WO2023116862A1 - Hydrogenated indole compound, and preparation method and medical use therefor - Google Patents

Abstract

Provided are a hydrogenated indole compound, and a preparation method and medical use therefor. In particular, provided are a hydrogenated indole compound represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing same, and a use thereof as a CDK4 inhibitor in the treatment of diseases or conditions related to CDK4 activity.

Description

Indoline compound, its preparation method and its application in medicine technical field

The disclosure belongs to the field of medicine, and relates to a hydrogenated indole compound, its preparation method and its application in medicine. In particular, the disclosure relates to indoline compounds represented by general formula (I), their preparation methods and pharmaceutical compositions containing such compounds, and their use as CDK4 inhibitors in the treatment of CDK4 activity-related diseases or disorders .

Background technique

An important feature that distinguishes tumor cells from normal cells is the abnormal regulation of the cell cycle, and uncontrolled cell replication is a basic feature of all cancers. Cyclin-dependent protein kinases (CDKs) are a group of serine/threonine protein kinases that are important factors in the regulation of cell cycle and transcription. Functionally, CDK family members can be divided into two categories: CDKs related to cell cycle (such as CDK 1/2/4/6) and CDKs related to cell transcription (such as CDK 7/9/12). CDK kinases need to combine with Cyclin to exert enzymatic activity.

CDK4/6 itself does not have enzymatic activity, and needs to be combined with cyclin D to be activated. The cyclin D-CDK4/6-Rb signaling pathway is a key pathway for advancing the cell cycle from G1 phase to S phase. Cyclin D is regulated by multiple mitotic signaling pathways, such as PI3K-AKT pathway, RAS-MEK pathway, and estrogen receptor pathway. Increased expression of cyclin D activates the kinase activity of CDK4/6 and phosphorylates the cell cycle negative regulator RB1, and non-phosphorylated RB1 has a transcriptional repressive effect on transcription factors E2F1/2/3. Phosphorylated RB1 is detached from E2F1/2/3, thereby releasing the transcriptional activity of E2F1/2/3, promoting the transcription of genes required for the cell to enter the S phase, prompting the cell to complete the G1-S phase transition, and the cell to complete the replication through mitosis . Other biological functions of CDK4 include regulation of aging, survival, genome stability, glycolysis, fat metabolism, and the mechanism is related to its kinase activity. CDK4 and its cyclin D expression are increased in a variety of tumors and are the ultimate targets of many oncogenic signals.

Although CDK4 and CDK6 have 70% amino acid homology, CDK4 is highly expressed in most tumor tissues, while CDK6 is weakly expressed, including mRNA and protein levels. In particular, the expression level of CDK4 in luminol, HER2-positive and triple-negative breast cancer is higher than that in normal tissues, and the three types are also similar, while the expression of CDK6 in breast cancer is not only weak, but also lower than normal Tissue expression level, among which the lowest expression in luminol-type breast cancer. Preclinical studies have shown that the occurrence and development of breast cancer mainly depends on CDK4. High expression of cyclin D1 is a pathogenic factor of breast cancer, but its downstream effector molecules have been unclear. Yu et al. (Cancer Cell (2006), 9(1), 23-32) found in the MMTV-ERBB2 mouse breast cancer model that knocking out CDK4 did not induce breast cancer at all, and all wild-type mice developed breast cancer. When the mammary gland tumors of wild mice were taken out and cultured in vitro, CDK4 was knocked down by siRNA and then inoculated back under the mammary fat pad of mice, breast cancer cells that did not express CDK4 could not regenerate tumors, while knocking down CDK6 did not affect tumor growth . Reddy et al. (Cancer Research (2005), 65 (22), 10174-10178) also confirmed in the MMTV-Neu and Ras mouse breast cancer models that the loss of CDK4 can reduce and delay the occurrence of mouse breast cancer, so the cyclin D1-CDK4 is the main factor driving breast cancer. CRISPR high-throughput knockout screens also confirmed that human breast cancer cell lines are more sensitive to loss of CDK4 and blood cell lines are more sensitive to loss of CDK6.

CDK4 gene knockout mice have no obvious hematopoietic system damage phenotype, but will suffer from body loss, decreased fertility in male mice, infertility in female mice, and insulin-deficient diabetes. CDK6 knockout mice showed damage to the hematopoietic system, including shrinkage of the thymus and atrophy of the cortex; normal white pulp in the spleen, shrinkage of the red pulp, and a slow cycle arrest in the S phase when T lymphocytes were activated. Preclinical studies have shown that CDK6 is a key factor for the activation of hematopoietic stem cells. Inhibition of CDK6 affects the reconstruction of the bone marrow hematopoietic system, thereby causing a decrease in hematopoietic or immune cells. No significant hematopoietic system damage has been found to be caused by inhibition of CDK4.

Breast cancer has surpassed lung cancer to become the largest cancer in the world. HR+, HER2- breast cancers are the most common subtype, accounting for about 70% of them. FDA currently approves 3 CDK4/6 drugs for the treatment of HR+, HER2- breast cancer. Neutropenia is the most serious side effect of these 3 drugs. Leukopenia will reduce the body's anti-infection ability, making it prone to various infections and death. Therefore, there is an urgent need to address neutropenia induced by CDK4/6 inhibitors.

Published CDK4 inhibitor patent applications include WO2019207463A1, WO2020224568A1, WO2017092635A1, WO2018045957A1, WO2014183520A1, etc.

Contents of the invention

The purpose of this disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

in:

Ring A is a heterocyclic group;

G is CR ^g or N;

Each R ¹ is the same or different, and each independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -(alkylene) _u - ^NRaRb , ^hydroxy , hydroxyalkyl , cycloalkyl, heterocyclyl, aryl and heteroaryl;

Or two ^R connected to the same carbon atom form a cycloalkyl or a heterocyclic group together with the carbon atom connected to it, and each of the cycloalkyl or heterocyclic groups is independently selected from the group consisting of halogen, alkyl, One or more of alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl and hydroxyalkyl are substituted;

^R is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group;

R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R and R ^g are the same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano , -(alkylene) _v -NR ^c R ^d , -C(O)R ^x , -C(O)NR ^y R ^z , hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and hetero Aryl, the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, Substituted by one or more of amino, hydroxyl and hydroxyalkyl;

R ⁸ and R ⁹ are the same or different, and each independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclic group, the alkyl, cycloalkyl and heterocyclic Each group is independently optionally selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -(alkylene) _w -NR ^e R ^f , hydroxyl and hydroxyalkyl multiple replaced;

Or R ⁸ and R ⁹ form a cycloalkyl or heterocyclic group together with the carbon atoms connected to them, and each of the cycloalkyl or heterocyclic groups is independently optionally selected from halogen, alkyl, alkoxy, haloalkyl , Haloalkoxy, cyano, -(alkylene) _y -NR ^m R ⁿ , hydroxyl and hydroxyalkyl are substituted by one or more;

Or R and ^R form a cycloalkyl group or a heterocyclic group together with the carbon atoms connected to them, and each of the cycloalkyl groups or heterocyclic groups is independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, One or more of haloalkoxy, cyano, -(alkylene) _z -NR ^j R ^k , hydroxyl and hydroxyalkyl;

R ^a , R ^b , R ^c , R ^d , Re , R ^f , R ^m , R ⁿ , R ^j , R ^k , ^{R y} and R ^z are the same or different, and each independently selected from a hydrogen atom, an alkyl group , haloalkyl, hydroxyalkyl and cycloalkyl;

R ^x is selected from alkyl, haloalkyl, hydroxyalkyl and cycloalkyl;

m is an integer from 0 to 15;

u is 0, 1, 2, 3 or 4;

v is 0, 1, 2, 3 or 4;

w is 0, 1, 2, 3 or 4;

y is 0, 1, 2, 3 or 4; and

z is 0, 1, 2, 3 or 4.

)。 In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is 3 to 8 membered heterocyclic group; preferably, ring A is 4 to 6 membered Heterocyclyl; Further preferably, Ring A is a 6-membered heterocyclyl; More preferably, Ring A is tetrahydropyranyl; Most preferably, Ring A is tetrahydropyran-4-yl (ie

).

In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein each R ¹ is the same or different, and each independently selected from hydrogen atom, halogen, C _{1- 6} alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, -(C _1-6 alkylene) _u -NR ^a R ^b , hydroxyl and C _1-6 hydroxyalkyl, R ^a , R ^b and u are as defined in the general formula (I); preferably, each R ¹ is the same or different, and each independently is a hydrogen atom or a hydroxyl group; more preferably, R ¹ For hydroxyl.

In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, 4, 5, 6 or 7; preferably, m is 0, 1 or 2; more preferably m is 1.

In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof:

in:

Q is selected from ^NRq , O and S;

^Rq is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group;

R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g and R ^1h are the same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy group, cyano group, -(alkylene) _u -NR ^a R ^b , hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclyl;

p is 0, 1 or 2;

q is 0, 1 or 2; and

G, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R, R ^a , R ^b and u are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R ² is selected from hydrogen atom, C _1-6 alkyl and C _{1- 6} haloalkyl; preferably, R ² is a hydrogen atom.

In some embodiments of the present disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein G is N.

In some embodiments of the present disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R ^g is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl.

In some embodiments of the present disclosure, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein p is 0 or 1; preferably, p is 1.

In some embodiments of the present disclosure, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein q is 0 or 1; preferably, q is 1.

In some embodiments of the present disclosure, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein R ^1c , R ^1d , R ^1e , R ^1f , R ^1g and R ^1h are the same or different, and each independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, -(C _1-6 Alkylene) _u -NR ^a R ^b , hydroxyl and C _1-6 hydroxyalkyl, R ^a , R ^b and u are as defined in general formula (II); preferably, R ^1c , R ^1d , R ^1e , R ^1f , R ^1g and R ^1h are the same or different, and each independently selected from a hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; more preferably, R ^1c , R ^1d , R ^1e , R ^1f , R ^1g and R ^1h are all hydrogen atoms.

In some embodiments of the present disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof :

in:

Q is selected from ^NRq , O and S;

^Rq is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group;

R ^1a and R ^1b are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -(alkylene) _u -NR ^a R ^b , Hydroxy, hydroxyalkyl, cycloalkyl and heterocyclyl;

R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R, R ^a , R ^b and u are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III-1) or Its pharmaceutically acceptable salts:

in:

Q is selected from ^NRq , O and S;

^Rq is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group;

R ^1a is selected from ^the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -(alkylene) _u - ^NRaRb , hydroxy, hydroxyalkyl, cycloalkyl and heterocyclyl;

R ^1b is ^selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -(alkylene) _u - ^NRaRb , hydroxyl, hydroxyalkyl, cycloalkyl and hetero ring group;

R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R, R ^a , R ^b and u are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R ⁸ and R ⁹ are the same or different, and each independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 hydroxyalkyl; or R ⁸ and R ⁹ together form 3 to 8-membered cycloalkyl or 3 to 8-membered heterocyclic group, each of the 3-8 membered cycloalkyl or 3-8 membered heterocyclic group is independently optionally selected from halogen, C _1-6 alkyl and C One or more of _1-6 haloalkyl groups are substituted; preferably, ^R8 and ^R9 are the same or different, and are each independently selected from hydrogen atom, halogen, _C1-6 alkyl, _C1-6 haloalkyl and C _1-6 hydroxyalkyl; or R ⁸ and R ⁹ form a 3 to 8-membered cycloalkyl group together with the carbon atoms they are connected to, and the 3 to 8-membered cycloalkyl group is optionally selected from halogen, C _1- One or more of ₆ alkyl and C _1-6 haloalkyl.

In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R ⁸ and R ⁹ are the same or different, and each independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 hydroxyalkyl, the C _1-6 alkyl is optionally selected from C One or more of _1-6 alkoxy, C _1-6 haloalkoxy, cyano and -(C _1-6 alkylene) _w -NR ^e R ^f are substituted; R ^e , R ^f and w As defined in general formula (I); preferably, R ⁸ and R ⁹ are the same or different, and each independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl and C _{1- 6} hydroxyalkyl; further preferably, ^R8 and ^R9 are the same or different, and each independently is a _C1-6 alkyl group; more preferably, ^R8 and ^R9 are the same or different, and each independently is a methyl group or ethyl.

In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R ⁸ and R ⁹ are connected to it The carbon atoms together form a 3 to 8 membered cycloalkyl group, and the 3 to 8 membered cycloalkyl group is optionally selected from one or more of halogen, C _1-6 alkyl and C _1-6 haloalkyl Substitution; preferably, R ⁸ and R ⁹ together form a 3 to 6 membered cycloalkyl group with the carbon atoms they are connected to, and the 3 to 6 membered cycloalkyl group is optionally selected from halogen, C _1-6 alkyl and C One or more of _1-6 haloalkyl groups are substituted; further preferably, R ⁸ and R ⁹ form cyclopentyl or cyclohexyl together with the carbon atoms they are connected to, and each of the cyclopentyl or cyclohexyl is independently any is optionally substituted by one or more selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl; more preferably, R ⁸ and R ⁹ together form a cyclopentyl group with the carbon atoms they are attached to, said The cyclopentyl of is optionally substituted by one or more selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl; most preferably, R ⁸ and R ⁹ together form a ring with the carbon atoms to which they are attached Amyl.

In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R ⁸ and R ⁹ are connected to it The carbon atoms together form a 3 to 8 membered cycloalkyl group or a 3 to 8 membered heterocyclic group, and each of the 3 to 8 membered cycloalkyl groups or the 3 to 8 membered heterocyclic group is independently optionally selected from halogen, C substituted by one or more of _1-6 alkyl and C _1-6 haloalkyl; preferably, R ⁸ and R ⁹ together form a 3 to 6 membered cycloalkyl or a 3 to 6 membered heterocyclic ring with the carbon atoms to which they are attached The 3 to 6-membered cycloalkyl group or the 3 to 6-membered heterocyclic group are each independently optionally selected from one or more of halogen, C _1-6 alkyl and C _1-6 haloalkyl Substitution; further preferably, R ⁸ and R ⁹ form tetrahydropyranyl, cyclopentyl or cyclohexyl together with the carbon atoms connected to them, and said tetrahydropyranyl, cyclopentyl or cyclohexyl are each independently any is optionally substituted by one or more selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl; more preferably, R ⁸ and R ⁹ form tetrahydropyranyl together with the carbon atoms they are connected to, The tetrahydropyranyl group is optionally substituted by one or more selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl; most preferably, R ⁸ and R ⁹ are connected to the carbon atoms together to form a tetrahydropyranyl group.

In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R ⁸ and R ⁹ are connected to it The carbon atoms together form a cyclohexyl group, and the cyclohexyl group is optionally substituted by one or more of halogen, C _1-6 alkyl and C _1-6 haloalkyl; preferably, R ⁸ and R ⁹ Together with the carbon atoms it is attached to form a cyclohexyl group.

In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R ⁸ and R ⁹ are connected to it The carbon atoms together form tetrahydropyranyl, cyclopentyl or cyclohexyl; preferably, R ⁸ and R ⁹ form cyclopentyl or cyclohexyl together with the carbon atoms they are connected to.

In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R and R ⁹ are linked to The carbon atoms together form a 3 to 8-membered heterocyclic group, and each of the 3 to 8-membered heterocyclic groups is independently optionally selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 One or more of ₆ haloalkyl, C _1-6 haloalkoxy, cyano, -(C _1-6 alkylene) _z -NR ^j R ^k , hydroxyl and C _1-6 hydroxyalkyl, R ^j , R ^k and z are as defined in general formula (I); preferably, R and R ⁹ form a 5 to 7-membered heterocyclic group together with the carbon atoms to which they are attached, and each of the 5 to 7-membered heterocyclic groups are independently optionally substituted by one or more selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, cyano, amino, hydroxyl and C _1-6 hydroxyalkyl.

In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R ⁷ is selected from a hydrogen atom, Halogen, C _1-6 alkyl, C _1-6 haloalkyl, cyano, -C(O)R ^x , -C(O)NR ^y R ^z and C _1-6 hydroxyalkyl, the C _{1 -6} alkyl is optionally substituted by one or more selected from C _1-6 alkoxy, C _1-6 haloalkoxy, cyano and amino, R ^x , R ^y and R ^z are as in the general formula ( I) defined; preferably, R ⁷ is selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 hydroxyalkyl; more preferably, R ⁷ is C _{1-6 6} alkyl or C _1-6 hydroxyalkyl; more preferably, R ⁷ is selected from methyl, isobutyl and C _1-6 hydroxyalkyl.

In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R ⁷ is selected from a hydrogen atom, Halogen, C _1-6 alkyl, C _1-6 haloalkyl, cyano, -C(O)R ^x , -C(O)NR ^y R ^z , C _1-6 hydroxyalkyl and 3 to 8 membered ring Alkyl, the C _1-6 alkyl and 3 to 8-membered cycloalkyl are optionally selected from one or more of C _1-6 alkoxy, C _1-6 haloalkoxy, cyano and amino R ^x , R ^y and R ^z are as defined in general formula (I); preferably, R ⁷ is selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _{1 -6} hydroxyalkyl groups and 3 to 8 membered cycloalkyl groups, the 3 to 8 membered cycloalkyl groups are optionally substituted by one or more hydroxyl groups; more preferably, R ⁷ is selected from C _1-6 alkyl, C _1-6 hydroxyalkyl groups and 3 to 8 membered cycloalkyl groups, the 3 to 8 membered cycloalkyl groups are optionally substituted by one or more hydroxyl groups; more preferably, ^R is selected from methyl, isopropyl, sec-butyl, cyclopentyl and cyclohexyl, said isopropyl, sec-butyl, cyclopentyl and cyclohexyl are each independently optionally substituted by one or more hydroxyl groups.

In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R ⁷ is selected from C _{1- 6} alkyl, C _1-6 hydroxyalkyl and 3 to 8 membered cycloalkyl, said 3 to 8 membered cycloalkyl is optionally substituted by one or more hydroxyl groups; preferably, R ⁷ is C _1-6 Alkyl or C _1-6 hydroxyalkyl.

In some embodiments of the present disclosure, the compound represented by general formula (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R ^1a is hydroxyl; and/or R ^1b is A hydrogen atom.

In some embodiments of the present disclosure, the compound represented by general formula (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R ^1a is selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, -(C _1-6 alkylene) _u -NR ^a R ^b , hydroxyl and C _1-6 hydroxyalkane R ^a , R ^b and u are as defined in general formula (I); preferably, R ^1a is selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 Haloalkyl, hydroxy and C _1-6 hydroxyalkyl; more preferably, R ^1a is hydroxy.

In some embodiments of the present disclosure, the compound represented by general formula (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R ^1a is selected from halogen, C _1-6 alkane radical, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, -(C _1-6 alkylene) _u -NR ^a R ^b , hydroxyl and C _{1- 6} hydroxyalkyl, R ^a , R ^b and u are as defined in general formula (I); preferably, R ^1a is selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 Haloalkyl, hydroxy and C _1-6 hydroxyalkyl; more preferably, R ^1a is hydroxy.

In some embodiments of the present disclosure, the compound represented by general formula (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R ^1b is selected from hydrogen atom, halogen, C _{1 -6} alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, -(C _1-6 alkylene) _u -NR ^a R ^b , hydroxyl and C _1-6 hydroxyalkyl, R ^a , R ^b and u are as defined in general formula (I); preferably, R ^1b is selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy group, C _1-6 haloalkyl, hydroxyl and C _1-6 hydroxyalkyl; more preferably, R ^1b is a hydrogen atom.

In some embodiments of the present disclosure, the compound represented by general formula (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein Q is NR ^q or O, and R ^q is as in general defined in formula (II); preferably, Q is O.

In some embodiments of the present disclosure, the compound represented by the general formula (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R ^q is a hydrogen atom or a C _1-6 alkane base.

In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R ³ is selected from hydrogen atom, Halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, -(C _1-6 alkylene) _v -NR ^c R ^d , -C(O)R ^x , -C(O)NR ^y R ^z , hydroxyl and C _1-6 hydroxyalkyl, the C _1-6 alkyl is optionally selected from C _1-6 alkoxy One or more of C _1-6 haloalkoxy, cyano and amino are substituted, R ^c , R ^d , R ^x , R ^y , R ^z and v are as defined in general formula (I); preferably Preferably, R ³ is selected from a hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; more preferably, R ³ is a hydrogen atom.

In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R ⁴ is selected from hydrogen atom, Halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, -(C _1-6 alkylene) _v -NR ^c R ^d , -C(O)R ^x , -C(O)NR ^y R ^z , hydroxyl and C _1-6 hydroxyalkyl, the C _1-6 alkyl is optionally selected from C _1-6 alkoxy One or more of C _1-6 haloalkoxy, cyano and amino are substituted, R ^c , R ^d , R ^x , R ^y , R ^z and v are as defined in general formula (I); preferably Preferably, R ⁴ is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; more preferably, R ⁴ is halogen; more preferably, R ⁴ is Cl.

In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a hydrogen atom; and /or R is a hydrogen atom.

In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from hydrogen atom, Halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, -(C _1-6 alkylene) _v -NR ^c R ^d , -C(O)R ^x , -C(O)NR ^y R ^z , hydroxyl and C _1-6 hydroxyalkyl, the C _1-6 alkyl is optionally selected from C _1-6 alkoxy One or more of C _1-6 haloalkoxy, cyano and amino are substituted, R ^c , R ^d , R ^x , R ^y , R ^z and v are as defined in general formula (I); preferably Preferably, R ⁵ is selected from a hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; more preferably, R ⁵ is a hydrogen atom.

In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R is selected from hydrogen atom, halogen , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, -(C _1-6 alkylene) _v -NR ^c R ^d , -C(O)R ^x , -C(O)NR ^y R ^z , hydroxyl and C _1-6 hydroxyalkyl, the C _1-6 alkyl is optionally selected from C _1-6 alkoxy , C _1-6 haloalkoxy, cyano and amino are substituted by one or more, R ^c , R ^d , R ^x , R ^y , R ^z and v are as defined in general formula (I); preferably , R is selected from a hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; more preferably, R is a hydrogen atom.

In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R ⁶ is selected from hydrogen atom, Halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, -(C _1-6 alkylene) _v -NR ^c R ^d , -C(O)R ^x , -C(O)NR ^y R ^z , hydroxyl and C _1-6 hydroxyalkyl, the C _1-6 alkyl is optionally selected from C _1-6 alkoxy One or more of C _1-6 haloalkoxy, cyano and amino are substituted, R ^c , R ^d , R ^x , R ^y , R ^z and v are as defined in general formula (I); preferably Preferably, R ⁶ is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; more preferably, R ⁶ is halogen; more preferably, R ⁶ is F.

In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R ^a and R ^b are the same or different, and each independently is a hydrogen atom or a C _1-6 alkyl group.

In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein u is 0, 1 or 2 .

In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R ^c and R ^d are the same or different, and each independently is a hydrogen atom or a C _1-6 alkyl group.

In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein v is 0, 1 or 2 .

In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R ^x is selected from C _{1- 6} alkyl, C _1-6 haloalkyl and C _1-6 hydroxyalkyl; preferably, R ^x is C _1-6 alkyl.

In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R ^y and R ^z are the same or different, and each independently is a hydrogen atom or a C _1-6 alkyl group.

In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R ^e and R ^f are the same or different, and each independently is a hydrogen atom or a C _1-6 alkyl group.

In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein w is 0, 1 or 2 .

In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R ^m and R ⁿ are the same or different, and each independently is a hydrogen atom or a C _1-6 alkyl group.

In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein y is 0, 1 or 2 .

In some embodiments of the present disclosure, the compound represented by general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein R ^j and R ^k are the same or different, and each independently is a hydrogen atom or a C _1-6 alkyl group.

In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein z is 0, 1 or 2 .

In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein Q is NR ^q or O, R ^q is a hydrogen atom or a C _1-6 alkyl group; G is CR ^g or N; R ^g is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; R ^1c , R ^1d , R ^1e , R ^1f , R ^1g and R ^1h are the same or different, and each independently selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; R ^1a is selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxyl and C _1-6 hydroxyalkyl, R ^1b is selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy and C _1-6 hydroxyalkyl; p is 0 or 1; q is 0 or 1; ^R is selected from hydrogen atom, C _1-6 alkyl and C _1-6 haloalkyl; R ⁸ and R ⁹ are the same or different, and each independently selected from a hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 hydroxyalkyl; or R ⁸ and R ⁹ form a 3 to 8-membered ring together with the carbon atoms to which they are attached Alkyl, the 3 to 8-membered cycloalkyl is optionally substituted by one or more selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl; R ⁷ is selected from hydrogen atom, halogen , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl and 3 to 8 membered cycloalkyl, said 3 to 8 membered cycloalkyl is optionally substituted by one or more hydroxyl groups ; R ³ is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; R ⁴ is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; R ⁵ is selected from R is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; R is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; and R ^is selected from hydrogen atom, Halogen, C _1-6 alkyl and C _1-6 haloalkyl.

In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein Q is NR ^q or O, R ^q is a hydrogen atom or a C _1-6 alkyl group; G is CR ^g or N; R ^g is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; R ^1c , R ^1d , R ^1e , R ^1f , R ^1g and R ^1h are the same or different, and each independently selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; R ^1a is selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxyl and C _1-6 hydroxyalkyl, R ^1b is selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy and C _1-6 hydroxyalkyl; p is 0 or 1; q is 0 or 1; ^R is selected from hydrogen atom, C _1-6 alkyl and C _1-6 haloalkyl; R ⁸ and R ⁹ are the same or different, and each independently selected from a hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 hydroxyalkyl; or R ⁸ and R ⁹ form a 3 to 8-membered ring together with the carbon atoms to which they are attached Alkyl, the 3 to 8-membered cycloalkyl is optionally substituted by one or more selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl; R ⁷ is selected from hydrogen atom, halogen , C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 hydroxyalkyl; R ³ is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; R ⁴ is selected from Hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; R ⁵ is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; R is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; and R ⁶ is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl.

In some embodiments of the present disclosure, the compound represented by the general formula (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein Q is O; R ^1a is selected from halogen, C _1-6 alkane radical, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxyl and C _1-6 hydroxyalkyl, R ^1b is selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy , C _1-6 haloalkyl, hydroxyl and C _1-6 hydroxyalkyl; R ⁸ and R ⁹ are the same or different, and are independently C _1-6 alkyl; or the carbon atom to which R ⁸ and R ⁹ are connected form cyclopentyl or cyclohexyl together, and said cyclopentyl or cyclohexyl is optionally substituted by one or more of halogen, C _1-6 alkyl and C _1-6 haloalkyl; R ^is selected from From C _1-6 alkyl, C _1-6 hydroxyalkyl and 3 to 8 membered cycloalkyl, said 3 to 8 membered cycloalkyl is optionally substituted by one or more hydroxyl groups; R ^is selected from hydrogen atom , halogen, C _1-6 alkyl and C _1-6 haloalkyl; R ⁴ is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; R ⁵ is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl ^; R is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; and R is selected from hydrogen atom, halogen, C _1-6 alkane and C _1-6 haloalkyl.

In some embodiments of the present disclosure, the compound represented by the general formula (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein Q is O; R ^1a is selected from halogen, C _1-6 alkane radical, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxyl and C _1-6 hydroxyalkyl, R ^1b is selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy , C _1-6 haloalkyl, hydroxyl and C _1-6 hydroxyalkyl; R ⁸ and R ⁹ are the same or different, and are independently C _1-6 alkyl; or the carbon atom to which R ⁸ and R ⁹ are connected Form cyclopentyl together, described cyclopentyl is optionally substituted by one or more selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl; R ⁷ is selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 hydroxyalkyl; R ³ is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; R ⁴ is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; R ⁵ is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; R is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; and R ⁶ is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl.

In some embodiments of the present disclosure, the compound represented by the general formula (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein Q is O; R ^1a is a hydroxyl group, and R ^1b is a hydrogen atom; R ⁸ and R ⁹ are the same or different, and each is independently a C _1-6 alkyl group; or R ⁸ and R ⁹ form tetrahydropyranyl, cyclopentyl or cyclohexyl together with the carbon atoms connected to them; R ⁷ is selected from From C _1-6 alkyl, C _1-6 hydroxyalkyl and 3 to 8 membered cycloalkyl, said 3 to 8 membered cycloalkyl is optionally substituted by one or more hydroxyl groups; R ³ is a hydrogen atom; ^R4 is halogen; ^R5 is a hydrogen atom; R is a hydrogen atom; and ^R6 is halogen.

In some embodiments of the present disclosure, the compound represented by the general formula (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein Q is O; R ^1a is a hydroxyl group, and R ^1b is a hydrogen atom; R ⁸ and R ⁹ are the same or different, and each is independently a C _1-6 alkyl group; or R ⁸ and R ⁹ form a cyclopentyl or cyclohexyl group together with the carbon atoms connected to them; R ⁷ is selected from methyl, isopropyl Base, sec-butyl, cyclopentyl and cyclohexyl, said isopropyl, sec-butyl, cyclopentyl and cyclohexyl are optionally substituted by one or more hydroxyl groups; R ³ is a hydrogen atom; R ⁴ is a halogen ; R ⁵ is a hydrogen atom; R is a hydrogen atom; and R ⁶ is a halogen.

In some embodiments of the present disclosure, the compound represented by the general formula (III) or (III-1) or a pharmaceutically acceptable salt thereof, wherein Q is O; R ^1a is a hydroxyl group, and R ^1b is a hydrogen atom; R ⁸ and R ⁹ are the same or different, and each is independently a C _1-6 alkyl group; or R ⁸ and R ⁹ form a cyclopentyl group together with the carbon atoms connected to them; R ⁷ is a C _1-6 alkyl group or C _{1 R is} a hydrogen atom; ^R is a halogen; R is a hydrogen ^atom ; R is a hydrogen atom; and ^{R is} a halogen.

Table A Typical compounds of the present disclosure include, but are not limited to:

Another aspect of the present disclosure relates to compounds represented by general formula (IA) or salts thereof:

in:

X is halogen; preferably, X is Cl;

^R is selected from Cl, Br, I, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -(alkylene) _v- ^NRcRd , ^hydroxyl , hydroxyalkyl, cycloalkyl, Heterocyclyl, aryl and heteroaryl, said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, alkyl, alkoxy, haloalkyl , Haloalkoxy, cyano, amino, hydroxyl and hydroxyalkyl are substituted by one or more;

G, R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R, R ^c , R ^d and v are as defined in the general formula (I).

Another aspect of the present disclosure relates to compounds represented by general formula (IIIA) or salts thereof:

in:

X is halogen; preferably, X is Cl;

^R is selected from Cl, Br, I, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -(alkylene) _v- ^NRcRd , ^hydroxyl , hydroxyalkyl, cycloalkyl, Heterocyclyl, aryl and heteroaryl, said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, alkyl, alkoxy, haloalkyl , Haloalkoxy, cyano, amino, hydroxyl and hydroxyalkyl are substituted by one or more;

R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R, R ^c , R ^d and v are as defined in the general formula (III).

Table B Typical compounds of the disclosure include, but are not limited to:

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound shown in general formula (IA) or its salt and the compound shown in general formula (IB) or its salt (preferably hydrochloride) generation coupling reaction, obtain the compound shown in general formula (I) or its salt medicinal salt,

in:

X is halogen; preferably, X is Cl;

Rings A, G, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R and m are as defined in general formula (I).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound shown in general formula (IA) or its salt and the compound shown in general formula (IIB) or its salt (preferably hydrochloride) generation coupling reaction, obtain the compound shown in general formula (II) or its salt medicinal salt,

in:

X is halogen; preferably, X is Cl;

G, Q, R ^1a , R ^1b , R 1c , R ^1d , R ^1e , R ^1f , R ^1g , R ^1h , R ² , R 3 , R ⁴ , R ⁵ , R ⁶ , R ⁷ , ^{R 8 , R 9} , R, p and q are as defined in the general formula (II).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound shown in general formula (IIIA) or its salt and the compound shown in general formula (IIIB) or its salt (preferably hydrochloride) generation coupling reaction, obtain the compound shown in general formula (III) or its salt medicinal salt,

in:

X is halogen; preferably, X is Cl;

Q, R ^1a , R ^1b , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R are as defined in general formula (III).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound shown in general formula (IIIA) or its salt and the compound shown in general formula (III-1B) or its salt (preferably hydrochloride) generation coupling reaction, obtain the compound shown in general formula (III-1) compound or a pharmaceutically acceptable salt thereof,

in:

X is halogen; preferably, X is Cl;

Q, R ^1a , R ^1b , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R are as defined in the general formula (III-1).

Another aspect of the present disclosure relates to a pharmaceutical composition containing the compounds shown in general formula (I), (II), (III), (III-1) and Table A of the present disclosure or its A pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The present disclosure further relates to compounds shown in general formula (I), (II), (III), (III-1) and Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them in the preparation of Use in medicines for inhibiting CDK; preferably, the CDK is CDK4.

The present disclosure further relates to compounds shown in general formula (I), (II), (III), (III-1) and Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them in the preparation of Use in medicines for the treatment and/or prevention of diseases or disorders mediated by CDK4; preferably, the diseases or disorders are selected from tumors, myelofibrosis, myelodysplastic syndrome, pulmonary hypertension, hypertension, neurodegeneration diseases and mucositis; more preferably, said disease or condition is cancer.

The present disclosure further relates to compounds shown in general formula (I), (II), (III), (III-1) and Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them in the preparation of Use in medicine for treating and/or preventing diseases or conditions; wherein said diseases or conditions are selected from breast cancer, endometrial cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, urinary Carcinoma of the road, urethra, prostate, testis, colorectum, sarcoma, bone, multiple myeloma, leukemia, myxoma, rhabdomyoma, leiomyoma, fibroma, lipoma, teratoma, laryngeal Carcinoma, nasopharyngeal cancer, oral cancer, lung cancer, lymphoma, mesothelioma, small intestine cancer, gastric cancer, esophageal cancer, pancreatic cancer, liver cancer, bile duct cancer, biliary tract cancer, gallbladder cancer, peritoneal cancer, thymus cancer, central nervous system tumor , retinoblastoma, glioblastoma multiforme, neurofibroma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, Brain cancer, salivary gland cancer and gastrointestinal stromal tumor; preferably, the disease or condition is breast cancer.

The present disclosure further relates to a method for inhibiting CDK, which comprises administering a therapeutically effective amount of a compound shown in general formula (I), (II), (III), (III-1) and Table A to a patient in need, or an alternative thereof A pharmaceutically acceptable salt, or a pharmaceutical composition comprising it; preferably, the CDK is CDK4.

The present disclosure further relates to a method of treating and/or preventing a disease or condition mediated by CDK4, which comprises administering a therapeutically effective amount of the general formula (I), (II), (III), (III-1) to a patient in need ) and a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it; preferably, the disease or disease is selected from tumors, myelofibrosis, myelodysplastic syndrome, pulmonary hypertension, Hypertension, neurodegenerative disease and mucositis; more preferably, said disease or condition is cancer.

The present disclosure further relates to a method for treating and/or preventing a disease or a disease, which comprises administering a therapeutically effective amount of the compounds of general formula (I), (II), (III), (III-1) and Table A to a patient in need. The compound or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising it; Wherein said disease or disease is selected from breast cancer, endometrial cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, cervical cancer, kidney cancer , bladder cancer, urothelial cancer, urethral cancer, prostate cancer, testicular cancer, colorectal cancer, sarcoma, bone cancer, multiple myeloma, leukemia, myxoma, rhabdomyoma, leiomyoma, fibroma, lipoma, Teratoma, laryngeal cancer, nasopharyngeal cancer, oral cancer, lung cancer, lymphoma, mesothelioma, small intestine cancer, stomach cancer, esophagus cancer, pancreatic cancer, liver cancer, bile duct cancer, biliary tract cancer, gallbladder cancer, peritoneal cancer, thymus cancer , central nervous system tumors, retinoblastoma, glioblastoma multiforme, neurofibroma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, brain cancer, salivary gland cancer and gastrointestinal stromal tumor; preferably, the disease or condition is breast cancer.

The present disclosure further relates to a compound shown in general formula (I), (II), (III), (III-1) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used for as medicine.

The present disclosure further relates to a compound shown in general formula (I), (II), (III), (III-1) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used for As a drug for inhibiting CDK; preferably, said CDK is CDK4.

The present disclosure further relates to a compound shown in general formula (I), (II), (III), (III-1) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used for As a medicine for treating and/or preventing diseases or diseases; wherein said diseases or diseases are selected from breast cancer, endometrial cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, urothelial Carcinoma, urethral cancer, prostate cancer, testicular cancer, colorectal cancer, sarcoma, bone cancer, multiple myeloma, leukemia, myxoma, rhabdomyoma, leiomyoma, fibroma, lipoma, teratoma, laryngeal cancer, Nasopharyngeal cancer, oral cancer, lung cancer, lymphoma, mesothelioma, small intestine cancer, stomach cancer, esophagus cancer, pancreatic cancer, liver cancer, bile duct cancer, biliary tract cancer, gallbladder cancer, peritoneal cancer, thymus cancer, central nervous system tumor, retina Blastoma, glioblastoma multiforme, neurofibroma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, brain cancer , salivary gland cancer and gastrointestinal stromal tumor; preferably, the disease or disease is breast cancer.

The disease or disease mediated by CDK4 described in the present disclosure is preferably selected from tumor, myelofibrosis, myelodysplastic syndrome, pulmonary hypertension, hypertension, neurodegenerative disease and mucositis; more preferably, the The disease or condition is cancer.

The disease or condition mediated by CDK4 described in the present disclosure is preferably selected from breast cancer, endometrial cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, urothelial cancer, urethral cancer , prostate cancer, testicular cancer, colorectal cancer, sarcoma, bone cancer, multiple myeloma, leukemia, myxoma, rhabdomyoma, leiomyoma, fibroma, lipoma, teratoma, laryngeal cancer, nasopharyngeal cancer, Oral cancer, lung cancer, lymphoma, mesothelioma, small intestine cancer, stomach cancer, esophagus cancer, pancreatic cancer, liver cancer, bile duct cancer, biliary tract cancer, gallbladder cancer, peritoneal cancer, thymus cancer, central nervous system tumor, retinoblastoma, Glioblastoma multiforme, neurofibroma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, brain cancer, salivary gland cancer, and Gastrointestinal stromal tumor; more preferably, the disease or condition is breast cancer.

Preferably, the lymphoma described in the present disclosure is selected from Hodgkin's disease and non-Hodgkin's lymphoma (e.g., mantle cell lymphoma, diffuse large B-cell lymphoma, follicle center lymphoma, marginal zone B-cell lymphoma) Lymphoma, lymphoplasmacytic lymphoma and peripheral T-cell lymphoma); said lung cancer is non-small cell lung cancer (NSCLC) (such as lung squamous cell carcinoma and lung adenocarcinoma, wherein lung adenocarcinoma is preferably bronchioloalveolar carcinoma) and Small cell lung cancer (SCLC); the kidney cancer is selected from renal cell carcinoma (RCC), clear cell and renal oncocytoma; the liver cancer is hepatocellular carcinoma (HCC); the neuroblastoma ( Also known as neuroblastoma) is medulloblastoma; the pancreatic cancer is pancreatic ductal adenocarcinoma; the sarcoma is chondrosarcoma; the colorectal cancer is colon cancer and rectal cancer; selected from chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myelogenous leukemia (CML) and acute myelogenous leukemia ( AML).

The compounds of the present disclosure or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising the same have higher selectivity for CDK4 than for CDK6.

As a general guide, the active compounds of the present disclosure are preferably presented in unit dosage form, or in such a form that the patient can self-administer as a single dose. The unit dosage form of a compound or composition of the present disclosure may be presented as a tablet, capsule, cachet, bottle, powder, granule, lozenge, suppository, reconstitution powder or liquid preparation. A suitable unit dosage may be from 0.1 to 1000 mg.

In addition to the active compound, the pharmaceutical composition of the present disclosure may contain one or more auxiliary materials selected from the following components: fillers (diluents), binders, wetting agents, disintegrants or excipients wait. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of active compound.

The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixir. Oral compositions can be prepared according to any method known in the art for the preparation of pharmaceutical compositions, and such compositions can contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, To provide pleasing and palatable medicinal preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over an extended period of time.

Oral formulations can also be provided in soft gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, or where the active ingredient is mixed with a water-soluble carrier or an oil vehicle.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

Oily suspensions can be formulated by suspending the active ingredient in a vegetable or mineral oil. The oily suspensions may contain a thickening agent. Sweetening and flavoring agents as mentioned above may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be vegetable oil, mineral oil or mixtures thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening agents, flavoring agents, preservatives and antioxidants. Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Among the acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase, and the injection or microemulsion can be injected into the patient's bloodstream by local bulk injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM. Model 5400 IV pump.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent. In addition, sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blended and fixed oil may be used. In addition, fatty acids are also used in the preparation of injectables.

The disclosed compounds may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

As is well known to those skilled in the art, the dosage of the drug to be administered depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the state of health of the patient, the behavior of the patient , the patient's diet, administration time, administration method, excretion rate, drug combination, disease severity, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dosage of the compound or the pharmaceutically acceptable salt Kinds can be validated against traditional treatment regimens.

Glossary

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated linear or branched aliphatic hydrocarbon group having 1 to 20 (for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie C _1-20 alkyl). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (ie, a C _1-12 alkyl group), more preferably an alkyl group having 1 to 6 carbon atoms (ie, a C _1-6 alkyl group). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl , 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 ,3-Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl , 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-di Methylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl , 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4 -Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3 -Ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. Alkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, substituents are preferably selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, ring One or more of alkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 1 to 20 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie C _1-20 alkylene). The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (ie, a C _1-12 alkylene group), more preferably an alkylene group having 1 to 6 carbon atoms (ie, a C _1-6 alkylene group). ). Non-limiting _examples include _{: -CH2-} , -CH( _CH3 )-, _-C ( _CH3 ) _2- , -CH2CH2-, -CH( _CH2CH3 )-, _-CH2CH (CH ₃ )-, -CH ₂ C(CH ₃ ) ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ -, etc. The alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents being preferably selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the definition of the alkyl group is as above, and it has 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (ie C _2-12 alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (ie, a C _2-6 alkenyl group). Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, and the like. Alkenyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents being preferably selected from D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, ring One or more of alkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein the definition of the alkyl group is as described above, and it has 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (ie C _2-12 alkynyl). The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (ie, a C _2-6 alkynyl group). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, the substituents being preferably selected from D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, ring One or more of alkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, and butoxy, and the like. Alkoxy may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, substituents are preferably selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic full carbocycle (ie monocyclic cycloalkyl) or polycyclic ring system (ie polycyclic cycloalkyl) having 3 to 20 (eg 3, 4 , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie 3 to 20 membered cycloalkyl). The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e. a 3 to 12 membered cycloalkyl group), more preferably a cycloalkyl group having 3 to 8 ring atoms (i.e. a 3 to 8 membered cycloalkyl group). ), most preferably a cycloalkyl group having 3 to 6 ring atoms (ie a 3 to 6 membered cycloalkyl group).

Said monocyclic cycloalkyl, non-limiting examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl , cycloheptatrienyl and cyclooctyl, etc.

The polycyclic cycloalkyl includes: spirocycloalkyl, condensed cycloalkyl and bridged cycloalkyl.

The term "spirocycloalkyl" refers to a polycyclic ring system that shares one carbon atom (called a spiro atom) between the rings, which may contain one or more double bonds in the ring, or may contain one or more rings selected from nitrogen, Oxygen and sulfur heteroatoms (the nitrogen may be optionally oxidized, i.e. form nitrogen oxides; the sulfur may be optionally oxo, i.e. form sulfoxides or sulfones, but excluding -O-O-, -O-S -or-S-S-), provided that it contains at least one full carbon ring and the point of attachment is on the full carbon ring, it has 5 to 20 (such as 5, 6, 7, 8, 9, 10, 11, 12, 13 , 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie 5 to 20 membered spirocycloalkyl). The spirocycloalkyl is preferably a spirocycloalkyl having 6 to 14 ring atoms (i.e. a 6 to 14 membered spirocycloalkyl), more preferably a spirocycloalkyl having 7 to 10 ring atoms (i.e. 7 to 10 member spirocycloalkyl). The spirocycloalkyl group includes single spirocycloalkyl and polyspirocycloalkyl (such as double spirocycloalkyl, etc.), preferably single spirocycloalkyl or double spirocycloalkyl, more preferably 3-membered/4-membered, 3-membered Yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/ 6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan/5 yuan or 7 yuan/6 yuan Single spirocycloalkyl. Non-limiting examples include:

其连接点可在任意位置；

Its connection point can be at any position;

等。

wait.

The term "fused cycloalkyl" refers to a polycyclic ring system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl to a heterocyclic One or more of cyclic groups, aryl groups or heteroaryl groups are condensed, wherein the point of attachment is on the monocyclic cycloalkyl group, which can contain one or more double bonds in the ring, and have 5 to 20 (for example, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie 5 to 20 membered fused cycloalkyl). The condensed cycloalkyl group is preferably a condensed cycloalkyl group having 6 to 14 ring atoms (i.e. a 6 to 14 membered fused cycloalkyl group), more preferably a fused cycloalkyl group having 7 to 10 ring atoms (i.e. 7 to 10 fused cycloalkyl). The fused cycloalkyl includes bicyclic fused cycloalkyl and polycyclic fused cycloalkyl (such as tricyclic fused cycloalkyl, tetracyclic fused cycloalkyl, etc.), preferably bicyclic fused cycloalkyl or tricyclic fused cycloalkyl , more preferably 3 yuan/4 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan , 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan Member/5-member or 7-member/6-membered bicyclic fused cycloalkyl group. Non-limiting examples include:

, its connection point can be at any position;

等。

wait.

The term "bridged cycloalkyl" refers to an all-carbon polycyclic ring system that shares two carbon atoms not directly connected between the rings, may contain one or more double bonds in the ring, and has 5 to 20 (for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie, 5 to 20 membered bridged cycloalkyl). The bridged cycloalkyl group is preferably a bridged cycloalkyl group having 6 to 14 carbon atoms (i.e. a 6 to 14 membered bridged cycloalkyl group), more preferably a bridged cycloalkyl group having 7 to 10 carbon atoms (i.e. 7 to 10 bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (such as tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl . Non-limiting examples include:

其连接点可在任意位置。

Its connection point can be anywhere.

Cycloalkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, substituents are preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkane One of oxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl or more.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e. monocyclic heterocyclyl) or polycyclic heterocyclic ring system (i.e. polycyclic heterocyclyl) containing at least one (eg 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e. form nitrogen oxides; the sulfur may optionally be oxo, i.e. form sulfoxides or sulfone, but not including -O-O-, -O-S- or -S-S-), with 3 to 20 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie 3 to 20 membered heterocyclyl). The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e. a 3 to 12 membered heterocyclic group); further preferably a heterocyclic group having 3 to 8 ring atoms (i.e. a 3 to 8 membered heterocyclic group) ); more preferably a heterocyclic group with 3 to 6 ring atoms (ie, a 3 to 6 membered heterocyclic group), a heterocyclic group with 4 to 6 ring atoms (ie, a 4 to 6 membered heterocyclic group) or a heterocyclic group with 5 A heterocyclyl group having up to 7 ring atoms (ie, a 5- to 7-membered heterocyclyl group); most preferably a heterocyclyl group having 5 or 6 ring atoms (ie, a 5- or 6-membered heterocyclyl group).

Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl , Thiomorpholinyl and Homopiperazinyl, etc.

The polycyclic heterocyclic groups include spiro heterocyclic groups, condensed heterocyclic groups and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system that shares one atom (called a spiro atom) between the rings, which may contain one or more double bonds in the ring, and at least one (such as 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e. to form nitrogen oxides; the sulfur may be optionally oxo, i.e. to form sulfoxides or sulfones, But not including -O-O-, -O-S- or -S-S-), the condition is to contain at least one monocyclic heterocyclic group and the point of attachment is on the monocyclic heterocyclic group, which has 5 to 20 (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie 5 to 20 membered spiroheterocyclyl). The spiroheterocyclyl is preferably a spiroheterocyclyl having 6 to 14 ring atoms (i.e. 6 to 14 membered spiroheterocyclyl), more preferably a spiroheterocyclyl having 7 to 10 ring atoms (i.e. 7 to 10 membered spiroheterocyclyl). The spiroheterocyclyl includes single spiroheterocyclyl and polyspiroheterocyclyl (such as double spiroheterocyclyl, etc.), preferably single spiroheterocyclyl or double spiroheterocyclyl, more preferably 3-membered/4-membered, 3-membered Yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/ 6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan/5 yuan or 7 yuan/6 yuan Monospiroheterocyclyl. Non-limiting examples include:

等。

wait.

The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system which shares two adjacent atoms between the rings, which may contain one or more double bonds, and which contains at least one (for example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e. to form nitrogen oxides; the sulfur may be optionally oxo, i.e. to form sulfoxides or sulfones, but not Including -O-O-, -O-S- or -S-S-), which is a monocyclic heterocyclic group fused with one or more monocyclic heterocyclic groups, or a monocyclic heterocyclic group with a cycloalkyl, aryl or heteroaryl One or more of the fused groups, wherein the point of attachment is on the monocyclic heterocyclic group, and there are 5 to 20 (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19 or 20) ring atoms (ie 5 to 20 membered fused heterocyclyl). The fused heterocyclic group is preferably a fused heterocyclic group having 6 to 14 ring atoms (ie, a 6 to 14 membered fused heterocyclic group), more preferably a condensed heterocyclic group having 7 to 10 ring atoms (ie, 7 to 10 membered fused heterocyclyl). The fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), preferably bicyclic fused heterocyclic groups or tricyclic fused heterocyclic groups, more preferably 3 Yuan/4 Yuan, 3 Yuan/5 Yuan, 3 Yuan/6 Yuan, 4 Yuan/4 Yuan, 4 Yuan/5 Yuan, 4 Yuan/6 Yuan, 5 Yuan/3 Yuan, 5 Yuan/4 Yuan, 5 Yuan/ 5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan/5 yuan Or a 7-membered/6-membered bicyclic condensed heterocyclic group. Non-limiting examples include:

等。

wait.

The term "bridged heterocyclyl" refers to a polycyclic heterocyclic ring system that shares two atoms that are not directly connected between the rings, and may contain one or more double bonds in the ring, and at least one (for example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e. to form nitrogen oxides; the sulfur may be optionally oxo, i.e. to form sulfoxides or sulfones, but not including -O-O-, -O-S- or -S-S-), which have 5 to 20 (eg 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie 5 to 20 membered bridged heterocyclyl). The bridged heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e. a 6 to 14 membered bridged heterocyclic group), more preferably a bridged heterocyclic group having 7 to 10 ring atoms (i.e. 7 to 10 bridged heterocyclyl). According to the number of rings, it can be divided into bicyclic bridged heterocyclic group and polycyclic bridged heterocyclic group (such as tricyclic bridged heterocyclic group, tetracyclic bridged heterocyclic group, etc.), preferably bicyclic bridged heterocyclic group or tricyclic bridged heterocyclic group base. Non-limiting examples include:

等。

wait.

The heterocyclyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkane One of oxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl or more.

The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., a monocyclic aryl) or a polycyclic aromatic ring system (i.e., a polycyclic aryl) having a conjugated π-electron system, which has 6 to 14 (e.g., 6 , 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (ie 6 to 14 membered aryl). The aryl group is preferably an aryl group having 6 to 10 ring atoms (ie, a 6 to 10 membered aryl group). The monocyclic aryl group, such as phenyl. Non-limiting examples of the polycyclic aryl group include: naphthyl, anthracenyl, phenanthrenyl and the like. The polycyclic aryl also includes the condensing of phenyl with one or more of heterocyclic or cycloalkyl, or the fused of naphthyl with one or more of heterocyclic or cycloalkyl, wherein the connection point On phenyl or naphthyl, and in this case, the number of ring atoms continues to mean the number of ring atoms in a polycyclic aromatic ring system, non-limiting examples include:

等。

wait.

Aryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, substituents are preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy one or Multiple.

The term "heteroaryl" refers to a monocyclic heteroaryl ring (ie, monocyclic heteroaryl) or a polycyclic heteroaryl ring system (ie, polycyclic heteroaryl) having a conjugated π-electron system, which contains at least one (eg 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e. form nitrogen oxides; the sulfur may optionally be oxo, i.e. forming sulfoxides or sulfones, but excluding -O-O-, -O-S- or -S-S-), which have 5 to 14 (eg 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ) ring atoms (ie 5 to 14 membered heteroaryl). The heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e. a 5 to 10 membered heteroaryl group), more preferably a heteroaryl group having 5 or 6 ring atoms (i.e. a 5 or 6 membered heteroaryl group). ).

等)、吡嗪基、哒嗪基等。 Non-limiting examples of the monocyclic heteroaryl include: furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl , pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (such as

etc.), pyrazinyl, pyridazinyl, etc.

The polycyclic heteroaryl, non-limiting examples include: indolyl, indazolyl, quinolinyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene group, quinazoline group, benzothiazolyl group, carbazolyl group, etc. The polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more aryls, wherein the point of attachment is on the aromatic ring, and in this case the number of ring atoms continues to represent the polycyclic heteroaryl The number of ring atoms in the system. The polycyclic heteroaryl also includes monocyclic heteroaryl fused with one or more of cycloalkyl or heterocyclic, wherein the point of attachment is on the monocyclic heteroaryl ring, and in this case, the ring The number of atoms continues to indicate the number of ring atoms in the polycyclic heteroaryl ring system. Non-limiting examples include:

等。

wait.

Heteroaryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, substituents are preferably selected from D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkane One or more of oxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "amino-protecting group" refers to an easily detachable group introduced on an amino group in order to keep the amino group unchanged when other parts of the molecule are reacted. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methoxycarbonyl (Fmoc), allyl Oxycarbonyl (Alloc), Trimethylsilylethoxycarbonyl (Teoc), Methoxycarbonyl, Ethoxycarbonyl, Phthalyl (Pht), p-Toluenesulfonyl (Tos), Trifluoroacetyl (Tfa), Trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl, etc.

The term "hydroxyl protecting group" refers to an easy-to-remove group introduced on the hydroxyl group, which is used to block or protect the hydroxyl group and react on other functional groups of the compound. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyl Diphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), methyl Acyl, acetyl, benzoyl, p-nitrobenzoyl, etc.

The term "cycloalkyloxy" refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.

The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

The term "aryloxy" refers to aryl-O-, wherein aryl is as defined above.

The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.

The term "alkylthio" refers to alkyl-S-, wherein alkyl is as defined above.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.

The term "deuteroalkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

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

The term "methylene" refers to = _CH2 .

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

The term "hydroxyl" refers to -OH.

The term "mercapto" refers to -SH.

The term "amino" refers to _-NH2 .

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

The term "oxo" or "oxo" refers to "=O".

The term "carbonyl" refers to C=O.

The term "carboxy" refers to -C(O)OH.

The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O )O-, wherein alkyl and cycloalkyl are as defined above.

Compounds of the present disclosure may exist in particular stereoisomeric forms. The term "stereoisomer" refers to isomers that are identical in structure but differ in the arrangement of the atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (e.g. racemates, mixtures of diastereomers) . Substituents in compounds of the present disclosure may be present with additional asymmetric atoms. All such stereoisomers, as well as mixtures thereof, are included within the scope of the present disclosure. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (L)-isomer. An isomer of a certain compound in the present disclosure can be prepared by asymmetric synthesis or chiral auxiliary agents, or, when the molecule contains a basic functional group (such as amino) or an acidic functional group (such as carboxyl), with appropriate optical Reactive acids or bases form diastereomeric salts, which are then resolved by conventional methods well known in the art to yield the pure isomers. Furthermore, separation of enantiomers and diastereomers is usually accomplished by chromatography.

表示未指定构型，即如果化学结构中存在手性异构体，键

可以为

或

或者同时包含

和

两种构型。对于所有的碳-碳双键，即使仅命名了一个构型，Z型和E型均包括在内。 In the chemical structures of the compounds described in this disclosure, the bond

Indicates that no configuration is specified, that is, if chiral isomers exist in the chemical structure, the bond

can be

or

or both

and

Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both Z and E forms are included.

The compounds of the present disclosure may exist in different tautomeric forms and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers that exist in equilibrium and are readily converted from one isomeric form to the other. It includes all possible tautomers, ie present as single isomers or as mixtures of said tautomers in any ratio. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactam, and the like. An example of a lactam-lactam equilibrium is shown below:

For example, when referring to pyrazolyl, it should be understood to include any one of the following two structures or a mixture of two tautomers:

All tautomeric forms are within the scope of the present disclosure, and the naming of compounds does not exclude any tautomers.

Compounds of the present disclosure include all suitable isotopic derivatives of their compounds. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that may be incorporated into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, etc., such as ² H (deuterium, D), respectively, ³ H (tritium, T), ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N ^{, 17} O, 18 O, ³² p, ³³ p, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹²⁹ I, and ¹³¹ I, etc., preferably deuterium.

Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic and side effects, increasing drug stability, enhancing curative effect, and prolonging the biological half-life of drugs. All permutations of isotopic composition of the disclosed compounds, whether radioactive or not, are included within the scope of the present disclosure. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom, wherein the replacement of deuterium may be partial or complete, and partial deuterium replacement means that at least one hydrogen is replaced by at least one deuterium.

In a compound of the present disclosure, when a position is specifically designated as "deuterium" or "D", this position is understood to mean that the abundance of deuterium is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e. at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (ie, at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (ie, at least 30% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (ie, at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (ie, at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (ie, at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (ie, at least 60% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (ie, at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (ie, at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (ie, at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (ie, at least 90% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (ie, at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (ie, at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (ie, at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% deuterium incorporation).

"Optionally" or "optionally" means that the subsequently described event or circumstance may but not necessarily occur, and it includes two situations in which the event or circumstance occurs or does not occur. For example, "alkyl optionally (optionally) substituted by halogen or cyano" includes the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen or cyano.

"Substituted" or "substituted" means that one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. Possible or impossible substitutions can be determined (by experiment or theory) by those skilled in the art without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated bond such as an alkene.

"Pharmaceutical composition" means a mixture containing one or more compounds described herein, or a pharmaceutically acceptable salt thereof, and other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.

"Pharmaceutically acceptable salt" refers to a salt of a compound of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals, and have proper biological activity. They can be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate group with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect. The determination of the therapeutically effective dose varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate therapeutically effective dose in individual cases can be determined by those skilled in the art according to routine tests.

As used herein, the term "pharmaceutically acceptable" means those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with patient tissues without undue toxicity, irritation, allergic reaction or Other problems or complications that have a reasonable benefit/risk ratio and are valid for the intended use.

As used herein, the singular forms "a", "an" and "the" include plural references and vice versa unless the context clearly dictates otherwise.

When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it means that the parameter may vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, the numbers are generally given for illustrative purposes only, and not for limitation.

Synthetic Methods of the Disclosed Compounds

In order to accomplish the purpose of this disclosure, this disclosure adopts the following technical solutions:

Option One

The preparation method of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof of the present disclosure, the method comprises:

The compound represented by general formula (IA) or its salt and the compound represented by general formula (IB) or its salt (preferably hydrochloride) take place coupling reaction under alkaline condition, obtain the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof,

in:

X is halogen; preferably, X is Cl;

Rings A, G, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R and m are as defined in general formula (I).

Option II

The preparation method of the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof of the present disclosure, the method comprises:

The compound represented by general formula (IA) or its salt and the compound represented by general formula (IIB) or its salt (preferably hydrochloride) take place coupling reaction under basic condition, obtain the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof,

in:

X is halogen; preferably, X is Cl;

G, Q, R ^1a , R ^1b , R 1c , R ^1d , R ^1e , R ^1f , R ^1g , R ^1h , R ² , R 3 , R ⁴ , R ⁵ , R ⁶ , R ⁷ , ^{R 8 , R 9} , R, p and q are as defined in the general formula (II).

third solution

The preparation method of the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof of the present disclosure, the method comprises:

The compound represented by the general formula (IIIA) or its salt and the compound represented by the general formula (IIIB) or its salt (preferably hydrochloride) undergo a coupling reaction under alkaline conditions to obtain the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof,

in:

X is halogen; preferably, X is Cl;

Q, R ^1a , R ^1b , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R are as defined in general formula (III).

Option four

The preparation method of the compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof of the present disclosure, the method comprises:

The compound shown in general formula (IIIA) or its salt and the compound shown in general formula (III-1B) or its salt (preferably hydrochloride) take place coupling reaction under alkaline condition, obtain general formula (III- 1) the indicated compound or its pharmaceutically acceptable salt,

in:

X is halogen; preferably, X is Cl;

Q, R ^1a , R ^1b , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R are as defined in the general formula (III-1).

The reagents that provide basic conditions in the above synthesis scheme include organic bases and inorganic bases. The organic bases include but are not limited to triethylamine, pyridine, N,N-diisopropylethylamine, n-butyllithium, Lithium diisopropylamide, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide or 1,8-diazabicycloundec-7-ene; the inorganic bases include but are not limited to Sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide and potassium hydroxide; preferably N,N-diisopropylethylamine.

The reaction of the above steps is preferably carried out in a solvent, and the solvent used includes but is not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, methylene chloride, petroleum ether, Ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromo Ethane and its mixtures.

Detailed ways

The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.

Example

Compound structures were determined by nuclear magnetic resonance (NMR) or/and mass spectroscopy (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). The determination of NMR is carried out with Bruker AVANCE NEO 500M, the determination solvent is deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard is tetramethyl Silane (TMS).

The determination of MS uses Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid mass spectrometer (manufacturer: Agilent, MS model: 6110/6120Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model : waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

High-performance liquid chromatography (HPLC) was analyzed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 liquid chromatograph.

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

Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs were used for HPLC preparation.

Chiral preparations were performed using Gilson GX-281 and Shimadzu LC-20AP preparative chromatographs.

The CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).

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 of thin-layer chromatography separation and purification products is 0.4mm. ~0.5mm.

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

Kinase average inhibition rate and IC ₅₀ value were measured with NovoStar microplate reader (BMG Company, Germany).

The known starting materials of the present disclosure can be adopted or synthesized according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui chemical companies.

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

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

The hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

The pressurized hydrogenation reaction uses Parr 3916EKX hydrogenation instrument and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation instrument.

The hydrogenation reaction is usually vacuumized and filled with hydrogen, and the operation is repeated 3 times.

For the microwave reaction, a CEM Discover-S 908860 microwave reactor was used.

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

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

The monitoring of the reaction process in the embodiment adopts thin-layer chromatography (TLC), the developer used for reaction, the eluent system of the column chromatography that purifies compound adopts and the developer system of thin-layer chromatography comprise: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and Alkaline or acidic reagents such as acetic acid for adjustment.

Example 1

(3S,4R)-4-((5-chloro-4-(3-ethyl-7-fluoro-2,3-dimethyl-3H-indol-5-yl)pyrimidin-2-yl)amino ) Tetrahydro

-2H-pyran-3-ol 1 (mixture of diastereoisomers)

first step

(4-Bromo-2-fluorophenyl)hydrazine hydrochloride 1b

Under ice bath, the compound 4-bromo-2-fluoroaniline 1a (20g, 105.25mmol, Shanghai Pide) was dissolved in concentrated hydrochloric acid (100mL), and an aqueous solution (10mL) of sodium nitrite (7.6g, 110.15mmol) was added, Stir for 30 minutes, add the reaction solution dropwise into a solution of stannous chloride dihydrate (72g, 319.08mmol) in concentrated hydrochloric acid (100mL), return to room temperature and react for 16 hours with stirring, filter, and filter cake with methyl tert-butyl ether After washing and drying the solid, the crude title compound 1b (22 g) was obtained, and the product was directly used in the next reaction without purification.

MS m/z (ESI): 204.9 [M+1].

second step

(±)-5-Bromo-3-ethyl-7-fluoro-2,3-dimethyl-3H-indole 1d

Compound 1b (0.2g, 828.19μmol), (±)-3-methylpentan-2-one 1c (107.83mg, 1.07mmol, Shanghai Bide) was dissolved in acetic acid (5mL), refluxed for 5 hours, and the reaction The liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 1d (100 mg, yield: 44.7%). MS m/z (ESI): 270.2 [M+1].

third step

(±)-3-Ethyl-7-fluoro-2,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-3H-indole 1e

Compound 1d (0.21g, 777.37μmol), pinacol diboronate (296.10mg, 1.16mmol, Shaoyuan, Shanghai) was dissolved in 1,4-dioxane (10mL), and potassium acetate (190.73mg, 1.94 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (126.86mg, 155.47μmol, Shanghai Titan), nitrogen replacement, 100 ℃ reaction After 3 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1e (190 mg, yield: 77%).

MS m/z (ESI): 318.2 [M+1].

the fourth step

(±)-5-(2,5-dichloropyrimidin-4-yl)-3-ethyl-7-fluoro-2,3-dimethyl-3H-indole 1g

Compound 1e (190mg, 598.9μmol), 2,4,5-trichloropyrimidine 1f (120.8mg, 658.8μmol, Shanghai Shaoyuan), tetrakis (triphenylphosphine) palladium (138.4mg, 119.7μmol, Shanghai Titan) , Potassium carbonate (165.3mg, 1.19mmol) was dissolved in a mixed solution of 6mL 1,4-dioxane and water (V:V=5:1). Under nitrogen atmosphere, reacted at 95°C for 8 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1g (150 mg, yield: 74%).

MS m/z (ESI): 338.2 [M+1].

the fifth step

(3S,4R)-4-((5-chloro-4-(3-ethyl-7-fluoro-2,3-dimethyl-3H-indol-5-yl)pyrimidin-2-yl)amino ) Tetrahydro-2H-pyran-3-ol 1 (mixture of diastereoisomers)

Compound 1g (150 mg, 455 μmol), (3S,4R)-4-amino-3-hydroxytetrahydropyran hydrochloride (104.91 mg, 683.01 μmol, Nanjing Yaoshi) was dissolved in the solvent dimethyl sulfoxide (2 mL) , add N,N-diisopropylethylamine (235.39mg, 1.82mmol), react at 100°C for 1.5 hours, the reaction solution is concentrated under reduced pressure, and the residue is subjected to high performance liquid chromatography (Waters-2545, chromatographic column: YMC Triart -Exrs, Prep 30*150mm, 5μm, C18; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-50%, flow rate: 30mL/min) purification to obtain the title compound 1 (10 mg, mixture of diastereomers, yield: 5.2%).

MS m/z (ESI): 419.2 [M+1].

¹ H NMR(500MHz,CD ₃ OD):δ8.35(s,1H),7.69-7.65(m,1H),7.60(dd,1H),4.01-3.95(m,2H),3.92(dd,1H ),3.61(td,1H),3.50(td,1H),3.23(dd,1H),2.35(s,3H),2.17-2.05(m,2H),1.97(dd,1H),1.68-1.61( m,1H),1.41(s,3H),0.45(t,3H).

Example 2

(3S,4R)-4-((5-Chloro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)pyrimidine-2 -yl)amino)tetrahydro-2H-pyran-3-ol 2

first step

5'-Bromo-7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole] 2b

Compound 1b (1g, 4.1410mmol), cyclopentyl ethyl ketone 2a (487.71mg, 4.34mmol, Shanghai Pide) were dissolved in acetic acid (5mL), and refluxed for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 2b (500 mg, yield: 42.7%).

MS m/z (ESI): 282.2 [M+1].

second step

7'-fluoro-2'-methyl-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)spiro[cyclopentane- 1,3'-indole]2c

Compound 2b (0.5g, 1.77mmol), pinacol diboronate (450mg, 1.77mmol) was dissolved in 1,4-dioxane (10mL), potassium acetate (43.5mg, 4.43mmol) was added, [1 , 1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (289mg, 354μmol), replaced with nitrogen, reacted at 100°C for 3 hours, the reaction solution was concentrated under reduced pressure, and the residue The material was purified by silica gel column chromatography with eluent system B to obtain the title compound 2c (500 mg, yield: 85.7%).

MS m/z (ESI): 330.2 [M+1].

third step

5'-(2,5-Dichloropyrimidin-4-yl)-7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]2d

Compound 2c (197 mg, 598.9 μmol), 2,4,5-trichloropyrimidine 1f (120.8 mg, 658.8 μmol), tetrakis(triphenylphosphine) palladium (138.4 mg, 119.7 μmol, adamas), potassium carbonate (165.3 mg, 1.19mmol) was dissolved in 6mL of a mixed solution of 1,4-dioxane and water (V:V=5:1). Under nitrogen atmosphere, reacted at 95°C for 8 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 2d (150 mg, yield: 71.5%).

MS m/z (ESI): 350.2 [M+1].

the fourth step

(3S,4R)-4-((5-Chloro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)pyrimidine-2 -yl)amino)tetrahydro-2H-pyran-3-ol 2

Compound 2d (140 mg, 399 μmol), (3S,4R)-4-amino-3-hydroxytetrahydropyran hydrochloride (105 mg, 683 μmol) was dissolved in dimethyl sulfoxide (2 mL), and N,N- Diisopropylethylamine (235.39 mg, 1.82 mmol) was reacted at 100°C for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs, Prep 30*150mm, 5 μm, C18; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and Acetonitrile, gradient ratio: acetonitrile 40%-55%, flow rate: 30 mL/min) was purified to obtain the title compound 2 (10 mg, yield: 5.2%).

MS m/z (ESI): 431.2 [M+1].

¹ H NMR (500MHz, CD ₃ OD): δ8.35(s,1H),7.74(d,1H),7.60(dd,1H),4.01-3.95(m,2H),3.95-3.90(m,1H ), 3.62(td,1H), 3.50(td,1H), 3.22(dd,1H), 2.41(s,3H), 2.24-09(m,8H), 1.92-1.83(m,2H).

Example 3

(3S,4R)-4-((5-chloro-4-(7-fluoro-2,3,3-trimethyl-3H-indol-5-yl)pyrimidin-2-yl)amino)tetrahydro -2H-pyran-3-ol 3

first step

5-Bromo-7-fluoro-2,3,3-trimethyl-3H-indole 3b

Compound 1b (1.5g, 6.2mmol), 3-methyl-2-butanone 3a (600mg, 6.9mmol, Shanghai Pide) was dissolved in acetic acid (5mL), and refluxed for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 3b (880 mg, yield: 55.3%).

MS m/z (ESI): 256.2 [M+1].

second step

7-Fluoro-2,3,3-trimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3H-ind indole 3c

Compound 3b (880mg, 3.43mmol), pinacol diboronate (900mg, 3.54mmol) were dissolved in 1,4-dioxane (25mL), potassium acetate (400mg, 4.07mmol) was added, [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (250 mg, 341 μmol), nitrogen replacement, 100 ° C reaction for 3 hours, the reaction solution was concentrated under reduced pressure, and the residue was used Purification by silica gel column chromatography with eluent system B gave the title compound 3c (910 mg, yield: 87.3%).

MS m/z (ESI): 304.2 [M+1].

third step

5-(2,5-Dichloropyrimidin-4-yl)-7-fluoro-2,3,3-trimethyl-3H-indole 3d

Compound 3c (350 mg, 1.15 mmol), compound 1f (180 mg, 981 μmol), tetrakis(triphenylphosphine) palladium (114 mg, 98.6 μmol), sodium carbonate (210 mg, 1.98 mmol) were dissolved in 6 mL of 1,4-dioxo Hexacyclic and water (V:V=5:1) mixed solution. Under nitrogen atmosphere, reacted at 95°C for 8 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 3d (240 mg, yield: 75.4%).

MS m/z (ESI): 324.2 [M+1].

the fourth step

(3S,4R)-4-((5-chloro-4-(7-fluoro-2,3,3-trimethyl-3H-indol-5-yl)pyrimidin-2-yl)amino)tetrahydro -2H-pyran-3-ol 3

Compound 3d (150 mg, 462 μmol), (3S,4R)-4-amino-3-hydroxytetrahydropyran hydrochloride (70 mg, 597 μmol) was dissolved in dimethyl sulfoxide (2 mL), and N,N- Diisopropylethylamine (120mg, 0.92mmol) was reacted at 110°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs, Prep 30*150mm, 5 μm, C18; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and Acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL/min) was purified to obtain the title compound 3 (43 mg, yield: 22.9%).

MS m/z (ESI): 405.2 [M+1].

¹ H NMR (500MHz, CD ₃ OD): δ8.35(s,1H),7.72(s,1H),7.63-7.58(d,1H),3.99-3.90(m,3H),3.63-3.59(m ,1H),3.52-3.47(m,1H),3.25-3.21(m,1H),2.39(s,3H),2.15-2.11(m,1H),1.68-1.60(m,1H),1.42(s ,6H).

Example 4

(3S,4R)-4-((5-chloro-4-(7-fluoro-2-(2-hydroxypropan-2-yl)-3,3-dimethyl-3H-indol-5-yl )pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol 4

first step

2-(5-Bromo-7-fluoro-3,3-dimethyl-3H-indol-2-yl)propan-2-ol 4b

Compound 1b (2g, 8.28mmol), 2,4-dimethyl-3-pentanone 4a (946mg, 8.28mol, Shanghai Titan) was dissolved in acetic acid (20mL), and refluxed for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs, Prep 30*150mm, 5 μm, C18; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and Acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL/min) was purified to obtain the title compound 4b (250 mg, yield: 10%).

MS m/z (ESI): 300.1 [M+1].

second step

2-(7-fluoro-3,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3H- Indol-2-yl)propan-2-ol 4c

Compound 4b (180mg, 599μmol), pinacol borate (228mg, 899μmol) was dissolved in 1,4-dioxane (10mL), potassium acetate (176mg, 1.79mmol) was added, [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (43mg, 60μmol), replaced with nitrogen, reacted at 100°C for 3 hours, concentrated the reaction solution under reduced pressure, and the residue was purified by silica gel column Purification by chromatography with eluent system B afforded the title compound 4c (176 mg, yield: 85.7%).

MS m/z (ESI): 348.2 [M+1].

third step

2-(5-(2,5-Dichloropyrimidin-4-yl)-7-fluoro-3,3-dimethyl-3H-indol-2-yl)propan-2-ol 4d

Compound 4c (240 mg, 691 μmol), compound 1f (126.7 mg, 691 μmol), tetrakis(triphenylphosphine) palladium (79.8 mg, 69.1 μmol), potassium acetate (135.6 mg, 1.38 mmol) were dissolved in 6 mL of 1,4- In the mixed solution of dioxane and water (V:V=5:1). Under nitrogen atmosphere, reacted at 95°C for 8 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 4d (216 mg, yield: 85%).

MS m/z (ESI): 368.2 [M+1].

the fourth step

(3S,4R)-4-((5-chloro-4-(7-fluoro-2-(2-hydroxypropan-2-yl)-3,3-dimethyl-3H-indol-5-yl )pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol 4

Compound 4d (270 mg, 733 μmol), (3S,4R)-4-amino-3-hydroxytetrahydropyran hydrochloride (168.9 mg, 1.1 mmol) was dissolved in dimethyl sulfoxide (5 mL), and N, N-Diisopropylethylamine (478mg, 3.6mmol) was reacted at 110°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs, Prep 30*150mm, 5 μm, C18; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and Acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL/min) was purified to obtain the title compound 4 (28 mg, yield: 8.5%).

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

¹ H NMR (500MHz, CDCl ₃ ): δ8.34(s,1H),7.54(dd,1H),7.51(d,1H),5.28(d,1H),4.68(s,1H),4.08(dd ,1H),4.01(m,1H),3.87(m,1H),3.69-3.60(m,1H),3.49(td,1H),3.21(dd,1H),3.04(s,1H),2.11- 2.01 (m, 1H), 1.79-1.70 (m, 1H), 1.69 (s, 6H), 1.61 (d, 6H).

Example 5

(3S,4R)-4-((5-chloro-4-(7-fluoro-2-(2-hydroxybutane-2-yl)-3,3-dimethyl-3H-indole-5- base) pyrimidin-2-yl) amino) tetrahydro-2H-pyran-3-ol 5 (mixture of diastereoisomers)

first step

2,4-Dimethylhexan-3-ol 5b (mixture of diastereomers)

Dissolve (±)-2-methylbutyraldehyde 5a (5g, 58.05mmol, Shanghai Titan) in tetrahydrofuran (100mL), add 1M tetrahydrofuran solution (100mL) of isopropylmagnesium bromide dropwise at -78°C, and keep the temperature for reaction After 1 hour, naturally return to room temperature and react for 14 hours. Add saturated ammonium chloride to the reaction solution to quench, extract with methyl tert-butyl ether (50mL×3), combine the organic phases, wash with saturated sodium chloride solution, anhydrous sulfuric acid Sodium-dried, filtered to remove the desiccant, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 5b (4 g, diastereoisomer mixture, yield: 52.9%).

second step

(±)-2,4-Dimethylhexan-3-one 5c

Dissolve compound 5b (4g, 30.71mmol) in dichloromethane (50mL), add pyridinium chlorochromate (13.24g, 61.42mmol, Shanghai Bide), silica gel (13g, 61.4mmol), and stir for 14 hours. liquid, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 5c (1.8 g), which was directly used in the next reaction without purification.

third step

(±)-2-(5-Bromo-7-fluoro-3,3-dimethyl-3H-indol-2-yl)butan-2-ol 5d

(±)-5-Bromo-2-(sec-butyl)-7-fluoro-3,3-dimethyl-3H-indole 5e

Compound 1b (1g, 4.14mmol), crude compound 5c (850mg, 6.62mol) were dissolved in acetic acid (20mL), and after 5 hours of reflux reaction, water (5mL) was added, and the reflux reaction was continued for 2 hours, and the reaction solution was concentrated under reduced pressure. The residue was subjected to high performance liquid chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs, Prep 30*150mm, 5 μm, C18; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: Acetonitrile 30%-45%, flow rate: 30mL/min) was purified to obtain the title compound 5d (94mg, yield: 7.2%) and 5e (100mg, yield: 8.1%)

Compound 5d: MS m/z (ESI): 314.2 [M+1].

Compound 5e: MS m/z (ESI): 298.2 [M+1].

the fourth step

(3S,4R)-4-((5-chloro-4-(7-fluoro-2-(2-hydroxybutane-2-yl)-3,3-dimethyl-3H-indole-5- base) pyrimidin-2-yl)

Amino)tetrahydro-2H-pyran-3-ol 5 (mixture of diastereoisomers)

Using the third step to the fifth step of the synthetic route in Example 1, the third step starting material compound 1d was replaced by compound 5d to obtain the title compound 5 (1 mg, diastereomer mixture, yield: 2%).

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

¹ H NMR (500MHz, CD ₃ OD): δ8.35(s,1H),7.64(d,1H),7.56(dd,1H),4.01-3.90(m,3H),3.61(td,1H), 3.50(td,1H),3.23(dd,1H),2.23-2.17(m,1H),2.17-2.11(m,1H),1.83(dq,2H),1.66(s,3H),1.62(s, 3H), 1.58(s, 3H), 0.97(t, 3H).

Example 6

(3S,4R)-4-((4-(2-(sec-butyl)-7-fluoro-3,3-dimethyl-3H-indol-5-yl)-5-chloropyrimidine-2- base)amino)tetrahydro-2H-pyran-3-ol 6 (mixture of diastereoisomers)

Using the third step to the fifth step of the synthetic route in Example 1, the third step starting material compound 1d was replaced by compound 5e to obtain the title compound 6 (10 mg, diastereomer mixture, yield: 21.3%).

MS m/z (ESI): 447.1 [M+1].

¹ H NMR(500MHz,CD ₃ OD):δ8.35(s,1H),7.70(d,1H),7.62-7.57(m,1H),3.99-3.90(m,3H),3.61(dt,1H ),3.50(td,1H),3.25-3.20(m,1H),2.88(q,1H),2.17-2.11(m,1H),1.97-1.91(m,1H),1.75-1.71(m,1H ), 1.64(dd,1H), 1.44(d,6H), 1.33(d,3H), 0.99(t,3H).

Example 7

(3S,4R)-4-((5-chloro-4-(7-fluoro-2-(1-hydroxycyclopentyl)-3,3-dimethyl-3H-indol-5-yl)pyrimidine -2-yl)amino)tetrahydro-2H-pyran-3-ol 7-p1

(3S,4R)-4-((5-Chloro-4-(7'-fluoro-2'-(2-hydroxypropan-2-yl)spiro[cyclopentane-1,3'-indole]- 5'-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol 7-p2

first step

1-(5-Bromo-7-fluoro-3,3-dimethyl-3H-indol-2-yl)cyclopent-1-ol 7b

2-(5'-Bromo-7'-fluorospiro[cyclopentane-1,3'-indol]-2'-yl)propan-2-ol 7c

5'-Bromo-7'-fluoro-2'-isopropylspiro[cyclopentane-1,3'-indole]7d

Compound 1b (1g, 4.14mmol), 1-cyclopentyl-2-methylpropan-1-one 7a (527.8mg, 3.76mol, using the known method "Journal of the American Chemical Society, 2004, vol.126 , #33, prepared from p10240-10241") was dissolved in acetic acid (10mL), and after reflux reaction for 5 hours, water (5mL) was added, and the reflux reaction was continued for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was analyzed by high performance liquid chromatography Method (Waters-2545, chromatographic column: YMC Triart-Exrs, Prep 30*150mm, 5μm, C18; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, Flow rate: 30 mL/min) to obtain a mixture of title compounds 7b and 7c (50 mg, yield: 4%) and 7d (70 mg, yield: 5.7%).

Compound 7b and Compound 7c: MS m/z (ESI): 326.2 [M+1].

Compound 7d: MS m/z (ESI): 310.2 [M+1].

second step

(3S,4R)-4-((5-chloro-4-(7-fluoro-2-(1-hydroxycyclopentyl)-3,3-dimethyl-3H-indol-5-yl)pyrimidine -2-yl)amino)tetrahydro-2H-pyran-3-ol 7-p1

(3S,4R)-4-((5-Chloro-4-(7'-fluoro-2'-(2-hydroxypropan-2-yl)spiro[cyclopentane-1,3'-indole]- 5'-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol 7-p2

Using the third step to the fifth step of the synthetic route in Example 1, the third step raw material compound 1d was replaced by a mixture of compounds 7b and 7c to obtain the title compound 7-p1 (5 mg, yield: 10.3%) and 7-p2 (4 mg, yield: 8.3%).

MS m/z (ESI): 475.2 [M+1].

Single configuration compound 7-p1:

MS m/z (ESI): 475.2 [M+1].

C18,2.7μm，3.0*30mm；流动相：水(1‰三氟醋酸)，乙腈，梯度配比：乙腈10％-95％)。 HPLC analysis: retention time 2.623 minutes, purity: 96% (chromatographic column:

C18, 2.7μm, 3.0*30mm; mobile phase: water (1‰ trifluoroacetic acid), acetonitrile, gradient ratio: acetonitrile 10%-95%).

¹ H NMR (500MHz, CDCl ₃ ): δ8.33(s,1H),7.69(ddt,1H),7.58(d,1H),5.28(d,1H),4.72-4.68(m,1H),4.08 (dd,1H),4.01(dd,1H),3.92-3.82(m,1H),3.65(tt,1H),3.49(td,1H),3.20(dd,1H),2.70(p,2H), 2.35 (s, 1H), 2.21-1.99 (m, 6H), 1.87-1.74 (m, 2H), 1.73 (s, 6H).

Single configuration compound 7-p2:

MS m/z (ESI): 475.2 [M+1].

C18,2.7μm，3.0*30mm；流动相：水(1‰三氟醋酸)，乙腈，梯度配比：乙腈10％-95％)。 HPLC analysis: retention time 2.670 minutes, purity: 95% (chromatographic column:

C18, 2.7μm, 3.0*30mm; mobile phase: water (1‰ trifluoroacetic acid), acetonitrile, gradient ratio: acetonitrile 10%-95%).

¹ H NMR (500MHz, CDCl ₃ ): δ8.34(s,1H),7.73-7.42(m,2H),5.27(d,1H),4.68(s,1H),4.08(dd,1H),4.01 (dt,1H),3.87(dddd,1H),3.70-3.61(m,1H),3.49(td,1H),3.21(dd,1H),2.34(qd,2H),2.13-1.85(m,7H ), 1.80-1.68(m,2H), 1.61(d,6H).

Example 8

(3S,4R)-4-((5-Chloro-4-(7'-fluoro-2'-isopropylspiro[cyclohexane-1,3'-indol]-5'-yl)pyrimidine- 2-yl)amino)tetrahydro-2H-pyran-3-ol 8-p1

(3S,4R)-4-((5-chloro-4-(2-cyclohexyl-7-fluoro-3,3-dimethyl-3H-indol-5-yl)pyrimidin-2-yl)amino ) Tetrahydro-2H-pyran-3-ol 8-p2

first step

(±)-1-Cyclohexyl-2-methylpropan-1-ol 8c

Dissolve isobutyraldehyde 8b (8.2g, 113.72mmol, 10.4mL, Shanghai Titan) in anhydrous tetrahydrofuran (80mL), add 1.3M tetrahydrofuran solution 8a (105mL) of cyclohexylmagnesium chloride dropwise under ice-cooling, and keep the temperature for reaction 1 After 1 hour, add water (105mL) to the reaction solution to quench, add 150mL of tetrahydrofuran to dilute, adjust to acidity with 1M dilute hydrochloric acid, extract with ethyl acetate (100mL×3), combine the organic phases, wash with saturated sodium chloride solution, anhydrous Dry over sodium sulfate, remove the desiccant by filtration, and concentrate the filtrate under reduced pressure to obtain the crude title compound 8c (18 g). The product is directly used in the next reaction without purification.

second step

1-cyclohexyl-2-methylpropan-1-one 8d

Dissolve the crude product 8c (18g, 115.2mmol) in 150mL of dichloromethane, add 20g of diatomaceous earth and pyridinium chlorochromate (PCC) (36.77g, 170.5mmol, Shanghai Bide), stir for 2 hours, filter, filter The cake was washed with ether (200 mL×2), the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 8d (8 g, yield: 45.1%).

third step

5'-Bromo-7'-fluoro-2'-isopropylspiro[cyclohexane-1,3'-indole] 8e

5-Bromo-2-cyclohexyl-7-fluoro-3,3-dimethyl-3H-indole 8f

2-(5'-Bromo-7'-fluorospiro[cyclohexane-1,3'-indol]-2'-yl)propan-2-ol 8g

1-(5-Bromo-7-fluoro-3,3-dimethyl-3H-indol-2-yl)cyclohex-1-ol 8h

Compound 1b (1g, 4.14mmol), compound 8d (958mg, 6.2mol) were dissolved in acetic acid (10mL), after reflux reaction for 5 hours, water (5mL) was added, and reflux reaction was continued for 48 hours, the reaction solution was concentrated under reduced pressure, and the residue Purification by silica gel column chromatography with eluent system B afforded a mixture of title compounds 8e and 8f (300 mg, yield: 22.3%) and a mixture of 8g and 8h (100 mg, yield: 7.4%).

Compound 8e and Compound 8f: MS m/z (ESI): 324.2 [M+1].

Compound 8g and Compound 8h: MS m/z (ESI): 340.2 [M+1].

the fourth step

(3S,4R)-4-((5-Chloro-4-(7'-fluoro-2'-isopropylspiro[cyclohexane-1,3'-indol]-5'-yl)pyrimidine- 2-yl)amino)tetrahydro-2H-pyran-3-ol 8-p1

(3S,4R)-4-((5-chloro-4-(2-cyclohexyl-7-fluoro-3,3-dimethyl-3H-indol-5-yl)pyrimidin-2-yl)amino ) Tetrahydro-2H-pyran-3-ol 8-p2

Using the third step to the fifth step of the synthetic route in Example 1, the third step raw material compound 1d was replaced by a mixture of compounds 8e and 8f to obtain the title compound 8-p1 (10 mg, yield: 4.1%) and 8-p2 (30 mg, yield: 12.4%).

Single configuration compound 8-p1:

MS m/z (ESI): 473.2 [M+1].

C18,1.7μm,2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。 ¹H NMR(500MHz,CD ₃OD):δ8.36(s,1H),8.15(s,1H),7.70(d,1H),3.99(dt,2H),3.95-3.89(m,1H),3.63(td,1H),3.49(t,1H),3.25-3.11(m,2H),2.19-2.12(m,1H),2.12-2.00(m,5H),1.97(d,1H),1.88(d,2H),1.68-1.55(m,2H),1.34(d,6H),1.28-1.32(m,1H)。 HPLC analysis: retention time 1.55 minutes, purity: 96% (chromatographic column: ACQUITY

C18, 1.7μm, 2.1*50mm; mobile phase: water (10mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%). ¹ H NMR(500MHz,CD ₃ OD):δ8.36(s,1H),8.15(s,1H),7.70(d,1H),3.99(dt,2H),3.95-3.89(m,1H), 3.63(td,1H),3.49(t,1H),3.25-3.11(m,2H),2.19-2.12(m,1H),2.12-2.00(m,5H),1.97(d,1H),1.88( d,2H), 1.68-1.55(m,2H), 1.34(d,6H), 1.28-1.32(m,1H).

Single configuration compound 8-p2:

MS m/z (ESI): 473.2 [M+1].

C18,1.7μm,2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。 ¹H NMR(500MHz,CD ₃OD):δ8.35(d,1H),7.69(s,1H),7.59(d,1H),3.97(dd,2H),3.92(d,1H),3.61(q,1H),3.50(t,1H),3.23(t,1H),2.79(t,1H),2.17-2.09(m,1H),1.92(s,1H),1.88(d,3H),1.81(d,1H),1.74(q,2H),1.64(q,1H),1.48(d,2H),1.43(s,6H),1.36-1.31(m,1H)。 HPLC analysis: retention time 1.59 minutes, purity: 95% (chromatographic column: ACQUITY

C18, 1.7μm, 2.1*50mm; mobile phase: water (10mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%). ¹ H NMR (500MHz, CD ₃ OD): δ8.35(d,1H),7.69(s,1H),7.59(d,1H),3.97(dd,2H),3.92(d,1H),3.61( q,1H),3.50(t,1H),3.23(t,1H),2.79(t,1H),2.17-2.09(m,1H),1.92(s,1H),1.88(d,3H),1.81 (d,1H), 1.74(q,2H), 1.64(q,1H), 1.48(d,2H), 1.43(s,6H), 1.36-1.31(m,1H).

Example 9

(3S,4R)-4-((5-Chloro-4-(7'-fluoro-2'-isopropylspiro[cyclopentane-1,3'-indol]-5'-yl)pyrimidine- 2-yl)amino)tetrahydro-2H-pyran-3-ol 9

Using the third step to the fifth step of the synthetic route in Example 1, the third step raw material compound 1d was replaced by compound 7d to obtain the title compound 9 (15 mg, yield: 18.7%).

MS m/z (ESI): 459.1 [M+1].

¹ H NMR (500MHz, CDCl ₃ ): δ8.33(d,1H),7.63(dd,1H),7.58(dt,1H),5.28(d,1H),4.69(d,1H),4.08(dt ,1H),4.01(d,1H),3.88(dq,1H),3.65(s,1H),3.49(tt,1H),3.21(td,1H),2.99(dd,1H),2.66(dt, 1H),2.60(td,1H),2.44(p,1H),2.25(q,1H),2.09-2.02(m,1H),1.88-1.79(m,1H),1.78-1.66(m,2H) ,1.54-1.45(m,1H),1.31-1.28(m,6H),1.13-1.06(m,1H).

Example 10

(3S,4R)-4-((5-chloro-4-(7-fluoro-2-isopropyl-3,3-dimethyl-3H-indol-5-yl)pyrimidin-2-yl) Amino)tetrahydro-2H-pyran-3-ol 10

first step

2-(5-Bromo-7-fluoro-3,3-dimethyl-3H-indol-2-yl)propan-2-ol 4b

5-Bromo-7-fluoro-2-isopropyl-3,3-dimethyl-3H-indole 10a

Compound 1b (1g, 4.14mmol), 2,4-dimethyl-3-pentanone 4a (472.8mg, 4.14mol) was dissolved in acetic acid (10mL), after reflux for 5 hours, water (5mL) was added, and Reflux reaction for 2 hours, the reaction solution was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs, Prep30*150mm, 5 μm, C18; mobile phase: aqueous phase (10mmol/L carbonic acid ammonium hydrogen) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30mL/min) to obtain the title compound 4b (460mg, yield: 37%) and 10a (100mg, yield: 8%).

Compound 4b: MS m/z (ESI): 300.2 [M+1].

Compound 10a: MS m/z (ESI): 284.2 [M+1].

second step

(3S,4R)-4-((5-chloro-4-(7-fluoro-2-isopropyl-3,3-dimethyl-3H-indol-5-yl)pyrimidin-2-yl) Amino)tetrahydro-2H-pyran-3-ol 10

Using the third step to the fifth step of the synthetic route in Example 1, the third step starting material compound 1d was replaced by compound 10a to obtain the title compound 10 (6 mg, yield: 10.9%).

MS m/z (ESI): 433.2 [M+1].

¹ H NMR (500MHz, CDCl ₃ ): δ8.33(s,1H),7.55(d,2H),5.27(d,1H),4.71(s,1H),4.08(dd,1H),4.01(dd ,1H),3.87(tt,1H),3.65(dt,1H),3.49(t,1H),3.21(t,1H),2.98(p,1H),2.07(dd,2H),1.41(s, 6H), 1.38(d, 6H).

Example 11

(3S,4R)-4-((5-Chloro-4-(7'-fluoro-2'-methylspiro[cyclohexane-1,3'-indol]-5'-yl)pyrimidine-2 -yl)amino)tetrahydro-2H-pyran-3-ol 11

Using the first step to the fifth step of the synthetic route in Example 1, the second step raw material compound 1c was replaced by the compound cyclohexyl ketone (Shanghai Pide) to obtain the title compound 11 (10 mg, yield: 8.1%).

MS m/z (ESI): 445.2 [M+1].

¹ H NMR(500MHz,CD ₃ OD):δ8.36(s,1H),8.14(s,1H),7.72-7.60(m,1H),4.03-3.96(m,2H),3.93(ddd,1H ),3.63(td,1H),3.49(td,1H),3.21(dd,1H),2.40(s,3H),2.15(ddd,1H),2.07-2.02(m,1H),2.01-1.94( m, 4H), 1.93-1.83 (m, 2H), 1.70-1.56 (m, 2H), 1.34 (d, 2H).

Example 12

(3S,4R)-4-((5-Chloro-4-(7'-fluoro-2'-(2-hydroxypropan-2-yl)spiro[cyclohexane-1,3'-indole]- 5'-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol 12-p1

(3S,4R)-4-((5-chloro-4-(7-fluoro-2-(1-hydroxycyclohexyl)-3,3-dimethyl-3H-indol-5-yl)pyrimidine- 2-yl)amino)tetrahydro-2H-pyran-3-ol 12-p2

Using the third step to the fifth step of the synthetic route in Example 1, the third step raw material compound 1d was replaced by a mixture of compounds 8g and 8h to obtain the title compound 12-p1 (3 mg, yield: 2.9%) and 12-p2 (10 mg, yield: 9.6%).

Single configuration compound 12-p1:

MS m/z (ESI): 489.2 [M+1].

C18,1.7μm,2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。 ¹H NMR(500MHz,CD3OD):δ8.36(s,1H),8.15(s,1H),7.67(d,1H),4.03-3.90(m,3H),3.63(td,1H),3.49(t,1H),3.21(t,1H),3.04(td,2H),2.24-2.12(m,2H),2.05(d,1H),1.98(d,3H),1.83(d,2H),1.67(d,1H),1.64(s,6H),1.59-1.55(m,1H)。 HPLC analysis: retention time 1.29 minutes, purity: 99% (chromatographic column: ACQUITY

C18, 1.7μm, 2.1*50mm; mobile phase: water (10mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%). ¹ H NMR (500MHz, CD3OD): δ8.36(s, 1H), 8.15(s, 1H), 7.67(d, 1H), 4.03-3.90(m, 3H), 3.63(td, 1H), 3.49( t,1H),3.21(t,1H),3.04(td,2H),2.24-2.12(m,2H),2.05(d,1H),1.98(d,3H),1.83(d,2H),1.67 (d,1H), 1.64(s,6H), 1.59-1.55(m,1H).

Single configuration compound 12-p2:

MS m/z (ESI): 489.2 [M+1].

C18,1.7μm,2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。 ¹H NMR(500MHz,CD ₃OD):δ8.34(s,1H),7.63(s,1H),7.56(d,1H),3.98(dt,2H),3.92(d,1H),3.61(td,1H),3.50(t,1H),3.23(t,1H),2.17-2.10(m,1H),2.04(td,2H),1.92(d,2H),1.79(dt,4H),1.66(s,2H),1.63(s,6H),1.62-1.61(m,1H)。 HPLC analysis: retention time 1.38 minutes, purity: 99% (chromatographic column: ACQUITY

C18, 1.7μm, 2.1*50mm; mobile phase: water (10mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%). ¹ H NMR (500MHz, CD ₃ OD): δ8.34(s, 1H), 7.63(s, 1H), 7.56(d, 1H), 3.98(dt, 2H), 3.92(d, 1H), 3.61( td,1H),3.50(t,1H),3.23(t,1H),2.17-2.10(m,1H),2.04(td,2H),1.92(d,2H),1.79(dt,4H),1.66 (s,2H), 1.63(s,6H), 1.62-1.61(m,1H).

Example 13

(3S,4R)-4-((5-chloro-4-(3,3-diethyl-7-fluoro-2-methyl-3H-indol-5-yl)pyrimidin-2-yl)amino ) Tetrahydro-2H-pyran-3-ol 13

Using the second step to the fifth step of the synthetic route in Example 1, the second step raw material compound 1c was replaced by 3-ethylpentan-2-one to obtain the title compound 13 (20 mg, yield: 3.2%).

MS m/z (ESI): 433.2 [M+1].

¹ H NMR(500MHz,CD ₃ OD):δ8.35(s,1H),7.65-7.58(m,2H),3.98(dt,2H),3.94-3.89(m,1H),3.61(td,1H ), 3.50(t,1H), 3.22(t,1H), 2.32(s,3H), 2.09(dtd,4H), 1.97(dq,2H), 0.43(t,6H).

Example 14

(3S,4R)-4-((5-Chloro-4-(7-fluoro-2-methyl-2',3',5',6'-tetrahydrospiro[indole-3,4'- Pyran]-5-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol 14

Using the second step to the fifth step of the synthetic route in Example 1, the second step raw material compound 1c was replaced by 1-(tetrahydro-2H-pyran-4-yl)ethanone to obtain the title compound 14 (15mg, yield rate: 8.2%).

MS m/z (ESI): 447.2 [M+1].

¹ H NMR (500MHz, CDCl ₃ ): δ8.36(s,1H),8.13(s,1H),7.66(d,1H),5.29(d,1H),4.16-4.08(m,4H),4.02 (dd,1H),3.89(dt,1H),3.66(s,1H),3.54-3.46(m,1H),3.21(t,1H),2.43(s,3H),2.26(dt,2H), 2.08 (d, 1H), 1.76 (td, 1H), 1.39-1.29 (m, 4H).

biological evaluation

The following further describes and explains the present disclosure in combination with test examples, but these test examples are not meant to limit the scope of the present disclosure.

Test example 1, the inhibitory effect of the disclosed compound on CDK4 enzyme

The following method was used to determine the inhibitory effect of the disclosed compounds on the CDK4 enzyme. The experimental method is briefly described as follows:

1. Experimental materials and instruments

1. CDK4/CycD3 (Carna biosciences, 04-105)

2. HTRF CDKs Kinase (CDK1/4/6/7/12) Kit (Cisbio, 63ADK000CB11PEG)

3. ATP (Sigma, A7699-1G)

4. DTT (Sigma, 43815-1G)

5. Magnesium chloride solution (Sigma, 68475-100ML-F)

6. 384-well plate (Corning, 4513)

7. U-bottom 96-well plate (Corning, 3795)

8. EnVision multi-mode detection platform (PerkinElmer, EnVision)

2. Experimental steps

CDK4 enzyme (final concentration 1ng/μL), mixed with small molecule compounds of different concentrations (first concentration 1μM, 3-fold serial dilution 11 concentrations), incubated at room temperature for 30 minutes, and then added CDKs substrate-biotin (Substrate-biotin) ) (final concentration 0.3 μM) and ATP solution (final concentration 10 μM), mixed and incubated at room temperature for 90 minutes. Then add CDKs antibody-cryptate (Antibody-Cryptate) diluted with detection buffer and streptavidin-XL665 (final concentration 37.5nM) diluted with detection buffer, mix well, After incubation at room temperature for 1 hour, the EnVision multi-mode detection platform was used to detect the signal in HTRF mode.

3. Experimental data

The EnVision multi-mode detection platform was used to detect the fluorescence values at 665nm and 620nm excited at 337nm in HTRF mode. Data were processed using GraphPad software, see Table 1.

Table 1 The IC ₅₀ of the compounds of the present disclosure on the inhibition of CDK4 enzyme activity

compound IC ₅₀ (nM) 1 0.9 2 4.1 3 4.0 4 9.6 7-p2 11.5 9 2.8 11 6.6 13 1.7

Conclusion: The disclosed compound has obvious inhibitory effect on CDK4 enzyme activity.

Test example 2, the inhibitory effect of the disclosed compound on CDK6 enzyme

The following method was used to determine the inhibitory effect of the disclosed compounds on the CDK6 enzyme. The experimental method is briefly described as follows:

1. Experimental materials and instruments

1. CDK6/CycD3 (Carna biosciences, 04-107)

2. HTRF CDKs Kinase (CDK1/4/6/7/12) Kit (Cisbio, 63ADK000CB11PEG)

3. ATP (Sigma, A7699-1G)

4. DTT (Sigma, 43815-1G)

5. Magnesium chloride solution (Sigma, 68475-100ML-F)

6. 384-well plate (Corning, 4513)

7. U-bottom 96-well plate (Corning, 3795)

8. EnVision multi-mode detection platform (PerkinElmer, EnVision)

2. Experimental steps

CDK6 enzyme (final concentration 2.5ng/μL) was mixed with small molecule compounds of different concentrations (first concentration 1μM, 3-fold serial dilution of 11 concentrations), incubated at room temperature for 30 minutes, and then CDKs substrate-biotin (Substrate-biotin) was added. ) (final concentration 0.3 μM) and ATP solution (final concentration 50 μM), mixed and incubated at room temperature for 180 minutes. Then add CDKs antibody-cryptate (Antibody-Cryptate) diluted with detection buffer and streptavidin-XL665 (final concentration 37.5nM) diluted with detection buffer, mix well, After incubation at room temperature for 1 hour, the EnVision multi-mode detection platform was used to detect the signal in HTRF mode.

3. Experimental data

The EnVision multi-mode detection platform was used to detect the fluorescence values at 665nm and 620nm excited at 337nm in HTRF mode. Data were processed using GraphPad software, see Table 2.

Table 2 The IC ₅₀ of the compounds of the present disclosure on the inhibition of CDK6 enzyme activity

compound IC ₅₀ (nM) 1 7.3 2 32.0 3 26.4 4 128.0 6 329.8 7-p1 700.4 8-p1 1038.0 12-p1 594.5 12-p2 329.1 14 427.6

Test example 3, MCF-7 cell proliferation experiment

1. Purpose of test

The purpose of this experiment is to test the inhibitory effect of the compound molecule on the proliferation activity of MCF-7 cells, and evaluate the in vitro activity of the molecule according to the IC ₅₀ size. MCF-7 cells are a CDK4-dependent human breast cancer cell line that is sensitive to CDK4-selective inhibitors. In this experiment, CellTite-Glo reagent was used to measure the luminescence value. The luminescence value is directly proportional to the amount of ATP, and ATP is positively correlated with the number of living cells. Therefore, the cell viability is reflected by detecting the ATP content in the cells. The inhibitory effect of the compounds on the proliferation of MCF-7 cells was evaluated according to the IC ₅₀ .

2. Experimental method

MCF-7 cells (ATCC, HTB-22) were digested with trypsin (Invitrogen, 25200-072), centrifuged and resuspended to prepare a single cell suspension, and cell culture medium (EMEM+10%FBS+0.01mg/mL insulin) was used Adjust the viable cell density to 8.4×10 ³ cells/mL, mix well, and add 180 μL/well to a 96-well cell culture plate (Corning, 3903). Plates were incubated in an incubator (37°C, 5% CO ₂ ) for 20-24 hours.

Compounds were dissolved in DMSO to prepare stock solutions with an initial concentration of 20 mM. The initial concentration of the small molecule compound is 0.6mM, 3-fold dilution, 10 points of dilution, the 11th and 12th points are DMSO. Take another 96-well plate, add 95 μL of cell culture medium (EMEM+10% FBS+0.01 mg/mL insulin) to each well, then add 5 μL of different concentrations of samples to be tested in each well, mix well, and then add to the cell culture plate Add 20 μL/well of different concentrations of samples to be tested, and duplicate wells for each sample. The plates were incubated in an incubator (37°C, 5% CO ₂ ) for 6 days. Take out the 96-well cell culture plate, add 90 μL CellTiter-Glo reagent (Promega, G7573) to each well, incubate at room temperature in the dark for 10 min, and take the chemiluminescent signal value in a microplate reader (PHERAstar, BMG labtech).

3. Experimental data

Data were processed and analyzed with Microsoft Excel and Graphpad Prism 5. The _IC50 values of the compounds were obtained and the results are shown in Table 3 below.

Table 3 IC ₅₀ of the compounds of the present disclosure on the proliferation inhibition of MCF-7 cells

compound IC ₅₀ (nM) 1 9.5 2 10.5 3 7.8 4 5.2 9 4.0 13 6.3

Conclusion: The disclosed compound has obvious growth inhibitory activity on MCF-7 cells.

Test example 4, Pfeiffer cell proliferation experiment

1. Purpose of test

The purpose of this experiment is to test the inhibitory effect of the compound molecule on the proliferation activity of Pfeiffer cells, and evaluate the in vitro activity of the molecule according to the IC ₅₀ size. Pfeiffer cells are a CDK6-dependent human diffuse large B-cell lymphoma cell line that is insensitive to CDK4-selective inhibitors. In this experiment, CellTite-Glo reagent was used to measure the luminescence value. The luminescence value is directly proportional to the amount of ATP, and ATP is positively correlated with the number of living cells. Therefore, the cell viability is reflected by detecting the ATP content in the cells. The inhibitory effect of compounds on the proliferation of Pfeiffer cells was evaluated according to IC ₅₀ .

2. Experimental method

Collect the Pfeiffer cell (ATCC, CRL-2632) culture suspension, centrifuge and resuspend to prepare a single cell suspension, and adjust the viable cell density to 4.4×10 ⁴ cells/mL with cell culture medium (RPMI-1640+10% FBS) , mix well, and add 180 μL/well to a 96-well cell culture plate (Corning, 3903). Plates were incubated in an incubator (37°C, 5% CO ₂ ) for 20-24 hours.

Compounds were dissolved in DMSO to prepare stock solutions with an initial concentration of 20 mM. The initial concentration of the small molecule compound is 2 mM, diluted 3 times, diluted 10 points, and the 11th and 12th points are DMSO. Take another 96-well plate, add 95 μL of cell culture medium (RPMI-1640+10% FBS) to each well, then add 5 μL of different concentrations of samples to be tested in each well, mix well, and then add 20 μL/well to the cell culture plate Samples to be tested at different concentrations, and each sample was duplicated. The plates were incubated in an incubator (37°C, 5% CO ₂ ) for 6 days. Take out the 96-well cell culture plate, add 90 μL CellTiter-Glo reagent (Promega, G7573) to each well, incubate at room temperature in the dark for 10 min, and take the chemiluminescent signal value in a microplate reader (PHERAstar, BMG labtech).

3. Experimental data

Data were processed and analyzed with Microsoft Excel and Graphpad Prism 5. The _IC50 values of the compounds were obtained and the results are shown in Table 4 below.

Table 4 _IC50 of the compounds of the present disclosure on the inhibition of Pfeiffer cell proliferation

compound IC ₅₀ (nM) 2 404 3 572.5

6 2296.0

Conclusion: Combining Table 3 and Table 4, the disclosed compound has stronger proliferation inhibitory activity on CDK4-dependent cells than CDK6-dependent cells, and has cell selectivity.

Test example 5, MOLM-13 cell proliferation experiment

1. Purpose of test

The purpose of this experiment is to test the inhibitory effect of the compound molecule on the proliferation activity of MOLM-13 cells, and evaluate the in vitro activity of the molecule according to the IC ₅₀ size. MOLM-13 cells are a CDK6-dependent human acute myeloid leukemia cell line that is insensitive to CDK4-selective inhibitors. In this experiment, CellTite-Glo reagent was used to measure the luminescence value. The luminescence value is directly proportional to the amount of ATP, and ATP is positively correlated with the number of living cells. Therefore, the cell viability is reflected by detecting the ATP content in the cells. The inhibitory effect of the compounds on the proliferation of MOLM-13 cells was evaluated according to the IC ₅₀ .

2. Experimental method

Collect the culture suspension of MOLM-13 cells (Kebai, CBP60678), centrifuge and resuspend to prepare a single cell suspension, and use cell culture medium (RPMI-1640+20% FBS) to adjust the viable cell density to 3.4× ¹⁰⁴ cells/ mL, mix well, and add 180 μL/well to a 96-well cell culture plate (Corning, 3903). Plates were incubated in an incubator (37°C, 5% CO ₂ ) for 20-24 hours.

Compounds were dissolved in DMSO to prepare stock solutions with an initial concentration of 20 mM. The initial concentration of the small molecule compound is 2 mM, diluted 3 times, diluted 10 points, and the 11th and 12th points are DMSO. Take another 96-well plate, add 95 μL of cell culture medium (RPMI-1640+20% FBS) to each well, then add 5 μL of different concentrations of samples to be tested in each well, mix well, and then add 20 μL/well to the cell culture plate Samples to be tested at different concentrations, and each sample was duplicated. The plates were incubated in an incubator (37°C, 5% CO ₂ ) for 6 days. Take out the 96-well cell culture plate, add 90 μL CellTiter-Glo reagent (Promega, G7573) to each well, incubate at room temperature in the dark for 10 min, and take the chemiluminescent signal value in a microplate reader (PHERAstar, BMG labtech).

3. Experimental data

Data were processed and analyzed with Microsoft Excel and Graphpad Prism 5. The _IC50 values of the compounds were obtained and the results are shown in Table 5 below.

Table 5 _{IC50 of} the compounds of the present disclosure on the inhibition of MOLM-13 cell proliferation

compound IC ₅₀ (nM) 2 1128 3 903 4 1879

Conclusion: Combining Table 3 and Table 5, the compounds of the present disclosure have stronger proliferation inhibitory activity on CDK4-dependent cells than CDK6-dependent cells, and have cell selectivity.

Test Example 6, Determination of Rat Brain Permeability of the Disclosed Compound

The rat brain permeability of the disclosed compound is determined by the following experimental method:

1. Experimental materials and instruments

1. RED device (Device Inserts) (Thermo Scientific, QL21291110)

2. API 4000 Q-trap triple quadrupole tandem mass spectrometer (Applied Biosystems)

3. LC-30A ultra-high pressure liquid chromatography system (Shimadzu)

4. pH7.4 PBS (100mM, stored in refrigerator at 4°C)

5. SD rats, provided by Weitong Lihua Experimental Animal Co., Ltd., animal production license number SCXK (Shanghai) 2019-0001

2. Experimental animal operation

There were 4 SD rats, half male and half male. Administration was administered by intragastric administration after an overnight fast. The dosage is 20mg/kg.

Blood collection: In the intragastric administration group, blood was collected from the orbit 2 hours after the administration (blood collection volume: 0.5ml), placed in an EDTA-K2 anticoagulant test tube, centrifuged at 10,000rpm for 1min (4°C), and the plasma was separated within 1h, which was recorded as plasma 1, - Store at 20°C for testing. The process from blood collection to centrifugation was operated under ice bath conditions.

Brain tissue collection: After rats were anesthetized with 20% urethane, cardiac perfusion was performed (open the abdominal cavity, cut open 3-4 parts of the liver, quickly insert a needle into the left apex and perfuse 30ml of normal saline), collect brain tissue after perfusion, and record it as brain tissue 1 , and stored at -20 degrees.

Another 3 animals were taken to take blank plasma and brain tissue 2, and the treatment method was the same as that of the administration group.

3. Plasma protein binding equilibrium dialysis process

3.1 Sample preparation

Dissolve the drug compound in DMSO to 30mM to obtain stock solution I; pipette an appropriate amount of stock solution I and dilute with methanol to obtain 200μM diluted stock solution II; pipette 10μl stock solution II into a 1.5mL Eppendorf tube, add 990μL blank plasma, and mix well A 2 μM plasma sample 2 (DMSO content≤0.2%) was obtained for the determination of the plasma protein binding rate at this concentration. Pipette 50 μL of the prepared plasma sample, add 50 μL of pH 7.4 phosphate buffered saline solution, and then add 250 μL of acetonitrile solution containing internal standard, record it as T ₀ , and store it in a -4°C refrigerator for testing.

3.2 Experimental process

Take the RED device and insert the balance dialysis tubing into the 96-well bottom plate. Take the prepared plasma sample 2 (300 mL) containing the analyte and place it in the well marked in red (plasma chamber). Take 500 μL of pH 7.4 phosphate-buffered saline solution and place it in another well marked in red (buffer chamber). According to the above-mentioned steps, each concentration of each compound is 2 samples. After that, the 96-well plate was covered with a sealing tape, and the entire bottom plate was placed in a thermomixer at 400 rpm to equilibrate at 37° C. for 4 hours. After the incubation, the 96-well bottom plate device was removed from the thermomixer to complete the equilibrium dialysis. Take 50 μL of balanced plasma sample or dialysate sample, add 50 μL of corresponding unbalanced drug-free blank phosphate buffer solution or drug-free blank plasma, add 250 μL of internal standard (prepared in acetonitrile), and vortex for 5 minutes , centrifuged for 15min (4000rpm), take 90uL of supernatant, add 90uL of water to dilute, take 5uL for LC/MS/MS analysis. The _T0 sample was not incubated, and the LC/MS/MS method established above was directly used to determine the chromatographic peak area ratio of the total drug (plasma chamber) and free drug (buffer chamber) to the internal standard, and calculate the free percentage (fu _plasma % ).

4. Brain tissue protein binding equilibrium dialysis process

Brain tissue protein binding equilibrium dialysis process: Blank brain tissue 2 was made into blank brain homogenate with pH 7.4 PBS according to the ratio of dilution factor = 11, and the compound was added to prepare 2 μM brain homogenate, and the rest of the operation was the same as that of plasma protein binding The chromatographic peak area ratio of the total drug (brain homo chamber) and free drug (buffer chamber) to the internal standard was determined by the established LC/MS/MS method, and the free percentage ( _{fu brain hom} %) was calculated.

5. Calculation method of brain permeabilization test data

5.1 Use the established LC/MS/MS method to measure the drug concentration in plasma 1 and brain tissue 1 of rats 2 hours after administration, which is the total concentration (C _total,p and C _total,b );

5.2 Using the RED Device Inserts device, measure the protein binding rate of the compound in rat plasma and brain tissue by equilibrium dialysis, and then calculate the free percentage (fu _plasma %, fu _brain %);

Plasma free percentage (fu _plasma %) = C _buffer / C _plasma × 100%;

Brain homogenate free percentage (f _{u brain hom} %) = C _buffer / C _{brain hom} × 100%;

Brain tissue free percentage (f _{u brain} %)=f _{u brain hom} /(Df-(Df-1)×f _{u brain hom} )×100%; where Df=11

5.3 Use the following formula to calculate the blood brain permeability index Kp-unbound.

6. Test results and discussion

Table 6 The brain permeability index of the disclosed compounds is as follows:

Conclusion: the disclosed compound has a high free drug concentration in the brain, has a strong ability to penetrate the blood-brain barrier, and has high brain permeability.

Claims (21)

A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

in: Ring A is a heterocyclic group; G is CR ^g or N; Each R ¹ is the same or different, and each independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -(alkylene) _u - ^NRaRb , ^hydroxy , hydroxyalkyl , cycloalkyl, heterocyclyl, aryl and heteroaryl; Or two ^R connected to the same carbon atom form a cycloalkyl or heterocyclic group together with the carbon atom connected to it, and each of the cycloalkyl or heterocyclic groups is independently selected from the group consisting of halogen, alkyl, One or more of alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl and hydroxyalkyl are substituted; ^R is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group; R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R and R ^g are the same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano , -(alkylene) _v -NR ^c R ^d , -C(O)R ^x , -C(O)NR ^y R ^z , hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and hetero Aryl, the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, Substituted by one or more of amino, hydroxyl and hydroxyalkyl; R ⁸ and R ⁹ are the same or different, and each independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclic group, the alkyl, cycloalkyl and heterocyclic Each group is independently optionally selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -(alkylene) _w -NR ^e R ^f , hydroxyl and hydroxyalkyl multiple replaced; Or R ⁸ and R ⁹ form a cycloalkyl or heterocyclic group together with the carbon atoms connected to them, and each of the cycloalkyl or heterocyclic groups is independently optionally selected from halogen, alkyl, alkoxy, haloalkyl , Haloalkoxy, cyano, -(alkylene) _y -NR ^m R ⁿ , hydroxyl and hydroxyalkyl are substituted by one or more; Or R and ^R form a cycloalkyl group or a heterocyclic group together with the carbon atoms connected to them, and each of the cycloalkyl groups or heterocyclic groups is independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, One or more of haloalkoxy, cyano, -(alkylene) _z -NR ^j R ^k , hydroxyl and hydroxyalkyl; R ^a , R ^b , R ^c , R ^d , Re , R ^f , R ^m , R ⁿ , R ^j , R ^k , R ^y and R ^z are the ^same or different, and each independently selected from a hydrogen atom, an alkyl group , haloalkyl, hydroxyalkyl and cycloalkyl; R ^x is selected from alkyl, haloalkyl, hydroxyalkyl and cycloalkyl; m is an integer from 0 to 15; u is 0, 1, 2, 3 or 4; v is 0, 1, 2, 3 or 4; w is 0, 1, 2, 3 or 4; y is 0, 1, 2, 3 or 4; and z is 0, 1, 2, 3 or 4. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is a 3- to 8-membered heterocyclic group. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof,

in: Q is selected from ^NRq , O and S; ^Rq is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group; R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f , R ^1g and R ^1h are the same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy group, cyano group, -(alkylene) _u -NR ^a R ^b , hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclyl; p is 0, 1 or 2; q is 0, 1 or 2; and G, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R, R ^a , R ^b and u are as defined in claim 1 . The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ² is a hydrogen atom. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, which is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof,

in: Q is selected from ^NRq , O and S; ^Rq is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group; R ^1a and R ^1b are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -(alkylene) _u -NR ^a R ^b , hydroxy, hydroxyalkyl, cycloalkyl, and heterocyclyl; and R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R, R ^a , R ^b and u are as defined in claim 1 . The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R ⁸ and R ⁹ are the same or different, and are each independently selected from a hydrogen atom, a halogen , C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 hydroxyalkyl; Or R ⁸ and R ⁹ together form a 3 to 8 membered cycloalkyl group or a 3 to 8 membered heterocyclic group, and each of the 3 to 8 membered cycloalkyl groups or the 3 to 8 membered heterocyclic group is independently optionally substituted by one or more selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl. According to the compound represented by general formula (I) or its pharmaceutically acceptable salt according to any one of claims 1 to 6, ^wherein R is selected from C _1-6 alkyl, C _1-6 hydroxyalkyl and 3 to 8-membered cycloalkyl, said 3 to 8-membered cycloalkyl is optionally substituted by one or more hydroxyl groups; preferably, R ⁷ is C _1-6 alkyl or C _1-6 hydroxyalkyl. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 7, wherein R ^1a is a hydroxyl group; and/or R ^1b is a hydrogen atom. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 8, wherein Q is O. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R ³ is a hydrogen atom. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R ⁴ is halogen. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R ⁵ is a hydrogen atom; and/or R is a hydrogen atom. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein R ⁶ is halogen. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, which is selected from the following compounds:

A compound or salt thereof shown in general formula (IA):

in: X is halogen; preferably, X is Cl; ^R is selected from Cl, Br, I, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -(alkylene) _v- ^NRcRd , ^hydroxyl , hydroxyalkyl, cycloalkyl, Heterocyclyl, aryl and heteroaryl, said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, alkyl, alkoxy, haloalkyl , Haloalkoxy, cyano, amino, hydroxyl and hydroxyalkyl are substituted by one or more; G, R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R, R ^c , R ^d and v are as defined in claim 1 . The compound or salt thereof represented by the formula (IA) according to claim 15, which is selected from the following compounds:

A method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, the method comprising:

Compounds represented by general formula (IA) or salts thereof are coupled with compounds represented by general formula (IB) or salts thereof to obtain compounds represented by general formula (I) or pharmaceutically acceptable salts thereof, in: X is halogen; preferably, X is Cl; Rings A, G, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R and m are as defined in claim 1 . A pharmaceutical composition, which contains a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, and one or more pharmaceutically acceptable carrier, diluent or excipient. According to the compound represented by the general formula (I) or its pharmaceutically acceptable salt according to any one of claims 1 to 14 or the pharmaceutical composition according to claim 18 in the preparation of medicines for inhibiting CDK Use; preferably, wherein said CDK is CDK4. According to the compound represented by the general formula (I) or its pharmaceutically acceptable salt according to any one of claims 1 to 14 or the pharmaceutical composition according to claim 18 in the preparation for the treatment and/or prevention of Use in medicine for CDK4-mediated diseases or disorders; preferably, the diseases or disorders are selected from tumors, myelofibrosis, myelodysplastic syndrome, pulmonary hypertension, hypertension, neurodegenerative diseases and mucositis; More preferably, the disease or condition is cancer. According to the compound represented by the general formula (I) according to any one of claims 1 to 14 or the pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 18 in the preparation for the treatment and/or prevention of diseases or diseases, wherein said diseases or diseases are selected from breast cancer, endometrial cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, urothelial cancer, urethral cancer , prostate cancer, testicular cancer, colorectal cancer, sarcoma, bone cancer, multiple myeloma, leukemia, myxoma, rhabdomyoma, leiomyoma, fibroma, lipoma, teratoma, laryngeal cancer, nasopharyngeal cancer, Oral cancer, lung cancer, lymphoma, mesothelioma, small intestine cancer, stomach cancer, esophagus cancer, pancreatic cancer, liver cancer, bile duct cancer, biliary tract cancer, gallbladder cancer, peritoneal cancer, thymus cancer, central nervous system tumor, retinoblastoma, Glioblastoma multiforme, neurofibroma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, brain cancer, salivary gland cancer, and Gastrointestinal stromal tumor; preferably, the disease or condition is breast cancer.