Piperidinopyrimidine derivatives, their preparation method and pharmaceutical use

Abstract

The present disclosure relates to piperidinopyrimidine derivatives, their preparation methods, and pharmaceutical uses. Specifically, the present disclosure relates to piperidinopyrimidine derivatives represented by general formula (I), their preparation methods, pharmaceutical compositions containing the derivatives, and their use as CDK7 inhibitors in the treatment of diseases or conditions associated with abnormal CDK7 activity. In general formula (I), each group is as defined in the specification. JPEG2025536384000075.jpg45170

Description

[Technical Field]

[0001] The present disclosure belongs to the pharmaceutical field and relates to piperidinopyrimidine derivatives, their preparation methods and pharmaceutical uses. In particular, the present disclosure relates to pyrimidine derivatives represented by general formula (I), their preparation methods and pharmaceutical compositions containing the derivatives, and their use as CDK7 inhibitors in the treatment of diseases or conditions associated with the activity of CDK7. [Background technology]

[0002] Cyclin-dependent kinases (CDKs) are an important class of kinases and play important roles in regulating cancer cell proliferation and oncogenic gene transcription. Currently discovered cyclin-dependent kinases (CDKs) have more than 20 isoforms, and due to the similarity in the sequences and structures of the kinase domains of CDK family members, Selective and precise regulation of each isoform is a significant challenge.

[0003] Cyclin-dependent kinase 7 (CDK7) is a unique member of the CDK family with dual functions in regulating cell division and transcription. CDK7 binds to cyclin H and MAT1 to form a trimeric cyclin-activated kinase (CAK). This kinase phosphorylates CDKs involved in cell cycle control (including CDK1, CDK2, CDK4, and CDK6), thereby activating the corresponding CDK kinases and completing cell cycle regulation. CDK7 is also involved in transcription co-regulation as a component of the canonical transcription factor II H (TFIIH), which couples to the transcription initiation process through phosphorylation of the Rbp1 subunit of RNA polymerase II (RNAPII). Subsequently, transcription elongation can be regulated by phosphorylation of the CDK9 complex.

[0004] Since uncontrolled cell proliferation and dysregulated transcription are key hallmarks of cancer, CDK7 inhibitors that simultaneously inhibit transcription and cell cycle processes are theoretically relatively viable targets for cancer treatment, but currently, no drugs that selectively regulate such targets are commercially available. The present inventors envision the development of highly selective CDK7 inhibitors for the treatment of diseases associated with CDK7 activity.

[0005] Disclosed CDK7 inhibitor patent applications include WO2016058544, WO2018013867, WO2019143719, WO2019143730, WO2019099298, WO2020093006 and WO2020093011, WO2022064009A, etc. Summary of the Invention

[0006] The present disclosure aims to provide a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] Among them, the above G1 is N or CR 1a and Above R 1 , R 2 , R 3 and R 1a are each independently hydrogen, deuterium, a cyano group, a hydroxy group, or C 1-6 alkyl groups or halogens (e.g., fluorine, chlorine, bromine, iodine), at least one of which is not hydrogen or deuterium; Above R 4 , R 5 , R 6 , R 7 , R 8 , R 9 are independently hydrogen, deuterium, halogen, C 1-6 Alkyl group, cyano group, C 2-6 Alkenyl group, C 2-6 alkynyl groups or 3- to 6-membered cycloalkyl groups, 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6The alkynyl group or the 3- to 6-membered cycloalkyl group may optionally be independently selected from R A and the R A is selected from deuterium, halogen, a hydroxy group, a cyano group, or a 3- to 6-membered cycloalkyl group; The above L1 is a chemical bond or C 1-6 alkylene groups, 1-6 The alkylene group may optionally be independently selected from R B and the R B is a deuterium, halogen, hydroxyl group, C 1-6 an alkoxy group, an amino group, or an oxo group; or two R groups linked to the same carbon atom; B together with the commonly linked carbon atoms form a 3- to 6-membered cycloalkyl group or a 3- to 7-membered heterocyclyl group, the heterocyclyl group containing at least one heteroatom selected from N, O, or S; the ring A is selected from a 3- to 6-membered cycloalkyl group, a 6- to 10-membered aryl group, a 5- to 12-membered heteroaryl group, and a 3- to 12-membered heterocyclyl group; Above R 10 are each independently a deuterium atom, a cyano group, a halogen atom, a hydroxyl group, an amino group, or C 2-6 Alkynyl group, C 2-6 Alkenyl group, -SC 1-6 Alkyl group, C 1-6 Alkoxy group, oxo, C 1-6 Alkyl group, 3- to 6-membered cycloalkyl group, 6- to 10-membered aryl group, 5- to 12-membered heteroaryl group, 3- to 12-membered heterocyclyl group, -NH-(C=O)-C 1-6 Alkyl group, -NH-(C=O)-C 3-6 Cycloalkyl groups, -NH(C=O)-OC 1-6 Alkyl group, -NH(C=O)-OC 3-6 Cycloalkyl groups, -O(C=O)NHC 1-6 Alkyl group, -O(C=O)NH-C 3-6 Cycloalkyl group, -(C=O)NH-C 1-6 Alkyl group, -(C=O)-NH-C 3-6 Cycloalkyl groups, -(C=O)-C1-6 Alkyl group, -(C=O)-C 3-6 Cycloalkyl group, -SO2-C 1-6 Alkyl group, -SO2-C 3-6 Cycloalkyl groups, -SO2-NH2, -SO2-NH-C 1-6 Alkyl group, -SO2-NH-C 3-6 Cycloalkyl groups, -SO2-N(C 1-6 alkyl)2, -SO2-NH(C 3-6 cycloalkyl)2, -S(O)(NH)-C 1-6 Alkyl group, -S(O)(NH)-C 3-6 cycloalkyl groups, Above C 1-6 The alkyl group, the 3- to 6-membered cycloalkyl group, the 6- to 10-membered aryl group, the 5- to 12-membered heteroaryl group, and the 3- to 12-membered heterocyclyl group may optionally be independently selected from R C and the R C is deuterium, halogen, C 1-6 Alkoxy group, hydroxy group, amino group, oxo, C 2-6 Alkynyl group, C 2-6 Alkenyl group, cyano group, C 1-6 Hydroxyalkyl groups, 3- to 12-membered heterocyclyl groups, C 1-6 Alkyl group, C 3-6 selected from a cycloalkyl group, a 6- to 10-membered aryl group, or a 5- to 12-membered heteroaryl group; Above R 11 is hydrogen, deuterium, halogen, cyano group, C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 6-membered cycloalkyl group, 3- to 12-membered heterocyclyl group, C 2-6 Alkenyl group, C 2-6 alkynyl groups, 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 6-membered cycloalkyl group, 3- to 12-membered heterocyclyl group, C 2-6 Alkenyl group, C 2-6 The alkynyl group may optionally be independently selected from R D and the R Drepresents hydrogen, deuterium, halogen, cyano group, hydroxy group, alkynyl group, C 1-6 Alkoxy group, C 1-6 selected from hydroxyalkyl groups and 3- to 6-membered cycloalkyl groups, The ring B is selected from a 5- to 12-membered heteroaryl group or a 6- to 12-membered aryl group, The above R' is hydrogen, a cyano group, C 1-6 an alkyl group, a 3- to 6-membered cycloalkyl group, and a 3- to 12-membered heterocyclyl group; 1-6 The alkyl group, the 3- to 6-membered cycloalkyl group, and the 3- to 12-membered heterocyclyl group may optionally be independently selected from R E and the R E represents hydrogen, deuterium, halogen, cyano group, hydroxy group, alkynyl group, C 1-6 Alkoxy group, C 1-6 selected from a hydroxyalkyl group, a 3- to 6-membered cycloalkyl group, and a 3- to 7-membered heterocyclyl group; The m is selected from 0 or 1, wherein n is selected from 0, 1, 2, 3, 4, or 5; The above o is selected from 0, 1, 2, 3, and 4.

[0007] In another aspect, the present disclosure provides a compound of formula (VI) or a pharmaceutically acceptable salt thereof: [ka] wherein L2 is selected from -NH- or -O-; the ring B is selected from a 5- to 12-membered heteroaryl group or a 6- to 12-membered aryl group; The above L3 is C 0-6 alkylene groups, 0-6 The alkylene group may optionally be independently selected from R I and the R I is a deuterium, halogen, oxo, hydroxy group, amino group or C 1-6 selected from alkyl groups, Above R 25 and R 26are each independently hydrogen, C 1-6 Alkyl group, halo C 1-6 alkyl groups, or R 25 and R 26 together with the nitrogen atom to which they are attached form a 4- to 7-membered nitrogen-containing heterocycle, and the 4- to 7-membered nitrogen-containing heterocycle may optionally be independently selected from R J and the R J is selected from halogen, a hydroxy group, a cyano group, a nitro group, or an amino group; Above R 27 are each independently a deuterium, a halogen, a hydroxy group, a carboxy group, or C 1-6 Alkyl group, halo C 1-6 Alkyl group, hydroxy C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, 3- to 6-membered cycloalkyl group, -SC 1-6 Alkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, -NH-C 1-6 Alkyl group, -NH(C 1-6 alkyl)2, -(C=O)-NH2, alkyl-(C=O)-NH-C 1-6 Alkyl group, -(C=O)-NH-(C 1-6 alkyl)2, -(C=O)C 1-6 Alkyl group, -NH-(C=O)C 1-6 selected from alkyl groups, wherein y is selected from 0, 1, 2, 3, or 4; Above R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , L1, Ring A, R 10 and n are as defined in claim 1, but as a prerequisite, 4 , R 5 is not hydrogen at the same time.

[0008] In an alternative embodiment, the present disclosure provides a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein L2 is -NH-.

[0009] In an alternative embodiment, the present disclosure provides a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein L2 is -O-.

[0010] In an alternative embodiment, the present disclosure provides a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein L3 is -CH2CH2-.

[0011] In an alternative embodiment, the present disclosure provides a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein ring B is a phenyl group or a pyridyl group.

[0012] In an alternative embodiment, the present disclosure provides a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein ring B is a phenyl group.

[0013] In an alternative embodiment, the present disclosure provides a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein R 27 are each independently hydrogen, deuterium, halogen, cyano group, hydroxy group, carboxy group, C 1-6 Alkyl group, halo C 1-6 Alkyl group, hydroxy C 1-6 Alkyl group, C 2-6 It is selected from an alkynyl group, a 3- to 6-membered cycloalkyl group, a 3- to 12-membered heterocycloalkyl group, a 5- to 12-membered aryl group, or a heteroaryl group.

[0014] In an alternative embodiment, the present disclosure provides a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein R 27 are each independently a halogen, C 1-6 Alkyl group, halo C 1-6 Alkyl group, C 2-6 alkynyl groups.

[0015] In an alternative embodiment, the present disclosure provides a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein R 27 are each independently selected from chlorine, fluorine, a trifluoromethyl group, or an ethynyl group.

[0016] In an alternative embodiment, the present disclosure provides a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein R 25 and R 26 are each independently hydrogen or C 1-6 It is selected from alkyl groups.

[0017] In an alternative embodiment, the present disclosure provides a compound of formula (I), (VI), or a pharmaceutically acceptable salt thereof, wherein R 4 , R 5 , R 6 , R 7 , R 8 , R 9 are each independently hydrogen, deuterium, halogen or C 1-6 It is selected from alkyl groups.

[0018] In an alternative embodiment, the present disclosure provides a compound of formula (I), (VI), or a pharmaceutically acceptable salt thereof, wherein R 4 is a methyl group.

[0019] In an alternative embodiment, the present disclosure provides a compound of formula (I), (VI), or a pharmaceutically acceptable salt thereof, wherein R 5 , R 6 , R 7 , R 8 , R 9 are each independently selected from hydrogen or deuterium.

[0020] In an alternative embodiment, the present disclosure provides a compound of formula (I), (VI), or a pharmaceutically acceptable salt thereof, wherein R 5 , R 6 , R7 , R 8 , R 9 are each independently selected from hydrogen or deuterium, and 4 is a methyl group.

[0021] In an alternative embodiment, the present disclosure provides a compound represented by formula (I), (VI), or a pharmaceutically acceptable salt thereof, wherein L1 is a chemical bond.

[0022] In an alternative embodiment, the present disclosure provides a compound of formula (I), (VI), or a pharmaceutically acceptable salt thereof, wherein L is C 1-6 alkylene groups, 1-6 The alkylene group may optionally be independently selected from R B and the R B is a deuterium, halogen, hydroxyl group, C 1-6 The alkoxy group is selected from the group consisting of alkoxy groups.

[0023] In an alternative embodiment, the present disclosure provides a compound of Formula (I), (VI), or a pharmaceutically acceptable salt thereof, wherein L is a methylene group, and the methylene group is optionally independently selected from R B and the R B is a deuterium, halogen, hydroxyl group, C 1-6 The alkoxy group is selected from the group consisting of alkoxy groups.

[0024] In an alternative embodiment, the present disclosure provides a compound represented by formula (I) or (VI) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from a pyrazole ring, an imidazole ring, a tetrahydropyran ring, a pyrimidine ring, or a cyclohexyl group.

[0025] In an alternative embodiment, the present disclosure provides a compound of formula (I), (VI), or a pharmaceutically acceptable salt thereof, wherein R 10 is a deuterium atom, a cyano group, and C 2-6 Alkynyl group, -SC 1-6 Alkyl group, C1-6 Alkoxy group, C 1-6 alkyl groups, 2-6 Alkynyl group, -SC 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 The alkyl group may optionally be independently selected from R C and the R C is deuterium, halogen, C 1-6 Alkoxy group, hydroxy group, amino group, oxo, C 2-6 alkynyl groups.

[0026] In an alternative embodiment, the present disclosure provides a compound represented by formula (I), (VI), or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] Selected from.

[0027] In some embodiments, the compound of formula (VI) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (VI-1) or formula (VI-2) or a pharmaceutically acceptable salt thereof: [ka] and wherein L2 is selected from -NH- or -O-; The ring B is selected from a 5- to 6-membered heteroaryl group or a 5- to 6-membered aryl group, The above L3 is C 1~3 alkylene groups (e.g., methylene, ethylidene, and propylidene groups), 1~3 The alkylene group may optionally be independently selected from R I and the R I is a deuterium, halogen, oxo, hydroxy group, amino group or C 1-6alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl groups); Above R 25 and R 26 are each independently hydrogen, C 1-6 alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl groups); 1-6 the alkyl group is optionally substituted with one or more deuterium atoms; Above R 27 are each independently a deuterium, a halogen, a hydroxy group, a carboxy group, or C 1-6 alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl), haloC 1-6 Alkyl group, hydroxy C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 alkylene-3 to 6-membered cycloalkyl group (for example, cyclopropyl group, cyclobutyl group), 3 to 6-membered cycloalkyl group (for example, cyclopropyl group, cyclobutyl group), -SC 1-6 Alkyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, -NH-C 1-6 Alkyl group, -NH(C 1-6 alkyl)2, wherein y is selected from 0, 1, 2, 3, or 4; Above R 4 is C 1-6 is an alkyl group, Above R 5 , R 6 , R 7 , R 8 , R 9 are each independently hydrogen, deuterium, halogen or C 1-6 selected from alkyl groups, The L1 is selected from a linking bond, or the L1 is selected from C 1-6alkylene groups (e.g., methylene, ethylidene, propylidene), or the L1 is selected from C 1-6 alkylene groups, 1-6 The alkylene groups are independently R B and the R B is deuterium, halogen, hydroxyl group, C 1-6 selected from alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl) or oxo; The ring A is selected from a 5- to 6-membered aryl group, a 5- to 6-membered heteroaryl group, and a 3- to 7-membered heterocyclyl group; Above R 10 is a deuterium atom, a cyano group, and C 2-6 Alkynyl group, -SC 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl), C 1-6 Alkylene-3 to 6-membered cycloalkyl group, 3 to 6-membered cycloalkyl group, 5 to 6-membered aryl group, 5 to 6-membered heteroaryl group, 5 to 12-membered heterocycloalkyl group, -NH(C=O)-OC 1-6 Alkyl group, -(C=O)NH-C 1-6 alkyl group or (C=O)NH2; Above C 2-6 Alkynyl group, -SC 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 The alkyl group, the 5- to 6-membered aryl group, the 5- to 6-membered heteroaryl group, and the 5- to 12-membered heterocycloalkyl group may optionally independently be R C and the R C is deuterium, halogen, C 1-6 Alkoxy group, C 1-6 Alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl), hydroxyl groups, amino groups, oxo, C 2-6alkynyl groups, The above n is selected from 0, 1, 2, and 3.

[0028] In some embodiments, the compound of formula (VI) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (VI-1) or a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, the present disclosure provides a compound represented by formula (VI-1) or formula (VI-2), or a pharmaceutically acceptable salt thereof, wherein L2 is -NH-.

[0030] In some embodiments, the present disclosure provides a compound represented by formula (VI-1) or (VI-2), or a pharmaceutically acceptable salt thereof, wherein the ring B is selected from a pyridyl group or a phenyl group, and the R 27 are each independently a deuterium, a halogen, a hydroxy group, a carboxy group, or C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 It is selected from alkylene-3 to 6-membered cycloalkyl groups.

[0031] In some embodiments, the present disclosure provides a compound represented by formula (VI-1) or (VI-2), or a pharmaceutically acceptable salt thereof, wherein ring B is a phenyl group, and R 27 are each independently a deuterium, a halogen, a hydroxy group, a carboxy group, or C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 It is selected from alkylene-3 to 6-membered cycloalkyl groups.

[0032] In some embodiments, the present disclosure provides a compound represented by formula (VI-1) or (VI-2), or a pharmaceutically acceptable salt thereof, wherein ring B is a phenyl group, and R 27 are each independently selected from deuterium.

[0033] In some embodiments, the present disclosure provides a compound represented by formula (VI-1) or (VI-2), or a pharmaceutically acceptable salt thereof, wherein ring B is a phenyl group, and R 27 are each independently selected from halogens.

[0034] In some embodiments, the present disclosure provides a compound represented by formula (VI-1) or (VI-2), or a pharmaceutically acceptable salt thereof, wherein ring B is a phenyl group, and R 27 are each independently, C 1-6 It is selected from alkyl groups.

[0035] In some embodiments, the present disclosure provides a compound represented by formula (VI-1) or (VI-2), or a pharmaceutically acceptable salt thereof, wherein ring B is a phenyl group, and R 27 are each independently selected from a methyl group or an ethyl group.

[0036] In some embodiments, the present disclosure provides a compound represented by formula (VI-1) or (VI-2), or a pharmaceutically acceptable salt thereof, wherein ring B is a phenyl group, and R 27 are each independently selected from methylene-cyclopropyl groups.

[0037] In some embodiments, the present disclosure provides a compound represented by formula (VI-1) or (VI-2), or a pharmaceutically acceptable salt thereof, wherein ring B is a phenyl group, and R 27 are each independently selected from a cyclopropyl group.

[0038] In some embodiments, the present disclosure provides a compound represented by formula (VI-1) or (VI-2), or a pharmaceutically acceptable salt thereof, wherein L is selected from methylene groups, and the methylene groups are optionally independently selected from R I and the R I is a deuterium, halogen, oxo, hydroxy group, amino group or C1-6 It is selected from alkyl groups (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl groups).

[0039] In some embodiments, the present disclosure provides a compound represented by formula (VI-1) or (VI-2), or a pharmaceutically acceptable salt thereof, wherein L is selected from an ethylidene group, and the ethylidene group is optionally independently selected from R I and the R I is a deuterium, halogen, oxo, hydroxy group, amino group or C 1-6 It is selected from alkyl groups (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl groups).

[0040] In some embodiments, the present disclosure provides a compound represented by formula (VI-1) or (VI-2), or a pharmaceutically acceptable salt thereof, wherein L is selected from a propylidene group, and the propylidene group is optionally independently selected from R I and the R I is a deuterium, halogen, oxo, hydroxy group, amino group or C 1-6 It is selected from alkyl groups (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl groups).

[0041] In some embodiments, the compound of formula (VI) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (VI-1-A) or (VI-1-B) or a pharmaceutically acceptable salt thereof: [ka] and Above R 5 , R 6 , R 7 , R 8 , R 9 , L1, Ring A, R 10 ,n,R25 , R 26 , R 27 and y are the same as the compounds represented by formula (VI-1-A) or formula (VI-1-B) or pharmaceutically acceptable salts thereof, respectively.

[0042] In an alternative embodiment, the compound of formula (VI) or a pharmaceutically acceptable salt thereof provided by the present disclosure is The compound is represented by formula (VI-1-A) or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B), or a pharmaceutically acceptable salt thereof, wherein L1 is a connecting bond.

[0044] In some embodiments, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein L is C 1-6 alkylene groups, or the above L1 is selected from C 1-6 alkylene groups, 1-6 The alkylene groups are independently R B and the R B is deuterium, C 1-6 It is selected from alkyl groups and oxo.

[0045] In some embodiments, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein L is C 1-6 It may be selected from alkylene groups, specifically, a methylene group or an ethylidene group.

[0046] In some embodiments, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein L is C 1-6alkylene groups, 1-6 The alkylene groups are independently R B and the R B is selected from deuterium, a methyl group, an ethyl group, or a propyl group.

[0047] In some embodiments, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein L is C 1-6 alkylene groups, 1-6 The alkylene groups are independently R B and the R B is selected from deuterium.

[0048] In some embodiments, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein L is C 1-6 alkylene groups, 1-6 The alkylene groups are independently R B and the R B is selected from methyl groups.

[0049] In some embodiments, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein L is C 1-6 alkylene groups, 1-6 The alkylene groups are independently R B and the R B is selected from oxo.

[0050] In some embodiments, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B), or a pharmaceutically acceptable salt thereof, wherein L is selected from a methylene group; or L is selected from a methylene group, and the methylene groups are independently selected from R B and the R B is deuterium or C 1-6 It is selected from alkyl groups (for example, methyl groups, ethyl groups).

[0051] In some embodiments, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B), or a pharmaceutically acceptable salt thereof, wherein L is selected from a methylene group; or L is selected from a methylene group, and the methylene groups are independently selected from R B and the R B is selected from deuterium and a methyl group.

[0052] In some embodiments, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B), or a pharmaceutically acceptable salt thereof, wherein L is selected from methylene groups, and the methylene groups are independently selected from R B and the R B is selected from oxo.

[0053] In some embodiments, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 5 , R 6 , R 7 , R 8 , R 9 are each independently selected from hydrogen or deuterium.

[0054] In some embodiments, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B), or a pharmaceutically acceptable salt thereof, wherein ring A is selected from a pyrazolyl group, an imidazolyl group, a pyridyl group, a phenyl group, a tetrahydropyranyl group, a pyrimidine group, and a cyclohexyl group.

[0055] In an alternative embodiment, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 is deuterium, C 1-6 Alkyl group, C 1-6 Alkylene-3 to 6-membered cycloalkyl group, 5 to 6-membered aryl group, 5 to 6-membered heteroaryl group, -NH(C=O)-OC 1-6 Alkyl group or -(C=O)NH-C 1-6 alkyl group or (C=O)NH2; Above C 1-6 The alkyl group, the 5- to 6-membered aryl group, and the 5- to 6-membered heteroaryl group may optionally be independently selected from R C and the R C are deuterium, halogen, C 1-6 Alkoxy group, C 1-6 Alkyl group, hydroxy group, amino group, oxo, C 2-6 alkynyl groups, The above n is selected from 1, 2, and 3.

[0056] In an alternative embodiment, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 is C 1-6 selected from alkyl groups, The above n is selected from 1, 2, and 3.

[0057] In an alternative embodiment, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from a methyl group, an ethyl group, or a propyl group; The above n is selected from 1, 2, and 3.

[0058] In an alternative embodiment, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from a methyl group, The above n is selected from 1, 2, and 3.

[0059] In an alternative embodiment, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 is C 1-6 alkylene-3 to 6-membered cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups); The above n is selected from 1, 2, and 3.

[0060] In an alternative embodiment, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from methylene-cyclopropyl groups, The above n is selected from 1, 2, and 3.

[0061] In an alternative embodiment, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from 3- to 6-membered cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups), The above n is selected from 1, 2, and 3.

[0062] In an alternative embodiment, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from a cyclopropyl group, The above n is selected from 1, 2, and 3.

[0063] In an alternative embodiment, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from phenyl groups, and the phenyl groups are optionally independently selected from R C and the R C is deuterium, halogen, C 1-6 Alkoxy group, C 1-6 Alkyl group, hydroxy group, amino group, oxo, C 2-6 alkynyl groups, The above n is selected from 1, 2, and 3.

[0064] In an alternative embodiment, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 are selected from 5- to 6-membered heteroaryl groups (e.g., pyridine, imidazole, pyrazole, thiazole, oxazole), and the 5- to 6-membered heteroaryl groups are optionally independently selected from R C and the R C is deuterium, halogen, C 1-6 Alkoxy group, C 1-6 Alkyl group, hydroxy group, amino group, oxo, C 2-6 alkynyl groups, The above n is selected from 1, 2, and 3.

[0065] In an alternative embodiment, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 is -NH(C=O)-OC 1-6 It is selected from alkyl groups (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl groups), where n is 1, 2, or 3.

[0066] In an alternative embodiment, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 is -(C=O)NH-C 1-6 It is selected from alkyl groups (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl groups), where n is 1, 2, or 3.

[0067] In an alternative embodiment, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from (C=O)NH2, and n is selected from 1, 2 or 3.

[0068] In an alternative embodiment, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 are selected from 5- to 10-membered heterocycloalkyl groups, and the heterocycloalkyl groups are optionally independently selected from R C and the R C is deuterium, halogen, C 1-6 Alkoxy group, C 1-6 Alkyl group, hydroxy group, amino group, oxo, C 2-6 alkynyl groups, The above n is selected from 1, 2, and 3.

[0069] In an alternative embodiment, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from a 5- to 10-membered bridged-heterocyclyl group, said bridged-heterocyclyl optionally being independently selected from R C and the R C is deuterium, halogen, C 1-6 Alkoxy group, C 1-6 Alkyl group, hydroxy group, amino group, oxo, C 2-6 alkynyl groups, said heterocyclyl groups containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; The above n is selected from 1, 2, and 3.

[0070] In some embodiments, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] Selected from.

[0071] In some embodiments, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 27 are independently deuterium, halogen, C 1-6 Alkyl group, halo C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 Alkylene-3 to 6-membered cycloalkyl group, 3 to 6-membered cycloalkyl group, haloC 1-6 Alkoxy group, -NH-C 1-6 Alkyl group, -NH(C 1-6alkyl)2.

[0072] In some embodiments, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 27 are each independently a halogen or C 1-6 It is selected from alkyl groups.

[0073] In some embodiments, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 27 are each independently selected from fluorine or chlorine; In some embodiments, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 27 are each independently selected from a methyl group.

[0074] In some embodiments, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 25 and R 26 are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl, and the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl groups are optionally substituted with one or more deuterium atoms.

[0075] In some embodiments, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 25 and R 26are each independently selected from hydrogen, a methyl group, and an ethyl group, and the methyl group and ethyl group are optionally substituted with one or more deuterium atoms.

[0076] In some embodiments, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 25 and R 26 are each independently selected from a methyl group, said methyl group optionally substituted with one or more deuterium atoms.

[0077] The present disclosure provides a compound shown below or a pharmaceutically acceptable salt thereof, which is [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9]

[0078] In another aspect, the present disclosure provides compounds of formula (I), (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B), or pharmaceutically acceptable salts thereof, and the compounds of Table a, and isotopic substitutions. In an alternative embodiment, the isotopic substitutions are deuterium atom substitutions.

[0079] The present disclosure provides a pharmaceutical composition comprising at least one compound represented by formula (I), (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof and a compound of Table a, an isotopic substitution thereof, or a compound prepared by the above method or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0080] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0081] In one embodiment, the pharmaceutical composition contains, based on the total weight of the composition, 0.01% to 99.99% of the compound or a medicinal salt thereof. In one embodiment, the pharmaceutical composition contains 0.1% to 99.9% of the compound or a medicinal salt thereof. In one embodiment, the pharmaceutical composition contains 0.5% to 99.5% of the compound or a medicinal salt thereof. In one embodiment, the pharmaceutical composition contains 1% to 99% of the compound or a medicinal salt thereof. In one embodiment, the pharmaceutical composition contains 2% to 98% of the compound or a medicinal salt thereof.

[0082] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable excipients, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable excipients.

[0083] In another aspect, the present disclosure provides use of the compounds represented by formula (I), (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or medicinal salts thereof, the compounds of Table a, isotopic substitutions, or compounds prepared by the above-mentioned methods or medicinal salts thereof, and the above-mentioned pharmaceutical compositions, in the preparation of a medicament for treating or preventing a disease or condition associated with abnormal activity of serine / threonine kinase.

[0084] In another aspect, the present disclosure provides use of the compounds represented by formula (I), (VI), (VI-1), (VI-2), (VI-1-A) or (VI-1-B) or medicinal salts thereof, the compounds of Table a, isotope substitutions, or compounds prepared by the above-mentioned methods or medicinal salts thereof, and the above-mentioned pharmaceutical compositions in the preparation of a medicament for treating and / or preventing a disease or condition associated with abnormal activity of CDK7.

[0085] In alternative embodiments, the disease or condition associated with abnormal activity of CDK7 is selected from a proliferative disease, an inflammatory disease, an autoinflammatory disease, an autoimmune disease, or an infectious disease.

[0086] In another aspect, the present disclosure provides use of the compounds represented by formula (I), (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or medicinal salts thereof, the compounds of Table a, isotopic derivatives thereof, or compounds prepared by the above-mentioned methods or medicinal salts thereof, and the above-mentioned pharmaceutical compositions in the preparation of a medicament for the treatment and / or prevention of a disease or condition, wherein the disease or condition is selected from a proliferative disease, an inflammatory disease, an autoinflammatory disease, an autoimmune disease, or an infectious disease.

[0087] In alternative embodiments, the disease or condition is a proliferative disease.

[0088] In an alternative embodiment, the proliferative disease is cancer.

[0089] In alternative embodiments, the cancer is selected from a hematological tumor and a solid tumor.

[0090] In alternative embodiments, the hematological tumor is selected from leukemias, including chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), T-cell acute lymphocytic leukemia (T-ALL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), and the like.

[0091] In alternative embodiments, the solid tumor is selected from breast cancer, intestinal cancer, lung cancer, pancreatic cancer, prostate cancer, Ewing's sarcoma, bone tumor, neuroblastoma, cervical cancer, ovarian cancer, gastric cancer, and liver cancer.

[0092] In alternative embodiments, the breast cancer is triple-negative breast cancer.

[0093] In an alternative embodiment, the breast cancer is ER / PR+HER2- breast cancer.

[0094] In an alternative embodiment, the breast cancer is ER / PR+HER2- breast cancer that is resistant to CDK4 / 6 inhibitors.

[0095] In an alternative embodiment, the CDK4 / 6 inhibitor is Palbociclib.

[0096] In an alternative embodiment, the lung cancer is non-small cell lung cancer.

[0097] In an alternative embodiment, the lung cancer is small cell lung cancer.

[0098] In an alternative embodiment, the intestinal cancer is colon cancer.

[0099] In an alternative embodiment, the intestinal cancer is rectal cancer.

[0100] In another aspect, the present disclosure provides a method for treating and / or preventing a disease or condition in a patient associated with abnormal activity of a serine / threonine kinase, comprising administering to the patient a therapeutically effective amount of a compound represented by Formula (I), (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a medicinal salt thereof, a compound of Table a, an isotopic substitution thereof, or a compound prepared by the above-described method or a medicinal salt thereof, and the above-described pharmaceutical composition.

[0101] In another aspect, the present disclosure provides a method for treating and / or preventing a disease or condition in a patient associated with abnormal CDK7 activity, comprising administering to the patient a therapeutically effective amount of a compound represented by Formula (I), (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a medicinal salt thereof, a compound of Table a, an isotopic substitution thereof, or a compound prepared by the above-mentioned method or a medicinal salt thereof, and the above-mentioned pharmaceutical composition.

[0102] In alternative embodiments, the disease or condition associated with abnormal activity of CDK7 is selected from a proliferative disease, an inflammatory disease, an autoinflammatory disease, an autoimmune disease, or an infectious disease.

[0103] In another aspect, the present disclosure provides a method for treating and / or preventing a disease or condition in a patient, comprising administering to the patient a therapeutically effective amount of a compound represented by Formula (I), (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a medicinal salt thereof, a compound of Table a, an isotopic substitution thereof, or a compound prepared by the above-described method or a medicinal salt thereof, and the above-described pharmaceutical composition, wherein the disease or condition is selected from a proliferative disease, an inflammatory disease, an autoinflammatory disease, an autoimmune disease, or an infectious disease, and in an alternative embodiment, the disease or condition is a proliferative disease.

[0104] In an alternative embodiment, the proliferative disease is cancer.

[0105] In alternative embodiments, the cancer is selected from a hematological tumor and a solid tumor.

[0106] In alternative embodiments, the hematological tumor is selected from leukemias, including chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), T-cell acute lymphocytic leukemia (T-ALL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), and the like.

[0107] In alternative embodiments, the solid tumor is selected from breast cancer, intestinal cancer, lung cancer, pancreatic cancer, prostate cancer, Ewing's sarcoma, bone tumor, neuroblastoma, cervical cancer, ovarian cancer, gastric cancer, and liver cancer.

[0108] In alternative embodiments, the breast cancer is triple-negative breast cancer.

[0109] In an alternative embodiment, the breast cancer is ER / PR+HER2- breast cancer.

[0110] In an alternative embodiment, the breast cancer is ER / PR+HER2- breast cancer that is resistant to CDK4 / 6 inhibitors.

[0111] In an alternative embodiment, the CDK4 / 6 inhibitor is Palbociclib.

[0112] In an alternative embodiment, the lung cancer is non-small cell lung cancer.

[0113] In an alternative embodiment, the lung cancer is small cell lung cancer.

[0114] In an alternative embodiment, the intestinal cancer is colon cancer.

[0115] In an alternative embodiment, the intestinal cancer is rectal cancer.

[0116] In another aspect, the present disclosure provides the use of a compound represented by formula (I), (VI), (VI-1), (VI-2), (VI-1-A), or (VI-1-B) or a pharmaceutically acceptable salt thereof, a compound of Table a, an isotopic substitution thereof, or a compound prepared by the above method, as a medicine.

[0117] The compounds provided by the present disclosure, or pharmaceutically acceptable salts thereof, may be prepared by synthetic methods known in the art, the following of which are exemplary methods.

[0118] The compound according to formula (VI) or a pharmaceutically acceptable salt thereof provided by the present disclosure may be prepared with reference to the method of patent WO2022064009A1.

[0119] The compound of formula (VI) provided by the present disclosure has two fragments A and B that are split during synthesis, respectively. [ka] .

[0120] The present disclosure provides a method for preparing a compound of formula (VI-1-A) or a medicinal salt thereof, or an isotopic derivative thereof, comprising the step of condensing a compound of formula (VI-1-A-01) or a medicinal salt thereof with a compound of formula (VI-1-A-02) or a medicinal salt thereof under the action of carbonyldiimidazole, phosgene or triphosgene, [ka] Above R 5 , R 6 , R 7 , R 8 , R 9 , L1, Ring A, R 10 ,n,R 25 , R 26 , R 27 and y are each as defined above.

[0121] In an alternative embodiment, the condensation reaction occurs in a basic environment, provided by an inorganic base (sodium hydroxide) or an organic base (e.g., triethylamine, pyridine, piperidine, or N,N-diisopropylethylamine), and the solvent in which the reaction occurs is a common solvent (e.g., DMF, DCM, or DMSO).

[0122] The present disclosure provides a method for preparing a compound of formula (VI-1-B) or a medicinal salt thereof, or an isotopic derivative thereof, comprising the step of condensing a compound of formula (VI-1-B-01) or a medicinal salt thereof with a compound of formula (VI-1-A-02) or a medicinal salt thereof under the action of carbonyldiimidazole, phosgene or triphosgene, [ka] Above R 5 , R 6 , R 7 , R 8 , R 9 , L1, Ring A, R 10 ,n,R 25 , R 26 , R 27 and y are each as defined above.

[0123] In an alternative embodiment, the condensation reaction occurs in a basic environment, provided by an inorganic base (sodium hydroxide) or an organic base (e.g., triethylamine, pyridine, piperidine, or N,N-diisopropylethylamine), and the solvent in which the reaction occurs is a common solvent (e.g., DMF, DCM, or DMSO).

[0124] Pharmaceutically acceptable salts of the compounds described in the present disclosure are selected from inorganic salts or organic salts, and the compounds described in the present disclosure can react with acidic or basic substances to produce the corresponding salts.

[0125] The present disclosure provides compounds of formula (I), (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof and the compounds of Table a, wherein the isotopic substitutions have excellent selectivity for CDK7 enzyme activity, and in selected embodiments, IC 50 is less than 100 nM, and in select embodiments, 50 is less than 50 nM, and in select embodiments, 50 is less than 30 nM, and in select embodiments, 50is less than 15 nM.

[0126] The compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. The present disclosure includes cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, e.g., enantiomerically or diastereomerically enriched mixtures, and all such compounds are intended to be within the scope of the present disclosure. Substituents such as alkyl groups may contain other asymmetric carbon atoms. All such isomers and mixtures thereof are included within the scope of the present disclosure. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0127] Optically active (R)- and (S)-isomers and D- and L-isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. Single enantiomers of certain compounds of the present disclosure can be prepared by asymmetric synthesis or derivatization with chiral auxiliaries, whereby the resulting diastereomeric mixture is isolated and the resulting diastereomeric mixture is cleaved to provide the desired enantiomer in pure form by cleavage of the corresponding groups. Alternatively, if the molecule contains a basic (e.g., amino) or acidic (e.g., carboxy) functional group, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by diastereomeric separation and recovery using conventional methods well known in the art to obtain the enantiomers in pure form. Separation of enantiomers and diastereomers is typically accomplished using chromatography, employing chiral stationary phases and optionally combined with chemical derivatization (e.g., carbamates from amines).

[0128] In the chemical structures of the compounds described in this disclosure, [ka] indicates that the configuration is not specified, i.e., chiral isomers exist in the chemical structure, [ka] The bond [ka] or [ka] The two arrangements may be included at the same time.

[0129] The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also called protolytic tautomers) include interconversions via protolysis, such as keto-enol and imine-enamine, lactam-lactim isomerizations. An illustrative example of a lactam-lactim equilibrium is between A and B shown below.

[0130] [ka] All of the compounds in this disclosure can be depicted as Form A or Form B. All tautomeric forms are within the scope of this disclosure. The naming of a compound does not exclude any tautomeric forms.

[0131] The present disclosure further includes some isotopically labeled compounds of the present disclosure that are the same as those described herein, except that one or more atoms have been replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Illustrative isotopes that can be attached to compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, for example, 2 H, 3 H, 11 C.13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.

[0132] Unless otherwise specified, when a position is specifically designated as deuterium (D), it should be understood that the position is deuterium (i.e., at least 10% deuterium incorporated) with an abundance at least 1000 times greater than the natural abundance of deuterium (which is 0.015%). For example, a compound having an abundance greater than the natural abundance of deuterium may be at least 1000 times more abundant, at least 2000 times more abundant, at least 3000 times more abundant, at least 4000 times more abundant, at least 5000 times more abundant, at least 6000 times more abundant, or even greater. The present disclosure further includes various deuterated forms of the compound of formula (I). Each available hydrogen atom connected to a carbon atom may be independently replaced with a deuterium atom. Those skilled in the art can synthesize deuterated forms of the compound of formula (I) by referring to relevant literature. Deuterated forms of compounds of formula (I), when prepared, may use commercially available deuterated starting materials or may be synthesized by conventional techniques with deuterated reagents, including, but not limited to, borane deuteride, borane tritide in tetrahydrofuran, lithium aluminum deuteride, deuterated iodoethane, and deuterated iodomethane.

[0133] "Optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, "C optionally substituted with a halogen or cyano group" 1-6By "alkyl group" is meant that a halogen or cyano group may be present, but is not necessarily present, and this description includes cases where the alkyl group is substituted with a halogen or cyano group and cases where the alkyl group is not substituted with a halogen or cyano group.

[0134] Explanation of terms: The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein or physiologically acceptable salts or prodrugs thereof with other chemical components, and other components such as physiologically acceptable carriers and excipients. The pharmaceutical composition is intended to facilitate administration to a living body and contribute to the absorption of the active ingredients to further exert their biological activity.

[0135] A "medicinal excipient" includes, but is not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonicity agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration and acceptable for use in humans or domestic animals.

[0136] As used herein, an "effective amount" or "therapeutically effective amount" includes an amount sufficient to ameliorate or prevent the symptoms or pathology of a medical condition. An effective amount also refers to an amount sufficient to enable or facilitate diagnosis. The effective amount used in a particular patient or veterinary subject can vary depending on factors such as the condition being treated, the patient's overall health, the route and dose of administration, and the severity of side effects. An effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.

[0137] Prefix “C” u-v " indicates that the following group has u to v carbon atoms. For example, "C 1-6 The term "alkyl group" refers to an alkyl group having 1 to 6 carbon atoms, and may specifically be an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms.

[0138] The term "alkyl group" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, an alkyl group is a group having 1 to 20 carbon atoms (i.e., C 1-20 alkyl group), 1 to 8 carbon atoms (i.e., C 1-8 alkyl group), 1 to 6 carbon atoms (i.e., C 1-6 alkyl group), or 1 to 4 carbon atoms (i.e., C 1-4 alkyl groups). Illustrative examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbon atoms is named by a chemical name or determined by a molecular formula, all positional isomers having that number of carbon atoms may be included. Thus, for example, a "butyl group" includes an n-butyl group (i.e., -(CH2)3CH3), a sec-butyl group (i.e., -CH(CH3)CH2CH3), an isobutyl group (i.e., -CH2CH(CH3)2), and a tert-butyl group (i.e., -C(CH3)3), and a "propyl group" includes an n-propyl group (i.e., -(CH2)2CH3) and an isopropyl group (i.e., -CH(CH3)2).

[0139] The term "alkenyl group" refers to an alkenyl group having 2 to 20 carbon atoms (i.e., C 2-20 alkenyl groups), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl groups), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl groups), or 2 to 4 carbon atoms (i.e., C 2-4 It refers to an alkyl group containing at least one carbon-carbon double bond, having an alkenyl group. Examples of alkenyl groups include ethenyl, propenyl, and butadienyl groups (including 1,2-butadienyl and 1,3-butadienyl groups).

[0140] The term "alkynyl group" refers to an alkynyl group having 2 to 20 carbon atoms (i.e., C 2-20 alkynyl groups), 2 to 8 carbon atoms (i.e., C 2-8alkynyl groups), 2 to 6 carbon atoms (i.e., C 2-6 alkynyl groups), or 2 to 4 carbon atoms (i.e., C 2-4 "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond, having an alkynyl group. Examples of "alkynyl" include ethynyl, propynyl (e.g., 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl, and 1-methylpent-2-ynyl.

[0141] The term "cycloalkyl group" or "carbocycle" refers to a saturated or partially unsaturated cyclic alkyl group having monocyclic or polycyclic rings (including fused, bridged, and spiro ring systems). The term "cycloalkyl group" includes cycloalkenyl groups (i.e., the cyclic group has at least one double bond). As used herein, a cyclic alkyl group is a group having 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl groups), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl groups), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl groups), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl groups), or 3 to 7 ring carbon atoms (i.e., C 3-7 cycloalkyl groups), or 3 to 6 ring carbon atoms (i.e., C 3-6 cycloalkyl groups). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, and cyclohexadienyl. The cycloalkyl rings may be fused to aryl or heteroaryl groups, where the ring connected to the parent structure is a cycloalkyl group; non-limiting examples include indanyl, tetrahydronaphthyl, and benzocycloheptanyl.

[0142] The term "heterocyclyl group" or "heterocycloalkyl" refers to a saturated or unsaturated cycloalkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, sulfur, and phosphorus. The term "heterocycloalkyl group" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bridged heterocyclyl groups, fused heterocyclyl groups, and spiro-heterocyclyl groups. Heterocyclyl groups can be monocyclic or polycyclic, of which polycyclic rings can be fused, bridged, or spiro. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl group that is independent of connectivity (i.e., may be bonded via a carbon atom or a heteroatom). The term heterocyclyl group is also intended to include any non-aromatic ring containing at least one heteroatom, which may be fused to an aryl or heteroaryl ring, regardless of connectivity to the rest of the molecule. As used herein, a heterocyclyl group has 3 to 20 ring atoms (i.e., a 3-20-membered heterocyclyl group), 3 to 12 ring atoms (i.e., a 3-12-membered heterocyclyl group), 3 to 10 ring atoms (i.e., a 3-10-membered heterocyclyl group), 3 to 8 ring atoms (i.e., a 3-8-membered heterocyclyl group), 3 to 7 ring atoms (i.e., a 3-7-membered heterocyclyl group), or 3 to 6 ring atoms (i.e., a 3-6-membered heterocyclyl group), and has 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, phosphorus, or oxygen. Examples of heterocyclyl groups include pyrrolidinyl, imidazolidinyl, oxetane, dioxolane, azetidinyl, tetrahydrofuranyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl groups.

[0143] As used herein, the term "bridged-heterocyclyl group" refers to a 4- to 10-membered ring moiety connected to one or more (e.g., 1 or 2) 4- to 10-membered ring moieties having at least one heteroatom at two non-adjacent atoms of the heterocyclyl group, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, and phosphorus. As used herein, "bridged-heterocyclyl group" includes bicyclic and tricyclic ring systems. As used herein, the term "spiro-heterocyclyl group" refers to a ring system in which a 3- to 10-membered heterocyclyl group has one or more additional rings, wherein the one or more additional rings are 3- to 10-membered cycloalkyl groups or 3- to 10-membered heterocyclyl groups, and wherein a single atom of the one or more additional rings is also an atom of the 3- to 10-membered heterocyclyl group. Examples of spiro-heterocyclyl rings include bicyclic and tricyclic ring systems such as 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl, and 6-oxa-1-azaspiro[3.3]heptyl. Examples of fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridyl, indolinyl, and isoindolinyl, wherein the heterocyclyl group can be attached via either ring of the fused system.

[0144] Non-limiting examples of "heterocyclyl groups" include: [ka] Includes:

[0145] The heterocyclyl ring may be fused to an aryl or heteroaryl group, wherein the ring connected to the parent structure is a heterocycloalkyl group, non-limiting examples of which are: [ka] Includes:

[0146] The term "aryl group" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl groups. The aryl ring may be fused to a heteroaryl group, heterocyclyl group, or cycloalkyl ring, where the ring connected to the parent structure is an aryl ring, non-limiting examples of which are: [ka] Includes:

[0147] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 6 to 12-membered, more preferably 5 or 6-membered. Non-limiting examples include imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidine, thiadiazolyl, pyrazinyl, and the like. [ka] Includes:

[0148] The heteroaryl ring may be fused to an aryl group, a heterocyclyl group, or a cycloalkyl ring, where the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which are: [ka] Includes:

[0149] The term "alkoxy" refers to the group "alkyl-O-", where alkyl is defined above. Examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, s-butoxy, n-pentyloxy, n-hexyloxy, and 1,2-dimethylbutoxy.

[0150] The terms "cycloalkyloxy group" and "heterocyclyloxy group" are defined the same as the above "alkoxy group".

[0151] The term "haloalkyl group" refers to an unbranched or branched alkyl group, as defined above, in which one or more hydrogen atoms have been replaced with halogen. For example, if a residue is substituted with two or more halogens, it may be referred to by using a prefix corresponding to the number of halogen moieties connected. Dihaloalkyl and trihaloalkyl groups refer to alkyl groups substituted with two or three halogen groups, which may, but are not necessarily, the same halogen. Illustrative examples of haloalkyl groups include difluoromethyl (-CHF) and trifluoromethyl (-CF).

[0152] The term "haloalkoxy" refers to an alkoxy group, as defined above, in which one or more hydrogen atoms have been replaced with a halogen.

[0153] The term "hydroxyalkyl group" refers to an alkyl group substituted with one or more hydroxy groups, where alkyl is as defined above.

[0154] The term "hydroxy" refers to an -OH group.

[0155] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0156] The term "cyano" refers to -CN.

[0157] The term "nitro group" refers to -NO2.

[0158] The term "oxo" refers to a ═O substituent.

[0159] The term "substituted" refers to one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, being independently replaced with a corresponding number of substituents. Of course, the substituents are located only at their chemically possible positions, and a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. DETAILED DESCRIPTION OF THE INVENTION

[0160] The present disclosure will be further described below in conjunction with examples, but these examples do not limit the scope of the present disclosure.

[0161] Example The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shifts (δ) are 10 -6 The values ​​are shown in units of ppm. NMR measurements were performed using a Bruker AVANCE-400 or Bruker AVANCE NEO 500M nuclear magnetic resonance spectrometer, with the solvents used being deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS).

[0162] For MS measurements, liquid chromatograph mass spectrometers Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS (manufacturer: Agilent, MS model number: 6110 / 6120 Quadrupole MS), waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model number: waters ACQuity Qda Detector / waters SQ Detector), and THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model number: THERMO Q Exactive) were used.

[0163] High performance liquid chromatography (HPLC) analysis was performed using high performance liquid chromatographs Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489.

[0164] For chiral HPLC analysis, a high performance liquid chromatograph, Agilent 1260 DAD, was used.

[0165] For high-performance liquid preparative chromatography, preparative chromatographs Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 were used.

[0166] For chiral separation, a preparative chromatograph Shimadzu LC-20AP was used.

[0167] Combiflash Rf200 (TELEDYNE ISCO) was used as the CombiFlash high-speed preparative chromatograph.

[0168] Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for thin-layer chromatography (TLC). The silica gel plate specifications for thin-layer chromatography (TLC) are 0.15 mm to 0.2 mm, and those for isolating and purifying products by thin-layer chromatography are 0.4 mm to 0.5 mm.

[0169] For silica gel column chromatography, 200-300 mesh silica gel manufactured by Yantai Huanghai Silica Gel was generally used as the carrier.

[0170] Mean kinase inhibition rate and IC 50 The values ​​were measured using a Pretreader NovoStar (BMG GmbH, Germany).

[0171] Known starting materials of the present disclosure may be synthesized by or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc.), Shanghai BiDe Pharmaceutical, and Darui Chemical.

[0172] In the examples, unless otherwise specified, all reactions can be carried out under an argon or nitrogen gas atmosphere.

[0173] The argon gas atmosphere or nitrogen gas atmosphere means that an argon gas or nitrogen gas balloon with a volume of about 1 L is connected to the reaction flask.

[0174] The hydrogen gas atmosphere refers to a hydrogen gas balloon with a volume of approximately 1 L connected to the reaction flask.

[0175] For the pressurized hydrogenation reaction, a Parr 3916EKX hydrogenation apparatus and a Seiran QL-500 hydrogen gas generator or an HC2-SS hydrogenation apparatus were used.

[0176] The hydrogenation reaction was usually carried out by repeating the procedure of evacuating and filling with hydrogen gas three times.

[0177] A CEM Discover-S 908860 microwave reactor was used for the microwave reactions.

[0178] In the examples, unless otherwise specified, the solution refers to an aqueous solution.

[0179] In the examples, unless otherwise specified, the reaction temperature is room temperature, 20°C to 30°C.

[0180] In the examples, thin layer chromatography (TLC) was used to monitor the progress of the reaction. The developing solvents used in the reaction, the eluent system of column chromatography for purifying the compounds, and the developing solvent system of thin layer chromatography included A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system, and D: petroleum ether / ethyl acetate / methanol. The volume ratio of the solvents was adjusted according to the polarity of the compounds, and may be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.

[0181] The abbreviations used in the following experiments have the following meanings:

[0182] TFA: trifluoroacetic acid, DCM: dichloromethane, m-CPBA: m-metachloroperbenzoic acid, EtONa: sodium ethanol, Boc: tert-butoxycarbonyl group, MeOH: methanol, HBTU: benzotriazazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, TsOH: p-toluenesulfonic acid, EtOAc: ethyl acetate, t-BuOH: tert-butanol, PdCl2 (TPP) 2: Dichlorobis(triphenylphosphine)palladium dichloride, XantPhos: 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene, Pd2dba3: tridibenzylideneacetonedipalladium, PdCl2(TPP) 2: Dichlorobis(triphenylphosphine)palladium dichloride, XantPhos: 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene, Pd2dba3: tridibenzylideneacetonedipalladium, DMF: N,N-dimethylformamide, CDI: N,N-carbonyldiimidazole, ACN: acetonitrile, DMP: Dess-Martin oxidant, DMAP: 4-dimethylaminopyridine.

[0183] Example 1 (3S,4S-3-(3-ethynylphenyl)-1-methylpiperidin-4-yl)((R)-6-methyl-2-(((1-methyl-1H-pyrazol-3-yl)methyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)methanone, (3R,4R)-3-(3-ethynylphenyl)-1-methylpiperidin-4-yl)((R)-6-methyl-2-(((1-methyl-1H-pyrazol-3-yl)methyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)methanone [ka] Step 1 Preparation of Compound 1c Under a N2 atmosphere, Na2CO3 (198 mL, 1 M, 198 mmol) and Pd(PPh3)2Cl2 (6.96 g, 9.92 mmol) were added to a solution of compound 1a (40.0 g, 99.2 mmol) and 1b (32.6 g, 149 mmol) in 1,4-dioxane (400 mL). o The mixture was heated to 100°C and stirred for 12 hours. The reaction mixture was filtered, and the filtrate was added with water (150 mL) and extracted with EtOAc (600 mL). The combined organic phases were dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography on silica gel using 10-30% ethyl acetate in petroleum ether as an eluent to give compound 1c (90.0 mg, 98.1% yield). 1 H NMR (400 MHz, DMSO-d6) δ7.11 - 6.97 (m, 1H), 6.57 (d, J = 8.0 Hz, 1H), 6.41 (s, 1H), 6.34 (d, J = 7.2 Hz, 1H), 5.15 (s, 2H), 4.09 (s, 2H), 3.92 (q, J = 7.2 Hz, 2H), 2.44 (s, 2H), 1.49 (s, 9H), 0.92 (t, J = 7.2 Hz, 3H).

[0184] Step 2 Preparation of Compound 1d Compound 1c (35.0 g, 101 mmol), Pd / C (10%, 24.0 g), and EtOH (400 mL) were added to a reaction flask at room temperature under a N2 atmosphere. The atmosphere was replaced with H2 three times, and the reaction solution was heated under a H2 (50 psi) atmosphere for 50 minutes. o The mixture was stirred for 12 hours under C. The reaction mixture was filtered, and the filtrate was concentrated to give crude product 1d (30.0 g, 86.1 mmol, 92.6%).

[0185] Step 3 Preparation of compound 1e 0 o Under C, a solution of 1d (10.0 g, 28.7 mmol) in CH3CN (100 mL) was added to an aqueous solution (7 mL) of TsOH (11.0 mL, 71.7 mmol), and the reaction mixture was stirred for 0.5 h. o The mixture was maintained at 10°C, and an aqueous solution of NaNO (2.30 mL, 43.0 mmol) was added thereto, and an aqueous solution (7.0 mL) of KI (2.35 mL, 43.0 mmol) was slowly added dropwise. After the addition was completed, the mixture was warmed to room temperature and stirred for 16 hours. Water was added to the reaction mixture, which was then extracted with EtOAc (300 mL x 3). The organic phase was dried over NaSO and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography on silica gel using 10-30% ethyl acetate in petroleum ether as eluent to give compound 1e (8.0 g, 17.4 mmol, 60.7% yield).

[0186] Step 4 Preparation of compound 1f Compound 1e (3.00 g, 6.53 mmol), trimethylsilylacetylene (21.4 mL, 150 mmol), CuI (0.111 mL, 3.26 mmol), and Pd(DTBPF)Cl (2.13 g, 3.266 mmol) were added to DMF (60 mL) under a N2 atmosphere, and the reaction mixture was cooled to 110°C. oThe mixture was heated to 200°C and stirred for 12 hours. Water (260 mL) was added to the reaction mixture, extracted with EtOAc (50 mL × 3), the organic phases were combined, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by flash column chromatography on silica gel using 1-5% ethyl acetate in petroleum ether as an eluent to give compound 1f (2.06 g, 2.88 mmol, 44.1% yield).

[0187] Step 5 Preparation of Compound 1g To a solution of compound 1f (1.00 g, 2.33 mmol) in 20 mL of EtOAc under a N atmosphere, HCl / EtOAc (15 mL) was added and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give crude product 1g (900 mg). To this was dissolved 60 mL of DCM, NaOAc (0.305 mL, 3.28 mmol), formaldehyde (399 mg, 4.92 mmol), and the mixture was stirred at room temperature for 1 h. NaBH(OAc) (1440.2 mg, 6.83 mmol) was added. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was washed once with 20 mL of 10% NaHCO, dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure to give crude product. The crude product was isolated and purified by preparative HPLC (column: Waters Xbridge BEH C18250*50mm*10μM, mobile phase: [water (NH4HCO3)-CH3CN], B%: 65%-90%) to obtain compound 1h (400mg, 1.07mmol, yield 39.2%). MS m / z (ESI): 344.2 [M+H] + .

[0188] Step 6 Preparation of intermediate 1j At room temperature, EtONa (0.456 mL, 5.822 mmol) was added to a solution of compound 1h (400 mg, 1.164 mmol) in EtOH (30 mL). oThe temperature was gradually raised to 10°C, and the mixture was stirred for 5 hours. The reaction mixture was then concentrated under reduced pressure to give crude product 1i. At room temperature, crude product 1i was added to a mixture of EtOH (15 mL) and HO (15 mL), and NaOH (118 mg, 2.95 mmol) was added. The mixture was stirred for 12 hours. The reaction mixture was then concentrated under reduced pressure to give crude product 1i. The crude product was isolated and purified by preparative HPLC (column: Phenomenex Luna C1875*30 mm*3 μM, mobile phase: [water (FA)-CHCN], B%: 65%-90%) to give compound 1j (150 mg, 0.555 mmol, 37.6%). MS m / z (ESI): 244.2 [M+H] + .

[0189] Step 7 Preparation of compound 1l DMF-DMA (12.3 g, 103 mmol, 13.7 mL, 2.00 eq) was slowly added dropwise to a solution of compound 1k (11.0 g, 51.6 mmol, 1.00 eq) in DMF (50 mL) at room temperature, and the reaction mixture was heated to 90°C. o The mixture was warmed to C and stirred for 18 h, water (150 mL) was added to the reaction mixture, and extracted with EtOAc (100 mL x 3). The organic phases were combined, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give crude product 1L (12 g). MS m / z (ESI): 269.1 [M+H] + .

[0190] Step 8 Preparation of Compound 1m Compound 1l (12.0 g, 44.7 mmol) and 2-methylisothiourea sulfate (24.9 g, 89.4 mmol, 2.00 eq) were dissolved in EtOH (200 mL) at room temperature, and EtONa (6.69 g, 98.4 mmol) was slowly added. The reaction mixture was heated to 90 °C and stirred for 12 h. The mixture was then cooled to room temperature, and HO (150 mL) was added. EtOAc (60 mL × 5) was added. The combined organic phases were dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography on silica gel using 10–30% ethyl acetate in petroleum ether as the eluent to give compound 1m (6.20 g, 21.0 mmol, 46.9% yield). MS m / z(ESI): 296.1 [M+H] + .

[0191] Step 9 Preparation of intermediate 1n 0 o Under C, m-CPBA (10.3 g, 50.7 mmol) was added to a solution of compound 1m (5.00 g, 17.0 mmol) in DCM (100 mL), and the mixture was stirred for 2 hours. The reaction mixture was then warmed to room temperature and stirred for 10 hours. o The temperature was lowered to C, and Na2SO3 (10%, 40 mL) was added to the reaction mixture, which was then extracted with DCM (30 mL x 3). The organic phases were combined, washed once with saturated brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography on silica gel using 10-30% ethyl acetate in petroleum ether as eluent to give compound 1n (2.7 g, 8.25 mmol, 48.7% yield). MS m / z (ESI): 328.1 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 5.08 ,5.02 (m, 1H), 4.82 (s, 1H), 4.33 - 4.27 (m, 1H), 3.29 (s, 3H), 3.13-3.06 (m, 1H), 2.67-2.63 (m, 1H), 1.45 (s, 9H), 1.05 -1.03 (m, 3H). Compound 1n was separated by chiral column separation (column: Chiralcel OD-3, 150 × 4.6 mm ID, 3 μM) using a mobile phase of A: supercritical CO2 fluid and B: methanol (0.1% IPAm, v / v) to give 1n-1 and 1n-2. Compound 1n-1 (retention time 2.770 min) MS m / z(ESI): 328.1 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 5.08 - 5.03 (m, 1H), 4.82 (br s, 1H), 4.32 - 4.27 (m, 1H), 3.29 (s, 3H), 3.13-3.06 (m, 1H), 2.67-2.63 (m, 1H), 1.43 (s, 9H), 1.05 -1.03 (m, 3H). Compound 1n-2 (retention time 2.469 min).

[0192] Step 10 Preparation of intermediate 1p At room temperature, 10 (380 mg, 3.42 mmol) was added to a solution of compound 1n-1 (140 mg, 0.428 mmol) in t-BuOH (2 mL). o The reaction mixture was heated to 200°C, stirred for 12 hours, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel using 1-5% ethyl acetate in petroleum ether as an eluent to give compound 1p (100 mg, 0.279 mmol, 45.7%). MS m / z (ESI): 359.1[M+H] + .

[0193] Step 11 Preparation of Compound 1 To a DCM solution of compound 1p (100 mg, 0.279 mmol), TFA (0.8 mL, 10.8 mmol) was added at room temperature and stirred for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure to give crude product 1q (96.0 mg, 0.186 mmol, 66.6%). MS (ESI): m / z =259.1 [M+H] + . Intermediate 1j (90.0 mg, 0.37 mmol) was added to DMF (3 mL) at room temperature. HBTU (421 mg, 1.11 mmol), DIEA (0.31 mL, 1.85 mmol), and crude product 1q (95.6 mg, 0.370 mmol) were added to the reaction mixture and stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to give crude product 1, which was isolated and purified by preparative HPLC (column: Phenomenex Luna C1875*30 mm*3 μM, mobile phase: [(NH4HCO3)-CH3CN], B%: 65%-90%) to give compound 1-1 (17.4 mg, 0.036 mmol, 9.18%) and compound 1-2 (17.0 mg, 0.035 mmol, 9.50%). Compound 1-1 MS (ESI): m / z =484.3 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ: 8.06-7.90 (m, 1H), 7.56 - 7.17 (m, 4H), 6.93-6.87 (m, 1H), 6.95 - 6.16 (m, 1H), 4.64-4.44 (m, 4H), 3.88-3.84 (m, 3H), 3.57-3.35 (m, 2H), 3.17 - 2.86 (m, 4H), 2.80-2.50 (m, 3H), 2.45- 2.22 (m, 5H), 2.18-2.04 (m, 1H), 1.96-1.87 (m, 1H), 1.03-0.78 (m, 3H). Compound 1-2 MS m / z (ESI): 484.3 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ: 8.06-7.92 (m, 1H), 7.55-7.17 (m, 5H), 6.25-6.15 (m, 1H), 4.73-4.51 (m, 4H), 3.90-3.83 (m, 4H), 3.46-3.45 (m, 1H), 3.04-2.71 (m, 6H), 2.45-2.25 (m, 5H), 2.17-1.86 (m, 3H), 1.15 -0.06 (m, 3H).

[0194] Example 2 (R)-N-((S)-2-(dimethylamino)-1-phenylethyl)-6-methyl-2-(((1-methyl-1H-pyrazol-3-yl)-methyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide [ka] Step 1 Preparation of Compound 2 Compound 2a (57.2 mg, 348 μmol) and N,N-carbonyldiimidazole (75.3 mg, 464 μmol) were dissolved in tetrahydrofuran, and triethylamine (1.16 mmol, 162 μL) was added to the solution, followed by stirring at room temperature for 0.5 hours. Compound 1q (60.0 mg, 232 μmol, synthesis of the compound described in Example 1) was added to the reaction solution, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to obtain crude product 2, which was isolated and purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μM, mobile phase: [water(NH4HCO3)-ACN], B%: 10%-40%) to obtain compound 2 (11.8 mg, 25.2 μmol, yield 10.8%). MS m / z (ESI): 449.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6):δ: 8.10 (s, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.39 - 7.25 (m, 4H), 7.23 - 7.10 (m, 2H), 6.78 (d, J = 7.6 Hz, 1H), 6.10 (d, J = 2.0 Hz, 1H), 4.93 - 4.83 (m, 1H), 4.72 - 4.55 (m, 2H), 4.47 - 4.34 (m, 2H), 3.96 (d, J = 18.4 Hz, 1H), 3.77 (s, 3H), 2.77 (dd, J = 5.4, 15.2 Hz, 1H), 2.69 - 2.59 (m, 1H), 2.42 (d, J = 15.2 Hz, 1H), 2.34 (dd, J = 5.9, 12.0 Hz, 1H), 2.17 (s, 6H), 0.94 (d, J = 6.8 Hz, 3H).

[0195] Example 3 (S)-N-((S)-2-(dimethylamino)-1-phenylethyl)-6-methyl-2-(((1-methyl-1H-pyrazol-3-yl)-methyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide [ka] Step 1 Preparation of Compound 3a To a solution of compound 1n-2 (200 mg, 0.611 mmol) in t-BuOH (2 mL) was added 1o (543 mg, 4.89 mmol) at room temperature. o The reaction mixture was heated to 200°C, stirred for 12 hours, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel using 1-5% ethyl acetate in petroleum ether as an eluent to give compound 3a (150 mg, 0.418 mmol, 68.51% yield). MS m / z (ESI): 359.2 [M+H] + .

[0196] Step 2 Preparation of Compound 3 To a solution of compound 3a (150 mg, 0.139 mmol) in DCM was added TFA (1 mL) at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure to give crude product 3b (80.0 mg, 0.135 mmol). MS m / z (ESI): 259.1 [M+H] + . Compound 2a (0.102 mL, 0.609 mmol) and N,N-carbonyldiimidazole (75.3 mg, 465 μmol) were dissolved in tetrahydrofuran, and triethylamine (118 mg, 1.16 mmol, 162 μL) was added to the solution, followed by stirring at room temperature for 0.5 h. Compound 3b (60.0 mg, 232 μmol) was added to the reaction mixture, which was then stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure to give crude product 3, which was isolated and purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μM, mobile phase: [water(NH4HCO3)-ACN], B%: 10%-40%) to give compound 3 (44.4 mg, 98.9 μmol, yield 42.6%). MS m / z (ESI): 449.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6):δ: 8.09 (s, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.34 - 7.30 (m, 2H), 7.30 - 7.25 (m, 2H), 7.22 - 7.12 (m, 2H), 6.77 (d, J = 7.2 Hz, 1H), 6.10 (d, J = 2.0 Hz, 1H), 4.93 - 4.82 (m, 1H), 4.70 - 4.59 (m, 2H), 4.45 - 4.37 (m, 2H), 3.93 (d, J = 18.0 Hz, 1H), 3.76 (s, 3H), 2.80 - 2.60 (m, 2H), 2.34 (dd, J = 6.0, 12.0 Hz, 2H), 2.17 (s, 6H), 0.95 (d, J = 6.8 Hz, 3H).

[0197] Example 4 8-Fluoro-3-methyl-7-(((1-methyl-1H-pyrazol-3-yl)methyl)amino)-3,4-dihydro-2,6-naphthyridin-2(1H)-yl)((3R,4R)-1-methyl-3-phenylpiperidin-4-yl)methanone [ka] Step 1 Preparation of compound 4b Compound 4a (5 g, 23.7 mmol) was dissolved in tetrahydrofuran and cooled to -78 °C. n-Butyllithium (11.4 mL, 28.5 mmol) was slowly added dropwise to the solution, and the mixture was stirred at -78 °C for 2 hours. Saturated ammonium chloride solution was slowly added to quench the reaction, followed by extraction, drying, and concentration to obtain the crude product. The crude product was isolated by normal phase chromatography to obtain the title compound 4b (4.5 g, 79% yield).

[0198] Step 2 Preparation of compound 4c Compound 4b (4.5 g, 18.873 mmol) was dissolved in N,N-dimethylformamide, and PdCl(TPP) (0.28 g, 0.47 mmol), cuprous iodide (90 mg, 0.47 mmol), triethylamine (6.5 mL, 47.2 mmol), and propyne (22.6 mL, 22.6 mmol) were added. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction mixture was extracted, concentrated, and dried. The resulting crude product was purified by normal phase chromatography to give 4c (2.6 g, 69% yield).

[0199] Step 3 Preparation of compound 4d Compound 4c (2.6 g, 13.2 mmol) was dissolved in toluene, and then p-toluenesulfonic acid (450 mg, 2.6 mmol) and tert-butylamine (7 mL, 65.8 mmol) were added. The reaction mixture was reacted at 90°C for 12 hours. The reaction mixture was extracted, concentrated, and dried. The resulting crude product was purified by normal phase chromatography to give 4d (1.3 g, 50% yield). MS m / z (ESI): 197.1 [M+H] + .

[0200] Step 4 Preparation of compound 4e Compound 4d was dissolved in acetonitrile, and then benzyl bromide was added. The reaction mixture was reacted at 80°C for 12 hours. After cooling to room temperature, diethyl ether was added to the reaction mixture. After filtration, washing, and drying, the crude product 4e was obtained, which could be used directly in the next reaction. MS m / z (ESI): 287.1 [M+H] + .

[0201] Step 5 Preparation of compound 4f Compound 4e was dissolved in methanol, and solid sodium borohydride was slowly added. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted, concentrated, and dried. The crude product was purified by normal phase chromatography to give 4f (0.4 g, 30% yield). MS m / z (ESI): 291.1 [M+H] + .

[0202] Step 6 Preparation of Compound 4g Compound 4f (130 mg, 0.45 mmol) was dissolved in 1,2-dichloroethane, and potassium carbonate was then added. The reaction mixture was heated under reflux for 3 hours. After filtration and concentration, an oily crude product was obtained. The crude product was dissolved in methanol and heated under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by normal phase chromatography to obtain compound 4g (70 mg, 78%). MS m / z (ESI): 201.1 [M+H] + .

[0203] Step 7 Preparation of compound 4h 1-Methyl-3-phenylhexahydropyridine-4-carboxylic acid (76.5 mg, 0.35 mmol) and N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (396.9 mg, 1.05 mmol) were dissolved in N,N-dimethylformamide and stirred for 10 min. N,N-diisopropylethylamine (193 μL, 1.05 mmol) and compound 4g were added. The reaction mixture was purified by preparative HPLC (Waters Xbridge Prep OBD C18 150*40 mm*10 μM column, mobile phase: [water(NH4HCO3)-ACN], B%: 10%-40%, 8 min) to give compound 4h (9 mg, 6% yield). MS m / z (ESI): 402.1 [M+H] + .

[0204] Step 8 Preparation of Compound 4 Compound 4h (9 mg, 0.022 mmol), (1-methyl-1H-pyrazol-3-yl)methanamine (4.98 mg, 0.045 mmol), XantPhos (0.65 mg, 0.001 mmol), Pd2dba3 (1.02 mg, 0.001 mmol), and potassium phosphate (14.26 mg, 0.067 mmol) were dissolved in dioxane under a nitrogen atmosphere and reacted in a microwave oven at 120 °C for 1 hour. The reaction mixture was cooled to room temperature, filtered, and the filtrate was collected, concentrated under reduced pressure, and then purified by normal phase chromatography to give the title compound 4 (2 mg, 18% yield). MS m / z (ESI) 478.2 [M+H] + .

[0205] Example 5 (R)-N-((S)-2-(dimethylamino)-1-phenylethyl)-6-methyl-2-(((R)-1-phenylethyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide [ka] Step 1 Preparation of Compound 5b A microwave tube was charged with t-BuOH (2 mL), compound 1n-1 (100 mg, 0.31 mmol), and 5a (0.39 mL, 3.05 mmol), and the mixture was microwave-reacted under nitrogen gas protection for 8 hours. The reaction mixture was concentrated, and the resulting crude product was isolated by reverse-phase column chromatography (0-100% water / acetonitrile) to give the target compound 5b (89 mg, 79% yield). MS m / z (ESI): 369.3 [M+H] + .

[0206] Step 2 Preparation of Compound 5c Compound 5b (89 mg, 0.24 mmol) was dissolved in DCM (1.0 mL), and TFA (0.18 mL, 2.4 mmol) was slowly added dropwise thereto. The mixture was stirred at room temperature for 7 hours, diluted with water, neutralized with KCO, extracted with DCM, and the organic phases were combined, dried over anhydrous NaSO, filtered, and the filtrate was concentrated to dryness. The crude product of target compound 5c obtained was used directly in the next reaction. MS m / z (ESI): 269.2 [M+H] + .

[0207] Step 3 Preparation of Compound 5 2a (30 mg, 0.18 mmol) was dissolved in DMF (0.5 mL), CDI (60 mg, 0.37 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. EtN (76 μL, 0.55 mmol) and compound 5b (34.3 mg, 0.13 mmol) were added sequentially, and the mixture was allowed to react at room temperature overnight. The reaction mixture was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μM, mobile phase: [water(NH4HCO3)-ACN]) to give compound 5 (20 mg, 23.9% yield). MS m / z (ESI): 459.4 [M+H] + . 1H NMR (400 MHz, CD3OD):δ 8.02 (s, 1H), 7.42 - 7.34 (m, 6H), 7.32 - 7.24 (m, 3H), 7.20 - 7.14 (m, 1H), 5.26 (dd, J = 11.4, 4.0 Hz, 1H), 5.11 (q, J = 6.9 Hz, 1H), 4.79 - 4.68 (m, 2H), 4.07 (d, J = 18.3 Hz, 1H), 3.37 - 3.33 (m, 1H), 3.06 (dd, J = 13.0, 4.1 Hz, 1H), 2.84 (dd, J = 15.6, 5.6 Hz, 1H), 2.73 (s, 6H), 2.48 (d, 16H), 1.50 (d, J = 7.0 Hz, 3H), 1.01 (d, 7.2 Hz, 3H).

[0208] Example 6 (R)-N-((S)-2-(dimethylamino)-1-phenylethyl)-6-methyl-2-(((S)-1-(pyridin-2-yl)ethyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide [ka] Step 1 Preparation of Compound 6b Compound 1n-1 (100 mg, 0.31 mmol) and 6a (0.37 mL, 3.05 mmol) were added to a microwave tube containing t-BuOH (2.0 mL), and the mixture was subjected to a microwave reaction under nitrogen gas protection for 5 hours. The reaction mixture was concentrated and isolated by reverse-phase column chromatography (0-100% water / acetonitrile) to give target compound 6b (97.9 mg, 86.8% yield). MS m / z (ESI): 370.3 [M+H] + .

[0209] Step 2 Preparation of Compound 6c Compound 6b (97.9 mg, 0.27 mmol) was dissolved in DCM (1.0 mL), and TFA (0.19 mL, 2.6 mmol) was slowly added dropwise thereto. The mixture was stirred at room temperature for 7 hours, diluted with water, neutralized with KCO, extracted with DCM, and the organic phases were combined, dried over anhydrous NaSO, filtered, and the filtrate was concentrated to dryness. The crude product of the target compound 6c obtained was used directly in the next reaction. MS m / z (ESI): 270.2 [M+H] + .

[0210] Step 3 Preparation of Compound 6 2a (30 mg, 0.18 mmol) was dissolved in DMF (0.5 mL), CDI (60 mg, 0.37 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. EtN (76 μL, 0.55 mmol) and compound 6c (34.4 mg, 0.13 mmol) were added sequentially, and the mixture was allowed to react overnight at room temperature. The reaction mixture was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μM, mobile phase: [water(NH4HCO3)-ACN]) to give compound 6 (40 mg, 47.7% yield). MS m / z (ESI): 460.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): 1H NMR (400 MHz, ) δ 8.50 (d, J = 4.4 Hz, 1H), 8.08 (s, 1H), 7.71 (td, J = 7.7, 1.8 Hz, 1H), 7.41 - 7.38 (m, 2H), 7.36 - 7.26 (m, 4H), 7.23 - 7.18 (m, 2H), 6.83 (d, J = 7.7 Hz, 1H), 5.12 (p, J = 7.1 Hz, 1H), 4.92 - 4.84 (m, 1H), 4.68 - 4.48 (m, 2H), 3.94 (d, J = 18.8 Hz, 1H), 2.77 - 2.64 (m, 2H), 2.44 - 2.35 (m, 2H), 2.19 (s, 6H), 1.45 (d, J = 7.0 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H).

[0211] Example 7 (R)-2-((2,3-dihydro-1H-inden-2-yl)-amino)-N-((S)-2-(dimethylamino)-1-phenylethyl)-6-methyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide [ka] The preparation of compound 7 was carried out according to the synthesis method in Example 5. Compound 7 (35 mg, 40.7% yield) was obtained from starting material 1 (100 mg, 0.31 mmol) and 7a (414.5 mg, 2.44 mmol) through a three-step reaction. The crude product, compound 7, was isolated and purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μM, mobile phase: [water(NH4HCO3)-ACN]). MS m / z (ESI): 471.4 [M+H] + . 1H NMR (400 MHz, CD3OD): δ 8.09 (s, 1H), 7.42 - 7.35 (m, 4H), 7.32 - 7.27 (m, 1H), 7.22 - 7.16 (m, 2H), 7.15 - 7.10 (m, 2H), 5.27 (dd, J = 11.4, 4.0 Hz, 1H), 4.82 - 4.64 (m, 3H), 4.17 (d, J = 18.2 Hz, 1H), 3.35 - 3.32 (m, 2H), 3.28 (s, 1H), 3.07 (dd, J = 13.0, 4.1 Hz, 1H), 2.93 - 2.85 (m, 3H), 2.73 (s, 6H), 2.53 (d, 15.6 Hz, 1H), 1.07 (d, J = 6.8 Hz, 3H).

[0212] Example 8 (R)-N-((S)-2-(ethyl(methyl)amino)-1-phenylethyl)-6-methyl-2-(((1-methyl-1H-pyrazol-3-yl)methyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide [ka] Step 1 Preparation of Compound 8c HBTU (1.33 g, 3.51 mmol) and K2CO3 (1.45 g, 10.52 mmol) were added to DCM (30 mL) containing 8a (1 g, 3.51 mmol), and the mixture was allowed to react at room temperature for 0.5 hours. 8b (0.5 g, 5.26 mmol) was added to the reaction mixture, and the resulting mixture was stirred for 40 minutes. o The reaction was allowed to proceed overnight at C. After completion of the reaction, the mixture was cooled to room temperature, filtered, and concentrated. The crude product was isolated by column chromatography (0-100% petroleum ether / ethyl acetate) to give the target compound 8c (973 mg, yield 85.1%). MS m / z (ESI): 327.2 [M+H] + .

[0213] Step 2 Preparation of Compound 8d Compound 8c (973 mg, 2.98 mmol) was dissolved in ethyl acetate (10 mL), and 10% Pd / C (300 mg) was added under nitrogen gas protection. The mixture was purged with H three times and reacted at room temperature for 6 hours under a H atmosphere. The mixture was filtered through Celite, and the filtrate was concentrated to give crude product, compound 8d, which was used directly in the next reaction. MS m / z (ESI): 193.2 [M+H] + .

[0214] Step 3 Preparation of compound 8e Under a nitrogen atmosphere, THF (6.0 mL) and LiAlH (4.7 mL, 1 M, THF) were sequentially added to a dry three-neck flask. The reaction mixture was placed in a dry ice-ethanol bath at -78 °C. Compound 8d (400 mg, 2.08 mmol) in THF (2 mL) was slowly added dropwise and refluxed overnight. After the addition, the reaction mixture was cooled to room temperature and placed in an ice bath. 0.5 mL of water and 0.2 mL of 15% NaOH solution were added sequentially. The mixture was dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The crude product was isolated by reverse-phase column chromatography (0-100% water / acetonitrile) to give 8e (177 mg, 47.7% yield) as a yellow liquid. MS m / z (ESI): 179.2 [M+H] + .

[0215] Step 4 Preparation of Compound 8 Compound 8e (30 mg, 0.17 mmol) was dissolved in DMF (0.5 mL), CDI (54.6 mg, 0.34 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. EtN (7 μL, 0.51 mmol) and compound 5d (30.4 mg, 0.12 mmol) were added, and the mixture was allowed to react overnight at room temperature. The reaction mixture was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μM, mobile phase: [water(NH4HCO3)-ACN]) to give compound 8 (20 mg, 25.7% yield). MS m / z (ESI): 463.4 [M+H]+ . 1 H NMR (400 MHz, ) δ 8.08 (s, 1H), 7.49 - 7.36 (m, 6H), 7.32 - 7.29 (m, 1H), 6.19 (d, J = 2.2 Hz, 1H), 5.41 - 5.34 (m, 1H), 4.82 - 4.73 (m, 2H), 4.53 (s, 2H), 4.14 (d, J = 18.2 Hz, 1H), 3.82 (s, 3H), 3.57 - 3.47 (m, 1H), 3.28 - 3.09 (m, 3H), 2.90 - 2.86 (s, 4H), 2.54 - 2.50 (m, 1H), 1.32 (t, J = 7.3 Hz, 3H), 1.06 (d, J = 7.0 Hz, 3H).

[0216] Example 9 (R)-N-((S)-2-(dimethylamino)-1-phenylethyl)-6-methyl-2(((S)-1-phenylethyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide [ka] For the preparation of Compound 9, refer to the synthesis method of Compound 5. Compound 9 (12 mg, 0.026 mmol) was obtained from the starting material 1n-1 (100 mg, 0.306 mmol) through a three-step reaction. MS m / z (ESI): 471.4 [M+H] + . 1H NMR (400 MHz, CD3OD): δ 8.03 (s, 1H), 7.37 - 7.25 (m, 8H), 7.24 - 7.14 (m, 2H), 5.13 (q, J = 7.0 Hz, 1H), 5.01 (dd, J = 10.7, 4.4 Hz, 1H), 4.77 - 4.69 (m, 1H), 4.66 (d, J = 18.3 Hz, 1H), 4.11 (d, J = 18.3 Hz, 1H), 2.91 - 2.78 (m, 2H), 2.48 (dd, J = 15.5, 1.7 Hz, 1H), 2.41 (dd, J = 12.8, 4.5 Hz, 1H), 2.30 (s, 6H), 1.51 (d, J = 7.0 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H).

[0217] Example 10 N-((S)-2-(dimethylamino)-1-phenylethyl)-6-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide [ka] Step 1 Preparation of Compound 10c Under nitrogen gas protection, DIPEA (1.63 mL, 9.89 mmol) and 10a (500 mg, 4.94 mmol) were added sequentially to a solution of 10b (1.09 g, 7.42 mmol) in DMF (3.0 mL). The mixture was allowed to react at room temperature for 48 h. The reaction mixture was concentrated, and the crude product was isolated by reverse-phase column chromatography (mobile phase: [water(NH4OH)-ACN]) to give the target compound 10c (400 mg, 56.5% yield). MS m / z (ESI): 144.2 [M+H] + .

[0218] Step 2 Preparation of Compound 10d Compound 10c (346.8 mg, 2.42 mmol) and compound 1l (500 mg, 1.86 mmol) were dissolved in EtOH (10 mL), and EtONa (279 mg, 4.1 mmol) was added thereto. o The reaction mixture was heated to 10°C and reacted overnight. The reaction mixture was cooled to room temperature, diluted with water, extracted three times with DCM, and the organic phases were combined, dried over anhydrous NaSO, filtered, and the filtrate was concentrated and isolated by reverse-phase column chromatography (mobile phase: [water(NHOH)-ACN]) to give target compound 10d (258 mg, yield 39.7%). MS m / z (ESI): 349.2 [M+H] + .

[0219] Step 3 Preparation of Compound 10e Compound 10d (258 mg, 0.74 mmol) was dissolved in a mixture of 1,4-dioxane and MeOH (4 mL, 3:1), and then a solution of hydrochloric acid in dioxane (1.8 mL, 4 M) was slowly added dropwise thereto. The mixture was allowed to react overnight at room temperature, diluted with water, neutralized with K2CO3 solution, and extracted three times with DCM. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to dryness to obtain crude product compound 10d, which was used directly in the next reaction. MS m / z (ESI): 249.2 [M+H] + .

[0220] Step 4 Preparation of Compound 10 To a solution of 2a (108 mg, 0.66 mmol) in DMF (3 mL), CDI (213.2 mg, 1.32 mmol) was added and stirred at room temperature for 5 min. EtN (0.27 mL, 1.97 mmol) and compound 10d (114.3 mg, 0.46 mmol) were added sequentially and the mixture was allowed to react overnight at room temperature. The reaction mixture was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μM, mobile phase: [water(NH4HCO3)-ACN]) to give compound 10 (80 mg, 27.7% yield). MS m / z (ESI): 439.3 [M+H] + 。 After separation by a chiral column (column: DAICEL ChiralPak IC (250×30 mm, 10 μm), mobile phase: A: supercritical CO2 fluid, B: ethanol (0.1% NH3H2O)), compounds 10-1 and 10-2 having the following structures were obtained:

Chemical formula

[0221] Example 11 (R)-N-((R)-2-(dimethylamino)-1-phenylethyl)-6-methyl-2-(((1-methyl-1H-pyrazol-3-yl)-methyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide [ka] Step 1 Preparation of Compound 11 Compound 11a (9.08 mg, 0.055 mmol) and CDI (18 mg, 0.111 mmol) were dissolved in DMF (2 mL), EtN (0.023 mL, 0.166 mmol) was added to the solution, and the mixture was stirred at room temperature for 0.5 hours. Compound 1q (10 mg, 0.039 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was purified by preparative HPLC to give compound 11 (5.0 mg, 0.011 mmol). MS m / z (ESI): 449.38 [M+H] + . 1H NMR (400 MHz, CD3OD) :δ 8.05 (s, 1H), 7.52 - 7.17 (m, 6H), 6.16 (s, 1H), 5.31 (d, J = 7.8 Hz, 1H), 4.78 - 4.58 (m, 2H), 4.50 (s, 2H), 4.16 (d, J = 18.4 Hz, 1H), 3.80 (s, 3H), 3.52-3.36 (m, 1H), 3.28 (s, 1H), 3.23 - 3.12 (m, 1H), 2.81 (s, 7H), 2.49 (d, J = 15.6 Hz, 1H), 1.05 (d, J = 6.8 Hz, 3H).

[0222] Example 12 (R)-N-((S)-2-(hexadeuterated dimethylamino)-1-phenylethyl)-6-methyl-2-(((1-methyl-1H-pyrazol-3-yl)-methyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide [ka] Step 1 Preparation of Compound 12c At room temperature, 12a (500 mg, 1.753 mmol) and HBTU (1329 mg, 3.5 mmol) were dissolved in DCM (7 mL) and stirred for 5 minutes. KCO (726 mg, 5.26 mmol) and 12b (134.4 mg, 2.63 mmol) were added. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was extracted, concentrated, and dried to give the crude product. The crude product was purified by column chromatography to give compound 12c (900 mg, 2.83 mmol). MS m / z (ESI): 319.2 [M+H] + .

[0223] Step 2 Preparation of Compound 12d Under a hydrogen gas atmosphere, 10% palladium Pd / C was added to a solution of compound 12c (900 mg, 2.83 mmol) in ethyl acetate (15 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and concentrated to give crude product 12d (260 mg). This crude product was used directly in the next reaction (260 mg). MS m / z (ESI): 185.1 [M+H] + .

[0224] Step 3 Preparation of Compound 12e Under a nitrogen gas atmosphere, LiAlH4 (82.0 mg, 2.17 mmol) was added to anhydrous THF (5.0 mL). After cooling to -78 °C, a THF solution of compound 12d was slowly added dropwise and stirred for 30 minutes. The reaction mixture was then heated to 50 °C and reacted for 2 hours, after which it was quenched by adding ammonium chloride solution. The crude product was obtained by extraction, concentration, and drying. The crude product was isolated and purified by preparative HPLC to obtain compound 12e (40.0 mg, 21% yield). MS m / z (ESI): 171.1 [M+H] + .

[0225] Step 4 Preparation of Compound 12 Compound 12e (20.0 mg, 0.094 mmol) and CDI (30 mg, 0.188 mmol) were dissolved in DMF (1.0 mL), EtN (0.039 mL, 0.282 mmol) was added to the solution, and the mixture was stirred at room temperature for 0.5 hours. Compound 1q (24.3 mg, 0.094 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was purified by preparative HPLC to give compound 12 (5.0 mg, 0.011 mmol). MS m / z (ESI): 455.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 8.10 (s, 1H), 7.53 (s, 1H), 7.38 - 7.27 (m, 4H), 7.24 - 7.16 (m, 2H), 6.86 (d, J = 7.8 Hz, 1H), 6.09 (s, 1H), 4.93 - 4.84 (m, 1H), 4.73 - 4.55 (m, 2H), 4.47 - 4.33 (m, 2H), 3.97 (d, J = 18.6 Hz, 1H), 3.76 (s, 3H), 2.81 - 2.71 (m, 2H), 2.45 - 2.39 (m, 2H), 0.93 (d, J = 6.7 Hz, 3H).

[0226] Example 13 (R)-N-((S)-1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-6-methyl-2-(((1-methyl-1H-pyrazol-3-yl)methyl)amino)5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide [ka] Step 1 Preparation of Compound 13b Compound 13a (300 mg, 1.616 mmol) was added to a THF solution of NaBH4, and the reaction mixture was cooled to 0 °C. A THF solution of I2 (451 mg, 1.78 mmol) was slowly added dropwise, and after the sample addition was completed, the mixture was allowed to react at room temperature for 2 hours. After the reaction was completed, an aqueous solution of KOH was added to quench the reaction. The crude product 13b obtained after extraction, drying, and concentration was used directly in the next reaction. MS m / z (ESI): 172.01 [M+H] + .

[0227] Step 2 Preparation of Compound 13c Di-tert-butyl dicarbonate (698.3 mg, 3.2 mmol) and EtN (485.7 mg, 4.8 mmol) were added to a solution of crude product 13b in DCM and stirred overnight at room temperature. The reaction mixture was extracted, dried, and concentrated to give the crude product, which was isolated by column chromatography to give target compound 13c (170 mg, 0.627 mmol). MS m / z (ESI): 294.09 [M+Na] + .

[0228] Step 3 Preparation of compound 13d DMP (212.07 mg, 0.5 mmol) was added to a solution of compound 13c in DCM and stirred at room temperature for 2 hours. The reaction mixture was purified by column chromatography to give target compound 13d (40 mg, 0.148 mmol).

[0229] Step 4 Preparation of Compound 13e Dimethylamine hydrochloride (57.08 mg, 0.7 mmol) was added to a methanol solution of compound 3d (40.4 mg, 0.15 mmol). After stirring at room temperature for 2 hours, NaBHCN (18.9 mg, 0.3 mmol) was slowly added and the mixture was stirred overnight at room temperature. The reaction mixture was directly purified by reverse-phase column chromatography to give compound 13e (12 mg, 0.04 mmol). MS m / z (ESI): 299.17 [M+H] + .

[0230] Step 5 Preparation of Compound 13f To a solution of compound 13e (12 mg, 0.04 mmol) in DCM (5.0 mL), excess TFA (1.0 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give a crude product, which was used directly in the next reaction. MS m / z (ESI): 199.02 [M+H] + .

[0231] Step 6 Preparation of Compound 13 Compound 13f (11.89 mg, 0.06 mmol) and CDI (19.5 mg, 0.12 mmol) were dissolved in DMF (2.0 mL), EtN (0.18 mmol) was added to the solution, and the mixture was stirred at room temperature for 0.5 hours. Compound 1q (15.5 mg, 0.06 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was purified by preparative HPLC to give compound 13 (2.0 mg, 0.004 mmol). MS m / z (ESI): 483.28 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 8.44 (s, 1H), 8.10 (s, 1H), 7.49 - 7.42 (m, 2H), 7.40 - 7.28 (m, 3H), 6.19 (d, J = 2.3 Hz, 1H), 5.24 (dd, J = 11.2, 4.1 Hz, 1H), 4.80 - 4.69 (m, 2H), 4.54 (s, 2H), 4.18 (d, J = 18.2 Hz, 1H), 3.84 (s, 3H), 3.25 (d, J = 12.0 Hz, 1H), 3.10 - 3.00 (m, 1H), 2.95 - 2.85 (m, 1H), 2.72 (s, 6H), 2.54 (dd, J = 15.6, 1.9 Hz, 1H), 2.03 (q, J = 6.4 Hz, 1H), 1.12 - 1.04 (m, 3H).

[0232] Example 14 (R)-N-((S)-2-(dimethylamino)-1-phenylethyl)-6-methyl-2-(((1-trideuteromethyl-1H-pyrazol-3-yl)methyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide [ka] Step 1 Preparation of Compound 14b To a solution of compound 14a (1.99 g, 15.8 mmol) and cesium carbonate (10.3 g, 31.7 mmol) in DMF (15.0 mL), CD3I (2.75 g, 19.0 mmol) was slowly added and the mixture was stirred at room temperature for 2 h. The reaction mixture was extracted, dried, and concentrated to give a crude product, which was isolated by column chromatography to give compound 14b (1.04 g, 7.26 mmol, 45% yield). MS m / z (ESI): 144.07 [M+H] + .

[0233] Step 2 Preparation of Compound 14c Compound 14b (1.04 g, 7.26 mmol) was dissolved in aqueous ammonia and stirred at room temperature for 4 hours. The reaction solution was dried under reduced pressure to give crude product 14c, which was used directly in the next reaction. MS m / z (ESI): 129.00 [M+H] + .

[0234] Step 3 Preparation of Compound 14d Under a nitrogen gas atmosphere, LiAlH4 (212.5 mg, 5.6 mmol) was added to anhydrous THF (5.0 ml). After cooling to -78 °C, a THF solution of compound 14c (2.8 mmol) was slowly added dropwise and stirred at the same temperature for 30 minutes. The reaction mixture was then reacted at 50 °C for 12 hours. After completion of the reaction, the mixture was quenched by adding an ammonium chloride solution. The crude product 14d obtained after extraction, concentration, and drying was used directly in the next reaction. MS m / z (ESI): 114.99 [M+H] + .

[0235] Preparation of Compound 14 Referring to the synthesis in Example 5, compound 14 (2 mg, 0.0044 mmol) was synthesized and prepared from compound 14d via a three-step reaction. MS m / z (ESI): 452.37 [M+H] + .

[0236] Example 15 (R)-N-((S)-2-(dimethylamino)-1-phenylethyl)-6-methyl-2-((2-methylpyridin-4-yl)amino)-5,8-dihydropyrido[3,4,-d]pyrimidine-7(6H)-carboxamide [ka] Step 1 Synthesis of compound 15c Compound 15a (50.0 g, 412.6 mmol) and compound 15b (67.3 mL, 474.5 mmol) were dissolved in DCM (500 mL) at room temperature, and NaBH(OAc) (174 g, 825 mmol) was added slowly in several portions. The mixture was stirred overnight at room temperature. The reaction mixture was extracted with DCM / MeOH (9:1, 500 × 2 mL), washed with saturated brine, and the organic phase was dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure to give crude product 15c (80 g, 249 mmol). MS m / z (ESI): 250.3 [M+H] + .

[0237] Step 2 Synthesis of compound 15e Compound 15c (80.0 g, 249 mmol) and compound 15d (31.7 mL, 320.8 mmol) were dissolved in DCM (1 L) at room temperature, and NaBH(OAc) (203 g, 962 mmol) was added slowly in several portions. The mixture was stirred at room temperature for 2 days. The reaction mixture was extracted with DCM / MeOH (9:1, 500 mL × 2), washed with saturated brine, dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel using 1-10% ethyl acetate in petroleum ether as eluent to give compound 15e (40 g, 249 mmol). MS m / z (ESI): 336.3 [M+H] + .

[0238] Step 3 Synthesis of compound 15f Compound 15e (40.0 g, 119.2 mmol) was dissolved in toluene (200 mL) at room temperature, and t-BuOK (33.5 g, 298 mmol) was added slowly in several portions. The mixture was stirred overnight at room temperature. The reaction mixture was extracted with ethyl acetate (100 mL × 2), washed with saturated brine, dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel using 1-10% ethyl acetate in petroleum ether as an eluent to give compound 15f (14 g, 48.4 mmol). MS m / z (ESI): 262.2 [M+H] + .

[0239] Step 4 Synthesis of compound 15g To a solution of 15f (14 g, 48.4 mmol) in anhydrous MeOH (200 mL) at room temperature, urea (11.6 mL, 193.5 mmol) and activated 4A MS (10 g) were added, and the mixture was heated to reflux and stirred overnight. The reaction mixture was extracted with ethyl acetate (100 mL × 2), washed with saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by C18 reverse-phase silica gel column chromatography to give compound 15g (8 g, 28 mmol). MS m / z (ESI): 272.2 [M+H] + .

[0240] Step 5 Synthesis of compound 15h Compound 15g (8 g, 28 mmol) was dissolved in POCl3 (30 mL) at room temperature, and the reaction mixture was stirred at reflux overnight. The reaction mixture was concentrated to give the crude product. The crude product was purified by flash column chromatography on silica gel using 1-20% ethyl acetate in petroleum ether as the eluent to give compound 15h (6 g, 18.6 mmol) as a white solid. MS m / z (ESI): 308.2 [M+H] + .

[0241] Step 6 Synthesis of compound 15i 15h (6 g, 18.6 mmol) and aqueous ammonia (8.0 mL) were dissolved in EtOH (100 mL) at room temperature. Activated Zn (15 g) was added, and the reaction mixture was heated to reflux and stirred overnight. The reaction mixture was extracted with ethyl acetate (100 mL × 2), washed with saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel using 1-10% ethyl acetate in petroleum ether as eluent to give compound 15i (3.5 g, 12.2 mmol) as a tan solid. MS m / z (ESI): 288.1 [M+H] + .

[0242] Step 7 Synthesis of compound 15k Compound 15i (240 mg, 0.83 mmol), compound 15j (108 mg, 1.0 mmol), Xantphos-G3-Pd (79 mg, 0.08 mmol), and CsCO (325 mg, 1.25 mmol) were dissolved in dioxane (5.0 mL) at room temperature, and the reaction mixture was heated to 100 °C under nitrogen gas protection and stirred for 4 h. The reaction mixture was concentrated to give the crude product. The crude product was purified by flash column chromatography on silica gel using 1-5% ethyl acetate in petroleum ether as the eluent to give compound 15k (100 mg, 33.4%). MS m / z (ESI): 360.3 [M+H] + .

[0243] Step 8 Synthesis of compound 15l To compound 15k (100 mg, 0.28 mmol) in MeOH (5.0 mL) at room temperature was added 10% Pd / C (50 mg), and the reaction was stirred overnight under a hydrogen gas atmosphere. The reaction was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel using 1-5% ethyl acetate in petroleum ether as the eluent to give compound 15l (60 mg, 84.5% yield). MS m / z (ESI): 256.3 [M+H] + .

[0244] Step 9 Synthesis of compound 15 To a solution of 15l (30 mg, 0.12 mmol) and compound 2a (20 mg, 0.12 mmol) in DMF (1.0 mL) was added CDI (38 mg, 0.24 mmol) and EtN (0.05 mL, 0.36 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature. The reaction mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by HPLC to give compound 15 (20 mg, 48.3%). MS m / z (ESI): 446.5 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 8.54 (s, 2H), 8.41(s, 1H), 8.25 (d, J = 6.7 Hz, 1H), 7.97 (dd, J = 6.7, 2.3 Hz, 1H), 7.92 (d, J = 2.2 Hz, 1H), 7.51 - 7.46 (m, 2H), 7.43 - 7.37 (m, 2H), 7.34 - 7.29 (m, 1H), 5.43 (dd, J = 12.1, 4.0 Hz, 1H), 5.05 - 4.97 (m, 1H), 4.91 - 4.82 (m, 1H), 4.33 (d, J = 18.6 Hz, 1H), 3.71 - 3.58 (m, 1H), 3.39 - 3.33 (m, 1H), 3.02 - 2.88 (m, 7H), 2.66 (d, J = 16.1, 1.5 Hz, 1H), 2.59 (s, 3H), 1.09 (d, J = 6.8 Hz, 3H).

[0245] Example 16 (R)-2-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)amino)-N-((S)-2-(dimethylamino)-1-phenylethyl)-6-methyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide [ka] Step 1 Synthesis of compound 16c A solution of compound 16a (1.0 g, 8.84 mmol), compound 16b (1.0 mL), and CsCO (5.7 g, 17.68 mmol) in DMF (10 mL) was stirred overnight at room temperature. The reaction mixture was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel using 1-5% ethyl acetate in petroleum ether as an eluent to give compound 16c (1.0 g, 67.6% yield).

[0246] Step 2 Synthesis of compound 16d To a solution of compound 16c (1.0 g, 6.0 mmol) in MeOH (20 mL) at room temperature, Pd / C (100 mg) was added, and the reaction was stirred overnight under a hydrogen gas atmosphere at room temperature. The reaction was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel using 1-5% ethyl acetate in petroleum ether as the eluent to give compound 16d (800 mg, 97.5% yield). MS m / z (ESI): 138.3 [M+H] + .

[0247] The synthesis of compound 16 is described in reference to compound 15. Compound 16d (33.9 mg, 0.25 mmol) was purified by a three-step reaction to give compound 16 (20.8 mg, 0.044 mmol). MS m / z (ESI): 475.4 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 8.17 (s, 1H), 8.00 (s, 1H), 7.61 (s, 1H), 7.45 - 7.32 (m, 4H), 7.28 - 7.23 (m, 1H), 5.17 (dd, J = 11.0, 4.3 Hz, 1H), 4.88 - 4.72 (m, 2H), 4.22 (d, J = 18.3 Hz, 1H), 3.94 (d, J = 7.0 Hz, 2H), 3.11 (t, J = 12.9, 11.0 Hz, 1H), 3.01 - 2.83 (m, 1H), 2.78 - 2.71 (m, 1H), 2.61 - 2.48 (m, 7H), 1.33 - 1.21 (m, 1H), 1.06 (d, J = 6.8 Hz, 3H), 0.66 - 0.53 (m, 2H), 0.48 - 0.35 (m, 2H).

[0248] Example 17 (R)-N-((S)-2-(dimethylamino)-1-phenylethyl)-6-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide [ka] Referring to the preparation method of compound 15, compound 17 (10 mg, 0.023 mmol) was obtained from compound 15i (80 mg, 0.278 mmol) by a three-step reaction. MS m / z (ESI): 435.4 [M+H] + .

[0249] Example 18 (R)-6-Methyl-2-(((1-methyl-1H-pyrazol-3-yl)methyl)amino)-N-((S)-2-(methylamino)-1-phenylethyl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide [ka] Step 1 Synthesis of compound 18b Compound 18a (1.1 g, 3.86 mmol) was dissolved in borane / tetrahydrofuran (20 mL, 20 mmol) at room temperature and stirred overnight. The reaction was quenched and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel using 1-5% ethyl acetate in petroleum ether as the eluent to give compound 18b (700 mg, 66.9% yield). MS m / z (ESI): 272.3 [M+H] + .

[0250] Step 2 Synthesis of compound 18c Compound 18a (300 mg, 1.1 mmol) was dissolved in DCM (5.0 mL) and DMP (930 mg, 2.2 mmol) was added at room temperature. The mixture was stirred for 1 h. After quenching, the reaction mixture was extracted with ethyl acetate (100 mL × 2), washed with saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel using 1-20% ethyl acetate in petroleum ether as an eluent to give compound 18c (100 mg, 33.6% yield). MS m / z (ESI): 270.3 [M+H] + .

[0251] Step 3 Synthesis of compound 18d Compound 18c (100 mg, 0.37 mmol) and methylamine hydrochloride (50 mg, 0.74 mmol) were dissolved in DCM (5 mL) at room temperature. NaBH(OAc) (235 mg, 1.1 mmol) was added slowly in several portions and stirred overnight at room temperature. The reaction mixture was extracted with DCM / MeOH (9:1, 500 mL × 2), washed with saturated brine, dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel using 1-10% ethyl acetate in petroleum ether as eluent to give compound 18c (60 mg, 56.8% yield). MS m / z (ESI): 285.3 [M+H] + .

[0252] Step 4 Synthesis of compound 18e Compound 18c (60 mg, 0.21 mmol) was dissolved in DCM (5.0 mL) and di-tert-butyl dicarbonate (69 mg, 0.32 mmol), DMAP (2 mg), and saturated Na2CO3 solution (1 mL) were added and stirred at room temperature for 1 h. The reaction mixture was extracted with ethyl acetate (100 mL × 2), washed with saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel using 1-20% ethyl acetate in petroleum ether as an eluent to give compound 18e (70 mg, 86.3% yield). MS m / z (ESI): 385.4 [M+H] + .

[0253] Step 5 Synthesis of compound 18f To a solution of compound 18e (70 mg, 0.18 mmol) in MeOH (10 mL) at room temperature, 10% Pd / C (30 mg) was added, and the reaction was stirred overnight under a hydrogen gas atmosphere at room temperature. The reaction was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel using 1-5% ethyl acetate in petroleum ether as the eluent to give compound 18f (30 mg, 65.8% yield). MS m / z (ESI): 251.5 [M+H] + .

[0254] Compound 18 was synthesized in accordance with the synthesis in Example 11, and was obtained by a two-step reaction of urea formation and Boc removal to give compound 18 (22 mg, 0.049 mmol). MS m / z (ESI): 251.5 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 8.09 (s, 1H), 7.48 - 7.46 (m, 1H), 7.41 - 7.34 (m, 4H), 7.32 - 7.26 (m, 1H), 6.19 (d, J = 2.3 Hz, 1H), 5.22 - 5.12 (m, 1H), 4.81 - 4.68 (m, 2H), 4.54 (s, 2H), 4.17 (d, J = 18.3 Hz, 1H), 3.84 (s, 3H), 3.25 - 3.13 (m, 2H), 2.95 - 2.85 (m, 1H), 2.61 (s, 3H), 2.53 (d, J = 15.8, 1.6 Hz, 1H), 1.07 (d, J = 6.8 Hz, 3H).

[0255] Example 19 (R)-N-((S)-2-Hexadeuterated dimethylamino-1-phenylethyl)-6-methyl-2-(((S)-1-(pyridin-2-yl)ethyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide [ka] Compound 19 (15 mg, 0.032 mmol) was synthesized as described in Example 6. MS m / z (ESI): 465.4 [M+H] + . 1H NMR (400 MHz, CDCl3):δ 8.49 (d, J = 4.4 Hz, 1H), 7.99 (s, 1H), 7.56 (td, J = 7.7, 1.8 Hz, 1H), 7.26 - 7.15 (m, 6H), 7.11 - 7.02 (m, 1H), 6.11 - 5.86 (m, 2H), 5.19 - 5.10 (m, 1H), 4.81 - 4.75 (m, 1H), 4.70 - 4.65 (m, 1H), 4.58 - 4.53 (d, J = 18.1 Hz, 1H), 4.08 (d, J = 18.1 Hz, 1H), 2.85 (dd, J = 15.4, 5.5 Hz, 1H), 2.70 - 2.65 (m, 1H), 2.42 - 2.32 (m, 2H), 1.49 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.7 Hz, 3H).

[0256] Biological evaluation The present disclosure will be further explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present disclosure.

[0257] Test Example 1 Test Example 1: Test of the inhibitory activity of the compounds of the present disclosure against ovarian cancer cells (OVCAR3) 1.1 Experimental materials and equipment (see Table 1) [Table 2]

[0258] 1.2 Experimental steps Ovarian cancer cells OVCAR3 were cultured in a cell incubator at 37% CO2 and 5% CO2 in RPMI 1640 medium containing 10% FBS. On the first day, cells were seeded into a 96-well plate at a cell density of 2500 cells per well and cultured overnight in the incubator. The next day, compounds were treated with 9 concentrations, including a 10 μM maximum concentration and 3-fold dilutions, with a final DMSO concentration of 0.1%. After culturing the cells in the incubator for 5 days, cell viability was tested using a Celltiter Glo assay kit (Promega). The test method was consistent with the procedure provided by the reagent kit. Data were processed using GraphPad Prism 8, and IC 50 was calculated.

[0259] The calculation formula is Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope)). X: logarithm of compound concentration, Y: % inhibition.

[0260] [Table 3]

[0261] The activity of the compounds of Examples 2, 5-10, 12-17, and 19 of the present disclosure was superior to that of Example 18.

[0262] Test Example 2 Test Example 2: Test of the inhibitory activity of compounds of the present disclosure against tumor cells 2.1 Experimental materials and equipment (see Table 3) [Table 4]

[0263] 2.2 Experimental steps Breast cancer cells MCF7 (ATCC #HTB-22) and T47D (ATCC #HTB-133), pancreatic cancer cells PANC-1 (ATCC #CRL-1469) were purchased from ATCC. Breast cancer cells MDA-MB-231 (Cell #CBP60382), HCC1806 (Cell #CBP60373), and MDA-MB-468 (Cell #CBP60387), colorectal cancer cells HCT-116 (Cell #CBP60028), and leukemia cells OCI-AML-3 (Cell #CBP60817) and MV-4-11 (Cell #CBP60522) were purchased from Nanjing Key Biotechnology Co., Ltd.

[0264] OCI-AML-3 was grown in RPMI 1640 medium with 20% FBS, HCC1806 and T47D in RPMI 1640 medium with 10% FBS, MCF7, MDA-MB-231, MDA-MB-468, and PANC-1 in DMEM medium with 10% FBS, MV-4-11 in IMDM medium with 20% FBS, and HCT-116 in MC'5A medium with 10% FBS.

[0265] Palbociclib-resistant cells were established on parental MCF7 cells labeled MCF7 Palbo-R under the same culture conditions as the parental cells. All tumor cells were cultured in a cell incubator at 37°C and 5% CO2. Cells were seeded into 384-well plates at the appropriate densities (600 cells / well for MDA-MB-231, 500 cells / well for MDA-MB-468, PANC-1, and HCT-116, 200 cells / well for MCF7 and HCC1806, 800 cells / well for MCF7 Palbo-R, and 3000 cells / well for OCI-AML-3 and MV-4-11) and cultured overnight in the incubator. The next day, compounds were treated at a maximum concentration of 10 μM, with three-fold dilutions and nine parallel wells for each concentration, with each concentration replicated in duplicate. The final DMSO concentration was 0.1%. The cells were cultured in an incubator. Among them, MDA-MB-231, PANC-1, MDA-MB-468, OCI-AML-3, and MV-4-11 were treated with drugs for 5 days, and HCC1806, MCF7, MCF7 Palbo-R, and HCT116 were treated with drugs for 7 days. Cell viability was tested using the Celltiter Glo assay kit (Promega). The test method was consistent with the operating instructions provided with the reagent kit. The cells were read using the Envision multifunctional microplate reader. Data were processed using GraphPad Prism 8, and IC was calculated. 50 was calculated.

[0266] Calculation formula Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)). X: logarithm of compound concentration, Y: % inhibition.

[0267] [Table 5] [Table 6]

[0268] The data in Tables 4 and 5 demonstrate that Examples 2, 6, 12 and 19 all exhibit high inhibitory activity in a variety of tumor cell lines.

[0269] Test 3 Test Example 3: Test of the inhibitory activity of compounds of the present disclosure against CDK kinase 3.1 Experimental steps The ADP-Glo ​​kinase assay was used to test CDK kinase activity. Compounds were diluted threefold from an initial concentration of 10 μM into a 384-well plate in an Echo™ system. Each concentration was diluted in 10 parallel wells, resulting in 10 concentration points. The final assay concentration was 1% DMSO. 2.5 μL of CDK kinase solution (final concentrations: 16.5 nM CDK1 / Cyclin B, 1 nM CDK2 / Cyclin E1, 16.3 nM CDK4 / Cyclin D1, 11.5 nM CDK5 / p25, 15.7 nM CDK6 / Cyclin D3, 80 nM CDK7 / Cyclin H / MAT1, 15.3 nM CDK9 / Cyclin T1, and 150 nM CDK12 / Cyclin K) prepared in assay buffer was added, and the enzyme and compounds were preincubated at room temperature for 10 minutes. 2.5 μL of ATP (concentration: K) was placed in assay buffer. m)&substrate solution (20μM ATP&0.1mg / mL Histone H1 Protein for CDK1 / CyclinB, 15μM ATP&0.1mg / mL Histone H1 Protein for CDK2 / CyclinE1, 200μM ATP&0.2mg / mL DYRKtide peptide for CDK4 / CyclinD1, 10μM ATP&0.1mg / mL Histone H1 Protein for CDK5 / p25, 200μM ATP&0.1mg / mL Histone H1 Protein for CDK6 / CyclinD3, 70μM ATP&0.2mg / mL MBP for CDK7 / Cyclin H / MAT1, 60μM ATP&0.2mg / mL PDKtide for CDK9 / Cyclin T1, 20μM ATP&80μM pS7-CTD peptide for After homogenization, the plates were incubated at room temperature for 120 minutes for CDK1 / 4 / 9 / 12 / 13 and 60 minutes for CDK2 / 5 / 6 / 7. 4 μL of ADP-Glo ​​reagents was added and the plates were incubated at room temperature for 40 minutes. 8 μL of kinase detection reagents was added and the plates were incubated at room temperature for 40 minutes. The plates were read using the Envision multifunctional microplate reader. GraphPad Prism 8 was used to process the data and calculate IC values. 50 was calculated.

[0270] The calculation formula is Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope)). X: logarithm of compound concentration, Y: % inhibition.

[0271] [Table 7]

[0272] The data in Table 6 demonstrate that Examples 2 and 6 are significantly superior to Janssen-01 in CDK2 / CDK7 selectivity.

[0273] Janssen-01 [ka] is prepared with reference to the method provided in WO2022064009A.

[0274] Test 4 Test Example 4. Metabolic Study of Human Liver Microsomes 222.5 μL of human liver microsomes (protein concentration: 1 mg / mL) was taken, and 25 μL of NADPH (10 nM) was added to an incubation plate, which was then preheated for 10 minutes. 2.5 μL of the control compound and test compound (100 μM) were added.

[0275] At 0.5, 5, 10, 15, 20, and 30 minutes, 30 μL aliquots were removed from the reaction mixture. The reaction was stopped by adding 5 volumes of cold acetonitrile containing IS (100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide). The mixture was centrifuged, and 100 μL of the supernatant was mixed with 100 μL of ultrapure HO and used for LC-MS / MS analysis.

[0276] The slope value k was determined by linear regression of the parent drug residuals against the natural logarithm of the incubation time curve.

[0277] In vitro half-life (in vitro T 1 / 2 ) is determined by the gradient value, T1 / 2=-(0.693 / k) The in vitro T (min) was calculated as the in vitro intrinsic clearance (in vitro CL) using the following equation (average of replicate measurements): int , converted to μL / min / mg protein),

number

[0278] Tables 7 and 8 show that compared with Janssen-01, Example 2 had more residual drug substance detected at each time point during the human liver microparticle incubation process, a significantly longer clearance half-life, a significantly slower clearance rate, and more stable metabolism.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 Among them, the above G １ is N or CR １ａ and The R １ , R ２ , R ３ and R １ａ are each independently hydrogen, deuterium, a cyano group, a hydroxy group, C １－６ alkyl groups or halogens (e.g., fluorine, chlorine, bromine, iodine), at least one of which is not hydrogen or deuterium; The R ４ , R ５ , R ６ , R ７ , R ８ , R ９ are each independently hydrogen, deuterium, halogen, or C １－６ Alkyl group, cyano group, C ２－６ Alkenyl group, C ２－６ alkynyl groups or 3- to 6-membered cycloalkyl groups, １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ The alkynyl group or the 3- to 6-membered cycloalkyl group may optionally be independently selected from R Ａ and the R Ａ is selected from deuterium, halogen, a hydroxy group, a cyano group, or a 3- to 6-membered cycloalkyl group; Said L １ is a chemical bond or C １－６ alkylene groups, １－６ The alkylene group may optionally be independently selected from R Ｂ and the R Ｂ is a deuterium, halogen, hydroxyl group, C １－６ an alkoxy group, an amino group, or an oxo group; or two R groups linked to the same carbon atom; Ｂ together with the commonly linked carbon atoms form a 3- to 6-membered cycloalkyl group or a 3- to 7-membered heterocyclyl group, said heterocyclyl group containing at least one heteroatom selected from N, O or S; the ring A is selected from a 3- to 6-membered cycloalkyl group, a 6- to 10-membered aryl group, a 5- to 12-membered heteroaryl group, or a 3- to 12-membered heterocyclyl group; The R １０ are each independently a deuterium atom, a cyano group, a halogen atom, a hydroxy group, an amino group, C ２－６ Alkynyl group, C ２－６ Alkenyl group, —S—C １－６ Alkyl group, C １－６ Alkoxy group, oxo, C １－６ Alkyl group, 3- to 6-membered cycloalkyl group, 6- to 10-membered aryl group, 5- to 12-membered heteroaryl group, 3- to 12-membered heterocyclyl group, —NH—(C═O)—C １－６ Alkyl group, —NH—(C═O)—C ３－６ Cycloalkyl groups, —NH(C═O)—OC １－６ Alkyl group, —NH(C═O)—OC ３－６ Cycloalkyl group, —O(C═O)NHC １－６ Alkyl group, —O(C═O)NH—C ３－６ Cycloalkyl group, —(C═O)NH—C １－６ Alkyl group, —(C═O)—NH—C ３－６ cycloalkyl group, —(C═O)—C １－６ Alkyl group, —(C═O)—C ３－６ Cycloalkyl group, —SO ２ -C １－６ Alkyl group, —SO ２ -C ３－６ Cycloalkyl group, —SO ２ -NH ２ , -SO ２ -NH-C １－６ Alkyl group, —SO ２ -NH-C ３－６ Cycloalkyl group, —SO ２ -N(C １－６ alkyl) ２ , -SO ２ -NH(C ３－６ cycloalkyl) ２ , -S(O)(NH)-C １－６ Alkyl group, —S(O)(NH)—C ３－６ cycloalkyl groups, Said C １－６ The alkyl group, the 3- to 6-membered cycloalkyl group, the 6- to 10-membered aryl group, the 5- to 12-membered heteroaryl group, and the 3- to 12-membered heterocyclyl group may optionally be independently selected from R Ｃ and the R Ｃ is deuterium, halogen, C １－６ Alkoxy group, hydroxy group, amino group, oxo, C ２－６ Alkynyl group, C ２－６ Alkenyl group, cyano group, C １－６ hydroxyalkyl group, 3- to 12-membered heterocyclyl group, C １－６ Alkyl group, C ３－６ selected from a cycloalkyl group, a 6- to 10-membered aryl group, or a 5- to 12-membered heteroaryl group; The R １１ is hydrogen, deuterium, halogen, cyano group, C １－６ Alkyl group, C １－６ an alkoxy group, a 3- to 6-membered cycloalkyl group, a 3- to 12-membered heterocyclyl group, C ２－６ Alkenyl group, C ２－６ alkynyl groups, １－６ Alkyl group, C １－６ an alkoxy group, a 3- to 6-membered cycloalkyl group, a 3- to 12-membered heterocyclyl group, C ２－６ Alkenyl group, C ２－６ The alkynyl group may optionally be independently selected from R Ｄ and the R Ｄ represents hydrogen, deuterium, halogen, cyano group, hydroxy group, alkynyl group, C １－６ Alkoxy group, C １－６ selected from hydroxyalkyl groups and 3- to 6-membered cycloalkyl groups; the ring B is selected from a 5- to 12-membered heteroaryl group or a 6- to 12-membered aryl group; The R' is hydrogen, a cyano group, C １－６ an alkyl group, a 3- to 6-membered cycloalkyl group, and a 3- to 12-membered heterocyclyl group; １－６ The alkyl group, the 3- to 6-membered cycloalkyl group, and the 3- to 12-membered heterocyclyl group may optionally be independently selected from R Ｅ and the R Ｅ represents hydrogen, deuterium, halogen, cyano group, hydroxy group, alkynyl group, C １－６ Alkoxy group, C １－６ selected from a hydroxyalkyl group, a 3- to 6-membered cycloalkyl group, and a 3- to 7-membered heterocyclyl group; The m is selected from 0 or 1, wherein n is selected from 0, 1, 2, 3, 4, or 5; The o is selected from 0, 1, 2, 3, or 4. A compound of formula (I) or a pharmaceutically acceptable salt thereof.

2. A compound of formula (VI) or a pharmaceutically acceptable salt thereof, 【Chemistry 2】 Among them, the above-mentioned L ２ is selected from —NH— or —O—; the ring B is selected from a 5- to 12-membered heteroaryl group or a 6- to 12-membered aryl group; Said L ３ is C ０－６ alkylene groups, ０－６ The alkylene group may optionally be independently selected from R Ｉ and the R Ｉ is a deuterium atom, a halogen atom, an oxo group, a hydroxy group, an amino group, or C １－６ selected from alkyl groups, The R ２５ and R ２６ are each independently hydrogen, C １－６ Alkyl group, halo C １－６ alkyl groups, or R ２５ and R ２６ together with the nitrogen atom to which they are attached form a 4- to 7-membered nitrogen-containing heterocycle, said 4- to 7-membered nitrogen-containing heterocycle optionally being independently R Ｊ and the R Ｊ is selected from halogen, a hydroxy group, a cyano group, a nitro group, or an amino group; The R ２７ are each independently deuterium, halogen, a hydroxy group, a carboxy group, C １－６ Alkyl group, halo C １－６ Alkyl group, hydroxy C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, 3- to 6-membered cycloalkyl group, —S—C １－６ Alkyl group, C １－６ Alkoxy group, halo C １－６ Alkoxy group, —NH—C １－６ Alkyl group, —NH(C １－６ alkyl) ２ , -(C=O)-NH ２ , alkyl-(C═O)-NH-C １－６ Alkyl group, -(C=O)-NH-(C １－６ alkyl) ２ , -(C=O)C １－６ Alkyl group, —NH—(C═O)C １－６ selected from alkyl groups, wherein y is selected from 0, 1, 2, 3, or 4; The R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , L １ , ring A, R １０ and n are as defined in claim 1, but it is assumed that R ４ , R ５ is not hydrogen at the same time, A compound of formula (VI) or a pharmaceutically acceptable salt thereof:

3. L ２ is -NH-, The compound of formula (VI) according to claim 2 or a pharmaceutically acceptable salt thereof.

4. L ２ is -O-, The compound of formula (VI) according to claim 2 or a pharmaceutically acceptable salt thereof.

5. L ３ Ha-CH ２ CH ２ -is, A compound of formula (VI) according to any one of claims 2 to 4 or a pharmaceutically acceptable salt thereof.

6. Ring B is a phenyl group or a pyridyl group, preferably a phenyl group. A compound of formula (VI) according to any one of claims 2 to 5 or a pharmaceutically acceptable salt thereof.

7. The R ２７ are each independently hydrogen, deuterium, a halogen, a cyano group, a hydroxy group, a carboxy group, C １－６ Alkyl group, halo C １－６ Alkyl group, hydroxy C １－６ Alkyl group, C ２－６ alkynyl group, 3- to 6-membered cycloalkyl group, 3- to 12-membered heterocycloalkyl group, 5- to 12-membered aryl group or heteroaryl group, preferably halogen, C １－６ Alkyl group, halo C １－６ Alkyl group, C ２－６ an alkynyl group, most preferably a chlorine, fluorine, trifluoromethyl group or ethynyl group; A compound of formula (VI) according to any one of claims 2 to 6 or a pharmaceutically acceptable salt thereof.

8. The R ２５ and R ２６ are each independently hydrogen or C １－６ selected from alkyl groups, A compound of formula (VI) according to any one of claims 2 to 7 or a pharmaceutically acceptable salt thereof.

9. The R ４ , R ５ , R ６ , R ７ , R ８ , R ９ are each independently hydrogen, deuterium, halogen or C １－６ selected from alkyl groups, 9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

10. The R ４ is a methyl group, 10. The compound of claim 9 or a pharmaceutically acceptable salt thereof.

11. The R ５ , R ６ , R ７ , R ８ , R ９ are each independently selected from hydrogen or deuterium; 11. The compound of claim 10 or a pharmaceutically acceptable salt thereof.

12. Said L １ is a chemical bond, 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

13. Said L １ is C １－６ alkylene groups, １－６ The alkylene group may optionally be independently selected from R Ｂ and the R Ｂ is a deuterium, halogen, hydroxyl group, C １－６ alkoxy groups, preferably the L １ is a methylene group, and said methylene group is optionally independently selected from R Ｂ and the R Ｂ is a deuterium, halogen, hydroxyl group, C １－６ selected from alkoxy groups, 13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.

14. the ring A is selected from a pyrazole ring, an imidazole ring, a tetrahydropyran ring, a pyrimidine ring, and a cyclohexyl group; 14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof.

15. The R １０ represents deuterium, cyano group, C ２－６ Alkynyl group, —S—C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ alkyl group, ２－６ Alkynyl group, —S—C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ The alkyl group may optionally be independently selected from R Ｃ and the R Ｃ is deuterium, halogen, C １－６ Alkoxy group, hydroxy group, amino group, oxo, C ２－６ alkynyl groups, 15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

16. The aforementioned 【Transformation 3】 teeth, 【Chemistry 4】 Selected from 16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof.

17. A compound represented by formula (VI-1) or formula (VI-2) or a medicinal salt thereof, preferably a compound represented by formula (VI-1) or a medicinal salt thereof, 【Transformation 5】 and Said L ２ is selected from —NH— or —O—; the ring B is selected from a 5- to 6-membered heteroaryl group or a 5- to 6-membered aryl group; Said L ３ is C １－３ alkylene groups (e.g., methylene groups), １－３ The alkylene group may optionally be independently selected from R Ｉ and the R Ｉ is a deuterium atom, a halogen atom, an oxo group, a hydroxy group, an amino group, or C １－６ selected from alkyl groups, The R ２５ and R ２６ are each independently hydrogen, C １－６ alkyl groups (e.g., methyl and ethyl groups), １－６ the alkyl group is optionally substituted with one or more deuterium atoms; The R ２７ are each independently deuterium, halogen, a hydroxy group, a carboxy group, C １－６ Alkyl groups (e.g., methyl groups), haloC １－６ Alkyl group, hydroxy C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkylene-3 to 6-membered cycloalkyl group, 3 to 6-membered cycloalkyl group, —S—C １－６ Alkyl group, C １－６ Alkoxy group, halo C １－６ Alkoxy group, —NH—C １－６ Alkyl group, —NH(C １－６ alkyl) ２ Selected from wherein y is selected from 0, 1, 2, 3, or 4; The R ４ is C １－６ is an alkyl group, The R ５ , R ６ , R ７ , R ８ , R ９ are each independently hydrogen, deuterium, halogen or C １－６ selected from alkyl groups, Said L １ is selected from a connecting bond, or １ is C １－６ alkylene groups (e.g., methylene groups), １－６ The alkylene groups are independently R Ｂ and the R Ｂ is deuterium, halogen, hydroxyl group, C １－６ selected from alkyl groups (e.g., methyl groups) or oxo; the ring A is selected from a 5- to 6-membered aryl group, a 5- to 6-membered heteroaryl group, or a 3- to 7-membered heterocyclyl group; The R １０ represents deuterium, cyano group, C ２－６ Alkynyl group, —S—C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkyl groups (e.g., methyl groups), C １－６ alkylene-3 to 6-membered cycloalkyl group, 3 to 6-membered cycloalkyl group, 5 to 6-membered aryl group, 5 to 6-membered heteroaryl group, 5 to 12-membered heterocycloalkyl group, —NH(C═O)—OC １－６ Alkyl group, —(C═O)NH—C １－６ Alkyl group or (C=O)NH ２ Selected from Said C ２－６ Alkynyl group, —S—C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ The alkyl group, the 5- to 6-membered aryl group, the 5- to 6-membered heteroaryl group, and the 5- to 12-membered heterocycloalkyl group may optionally be independently selected from R Ｃ and the R Ｃ is deuterium, halogen, C １－６ Alkoxy group, C １－６ Alkyl group (e.g., methyl group), hydroxy group, amino group, oxo, C ２－６ alkynyl groups, wherein n is selected from 0, 1, 2, or 3; The compound of formula (VI) according to claim 2 or a pharmaceutically acceptable salt thereof.

18. Said L ２ is -NH-, 18. The compound of claim 17 or a pharmaceutically acceptable salt thereof.

19. The ring B is selected from a pyridyl group and a phenyl group, and is preferably a phenyl group. ２７ are each independently deuterium, halogen, a hydroxy group, a carboxy group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ alkylene-3 to 6-membered cycloalkyl group or 3 to 6-membered cycloalkyl group, 19. A compound according to any one of claims 17 or 18, or a pharmaceutically acceptable salt thereof.

20. A compound represented by formula (VI-1-A) or formula (VI-1-B) or a medicinal salt thereof, preferably a compound represented by formula (VI-1-A) or a medicinal salt thereof, 【Transformation 6】 and The R ５ , R ６ , R ７ , R ８ , R ９ , L １ , ring A, R １０ , n, R ２５ , R ２６ , R ２７ and y are each as defined in claim 17; 20. The compound according to any one of claims 17 to 19, or a pharmaceutically acceptable salt thereof.

21. Said L １ is a connected bond, 21. The compound according to any one of claims 17 to 20, or a pharmaceutically acceptable salt thereof.

22. Said L １ is C １－６ alkylene groups, or the L １ is C １－６ alkylene groups, １－６ The alkylene groups are independently R Ｂ and the R Ｂ is deuterium, C １－６ selected from alkyl groups (e.g., methyl groups) or oxo; 21. The compound according to any one of claims 17 to 20, or a pharmaceutically acceptable salt thereof.

23. Said L １ is selected from a methylene group, or １ are selected from methylene groups, and the methylene groups are independently selected from R Ｂ and the R Ｂ is deuterium or C １－６ alkyl groups (e.g., methyl groups); 23. The compound of claim 22 or a pharmaceutically acceptable salt thereof.

24. Said L １ are selected from methylene groups, and the methylene groups are independently selected from R Ｂ and the R Ｂ is selected from oxo, 23. The compound of claim 22 or a pharmaceutically acceptable salt thereof.

25. The R ５ , R ６ , R ７ , R ８ , R ９ are each independently selected from hydrogen or deuterium; 25. The compound according to any one of claims 17 to 24, or a pharmaceutically acceptable salt thereof.

26. the ring A is selected from a pyrazolyl group, an imidazolyl group, a pyridyl group, a phenyl group, a tetrahydropyranyl group, a pyrimidine group, and a cyclohexyl group; 26. The compound according to any one of claims 17 to 25, or a pharmaceutically acceptable salt thereof.

27. The R １０ is deuterium, C １－６ Alkyl group, C １－６ alkylene-3 to 6-membered cycloalkyl group, 3 to 6-membered cycloalkyl group, 5 to 6-membered aryl group, 5 to 6-membered heteroaryl group, 5 to 12-membered heterocycloalkyl group, —NH(C═O)—OC １－６ Alkyl group or -(C=O)NH-C １－６ Alkyl group or (C=O)NH ２ Selected from Said C １－６ The alkyl group, the 5- to 6-membered aryl group, and the 5- to 6-membered heteroaryl group may optionally be independently selected from R Ｃ and the R Ｃ is deuterium, halogen, C １－６ Alkoxy group, C １－６ Alkyl group, hydroxy group, amino group, oxo, C ２－６ alkynyl groups, wherein n is selected from 1, 2, or 3; Preferably, the R １０ is selected from a methyl group, a methylene-cyclopropyl group, and a cyclopropyl group, and the methyl group, the methylene-cyclopropyl group, and the cyclopropyl group are optionally independently selected from R Ｃ and the R Ｃ is selected from deuterium, 27. The compound according to any one of claims 17 to 26, or a pharmaceutically acceptable salt thereof.

28. The aforementioned 【Transformation 7】 teeth, 【Transformation 8】 Selected from 28. The compound according to any one of claims 17 to 27, or a pharmaceutically acceptable salt thereof.

29. The R ２７ are each independently deuterium, halogen, or C １－６ Alkyl group, halo C １－６ Alkyl group, C ２－６ Alkynyl group, C １－６ Alkylene-3 to 6-membered cycloalkyl group, haloC １－６ Alkoxy group, —NH—C １－６ Alkyl group, —NH(C １－６ alkyl) ２ Preferably, the R ２７ are each independently a halogen or C １－６ alkyl groups, most preferably fluorine, chlorine or methyl groups; 29. The compound according to any one of claims 17 to 28, or a pharmaceutically acceptable salt thereof.

30. 30. A compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 Selected from 30. A compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof.

31. An isotopically substituted compound of the compound according to any one of claims 1 to 29, preferably The isotope substitution is a deuterium atom substitution. Isotopically substituted compounds.

32. A method for preparing a compound of formula (VI-1-A) or formula (VI-1-B) according to any one of claims 20 to 31, or a medicinal salt thereof, or an isotopic substitution thereof, comprising the step of condensing a compound of formula (VI-1-A-01) or a medicinal salt thereof, or a compound of formula (VI-1-B-01) or a medicinal salt thereof with a compound of formula (VI-1-A-02) or a medicinal salt thereof under the action of carbonyldiimidazole, phosgene or triphosgene, 【Chemistry 13】 The R ５ , R ６ , R ７ , R ８ , R ９ , L １ , ring A, R １０ , n, R ２５ , R ２６ , R ２７ and y are each as defined in claim 17.

33. A compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof, or an isotopic derivative according to claim 31, comprising the compound or a pharmaceutically acceptable excipient. Pharmaceutical compositions.

34. In preparing a medicament for treating and / or preventing a disease or condition associated with abnormal activity of serine / threonine kinase, the compound according to any one of claims 1 to 30 or a medicament salt thereof, or the isotope-substituted compound according to claim 31, or the pharmaceutical composition according to claim 33, use.

35. Use of the compound according to any one of claims 1 to 30 or a medicamentable salt thereof, or the isotope-substituted compound according to claim 31, or the pharmaceutical composition according to claim 33, in the preparation of a medicament for the treatment and / or prevention of a disease or condition associated with abnormal activity of CDK7, preferably, the disease or condition associated with abnormal activity of CDK7 is selected from a proliferative disease, an inflammatory disease, an autoinflammatory disease, an autoimmune disease, or an infectious disease. use.

36. Use of the compound according to any one of claims 1 to 30 or a medicament salt thereof, or the isotopic derivative according to claim 31, or the pharmaceutical composition according to claim 33, in the preparation of a medicament for the treatment and / or prevention of a disease or condition, wherein the disease or condition is selected from a proliferative disease, an inflammatory disease, an autoinflammatory disease, an autoimmune disease, or an infectious disease. use.

37. The proliferative disease is cancer, and preferably, the cancer is selected from hematological tumors and solid tumors, the hematological tumors are selected from chronic lymphocytic leukemia, acute lymphocytic leukemia, T-cell acute lymphocytic leukemia, chronic myeloid leukemia, and acute myeloid leukemia, and the solid tumors are selected from breast cancer, intestinal cancer, lung cancer, pancreatic cancer, prostate cancer, Ewing's sarcoma, bone tumors, neuroblastoma, cervical cancer, ovarian cancer, gastric cancer, and liver cancer.

37. Use according to any one of claims 35 or 36.

38. The breast cancer is triple-negative breast cancer or ER / PR+HER2- breast cancer, and preferably the ER / PR+HER2- breast cancer is ER / PR+HER2- breast cancer that has drug resistance to a CDK4 / 6 inhibitor; the lung cancer is selected from non-small cell lung cancer or small cell lung cancer; and the intestinal cancer is selected from colon cancer or rectal cancer.

38. The use according to claim 37.

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