Piperidinopyrimidine derivative, preparation method thereof and application of piperidinopyrimidine derivative in medicine

Abstract

The invention relates to piperidinopyrimidine derivatives, a preparation method thereof and application of the piperidinopyrimidine derivatives in medicine. Specifically, the invention relates to a piperidinopyrimidine derivative shown in a general formula (I), a preparation method of the piperidinopyrimidine derivative, a pharmaceutical composition containing the piperidinopyrimidine derivative, and application of the piperidinopyrimidine derivative serving as a CDK7 inhibitor to treatment of diseases or symptoms related to abnormal activity of CDK7. Wherein each group in the general formula (I) is defined in the specification. # imgabs0 #

Description

Piperidopyrimidine derivatives, preparation methods thereof and their use in medicine Technical Field

[0001] The present disclosure relates to the field of medicine and relates to piperidopyrimidine derivatives, methods for preparing the same, and their pharmaceutical applications. In particular, the present disclosure relates to pyrimidine derivatives represented by general formula (I), methods for preparing the same, pharmaceutical compositions containing the same, and their use as CDK7 inhibitors in the treatment of diseases or conditions associated with CDK7 activity. Background Art

[0002] Cyclin kinases (CDKs) are an important class of kinases and play a crucial role in the division and proliferation of cancer cells and the transcriptional regulation of oncogenes. Currently, there are more than 20 subtypes of cyclin kinases (CDKs) discovered. Due to the sequence and structural similarities of the kinase domains of CDK family members, selective and precise regulation of each subtype is a major challenge.

[0003] Cyclin-dependent kinase 7 (CDK7) is a specialized member of the CDK family, with dual functions in regulating both cell division and transcription. CDK7 binds to cyclin H and MAT1 to form a trimeric cyclin-activated kinase (CAK). This kinase regulates the cell cycle by phosphorylating CDKs involved in cell cycle control (including CDK1, CDK2, CDK4, and CDK6), thereby activating the activity of the corresponding CDK kinases. CDK7 also participates in the co-regulation of transcription as a component of the common transcription factor II H (TFIIH). It is involved in transcription initiation by phosphorylating the Rbp1 subunit of RNA polymerase II (RNAPII), and then regulates transcription elongation by phosphorylating the CDK9 complex.

[0004] Key hallmarks of cancer are uncontrolled cell proliferation and dysregulated transcription. Therefore, CDK7 inhibitors that simultaneously inhibit both transcription and cell cycle progression are theoretically promising targets for cancer treatment. Currently, no drugs are available that selectively regulate this target. We envision developing a highly selective CDK7 inhibitor to treat diseases associated with CDK7 activity.

[0005] Published patent applications for CDK7 inhibitors include WO2016058544, WO2018013867, WO2019143719, WO2019143730, WO2019099298, WO2020093006, WO2020093011, WO2022064009A, etc.

[0006] Summary of the Invention

[0007] The purpose of the present disclosure is to provide a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

[0008] Wherein, G1 is N or CR 1a ;

[0009] The R 1 、R 2 、R 3 and R 1a are independently selected from hydrogen, deuterium, cyano, hydroxyl, C 1-6 Alkyl or halogen (e.g., fluorine, chlorine, bromine, iodine), at least one of which is not hydrogen or deuterium;

[0010] The R 4 、R 5 、R 6 、R 7 、R 8 、R 9 are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl or 3 to 6 membered cycloalkyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or 3 to 6 membered cycloalkyl optionally substituted by one or more independently selected from R A Substituents substituted, the R A is selected from deuterium, halogen, hydroxy, cyano or 3- to 6-membered cycloalkyl;

[0011] The L1 is selected from a chemical bond or C 1-6 Alkylene, the C 1-6 Alkylene is optionally substituted by one or more independently selected from R B Substituents substituted, the R B Selected from deuterium, halogen, hydroxyl, C 1-6 Alkoxy, amino, oxo, or two R groups attached to the same carbon atom B Together with the carbon atom to which they are attached, they form a 3- to 6-membered cycloalkyl group or a 3- to 7-membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O or S;

[0012] 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;

[0013] The R 10 are independently selected from deuterium, cyano, halogen, hydroxyl, amino, C 2-6 Alkynyl, C 2-6 Alkenyl, -SC 1-6 Alkyl, C 1-6Alkoxy, oxo, C 1-6 alkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 5- to 12-membered heteroaryl, 3- to 12-membered heterocyclyl, -NH-(C=O)-C 1-6 Alkyl, -NH-(C=O)-C 3-6 Cycloalkyl, -NH(C=O)-OC 1-6 Alkyl, -NH(C=O)-OC 3-6 Cycloalkyl, -O(C=O)NHC 1-6 Alkyl, -O(C=O)NH-C 3-6 Cycloalkyl, -(C=O)NH-C 1-6 Alkyl, -(C=O)-NH-C 3-6 Cycloalkyl, -(C=O)-C 1-6 Alkyl, -(C=O)-C 3-6 Cycloalkyl, -SO2-C 1-6 Alkyl, -SO2-C 3-6 Cycloalkyl, -SO2-NH2, -SO2-NH-C 1-6 Alkyl, -SO2-NH-C 3-6 Cycloalkyl, -SO2-N(C 1-6 Alkyl)2, -SO2-NH(C 3- 6-cycloalkyl)2, -S(O)(NH)-C 1-6 Alkyl, -S(O)(NH)-C 3-6 Cycloalkyl,

[0014] The C 1-6 alkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 5- to 12-membered heteroaryl, 3- to 12-membered heterocyclyl, optionally substituted by one or more independently selected R C Substituents substituted, the R C Selected from deuterium, halogen, C 1-6 Alkoxy, hydroxy, amino, oxo, C 2-6 Alkynyl, C 2-6 Alkenyl, cyano, C 1-6 Hydroxyalkyl, 3 to 12 membered heterocyclic group, C 1-6 Alkyl, C 3-6 cycloalkyl, 6- to 10-membered aryl, or 5- to 12-membered heteroaryl;

[0015] The R 11 Selected from hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 6 membered cycloalkyl, 3 to 12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, the C 1-6 Alkyl, C 1-6Alkoxy, 3 to 6 membered cycloalkyl, 3 to 12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, optionally substituted by one or more independently selected from R D Substituents substituted, the R D Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, alkynyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, 3- to 6-membered cycloalkyl;

[0016] The ring B is selected from a 5- to 12-membered heteroaryl group or a 6- to 12-membered aryl group;

[0017] The R' is selected from hydrogen, cyano, C 1-6 alkyl, 3 to 6 membered cycloalkyl, 3 to 12 membered heterocyclic group, the C 1-6 Alkyl, 3 to 6 membered cycloalkyl, 3 to 12 membered heterocyclic group are optionally substituted by one or more independently selected R E Substituents substituted, the R E Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, alkynyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, 3- to 6-membered cycloalkyl, 3- to 7-membered heterocyclic group;

[0018] The m is selected from 0 or 1;

[0019] Said n is selected from 0, 1, 2, 3, 4 or 5;

[0020] The o is selected from 0, 1, 2, 3 or 4.

[0021] Another aspect of the present disclosure provides a compound represented by formula (VI) or a pharmaceutically acceptable salt thereof,

[0022] Wherein, L2 is selected from -NH- or -O-;

[0023] The B ring is selected from a 5- to 12-membered heteroaryl group or a 6- to 12-membered aryl group;

[0024] The L3 is selected from C 0-6 Alkylene, the C 0-6 Alkylene is optionally substituted by one or more independently selected from R I Substituents substituted, the R I Selected from deuterium, halogen, oxo, hydroxyl, amino or C 1-6 alkyl;

[0025] The R 25 and R 26 are each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or R 25 and R26 The nitrogen atom to which it is connected forms a 4- to 7-membered nitrogen-containing heterocyclic ring, wherein the 4- to 7-membered nitrogen-containing heterocyclic ring is optionally substituted by one or more independently selected from R J Substituents substituted, the R J is selected from halogen, hydroxy, cyano, nitro or amino;

[0026] The R 27 Each independently selected from deuterium, halogen, hydroxyl, carboxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 6 membered cycloalkyl, -SC 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -NH-C 1-6 Alkyl, -NH(C 1-6 Alkyl)2, -(C=O)-NH2, Alkyl-(C=O)-NH-C 1-6 Alkyl, -(C=O)-NH-(C 1-6 alkyl)2, -(C=O)C 1-6 Alkyl, -NH-(C=O)C 1-6 alkyl;

[0027] Said y is selected from 0, 1, 2, 3 or 4;

[0028] The 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, provided that said R 4 、R 5 Not hydrogen at the same time.

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

[0030] In an optional embodiment, the present disclosure provides a compound represented by formula (VI) or a pharmaceutically acceptable salt thereof, wherein L2 is -O-.

[0031] In an optional embodiment, the present disclosure provides a compound represented by formula (VI) or a pharmaceutically acceptable salt thereof, wherein L3 is -CH2CH2-.

[0032] In an optional embodiment, the present disclosure provides a compound represented by formula (VI) or a pharmaceutically acceptable salt thereof, wherein, wherein, ring B is phenyl or pyridyl.

[0033] In an optional embodiment, the present disclosure provides a compound represented by formula (VI) or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl.

[0034] In an optional embodiment, the present disclosure provides a compound represented by formula (VI) or a pharmaceutically acceptable salt thereof, wherein the R 27 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 2-6 alkynyl, 3 to 6 membered cycloalkyl, 3 to 12 membered heterocycloalkyl, 5-12 membered aryl or heteroaryl.

[0035] In an optional embodiment, the present disclosure provides a compound represented by formula (VI) or a pharmaceutically acceptable salt thereof, wherein the R 27 are each independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkynyl.

[0036] In an optional embodiment, the present disclosure provides a compound represented by formula (VI) or a pharmaceutically acceptable salt thereof, wherein the R 27 Each is independently selected from chloro, fluoro, trifluoromethyl or ethynyl.

[0037] In an optional embodiment, the present disclosure provides a compound represented by formula (VI) or a pharmaceutically acceptable salt thereof, wherein the R 25 and R 26 Each independently selected from hydrogen or C 1-6 alkyl.

[0038] In an optional embodiment, the present disclosure provides a compound represented by formula (I), (VI) or a pharmaceutically acceptable salt thereof, wherein the R 4 、R 5 、R 6 、R 7 、R 8 、R 9 are each independently selected from hydrogen, deuterium, halogen or C 1-6 alkyl.

[0039] In an optional embodiment, the present disclosure provides a compound represented by formula (I), (VI) or a pharmaceutically acceptable salt thereof, wherein R 4 It is a methyl group.

[0040] In an optional embodiment, the present disclosure provides a compound represented by 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.

[0041] In an optional embodiment, the present disclosure provides a compound represented by 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, said R 4 It is a methyl group.

[0042] In an optional embodiment, the present disclosure provides compounds represented by formula (I) or (VI) or pharmaceutically acceptable salts thereof, wherein L1 is a chemical bond.

[0043] In an optional embodiment, the present disclosure provides a compound represented by formula (I), (VI) or a pharmaceutically acceptable salt thereof, wherein L1 is selected from C 1-6 Alkylene, the C 1-6 Alkylene is optionally substituted by one or more independently selected from R B Substituents substituted, the R B Selected from deuterium, halogen, hydroxyl, C 1-6 Alkoxy.

[0044] In an optional embodiment, the present disclosure provides a compound represented by formula (I), (VI) or a pharmaceutically acceptable salt thereof, wherein L1 is a methylene group, and the methylene group is optionally replaced by one or more independently selected R B Substituents substituted, the R B Selected from deuterium, halogen, hydroxyl, C 1-6 Alkoxy.

[0045] In an optional embodiment, the present disclosure provides a compound represented by formula (I) or (VI) or a pharmaceutically acceptable salt thereof, wherein the ring A is selected from a pyrazole ring, an imidazole ring, a tetrahydropyran ring, a pyrimidine ring or a cyclohexyl ring.

[0046] In an optional embodiment, the present disclosure provides a compound represented by formula (I), (VI) or a pharmaceutically acceptable salt thereof, wherein R 10 Selected from deuterium, cyano, C 2-6 Alkynyl, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, the C 2-6 Alkynyl, -SC 1-6 Alkyl, C1-6 Alkoxy, C 1-6 The alkyl group is optionally substituted by one or more independently selected R C Substituents substituted, the R C Selected from deuterium, halogen, C 1-6 Alkoxy, hydroxy, amino, oxo, C 2-6 Alkynyl.

[0047] In an optional embodiment, the present disclosure provides a compound represented by formula (I), (VI) or a pharmaceutically acceptable salt thereof, wherein

[0048] Selected from

[0049] 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,

[0050] Said L2 is selected from -NH- or -O-;

[0051] The ring B is selected from a 5- to 6-membered heteroaryl group or a 5- to 6-membered aryl group;

[0052] The L3 is selected from C 1-3 Alkylene (e.g. methylene, ethylene, propylene), the C 1-3 Alkylene is optionally substituted by one or more independently selected from R I Substituents substituted, the R I Selected from deuterium, halogen, oxo, hydroxyl, amino or C 1-6 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl);

[0053] The R 25 and R 26 are each independently selected from hydrogen, C 1-6 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl), the C 1-6 The alkyl group is optionally substituted with one or more deuterium groups;

[0054] The R 27 Each independently selected from deuterium, halogen, hydroxyl, carboxyl, C 1-6 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl), halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6Alkylene-3 to 6-membered cycloalkyl (e.g., cyclopropyl, cyclobutyl), 3 to 6-membered cycloalkyl (e.g., cyclopropyl, cyclobutyl), -SC 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -NH-C 1-6 Alkyl, -NH(C 1-6 Alkyl)2;

[0055] Said y is selected from 0, 1, 2, 3 or 4;

[0056] The R 4 C 1-6 alkyl;

[0057] The R 5 、R 6 、R 7 、R 8 、R 9 are each independently selected from hydrogen, deuterium, halogen or C 1-6 alkyl;

[0058] The L1 is selected from a connecting bond, or the L1 is selected from C 1-6 Alkylene (e.g. methylene, ethylene, propylene), or said L1 is selected from C 1-6 Alkylene, the C 1-6 Alkylene is composed of one or more independently selected R B Substituents substituted, the R B Selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl) or oxo;

[0059] 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 heterocyclic group;

[0060] The R 10 Selected from deuterium, cyano, C 2-6 Alkynyl, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl), C 1-6 Alkylene-3 to 6-membered cycloalkyl, 3 to 6-membered cycloalkyl, 5 to 6-membered aryl, 5 to 6-membered heteroaryl, 5 to 12-membered heterocycloalkyl, -NH(C=O)-OC 1-6 Alkyl, -(C=O)NH-C 1-6 Alkyl or (C=O)NH2;

[0061] The C 2-6 Alkynyl, -SC 1-6 Alkyl, C1-6 Alkoxy, C 1-6 alkyl, 5 to 6 membered aryl, 5 to 6 membered heteroaryl, 5 to 12 membered heterocycloalkyl, optionally substituted by one or more independently selected R C Substituents substituted, the R C Selected from deuterium, halogen, C 1-6 Alkoxy, C 1-6 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl), hydroxy, amino, oxo, C 2-6 Alkynyl;

[0062] The n is selected from 0, 1, 2 or 3.

[0063] In some embodiments, the present disclosure provides a compound of formula (VI) or a pharmaceutically acceptable salt thereof, which is a compound of formula (VI-1) or a pharmaceutically acceptable salt thereof.

[0064] 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-.

[0065] In some embodiments, the present disclosure provides a compound of formula (VI-1) or formula (VI-2) or a pharmaceutically acceptable salt thereof, wherein the ring B is selected from pyridyl or phenyl, and the R 27 Each independently selected from deuterium, halogen, hydroxyl, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylene-3 to 6-membered cycloalkyl.

[0066] In some embodiments, the present disclosure provides a compound of formula (VI-1) or formula (VI-2) or a pharmaceutically acceptable salt thereof, wherein the ring B is phenyl, and the R 27 Each independently selected from deuterium, halogen, hydroxyl, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylene-3 to 6-membered cycloalkyl.

[0067] In some embodiments, the present disclosure provides a compound of formula (VI-1) or formula (VI-2) or a pharmaceutically acceptable salt thereof, wherein the ring B is phenyl, and the R 27 are each independently selected from deuterium.

[0068] In some embodiments, the present disclosure provides a compound of formula (VI-1) or formula (VI-2) or a pharmaceutically acceptable salt thereof, wherein the ring B is phenyl, and the R 27 are each independently selected from halogen.

[0069] In some embodiments, the present disclosure provides a compound of formula (VI-1) or formula (VI-2) or a pharmaceutically acceptable salt thereof, wherein the ring B is phenyl, and the R 27 Each independently selected from C 1-6 alkyl.

[0070] In some embodiments, the present disclosure provides a compound of formula (VI-1) or formula (VI-2) or a pharmaceutically acceptable salt thereof, wherein the ring B is phenyl, and the R 27 Each is independently selected from methyl or ethyl.

[0071] In some embodiments, the present disclosure provides a compound of formula (VI-1) or formula (VI-2) or a pharmaceutically acceptable salt thereof, wherein the ring B is phenyl, and the R 27 Each is independently selected from methylene-cyclopropyl.

[0072] In some embodiments, the present disclosure provides a compound of formula (VI-1) or formula (VI-2) or a pharmaceutically acceptable salt thereof, wherein the ring B is phenyl, and the R 27 are each independently selected from cyclopropyl.

[0073] In some embodiments, the present disclosure provides a compound of formula (VI-1) or formula (VI-2) or a pharmaceutically acceptable salt thereof, wherein L3 is selected from a methylene group, and the methylene group is optionally replaced by one or more independently selected groups selected from R I Substituents substituted, the R I Selected from deuterium, halogen, oxo, hydroxyl, amino or C 1-6 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl).

[0074] In some embodiments, the present disclosure provides a compound of formula (VI-1) or formula (VI-2) or a pharmaceutically acceptable salt thereof, wherein L3 is selected from ethylene, and the ethylene is optionally replaced by one or more independently selected from R I Substituents substituted, the R I Selected from deuterium, halogen, oxo, hydroxyl, amino or C 1-6 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl).

[0075] In some embodiments, the present disclosure provides a compound of formula (VI-1) or formula (VI-2) or a pharmaceutically acceptable salt thereof, wherein L3 is selected from a propylene group, and the propylene group is optionally replaced by one or more independently selected from R I Substituents substituted, the R I Selected from deuterium, halogen, oxo, hydroxyl, amino or C 1-6Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl).

[0076] In some embodiments, the present disclosure provides a compound of formula (VI) or a pharmaceutically acceptable salt thereof, which is a compound of formula (VI-1-A) or formula (VI-1-B) or a pharmaceutically acceptable salt thereof,

[0077] The 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 compounds represented by formula (VI-1-A) or formula (VI-1-B) or pharmaceutically acceptable salts thereof.

[0078] In an optional embodiment, the present disclosure provides a compound represented by formula (VI) or a pharmaceutically acceptable salt thereof, which is a compound represented by formula (VI-1-A) or a pharmaceutically acceptable salt thereof.

[0079] In some embodiments, the present disclosure provides compounds represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein L1 is a connecting bond.

[0080] In some embodiments, the present disclosure provides compounds represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein L1 is selected from C 1-6 Alkylene, or said L1 is selected from C 1-6 Alkylene, the C 1-6 Alkylene is composed of one or more independently selected R B Substituents substituted, the R B Selected from deuterium, C 1-6 Alkyl or oxo.

[0081] In some embodiments, the present disclosure provides compounds represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein L1 is selected from C 1-6 The alkylene group can specifically be a methylene group or an ethylene group.

[0082] In some embodiments, the present disclosure provides compounds represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein L1 is selected from C 1-6Alkylene, the C 1-6 Alkylene is composed of one or more independently selected R B Substituents substituted, the R B Selected from deuterium, methyl, ethyl or propyl.

[0083] In some embodiments, the present disclosure provides compounds represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein L1 is selected from C 1-6 Alkylene, the C 1-6 Alkylene is composed of one or more independently selected R B Substituents substituted, the R B Selected from deuterium.

[0084] In some embodiments, the present disclosure provides compounds represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein L1 is selected from C 1-6 Alkylene, the C 1-6 Alkylene is composed of one or more independently selected R B Substituents substituted, the R B Selected from methyl.

[0085] In some embodiments, the present disclosure provides compounds represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein L1 is selected from C 1-6 Alkylene, the C 1-6 Alkylene is composed of one or more independently selected R B Substituents substituted, the R B Selected from oxo.

[0086] In some embodiments, the present disclosure provides compounds represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein L1 is selected from methylene, or L1 is selected from methylene, and the methylene is replaced by one or more independently selected R B Substituents substituted, the R B Selected from deuterium or C 1-6 Alkyl (eg, methyl, ethyl).

[0087] In some embodiments, the present disclosure provides compounds represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein L1 is selected from methylene, or L1 is selected from methylene, and the methylene is replaced by one or more independently selected R B Substituents substituted, the R BSelected from deuterium or methyl.

[0088] In some embodiments, the present disclosure provides compounds represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein L1 is selected from methylene, and the methylene is replaced by one or more independently selected R B Substituents substituted, the R B Selected from oxo.

[0089] In some embodiments, the present disclosure provides compounds represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein R 5 、R 6 、R 7 、R 8 、R 9 are each independently selected from hydrogen or deuterium.

[0090] In some embodiments, the present disclosure provides compounds represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein ring A is selected from pyrazolyl, imidazolyl, pyridinyl, phenyl, tetrahydropyranyl, pyrimidinyl, and cyclohexyl.

[0091] In an optional embodiment, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 Selected from deuterium, C 1-6 Alkyl, C 1-6 Alkylene-3 to 6-membered cycloalkyl, 5 to 6-membered aryl, 5 to 6-membered heteroaryl, -NH(C=O)-OC 1-6 Alkyl or -(C=O)NH-C 1-6 Alkyl or (C=O)NH2;

[0092] The C 1-6 Alkyl, 5 to 6 membered aryl, 5 to 6 membered heteroaryl are optionally substituted by one or more independently selected R C Substituents substituted, the R C Selected from deuterium, halogen, C 1-6 Alkoxy, C 1-6 Alkyl, hydroxy, amino, oxo, C 2-6 Alkynyl;

[0093] The n is selected from 1, 2 or 3.

[0094] In an optional embodiment, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 Selected from C 1-6 alkyl;

[0095] The n is selected from 1, 2 or 3.

[0096] In an optional embodiment, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from methyl, ethyl or propyl;

[0097] The n is selected from 1, 2 or 3.

[0098] In an optional embodiment, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 selected from methyl;

[0099] The n is selected from 1, 2 or 3.

[0100] In an optional embodiment, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 Selected from C 1-6 Alkylene-3 to 6-membered cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl);

[0101] The n is selected from 1, 2 or 3.

[0102] In an optional embodiment, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from methylene-cyclopropyl;

[0103] The n is selected from 1, 2 or 3.

[0104] In an optional embodiment, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (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, cyclohexyl);

[0105] The n is selected from 1, 2 or 3.

[0106] In an optional embodiment, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from cyclopropyl;

[0107] The n is selected from 1, 2 or 3.

[0108] In an optional embodiment, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from phenyl, said phenyl being optionally substituted by one or more independently selected from R C Substituents substituted, the R C Selected from deuterium, halogen, C 1-6 Alkoxy, C 1-6 Alkyl, hydroxy, amino, oxo, C 2-6 Alkynyl;

[0109] The n is selected from 1, 2 or 3.

[0110] In an optional embodiment, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from 5- to 6-membered heteroaryl (eg, pyridine, imidazole, pyrazole, thiazole, oxazole), wherein the 5- to 6-membered heteroaryl is optionally substituted by one or more independently selected R C Substituents substituted, the R C Selected from deuterium, halogen, C 1-6 Alkoxy, C 1-6 Alkyl, hydroxy, amino, oxo, C 2-6 Alkynyl;

[0111] The n is selected from 1, 2 or 3.

[0112] In an optional embodiment, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 Selected from -NH(C=O)-OC 1-6 Alkyl (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl), wherein n is selected from 1, 2 or 3.

[0113] In an optional embodiment, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 Selected from -(C=O)NH-C 1-6Alkyl (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl), wherein n is selected from 1, 2 or 3.

[0114] In an optional embodiment, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from (C=O)NH2, wherein n is selected from 1, 2 or 3.

[0115] In an optional embodiment, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from a 5- to 10-membered heterocycloalkyl group, optionally substituted by one or more independently selected from R C Substituents substituted, the R C Selected from deuterium, halogen, C 1-6 Alkoxy, C 1-6 Alkyl, hydroxy, amino, oxo, C 2-6 Alkynyl,

[0116] The n is selected from 1, 2 or 3.

[0117] In an optional embodiment, the present disclosure provides a compound represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from a 5- to 10-membered bridged heterocyclic group, the bridged heterocyclic group being optionally substituted by one or more independently selected R C Substituents substituted, the R C Selected from deuterium, halogen, C 1-6 Alkoxy, C 1-6 Alkyl, hydroxy, amino, oxo, C 2-6 Alkynyl, wherein the heterocyclic group contains 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0118] The n is selected from 1, 2 or 3.

[0119] In some embodiments, the present disclosure provides compounds represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein Selected from

[0120] In some embodiments, the present disclosure provides compounds represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein R27 are each independently selected from deuterium, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkylene-3 to 6-membered cycloalkyl, 3 to 6-membered cycloalkyl, halo-C 1-6 Alkoxy, -NH-C 1-6 Alkyl, -NH(C 1-6 Alkyl)2.

[0121] In some embodiments, the present disclosure provides compounds represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein R 27 are each independently selected from halogen or C 1-6 alkyl.

[0122] In some embodiments, the present disclosure provides compounds represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein R 27 are each independently selected from fluorine or chlorine;

[0123] In some embodiments, the present disclosure provides compounds represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein R 27 are each independently selected from methyl.

[0124] In some embodiments, the present disclosure provides compounds represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein R 25 and R 26 Each is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl is optionally substituted with one or more deuteriums.

[0125] In some embodiments, the present disclosure provides compounds represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein R 25 and R 26 Each is independently selected from hydrogen, methyl, ethyl, and the methyl and ethyl groups are optionally substituted with one or more deuterium groups.

[0126] In some embodiments, the present disclosure provides compounds represented by formula (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof, wherein R 25 and R26 are each independently selected from methyl, said methyl being optionally substituted with one or more deuterium.

[0127] The present disclosure provides a compound as shown below or a pharmaceutically acceptable salt thereof, which is selected from:

[0128] Table a

[0129] Another aspect of the present disclosure provides a compound represented by Formula (I), (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B), or a pharmaceutically acceptable salt thereof, and a compound of Table a, and isotopic substitutions. In an optional embodiment, the isotopic substitution is a deuterium atom substitution.

[0130] The present disclosure also provides a pharmaceutical composition comprising at least one compound represented by formula (I), (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof and a compound of Table a, an isotope-substituted compound, or a compound or a pharmaceutically acceptable salt thereof prepared by the aforementioned method and a pharmaceutically acceptable excipient.

[0131] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0132] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or a pharmaceutically acceptable salt thereof.

[0133] In certain embodiments, the pharmaceutical composition comprises 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of a pharmaceutically acceptable excipient.

[0134] On the other hand, the present disclosure provides the use of the compounds represented by the aforementioned formulas (I), (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or their pharmaceutically acceptable salts and the compounds in Table a, isotopic substitutions, or the compounds or their pharmaceutically acceptable salts prepared by the aforementioned methods, as well as the aforementioned pharmaceutical compositions, in the preparation of drugs for treating or preventing diseases or conditions associated with abnormal activity of serine / threonine kinases.

[0135] On the other hand, the present disclosure provides the use of the compounds represented by the aforementioned formulas (I), (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or pharmaceutically acceptable salts thereof and the compounds of Table a, isotopic substitutions, or compounds or pharmaceutically acceptable salts thereof prepared by the aforementioned methods, as well as the aforementioned pharmaceutical compositions, in the preparation of drugs for treating and / or preventing diseases or conditions associated with abnormal activity of CDK7.

[0136] In an alternative embodiment, the disease or disorder 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.

[0137] On the other hand, the present disclosure provides the compounds represented by the aforementioned formulas (I), (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or their pharmaceutically acceptable salts and the compounds of Table a, isotopic substitutions, or the compounds or their pharmaceutically acceptable salts prepared by the aforementioned methods, as well as the use of the aforementioned pharmaceutical compositions in the preparation of drugs for treating and / or preventing diseases or conditions, wherein the diseases or conditions are selected from proliferative diseases, inflammatory diseases, autoinflammatory diseases, autoimmune diseases or infectious diseases.

[0138] In alternative embodiments, the disease or disorder is a proliferative disease.

[0139] In alternative embodiments, the proliferative disease is cancer.

[0140] In alternative embodiments, the cancer is selected from the group consisting of hematological tumors and solid tumors.

[0141] In an optional embodiment, the blood tumor is selected from leukemia, specifically including: chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), T-cell acute lymphocytic leukemia (T-ALL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), etc.).

[0142] In an optional embodiment, the solid tumor is selected from breast cancer, intestinal cancer, lung cancer, pancreatic cancer, prostate cancer, Ewing's sarcoma, osteoma, neuroblastoma, cervical cancer, ovarian cancer, gastric cancer, and liver cancer.

[0143] In an alternative embodiment, the breast cancer is triple-negative breast cancer.

[0144] In an alternative embodiment, the breast cancer is ER / PR+HER2- breast cancer.

[0145] In an alternative embodiment, the breast cancer is ER / PR+HER2- breast cancer that is resistant to CDK4 / 6 inhibitors.

[0146] In an alternative embodiment, the CDK4 / 6 inhibitor is Palbociclib.

[0147] In an alternative embodiment, the lung cancer is non-small cell lung cancer.

[0148] In an alternative embodiment, the lung cancer is small cell lung cancer.

[0149] In an alternative embodiment, the intestinal cancer is colon cancer.

[0150] In an alternative embodiment, the intestinal cancer is rectal cancer.

[0151] Another aspect of the present disclosure provides a method for treating and / or preventing a disease or condition associated with abnormal activity of serine / threonine kinase 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), (VI-1-B) or a pharmaceutically acceptable salt thereof, and a compound of Table A, an isotopic substitution thereof, or a compound or a pharmaceutically acceptable salt thereof prepared by the aforementioned method, as well as the aforementioned pharmaceutical composition.

[0152] Another aspect of the present disclosure provides a method for treating and / or preventing a disease or condition associated with abnormal CDK7 activity 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), (VI-1-B), or a pharmaceutically acceptable salt thereof, and a compound of Table a, an isotopic substitution thereof, or a compound or a pharmaceutically acceptable salt thereof prepared by the aforementioned method, as well as the aforementioned pharmaceutical composition.

[0153] In an alternative embodiment, the disease or disorder 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.

[0154] Another aspect of the present disclosure provides a method for treating and / or preventing a disease or condition in a patient, wherein the patient is administered a therapeutically effective amount of a compound represented by Formula (I), (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof and a compound of Table a, an isotopic substitution, or a compound or a pharmaceutically acceptable salt thereof and the pharmaceutical composition prepared by the aforementioned method, wherein the disease or condition is selected from a proliferative disease, an inflammatory disease, an autoinflammatory disease, an autoimmune disease, or an infectious disease; in an optional embodiment, the disease or condition is a proliferative disease.

[0155] In alternative embodiments, the proliferative disease is cancer.

[0156] In alternative embodiments, the cancer is selected from the group consisting of hematological tumors and solid tumors.

[0157] In an optional embodiment, the blood tumor is selected from leukemia, specifically including: chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), T-cell acute lymphocytic leukemia (T-ALL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), etc.).

[0158] In an optional embodiment, the solid tumor is selected from breast cancer, intestinal cancer, lung cancer, pancreatic cancer, prostate cancer, Ewing's sarcoma, osteoma, neuroblastoma, cervical cancer, ovarian cancer, gastric cancer, and liver cancer.

[0159] In an alternative embodiment, the breast cancer is triple-negative breast cancer.

[0160] In an alternative embodiment, the breast cancer is ER / PR+HER2- breast cancer.

[0161] In an alternative embodiment, the breast cancer is ER / PR+HER2- breast cancer that is resistant to CDK4 / 6 inhibitors.

[0162] In an alternative embodiment, the CDK4 / 6 inhibitor is Palbociclib.

[0163] In an alternative embodiment, the lung cancer is non-small cell lung cancer.

[0164] In an alternative embodiment, the lung cancer is small cell lung cancer.

[0165] In an alternative embodiment, the intestinal cancer is colon cancer.

[0166] In an alternative embodiment, the intestinal cancer is rectal cancer.

[0167] Another aspect of the present disclosure provides a compound represented by Formula (I), (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof and a compound of Table a, an isotope-substituted product, or the use of a compound prepared by the aforementioned method as a medicine.

[0168] The compounds provided herein or their pharmaceutically acceptable salts can be prepared using synthetic methods commonly used in the art. An exemplary method is provided below:

[0169] The compound of formula (VI) or a pharmaceutically acceptable salt thereof provided in the present disclosure can be prepared by referring to the method of patent WO2022064009A1.

[0170] The compound of formula (VI) provided in the present disclosure is split into two fragments during the synthesis process, namely A and B.

[0171] The present disclosure provides a method for preparing a compound represented by formula (VI-1-A) or a pharmaceutically acceptable salt thereof, or an isotope-substituted product thereof, comprising the steps of condensing a compound represented by formula (VI-1-A-01) or a pharmaceutically acceptable salt thereof with a compound represented by formula (VI-1-A-02) or a pharmaceutically acceptable salt thereof under the action of carbonyldiimidazole, phosgene or triphosgene.

[0172] The 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 as defined above.

[0173] In an optional embodiment, the condensation reaction occurs in an alkaline environment, which is provided by an inorganic base (sodium hydroxide) or an organic base (such as triethylamine, pyridine, piperidine or N,N-diisopropylethylamine), and the solvent in which the reaction occurs is a common solvent (such as DMF, DCM or DMSO).

[0174] The present disclosure provides a method for preparing a compound represented by formula (VI-1-B) or a pharmaceutically acceptable salt thereof, or an isotope substituted product thereof, comprising the steps of condensing a compound represented by formula (VI-1-B-01) or a pharmaceutically acceptable salt thereof with a compound represented by formula (VI-1-A-02) or a pharmaceutically acceptable salt thereof under the action of carbonyldiimidazole, phosgene or triphosgene.

[0175] The R5 、R 6 、R 7 、R 8 、R 9 , L1, Ring A, R 10 ,n,R 25 、R 26 、R 27 and y are as defined above.

[0176] In an optional embodiment, the condensation reaction occurs in an alkaline environment, which is provided by an inorganic base (sodium hydroxide) or an organic base (such as triethylamine, pyridine, piperidine or N,N-diisopropylethylamine), and the solvent in which the reaction occurs is a common solvent (such as DMF, DCM or DMSO).

[0177] The pharmaceutically acceptable salts of the compounds described in the present disclosure are selected from inorganic salts or organic salts. The compounds described in the present disclosure can react with acidic or basic substances to form corresponding salts.

[0178] The present disclosure provides a compound represented by formula (I), (VI), (VI-1), (VI-2), (VI-1-A), (VI-1-B) or a pharmaceutically acceptable salt thereof and a compound of Table a, wherein the isotope substitution has excellent selectivity on CDK7 enzyme activity, and in an optional embodiment, IC 50 Less than 100 nM, in an optional embodiment, IC 50 Less than 50 nM, in an optional embodiment, IC 50 Less than 30 nM, in an optional embodiment, IC 50 Less than 15nM.

[0179] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure form or in racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

[0180] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0181] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both Two configurations.

[0182] Compounds and intermediates of the present disclosure can also exist in different tautomeric forms, and all such forms are included in the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as prototransfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerization. The lactam-lactim equilibrium example is between A and B as shown below.

[0183] All compounds in this disclosure can be drawn as either Form A or Form B. All tautomeric forms are within the scope of this disclosure. The naming of the compounds does not exclude any tautomers.

[0184] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 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 et al.

[0185] Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to have at least 1000 times the abundance of deuterium greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). In the example, the compound has a natural abundance greater than deuterium that can be at least 1000 times the abundance of deuterium, at least 2000 times the abundance of deuterium, at least 3000 times the abundance of deuterium, at least 4000 times the abundance of deuterium, at least 5000 times the abundance of deuterium, at least 6000 times the abundance of deuterium or more abundant deuterium. The disclosure also includes various deuterated forms of formula (I) compounds. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of formula (I) compounds with reference to relevant literature. Commercially available deuterated starting materials may be used in the preparation of deuterated forms of the compounds of formula (I), or they may be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.

[0186] "Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "optionally substituted C 1-6 The term "alkyl" means that halogen or cyano may but need not be present, and the description includes both the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano.

[0187] Explanation of terms:

[0188] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0189] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that has been approved by the U.S. Food and Drug Administration for use in humans or domestic animals.

[0190] As used herein, an "effective amount" or "therapeutically effective amount" encompasses an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical condition. An effective amount also refers to an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.

[0191] The prefix "C u-v " indicates that the following group has from u to v carbon atoms. For example, "C 1-6 The term "alkyl" refers to an alkyl group having 1 to 6 carbon atoms, and specifically may be an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms.

[0192] The term "alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, an alkyl group has 1 to 20 carbon atoms (i.e., C 1-20 alkyl), 1 to 8 carbon atoms (i.e., C 1-8 alkyl), 1 to 6 carbon atoms (i.e., C 1- 6 alkyl), or 1 to 4 carbon atoms (i.e., C 1-4 Alkyl). 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 chemical name or determined by molecular formula, all isomers having that number of carbon atoms are included; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3); and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0193] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond, having from 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), or 2 to 4 carbon atoms (ie, C 2-4 Examples of the alkenyl group include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0194] The term "alkynyl" refers to an alkyl group having at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C 2-20Alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 Alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl), or 2 to 4 carbon atoms (i.e., C 2-4 Examples of “alkynyl” include ethynyl, propynyl (e.g., 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl, and 1-methylpent-2-ynyl.

[0195] The term "cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated cyclic alkyl group having a monocyclic or polycyclic ring (including fused, bridged, and spirocyclic ring systems). The term "cycloalkyl" includes cycloalkenyl groups (i.e., the cyclic group has at least one double bond). As used herein, a cycloalkyl group has 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl), or 3 to 7 ring carbon atoms (i.e., C 3-7 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 Cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, cyclohexenyl, and cyclohexadienyl. The cycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like.

[0196] The term "heterocyclyl" 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" includes heterocycloalkenyl (i.e., a heterocyclyl group having at least one double bond), bridged-heterocyclyl, fused heterocyclyl and spiro-heterocyclyl. A heterocyclyl group can be monocyclic or polycyclic, wherein the polycyclic rings can be fused, bridged or spirocyclic. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl group, regardless of connection (i.e., it can be bound by carbon atoms or heteroatoms). In addition, the term heterocyclyl is intended to include any non-aromatic ring containing at least one heteroatom, which ring can be fused to an aryl or heteroaryl ring, regardless of connection to the rest of the molecule. As used herein, the heterocyclyl group has 3 to 20 ring atoms (i.e., 3- to 20-membered heterocyclyl), 3 to 12 ring atoms (i.e., 3- to 12-membered heterocyclyl), 3 to 10 ring atoms (i.e., 3- to 10-membered heterocyclyl), 3 to 8 ring atoms (i.e., 3- to 8-membered heterocyclyl), 3 to 7 ring atoms (i.e., 3- to 7-membered heterocyclyl), 3 to 6 ring atoms (i.e., 3- to 6-membered heterocyclyl); 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, the ring heteroatoms being independently selected from nitrogen, sulfur, phosphorus, or oxygen. Examples of heterocyclic groups include pyrrolidinyl, imidazolidinyl, oxetanyl, dioxolanyl, azetidinyl, tetrahydrofuranyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl.

[0197] As used herein, the term "bridged-heterocyclic radical" refers to a 4 to 10 ring moiety that is connected to a 4 to 10 ring moiety having at least one heteroatom at two non-adjacent atoms of a heterocyclic radical with one or more (e.g., 1 or 2), wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, and phosphorus. As used herein, "bridged-heterocyclic radical" includes bicyclic and tricyclic ring systems. In addition, as used herein, the term "spiro-heterocyclic radical" refers to a ring system in which a 3 to 10-membered heterocyclic radical has one or more other rings, wherein the one or more other rings are 3 to 10-membered cycloalkyl or 3 to 10-membered heterocyclic radicals, wherein the single atom of the one or more other rings is also an atom of the 3 to 10-membered heterocyclic radical. 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]pyridinyl, indolinyl, and isoindolinyl, wherein the heterocyclyl group may be attached through any ring of the fused system.

[0198] Non-limiting examples of "heterocyclyl" include:

[0199] wait.

[0200] The heterocyclyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0201] wait.

[0202] The term "aryl" 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. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring, non-limiting examples of which include:

[0203] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 6 to 12-membered, more preferably 5-membered or 6-membered. For example, non-limiting examples include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine, etc.

[0204] The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0205] The term "alkoxy" refers to the group "alkyl-O-," wherein alkyl is as defined above. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0206] The terms "cycloalkyloxy" and "heterocyclyloxy" are defined in the same manner as "alkoxy" above.

[0207] The term "haloalkyl" refers to an unbranched or branched alkyl group as defined above in which one or more hydrogen atoms are replaced by a halogen. For example, when a residue is substituted with more than one halogen, it may be referred to using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted with two or three halogen groups, which may be, but need not be, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0208] The term "haloalkoxy" refers to an alkoxy group as defined above wherein one or more hydrogen atoms are replaced by a halogen.

[0209] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0210] The term "hydroxy" refers to an -OH group.

[0211] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0212] The term "cyano" refers to -CN.

[0213] The term "nitro" refers to -NO2.

[0214] The term "oxo" refers to a =0 substituent.

[0215] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) whether substitution is possible or not without undue effort. DETAILED DESCRIPTION

[0216] The present disclosure is further described below with reference to the following embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0217] Example

[0218] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), or deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as the internal standard.

[0219] MS was measured using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid spectrometer / mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a Waters ACQuity UPLC-QD / SQD (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector), and a THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0220] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high performance liquid chromatographs.

[0221] Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.

[0222] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0223] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0224] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0225] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0226] Silica gel column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0227] Average kinase inhibition rate and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG, Germany).

[0228] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, J&K, Accela ChemBio Inc, Shanghai Bid Pharmaceutical, Darui Chemicals, and other companies.

[0229] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0230] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0231] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0232] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0233] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0234] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0235] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0236] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0237] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compound, and the developing solvent system for 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 solvent was adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0238] The abbreviations used in the following experiments have the following meanings:

[0239] TFA: trifluoroacetic acid; DCM: dichloromethane; m-CPBA: m-chloroperbenzoic acid; EtONa: sodium ethoxide; Boc: tert-butyloxycarbonyl; MeOH: methanol; HBTU: benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate; TsOH: p-toluenesulfonic acid; EtOAc: ethyl acetate; t-BuOH: tert-butyl alcohol; PdCl2(TPP) 2:Dichlorobis(triphenylphosphine)palladium; XantPhos: 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene; Pd2dba3: trisdibenzylideneacetone dipalladium; PdCl2(TPP) 2: Dichlorobis(triphenylphosphine)palladium; XantPhos: 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene; Pd2dba3: trisdibenzylideneacetone dipalladium; DMF: N,N-dimethylformamide; CDI: N,N-carbonyldiimidazole; ACN: acetonitrile; DMP: Dess-Martin periodinane; DMAP: 4-dimethylaminopyridine.

[0240] Example 1

[0241] ((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

[0242] first step

[0243] Preparation of compound 1c

[0244] Under N₂ atmosphere, Na₂CO₃ (198 mL, 1 M, 198 mmol) and Pd(PPh₃)₂Cl₂ (6.96 g, 9.92 mmol) were added to 1,4-dioxane (400 mL) containing compounds 1a (40.0 g, 99.2 mmol) and 1b (32.6 g, 149 mmol). The mixture was heated to 90°C under N₂ atmosphere 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 organic phases were combined, dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to obtain 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 afford compound 1c (90.0 mg, 98.1% yield).

[0245] 1H NMR (400MHz, DMSO-d6) δ7.11-6.97(m,1H),6.57(d,J=8.0Hz,1H),6.41(s,1H),6.34(d,J=7.2Hz,1H),5.15(s,2H),4.09(s,2H),3.92(q,J=7.2Hz, 2H), 2.44 (s, 2H), 1.49 (s, 9H), 0.92 (t, J = 7.2Hz, 3H).

[0246] Step 2

[0247] Preparation of compound 1d

[0248] To a reaction flask containing EtOH (400 mL) at room temperature under N2 atmosphere, compound 1c (35.0 g, 101 mmol) and Pd / C (10%, 24.0 g) were added. The mixture was then replaced with H2 three times. The reaction mixture was stirred at 50°C under H2 (50 psi) for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated to afford crude product 1d (30.0 g, 86.1 mmol, 92.6%).

[0249] Step 3

[0250] Preparation of compound 1e

[0251] To a solution of 1d (10.0 g, 28.7 mmol) in CH3CN (100 mL) was added an aqueous solution (7 mL) of TsOH (11.0 mL, 71.7 mmol) at 0°C. The reaction solution was stirred for 0.5 h. The reaction solution was maintained at 0°C, and an aqueous solution of NaNO2 (2.30 mL, 43.0 mmol) was added thereto. An aqueous solution (7.0 mL) of KI (2.35 mL, 43.0 mmol) was slowly added dropwise. After the addition was complete, the temperature was raised to room temperature and stirred for 16 h. The reaction solution was added with water and extracted with EtOAc (300 mL x 3). The organic phase was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the crude product.

[0252] The crude product was purified by flash column chromatography on silica gel with 10-30% ethyl acetate in petroleum ether as eluent to afford compound 1e (8.0 g, 17.4 mmol, yield 60.7%).

[0253] Step 4

[0254] Preparation of compound 1f

[0255] Under N2 atmosphere, compound 1e (3.00 g, 6.53 mmol), trimethylsilyl acetylene (21.4 mL, 150 mmol), CuI (0.111 mL, 3.26 mmol) and Pd(DTBPF)Cl2 (2.13 g, 3.266 mmol) were added to DMF (60 mL). The reaction solution was heated to 110°C and stirred for 12 hours. Water (260 mL) was added to the reaction solution, and EtOAc (50 mL x 3) was added to extract. The organic phases were combined and 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 with 1-5% ethyl acetate in petroleum ether as the eluent to give compound 1f (2.06 g, 2.88 mmol, yield 44.1%).

[0256] Step 5

[0257] Preparation of compound 1g

[0258] Under N2 atmosphere, HCl / EtOAc (15 mL) was added to a solution of compound 1f (1.00 g, 2.33 mmol) in EtOAc (20 mL). The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give a crude product 1g (900 mg). The crude product 1g was dissolved in DCM (60 mL), and NaOAc (0.305 mL, 3.28 mmol) and formaldehyde (399 mg, 4.92 mmol) were added. The mixture was stirred at room temperature for 1 hour, and NaBH(OAc)3 (1440.2 mg, 6.83 mmol) was added. The mixture was allowed to react at room temperature and stirred for 12 hours. The reaction solution was washed once with 10% NaHCO3 (20 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the crude product.

[0259] The crude product was separated and purified by preparative HPLC (column: Waters Xbridge BEH C18 250*50mm*10um; mobile phase: [water (NH4HCO3)-CH3CN]; B%: 65%-90%) to obtain compound 1h (400 mg, 1.07 mmol, yield 39.2%).

[0260] MS m / z(ESI):344.2[M+H] + .

[0261] Step 6

[0262] Preparation of intermediate 1j

[0263] To a solution of compound 1h (400 mg, 1.164 mmol) in EtOH (30 mL) was added EtONa (0.456 mL, 5.822 mmol) at room temperature. The reaction mixture was gradually heated to 85°C and stirred for 5 hours. The reaction solution was concentrated under reduced pressure to obtain crude product 1i. Crude product 1i was added to a mixed solution of EtOH (15 mL) and H2O (15 mL) at room temperature, followed by the addition of NaOH (118 mg, 2.95 mmol). The mixture was stirred for 12 hours, and the reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative HPLC (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [water (FA)-CH3CN]; B%: 65%-90%) to obtain compound 1j (150 mg, 0.555 mmol, 37.6%).

[0264] MS m / z(ESI):244.2[M+H] + .

[0265] Step 7

[0266] Preparation of compound 11

[0267] To a solution of compound 1k (11.0 g, 51.6 mmol, 1.00 eq) in DMF (50 mL) was slowly added dropwise DMF-DMA (12.3 g, 103 mmol, 13.7 mL, 2.00 eq) at room temperature. The reaction solution was heated to 90°C and stirred for 18 hours. Water (150 mL) was added to the reaction solution, and extraction was performed 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).

[0268] MS m / z(ESI):269.1[M+H] + .

[0269] Step 8

[0270] Preparation of compound 1m

[0271] To compound 1l (12.0 g, 44.7 mmol) and 2-methylisothiourea sulfate (24.9 g, 89.4 mmol, 2.00 eq) dissolved in EtOH (200 mL) at room temperature was slowly added EtONa (6.69 g, 98.4 mmol). The reaction mixture was heated to 90°C and stirred for 12 hours. The mixture was cooled to room temperature, and H2O (150 mL) was added. The mixture was extracted with EtOAc (60 mL x 5). The organic phases were combined, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain 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 obtain compound 1m (6.20 g, 21.0 mmol, 46.9% yield).

[0272] MS m / z(ESI):296.1[M+H] + .

[0273] Step 9

[0274] Preparation of intermediate 1n

[0275] To a solution of compound 1m (5.00 g, 17.0 mmol) in DCM (100 mL) at 0°C was added m-CPBA (10.3 g, 50.7 mmol) and stirred for 2 hours. The reaction mixture was allowed to warm to room temperature and stirred for 10 hours. The temperature was then lowered to 0°C, and NaSO (10%, 40 mL) was added to the reaction mixture. The mixture was extracted with DCM (30 mL x 3). The combined organic phases were washed once with saturated brine (50 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product.

[0276] The crude product was purified by flash column chromatography on silica gel with 10-30% ethyl acetate in petroleum ether as eluent to afford compound 1n (2.7 g, 8.25 mmol, yield 48.7%).

[0277] MS m / z(ESI):328.1[M+H] + .

[0278] 1H NMR(400MHz, CDCl3)δ8.59(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).

[0279] Compound 1n was separated by chiral column (chromatographic column: Chiralcel OD-3, 150×4.6mm ID, 3um), mobile phase: A: supercritical CO2 fluid B: methanol (0.1% IPAm, v / v), to obtain 1n-1 and 1n-2.

[0280] Compound 1n-1 (retention time 2.770 minutes)

[0281] MS m / z(ESI):328.1[M+H] + .

[0282] 1H NMR (400MHz, CDCl3) δ8.59 (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)

[0283] Compound 1n-2 (retention time 2.469 minutes).

[0284] Step 10

[0285] Preparation of intermediate 1p

[0286] To a solution of compound 1n-1 (140 mg, 0.428 mmol) in t-BuOH (2 mL) at room temperature was added 1o (380 mg, 3.42 mmol). The reaction mixture was heated to 100°C and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography on silica gel using 1-5% ethyl acetate in petroleum ether as the eluent to obtain compound 1p (100 mg, 0.279 mmol, 45.7%).

[0287] MS m / z(ESI):359.1[M+H] + .

[0288] Step 11

[0289] Preparation of compound 1

[0290] To a solution of compound 1p (100 mg, 0.279 mmol) in DCM was added TFA (0.8 mL, 10.8 mmol) at room temperature and stirred for 1 hour. The reaction solution was concentrated to dryness under reduced pressure to obtain crude product 1q (96.0 mg, 0.186 mmol, 66.6%).

[0291] MS (ESI): m / z = 259.1 [M+H] + .

[0292] At room temperature, intermediate 1j (90.0 mg, 0.37 mmol) was added to DMF (3 mL), and 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 solution. The mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to obtain crude product 1, which was separated and purified by preparative HPLC (chromatographic column: Phenomenex Luna C18 75*30mm*3um; mobile phase: [(NH4HCO3)-CH3CN]; B%: 65%-90%) to obtain compound 1-1 (17.4 mg, 0.036 mmol, 9.18%) and compound 1-2 (17.0 mg, 0.035 mmol, 9.50%).

[0293] Compound 1-1

[0294] MS (ESI): m / z = 484.3 [M+H] + .

[0295] 1 H NMR (400MHz, 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).

[0296] Compound 1-2

[0297] MSm / z(ESI):484.3[M+H] + .

[0298] 1 H NMR (400MHz, 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).

[0299] Example 2

[0300] (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

[0301] first step

[0302] Preparation of compound 2

[0303] Compound 2a (57.2 mg, 348 μmol) and N,N-carbonyldiimidazole (75.3 mg, 464 μmol) were dissolved in tetrahydrofuran. 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, described in Synthesis 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 then 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%).

[0304] MS m / z(ESI):449.3[M+H] + .

[0305] 1 H NMR (400MHz, DMSO-d6): δ: 8.10 (s, 1H), 7.53 (d, J = 2.0Hz, 1H), 7.39-7.25 (m, 4H), 7.23-7.10 (m, 2H), 6.78 (d, J = 7.6H) z,1H),6.10(d,J=2.0Hz,1H),4.93-4.83(m,1H),4.72-4.55(m,2H),4.47-4.34(m,2H),3.96(d,J=18.4Hz,1H),3.77 (s,3H),2.77(dd,J=5.4,15.2Hz,1H),2.69-2.59(m,1H),2.42(d,J=15.2Hz,1H),2.34(dd,J=5.9,12.0Hz,1H),2.17(s,6H),0.94(d,J=6.8Hz,3H).

[0306] Example 3

[0307] (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

[0308] first step

[0309] Preparation of compound 3a

[0310] To a solution of compound 1n-2 (200 mg, 0.611 mmol) in t-BuOH (2 mL) at room temperature was added 1o (543 mg, 4.89 mmol). The reaction mixture was heated to 100°C and stirred for 12 hours. The reaction mixture was then concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography on silica gel using 1-5% ethyl acetate in petroleum ether as the eluent to afford compound 3a (150 mg, 0.418 mmol, 68.51% yield).

[0311] MS m / z(ESI):359.2[M+H] + .

[0312] Step 2

[0313] Preparation of compound 3

[0314] To a solution of compound 3a (150 mg, 0.139 mmol) in DCM was added TFA (1 mL) at room temperature and stirred for 1 hour. The reaction solution was concentrated to dryness under reduced pressure to obtain crude product 3b (80.0 mg, 0.135 mmol).

[0315] MS m / z(ESI):259.1[M+H] + .

[0316] Compound 2a (0.102 mL, 0.609 mmol) and N,N-carbonyldiimidazole (75.3 mg, 465 μmol) were dissolved in tetrahydrofuran. Triethylamine (118 mg, 1.16 mmol, 162 μL) was added to the solution and stirred at room temperature for 0.5 hour. Compound 3b (60.0 mg, 232 μmol) was added to the reaction solution and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to obtain crude product 3, which was then 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 3 (44.4 mg, 98.9 μmol, yield 42.6%).

[0317] MS m / z(ESI):449.3[M+H] + .

[0318] 1 H NMR (400MHz, DMSO-d6): δ: 8.09 (s, 1H), 7.53 (d, J = 2.0Hz, 1H), 7.34- 7.30(m,2H),7.30-7.25(m,2H),7.22-7.12(m,2H),6.77(d,J=7.2Hz,1H),6.10(d,J=2.0Hz,1H),4.93-4.82(m,1H),4.70-4.59(m,2H),4. 45-4.37(m,2H),3.93(d,J=18.0Hz,1H),3.76(s,3H),2.80-2.60(m,2H),2.34(dd,J=6.0,12.0Hz,2H),2.17(s,6H),0.95(d,J=6.8Hz,3H).

[0319] Example 4

[0320] 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

[0321] first step

[0322] Preparation of compound 4b

[0323] Compound 4a (5 g, 23.7 mmol) was dissolved in tetrahydrofuran and cooled to -78°C. n-Butyl lithium (11.4 mL, 28.5 mmol) was added dropwise to the solution, and the mixture was stirred at -78°C for 2 hours. The reaction was quenched by slowly adding saturated ammonium chloride solution. The crude product was extracted, dried, and concentrated to afford the title compound 4b (4.5 g, 79% yield).

[0324] Step 2

[0325] Preparation of compound 4c

[0326] Compound 4b (4.5 g, 18.873 mmol) was dissolved in N,N-dimethylformamide, and PdCl2(TPP)2 (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 to obtain a crude product, which was then purified by normal phase purification to afford 4c (2.6 g, 69% yield).

[0327] Step 3

[0328] Preparation of compound 4d

[0329] Compound 4c (2.6 g, 13.2 mmol) was dissolved in toluene, followed by the addition of p-toluenesulfonic acid (450 mg, 2.6 mmol) and tert-butylamine (7 mL, 65.8 mmol). The reaction mixture was allowed to react at 90°C for 12 hours. The reaction mixture was extracted, concentrated, and dried to obtain the crude product, which was then purified by normal phase purification to afford 4d (1.3 g, 50% yield).

[0330] MS m / z(ESI):197.1[M+H] + .

[0331] Step 4

[0332] Preparation of compound 4e

[0333] Compound 4d was dissolved in acetonitrile, followed by the addition of benzyl bromide. The reaction mixture was incubated 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 was used directly in the next reaction.

[0334] MS m / z(ESI):287.1[M+H] + .

[0335] Step 5

[0336] Preparation of compound 4f

[0337] Compound 4e was dissolved in methanol, and solid sodium borohydride was slowly added. The reaction solution was stirred at room temperature for 30 minutes. The reaction solution was extracted, concentrated, and dried to obtain a crude product, which was purified by normal phase purification to obtain 4f (0.4 g, 30% yield).

[0338] MS m / z(ESI):291.1[M+H] + .

[0339] Step 6

[0340] Preparation of compound 4g

[0341] Compound 4f (130 mg, 0.45 mmol) was dissolved in 1,2-dichloroethane, followed by the addition of potassium carbonate. The reaction mixture was heated at reflux for 3 hours. The mixture was filtered and concentrated to yield a crude oil. This crude oil was dissolved in methanol and heated at reflux for 1 hour. The reaction mixture was concentrated under reduced pressure to yield the crude product, which was then purified by normal phase purification to yield compound 4g (70 mg, 78%).

[0342] MS m / z(ESI):201.1[M+H] + .

[0343] Step 7

[0344] Preparation of compound 4h

[0345] 1-Methyl-3-phenylpiperidine-4-carboxylic acid (76.5 mg, 0.35 mmol) and O-benzotriazole-tetramethyluronium hexafluorophosphate (396.9 mg, 1.05 mmol) were dissolved in N,N-dimethylformamide and stirred for 10 minutes. N,N-diisopropylethylamine (193 μL, 1.05 mmol) and compound 4g were then added. The reaction mixture was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water(NH4HCO3)-ACN]; B%: 10%-40%, 8 min) to afford compound 4h (9 mg, 6% yield).

[0346] MS m / z(ESI):402.1[M+H] + .

[0347] Step 8

[0348] Preparation of compound 4

[0349] Under a nitrogen atmosphere, compound 4h (9 mg, 0.022 mmol), 1-methyl-1-vinylethazanemethylamine (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 and reacted in a microwave oven at 120°C for 1 hour. The reaction solution was cooled to room temperature, filtered, and the filtrate was collected, concentrated under reduced pressure, and separated by normal phase to afford the title compound 4 (2 mg, 18% yield).

[0350] MS m / z(ESI)478.2[M+H] + .

[0351] Example 5

[0352] (R)-N-((S)-2-(dimethylamino)-1-phenylethyl)-6-methyl-2-(((R)-1-phenylethyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide

[0353] first step

[0354] Preparation of compound 5b

[0355] To a microwave tube, add t-BuOH (2 mL), compound 1n-1 (100 mg, 0.31 mmol), and 5a (0.39 mL, 3.05 mmol). Microwave the mixture under nitrogen for 8 hours. Concentrate the reaction mixture to obtain a crude product, which is then separated by reverse-phase column chromatography (0-100% water / acetonitrile) to afford the title compound 5b (89 mg, 79% yield).

[0356] MS m / z(ESI):369.3[M+H] + .

[0357] Step 2

[0358] Preparation of compound 5c

[0359] 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. The mixture was stirred at room temperature for 7 h, diluted with water, neutralized with K2CO3, and extracted with DCM. The organic phases were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was spin-dried to obtain the crude target compound 5c, which was used directly in the next reaction.

[0360] MS m / z(ESI):269.2[M+H] + .

[0361] Step 3

[0362] Preparation of compound 5

[0363] 2a (30 mg, 0.18 mmol) was dissolved in DMF (0.5 mL), and CDI (60 mg, 0.37 mmol) was added. The mixture was stirred at room temperature for 5 minutes. Et3N (76 μL, 0.55 mmol) and compound 5b (34.3 mg, 0.13 mmol) were then added sequentially. The mixture was allowed to react overnight at room temperature. The reaction solution was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [water(NH4HCO3)-ACN]) to afford compound 5 (20 mg, 23.9% yield).

[0364] MS m / z(ESI):459.4[M+H] + .

[0365] 1 H NMR (400MHz, CD3OD): δ8.02(s,1H),7.42-7.34(m,6H),7.32-7.24(m,3H),7.20-7.1 4(m,1H),5.26(dd,J=11.4,4.0Hz,1H),5.11(q,J=6.9Hz,1H),4.79-4.68(m,2H),4.0 7(d,J=18.3Hz,1H),3.37-3.33(m,1H),3.06(dd,J=13.0,4.1Hz,1H),2.84(dd,J=15. 6, 5.6Hz, 1H), 2.73 (s, 6H), 2.48 (d, 16H), 1.50 (d, J = 7.0Hz, 3H), 1.01 (d, 7.2Hz, 3H).

[0366] Example 6

[0367] (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

[0368] first step

[0369] Preparation of compound 6b

[0370] To a microwave tube containing t-BuOH (2.0 mL) were added compound 1n-1 (100 mg, 0.31 mmol) and 6a (0.37 mL, 3.05 mmol). The reaction was carried out in a microwave oven under nitrogen for 5 h. The reaction solution was concentrated and separated by reverse phase column chromatography (0-100% water / acetonitrile) to obtain the title compound 6b (97.9 mg, 86.8% yield).

[0371] MS m / z(ESI):370.3[M+H] + .

[0372] Step 2

[0373] Preparation of compound 6c

[0374] 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. The mixture was stirred at room temperature for 7 h, diluted with water, neutralized with K2CO3, and extracted with DCM. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was dried to give the crude target compound 6c, which was used directly in the next reaction.

[0375] MS m / z(ESI):270.2[M+H] + .

[0376] Step 3

[0377] Preparation of compound 6

[0378] 2a (30 mg, 0.18 mmol) was dissolved in DMF (0.5 mL), and CDI (60 mg, 0.37 mmol) was added. The mixture was stirred at room temperature for 5 minutes. Et3N (76 μL, 0.55 mmol) and compound 6c (34.4 mg, 0.13 mmol) were then added sequentially. The mixture was allowed to react overnight at room temperature. The reaction solution was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [water(NH4HCO3)-ACN]) to afford compound 6 (40 mg, 47.7% yield).

[0379] MS m / z(ESI):460.3[M+H] + .

[0380] 1 H NMR (400 MHz, DMSO-d6): 1 H NMR(400MHz,)δ8.50(d,J=4.4Hz,1H),8.08(s,1H),7.71(td,J=7.7,1.8Hz,1H),7.41 -7.38(m,2H),7.36-7.26(m,4H),7.23-7.18(m,2H),6.83(d,J=7.7Hz,1H),5.12(p,J= 7.1Hz,1H),4.92-4.84(m,1H),4.68-4.48(m,2H),3.94(d,J=18.8Hz,1H),2.77-2.64 (m,2H),2.44-2.35(m,2H),2.19(s,6H),1.45(d,J=7.0Hz,3H),0.93(d,J=6.7Hz,3H).

[0381] Example 7

[0382] (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

[0383] Compound 7 was prepared by referring to the synthetic method of Example 5. Starting materials 1 (100 mg, 0.31 mmol) and 7a (414.5 mg, 2.44 mmol) were reacted in three steps to obtain compound 7 (35 mg, 40.7% yield). The crude 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]).

[0384] MS m / z(ESI):471.4[M+H] + .

[0385] 1 H NMR (400MHz, CD3OD): δ8.09(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=11.4,4.0Hz,1H),4.82-4.64(m,3H), 4.17(d,J=18.2Hz,1H),3.35-3.32(m,2H),3.28(s,1H),3.07(dd,J=13.0,4.1Hz, 1H), 2.93-2.85 (m, 3H), 2.73 (s, 6H), 2.53 (d, 15.6Hz, 1H), 1.07 (d, J = 6.8Hz, 3H).

[0386] Example 8

[0387] (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

[0388] first step

[0389] Preparation of compound 8c

[0390] To 8a (1 g, 3.51 mmol) dissolved in DCM (30 mL) were added HBTU (1.33 g, 3.51 mmol) and KCO (1.45 g, 10.52 mmol). The mixture was allowed to react at room temperature for 0.5 hour. 8b (0.5 g, 5.26 mmol) was then added to the reaction mixture and allowed to react at 40°C overnight. After the reaction was completed, the mixture was cooled to room temperature, filtered, and concentrated to afford a crude product. The crude product was separated by column chromatography (0-100% petroleum ether / ethyl acetate) to afford the target compound 8c (973 mg, 85.1% yield).

[0391] MS m / z(ESI):327.2[M+H] + .

[0392] Step 2

[0393] Preparation of compound 8d

[0394] Compound 8c (973 mg, 2.98 mmol) was dissolved in ethyl acetate (10 mL). Under nitrogen protection, 10% Pd / C (300 mg) was added and H2 was replaced three times. The reaction was carried out at room temperature under H2 atmosphere for 6 hours. The mixture was filtered through celite and the filtrate was concentrated to obtain crude compound 8d, which was used directly in the next reaction.

[0395] MS m / z(ESI):193.2[M+H] + .

[0396] Step 3

[0397] Preparation of compound 8e

[0398] Under nitrogen, THF (6.0 mL) and LiAlH₄ (4.7 mL, 1 M, THF) were added sequentially to a dry three-necked flask. The reaction solution was placed in a dry ice-ethanol bath at -78°C, and compound 8d (400 mg, 2.08 mmol) in THF (2 mL) was slowly added dropwise. After the addition was complete, the reaction mixture was refluxed overnight. After cooling to room temperature, the reaction solution was placed in an ice bath, and 0.5 mL of water and 0.2 mL of 15% NaOH solution were added sequentially. The solution was dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then separated by reverse-phase column chromatography (0-100% water / acetonitrile) to afford 8e (177 mg, 47.7% yield) as a yellow liquid.

[0399] MS m / z(ESI):179.2[M+H] + .

[0400] Step 4

[0401] Preparation of compound 8

[0402] Compound 8e (30 mg, 0.17 mmol) was dissolved in DMF (0.5 mL), and CDI (54.6 mg, 0.34 mmol) was added. The mixture was stirred at room temperature for 5 minutes. Et3N (7 μL, 0.51 mmol) and compound 5d (30.4 mg, 0.12 mmol) were then added and allowed to react overnight at room temperature. The reaction solution was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [water(NH4HCO3)-ACN]) to afford compound 8 (20 mg, yield: 25.7%).

[0403] MS m / z(ESI):463.4[M+H] + .

[0404] 1 H NMR(400MHz,)δ8.08(s,1H),7.49-7.36(m,6H),7.32-7.29(m,1H),6.19(d ,J=2.2Hz,1H),5.41-5.34(m,1H),4.82-4.73(m,2H),4.53(s,2H),4.14(d, J=18.2Hz,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 = 7.3Hz, 3H), 1.06 (d, J = 7.0Hz, 3H).

[0405] Example 9

[0406] (R)-N-((S)-2-(dimethylamino)-1-phenylethyl)-6-methyl-2-(((S)-1-phenylethyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide

[0407] The preparation of compound 9 was carried out by referring 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 three steps.

[0408] MS m / z(ESI):471.4[M+H] + .

[0409] 1H NMR (400MHz, CD3OD): δ8.03(s,1H),7.37-7.25(m,8H),7.24-7.14(m,2H),5.13(q, J=7.0Hz,1H),5.01(dd,J=10.7,4.4Hz,1H),4.77-4.69(m,1H),4.66(d,J=18.3Hz, 1H),4.11(d,J=18.3Hz,1H),2.91-2.78(m,2H),2.48(dd,J=15.5,1.7Hz,1H),2.41 (dd,J=12.8,4.5Hz,1H),2.30(s,6H),1.51(d,J=7.0Hz,3H),1.02(d,J=6.8Hz,3H).

[0410] Example 10

[0411] 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

[0412] first step

[0413] Preparation of compound 10c

[0414] Under nitrogen, to a solution of 10b (1.09 g, 7.42 mmol) in DMF (3.0 mL) were added DIPEA (1.63 mL, 9.89 mmol) and 10a (500 mg, 4.94 mmol) in sequence. The mixture was reacted at room temperature for 48 h. The reaction solution was concentrated and the crude product was separated by reverse-phase column chromatography (mobile phase: [water(NH4OH)-ACN]) to obtain the title compound 10c (400 mg, yield 56.5%).

[0415] MS m / z(ESI):144.2[M+H] + .

[0416] Step 2

[0417] Preparation of compound 10d

[0418] 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. The temperature was raised to 50°C and the reaction was allowed to react overnight. The reaction solution was cooled to room temperature, diluted with water, and extracted three times with DCM. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and separated by reverse phase column chromatography (mobile phase: [water(NH4OH)-ACN]) to obtain the target compound 10d (258 mg, yield: 39.7%).

[0419] MS m / z(ESI):349.2[M+H] + .

[0420] Step 3

[0421] Preparation of compound 10e

[0422] Compound 10d (258 mg, 0.74 mmol) was dissolved in a mixture of 1,4-dioxane and MeOH (4 mL, 3:1). Dioxane hydrochloride solution (1.8 mL, 4 M) was slowly added dropwise. The mixture was reacted at room temperature overnight, diluted with water, neutralized with K2CO3 solution, and extracted three times with DCM. The organic phases were combined, dried over Na2SO4, filtered, and the filtrate was spin-dried to obtain crude compound 10d, which was used directly in the next reaction.

[0423] MS m / z(ESI):249.2[M+H] + .

[0424] Step 4

[0425] Preparation of compound 10

[0426] To a solution of 2a (108 mg, 0.66 mmol) in DMF (3 mL) was added CDI (213.2 mg, 1.32 mmol). The mixture was stirred at room temperature for 5 min. EtN (0.27 mL, 1.97 mmol) and compound 10d (114.3 mg, 0.46 mmol) were then added sequentially. The mixture was allowed to react overnight at room temperature. The reaction solution was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [water(NH4HCO3)-ACN]) to afford compound 10 (80 mg, yield: 27.7%).

[0427] MS m / z(ESI):439.3[M+H] + .

[0428] After chiral column separation (chromatographic 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 were obtained, with the following structures:

[0429] Compound 10-1 (retention time 3.43 minutes)

[0430] MS m / z(ESI):439.3[M+H] + .

[0431] 1 H NMR (400MHz, CDCl3) δ8.00 (s, 1H), 7.24-7.13 (m, 5H), 5.68 (s, 1H), 4.86 (d, J = 8.0Hz, 1H),4.81-4.66(m,2H),4.53(d,J=17.9Hz,1H),4.10(d,J=17.8Hz,1H),3.99-3.89(m, 3H),3.57-3.40(m,2H),2.84(dd,J=15.8,5.8Hz,1H),2.53(t,J=11.7Hz,1H),2.37-2 .27(m,2H),2.21(s,6H),2.04-1.88(m,2H),1.52-1.44(m,2H),1.01(d,J=6.8Hz,3H).

[0432] Compound 10-2 (retention time 6.29 minutes)

[0433] MS m / z(ESI):439.3[M+H] + .

[0434] 1 H NMR(400MHz, CDCl3)δ8.00(s,1H),7.27-7.18(s,5H),5.95(s,1H),4.97(s,1H),4.83 -4.72(m,1H),4.71-4.62(m,1H),4.55(d,J=18.2Hz,1H),4.06(d,J=18.2Hz,1H),4.0 6-3.89(m,3H),3.51-3.41(m,2H),2.91-2.83(m,1H),2.65(t,J=11.8Hz,1H),2.39-2 .32(m,3H),2.24(s,6H),1.98-1.94(m,2H),1.49-1.45(m,2H),0.99(d,J=6.8Hz,3H).

[0435] Example 11

[0436] (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

[0437] first step

[0438] Preparation of compound 11

[0439] Compound 11a (9.08 mg, 0.055 mmol) and CDI (18 mg, 0.111 mmol) were dissolved in DMF (2 mL). Et3N (0.023 mL, 0.166 mmol) was added to the solution, followed by stirring at room temperature for 0.5 hour. Compound 1q (10 mg, 0.039 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 12 hours. The reaction solution was separated and purified by preparative HPLC to yield compound 11 (5.0 mg, 0.011 mmol).

[0440] MS m / z(ESI):449.38[M+H] + .

[0441] 1 H NMR (400MHz, CD3OD): δ8.05(s,1H),7.52-7.17(m,6H),6.16(s,1H),5.31(d,J=7.8Hz,1H),4.78-4.58(m,2H),4.50(s,2H),4.16(d,J=1 8.4Hz,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=15.6Hz,1H),1.05(d,J=6.8Hz,3H).

[0442] Example 12

[0443] (R)-N-((S)-2-(Hexadeuteratedimethylamino)-1-phenylethyl)-6-methyl-2-(((1-methyl-1H-pyrazol-3-yl)-methyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide

[0444] first step

[0445] Preparation of compound 12c

[0446] 12a (500 mg, 1.753 mmol) and HBTU (1329 mg, 3.5 mmol) were dissolved in DCM (7 mL) at room temperature and stirred for 5 minutes. KCO (726 mg, 5.26 mmol) and 12b (134.4 mg, 2.63 mmol) were then added. The reaction was stirred at room temperature for 12 hours. The reaction solution was extracted, concentrated, and dried to obtain a crude product. The crude product was purified by column chromatography to afford compound 12c (900 mg, 2.83 mmol).

[0447] MS m / z(ESI):319.2[M+H] + .

[0448] Step 2

[0449] Preparation of compound 12d

[0450] Under a hydrogen 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 afford crude product 12d (260 mg). This crude product was used directly in the next reaction (260 mg).

[0451] MS m / z(ESI):185.1[M+H] +

[0452] Step 3

[0453] Preparation of compound 12e

[0454] Under a nitrogen 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 added dropwise and stirred for 30 minutes. The reaction solution was then warmed to 50°C and allowed to react for 2 hours before being quenched by the addition of ammonium chloride solution. The crude product was extracted, concentrated, and dried to afford the product. The crude product was purified by preparative HPLC to afford compound 12e (40.0 mg, 21% yield).

[0455] MS m / z(ESI):171.1[M+H] +

[0456] Step 4

[0457] Preparation of compound 12

[0458] Compound 12e (20.0 mg, 0.094 mmol) and CDI (30 mg, 0.188 mmol) were dissolved in DMF (1.0 mL). Et3N (0.039 mL, 0.282 mmol) was added to the solution, followed by stirring at room temperature for 0.5 hour. Compound 1q (24.3 mg, 0.094 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 12 hours. The reaction solution was separated and purified by preparative HPLC to yield compound 12 (5.0 mg, 0.011 mmol).

[0459] MS m / z(ESI):455.4[M+H] + .

[0460] 1 H NMR (400MHz, DMSO-d6): δ8.10(s,1H),7.53(s,1H),7.38-7.27(m,4H),7.24-7.16(m,2H),6.86(d,J=7.8Hz,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=18.6Hz,1H),3.7 6(s,3H),2.81-2.71(m,2H),2.45-2.39(m,2H),0.93(d,J=6.7Hz,3H).

[0461] Example 13

[0462] (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

[0463] first step

[0464] Preparation of compound 13b

[0465] Compound 13a (300 mg, 1.616 mmol) was added to a solution of NaBH4 in THF, and the reaction was cooled to 0°C. A solution of I2 (451 mg, 1.78 mmol) in THF was added dropwise. After addition, the mixture was allowed to react at room temperature for 2 hours. The reaction was quenched by addition of aqueous KOH. Extraction, drying, and concentration afforded the crude product 13b, which was used directly in the next reaction.

[0466] MS m / z(ESI):172.01[M+H] + .

[0467] Step 2

[0468] Preparation of compound 13c

[0469] Di-tert-butyl dicarbonate (698.3 mg, 3.2 mmol) and Et3N (485.7 mg, 4.8 mmol) were added to a DCM solution of the crude product 13b and stirred at room temperature overnight. The reaction solution was extracted, dried, and concentrated to obtain the crude product, which was then separated by column chromatography to yield the target compound 13c (170 mg, 0.627 mmol).

[0470] MS m / z(ESI):294.09[M+Na] + .

[0471] Step 3

[0472] Preparation of compound 13d

[0473] DMP (212.07 mg, 0.5 mmol) was added to a DCM solution of compound 13c and stirred at room temperature for 2 hours. The reaction solution was purified by crude chromatography to obtain the target compound 13d (40 mg, 0.148 mmol).

[0474] Step 4

[0475] Preparation of compound 13e

[0476] 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, NaBH3CN (18.9 mg, 0.3 mmol) was slowly added and stirred at room temperature overnight. The reaction mixture was directly separated by reverse-phase column chromatography to obtain compound 13e (12 mg, 0.04 mmol).

[0477] MS m / z(ESI):299.17[M+H] + .

[0478] Step 5

[0479] Preparation of compound 13f

[0480] To a solution of compound 13e (12 mg, 0.04 mmol) in DCM (5.0 mL) was added excess TFA (1.0 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next reaction.

[0481] MS m / z(ESI):199.02[M+H] + .

[0482] Step 6

[0483] Preparation of compound 13

[0484] Compound 13f (11.89 mg, 0.06 mmol) and CDI (19.5 mg, 0.12 mmol) were dissolved in DMF (2.0 mL). Et3N (0.18 mmol) was added to the solution, followed by stirring at room temperature for 0.5 hour. Compound 1q (15.5 mg, 0.06 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 12 hours. The reaction solution was separated and purified by preparative HPLC to yield compound 13 (2.0 mg, 0.004 mmol).

[0485] MS m / z(ESI):483.28[M+H] + .

[0486] 1 H NMR(400MHz,CD3OD)δ8.44(s,1H),8.10(s,1H),7.49-7.42(m,2H),7.40-7.28(m,3H),6. 19(d,J=2.3Hz,1H),5.24(dd,J=11.2,4.1Hz,1H),4.80-4.69(m,2H),4.54(s,2H),4.18( d,J=18.2Hz,1H),3.84(s,3H),3.25(d,J=12.0Hz,1H),3.10-3.00(m,1H),2.95-2.85(m, 1H), 2.72 (s, 6H), 2.54 (dd, J = 15.6, 1.9Hz, 1H), 2.03 (q, J = 6.4Hz, 1H), 1.12-1.04 (m, 3H).

[0487] Example 14

[0488] (R)-N-((S)-2-(Dimethylamino)-1-phenylethyl)-6-methyl-2-(((1-trideuteriomethyl-1H-pyrazol-3-yl)methyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide

[0489] first step

[0490] Preparation of compound 14b

[0491] 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) was slowly added CD3I (2.75 g, 19.0 mmol) and stirred at room temperature for 2 hours. The reaction solution was extracted, dried, and concentrated to obtain a crude product, which was then separated by column chromatography to afford compound 14b (1.04 g, 7.26 mmol, 45% yield).

[0492] MS m / z(ESI):144.07[M+H] + .

[0493] Step 2

[0494] Preparation of compound 14c

[0495] 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 obtain a crude product 14c, which was used directly in the next reaction.

[0496] MS m / z(ESI):129.00[M+H] + .

[0497] Step 3

[0498] Preparation of compound 14d

[0499] Under a nitrogen 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 added dropwise and stirred at this temperature for 30 minutes. The reaction solution was then allowed to react at 50°C for 12 hours. After completion of the reaction, ammonium chloride solution was added to quench the reaction. Extraction, concentration, and drying gave the crude product 14d, which was used directly in the next reaction.

[0500] MS m / z(ESI):114.99[M+H] + .

[0501] Preparation of compound 14

[0502] Referring to the synthesis of Example 5, compound 14 (2 mg, 0.0044 mmol) was synthesized from compound 14d via three steps.

[0503] MS m / z(ESI):452.37[M+H] + .

[0504] Example 15

[0505] (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

[0506] first step

[0507] Synthesis of compound 15c

[0508] 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. NaBH(OAc)₃ (174 g, 825 mmol) was slowly added portionwise and stirred at room temperature overnight. The reaction mixture was extracted with DCM / MeOH (9:1, 500 × 2 mL) and washed with saturated brine. The organic phase was dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to afford crude compound 15c (80 g, 249 mmol).

[0509] MS m / z(ESI):250.3[M+H] +

[0510] Step 2

[0511] Synthesis of compound 15e

[0512] 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. NaBH(OAc)₃ (203 g, 962 mmol) was slowly added portionwise and stirred at room temperature for 2 days. The reaction solution was extracted with DCM / MeOH (9:1, 500 mL x 2) and washed with saturated brine. The organic phase was dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography on silica gel with 1-10% ethyl acetate in petroleum ether as the eluent to obtain compound 15e (40 g, 249 mmol).

[0513] MS m / z(ESI):336.3[M+H] +

[0514] Step 3

[0515] Synthesis of compound 15f

[0516] 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 slowly added in portions. The mixture was stirred at room temperature overnight. The reaction solution was extracted with ethyl acetate (100 mL x 2) and washed with saturated brine. The organic phase was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography on silica gel with 1-10% ethyl acetate in petroleum ether as the eluent to obtain compound 15f (14 g, 48.4 mmol).

[0517] MS m / z(ESI):262.2[M+H] + .

[0518] Step 4

[0519] Synthesis of compound 15g

[0520] To a solution of 15f (14 g, 48.4 mmol) in anhydrous MeOH (200 mL) at room temperature was added urea (11.6 mL, 193.5 mmol) and activated 4AMS (10 g). The mixture was heated to reflux and stirred overnight. The reaction solution was extracted with ethyl acetate (100 mL x 2) and washed with saturated brine. The organic phase was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by C18 reverse-phase silica gel column chromatography to afford compound 15g (8 g, 28 mmol).

[0521] MS m / z(ESI):272.2[M+H] + .

[0522] Step 5

[0523] Synthesis of compound 15h

[0524] 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 obtain 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 obtain compound 15h (6 g, 18.6 mmol) as a white solid.

[0525] MS m / z(ESI):308.2[M+H] +

[0526] Step 6

[0527] Synthesis of compound 15i

[0528] At room temperature, 15h (6 g, 18.6 mmol) and aqueous ammonia (8.0 mL) were dissolved in EtOH (100 mL). Activated Zn (15 g) was added, and the reaction mixture was heated under reflux with stirring overnight. The reaction mixture was extracted with ethyl acetate (100 mL x 2) and washed with saturated brine. The organic phase was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography on silica gel with 1-10% ethyl acetate in petroleum ether as the eluent to afford compound 15i (3.5 g, 12.2 mmol) as a tan solid.

[0529] MS m / z(ESI):288.1[M+H] + .

[0530] Step 7

[0531] Synthesis of compound 15k

[0532] Compound 15i (240 mg, 0.83 mmol), compound 15j (108 mg, 1.0 mmol), Xantphos-G3-Pd (79 mg, 0.08 mmol), and Cs2CO3 (325 mg, 1.25 mmol) were dissolved in dioxane (5.0 mL) and heated to 100°C under nitrogen for 4 hours at room temperature. The reaction solution was concentrated to obtain 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 obtain compound 15k (100 mg, 33.4%).

[0533] MS m / z(ESI):360.3[M+H] + .

[0534] Step 8

[0535] Synthesis of compound 15l

[0536] To compound 15k (100 mg, 0.28 mmol) in MeOH (5.0 mL) at room temperature was added 10% Pd / C (50 mg). The reaction was stirred at room temperature overnight under a hydrogen atmosphere. The reaction solution was concentrated to obtain 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 afford compound 15l (60 mg, yield: 84.5%).

[0537] MS m / z(ESI):256.3[M+H] +

[0538] Step 9

[0539] Synthesis of compound 15

[0540] To a solution of 151 (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 Et3N (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 Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by HPLC to yield compound 15 (20 mg, 48.3%).

[0541] MS m / z(ESI):446.5[M+H] + .

[0542] 1 H NMR (400MHz, CD3OD): δ8.54(s,2H),8.41(s,1H),8.25(d,J=6.7Hz,1H),7.97(dd,J=6.7,2.3Hz,1H ),7.92(d,J=2.2Hz,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 ,4.0Hz,1H),5.05-4.97(m,1H),4.91-4.82(m,1H),4.33(d,J=18.6Hz,1H),3.71-3.58(m,1H),3.3 9-3.33(m,1H),3.02-2.88(m,7H),2.66(d,J=16.1,1.5Hz,1H),2.59(s,3H),1.09(d,J=6.8Hz,3H).

[0543] Example 16

[0544] (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

[0545] first step

[0546] Synthesis of compound 16c

[0547] 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 solution was concentrated to obtain the crude product. This crude product was purified by flash column chromatography on silica gel using 1-5% ethyl acetate in petroleum ether as the eluent to afford compound 16c (1.0 g, yield: 67.6%).

[0548] Step 2

[0549] Synthesis of compound 16d

[0550] To compound 16c (1.0 g, 6.0 mmol) in MeOH (20 mL) at room temperature was added Pd / C (100 mg). The reaction was stirred at room temperature overnight under a hydrogen atmosphere. The reaction solution was concentrated to obtain 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 afford compound 16d (800 mg, 97.5% yield).

[0551] MS m / z(ESI):138.3[M+H] + .

[0552] The synthesis of compound 16 was based on compound 15. Compound 16d (33.9 mg, 0.25 mmol) was purified by three steps to obtain 16 (20.8 mg, 0.044 mmol).

[0553] MS m / z(ESI):475.4[M+H] + .

[0554] 1 H NMR(400MHz,CD3OD)δ8.17(s,1H),8.00(s,1H),7.61(s,1H),7.45-7.32(m,4H),7.28-7.2 3(m,1H),5.17(dd,J=11.0,4.3Hz,1H),4.88-4.72(m,2H),4.22(d,J=18.3Hz,1H),3.94(d, J=7.0Hz,2H),3.11(t,J=12.9,11.0Hz,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=6.8Hz,3H),0.66-0.53(m,2H),0.48-0.35(m,2H).

[0555] Example 17

[0556] (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

[0557] With reference to the preparation method of compound 15, compound 17 (10 mg, 0.023 mmol) was obtained from compound 15i (80 mg, 0.278 mmol) through three steps.

[0558] MS m / z(ESI):435.4[M+H] + .

[0559] Example 18

[0560] (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

[0561] first step

[0562] Synthesis of compound 18b

[0563] 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 mixture was quenched and concentrated to yield 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 afford compound 18b (700 mg, yield: 66.9%).

[0564] MS m / z(ESI):272.3[M+H] + .

[0565] Step 2

[0566] Synthesis of compound 18c

[0567] To compound 18a (300 mg, 1.1 mmol) dissolved in DCM (5.0 mL) was added DMP (930 mg, 2.2 mmol) at room temperature and stirred at room temperature for 1 hour. The reaction mixture was quenched and extracted with ethyl acetate (100 mL x 2), washed with saturated brine, and the organic phase was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography on silica gel with 1-20% ethyl acetate in petroleum ether as the eluent to afford compound 18c (100 mg, yield: 33.6%).

[0568] MS m / z(ESI):270.3[M+H] + .

[0569] Step 3

[0570] Synthesis of compound 18d

[0571] 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)₃ (235 mg, 1.1 mmol) was slowly added portionwise, and the mixture was stirred overnight at room temperature. The reaction solution was extracted with DCM / MeOH (9:1, 500 mL x 2), washed with saturated brine, and the organic phase was dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography on silica gel using 1-10% ethyl acetate in petroleum ether as the eluent to afford compound 18c (60 mg, yield: 56.8%).

[0572] MS m / z(ESI):285.3[M+H] + .

[0573] Step 4

[0574] Synthesis of compound 18e

[0575] To compound 18c (60 mg, 0.21 mmol) dissolved in DCM (5.0 mL) were added di-tert-butyl dicarbonate (69 mg, 0.32 mmol), DMAP (2 mg), and saturated Na2CO3 solution (1 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then extracted with ethyl acetate (100 mL × 2), washed with saturated brine, and the organic phase was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by flash column chromatography on silica gel using 1-20% ethyl acetate in petroleum ether as the eluent to afford compound 18e (70 mg, yield: 86.3%).

[0576] MS m / z(ESI):385.4[M+H] + .

[0577] Step 5

[0578] Synthesis of compound 18f

[0579] To compound 18e (70 mg, 0.18 mmol) in MeOH (10 mL) at room temperature was added 10% Pd / C (30 mg). The reaction was stirred at room temperature overnight under a hydrogen atmosphere. The reaction solution was concentrated to obtain 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 afford compound 18f (30 mg, yield: 65.8%).

[0580] MS m / z(ESI):251.5[M+H] + .

[0581] Compound 18 was synthesized according to Example 11, and compound 18 (22 mg, 0.049 mmol) was obtained through two steps of urea formation and Boc removal.

[0582] MS m / z(ESI):251.5[M+H] + .

[0583] 1 H NMR(400MHz,CD3OD)δ8.09(s,1H),7.48-7.46(m,1H),7.41-7.34(m,4H),7.3 2-7.26(m,1H),6.19(d,J=2.3Hz,1H),5.22-5.12(m,1H),4.81-4.68(m,2H), 4.54(s,2H),4.17(d,J=18.3Hz,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=15.8,1.6Hz,1H),1.07(d,J=6.8Hz,3H).

[0584] Example 19

[0585] (R)-N-((S)-2-Hexadeuteriodimethylamino-1-phenylethyl)-6-methyl-2-(((S)-1-(pyridin-2-yl)ethyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide

[0586] Compound 19 (15 mg, 0.032 mmol) was synthesized according to Example 6.

[0587] MS m / z(ESI):465.4[M+H] + .

[0588] 1H NMR (400MHz, CDCl3): δ8.49 (d, J=4.4Hz, 1H), 7.99 (s, 1H), 7.56 (td, J=7.7, 1.8Hz, 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=18.1Hz,1H),4.08(d,J=18.1Hz,1H),2.85(dd,J=15.4,5. 5Hz, 1H), 2.70-2.65 (m, 1H), 2.42-2.32 (m, 2H), 1.49 (d, J = 6.8Hz, 3H), 0.97 (d, J = 6.7Hz, 3H).

[0589] Biological evaluation

[0590] The present disclosure is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present disclosure.

[0591] Test Example 1

[0592] Test Example 1. Test of the inhibitory activity of the disclosed compounds on ovarian cancer cells (OVCAR3)

[0593] 1.1 Experimental materials and instruments (see Table 1)

[0594] Table 1 Experimental materials and instruments

[0595] 1.2 Experimental steps

[0596] Ovarian cancer cells OVCAR3 were cultured in RPMI 1640 with 10% FBS in a cell culture incubator at 37% and 5% CO2. On the first day, cells were plated in 96-well plates at a cell density of 2500 cells / well and cultured overnight in an incubator. Compound treatment was performed on the second day. The highest concentration of compound treatment was 10uM, 3-fold dilution, 9 concentrations, and the final concentration of DMSO was 0.1%. After the cells were cultured in the incubator for 5 days, the cell viability was tested using the Celltiter Glo assay kit (Promega). The test method was consistent with the operating method provided by the kit. GraphPad Prism 8 was used to process the data and calculate the IC 50 .

[0597] Calculation formula: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope)).

[0598] X: logarithmic value of compound concentration; Y: % inhibition.

[0599] Table 2. IC values ​​of the compounds disclosed herein against OVCAR3 50 (nM)

[0600] The activities of the compounds of Examples 2, 5-10, 12-17, and 19 of the present disclosure are better than those of Example 18.

[0601] Test Example 2

[0602] Test Example 2. Test of the inhibitory activity of the disclosed compounds on tumor cells

[0603] 2.1 Experimental materials and instruments (see Table 3)

[0604] Table 3 Experimental materials and instruments

[0605] 2.2 Experimental steps

[0606] Breast cancer cells MCF7 (ATCC #HTB-22) and T47D (ATCC #HTB-133) and pancreatic cancer cell line PANC-1 (ATCC #CRL-1469) were purchased from ATCC. Breast cancer cells MDA-MB-231 (Kebai #CBP60382), HCC1806 (Kebai #CBP60373), and MDA-MB-468 (Kebai #CBP60387), colorectal cancer cell line HCT-116 (Kebai #CBP60028), and leukemia cells OCI-AML-3 (Kebai #CBP60817) and MV-4-11 (Kebai #CBP60522) were purchased from Nanjing Kebai Biotechnology Co., Ltd.

[0607] OCI-AML-3 uses RPMI 1640 medium with 20% FBS; HCC1806 and T47D use RPMI 1640 medium with 10% FBS; MCF7, MDA-MB-231, MDA-MB-468 and PANC-1 use DMEM medium with 10% FBS; MV-4-11 uses IMDM medium with 20% FBS; HCT-116 uses MC'5A medium with 10% FBS.

[0608] Palbociclib-resistant cells were constructed from MCF7 parental cells and labeled MCF7 Palbo-R. Culture conditions were identical to those for the parental cells. All tumor cells were cultured at 37°C in a cell culture incubator with 5% CO2. Cells were seeded in 384-well plates at the appropriate cell 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 a humidified incubator. Compounds were treated the next day at a maximum concentration of 10 μM, with three-fold dilutions across nine concentrations, each in duplicate. The final DMSO concentration was 0.1%. Cells were cultured in an incubator. MDA-MB-231, PANC-1, MDA-MB-468, OCI-AML-3, and MV-4-11 were treated with drugs for 5 days; HCC1806, MCF7, MCF7Palbo-R, and HCT116 were treated with drugs for 7 days. Cell viability was assessed using the Celltiter Glo assay kit (Promega) using the same protocol as provided in the kit. Readings were performed using the Envision multi-function microplate reader. Data were processed and IC values ​​were calculated using GraphPad Prism 8. 50 .

[0609] Calculation formula Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)).

[0610] X: logarithmic value of compound concentration; Y: % inhibition.

[0611] Table 4. IC values ​​of the compounds of the present disclosure on tested tumor cells 50 (nM)

[0612] Table 5. IC values ​​of the compounds of the present disclosure on tested tumor cells 50 (nM)

[0613] The data in Tables 4 and 5 show that Examples 2, 6, 12 and 19 exhibit high inhibitory activity on various tumor cell lines.

[0614] Test 3

[0615] Test Example 3. Inhibitory activity test of the disclosed compounds on CDK kinases

[0616] 3.1 Experimental steps

[0617] The ADP-Glo ​​kinase assay is used to measure CDK kinase activity. Compounds were diluted in a 384-well plate using an Echo assay. A 3-fold serial dilution was performed starting at 10 μM, with duplicates for each concentration. The final DMSO concentration in the assay was 1%. 2.5 μL of CDK kinase solution prepared in assay buffer (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, 150 nM CDK12 / Cyclin K) was added, and the enzyme and compound were preincubated at room temperature for 10 minutes. Add 2.5uL of ATP prepared with assay buffer (concentration K m)&substrate solution (20uM ATP&0.1mg / mL Histone H1 Protein for CDK1 / CyclinB, 15uM ATP&0.1mg / mL Histone H1 Protein for CDK2 / CyclinE1, 200uM ATP&0.2mg / mL DYRKtide peptide for CDK4 / CyclinD1, 10uM ATP&0.1mg / mL Histone H1 Protein for CDK5 / p25, 200uM ATP&0.1mg / mL Histone H1 Protein for CDK6 / CyclinD3, 70uM ATP&0.2mg / mL MBP for CDK7 / Cyclin H / MAT1, 60uM ATP&0.2mg / mL PDKtide for CDK9 / Cyclin T1, 20uM ATP&80uM pS7-CTD peptide for CDK12 / CyclinK) was mixed and incubated at room temperature. CDK1 / 4 / 9 / 12 / 13 was incubated for 120 minutes, and CDK2 / 5 / 6 / 7 was incubated for 60 minutes. 4 μL ADP-Glo ​​reagent was added and incubated at room temperature for 40 minutes. 8 μL kinase detection reagent was added and incubated at room temperature for 40 minutes. The plate was read using the Envision multi-function microplate reader. Data were processed and IC was calculated using GraphPad Prism 8. 50 .

[0618] Calculation formula: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope)).

[0619] X: logarithmic value of compound concentration; Y: % inhibition.

[0620] Table 6. Inhibitory activity of the compounds of the present disclosure on CDK kinases (IC 50 , nM)

[0621] The data in Table 6 show that Examples 2 and 6 are significantly better than Janssen-01 in CDK2 / CDK7 selectivity.

[0622] Janssen-01 Prepared according to the method provided in WO2022064009A.

[0623] Test 4

[0624] Test Example 4. Human Liver Microsome Metabolism Study

[0625] 222.5 μL of human liver microsomes (protein concentration: 1 mg / mL) and 25 μL of NADPH (10 nM) were added to the incubation plate and preheated for 10 minutes. 2.5 μL of control compound and test compound (100 μM) were then added.

[0626] 30 μL aliquots were taken from the reaction solution at 0.5, 5, 10, 15, 20, and 30 minutes. The reaction was terminated by adding 5 volumes of cold acetonitrile containing IS (100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide), centrifuged, and 100 μL of the supernatant was mixed with 100 μL of ultrapure HO and used for LC-MS / MS analysis.

[0627] The slope value, k, was determined by linear regression of the percent parent drug remaining versus the natural logarithm of the incubation time curve.

[0628] In vitro half-life (in vitro T 1 / 2 ) is determined by the slope value: T1 / 2 = -(0.693 / k)

[0629] The in vitro T1 / 2 (minutes) was converted to in vitro intrinsic clearance (in vitro CL) using the following equation (mean of replicates): int , units are μL / min / mg protein):

[0630] Table 7 Residues of test compounds at different time points during incubation of human liver microsomes

[0631] Table 8 Metabolic elimination half-life and clearance rate of test compounds in human liver microsomes

[0632] Tables 7 and 8 show that compared with Example 2 and Janssen-01, more original drug residues were detected at various time points during the incubation of human liver microsomes, the elimination half-life was significantly longer, and the clearance rate was significantly slower, indicating that the metabolism was more stable.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, in, G1 is N or CR 1a ; The R 1 、R 2 、R 3 and R 1a are independently selected from hydrogen, deuterium, cyano, hydroxyl, C 1-6 Alkyl or halogen (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 selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl or 3 to 6 membered cycloalkyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or 3 to 6 membered cycloalkyl optionally substituted by one or more independently selected from R A Substituents substituted, the R A is selected from deuterium, halogen, hydroxy, cyano or 3- to 6-membered cycloalkyl; The L1 is selected from a chemical bond or C 1-6 Alkylene, the C 1-6 Alkylene is optionally substituted by one or more independently selected from R B Substituents substituted, the R B Selected from deuterium, halogen, hydroxyl, C 1-6 Alkoxy, amino, oxo, or two R groups attached to the same carbon atom B Together with the carbon atom to which they are attached, they form a 3- to 6-membered cycloalkyl group or a 3- to 7-membered heterocyclic group, wherein the heterocyclic group contains 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 independently selected from deuterium, cyano, halogen, hydroxyl, amino, C 2-6 Alkynyl, C 2-6 Alkenyl, -SC 1-6 Alkyl, C 1-6 Alkoxy, oxo, C 1-6 alkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 5- to 12-membered heteroaryl, 3- to 12-membered heterocyclyl, -NH-(C=O)-C 1-6 Alkyl, -NH-(C=O)-C 3-6 Cycloalkyl, -NH(C=O)-OC 1-6 Alkyl, -NH(C=O)-OC 3-6 Cycloalkyl, -O(C=O)NHC 1-6 Alkyl, -O(C=O)NH-C 3-6 Cycloalkyl, -(C=O)NH-C 1-6 Alkyl, -(C=O)-NH-C 3-6 Cycloalkyl, -(C=O)-C 1- 6-alkyl, -(C=O)-C 3-6 Cycloalkyl, -SO2-C 1-6 Alkyl, -SO2-C 3-6 Cycloalkyl, -SO2-NH2, -SO2-NH-C 1-6 Alkyl, -SO2-NH-C 3-6 Cycloalkyl, -SO2-N(C 1-6 Alkyl)2, -SO2-NH(C 3-6 Cycloalkyl)2, -S(O)(NH)-C 1-6 Alkyl, -S(O)(NH)-C 3-6 Cycloalkyl, The C 1-6 alkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 5- to 12-membered heteroaryl, 3- to 12-membered heterocyclyl, optionally substituted by one or more independently selected R C Substituents substituted, the R C Selected from deuterium, halogen, C 1-6 Alkoxy, hydroxy, amino, oxo, C 2-6 Alkynyl, C 2-6 Alkenyl, cyano, C 1-6 Hydroxyalkyl, 3 to 12 membered heterocyclic group, C 1-6 Alkyl, C 3-6 cycloalkyl, 6- to 10-membered aryl, or 5- to 12-membered heteroaryl; The R 11 Selected from hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 6 membered cycloalkyl, 3 to 12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, the C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 6 membered ring Alkyl, 3 to 12 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, optionally substituted by one or more independently selected from R D Substituents substituted, the R D Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, alkynyl, C 1-6 Alkoxy, C 1- 6-hydroxyalkyl, 3- to 6-membered cycloalkyl; The ring B is selected from a 5- to 12-membered heteroaryl group or a 6- to 12-membered aryl group; The R' is selected from hydrogen, cyano, C 1-6 alkyl, 3 to 6 membered cycloalkyl, 3 to 12 membered heterocyclic group, the C 1- 6-membered alkyl, 3 to 6-membered cycloalkyl, 3 to 12-membered heterocyclic group, optionally substituted by one or more independently selected R E Substituents substituted, the R E Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, alkynyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, 3- to 6-membered cycloalkyl, 3- to 7-membered heterocyclic group; The m is selected from 0 or 1; Said n is selected from 0, 1, 2, 3, 4 or 5; The o is selected from 0, 1, 2, 3 or 4.

2. A compound represented by formula (VI) or a pharmaceutically acceptable salt thereof, in, Said, L2 is selected from -NH- or -O-; The B ring is selected from a 5- to 12-membered heteroaryl group or a 6- to 12-membered aryl group; The L3 is selected from C 0-6 Alkylene, the C 0-6 Alkylene is optionally substituted by one or more independently selected from R I Substituents substituted, the R I Selected from deuterium, halogen, oxo, hydroxyl, amino or C 1-6 alkyl; The R 25 and R 26 are each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or R 25 and R 26 The nitrogen atom to which it is connected forms a 4- to 7-membered nitrogen-containing heterocyclic ring, wherein the 4- to 7-membered nitrogen-containing heterocyclic ring is optionally substituted by one or more independently selected from R J Substituents substituted, the R J is selected from halogen, hydroxy, cyano, nitro or amino; The R 27 Each independently selected from deuterium, halogen, hydroxyl, carboxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 6 membered cycloalkyl, -SC 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -NH-C 1-6 Alkyl, -NH(C 1-6 Alkyl)2, -(C=O)-NH2, Alkyl-(C=O)-NH-C 1-6 Alkyl, -(C=O)-NH-(C 1-6 alkyl)2, -(C=O)C 1-6 Alkyl, -NH-(C=O)C 1-6 alkyl; Said y is selected from 0, 1, 2, 3 or 4; The 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, provided that said R 4 、R 5 Not hydrogen at the same time.

3. The compound represented by formula (VI) or a pharmaceutically acceptable salt thereof according to claim 2, wherein L2 is -NH-.

4. The compound represented by formula (VI) or a pharmaceutically acceptable salt thereof according to claim 2, wherein L2 is -O-.

5. The compound represented by formula (VI) or a pharmaceutically acceptable salt thereof according to any one of claims 2 to 4, wherein L3 is -CH2CH2-.

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

7. The compound of formula (VI) or a pharmaceutically acceptable salt thereof according to any one of claims 2 to 6, wherein The R 27 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 2-6 Alkynyl, 3 to 6 membered cycloalkyl, 3 to 12 membered heterocycloalkyl, 5-12 membered aryl or heteroaryl; preferably halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkynyl; most preferably chloro, fluoro, trifluoromethyl or ethynyl.

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

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

10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 4 It is a methyl group.

11. The compound according to claim 10 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. 12 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 1 is a chemical bond.

13. The compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein L1 is selected from C 1-6 Alkylene, the C 1-6 Alkylene is optionally substituted by one or more independently selected from R B Substituents substituted, the R B Selected from deuterium, halogen, hydroxyl, C 1-6 Alkoxy; preferably, said L1 is methylene, said methylene optionally being independently selected from one or more R B Substituents substituted, the R B Selected from deuterium, halogen, hydroxyl, C 1-6 Alkoxy. 14 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the ring A is selected from a pyrazole ring, an imidazole ring, a tetrahydropyran ring, a pyrimidine ring or a cyclohexyl ring.

15. The compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein R 10 Selected from deuterium, cyano, C 2-6 Alkynyl, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, the C 2-6 Alkynyl, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 The alkyl group is optionally substituted by one or more independently selected R C Substituents substituted, the R C Selected from deuterium, halogen, C 1-6 Alkoxy, hydroxy, amino, oxo, C 2-6 Alkynyl.

16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, Selected from 17. The compound of formula (VI) or a pharmaceutically acceptable salt thereof according to claim 2, which is a compound of formula (VI-1) or formula (VI-2) or a pharmaceutically acceptable salt thereof, preferably a compound of formula (VI-1) or a pharmaceutically acceptable salt thereof, Said 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 L3 is selected from C 1-3 Alkylene (e.g. methylene), the C 1-3 Alkylene is optionally substituted by one or more independently selected from R I Substituents substituted, the R I Selected from deuterium, halogen, oxo, hydroxyl, amino or C 1-6 alkyl; The R 25 and R 26 are each independently selected from hydrogen, C 1-6 Alkyl (such as methyl, ethyl), the C 1-6 The alkyl group is optionally substituted with one or more deuterium groups; The R 27 Each independently selected from deuterium, halogen, hydroxyl, carboxyl, C 1-6 Alkyl (such as methyl), halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylene-3 to 6-membered cycloalkyl, 3 to 6-membered cycloalkyl, -SC 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -NH-C 1-6 Alkyl, -NH(C 1- 6 alkyl)2; Said y is selected from 0, 1, 2, 3 or 4; The R 4 C 1-6 alkyl; The R 5 、R 6 、R 7 、R 8 、R 9 are each independently selected from hydrogen, deuterium, halogen or C 1-6 alkyl; The L1 is selected from a connecting bond, or the L1 is selected from C 1-6 Alkylene (e.g. methylene), the C 1-6 Alkylene is composed of one or more independently selected R B Substituents substituted, the R B Selected from deuterium, halogen, hydroxyl, C 1-6 alkyl (e.g., methyl) 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 heterocyclic group; The R 10 Selected from deuterium, cyano, C 2-6 Alkynyl, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl (such as methyl), C 1-6 Alkylene-3 to 6-membered cycloalkyl, 3 to 6-membered cycloalkyl, 5 to 6-membered aryl, 5 to 6-membered heteroaryl, 5 to 12-membered heterocycloalkyl, -NH(C=O)-OC 1-6 Alkyl, -(C=O)NH-C 1-6 Alkyl or (C=O)NH2; The C 2-6 Alkynyl, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl, 5 to 6 membered aryl, 5 to 6 membered heteroaryl, 5 to 12 membered heterocycloalkyl, optionally substituted by one or more independently selected R C Substituents substituted, the R C Selected from deuterium, halogen, C 1-6 Alkoxy, C 1-6 Alkyl (such as methyl), hydroxy, amino, oxo, C 2-6 Alkynyl; The n is selected from 0, 1, 2 or 3. The compound or pharmaceutically acceptable salt thereof according to claim 17, wherein L2 is -NH-.

19. The compound according to any one of claims 17 or 18, or a pharmaceutically acceptable salt thereof, wherein the ring B is selected from pyridyl or phenyl, preferably phenyl, and the R 27 Each independently selected from deuterium, halogen, hydroxyl, carboxyl, C 1- 6 alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylene-3 to 6-membered cycloalkyl or 3 to 6-membered cycloalkyl.

20. The compound according to any one of claims 17 to 19, or a pharmaceutically acceptable salt thereof, which is a compound represented by formula (VI-1-A) or formula (VI-1-B) or a pharmaceutically acceptable salt thereof, preferably a compound represented by formula (VI-1-A) or a pharmaceutically acceptable salt thereof, The 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 respectively as defined in claim 17.

21. The compound according to any one of claims 17 to 20 or a pharmaceutically acceptable salt thereof, wherein L1 is a linking bond.

22. The compound according to any one of claims 17 to 20, or a pharmaceutically acceptable salt thereof, wherein L1 is selected from C 1-6 Alkylene, or said L1 is selected from C 1-6 Alkylene, the C 1-6 Alkylene is composed of one or more independently selected R B Substituents substituted, the R B Selected from deuterium, C 1-6 alkyl (eg methyl) or oxo.

23. The compound according to claim 22 or a pharmaceutically acceptable salt thereof, wherein L1 is selected from methylene, or L1 is selected from methylene, and the methylene is replaced by one or more independently selected R B Substituents substituted, the R B Selected from deuterium or C 1-6 Alkyl (eg, methyl).

24. The compound according to claim 22 or a pharmaceutically acceptable salt thereof, wherein L1 is selected from a methylene group, and the methylene group is replaced by one or more independently selected from R B Substituents substituted, the R B Selected from oxo.

25. The compound according to any one of claims 17 to 24, 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.

26. The compound according to any one of claims 17 to 25, or a pharmaceutically acceptable salt thereof, wherein the ring A is selected from pyrazolyl, imidazolyl, pyridinyl, phenyl, tetrahydropyranyl, pyrimidinyl, and cyclohexyl.

27. The compound according to any one of claims 17 to 26, or a pharmaceutically acceptable salt thereof, wherein R 10 Selected from deuterium, C 1-6 Alkyl, C 1-6 Alkylene-3 to 6-membered cycloalkyl, 3 to 6-membered cycloalkyl, 5 to 6-membered aryl, 5 to 6-membered heteroaryl, 5 to 12-membered heterocycloalkyl, -NH(C=O)-OC 1-6 Alkyl or -(C=O)NH-C 1-6 Alkyl or (C=O)NH2; The C 1-6 Alkyl, 5 to 6 membered aryl, 5 to 6 membered heteroaryl are optionally substituted by one or more independently selected R C Substituents substituted, the R C Selected from deuterium, halogen, C 1-6 Alkoxy, C 1-6 Alkyl, hydroxy, amino, oxo, C 2-6 Alkynyl; Said n is selected from 1, 2 or 3; Preferably, the R 10 is selected from methyl, methylene-cyclopropyl, cyclopropyl, wherein the methyl, methylene-cyclopropyl, cyclopropyl is optionally substituted by one or more independently selected from R C Substituents substituted, the R C Selected from deuterium.

28. The compound according to any one of claims 17 to 27, or a pharmaceutically acceptable salt thereof, Selected from 29. The compound according to any one of claims 17 to 28, or a pharmaceutically acceptable salt thereof, wherein R 27 are each independently selected from deuterium, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkylene-3 to 6-membered cycloalkyl, halo-C 1-6 Alkoxy, -NH-C 1-6 Alkyl, -NH(C 1-6 Alkyl) 2, preferably, the R 27 are each independently selected from halogen or C 1-6 Alkyl, most preferably fluoro, chloro or methyl.

30. The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, selected from:

31. An isotope substitution of the compound according to any one of claims 1 to 29, preferably, the isotope substitution is deuterium atom substitution.

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 pharmaceutically acceptable salt thereof, or an isotope-substituted product thereof, comprising the steps of condensing formula (VI-1-A-01) or a pharmaceutically acceptable salt thereof, or (VI-1-B-01) or a pharmaceutically acceptable salt thereof, with formula (VI-1-A-02) or a pharmaceutically acceptable salt thereof in the presence of carbonyldiimidazole, phosgene, or triphosgene. The 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 respectively as defined in claim 17.

33. A pharmaceutical composition comprising the compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof, or the isotope-substituted compound according to claim 31, and a pharmaceutically acceptable excipient.

34. Use of the compound according to any one of claims 1 to 30 or a pharmaceutically acceptable 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 treating and / or preventing a disease or condition associated with abnormal activity of serine / threonine kinase.

35. Use of the compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof, or the isotopic substitution according to claim 31 or the pharmaceutical composition according to claim 33 in the preparation of a medicament for treating and / or preventing 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.

36. Use of a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof, or an isotopic substitution according to claim 31 or a pharmaceutical composition according to claim 33 in the preparation of a medicament for treating and / or preventing a disease or condition selected from a proliferative disease, an inflammatory disease, an autoinflammatory disease, an autoimmune disease or an infectious disease.

37. The use according to any one of claims 35 or 36, wherein the proliferative disease is cancer; preferably, the cancer is selected from hematological tumors and solid tumors, the hematological tumor is selected from chronic lymphocytic leukemia, acute lymphocytic leukemia, T-cell acute lymphocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, and the solid tumor is selected from breast cancer, intestinal cancer, lung cancer, pancreatic cancer, prostate cancer, Ewing's sarcoma, osteoma, neuroblastoma, cervical cancer, ovarian cancer, gastric cancer, and liver cancer.

38. The use according to claim 37, wherein the breast cancer is triple-negative breast cancer or ER / PR+HER2-breast cancer, preferably, the ER / PR+HER2-breast cancer is ER / PR+HER2-breast cancer resistant to CDK4 / 6 inhibitors; 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.

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