1 mL) was added, and the mixture was reacted at 25°C for 2 h. After the reaction was completed, methanol (1 ml) was added to the reaction solution to quench the reaction, and then ammonia (2 mL) was added until the system Ph was alkaline, and the mixture was concentrated to obtain a crude product (40 mg), which was purified by preparative liquid phase and freeze-dried to obtain compound 2 (4 mg).

[0346] MS (ESI, m / z): 354.2 [M+H] + .

[0347] 1 H NMR (400MHz, DMSO-d6): δ10.18(s,1H),7.86(s,1H),7.50(s,2H),7.02(s,2H),6.86-6.84(d,J=11.2,1H),2.48(s,3H),1.70(s,3H),1.64(s,3H).

[0348] Step 7: Separation of Compound 2

[0349] Compound 2 (280 mg) was separated by SFC (chiral column: DAICEL CHIRALCEL OX (250 mm*30 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% v / v NH3H2O)]; B%: 50% v / v) to obtain compound 2-peak 1 (RT=1.974 min) (102.15 mg) and compound 2-peak 2 (RT=2.287 min) (105.43 mg).

[0350] Compound 2-Peak 1: 1 H NMR (400MHz, DMSO-d6): δ10.11(s,1H),7.86(s,1H),7.48(s,2H),7.01(s,2 H), 6.84 (d, J = 11.2Hz, 1H), 2.47 (s, 3H), 1.70 (d, J = 1.2Hz, 3H), 1.65 (s, 3H).

[0351] Compound 2-Peak 2: 1 H NMR (400MHz, DMSO-d6): δ10.11(s,1H),7.86(s,1H),7.48(s,2H),7.01(s,2 H), 6.84 (d, J = 11.2Hz, 1H), 2.47 (s, 3H), 1.70 (d, J = 1.2Hz, 3H), 1.65 (s, 3H).

[0352] Example 3: Synthesis of 2-amino-7-cyano-1-(6-fluoro-5-methyl-1H-indazol-4-yl)-5-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxamide

[0353]

[0354] Step 1: Synthesis of 4-chloro-5-((6-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)amino)-2-methylpyridine 1-oxide (Compound 12-2)

[0355] Compound 1-2 (600 mg, 2.70 mmol) and compound 12-1 (706 mg, 2.83 mmol) were dissolved in 1,4-dioxane (10 mL), and then Pd2(dba)3 (247 mg, 270 μmol), Xantphos (312 mg, 539 μmol) and Cs2CO3 (2.64 g, 8.09 mmol) were added in sequence under a nitrogen atmosphere. The reaction temperature was raised to 100°C and stirred for 2 h. LC-MS and TLC (DCM / MeOH=10 / 1, v / v, Rf=0.4) detected that the reaction was complete, and then directly concentrated, separated and purified by silica gel column chromatography (DCM / MeOH=100 / 1 to 10 / 1, v / v), and concentrated to obtain compound 12-2 (1.00 g).

[0356] MS (ESI, m / z): 391.1 [M+H] + .

[0357] Step 2: Synthesis of 4-chloro-3-((6-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)amino)-6-methylpyridinecarbonitrile (Compound 12-3)

[0358] Compound 12-2 (1.00 g, 1.66 mmol) was dissolved in DMF (10 mL), and then TEA (1.35 g, 13.3 mmol, 1.85 mL) and TMSCN (2.20 g, 22.2 mmol, 2.77 mL) were added under nitrogen atmosphere. The reaction temperature was raised to 100 °C and stirred for 10 h. LC-MS and TLC (CH2Cl2 / MeOH=10 / 1, v / v, R f =0.42) detected that the reaction was complete. After the reaction solution was cooled to room temperature, H2O (200 mL) was added, and then extracted with EtOAc (200 mL). The organic phases were combined, washed with saturated brine (60 mL), and then dried over anhydrous Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (CH2Cl2 / MeOH=100 / 0 to 10 / 1, v / v). Concentrated to obtain compound 12-3 (460 mg).

[0359] MS (ESI, m / z): 422.0 [M+H] + .

[0360] Step 3: Synthesis of tert-butyl 2-amino-7-cyano-1-(6-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (Compound 12-5)

[0361] Compound 12-4 (1.20 g, 8.50 mmol, 1.22 mL) was dissolved in DME (10 mL), and then NaH (510 mg, 12.8 mmol) was added and reacted at 25°C for 0.5 hr, and then compound 12-3 (340 mg, 850 μmol) and Pd(dppf)Cl2·CH2Cl2 (347 mg, 425 μmol) were added, and nitrogen was replaced three times, and then the temperature was raised to 100°C and stirred for 2 hr. LC-MS and TLC (CH2Cl2 / MeOH=10 / 1, v / v, R f =0.4) to monitor the completion of the reaction. After the reaction solution was cooled to room temperature, H2O (50 mL) was added, and then extracted three times with EtOAc (50 mL x 3). The organic phases were combined, dried over anhydrous Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (CH2Cl2 / MeOH=100 / 1 to 10 / 1, v / v). Concentrated to obtain compound 12-5 (110 mg).

[0362] MS (ESI, m / z): 505.5 [M+H] + .

[0363] Step 4: Synthesis of 2-amino-7-cyano-1-(6-fluoro-5-methyl-1H-indazol-4-yl)-5-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid (Compound 12-6)

[0364] Compound 12-5 (100 mg, 198 μmol) was dissolved in TFA (3 mL), and the reaction was stirred at 25° C. for 1 hr. The reaction was complete as monitored by LC-MS, and compound 12-6 (70.0 mg, crude product) was obtained after direct concentration.

[0365] MS (ESI, m / z): 365.2 [M+H] + .

[0366] Step 5: Synthesis of 2-amino-7-cyano-1-(6-fluoro-5-methyl-1H-indazol-4-yl)-5-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (Compound 12)

[0367] Compound 12-6 (70.0 mg, 192 μmol) was dissolved in DMF (3 mL), and then HATU (110 mg, 288 μmol), DIEA (74.5 mg, 576 μmol, 100 μL) and NH4Cl (41.1 mg, 769 μmol) were added, and the mixture was reacted at 25°C for 1 hr. After the reaction was completed by LC-MS monitoring, H2O (30 mL) and CH2Cl2 / MeOH=10 / 1 (10 mL x 3) were added for extraction, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, separated and purified by prep-HPLC, and freeze-dried to obtain compound 12 (6.05 mg).

[0368] MS (ESI, m / z): 364.2 [M+H] + .

[0369] 1 H NMR (400MHz, DMSO-d6): δ13.33-13.55(m,1H),7.90(s,1H),7.66(d,J=9.8Hz,1H),7.58-7.63(m,1H),7.50-7.58(m,2H),7.05(br s, 2H), 2.48 (s, 3H), 1.96 (d, J = 2.1Hz, 3H).

[0370] Example 4: 2-amino-7-cyano-5-methyl-1-(5-methyl-1H-indazol-4-yl)-1H-pyrrolo[2,3-c]pyridine-3-carboxamide

[0371]

[0372] Step 1: Synthesis of N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1,1-diphenylmethanimine (Compound 11-3)

[0373] Compound 11-1 (3.35 g, 11.35 mmol), compound 11-2 (3.09 g, 17.03 mmol), Pd2(dba)3 (1.04 g, 1.135 mmol), Xantphos (1.31 g, 2.27 mmol), Cs2CO3 (10.73 g, 34.05 mmol) and 1,4-dioxane (40 mL) were added to a 100 mL reaction bottle in sequence, and after nitrogen replacement, the temperature was raised to 100 ° C and stirred for 16 h. After the reaction was completed, direct silica gel column chromatography (PE / EA = 0-30%, v / v) was performed to obtain compound 11-3 (3.78 g).

[0374] MS (ESI, m / z): 396.2 [M+H] + .

[0375] Step 2: Synthesis of 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (Compound 11-4)

[0376] Compound 11-3 (3.78 g, 9.55 mmol), ammonium formate (5.93 g, 95.5 mmol) and Pd / C (10%) (1.89 g, 50% M / M) were added to MeOH (50 mL). The temperature was raised to 60°C and stirred for 2 h. After the reaction was completed, the temperature was lowered and filtered. The filter cake was rinsed with ethyl acetate (100 mL). The filtrate was dried by rotary evaporation, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by silica gel flash column chromatography (DCM: MeOH = 0 ~ 6%, v / v) to obtain compound 11-4 (2.1 g).

[0377] MS (ESI, m / z): 232.2 [M+H] + .

[0378] Step 3: Synthesis of 4-chloro-2-methyl-5-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)amino)pyridine 1-oxide (Compound 11-5)

[0379] Compound 11-4 (1.1 g, 4.75 mmol), compound 1-2 (0.96 g, 4.32 mmol), Pd2(dba)3 (395.60 mg, 432.0 μmol), Xantphos (499.93 mg, 864.0 μmol), Cs2CO3 (4.22 g, 12.96 mmol) and 1,4-dioxane (20 mL) were added to a 100 mL reaction bottle, and after nitrogen replacement, the temperature was raised to 100 ° C and stirred for 4 h. After the reaction was completed, direct silica gel column chromatography (PE / EA = 0-35%, v / v) was performed to obtain compound 11-5 (1.46 g).

[0380] MS (ESI, m / z): 373.2 [M+H] + .

[0381] Step 4: Synthesis of 4-chloro-6-methyl-3-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)amino)pyridinecarbonitrile (Compound 11-6)

[0382] Compound 11-5 (1.40 g, 3.76 mmol), TEA (3.81 g, 37.6 mmol) and TMSCN (3.73 g, 37.6 mmol) were added to DMF (25 mL), the temperature was raised to 125°C, and the mixture was stirred for 2 h. After the reaction was completed, the temperature was lowered and aqueous solution was added to quench the reaction. The reaction was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel flash column chromatography (PE / EA=0-30%, v / v) to obtain compound 11-6 (1.35 g).

[0383] MS (ESI, m / z): 382.3 [M+H] + .

[0384] Step 5: Synthesis of tert-butyl 2-amino-7-cyano-5-methyl-1-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (Compound 11-7)

[0385] Dissolve tert-butyl cyanoacetate (889.37 mg, 6.30 mmol) and t-BuOK (706.92 mg, 6.30 mmol) in 1,4-dioxane (8 mL), stir for 30 min under nitrogen protection, then add compound 11-6 (800.0 mg, 2.10 mmol) and Xantphos G3 Pd (226.3 mg, 0.27 mmol) in turn, replace nitrogen three times, react at 100 ° C in a microwave reactor for 2 h, after the reaction is completed, stir the sample, and perform silica gel column chromatography (PE / EA=0~35%, v / v) to obtain compound 11-7 (90 mg).

[0386] MS (ESI, m / z): 487.2 [M+H] + .

[0387] Step 6: Synthesis of 2-amino-7-cyano-5-methyl-1-(5-methyl-1H-indazol-4-yl)-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid (Compound 11-8)

[0388] Compound 11-7 (75 mg, 0.15 mmol) was added to DCM (4 mL), TFA (2 mL) was added dropwise, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction system was slowly added to a sodium bicarbonate solution, and extracted twice with ethyl acetate (30 mL), and the organic phases were combined and concentrated to obtain compound 11-8 (35 mg).

[0389] MS (ESI, m / z): 347.4 [M+H] + .

[0390] Step 7: Synthesis of 2-amino-7-cyano-5-methyl-1-(5-methyl-1H-indazol-4-yl)-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (Compound 11)

[0391] Compound 11-8 (35 mg, 0.10 mmol), HATU (76.1 mg, 0.20 mmol), and DIEA (25.85 mg, 0.2 mmol) were added to DMAC (2 mL), and reacted at 25°C for 10 min under nitrogen protection. NH4Cl (53.5 mg, 1.0 mmol) was added and stirred for 16 h. After the reaction was completed, the mixture was directly concentrated to dryness, methanol was added and concentrated again, and the crude product was purified by HPLC to obtain compound 11 (4.0 mg).

[0392] MS (ESI, m / z): 346.1 [M+H] + .

[0393] 1 H NMR (400MHz, DMSO-d6): δ13.37(s,1H),7.90(s,1H),7.72(d,J=11.2,1H),7.58(s,1H),7.52–7.38(m,3H),7.04(s,2H),2.48(s,3H),2.05(s,3H).

[0394] Separation methods

[0395] The Prep-HPLC purification of the compounds in the examples was performed using Aglient 1260 or Waters 2489 HPLC, and the separation column model was Waters SunFire Prep C 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), the column temperature was 25°C, the detection wavelength was 214nm, 254nm or 280nm, the mobile phase A was acetonitrile, the mobile phase B was 0.05% v / v formic acid aqueous solution or 0.05% w / v ammonium bicarbonate aqueous solution or 0.05% TFA v / v aqueous solution, the volume ratio of the two phases in the mobile phase was adjusted according to the polarity of the compound; the flow rate of the mobile phase was 28mL / min.

[0396] Reference Example 1:

[0397]

[0398] Obtained by referring to the preparation process of compound 182 in WO2021195781A1.

[0399] Biological evaluation

[0400] Experimental Example 1: Test of the inhibitory effect of compounds on PKMYT1 enzyme activity

[0401] 1. Test system

[0402] Enzyme: PKMYT1 (purchased from Carna, 05-176 / Thermo Fisher, A30984)

[0403] Substrate: Unactive CDK1 (purchased from Signalchem, C22-14G)

[0404] ATP, ADP-Glo ​​Reagent, Detection Solution: all from ADP-Glo ​​Kinase Assay Kit (Promega, V9101)

[0405] 2. Test steps

[0406] Compounds diluted with enzyme assay buffer (40 mM Tris-HCl buffer (pH 7.6), 20 mM MgCl2, 0.01% BSA, 3 mM MnCl2, 1.2 mM DTT) and DMSO were added to a 384-well plate, and the final concentration of the compound was 100, 10, 1 nM or 100, 30, 10, 3 nM; PKMYT1 enzyme working solution diluted with enzyme assay buffer was added to the 384-well plate, centrifuged at 1000 rpm for 1 min, and incubated at 25°C for 15 min; a mixed working solution of substrate and ATP prepared with enzyme assay buffer was added to the 384-well plate, centrifuged at 1000 rpm for 1 min, and incubated at 30°C for 180 min; the 384-well plate and ADP-Glo Reagent was equilibrated to room temperature, and then ADP-Glo ​​Reagent was added to each well, centrifuged at 1000 rpm for 1 min, and incubated in the dark at 25°C for 40 min; Detection Reagent was added to the 384-well plate, centrifuged at 1000 rpm for 1 min, incubated in the dark at 25°C for 40 min, and 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 inhibitory activity percentage (i.e., inhibition rate) of compounds at different concentrations was calculated according to the following formula. When the percentage inhibition rate of a certain concentration of the compound was close to 50%, the half inhibition concentration IC was calculated using the single-point method. 50 :

[0407] Relative inhibitory activity percentage = (1-(different concentration compound groups-blank control) / (negative control-blank control)) × 100%;

[0408] IC 50 =(100-average percentage inhibition rate at a certain concentration) / average relative inhibition activity percentage at a certain concentration*corresponding compound concentration.

[0409] The inhibitory effect of the compounds on PKMYT1 enzyme was determined according to the above method, and the results are shown in Table 1.

[0410] Table 1. Inhibitory activity of the compounds of the present invention on PKMYT1

[0411] Compound No. <![CDATA[PKMYT1(IC 50 ,nM)]]> 1 7.78 1-Peak 1 7.37 2 7.22 2-Peak 1 2.82 11 9.69 12 18.47 13 19.06

[0412] The experimental results show that the compounds of the present invention have a strong inhibitory effect on the PKMYT1 enzyme and can be used to prevent or treat diseases or conditions related to PKMYT1 activity.

[0413] Experimental Example 2: Liver microsome stability test

[0414] The human / mouse liver microsome solution was used to examine the stability of the compounds of the present invention and reference example compounds in microsomes.

[0415] The compound of the present invention and the reference example compound were added to the liver microsome solution and mixed by blowing, 50 μl was mixed with 25 μl PBS, and NADPH (25 μl) was added after pre-incubation (37°C) for 5 minutes, so that the final concentration of the compound to be tested was 1 μM, the final concentration of human / mouse liver microsome protein was 0.5 mg / ml, and the incubation time was 0 and 15 minutes. After the corresponding reaction time, 300 μl of ice acetonitrile containing internal standard was added to terminate the reaction, vortexed, and temporarily stored at -80°C for testing. The prototype of the test compound in the sample was detected by LC-MS / MS method, and the prototype residual rate after incubation for 15 minutes was calculated. The results of the liver microsome stability test are shown in Table 2 below.

[0416] Table 2. The residual rate of the original form of the compounds of the present invention and the reference example compounds after incubation in human / mouse liver microsomes for 15 minutes

[0417]

[0418] The experimental results show that the compounds of the present invention are relatively stable in human / mouse liver microsomes.

[0419] In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in the present invention (including all patents, patent applications, journal articles, books and any other disclosures) is incorporated herein by reference in its entirety.

Claims

1. A compound of formula I or a pharmaceutically acceptable form thereof: in: X 1 , X 2 and X 3 Each independently selected from CR 5 or N; Y and Z are each independently selected from CR 13 or N; R 1 , R 2 and R 6 are each 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 6 Together with the atoms to which it is attached, it forms C 5-8 aliphatic ring, 5-8 membered heterocyclic ring or 5-10 membered heteroaromatic ring, wherein the aliphatic ring, heterocyclic ring or heteroaromatic ring is optionally substituted by one or more halogen, -OH, -CN, -NH2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Substituted with cycloalkoxy or 3-6 membered heterocyclic group; R 3 Selected from H or -NR 8 R 9 ; R 4 Selected from -C(=O)NH(R 10 ), -C(=O)R 11 、-SO2R 11 or -S(=O)2N(R 10 )2; R 5 is independently selected at each occurrence from H, halogen, -CN, -NR 8 R 9 、-C(=O)R 11 、-C(=O)NH(R 10 )、-NHC(=O)R 11 、-SO2R 11 、-OR 12 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 3-8 Cycloalkoxy, C 6-10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl or heteroaryl optionally substituted by one or more R 7 Replacement; or two adjacent R 5 Together with the atoms to which it is attached, it forms C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; R 7 is independently selected at each occurrence from H, halogen, -OH, -CN, -NR 8 R 9 、-C(=O)R 11 、-NHC(=O)R 11 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic group, C 6-10 The alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl or heteroaryl radicals are optionally substituted with one or more halogen, -OH, -CN, -NR 8 R 9 , -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Substituted with cycloalkoxy or 3-6 membered heterocyclic group; R 8 and R 9 Each occurrence is independently selected from H, C 1-4 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl or -SO2R 11 The alkyl, cycloalkyl, aryl or heteroaryl groups are optionally substituted with one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl substituted; R 10 Each occurrence is independently selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, the alkyl, alkoxy, cycloalkyl, aryl or heteroaryl group is optionally substituted by one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl substituted; R 11 Each occurrence is independently selected from C 1-4 Alkyl, C 3-8 Cycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, the alkyl, cycloalkyl, aryl or heteroaryl group is optionally substituted by one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl or C 1-4 Haloalkyl substitution; R 12 Each occurrence is independently selected from H, C 6-10 aryl or 5-10 membered heteroaryl, the aryl or heteroaryl is optionally substituted by one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Substituted with cycloalkoxy or 3-6 membered heterocyclic group; R 13 is independently selected at each occurrence from H, halogen, -OH, -CN, C 1-4 Alkyl or C 1-4 Haloalkyl; The pharmaceutically acceptable form is selected from a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, ester, polymorph, solvate, N-oxide, metabolite or prodrug.

2. The compound according to claim 1 or a pharmaceutically acceptable form thereof, wherein: R 4 Selected from -C(=O)NH(R 10 ), -C(=O)R 11 or-SO2R 11 .

3. A compound according to claim 1 or 2, or a pharmaceutically acceptable form thereof, wherein: X 1 and X 2 Each independently selected from CR 5 , X 3 Selected from N; Preferably, X 1 Selected from CH, X 2 Selected from CR 5 , X 3 Selected from N.

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable form thereof, wherein: Y and Z are each independently selected from CR 13 or N, where R 13 is selected from H, halogen, -OH, -CN, methyl, ethyl, propyl, halomethyl, haloethyl or halopropyl; Preferably, Y and Z are each independently selected from CR 13 or N, where R 13 is selected from H or halogen; More preferably, Y and Z are both CR 13 , where R 13 is selected from H or halogen; More preferably, Y and Z are both CH; or More preferably, Y is CH, and Z is CF or CCl.

5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable form thereof, wherein: R 1 and R 2 are each independently selected from H, halogen, C 1-4 Alkyl or C 1-4 Haloalkyl; Preferably, R 1 and R 2 are each independently selected from halogen or C 1-4 Alkyl; or Preferably, R 1 and R 2 Both C 1-4 alkyl; More preferably, R 1 and R 2 Each independently selected from methyl, ethyl, propyl and butyl; More preferably, R 1 and R 2 All are methyl.

6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable form thereof, wherein: R 6 is -OH; or R 1 and R 6 Together with the atoms to which they are attached, they form a 5-10 membered heteroaromatic ring, which is optionally substituted by one or more halogen, -OH, -CN, -NH2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Substituted with cycloalkoxy or 3-6 membered heterocyclic group; Preferably, R 1 and R 6 Together with the atoms to which it is attached, it forms a pyrazole ring, which is optionally substituted with one or more halogens or C 1-4 Alkyl substitution; More preferably, R 1 and R 6 Together with the atoms to which it is attached, it forms a pyrazole ring.

7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable form thereof, wherein: R 3 For-NR 8 R 9 , where R 8 and R 9 Each independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl or -SO2R 11 The alkyl, cycloalkyl, aryl or heteroaryl groups are optionally substituted with one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl substituted; Preferably, R 3 For-NR 8 R 9 , where R 8 and R 9 Each independently selected from H or C 1-4 Alkyl, the alkyl group is optionally substituted by one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl substituted; More preferably, R 3 For-NR 8 R 9 , where R 8 and R 9 Each independently selected from H, methyl, ethyl, propyl and butyl; More preferably, R 3 is -NH2.

8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable form thereof, wherein: R 4 Selected from -C(=O)NH(R 10 ), -C(=O)R 11 、-SO2R 11 or -S(=O)2N(R 10 )2, where R 10 Selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 6-10 Aryl or 5-6 membered heteroaryl, the alkyl, alkoxy, cycloalkyl, aryl or heteroaryl is optionally substituted by one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 6-10 Aryl or 5-6 membered heteroaryl substituted; R 11 Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl or 5-6 membered heteroaryl, the alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted by one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl or C 1-4 Haloalkyl substitution; Preferably, R 4 Selected from -C(=O)NH(R 10 ), -C(=O)R 11 or-SO2R 11 , where R 10 Selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 6-10 Aryl or 5-6 membered heteroaryl, the alkyl, alkoxy, cycloalkyl, aryl or heteroaryl is optionally substituted by one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, C 6-10 Aryl or 5-6 membered heteroaryl substituted; R 11 Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl or 5-6 membered heteroaryl, the alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted by one or more halogen, -OH, -CN, -C(=O)CH3, C 1-4 Alkyl or C 1-4 Haloalkyl substitution; Preferably, R 4 -C(=O)NH(R 10 ), R 10 Select from H or C 1-4 alkyl; More preferably, R 4 -C(=O)NH(R 10 ), R 10 is selected from H, methyl, ethyl, propyl and butyl; More preferably, R 4 It is -C(=O)NH2.

9. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable form thereof, wherein: R 5 is independently selected at each occurrence from H, halogen, -CN, -NR 8 R 9 、-C(=O)R 11 、-C(=O)NH(R 10 )、-NHC(=O)R 11 、-SO2R 11 、-OR 12 , C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 2-4 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 3-6 Cycloalkoxy, C 6-10 aryl or 5-6 membered heteroaryl, the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl or heteroaryl optionally substituted by one or more R 7 Replacement; or two adjacent R 5 Together with the atoms to which it is attached, it forms C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; Preferably, R 5 is independently selected at each occurrence from H, halogen, -CN, -NR 8 R 9 , hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 aryl or 5-6 membered heteroaryl, the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R 7 replace; More preferably, R 5 is independently selected at each occurrence from H, halogen, -CN, -NR 8 R 9 , hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally substituted by one or more halogen or C 1-4 Alkyl substitution; More preferably, R 5 is independently selected at each occurrence from halogen, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Cycloalkyl, said alkyl, alkoxy or cycloalkyl being optionally substituted by one or more halogens; or, More preferably, R 5 Each occurrence is independently selected from H, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Cycloalkyl, the alkyl, alkoxy or cycloalkyl is optionally substituted by one or more halogens.

10. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable form thereof, wherein: The compound represented by the formula I is a compound represented by the following formula I-1 or I-2: Preferably, in Formula I-1, R 13 is H or F; or, Preferably, in formula I-2, R 13 is H or F; or Preferably, in Formula I-1 or Formula I-2, R 5 is selected from methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable form thereof, wherein: R 4 and / or R 5 and / or R 8 and / or R 9 -SO2R in definition 11 Selected from -S(=O)2R 11 .

12. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable form thereof, wherein: The compound represented by the formula I is a compound represented by the following formula I-1-A or I-2-A: Preferably, in Formula I-1-A, R 13 is H or F; or, Preferably, in formula I-2-A, R 13 is H or F; or Preferably, in Formula I-1-A or Formula I-2-A, R 5 is selected from methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

13. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable form thereof, wherein the compound is selected from:

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable form thereof; Preferably, it further comprises one or more pharmaceutically acceptable carriers.

15. Use of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable form thereof, or a pharmaceutical composition according to claim 14, in the preparation of a medicament for preventing or treating a disease or condition associated with PKMYT1 activity; Preferably, the disease or condition associated with PKMYT1 activity is a cancer or tumor with CCNE1 amplification; More preferably, the cancer or tumor is thyroid cancer, gastric cancer, lung cancer, breast cancer or ovarian cancer.

16. A method for preparing a compound of formula I-1-A or a pharmaceutically acceptable form thereof, comprising the seventh step, optionally the sixth step, optionally the fifth step, optionally the fourth step, optionally the third step, optionally the second step, and optionally the first step: Step 1: Compound Int-1-1 undergoes halogenation reaction to generate compound Int-1-2; Step 2: Compound Int-1-2 reacts with amine via Buchwald cross-coupling reaction to generate compound Int-1-3; Step 3: Compound Int-1-3 reacts with a cyanation reagent to generate compound Int-1-4; Step 4: Compound Int-1-4 and tert-butyl cyanoacetate are reacted via Buchwald cross-coupling ring-closing tandem reaction to generate compound Int-1-5; Step 5: Compound Int-1-5 is hydrolyzed to generate compound Int-1-6; Step 6: Compound Int-1-6 undergoes condensation reaction to generate compound Int-1-7; Step 7: Compound Int-1-7 is subjected to a deprotection reaction to generate a compound of formula I-1-A; in: R 5 , R 13 As defined in any one of claims 1 to 13; The pharmaceutically acceptable form is selected from a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, ester, polymorph, solvate, N-oxide, metabolite or prodrug.

17. A method for preparing a compound of formula I-2-A or a pharmaceutically acceptable form thereof, comprising the sixth step, optionally the fifth step, optionally the fourth step, optionally the third step, optionally the second step, and optionally the first step: Step 1: Compound Int-1-1 undergoes halogenation reaction to generate compound Int-1-2; Step 2: Compound Int-1-2 reacts with amine via Buchwald cross-coupling reaction to generate compound Int-2-1; Step 3: Compound Int-2-1 reacts with a cyanation reagent to generate compound Int-2-2; Step 4: Compound Int-2-2 and tert-butyl cyanoacetate are reacted via Buchwald cross-coupling ring-closing tandem reaction to generate compound Int-2-3; Step 5: Compound Int-2-3 is hydrolyzed to generate compound Int-2-4; Step 6: Compound Int-2-4 undergoes condensation reaction to generate a compound of formula I-2-A; in: THP stands for tetrahydro-2H-pyran-2-yl; R 5 , R 13 As defined in any one of claims 1 to 13; The pharmaceutically acceptable form is selected from a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, ester, polymorph, solvate, N-oxide, metabolite or prodrug.

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