N-(1H-pyrazol-3-yl) heterocyclic amine derivative as well as preparation method and application thereof

Abstract

The invention relates to an N-(1H-pyrazol-3-yl) heterocyclic amine derivative, a preparation method thereof and application of a pharmaceutical composition containing the derivative in medicine. Specifically, the invention relates to N-(1H-pyrazol-3-yl) heterocyclic amine derivatives as shown in a general formula (I), a preparation method and pharmaceutically acceptable salts thereof, and application of the N-(1H-pyrazol-3-yl) heterocyclic amine derivatives and the pharmaceutically acceptable salts thereof as therapeutic agents, especially as PLK4 inhibitors, and definitions of substituent groups in the general formula (I) are the same as those in the specification.

Description

Technical Field

[0001] This invention relates to an N-(1H-pyrazol-3-yl)heterocyclic amine derivative, its preparation method, pharmaceutical compositions containing the derivative, and its use as a therapeutic agent, particularly as a PLK4 inhibitor. Background Technology

[0002] Mitotic disorders are associated with the occurrence and development of many diseases, especially tumors. Some mitosis-related proteases, such as cyclin-dependent kinases (CDKs), aurora kinases (AURKs), NIMA-associated kinases (NEKs), and Polo-like kinases (PLKs), play unique and crucial roles in cell division. Research has found that one of the most effective methods for treating cancer is to block cell division by inhibiting mitosis. Therefore, mitosis-related proteases are potential targets for cancer intervention and treatment. PLKs are a highly conserved family of serine / threonine protein kinases, including PLK1, PLK2 (Snk), PLK3 (Fnk / Prk), PLK4 (Sak), and PLK5, which are closely related to maintaining genome integrity and regulating mitosis. Except for PLK5, PLK1-4 possess similar N-terminal (Ser / Thr) catalytic domains. However, PLK4 differs from PLK1-3 in its C-terminal domain, possessing a single "polo-box" and "cryptic polobox" domain, which can be located in the centrosome and is a major regulator of centriole replication and mitosis.

[0003] Numerous studies have found that PLK4 is almost not expressed in normal, non-dividing cells. However, its expression is significantly elevated in normal, dividing cells. PLK4 is highly expressed in cancers such as breast cancer, lung cancer, colorectal cancer, pancreatic cancer, cervical cancer, endometrial cancer, gastric cancer, esophageal cancer, and prostate cancer. Knocking out the PLK4 gene induces tumor cell death while having no effect on normal cells; knocking out this gene in mouse tumor-bearing models also inhibits tumor cell proliferation.

[0004] Numerous studies have shown that PLK4 overexpression can lead to centrosome amplification and induce cancer. Currently, designing small-molecule ATP-competitive inhibitors of PLK4 has become an important approach for treating tumors induced by centrosome error replication. Furthermore, PLK4 inhibitors can achieve precise treatment of tumors containing TRIM37 gene amplification, a finding already confirmed in breast cancer and glioblastoma. Simultaneously, research indicates that PLK4 could serve as a novel targeted therapy for treating acute myeloid leukemia (AML) caused by TP53 gene mutations.

[0005] Currently, no PLK4 inhibitors are on the market. Only CFI-400945, developed by The University Health Network, is in Phase II clinical trials, and RP-1664 from Repare is in Phase I clinical trials. Therefore, there is still enormous room for exploration in research related to the PLK4 target. Finding novel PLK4 inhibitors that are highly efficient, selective, and have good in vivo properties has significant scientific value and research significance. Summary of the Invention

[0006] To address the aforementioned technical problems, the present invention provides a compound of general formula (I) or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically usable salts thereof:

[0007]

[0008] in:

[0009] X is selected from N or CR d ;

[0010] R d Selected from hydrogen atom, halogen, cyano group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 6-10 Aryl, 3-8 membered heterocyclic, 5-10 membered heteroaryl, -OR 5 -S (=O) r R 5 -NR 6 R 7 or -C(=O)R 5 The alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl groups thereon may optionally be further selected from one or more C10 groups. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Substituted by a haloalkoxy, halogen, hydroxyl, cyano, or amino group;

[0011] R 1 Selected from hydrogen atom, halogen, cyano group, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl groups, -S (=O) r R 5 or -NR 6 R 7 The alkyl, alkoxy, alkenyl, alkynyl, or cycloalkyl groups thereon may optionally be further selected from one or more C16 groups.1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Substituted by a haloalkoxy, halogen, hydroxyl, cyano, or amino group;

[0012] R 2 Selected from hydrogen atoms; or R 1 R 2 The atoms connected to them together form a C 3-8 cycloalkyl, C 6-10 aryl, 3-8 membered heterocyclic, or 5-10 membered heteroaryl; wherein the cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally further selected from one or more C16 groups. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Substituted by a haloalkoxy, halogen, hydroxyl, or cyano group;

[0013] Ring A is selected from 3-10 membered heterocyclic groups, 5-10 membered heteroaryl groups, and C. 6-10 Aryl, C 3-8 Cycloalkyl or 6-10 fused rings;

[0014] R 4 Each is independently selected from hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl or C 1-6 Alkoxy, wherein the alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or alkoxy group is optionally further selected from one or more C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Substituted by a haloalkoxy, halogen, hydroxyl, cyano, or amino group;

[0015] Or, two Rs 4 Together with the same carbon atom they are attached to, they form a -C (=O);

[0016] Ring B is selected from 3-8 membered heterocyclic groups, 5-10 membered heteroaryl groups, and C. 6-10 Aryl or C 3-8 cycloalkyl;

[0017] R 3 Each is independently selected from deuterium, hydroxyl, halogen, nitro, cyano, and C atoms. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -SF5, -OR 5 -OC(=O)R 5 -C(=O)R 5 -C(=O)OR 5 -N(R) 6 )C(=O)R 7 -N(R) 6 )C(=O)OR 7 -NR 6 R7、-C(=O)NR 6 R 7 -S (=O) r NR 6 R 7 Or -S (=O) r R 5 The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups thereon may optionally be further selected from one or more groups selected from hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -OR 8 =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 -N(R) 9 )C(=O)R 10 or -N(R) 9 )C(=O)OR 10 The substituents are replaced;

[0018] Or, two Rs 3 Together with the same carbon atom they are attached to, they form a -C (=O);

[0019] L is selected from -O-, -S-, -NR a -or-CR b R c -;

[0020] R a R b R c Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, -OR 5 -S (=O) r R 5 -NR 6 R 7 C 3-8 cycloalkyl, C 6-10 aryl, 3-8 membered heterocyclic, or 5-10 membered heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally further selected from one or more groups selected from hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -OR 8 =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 -N(R) 9 )C(=O)R 10 or -N(R) 9 )C(=O)OR 10 The substituents are replaced;

[0021] Or, R a R 3 The atoms bonded to them together form a 4-8 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 4-8 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally further composed of one or more elements selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced;

[0022] R 5 Each is independently selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may optionally be further selected from one or more of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -SO2NR 9 R 10 or -NR 9 C(=O)R 10 The substituents are replaced;

[0023] R 6 and R 7 Each is independently selected from hydrogen atom, hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further selected from one or more of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -SO2NR 9 R 10 or -NR 9 C(=O)R 10 The substituents are replaced;

[0024] Or, R 6 and R 7 The atoms bonded to them together form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O, or S(O)r, and the 4- to 8-membered heterocyclic group is optionally further composed of one or more elements selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R. 8 -C(=O)OR8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -SO2NR 9 R 10 or -NR 9 C(=O)R 10 The substituents are replaced;

[0025] R 8 R 9 and R 10 Each is independently selected from hydrogen atoms, alkyl, amino, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further substituted by one or more substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl or carboxylic ester group;

[0026] m can be 0, 1, 2, 3, or 4;

[0027] n is 0, 1, 2, 3 or 4;

[0028] r can be 0, 1, or 2 independently.

[0029] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein X is selected from N.

[0030] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein L is selected from -NR. a -, R a The definition is as stated in general formula (I).

[0031] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein ring B is selected from C. 6-10 Aryl, preferably phenyl.

[0032] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated product or a pharmaceutically acceptable salt thereof, wherein the compound of general formula (II) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof is:

[0033]

[0034] Among them: rings A and R 1 R 2 R3 R 4 R a The definitions of m or n are as described in general formula (I).

[0035] A preferred embodiment of the present invention is a compound of formula (I) or (II) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R a Selected from hydrogen atoms or C 1-6 Alkyl, the C 1-6 Alkyl groups are preferably methyl groups.

[0036] A preferred embodiment of the present invention is a compound of formula (I) or (II) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R 1 Selected from hydrogen atom, halogen, cyano group, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 Cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl group is optionally further selected from one or more halogens, hydroxyl groups, cyano groups, amino groups, or C6 groups. 1-6 The alkoxy group is replaced by a substituent.

[0037] A preferred embodiment of the present invention is a compound of formula (I) or (II) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R 1 Selected from -CH3, -Cl, -OCH3, -CH2OCH3, -CN, -CH2F, -CHF2, -CF3, cyclopropyl or cyclobutyl.

[0038] A preferred embodiment of the present invention is a compound of formula (I) or (II) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R 2 It is a hydrogen atom.

[0039] A preferred embodiment of the present invention is a compound of formula (I) or (II) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R 3 Each is independently selected from halogens or -S (=O). r R 5 ;

[0040] R 5 Selected from C 1-6 Alkyl group, r = 2.

[0041] A preferred embodiment of the present invention is a compound of formula (I) or (II) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R 3 Each is independently selected from F or -S(=O)2CH3.

[0042] A preferred embodiment of the present invention is a compound of formula (I) or (II) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein... for

[0043] A preferred embodiment of the present invention is a compound of general formula (I) or (II) or a stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt thereof, wherein ring A is selected from a 5-membered heteroaryl, a 3-10-membered heterocyclic group, a phenyl or an 8-10-membered bicyclic fused ring.

[0044] A preferred embodiment of the present invention is a compound of formula (I) or (II) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein... Selected from the following groups:

[0045]

[0046] A preferred embodiment of the present invention is a compound of formula (I) or (II) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R 4 Each was independently selected from C 1-6 Alkyl, C 3-6 cycloalkyl, 5-6 membered heterocyclic, 5-6 membered heteroaryl or C 1-6 Alkoxy; wherein the alkyl, cycloalkyl, heterocyclic, heteroaryl, or alkoxy group is optionally further selected from one or more C16 groups. 1-6 Alkyl, C 1-6 Substituted by alkoxy, halogen, hydroxyl, cyano or amino substituents;

[0047] Or, two Rs 4 Together with the same carbon atom they are attached to, they form a -C (=O).

[0048] A preferred embodiment of the present invention is a compound of formula (I) or (II) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R 4 Each is independently selected from methyl, isopropyl, cyclopropyl, methoxy, tetrahydropyranyl, Or, two Rs 4 Together with the same carbon atom they are attached to, they form a -C (=O).

[0049] In a preferred embodiment of the present invention, the compounds of the general formula are selected from:

[0050]

[0051]

[0052]

[0053]

[0054] Or its stereoisomers, tautomers, or medicinal salts.

[0055] Note: If there is a difference between the drawn structure and the given name of the structure, the drawn structure will be given greater weight.

[0056] Furthermore, the present invention provides a pharmaceutical composition comprising an effective dose of a compound of general formula (I) or (II) or a stereoisomer, tautomer, deuterated compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or combination thereof.

[0057] The present invention provides the use of a compound of general formula (I) or (II) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of PLK4 inhibitors.

[0058] The present invention also provides the use of a compound of formula (I) or (II) or a stereoisomer, tautomer, deuterated product or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating PLK4-mediated diseases, wherein the PLK4-mediated diseases are preferably cancers; wherein the PLK4-mediated diseases are selected from esophageal cancer, breast cancer, lung cancer, colorectal cancer, pancreatic cancer, cervical cancer, endometrial cancer, glioblastoma, gastric cancer, prostate cancer or acute myeloid leukemia.

[0059] The present invention further provides the use of a compound of general formula (I) or (II) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a treatment for cancer.

[0060] The present invention provides the use of a compound of general formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for treating esophageal cancer, breast cancer, lung cancer, colorectal cancer, pancreatic cancer, cervical cancer, endometrial cancer, glioblastoma, gastric cancer, prostate cancer or acute myeloid leukemia.

[0061] Detailed description of the invention

[0062] Unless otherwise stated, some terms used in this specification and claims are defined as follows:

[0063] When "alkyl" is used as a group or part of a group, it refers to a group consisting of C1-C2. 20Straight-chain or branched aliphatic hydrocarbon groups. Preferably C1-C. 10 Alkyl groups, more preferably C1-C6 alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group may be substituted or unsubstituted.

[0064] "Alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond. Representative examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl. C2-C4 alkenyl groups are preferred. Alkenyl groups may be optionally substituted or unsubstituted.

[0065] "Alkyne group" refers to an aliphatic hydrocarbon group containing a single carbon-carbon triple bond, which can be straight-chain or branched. C2-C is preferred. 10 The alkynyl group is preferred, more preferably C2-C6 alkynyl, and most preferably C2-C4 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl. The alkynyl group may be substituted or unsubstituted.

[0066] "Cycloalkyl" refers to a non-aromatic cyclic alkyl group in which one or more cyclic atoms are carbon atoms and the ring contains 0, 1 or more double bonds, including monocyclic, polycyclic, fused ring, bridged ring and spirocyclic, preferably having a 3 to 7 member monocyclic or a 5 to 18 member bicyclic or tricyclic.

[0067] Examples of "monocycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl,

[0068] Monocyclic alkyl groups can be substituted or unsubstituted.

[0069] "Spirocycloalkyl" refers to a polycyclic group consisting of 5 to 18 quintiles, two or more cyclic structures, where the monocyclic rings share a carbon atom (called a spiro atom) with each other, containing 0, 1, or more double bonds within the rings, but without any ring having fully conjugated π electrons. Preferably, it is a 6 to 14 quintile group, more preferably a 7 to 10 quintile group. Based on the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified as monospiro, bispiro, or polyspirocycloalkyl groups, preferably monospiro and bispirocycloalkyl groups, and preferably 4 / 5, 4 / 4, 4 / 6, 3 / 6, 5 / 5, or 5 / 6 quintile groups. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl, Spirocycloalkyl groups can be substituted or unsubstituted.

[0070] "Fused cycloalkyl" refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms. One or more rings may contain 0, 1, or more double bonds, but none of the rings has fully conjugated π electrons. It is preferably a 6- to 14-membered aromatic system, more preferably a 6- to 10-membered system. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 3-membered / 5-membered, 5-membered / 5-membered, or 5-membered / 6-membered bicyclic fused cycloalkyl. Non-limiting examples of "fused cycloalkyl" include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decahydronaphthyl, tetradecahydrophenanthrene, etc. The fused cycloalkyl group can be substituted or unsubstituted.

[0071] "Bridged cycloalkyl" refers to an aromatic system with 5 to 18 members, containing two or more cyclic structures, sharing two non-directly connected carbon atoms, and one or more rings may contain 0, 1, or more double bonds, but none of the rings has fully conjugated π electrons. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl, Bridged cycloalkyl groups can be substituted or unsubstituted.

[0072] The terms “heterocyclic group,” “heterocyclic alkyl group,” “heterocyclic,” or “heterocyclic” are used interchangeably in this application and all refer to a non-aromatic heterocyclic group in which one or more cyclic atoms are selected from nitrogen, oxygen, or S(O). r (where r is selected from 0, 1 or 2) heteroatoms, containing 0, 1 or more double bonds in the ring, including monocyclic, polycyclic, fused ring, bridged ring and spirocyclic, preferably having 3 to 8-membered monocyclic or 5 to 18-membered bicyclic or tricyclic, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and / or sulfur.

[0073] The heterocyclic group can be substituted or unsubstituted.

[0074] Examples of "monocyclic heterocyclic groups" include, but are not limited to, morpholino, oxetane, azabolane, thiomorpholino, tetrahydrofurano, tetrahydropyrano, 1,1-dioxo-thiomorpholino, piperidino, 2-oxo-piperidino, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazine-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazine, hexahydropyrimidine,

[0075] "Spirocyclone" refers to a polycyclic aromatic group with 5 to 18 members, two or more ring structures, in which the monocyclic rings share an atom with each other, and contains 0, 1 or more double bonds within the rings, but none of the rings has fully conjugated π electrons. One or more ring atoms are selected from nitrogen, oxygen or S(O). r (where r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably, it is 6 to 14 membered, more preferably 7 to 10 membered. Spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl or polyspirocycloalkyl groups according to the number of shared spiroatoms between rings, preferably monospirocycloalkyl and bispirocycloalkyl. More preferably, it is 3 / 6 membered, 4 / 4 membered, 4 / 5 membered, 4 / 6 membered, 5 / 5 membered, 5 / 6 membered or 6 / 6 membered monospirocycloalkyl. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl,

[0076] "Densely fused cyclic groups" refer to polycyclic groups containing two or more ring structures that share a pair of atoms with each other. One or more rings may contain 0, 1, or more double bonds, but none of the rings have fully conjugated π electrons. One or more ring atoms are selected from nitrogen, oxygen, or S(O). r(where r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting embodiments of "fused heterocyclic group" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrol, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxin,

[0077] "Bridged heterocyclic group" refers to a polycyclic group with 5 to 18 members, containing two or more ring structures that share two atoms that are not directly connected. One or more rings may contain 0, 1 or more double bonds, but none of the rings have fully conjugated π electrons. One or more ring atoms are selected from nitrogen, oxygen or S(O). r (where r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting embodiments of "bridged heterocyclic groups" include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 2-azabicyclo[3.3.2]decyl.

[0078] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, and tetrahydronaphthyl aromatic groups. Preferably, the aryl group is C6-C. 10 Aryl, more preferably phenyl and naphthyl, most preferably naphthyl. The aryl group can be substituted or unsubstituted.

[0079] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and / or sulfur. Examples of "heteroaryl" compounds include, but are not limited to, furanyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiopheneyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrroleyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo[m]dioxacyclopentenyl, benzo[thiophene], benzimidazolyl, indoleyl, isoyindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indoleyl, benzo[isothiazolyl], benzo[oxazolyl], benzo[isothiazolyl], isothiazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, pyridyl, pyridine- 2(1H)-keto, pyrimidinyl, pyrazin-2(1H)-keto, pyrimidin-4(3H)-keto, pyrimidin-2(1H)-keto, pyridazin-3(2H)-keto, 1H-indolyl, 1H-benzo[d]imidazolyl, 1H-pyrrolo[2,3-c]pyridyl, 3H-imidazo[4,5-c]pyridyl, isoquinolinyl, quinazolinyl, 2H-isoindolyl, furan[3,2-b]pyridyl, furan[2,3-c]pyridyl, thieno[2,3-c]pyridyl, benzofuranyl, benzo[b]thienoyl, 1H-pyrrolo[3,2-b]pyridyl, 2H-pyrrolo[3,4-c]pyridyl

[0080]

[0081] The heteroaryl group can be substituted or unsubstituted.

[0082] A "fused ring" refers to a polycyclic group in which two or more ring structures share a pair of atoms, wherein at least one ring has a fully conjugated π electron aromatic system, and one or more rings may contain 0, 1 or more double bonds, but at least one ring does not have a fully conjugated π electron aromatic system, wherein the ring atoms are selected from 0, 1 or more nitrogen, oxygen or S(O). r (where r is selected from 0, 1, or 2) heteroatoms, and the remaining ring atoms are carbon. The fused ring preferably comprises a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group with a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably, it is 6 to 14 quinary, more preferably 8 to 10 quinary. Examples of "fused rings" include, but are not limited to:

[0083]

[0084] "Alkoxy" refers to an (alkyl-O-) group. Alkyl groups are defined in the relevant section of this document. C1-C6 alkoxy groups are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

[0085] "Alkylthio" refers to a (alkyl-S-) group. Alkyl groups are defined in the relevant section of this document. C1-C6 alkylthio groups are preferred. Examples include, but are not limited to: methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, etc.

[0086] "Nitro" refers to the -NO2 group.

[0087] "Hydroxy" refers to the -OH group.

[0088] "Halogens" refer to fluorine, chlorine, bromine, and iodine.

[0089] "Amino" refers to -NH2.

[0090] "Hydroxyamino group" refers to -NHOH.

[0091] “Cyano” refers to -CN.

[0092] "Benzyl" refers to -CH2-phenyl.

[0093] "Carboxyl group" refers to -C(=O)OH.

[0094] "Carboxylic acid ester group" refers to -C(=O)O-alkyl or -C(=O)O-cycloalkyl, where the definitions of alkyl and cycloalkyl are as described above.

[0095] “Hydroxyalkyl” refers to an alkyl group substituted with a hydroxyl group, where the definition of alkyl is as described above.

[0096] "Aminoalkyl" refers to an amino-substituted alkyl group, where the definition of alkyl is as described above.

[0097] "Halogenated alkyl" refers to halogen-substituted alkyl groups, where the definition of alkyl is as described above.

[0098] "Haloalkoxy" refers to halogen-substituted alkoxy groups, where the definition of alkoxy groups is as described above.

[0099] "DMSO" refers to dimethyl sulfoxide.

[0100] “BOC” refers to tert-butoxycarbonyl.

[0101] “Bn” refers to benzyl.

[0102] "THP" refers to 2-tetrahydropyranyl.

[0103] "TFA" refers to trifluoroacetic acid.

[0104] “Ts” refers to p-toluenesulfonyl group.

[0105] “Bn” refers to benzyl.

[0106] “SEM” refers to (trimethylsilyl)ethoxymethyl.

[0107] A "leaving group," or simply a group, is an atom or functional group that breaks off from a larger molecule in a chemical reaction. It's a term used in nucleophilic substitution and elimination reactions. In a nucleophilic substitution reaction, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks off with a pair of electrons from the substrate molecule is called the leaving group. Groups that readily accept electrons and have a strong ability to accept negative charges are desirable leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to break off from other molecules. This is because a smaller pKa means the leaving group doesn't need to bond with other atoms and has a stronger tendency to exist as an anion (or an electrically neutral leaving group). Common leaving groups include, but are not limited to, halogens, methanesulfonyl groups, -OTs, or -OH.

[0108] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0109] Unless otherwise specified, the terms "substitution" or "substituted" in this specification refer to the substitution of a group by one or more groups selected from the following: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylic acid ester, =O, OR 5 -C(=O)R 5 -C(=O)OR 5 -NHC(=O)R 5 -NHC(=O)OR 5 -NR 6 R 7 -C(=O)NR 6 R 7 -CH2NHC(=O)OR 5 -CH2NR 6 R 7or -S(O) r R 5 The substituents are replaced;

[0110] R 5 Each is independently selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may optionally be further selected from one or more of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -SO2NR 9 R 10 or -NR 9 C(=O)R 10 The substituents are replaced;

[0111] R 6 and R 7 Each is independently selected from hydrogen atom, hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further selected from one or more of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -SO2NR 9 R 10 or -NR 9 C(=O)R 10 The substituents are replaced;

[0112] Or, R 6 and R 7 The atoms bonded to them together form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O, or S(O)r, and the 4- to 8-membered heterocyclic group is optionally further composed of one or more elements selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R. 8 -C(=O)OR 8-OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -SO2NR 9 R 10 or -NR 9 C(=O)R 10 The substituents are replaced;

[0113] R 8 R 9 and R 10 Each is independently selected from hydrogen atoms, alkyl, amino, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further substituted by one or more substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl or carboxylic ester group;

[0114] r can be 0, 1, or 2 independently.

[0115] The compounds of this invention may contain asymmetric or chiral centers, and thus exist in different stereoisomer forms. It is contemplated that all stereoisomer forms of the compounds of this invention, including but not limited to diastereomers, enantiomers, atropisomers, and geometric (conformal) isomers, and mixtures thereof, such as racemic mixtures, are within the scope of this invention.

[0116] Unless otherwise stated, the structures described in this invention also include all isomers of this structure (e.g., diastereomers, enantiomers, and trans-isomers, and geometric (conformal) isomers; for example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers). Therefore, individual stereoisomers of the compounds of this invention, as well as mixtures of enantiomers, mixtures of diastereomers, and mixtures of geometric (conformal) isomers, are all within the scope of this invention.

[0117] "Medicinal salts" refer to certain salts of the above-mentioned compounds that retain their original biological activity and are suitable for medicinal use. Medicinal salts of compounds represented by general formula (I) can be metal salts or amine salts formed with suitable acids.

[0118] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity. Detailed Implementation

[0119] The following embodiments are used to further describe the present invention, but these embodiments are not intended to limit the scope of the present invention.

[0120] Example

[0121] The examples provide preparation and structural identification data for representative compounds represented by formula (I). It must be noted that the following examples are illustrative of the invention and not intended to limit it. 1 The 1H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 H NMR representation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublet, dt = doublet of triplet. If the coupling constant is provided, the unit is Hz.

[0122] Mass spectrometry is performed using an LC / MS instrument, and the ionization method can be ESI or APCI.

[0123] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0124] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0125] In the following examples, all temperatures are in Celsius unless otherwise specified. Unless otherwise specified, all starting materials and reagents are commercially available or synthesized according to known methods. Commercially available materials and reagents are used directly without further purification. Unless otherwise specified, they are purchased from manufacturers including but not limited to Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Guangzan Chemical Technology Co., Ltd., and Jingyan Chemical Technology Co., Ltd.

[0126] CD3OD: Deuterated methanol.

[0127] CDCl3: Deuterated chloroform.

[0128] DMSO-d6: Deuterated dimethyl sulfoxide.

[0129] Argon atmosphere refers to a reaction flask connected to an argon gas balloon with a volume of approximately 1L.

[0130] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0131] The compounds were purified using silica gel column chromatography and reversed-phase column chromatography. The eluent system was selected from: A: petroleum ether and ethyl acetate; B: dichloromethane and methanol; C: dichloromethane: ethyl acetate; D: trifluoroacetic acid aqueous solution and acetonitrile. The volume ratio of the solvent varied depending on the polarity of the compound and could be adjusted by adding small amounts of acidic or basic reagents, such as acetic acid or triethylamine.

[0132] Example 1

[0133] N 6 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(5-methyl-1H-pyrazol-3-yl)-1-(tetrahydro-2H-

[0134] pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine N 6 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-N 4 -(5-methyl-1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4,6-diamine

[0135]

[0136] first step

[0137] 6-chloro-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-4-

[0138] yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

[0139] 6-Chloro-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

[0140] 4,6-Dichloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine 1a (0.60 g, 2.20 mmol, prepared by a known method, “European Journal of Medicinal Chemistry, 238(2022), 114424”) and 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine 1b (0.44 g, 2.42 mmol, prepared by a known method, “patent WO2023159307A1”) were added to ethanol (16 mL), and then N,N-diisopropylethylamine (1.42 g, 10.98 mmol) was added to the system. The reaction was heated to 80°C and carried out for 3.5 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give 6-chloro-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 1c (0.90 g), yield 98.0%. MS m / z (ESI): 418.2 [M+1]

[0141] Step 2

[0142] 6-chloro-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1-

[0143] (tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

[0144] 6-Chloro-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

[0145] 6-chloro-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 1c (0.83 g, 1.99 mmol) and potassium carbonate (0.82 g, 5.96 mmol) were added to N,N-dimethylformamide (20 mL), and 1-(chloromethyl)-4-methoxybenzene 1d (0.93 g, 5.96 mmol) was added dropwise with stirring. The reaction was heated to 80°C and reacted for 8 hours. After cooling to room temperature, the mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 2), and the organic phase was washed with saturated sodium chloride solution (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give 0.47 g of 6-chloro-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine 1e, with a yield of 44%.

[0146] MS m / z (ESI): 538.2 [M+1]

[0147] Step 3

[0148] N 6 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-methoxybenzyl)-N 4 -(5-methyl-1-

[0149] (tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-

[0150] d]pyrimidine-4,6-diamine

[0151] N 6 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4,6-diamine

[0152] 6-chloro-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 1e (0.44 g, 0.82 mmol), 2,6-difluoro-4-(methanesulfonyl)aniline 1f (0.25 g, 1.23 mmol), tris(dibenzylideneacetone)dipalladium (0.15 g, 0.16 mmol), R-(+)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.10 g, 0.16 mmol) and sodium tert-butoxide (0.24 g, 2.45 mmol) were added sequentially to 1,4-dioxane (20 mL), and the mixture was heated to 100 °C for 4 hours under nitrogen protection. After cooling to room temperature, dilute with water (20 mL), extract with ethyl acetate (20 mL × 2), wash the organic phase with saturated sodium chloride solution (20 mL), dry to anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate and purify the residue by silica gel column chromatography (eluent: system A) to obtain N. 6 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine 1 g (0.57 g), yield 98.3%.

[0153] MS m / z (ESI): 709.3 [M+1]

[0154] Step 4

[0155] N 6 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-methoxybenzyl)-N 4 -(5-methyl-1H-pyrazol-3-

[0156] yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

[0157] N 6 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 4-(5-methyl-1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4,6-diamine

[0158] N 6 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 4 1 g (0.14 g, 0.20 mmol) of 1,4-dioxane-5-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine was dissolved in a solution of 1,4-dioxane in hydrogen chloride (4 M, 5 mL). The reaction was carried out at room temperature for 16 hours, followed by concentration under reduced pressure to give crude product N. 6 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 4 -(5-methyl-1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine 1h, no purification required, directly used for the next step. MS m / z (ESI): 625.2 [M+1]

[0159] Step 5

[0160] N 6 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(5-methyl-1H-pyrazol-3-yl)-1-(tetrahydro-2H-

[0161] pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

[0162] N 6 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-N 4 -(5-methyl-1H-pyrazole-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-

[0163] Pyrazolo[3,4-d]pyrimidine-4,6-diamine

[0164] The crude product N from the previous step 6 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 4-(5-methyl-1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine was dissolved in trifluoroacetic acid (1 mL) for 1 hour, heated to 80 °C and reacted for 2 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to remove most of the trifluoroacetic acid. It was then diluted with dichloromethane (10 mL), neutralized to pH 8-9 with sodium hydroxide solution (2 M), and extracted with a mixed solvent of dichloromethane and methanol (V / V = 10 / 1) (10 mL × 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to obtain N 6 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-N 4 -(5-methyl-1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine 1 (99 mg), two-step yield 64%.

[0165] MS m / z (ESI): 505.2 [M+1]

[0166] 1 H NMR (400MHz, DMSO-d6) δ11.98(s,1H),10.46(s,1H),9.25(s,1H),8.22(s,1H),7.78(d,J=6.4Hz,2H),5.92(s,1 H),4.72-4.60(m,1H),4.01-3.97(m,2H),3.51-3.43(m,2H),3.35(s,3H),2.19-2.07(m,5H),1.85-1.81(m,2H).

[0167] Example 2

[0168] N 6 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 6 -methyl-N 4 -(5-methyl-1H-pyrazol-3-yl)-1-

[0169] (tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamineN 6 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-N 6 -Methyl-N 4-(5-methyl-1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4,6-diamine

[0170]

[0171] first step

[0172] N 6 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-methoxybenzyl)-N 6 -methyl-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-

[0173] d]pyrimidine-4,6-diamine

[0174] N 6 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 6 -Methyl-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4,6-diamine

[0175] N 6 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 41 g (0.26 g, 0.36 mmol) of 1 g (5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine) was dissolved in N,N-dimethylformamide (20 mL), and sodium hydride (60% dispersed in mineral oil, 44 mg, 1.10 mmol) was added. The mixture was stirred at room temperature for 0.5 hours, followed by the addition of a solution of iodomethane (57 mg, 0.40 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was then stirred at room temperature for another 2 hours. The reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (20 mL × 3), and the organic phase was washed with saturated sodium chloride solution (20 mL). The phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system B) to obtain N... 6 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 6 -Methyl-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine 2a (0.23 g), yield 88.5%.

[0176] MS m / z (ESI): 723.3 [M+1]

[0177] Step 2

[0178] N 6 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 6 -methyl-N 4 -(5-methyl-1H-pyrazol-3-yl)-1-

[0179] (tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

[0180] N 6 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-N 6 -Methyl-N 4 -(5-methyl-1H-pyrazole-3-yl)-1-(tetrahydro-2H-pyran-4-yl)

[0181] )-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

[0182] N 6 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 6 -Methyl-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine 2a (0.23 g, 0.32 mmol) was dissolved in trifluoroacetic acid (1 mL), heated to 80 °C and reacted for 2 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to remove most of the trifluoroacetic acid. The solution was diluted with dichloromethane (10 mL), neutralized to pH 8-9 with sodium hydroxide solution (2 M), and extracted with a mixed solvent of dichloromethane and methanol (V / V = 10 / 1) (10 mL × 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to obtain N 6 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-N 6 -Methyl-N 4 -(5-methyl-1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine 2 (165 mg), two-step yield 66.7%.

[0183] MS m / z (ESI): 519.2 [M+1]

[0184] 1 H NMR (400MHz, DMSO-d6) δ11.95(s,1H),10.46(s,1H),8.23(s,1H),7.88(d,J=6.8Hz,2H),5.32(s,1H),4.84-4.66(m,1H ),4.04-3.95(m,2H),3.58-3.46(m,2H),3.44(s,3H),3.37(s,3H),2.23-2.09(m,2H),2.03(s,3H),1.91-1.81(m,2H).

[0185] Example 3

[0186] N 6 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-1-isopropyl-N 4 -(5-methyl-1H-pyrazol-3-yl)-1H-

[0187] pyrazolo[3,4-d]pyrimidine-4,6-diamineN 6 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-1-isopropyl-N 4 -(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-

[0188] 4,6-Diamine

[0189]

[0190] first step

[0191] 6-chloro-1-isopropyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-

[0192] pyrazolo[3,4-d]pyrimidin-4-amine

[0193] 6-Chloro-1-isopropyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-

[0194] 4-amine

[0195] 4,6-Dichloro-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine 3a (0.20 g, 0.88 mmol, prepared according to published patent "WO2023007185") and 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine 1b (0.16 g, 0.88 mmol) were added to ethanol (6 mL), and then N,N-diisopropylethylamine was added to the system. 0.34 g (2.65 mmol) was heated to 80 °C and reacted for 3.5 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: system A) to give 6-chloro-1-isopropyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine 3b (0.23 g), with a yield of 69.7%.

[0196] MS m / z (ESI): 376.1 [M+1]

[0197] Step 2

[0198] N 6-(2,6-difluoro-4-(methylsulfonyl)phenyl)-1-isopropyl-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

[0199] N 6 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-1-isopropyl-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

[0200] The following ingredients were added: 6-chloro-1-isopropyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 3b (0.10 g, 0.27 mmol), 2,6-difluoro-4-(methanesulfonyl)aniline 1f (60 mg, 0.29 mmol), tris(dibenzylideneacetone)dipalladium (48 mg, 53 μmol), and R-(+)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine) 33 mg (53 μmol) and sodium tert-butoxide (76 mg, 0.80 mmol) were added sequentially to 1,4-dioxane (5 mL). Under nitrogen protection, the mixture was heated to 100 °C and reacted for 2.5 hours. After cooling to room temperature, the mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 2), and the organic phase was washed with saturated sodium chloride solution (10 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to obtain N. 6 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-1-isopropyl-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine 3c (100 mg), yield 68.7%. MS m / z (ESI): 547.2 [M+1]

[0201] Step 3

[0202] N 6 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-1-isopropyl-N 4 -(5-methyl-1H-pyrazol-3-yl)-1H-

[0203] pyrazolo[3,4-d]pyrimidine-4,6-diamine

[0204] N 6 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-1-isopropyl-N 4 -(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]

[0205] Pyrimidine-4,6-diamine

[0206] N 6 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-1-isopropyl-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine 3c (100 mg, 0.18 mmol) was dissolved in dichloromethane (1 mL), and a solution of 1,4-dioxane in hydrochloric acid (4 mL, 4 M) was added. The mixture was stirred at room temperature for 16 hours. The solution was neutralized to pH 8-9 with sodium hydroxide solution (2 M), and extracted with a mixed solvent of dichloromethane and methanol (V / V = 10 / 1) (10 mL × 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to obtain N 6 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-1-isopropyl-N 4 -(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine 3 (20 mg), yield 23.6%.

[0207] MS m / z (ESI): 463.1 [M+1]

[0208] 1 H NMR (400MHz, DMSO-d6) δ11.99(s,1H),10.43(s,1H),9.20(s,1H),8.20(s,1H),7.78(d,J=6 .4Hz,2H),6.02(s,1H),4.81-4.76(m,1H),3.35(s,3H),2.11(s,3H),1.41(d,J=6.4Hz,6H).

[0209] According to the preparation method of Example 3 of the present invention, Examples 5 and 7 were prepared, and their specific structures and structural characterizations are as follows:

[0210]

[0211]

[0212] Example 4

[0213] N 6 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-1-isopropyl-N 6 -methyl-N 4 -(5-methyl-1H-pyrazol-3-

[0214] yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

[0215] N 6 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-1-isopropyl-N 6 -Methyl-N 4 -(5-methyl-1H-pyrazole-3-yl)-1H-pyrazole

[0216] [3,4-d]pyrimidine-4,6-diamine

[0217]

[0218] first step

[0219] 2,6-difluoro-N-methyl-4-(methylsulfonyl)aniline

[0220] 2,6-Difluoro-N-methyl-4-(methanesulfonyl)aniline

[0221] 2,6-Difluoro-4-(methanesulfonyl)aniline 1f (4.04 g, 19.50 mmol) was dissolved in methanol (130 mL), followed by the addition of sodium methoxide (5.50 g, 101.81 mmol) and paraformaldehyde (3.40 g, 113.22 mmol). The mixture was heated to 60 °C and reacted for 3.5 h. After the reaction mixture was cooled to 0 °C, sodium borohydride (3.69 g, 97.50 mmol) was slowly added. After the addition was complete, the mixture was heated to 60 °C and stirred for 2 h. The mixture was then cooled to room temperature, concentrated under reduced pressure, diluted with water (200 mL), extracted with ethyl acetate (200 mL × 2), washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 2,6-difluoro-N-methyl-4-(methanesulfonyl)aniline 4a (3 g), with a yield of 69.6%. 1H NMR (400Hz, CDCl3) δ7.38 (dd, J = 6.8, 2.4Hz, 2H), 4.17 (s, 1H), 3.19-3.15 (m, 3H), 3.02 (s, 3H).

[0222] Step 2

[0223] N 6 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-1-isopropyl-N 6 -methyl-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

[0224] N 6 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-1-isopropyl-N 6 -Methyl-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-

[0225] 1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

[0226] The following ingredients were added: 6-chloro-1-isopropyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 3b (0.16 g, 0.42 mmol), 2,6-difluoro-N-methyl-4-(methanesulfonyl)aniline 4a (94 mg, 0.42 mmol), tris(dibenzylideneacetone)dipalladium (78 mg, 85 μmol), and R-(+)-1,1'-binaphthyl-2,2'- Bis-diphenylphosphine (53 mg, 85 μmol) and sodium tert-butoxide (0.12 g, 1.28 mmol) were added sequentially to 1,4-dioxane (10 mL). The mixture was heated to 100 °C for 6 hours under nitrogen protection. After cooling to room temperature, the mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 2), washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to obtain N... 6 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-1-isopropyl-N 6 -Methyl-N 4-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine 4b (0.15 g), yield 62.5%.

[0227] MS m / z (ESI): 561.2 [M+1]

[0228] Step 3

[0229] N 6 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-1-isopropyl-N 6 -methyl-N 4 -(5-methyl-1H-pyrazol-3-

[0230] yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

[0231] N 6 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-1-isopropyl-N 6 -Methyl-N 4 -(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

[0232] N 6 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-1-isopropyl-N 6 -Methyl-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine 4b (0.15 g, 0.27 mmol) was dissolved in dichloromethane (5 mL), and a solution of 1,4-dioxane in hydrochloric acid (6 mL, 4 M) was added. The mixture was stirred at room temperature for 16 hours. The solution was neutralized to pH 8-9 with sodium hydroxide solution (2 M), and extracted with a mixed solvent of dichloromethane and methanol (V / V = 10 / 1) (10 mL × 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to obtain N 6 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-1-isopropyl-N 6 -Methyl-N 4 -(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine 4 (36 mg), yield 28.0%.

[0233] MS m / z (ESI): 477.1 [M+1]

[0234] 1 H NMR (400MHz, DMSO-d6) δ11.96(s,1H),10.45(s,1H),8.21(s,1H),7.88(d,J=6.8Hz,2 H),5.32(s,1H),4.97-4.83(m,1H),3.43(s,6H),2.03(s,3H),1.45(d,J=4.4Hz,6H).

[0235] According to the preparation method of Example 4 of the present invention, Examples 6 and 10 were prepared, and their specific structures and structural characterizations are as follows:

[0236]

[0237]

[0238] Example 8

[0239] N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 2 -methyl-N 4 -(5-methyl-1H-pyrazol-3-yl)-2',3',5',6'-

[0240] tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,4'-pyran]-2,4-diamine N 2 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-N 2 -Methyl-N 4 -(5-methyl-1H-pyrazol-3-yl)-2',3',5',6'-tetrahydro-5H-spiro[furano[3,4-d]pyrimidin-7,4'-pyran]-2,4-diamine

[0241]

[0242] first step

[0243] methyl 4-oxo-1,8-dioxaspiro[4.5]decane-3-carboxylate

[0244] 4-O-1,8-dioxospiro[4.5]decane-3-carboxylic acid methyl ester

[0245] Methyl 4-hydroxytetrahydro-2H-pyran-4-carboxylic acid 8a (11.8 g, 73.67 mmol, prepared by a known method, patent WO2013106717A1) was dissolved in tetrahydrofuran (120 mL). Sodium hydride (2.95 g, 73.67 mmol, 60% purity) was added at 0 °C, and the mixture was stirred at 20 °C for 30 minutes. The solvent was then removed by concentration under reduced pressure. The residue was diluted with dimethyl sulfoxide (120 mL), and methyl acrylate 8b (6.98 g, 81.04 mmol) was added. The reaction mixture was then reacted at 20 °C for 30 minutes. The reaction solution was poured into hydrochloric acid solution (1M, 300mL), extracted with ethyl acetate (120mL × 3), and the organic phase was washed with saturated sodium bicarbonate solution (150mL) and saturated sodium chloride solution (120mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: system A) to give methyl 4-oxo-1,8-dioxospiro[4.5]decane-3-carboxylic acid 8c (10.1g), yield 64.0%.

[0246] MS m / z(ESI): 215.3 [M+1]

[0247] Step 2

[0248] 2-(methylthio)-2',3',5',6'-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,4'-pyran]-4-ol

[0249] 2-(methylthio)-2',3',5',6'-tetrahydro-5H-spiro[furano[3,4-d]pyrimidine-7,4'-pyran]-4-ol

[0250] Methyl 4-oxo-1,8-dioxospiro[4,5]decane-3-carboxylic acid ester 8c (10.1 g, 47.15 mmol) and methyl aminomethylthioate ester 8d (4.46 g, 49.51 mmol) were dissolved in water (120 mL), and sodium carbonate (10.24 g, 96.66 mmol) was added. The mixture was reacted at 30 °C for 36 hours. The reaction solution was poured into hydrochloric acid solution (2 M, 100 mL), extracted with dichloromethane (100 mL × 3), washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-(methylthio)-2',3',5',6'-tetrahydro-5H-spiro[furano[3,4-d]pyrimidin-7,4'-pyran]-4-ol 8e (7.1 g), yield 59.2%. MS m / z(ESI): 255.0 [M+H]

[0251] Step 3

[0252] 4-chloro-2-(methylthio)-2',3',5',6'-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,4'-pyran]

[0253] 4-Chloro-2-(methylthio)-2',3',5',6'-tetrahydro-5H-spiro[furano[3,4-d]pyrimidine-7,4'-pyran]

[0254] 2-(methylthio)-2',3',5',6'-tetrahydro-5H-spiro[furano[3,4-d]pyrimidine-7,4'-pyran]-4-ol 8e (7.1 g, 27.92 mmol) was added to phosphorus oxychloride (60 mL), and the reaction mixture was stirred at 110 °C for 3 hours. The reaction solution was concentrated under reduced pressure to remove phosphorus oxychloride, diluted with dichloromethane (80 mL), and quenched slowly in a saturated sodium bicarbonate aqueous solution (80 mL). Extraction was performed with dichloromethane (60 mL × 3). The organic phase was washed with a saturated sodium chloride solution (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to obtain 4-chloro-2-(methylthio)-2',3',5',6'-tetrahydro-5H-spiro[furano[3,4-d]pyrimidine-7,4'-pyran]8f (3.5 g), with a yield of 45.9%.

[0255] MS m / z(ESI): 272.9 [M+H]

[0256] Step 4

[0257] 4-chloro-2-(methylsulfonyl)-2',3',5',6'-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,4'-pyran]

[0258] 4-Chloro-2-(methanesulfonyl)-2',3',5',6'-tetrahydro-5H-spiro[furano[3,4-d]pyrimidine-7,4'-pyran]

[0259] 4-Chloro-2-(methylthio)-2',3',5',6'-tetrahydro-5H-spiro[furano[3,4-d]pyrimidine-7,4'-pyran]8f (2.4 g, 8.80 mmol) was dissolved in dichloromethane (40 mL), and m-chloroperoxybenzoic acid (3.80 g, 22.00 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 4-chloro-2-(methanesulfonyl)-2',3',5',6'-tetrahydro-5H-spiro[furano[3,4-d]pyrimidine-7,4'-pyran]8 g (1.75 g), with a yield of 65.3%.

[0260] MS m / z (ESI): 304.9 [M+H]

[0261] Step 5

[0262] 4-chloro-N-(2,6-difluoro-4-(methylsulfonyl)phenyl)-2',3',5',6'-tetrahydro-5H-spiro[furo[3,4-

[0263] d]pyrimidine-7,4'-pyran]-2-amine

[0264] 4-Chloro-N-(2,6-difluoro-4-(methanesulfonyl)phenyl)-2',3',5',6'-tetrahydro-5H-spiro[furano[3,4-d]pyrimidine-7,4'-pyran]-2-

[0265] amine

[0266] 2,6-Difluoro-4-(methanesulfonyl)aniline 1f (600 mg, 2.90 mmol) and molecular sieve 1.50 g of the product was added to N,N-dimethylpropenylurea (15 mL), followed by sodium bis(trimethylsilyl)amino (1 M, 4.92 mL). After stirring for 10 minutes, 8 g (750 mg, 2.46 mmol) of 4-chloro-2-(methanesulfonyl)-2',3',5',6'-tetrahydro-5H-spiro[furano[3,4-d]pyrimidine-7,4'-pyran] was added. The mixture was stirred at 25 °C for 2 hours to obtain 4-chloro-N-(2,6-difluoro-4-(methanesulfonyl)phenyl)-2',3',5',6'-tetrahydro-5H-spiro[furano[3,4-d]pyrimidine-7,4'-pyran]-2-amine for 8 hours. The reaction solution was directly used for the next step. MS m / z (ESI): 432.0 [M+H]

[0267] Step 6

[0268] 4-chloro-N-(2,6-difluoro-4-(methylsulfonyl)phenyl)-N-methyl-2',3',5',6'-tetrahydro-5H-

[0269] spiro[furo[3,4-d]pyrimidine-7,4'-pyran]-2-amine 4-chloro-N-(2,6-difluoro-4-(methanesulfonyl)phenyl)-N-methyl-2',3',5',6'-tetrahydro-5H-spiro[furano[3,4-d]pyrimidine-7,4'-pyran]-2-amine

[0270] Iodomethane (1.05 g, 7.36 mmol) was added to the reaction solution from the previous step, and the mixture was stirred at 25 °C for 1 hour. The reaction solution was filtered, and the filtrate was purified by reversed-phase column chromatography (Isolera-Biotage Column: Agela C18 120 g; Mobile Phase A: 0.1% TFA, Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 50% B to 65% B in 30 min; Detector: UV 210 nm) to give 8i (175 mg) of 4-chloro-N-(2,6-difluoro-4-(methanesulfonyl)phenyl)-N-methyl-2',3',5',6'-tetrahydro-5H-spiro[furano[3,4-d]pyrimidine-7,4'-pyran]-2-amine, with a two-step yield of 16.0%.

[0271] MS m / z (ESI): 446.1 [M+H]

[0272] Step 7

[0273] N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 2 -methyl-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2',3',5',6'-tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,4'-pyran]-2,4-

[0274] diamine N 2 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-N 2 -Methyl-N 4-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2',3',5',6'-tetrahydro-5H-spiro[furano[3,4-d]pyrimidin-7,4'-pyran]-2,4-diamine

[0275] 4-Chloro-N-(2,6-difluoro-4-(methanesulfonyl)phenyl)-N-methyl-2',3',5',6'-tetrahydro-5H-spiro[furano[3,4-d]pyrimidin-7,4'-pyran]-2-amine 8i (150 mg, 336 μmol), 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-amine 1b (122 mg, 672 μmol), and potassium carbonate (139 mg, 1.01 mmol) were added. Palladium acetate (15.1 mg, 67 μmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (77.8 mg, 134 μmol), and methanesulfonic acid (9,9-dimethyl-4,5-bis(diphenylphosphine-oxanthracene))(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (31.9 mg, 34 μmol) were added to 1,4-dioxane (4 mL). The mixture was reacted in a sealed tube at 100 °C under a nitrogen atmosphere for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to obtain N 2 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-N 2 -Methyl-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2',3',5',6'-tetrahydro-5H-spiro[furano[3,4-d]pyrimidine-7,4'-pyran]-2,4-diamine 8j (190 mg), yield 95.6%.

[0276] MS m / z (ESI): 591.5 [M+H]

[0277] Step 8

[0278] N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 2 -methyl-N 4 -(5-methyl-1H-pyrazol-3-yl)-2',3',5',6'-

[0279] tetrahydro-5H-spiro[furo[3,4-d]pyrimidine-7,4'-pyran]-2,4-diamine N 2-(2,6-Difluoro-4-(methanesulfonyl)phenyl)-N 2 -Methyl-N 4 -(5-methyl-1H-pyrazol-3-yl)-2',3',5',6'-tetrahydro-5H-spiro[furano[3,4-d]pyrimidin-7,4'-pyran]-2,4-diamine

[0280] N 2 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-N 2 -Methyl-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2',3',5',6'-tetrahydro-5H-spiro[furano[3,4-d]pyrimidine-7,4'-pyran]-2,4-diamine 8j (190 mg, 0.32 mmol) was added to trifluoroacetic acid (2 mL) and stirred at 80 °C for 0.5 hours. The reaction solution was concentrated under reduced pressure and purified by preparative liquid chromatography (Waters 3767 / QDA Column: SunFire Sunfire C18, 19*250 mm, 10 μm; Mobile Phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min; gradient: 40-50% Retention Time: 8.8 min of 16 min) to obtain product N. 2 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-N 2 -Methyl-N 4 -(5-methyl-1H-pyrazol-3-yl)-2',3',5',6'-tetrahydro-5H-spiro[furano[3,4-d]pyrimidine-7,4'-pyran]-2,4-diamine 9 (0.12 g), yield 73.6%.

[0281] MS m / z (ESI): 507.4 [M+H]

[0282] 1 H NMR (400MHz, DMSO-d6) δ11.86(s,1H),9.54(s,1H),7.86(d,J=6.8Hz,2H),5.33(s,1H),4.84(s,2H),3.93-3 .80(m,2H),3.70-3.60(m,2H),3.40(s,3H),3.37(s,3H),2.03(s,3H),1.96-1.83(m,2H),1.56-1.51(m,2H).

[0283] Example 9

[0284] N2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-7-methyl-N 4 -(5-methyl-1H-pyrazol-3-yl)-5,6,7,8-

[0285] tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine

[0286] N 2 -(2,6-difluoro-4-(methanesulfonyl)phenyl)-7-methyl-N 4 -(5-methyl-1H-pyrazole-3-yl)-5,6,7,8-tetrahydropyrido[3,4-]

[0287] d]Pyrimidine-2,4-diamine

[0288]

[0289]

[0290] first step

[0291] tert-butyl 2-chloro-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)-5,8-

[0292] dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate

[0293] 2-Chloro-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-

[0294] 7(6H)-tert-butyl carboxylate

[0295] 2,4-Dichloro-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid tert-butyl ester 9a (0.42 g, 1.38 mmol, prepared according to the published patent "WO2014015291") and 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-amine 1b (0.25 g, 1.38 mmol) were added to ethanol (20 mL), and then N,N-diisopropylethylamine (0.53 g, 4.14 mmol) was added to the system. The mixture was heated to 90°C and reacted for 16 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was then separated and purified by silica gel column chromatography (eluent: system A) to give 0.16 g of tert-butyl 2-chloro-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid 9b, with a yield of 25.8%.

[0296] MS m / z (ESI): 449.2 [M+1]

[0297] Step 2

[0298] tert-butyl 2-((2,6-difluoro-4-(methylsulfonyl)phenyl)amino)-4-((5-methyl-1-(tetrahydro-2H-

[0299] pyran-2-yl)-1H-pyrazol-3-yl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate

[0300] 2-((2,6-difluoro-4-(methanesulfonyl)phenyl)amino)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid tert-butyl ester

[0301] 2-chloro-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid tert-butyl ester 9b (0.16 g, 356 μmol), 2,6-difluoro-4-(methanesulfonyl)aniline 1f (81 mg, 392 μmol), tris(dibenzylideneacetone)dipalladium (65.3 mg, 71.3 μmol), R-(+)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine (44.4 mg, 71.3 μmol) and sodium tert-butoxide (102 mg, 1.07 mmol) were sequentially added to 1,4-dioxane (10 mg) In L), under nitrogen protection, the reaction was heated to 100℃ for 4 hours, cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (10 mL × 2), the organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: system A) to give 2-((2,6-difluoro-4-(methanesulfonyl)phenyl)amino)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid tert-butyl ester 9c (0.16 g), yield 72.7%.

[0302] MS m / z (ESI): 620.2 [M+1]

[0303] Step 3

[0304] N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(5-methyl-1H-pyrazol-3-yl)-5,6,7,8-

[0305] tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine

[0306] N 2 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-N 4 -(5-methyl-1H-pyrazol-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine

[0307] 0.16 g (0.26 mmol) of 2-((2,6-difluoro-4-(methanesulfonyl)phenyl)amino)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid tert-butyl ester 9c was dissolved in 1,4-dioxane hydrochloric acid solution (4 M, 5 mL). The reaction was carried out at room temperature for 4.5 hours, and the solution was concentrated under reduced pressure to give crude product N. 2 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-N 4 -(5-methyl-1H-pyrazol-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine 9d, no purification required, can be used directly in the next step.

[0308] MS m / z (ESI): 436.1 [M+1]

[0309] Step 4

[0310] N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-7-methyl-N 4 -(5-methyl-1H-pyrazol-3-yl)-5,6,7,8-

[0311] tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine

[0312] N 2 -(2,6-difluoro-4-(methanesulfonyl)phenyl)-7-methyl-N 4 -(5-methyl-1H-pyrazole-3-yl)-5,6,7,8-tetrahydropyridine

[0313] [3,4-d]pyrimidine-2,4-diamine

[0314] The crude product N from the previous step 2 -(2,6-Difluoro-4-(methanesulfonyl)phenyl)-N 4-(5-methyl-1H-pyrazol-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine 9d was dissolved in methanol (10 mL), and acetic acid (1 mL) and formaldehyde aqueous solution (2 mL) were added sequentially at room temperature. Then, sodium triacetoxyborohydride (0.27 g, 1.26 mmol) was added in portions, and the mixture was stirred at room temperature for 24 hours. The reaction solution was neutralized to pH 8-9 with sodium hydroxide solution (2 M), and extracted with a mixed solvent of dichloromethane and methanol (V / V = 10 / 1) (15 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to obtain N 2 -(2,6-difluoro-4-(methanesulfonyl)phenyl)-7-methyl-N 4 -(5-methyl-1H-pyrazol-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine 9 (37 mg), two-step yield 31.5%.

[0315] MS m / z (ESI): 450.1 [M+1]

[0316] 1 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),9.24(s,1H),9.17(s,1H),7.77(d,J=6.4Hz,2H),5.97(s,1H),4 .21-3.99(m,2H),3.74-3.69(m,1H),3.36-3.32(m,4H),2.93(s,3H),2.84-2.78(m,2H),2.11(s,3H).

[0317] Biological evaluation

[0318] Test Example 1: Test on the inhibition of PLK4 enzyme activity by the compounds of the present invention.

[0319] The following method was used to determine the degree of inhibition of recombinant human PLK4 ATPase activity by the compounds of this invention under in vitro conditions. This method uses Promega's ADP-Glo TM Kinase Assay kit (catalog number V9102). For detailed experimental procedures, please refer to the kit instructions.

[0320] The experimental procedure is briefly described as follows: The test compound was first dissolved in DMSO to prepare a stock solution, and then serially diluted using reaction buffer (20 mM MgCl2, 50 uM DTT, 0.1 mg / ml BSA, 40 mM Tris, pH = 7.5). The final concentration range of the test compound in the reaction system was 1000 nM to 0.004 nM. PLK4 protein (purchased from Signalchem, catalog number P44-11G), substrate MBP (purchased from Signalchem, catalog number M42-51N), and ATP working solution (from ADP-Globe) were prepared using the reaction buffer. TM Kinase Assay kit component V915B, 10 μM). The reaction was performed in 384-well microplates. First, 1 μL of the compound and 2 μL of recombinant human PLK4 protein (2.4 ng / μL) were added to the wells and incubated at room temperature for 5 minutes. Then, 1 μL of MBP solution (0.1 μg / μL) and 1 μL of ATP solution (10 μM) were added, and the mixture was incubated at room temperature for 60 minutes. Next, 5 μL of ADP-Glo ​​Reagent was added, and the mixture was incubated at room temperature for 40 minutes. Finally, 10 μL of Kinase Detection Reagent was added, and the mixture was incubated at room temperature for 30 minutes. After incubation, the chemiluminescence intensity of each well was measured using a microplate reader in Luminescence mode. The percentage inhibition rate of the compound at each concentration was calculated by comparing the chemiluminescence intensity ratio with that of the control group (0.1% DMSO). The IC50 of the compound was obtained by nonlinear regression analysis of the compound concentration versus inhibition rate using GraphPad Prism 9 software. 50 Values. See Table 1.

[0321] Table 1. IC50 of the compounds of this invention inhibiting PLK4 enzyme activity 50

[0322] Example number <![CDATA[IC 50 (nM)]]> Example number <![CDATA[IC 50 (nM)]]> Example number <![CDATA[IC 50 (nM)]]> 1 4.2 5 3.8 9 11.5 2 5.5 6 6.0 10 8.6 3 6.9 7 5.7 4 3.6 8 7.0

[0323] Test Example 2: Determination of the inhibitory effect of the compound of the present invention on the proliferation of IMR-32 cells.

[0324] The following methods were used to determine the effect of the compounds of this invention on the proliferation of IMR-32 cells. IMR-32 cells were purchased from the Cell Bank of the Chinese Academy of Sciences and cultured in DMEM medium containing 10% fetal bovine serum, 100 U penicillin, and 100 μg / mL streptomycin. Cell viability was determined by... The Luminescent Cell Viability Assay kit (Promega, catalog number G7573) was used for the determination.

[0325] The experimental method was performed according to the kit instructions, and is briefly described below: The test compound was first dissolved in DMSO to prepare a 10 mM stock solution, which was then diluted with culture medium to prepare the test sample. The final concentration range of the compound was 10000 nM-1.52 nM. Cells in the logarithmic growth phase were seeded at a density of 1000 cells per well into 96-well cell culture plates and cultured overnight at 37°C in a CO2 incubator. The test compound was then added, and the cells were cultured for another 120 hours. After culture, 40 μL of CellTiter-Glo assay solution was added to each well, shaken for 5 minutes, and allowed to stand for 10 minutes. The fluorescence values ​​of each well were then read using the Luminescence mode on a microplate reader. The percentage inhibition rate of the compound at each concentration was calculated by comparing the values ​​with the control group (0.1% DMSO). Then, a nonlinear regression analysis was performed in GraphPad Prism 9 software using the logarithm of the compound concentration versus the inhibition rate to obtain the IC50 of the compound inhibiting cell proliferation. 50 Values ​​are shown in Table 2.

[0326] Table 2. IC50 of the compounds of this invention on the inhibitory effect of IMR-32 cell proliferation. 50 data

[0327] Example number <![CDATA[IC 50 (nM)]]> Example number <![CDATA[IC 50 (nM)]]> Example number <![CDATA[IC 50 (nM)]]> 1 10.9 4 4.6 7 75.8 2 12.1 5 36.5 8 55.9 3 16.2 6 4.8 9 28.0

Claims

1. A compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof: in: X is selected from N or CR d ; R d Selected from hydrogen atom, halogen, cyano group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 6-10 Aryl, 3-8 membered heterocyclic, 5-10 membered heteroaryl, -OR 5 -S (=O) r R 5 -NR 6 R 7 or -C(=O)R 5 The alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl groups thereon may optionally be further selected from one or more C10 groups. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Substituted by a haloalkoxy, halogen, hydroxyl, cyano, or amino group; R 1 Selected from hydrogen atom, halogen, cyano group, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl groups, -S (=O) r R 5 or -NR 6 R 7 The alkyl, alkoxy, alkenyl, alkynyl, or cycloalkyl groups thereon may optionally be further selected from one or more C16 groups. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Substituted by a haloalkoxy, halogen, hydroxyl, cyano, or amino group; R 2 Selected from hydrogen atoms; or R 1 R 2 The atoms connected to them together form a C 3-8 cycloalkyl, C 6-10 aryl, 3-8 membered heterocyclic, or 5-10 membered heteroaryl; wherein the cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally further selected from one or more C16 groups. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Substituted by a haloalkoxy, halogen, hydroxyl, or cyano group; Ring A is selected from 3-10 membered heterocyclic groups, 5-10 membered heteroaryl groups, and C. 6-10 Aryl, C 3-8 Cycloalkyl or 6-10 fused rings; R 4 Each is independently selected from hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl or C 1-6 Alkoxy, wherein the alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or alkoxy group is optionally further selected from one or more C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Substituted by a haloalkoxy, halogen, hydroxyl, cyano, or amino group; Or, two Rs 4 Together with the same carbon atom they are attached to, they form a -C (=O); Ring B is selected from 3-8 membered heterocyclic groups, 5-10 membered heteroaryl groups, and C. 6-10 Aryl or C 3-8 cycloalkyl; R 3 Each is independently selected from deuterium, hydroxyl, halogen, nitro, cyano, and C atoms. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -SF5, -OR 5 -OC(=O)R 5 -C(=O)R 5 -C(=O)OR 5 -N(R) 6 )C(=O)R 7 -N(R) 6 )C(=O)OR 7 -NR 6 R7、-C(=O)NR 6 R 7 -S (=O) r NR 6 R 7 Or -S (=O) r R 5 The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups thereon may optionally be further selected from one or more groups selected from hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -OR 8 =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 -N(R) 9 )C(=O)R 10 or -N(R) 9 )C(=O)OR 10 The substituents are replaced; Or, two Rs 3 Together with the same carbon atom they are attached to, they form a -C (=O); L is selected from -O-, -S-, -NR a -or-CR b R c -; R a R b R c Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, -OR 5 -S (=O) r R 5 -NR 6 R 7 C 3-8 cycloalkyl, C 6-10 aryl, 3-8 membered heterocyclic, or 5-10 membered heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally further selected from one or more groups selected from hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -OR 8 =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 -N(R) 9 )C(=O)R 10 or -N(R) 9 )C(=O)OR 10 The substituents are replaced; Or, R a R 3 The atoms bonded to them together form a 4-8 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 4-8 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally further composed of one or more elements selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced; R 5 Each is independently selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may optionally be further selected from one or more of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -SO2NR 9 R 10 or -NR 9 C(=O)R 10 The substituents are replaced; R 6 and R 7 Each is independently selected from hydrogen atom, hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further selected from one or more of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -SO2NR 9 R 10 or -NR 9 C(=O)R 10 The substituents are replaced; Or, R 6 and R 7 The atoms bonded to them together form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O, or S(O)r, and the 4- to 8-membered heterocyclic group is optionally further composed of one or more elements selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R. 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -SO2NR 9 R 10 or -NR 9 C(=O)R 10 The substituents are replaced; R 8 R 9 and R 10 Each is independently selected from hydrogen atoms, alkyl, amino, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further substituted by one or more substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl or carboxylic ester group; m can be 0, 1, 2, 3, or 4; n can be 0, 1, 2, 3, or 4; r can be 0, 1, or 2 independently.

2. The compound according to claim 1, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein X is selected from N.

3. The compound according to claim 1 or 2, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein L is selected from -NR. a -, R a The definition is as described in claim 1.

4. The compound according to any one of claims 1-3, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein ring B is selected from C. 6-10 Aryl, preferably phenyl.

5. The compound according to any one of claims 1-4, or a stereoisomer, tautomer, deuterated product, or pharmaceutically acceptable salt thereof, wherein the compound is a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of general formula (II): in: Rings A and R 1 R 2 R 3 R 4 R a The definitions of m or n are as described in claim 1.

6. The compound according to any one of claims 1-5, or a stereoisomer, tautomer, deuterated product, or pharmaceutically acceptable salt thereof, wherein R a Selected from hydrogen atoms or C 1-6 Alkyl, the C 1-6 Alkyl groups are preferably methyl groups.

7. The compound according to any one of claims 1-6, or a stereoisomer, tautomer, deuterated product, or pharmaceutically acceptable salt thereof, wherein R 1 Selected from hydrogen atom, halogen, cyano group, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 Cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl group is optionally further selected from one or more halogens, hydroxyl groups, cyano groups, amino groups, or C6 groups. 1-6 The alkoxy group is replaced by a substituent.

8. The compound according to claim 7, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein R 1 Selected from -CH3, -Cl, -OCH3, -CH2OCH3, -CN, -CH2F, -CHF2, -CF3, cyclopropyl or cyclobutyl.

9. The compound according to any one of claims 1-8, or a stereoisomer, tautomer, deuterated product, or pharmaceutically acceptable salt thereof, wherein R 2 It is a hydrogen atom.

10. The compound according to any one of claims 1-9, or a stereoisomer, tautomer, deuterated product, or pharmaceutically acceptable salt thereof, wherein R 3 Each is independently selected from halogens or -S (=O). r R 5 ; R 5 Selected from C 1-6 Alkyl group, r = 2.

11. The compound of claim 10 or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, wherein R 3 Each is independently selected from F or -S(=O)2CH3.

12. The compound according to claim 11, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein... for 13. The compound according to any one of claims 1-12, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein ring A is selected from 5-membered heteroaryl, 3-10-membered heterocyclic, phenyl, or 8-10-membered bicyclic fused rings.

14. The compound according to claim 13, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein... Selected from the following groups:

15. The compound according to any one of claims 1-14, or a stereoisomer, tautomer, deuterated product, or pharmaceutically acceptable salt thereof, wherein R 4 Each is independently selected from C 1-6 Alkyl, C 3-6 cycloalkyl, 5-6 membered heterocyclic, 5-6 membered heteroaryl or C 1-6 Alkoxy; wherein the alkyl, cycloalkyl, heterocyclic, heteroaryl, or alkoxy group is optionally further selected from one or more C16 groups. 1-6 Alkyl, C 1-6 Substituted by alkoxy, halogen, hydroxyl, cyano or amino substituents; Or, two Rs 4 Together with the same carbon atom they are attached to, they form a -C (=O).

16. The compound according to claim 15, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein R 4 Each is independently selected from methyl, isopropyl, cyclopropyl, methoxy, tetrahydropyranyl, Or, two Rs 4 Together with the same carbon atom they are attached to, they form a -C (=O).

17. The compound according to any one of claims 1-16, or a stereoisomer, tautomer, deuterated product, or pharmaceutically acceptable salt thereof, wherein the compound is:

18. A pharmaceutical composition comprising an effective dose of the compound according to any one of claims 1-17 or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient or combination thereof.

19. Use of the compound or stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof according to any one of claims 1-17, or the pharmaceutical composition according to claim 18, in the preparation of a PLK4 inhibitor.

20. Use of the compound or stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof according to any one of claims 1-17, or the pharmaceutical composition according to claim 18, in the preparation of a medicament for treating PLK4-mediated diseases; preferably, wherein the PLK4-mediated disease is cancer; preferably, wherein the cancer is selected from esophageal cancer, breast cancer, lung cancer, colorectal cancer, pancreatic cancer, cervical cancer, endometrial cancer, glioblastoma, gastric cancer, prostate cancer or acute myeloid leukemia.

21. The use of the compound or its stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 18, in the preparation of a medicament for treating cancer; preferably, wherein the cancer is selected from esophageal cancer, breast cancer, lung cancer, colorectal cancer, pancreatic cancer, cervical cancer, endometrial cancer, glioblastoma, gastric cancer, prostate cancer or acute myeloid leukemia.

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